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Sample records for antiparkinsonian drug-induced sleepiness

  1. Antipsychotics dosage and antiparkinsonian prescriptions

    Directory of Open Access Journals (Sweden)

    Gasquet Isabelle

    2007-09-01

    Full Text Available Abstract Background To study the link between the dosage of several antipsychotics and the prescription of antiparkinsonians in an observational study. Methods In the context of a national naturalistic prospective observational study, a database containing all the prescriptions from 100 French psychiatrists during the year 2002 was analysed. The inclusion criteria were a diagnosis of schizophrenia or schizoaffective disorder and age over 18. The mean dosage of antipsychotics with and without antiparkinsonians was compared. Since there were multiple prescriptions for a given subject, generalised mixed linear models were also used to study the link between antiparkinsonian prescription and antipsychotic dosage. Results antiparkinsonians were prescribed to 32,9% of the patients. Two groups of antipsychotics were observed relating to differences in dosage when an antiparkinsonian was co prescribed or not : a first group, where the mean dosage was higher with antiparkinsonians (risperidone, amisulpride and haloperidol and a second group (clozapine, olanzapine, in which antiparkinsonian co prescription was not related to the dosage of antipsychotics. Conclusion As a conclusion, it can be said that it is important to consider the dosage and the type of antipsychotic in the treatment of patients suffering of schizophrenia, because neurological side effects are frequent and can impair quality of life. Moreover the prescription of antiparkinsonians can lead to different side effects such anticholinergic effects.

  2. Excessive Daytime Sleepiness

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    Yavuz Selvi

    2016-06-01

    Full Text Available Excessive daytime sleepiness is one of the most common sleep-related patient symptoms, with preva-lence in the community estimated to be as high as 18%. Patients with excessive daytime sleepiness may exhibit life threatening road and work accidents, social maladjustment, decreased academic and occupational performance and have poorer health than comparable adults. Thus, excessive daytime sleepiness is a serious condition that requires investigation, diagnosis and treatment primarily. As with most medical condition, evaluation of excessive daytime sleepiness begins a precise history and various objective and subjective tools have been also developed to assess excessive daytime sleepiness. The most common causes of excessive daytime sleepiness are insufficient sleep hygiene, chronic sleep deprivation, medical and psychiatric conditions and sleep disorders, such as obstructive sleep apnea, medications, and narcolepsy. Treatment option should address underlying contributors and promote sleep quantity by ensuring good sleep hygiene. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2016; 8(2: 114-132

  3. Sleepiness at the wheel

    OpenAIRE

    Anund, Anna

    2009-01-01

    Prevention of road crashes is a major priority in most countries. The present thesis focuses on driver sleepiness and road crashes. The general aim of the thesis was to explore the relation between driver sleepiness and driver impairment and the changes that precede a crash or a similar safety-critical event, but also what constitutes good reliable behavioural / physiological measures of sleepiness. A second question concerned particular groups and situations is post-night s...

  4. Drug-induced hepatitis

    Science.gov (United States)

    Toxic hepatitis ... to get liver damage. Some drugs can cause hepatitis with small doses, even if the liver breakdown ... liver. Many different drugs can cause drug-induced hepatitis. Painkillers and fever reducers that contain acetaminophen are ...

  5. Vitiligo, drug induced (image)

    Science.gov (United States)

    ... this person's face have resulted from drug-induced vitiligo. Loss of melanin, the primary skin pigment, occasionally ... is the case with this individual. The typical vitiligo lesion is flat (macular) and depigmented, but maintains ...

  6. Sleepiness and vigilance tests.

    Science.gov (United States)

    Mathis, J; Hess, C W

    2009-04-18

    Objective assessments of subjective complaints such as sleepiness, tiredness or fatigue using sleepiness and vigilance tests aim to identify its causes and to judge the fitness to drive or to work of the affected person. "Vigilance" comprises wakefulness, alertness and attention and is therefore not merely reciprocal to sleepiness. Since it is a complex phenomenon with several dimensions it is unlikely to be appropriately assessed by one single "vigilance test". One important dimension of vigilance discussed here is wakefulness with its counterpart of overt sleep and the whole spectrum of various levels in between. The transit zone between full wakefulness and overt sleep is mainly characterised by the subjective complaint of sleepiness, which cannot be measured directly. Only the consequences of reduced wakefulness such as a shortened sleep latency, slowed cognitive function and prolonged reaction time can be measured objectively. It is, therefore, more promising to combine a battery of subjective and objective tests to answer a specific question in order to achieve the most appropriate description for a given clinical or medicolegal situation. However even then we must keep in mind that many other important aspects of fitness to drive / fitness to work such as neurological, psychiatric and neuropsychological functions including risk taking behaviour are not covered by vigilance tests. A comprehensive, multidisciplinary approach is essential in such situations. PMID:19418304

  7. A STUDY OF PROPHYLACTIC VALUE OF ANTIPARKINSONIAN DRUG

    OpenAIRE

    Behere, P.B.; Ramakrishna, P.

    1983-01-01

    SUMMARY The present prospective study is conducted to determine the prophylactic value of antiparkinsonian drug (A.P.) at the time of initiation of antipsychotic therapy. Seventy patients were selected who fulfilled the selection criteria. Thirty five patients received antipsychotic drugs alone (Group A), while another thirty five patients received A.P. drugs concurrently with antipsychotic drugs (Group B.) These patients were assessed weekly for 4 weeks for any extra pyramidal symptoms (E.P....

  8. Drug-induced hyperkalemia.

    Science.gov (United States)

    Ben Salem, Chaker; Badreddine, Atef; Fathallah, Neila; Slim, Raoudha; Hmouda, Houssem

    2014-09-01

    Hyperkalemia is a common clinical condition that can be defined as a serum potassium concentration exceeding 5.0 mmol/L. Drug-induced hyperkalemia is the most important cause of increased potassium levels in everyday clinical practice. Drug-induced hyperkalemia may be asymptomatic. However, it may be dramatic and life threatening, posing diagnostic and management problems. A wide range of drugs can cause hyperkalemia by a variety of mechanisms. Drugs can interfere with potassium homoeostasis either by promoting transcellular potassium shift or by impairing renal potassium excretion. Drugs may also increase potassium supply. The reduction in renal potassium excretion due to inhibition of the renin-angiotensin-aldosterone system represents the most important mechanism by which drugs are known to cause hyperkalemia. Medications that alter transmembrane potassium movement include amino acids, beta-blockers, calcium channel blockers, suxamethonium, and mannitol. Drugs that impair renal potassium excretion are mainly represented by angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, direct renin inhibitors, nonsteroidal anti-inflammatory drugs, calcineurin inhibitors, heparin and derivatives, aldosterone antagonists, potassium-sparing diuretics, trimethoprim, and pentamidine. Potassium-containing agents represent another group of medications causing hyperkalemia. Increased awareness of drugs that can induce hyperkalemia, and monitoring and prevention are key elements for reducing the number of hospital admissions, morbidity, and mortality related to drug-induced hyperkalemia.

  9. Drug-induced lupus.

    Science.gov (United States)

    Rubin, Robert L

    2005-04-15

    Autoantibodies and, less commonly, systemic rheumatic symptoms are associated with treatment with numerous medications and other types of ingested compounds. Distinct syndromes can be distinguished, based on clinical and laboratory features, as well as exposure history. Drug-induced lupus has been reported as a side-effect of long-term therapy with over 40 medications. Its clinical and laboratory features are similar to systemic lupus erythematosus, except that patients fully recover after the offending medication is discontinued. This syndrome differs from typical drug hypersensitivity reactions in that drug-specific T-cells or antibodies are not involved in induction of autoimmunity, it usually requires many months to years of drug exposure, is drug dose-dependent and generally does not result in immune sensitization to the drug. Circumstantial evidence strongly suggests that oxidative metabolites of the parent compound trigger autoimmunity. Several mechanisms for induction of autoimmunity will be discussed, including bystander activation of autoreactive lymphocytes due to drug-specific immunity or to non-specific activation of lymphocytes, direct cytotoxicity with release of autoantigens and disruption of central T-cell tolerance. The latter hypothesis will be supported by a mouse model in which a reactive metabolite of procainamide introduced into the thymus results in lupus-like autoantibody induction. These findings, as well as evidence for thymic function in drug-induced lupus patients, support the concept that abnormalities during T-cell selection in the thymus initiate autoimmunity.

  10. Sleepiness phenomics: modeling individual differences in subjective sleepiness profiles.

    Science.gov (United States)

    Mairesse, Olivier; De Valck, Elke; Quanten, Stijn; Neu, Daniel; Cortoos, Aisha; Pattyn, Nathalie; Theuns, Peter; Cluydts, Raymond; Hofmans, Joeri

    2014-07-01

    The present study investigates individual differences in subjective sleepiness profiles during 36 h of sustained wakefulness in a modified constant routine protocol. Twenty-three volunteers (11 females), aged between 18 and 47 yrs (M age = 30.41, SD = 10.26) enrolled in the study. Subjective sleepiness ratings were collected every 2 h by means of visual analogue scales. Circadian rhythmicity was assessed by means of salivary cortisol. Subjective sleepiness data were analyzed using functional principal component analysis (fPCA). Our results show that approximately 80% of the variance is accounted for by three functional components. The first component explains 50.28% of the variance and is characterized by a profile of exclusively positive loadings, representing vertical shifts from the mean sleepiness profile. Scores on this component are positively related to self-reported habitual sleep times and mean slow wave activity (SWA) during wake. Positive scores on the second component (18.40% of the variance) are characterized by a higher than average peak-to-trough amplitude in subjective sleepiness profiles. Participants with higher than average scores on this component show a significantly higher amplitude in salivary cortisol profiles as opposed to participants with lower than average scores. Participants with positive scores on the third component (10.09% of the variance) show higher than average levels of subjective sleepiness during morning hours, a buildup of wake effort occurring later and more afternoon sleepiness after sleep deprivation than negative scorers. Peak levels of salivary cortisol occur significantly later in these participants. Taken together, our results suggest that component 1 represents tonic differences in sleepiness profiles primarily related to mechanisms of sleep homeostasis, component 2 to circadian amplitude differences and component 3 to diurnal preference. However, since the components are additions to a mean profile, each of the three

  11. SLEEPINESS AMONG IRANIAN LORRY DRIVERS

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    K. Sadeghniiat Y. Labbafinejad

    2007-06-01

    Full Text Available Excessive daytime sleepiness (EDS denotes a propensity to doze off or fall asleep unintentionally during the day, particularly in passive situations. There is cumulative evidence pointing to an association between sleepiness and probability of involvement in motor vehicle crashes. This study was designed to determine the prevalence of sleepiness in a group of Iranian lorry drivers and its association with accidents. A cross-sectional study was carried out in lorry drivers of Tehran goods transportation terminal in 2005. This study used a questionnaire and the Epworth Sleepiness Scale (ESS. The questionnaire included questions regarding demographic features, professional data, sleep habits and excessive daytime sleepiness. A total of 386 male drivers, aged 43.23 ± 9.72 years were included in the study. ESS was higher than 10 points in 9.1% of the interviewees; 50.8% never have driven drowsy, although 36% rarely, 7.3% half of the times, 4.9% almost always and 1% always have driven drowsy. Logistic regression analysis indicated that EDS, age and job satisfaction were associated with an increased risk of accidents. Sleepiness is a prevailing symptom in lorry drivers and is probably related to accidents.

  12. Drug-induced pulmonary disease

    Science.gov (United States)

    ... medlineplus.gov/ency/article/000104.htm Drug-induced pulmonary disease To use the sharing features on this page, ... take longer to improve. Some drug-induced lung diseases, such as pulmonary fibrosis, may never go away. Possible Complications Complications ...

  13. Drug-induced cholestasis.

    Science.gov (United States)

    Zimmerman, H J; Lewis, J H

    1987-01-01

    Intrahepatic cholestasis, defined as arrested bile flow, mimics extrahepatic obstruction in its biochemical, clinical and morphological features. It may be due to hepatocyte lesions of which there are three types, termed canalicular, hepatocanalicular and hepatocellular, respectively; or it may be due to ductal lesions at the level of the cholangiole or portal or septal ducts. Defective bile flow due to hepatic lesions reflects abnormal modification of the ductular bile. Defective formation of canalicular bile may involve bile acid-dependent or independent flow. It appears to result most importantly from defective secretion of bile acid-dependent flow secondary to defective uptake from sinusoidal blood, defective transcellular transport and defective secretion; or from regurgitation of secreted bile via leaky tight junctions. An independent defect in bile acid-independent flow is less clear. Defective flow of bile along the canaliculus may reflect increased viscosity and impaired canalicular contractility secondary to injury of the pericanalicular microfibrillar network. Impaired flow beyond the canaliculus may result from ductal injury. Sites of lesions that contribute to cholestasis include the sinusoidal and canalicular plasma membrane, the pericanalicular network and the tight junction and, less certainly, microtubules and microfilaments and Golgi apparatus. A number of drugs that lead to cholestasis have been found to lead to injury at one or more of these sites. Other agents (alpha-naphthylisothiocyanate, methylenedianiline, contaminated rapeseed oil, paraquat) lead to ductal injury resulting in cholestasis. Reports of inspissated casts in ductules (benoxaprofen jaundice) and injury to the major excretory tree (5-fluorouridine after hepatic artery infusion) have led to other forms of ductal cholestasis. Most instances of drug-induced cholestasis present as acute, transient illness, although important chronic forms also occur. The clinical features include the

  14. Drug-Induced Hematologic Syndromes

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    David M. Mintzer

    2009-01-01

    Full Text Available Objective. Drugs can induce almost the entire spectrum of hematologic disorders, affecting white cells, red cells, platelets, and the coagulation system. This paper aims to emphasize the broad range of drug-induced hematological syndromes and to highlight some of the newer drugs and syndromes. Methods. Medline literature on drug-induced hematologic syndromes was reviewed. Most reports and reviews focus on individual drugs or cytopenias. Results. Drug-induced syndromes include hemolytic anemias, methemoglobinemia, red cell aplasia, sideroblastic anemia, megaloblastic anemia, polycythemia, aplastic anemia, leukocytosis, neutropenia, eosinophilia, immune thrombocytopenia, microangiopathic syndromes, hypercoagulability, hypoprothrombinemia, circulating anticoagulants, myelodysplasia, and acute leukemia. Some of the classic drugs known to cause hematologic abnormalities have been replaced by newer drugs, including biologics, accompanied by their own syndromes and unintended side effects. Conclusions. Drugs can induce toxicities spanning many hematologic syndromes, mediated by a variety of mechanisms. Physicians need to be alert to the potential for iatrogenic drug-induced hematologic complications.

  15. Drug-induced cutaneous vasculitides.

    Science.gov (United States)

    Antiga, E; Verdelli, A; Bonciani, D; Bonciolini, V; Quintarelli, L; Volpi, W; Fabbri, P; Caproni, M

    2015-04-01

    Cutaneous vasculitides (CV) can be idiopathic or secondary to several triggers, including drugs, which account for up to 30% of all the cases of CV. Several drugs can induce CV, including some medications commonly used in dermatology, including minocycline, and several new drugs, such as anti-TNF agents. Different pathomecanisms are involved in the development of drug-induced CV, including the formation and deposition of immune complexes, the induction of neutrophil apoptosis, the formation of neoantigens between the drugs and proteins from the host, the shift of the immune response, and others. Although the diagnosis is difficult, because the clinical picture of drug-induced CV is in general indistinguishable from that of other forms of CV, it is important to recognize such entities in order to correctly manage the patient. Anamnesis, diagnostic algorithms to assess the likelihood of the association between a drug and a cutaneous reaction, skin biopsy and laboratory testing (including the search for antineutrophil cytoplasmic antibodies) are useful tools to make a diagnosis of drug-induced CV. About the therapy, while in idiopathic vasculitides the treatment is usually more aggressive and long-lasting, very often requiring a maintenance therapy with immunosuppressive drugs, in drug-induced CV the discontinuation of the suspected drug alone is usually enough to achieve complete remission, making the prognosis usually very good.

  16. D1 dopamine receptor activity of anti-parkinsonian drugs.

    Science.gov (United States)

    Fici, G J; Wu, H; VonVoigtlander, P F; Sethy, V H

    1997-01-01

    Clinical and preclinical investigations suggest that stimulation of D1 dopamine receptors may be responsible for dyskinesias induced by dopamine agonist treatment of Parkinson's Disease (PD), and that these dyskinesias may be decreased by treatment with a D1 antagonist (clozapine). Therefore, the effects of dopamine agonists and antagonists have been investigated in a primary cerebellar granule cell model of cAMP formation that seems to be highly responsive to the D1 receptors. SKF 38393, lisuride, apomorphine, pergolide, dopamine, bromocriptine and 7-OH-DPAT showed concentration-dependent increases in cAMP formation, with EC50s (in microM) of 0.013, 0.053, 0.25, 1.04, 2.18, 50.9 and 54.4, respectively. SKF 38393, apomorphine, dopamine and pergolide had similar intrinsic activity (100%), while the intrinsic activities of 7-OH-DPAT, bromocriptine and lisuride were 28.0%, 20.7% and 17.2%, respectively. SCH 23390, a selective D1 dopamine receptor antagonist, blocked an increase in cAMP formation produced by EC50 concentrations of all of the dopamine agonists investigated in this study. Clozapine concentration-dependently blocked pergolide-induced increases in cAMP and was approximately 1700-fold less potent than SCH 23390 (IC50: 0.97 microM and 0.56 nM, respectively). U-95666A (1-1000 microM), selective for the D2 receptors, showed no significant effect on cAMP, while pramipexole (0.1-100 microM), a D3 preferring agonist, did not elevate cAMP. These data suggest that primary cerebellar granule cell cultures are an excellent model for measuring D1 dopamine receptor-mediated changes in cellular cAMP. The results are discussed with reference to the relationship between the D1 receptor-stimulated increase in cAMP formation and the induction of dyskinesia in humans by these anti-parkinsonian drugs. PMID:9126882

  17. Drug-induced hepatic steatosis.

    Science.gov (United States)

    Amacher, David E; Chalasani, Naga

    2014-05-01

    Several drugs have been associated with the potential for drug-induced hepatic steatosis (DIHS) and/or phospholipidosis (DIPL), a lysosomal storage disorder. Drug-induced hepatic steatosis is generally a chronic but reversible affliction and may involve drug accumulation in the liver. Fat accumulation may be either macrovesicular or microvesicular in nature. Commonly used medications associated with DIHS include amiodarone, valproate, tamoxifen, methotrexate, and some chemotherapeutic and antiretroviral agents. Two recently approved medications for the treatment of hereditary homozygous hypercholesterolemia have also been noted to cause hepatic steatosis. For some compounds such as methotrexate and tamoxifen, the underlying metabolic risk factors such as obesity and metabolic syndrome may exacerbate their potential to cause DIHS and its progression. In this article, the authors discuss the preclinical screening and mechanisms of DIHS and DIPL, and review specific examples of drugs commonly used in clinical practice that are known to cause DIHS. PMID:24879984

  18. Drug-induced hair loss.

    Science.gov (United States)

    2016-05-01

    Hair loss can have major psychological consequences. It can be due to a wide variety of causes, including hormonal disorders, dietary factors, infections, inflammation, trauma, emotional factors, and cancer. Drugs can also induce hair loss, by interacting with the hair growth cycle. Drug-induced hair loss may be immediate or delayed, sudden or gradual, and diffuse or localised. It is usually reversible after drug discontinuation. The drugs most often implicated in hair loss are anticancer agents, interferon, azole antifungals, lithium, immunosuppressants, and many other drugs belonging to a variety of pharmacological classes.

  19. Drug-induced peripheral neuropathy

    DEFF Research Database (Denmark)

    Vilholm, Ole Jakob; Christensen, Alex Alban; Zedan, Ahmed;

    2014-01-01

    Peripheral neuropathy can be caused by medication, and various descriptions have been applied for this condition. In this MiniReview, the term 'drug-induced peripheral neuropathy' (DIPN) is used with the suggested definition: Damage to nerves of the peripheral nervous system caused by a chemical...... substance used in the treatment, cure, prevention or diagnosis of a disease. Optic neuropathy is included in this definition. A distinction between DIPN and other aetiologies of peripheral neuropathy is often quite difficult and thus, the aim of this MiniReview is to discuss the major agents associated...

  20. Drug-induced status epilepticus.

    Science.gov (United States)

    Cock, Hannah R

    2015-08-01

    Drug-induced status epilepticus (SE) is a relatively uncommon phenomenon, probably accounting for less than 5% of all SE cases, although limitations in case ascertainment and establishing causation substantially weaken epidemiological estimates. Some antiepileptic drugs, particularly those with sodium channel or GABA(γ-aminobutyric acid)-ergic properties, frequently exacerbate seizures and may lead to SE if used inadvertently in generalized epilepsies or less frequently in other epilepsies. Tiagabine seems to have a particular propensity for triggering nonconvulsive SE sometimes in patients with no prior history of seizures. In therapeutic practice, SE is most commonly seen in association with antibiotics (cephalosporins, quinolones, and some others) and immunotherapies/chemotherapies, the latter often in the context of a reversible encephalopathy syndrome. Status epilepticus following accidental or intentional overdoses, particularly of antidepressants or other psychotropic medications, has also featured prominently in the literature: whilst there are sometimes fatal consequences, this is more commonly because of cardiorespiratory or metabolic complications than as a result of seizure activity. A high index of suspicion is required in identifying those at risk and in recognizing potential clues from the presentation, but even with a careful analysis of patient and drug factors, establishing causation can be difficult. In addition to eliminating the potential trigger, management should be as for SE in any other circumstances, with the exception that phenobarbitone is recommended as a second-line treatment for suspected toxicity-related SE where the risk of cardiovascular complications is higher anyways and may be exacerbated by phenytoin. There are also specific recommendations/antidotes in some situations. The outcome of drug-induced status epilepticus is mostly good when promptly identified and treated, though less so in the context of overdoses. This article is

  1. Antiparkinsonian treatment for depression in Parkinson’s disease:Are selective serotonin reuptake inhibitors recommended?

    Institute of Scientific and Technical Information of China (English)

    Philippe De Deurwaerdre; Yuqiang Ding

    2016-01-01

    Depression is a frequent comorbid syndrome in Parkinson’s disease. It is a difficult symptom to manage, as patients continuously receive antiparkinsonian medication and may also have to be treated for the amelioration of the side-effects of antiparkinsonian therapy. The first-line treatment for depression in Parkinson’s disease is the use of selective serotonin reuptake inhibitors (SSRIs). The clinical efficacy of these medications in patients with Parkinson’s disease is questionable. In fact, based on their mechanism of action, which requires at least a functional serotonergic system, it is predicted that SSRIs will have lower efficacy in patients with Parkinson’s disease. Here, we consider the mechanism of action of SSRIs in the context of Parkinson’s disease by investigating the fall in the levels of serotonergic markers and the inhibitory outcomes of antiparkinsonian treatment on serotonergic nerve activity. Because certain classes of antidepressant drugs are widely available, it is necessary to perform translational research to address different strategies used to manage depression in Parkinson’s disease.

  2. Drugs induced pulmonary arterial hypertension.

    Science.gov (United States)

    Seferian, Andrei; Chaumais, Marie-Camille; Savale, Laurent; Günther, Sven; Tubert-Bitter, Pascale; Humbert, Marc; Montani, David

    2013-09-01

    Pulmonary arterial hypertension (PAH) is a rare disorder characterized by progressive obliteration of the pulmonary microvasculature, resulting in elevated pulmonary vascular resistance and premature death. According to the current classification, PAH can be associated with exposure to certain drugs or toxins, particularly appetite suppressant drugs, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary arterial smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used but are also considered as possible risk factors for PAH. Dasatinib, a dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, in part reversible after its withdrawal. Recently several studies raised the potential endothelial dysfunction that could be induced by interferon, and few cases of PAH have been reported with interferon therapy. Other possible risk factors for PAH include: nasal decongestants, like phenylpropanolamine, dietary supplement - L-Tryptophan, selective serotonin reuptake inhibitors, pergolide and other drugs that could act on 5HT2B receptors. Interestingly, PAH remains a rare complication of these drugs, suggesting possible individual susceptibility and further studies are needed to identify patients at risk of drugs induced PAH. PMID:23972547

  3. Drug-induced hepatic injury

    DEFF Research Database (Denmark)

    Friis, Henrik; Andreasen, P B

    1992-01-01

    The Danish Committee on Adverse Drug Reactions received 1100 reports of suspected drug-induced hepatic injury during the decade 1978-1987. The causal relationship between drug and hepatic injury was classified as definite in 57 (5.2%) reports, probable in 989 (89.9%) reports, possible in 50 (4.......5%) reports and unclassifiable in four (0.4%) reports. Hepatic injuries accounted for 5.9% of all adverse drug reactions reported, and 14.7% of the lethal adverse drug reactions. A total of 47.2% were classified as acute cytotoxic, 16.2% as acute cholestatic and 26.9% as abnormal hepatic function. In 52 (4.......7%) cases the hepatic injury was lethal; only 14 (1.3%) cases were chronic. Halothane accounted for 25% of the cases. The incidence of halothane-induced hepatic injury is decreasing, and only one lethal case has been reported since 1981. Next to halothane, sulfasalazine was the drug most often suspected...

  4. Factors influencing excessive daytime sleepiness in adolescents

    Directory of Open Access Journals (Sweden)

    Thiago de Souza Vilela

    2016-04-01

    Full Text Available Abstract Objective: Sleep deprivation in adolescents has lately become a health issue that tends to increase with higher stress prevalence, extenuating routines, and new technological devices that impair adolescents' bedtime. Therefore, this study aimed to assess the excessive sleepiness frequency and the factors that might be associated to it in this population. Methods: The cross-sectional study analyzed 531 adolescents aged 10–18 years old from two private schools and one public school. Five questionnaires were applied: the Cleveland Adolescent Sleepiness Questionnaire; the Sleep Disturbance Scale for Children; the Brazilian Economic Classification Criteria; the General Health and Sexual Maturation Questionnaire; and the Physical Activity Questionnaire. The statistical analyses were based on comparisons between schools and sleepiness and non-sleepiness groups, using linear correlation and logistic regression. Results: Sleep deprivation was present in 39% of the adolescents; sleep deficit was higher in private school adolescents (p < 0.001, and there was a positive correlation between age and sleep deficit (p < 0.001; r = 0.337. Logistic regression showed that older age (p = 0.002; PR: 1.21 [CI: 1.07–1.36] and higher score level for sleep hyperhidrosis in the sleep disturbance scale (p = 0.02; PR: 1.16 [CI: 1.02–1.32] were risk factors for worse degree of sleepiness. Conclusions: Sleep deficit appears to be a reality among adolescents; the results suggest a higher prevalence in students from private schools. Sleep deprivation is associated with older age in adolescents and possible presence of sleep disorders, such as sleep hyperhidrosis.

  5. Longitudinal change in sleep and daytime sleepiness in postpartum women.

    Directory of Open Access Journals (Sweden)

    Ashleigh J Filtness

    Full Text Available Sleep disruption strongly influences daytime functioning; resultant sleepiness is recognised as a contributing risk-factor for individuals performing critical and dangerous tasks. While the relationship between sleep and sleepiness has been heavily investigated in the vulnerable sub-populations of shift workers and patients with sleep disorders, postpartum women have been comparatively overlooked. Thirty-three healthy, postpartum women recorded every episode of sleep and wake each day during postpartum weeks 6, 12 and 18. Although repeated measures analysis revealed there was no significant difference in the amount of nocturnal sleep and frequency of night-time wakings, there was a significant reduction in sleep disruption, due to fewer minutes of wake after sleep onset. Subjective sleepiness was measured each day using the Karolinska Sleepiness Scale; at the two earlier time points this was significantly correlated with sleep quality but not to sleep quantity. Epworth Sleepiness Scores significantly reduced over time; however, during week 18 over 50% of participants were still experiencing excessive daytime sleepiness (Epworth Sleepiness Score ≥12. Results have implications for health care providers and policy makers. Health care providers designing interventions to address sleepiness in new mothers should take into account the dynamic changes to sleep and sleepiness during this initial postpartum period. Policy makers developing regulations for parental leave entitlements should take into consideration the high prevalence of excessive daytime sleepiness experienced by new mothers, ensuring enough opportunity for daytime sleepiness to diminish to a manageable level prior to reengagement in the workforce.

  6. Pharmacotherapy of Excessive Sleepiness: Focus on Armodafinil

    OpenAIRE

    Michael Russo

    2009-01-01

    Excessive sleepiness (ES) is responsible for significant morbidity and mortality due to its association with cardiovascular disease, cognitive impairment, and occupational and transport accidents. ES is also detrimental to patients’ quality of life, as it affects work and academic performance, social interactions, and personal relationships. Armodafinil is the R-enantiomer of the established wakefulness-promoting agent modafinil, which is a racemic mixture of both the R- and S-enantiomers. R-...

  7. Drug-induced hyperthermia in Huntington's disease.

    NARCIS (Netherlands)

    Gaasbeek, D.; Naarding, P.; Stor, T.; Kremer, H.P.H.

    2004-01-01

    Until now, only three patients with Huntington's disease (HD) and a neuroleptic malignant syndrome (NMS) have been reported in the literature. We describe four cases with advanced stage Huntington's disease who within a period of one year developed drug-induced hyperthermia, either the neuroleptic m

  8. Drug-induced regulation of target expression

    DEFF Research Database (Denmark)

    Iskar, Murat; Campillos, Monica; Kuhn, Michael;

    2010-01-01

    further newly identified drug-induced differential regulation of Lanosterol 14-alpha demethylase, Endoplasmin, DNA topoisomerase 2-alpha and Calmodulin 1. The feedback regulation in these and other targets is likely to be relevant for the success or failure of the molecular intervention....

  9. Using Latent Sleepiness to Evaluate an Important Effect of Promethazine

    Science.gov (United States)

    Feiveson, Alan H.; Hayat, Matthew; Vksman, Zalman; Putcha, Laksmi

    2007-01-01

    Astronauts often use promethazine (PMZ) to counteract space motion sickness; however PMZ may cause drowsiness, which might impair cognitive function. In a NASA ground study, subjects received PMZ and their cognitive performance was then monitored over time. Subjects also reported sleepiness using the Karolinska Sleepiness Score (KSS), which ranges from 1 - 9. A problem arises when using KSS to establish an association between true sleepiness and performance because KSS scores tend to overly concentrate on the values 3 (fairly awake) and 7 (moderately tired). Therefore, we defined a latent sleepiness measure as a continuous random variable describing a subject s actual, but unobserved true state of sleepiness through time. The latent sleepiness and observed KSS are associated through a conditional probability model, which when coupled with demographic factors, predicts performance.

  10. Causes and consequences of sleepiness among college students

    OpenAIRE

    Hershner SD; Chervin RD

    2014-01-01

    Shelley D Hershner, Ronald D ChervinDepartment of Neurology, University of Michigan, Ann Arbor, MI, USAAbstract: Daytime sleepiness, sleep deprivation, and irregular sleep schedules are highly prevalent among college students, as 50% report daytime sleepiness and 70% attain insufficient sleep. The consequences of sleep deprivation and daytime sleepiness are especially problematic to college students and can result in lower grade point averages, increased risk of academic failure, compromised ...

  11. Drug-induced valvulopathy: an update.

    Science.gov (United States)

    Elangbam, Chandikumar S

    2010-10-01

    Drug-induced valvulopathy is a serious liability for certain compound classes in development and for some marketed drugs intended for human use. Reports of valvulopathy led to the withdrawal of fenfluramines (anorexigens) and pergolide (antiparkinson drug) from the United States market in 1997 and 2007, respectively. The mechanism responsible for the pathogenesis of valvulopathy by these drugs is likely a result of an "off-target" effect via activation of 5-hydroxytryptamine (5-HT) 2B receptor (5-HT2BR) expressed on heart valve leaflets. Microscopically, the affected valve leaflets showed plaques of proliferative myofibroblasts in an abundant extracellular matrix, composed primarily of glycosaminoglycans. However, the valvular effects caused by fenfluramines and pergolide were not initially predicted from routine preclinical toxicity studies, and to date there are no specific validated animal models or preclinical/toxicologic screens to accurately predict drug-induced valvulopathy. This review covers the structure and function of heart valves and highlights major advances toward understanding the 5-HT2BR-mediated pathogenesis of the lesion and subsequently, development of appropriate animal models using novel techniques/experiments, use of functional screens against 5-HT2BR, and more consistent sampling and pathologic evaluation of valves in preclinical studies that will aid in avoidance of future drug-induced valvulopathy in humans. PMID:20716786

  12. Recent Advances in Drug-Induced Angioedema

    Directory of Open Access Journals (Sweden)

    Naoko Inomata

    2012-01-01

    Full Text Available Angioedema is the end result of deep dermal, subcutaneous and/or mucosal swelling, and is potentially a life- threatening condition in cases where the pharynx or larynx is involved. Drug-induced angioedema has been reported to occur in response to a wide range of drugs and vaccines. Drug-induced angioedema, like other cutaneous drug reactions, has been reported to be most frequently elicited by beta-lactam antibiotics and nonsteroidal anti-inflammatory drugs, although reliable data from epidemiologic studies are scarce. Recent reports suggested an increasing role of angiotensin-converting enzyme inhibitors (ACEIs in the causation of life- threatening angioedema. ACEI-related angioedema is never accompanied by urticaria and occurs via a kinin- dependent mechanism. ACEI-related angioedema not only can start years after beginning the treatment, but it can then recur irregularly while under that treatment. Furthermore, allergy tests are unreliable for the diagnosis of ACEI-related angioedema, and so the relationship between angioedema and ACEIs is often missed and consequently quite underestimated. Accordingly, better understanding of the kinin-dependent mechanism, which is particular to angioedema, is necessary for the appropriate management of drug-induced angioedema.

  13. Drug induced lung disease - amiodarone in focus

    Directory of Open Access Journals (Sweden)

    Vasić Nada R.

    2014-01-01

    Full Text Available More than 380 medications are known to cause pulmonary toxicity. Selected drugs that are important causes of pulmonary toxicity fall into the following classes: cytotoxic, cardiovascular, anti-inflammatory, antimicrobial, illicit drugs, miscellaneous. The adverse reactions can involve the pulmonary parenchyma, pleura, the airways, pulmonary vascular system, and mediastinum. Drug-induced lung diseases have no pathognomonic clinical, laboratory, physical, radiographic or histological findings. A drug-induced lung disease is usually considered a diagnosis of exclusion of other diseases. The diagnosis of drug-mediated pulmonary toxicity is usually made based on clinical findings. In general, laboratory analyses do not help in establishing the diagnosis. High-resolution computed tomography scanning is more sensitive than chest radiography for defining radiographic abnormalities. The treatment of drug-induced lung disease consists of immediate discontinuation of the offending drug and appropriate management of the pulmonary symptoms. Glucocorticoids have been associated with rapid improvement in gas exchange and reversal of radiographic abnormalities. Before starting any medication, patients should be educated about the potential adverse effects of the drug. Amiodarone is an antiarrhythmic agent used in the treatment of many types of tachyarrhythmia. Amiodarone-caused pulmonary toxicity is a well-known side effect (complication of this medication. The incidence of amiodarone-induced lung disease is approximately 5-7%.

  14. Determinants of sleepiness at work among railway control workers.

    Science.gov (United States)

    Cotrim, Teresa; Carvalhais, José; Neto, Catarina; Teles, Júlia; Noriega, Paulo; Rebelo, Francisco

    2017-01-01

    In the last two decades the control of the Portuguese railway network has become much more centralized in three centres, there integrating the functions of route flow management, electrical control and signalling. This study aimed to investigate the influence of work and individual determinants in sleepiness among railway control workers, namely socio-demographic factors, work ability, psychosocial factors, shiftwork characteristics, fatigue perception, and sleep. Sleepiness by shift was associated with quality of sleep, job satisfaction, fatigue perception, quantitative demands, and age. The results indicate a high prevalence of sleepiness during the night shift and show the relevance of the quality of sleep as a predictor in the three models of sleepiness for morning, afternoon and night shifts. This study, done at the major Portuguese railway control centre, alerted managers to the importance of schedule planning as well as sleepiness prevention plans and makes these results a reference for future research.

  15. Determinants of sleepiness at work among railway control workers.

    Science.gov (United States)

    Cotrim, Teresa; Carvalhais, José; Neto, Catarina; Teles, Júlia; Noriega, Paulo; Rebelo, Francisco

    2017-01-01

    In the last two decades the control of the Portuguese railway network has become much more centralized in three centres, there integrating the functions of route flow management, electrical control and signalling. This study aimed to investigate the influence of work and individual determinants in sleepiness among railway control workers, namely socio-demographic factors, work ability, psychosocial factors, shiftwork characteristics, fatigue perception, and sleep. Sleepiness by shift was associated with quality of sleep, job satisfaction, fatigue perception, quantitative demands, and age. The results indicate a high prevalence of sleepiness during the night shift and show the relevance of the quality of sleep as a predictor in the three models of sleepiness for morning, afternoon and night shifts. This study, done at the major Portuguese railway control centre, alerted managers to the importance of schedule planning as well as sleepiness prevention plans and makes these results a reference for future research. PMID:27633225

  16. Sonolência excessiva Excessive daytime sleepiness

    Directory of Open Access Journals (Sweden)

    Lia Rita Azeredo Bittencourt

    2005-05-01

    Full Text Available A sonolência é uma função biológica, definida como uma probabilidade aumentada para dormir. Já a sonolência excessiva (SE, ou hipersonia, refere-se a uma propensão aumentada ao sono com uma compulsão subjetiva para dormir, tirar cochilos involuntários e ataques de sono, quando o sono é inapropriado. As principais causas de sonolência excessiva são a privação crônica de sono (sono insuficiente, a Síndrome da Apnéia e Hipopnéia Obstrutiva do Sono (SAHOS, a narcolepsia, a Síndrome das Pernas Inquietas/Movimentos Periódicos de Membros (SPI/MPM, Distúrbios do Ritmo Circadiano, uso de drogas e medicações e a hipersonia idiopática. As principais conseqüências são prejuízo no desempenho nos estudos, no trabalho, nas relações familiares e sociais, alterações neuropsicológicas e cognitivas e risco aumentado de acidentes. O tratamento da sonolência excessiva deve estar voltado para as causas específicas. Na privação voluntária do sono, aumentar o tempo de sono e higiene do sono, o uso do CPAP (Continuous Positive Airway Pressure na Síndrome da Apnéia e Hipopnéia Obstrutiva do Sono, exercícios e agentes dopaminérgicos na Síndrome das Pernas Inquietas/Movimentos Periódicos de Membros, fototerapia e melatonina nos Distúrbios do Ritmo Circadiano, retiradas de drogas que causam sonolência excessiva e uso de estimulantes da vigília.Sleepiness is a physiological function, and can be defined as increased propension to fall asleep. However, excessive sleepiness (ES or hypersomnia refer to an abnormal increase in the probability to fall asleep, to take involuntary naps, or to have sleep atacks, when sleep is not desired. The main causes of excessive sleepiness is chronic sleep deprivation, sleep apnea syndrome, narcolepsy, movement disorders during sleep, circadian sleep disorders, use of drugs and medications, or idiopathic hypersomnia. Social, familial, work, and cognitive impairment are among the consequences of

  17. [Drug-induced impairment of renal function].

    Science.gov (United States)

    Krüger, B; Benck, U; Singer, T; Krämer, B K

    2012-09-01

    Acute kidney injury (AKI) of any origin is a common complication/disease in hospitalized patients, going along with significantly increased mortality and morbidity, as well as hospitalization duration and expenses. Drug-induced AKI is usually seen in patients with concurrent risk factors such as existing kidney disease, dehydration with or without hypotension, older age or diabetes mellitus. In cases with multiple risk factors or therapies the triggering drug is often impossible to define. Hemodynamic alterations, intrinsic tubulointerstitial damages and intrarenal (i. e. tubular) obstructions as a result of drug precipitations are the pathophysiological basis of this disease entity. Clinically the AKI is perceived as the most important problem, due to the development of hyperhydration (including pulmonary edema) and reduced/lacking clearance of toxic metabolites. The prognosis of drug-induced AKI is usually good, especially if the agents are stopped early in the process, but nevertheless some patients experience severe acute AKI requiring dialysis with/without subsequent restoration. Considering and recognizing potential risk factors may help to identify patients at risk and lead to introduction of prophylactic actions. Identification of risk factors and the introduction of prevention strategies should be an integral part of everybody's daily clinical work, especially in intensive care medicine due to the high susceptibility to AKI. PMID:22971974

  18. Antipsychotic drug-induced hematologic disorders

    Directory of Open Access Journals (Sweden)

    Theocharis Kyziridis

    2014-01-01

    Full Text Available Over half a century after the discovery of chlorpromazine and haloperidol, antipsychotic drugs showed a true evolutionary revolution. The knowledge of their adverse effects is of outmost importance as it may contribute to the prevention of unwanted sequelae, to the decrease of the duration and cost of hospitalization, it may improve the quality of life of patients, minimize the problems and maximize the therapeutic gain. Aim: The aim of this review was the presentation of the hematologic side-effects of antipsychotic drugs, and most particularly their frequency and association with the different classes of these drugs, their clinical picture and their pathophysiologic mechanisms. Material-method: This paper is a review of the literature (mainly articles from journals, PubMed, as well as books and monographs of the period 1978-2012. Key-words used included antipsychotics, hematologic adverse effects, drug-induced adverse effects. Results: Antipsychotic-drug induced hematologic side-effects are not particularly highly prevalent, while many of them are found in case reports. For this reason they have not drawn much of attention. These hematologic dyscrasias may concern all the blood cell series as well as the coagulation mechanism. Excluded from this rule is the case of clozapine-induced agranulocytosis, which demands increased clinical vigilance. In fact, agranulocytosis was the reason why the drug was drawn away from circulation approximately 35 years ago. Conclusions: In any case the appearance of a hematologic disorder in a patient receiving antipsychotic medications should prompt careful evaluation.

  19. The Antiparkinsonian and Antidyskinetic Mechanisms of Mucuna pruriens in the MPTP-Treated Nonhuman Primate.

    Science.gov (United States)

    Lieu, Christopher A; Venkiteswaran, Kala; Gilmour, Timothy P; Rao, Anand N; Petticoffer, Andrew C; Gilbert, Erin V; Deogaonkar, Milind; Manyam, Bala V; Subramanian, Thyagarajan

    2012-01-01

    Chronic treatment with levodopa (LD) in Parkinson's disease (PD) can cause drug induced dyskinesias. Mucuna pruriens endocarp powder (MPEP) contains several compounds including natural LD and has been reported to not cause drug-induced dyskinesias. We evaluated the effects of Mucuna pruriens to determine if its underlying mechanistic actions are exclusively due to LD. We first compared MPEP with and without carbidopa (CD), and LD+CD in hemiparkinsonian (HP) monkeys. Each treatment ameliorated parkinsonism. We then compared the neuronal firing properties of the substantia nigra reticulata (SNR) and subthalamic nucleus (STN) in HP monkeys with MPEP+CD and LD+CD to evaluate basal ganglia circuitry alterations. Both treatments decreased SNR firing rate compared to HP state. However, LD+CD treatments significantly increased SNR bursting firing patterns that were not seen with MPEP+CD treatments. No significant changes were seen in STN firing properties. We then evaluated the effects of a water extract of MPEP. Oral MPWE ameliorated parkinsonism without causing drug-induced dyskinesias. The distinctive neurophysiological findings in the basal ganglia and the ability to ameliorate parkinsonism without causing dyskinesias strongly suggest that Mucuna pruriens acts through a novel mechanism that is different from that of LD. PMID:22997535

  20. Republished: drug-induced valvular heart disease.

    Science.gov (United States)

    Cosyns, Bernard; Droogmans, Steven; Rosenhek, Raphael; Lancellotti, Patrizio

    2013-03-01

    Drug-induced valvular heart disease (DIVHD) was first described in the 1960s. Initially, associations with ergot derivatives used for migraine prevention, or with anorectic drugs, were described. Drugs used for the treatment of Parkinson's disease and endocrine diseases, like hyperprolactinemia, may also induce VHD. More recently, the use of 3,4-methylendioxymetamphetamine (MDMA, 'Ecstasy') and benfluorexhave been found to be associated with DIVHD. Although some of these drugs were withdrawn from the market, several cases of patients requiring valve surgery even years after the cessation of therapy have been reported. DIVHD is not infrequent, may be severe, and has been described in association with several drugs. Even after drug cessation, long-term implications of this type of VHD may persist. The present review underlines the need for a careful evaluation of the associated clinical and echocardiographic risk factors to allow early recognition so as not to delay appropriate management. PMID:23417686

  1. Drug-induced valvular heart disease.

    Science.gov (United States)

    Cosyns, Bernard; Droogmans, Steven; Rosenhek, Raphael; Lancellotti, Patrizio

    2013-01-01

    Drug-induced valvular heart disease (DIVHD) was first described in the 1960s. Initially, associations with ergot derivatives used for migraine prevention, or with anorectic drugs, were described. Drugs used for the treatment of Parkinson's disease and endocrine diseases, like hyperprolactinemia, may also induce VHD. More recently, the use of 3,4-methylendioxymetamphetamine (MDMA, 'Ecstasy') and benfluorexhave been found to be associated with DIVHD. Although some of these drugs were withdrawn from the market, several cases of patients requiring valve surgery even years after the cessation of therapy have been reported. DIVHD is not infrequent, may be severe, and has been described in association with several drugs. Even after drug cessation, long-term implications of this type of VHD may persist. The present review underlines the need for a careful evaluation of the associated clinical and echocardiographic risk factors to allow early recognition so as not to delay appropriate management. PMID:22875739

  2. The discovery of drug-induced illness.

    Science.gov (United States)

    Jick, H

    1977-03-01

    The increased use of drugs (and the concurrent increased risks of drug-induced illness) require definition of relevant research areas and strategy. For established marketed drugs, research needs depend on the magnitudes of risk of an illness from a drug and the base-line risk. With the drug risk high and the base-line risk low, the problem surfaces in premarketing studies or through the epidemic that develops after marketing. If the drug adds slightly to a high base-line risk, the effect is undetectable. When both risks are low, adverse effects can be discovered by chance, but systematic case-referent studies can speed discovery. If both risks are high, clinical trials and nonexperimental studies may be used. With both risks intermediate, systematic evaluations, especially case-referent studies are needed. Newly marketed drugs should be routinely evaluated through compulsory registration and follow-up study of the earliest users.

  3. Pathogenesis of drug induced acneform eruptions

    Directory of Open Access Journals (Sweden)

    Lobo Audrey

    1992-01-01

    Full Text Available To determine the pathogenesis of drug induced acneform eruption (DAE, 44 patients were evaluated clinically and representative samples histologically. INAH and corticosteroids were the main offenders in 38.6 percent and 36.4 percent patients respectively. Chloroquin precipitated lesions in 9.1 percent of the patients. There were significant differences in the duration of drug-intake before onset, morphology and severity of lesions. Histological differences with different drugs were also noted. Based on clinical and histological findings, pathogenesis of lesions caused by different drugs could be suggested. Keratinization of follicular epithelium was the main effect with corticosteroids and INAH. Suppuration of follicular epithelium was an additional early event with corticosteroids. Type III allergic reaction was responsible for iodine lesions and delayed hypersensitivity for chlorpromazine and chloroquine induced lesions.

  4. Circulating KL-6 levels in patients with drug induced pneumonitis

    OpenAIRE

    Ohnishi, Hiroshi; Yokoyama, Akihito; Yasuhara, Yoshifumi; Watanabe, Akira; Naka, Tetsuji; Hamada, Hironobu; Abe, Masahiro; Nishimura, Kazutaka; Higaki, Jitsuo; Ikezoe, Junpei; Kohno, Nobuoki

    2003-01-01

    Background: The circulating level of KL-6/MUC1 is a sensitive marker for various interstitial lung diseases. Previous case reports have suggested that KL-6 may also be increased in some patients with drug induced pneumonitis. A study was undertaken to determine whether serum KL-6 could be a marker for particular types of drug induced pneumonitis. Methods: The findings of high resolution computed tomographic (HRCT) chest scans of 30 patients with drug induced pneumonitis were reviewed separate...

  5. Sleepiness in sleepwalking and sleep terrors: a higher sleep pressure?

    OpenAIRE

    Carrillo-Solano, Marisol; Leu-Semenescu, Smaranda; Golmard, Jean-Louis; Groos, Elisabeth; Arnulf, Isabelle

    2016-01-01

    International audience ObjectiveTo identify the determinants of excessive daytime sleepiness in adults with sleepwalking or sleep terrors (SW/ST).MethodsWe collected the charts of all consecutive adult patients admitted from 2012 to 2014 for SW/ST. They had completed the Paris Arousal Disorders Severity Scale and the Epworth Sleepiness Scale, and had undergone one (n = 34) or two consecutive (n = 124) nocturnal videopolysomnographies. The demographic, clinical, and sleep determinants of ex...

  6. Relationships between affect, vigilance, and sleepiness following sleep deprivation

    OpenAIRE

    Franzen, Peter L.; Siegle, Greg J.; Buysse, Daniel J.

    2008-01-01

    This pilot study examined the relationships between the effects of sleep deprivation on subjective and objective measures of sleepiness and affect, and psychomotor vigilance performance. Following an adaptation night in the laboratory, healthy young adults were randomly assigned to either a night of total sleep deprivation (SD group; n = 15) or to a night of normal sleep (non-SD group; n = 14) under controlled laboratory conditions. The following day, subjective reports of mood and sleepiness...

  7. Daytime sleepiness and sleep quality among Malaysian medical students.

    Science.gov (United States)

    Zailinawati, A H; Teng, C L; Chung, Y C; Teow, T L; Lee, P N; Jagmohni, K S

    2009-06-01

    Poor sleep quality and daytime somnolence is reported to be associated with cardiovascular events, road traffic accident, poor academic performance and psychological distress. Some studies documented that it is prevalent in most populations but its frequency among medical students has not been documented in Malaysia. This is a self-administered questionnaire survey of medical students from International Medical University, Malaysia. Daytime sleepiness of medical students was assessed using Epworth Sleepiness Scale (ESS). Student scoring ESS > 11 was regarded as having excessive daytime sleepiness. Psychological distress was measured using 12-item General Health Questionnaire (GHQ-12). A total of 799 medical students participated in this survey (response rate 69.5%). Daytime sleepiness occurred in 35.5%, psychological distress was present in 41.8% and 16.1% reported bad sleep quality. Daytime sleepiness was significantly more common among the clinical students, those with self-reported bad sleep quality and psychological distress; but unrelated to the number of hours sleep at night. We have documented high prevalence of daytime sleepiness, poor sleep quality and psychological distress. Higher frequency among clinical students and the significant relationship with psychological distress suggest possible link to the stressful clinical training. PMID:20058567

  8. Schooltime subjective sleepiness and performance in Italian primary school children.

    Science.gov (United States)

    Cerasuolo, Mariangela; Giganti, Fiorenza; Conte, Francesca; Costanzo, Lucia Maria; Della Monica, Ciro; Arzilli, Cinzia; Marchesano, Rosa; Perrella, Arianna; Ficca, Gianluca

    2016-01-01

    Despite its clinical importance, the issue of the diurnal time course of sleepiness and performance in children remains largely unexplored. The objective of this study is to draw a profile of daytime subjective sleepiness and performance, at simple and complex tasks, in a cohort of Italian primary school children.To this aim, a sample of 316 children (age range: 5-11 years; mean 8.2 ± 1.5) was recruited and sub-divided into three groups, according to age: Group 1 (5-7 years; N = 127), Group 2 (8-9 years; N = 108), Group 3 (10-11 years; N = 81). Subjective sleepiness and simple performance were evaluated, respectively, through the Pictorial Sleepiness Scale and the Simple Reaction Time Task. Executive functions were addressed by means of the "Go/No-Go Task." Measurements were made in the children's class three times a day, one day a week over a 3-week period in order to reliably reflect the habitual time course of sleepiness and performance, within the following time intervals: a) 8:30 am-10:30 am; b) 11 am-1 pm; c) 2 pm-4 pm.For the global sample, a significant increase of subjective sleepiness was found at the end of school day (2-4 pm), although at relatively low levels. No significant differences were observed in reaction times across the day, whereas a significant worsening was detected in performance at complex task already since mid-morning. Significant correlations were found between subjective sleepiness and complex performance at all points.Slight age-related differences were found in the time courses of subjective sleepiness: in fact, a significant overday reduction of vigilance levels, from mid-morning onwards, was observed in children aged 5-9 years, but not in the older children (10-11 years). However, the daily time course of both simple and complex performances did not differ among children of the three age groups. Our results show changes in vigilance and cognitive functions across a typical school day in childhood, as well as age

  9. Causes and consequences of sleepiness among college students

    Directory of Open Access Journals (Sweden)

    Hershner SD

    2014-06-01

    Full Text Available Shelley D Hershner, Ronald D ChervinDepartment of Neurology, University of Michigan, Ann Arbor, MI, USAAbstract: Daytime sleepiness, sleep deprivation, and irregular sleep schedules are highly prevalent among college students, as 50% report daytime sleepiness and 70% attain insufficient sleep. The consequences of sleep deprivation and daytime sleepiness are especially problematic to college students and can result in lower grade point averages, increased risk of academic failure, compromised learning, impaired mood, and increased risk of motor vehicle accidents. This article reviews the current prevalence of sleepiness and sleep deprivation among college students, contributing factors for sleep deprivation, and the role of sleep in learning and memory. The impact of sleep and sleep disorders on academics, grade point average, driving, and mood will be examined. Most importantly, effective and viable interventions to decrease sleepiness and sleep deprivation through sleep education classes, online programs, encouragement of naps, and adjustment of class time will be reviewed. This paper highlights that addressing sleep issues, which are not often considered as a risk factor for depression and academic failure, should be encouraged. Promotion of university and college policies and class schedules that encourage healthy and adequate sleep could have a significant impact on the sleep, learning, and health of college students. Future research to investigate effective and feasible interventions, which disseminate both sleep knowledge and encouragement of healthy sleep habits to college students in a time and cost effective manner, is a priority.Keywords: grade point average, GPA, sleep deprivation, academic performance, adolescence, sleep education programs

  10. Causes and consequences of sleepiness among college students.

    Science.gov (United States)

    Hershner, Shelley D; Chervin, Ronald D

    2014-01-01

    Daytime sleepiness, sleep deprivation, and irregular sleep schedules are highly prevalent among college students, as 50% report daytime sleepiness and 70% attain insufficient sleep. The consequences of sleep deprivation and daytime sleepiness are especially problematic to college students and can result in lower grade point averages, increased risk of academic failure, compromised learning, impaired mood, and increased risk of motor vehicle accidents. This article reviews the current prevalence of sleepiness and sleep deprivation among college students, contributing factors for sleep deprivation, and the role of sleep in learning and memory. The impact of sleep and sleep disorders on academics, grade point average, driving, and mood will be examined. Most importantly, effective and viable interventions to decrease sleepiness and sleep deprivation through sleep education classes, online programs, encouragement of naps, and adjustment of class time will be reviewed. This paper highlights that addressing sleep issues, which are not often considered as a risk factor for depression and academic failure, should be encouraged. Promotion of university and college policies and class schedules that encourage healthy and adequate sleep could have a significant impact on the sleep, learning, and health of college students. Future research to investigate effective and feasible interventions, which disseminate both sleep knowledge and encouragement of healthy sleep habits to college students in a time and cost effective manner, is a priority. PMID:25018659

  11. Drug-induced parkinsonism: diagnosis and management

    Directory of Open Access Journals (Sweden)

    Blanchet PJ

    2016-09-01

    Full Text Available Pierre J Blanchet,1–3 Veronika Kivenko1–3 1Department of Stomatology, Faculty of Dental Medicine, University of Montreal, 2Andre-Barbeau Movement Disorders Unit, University of Montreal Hospital Center (CHU Montreal, 3Montreal Mental Health University Institute, Montreal, QC, Canada Abstract: Drug-induced parkinsonism (DIP has been known for >60 years. It is the second leading cause of parkinsonism, but still underdiagnosis is likely to influence reported incidence figures. Since DIP is clinically undistinguishable from Lewy-body Parkinson’s disease, any new case of parkinsonism should prompt the search for an offending antipsychotic, hidden neuroleptic, or nonneuroleptic agent that may produce DIP. DIP is reversible upon drug withdrawal in most cases. There is no consensus regarding the duration of the recovery period to allow motor signs to fully remit in order to confirm the diagnosis of DIP following removal of the causative agent, but a drug-free interval of at least 6 months is generally recommended. Interestingly, up to 30% of DIP cases may show persisting or worsening motor signs beyond 6 months following drug withdrawal or adjustment, due to complex postsynaptic and presynaptic factors that may variably interact to negatively influence nigrostriatal dopamine transmission in a so-called “double-hit” hypothesis. The condition significantly impacts on quality of life and increases the risks of morbidity and mortality. Management is challenging in psychiatric patients and requires a team approach to achieve the best outcome. Keywords: neuroleptic drugs, extrapyramidal side effects, second generation antipsychotics, calcium channel blockers, valproic acid, tetrabenazine 

  12. Drug induced exfoliative dermatitis: state of the art.

    Science.gov (United States)

    Yacoub, Mona-Rita; Berti, Alvise; Campochiaro, Corrado; Tombetti, Enrico; Ramirez, Giuseppe Alvise; Nico, Andrea; Di Leo, Elisabetta; Fantini, Paola; Sabbadini, Maria Grazia; Nettis, Eustachio; Colombo, Giselda

    2016-01-01

    Drug induced exfoliative dermatitis (ED) are a group of rare and severe drug hypersensitivity reactions (DHR) involving skin and usually occurring from days to several weeks after drug exposure. Erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are the main clinical presentations of drug induced ED. Overall, T cells are the central player of these immune-mediated drug reactions. Here we provide a systematic review on frequency, risk factors, pathogenesis, clinical features and management of patients with drug induced ED. PMID:27551239

  13. Anticancer drug-induced kidney disorders.

    Science.gov (United States)

    Kintzel, P E

    2001-01-01

    Nephrotoxicity is an inherent adverse effect of certain anticancer drugs. Renal dysfunction can be categorised as prerenal uraemia, intrinsic damage or postrenal uraemia according to the underlying pathophysiological process. Renal hypoperfusion promulgates prerenal uraemia. Intrinsic renal damage results from prolonged hypoperfusion, exposure to exogenous or endogenous nephrotoxins, renotubular precipitation of xenobiotics or endogenous compounds, renovascular obstruction, glomerular disease, renal microvascular damage or disease, and tubulointerstitial damage or disease. Postrenal uraemia is a consequence of clinically significant urinary tract obstruction. Clinical signs of nephrotoxicity and methods used to assess renal function are discussed. Mechanisms of chemotherapy-induced renal dysfunction generally include damage to vasculature or structures of the kidneys, haemolytic uraemic syndrome and prerenal perfusion deficits. Patients with cancer are frequently at risk of renal impairment secondary to disease-related and iatrogenic causes. This article reviews the incidence, presentation, prevention and management of anticancer drug-induced renal dysfunction. Dose-related nephrotoxicity subsequent to administration of certain chloroethylnitrosourea compounds (carmustine, semustine and streptozocin) is commonly heralded by increased serum creatinine levels, uraemia and proteinuria. Additional signs of streptozocin-induced nephrotoxicity include hypophosphataemia, hypokalaemia, hypouricaemia, renal tubular acidosis, glucosuria, aceturia and aminoaciduria. Cisplatin and carboplatin cause dose-related renal dysfunction. In addition to increased serum creatinine levels and uraemia, electrolyte abnormalities, such as hypomagnesaemia and hypokalaemia, are commonly reported adverse effects. Rarely, cisplatin has been implicated as the underlying cause of haemolytic uraemic syndrome. Pharmaceutical antidotes to cisplatin-induced nephrotoxicity include amifostine, sodium

  14. Drug Induced Hearing Loss: Researchers Study Strategies to Preserve Hearing

    Science.gov (United States)

    ... of this page please turn JavaScript on. Feature: Drug-Induced Hearing Loss Researchers Study Strategies to Preserve ... brain there was a sound. What are ototoxic drugs and why are they important? Ototoxic drugs are ...

  15. Effect of AND#945;-tocopherol on antitubercular drugs induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Rajiv Nehra

    2016-04-01

    Conclusions: and #945;-tocopherol (200 mg/kg bw, oral was found to have hepatoprotective effect against antitubercular drugs induced hepatotoxicity in albino rabbits. [Int J Res Med Sci 2016; 4(4.000: 1158-1162

  16. Drug-induced pancreatitis: A Potentially Serious and Underreported Problem

    OpenAIRE

    Kaufman, Michele B.

    2013-01-01

    There have been many published reports of possible cases of drug-induced pancreatitis. In addition, some disease states and patient characteristics predispose particular populations to the development of this condition. Three case histories are presented.

  17. Drug-Induced Bullous Sweet Syndrome with Multiple Autoimmune Features

    OpenAIRE

    2010-01-01

    Sweet syndrome (SS) (Acute Febrile Neutrophilic Dermatosis) has been reported in association with autoimmune phenomena including relapsing polychondritis, drug-induced lupus, and the development of antineutrophil cytoplasmic antibodies (ANCAs). However, a combination of these autoimmune features has not been reported. Herein, we report a case of drug-induced bullous SS with ocular and mucosal involvement, glomerulonephritis, and multiple autoimmune features including clinical polychondritis w...

  18. Drug-Path: a database for drug-induced pathways.

    Science.gov (United States)

    Zeng, Hui; Qiu, Chengxiang; Cui, Qinghua

    2015-01-01

    Some databases for drug-associated pathways have been built and are publicly available. However, the pathways curated in most of these databases are drug-action or drug-metabolism pathways. In recent years, high-throughput technologies such as microarray and RNA-sequencing have produced lots of drug-induced gene expression profiles. Interestingly, drug-induced gene expression profile frequently show distinct patterns, indicating that drugs normally induce the activation or repression of distinct pathways. Therefore, these pathways contribute to study the mechanisms of drugs and drug-repurposing. Here, we present Drug-Path, a database of drug-induced pathways, which was generated by KEGG pathway enrichment analysis for drug-induced upregulated genes and downregulated genes based on drug-induced gene expression datasets in Connectivity Map. Drug-Path provides user-friendly interfaces to retrieve, visualize and download the drug-induced pathway data in the database. In addition, the genes deregulated by a given drug are highlighted in the pathways. All data were organized using SQLite. The web site was implemented using Django, a Python web framework. Finally, we believe that this database will be useful for related researches. PMID:26130661

  19. Excessive daytime sleepiness in multiple system atrophy (SLEEMSA study)

    NARCIS (Netherlands)

    Moreno-Lopez, C.; Santamaria, J.; Salamero, M.; Del Sorbo, F.; Albanese, A.; Pellecchia, M.T.; Barone, P.; Overeem, S.; Bloem, B.R.; Aarden, W.C.C.A.; Canesi, M.; Antonini, A.; Duerr, S.; Wenning, G.K.; Poewe, W.; Rubino, A.; Meco, G.; Schneider, S.A.; Bhatia, K.P.; Djaldetti, R.; Coelho, M.; Sampaio, C.; Cochen, V.; Hellriegel, H.; Deuschl, G.; Colosimo, C.; Marsili, L.; Gasser, T.; Tolosa, E.

    2011-01-01

    BACKGROUND: Sleep disorders are common in multiple system atrophy (MSA), but the prevalence of excessive daytime sleepiness (EDS) is not well known. OBJECTIVE: To assess the frequency and associations of EDS in MSA. DESIGN: Survey of EDS in consecutive patients with MSA and comparison with patients

  20. Contemporary review of drug-induced pancreatitis: A different perspective

    Institute of Scientific and Technical Information of China (English)

    Whitney; Y; Hung; Odaliz; Abreu; Lanfranco

    2014-01-01

    Although gallstone and alcohol use have been consid-ered the most common causes of acute pancreatitis, hundreds of frequently prescribed medications are as-sociated with this disease state. The true incidence is unknown since there are few population based studies available. The knowledge of drug induced acute pan-creatitis is limited by the availability and the quality of the evidence as the majority of data is extrapolated from case reports. Establishing a definitive causal rela-tionship between a drug and acute pancreatitis poses a challenge to clinicians. Several causative agent classifi-cation systems are often used to identify the suspected agents. They require regular updates since new drug induced acute pancreatitis cases are reported continu-ously. In addition, infrequently prescribed medications and herbal medications are often omitted. Furthermore, identification of drug induced acute pancreatitis with new medications often requires accumulation of post market case reports. The unrealistic expectation for a comprehensive list of medications and the multifacto-rial nature of acute pancreatitis call for a different ap-proach. In this article, we review the potential mecha-nisms of drug induced acute pancreatitis and providethe perspective of deductive reasoning in order to allow clinicians to identify potential drug induced acute pan-creatitis with limited data.

  1. Contemporary review of drug-induced pancreatitis: A different perspective.

    Science.gov (United States)

    Hung, Whitney Y; Abreu Lanfranco, Odaliz

    2014-11-15

    Although gallstone and alcohol use have been considered the most common causes of acute pancreatitis, hundreds of frequently prescribed medications are associated with this disease state. The true incidence is unknown since there are few population based studies available. The knowledge of drug induced acute pancreatitis is limited by the availability and the quality of the evidence as the majority of data is extrapolated from case reports. Establishing a definitive causal relationship between a drug and acute pancreatitis poses a challenge to clinicians. Several causative agent classification systems are often used to identify the suspected agents. They require regular updates since new drug induced acute pancreatitis cases are reported continuously. In addition, infrequently prescribed medications and herbal medications are often omitted. Furthermore, identification of drug induced acute pancreatitis with new medications often requires accumulation of post market case reports. The unrealistic expectation for a comprehensive list of medications and the multifactorial nature of acute pancreatitis call for a different approach. In this article, we review the potential mechanisms of drug induced acute pancreatitis and provide the perspective of deductive reasoning in order to allow clinicians to identify potential drug induced acute pancreatitis with limited data. PMID:25400984

  2. Visual contrast sensitivity in drug-induced Parkinsonism.

    Science.gov (United States)

    Bulens, C; Meerwaldt, J D; van der Wildt, G J; Keemink, C J

    1989-01-01

    The influence of stimulus orientation on contrast sensitivity function was studied in 10 patients with drug-induced Parkinsonism. Nine of the 10 patients had at least one eye with contrast sensitivity deficit for vertical and/or horizontal stimuli. Only generalised contrast sensitivity loss, observed in two eyes, was stimulus orientation independent. All spatial frequency-selective contrast deficits in 15 eyes were orientation dependent. The striking similarity between the pattern of contrast sensitivity loss in drug-induced Parkinsonism and that in idiopathic Parkinson's disease, suggests that generalised dopaminergic deficiency, from whatever cause, affects visual function in an analogous way. PMID:2926418

  3. Drug-Induced Metabolic Acidosis [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Amy Quynh Trang Pham

    2015-12-01

    Full Text Available Metabolic acidosis could emerge from diseases disrupting acid-base equilibrium or from drugs that induce similar derangements. Occurrences are usually accompanied by comorbid conditions of drug-induced metabolic acidosis, and clinical outcomes may range from mild to fatal. It is imperative that clinicians not only are fully aware of the list of drugs that may lead to metabolic acidosis but also understand the underlying pathogenic mechanisms. In this review, we categorized drug-induced metabolic acidosis in terms of pathophysiological mechanisms, as well as individual drugs’ characteristics.

  4. Drug-Induced Extrapyramidal Syndromes: Implications for Contemporary Practice.

    Science.gov (United States)

    Caroff, Stanley N; Campbell, E Cabrina

    2016-09-01

    The development of drugs to treat psychosis is a fascinating nexus for understanding mechanisms underlying disorders of mind and movement. Although the risk of drug-induced extrapyramidal syndromes has been mitigated by the acceptance of less potent dopamine antagonists, expansive marketing and off-label use has increased the number of susceptible people who may be at risk for these neurologic effects. Clinicians need to be familiar with advances in diagnosis and management, which are reviewed herein. A better understanding of drug-induced effects on the motor circuit may improve patient safety, enhance antipsychotic effectiveness, and provide insights into mechanisms underlying antipsychotic activity in parallel brain circuits. PMID:27514296

  5. Visual contrast sensitivity in drug-induced Parkinsonism.

    Science.gov (United States)

    Bulens, C; Meerwaldt, J D; van der Wildt, G J; Keemink, C J

    1989-03-01

    The influence of stimulus orientation on contrast sensitivity function was studied in 10 patients with drug-induced Parkinsonism. Nine of the 10 patients had at least one eye with contrast sensitivity deficit for vertical and/or horizontal stimuli. Only generalised contrast sensitivity loss, observed in two eyes, was stimulus orientation independent. All spatial frequency-selective contrast deficits in 15 eyes were orientation dependent. The striking similarity between the pattern of contrast sensitivity loss in drug-induced Parkinsonism and that in idiopathic Parkinson's disease, suggests that generalised dopaminergic deficiency, from whatever cause, affects visual function in an analogous way.

  6. [THREE CASES OF DRUG-INDUCED PNEUMONIA CAUSED BY MESALAZINE].

    Science.gov (United States)

    Akiyama, Norimichi; Yokomura, Koshi; Nozue, Tsuyoshi; Abe, Takefumi; Matsui, Takashi; Suda, Takafumi

    2015-12-01

    We report three cases of drug-induced pneumonia caused by mesalazine. They were all diagnosed as ulcerative colitis and treated with mesalazine orally. Our three cases and literature review revealed that mesalazine-induced pneumonia resemble like eosinophilic pneumonia or organizing pneumonia and that have good prognosis with drug cessation or administration of corticosteroid. The patient of ulcerative colitis is increasing every year and it is anticipated that the patient with mesalazine-induced pneumonia may also increase. In the treatment of ulcerative colitis with mesalazine, we should pay attention with patient's cough or fever for early detection of drug-induced pneumonia.

  7. Drug-Induced Bullous Sweet Syndrome with Multiple Autoimmune Features

    Directory of Open Access Journals (Sweden)

    Jared J. Lund

    2010-01-01

    Full Text Available Sweet syndrome (SS (Acute Febrile Neutrophilic Dermatosis has been reported in association with autoimmune phenomena including relapsing polychondritis, drug-induced lupus, and the development of antineutrophil cytoplasmic antibodies (ANCAs. However, a combination of these autoimmune features has not been reported. Herein, we report a case of drug-induced bullous SS with ocular and mucosal involvement, glomerulonephritis, and multiple autoimmune features including clinical polychondritis with antitype II collagen antibodies, ANCAs, antinuclear (HEp-2, and antihistone antibodies in a patient on hydralazine and carbamazepine.

  8. Children's Sleep, Sleepiness, and Performance on Cognitive Tasks

    OpenAIRE

    Buckhalt, Joseph A.

    2011-01-01

    While causal connections between sleep deprivation and attention, learning, and memory have been well established in adults, much less research has been done with children. Relations between the amount and quality of sleep and daytime sleepiness have been found for a number of cognitive and academic tasks in several groups of children. These relations have been found for children who have sleep disorders, for children with disorders involving cognitive impairment, and for typically developing...

  9. Drug-induced pulmonary injury: CT findings in hemopathic patients

    International Nuclear Information System (INIS)

    Objective: To investigate the spiral CT findings in hemopathic patients with drug-induced pulmonary injury. Methods: CT images obtained in 11 patients with drug-induced pulmonary injury were retrospectively analyzed. Six patients had antineoplastic agent-induced pulmonary injury and 5 patients had non-neoplastic agent-induced pulmonary injury (immunosuppressor in 2 patients, antifungal in 2 patients, antineoplastic immunomodulators in 1 patient). CT findings were reviewed by a chest radiologist. Results: All 11 patients had parenchymal abnormalities on MSCT scans, including ground-glass opacities (n=8), consolidation (n=5),interlobular septal thickening (n=3) and focal fibrosis (n=2). The abnormalities were bilateral and asymmetric in all patients. They were mainly in the peripheral lung regions in 6 patients, in the central lung regions in four, and irregularly located in one. The abnormalities involved mainly the lower lung zones in six patients, the upper lung zones in two,and all lung zones homogeneously in three. One patient had fluid in bilateral pleural cavities. Three patients were given the same agent once more after the imaging turned to normal, and they presented with same clinical symptoms and similar but more serious imaging findings. Conclusions: Drug-induced pulmonary injury usually manifests as areas of ground-glass opacity and consolidation, which most commonly involves the peripheral lungs and lower lung zones. Drug-induced pulmonary injury shows reproducible but more serious lesions when the patient is given the same agent once more. (authors)

  10. Periodic paralysis: An unusual presentation of drug-induced hyperkalemia

    Directory of Open Access Journals (Sweden)

    Poonam Agrawal

    2014-01-01

    Full Text Available Hyperkalemia is a life-threatening electrolyte abnormality. The most common cause of hyperkalemia includes renal disease and ingestion of medications. Drug-induced hyperkalemia may develop in patients with underlying renal impairment, disturbed cellular uptake of potassium load, excessive ingestion or infusion of potassium-containing substances. We report a case of "drug-induced severe hyperkalemia" presenting as periodic paralysis. A 67-year-old diabetic and hypertensive woman presented to emergency department with the complaint of intermittent episode of inability to walk for the past 5 days. Each episode lasted for 15-20 minutes and was associated with breathlessness and restlessness. There was no family history of periodic paralysis and drug history revealed that the patient was onolmesartan 20 mg per day (for past 2 years, perindopril 4 mg per day (for past 16 months, and torsemide 10 mg/day. On examination patient was found to be conscious, alert, and afebrile. Vitals were normal. Examination of cardiovascular and respiratory system did not reveal any significant finding. Blood report of the patient showed serum K+ level 8.6 mmol/l. All other investigations were within normal limits. A diagnosis of drug-induced hyperkalemia was made. Patient responded well to the symptomatic treatment. To the best of the author′s knowledge, this is the first case report of drug-induced hyperkalemia presenting as periodic paralysis.

  11. Prolonged drug-induced hypothermia in experimental stroke

    DEFF Research Database (Denmark)

    Johansen, Flemming Fryd; Jørgensen, Henrik Stig; Reith, Jakob

    2007-01-01

    In experimental and human stroke, hypothermia is strongly related to a favorable outcome. Previous attempts to manipulate the core temperature in focal cerebral ischemia have been based on mechanical cooling. The purpose of the study is to establish a model for long-term drug-induced hypothermia...

  12. Role of endoplasmic reticulum stress in drug-induced toxicity.

    Science.gov (United States)

    Foufelle, Fabienne; Fromenty, Bernard

    2016-02-01

    Drug-induced toxicity is a key issue for public health because some side effects can be severe and life-threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug-induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug-induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug-induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models. PMID:26977301

  13. Clinical Implications of Daytime Sleepiness for the Academic Performance of Middle School Age Adolescents with ADHD

    OpenAIRE

    Langberg, Joshua M.; Dvorsky, Melissa R.; Marshall, Stephen; Evans, Steven W.

    2013-01-01

    This study investigated the relative impact of total time slept per night and daytime sleepiness on the academic functioning of 100 middle school age youth (Mage = 11.9) with Attention-Deficit/Hyperactivity Disorder (ADHD). The primary goal of the study was to determine if total time slept per night and/or daytime sleepiness, as measured by youth self-report on the Pediatric Daytime Sleepiness Scale (PDSS), predicted academic functioning above and beyond symptoms of ADHD and relevant covariat...

  14. Subjective symptoms in idiopathic hypersomnia: beyond excessive sleepiness.

    Science.gov (United States)

    Vernet, Cyrille; Leu-Semenescu, Smaranda; Buzare, Marie-Annick; Arnulf, Isabelle

    2010-12-01

    Patients with idiopathic hypersomnia never feel fully alert despite a normal or long sleep night. The spectrum of the symptoms is insufficiently studied. We interviewed 62 consecutive patients with idiopathic hypersomnia (with a mean sleep latency lower than 8 min or a sleep time longer than 11 h) and 50 healthy controls using a questionnaire on sleep, awakening, sleepiness, alertness and cognitive, psychological and functional problems during daily life conditions. Patients slept 3 h more on weekends, holidays and in the sleep unit than on working days. In the morning, the patients needed somebody to wake them, or to be stressed, while routine, light, alarm clocks and motivation were inefficient. Three-quarters of the patients did not feel refreshed after short naps. During the daytime, their alertness was modulated by the same external conditions as controls, but they felt more sedated in darkness, in a quiet environment, when listening to music or conversation. Being hyperactive helped them more than controls to resist sleepiness. They were more frequently evening-type and more alert in the evening than in the morning. The patients were able to focus only for 1 h (versus 4 h in the controls). They complained of attention and memory deficit. Half of them had problems regulating their body temperature and were near-sighted. Mental fatigability, dependence on other people for awakening them, and a reduced benefit from usually alerting conditions (except being hyperactive or stressed) seem to be more specific of the daily problems of patients with idiopathic hypersomnia than daytime sleepiness. PMID:20408941

  15. Sleep and sleepiness of fishermen on rotating schedules.

    Science.gov (United States)

    Gander, Philippa; van den Berg, Margo; Signal, Leigh

    2008-04-01

    Seafaring is a hazardous occupation with high death and injury rates, but the role of seafarer fatigue in these events is generally not well documented. The International Maritime Organization has identified seafarer fatigue as an important health and safety issue. Most research to date has focused on more regularly scheduled types of operations (e.g., merchant vessels, ferries), but there is relatively little information on commercial fishing, which often involves high day-to-day and seasonal variability in work patterns and workload. The present study was designed to monitor the sleep and sleepiness of commercial fishermen at home and during extended periods at sea during the peak of the hoki fishing season, with a view to developing better fatigue management strategies for this workforce. Sleep (wrist actigraphy and sleep diaries) and sleepiness (Karolinska Sleepiness Scale [KSS] before and after each sleep period) of 20 deckhands were monitored for 4-13 days at home and for 5-9 days at sea while working a nominal 12 h on/6 h off schedule. On the 12 h on/6 hoff schedule, there was still a clear preference for sleep at night. Comparing the last three days at home and the first three days at sea showed that fishermen were more likely to have split sleep at sea (Wilcoxon signed ranks p or= 7 on 24% of days at sea vs. 9% of days at home (Wilcoxon signed ranks p loss, and residual sleepiness after sleep, were much more common at sea than at home. The longer duration of trips during the peak of the fishing season increases the risk of performance impairment due to greater cumulative sleep loss than would be expected on typical three-day trips. Key fatigue management strategies in this environment include that fishermen report to work as well rested as possible. Once at sea, the day-to-day variability in activities due to uncontrollable factors, such as fishing success, repairing gear, and weather conditions, mean that contingency planning is required for managing

  16. Imaging of Drug-induced Complications in the Gastrointestinal System.

    Science.gov (United States)

    McGettigan, Melissa J; Menias, Christine O; Gao, Zhenqiang J; Mellnick, Vincent M; Hara, Amy K

    2016-01-01

    Drug-induced injury commonly affects the gastrointestinal and hepatobiliary systems because of the mechanisms of absorption and metabolism. In pill esophagitis, injury is frequently related to direct contact with the esophageal mucosa, resulting in small superficial ulcers in the mid esophagus. Nonsteroidal anti-inflammatory drugs can lead to gastrointestinal tract ulcers and small bowel mucosal diaphragms (thin weblike strictures). Injury to the pancreatic and hepatobiliary systems can manifest as pancreatitis, acute or chronic hepatitis, cholestasis, or steatosis and steatohepatitis (which may progress to cirrhosis). Various drugs may also insult the hepatic vasculature, resulting in Budd-Chiari and sinusoidal obstructive syndromes. Focal lesions such as hepatic adenomas may develop after use of oral contraceptives or anabolic steroids. Ultrasonography, computed tomography, and magnetic resonance imaging can aid in diagnosis of drug-induced injuries and often are necessary to exclude other causes. PMID:26761532

  17. Drug-induced liver injury: Is it somehow foreseeable?

    Institute of Scientific and Technical Information of China (English)

    Giovanni Tarantino; Matteo Nicola Dario Di Minno; Domenico Capone

    2009-01-01

    The classic view on the pathogenesis of drug-induced liver injury is that the so-called parent compounds are made hepatotoxic by metabolism (formation of neosubstances that react abnormally), mainly by cytochromes -450 (CYP), with further pathways, such as mitochondrial dysfunction and apoptosis, also playing a role. Risk factors for drug-induced liver injury include concomitant hepatic diseases, age and genetic polymorphisms of CYP. However, some susceptibility can today be predicted before drug administration, working on the common substrate, by phenotyping and genotyping studies and by taking in consideration patients' health status. Physicians should always think of this adverse effect in the absence of other clear hepatic disease. Ethical and legal problems towards operators in the health care system are always matters to consider.

  18. Troponin leak associated with drug-induced methemoglobinemia.

    Science.gov (United States)

    Cannon, Robert D; Wagner, Michael; Jacoby, Jeanne L

    2014-10-01

    Drug-induced methemoglobinemia is a well-described entity but has not been previously associated with elevated troponins in the absence of cardiac symptoms. We report a case of a patient presenting to the emergency department (ED) with complaints related to an exacerbation of her long-standing cystitis. A low pulse oximetry reading prompted an evaluation, revealing a troponin leak, which peaked at 10 hours. Her methemoglobin level was found to be elevated at 11.4%, but a preexisting anemia apparently prevented the clinical recognition of cyanosis. The methemoglobinemia was determined to be secondary to her ingestion of phenazopyridine and trimethoprim-sulfa methoxizole. Although phenazopyridine and sulfa agents have long been known to cause methemoglobinemia, our patient exhibited an asymptomatic troponin leak that has not been previously reported as a complication of drug-induced methemoglobinemia. Clinicians should be aware of this potential association. PMID:24686024

  19. Role of endoplasmic reticulum stress in drug-induced toxicity

    OpenAIRE

    Foufelle, Fabienne; Fromenty, Bernard

    2016-01-01

    International audience Drug-induced toxicity is a key issue for public health because some side effects can be severe and life-threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to...

  20. Drug-induced valvular heart disease: an update.

    Science.gov (United States)

    Andrejak, Michel; Tribouilloy, Christophe

    2013-05-01

    Numerous reports have shown an unquestionable association between fibrotic valve disease and the following drugs: ergot alkaloids (such as methysergide and ergotamine), ergot-derived dopaminergic agonists (such as pergolide and cabergoline) and drugs metabolized into norfenfluramine (such as fenfluramine, dexfenfluramine and benfluorex). This review focuses on different aspects of drug-induced valvular heart disease: historical background; echocardiographic features; different drugs recognized as being responsible for valvular heart disease; and pathophysiology. PMID:23769407

  1. Development of a controlled-release anti-parkinsonian nanodelivery system using levodopa as the active agent

    Directory of Open Access Journals (Sweden)

    Kura AU

    2013-03-01

    Full Text Available Aminu Umar Kura,1 Samer Hasan Hussein Al Ali,2 Mohd Zobir Hussein,3 Sharida Fakurazi,1,4 Palanisamy Arulselvan11Laboratory of Vaccine and Immunotherapeutics, Institute of Bioscience, 2Laboratory of Molecular Biomedicine, Institute of Bioscience, 3Materials Synthesis and Characterization Laboratory, Institute of Advanced Technology, 4Faculty of Medicine and Health Science, Pharmacology Unit, Universiti Putra Malaysia, Selangor, MalaysiaAbstract: A new layered organic–inorganic nanocomposite material with an anti-parkinsonian active compound, L-3-(3,4-dihydroxyphenyl alanine (levodopa, intercalated into the inorganic interlayers of a Zn/Al-layered double hydroxide (LDH was synthesized using a direct coprecipitation method. The resulting nanocomposite was composed of the organic moiety, levodopa, sandwiched between Zn/Al-LDH inorganic interlayers. The basal spacing of the resulting nanocomposite was 10.9 Å. The estimated loading of levodopa in the nanocomposite was approximately 16% (w/w. A Fourier transform infrared study showed that the absorption bands of the nanocomposite were characteristic of both levodopa and Zn/Al-LDH, which further confirmed intercalation, and that the intercalated organic moiety in the nanocomposite was more thermally stable than free levodopa. The resulting nanocomposite showed sustained-release properties, so can be used in a controlled-release formulation. Cytotoxicity analysis using an MTT assay also showed increased cell viability of 3T3 cells exposed to the newly synthesized nanocomposite compared with those exposed to pure levodopa after 72 hours of exposure.Keywords: levodopa, layered double hydroxides, coprecipitation, sustained release

  2. Daytime Sleepiness and Sleep Inadequacy as Risk Factors for Dementia

    Directory of Open Access Journals (Sweden)

    Angeliki Tsapanou

    2015-07-01

    Full Text Available Background/Aims: To examine the association between self-reported sleep problems and incidence of dementia in community-dwelling elderly people. Methods: 1,041 nondemented participants over 65 years old were examined longitudinally. Sleep problems were estimated using the RAND Medical Outcomes Study Sleep Scale examining sleep disturbance, snoring, sleep short of breath or with a headache, sleep adequacy, and sleep somnolence. Cox regression analysis was used to examine the association between sleep problems and risk for incident dementia. Age, gender, education, ethnicity, APOE-ε4, stroke, heart disease, hypertension, diabetes, and depression were included as covariates. Results: Over 3 years of follow-up, 966 (92.8% participants remained nondemented, while 78 (7.2% developed dementia. In unadjusted models, sleep inadequacy (‘Get the amount of sleep you need' at the initial visit was associated with increased risk of incident dementia (HR = 1.20; 95% CI 1.02-1.42; p = 0.027. Adjusting for all the covariates, increased risk of incident dementia was still associated with sleep inadequacy (HR = 1.20; 95% CI 1.01-1.42; p = 0.040, as well as with increased daytime sleepiness (‘Have trouble staying awake during the day' (HR = 1.24; 95% CI 1.00-1.54; p = 0.047. Conclusion: Our results suggest that sleep inadequacy and increased daytime sleepiness are risk factors for dementia in older adults, independent of demographic and clinical factors.

  3. Sleep patterns and sleepiness of working college students.

    Science.gov (United States)

    Teixeira, Liliane; Lowden, Arne; da Luz, Andrea Aparecida; Turte, Samantha Lemos; Valente, Daniel; Matsumura, Roberto Jun; de Paula, Leticia Pickersgill; Takara, Meire Yuri; Nagai-Manelli, Roberta; Fischer, Frida Marina

    2012-01-01

    The double journey (work and study) may result or aggravate health problems, including sleep disturbances, as observed in previous studies with high school students. The aim of this study is to analyze the sleep-wake cycle and perceived sleepiness of working college students during weekdays. Twenty-three healthy college male students, 21-24 years old, working during the day and attending classes in the evening, participated in this study. During five consecutive days, the students filled out daily activities logs and wore actigraphs. Mean sleeping time was lower than 6 hours per night. No significant differences were observed in the sleep-wake cycle during the weekdays. The observed lack of changes in the sleepwake cycle of these college students might occur as participants were not on a free schedule, but exposed to social constraints, as was the regular attendance to evening college and day work activities. Sleepiness worsened over the evening school hours. Those results show the burden carried by College students who perform double activities - work and study. PMID:22317611

  4. Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias.

    Science.gov (United States)

    Cubeddu, Luigi X

    2016-01-01

    Risk of severe and fatal ventricular arrhythmias, presenting as Torsade de Pointes (TdP), is increased in congenital and acquired forms of long QT syndromes (LQTS). Drug-induced inhibition of K+ currents, IKs, IKr, IK1, and/or Ito, delay repolarization, prolong QT, and increase the risk of TdP. Drug-induced interference with IKr is the most common cause of acquired LQTS/TdP. Multiple drugs bind to KNCH2-hERG-K+ channels affecting IKr, including antiarrythmics, antibiotics, antivirals, azole-antifungals, antimalarials, anticancer, antiemetics, prokinetics, antipsychotics, and antidepressants. Azithromycin has been recently added to this list. In addition to direct channel inhibition, some drugs interfere with the traffic of channels from the endoplasmic reticulum to the cell membrane, decreasing mature channel membrane density; e.g., pentamidine, geldalamicin, arsenic trioxide, digoxin, and probucol. Other drugs, such as ketoconazole, fluoxetine, norfluoxetine, citalopram, escitalopram, donepezil, tamoxifen, endoxifen, atazanavir, and roxitromycin, induce both direct channel inhibition and impaired channel trafficking. Although many drugs prolong the QT interval, TdP is a rare event. The following conditions increase the risk of drug-induced TdP: a) Disease states/electrolyte levels (heart failure, structural cardiac disease, bradycardia, hypokalemia); b) Pharmacogenomic variables (presence of congenital LQTS, subclinical ion-channel mutations, history of or having a relative with history of drug-induced long QT/TdP); c) Pharmacodynamic and kinetic factors (high doses, women, elderly, metabolism inhibitors, combining two or more QT prolonging drugs, drugs that prolong the QT and increase QT dispersion, and drugs with multiple actions on ion channels). Because most of these conditions are preventable, careful evaluation of risk factors and increased knowledge of drug use associated with repolarization abnormalities are strongly recommended. PMID:26926294

  5. Relationship between Daytime Sleepiness and Intrinsically Photosensitive Retinal Ganglion Cells in Glaucomatous Disease

    Directory of Open Access Journals (Sweden)

    Carolina P. B. Gracitelli

    2016-01-01

    Full Text Available Patients with glaucoma showed to have higher daytime sleepiness measured by Epworth sleepiness scale. In addition, this symptom was associated with pupillary reflex and polysomnography parameters. These ipRGC functions might be impaired in patients with glaucoma, leading to worse quality of life.

  6. Sleep patterns and school performance of Korean adolescents assessed using a Korean version of the pediatric daytime sleepiness scale

    OpenAIRE

    Seon kyeong Rhie; Sihyoung Lee; Kyu Young Chae

    2011-01-01

    Purpose: Korean adolescents have severe nighttime sleep deprivation and daytime sleepiness because of their competitive educational environment. However, daytime sleep patterns and sleepiness have never been studied using age-specific methods, such as the pediatric daytime sleepiness scale (PDSS). We surveyed the daytime sleepiness of Korean adolescents using a Korean translation of the PDSS. Methods: We distributed the 27-item questionnaire, including the PDSS and questions related to sleep ...

  7. Sleep length and quality, sleepiness and urinary melatonin among healthy Danish nurses with shift work during work and leisure time

    DEFF Research Database (Denmark)

    Garde, Anne Helene; Hansen, Åse Marie; Hansen, Johnni

    2009-01-01

    Sleep problems are common effects of shift work. The aim of the present study was to evaluate how different types of shift affect sleep and sleepiness, and to relate sleepiness to urinary 6-sulfatoxymelatonin.......Sleep problems are common effects of shift work. The aim of the present study was to evaluate how different types of shift affect sleep and sleepiness, and to relate sleepiness to urinary 6-sulfatoxymelatonin....

  8. Correntropy measures to detect daytime sleepiness from EEG signals

    International Nuclear Information System (INIS)

    Excessive daytime sleepiness (EDS) is one of the main symptoms of several sleep related disorders and has a great impact on patients’ lives. While many studies have been carried out in order to assess daytime sleepiness, automatic EDS detection still remains an open problem. In this work, a novel approach to this issue based on correntropy function analysis of EEG signals was proposed in order to detect patients suffering from EDS. Multichannel EEG signals were recorded during five Maintenance of Wakefulness Tests (MWT) and Multiple Sleep Latency Tests (MSLT) alternated throughout the day for patients suffering from sleep disordered breathing (SDB). A group of 20 patients with EDS was compared with a group of 20 patients without daytime sleepiness (WDS), by analyzing 60 s EEG windows in a waking state. Measures obtained from the cross-correntropy function (CCORR) and auto-correntropy function (ACORR) were calculated in the EEG frequency bands: δ, 0.1–4 Hz; θ, 4–8 Hz; α, 8–12 Hz; β, 12–30 Hz; total band TB, 0.1–45 Hz. These functions permitted the quantification of complex signal properties and the non-linear couplings between different areas of the scalp. Statistical differences between EDS and WDS groups were mainly found in the β band during MSLT events (p-value < 0.0001). The WDS group presented more complexity in the occipital zone than the EDS group, while a stronger nonlinear coupling between the occipital and frontal regions was detected in EDS patients than in the WDS group. At best, ACORR and CCORR measures yielded sensitivity and specificity above 80% and the area under ROC curve (AUC) was above 0.85 in classifying EDS and WDS patients. These performances represent an improvement with respect to classical EEG indices applied in the same database (sensitivity and specificity were never above 80% and AUC was under 0.75). (paper)

  9. In silico modeling to predict drug-induced phospholipidosis

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Sydney S.; Kim, Jae S.; Valerio, Luis G., E-mail: luis.valerio@fda.hhs.gov; Sadrieh, Nakissa

    2013-06-01

    Drug-induced phospholipidosis (DIPL) is a preclinical finding during pharmaceutical drug development that has implications on the course of drug development and regulatory safety review. A principal characteristic of drugs inducing DIPL is known to be a cationic amphiphilic structure. This provides evidence for a structure-based explanation and opportunity to analyze properties and structures of drugs with the histopathologic findings for DIPL. In previous work from the FDA, in silico quantitative structure–activity relationship (QSAR) modeling using machine learning approaches has shown promise with a large dataset of drugs but included unconfirmed data as well. In this study, we report the construction and validation of a battery of complementary in silico QSAR models using the FDA's updated database on phospholipidosis, new algorithms and predictive technologies, and in particular, we address high performance with a high-confidence dataset. The results of our modeling for DIPL include rigorous external validation tests showing 80–81% concordance. Furthermore, the predictive performance characteristics include models with high sensitivity and specificity, in most cases above ≥ 80% leading to desired high negative and positive predictivity. These models are intended to be utilized for regulatory toxicology applied science needs in screening new drugs for DIPL. - Highlights: • New in silico models for predicting drug-induced phospholipidosis (DIPL) are described. • The training set data in the models is derived from the FDA's phospholipidosis database. • We find excellent predictivity values of the models based on external validation. • The models can support drug screening and regulatory decision-making on DIPL.

  10. Serious drug-induced liver disease secondary to ezetimibe

    OpenAIRE

    Castellote, José; Ariza, Javier; Rota, Rosa; Girbau, Anna; Xiol, Xavier

    2008-01-01

    Ezetimibe is the first member of a new family of lipid-lowering drugs that inhibits uptake of dietary and biliary cholesterol. It was approved by the FDA in 2002 for hypercholesterolemia alone or in combination with statins. Its use has been spreading over the last years. Ezetimibe was considered a safe drug. We report a case of a woman who developed a serious hepatocellular drug-induced liver disease after 4 mo therapy with 10 mg daily of ezetimibe. After withdrawal of the drug, the patient ...

  11. Drug-induced fulminant hepatic failure in pregnancy.

    Science.gov (United States)

    Firoz, Tabassum; Webber, Douglas; Rowe, Hilary

    2015-12-01

    Liver disease in pregnancy can be classified as predating, co-incidental or unique to pregnancy. Medications are often overlooked as a significant cause of liver disease. We present the case of a 39-year-old patient who presented at 20 weeks with jaundice, elevated liver enzymes, and abnormal liver function progressing eventually to fulminant hepatic failure. The patient was on methyldopa and labetalol from 12 weeks' gestational age. Liver biopsy was consistent with drug-induced liver injury. Both methyldopa and labetalol have been associated with hepatotoxicity including liver failure. This case highlights the importance of including medications as a cause of liver failure in pregnant patients.

  12. Role of mitochondria in drug-induced cholestatic injury.

    Science.gov (United States)

    Kass, George E N; Price, Shirley C

    2008-02-01

    Mitochondria have multiple functions in eukaryotic cells and are organized into dynamic tubular networks that continuously undergo changes through coordinated fusion and fission and migration through the cytosol. Mitochondria integrate cell-signaling networks, especially those involving the intracellular messenger Ca(2+), into the regulation of metabolic pathways. Recently, it has become clear that mitochondria are central to the three main cell death pathways, namely necrosis, apoptosis, and autophagic cell death. This article discusses the role of mitochondria in drug-induced cholestatic injury to the liver. The role of mitochondria in the cellular adaptation against the toxic effects of bile acids is discussed also. PMID:18242496

  13. Drug-induced immune thrombocytopenia due to moxifloxacin

    OpenAIRE

    Coker, Timothy J

    2013-01-01

    A 39-year-old woman with 1 day of oral petechiae, leg ecchymoses and epistaxis was found to have isolated thrombocytopenia. She had recently completed a 10-day course of moxifloxacin for an upper respiratory infection. On further questioning, she had developed thrombocytopenia 2 years earlier after a treatment course with moxifloxacin. After ruling out other causes, drug-induced immune thrombocytopenia due to moxifloxacin was diagnosed. Her platelets returned to normal range 15 days after fin...

  14. Potent activation of dopamine D3/D2 heterodimers by the antiparkinsonian agents, S32504, pramipexole and ropinirole.

    Science.gov (United States)

    Maggio, Roberto; Scarselli, Marco; Novi, Francesca; Millan, Mark J; Corsini, Giovanni U

    2003-11-01

    Recombinant, human dopamine D3 and D2 receptors form functional heterodimers upon co-expression in COS-7 cells. Herein, actions of the antiparkinsonian agents, S32504, ropinirole and pramipexole, at D3/D2L heterodimers were compared to their effects at the respective monomers and at split, chimeric D3trunk/D2tail and D2trunk/D3tail receptors: the trunk incorporated transmembrane domains (TDs) I-V and the tail TDs VI and VII. In binding assays with the antagonist [3H]nemonapride, all agonists were potent ligands of D3 receptors showing, respectively, 100-, 18- and 56-fold lower affinity at D2L receptors, mimicking the selective D3 receptor antagonist, S33084 (100-fold). At D3trunk/D2tail receptors, except for ropinirole, all drugs showed lower affinities than at D3 sites, whereas for D2trunk/D3tail receptors, affinities of all drugs were higher than at D2L sites. The proportion of high affinity binding sites recognized by S32504, pramipexole and ropinirole in membranes derived from cells co-expressing D3 and D2L sites was higher than in an equivalent mixture of membranes from cells expressing D3 or D2L sites, consistent with the promotion of heterodimer formation. In contrast, the percentage of high and low affinity sites (biphasic isotherms) recognized by S33084 was identical. Functional actions were determined by co-transfection of a chimeric adenylyl cyclase (AC)-V/VI insensitive to D3 receptors. Accordingly, D3 receptor-transfected cells were irresponsive whereas, in D2L receptor-transfected cells, agonists suppressed forskolin-stimulated cAMP production with modest potencies. In cells co-transfected with D3 and D2L receptors, S32504, ropinirole and pramipexole potently suppressed AC-V/VI with EC50s 33-, 19- and 11-fold lower than at D2L receptors, respectively. S32504 also suppressed AC-V/VI activity at split D3trunk/D2tail and D2trunk/D3tail chimeras transfected into COS-7 cells. In conclusion, antiparkinson agents behave as potent agonists at D3/D2

  15. Children's Sleep, Sleepiness, and Performance on Cognitive Tasks.

    Science.gov (United States)

    Buckhalt, Joseph A

    2011-01-01

    While causal connections between sleep deprivation and attention, learning, and memory have been well established in adults, much less research has been done with children. Relations between the amount and quality of sleep and daytime sleepiness have been found for a number of cognitive and academic tasks in several groups of children. These relations have been found for children who have sleep disorders, for children with disorders involving cognitive impairment, and for typically developing children with no known disorders. The research is reviewed here with a focus on the types of cognitive and academic tasks that have been related to insufficient sleep. A series of studies is described that relates sleep parameters to the Woodcock-Johnson® III Tests of Cognitive Abilities and other, similar measures. Implications for educators and psychologists who work with children are discussed. PMID:25279390

  16. A Practical Approach to Excessive Daytime Sleepiness: A Focused Review.

    Science.gov (United States)

    Murray, Brian J

    2016-01-01

    Excessive daytime sleepiness (EDS) is a common problem that is important to recognize and address. Initial steps in management are generally straightforward and only the most advanced cases would require referral to a subspecialist. Of particular concern is that of driving safety. There is a broad differential diagnosis for conditions contributing to EDS but a few common conditions account for the majority of clinical presentations. Subjective self-reporting will often lead to identification of potential problems, but this is often unreliable. Traditional neurophysiologic tests can help in objectively quantifying symptoms but current tests are not always practical clinically and may have little validation in real world situations. There are many treatment options that should generally be able to sufficiently manage most patients presenting with hypersomnolence. This review provides a practical clinical approach to the problem based on current guidelines. PMID:27445538

  17. A Practical Approach to Excessive Daytime Sleepiness: A Focused Review

    Directory of Open Access Journals (Sweden)

    Brian J. Murray

    2016-01-01

    Full Text Available Excessive daytime sleepiness (EDS is a common problem that is important to recognize and address. Initial steps in management are generally straightforward and only the most advanced cases would require referral to a subspecialist. Of particular concern is that of driving safety. There is a broad differential diagnosis for conditions contributing to EDS but a few common conditions account for the majority of clinical presentations. Subjective self-reporting will often lead to identification of potential problems, but this is often unreliable. Traditional neurophysiologic tests can help in objectively quantifying symptoms but current tests are not always practical clinically and may have little validation in real world situations. There are many treatment options that should generally be able to sufficiently manage most patients presenting with hypersomnolence. This review provides a practical clinical approach to the problem based on current guidelines.

  18. Gender differences in excessive daytime sleepiness among Japanese workers.

    Science.gov (United States)

    Doi, Yuriko; Minowa, Masumi

    2003-02-01

    Excessive daytime sleepiness (EDS) is serious concern in the workplace with respect to errors, accidents, absenteeism, reduced productivity and impaired personal or professional life. Previous community studies found a female preponderance of EDS, however, there is little research on EDS and gender in occupational settings. We examined the gender differences in prevalence and risk factors of EDS among employees working at a telecommunications company in the Tokyo metropolitan area. Our outcome measure of EDS was the Epworth Sleepiness Scale (ESS). A self-administered questionnaire on health and sleep including ESS was distributed to 5,571 workers between December 1999 and January 2000, and 5,072 responses were returned (91.0%). A total of 4,722 full-time, non-manual and non-shift employees aged 20-59 were used for analysis (3,909 men and 813 women). Chi-squared tests and multiple logistic regression analyses were applied for examining the gender differences in the prevalence and risk factors of EDS. The prevalence rates of EDS were 13.3% for women and 7.2% for men (Pgenders, and being married worked as a protective factor against EDS for men alone. It is obvious that a ban on overtime work and a provision of mental health hygiene are the general strategies for reducing EDS at worksites. In the case of women, we suggest the formation of effective strategies for improving women's status at home and in the workplace must also be a solution for the prevention of EDS (e.g. promoting gender equality in the division of labor at home and strengthening family care policies for working women). PMID:12560020

  19. Mitochondrial involvement in drug-induced liver injury.

    Science.gov (United States)

    Pessayre, Dominique; Mansouri, Abdellah; Berson, Alain; Fromenty, Bernard

    2010-01-01

    Mitochondrial dysfunction is a major mechanism of liver injury. A parent drug or its reactive metabolite can trigger outer mitochondrial membrane permeabilization or rupture due to mitochondrial permeability transition. The latter can severely deplete ATP and cause liver cell necrosis, or it can instead lead to apoptosis by releasing cytochrome c, which activates caspases in the cytosol. Necrosis and apoptosis can trigger cytolytic hepatitis resulting in lethal fulminant hepatitis in some patients. Other drugs severely inhibit mitochondrial function and trigger extensive microvesicular steatosis, hypoglycaemia, coma, and death. Milder and more prolonged forms of drug-induced mitochondrial dysfunction can also cause macrovacuolar steatosis. Although this is a benign liver lesion in the short-term, it can progress to steatohepatitis and then to cirrhosis. Patient susceptibility to drug-induced mitochondrial dysfunction and liver injury can sometimes be explained by genetic or acquired variations in drug metabolism and/or elimination that increase the concentration of the toxic species (parent drug or metabolite). Susceptibility may also be increased by the presence of another condition, which also impairs mitochondrial function, such as an inborn mitochondrial cytopathy, beta-oxidation defect, certain viral infections, pregnancy, or the obesity-associated metabolic syndrome. Liver injury due to mitochondrial dysfunction can have important consequences for pharmaceutical companies. It has led to the interruption of clinical trials, the recall of several drugs after marketing, or the introduction of severe black box warnings by drug agencies. Pharmaceutical companies should systematically investigate mitochondrial effects during lead selection or preclinical safety studies. PMID:20020267

  20. [Imaging features of drug-induced lung diseases].

    Science.gov (United States)

    Mellot, F; Scherrer, A

    2005-05-01

    Drug-induced lung diseases are an increasingly frequent cause of morbidity. Over 350 drugs are now recognized as being implicated in drug-induced lung diseases. Early diagnosis is critical. Discontinuing the drug may result in regression of the adverse effect. Diagnosis is based on a history of drug exposure with a temporal relationship between the introduction of the drug and the onset of symptoms, histologic evidence of lung damage and exclusion of other causes of lung injury. Unfortunately there is no specific test available. Histologic and radiologic findings are often non specific and diagnosis can be difficult. Drugs can cause a constellation of distinct patterns of respiratory involvement and all anatomic compartments of the lungs may be involved. The most common patterns are: non specific interstitial pneumonia and fibrosis, pulmonary eosinophilia, hypersensitivity pneumonitis, pulmonary edema with or without diffuse alveolar damage, bronchiolitis obliterans organizing pneumonia, pulmonary hemorrhage and vasculitis. It is important to be familiar with their common radiologic appearances. PMID:16106793

  1. Drug-induced nail disorders: incidence, management and prognosis.

    Science.gov (United States)

    Piraccini, B M; Tosti, A

    1999-09-01

    A large number of drugs of different classes, ranging from antibacterials to chemotherapeutic agents to psoralens, can be responsible for the development of nail changes. Drug-induced nail changes usually involve several or all 20 nails and appear in temporal correlation with drug intake. Some nail changes are asymptomatic and only cause cosmetic problems, while others cause pain and discomfort and impair manual activities or deambulation. Drug-induced nail abnormalities are usually transitory and disappear with drug withdrawal, but sometimes persist in time. The pathogenesis of the nail changes is usually a toxic effect of the drug on the different nail constituents, but other mechanisms can be involved. Drugs that are well known to produce nail abnormalities include cancer chemotherapeutic agents, psoralens, retinoids, tetracyclines, antimalarials and zidovudine. Arsenic poisoning is also always associated with nail changes that have medico-legal importance. Some drugs taken during pregnancy may impair nail development of the fetus, and nail hypoplasia or other nail dystrophies will be evident in the newborn.

  2. Recovering drug-induced apoptosis subnetwork from Connectivity Map data.

    Science.gov (United States)

    Yu, Jiyang; Putcha, Preeti; Silva, Jose M

    2015-01-01

    The Connectivity Map (CMAP) project profiled human cancer cell lines exposed to a library of anticancer compounds with the goal of connecting cancer with underlying genes and potential treatments. Since the therapeutic goal of most anticancer drugs is to induce tumor-selective apoptosis, it is critical to understand the specific cell death pathways triggered by drugs. This can help to better understand the mechanism of how cancer cells respond to chemical stimulations and improve the treatment of human tumors. In this study, using CMAP microarray data from breast cancer cell line MCF7, we applied a Gaussian Bayesian network modeling approach and identified apoptosis as a major drug-induced cellular-pathway. We then focused on 13 apoptotic genes that showed significant differential expression across all drug-perturbed samples to reconstruct the apoptosis network. In our predicted subnetwork, 9 out of 15 high-confidence interactions were validated in the literature, and our inferred network captured two major cell death pathways by identifying BCL2L11 and PMAIP1 as key interacting players for the intrinsic apoptosis pathway and TAXBP1 and TNFAIP3 for the extrinsic apoptosis pathway. Our inferred apoptosis network also suggested the role of BCL2L11 and TNFAIP3 as "gateway" genes in the drug-induced intrinsic and extrinsic apoptosis pathways. PMID:25883971

  3. Sustainable Reduction of Sleepiness through Salutogenic Self-Care Procedure in Lunch Breaks: A Pilot Study

    Directory of Open Access Journals (Sweden)

    Sebastian Schnieder

    2013-01-01

    Full Text Available The aim of the study was to elucidate the immediate, intermediate, and anticipatory sleepiness reducing effects of a salutogenic self-care procedure called progressive muscle relaxation (PMR, during lunch breaks. The second exploratory aim deals with determining the onset and long-term time course of sleepiness changes. In order to evaluate the intraday range and interday change of the proposed relaxation effects, 14 call center agents were assigned to either a daily 20-minute self-administered PMR or a small talk (ST group during a period of seven months. Participants’ levels of sleepiness were analyzed in a controlled trial using anticipatory, postlunchtime, and afternoon changes of sleepiness as indicated by continuously determined objective reaction time measures (16,464 measurements and self-reports administered five times per day, once per month (490 measurements. Results indicate that, in comparison to ST, the PMR break (a induces immediate, intermediate, and anticipatory reductions in sleepiness; (b these significant effects remarkably show up after one month, and sleepiness continues to decrease for at least another five months. Although further research is required referring to the specific responsible mediating variables, our results suggest that relaxation based lunch breaks are both accepted by employees and provide a sustainable impact on sleepiness.

  4. Risk Factors for Cardiovascular Disease, Metabolic Syndrome and Sleepiness in Truck Drivers

    Directory of Open Access Journals (Sweden)

    Antonio de Padua Mansur

    2015-01-01

    Full Text Available AbstractBackground:Truck driver sleepiness is a primary cause of vehicle accidents. Several causes are associated with sleepiness in truck drivers. Obesity and metabolic syndrome (MetS are associated with sleep disorders and with primary risk factors for cardiovascular diseases (CVD. We analyzed the relationship between these conditions and prevalence of sleepiness in truck drivers.Methods:We analyzed the major risk factors for CVD, anthropometric data and sleep disorders in 2228 male truck drivers from 148 road stops made by the Federal Highway Police from 2006 to 2011. Alcohol consumption, illicit drugs and overtime working hours were also analyzed. Sleepiness was assessed using the Epworth Sleepiness Scale.Results:Mean age was 43.1 ± 10.8 years. From 2006 to 2011, an increase in neck (p = 0.011 and abdominal circumference (p < 0.001, total cholesterol (p < 0.001, triglyceride plasma levels (p = 0.014, and sleepiness was observed (p < 0.001. In addition, a reduction in hypertension (39.6% to 25.9%, p < 0.001, alcohol consumption (32% to 23%, p = 0.033 and overtime hours (52.2% to 42.8%, p < 0.001 was found. Linear regression analysis showed that sleepiness correlated closely with body mass index (β = 0.19, Raj2 = 0.659, p = 0.031, abdominal circumference (β = 0.24, Raj2 = 0.826, p = 0.021, hypertension (β = -0.62, Raj2 = 0.901, p = 0.002, and triglycerides (β = 0.34, Raj2 = 0.936, p = 0.022. Linear multiple regression indicated that hypertension (p = 0.008 and abdominal circumference (p = 0.025 are independent variables for sleepiness.Conclusions:Increased prevalence of sleepiness was associated with major components of the MetS.

  5. Subjective sleepiness is a sensitive indicator of insufficient sleep and impaired waking function.

    Science.gov (United States)

    Akerstedt, Torbjörn; Anund, Anna; Axelsson, John; Kecklund, Göran

    2014-06-01

    The main consequence of insufficient sleep is sleepiness. While measures of sleep latency, continuous encephalographical/electro-oculographical (EEG/EOG) recording and performance tests are useful indicators of sleepiness in the laboratory and clinic, they are not easily implemented in large, real-life field studies. Subjective ratings of sleepiness, which are easily applied and unobtrusive, are an alternative, but whether they measure sleepiness sensitively, reliably and validly remains uncertain. This review brings together research relevant to these issues. It is focused on the Karolinska Sleepiness Scale (KSS), which is a nine-point Likert-type scale. The diurnal pattern of sleepiness is U-shaped, with high KSS values in the morning and late evening, and with great stability across years. KSS values increase sensitively during acute total and repeated partial sleep deprivation and night work, including night driving. The effect sizes range between 1.5 and 3. The relation to driving performance or EEG/EOG indicators of sleepiness is highly significant, strongly curvilinear and consistent across individuals. High (>6) KSS values are associated particularly with impaired driving performance and sleep intrusions in the EEG. KSS values are also increased in many clinical conditions such as sleep apnea, depression and burnout. The context has a strong influence on KSS ratings. Thus, physical activity, social interaction and light exposure will reduce KSS values by 1-2 units. In contrast, time-on-task in a monotonous context will increase KSS values by 1-2 units. In summary, subjective ratings of sleepiness as described here is as sensitive and valid an indicator of sleepiness as objective measures, and particularly suitable for field studies. PMID:24750198

  6. Driver Sleepiness and Risk of Car Crashes in Shenyang, a Chinese Northeastern City: Population-based Case-control Study

    Institute of Scientific and Technical Information of China (English)

    GAI-FEN LIU; SONG HAN; DUO-HONG LIANG; FENG-ZHI WANG; XIN-ZHU SHI; JIAN YU; ZHENG-LAI WU

    2003-01-01

    To estimate the association of driver sleepiness with the risk of car crashes.Methods A population-based case-control study was conducted in Shenyang, a northeastern city in China, between November 2001 and July 2002. The case group comprised 406 car drivers involved in crashes, and 438 car drivers recruited at randomly selected sites, and on the day of week, and the time of day when they were driving on highways in the study region during the study period were used as control groups. Face-to-face interviews with drivers were conducted according to a well-structured questionnaire covering the circumstances of their current trip and their background information.Stanford sleepiness scale and Epworth sleepiness scale were used to quantify acute sleepiness and chronic sleepiness respectively. Results There was a strong association between chronic sleepiness and the risk of car crash. Significantly increased risk of crash was associated with drivers who identified themselves as sleepy (Epworth sleepiness score ≥ 10 vs <10; adjusted odds ratio 2.07, 95%confidence interval 1.30 to 3.29), but no increased risk was associated with measures of acute sleepiness. Conclusions Chronic sleepiness in car drivers significantly increases the risk of car crash. Reductions in road traffic injuries may be achieved if fewer people drive when they are sleepy.

  7. Genetic association studies in drug-induced liver injury.

    Science.gov (United States)

    Daly, Ann K; Day, Chris P

    2009-11-01

    Genetic studies on drug-induced liver injury (DILI) have proved challenging, both because of their rarity and their difficulty in replicating observed effects. However, significant progress has now been achieved by both candidate-gene and genome-wide association studies. These two approaches are considered in detail, together with examples of DILI due to specific drugs where consistent associations have been reported. Particular consideration is given to associations between antituberculosis drug-related liver injury and the "slow acetylator" genotype for N-acetyltransferase 2, amoxicillin/clavulanate-related liver injury, and the human leukocyte antigen (HLA) class II DRB1*1501 allele and flucloxacillin-related injury and the HLA class I B*5701 allele. Although these associations are drug-specific, the possibility that additional, more general susceptibility genes for DILI exist requires further investigation, ideally by genome-wide association studies involving international collaboration. The possibility of interethnic variation in susceptibility to DILI also requires further study.

  8. Deep Learning for Drug-Induced Liver Injury.

    Science.gov (United States)

    Xu, Youjun; Dai, Ziwei; Chen, Fangjin; Gao, Shuaishi; Pei, Jianfeng; Lai, Luhua

    2015-10-26

    Drug-induced liver injury (DILI) has been the single most frequent cause of safety-related drug marketing withdrawals for the past 50 years. Recently, deep learning (DL) has been successfully applied in many fields due to its exceptional and automatic learning ability. In this study, DILI prediction models were developed using DL architectures, and the best model trained on 475 drugs predicted an external validation set of 198 drugs with an accuracy of 86.9%, sensitivity of 82.5%, specificity of 92.9%, and area under the curve of 0.955, which is better than the performance of previously described DILI prediction models. Furthermore, with deep analysis, we also identified important molecular features that are related to DILI. Such DL models could improve the prediction of DILI risk in humans. The DL DILI prediction models are freely available at http://www.repharma.cn/DILIserver/DILI_home.php. PMID:26437739

  9. Role of dermatology in pharmacogenomics: drug-induced skin injury.

    Science.gov (United States)

    Borroni, Riccardo G

    2015-01-01

    Different individuals may respond diversely to the same drug, in terms of efficacy and toxicity. Adverse drug reactions cause about 6% of all hospital admissions and account for up to 9% of hospitalization costs. Drug-induced skin injury (DISI) is the most common presentation of adverse drug reactions, ranging from maculopapular eruptions to severe adverse cutaneous drug reactions (SCARs) with mortality of up to 40%. Specific genetic polymorphisms confer susceptibility to different types of DISI. Identifying patients genetically at risk for SCARs is one of the goals of pharmacogenomics. In this article, the aspects of clinical dermatology relevant to the pharmacogenetics of DISI are reviewed. Many SCARs are now preventable, with consequent reduction of morbidity, mortality and healthcare costs.

  10. Serious drug-induced liver disease secondary to ezetimibe

    Institute of Scientific and Technical Information of China (English)

    José Castellote; Javier Adza; Rosa Rota; Anna Girbau; Xavier Xiol

    2008-01-01

    Ezetimibe is the first member of a new family of lipidlowering drugs that inhibits uptake of dietary and biliary cholesterol. It was approved by the FDA in 2002for hypercholesterolemia alone or in combination with statins. Its use has been spreading over the last years.Ezetimibe was considered a safe drug. We report a case of a woman who developed a serious hepatocellular drug-induced liver disease after 4 mo therapy with 10 mg daily of ezetimibe. After withdrawal of the drug, the patient recovered slowly. Ezetimibe may produce serious toxic hepatitis and prompt withdrawal is mandatory in case of a significant abnormality in liver testing after beginning or during treatment with ezetimibe.

  11. Lupus in a patient with cystinosis: is it drug induced?

    Science.gov (United States)

    Eroglu, F K; Besbas, N; Ozaltin, F; Topaloglu, R; Ozen, S

    2015-11-01

    A 9-year-old girl with a diagnosis of cystinosis since 2 years of age, on cysteamine therapy, presented with complaints of serositis and arthritis, and laboratory tests revealed high antinuclear antibody titers with hypocomplementemia. Kidney biopsy was not consistent with lupus nephritis. With prednisolone treatment her complaints resolved and creatinine level decreased, but on follow-up, serological features of systemic lupus erythematosus (SLE) continued. Six years after cessation of prednisolone, lupus features were reactivated, with positive antihistone antibodies and ANCA. Coincidence of cystinosis and SLE is very rare, and to the best of our knowledge this is the fourth case reported in the literature. Physicians should be aware that cystinosis patients may have some autoimmune manifestations with features of true or drug-induced lupus. In the light of this case, pathophysiology and treatment are discussed.

  12. An Update on Drug-induced Liver Injury.

    Science.gov (United States)

    Devarbhavi, Harshad

    2012-09-01

    Idiosyncratic drug-induced liver injury (DILI) is an important cause of morbidity and mortality following drugs taken in therapeutic doses. Hepatotoxicity is a leading cause of attrition in drug development, or withdrawal or restricted use after marketing. No age is exempt although adults and the elderly are at increased risk. DILI spans the entire spectrum ranging from asymptomatic elevation in transaminases to severe disease such as acute hepatitis leading to acute liver failure. The liver specific Roussel Uclaf Causality Assessment Method is the most validated and extensively used for determining the likelihood that an implicated drug caused DILI. Asymptomatic elevation in liver tests must be differentiated from adaptation. Drugs producing DILI have a signature pattern although no single pattern is characteristic. Antimicrobial and central nervous system agents including antiepileptic drugs are the leading causes of DILI worldwide. In the absence of a diagnostic test or a biomarker, the diagnosis rests on the evidence of absence of competing causes such as acute viral hepatitis, autoimmune hepatitis and others. Recent studies show that antituberculosis drugs given for active or latent disease are still a major cause of drug-induced liver injury in India and the West respectively. Presence of jaundice signifies a severe disease and entails a worse outcome. The pathogenesis is unclear and is due to a mix of host, drug metabolite and environmental factors. Research has evolved from incriminating candidate genes to genome wide analysis studies. Immediate cessation of the drug is key to prevent or minimize progressive damage. Treatment is largely supportive. N-acetylcysteine is the antidote for paracetamol toxicity. Carnitine has been tried in valproate injury whereas steroids and ursodeoxycholic acid may be used in DILI associated with hypersensitivity or cholestatic features respectively. This article provides an overview of the epidemiology, the patterns of

  13. PTTG1 attenuates drug-induced cellular senescence.

    Directory of Open Access Journals (Sweden)

    Yunguang Tong

    Full Text Available As PTTG1 (pituitary tumor transforming gene abundance correlates with adverse outcomes in cancer treatment, we determined mechanisms underlying this observation by assessing the role of PTTG1 in regulating cell response to anti-neoplastic drugs. HCT116 cells devoid of PTTG1 (PTTG1(-/- exhibited enhanced drug sensitivity as assessed by measuring BrdU incorporation in vitro. Apoptosis, mitosis catastrophe or DNA damage were not detected, but features of senescence were observed using low doses of doxorubicin and TSA. The number of drug-induced PTTG1(-/- senescent cells increased ∼4 fold as compared to WT PTTG1-replete cells (p<0.001. p21, an important regulator of cell senescence, was induced ∼3 fold in HCT116 PTTG1(-/- cells upon doxorubicin or Trichostatin A treatment. Binding of Sp1, p53 and p300 to the p21 promoter was enhanced in PTTG1(-/- cells after treatment, suggesting transcriptional regulation of p21. p21 knock down abrogated the observed senescent effects of these drugs, indicating that PTTG1 likely suppresses p21 to regulate drug-induced senescence. PTTG1 also regulated SW620 colon cancer cells response to doxorubicin and TSA mediated by p21. Subcutaneously xenografted PTTG1(-/- HCT116 cells developed smaller tumors and exhibited enhanced responses to doxorubicin. PTTG1(-/- tumor tissue derived from excised tumors exhibited increased doxorubicin-induced senescence. As senescence is a determinant of cell responses to anti-neoplastic treatments, these findings suggest PTTG1 as a tumor cell marker to predict anti-neoplastic treatment outcomes.

  14. "Sleepiness" is serious in adolescence: Two surveys of 3235 Canadian students

    OpenAIRE

    Ogilvie Robert; Trajanovic Nik; Molnar Danielle; O'Brien Susan; Thabane Lehana; Powles AC Peter; Gibson Edward S; Shapiro Colin; Yan Mi; Chilcott-Tanser Lisa

    2006-01-01

    Abstract Background Evidence is growing that sleep problems in adolescents are significant impediments to learning and negatively affect behaviour, attainment of social competence and quality of life. The objectives of the study were to determine the level of sleepiness among students in high school, to identify factors to explain it, and to determine the association between sleepiness and performance in both academic and extracurricular activities Methods A cross-sectional survey of 2201 hig...

  15. Lack of Impact of Mild Obstructive Sleep Apnea on Sleepiness, Mood and Quality of Life

    OpenAIRE

    Quan SF; Budhiraja R; Batool-Anwar S; Gottlieb DJ; Eichling P; Patel S; Shen W; Walsh JK; Kushida CA

    2014-01-01

    Background and Objectives: Obstructive sleep apnea (OSA) is associated with sleepiness, depression and reduced quality of life. However, it is unclear whether mild OSA has these negative impacts. Using data from the Apnea Positive Pressure Long-term Efficacy Study (APPLES), this study determined whether participants with mild OSA had greater sleepiness, more depressive symptoms and poorer quality of life in comparison to those without OSA. Methods: 239 persons evaluated for participation ...

  16. Eveningness Chronotype, Daytime Sleepiness, Caffeine Consumption, and Use of Other Stimulants Among Peruvian University Students.

    Science.gov (United States)

    Whittier, Anjalene; Sanchez, Sixto; Castañeda, Benjamín; Sanchez, Elena; Gelaye, Bizu; Yanez, David; Williams, Michelle A

    2014-03-01

    Objectives: The aims of this study were to evaluate patterns of circadian preferences and daytime sleepiness, and to examine the extent to which the consumption of stimulant beverages is associated with daytime sleepiness and evening chronotype among Peruvian college-age students. Methods: A total of 2,581 undergraduate students completed a self-administered comprehensive questionnaire that gathered information about sleep habits, sociodemographic and lifestyle characteristics, and the use of caffeinated beverages. The Morningness-Eveningness Questionnaire (MEQ) and Epworth Sleepiness Scale (ESS) were used to assess chronotype and daytime sleepiness. We used multivariable linear and logistic regression procedures to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the associations of sleep disorders with sociodemographic and behavioral factors. Results: The prevalence of daytime sleepiness was 35% [95% CI 32.7-36.4] and eveningness chronotype was 10% [95% CI 8.8-11.1%]. Age, sex, cigarette smoking, and alcohol consumption were significantly associated with an evening chronotype. After adjusting for age, sex, smoking, body mass index, and physical activity, students who reported consumption of any stimulant beverages had 1.25 increased odds of excessive daytime sleepiness (OR=1.25 [95% CI 1.03-1.53]) compared with students who did not consume stimulant beverages. Consumption of any stimulant beverages was not statistically significantly associated with being an evening chronotype (OR=1.30 [95% CI 0.86-1.96]). Conclusions: Excessive daytime sleepiness and eveningness chronotype are common among Peruvian college students. MEQ scores were associated with age, sex, smoking, and alcohol consumption. Regular stimulant beverage consumption tended to be positively associated with excessive daytime sleepiness. PMID:24868492

  17. Excessive Daytime Sleepiness in Stroke Survivors: An Integrative Review.

    Science.gov (United States)

    Ding, Qinglan; Whittemore, Robin; Redeker, Nancy

    2016-07-01

    Excessive daytime sleepiness (EDS) is a prevalent symptom among stroke survivors. This symptom is an independent risk factor for stroke and may reduce stroke survivors' quality of life, cognitive functioning, and daytime functional performance. The lack of a universally accepted definition of EDS makes it difficult to measure EDS and synthesize research. The purpose of this integrative review is to describe poststroke EDS, ascertain conceptual and operational definitions of EDS, identify factors that contribute to EDS in stroke survivors, and explore outcomes associated with EDS in stroke survivors. We searched the following databases: PubMed and MEDLINE (OvidSP 1946-April; Week 2, 2015), Embase (OvidSP 1974-March; Week 1, 2015), and PsycINFO (OvidSP 1967-April; Week 2, 2015). Our search yielded 340 articles, 27 of which met inclusion criteria. The literature reveals EDS to be a multidimensional construct that is operationalized with both subjective and objective measures. Choosing measures that can quantify both the objective and subjective components is useful for gaining a comprehensive understanding of EDS. The antecedents of EDS are stroke, sleep-disordered breathing, reversed Robin Hood syndrome, and depression. The outcomes associated with EDS in stroke patients are serious and negative. Via synthesis of this research, we propose a possible framework for poststroke EDS, which may be of use in clinical practice and in research to identify valid quantifying methods for EDS as well as to prevent harmful outcomes in stroke survivors. PMID:26792913

  18. Excessive Daytime Sleepiness and Epilepsy: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Andre S. Giorelli

    2013-01-01

    Full Text Available Background. Sleep complaints are common in patients with epilepsy (PWE. Excessive daytime sleepiness (EDS is one of the most reported complaints and its impact is still a matter of debate. Objective. Evaluate the relationship between EDS and epilepsy, with emphasis on prevalence, assessment, and causes. Methods. A systematic review on PubMed database in the last 10 years (2002 to 2012. The search returned 53 articles and 34 were considered relevant. After citation analysis, 3 more articles were included. Results. Most studies were cross-sectional and questionnaire based. 14 papers addressed EDS as the primary endpoint. 14 adult and 3 children studies used subjective and objective analysis as methodology. The number of studies increased throughout the decade, with 21 in the last 5 years. Adult studies represent almost three times the number of children studies. EDS prevalence in PWE varies from 10 to 47.5%. Prevalence was higher in developing countries. Conclusion. EDS seems to be related more frequently to undiagnosed sleep disorders than to epilepsy-related factors, and although it affects the quality of life of PWE, it can be improved by treating comorbid primary sleep disorders.

  19. Traffic crash accidents in Tehran, Iran: Its relation with circadian rhythm of sleepiness

    Institute of Scientific and Technical Information of China (English)

    Khosro Sadeghniiat-Haghighi; Zohreh Yazdi; Mohsen Moradinia; Omid Aminian; Alireza Esmaili

    2015-01-01

    Purpose:Road traffic accidents are one of main problems in Iran.Multiple factors cause traffic accidents and the most important one is sleepiness.This factor,however,is given less attention in our country.Road traffic accidents relevant to sleepiness are studied.Methods:In this cross-sectional study,all road traffic accidents relevant to sleepiness,which were reported by police,were studied in Tehran province in 2009.Results:The risk of road traffic accidents due to sleepiness was increased by more than sevenfold (odds ratio =7.33) in low alertness hours (0:00-6:00) compared to other time of day.The risk of road traffic accidents due to sleepiness was decreased by 0.15-fold (odds ratio-0.15) in hours with maximum of alertness (18:00-22:00) of circadian rhythm compared to other time of day.Conclusion:The occurrence of road traffic accidents due to sleepiness has significant statistical relations with driving during lowest point of alertness of circadian rhythm.

  20. "Sleepiness" is serious in adolescence: Two surveys of 3235 Canadian students

    Directory of Open Access Journals (Sweden)

    Ogilvie Robert

    2006-05-01

    Full Text Available Abstract Background Evidence is growing that sleep problems in adolescents are significant impediments to learning and negatively affect behaviour, attainment of social competence and quality of life. The objectives of the study were to determine the level of sleepiness among students in high school, to identify factors to explain it, and to determine the association between sleepiness and performance in both academic and extracurricular activities Methods A cross-sectional survey of 2201 high school students in the Hamilton Wentworth District School Board and the Near North District School Board in Ontario was conducted in 1998/9. A similar survey was done three years later involving 1034 students in the Grand Erie District School Board in the same Province. The Epworth Sleepiness Scale (ESS was used to measure sleepiness and we also assessed the reliability of this tool for this population. Descriptive analysis of the cohort and information on various measures of performance and demographic data were included. Regression analysis, using the generalised estimating equation (GEE, was utilized to investigate factors associated with risk of sleepiness (ESS>10. Results Seventy per cent of the students had less than 8.5 hours weeknight sleep. Bedtime habits such as a consistent bedtime routine, staying up late or drinking caffeinated beverages before bed were statistically significantly associated with ESS, as were weeknight sleep quantity and gender. As ESS increased there was an increase in the proportion of students who felt their grades had dropped because of sleepiness, were late for school, were often extremely sleepy at school, and were involved in fewer extracurricular activities. These performance measures were statistically significantly associated with ESS. Twenty-three percent of the students felt their grades had dropped because of sleepiness. Most students (58–68% reported that they were "really sleepy" between 8 and 10 A

  1. Multiple Targets for Drug-Induced Mitochondrial Toxicity.

    Science.gov (United States)

    Wallace, Kendall B

    2015-01-01

    Mitochondrial toxicity is rapidly gaining the interest of researchers and practitioners as a prominent liability in drug discovery and development, accounting for a growing proportion of preclinical drug attrition and post-market withdrawals or black box warnings by the U.S. FDA. To date, the focus of registries of drugs that elicit mitochondrial toxicity has been largely restricted to those that either inhibit the mitochondrial electron transport chain (ETC) or uncouple mitochondrial oxidative phosphorylation. Less appreciated are the toxicities that are secondary to the drug affecting either the molecular regulation, assembly or incorporation of the ETC into the inner mitochondrial membrane or those that limit substrate availability. The current article describes the complexities of molecular events and biochemical pathways required to sustain mitochondrial fidelity and substrate homeostasis with examples of drugs that interfere which the various pathways. The principal objective of this review is to shed light on the broader scope of drug-induced mitochondrial toxicities and how these secondary targets may account for a large portion of drug failures. PMID:25973981

  2. Drug-induced hypersensitivity syndrome with human herpesvirus-6 reactivation

    Directory of Open Access Journals (Sweden)

    Najeeba Riyaz

    2012-01-01

    Full Text Available A 45-year-old man, on carbamazepine for the past 3 months, was referred as a case of atypical measles. On examination, he had high-grade fever, generalized itchy rash, cough, vomiting and jaundice. A provisional diagnosis of drug hypersensitivity syndrome to carbamazepine was made with a differential diagnosis of viral exanthema with systemic complications. Laboratory investigations revealed leukocytosis with eosnophilia and elevated liver enzymes. Real-time multiplex polymerase chain reaction (PCR on throat swab and blood was suggestive of human herpesvirus-6 (HHV-6. Measles was ruled out by PCR and serology. The diagnosis of drug-induced hypersensitivity syndrome (DIHS was confirmed, which could explain all the features manifested by the patient. HHV-6 infects almost all humans by age 2 years. It infects and replicates in CD4 T lymphocytes and establishes latency in human peripheral blood monocytes or macrophages and early bone marrow progenitors. In DIHS, allergic reaction to the causative drug stimulates T cells, which leads to reactivation of the herpesvirus genome. DIHS is treated by withdrawal of the culprit drug and administration of systemic steroids. Our patient responded well to steroids and HHV-6 was negative on repeat real-time multiplex PCR at the end of treatment.

  3. Drug-induced pulmonary arterial hypertension: a recent outbreak

    Directory of Open Access Journals (Sweden)

    Gérald Simonneau

    2013-09-01

    Full Text Available Pulmonary arterial hypertension (PAH is a rare disorder characterised by progressive obliteration of the pulmonary microvasculature resulting in elevated pulmonary vascular resistance and premature death. According to the current classification PAH can be associated with exposure to certain drugs or toxins, particularly to appetite suppressant intake drugs, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary artery smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used, but are considered possible risk factors, for PAH. Dasatinib, dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, potentially in part reversible after dasatinib withdrawal. Recently, several studies have raised the issue of potential endothelial dysfunction that could be induced by interferon, and a few cases of PAH have been reported with interferon therapy. PAH remains a rare complication of these drugs, suggesting possible individual susceptibility, and further studies are needed to identify patients at risk of drug-induced PAH.

  4. Drug-induced pulmonary arterial hypertension: a recent outbreak.

    Science.gov (United States)

    Montani, David; Seferian, Andrei; Savale, Laurent; Simonneau, Gérald; Humbert, Marc

    2013-09-01

    Pulmonary arterial hypertension (PAH) is a rare disorder characterised by progressive obliteration of the pulmonary microvasculature resulting in elevated pulmonary vascular resistance and premature death. According to the current classification PAH can be associated with exposure to certain drugs or toxins, particularly to appetite suppressant intake drugs, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary artery smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used, but are considered possible risk factors, for PAH. Dasatinib, dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, potentially in part reversible after dasatinib withdrawal. Recently, several studies have raised the issue of potential endothelial dysfunction that could be induced by interferon, and a few cases of PAH have been reported with interferon therapy. PAH remains a rare complication of these drugs, suggesting possible individual susceptibility, and further studies are needed to identify patients at risk of drug-induced PAH. PMID:23997051

  5. Disrupted sleep without sleep curtailment induces sleepiness and cognitive dysfunction via the tumor necrosis factor-α pathway

    OpenAIRE

    Ramesh Vijay; Nair Deepti; Zhang Shelley X L; Hakim Fahed; Kaushal Navita; Kayali Foaz; Wang Yang; Li Richard C; Carreras Alba; Gozal David

    2012-01-01

    Abstract Background Sleepiness and cognitive dysfunction are recognized as prominent consequences of sleep deprivation. Experimentally induced short-term sleep fragmentation, even in the absence of any reductions in total sleep duration, will lead to the emergence of excessive daytime sleepiness and cognitive impairments in humans. Tumor necrosis factor (TNF)-α has important regulatory effects on sleep, and seems to play a role in the occurrence of excessive daytime sleepiness in children who...

  6. Effects of Shift Work on Cognitive Performance, Sleep Quality, and Sleepiness among Petrochemical Control Room Operators.

    Science.gov (United States)

    Kazemi, Reza; Haidarimoghadam, Rashid; Motamedzadeh, Majid; Golmohamadi, Rostam; Soltanian, Alireza; Zoghipaydar, Mohamad Reza

    2016-01-01

    Shift work is associated with both sleepiness and reduced performance. The aim of this study was to examine cognitive performance, sleepiness, and sleep quality among petrochemical control room shift workers. Sixty shift workers participated in this study. Cognitive performance was evaluated using a number of objective tests, including continuous performance test, n-back test, and simple reaction time test; sleepiness was measured using the subjective Karolinska Sleepiness Scale (KSS); and sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire. ANCOVA, t-test, and repeated-measures ANOVA were applied for statistical analyses, and the significance level was set at p cognitive performance, except for omission error, significantly decreased at the end of both day and night shifts (p cycle of sleep, induced cognitive performance decline at the end of both day and night shifts, and increased sleepiness in night shift. It, thus, seems necessary to take ergonomic measures such as planning for more appropriate shift work and reducing working hours. PMID:27103934

  7. Tired of blunt tools? Sharpening the clinical assessment of fatigue and sleepiness.

    Science.gov (United States)

    Mairesse, Olivier; Neu, Daniel

    2016-04-30

    Fatigue and sleepiness are ubiquitous symptoms in various conditions and are frequently associated to impaired sleep quality. While separate fatigue and sleepiness scales exist, both constructs are often confused. Unraveling this issue requires estimating the instruments' measurement properties, potential scale recalibration and re-evaluation of symptom intensities on a comparable basis. This study aims at improving the assessment of these symptoms and quantifying their degree of overlap using common-person-equating (CPE). One hundred fifty-nine patients, either with complaints of fatigue, sleepiness and/or non-restorative sleep, addressed to an academic sleep unit for a full-night polysomnography (PSG), enrolled in the study. Symptom levels were measured with the Fatigue Severity (FSS) and Epworth Sleepiness (ESS) scales. Sleep quality was assessed by the Pittsburgh Sleep Quality Index, defining 'good' and 'poor' sleeper groups. Good and poor sleepers did not differ statistically regarding demographics and PSG parameters. Rasch analysis revealed that, considering proper calibration, the ESS and FSS generate reliable and valid, unidimensional linear measures and to be invariant to perceived sleep quality. CPE showed predominantly fatigued, rather than sleepy patients, being more likely to present as poor sleepers. A concordance diagram based on scale scores is provided, in order to improve the differentiation of both symptoms. PMID:27086218

  8. Effects of Shift Work on Cognitive Performance, Sleep Quality, and Sleepiness among Petrochemical Control Room Operators.

    Science.gov (United States)

    Kazemi, Reza; Haidarimoghadam, Rashid; Motamedzadeh, Majid; Golmohamadi, Rostam; Soltanian, Alireza; Zoghipaydar, Mohamad Reza

    2016-02-03

    Shift work is associated with both sleepiness and reduced performance. The aim of this study was to examine cognitive performance, sleepiness, and sleep quality among petrochemical control room shift workers. Sixty shift workers participated in this study. Cognitive performance was evaluated using a number of objective tests, including continuous performance test, n-back test, and simple reaction time test; sleepiness was measured using the subjective Karolinska Sleepiness Scale (KSS); and sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire. ANCOVA, t-test, and repeated-measures ANOVA were applied for statistical analyses, and the significance level was set at p sleep quality on both day and night shifts, and there were significant differences between the day and night shifts in terms of subjective sleep quality and quantity (p sleep, induced cognitive performance decline at the end of both day and night shifts, and increased sleepiness in night shift. It, thus, seems necessary to take ergonomic measures such as planning for more appropriate shift work and reducing working hours.

  9. Factors associated with self-reported driver sleepiness and incidents in city bus drivers.

    Science.gov (United States)

    Anund, Anna; Ihlström, Jonas; Fors, Carina; Kecklund, Göran; Filtness, Ashleigh

    2016-08-01

    Driver fatigue has received increased attention during recent years and is now considered to be a major contributor to approximately 15-30% of all crashes. However, little is known about fatigue in city bus drivers. It is hypothesized that city bus drivers suffer from sleepiness, which is due to a combination of working conditions, lack of health and reduced sleep quantity and quality. The overall aim with the current study is to investigate if severe driver sleepiness, as indicated by subjective reports of having to fight sleep while driving, is a problem for city based bus drivers in Sweden and if so, to identify the determinants related to working conditions, health and sleep which contribute towards this. The results indicate that driver sleepiness is a problem for city bus drivers, with 19% having to fight to stay awake while driving the bus 2-3 times each week or more and nearly half experiencing this at least 2-4 times per month. In conclusion, severe sleepiness, as indicated by having to fight sleep during driving, was common among the city bus drivers. Severe sleepiness correlated with fatigue related safety risks, such as near crashes. PMID:27098307

  10. Excessive Daytime Sleepiness and Unintended Sleep Episodes Associated with Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Fatai Salawu

    2015-01-01

    Full Text Available This article looks at the issues of excessive daytime sleepiness and unintended sleep episodes in patients with Parkinson’s disease (PD and explores the reasons why patients might suffer from these symptoms, and what steps could be taken to manage them. During the last decade, understanding of sleep/wake regulation has increased. Several brainstem nuclei and their communication pathways in the ascending arousing system through the hypothalamus and thalamus to the cortex play key roles in sleep disorders. Insomnia is the most common sleep disorder in PD patients, and excessive daytime sleepiness is also common. Excessive daytime sleepiness affects up to 50% of PD patients and a growing body of research has established this sleep disturbance as a marker of preclinical and premotor PD. It is a frequent and highly persistent feature in PD, with multifactorial underlying pathophysiology. Both age and disease-related disturbances of sleep-wake regulation contribute to hypersomnia in PD. Treatment with dopamine agonists also contribute to excessive daytime sleepiness. Effective management of sleep disturbances and excessive daytime sleepiness can greatly improve the quality of life for patients with PD.

  11. Hepatic necrosis associated with drug-induced hypersensitivity syndrome

    Directory of Open Access Journals (Sweden)

    Fernando Peixoto Ferraz de Campos

    2012-12-01

    Full Text Available Drug-induced hypersensitivity syndrome (DIHS; also known as drug reaction with eosinophilia and systemic symptoms [DRESS] is a life-threatening condition first described by Chaikenetal. in 1950. It is characterized by extensive mucocutaneous rash; fever; lymphadenopathy; hepatitis; hematological abnormalities; damage to several organs such as kidney, heart, lungs, and pancreas; and possible reactivation of human herpesvirus-6 (HHV-6 or other herpes virus. Rare and severe cases may present hepatic necrosis, and about 15% of them result in death or liver transplantation. A hallmark of this syndrome is the late onset of symptoms after the drug exposure. The most common culprit drugs are the aromatic anticonvulsants (in almost 30% of the cases and the antibiotics (which in some series represent 20% of the cases. The authors report a case of a 41-year-old female who presented to the emergency department with erythroderma, acute hepatitis, acute pancreatitis and acute renal failure, and was then treated with corticosteroid after the diagnosis of DIHS/DRESS. A specific culprit drug could not confidently be determined due to the presence of multiple drugs used by the patient. The clinical and laboratory outcome was apparently satisfactory, but unexpectedly, on the sixth day of hospitalization, the patient complained of nonspecific malaise, drowsiness, which progressed in a few hours with signs and symptoms of hepatic failure, refractory shock, and death. The autopsy findings showed submassive hepatic necrosis, and the immediate cause of death was attributed to hepatic failure.

  12. Drug-Induced gingival overgrowth: The genetic dimension

    Directory of Open Access Journals (Sweden)

    Noronha Shyam Curtis Charles

    2014-01-01

    Full Text Available Background: Currently, the etiology of drug-induced gingival overgrowth is not entirely understood but is clearly multifactorial. Phenytoin, one of the common drugs implicated in gingival enlargement, is metabolized mainly by cytochrome P450 (CYP2C9 and partly by CYP2C19. The CYP2C9 and CYP2C19 genes are polymorphically expressed and most of the variants result in decreased metabolism of the respective substrates. Aims: The present study was undertaken to investigate the influence of the CYP2C9FNx012 and FNx013 variant genotypes on phenytoin hydroxylation in subjects diagnosed with epilepsy from South India, thus establishing the genetic polymorphisms leading to its defective hydroxylation process. Materials and Methods: Fifteen epileptic subjects, age 9 to 60 years were included in the study. Among the study subjects, 8 were males and 7 were females. Genomic DNA was extracted from patients′ blood using Phenol-chloroform method and genotyping was done for CYP2C9 using customized TaqMan genotyping assays on a real time thermocycler, by allelic discrimination method. The genetic polymorphisms FNx011, FNx012 and FNx013 on CYP2C9 were selected based on their function and respective allele frequencies in Asian subcontinent among the Asian populations. Results: CYP2C9FNx011FNx012 and CYP2C9FNx013/FNx013 were identified with equal frequency in the study population. There were seven subjects with CYP2C9FNx011/FNx012 genotype (heterozygous mutant, one subject with CYP2C9FNx011/FNx011 (wild type and seven study subjects with CYP2C9FNx013/FNx013 (homozygous mutant. Conclusion: The results obtained in the present study will be helpful in the medical prescription purposes of phenytoin, and a more personalized patient approach with its administration can be advocated.

  13. Unusual case of drug-induced cholestasis due to glucosamine and chondroitin sulfate

    Institute of Scientific and Technical Information of China (English)

    Stephen; Ip; Rachel; Jeong; David; F; Schaeffer; Eric; M; Yoshida

    2015-01-01

    Glucosamine(GS) and chondroitin sulfate(CS) are common over-the-counter(OTC) supplements used in the treatment of osteoarthritis. These medications are seemingly safe, but there are increasing reports of hepatotoxicity with these supplements. We reported a unique case of drug-induced cholestasis caused by GS and CS in a combination tablet. The etiology of the jaundice was overlooked despite extensive investigations over a three-month period. Unlike drug-induced hepatocellular injury, drug-induced cholestatic jaundice with GS and CS has only been reported twice before. This case emphasizes the importance of a complete medication history, especially OTC supplements, in the assessment of cholestasis.

  14. Recent advances in the treatment and management of excessive daytime sleepiness.

    Science.gov (United States)

    Black, Jed; Duntley, Stephen P; Bogan, Richard K; O'Malley, Mary B

    2007-02-01

    Excessive daytime sleepiness (EDS) is a prevalent complaint among patients in psychiatric care. Patients with conditions of EDS have often been misdiagnosed with depression due to their complaints of lack of energy, poor concentration, memory disturbance, and a reduced interest in life. Impaired alertness associated with EDS can be detrimental to a person's quality of life by causing decreased work performance, self-consciousness, low self esteem, and social isolation. Excessive sleepiness is also associated with various health problems, comorbid medical and psychiatric conditions, and fatal accidents occurring after the driver has fallen asleep at the wheel. Contributing factors leading to EDS range from insufficient sleep hours to central nervous system-mediated debilitating hypersomnolence. Circadian rhythm disorders, sleep disorders such as obstructive sleep apnea and narcolepsy, and medications that cause sleepiness may also contribute to symptoms of EDS. Recognition of the symptoms of sleep deprivation is essential, as many such patients do not have a clear awareness of their own sleepiness. Treatment options, depending upon the condition, include light therapy or appropriate airway management techniques such as nasal continuous positive airway pressure (CPAP). Occasionally, wakefulness-promoting medications are necessary, particularly in patients with narcolepsy. In this expert roundtable supplement, Stephen P. Duntley, MD, reviews the definition and prevalence of EDS and discusses the contributing factors and consequences of daytime sleepiness. Next, Richard K. Bogan, MD, FCCP, gives an overview of the differential diagnosis of EDS and the assessment tools available for identifying sleepiness in symptomatic patients. Finally, Mary B. O'Malley, MD, PhD, reviews treatment of EDS, including counseling on sleep hygiene and duration of sleep, mechanical treatments, bright-light therapy, and wake-promoting medications. PMID:17277717

  15. Recent advances in the treatment and management of excessive daytime sleepiness.

    Science.gov (United States)

    Black, Jed; Duntley, Stephen P; Bogan, Richard K; O'Malley, Mary B

    2007-02-01

    Excessive daytime sleepiness (EDS) is a prevalent complaint among patients in psychiatric care. Patients with conditions of EDS have often been misdiagnosed with depression due to their complaints of lack of energy, poor concentration, memory disturbance, and a reduced interest in life. Impaired alertness associated with EDS can be detrimental to a person's quality of life by causing decreased work performance, self-consciousness, low self esteem, and social isolation. Excessive sleepiness is also associated with various health problems, comorbid medical and psychiatric conditions, and fatal accidents occurring after the driver has fallen asleep at the wheel. Contributing factors leading to EDS range from insufficient sleep hours to central nervous system-mediated debilitating hypersomnolence. Circadian rhythm disorders, sleep disorders such as obstructive sleep apnea and narcolepsy, and medications that cause sleepiness may also contribute to symptoms of EDS. Recognition of the symptoms of sleep deprivation is essential, as many such patients do not have a clear awareness of their own sleepiness. Treatment options, depending upon the condition, include light therapy or appropriate airway management techniques such as nasal continuous positive airway pressure (CPAP). Occasionally, wakefulness-promoting medications are necessary, particularly in patients with narcolepsy. In this expert roundtable supplement, Stephen P. Duntley, MD, reviews the definition and prevalence of EDS and discusses the contributing factors and consequences of daytime sleepiness. Next, Richard K. Bogan, MD, FCCP, gives an overview of the differential diagnosis of EDS and the assessment tools available for identifying sleepiness in symptomatic patients. Finally, Mary B. O'Malley, MD, PhD, reviews treatment of EDS, including counseling on sleep hygiene and duration of sleep, mechanical treatments, bright-light therapy, and wake-promoting medications.

  16. Excessive daytime sleepiness in the elderly: association with cardiovascular risk, obesity and depression

    Directory of Open Access Journals (Sweden)

    Johnnatas Mikael Lopes

    2013-12-01

    Full Text Available OBJECTIVE: To observe the relationship between Excessive Daytime Sleepiness (EDS and the presence of risk factors for cardiovascular dysfunction, depression and obesity in the elderly. METHODS: We interviewed 168 elderly from the community of Campina Grande, Paraíba. They were selected according to health districts in the period of 2010. We used the Epworth Sleepiness Scale to diagnose excessive daytime sleepiness (> 10 points; waist circumference for the risk of cardiovascular dysfunction (> 94 or > 80 cm; Geriatric Depression Scale for depression (>10 points and body mass index for obesity (> 25 kg/m2. Association analysis was performed by the Chi-square test adjusted for sex and age group, adopting α < 0.05. RESULTS: One hundred and sixty eight elderly individuals with mean age of 72.34 ± 7.8 years old participated in this study, being 122 (72.6% women. EDS was identified in 53 (31.5% of them; depression, in 72 (42.9%; overweight/obesity, in 95 (64.46%; and risk of cardiovascular dysfunction, in 129 (79.6%. Depressed men (78.6%, p = 0.0005 and risk of cardiovascular dysfunction (57.1%, p = 0.02 were more prone to EDS. In women, only obesity was related to sleepiness (42.1%, p = 0.01. Only those aged between 70 - 79 years old showed association between sleepiness and obesity. CONCLUSION: It was found that obesity for women, and depression and cardiovascular dysfunction risking for men were associated with EDS in the elderly. The variable sex is a confusion condition for the association with sleepiness.

  17. Chronic headaches and sleepiness caused by facial soap (containing hydrolyzed wheat proteins)-induced wheat allergy.

    Science.gov (United States)

    Iseki, Chifumi; Kawanami, Toru; Tsunoda, Takahiko; Chinuki, Yuko; Kato, Takeo

    2014-01-01

    A 38-year-old woman was suffering from irregular headaches and sleepiness. She had used soap containing Glupearl 19S (hydrolyzed wheat proteins) every day for approximately one year and had experienced an episode of rash eruption on her face seven months ago. Wheat-specific IgE antibodies were detected in her serum. A Western blot analysis revealed a high titer of IgE antibodies against Glupearl 19S and wheat proteins. The patient was sensitive to these compounds in a skin prick test. After avoiding eating wheat, her headaches and sleepiness disappeared. A hidden food allergy is a possible cause of these symptoms.

  18. In-car countermeasures open window and music revisited on the real road: popular but hardly effective against driver sleepiness

    NARCIS (Netherlands)

    Schwarz, J.F.A.; Ingre, M.; Fors, C.; Anund, A.; Kecklund, L.G.; Taillard, J.; Philip, P.; Äkerstedt, T.

    2012-01-01

    This study investigated the effects of two very commonly used countermeasures against driver sleepiness, opening the window and listening to music, on subjective and physiological sleepiness measures during real road driving. In total, 24 individuals participated in the study. Sixteen participants r

  19. Involvement of FKHR-Dependent TRADD Expression in Chemotherapeutic Drug-Induced Apoptosis

    OpenAIRE

    Rokudai, Susumu; Fujita, Naoya; Kitahara, Osamu; NAKAMURA, Yusuke; Tsuruo, Takashi

    2002-01-01

    Chemotherapeutic drugs exhibit their cytotoxic effect by inducing apoptosis in tumor cells. Because the serine/threonine kinase Akt is involved in apoptosis suppression, we investigated the relationship between Akt activity and drug sensitivity. We discovered that certain chemotherapeutic drugs induced apoptosis with caspase activation only when Akt was inactivated after drug treatment, while inactivation of Akt was not observed when tumor cells showed resistance to the drug-induced caspase a...

  20. Drug-Induced Liver Toxicity and Prevention by Herbal Antioxidants: An Overview

    OpenAIRE

    Singh, Divya; Cho, William C.; Upadhyay, Ghanshyam

    2016-01-01

    The liver is the center for drug and xenobiotic metabolism, which is influenced most with medication/xenobiotic-mediated toxic activity. Drug-induced hepatotoxicity is common and its actual frequency is hard to determine due to underreporting, difficulties in detection or diagnosis, and incomplete observation of exposure. The death rate is high, up to about 10% for drug-induced liver damage. Endorsed medications represented >50% of instances of intense liver failure in a study from the Acute ...

  1. Judgment of Daytime Sleepiness in Self-Reported Short, Long and Midrange Sleepers

    Science.gov (United States)

    Mairesse, Olivier; Neu, Daniel; Migeotte, Pierre-Francois; Pattyn, Nathalie; Hofmans, Joeri; Theuns, Peter; Cluydts, Raymond; De Valck, Elke

    2012-01-01

    Sleep-wake behavior, as well as sleepiness, is regulated by the joint action of an exponentially increasing drive for sleep--sleep homeostasis--and by variations in sleep propensity due to a biological circadian oscillator. However, large inter-individual differences remain. Short and long sleepers have been known to differ in the amount of…

  2. Insomnia, Sleepiness, and Depression in Adolescents Living in Residential Care Facilities

    Science.gov (United States)

    Moreau, Vincent; Belanger, Lynda; Begin, Gilles; Morin, Charles M.

    2009-01-01

    The main objective of this study was to document sleep patterns and disturbances reported by youths temporarily living in residential care facilities. A secondary objective was to examine the relationships between sleep disturbances and mood and daytime sleepiness. A self-reported questionnaire on sleep patterns and habits assessing duration,…

  3. "Koi Sleepy Disease" voor het eerst in Nederland aangetoond in koikarpers

    NARCIS (Netherlands)

    Haenen, O.L.M.; Way, K.; Stone, D.; Engelsma, M.Y.

    2014-01-01

    Eind september 2013 is de koikarperziekte 'Koi Sleepy Disease'(KSD) voor het eerst aangetoond in Nederland door het Vis-, schaal- en schelpdierziektelaboratorium van Central Veterinary Institute, onderdeel van Wageningen UR. De klinische verdenking werd bevestigd door het zusterlab CEFAS in Engeland

  4. Koi Sleepy Disease (KSD) door 'Carp Edema virus' : eerste detectie in Nederlandse Koi

    NARCIS (Netherlands)

    Haenen, O.L.M.; Way, K.; Stone, D.; Engelsma, M.Y.

    2013-01-01

    De koi sector is bekend met verschillende ziekten van koi, zoals koi herpesvirus (KHV) en columnaris disease door Flavobacterium columnare. Dit najaar is echter een in Nederland nog niet eerder aangetoonde ziekte aangetroffen in koi: het koi sleepy disease (KSD). We gaan in dit artikel in op deze zi

  5. Daytime Sleepiness, Poor Sleep Quality, Eveningness Chronotype, and Common Mental Disorders among Chilean College Students

    Science.gov (United States)

    Concepcion, Tessa; Barbosa, Clarita; Vélez, Juan Carlos; Pepper, Micah; Andrade, Asterio; Gelaye, Bizu; Yanez, David; Williams, Michelle A.

    2014-01-01

    Objectives: To evaluate whether daytime sleepiness, poor sleep quality, and morningness and eveningness preferences are associated with common mental disorders (CMDs) among college students. Methods: A total of 963 college students completed self-administered questionnaires that collected information about sociodemographic characteristics, sleep…

  6. Attention Deficit Hyperactivity Disorder Symptoms, Sleepiness and Accidental Risk in 36140 Regularly Registered Highway Drivers.

    Directory of Open Access Journals (Sweden)

    Pierre Philip

    Full Text Available Attention Deficit Hyperactivity Disorder (ADHD is a frequent neurodevelopmental disorder that increases accidental risk. Recent studies show that some patients with ADHD can also suffer from excessive daytime sleepiness but there are no data assessing the role of sleepiness in road safety in patients with ADHD. We conducted an epidemiological study to explore sleep complaints, inattention and driving risks among automobile drivers.From August to September 2014, 491186 regular highway users were invited to participate in an Internet survey on driving habits. 36140 drivers answered a questionnaire exploring driving risks, sleep complaints, sleepiness at the wheel, ADHD symptoms (Adult ADHD Self-Report Scale and distraction at the wheel. 1.7% of all drivers reported inattention-related driving accidents and 0.3% sleep-related driving accidents in the previous year. 1543 drivers (4.3% reported ADHD symptoms and were more likely to report accidents than drivers without ADHD symptoms (adjusted OR = 1.24, [1.03-1.51], p 15 versus 3.2% of drivers without ADHD symptoms and 20.5% reported severe sleepiness at the wheel versus 7.3%. Drivers with ADHD symptoms reported significantly more sleep-related (adjusted OR = 1.4, [1.21-1.60], p < .0001 and inattention-related (adjusted OR = 1.9, [1.71-2.14], p<0001 near misses than drivers without ADHD symptoms. The fraction of near-misses attributable to severe sleepiness at the wheel was 4.24% for drivers without ADHD symptoms versus 10,35% for drivers with ADHD symptoms.Our study shows that drivers with ADHD symptoms have more accidents and a higher level of sleepiness at the wheel than drivers without ADHD symptoms. Drivers with ADHD symptoms report more sleep-related and inattention-related near misses, thus confirming the clinical importance of exploring both attentional deficits and sleepiness at the wheel in these drivers. Road safety campaigns should be improved to better inform drivers of these accidental

  7. Lack of impact of mild obstructive sleep apnea on sleepiness, mood and quality of life

    Directory of Open Access Journals (Sweden)

    Quan SF

    2014-07-01

    Full Text Available Background and Objectives: Obstructive sleep apnea (OSA is associated with sleepiness, depression and reduced quality of life. However, it is unclear whether mild OSA has these negative impacts. Using data from the Apnea Positive Pressure Long-term Efficacy Study (APPLES, this study determined whether participants with mild OSA had greater sleepiness, more depressive symptoms and poorer quality of life in comparison to those without OSA. Methods: 239 evaluated for participation in APPLES with a baseline apnea hypopnea index (AHI < 15 /hour were assigned to 1 of 2 groups: No OSA (N=40, AHI < 5 /hour or Mild OSA (N=199, 5 to <15 /hour based on their screening polysomnogram. Scores on their Epworth Sleepiness Scale (ESS, Stanford Sleepiness Scale (SSS, Hamilton Rating Scale for Depression (HAM-D, Profile of Mood States (POMS and Sleep Apnea Quality of Life Index (SAQLI were compared between groups. Results: There were no significant differences between the No OSA and Mild OSA groups on any of the 5 measures: ESS (OSA, 9.8 + 3.5 vs Mild OSA, 10.6 + 4.3, p=0.26, SSS,(2.8 + 0.9 vs. 2.9 + 1.0, p=0.52, HAM-D (4.6 + 3.0 vs. 4.9 + 4.7, p=0.27, POMS (33.5 + 22.3 vs. 28.7 + 22.0, p=0.70, SAQLI (4.5 + 0.8 vs. 4.7 + 0.7, p=0.39. Conclusion: Individuals with mild OSA in this cohort do not have worse sleepiness, mood or quality of life in comparison to those without OSA.

  8. Comparison of clinical features between primary and drug-induced sleep-related eating disorder

    Directory of Open Access Journals (Sweden)

    Komada Y

    2016-05-01

    Full Text Available Yoko Komada,1 Yoshikazu Takaesu,2 Kentaro Matsui,3 Masaki Nakamura,3 Shingo Nishida,3 Meri Kanno,3,† Akira Usui,3 Yuichi Inoue1,3 1Department of Somnology, 2Department of Psychiatry, Tokyo Medical University, 3Japan Somnology Center, Institute of Neuropsychiatry, Tokyo, Japan †Meri Kanno passed away on March 1, 2016 Purpose: The aim of this study was to ascertain the clinical characteristics of drug-induced sleep-related eating disorder (SRED. Patients and methods: We retrospectively reviewed the medical records of 30 patients with primary SRED (without any comorbid sleep disorders and who were not taking any possible causative medications, and ten patients with drug-induced SRED (occurrence of SRED episodes after starting nightly medication of sedative drugs, which completely resolved after dose reduction or discontinuation of the sedatives. Results: All patients with drug-induced SRED took multiple types of sedatives, such as benzodiazepines or benzodiazepine receptor agonists. Clinical features of drug-induced SRED compared with primary SRED were as follows: higher mean age of onset (40 years old in drug-induced SRED vs 26 years old in primary SRED, significantly higher rate of patients who had total amnesia during most of their SRED episodes (75.0% vs 31.8%, significantly lower rate of comorbidity of night eating syndrome (0% vs 63.3%, and significantly lower rate of history of sleepwalking (10.0% vs 46.7%. Increased doses of benzodiazepine receptor agonists may be responsible for drug-induced SRED. Conclusion: The clinical features of drug-induced SRED were different from those of primary SRED, possibly reflecting differences in the underlying mechanisms between these two categories of SREDs. Keywords: nocturnal eating syndrome, night eating, eating disorder, hypnotics, amnesia, sleepwalking, benzodiazepine

  9. Subjective sleepiness in heart failure patients with sleep-related breathing disorder

    Institute of Scientific and Technical Information of China (English)

    WANG Han-qiao; CHEN Gang; LI Jing; HAO Shu-min; GU Xin-shun; PANG Jiang-na; FU Xiang-hua

    2009-01-01

    Background Previous studies show that sleep-related breathing disorder (SRBD) is common in patients with heart failure (HF) and is associated with increased mortality. This study aimed to determine whether there was significant difference of subjective daytime sleepiness between HF patients with and without SRBD.Methods We enrolled, prospectively, 195 consecutive HF patients with left ventricular ejection fractions (LVEF)≮45%and all subjects underwent polysomnography to measure the sleep structure between 2005 and 2008. Patients were then assigned to those with SRBD including obstructive and central sleep apnea (apnea-hypopnea index (AHI)≯5/hour of sleep) and those without SRBD (AHI<5/hour) according to the sleep study. The subjective sleepiness was assessed withEpworth sleepiness scale (ESS).Results Among 195 HF patients, the prevalence of obstructive sleep apnea (OSA) was 53% and of central sleep apnea (CSA) was 27%. There was no significant difference of ESS scores between patients without SRBD (NSA) and with SRBD (NSA vs OSA: 6.7±0.6 VS 7.6±0.4, P=0.105 and NSA vs CSA: 6.7±0.6 vs 7.4±0.5, ,P=0.235, respectively),indicating that SRBD patients had no more subjective daytime sleepiness. Compared with NSA, patients with SRBD had increased arousal index (Arl) (NSA vs OSA: 14.1±1.4 vs 26.3±1.5, P <0.001 and NSA vs CSA: 14.1±1.4 vs 31.3±3.5, P <0.001, respectively), more awake number after sleep onset (NSA vs OSA: 19.2±1.5 vs 26.2±1.4, P=0.01 and NSA vs CSA: 19.2±1.5 vs 36.9±4.4, P <0.001, respectively), and reduced proportion of slow-wave sleep (SWS) (NSA vs OSA: 13.8±1.7 vs 9.3±0.7, ,P=0.024 and NSA vs CSA: 13.8±1.7 vs 8.9±0.9, P=0.024, respectively). Conclusions OSA and CSA remain common in patients with HF on optimal contemporary therapy. Patients with both HF and SRBD have no significant subjective daytime sleepiness compared with patients without SRBD, despite of significantly increased awake number, arousal and decreased proportion of deep

  10. Hepatocyte-based in vitro model for assessment of drug-induced cholestasis

    Energy Technology Data Exchange (ETDEWEB)

    Chatterjee, Sagnik, E-mail: Sagnik.Chatterjee@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium); Richert, Lysiane, E-mail: l.richert@kaly-cell.com [KaLy-Cell, 20A rue du Général Leclerc, 67115 Plobsheim (France); Augustijns, Patrick, E-mail: Patrick.Augustijns@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium); Annaert, Pieter, E-mail: Pieter.Annaert@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium)

    2014-01-01

    Early detection of drug-induced cholestasis remains a challenge during drug development. We have developed and validated a biorelevant sandwich-cultured hepatocytes- (SCH) based model that can identify compounds causing cholestasis by altering bile acid disposition. Human and rat SCH were exposed (24–48 h) to known cholestatic and/or hepatotoxic compounds, in the presence or in the absence of a concentrated mixture of bile acids (BAs). Urea assay was used to assess (compromised) hepatocyte functionality at the end of the incubations. The cholestatic potential of the compounds was expressed by calculating a drug-induced cholestasis index (DICI), reflecting the relative residual urea formation by hepatocytes co-incubated with BAs and test compound as compared to hepatocytes treated with test compound alone. Compounds with clinical reports of cholestasis, including cyclosporin A, troglitazone, chlorpromazine, bosentan, ticlopidine, ritonavir, and midecamycin showed enhanced toxicity in the presence of BAs (DICI ≤ 0.8) for at least one of the tested concentrations. In contrast, the in vitro toxicity of compounds causing hepatotoxicity by other mechanisms (including diclofenac, valproic acid, amiodarone and acetaminophen), remained unchanged in the presence of BAs. A safety margin (SM) for drug-induced cholestasis was calculated as the ratio of lowest in vitro concentration for which was DICI ≤ 0.8, to the reported mean peak therapeutic plasma concentration. SM values obtained in human SCH correlated well with reported % incidence of clinical drug-induced cholestasis, while no correlation was observed in rat SCH. This in vitro model enables early identification of drug candidates causing cholestasis by disturbed BA handling. - Highlights: • Novel in vitro assay to detect drug-induced cholestasis • Rat and human sandwich-cultured hepatocytes (SCH) as in vitro models • Cholestatic compounds sensitize SCH to toxic effects of accumulating bile acids • Drug-induced

  11. Correlation of Epworth Sleepiness Scale with multiple sleep latency test and its diagnostic accuracy in assessing excessive daytime sleepiness in patients with obstructive sleep apnea hypopnea syndrome

    Institute of Scientific and Technical Information of China (English)

    CAI Si-jie; CHEN Rui; ZHANG Yan-lin; XIONG Kang-ping; LIAN Yi-xin; LI Jie; SHEN Jiu-cheng

    2013-01-01

    Background Excessive daytime sleepiness (EDS) is often associated with obstructive sleep apnea hypopnea syndrome (OSAHS) and contributes to a number of comorbidities in these patients.Therefore,eady detection of EDS is critical in disease management.We examined the association between Epworth Sleepiness Scale (ESS) and multiple sleep latency test (MSLT) and diagnostic accuracy of ESS in assessing EDS in OSAHS patients.Methods The ESS,MSLT and overnight polysomnography were administered to 107 Chinese patients to assess EDS and its correlations with polysomnographic parameters.The diagnostic accuracy of ESS in classifying EDS (mean sleep latency (MSL) <10 minutes) was evaluated by calculating the area under ROC curve.Results As the severity of OSAHS increased,MSL decreased with increase in ESS score.Conversely,patients with worsening EDS (shorter MSL) were characterized by advanced nocturnal hypoxaemia and sleep disruption compared to those with normal MSL,suggesting EDS is associated with more severe OSAHS.There was a negative correlation between ESS score and MSL and both moderately correlated with some polysomnographic nocturnal hypoxaemic parameters.The area under ROC curve of ESS for identifying EDS was 0.80 (95% C/:0.71 to 0.88) and ESS score >12provided the best predictive value with a sensitivity of 80% and specificity of 69%.Conclusion The ESS score moderately correlates with MSL and our ROC study supports ESS as a screening strategy for assessing EDS in OSAHS.

  12. Sleepiness and health in midlife women: results of the National Sleep Foundation's 2007 Sleep in America poll.

    Science.gov (United States)

    Chasens, Eileen R; Twerski, Sarah R; Yang, Kyeongra; Umlauf, Mary Grace

    2010-01-01

    The 2007 Sleep in America poll, a random-sample telephone survey, provided data for this study of sleep in community-dwelling women aged 40 to 60 years. The majority of the respondents were post- or perimenopausal, overweight, married or living with someone, and reported good health. A subsample (20%) reported sleepiness that consistently interfered with daily life; the sleepy subsample reported more symptoms of insomnia, restless legs syndrome, obstructive sleep apnea, depression and anxiety, as well as more problems with health-promoting behaviors, drowsy driving, job performance, household duties, and personal relationships. Hierarchical regression showed that sleepiness along with depressive symptoms, medical comorbidities, obesity, and lower education were associated with poor self-rated health, whereas menopause status (pre-, peri- or post-) was not. These results suggest that sleep disruptions and daytime sleepiness negatively affect the daily life of midlife women. PMID:20582759

  13. Combined electrocardiogram and photoplethysmogram measurements as an indicator of objective sleepiness

    International Nuclear Information System (INIS)

    There is considerable interest in unobtrusive and portable methods of monitoring sleepiness outside the laboratory setting. This study evaluates the usefulness of combined electrocardiogram (ECG) and photoplethysmogram (PPG) measurements for estimating psychomotor vigilance. The psychomotor vigilance test (PVT) was performed at various points over the course of a day, and one channel each of ECG and PPG was recorded simultaneously. Features derived from ECG and PPG were entered into multiple linear regression models to estimate PVT values. A double-loop, subject-independent validation scheme was used to develop and validate the models. We show that features obtained from the RR interval were reasonably useful for estimating absolute PVT levels, but were somewhat inadequate for estimating within-subject PVT changes. Combined ECG and PPG measurements appear to be useful for predicting PVT values, and deserve further investigation for portable sleepiness monitoring

  14. Mood states and sleepiness in college students: influences of age, sex, habitual sleep, and substance use.

    Science.gov (United States)

    Jean-Louis, G; von Gizycki, H; Zizi, F; Nunes, J

    1998-10-01

    Survey and laboratory evidence suggests several factors affecting sleep-wake patterns of college students. These factors include social and academic demands, diminution of parental guidance, reduction of total sleep time, delayed bedtime, and increased nap episodes. In this study, we examined the problem of falling asleep in school as a correlate of negative moods in this population (N = 294). A multivariate analysis showed significant main effects of sleepiness on mood states based on the Profile of Mood States. Students who fell asleep in school reported higher negative mood states. Significant interactions were observed among sleepiness and age, sex, race, and duration of sleep. Specifically, younger men reported higher negative moods. No interactions were noted for alcohol and marijuana consumption; however, students who fell asleep in school consumed more alcoholic beverages and smoked more than those who did not. Perhaps falling asleep in school could be used as an index that characterizes students who manifest adaptive or psychological difficulty. PMID:9842593

  15. Evaluation of Physiological Indices to Indicate Sleepy or Relaxed States Using Illuminance Stimulation

    Science.gov (United States)

    Shibagaki, Yumi; Ogawa, Kozue; Hagiwara, Hiroshi

    The purpose of the present study was to clarify the ability of physiological indices to reflect the degree of sleepiness or relaxation of an individual due to stress, fatigue and other factors. Several studies have investigated the use of high-frequency (HF) components (0.15-0.40Hz) in heart rate variability to evaluate parasympathetic nervous activity. However, it has been difficult to assess the differences between states of sleepiness and relaxation using this method. In the present study, in order to evaluate the indices, two experimental illuminance conditions, 100 and 1,500 lx, reflecting differing states of arousal, were used during a cognitive judgment test lasting for 30 minutes. During the cognitive judgment test, electroencephalograms (EEG), electrocardiograms (ECG), physiological state and reaction time were measured, and results indicated that the two illuminance conditions could be differentiated from the recorded physiological data. More specifically, in the 1,500-lx condition, arousal level, activity level and test performance increased, and the level of HF components decreased. Opposite tendencies were observed in the 100-lx condition. Two indices of Lorenz plots (LP) at ECG RR intervals, center (C of LP) and ellipse area (S of LP), were subsequently determined from the physiological data. Subjects were then divided according to these LP indices based on their exhibited physiological responses, and we evaluated the effectiveness of the indices in differentiating between states of sleepiness and relaxation by comparing arousal level, psychological state, and reaction time. Results indicated that the C of LP and S of LP are possible indices for evaluating sleepiness or relaxation and suggest that these two indices may also be able to evaluate the relationship between physiological changes and other, subjective feelings.

  16. Insomnia and daytime sleepiness are risk factors for depressive symptoms in the elderly.

    OpenAIRE

    Jaussent, Isabelle; BOUYER, Jean; Ancelin, Marie-Laure; Akbaraly, Tasnime; Pérès, Karine; Ritchie, Karen; Besset, Alain; Dauvilliers, Yves

    2011-01-01

    International audience STUDY OBJECTIVES: Previous studies have reported that insomnia and excessive daytime sleepiness (EDS) may predict depression in adults. However, these associations have not been investigated in community-dwelling elderly taking into account insomnia symptoms, EDS, and sleep medication. DESIGN: Four-year longitudinal study. SETTING: The French Three-City Study. PARTICIPANTS: 3824 subjects aged ≥ 65 years and free of depressive symptoms at baseline. MEASUREMENTS AND RE...

  17. Correlates of excessive daytime sleepiness in community-dwelling older adults: an exploratory study.

    Science.gov (United States)

    Lima, Camila Astolphi; Soares, Wuber Jefferson de Souza; Bilton, Tereza Loffredo; Dias, Rosângela Corrêa; Ferrioll, Eduardo; Perracini, Monica Rodrigues

    2015-01-01

    Excessive daytime sleepiness (EDS) imposes a wide range of adverse health-related outcomes in older people, such as disability, which impair everyday activities and may increase the risk of fall. Few studies have explored EDS in Brazilian older people living in the community who are typically cared in primary health services. This study aims to investigate the prevalence of EDS and its sociodemographic, physical and mental health correlates among community-dwelling older adults. This is an exploratory, population-based study derived from Frailty in Brazilian Older Adults (FIBRA) study including adults aged 65 years and older. Participants with a score ≥ 11 points on the Epworth Sleepiness Scale were considered as having excessive daytime sleepiness. A structured, multidimensional questionnaire was used to investigate sociodemographic, physical and mental health, and self-rated health variables. The sample was composed of 776 older adults, of whom 21% (n = 162) presented excessive daytime sleepiness. Multivariate regression analysis revealed that EDS is associated with obesity (OR = 1.50; 95%CI 1.02 - 2.20), urinary incontinence (OR = 1.53; 95%CI 1.01 - 2.31), poor self-rated health (OR = 1.54; 95%CI 1.06 - 2.24), and depression symptoms (OR = 1.49; 95%CI 1.00 - 2.20). Our results suggest that healthcare professionals should identify older adults with EDS and implement intervention strategies to minimize the negative impact of the co-occurrence of this condition with obesity, depression and urinary incontinence over health and quality of life. PMID:26247185

  18. Correlates of excessive daytime sleepiness in community-dwelling older adults: an exploratory study.

    Science.gov (United States)

    Lima, Camila Astolphi; Soares, Wuber Jefferson de Souza; Bilton, Tereza Loffredo; Dias, Rosângela Corrêa; Ferrioll, Eduardo; Perracini, Monica Rodrigues

    2015-01-01

    Excessive daytime sleepiness (EDS) imposes a wide range of adverse health-related outcomes in older people, such as disability, which impair everyday activities and may increase the risk of fall. Few studies have explored EDS in Brazilian older people living in the community who are typically cared in primary health services. This study aims to investigate the prevalence of EDS and its sociodemographic, physical and mental health correlates among community-dwelling older adults. This is an exploratory, population-based study derived from Frailty in Brazilian Older Adults (FIBRA) study including adults aged 65 years and older. Participants with a score ≥ 11 points on the Epworth Sleepiness Scale were considered as having excessive daytime sleepiness. A structured, multidimensional questionnaire was used to investigate sociodemographic, physical and mental health, and self-rated health variables. The sample was composed of 776 older adults, of whom 21% (n = 162) presented excessive daytime sleepiness. Multivariate regression analysis revealed that EDS is associated with obesity (OR = 1.50; 95%CI 1.02 - 2.20), urinary incontinence (OR = 1.53; 95%CI 1.01 - 2.31), poor self-rated health (OR = 1.54; 95%CI 1.06 - 2.24), and depression symptoms (OR = 1.49; 95%CI 1.00 - 2.20). Our results suggest that healthcare professionals should identify older adults with EDS and implement intervention strategies to minimize the negative impact of the co-occurrence of this condition with obesity, depression and urinary incontinence over health and quality of life.

  19. Which diagnostic findings in disorders with excessive daytime sleepiness are really helpful? A retrospective study.

    Science.gov (United States)

    Kretzschmar, Ute; Werth, Esther; Sturzenegger, Christian; Khatami, Ramin; Bassetti, Claudio L; Baumann, Christian R

    2016-06-01

    Due to extensive clinical and electrophysiological overlaps, the correct diagnosis of disorders with excessive daytime sleepiness is often challenging. The aim of this study was to provide diagnostic measures that help discriminating such disorders, and to identify parameters, which don't. In this single-center study, we retrospectively identified consecutive treatment-naïve patients who suffered from excessive daytime sleepiness, and analyzed clinical and electrophysiological measures in those patients in whom a doubtless final diagnosis could be made. Of 588 patients, 287 reported subjective excessive daytime sleepiness. Obstructive sleep apnea is the only disorder that could be identified by polysomnography alone. The diagnosis of insufficient sleep syndrome relies on actigraphy as patients underestimate their sleep need and the disorder shares several clinical and electrophysiological properties with both narcolepsy type 1 and idiopathic hypersomnia. Sleep stage sequencing on MSLT appears helpful to discriminate between insufficient sleep syndrome and narcolepsy. Sleep inertia is a strong indicator for idiopathic hypersomnia. There are no distinctive electrophysiological findings for the diagnosis of restless legs syndrome. Altogether, EDS disorders are common in neurological sleep laboratories, but usually cannot be diagnosed based on PSG and MSLT findings alone. The diagnostic value of actigraphy recordings can hardly be overestimated. PMID:26864219

  20. Residual sleepiness after N2O sedation: a randomized control trial [ISRCTN88442975

    Directory of Open Access Journals (Sweden)

    Lichtor J Lance

    2004-05-01

    Full Text Available Abstract Background Nitrous oxide (N2O provides sedation for procedures that result in constant low-intensity pain. How long do individuals remain sleepy after receiving N2O? We hypothesized that drug effects would be apparent for an hour or more. Methods This was a randomized, double blind controlled study. On three separate occasions, volunteers (N = 12 received 100% oxygen or 20% or 40% N2O for 30 min. Dependent measures included the multiple sleep latency test (MSLT, a Drug Effects/Liking questionnaire, visual analogue scales, and five psychomotor tests. Repeated measures analysis of variance was performed with drug and time as factors. Results During inhalation, drug effects were apparent based on the questionnaire, visual analogue scales, and psychomotor tests. Three hours after inhaling 100% oxygen or 20% N2O, subjects were sleepier than if they breathed 40% N2O. No other drug effects were apparent 1 hour after inhalation ceased. Patients did not demonstrate increased sleepiness after N2O inhalation. Conclusion We found no evidence for increased sleepiness greater than 1 hour after N2O inhalation. Our study suggests that long-term effects of N2O are not significant.

  1. Excessive daytime sleepiness in patients with ADHD--diagnostic and management strategies.

    Science.gov (United States)

    Bioulac, Stéphanie; Micoulaud-Franchi, Jean-Arthur; Philip, Pierre

    2015-08-01

    The links between attention-deficit hyperactivity disorder (ADHD) and sleep disorders remain unclear. Specific sleep disorders are a frequent comorbid condition associated with ADHD according to a categorical approach. However, sleep disorders can also induce ADHD-like symptoms according to a dimensional approach and are thought to be the consequence of excessive daytime sleepiness. It may thus be difficult for clinicians to differentiate the diagnosis of ADHD comorbid with a sleep disorder from sleep disorders with ADHD-like symptoms. This distinction could be important for the appropriate management of patients with dual complaints of trouble maintaining attention and daytime sleepiness. This paper summarizes the main sleep disorders associated with ADHD: sleep-related breathing disorders, sleep-related movement disorders, circadian rhythm sleep-wake disorders, and central disorders of hypersomnolence (aka hypersomnias). The history of presenting symptoms should be taken into account since ADHD is a neurodevelopmental disorder whereas ADHD symptoms comorbid with sleep disorder are not. Finally, we propose a model to clarify the links between ADHD, ADHD symptoms, and excessive daytime sleepiness induced by sleep disorders. Clinicians should therefore routinely assess, monitor, and manage the sleep problems of patients with ADHD who have both comorbidities and should search for the presence of ADHD symptoms in subjects with sleep disorders. PMID:26122671

  2. Sonolência e acidentes automobilísticos Sleepiness and motor vehicle accidents

    Directory of Open Access Journals (Sweden)

    SIMONE FAGONDES CANANI

    2001-03-01

    Full Text Available Objetivo: Este artigo tem por finalidade apresentar uma sucinta revisão sobre as repercussões da sonolência excessiva no desempenho dos motoristas no trânsito, enfatizando a necessidade da maior valorização do tema abordado. Métodos: Revisão bibliográfica da literatura nacional e internacional, abrangendo artigos originais e publicações oficiais da American Thoracic Society e da American Sleep Apnea Association. Resultados: As evidências de que a sonolência é um fator que pode contribuir de forma decisiva para a ocorrência de acidentes automobilísticos são crescentes. As dificuldades com relação à caracterização da sonolência precedendo o acidente são discutidas no texto. Muitas são as causas de sonolência excessiva; felizmente, sua maioria é passível de identificação e manejo adequado. Conclusões: É importante que haja maior entendimento do problema em nosso meio, para que possam ocorrer modificações na abordagem do paciente com sonolência excessiva e também discussões acerca das leis de trânsito vigentes e das obrigações legais do médico com relação a este problema.Objective: The purpose of this article is to present a brief review of the effects of excessive sleepiness on driving performance, and to emphasize the importance of the subject. Methods: Bibliographic review of national and international literature, including original articles and official publications from the American Thoracic Society and the American Sleep Apnea Association. Results: There is growing evidence that excessive sleepiness may be an important factor related to the occurrence of motor vehicle accidents. Difficulties regarding the identification of sleepiness as a preceding factor related to motor vehicle crashes are discussed on the text. There are many causes for excessive sleepiness. Fortunately most of them are easy to recognize and have specific treatment. Conclusions: A better understanding of the problem is fundamental

  3. Weight loss during tuberculosis treatment is an important risk factor for drug-induced hepatotoxicity

    NARCIS (Netherlands)

    Warmelink, Ina; ten Hacken, Nick H.; van der Werf, Tjip S.; van Altena, Richard

    2011-01-01

    The objective of this study was to determine the association between weight loss and drug-induced hepatotoxicity (DIH). A retrospective observational study of 192 active tuberculosis (TB) patients consecutively admitted in a tertiary referral TB centre in the Netherlands was conducted. The outcome m

  4. Spontaneous reports on drug-induced pancreatitis in Denmark from 1968 to 1999

    DEFF Research Database (Denmark)

    Andersen, V; Sonne, J; Andersen, M

    2001-01-01

    (measles" mumps/rubella) vaccination. CONCLUSION: Drug-induced pancreatitis is rarely reported. The incidence may be increasing and the course is often serious. This is the first report on definite simvastatin-induced pancreatitis. Further studies on the pancreotoxic potential of drugs are warranted....

  5. Drug-induced hepatotoxicity in a tertiary care hospital in Rural South India

    Directory of Open Access Journals (Sweden)

    Heethal Jaiprakash

    2012-01-01

    Full Text Available Background: Liver is the main organ for metabolism of drugs and hepatotoxicity is a potential adverse effect for most drugs. Aims: This study was to study the frequency of drug-induced hepatotoxicity and to find the common drugs causing hepatotoxicity. Materials and Methods: The study was conducted at a tertiary care hospital in rural India. It is a study based on case series analysis. All patients with an abnormal liver function report, between July 2006 and July 2007, were included in the study. Results : The study included 411 patients. Among them 141 patients were females and 270 males. The common cause for abnormal liver function was alcoholic liver disease (30.4% followed by drug-induced hepatotoxicity (15.8% and malaria (15.3%. Drug-induced hepatotoxicity was seen in 65 patients. It was common in males (55% compared to females (44%. The mean age of the patients with drug-induced hepatotoxicity was 43±15.9. Antitubercular drugs were the commonly encountered drugs (44% causing hepatotoxicity followed by lipid lowering agents (41%. The others drugs included antiretroviral drugs (6%,steroids (5% and chlorpromazine (2%. Conclusion : A thorough history of drug intake must be taken in all patients presenting with abnormal hepatic function.

  6. Drug-induced liver toxicity and prevention by herbal antioxidants: an overview

    Directory of Open Access Journals (Sweden)

    Divya eSingh

    2016-01-01

    Full Text Available The liver is the center for drug and xenobiotic metabolism, which is influenced most with medication/xenobiotic-mediated toxic activity. Drug-induced hepatotoxicity is common and its actual frequency is hard to determine due to underreporting, difficulties in detection or diagnosis, and incomplete observation of exposure. The death rate is high, up to about 10% for medication instigated liver danger. Endorsed medications (counting acetaminophen represented >50% of instances of intense liver failure in a study from the Acute Liver Failure Study Group (ALFSG of the patients admitted in 17 US healing facilities. Albeit different studies are accessible uncovering the mechanistic aspects of medication prompted hepatotoxicity, we are in the dilemma about the virtual story. The expanding prevalence and effectiveness of Ayurveda and herbal products in the treatment of various disorders led the investigators to look into their potential in countering drug-induced liver toxicity. Several plant products have been reported to date to mitigate the drug-induced toxicity. The dietary nature and less side reactions of the herbs provide them an extra edge over other candidates of supplementary medication. In this paper, we have discussed on the mechanism involved in drug-induced liver toxicity and the potential of herbal antioxidants as supplementary medication.

  7. Interdisciplinary management of a patient with a drug-induced gingival hyperplasia.

    Science.gov (United States)

    Devanna, Raghu; Asif, K

    2010-07-01

    Interdisciplinary treatment is becoming an ever-increasing part of modern-day orthodontic practice. This case report details the successful orthodontic-periodontal management of an epileptic patient with a significant drug-induced gingival hyperplasia. The problems that such patient's present are discussed before considering the specific orthodontic techniques employed. Recommendations are made for practitioners managing such cases.

  8. Interdisciplinary management of a patient with a drug-induced gingival hyperplasia

    OpenAIRE

    Raghu Devanna; K Asif

    2010-01-01

    Interdisciplinary treatment is becoming an ever-increasing part of modern-day orthodontic practice. This case report details the successful orthodontic-periodontal management of an epileptic patient with a significant drug-induced gingival hyperplasia. The problems that such patient's present are discussed before considering the specific orthodontic techniques employed. Recommendations are made for practitioners managing such cases.

  9. Genetic Determinants of Drug-induced Cholestasis and Intrahepatic Cholestasis of Pregnancy

    NARCIS (Netherlands)

    C. Pauli-Magnus; P.J. Meier; B. Stieger

    2010-01-01

    Intrahepatic cholestasis of pregnancy and drug-induced cholestasis are two clinically important forms of acquired cholestatic liver disease. The understanding of the underlying mechanisms of acquired cholestasis has recently made considerable progress by the identification of canalicular ATP-binding

  10. Psychosocial work characteristics predicting daytime sleepiness in day and shift workers.

    Science.gov (United States)

    Takahashi, Masaya; Nakata, Akinori; Haratani, Takashi; Otsuka, Yasumasa; Kaida, Kosuke; Fukasawa, Kenji

    2006-01-01

    Characteristics of work organization other than working time arrangements may contribute importantly to daytime sleepiness. The present study was designed to identify the psychosocial factors at work that predict daytime sleepiness in a sample of day and shift workers. Participants working at a pulp and chemical factory completed an annual questionnaire regarding psychosocial factors at work using the U.S. National Institute for Occupational Safety and Health Generic Job Stress Questionnaire (i.e., quantitative workload, variance in workload, job control, support from supervisor, coworkers, or family/friends, job satisfaction, and depressive symptoms), as well as daytime sleepiness (through the Epworth Sleepiness Scale [ESS]) and sleep disturbances for three years starting in 2002 (response rates, 94.6-99.0%). The present analysis included 55 day workers (11 women) and 57 shift workers (all men) who participated in all three years of the study, worked under the same work schedule throughout the study period, and had no missing data on any of the daytime sleep items. A repeated-measures analysis of covariance (ANCOVA) was used to test the effects of work schedule (day vs. shift work) and psychosocial factors at work in 2002 on the ESS scores in subsequent years, with sleep duration, insomnia symptoms, chronic diseases, and sleepiness levels at baseline as covariates. Given significant and near-significant interactions of work schedules with psychosocial factor or study year, the ANCOVA, with the factors of psychosocial work characteristics and study year, was performed by type of work schedule. The results indicated a significant main effect of psychosocial work characteristics (p = 0.010, partial eng2 = 0.14) and an almost significant main effect of study year (p = 0.067, partial eng2 = 0.06) and interaction between psychosocial work characteristics and study year (p = 0.085, partial eng2 = 0.06) for variance in workload among the day work group. The day workers

  11. Quantitative measurement of handwriting in the assessment of drug-induced parkinsonism.

    Science.gov (United States)

    Caligiuri, Michael P; Teulings, Hans-Leo; Filoteo, J Vincent; Song, David; Lohr, James B

    2006-10-01

    Monitoring drug-induced side effects is especially important for patients who undergo treatment with antipsychotic medications, as these drugs often produce extrapyramidal side effects (EPS) resulting in movement abnormalities similar to parkinsonism. Scientists have developed several objective laboratory tests to measure and research drug-induced movement disorders, but equipment and tests are complex and costly and have not become accepted in large-scale, multi-site clinical trials. The goals of this study were to test whether a simple handwriting measure can discriminate between individuals with psychotropic-induced parkinsonism, Parkinson's disease, and healthy individuals, and to examine some of the psychometric properties of the measure. We examined pen movement kinematics during cursive writing of a standard word in 13 patients with idiopathic Parkinson's disease (PD), 10 schizophrenia patients with drug-induced parkinsonism (SZ), and 12 normal healthy control participants (NC). Participants were instructed to write the word "hello" in cursive twice, at three vertical height scales. Software was used for data acquisition and analysis of vertical stroke velocities, velocity scaling, and smoothness. There were four important results from this study: (1) both SZ patients with drug-induced EPS and PD participants exhibited impaired movement velocities and velocity scaling; (2) performance on the velocity scaling measure distinguished drug-induced EPS from normal with 90% accuracy; (3) SZ, but not PD participants displayed abnormalities in movement smoothness; and (4) there was a positive correlation between age and magnitude of the velocity scaling deficit in PD participants. This study demonstrates that kinematic analyses of pen movements during handwriting may be useful in detecting and monitoring subtle changes in motor control related to the adverse effects of psychotropic medications. PMID:16647772

  12. THE APPLICATION OF HEMATOPOIETIC GROWTH-FACTORS IN DRUG-INDUCED AGRANULOCYTOSIS - A REVIEW OF 70 CASES

    NARCIS (Netherlands)

    SPRIKKELMAN, A; DEWOLF, JTM; VELLENGA, E

    1994-01-01

    Since 1989, granulocyte-macrophage and granulocyte colony-stimulating factors (GM-CSF, G-CSF) have been increasingly applied in the treatment of drug-induced agranulocytosis. In order to evaluate the effectiveness of GM-CSF and G-CSF in the treatment of drug-induced agranulocytosis, we have studied

  13. 78 FR 5817 - Detecting and Evaluating Drug-Induced Liver Injury; What's Normal, What's Not, and What Should We...

    Science.gov (United States)

    2013-01-28

    ...: Premarketing Clinical Evaluation'' (74 FR 38035; July 30, 2009). This guidance explained that drug-induced... Normal, What's Not, and What Should We Do About It?; Public Conference; Request for Comments AGENCY: Food... Evaluating Drug-Induced Liver Injury; What's Normal, What's Not, and What Should We Do About It?''...

  14. The prevalence of excessive daytime sleepiness among academic physicians and its impact on the quality of life and occupational performance

    Directory of Open Access Journals (Sweden)

    Aclan Ozder

    2015-08-01

    Full Text Available Objectives: Sleep disorders can affect health and occupational performance of physicians as well as outcomes in patients. The purpose of this study was to assess the prevalence of excessive daytime sleepiness (EDS measured by the Epworth Sleepiness Scale (ESS among academic physicians at a tertiary academic medical center in an urban area in the northwest region of Turkey, and to establish a relationship between the self-perceived sleepiness and the quality of life using the EuroQol-5 dimensions (EQ-5D. Material and Methods: A questionnaire prepared by the researchers after scanning the literature on the subject was e-mailed to the academic physicians of a tertiary academic medical center in Istanbul. The ESS and the EQ-5D were also included in the survey. The e-mail database of the institution directory was used to compile a list of active academic physicians who practiced clinical medicine. Paired and independent t tests were used for the data analysis at a significance level of p 10 (p < 0.001. In the case of the EQ-5D index and visual analogue scale of the EQ-5D questionnaire (EQ-5D VAS, the status of sleepiness of academic physicians was associated with a poorer quality of life (p < 0.001. Conclusions: More than a 1/4 of the academic physicians suffered from sleepiness. There was an association between the poor quality of life and daytime sleepiness. There was also a positive relationship between habitual napping and being sleepy during the day.

  15. Insomnia, Excessive Sleepiness, Excessive Fatigue, Anxiety, Depression and Shift Work Disorder in Nurses Having Less than 11 Hours in-Between Shifts

    OpenAIRE

    Maria Fagerbakke Eldevik; Elisabeth Flo; Bente Elisabeth Moen; Ståle Pallesen; Bjørn Bjorvatn

    2013-01-01

    STUDY OBJECTIVE: To assess if less than 11 hours off work between work shifts (quick returns) was related to insomnia, sleepiness, fatigue, anxiety, depression and shift work disorder among nurses. METHODS: A questionnaire including established instruments measuring insomnia (Bergen Insomnia Scale), sleepiness (Epworth Sleepiness Scale), fatigue (Fatigue Questionnaire), anxiety/depression (Hospital Anxiety and Depression Scale) and shift work disorder was administered. Among the 1990 Norwegia...

  16. Epworth's sleepiness scale in outpatients with different values of arterial blood pressure

    Directory of Open Access Journals (Sweden)

    Gus Miguel

    2002-01-01

    Full Text Available OBJECTIVE: To compare sleepiness scores of the Epworth scale in patients with different levels of arterial pressure when undergoing outpatient monitoring within the context of clinical evaluation. METHODS: A total of 157 patients selected for outpatient monitoring of arterial pressure during hypertension evaluation were divided into 3 groups: group 1 - normotensive; group 2 - hypertensive; group 3 - resistant hypertensive. For analysis, values > or = 11 were considered as associated with respiratory disturbances during sleep. RESULTS: Seventeen (10.8% patients in group 1, 112 (71.3% in group 2, and 28 (17.8% in group 3, which was composed of aged, more severely hypertensive individuals, were analyzed. Groups were similar relative to sex and body mass index, but different in relation to systolic and diastolic pressure levels and age. Despite an absolute difference, no statistically significant difference occurred between Epworth scores and in the proportion of patients with values > or = 11 (5.9% vs. 18.8% vs. 212.4%; P=0.37. Despite the positive association between degree of sleepiness measured with the scale and the severity of the hypertension, no statistical significance occurred following control by age (p=0.18. CONCLUSION: A positive correlation exists between degree of sleepiness and hypertension severity. The absence of a statistical significance shown in the present study could be due to a beta type of error. Instruments that render this complaint into an objective finding could help in the pursuit of an investigation of respiratory disturbances during sleep in more severely hypertensive patients, and should therefore be studied better.

  17. Effects of driver behavior style differences and individual differences on driver sleepiness detection

    Directory of Open Access Journals (Sweden)

    Keyong Li

    2015-04-01

    Full Text Available Driving sleepiness is still a major causes of traffic accidents. Individual drivers, under various conditions, act and respond in different manners. This article presents the attempt of a straight-line driving simulator study that examined the effects of driver behavior style differences and individual differences on driver sleepiness detection which is based on driving performance measures. A total of 15 drivers who were classified into two categories through subjective assessment based on a Driver Behavior Questionnaire participated in driving simulator experiments. A total of 18 detection models, including 15 SE models for each subject, an A model for the aggressive drivers, an NA model for the non-aggressive drivers, and a G model for all experiment participants, were developed using support vector machine method based on driving performance characteristic parameters. The results show that the G model is not suitable for all drivers due to its lower mean accuracy of 69.88% (standard deviation = 7.70% and higher standard deviation. The SE models for each subject show the best detection accuracy performance of 84.26% (standard deviation = 5.38%; however, it is impossible to set up a special detection model for every individual driver. The SD models on different style categories show an accuracy value of 77.54% (standard deviation = 5.78%. The results demonstrate that driver style differences as well as individual differences have great effects on driver sleepiness detection (F = 19.148, p < 0.000.

  18. Frequency of Burnout, Sleepiness and Depression in Emergency Medicine Residents with Medical Errors in the Emergency Department

    Directory of Open Access Journals (Sweden)

    Alireza Aala

    2014-07-01

    Full Text Available Aims: Medical error is a great concern of the patients and physicians. It usually occurs due to physicians’ exhaustion, distress and fatigue. In this study, we aimed to evaluate frequency of distress and fatigue among emergency medicine residents reporting a medical error.Materials and Methods: The study population consisted of emergency medicine residents who completed an emailed questionnaire including self-assessment of medical errors, the Epworth Sleepiness Scale (ESS score, the Maslach Burnout Inventory, and PRIME-MD validated depression screening tool.  Results: In this survey, 100 medical errors were reported including diagnostic errors in 53, therapeutic errors in 24 and following errors in 23 subjects. Most errors were reported by males and third year residents. Residents had no signs of depression, but all had some degrees of sleepiness and burnout. There were significant differences between errors subtypes and age, residency year, depression, sleepiness and burnout scores (p<0.0001.  Conclusion: In conclusion, residents committing a medical error usually experience burnout and have some grades of sleepiness that makes them less motivated increasing the probability of medical errors. However, as none of the residents had depression, it could be concluded that depression has no significant role in medical error occurrence and perhaps it is a possible consequence of medical error.  Keywords: Residents; Medical error; Burnout; Sleepiness; Depression

  19. Rotating shift work, sleep, and accidents related to sleepiness in hospital nurses

    Science.gov (United States)

    Gold, D. R.; Rogacz, S.; Bock, N.; Tosteson, T. D.; Baum, T. M.; Speizer, F. E.; Czeisler, C. A.

    1992-01-01

    A hospital-based survey on shift work, sleep, and accidents was carried out among 635 Massachusetts nurses. In comparison to nurses who worked only day/evening shifts, rotators had more sleep/wake cycle disruption and nodded off more at work. Rotators had twice the odds of nodding off while driving to or from work and twice the odds of a reported accident or error related to sleepiness. Application of circadian principles to the design of hospital work schedules may result in improved health and safety for nurses and patients.

  20. Drug-induced long QT syndrome increases the risk of drowning.

    Science.gov (United States)

    Vincenzi, Frank F

    2016-02-01

    There is strong evidence linking inherited long QT syndromes with an increased risk of drowning due to fatal arrhythmias in the water. Drug-induced long QT syndrome (DILQTS) is hypothesized to increase the risk of drowning by similar mechanisms. It is suggested that QT prolongation caused by a drug or drugs, when combined with the autonomic conflict associated with the mammalian dive reflex and/or the cold shock reflex, sets up conditions that may result in a sudden fatal arrhythmia while in water - thus an increased risk of drowning related to a drug-induced prolongation of the QT interval. Many widely used drugs prolong the QT interval thus raising a drug safety issue that needs confirmation or refutation.

  1. Factors affecting drug-induced liver injury: antithyroid drugs as instances.

    Science.gov (United States)

    Heidari, Reza; Niknahad, Hossein; Jamshidzadeh, Akram; Abdoli, Narges

    2014-09-01

    Methimazole and propylthiouracil have been used in the management of hyperthyroidism for more than half a century. However, hepatotoxicity is one of the most deleterious side effects associated with these medications. The mechanism(s) of hepatic injury induced by antithyroid agents is not fully recognized yet. Furthermore, there are no specific tools for predicting the occurrence of hepatotoxicity induced by these drugs. The purpose of this article is to give an overview on possible susceptibility factors in liver injury induced by antithyroid agents. Age, gender, metabolism characteristics, alcohol consumption, underlying diseases, immunologic mechanisms, and drug interactions are involved in enhancing antithyroid drugs-induced hepatic damage. An outline on the clinically used treatments for antithyroid drugs-induced hepatotoxicity and the potential therapeutic strategies found to be effective against this complication are also discussed.

  2. Drug-induced Hepatotoxicity of Anti-tuberculosis Drugs and Their Serum Levels

    OpenAIRE

    Jeong, Ina; Park, Jong-Sun; Cho, Young-Jae; Yoon, Ho Il; Song, Junghan; Lee, Choon-Taek; Lee, Jae-Ho

    2015-01-01

    The correlation between serum anti-tuberculosis (TB) drug levels and the drug-induced hepatotoxicity (DIH) remains unclear. The purpose of this study was to investigate whether anti-TB DIH is associated with basal serum drug levels. Serum peak levels of isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB) were analyzed in blood samples 2 hr after the administration of anti-TB medication. Anti-TB DIH and mild liver function test abnormality were diagnosed on the basis of...

  3. Antituberculosis Drug-Induced Hepatotoxicity in IranianTuberculosis Patients: Role of Isoniazid Metabolic Polymorphism

    OpenAIRE

    Sistanizad, Mohammad; Azizi, Ebrahim; KHALILI, Hosein; Hajiabdolbaghi, Mahboobeh; Gholami, Kheirollah; Mahjub, Reza

    2011-01-01

    The aim of this study was to determine the association of n-acetyltransferase-2 polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in Iranian pulmonary tuberculosis patients. Acetylating phenotypes was studied in 50 Iranian pulmonary tuberculosis patients using metabolic ratio of plasma acetyl-Isoniazid to Isoniazid. The association between hepatotoxicity and the n-acetyltransferase-2 phenotype was evaluated by using the chi-square (x2) test. The metabolic ratio had a bimodal dis...

  4. Drug-Induced Myocardial Infarction Secondary to Coronary Artery Spasm in Teenagers and Young Adults

    Directory of Open Access Journals (Sweden)

    Menyar Ayman

    2006-01-01

    Full Text Available There is no published registry for drug-induced acute myocardial infarction (AMI with subsequent patent coronary angiogram in teenagers. To highlight the mechanism and impact of drug-induced MI with patent coronary arteries among teenagers who have relatively few coronary risk factors in comparison with older patients, we conducted a review of the literature. In this review most of the pertinent published (English and non-English articles through the Medline, Scopus, Cochrane Database of Systematic Reviews, and EBSCO Host research databases from 1970 to 2005 have been revised. Teenagers and young adults with AMI and subsequent patent coronary angiogram were included. In those cases drug-induced coronary spasm was highlighted. Among 220 articles (>12000 cases related with AMI with normal coronary angiogram, 50 articles (~100 cases reported the role of drug in AMI secondary to coronary artery spasm (CAS. There is no well-conducted trial for AMI secondary to CAS in young adults but only a series of case reports, and the diagnosis in most of cases was based on the clinical and laboratory findings without provocation. CAS was associated with 12 illicit substances in teenagers (i.e., cocaine, marijuana, alcohol, butane, and amphetamine. Smoking is not only the initiative but also might harbor other illicit substances that increase the risk for CAS. Cocaine-associated AMI is the most frequent in various research papers. CAS was reported with 19 types of medications (i.e., over-the-counter, chemotherapy, antimigraine, and antibiotics without strong relation to age. Despite drug-induced AMI being not a common event, attention to smoking and drugs in teenagers and young adults will have major therapeutic and prognostic implications.

  5. Drug-induced liver toxicity and prevention by herbal antioxidants: an overview

    OpenAIRE

    Divya eSingh; William eCho; Ghanshyam eUpadhyay

    2016-01-01

    The liver is the center for drug and xenobiotic metabolism, which is influenced most with medication/xenobiotic-mediated toxic activity. Drug-induced hepatotoxicity is common and its actual frequency is hard to determine due to underreporting, difficulties in detection or diagnosis, and incomplete observation of exposure. The death rate is high, up to about 10% for medication instigated liver danger. Endorsed medications (counting acetaminophen) represented >50% of instances of intense liver ...

  6. Chinese Skullcap in Move Free Arthritis Supplement Causes Drug Induced Liver Injury and Pulmonary Infiltrates

    OpenAIRE

    Renumathy Dhanasekaran; Victoria Owens; William Sanchez

    2013-01-01

    Herbal medications are being increasingly used by the American population especially for common conditions like arthritis. They have been reported to cause adverse effects, including significant hepatotoxicity, but reporting remains sporadic. We report here a patient who developed drug induced liver injury following the intake of Move Free, which is an over-the-counter arthritis supplement. We propose that Chinese skullcap, which is one of the herbal ingredients of the medication, is responsi...

  7. Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria

    OpenAIRE

    Han, Derick; Dara, Lily; Win, Sanda; Than, Tin Aung; Yuan, Liyun; Abbasi, Sadeea Q; Liu, Zhang-Xu; Kaplowitz, Neil

    2013-01-01

    Drugs that cause liver injury often “stress” mitochondria and activate signal transduction pathways important in determining cell survival or death. In most cases, hepatocytes adapt to the drug-induced stress by activating adaptive signaling pathways, such as mitochondrial adaptive responses and erythroid 2-related factor 2 (Nrf-2), a transcription factor that upregulates antioxidant defenses. Due to adaptation, drugs alone rarely cause liver injury, with acetaminophen being the notable excep...

  8. Interdisciplinary management of a patient with a drug-induced gingival hyperplasia

    Directory of Open Access Journals (Sweden)

    Raghu Devanna

    2010-01-01

    Full Text Available Interdisciplinary treatment is becoming an ever-increasing part of modern-day orthodontic practice. This case report details the successful orthodontic-periodontal management of an epileptic patient with a significant drug-induced gingival hyperplasia. The problems that such patient′s present are discussed before considering the specific orthodontic techniques employed. Recommendations are made for practitioners managing such cases.

  9. Prevalence and Complications of Drug-induced Seizures in Baharloo Hospital, Tehran, Iran

    Directory of Open Access Journals (Sweden)

    Behnam Behnoush

    2012-05-01

    Full Text Available Background: Seizure is a frequent and important finding in the field of clinical toxicology. Almost all poisons and drugs can produce seizure. We have evaluated frequency and complications of drug-induced seizure in present study. Methods: The present descriptive cross-sectional study was done on patients who were referred to Baharloo Hospital, Tehran, Iran, that had developed seizure before or after hospitalization following intoxication between 20 March 2010 and 20 March 2011. The exclusion criteria were a positive history of epilepsy, head trauma, or abnormal findings in EEG or brain CT scan. Results: Tramadol and tricyclic antidepressants were the most common causes of drug-induced seizure (31.5% and 14.7% of the cases, respectively. Overall, 6 patients (4.2% had developed persistent vegetative state in consequence of brain hypoxia, 16 patients (11.2% had died due to complications of seizure or the poisoning itself. Tramadol was the leading cause of drug-induced seizure and its morbidity and mortality. Tonic-colonic seizure was the most common type of drug-induced seizure. Seizure had occurred once in 58% of the patients, twice in 37.1% of the patients, and had been revolutionized to status epilepticus in 4.9% of them. Among the 7 patients who had developed status epilepticus, 3 cases had died. Conclusion: Appropriate measures for treatment of seizure and prevention of its complications should be taken when patients with drug poisoning are admitted into hospital, especially when the offending drug(s has a higher likelihood to induce seizure.

  10. The Role of Bile Salt Export Pump Gene Repression in Drug-Induced Cholestatic Liver Toxicity

    OpenAIRE

    Garzel, Brandy; Yang, Hui; Zhang, Lei; Huang, Shiew-Mei; Polli, James E.; Wang, Hongbing

    2014-01-01

    The bile salt export pump (BSEP, ABCB11) is predominantly responsible for the efflux of bile salts, and disruption of BSEP function is often associated with altered hepatic homeostasis of bile acids and cholestatic liver injury. Accumulating evidence suggests that many drugs can cause cholestasis through interaction with hepatic transporters. To date, a relatively strong association between drug-induced cholestasis and attenuated BSEP activity has been proposed. However, whether repression of...

  11. Role of membrane transport in hepatotoxicity and pathogenesis of drug-induced cholestasis

    OpenAIRE

    Stieger, Bruno; Kullak-Ublick, Gerd A.

    2013-01-01

    Drug-induced liver injury is an important clinical entity, which can be grouped into cholestatic liver injury, hepatocellular liver injury, and mixed liver injury. Cholestatic liver injury is characterized by a reduction in bile flow and the retention within hepatocytes of cholephilic compounds such as bile salts that cause hepatotoxicity. Bile salts are taken up by hepatocytes in a largely sodium-dependent manner and to a lesser extent in a sodium-independent manner. The former process is...

  12. Genetic determinants of drug-induced cholestasis and intrahepatic cholestasis of pregnancy

    OpenAIRE

    Pauli-Magnus, Christiane; Meier, Peter J; Stieger, Bruno

    2010-01-01

    Intrahepatic cholestasis of pregnancy and drug-induced cholestasis are two clinically important forms of acquired cholestatic liver disease. The understanding of the underlying mechanisms of acquired cholestasis has recently made considerable progress by the identification of canalicular ATP-binding cassette (ABC) transporters as likely targets for these forms of cholestasis. Cholestasis of pregnancy is linked to estrogen and progesterone metabolites. These metabolites have been shown to impa...

  13. Drug-induced lung disease: High-resolution CT and histological findings

    Energy Technology Data Exchange (ETDEWEB)

    Cleverley, Joanne R.; Screaton, Nicholas J.; Hiorns, Melanie P.; Flint, Julia D.A.; Mueller, Nestor L

    2002-04-01

    AIM: To compare the parenchymal high-resolution computed tomography (HRCT) appearances with histological findings in patients with drug-induced lung disease and to determine the prognostic value of HRCT. MATERIALS AND METHODS: Drug history, HRCT features, histological findings and outcome at 3 months in 20 patients with drug induced-lung disease were reviewed retrospectively. The HRCT images were assessed for the pattern and distribution of abnormalities and classified as most suggestive of interstitial pneumonitis/fibrosis, diffuse alveolar damage (DAD), organizing pneumonia (OP) reaction, or a hypersensitivity reaction. RESULTS: On histopathological examination there were eight cases of interstitial pneumonitis/fibrosis, five of DAD, five of OP reactions, one of hypersensitivity reaction and one of pulmonary eosinophilia. The most common abnormalities on HRCT were ground-glass opacities (n = 17), consolidation (n = 14), interlobular septal thickening (n = 15) and centrilobular nodules (n 8). HRCT interpretation and histological diagnosis were concordant in only nine (45%) of 20 patients. The pattern, distribution, and extent of HRCT abnormalities were of limited prognostic value: all eight patients with histological findings of OP, hypersensitivity reaction, or eosinophilic infiltrate improved on follow-up compared to only five of 13 patients with interstitial pneumonitis/fibrosis or DAD. CONCLUSION: In many cases of drug-induced lung injury HRCT is of limited value in determining the histological pattern and prognosis. Cleverly, J.R. et al.

  14. In silico Prediction of Drug Induced Liver Toxicity Using Substructure Pattern Recognition Method.

    Science.gov (United States)

    Zhang, Chen; Cheng, Feixiong; Li, Weihua; Liu, Guixia; Lee, Philip W; Tang, Yun

    2016-04-01

    Drug-induced liver injury (DILI) is a leading cause of acute liver failure in the US and less severe liver injury worldwide. It is also one of the major reasons of drug withdrawal from the market. Thus, DILI has become one of the most important concerns of drugs, and should be predicted in very early stage of drug discovery process. In this study, a comprehensive data set containing 1317 diverse compounds was collected from publications. Then, high accuracy classification models were built using five machine learning methods based on MACCS and FP4 fingerprints after evaluating by substructure pattern recognition method. The best model was built using SVM method together with FP4 fingerprint at the IG value threshold of 0.0005. Its overall predictive accuracies were 79.7 % and 64.5 % for the training and test sets, separately, which yielded overall accuracy of 75.0 % for the external validation dataset, consisting of 88 compounds collected from a benchmark DILI database - the Liver Toxicity Knowledge Base. This model could be used for drug-induced liver toxicity prediction. Moreover, some key substructure patterns correlated with drug-induced liver toxicity were also identified as structural alerts. PMID:27491923

  15. Clinical analysis of 275 cases of acute drug-induced liver disease

    Institute of Scientific and Technical Information of China (English)

    LI Lei; JIANG Wei; WANG Jiyao

    2007-01-01

    In order to analyze the causative drugs,clinical manifestation and pathological characteristics of the patients with acute drug-induced liver disease,from January 2000 to December 2005,275 cases diagnosed as acute druginduced liver diseases according to Maria Criterion and hospitalized in Zhongshan Hospital of Fudan University were retrospectively reviewed.Each was determined by drug history,clinical symptoms and signs,laboratory tests and therapeutic effects.In 41 cases,the diagnosis was confirmed by liver biopsy.The proportion of acute drug-induced liver disease among all of the acute liver injuries was annually increased.The most common drugs which induced acute liver injuries were traditional Chinese herb medicine (23.3 %,64/275 cases),antineoplastics (15.3%,42/275),hormones and other immunosuppressant agents (13.8%,38/275),antihypertensive drugs and other cardiovascular drugs (10.2 %,28/275),NSAIDs (8.7%,24/275) respectively.Hepatocellular injury was the predominant type in these cases (132 cases,48%).The principal clinical manifestation included nausea (54.8%),fatigue (50.2%),jaundice (35.6%).27.9% patients were asymptomatic.Most patients were cured with good prognosis.The total effective rate was 94.2% after treatment.The clinicians should pay attention to the prevention,diagnosis and therapy of drug-induced liver disease.

  16. Assessment of mitochondrial dysfunction-related, drug-induced hepatotoxicity in primary rat hepatocytes.

    Science.gov (United States)

    Liu, Cong; Sekine, Shuichi; Ito, Kousei

    2016-07-01

    Evidence that mitochondrial dysfunction plays a central role in drug-induced liver injury is rapidly accumulating. In contrast to physiological conditions, in which almost all adenosine triphosphate (ATP) in hepatocytes is generated in mitochondria via aerobic respiration, the high glucose content and limited oxygen supply of conventional culture systems force primary hepatocytes to generate most ATP via cytosolic glycolysis. Thus, such anaerobically poised cells are resistant to xenobiotics that impair mitochondrial function, and are not suitable to identify drugs with mitochondrial liabilities. In this study, primary rat hepatocytes were cultured in galactose-based medium, instead of the conventional glucose-based medium, and in hyperoxia to improve the reliance of energy generation on aerobic respiration. Activation of mitochondria was verified by diminished cellular lactate release and increased oxygen consumption. These conditions improved sensitivity to the mitochondrial complex I inhibitor rotenone. Since oxidative stress is also a general cause of mitochondrial impairment, cells were exposed to test compounds in the presence of transferrin to increase the generation of reactive oxygen species via increased uptake of iron. Finally, 14 compounds with reported mitochondrial liabilities were tested to validate this new drug-induced mitochondrial toxicity assay. Overall, the culture of primary rat hepatocytes in galactose, hyperoxia and transferrin is a useful model for the identification of mitochondrial dysfunction-related drug-induced hepatotoxicity. PMID:27095095

  17. An Overview on the Proposed Mechanisms of Antithyroid Drugs-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Reza Heidari

    2015-03-01

    Full Text Available Drug-induced liver injury (DILI is a major problem for pharmaceutical industry and drug development. Mechanisms of DILI are many and varied. Elucidating the mechanisms of DILI will allow clinicians to prevent liver failure, need for liver transplantation, and death induced by drugs. Methimazole and propylthiouracil (PTU are two convenient antithyroid agents which their administration is accompanied by hepatotoxicity as a deleterious side effect. Although several cases of antithyroid drugs-induced liver injury are reported, there is no clear idea about the mechanism(s of hepatotoxicity induced by these medications. Different mechanisms such as reactive metabolites formation, oxidative stress induction, intracellular targets dysfunction, and immune-mediated toxicity are postulated to be involved in antithyroid agents-induced hepatic damage. Due to the idiosyncratic nature of antithyroid drugs-induced hepatotoxicity, it is impossible to draw a specific conclusion about the mechanisms of liver injury. However, it seems that reactive metabolite formation and immune-mediated toxicity have a great role in antithyroids liver toxicity, especially those caused by methimazole. This review attempted to discuss different mechanisms proposed to be involved in the hepatic injury induced by antithyroid drugs.

  18. An overview on the proposed mechanisms of antithyroid drugs-induced liver injury.

    Science.gov (United States)

    Heidari, Reza; Niknahad, Hossein; Jamshidzadeh, Akram; Eghbal, Mohammad Ali; Abdoli, Narges

    2015-03-01

    Drug-induced liver injury (DILI) is a major problem for pharmaceutical industry and drug development. Mechanisms of DILI are many and varied. Elucidating the mechanisms of DILI will allow clinicians to prevent liver failure, need for liver transplantation, and death induced by drugs. Methimazole and propylthiouracil (PTU) are two convenient antithyroid agents which their administration is accompanied by hepatotoxicity as a deleterious side effect. Although several cases of antithyroid drugs-induced liver injury are reported, there is no clear idea about the mechanism(s) of hepatotoxicity induced by these medications. Different mechanisms such as reactive metabolites formation, oxidative stress induction, intracellular targets dysfunction, and immune-mediated toxicity are postulated to be involved in antithyroid agents-induced hepatic damage. Due to the idiosyncratic nature of antithyroid drugs-induced hepatotoxicity, it is impossible to draw a specific conclusion about the mechanisms of liver injury. However, it seems that reactive metabolite formation and immune-mediated toxicity have a great role in antithyroids liver toxicity, especially those caused by methimazole. This review attempted to discuss different mechanisms proposed to be involved in the hepatic injury induced by antithyroid drugs.

  19. Immunoexpression of interleukin-6 in drug-induced gingival overgrowth patients

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    P R Ganesh

    2016-01-01

    Full Text Available Background: To analyze the role of proinflammatory cytokines in drug-induced gingival enlargement in Indian population. Aim: To evaluate for the presence of interleukin-6 (IL-6 in drug-induced gingival enlargement and to compare it with healthy control in the absence of enlargement. Materials and Methods: Thirty-five patients selected for the study and divided into control group (10 and study group (25 consisting of phenytoin (10; cyclosporin (10 and nifedipine (5 induced gingival enlargement. Gingival overgrowth index of Seymour was used to assess overgrowth and allot groups. Under LA, incisional biopsy done, tissue sample fixed in 10% formalin and immunohistochemically evaluated for the presence of IL-6 using LAB-SA method, Labeled- Streptavidin-Biotin Method (LAB-SA kit from Zymed- 2nd generation LAB-SA detection system, Zymed Laboratories, CA. The results of immunohistochemistry were statistically analyzed using Kruskaal–Wallis and Mann–Whitney test. Results: The data obtained from immunohistochemistry assessment shows that drug-induced gingival overgrowth (DIGO samples express more IL-6 than control group and cyclosporin expresses more IL-6 followed by phenytoin and nifedipine. Conclusion: Increased IL-6 expression was noticed in all three DIGO groups in comparison with control group. Among the study group, cyclosporin expressed maximum IL-6 expression followed by phenytoin and nifedipine.

  20. Subjective sleep quality and daytime sleepiness in late midlife and their association with age-related changes in cognition

    DEFF Research Database (Denmark)

    Waller, Katja Linda; Mortensen, Erik Lykke; Avlund, Kirsten;

    2016-01-01

    UNLABELLED: In an increasingly aged population, sleep disturbances and neurodegenerative disorders have become a major public health concern. Poor sleep quality and cognitive changes are complex health problems in aging populations that are likely to be associated with increased frailty, morbidity......, and mortality, and to be potential risk factors for further cognitive impairment. We aimed to evaluate whether sleep quality and excessive daytime sleepiness may be considered as early predictors of cognitive impairment. STUDY OBJECTIVES: The objective of this study was to examine whether subjective sleep......) or cognitively impaired (N = 92). METHODS: The Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale measured subjective sleep quality and daytime sleepiness, respectively. Depressive symptoms were determined using Beck's Depression Inventory (BDI-II). A neuropsychological battery was administered...

  1. Using saliva nitrite and nitrate levels as a biomarker for drug induced gingival overgrowth

    Directory of Open Access Journals (Sweden)

    Erkan eSukuroglu

    2015-12-01

    Full Text Available Aim: Drug-induced gingival overgrowth has a multifactorial nature and the pathogenesis is still uncertain. It has been suggested that Nitric Oxide (NO might play a role in the pathogenesis of drug-induced gingival overgrowth due to the contribution of NO to immune response and matrix degradation. NO levels in biological fluids have been used as a diagnostic biomarker in many diseases. The aim of this study is to determine whether NO levels in plasma, saliva and gingival crevicular fluid (GCF can serve as a potential biomarker for the evaluation of drug-induced gingival overgrowth risk. Material and Methods: A total of 104 patients, receiving cyclosporine A (n=35, phenytoin (n=25, nifedipine (n=26 or diltiazem (n=18 participated in the study. The amount of gingival overgrowth was evaluated with two indices and was given as percentage. Periodontal clinical parameters including plaque index (PI, gingival index (GI, gingival bleeding time index (GBTI and probing depth (PD were also assessed. Saliva, GCF and plasma samples were obtained from each participants. Nitrite and nitrate levels in saliva, GCF and plasma were analyzed by Griess reagent. Results: Salivary nitrite and nitrate levels in responders were significantly higher than those in non-responders in only phenytoin group (p˂0.05. Nitrite and nitrate levels of gingival crevicular fluid and plasma did not significantly differ between responders and non-responders in all study groups (p˃0.05. Salivary nitrite levels exhibited a significant correlation with PD, GBTI, severity of gingival overgrowth (%GO and GCF volume (p˂0.05. Additionally, a strong positive correlation was detected between saliva and plasma nitrate levels (p˂0.005. However, both nitrite and nitrate levels in GCF and plasma demonstrated no significant correlation with clinical parameters, GO severity and GCF volume (p˃0.05.Conclusion: Salivary nitrite and nitrate levels could be used as periodontal disease biomarkers in

  2. Using Salivary Nitrite and Nitrate Levels as a Biomarker for Drug-Induced Gingival Overgrowth

    Science.gov (United States)

    Sukuroglu, Erkan; Güncü, Güliz N.; Kilinc, Kamer; Caglayan, Feriha

    2015-01-01

    Aim: Drug-induced gingival overgrowth has a multifactorial nature and the pathogenesis is still uncertain. It has been suggested that Nitric Oxide (NO) might play a role in the pathogenesis of drug-induced gingival overgrowth due to the contribution of NO to immune response and matrix degradation. NO levels in biological fluids have been used as a diagnostic biomarker in many diseases. The aim of this study is to determine whether NO levels in plasma, saliva, and gingival crevicular fluid (GCF) can serve as a potential biomarker for the evaluation of drug-induced gingival overgrowth risk. Materials and Methods: A total of 104 patients, receiving cyclosporine A (n = 35), phenytoin (n = 25), nifedipine (n = 26), or diltiazem (n = 18) participated in the study. The amount of gingival overgrowth was evaluated with two indices and was given as percentage. Periodontal clinical parameters including plaque index (PI), gingival index (GI), gingival bleeding time index (GBTI), and probing depth (PD) were also assessed. Saliva, GCF, and plasma samples were obtained from each participants. Nitrite and nitrate levels in saliva, GCF, and plasma were analyzed by Griess reagent. Results: Salivary nitrite and nitrate levels in responders were significantly higher than those in non-responders in only phenytoin group (p Nitrite and nitrate levels of gingival crevicular fluid and plasma did not significantly differ between responders and non-responders in all study groups (p > 0.05). Salivary nitrite levels exhibited a significant correlation with PD, GBTI, severity of gingival overgrowth (%GO), and GCF volume (p nitrate levels (p nitrite and nitrate levels in GCF and plasma demonstrated no significant correlation with clinical parameters, GO severity, and GCF volume (p > 0.05). Conclusion: Salivary nitrite and nitrate levels could be used as periodontal disease biomarkers in phenytoin induced gingival overgrowth, and that saliva seems to have a better diagnostic potential than GCF

  3. Nocturnal sleep, daytime sleepiness, and quality of life in stable patients on hemodialysis

    Directory of Open Access Journals (Sweden)

    Bliwise Donald L

    2003-11-01

    Full Text Available Abstract Background Although considerable progress has been made in the treatment of chronic kidney disease, compromised quality of life continues to be a significant problem for patients receiving hemodialysis (HD. However, in spite of the high prevalence of sleep complaints and disorders in this population, the relationship between these problems and quality of life remains to be well characterized. Thus, we studied a sample of stable HD patients to explore relationships between quality of life and both subjective and objective measures of nocturnal sleep and daytime sleepiness Methods The sample included forty-six HD patients, 24 men and 22 women, with a mean age of 51.6 (10.8 years. Subjects underwent one night of polysomnography followed the next morning by a Multiple Sleep Latency Test (MSLT, an objective measure of daytime sleepiness. Subjects also completed: 1 a brief nocturnal sleep questionnaire; 2 the Epworth Sleepiness Scale; and, 3 the Quality of Life Index (QLI, Dialysis Version which provides an overall QLI score and four subscale scores for Health & Functioning (H&F, Social & Economic (S&E, Psychological & Spiritual (P&S, and Family (F. (The range of scores is 0 to 30 with higher scores indicating better quality of life. Results The mean (standard deviation; SD of the overall QLI was 22.8 (4.0. The mean (SD of the four subscales were as follows: H&F – 21.1 (4.7; S&E – 22.0 (4.8; P&S – 24.5 (4.4; and, F – 26.8 (3.5. H&F (rs = -0.326, p = 0.013 and F (rs = -0.248, p = 0.048 subscale scores were negatively correlated with periodic limb movement index but not other polysomnographic measures. The H&F subscale score were positively correlated with nocturnal sleep latency (rs = 0.248, p = 0.048 while the H&F (rs = 0.278, p = 0.030 and total QLI (rs = 0.263, p = 0.038 scores were positively associated with MSLT scores. Both of these latter findings indicate that higher life quality is associated with lower sleepiness levels. ESS

  4. Excessive daytime sleepiness and body composition: a population-based study of adults.

    Directory of Open Access Journals (Sweden)

    Amie C Hayley

    Full Text Available BACKGROUND: Excessive daytime sleepiness (EDS is often associated with increased adiposity, particularly when assessed in the context of samples of sleep-disordered patients; however, it is unclear if this relationship is sustained among non-clinical, population-based cohorts. This study aimed to investigate the relationship between EDS and a number of body composition markers among a population-based sample of men and women. METHODS: This study assessed 1066 women aged 21-94 yr (median = 51 yr, IQR 35-66, and 911 men aged 24-92 yr (median = 60 yr, IQR 46-73 who participated in the Geelong Osteoporosis Study (GOS between the years 2001 and 2008. Total body fat mass was determined from whole body dual-energy X-ray absorptiometry scans, and anthropometric parameters (weight, height, and waist circumference were measured. Lifestyle and health information was collected via self-report. Sleepiness was assessed using the Epworth Sleepiness Scale (ESS. Scores of ≥ 10 were considered indicative of EDS. RESULTS: Women: After adjusting for age, alcohol intake, antidepressant medication use and physical activity, EDS was associated with greater waist circumference and body mass index (BMI. EDS was also associated with 1.5-1.6-fold increased odds of being overweight or obese. Men: After adjusting for age, alcohol use, physical activity and smoking status, EDS was associated with greater BMI. These findings were not explained by the use of sedative or antidepressant medication. EDS was also associated with 1.5-fold increased likelihood of being obese, independent of these factors. No differences in lean mass, %body fat, or %lean mass were detected between those with and without EDS for men or women. CONCLUSIONS: These data suggest that EDS is associated with several anthropometric adiposity profiles, independent of associated lifestyle and health factors. Among women, symptoms of EDS are pervasive at both overweight and obese BMI classifications

  5. The role of drug-induced sleep endoscopy in the diagnosis and management of obstructive sleep apnoea syndrome: our personal experience.

    Science.gov (United States)

    DE Corso, E; Fiorita, A; Rizzotto, G; Mennuni, G F; Meucci, D; Giuliani, M; Marchese, M R; Levantesi, L; Della Marca, G; Paludetti, G; Scarano, E

    2013-12-01

    Nowadays, drug-induced sleep endoscopy (DISE) is performed widely and its validity and reliability has been demonstrated by several studies; in fact, it provides clinical information not available by routine clinical inspection alone. Its safety and utility are promising, but still needs to be improved to reach the level of excellence expected of gold standard tests used in clinical practice. Our study compares the results of clinical and diagnostic evaluation with those of sleep endoscopy, evaluating the correlation between clinical indexes of routine clinical diagnosis and sites of obstruction in terms of number of sites involved, entity of obstruction and pattern of closure. This study consists in a longitudinal prospective evaluation of 138 patients who successfully underwent sleep endoscopy at our institution. Patients were induced to sleep with a low dose of midazolam followed by titration with propofol. Sedation level was monitored using bispectral index monitoring. Our results suggest that the multilevel complete collapse was statistically significantly associated with higher apnoea hypopnea index values. By including partial sites of obstruction greater than 50%, our results also suggest that multilevel collapse remains statistically and significantly associated with higher apnoea hypopnoea index values. Analyzing BMI distribution based on number of sites with complete and partial obstruction there was no significant difference. Finally, analyzing Epworth Sleepiness Score distribution based on number of sites with complete obstruction, there was a statistically significant difference between patients with 3-4 sites of obstruction compared to those with two sites or uni-level obstruction. In conclusion, our data suggest that DISE is safe, easy to perform, valid and reliable, as previously reported. Furthermore, we found a good correlation between DISE findings and clinical characteristics such as AHI and EPS. Consequently, adequate assessment by DISE of all

  6. Drug-induced interstitial lung diseases%药源性间质性肺疾病

    Institute of Scientific and Technical Information of China (English)

    王晓芳; 张运剑; 夏国光

    2012-01-01

    Drug-induced interstitial lung disease is the most common type of drug-induced respiratory diseases. It is known that a lot of drugs can cause interstitial lung diseases. The underlying mechanism may be associated with allergy and the direct cellular toxicity. Its clinical symptoms, imaging, and histopathology were untypical. Clinical diagnosis of the disease was based on the medical history ( medication history), clinical features, chest imaging, hi sto pathological changes, and response to treatment. If interstitial lung diseases were suspected to be; drug-induced, the drug should be discontinued immediately and glucocorticoid could be given. The prognosis is good if intervention is rapid.%药源性间质性肺疾病(DI-ILD)是最常见的药源性肺部疾病,目前已知多种药物可导致间质性肺疾病,其发病机制与药物引起的变态反应和直接细胞毒性作用有关.此类疾病临床症状、影像学及组织病理学表现均无特异性,临床诊断DI-ILD需根据病史(用药史)、临床特点、胸部影像学、组织病理学改变及治疗效果.临床疑诊DI-ILD时应立刻停药并应用糖皮质激素.若及时干预,预后良好.

  7. Hepatitis E virus detection in liver tissue from patients with suspected drug-induced liver injury

    Directory of Open Access Journals (Sweden)

    Obinna eChijioke

    2015-03-01

    Full Text Available Hepatitis E virus (HEV infection is increasingly recognized as a cause of acute hepatitis in the industrialized world. We aimed to determine the frequency of acute Hepatitis E virus (HEV infection in cases of suspected drug-induced liver injury (DILI, mainly a diagnosis of exclusion. To this aim, formalin-fixed, paraffin-embedded (FFPE liver tissues of all cases routinely processed in our institute during a 2 ½ years period in which DILI was amongst the differential diagnoses (157 liver biopsies, one liver explant were subjected to semi-nested RT-PCR for the detection of hepatitis E virus (HEV RNA. Histopathology was re-evaluated on all cases tested positive. HEV RNA was detectable in three of 158 cases (2% tested, comprising autochthonic as well as travel-related infections with genotypes 1, 3, and 4 each found once, respectively. Histopathologic findings comprised one case with subtotal hepatic necrosis and two cases of acute (cholestatic hepatitis not distinguishable from acute hepatitis of other etiology. Thus, the overall frequency of acute hepatitis E virus (HEV infection as determined by detection of hepatitis E virus (HEV RNA in liver tissue is substantially increased in patients with suspected drug-induced liver injury compared to the healthy population, emphasizing the need to actively look for hepatitis E virus (HEV infection in cases of suspected drug-induced liver injury (DILI. Molecular testing for hepatitis E virus (HEV RNA in routinely processed formalin-fixed, paraffin-embedded (FFPE liver tissues can be applied to cases with undetermined hepatitis E virus (HEV status.

  8. Subjective sleepiness and sleep quality in adolescents are related to objective and subjective measures of school performance

    Directory of Open Access Journals (Sweden)

    Annemarie eBoschloo

    2013-02-01

    Full Text Available This study investigated the relation between sleep and school performance in a large sample of 561 adolescents aged 11-18 years. Three subjective measures of sleep were used: sleepiness, sleep quality and sleep duration. They were compared to three measures of school performance: objective school grades, self-reported school performance, and parent-reported school performance. Sleepiness – ‘I feel sleepy during the first hours at school’ – appeared to predict both school grades and self-reported school performance. Sleep quality on the other hand – as a measure of (uninterrupted sleep and/or problems falling asleep or waking up – predicted parent-reported school performance. Self- and parent-reported school performance correlated only moderately with school grades. So it turns out that the measures used to measure either sleep or school performance impacts whether or not a relation is found. Further research on sleep and school performance should take this into account. The findings do underscore the notion that sleep in adolescence can be important for learning. They are compatible with the hypothesis that a reduced sleep quality can give rise to sleepiness in the first hours at school which results in lower school performance. This notion could have applied value in counseling adolescents and their parents in changing adolescents’ sleep behavior.

  9. Subjective sleepiness and sleep quality in adolescents are related to objective and subjective measures of school performance

    NARCIS (Netherlands)

    Boschloo, A.; Krabbendam, L.; Dekker, S.; Lee, N.; Groot, R. de; Jolles, J.

    2013-01-01

    This study investigated the relation between sleep and school performance in a large sample of 561 adolescents aged 11-18 years. Three subjective measures of sleep were used: sleepiness, sleep quality, and sleep duration. They were compared to three measures of school performance: objective school g

  10. Subjective sleepiness and sleep quality in adolescents are related to objective and subjective measures of school performance

    NARCIS (Netherlands)

    Boschloo, Annemarie; Krabbendam, Lydia; Dekker, Sanne; Lee, Nikki; De Groot, Renate; Jolles, Jelle

    2016-01-01

    This study investigated the relation between sleep and school performance in a large sample of 561 adolescents aged 11–18 years. Three subjective measures of sleep were used: sleepiness, sleep quality, and sleep duration. They were compared to three measures of school performance: objective school g

  11. Does more sleep matter? Differential effects of NREM- and REM-dominant sleep on sleepiness and vigilance.

    Science.gov (United States)

    Neu, D; Mairesse, O; Newell, J; Verbanck, P; Peigneux, P; Deliens, G

    2015-05-01

    We investigated effects of NREM and REM predominant sleep periods on sleepiness and psychomotor performances measured with visual analog scales and the psychomotor vigilance task, respectively. After one week of stable sleep-wake rhythms, 18 healthy sleepers slept 3hours of early sleep and 3hours of late sleep, under polysomnographic control, spaced by two hours of sustained wakefulness between sleep periods in a within subjects split-night, sleep interruption protocol. Power spectra analysis was applied for sleep EEG recordings and sleep phase-relative power proportions were computed for six different frequency bands (delta, theta, alpha, sigma, beta and gamma). Both sleep periods presented with similar sleep duration and efficiency. As expected, phasic NREM and REM predominances were obtained for early and late sleep conditions, respectively. Albeit revealing additive effects of total sleep duration, our results showed a systematic discrepancy between psychomotor performances and sleepiness levels. In addition, sleepiness remained stable throughout sustained wakefulness during both conditions, whereas psychomotor performances even decreased after the second sleep period. Disregarding exchanges for frequency bands in NREM or stability in REM, correlations between outcome measures and EEG power proportions further evidenced directional divergence with respect to sleepiness and psychomotor performances, respectively. Showing that the functional correlation pattern changed with respect to early and late sleep condition, the relationships between EEG power and subjective or behavioral outcomes might however essentially be related to total sleep duration rather than to the phasic predominance of REM or NREM sleep.

  12. Drug-induced hypersensitivity syndrome due to anticonvulsants in a two-year-old boy.

    Science.gov (United States)

    Criado, Paulo Ricardo; Criado, Roberta F J; Vasconcellos, Cidia; Pegas, Jose Roberto P; Cera, Patrícia Calil

    2004-12-01

    Drug-induced hypersensitivity syndrome (DIHS) usually refers to severe cutaneous drug eruption associated with systemic involvement and potentially fatal outcome. We report a 2-year-old Caucasian boy who developed DIHS due to phenytoin and phenobarbital and who showed extensive internal organ involvement. We are alerting that failure to recognize this drug eruption and discontinue the culprit drug may result in increased severity, greater extent of internal organ involvement, and fatal outcome. The recent research about the influence of human herpesvirus 6 co-infection on the pathogenesis of DIHS is also discussed by the authors in this paper. PMID:15801266

  13. ANTIHEPATOTOXIC EFFECT OF BARLERIA MONTANA LEAVES AGAINST ANTI-TB DRUGS INDUCED HEPATOTOXICITY

    OpenAIRE

    Jyothi Basini; S. Mohana lakshmi; K.Anitha

    2013-01-01

    Introduction: The present study was undertaken to evaluate the protective activity of 95% hydroalcoholic extract of Barleria Montana leaves against anti-TB drugs induced hepatotoxicity. Methods: Hepatotoxicity was induced by anti-TB drugs once daily for 35 days and simultaneously 95% hydroalcoholic extract of Barleria Montana (250 & 500 mg/kg p.o.) was administered one hour prior administration of anti-TB drugs. Silymarin was used as standard drug (100 mg/kg p.o.). Results: Elevated levels of...

  14. Organization and logistics of drug-induced sleep endoscopy in a training hospital.

    Science.gov (United States)

    Benoist, L B L; de Vries, N

    2015-09-01

    Drug-induced sleep endoscopy (DISE) is a rapidly growing method to evaluate airway collapse in patients receiving non-CPAP therapies for sleep-disordered breathing (SDB). The growing number of DISEs has consequences for the organization of clinical protocols. In this paper we present our recent experiences with DISE, performed by an ENT resident, with sedation given by a nurse anesthetist, in an outpatient endoscopy setting, while the staff member/sleep surgeon discusses the findings and the recommended treatment proposal on the same day.

  15. Characteristics of Mononuclear Extracellular Traps in the Offspring of Female Rats with Drug-Induced Hepatitis.

    Science.gov (United States)

    Bryukhin, G V; Shopova, A V

    2015-08-01

    We studied the effect of experimental tetracycline-induced liver injury in mothers on the capacity of macrophages from various compartments to form traps and on activity of extracellular macrophage traps in the offspring. Trap-forming capacity was evaluated by the number of traps. We found reduction in the number and suppression of activity of the macrophage extracellular traps in the offspring of females with experimental liver injury. The findings suggest that mothers with drug-induced liver injury produce physiologically immature offspring with reduced unspecific resistance. PMID:26388577

  16. Drug-induced Hypothermia by 5HT1A Agonists Provide Neuroprotection in Experimental Stroke

    DEFF Research Database (Denmark)

    Johansen, Flemming Fryd; Hasseldam, Henrik; Nybro Smith, Matthias;

    2014-01-01

    BACKGROUND: Drug-induced hypothermia reduces brain damage in animal stroke models and is an undiscovered potential in human stroke treatment. We studied hypothermia induced by the serotonergic agonists S14671 (1-[2-(2-thenoylamino)ethyl]-4[1-(7- methoxynaphtyl)]piperazine) and ipsapirone in a rat...... of .06 mg/kg hour(-1) S14671 for 20 hours. Other MCAO rats (n = 7) had bolus of ipsapirone (.75 mg/kg) and continuous infusion of .25 mg/kg hour(-1) ipsapirone for 3 hours. Controls (n = 9; n = 5) received similar amounts of vehicle as bolus and continuous infusion for 20 hours/3 hours. Additional...

  17. Pharmaco-epidemiological, clinical and laboratory characteristics of drug-induced liver injury in tuberculosis

    Directory of Open Access Journals (Sweden)

    M. V. Koroleva

    2015-01-01

    Full Text Available Objective: improving the efficiency of pharmacotherapy of drug-induced liver injury in tuberculosis by clarifying pharmaco-epidemiological, clinical and laboratory features.Materials and Methods: A retrospective analysis of primary medical records of 250 patients with pulmonary tuberculosis, patients «Volgograd Regional Clinical TB Dispensary № 1». We evaluated the dynamics of biochemical parameters characterizing the development of hepatic cytolytic syndrome, examined the impact of gender and age on the incidence of liver damage, we investigated the relationship of clinical tuberculosis and chemotherapy regimen with the incidence of drug-induced liver injury, examined the clinical manifestations of liver disease.Results: Drug-induced liver injury as a complication of a specific anti-TB treatment was diagnosed in 67 patients (26,8%. In 170 patients (68,0% showed increase in alanine aminotransferase and asparaginaminotrasferazy. Hepatotoxicity significantly more common in patients with disseminated tuberculosis with the collapse of the lung tissue, smear, and a high degree of disease severity. Risk factors for drug liver damage were female gender and age older than 50 years. Women develop liver disease at an earlier date, and displays it harder than men. The earliest and most informative routine biochemical tests, reflecting the state of the liver in the dynamics are ALT and AST. It was found that the mode of the standard anti-TB treatment determines the type of liver injury: the first, 2a and 3rd modes prevails cytolytic hepatocellular type, with 2b mode – combined (mixed type 4th – type of cholestatic liver damage. It was found that repeated, after the development of hepatotoxic reactions, the appointment of anti-TB drugs without gepatoprotektsii in 94% of patients leads to repeated drug-induced liver damage. Cancel specific therapy against the background of cytolytic syndrome promotes the formation of

  18. Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death

    DEFF Research Database (Denmark)

    De Bruin, M L; Pettersson, M; Meyboom, R H B;

    2005-01-01

    AIMS: Drug-induced QTc-prolongation, resulting from inhibition of HERG potassium channels may lead to serious ventricular arrhythmias and sudden death. We studied the quantitative anti-HERG activity of pro-arrhythmic drugs as a risk factor for this outcome in day-to-day practice. METHODS AND RESU...... with the risk of reports of serious ventricular arrhythmias and sudden death in the WHO-UMC database. These findings are in support of the value of pre-clinical HERG testing to predict pro-arrhythmic effects of medicines....

  19. 药源性血栓栓塞症%Drug-induced thromboembolism

    Institute of Scientific and Technical Information of China (English)

    杨文君; 徐翔

    2014-01-01

    药源性血栓栓塞症是指因某些药物使血管内血栓形成和/或栓塞并导致组织和器官功能受损的疾病.药源性血栓栓塞症的发病机制主要为血管内皮细胞损伤、血液成分改变和血流动力学异常.导致血栓栓塞症的常见药物有造影剂、化疗药、免疫抑制剂、免疫增强剂、环氧化酶2抑制剂、抗精神病药和激素等.药源性血栓栓塞症以门静脉、脾静脉、肾静脉或脑静脉窦等深静脉血栓形成较常见,动脉血栓较为少见.药源性血栓栓塞症可应用普通肝素、低分子肝素、磺达肝癸钠、华法林、尿激酶、阿替普酶、阿加曲班、重组水蛭素或达那肝素钠治疗.%The term of drug-induced thromboembolism refers to intravascular thrombosis and/or thromboembolism due to drugs and resulting in impaired tissue and organ function.The main mechanisms of drug-induced thromboembolism involve injury of endothelial cells,the change of blood components and hemodynamic abnormality.Drugs which cause thrombosis mainly include contrast media,chemotherapeutic agents,immunosuppressive agents,immunopotentiators,cyclooxygenase-2 inhibitors,antipsychotic agents,and hormones.The most common drug-induced thrombosis is deep vein thrombosis such as portal vein,splenic vein,renal vein,or cerebral venous sinus.Arterial thrombosis is less common.Drug-induced thrombosis could be treated with unfractionated heparin,low molecular weight heparin,fondaparinux sodium,warfarin,urokinase,alteplase,argatroban,recombinant hirudin or danaparoid sodium.

  20. Exploring BSEP Inhibition-Mediated Toxicity with a Mechanistic Model of Drug-Induced Liver Injury

    OpenAIRE

    Woodhead, Jeffrey L; Kyunghee eYang; Siler, Scott Q.; Paul Brent Watkins; Brouwer, Kim L.R.; Barton, Hugh A.; Howell, Brett A.

    2014-01-01

    Inhibition of the bile salt export pump (BSEP) has been linked to incidence of drug-induced liver injury (DILI), presumably by the accumulation of toxic bile acids in the liver. We have previously constructed and validated a model of bile acid disposition within DILIsym®, a mechanistic model of DILI. In this paper, we use DILIsym® to simulate the DILI response of the hepatotoxic BSEP inhibitors bosentan and CP-724,714 and the non-hepatotoxic BSEP inhibitor telmisartan in humans in order to ex...

  1. Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury

    OpenAIRE

    Woodhead, Jeffrey L; Yang, Kyunghee; Siler, Scott Q.; Watkins, Paul B.; Brouwer, Kim L.R.; Barton, Hugh A.; Howell, Brett A.

    2014-01-01

    Inhibition of the bile salt export pump (BSEP) has been linked to incidence of drug-induced liver injury (DILI), presumably by the accumulation of toxic bile acids in the liver. We have previously constructed and validated a model of bile acid disposition within DILIsym®, a mechanistic model of DILI. In this paper, we use DILIsym® to simulate the DILI response of the hepatotoxic BSEP inhibitors bosentan and CP-724,714 and the non-hepatotoxic BSEP inhibitor telmisartan in humans in order to ex...

  2. Daytime Sleepiness Is Associated With Reduced Integration of Temporally Distant Outcomes on the Iowa Gambling Task.

    Science.gov (United States)

    Olson, Elizabeth A; Weber, Mareen; Rauch, Scott L; Killgore, William D S

    2016-01-01

    Sleep deprivation is associated with performance decrements on some measures of executive functioning. For instance, sleep deprivation results in altered decision making on the Iowa Gambling Task. However, it is unclear which component processes of the task may be driving the effect. In this study, Iowa Gambling task performance was decomposed using the Expectancy-Valence model. Recent sleep debt and greater daytime sleepiness were associated with higher scores on the updating parameter, which reflects the extent to which recent experiences are emphasized over remote ones. Findings suggest that the effects of insufficient sleep on IGT performance are due to shortening of the time horizon over which decisions are integrated. These findings may have clinical implications in that individuals with sleep problems may not integrate more temporally distant information when making decisions.

  3. Discussion of causes and consequences of sleepiness among college students, 2014

    Directory of Open Access Journals (Sweden)

    Wolgast B

    2016-05-01

    Full Text Available Brad WolgastCenter for Counseling and Student Development, University of Delaware, Newark, DE, USAI was recently directed to, “Causes and consequences of sleepiness among college students”, from Hershner and Chervin.1 As a psychologist who specializes in treating college student sleep problems, I was very pleased to see this article. Overall, it is a gem: thorough, well-conceived, and thoughtful. However, I have concerns about two sections. First, on page 74, Hershner and Chervin1 write, “How much sleep a young adult needs is not clearly known, but is thought to be 8 hours.” They then cite Wehr et al2 as well as Van Dongen et al.3 These choices are surprising as reference for the assertion that young adults need approximately 8 hours of sleep.View original paper by Hershner and Chervin.

  4. Daytime sleepiness and academic performance of medical students in a Colombian public university

    Directory of Open Access Journals (Sweden)

    Ulloque-Caamaño Liezel

    2013-06-01

    Full Text Available Introduction: Sleep is an important physiological function for the adequate physical,psychological, cognitive and intellectual performance. Excessive daytime sleepinessclassified as moderate or severe is a sleep disorder and its presence in medical studentscould affect in the academic performance.Objective: Establish the prevalence of normal and pathological daytime sleepiness inmedical students.Methods: Prospective and cross-sectional study. Medical students of Medicine of theUniversidad de Cartagena, Colombia in the second academic period of 2011 wereincluded. A survey for the compilation of socio-demographic and academic data andthe Epworth Scale for the assessment of daytime sleepiness were applied. The higherthe score indicates higher daytime sleepiness of the respondent. The participation wasvoluntary and anonymous. A stratified sample by gender and semester was chosen. Dataanalysis was performed using the EPI-INFO statistical program (Version 3.5.1. A p value< 0.05 was considered as statistically significant.Results: 210 medical students filled completely the surveys. The mean age was 19.7±2.0years. 51.0% [CI 95%: 44.0-57.9%] were women and 49.0% [CI95%: 42.1-56.0%]were men. 69% [CI95%: 62.3-75.2%] came from Cartagena and the remaining 31%[CI95%: 24.8-37.7%] came from different provinces. 53.8% [CI95%: 49.8%-60.7%]had sexually active life. The academic mean of all population of students was 3.8±0.28.31.4% [CI95%: 25.2%-38.2%] had high grades, 50.5% [CI95%: 43.5%-57.4%] hadaverage grades and 18.1% [CI95%: 13.1%-24.0%] had regular grades. 19.0% [IC95%:14.0%-25.0%] did not have abnormal daytime sleepiness, 21.4% [CI95%: 16.1%-27.0%] had mild daytime sleepiness, 49.0% [CI95%: 42.1%-56.0%] moderate daytimesleepiness and 10.5% [CI95%: 6.7%-15.4%] had severe daytime sleepiness. 60% ofthe students had pathological daytime sleepiness. The average score of Epworth scale inthe population was 10.6±3.7. Significant difference of diurnal somnolence

  5. Sleep patterns and school performance of Korean adolescents assessed using a Korean version of the pediatric daytime sleepiness scale

    Directory of Open Access Journals (Sweden)

    Seon kyeong Rhie

    2011-01-01

    Full Text Available Purpose: Korean adolescents have severe nighttime sleep deprivation and daytime sleepiness because of their competitive educational environment. However, daytime sleep patterns and sleepiness have never been studied using age-specific methods, such as the pediatric daytime sleepiness scale (PDSS. We surveyed the daytime sleepiness of Korean adolescents using a Korean translation of the PDSS. Methods: We distributed the 27-item questionnaire, including the PDSS and questions related to sleep pattern, sleep satisfaction, and emotional state, to 3,370 students in grades 5-12. Results: The amount of nighttime sleep decreased significantly with increasing age. During weekday nights, 5- 6th graders slept for 7.95¡?#?.05; h, 7-9th graders for 7.57¡?#?.05; h, and 10-12th graders for 5.78¡?#?.13; h. However, the total amounts of combined daytime and nighttime sleep during weekdays were somewhat greater, 8.15¡?#?.12; h for 5- 6th graders, 8.17¡?#?.20; h for 7-9th graders, and 6.87¡?#?.40; h for 10-12th graders. PDSS scores increased with age, 11.89¡?#?.56; for 5- 6th graders, 16.57¡?#?.57; for 7-9th graders, and 17.71¡?#?.24; for 10-12th graders. Higher PDSS scores were positively correlated with poor school performance and emotional instability. Conclusion: Korean teenagers sleep to an unusual extent during the day because of nighttime sleep deprivation. This negatively affects school performance and emotional stability. A Korean translation of the PDSS was effective in evaluating the severity of daytime sleepiness and assessing the emotional state and school performance of Korean teenagers.

  6. Circadian rhythms of psychomotor vigilance, mood, and sleepiness in the ultra-short sleep/wake protocol

    Science.gov (United States)

    Kline, Christopher E.; Durstine, J. Larry; Davis, J. Mark; Moore, Teresa A.; Devlin, Tina M.; Youngstedt, Shawn D.

    2011-01-01

    Despite its advantages as a chronobiological technique, the ultra-short sleep/wake protocol remains underutilized in circadian rhythm research. The purpose of this study was to examine circadian rhythms of psychomotor vigilance (PVT), mood, and sleepiness in a sample (n = 25) of healthy young adults while they adhered to a 3-h ultra-short sleep/wake protocol. The protocol involved 1-h sleep intervals in darkness followed by 2-h wake intervals in dim light, repeated for 50–55 h. A 5-min PVT test was conducted every 9 h with the standard metrics of mean reaction time (RT; RTmean), median RT (RTmed), fastest 10% of responses (RT10fast), and the reciprocal of the 10% slowest responses (1/RT10slow). Subjective measures of mood and sleepiness were assessed every 3 h. A cosine fit of intra-aural temperature, assessed three times per wake period, established the time of the body temperature minimum (Tmin). Mood, sleepiness, and PVT performances were expressed relative to individual means and compared across eight times of day and across twelve 2-h intervals relative to Tmin. Significant time-of-day and circadian patterns were demonstrated for each of the PVT metrics, as well as for mood and sleepiness. Most mood subscales exhibited significant deterioration in day 2 of the protocol without an alteration of circadian pattern. However, neither sleepiness nor performance was worse on the second day of observation compared to the first day. These data provide further support for the use of the ultra-short sleep/wake protocol for measurement of circadian rhythms. PMID:20205564

  7. [DRUG-INDUCED LUPUS CAUSED BY LONG TERM MINOCYCLINE TREATMENT FOR ACNE VULGARIS].

    Science.gov (United States)

    Hanai, Shunichiro; Sato, Takeo; Takeda, Koichi; Nagatani, Katsuya; Iwamoto, Masahiro; Minota, Seiji

    2015-09-01

    An 18-year-old Japanese girl had received oral minocycline 200mg daily for treatment of acne vulgaris since 16 years old. She had a fever three months before admission, followed by joint pains in her knees, elbows and several proximal interphalangeal joints one month before admission. She was referred to our hospital because of a high serum level of anti-DNA antibody. She had already discontinued oral minocycline five weeks before admission, because she missed her medication refilled. On admission, the arthralgia and fever spontaneously resolved, and there were no laboratory evidence of hypocomplementemia and cytopenia. She had neither erythema nor internal organ involvements. Because her symptoms subsided spontaneously after the cessation of minocycline, she was considered to have drug-induced lupus. Both the arthralgia and fever did not relapse, and anti-ds DNA antibody returned to normal during a follow-up period without treatment. There are few reports of drug-induced lupus caused by minocycline in Japan. This case highlights the importance of considering minocycline-induced lupus.

  8. Pharmacoepidemiological characterization of drug-induced adverse reaction clusters towards understanding of their mechanisms.

    Science.gov (United States)

    Mizutani, Sayaka; Noro, Yousuke; Kotera, Masaaki; Goto, Susumu

    2014-06-01

    A big challenge in pharmacology is the understanding of the underlying mechanisms that cause drug-induced adverse reactions (ADRs), which are in some cases similar to each other regardless of different drug indications, and are in other cases different regardless of same drug indications. The FDA Adverse Event Reporting System (FAERS) provides a valuable resource for pharmacoepidemiology, the study of the uses and the effects of drugs in large human population. However, FAERS is a spontaneous reporting system that inevitably contains noise that deviates the application of conventional clustering approaches. By performing a biclustering analysis on the FAERS data we identified 163 biclusters of drug-induced adverse reactions, counting for 691 ADRs and 240 drugs in total, where the number of ADR occurrences are consistently high across the associated drugs. Medically similar ADRs are derived from several distinct indications for use in the majority (145/163=88%) of the biclusters, which enabled us to interpret the underlying mechanisms that lead to similar ADRs. Furthermore, we compared the biclusters that contain same drugs but different ADRs, finding the cases where the populations of the patients were different in terms of age, sex, and body weight. We applied a biclustering approach to catalogue the relationship between drugs and adverse reactions from a large FAERS data set, and demonstrated a systematic way to uncover the cases different drug administrations resulted in similar adverse reactions, and the same drug can cause different reactions dependent on the patients' conditions. PMID:24534381

  9. Drug Repositioning for Cancer Therapy Based on Large-Scale Drug-Induced Transcriptional Signatures.

    Directory of Open Access Journals (Sweden)

    Haeseung Lee

    Full Text Available An in silico chemical genomics approach is developed to predict drug repositioning (DR candidates for three types of cancer: glioblastoma, lung cancer, and breast cancer. It is based on a recent large-scale dataset of ~20,000 drug-induced expression profiles in multiple cancer cell lines, which provides i a global impact of transcriptional perturbation of both known targets and unknown off-targets, and ii rich information on drug's mode-of-action. First, the drug-induced expression profile is shown more effective than other information, such as the drug structure or known target, using multiple HTS datasets as unbiased benchmarks. Particularly, the utility of our method was robustly demonstrated in identifying novel DR candidates. Second, we predicted 14 high-scoring DR candidates solely based on expression signatures. Eight of the fourteen drugs showed significant anti-proliferative activity against glioblastoma; i.e., ivermectin, trifluridine, astemizole, amlodipine, maprotiline, apomorphine, mometasone, and nortriptyline. Our DR score strongly correlated with that of cell-based experimental results; the top seven DR candidates were positive, corresponding to an approximately 20-fold enrichment compared with conventional HTS. Despite diverse original indications and known targets, the perturbed pathways of active DR candidates show five distinct patterns that form tight clusters together with one or more known cancer drugs, suggesting common transcriptome-level mechanisms of anti-proliferative activity.

  10. Drug Repositioning for Cancer Therapy Based on Large-Scale Drug-Induced Transcriptional Signatures.

    Science.gov (United States)

    Lee, Haeseung; Kang, Seungmin; Kim, Wankyu

    2016-01-01

    An in silico chemical genomics approach is developed to predict drug repositioning (DR) candidates for three types of cancer: glioblastoma, lung cancer, and breast cancer. It is based on a recent large-scale dataset of ~20,000 drug-induced expression profiles in multiple cancer cell lines, which provides i) a global impact of transcriptional perturbation of both known targets and unknown off-targets, and ii) rich information on drug's mode-of-action. First, the drug-induced expression profile is shown more effective than other information, such as the drug structure or known target, using multiple HTS datasets as unbiased benchmarks. Particularly, the utility of our method was robustly demonstrated in identifying novel DR candidates. Second, we predicted 14 high-scoring DR candidates solely based on expression signatures. Eight of the fourteen drugs showed significant anti-proliferative activity against glioblastoma; i.e., ivermectin, trifluridine, astemizole, amlodipine, maprotiline, apomorphine, mometasone, and nortriptyline. Our DR score strongly correlated with that of cell-based experimental results; the top seven DR candidates were positive, corresponding to an approximately 20-fold enrichment compared with conventional HTS. Despite diverse original indications and known targets, the perturbed pathways of active DR candidates show five distinct patterns that form tight clusters together with one or more known cancer drugs, suggesting common transcriptome-level mechanisms of anti-proliferative activity. PMID:26954019

  11. A Rare Complication of Trimethoprim-Sulfamethoxazole: Drug Induced Aseptic Meningitis.

    Science.gov (United States)

    Jha, Pinky; Stromich, Jeremiah; Cohen, Mallory; Wainaina, Jane Njeri

    2016-01-01

    Drug induced aseptic meningitis is a rare but challenging diagnosis, most commonly reported with nonsteroidal anti-inflammatory drugs and antibiotics. Trimethoprim/sulfamethoxazole is a sulfonamide that is widely used in clinical practice for the treatment and prophylaxis of various infections. Drug induced aseptic meningitis, when seen with trimethoprim/sulfamethoxazole, occurs predominantly in patients with some degree of immune compromise and is less commonly seen in immune competent individuals. The patient often exhibits the classic symptoms of meningitis. Early diagnosis is important, since the cessation of the antibiotic leads to rapid clinical improvement. Trimethoprim/sulfamethoxazole induced aseptic meningitis has been underreported to FDA/MED-WATCH program. Here we report two cases of trimethoprim/sulfamethoxazole: an immune competent individual and immune compromised individual, both of which presented with signs of meningitis and a negative infectious workup. Trimethoprim/sulfamethoxazole is an uncommon and mysterious adverse reaction to a commonly used antibiotic. It should be considered in the differential diagnosis of patients presenting with acute signs and symptoms of meningitis especially after infectious causes have been ruled out. PMID:27579194

  12. Monitoring drug induced apoptosis and treatment sensitivity in non-small cell lung carcinoma using dielectrophoresis.

    Science.gov (United States)

    Taruvai Kalyana Kumar, Rajeshwari; Liu, Shanshan; Minna, John D; Prasad, Shalini

    2016-09-01

    Non-invasive real time methods for characterizing biomolecular events that contribute towards apoptotic kinetics would be of significant importance in the field of cancer biology. Effective drug-induced apoptosis is an important factor for establishing the relationship between cancer genetics and treatment sensitivity. The objective of this study was to develop a non-invasive technique to characterize cancer cells that are undergoing drug-induced apoptosis. We used dielectrophoresis to determine apoptotic cells as early as 2h post drug treatment as compared to 24h with standard flow cytometry method using non-small cell lung cancer (NSCLC) adenocarcinoma cell line (HCC1833) as a study model. Our studies have shown significant differences in apoptotic cells by chromatin condensation, formation of apoptotic bodies and exposure of phosphatidylserine (PS) on the extracellular surface when the cells where treated with a potent Bcl-2 family inhibitor drug (ABT-263). Time lapse dielectrophoretic studies were performed over 24h period after exposure to ABT-263 at clinically relevant concentrations. The dielectrophoretic studies were compared to Annexin-V FITC flow assay for the detection of PS in mid-stage apoptosis using flow cytometry. As a result of physical and biochemical changes, inherent dielectric properties of cells undergoing varying stages of apoptosis showed amplified changes in their cytoplasmic and membrane capacitance. In addition, zeta potential of these fixed isolated cells was measured to obtain direct correlation to biomolecular events. PMID:27262539

  13. Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria.

    Science.gov (United States)

    Han, Derick; Dara, Lily; Win, Sanda; Than, Tin Aung; Yuan, Liyun; Abbasi, Sadeea Q; Liu, Zhang-Xu; Kaplowitz, Neil

    2013-04-01

    Drugs that cause liver injury often 'stress' mitochondria and activate signal transduction pathways important in determining cell survival or death. In most cases, hepatocytes adapt to the drug-induced stress by activating adaptive signaling pathways, such as mitochondrial adaptive responses and nuclear factor erythroid 2-related factor 2 (Nrf-2), a transcription factor that upregulates antioxidant defenses. Owing to adaptation, drugs alone rarely cause liver injury, with acetaminophen (APAP) being the notable exception. Drug-induced liver injury (DILI) usually involves other extrinsic factors, such as the adaptive immune system, that cause 'stressed' hepatocytes to become injured, leading to idiosyncratic DILI, the rare and unpredictable adverse drug reaction in the liver. Hepatocyte injury, due to drug and extrinsic insult, causes a second wave of signaling changes associated with adaptation, cell death, and repair. If the stress and injury reach a critical threshold, then death signaling pathways such as c-Jun N-terminal kinase (JNK) become dominant and hepatocytes enter a failsafe mode to undergo self-destruction. DILI can be seen as an active process involving recruitment of death signaling pathways that mediate cell death rather than a passive process due to overwhelming biochemical injury. In this review, we highlight the role of signal transduction pathways, which frequently involve mitochondria, in the development of DILI. PMID:23453390

  14. Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

    Institute of Scientific and Technical Information of China (English)

    Ignazio Grattagliano; Leonilde Bonfrate; Catia V Diogo; Helen H Wang; David QH Wang; Piero Portincasa

    2009-01-01

    Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local O_2 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca~(2+)-dependent ATPase, reduced capability to sequester Ca~(2+) within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.

  15. Evaluation of the Relative Performance of Drug-Induced Skeletal Muscle Injury Biomarkers in Rats.

    Science.gov (United States)

    Burch, Peter M; Greg Hall, David; Walker, Elizabeth G; Bracken, William; Giovanelli, Richard; Goldstein, Richard; Higgs, Richard E; King, Nicholas M P; Lane, Pamela; Sauer, John-Michael; Michna, Laura; Muniappa, Nagaraja; Pritt, Michael L; Vlasakova, Katerina; Watson, David E; Wescott, Debra; Zabka, Tanja S; Glaab, Warren E

    2016-03-01

    Novel skeletal muscle (SKM) injury biomarkers that have recently been identified may outperform or add value to the conventional SKM injury biomarkers aspartate transaminase (AST) and creatine kinase (CK). The relative performance of these novel biomarkers of SKM injury including skeletal troponin I (sTnI), myosin light chain 3 (Myl3), CK M Isoform (Ckm), and fatty acid binding protein 3 (Fabp3) was assessed in 34 rat studies including both SKM toxicants and compounds with toxicities in tissues other than SKM. sTnI, Myl3, Ckm, and Fabp3 all outperformed CK or AST and/or added value for the diagnosis of drug-induced SKM injury (ie, myocyte degeneration/necrosis). In addition, when used in conjunction with CK and AST, sTnI, Myl3, CKm, and Fabp3 individually and collectively improved diagnostic sensitivity and specificity, as well as diagnostic certainty, for SKM injury and responded in a sensitive manner to low levels of SKM degeneration/necrosis in rats. These findings support the proposal that sTnI, Myl3, Ckm, and Fabp3 are suitable for voluntary use, in conjunction with CK and AST, in regulatory safety studies in rats to monitor drug-induced SKM injury and the potential translational use of these exploratory biomarkers in early clinical trials to ensure patient safety. PMID:26721300

  16. Compensatory variances of drug-induced hepatitis B virus YMDD mutations.

    Science.gov (United States)

    Cai, Ying; Wang, Ning; Wu, Xiaomei; Zheng, Kai; Li, Yan

    2016-01-01

    Although the drug-induced mutations of HBV have been ever documented, the evolutionary mechanism is still obscure. To deeply reveal molecular characters of HBV evolution under the special condition, here we made a comprehensive investigation of the molecular variation of the 3432 wild-type sequences and 439 YMDD variants from HBV genotype A, B, C and D, and evaluated the co-variant patterns and the frequency distribution in the different YMDD mutation types and genotypes, by using the naïve Bayes classification algorithm and the complete induction method based on the comparative sequence analysis. The data showed different compensatory changes followed by the rtM204I/V. Although occurrence of the YMDD mutation itself was not related to the HBV genotypes, the subsequence co-variant patterns were related to the YMDD variant types and HBV genotypes. From the hierarchy view, we clarified that historical mutations, drug-induced mutation and compensatory variances, and displayed an inter-conditioned relationship of amino acid variances during multiple evolutionary processes. This study extends the understanding of the polymorphism and fitness of viral protein. PMID:27588233

  17. Complement-fixing properties of antinuclear antibodies distinguish drug-induced lupus from systemic lupus erythematosus.

    Science.gov (United States)

    Rubin, R L; Teodorescu, M; Beutner, E H; Plunkett, R W

    2004-01-01

    The immunofluorescence antinuclear antibody (ANA) test has been widely used to monitor autoimmune disease, but its value for diagnostic purposes is compromised by low specificity and high prevalence in disease-free individuals. The capacity of autoantibodies to fix serum complement proteins when bound to antigen is an important effector function because this property is associated with acute and chronic inflammatory processes. The current study evaluates the complement-fixing properties of antinuclear antibodies (CANA) in three well-defined and clinically-related patient groups: systemic lupus erythematosus (SLE), drug-induced lupus (DIL) and drug-induced autoimmunity (DIA). Of 20 patients diagnosed with SLE, 90% displayed complement-fixing ANA while this feature was present in only two of 18 patients with DIL and no patients with DIA without associated disease even though the mean ANA titres were similar among these patient groups. CANA was significantly correlated with anti-Sm activity. Because SLE but not DIL or DIA can be a life-threatening disease associated with complement consumption in vivo, these results demonstrate that measurement of CANA is a diagnostically useful tool and may have immunopathologic implications.

  18. Disrupted sleep without sleep curtailment induces sleepiness and cognitive dysfunction via the tumor necrosis factor-α pathway

    Directory of Open Access Journals (Sweden)

    Ramesh Vijay

    2012-05-01

    Full Text Available Abstract Background Sleepiness and cognitive dysfunction are recognized as prominent consequences of sleep deprivation. Experimentally induced short-term sleep fragmentation, even in the absence of any reductions in total sleep duration, will lead to the emergence of excessive daytime sleepiness and cognitive impairments in humans. Tumor necrosis factor (TNF-α has important regulatory effects on sleep, and seems to play a role in the occurrence of excessive daytime sleepiness in children who have disrupted sleep as a result of obstructive sleep apnea, a condition associated with prominent sleep fragmentation. The aim of this study was to examine role of the TNF-α pathway after long-term sleep fragmentation in mice. Methods The effect of chronic sleep fragmentation during the sleep-predominant period on sleep architecture, sleep latency, cognitive function, behavior, and inflammatory markers was assessed in C57BL/6 J and in mice lacking the TNF-α receptor (double knockout mice. In addition, we also assessed the above parameters in C57BL/6 J mice after injection of a TNF-α neutralizing antibody. Results Mice subjected to chronic sleep fragmentation had preserved sleep duration, sleep state distribution, and cumulative delta frequency power, but also exhibited excessive sleepiness, altered cognitive abilities and mood correlates, reduced cyclic AMP response element-binding protein phosphorylation and transcriptional activity, and increased phosphodiesterase-4 expression, in the absence of AMP kinase-α phosphorylation and ATP changes. Selective increases in cortical expression of TNF-α primarily circumscribed to neurons emerged. Consequently, sleepiness and cognitive dysfunction were absent in TNF-α double receptor knockout mice subjected to sleep fragmentation, and similarly, treatment with a TNF-α neutralizing antibody abrogated sleep fragmentation-induced learning deficits and increases in sleep propensity. Conclusions Taken together

  19. Exenatide improves excessive daytime sleepiness and wakefulness in obese patients with type 2 diabetes without obstructive sleep apnoea.

    Science.gov (United States)

    Idris, Iskandar; Abdulla, Haitham; Tilbrook, Sean; Dean, Roy; Ali, Nabeel

    2013-02-01

    We investigate the effects of exenatide on excessive daytime sleepiness (EDS), driving performance and depression score in patients with type 2 diabetes with EDS. Eight obese patients with diabetes but without obstructive sleep apnoea (OSA) participated in a placebo-controlled single-blind study during which multiple wakefulness and sleep latency test, Epworth score, driving performance, depression score, fasting glucose and glycated haemoglobin (HbA1c) levels were assessed at baseline, end of placebo and treatment phase at baseline and after 22 weeks of treatment. Mean (±standard error of the mean) age, body mass index (kg m(2) ) and HbA1c [mmol mol(-1) (%)] of patients at baseline were 50 ± 4.9 years, 37.6 ± 1.1 and 65 ± 19 (8.06 ± 0.41), respectively. When compared to placebo, exenatide treatment was associated with a decrease in both subjective and objective sleepiness, based on the Epworth score reduction and the sleep latency increase assessed by multiple objective sleepiness and sustained attention (OSLER) tests, respectively. Mean sleep latency time (adjusted for change in HbA1c and weight) were 32.1 ± 1.7, 29.1 ± 1.7 and 37.7 ± 1.7, respectively (P = 0.002). Modelling for covariates suggested that improvement in mean sleep latency time is predicted by changes in weight (P = 0.003), but not by changes in HbA1c (P = 0.054). Epworth sleepiness score was reduced significantly (values for placebo versus exenatide: 11.3 ± 1.2 versus 5.7 ± 1.3; P = 0.003). No significant change was noted in the depression score and driving performance. Exenatide is associated with a significant reduction in objective sleepiness in obese patients with type 2 diabetes without OSA, independent of HbA1c levels. These findings could form a basis for further studies to investigate the pathophysiological mechanisms of sleepiness in obese patients with type 2 diabetes. PMID:22716195

  20. Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment

    Energy Technology Data Exchange (ETDEWEB)

    Cros, C., E-mail: caroline.cros@hotmail.co.uk [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Skinner, M., E-mail: Matthew.Skinner@astrazeneca.com [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Moors, J. [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Lainee, P. [Sanofi-Aventis R and D, 371, rue du Pr Joseph Blayac, 34184 Montpellier Cedex 04 (France); Valentin, J.P. [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom)

    2012-12-01

    Background: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I{sub Na}) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I{sub Na}, this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. Methods: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1 h period from 1 h pre-dose to 5 h post-dose. Results: Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E{sub max} 13% and 20% respectively, P < 0.01–0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of + 0.7 ± 0.5 ms (quinidine, NS), + 1.8 ± 0.8 ms (mexiletine, P < 0.05) and + 2.8 ± 0.8 ms (flecainide, P < 0.01) (calculated as QRS at basal HR-QRS at high HR). Conclusion: Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function. -- Highlights: ► We aimed to improve detection of drug-induced QRS prolongation in safety screening. ► We used telemetered dogs to test class I antiarrhythmics at low and high heart rate. ► At low heart rate only quinidine and flecainide induced an increase in QRS duration. ► At high heart rate the effects of two

  1. Dynamically observing the value of the changes of serum sex hormone levels of early pregnancy after drug-induced abortion

    International Nuclear Information System (INIS)

    Objective: To observe the value of the changes of serum β-human chorionic gonadotropin (β-HCG), estradiol (E), progesterone (P) Levels of early pregnancy after drug-induced abortion dynamically. Methods: Assessing 55 women proved pregnant by urine or blood HCG retrospecticly, who had terminated their pregnancy by mifepristonr and misoprostol. Meanwhile the serum levels of β-HCG, E, P were monitored dynamically. Results: Among the 55 patients, the levels of β-HCG, E and P had significant decreased (tβ-HCG=4.845, tE=7.655, tP=11.390, PE=9.089, PP=2.910, P<0.05). Conclusion: Detectint the serum hormone's levels after drug-induced abortion by chemiluminescent immunoassay, we can assess indirectly the value of administration of mifepristone and misoprostol, predict the prolonged vaginal bleeding after drug-induced abortion, and the outcome of the treatment, which determine wether need another curestage. (authors)

  2. Elevated thyroid stimulating hormone in a neonate: Drug induced or disease?

    Directory of Open Access Journals (Sweden)

    Sunil Kumar Kota

    2011-01-01

    Full Text Available Dyshormonogenesis is an uncommon cause of congenital hypothyroidism. The most common abnormality is absent or insufficient thyroid peroxidase enzyme. Maternal intake of antithyroid drug can also lead to elevated thyroid stimulating hormone (TSH in a neonate, albeit the scenario is temporary. We report one such interesting case where a clinically euthyroid neonate borne to a mother on antithyroid drug presents on 12 th day of life with reports of elevated TSH and increased tracer uptake in 99mTc thyroid scan. Disproportionately high TSH in comparison to low maternal antithyroid drug dosage and further elevation of TSH after stopping mother′s antithyroid drugs ruled out maternal antithyroid drug-induced congenital hypothyroidism in the baby. Early institution of therapy in these patients can prevent mental retardation and other features of hypothyroidism.

  3. Caenorhabditis elegans as a Model System for Studying Drug Induced Mitochondrial Toxicity.

    Directory of Open Access Journals (Sweden)

    Richard de Boer

    Full Text Available Today HIV-1 infection is recognized as a chronic disease with obligatory lifelong treatment to keep viral titers below detectable levels. The continuous intake of antiretroviral drugs however, leads to severe and even life-threatening side effects, supposedly by the deleterious impact of nucleoside-analogue type compounds on the functioning of the mitochondrial DNA polymerase. For detailed investigation of the yet partially understood underlying mechanisms, the availability of a versatile model system is crucial. We therefore set out to develop the use of Caenorhabditis elegans to study drug induced mitochondrial toxicity. Using a combination of molecular-biological and functional assays, combined with a quantitative analysis of mitochondrial network morphology, we conclude that anti-retroviral drugs with similar working mechanisms can be classified into distinct groups based on their effects on mitochondrial morphology and biochemistry. Additionally we show that mitochondrial toxicity of antiretroviral drugs cannot be exclusively attributed to interference with the mitochondrial DNA polymerase.

  4. [A Case of Drug-Induced Thrombocytopenia Resulting from Sensitivity to Oxaliplatin].

    Science.gov (United States)

    Masuda, Taiki; Nagai, Kagami; Sanada, Katsuya

    2015-11-01

    A 67-year-old man was diagnosed with pulmonary metastasis from advanced transverse colon cancer. Thus, a local resection was performed. Adjuvant chemotherapy with mFOLFOX6 was started. Sixteen courses were carried out without problems. However, he complained of chills and chest discomfort 2 hours after beginning the 17th course of chemotherapy. Laboratory data showed remarkable thrombocytopenia, and platelet-associated IgG level was high. After administration of steroids and platelet transfusions, the platelet count improved. Therefore, we diagnosed drug-induced thrombocytopenia resulting from sensitivity to oxaliplatin (L-OHP). Since then, sLV5FU2 therapy was started, and the patient received the whole adjuvant chemotherapy without problems. Thrombocytopenia resulting from sensitivity to L-OHP is a relatively rare side effect. We herein report this case with a review of the relevant literature. PMID:26805296

  5. Modulating sensitivity to drug-induced apoptosis: the future for chemotherapy?

    International Nuclear Information System (INIS)

    Drug resistance is a fundamental problem in the treatment of most common human cancers. Our understanding of the cellular mechanisms underlying death and survival has allowed the development of rational approaches to overcoming drug resistance. The mitogen activated protein kinase family of protein serine/threonine kinases has been implicated in this complex web of signalling, with some members acting to enhance death and other members to prevent it. A recent publication by MacKeigan et al is the first to demonstrate an enhancement of drug-induced cell death by simultaneous blockade of MEK-mediated survival signalling, and offers the potential for targeted adjuvant therapy as a means of overcoming drug resistance

  6. Drug-Induced Liver Injury Network Causality Assessment: Criteria and Experience in the United States

    Directory of Open Access Journals (Sweden)

    Paul H. Hayashi

    2016-02-01

    Full Text Available Hepatotoxicity due to drugs, herbal or dietary supplements remains largely a clinical diagnosis based on meticulous history taking and exclusion of other causes of liver injury. In 2004, the U.S. Drug-Induced Liver Injury Network (DILIN was created under the auspices of the U.S. National Institute of Diabetes and Digestive and Kidney Diseases with the aims of establishing a large registry of cases for clinical, epidemiological and mechanistic study. From inception, the DILIN has used an expert opinion process that incorporates consensus amongst three different DILIN hepatologists assigned to each case. It is the most well-established, well-described and vigorous expert opinion process for DILI to date, and yet it is an imperfect standard. This review will discuss the DILIN expert opinion process, its strengths and weaknesses, psychometric performance and future.

  7. [Importance of drug-induced ulceration in endoscopic lesions of the esophagus].

    Science.gov (United States)

    Baeriswyl, G; Bengoa, J; de Peyer, R; Loizeau, E

    1985-01-01

    Drug-induced ulcers of the oesophagus represent a rare but probably under-recorded complication. In a series of 5900 endoscopies performed in 32 months, oesophageal ulcers were seen in 4 cases following the intake of doxycycline, and in one case after ingestion of pinaverium bromide and a bulk laxative respectively. Oesophageal ulcers were seen mainly in young patients without underlying oesophageal disease, presenting with chest pain and odynophagia. The most common site of involvement was at the aortic notch in the middle third of the oesophagus. The course was quickly favorable within 5-10 days after the drug was discontinued, but transient complete abstention from oral intake was required in some cases. Ulceration is thought to be secondary to drug stasis and local cytotoxic effects. Oesophageal ulcers can be prevented simply by recommending intake of the drug with sufficient water in the upright position at least two hours before retiring. PMID:3864236

  8. Radiation- and drug-induced DNA repair in mammalian oocytes and embryos

    International Nuclear Information System (INIS)

    A review of studies showing ultraviolet- or drug-induced unscheduled DNA synthesis in mammalian oocytes and embryos suggests that the female gamete has an excision repair capacity from the earliest stages of oocyte growth. The oocyte's demonstrable excision repair capacity decreases at the time of meiotic maturation for unknown reasons, but the fully mature oocyte maintans a repair capacity, in contrast to the mature sperm, and contributes this to the zygote. Early embryo cells maintain relatively constant levels of excision repair until late fetal stages, when they lose their capacity for excision repair. These apparent changes in excision repair capacity do not have a simple relationship to known differences in radiation sensitivity of germ cells and embryos

  9. Recurrent drug-induced liver injury (DILI) with ciprofloxacin and amoxicillin/clavulanic.

    Science.gov (United States)

    Moreno, Luís; Sánchez-Delgado, Jordi; Vergara, Mercedes; Casas, Meritxell; Miquel, Mireia; Dalmau, Blai

    2015-12-01

    Ciprofloxacin and amoxicillin/clavulanic are two widely used antibiotics due to their high efficacy and few side effects. While the percentage of hepatotoxicity of these antibiotics is low, their frequent use has led to a progressive increase in the number of cases. Both antibiotics have been associated with a wide variety of hepatotoxic reactions, from a slight rise of transaminases to fulminant hepatitis. Once hepatotoxicity secondary to a drug appears, the first step is to discontinue the drug. Physicians may opt to administer an alternative treatment with a different chemical structure. It should be borne in mind, however, that different chemical structures may also cause recurrent drug-induced liver injuries (DILI). We present the case of a patient who consecutively developed DILI due to ciprofloxacin and amoxicillin/clavulanic.

  10. Virus reactivation and intravenous immunoglobulin (IVIG) therapy of drug-induced hypersensitivity syndrome.

    Science.gov (United States)

    Kano, Yoko; Inaoka, Miyuki; Sakuma, Keiichi; Shiohara, Tetsuo

    2005-04-15

    Drug-induced hypersensitivity syndrome (DIHS) is a severe multi-organ system reaction caused by specific drugs. Many reports have revealed that human herpesvirus 6 (HHV-6) reactivation contributes to the development of DIHS. In addition, recent articles have shown that reactivation of other herpesviruses such as human herpesvirus 7 (HHV-7), Epstein-Barr virus (EBV), cytomegalovirus (CMV) might be also implicated in the development of DIHS. These observations suggest that not only HHV-6 but also other herpesvirses might reactivate from the latency and play an important role in the appearance of clinical manifestations of DIHS. Several patients with DIHS were treated with intravenous immunoglobulin (IVIG) in addition to systemic corticosteroids. The results have been encouraging although virus reactivation could not be suppressed. Although the pathomechanism of IVIG treatment in patients with DIHS remains unknown, the therapeutic effects of IVIG could be dependent, in part, on functional capabilities of anti-virus IgG contained in IVIG. PMID:15767030

  11. Assessment of drug-induced hepatotoxicity in clinical practice: A challenge for gastroenterologists

    Institute of Scientific and Technical Information of China (English)

    Raúl J Andrade; Mercedes Robles; Alejandra Fernández-Casta(n)er; Susana López-Ortega; M Carmen López-Vega; M Isabel Lucena

    2007-01-01

    Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and postcommercialization regulatory decisions. The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice.To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug's hepatotoxic potential, the exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology. This process is time-consuming and the final result is frequently inaccurate. Diagnostic algorithms may add consistency to the diagnostic process by translating the suspicion into a quantitative score. Such scales are useful since they provide a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction as well. Current efforts in collecting bona fide cases of drug-induced hepatotoxicity will make refinements of existing scales feasible. It is now relatively easy to accommodate relevant data within the scoring system and to delete low-impact items. Efforts should also be directed toward the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be made. The instrument chosen would enable a confident diagnosis to be made on admission of the patient and treatment to be finetuned as further information is collected.

  12. A Novel SCN5A Mutation Associated with Drug Induced Brugada Type ECG

    Science.gov (United States)

    Turker, Isik; Makiyama, Takeru; Vatta, Matteo; Itoh, Hideki; Ueyama, Takeshi; Shimizu, Akihiko

    2016-01-01

    Background Class IC antiarrhythmic agents may induce acquired forms of Brugada Syndrome. We have identified a novel mutation in SCN5A, the gene that encodes the α-subunit of the human cardiac sodium channel (hNav1.5), in a patient who exhibited Brugada- type ECG changes during pharmacotherapy of atrial arrhythmias. Objective To assess whether the novel mutation p.V1328M can cause drug induced Brugada Syndrome. Methods Administration of pilsicainide, a class IC antiarrhythmic agent, caused Brugada- type ST elevation in a 66-year-old Japanese male who presented with paroxysmal atrial fibrillation (PAF), type I atrial flutter and inducible ventricular fibrillation (VF) during electrophysiological study. Genetic screening using direct sequencing identified a novel SCN5A variant, p.V1328M. Electrophysiological parameters of WT and p.V1328M and their effects on drug pharmacokinetics were studied using the patch-clamp method. Results Whole-cell sodium current densities were similar for WT and p.V1328M channels. While p.V1328M mutation did not affect the voltage-dependence of the activation kinetics, it caused a positive shift of voltage-dependent steady-state inactivation by 7 mV. The tonic block in the presence of pilsicainide was similar in WT and p.V1328M, when sodium currents were induced by a low frequency pulse protocol (q15s). On the contrary, p.V1328M mutation enhanced pilsicainide induced use-dependent block at 2 Hz. (Ki: WT, 35.8 μM; V1328M, 19.3 μM). Conclusion Our study suggests that a subclinical SCN5A mutation, p.V1328M, might predispose individuals harboring it to drug-induced Brugada Syndrome. PMID:27560382

  13. Detection of metabolic activation leading to drug-induced phospholipidosis in rat hepatocyte spheroids.

    Science.gov (United States)

    Takagi, Masashi; Sanoh, Seigo; Santoh, Masataka; Ejiri, Yoko; Kotake, Yaichiro; Ohta, Shigeru

    2016-02-01

    Drug-induced phospholipidosis (PLD) is one of the adverse reactions to treatment with cationic amphiphilic drugs. Recently, simple and reliable evaluation methods for PLD have been reported. However, the predictive power of these methods for in vivo PLD induction is insufficient in some cases. To accurately predict PLD, we focused on drug metabolism and used three-dimensional cultures of hepatocytes known as spheroids. Here we used the fluorescent phospholipid dye N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine (NBD-PE) to detect PLD induction. After 48 hr exposure to 20 µM amiodarone and amitriptyline, PLD inducers, NBD-PE fluorescence in the spheroids was significantly higher than that in the control. In contrast, 1 mM acetaminophen, as a negative control, did not increase fluorescence. Furthermore, the combination of NBD-PE fluorescence and LysoTracker Red fluorescence and the accumulation of intrinsic phospholipids reflected PLD induction in spheroids. To evaluate metabolic activation, we assessed PLD induction by loratadine. NBD-PE fluorescence intensity was significantly increased by 50 µM loratadine treatment. However, the fluorescence was markedly decreased by co-treatment with 500 µM 1-aminobenzotriazole, a broad cytochrome P450 inhibitor. The formation of desloratadine, a metabolite of loratadine, was observed in spheroids after treatment with loratadine alone. These results showed that metabolic activation is the key factor in PLD induction by treatment with loratadine. We demonstrated that rat primary hepatocyte spheroid culture is a useful model for evaluating drug-induced PLD induction mediated by metabolic activation of the drug using the fluorescence probe technique. PMID:26763403

  14. Serotonergic Hyperactivity as a Potential Factor in Developmental, Acquired and Drug-Induced Synesthesia

    Directory of Open Access Journals (Sweden)

    Berit eBrogaard

    2013-10-01

    Full Text Available Though synesthesia research has seen a huge growth in recent decades, and tremendous progress has been made in terms of understanding the mechanism and cause of synesthesia, we are still left mostly in the dark when it comes to the mechanistic commonalities (if any among developmental, acquired and drug-induced synesthesia. We know that many forms of synesthesia involve aberrant structural or functional brain connectivity. Proposed mechanisms include direct projection and disinhibited feedback mechanisms, in which information from two otherwise structurally or functionally separate brain regions mix. We also know that synesthesia sometimes runs in families. However, it is unclear what causes its onset. Studies of psychedelic drugs, such as psilocybin, LSD and mescaline, reveal that exposure to these drugs can induce synesthesia. One neurotransmitter suspected to be central to the perceptual changes is serotonin. Excessive serotonin in the brain may cause many of the characteristics of psychedelic intoxication. Excessive serotonin levels may also play a role in synesthesia acquired after brain injury. In brain injury sudden cell death floods local brain regions with serotonin and glutamate. This neurotransmitter flooding could perhaps result in unusual feature binding. Finally, developmental synesthesia that occurs in individuals with autism may be a result of alterations in the serotonergic system, leading to a blockage of regular gating mechanisms. I conclude on these grounds that one commonality among at least some cases of acquired, developmental and drug-induced synesthesia may be the presence of excessive levels of serotonin, which increases the excitability and connectedness of sensory brain regions.

  15. Nucleoside drugs induce cellular differentiation by caspase-dependent degradation of stem cell factors.

    Directory of Open Access Journals (Sweden)

    Tanja Musch

    Full Text Available BACKGROUND: Stem cell characteristics are an important feature of human cancer cells and play a major role in the therapy resistance of tumours. Strategies to target cancer stem cells are thus of major importance for cancer therapy. Differentiation therapy by nucleoside drugs represents an attractive approach for the elimination of cancer stem cells. However, even if it is generally assumed that the activity of these drugs is mediated by their ability to modulate epigenetic pathways, their precise mode of action remains to be established. We therefore analysed the potential of three nucleoside analogues to induce differentiation of the embryonic cancer stem cell line NTERA 2 D1 and compared their effect to the natural ligand retinoic acid. METHODOLOGY/PRINCIPAL FINDINGS: All nucleoside analogues analyzed, but not retinoic acid, triggered proteolytic degradation of the Polycomb group protein EZH2. Two of them, 3-Deazaneplanocin A (DZNep and 2'-deoxy-5-azacytidine (decitabine, also induced a decrease in global DNA methylation. Nevertheless, only decitabine and 1beta-arabinofuranosylcytosine (cytarabine effectively triggered neuronal differentiation of NT2 cells. We show that drug-induced differentiation, in contrast to retinoic acid induction, is caused by caspase activation, which mediates depletion of the stem cell factors NANOG and OCT4. Consistent with this observation, protein degradation and differentiation could be counteracted by co-treatment with caspase inhibitors or by depletion of CASPASE-3 and CASPASE-7 through dsRNA interference. In agreement with this, OCT4 was found to be a direct in-vitro-target of CASPASE-7. CONCLUSIONS/SIGNIFICANCE: We show that drug-induced differentiation is not a consequence of pharmacologic epigenetic modulation, but is induced by the degradation of stem-cell-specific proteins by caspases. Our results thus uncover a novel pathway that induces differentiation of embryonic cancer stem cells and is triggered by

  16. Frequent nocturnal awakening in children: prevalence, risk factors, and associations with subjective sleep perception and daytime sleepiness

    OpenAIRE

    Li, Liwen; Ren, Jiwei; Shi, Lei; Jin, Xinming; Yan, Chonghuai; Jiang, Fan; Shen, Xiaoming; Li, Shenghui

    2014-01-01

    Background Nocturnal awakening is the most frequent insomnia complaint in the general population. In contrast to a growing knowledge based on adults, little is known about its prevalence, correlated factors, and associations with subjective sleep perception and daytime sleepiness in children. This study was designed to assess the prevalence and the correlate factors of frequent nocturnal awakening (FNA) among Chinese school-aged children. Furthermore, the associations of FNA with subjective s...

  17. Associations between night work and anxiety, depression, insomnia, sleepiness and fatigue in a sample of Norwegian nurses.

    Directory of Open Access Journals (Sweden)

    Nicolas M F Øyane

    Full Text Available BACKGROUND: Night work has been reported to be associated with various mental disorders and complaints. We investigated relationships between night work and anxiety, depression, insomnia, sleepiness and fatigue among Norwegian nurses. METHODS: The study design was cross-sectional, based on validated self-assessment questionnaires. A total of 5400 nurses were invited to participate in a health survey through the Norwegian Nurses' Organization, whereof 2059 agreed to participate (response rate 38.1%. Nurses completed a questionnaire containing items on demographic variables (gender, age, years of experience as a nurse, marital status and children living at home, work schedule, anxiety/depression (Hospital Anxiety and Depression Scale, insomnia (Bergen Insomnia Scale, sleepiness (Epworth Sleepiness Scale and fatigue (Fatigue Questionnaire. They were also asked to report number of night shifts in the last 12 months (NNL. First, the parameters were compared between nurses i never working nights, ii currently working nights, and iii previously working nights, using binary logistic regression analyses. Subsequently, a cumulative approach was used investigating associations between NNL with the continuous scores on the same dependent variables in hierarchical multiple regression analyses. RESULTS: Nurses with current night work were more often categorized with insomnia (OR = 1.48, 95% CI = 1.10-1.99 and chronic fatigue (OR = 1.78, 95% CI = 1.02-3.11 than nurses with no night work experience. Previous night work experience was also associated with insomnia (OR = 1.45, 95% CI = 1.04-2.02. NNL was not associated with any parameters in the regression analyses. CONCLUSION: Nurses with current or previous night work reported more insomnia than nurses without any night work experience, and current night work was also associated with chronic fatigue. Anxiety, depression and sleepiness were not associated with night work, and no cumulative effect of night shifts

  18. Daytime sleepiness, cognitive performance and mood after continuous positive airway pressure for the sleep apnoea/hypopnoea syndrome.

    OpenAIRE

    Engleman, H. M.; Cheshire, K. E.; Deary, I.J.; Douglas, N.J.

    1993-01-01

    BACKGROUND--Patients with the sleep apnoea/hypopnoea syndrome often receive continuous positive airway pressure to improve their symptoms and daytime performance, yet objective evidence of the effect of this treatment on cognitive performance is lacking. METHODS--A prospective parallel group study was performed comparing the change in objective daytime sleepiness as assessed by multiple sleep latency, cognitive function, and mood in 21 patients (mean (SE) number of apnoeas and hypopnoeas/hour...

  19. Excessive Daytime Sleepiness among Hypertensive US-Born Blacks and Foreign-Born Blacks: Analysis of the CAATCH Data

    Directory of Open Access Journals (Sweden)

    N. Williams

    2013-01-01

    Full Text Available Background. Evidence shows that blacks exhibit greater daytime sleepiness compared with whites, based on the Epworth Sleepiness Scale. In addition, sleep complaints might differ based on individuals’ country of origin. However, it is not clear whether individuals’ country of origin has any influence on excessive daytime sleepiness (EDS. Study Objectives. We tested the hypothesis that US-born blacks would show a greater level of EDS compared with foreign-born blacks. The potential effects of sociodemographic and medical risk were also determined. Design. We used the Counseling African-Americans to Control Hypertension (CAATCH data. CAATCH is a group randomized clinical trial that was conducted among 30 community healthcare centers in New York, yielding baseline data for 1,058 hypertensive black patients. Results. Results of univariate logistic regression analysis indicated that US-born blacks were nearly twice as likely as their foreign-born black counterparts to exhibit EDS (OR=1.87, 95% CI: 1.30–2.68, P<0.001. After adjusting for effects of age, sex, education, employment, body mass index, alcohol consumption, and smoking habit, US-born blacks were 69% more likely than their counterparts to exhibit EDS (OR=1.69, 95% CI: 1.11–2.57, P<0.01. Conclusion. Findings demonstrate the importance of considering individuals’ country of origin, in addition to their race and ethnicity, when analyzing epidemiologic sleep data.

  20. Morningness/eveningness chronotype, poor sleep quality, and daytime sleepiness in relation to common mental disorders among Peruvian college students.

    Science.gov (United States)

    Rose, Deborah; Gelaye, Bizu; Sanchez, Sixto; Castañeda, Benjamín; Sanchez, Elena; Yanez, N David; Williams, Michelle A

    2015-01-01

    The study was designed to investigate the association between sleep disturbances and common mental disorders (CMDs) among Peruvian college students. A total of 2538 undergraduate students completed a self-administered questionnaire to gather information about sleep characteristics, sociodemographic, and lifestyle data. Evening chronotype, sleep quality, and daytime sleepiness were assessed using the Horne and Ostberg morningness-eveningness questionnaire, Pittsburgh Sleep Quality Index, and Epworth Sleepiness Scale, respectivelty. Presence of CMDs was evaluated using the General Health Questionnaire. Logistic regression procedures were used to examine the associations of sleep disturbances with CMDs while accounting for possible confounding factors. Overall, 32.9% of the participants had prevalent CMDs (39.3% among females and 24.4% among males). In multivariable-adjusted logistic models, those with evening chronotype (odds ratios (OR) = 1.43; 95% CI 1.00-2.05), poor sleep quality (OR = 4.50; 95% CI 3.69-5.49), and excessive daytime sleepiness (OR = 1.68; 95% CI 1.41-2.01) were at a relative increased odds of CMDs compared with those without sleep disturbances. In conclusion, we found strong associations between sleep disturbances and CMDs among Peruvian college students. Early education and preventative interventions designed to improve sleep habits may effectively alter the possibility of developing CMDs among young adults. PMID:25162477

  1. Comparative Analysis of Lateral Pharyngoplasty and Uvulopalatopharyngoplasty Techniques With Polisomnography and Epworth Sleepiness Scales.

    Science.gov (United States)

    Dizdar, Denizhan; Civelek, Şenol; Çaliş, Zeynep Asli Batur; Dizdar, Senem Kurt; Coşkun, Berna Uslu; Vural, Alperen

    2015-10-01

    Snoring is caused by the vibration of structures of the oral cavity, such as the soft palate, uvula, tonsils, base of the tongue, epiglottis, and lateral pharyngeal walls. When these structures collapse and obstruct the airway, apnea occurs. Obstructive sleep apnea syndrome (OSAS) is characterized by repeated periods of upper airway obstruction, a decrease in arterial oxygen saturation, and interrupted sleep. The prevalence of OSAS is 1% to 5% in men and 1.2% to 2.5% in women. Crucial factors in deciding the surgical approach include a detailed ear-nose-throat examination, Muller maneuver, sleep endoscopy, and apnea hypopnea index scores. Accepted treatments include continuous positive airway pressure (CPAP), surgeries of the base of the tongue and/or palate, and multi-level surgeries. It, however, is important to continue to evaluate the efficacies of such procedures. The authors evaluated the outcomes of 23 patients who underwent surgery for OSAS, using preoperative and postoperative polysomnography (PSG) and the Epworth sleepiness scale (ESS). The results were compared before and after surgery. In all, 14 patients had lateral pharyngoplasty and 9 had uvulopalatopharyngoplasty (UPPP). The PSG and Epworth scale values were significantly lower in both groups, postoperatively. Patients indicated that their quality of life had improved. In conclusion, the surgeries were successful. In line with the literature, our results indicate that lateral pharyngoplasty and UPPP can be used in appropriate patients. Longer-term studies on more patients will provide more detailed information in the future. PMID:26468852

  2. 76 FR 4918 - Drug-Induced Liver Injury: Are We Ready to Look?; Public Conference; Request for Comments

    Science.gov (United States)

    2011-01-27

    ... DILI by periodic tests of serum enzyme activities and bilirubin concentration elevations, and how those...). The purpose of this conference is to consider the effect of the recommendations in the guidance for... for industry entitled ``Drug-Induced Liver Injury: Premarketing Clinical Evaluation'' (see 74 FR...

  3. MicroRNA changes in rat mesentery and serum associated with drug-induced vascular injury

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, Roberta A., E-mail: Roberta.A.Thomas@gsk.com; Scicchitano, Marshall S.; Mirabile, Rosanna C.; Chau, Nancy T.; Frazier, Kendall S.; Thomas, Heath C.

    2012-08-01

    Regulatory miRNAs play a role in vascular biology and are involved in biochemical and molecular pathways dysregulated during vascular injury. Collection and integration of functional miRNA data into these pathways can provide insight into pathogenesis at the site of injury; the same technologies applied to biofluids may provide diagnostic or surrogate biomarkers. miRNA was analyzed from mesentery and serum from rats given vasculotoxic compounds for 4 days. Fenoldopam, dopamine and midodrine each alter hemodynamics and are associated with histologic evidence of vascular injury, while yohimbine is vasoactive but does not cause histologic evidence of vascular injury in rat. There were 38 and 35 miRNAs altered in a statistically significant manner with a fold change of 2 or greater in mesenteries of fenoldopam- and dopamine-dosed rats, respectively, with 9 of these miRNAs shared. 10 miRNAs were altered in rats given midodrine; 6 were shared with either fenoldopam or dopamine. In situ hybridization demonstrated strong expression and co-localization of miR-134 in affected but not in adjacent unaffected vessels. Mesenteric miRNA expression may provide clarity or avenues of research into mechanisms involved in vascular injury once the functional role of specific miRNAs becomes better characterized. 102 miRNAs were altered in serum from rats with drug-induced vascular injury. 10 miRNAs were commonly altered in serum from dopamine and either fenoldopam or midodrine dosed rats; 18 of these 102 were also altered in mesenteries from rats with drug-induced vascular injury, suggesting their possible utility as peripheral biomarkers. -- Highlights: ► Mesentery and serum were examined from rats given vasoactive compounds for 4 days. ► 72 miRNAs were altered in mesenteries from rats with vascular injury. ► miR-134 was localized to affected but not adjacent unaffected vessels. ► 102 miRNAs were changed in serum from rats with vascular injury. ► 18 miRNAs changed in both

  4. Drug-induced interstitial lung diseases. Often forgotten; Medikamenteninduzierte interstitielle Lungenerkrankungen. Haeufig vergessen

    Energy Technology Data Exchange (ETDEWEB)

    Poschenrieder, F.; Stroszczynski, C. [Universitaetsklinikum Regensburg, Institut fuer Roentgendiagnostik, Regensburg (Germany); Hamer, O.W. [Universitaetsklinikum Regensburg, Institut fuer Roentgendiagnostik, Regensburg (Germany); Lungenfachklinik Donaustauf, Donaustauf (Germany)

    2014-12-15

    Drug-induced interstitial lung diseases (DILD) are probably more common than diagnosed. Due to their potential reversibility, increased vigilance towards DILD is appropriate also from the radiologist's point of view, particularly as these diseases regularly exhibit radiological correlates in high-resolution computed tomography (HRCT) of the lungs. Based on personal experience typical relatively common manifestations of DILD are diffuse alveolar damage (DAD), eosinophilic pneumonia (EP), hypersensitivity pneumonitis (HP), organizing pneumonia (OP), non-specific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP). These patterns are presented based on case studies, whereby emphasis is placed on the clinical context. This is to highlight the relevance of interdisciplinary communication and discussion in the diagnostic field of DILD as it is a diagnosis of exclusion or of probability in most cases. Helpful differential diagnostic indications for the presence of DILD, such as an accompanying eosinophilia or increased attenuation of pulmonary consolidations in amiodarone-induced pneumopathy are mentioned and the freely available online database http://www.pneumotox.com is presented. (orig.) [German] Medikamenteninduzierte interstitielle Lungenerkrankungen (engl. ''drug-induced interstitial lung diseases'', DILD) sind wahrscheinlich haeufiger, als sie diagnostiziert werden. Aufgrund ihrer potenziellen Reversibilitaet ist eine erhoehte Vigilanz gegenueber DILD auch seitens der Radiologie angebracht, da diese regelmaessig ein radiomorphologisches Korrelat in der hochaufloesenden Computertomographie (''high-resolution CT'', HRCT) der Lunge aufweisen. Typische, nach eigener Erfahrung relativ haeufige Manifestationsformen von DILD sind der diffuse Alveolarschaden (engl. ''diffuse alveolar damage'', DAD), die eosinophile Pneumonie (EP), die Hypersensitivitaetspneumonitis (HP), die organisierende

  5. Insomnia, daytime sleepiness and cardio-cerebrovascular diseases in the elderly: a 6-year prospective study.

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    Isabelle Jaussent

    Full Text Available OBJECTIVE: To examine 1 the associations between history of cardio-cerebrovascular diseases (CVD and insomnia complaints and excessive daytime sleepiness (EDS, and 2 the relationships between sleep complaints and future CVD in persons over 65. METHODS: CVD was assessed at baseline and during two, four, and six-year follow-up in 5494 non-demented subjects. Self-reported insomnia complaints (poor sleep quality, difficulty in initiating sleep, difficulty in maintening sleep, and early morning awakening, EDS and sleep medication use were evaluated at baseline. Logistic regression models and Cox proportional hazard models, with delayed entry and age of participants as the time scale, were adjusted for socio-demographic, lifestyle and clinical variables. RESULTS: At baseline, 748 participants had a past-history of CVD. A past-history of CVD was associated with EDS (OR = 1.28 95%CI = [1.05-1.57] and the number of insomnia complaints (OR = 1.26 95%CI = [1.03-1.55] for 1-2 insomnia complaints; OR = 1.32 95%CI = [1.03-1.71] for ≥3 complaints. In longitudinal analyses, neither the four components of insomnia nor the number of insomnia complaints were significantly associated with first or recurrent CVD events (n = 391 events. EDS was independently associated with future CVD events even after adjusting for prescribed sleep medication and past-history of CVD (HR = 1.35 95%CI = [1.06-1.71]. CONCLUSION: Our results suggest that the relationships between sleep complaints and CVD could be complex. Insomnia complaints are more likely a consequence of CVD, whereas EDS appears to be a determinant of CVD independently of past-history of CVD. EDS screening may thus constitute a means of detecting persons at high risk of CVD.

  6. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives.

    Science.gov (United States)

    Fontana, Robert J

    2014-04-01

    Idiosyncratic drug-induced liver injury (DILI) is a rare disease that develops independently of drug dose, route, or duration of administration. Furthermore, idiosyncratic DILI is not a single disease entity but rather a spectrum of rare diseases with varying clinical, histological, and laboratory features. The pathogenesis of DILI is not fully understood. Standardization of the DILI nomenclature and methods to assess causality, along with the information provided by the LiverTox Web site, will harmonize and accelerate research on DILI. Studies of new serum biomarkers such as glutamate dehydrogenase, high mobility group box protein 1, and microRNA-122 could provide information for use in diagnosis and prognosis and provide important insights into the mechanisms of the pathogenesis of DILI. Single nucleotide polymorphisms in the HLA region have been associated with idiosyncratic hepatotoxicity attributed to flucloxacillin, ximelagatran, lapatinib, and amoxicillin-clavulanate. However, genome-wide association studies of pooled cases have not associated any genetic factors with idiosyncratic DILI. Whole genome and whole exome sequencing analyses are under way to study cases of DILI attributed to a single medication. Serum proteomic, transcriptome, and metabolome as well as intestinal microbiome analyses will increase our understanding of the mechanisms of this disorder. Further improvements to in vitro and in vivo test systems should advance our understanding of the causes, risk factors, and mechanisms of idiosyncratic DILI.

  7. Drug-induced liver injury secondary to testosterone prohormone dietary supplement use.

    Science.gov (United States)

    Hoedebecke, Kyle; Rerucha, Caitlyn; Maxwell, Kimberly; Butler, Jason

    2013-01-01

    Dietary supplementation has become progressively more prevalent, with over half of the American population reporting use of various products. An increased incidence of supplement use has been reported in the military especially within Special Operations Forces (SOF) where training regimens rival those of elite athletes. Federal regulations regarding dietary supplements are minimal, allowing for general advertisement to the public without emphasis on the potentially harmful side effects. Subsequent medical care for these negative effects causes financial burden on the military in addition to the unit?s loss of an Operator and potential mission compromise. This report reviews a case of an Operator diagnosed with drug-induced liver injury secondary to a testosterone prohormone supplement called Post Cycle II. Clinical situations like this emphasize the necessity that SOF Operators and clinicians be aware of the risks and benefits of these minimally studied substances. Providers should also be aware of the Human Performance Resource Center for Health Information and Natural Medicines Comprehensive Database supplement safety ratings as well as the Food and Drug Administration?s MedWatch and Natural Medicines WATCH, to which adverse reactions should be reported. PMID:24227554

  8. Drug-Induced Dyskinesia, Part 1: Treatment of Levodopa-Induced Dyskinesia.

    Science.gov (United States)

    Vijayakumar, Dhanya; Jankovic, Joseph

    2016-05-01

    Dyskinesias encompass a variety of different hyperkinetic phenomenologies, particularly chorea, dystonia, stereotypies, and akathisia. Levodopa-induced dyskinesia (LID) is one of the main types of drug-induced dyskinesia, occurring in patients with Parkinson's disease (PD) who have been treated with levodopa for long time, but this side effect may be encountered even within a few weeks or months after initiation of levodopa therapy. Based on the temporal pattern in relationship to levodopa dosing, LIDs are divided into "peak-dose dyskinesia," "diphasic dyskinesia," and "wearing off" or "off-period" dyskinesia, of which peak-dose dyskinesia is the most common, followed by off-period, and then diphasic dyskinesia. Treatment strategy includes identifying the kind of dyskinesia and tailoring treatment accordingly. Peak-dose dyskinesia is treated mainly by reducing individual doses of levodopa and adding amantadine and dopamine agonists, whereas off-period dystonia often responds to baclofen and botulinum toxin injections. Diphasic dyskinesias, occurring particularly in patients with young-onset PD, are the most difficult to treat. While fractionation of levodopa dosage is the most frequently utilized strategy, many patients require deep brain stimulation to control their troublesome motor fluctuations and LIDs. A variety of emerging (experimental) drugs currently in development promise to provide better control of LIDs and other levodopa-related complications in the near future. PMID:27091215

  9. [Amiodaron neuropathy: clinical and pathological study of a new drug induced lipidosis (author's transl)].

    Science.gov (United States)

    Dudognon, P; Hauw, J J; de Baecque, C; Derrida, J P; Escourolle, R; Nick, E J

    1979-01-01

    The authors report a case of amiodaron-induced neuropathy in a seventy one years old man. First signs appeared seventeen months after the treatment was started with 400 mg/day for one year and continued with 200 mg/day. Examination on the 29th month disclosed a severe sensory and motor deficit of the limbs with distal predominancy. Motor nerve conduction velocity was strongly impaired without modification of distal latencies. Fundi were normal. The patient improved quickly after drug withdrawal. The authors review the rare similar cases reported in the literature and attempt to describe the clinical caracteristics of amiodaron neuropathy. Qualitative and quantitative light and electron microscopical studies of nerve, muscle and skin biopsies, including teased fibers preparations were performed and they disclosed a marked reduction of the number of myelinated fibers. Wallerian degeneration predominated (31 p. 100) other segmental demyalination (25 p. 100). Numerous polymorphous lipid-laden lysosomes were present in Schwann cells, fibrocytes, pericytes, endothelial and muscle cells. These previously undescribed morphological findings are similar to those present in perhexiline maleate intoxications. We believe amiodaron neuropathy is a new neuropathy with drug-induced lipidosis. PMID:531409

  10. ANTIHEPATOTOXIC EFFECT OF BARLERIA MONTANA LEAVES AGAINST ANTI-TB DRUGS INDUCED HEPATOTOXICITY

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    Jyothi Basini

    2013-06-01

    Full Text Available Introduction: The present study was undertaken to evaluate the protective activity of 95% hydroalcoholic extract of Barleria Montana leaves against anti-TB drugs induced hepatotoxicity. Methods: Hepatotoxicity was induced by anti-TB drugs once daily for 35 days and simultaneously 95% hydroalcoholic extract of Barleria Montana (250 & 500 mg/kg p.o. was administered one hour prior administration of anti-TB drugs. Silymarin was used as standard drug (100 mg/kg p.o.. Results: Elevated levels of SGOT, SGPT, ALP, TB & total cholesterol and decreased total HDL following anti-TB drugs administration. Pretreatment of 95% hydroalcoholic extract of Barleria Montana with anti-TB drugs were significantly reduced biochemical markers and increased total HDL. In vivo antioxidant parameters such as SOD, CAT, GSH, GPx and GRx were suppressed in hepatic control animals. Pre treatment of 95% hydroalcoholic extract of Barleria Montana with anti-TB drugs significantly reduced lipid per oxidation and increased antioxidant activities. Conclusion: The result of the present study was indicated that Barleria Montana showed protective effect on liver toxicity induced by anti-TB drugs might be attributed to its antioxidant activity.

  11. Drug-Induced Nephrotoxicity and Dose Adjustment Recommendations: Agreement Among Four Drug Information Sources

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    Millena Drumond Bicalho

    2015-09-01

    Full Text Available : Hospitalized patients require the use of a variety of drugs, many of which individually or in combination have the potential to cause kidney damage. The use of potentially nephrotoxic drugs is often unavoidable, and the need for dose adjustment should be evaluated. This study is aimed at assessing concordance in information on drug-induced nephrotoxicity and dose adjustment recommendations by comparing four drug information sources (DRUGDEX®, UpToDate®, Medscape® and the Brazilian Therapeutic Formulary using the formulary of a Brazilian public hospital. A total of 218 drugs were investigated. The global Fleiss’ kappa coefficient was 0.265 for nephrotoxicity (p < 0.001; CI 95%, 0.211–0.319 and 0.346 for recommendations (p < 0.001; CI 95%, 0.292–0.401, indicating fair concordance among the sources. Anti-infectives and anti-hypertensives were the main drugs cited as nephrotoxic by the different sources. There were no clear definitions for qualitative data or quantitative values for dose adjustments among the four information sources. There was no advice for dosing for a large number of the drugs in the international databases. The National Therapeutic Formulary offered imprecise dose adjustment recommendations for many nephrotoxic drugs. Discrepancies among information sources may have a clinical impact on patient care and contribute to drug-related morbidity and mortality.

  12. Drug-Induced Nephrotoxicity and Dose Adjustment Recommendations: Agreement Among Four Drug Information Sources.

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    Bicalho, Millena Drumond; Soares, Danielly Botelho; Botoni, Fernando Antonio; Reis, Adriano Max Moreira; Martins, Maria Auxiliadora Parreiras

    2015-09-09

    : Hospitalized patients require the use of a variety of drugs, many of which individually or in combination have the potential to cause kidney damage. The use of potentially nephrotoxic drugs is often unavoidable, and the need for dose adjustment should be evaluated. This study is aimed at assessing concordance in information on drug-induced nephrotoxicity and dose adjustment recommendations by comparing four drug information sources (DRUGDEX(®), UpToDate(®), Medscape(®) and the Brazilian Therapeutic Formulary) using the formulary of a Brazilian public hospital. A total of 218 drugs were investigated. The global Fleiss' kappa coefficient was 0.265 for nephrotoxicity (p < 0.001; CI 95%, 0.211-0.319) and 0.346 for recommendations (p < 0.001; CI 95%, 0.292-0.401), indicating fair concordance among the sources. Anti-infectives and anti-hypertensives were the main drugs cited as nephrotoxic by the different sources. There were no clear definitions for qualitative data or quantitative values for dose adjustments among the four information sources. There was no advice for dosing for a large number of the drugs in the international databases. The National Therapeutic Formulary offered imprecise dose adjustment recommendations for many nephrotoxic drugs. Discrepancies among information sources may have a clinical impact on patient care and contribute to drug-related morbidity and mortality.

  13. Anti-rods/rings: a human model of drug-induced autoantibody generation

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    S. John eCalise

    2015-02-01

    Full Text Available In recent years, autoantibodies targeting subcellular structures described as the rods and rings pattern in HEp-2 ANA have been presented as a unique case of autoantibody generation. These rod and ring structures (RR are at least partially composed of inosine monophosphate dehydrogenase type 2 (IMPDH2, and their formation can be induced in vitro by several small-molecule inhibitors, including some IMPDH2 inhibitors. Autoantibodies targeting these relatively unknown structures have been almost exclusively observed in hepatitis C (HCV patients who have undergone treatment with pegylated interferon-α/ribavirin (IFN/RBV combination therapy. To date, anti-RR antibodies have not been found in treatment-naïve HCV patients or in patients from any other disease groups, with few reported exceptions. Here, we describe recent advances in characterizing the RR structure and the strong association between anti-RR antibody response and HCV patients treated with IFN/RBV, detailing why anti-RR can be considered a human model of drug-induced autoantibody generation.

  14. Metabolomics approaches for discovering biomarkers of drug-induced hepatotoxicity and nephrotoxicity.

    Science.gov (United States)

    Beger, Richard D; Sun, Jinchun; Schnackenberg, Laura K

    2010-03-01

    Hepatotoxicity and nephrotoxicity are two major reasons that drugs are withdrawn post-market, and hence it is of major concern to both the FDA and pharmaceutical companies. The number of cases of serious adverse effects (SAEs) in marketed drugs has climbed faster than the number of total drug prescriptions issued. In some cases, preclinical animal studies fail to identify the potential toxicity of a new chemical entity (NCE) under development. The current clinical chemistry biomarkers of liver and kidney injury are inadequate in terms of sensitivity and/or specificity, prompting the need to discover new translational specific biomarkers of organ injury. Metabolomics along with genomics and proteomics technologies have the capability of providing translational diagnostic and prognostic biomarkers specific for early stages of liver and kidney injury. Metabolomics has several advantages over the other omics platforms such as ease of sample preparation, data acquisition and use of biofluids collected through minimally invasive procedures in preclinical and clinical studies. The metabolomics platform is reviewed with particular emphasis on applications involving drug-induced hepatotoxicity and nephrotoxicity. Analytical platforms for metabolomics, chemometrics for mining metabolomics data and the applications of the metabolomics technologies are covered in detail with emphasis on recent work in the field.

  15. Psychobiology of drug-induced religious experience: from the brain "locus of religion" to cognitive unbinding.

    Science.gov (United States)

    Nencini, Paolo; Grant, Kathleen A

    2010-11-01

    The recent interest in the psychopharmacological underpinnings of religious experiences has led to both the laboratory characterizations of drug-induced mystical events and psychobiological models of religious experiences rooted in evolution and fitness. Our examination of this literature suggests that these theories may be congruent only within more modern religious and cultural settings and are not generalizable to all historical beliefs, as would be expected from an evolutionarily conserved biological mechanism. The strong influence of culture on the subjective effects of drugs as well as religious thoughts argues against the concept of a common pathway in the brain uniquely responsible for these experiences. Rather, the role of personal beliefs, expectations and experiences may interject bias into the interpretation of psychoactive drug action as a reflection of biologically based religious thought. Thus, psychobiological research proposing specific brain mechanisms should consider anthropological and historical data to address alternative explanations to the "fitness" of religious thought. A psychobiological model of the religious experience based on the concept of cognitive unbinding seems to accommodate these data better than that of a specific brain locus of religion.

  16. Ice water submersion for rapid cooling in severe drug-induced hyperthermia

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    Laskowski, Larissa K.; Landry, Adaira; Vassallo, Susi U.; Hoffman, Robert S.

    2015-01-01

    Context The optimal method of cooling hyperthermic patients is controversial. Although controlled data support ice water submersion, many authorities recommend a mist and fan technique. We report two patients with drug-induced hyperthermia, to demonstrate the rapid cooing rates of ice water submersion. Case details Case 1. A 27-year-old man presented with a sympathomimetic toxic syndrome and a core temperature of 41.4°C after ingesting 4-fluoroamphetamine. He was submerged in ice water and his core temperature fell to 38°C within 18 minutes (a mean cooling rate of 0.18°C/min). His vital signs stabilized, his mental status improved and he left on hospital day 2. Case 2. A 32-year-old man with a sympathomimetic toxic syndrome after cocaine use was transported in a body bag and arrived with a core temperature of 44.4°C. He was intubated, sedated with IV benzodiazepines, and submerged in ice water. After 20 minutes his temperature fell to 38.8°C (a cooling rate of 0.28°C/min). He was extubated the following day, and discharged on day 10. Discussion In these two cases, cooling rates exceeded those reported for mist and fan technique. Since the priority in hyperthermia is rapid cooling, clinical data need to be collected to reaffirm the optimal approach. PMID:25695144

  17. [Role of ABC efflux transporters in the oral bioavailability and drug-induced intestinal toxicity].

    Science.gov (United States)

    Yokooji, Tomoharu

    2013-01-01

    The gastrointestinal tract is the organ that absorbs nutrients and water from foods and drinks. This organ is often exposed to various harmful xenobiotics, and therefore possesses various detoxification/barrier systems, including metabolizing enzymes and efflux transporters. Intestinal epithelial cells express ATP-binding cassette (ABC) efflux transporters such as P-glycoprotein, multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein, in addition to various solute carrier (SLC) influx transporters. These transporters are expressed site- and membrane-specifically in enterocytes, which affects the bioavailability of ingested substrate drugs. Expression and/or function of transporters can be modulated by various compounds, including therapeutic drugs, herbal products, some foods, and by disease states. The modulation of transporters could cause unexpectedly higher or lower blood concentrations, marked inter- and intra-individual variations in pharmacokinetics, and unreliable pharmacological actions in association with toxicities of substrates. Recently, we found that hyperbilirubinemia, which occurs in some disease states, increased intestinal accumulation and toxicity of methotrexate, an MRP substrate, because of the suppression of MRP function by high plasma concentrations of conjugated bilirubin. We also attempted to ameliorate the intestinal toxicity of irinotecan hydrochloride by modulating the hepatic and intestinal functions of MRP2. This review summarizes our findings regarding the role of ABC transporters, especially MRPs, in oral bioavailability and in drug-induced intestinal toxicity. Our approach to treat intestinal toxicity using an MRP2 modulator is also described. PMID:23811769

  18. Integrated Analysis of Drug-Induced Gene Expression Profiles Predicts Novel hERG Inhibitors

    Science.gov (United States)

    Babcock, Joseph J.; Du, Fang; Xu, Kaiping; Wheelan, Sarah J.; Li, Min

    2013-01-01

    Growing evidence suggests that drugs interact with diverse molecular targets mediating both therapeutic and toxic effects. Prediction of these complex interactions from chemical structures alone remains challenging, as compounds with different structures may possess similar toxicity profiles. In contrast, predictions based on systems-level measurements of drug effect may reveal pharmacologic similarities not evident from structure or known therapeutic indications. Here we utilized drug-induced transcriptional responses in the Connectivity Map (CMap) to discover such similarities among diverse antagonists of the human ether-à-go-go related (hERG) potassium channel, a common target of promiscuous inhibition by small molecules. Analysis of transcriptional profiles generated in three independent cell lines revealed clusters enriched for hERG inhibitors annotated using a database of experimental measurements (hERGcentral) and clinical indications. As a validation, we experimentally identified novel hERG inhibitors among the unannotated drugs in these enriched clusters, suggesting transcriptional responses may serve as predictive surrogates of cardiotoxicity complementing existing functional assays. PMID:23936032

  19. Hyperacute drug-induced hepatitis with intravenous amiodarone: case report and review of the literature

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    Nasser M

    2013-09-01

    Full Text Available Mohammad Nasser, Timothy R Larsen, Barryton Waanbah, Ibrahim Sidiqi, Peter A McCullough Providence Hospitals and Medical Centers, Department of Medicine, Division of Cardiology, Southfield and Novi, MI, USA Abstract: Amiodarone is a benzofuran class III antiarrhythmic drug used to treat a wide spectrum of ventricular tachyarrhythmias. The parenteral formulation is prepared in polysorbate 80 diluent. We report an unusual case of acute elevation of aminotransaminase concentrations after the initiation of intravenous amiodarone. An 88-year-old Caucasian female developed acute hepatitis and renal failure after initiating intravenous amiodarone for atrial fibrillation with a rapid ventricular response in the setting of acutely decompensated heart failure and hepatic congestion. Liver transaminases returned to baseline within 7 days after discontinuing the drug. Researchers hypothesized that this type of injury is related to liver ischemia with possible superimposed direct drug toxicity. The CIOMS/RUCAM scale identifies our patient’s acute hepatitis as a highly probable adverse drug reaction. Future research is needed to understand the mechanisms by which hyperacute drug toxicity occurs in the setting of impaired hepatic perfusion and venous congestion. Keywords: intravenous amiodarone, acute hepatotoxicity, liver transaminases, drug-induced liver toxicity

  20. Female gender as a susceptibility factor for drug-induced liver injury.

    Science.gov (United States)

    Amacher, David E

    2014-09-01

    Adverse drug reactions (ADRs) can involve all tissues and organs, but liver injuries are considered among the most serious. A number of prospective, multicenter studies have confirmed a higher risk of ADRs in general among female subjects compared to a male cohort. Although drug-induced liver injury (DILI) is infrequently encountered, the preponderance of evidence suggests that women appear to be more susceptible than men to fulminate hepatic/acute liver failure especially in response to some anti-infective drugs and to autoimmune-like hepatitis following exposure to certain other therapeutic drugs. A number of hypotheses have been proposed to explain this sex difference in susceptibility to DILI. Collectively, these hypotheses suggest three basic sex-dependent mechanisms that include differences in various aspects of drug pharmacokinetics (PK) or pharmacodynamics following the administration of certain drugs; specific hormonal effects or interactions with immunomodulating agents or signaling molecules; and differences in the adverse response of the immune system to some drugs, reactive drug metabolites, or drug-protein adducts. At the preclinical drug safety stage, there is a need for more research on hormonal effects on drug PK and for additional research on gender differences in aberrant immune responses that may lead to idiosyncratic DILI in some female patients. Because the detection of rare but serious hepatic ADRs requires the exposure of very large patient populations, pharmacovigilance networks will continue to play a key role in the postmarketing surveillance for their detection and reporting. PMID:24299907

  1. Drug induced immune haemolytic anaemia in the Berlin Case-Control Surveillance Study.

    Science.gov (United States)

    Garbe, Edeltraut; Andersohn, Frank; Bronder, Elisabeth; Klimpel, Andreas; Thomae, Michael; Schrezenmeier, Hubert; Hildebrandt, Martin; Späth-Schwalbe, Ernst; Grüneisen, Andreas; Mayer, Beate; Salama, Abdulgabar; Kurtal, Hanife

    2011-09-01

    Drug-induced immune haemolytic anaemia is a rare but serious condition. This study investigated the possibility of drug aetiology of immune haemolytic anaemia (IHA) in 134 patients with new onset of IHA who were identified in the Berlin Case-Control Surveillance Study between 2000 and 2009. Single drugs related to IHA in three or more patients and assessed more than once as a certain or probable cause of IHA in a standardized causality assessment included diclofenac, fludarabine, oxaliplatin, ceftriaxone and piperacillin. In a case-control study including all 124 IHA cases developed in outpatient care and 731 controls, significantly increased odds ratios (OR) were observed for beta-lactam antibiotics (OR=8·8; 95% confidence interval [CI] 3·2-25·2), cotrimoxazole (OR=6·5; CI 1·1-37·9), ciprofloxacin (OR=6·9, CI 1·3-38·5), fludarabine (OR=22·2; CI: 2·8-454·5) and lorazepam (OR=5·3; CI: 1·2-21·2). Excluding new onset cases with a chronic IHA disease course, an increased risk became also apparent for diclofenac with an OR of 3·1 (CI 1·3-7·0). This is the first case-control study investigating drugs as risk factors for IHA. It corroborates an increased risk for several drugs that have been implicated as a cause of IHA in the standardized causality assessment of individual cases. PMID:21749359

  2. Chinese Skullcap in Move Free Arthritis Supplement Causes Drug Induced Liver Injury and Pulmonary Infiltrates

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    Renumathy Dhanasekaran

    2013-01-01

    Full Text Available Herbal medications are being increasingly used by the American population especially for common conditions like arthritis. They have been reported to cause adverse effects, including significant hepatotoxicity, but reporting remains sporadic. We report here a patient who developed drug induced liver injury following the intake of Move Free, which is an over-the-counter arthritis supplement. We propose that Chinese skullcap, which is one of the herbal ingredients of the medication, is responsible for the adverse event. There was a strong temporal association between the intake of supplement and onset of symptoms, and also there have been a few recent case reports implicating the same component. A unique observation in our case is the occurrence of pulmonary infiltrates simultaneously with the hepatotoxicity, and this side effect has not been well documented before. Both the hepatic and pulmonary complications completely resolved over few weeks after the patient stopped taking the medication. Since these supplements are readily available over the counter, we feel that it is important to document possible adverse outcomes to raise awareness in the medical community and also among patients.

  3. Drug-induced diseases (DIDs: An experience of a tertiary care teaching hospital from India

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    Vishal R Tandon

    2015-01-01

    Full Text Available Background & objectives: Drug-induced diseases (DIDs are well known but least studied. Data on DIDs from India are not available. Hence, this retrospective cross-sectional study was undertaken using suspected adverse drug reaction (ADR data collected form Pharmacovigilance Programme of India (PvPI to evaluate profile of DIDs over two years, in a tertiary care teaching hospital from north India. Methods: The suspected ADRs in the form of DID were evaluated for drug and disease related variables and were classified in terms of causality. Results: DID rate was 38.80 per cent. Mean duration of developing DIDs was 26.05 ± 9.6 days; 25.16 per cent had more than one co-morbid condition. Geriatric population (53.99% accounted for maximum DIDs followed by adult (37.79% and paediatric (8.21%. Maximum events were probable (93.98% followed by possible (6.04%. All DIDs required intervention. Gastritis (7.43%, diarrhoea (5.92%, anaemia (4.79%, hypotension (2.77%, hepatic dysfunction (2.69%, hypertension (1.51%, myalgia (1.05%, and renal dysfunction (1.01% were some of the DIDs. Anti-tubercular treatment (ATT, anti- retroviral treatment (ART, ceftriaxone injection, steroids, non-steroidal anti-inflammatory drugs, antimicrobials and anticancer drugs were found as commonly offending drugs. Interpretation & conclusions: Our findings show that DIDs are a significant health problem in our country, which need more attention.

  4. Drug-induced hepatitis superimposed on the presence of anti-SLA antibody: a case report

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    Etxagibel Aitziber

    2008-01-01

    Full Text Available Abstract Introduction Autoimmune hepatitis is a necroinflammatory disorder of unknown etiology characterized by the presence of circulating antibodies, hypergammaglobulinemia, and response to immunosuppression. It has the histological features of chronic hepatitis. The onset is usually insidious, but in some patients the presentation may be acute and occasionally severe. Certain drugs can induce chronic hepatitis mimicking autoimmune hepatitis. Different autoantibodies have been associated with this process but they are not detectable after drug withdrawal and clinical resolution. Case presentation We describe a case of drug-induced acute hepatitis associated with antinuclear, antisoluble liver-pancreas and anti-smooth muscle autoantibodies in a 66-year-old woman. Abnormal clinical and biochemical parameters resolved after drug withdrawal, but six months later anti-soluble liver-pancreas antibodies remained positive and liver biopsy showed chronic hepatitis and septal fibrosis. Furthermore, our patient has a HLA genotype associated with autoimmune hepatitis. Conclusion Patient follow-up will disclose whether our patient suffers from an autoimmune disease and if the presence of anti-soluble liver antigens could precede the development of an autoimmune hepatitis, as the presence of antimitochondrial antibodies can precede primary biliary cirrhosis.

  5. From Drug-Induced Developmental Neuroapoptosis to Pediatric Anesthetic Neurotoxicity-Where Are We Now?

    Science.gov (United States)

    Creeley, Catherine E

    2016-01-01

    The fetal and neonatal periods are critical and sensitive periods for neurodevelopment, and involve rapid brain growth in addition to natural programmed cell death (i.e., apoptosis) and synaptic pruning. Apoptosis is an important process for neurodevelopment, preventing redundant, faulty, or unused neurons from cluttering the developing brain. However, animal studies have shown massive neuronal cell death by apoptosis can also be caused by exposure to several classes of drugs, namely gamma-aminobutyric acid (GABA) agonists and N-methyl-d-aspartate (NMDA) antagonists that are commonly used in pediatric anesthesia. This form of neurotoxic insult could cause a major disruption in brain development with the potential to permanently shape behavior and cognitive ability. Evidence does suggest that psychoactive drugs alter neurodevelopment and synaptic plasticity in the animal brain, which, in the human brain, may translate to permanent neurodevelopmental changes associated with long-term intellectual disability. This paper reviews the seminal animal research on drug-induced developmental apoptosis and the subsequent clinical studies that have been conducted thus far. In humans, there is growing evidence that suggests anesthetics have the potential to harm the developing brain, but the long-term outcome is not definitive and causality has not been determined. The consensus is that there is more work to be done using both animal models and human clinical studies. PMID:27537919

  6. Simple and sensitive method for monitoring drug-induced cell injury in cultured cells

    Energy Technology Data Exchange (ETDEWEB)

    Shirhatti, V.; Krishna, G.

    1985-06-01

    A simple, sensitive method has been developed for evaluating cell injury noninvasively in monolayer cells in culture. The cell ATP pool was radiolabeled by incubating the cells with (/sup 14/C)adenine. The uptake and incorporation of (/sup 14/C)adenine was shown to proportional to the number of cells. As determined by HPLC, about 65-70% of the incorporated /sup 14/C label was in the ATP pool, 15-20% was in the ADP pool, and the rest was in the 5'-AMP pool. When prelabeled cells were exposed to toxic drugs (acetaminophen, calcium ionophore A-23187, or daunomycin) there was a marked decrease in cell ATP with a concomitant increase in leakage of labeled nucleotides, mainly 5'-AMP and 5'IMP. The authors have shown that leakage of /sup 14/C label into the medium from the prelabeled cells may be employed for quantitation of cell injury. This new measure of toxicity was shown to correlate very well with LDH leakage from the cells, which is a well accepted measure of cell injury. The leakage of 5'-(/sup 14/C)AMP also correlated very well with the reduction of cell ATP in cardiac myocytes. This method has been used for monitoring drug-induced toxicity in liver cells, cardiac myocytes, and LB cells.

  7. Advances in Engineered Liver Models for Investigating Drug-Induced Liver Injury

    Science.gov (United States)

    Lin, Christine

    2016-01-01

    Drug-induced liver injury (DILI) is a major cause of drug attrition. Testing drugs on human liver models is essential to mitigate the risk of clinical DILI since animal studies do not always suffice due to species-specific differences in liver pathways. While primary human hepatocytes (PHHs) can be cultured on extracellular matrix proteins, a rapid decline in functions leads to low sensitivity (<50%) in DILI prediction. Semiconductor-driven engineering tools now allow precise control over the hepatocyte microenvironment to enhance and stabilize phenotypic functions. The latest platforms coculture PHHs with stromal cells to achieve hepatic stability and enable crosstalk between the various liver cell types towards capturing complex cellular mechanisms in DILI. The recent introduction of induced pluripotent stem cell-derived human hepatocyte-like cells can potentially allow a better understanding of interindividual differences in idiosyncratic DILI. Liver models are also being coupled to other tissue models via microfluidic perfusion to study the intertissue crosstalk upon drug exposure as in a live organism. Here, we review the major advances being made in the engineering of liver models and readouts as they pertain to DILI investigations. We anticipate that engineered human liver models will reduce drug attrition, animal usage, and cases of DILI in humans. PMID:27725933

  8. Dynamic Drug-Induced Sleep Computed Tomography in Adults With Obstructive Sleep Apnea

    Science.gov (United States)

    Li, Hsueh-Yu; Lo, Yu-Lun; Wang, Chao-Jan; Hsin, Li-Jen; Lin, Wan-Ni; Fang, Tuan-Jen; Lee, Li-Ang

    2016-01-01

    Surgical success for obstructive sleep apnea (OSA) depends on identifying sites of obstruction in the upper airway. In this study, we investigated sites of obstruction by evaluating dynamic changes in the upper airway using drug-induced sleep computed tomography (DI-SCT) in patients with OSA. Thirty-five adult patients with OSA were prospectively enrolled. Sleep was induced with propofol under light sedation (bispectral index 70–75), and low-dose 320-detector row CT was performed for 10 seconds over a span of 2–3 respiratory cycles with supporting a continuous positive airway pressure model. Most (89%) of the patients had multi-level obstructions. Total obstruction most commonly occurred in the velum (86%), followed by the tongue (57%), oropharyngeal lateral wall (49%), and epiglottis (26%). There were two types of anterior-posterior obstruction of the soft palate, uvular (94%) and velar (6%), and three types of tongue obstruction, upper (30%), lower (37%), and upper plus lower obstruction (33%). DI-SCT is a fast and safe tool to identify simulated sleep airway obstruction in patients with OSA. It provides data on dynamic airway movement in the sagittal view which can be used to differentiate palate and tongue obstructions, and this can be helpful when planning surgery for patients with OSA. PMID:27762308

  9. The role of eNOS phosphorylation in causing drug-induced vascular injury.

    Science.gov (United States)

    Tobin, Grainne A McMahon; Zhang, Jun; Goodwin, David; Stewart, Sharron; Xu, Lin; Knapton, Alan; González, Carlos; Bancos, Simona; Zhang, Leshuai; Lawton, Michael P; Enerson, Bradley E; Weaver, James L

    2014-06-01

    Previously we found that regulation of eNOS is an important part of the pathogenic process of Drug-induced vascular injury (DIVI) for PDE4i. The aims of the current study were to examine the phosphorylation of eNOS in mesentery versus aorta at known regulatory sites across DIVI-inducing drug classes and to compare changes across species. We found that phosphorylation at S615 in rats was elevated 35-fold 2 hr after the last dose of CI-1044 in mesentery versus 3-fold in aorta. Immunoprecipitation studies revealed that many of the upstream regulators of eNOS activation were associated with eNOS in 1 or more signalosome complexes. Next rats were treated with drugs from 4 other classes known to cause DIVI. Each drug was given alone and in combination with SIN-1 (NO donor) or L-NAME (eNOS inhibitor), and the level of eNOS phosphorylation in mesentery and aorta tissue was correlated with the extent of vascular injury and measured serum nitrite. Drugs or combinations produced altered serum nitrite levels as well as vascular injury score in the mesentery. The results suggested that phosphorylation of S615 may be associated with DIVI activity. Studies with the species-specific A2A adenosine agonist CI-947 in rats versus primates showed a similar pattern.

  10. Acute liver failure caused by drug-induced hypersensitivity syndrome associated with hyperferritinemia

    Institute of Scientific and Technical Information of China (English)

    Masayuki Miyazaki; Masatake Tanaka; Akihiro Ueda; Tsuyoshi Yoshimoto; Masaki Kato; Makoto Nakamuta; Kazuhiro Kotoh; Ryoichi Takayanagi

    2011-01-01

    Drug-induced hypersensitivity syndrome (DIHS) is a se-vere reaction usually characterized by fever, rash, and multiorgan failure, occurring 2-6 wk after drug introduction.It is an immune-mediated reaction involving macrophage and T-lymphocyte activation and cytokine release. A 54-year-old woman was diagnosed with rheumatic arthritis and initiated salazosulfapyridine by mouth. About 10 d later, she had a high fever, skin rash and liver dysfunction. She was admitted to hospital and diagnosed with a drug eruption. She was treated with oral prednisolone 30 mg/d; however, she developed high fever again and her blood tests showed acute liver failure and cytopenia associated with hyperferritinemia. She was diagnosed with acute liver failure and hemophagocytosis caused by DIHS. She was transferred to the Department of Medicine and Bioregulatory Science, Kyushu University, where she was treated with arterial steroid injection therapy. Following this treatment, her liver function improved and serum ferritin immediately decreased. We hypothesized that an immune-mediated reaction in DIHS may have generated over-activation of macrophages and T-lymphocytes, followed by a cytokine storm that affected various organs. The measurement of serum ferritin might be a useful marker of the severity of DIHS.

  11. Generation of Pig Induced Pluripotent Stem Cells with a Drug-Inducible System

    Institute of Scientific and Technical Information of China (English)

    Zhao Wu; Jijun Chen; Jiangtao Ren; Lei Bao; Jing Liao; Chun Cui; Linjun Rao; Hui Li; Yijun Gu; Huiming Dai; Hui Zhu; Xiaokun Teng; Lu Cheng; Lei Xiao

    2009-01-01

    Domesticated ungulate pluripotent embryonic stem (ES) cell lines would be useful for generating precise gene-modified animals. To date, many efforts have been made to establish domesticated ungulate pluripotent ES cells from early embryos without success.Here, we report the generation of porcine-induced pluripotent stem (iPS) cells using drug-inducible expression of defined factors.We showed that porcine iPS cells expressed alkaline phosphatase, SSEA3, SSEA4, Tra-1-60, Tra-1-81, Oct3/4, Nanog, Sox2, Rex1 and CDH1. Pig iPS cells expressed high levels of telomerase activity and showed normal karyotypes. These cells could differentiate into cell types of all three germ layers in vitro and in teratomas. Our study reveals properties of porcine pluripotent stem cells that may facilitate the eventual establishment of porcine ES cells. Moreover, the porcine iPS cells produced may be directly useful for the generation of precise gene-modified pigs.

  12. Integrated analysis of drug-induced gene expression profiles predicts novel hERG inhibitors.

    Directory of Open Access Journals (Sweden)

    Joseph J Babcock

    Full Text Available Growing evidence suggests that drugs interact with diverse molecular targets mediating both therapeutic and toxic effects. Prediction of these complex interactions from chemical structures alone remains challenging, as compounds with different structures may possess similar toxicity profiles. In contrast, predictions based on systems-level measurements of drug effect may reveal pharmacologic similarities not evident from structure or known therapeutic indications. Here we utilized drug-induced transcriptional responses in the Connectivity Map (CMap to discover such similarities among diverse antagonists of the human ether-à-go-go related (hERG potassium channel, a common target of promiscuous inhibition by small molecules. Analysis of transcriptional profiles generated in three independent cell lines revealed clusters enriched for hERG inhibitors annotated using a database of experimental measurements (hERGcentral and clinical indications. As a validation, we experimentally identified novel hERG inhibitors among the unannotated drugs in these enriched clusters, suggesting transcriptional responses may serve as predictive surrogates of cardiotoxicity complementing existing functional assays.

  13. Antinuclear antibody-negative, drug-induced lupus caused by lisinopril.

    Science.gov (United States)

    Carter, J D; Valeriano-Marcet, J; Kanik, K S; Vasey, F B

    2001-11-01

    The clinical symptoms of drug-induced lupus (DIL) are similar to those of idiopathic systemic lupus erythematosus. The literature indicates that in patients with DIL, sera generally contain antinuclear antibodies (ANAs); however, ANA-negative DIL has been reported. The list of medications implicated as etiologic agents in DIL continues to grow. This list includes two different types of angiotensin-converting enzyme inhibitors--captopril and enalapril. We report the first case of DIL caused by lisinopril. Our patient had negative results on ANA testing and had histone antibodies (IgG anti-[H2A-H2B]-DNA) mirroring the disease course. Antibodies to the (H2A-H2B)-DNA complex are seen in more than 90% of patients with active DIL, excluding those with DIL due to hydralazine. Thus, it is important to recognize the clinical significance of IgG anti-(H2A-H2B)-DNA antibodies and that negative ANA test results do not preclude the diagnosis of DIL.

  14. Metabolomics approaches for discovering biomarkers of drug-induced hepatotoxicity and nephrotoxicity

    International Nuclear Information System (INIS)

    Hepatotoxicity and nephrotoxicity are two major reasons that drugs are withdrawn post-market, and hence it is of major concern to both the FDA and pharmaceutical companies. The number of cases of serious adverse effects (SAEs) in marketed drugs has climbed faster than the number of total drug prescriptions issued. In some cases, preclinical animal studies fail to identify the potential toxicity of a new chemical entity (NCE) under development. The current clinical chemistry biomarkers of liver and kidney injury are inadequate in terms of sensitivity and/or specificity, prompting the need to discover new translational specific biomarkers of organ injury. Metabolomics along with genomics and proteomics technologies have the capability of providing translational diagnostic and prognostic biomarkers specific for early stages of liver and kidney injury. Metabolomics has several advantages over the other omics platforms such as ease of sample preparation, data acquisition and use of biofluids collected through minimally invasive procedures in preclinical and clinical studies. The metabolomics platform is reviewed with particular emphasis on applications involving drug-induced hepatotoxicity and nephrotoxicity. Analytical platforms for metabolomics, chemometrics for mining metabolomics data and the applications of the metabolomics technologies are covered in detail with emphasis on recent work in the field.

  15. Liver injury from Herbals and Dietary Supplements in the US Drug Induced Liver Injury Network

    Science.gov (United States)

    Navarro, Victor J.; Barnhart, Huiman; Bonkovsky, Herbert L.; Davern, Timothy; Fontana, Robert J.; Grant, Lafaine; Reddy, K. Rajender; Seeff, Leonard B.; Serrano, Jose; Sherker, Averell H.; Stolz, Andrew; Talwalkar, Jayant; Vega, Maricruz; Vuppalanchi, Raj

    2014-01-01

    Background The Drug-Induced Liver Injury Network (DILIN) studies hepatotoxicity due to conventional medications as well as herbals and dietary supplements (HDS). Rationale To characterize hepatotoxicity and its outcomes from HDS versus medications, patients with hepatotoxicity attributed to medications or HDS were enrolled prospectively between 2004 and 2013. The study took place among eight US referral centers that are part of the DILIN. Consecutive patients with liver injury referred to a DILIN center were eligible. The final sample comprised 130 (15.5%) of all subjects enrolled (839) who were judged to have experienced liver injury due to HDS. Hepatotoxicity due to HDS was evaluated by expert opinion. Demographic and clinical characteristics and outcome assessments including death and liver transplantation were ascertained. Cases were stratified and compared according to the type of agent implicated in liver injury; 45 had injury due to bodybuilding HDS, 85 due to non-bodybuilding HDS, and 709 due to medications. Main Results Liver injury due to HDS increased from 7% to 20% (p Bodybuilding HDS caused prolonged jaundice (median 91 days) in young men but did not result in any fatalities or liver transplantation. The remaining HDS cases presented as hepatocellular injury, predominantly in middle-aged women and more frequently led to death or transplantation compared to injury from medications (13% vs. 3%, p bodybuilding HDS is more severe than from bodybuilding HDS or medications, as evidenced by differences in unfavorable outcomes; death and transplantation. PMID:25043597

  16. The effect of split sleep schedules (6h-on/6h-off) on neurobehavioural performance, sleep and sleepiness.

    Science.gov (United States)

    Short, Michelle A; Centofanti, Stephanie; Hilditch, Cassie; Banks, Siobhan; Lushington, Kurt; Dorrian, Jillian

    2016-05-01

    Shorter, more frequent rosters, such as 6h-on/6h-off split shifts, may offer promise to sleep, subjective sleepiness and performance by limiting shift length and by offering opportunities for all workers to obtain some sleep across the biological night. However, there exists a paucity of studies that have examined these shifts using objective measures of sleep and performance. The present study examined neurobehavioural performance, sleepiness and sleep during 6h-on/6h-off split sleep schedules. Sixteen healthy adults (6 males, 26.13 y ± 4.46) participated in a 9-day laboratory study that included two baseline nights (BL, 10h time in bed (TIB), 2200 h-0800 h), 4 days on one of two types of 6h-on/6h-off split sleep schedules with 5h TIB during each 'off' period (6h early: TIB 0300 h-0800 h and 1500 h-20000 h, or 6-h late: TIB 0900 h-1400 h and 2100 h-0200 h), and two recovery nights (10h TIB per night, 2200 h-0800 h). Participants received 10h TIB per 24h in total across both shift schedules. A neurobehavioural test bout was completed every 2 h during wake, which included the Psychomotor Vigilance Task (PVT) and the Karolinska Sleepiness Scale (KSS). Linear mixed effects models were used to assess the effect of day (BL, shift days 1-4), schedule (6h early, 6h late) and trial (numbers 1-6) on PVT lapses (operationalised as the number of reaction times >500 ms), PVT total lapse time, PVT fastest 10% of reaction times and KSS. Analyses were also conducted examining the effect of day and schedule on sleep variables. Overall, PVT lapses and total lapse time did not differ significantly between baseline and shift days, however, peak response speeds were significantly slower on the first shift day when compared to baseline, but only for those in the 6h-late condition. Circadian variations were apparent in performance outcomes, with individuals in the 6h-late condition demonstrated significantly more and longer lapses and slower peak reaction times at the end of their

  17. Insomnia, excessive sleepiness, excessive fatigue, anxiety, depression and shift work disorder in nurses having less than 11 hours in-between shifts.

    Directory of Open Access Journals (Sweden)

    Maria Fagerbakke Eldevik

    Full Text Available STUDY OBJECTIVE: To assess if less than 11 hours off work between work shifts (quick returns was related to insomnia, sleepiness, fatigue, anxiety, depression and shift work disorder among nurses. METHODS: A questionnaire including established instruments measuring insomnia (Bergen Insomnia Scale, sleepiness (Epworth Sleepiness Scale, fatigue (Fatigue Questionnaire, anxiety/depression (Hospital Anxiety and Depression Scale and shift work disorder was administered. Among the 1990 Norwegian nurses who participated in the study; 264 nurses had no quick returns, 724 had 1-30 quick returns and 892 had more than 30 quick returns during the past year. 110 nurses did not report the number of quick returns during the past year. The prevalence of insomnia, excessive sleepiness, excessive fatigue, anxiety, depression and shift work disorder was calculated within the three groups of nurses. Crude and adjusted logistic regression analyses were performed to assess the relation between quick returns and such complaints. RESULTS: We found a significant positive association between quick returns and insomnia, excessive sleepiness, excessive fatigue and shift work disorder. Anxiety and depression were not related to working quick returns. CONCLUSIONS: There is a health hazard associated with quick returns. Further research should aim to investigate if workplace strategies aimed at reducing the number of quick returns may reduce complaints among workers.

  18. Circadian rhythms of psychomotor vigilance, mood, and sleepiness in the ultra-short sleep/wake protocol

    OpenAIRE

    KLINE, Christopher E; Durstine, J. Larry; Davis, J. Mark; Moore, Teresa A.; DEVLIN, Tina M; Youngstedt, Shawn D.

    2010-01-01

    Despite its advantages as a chronobiological technique, the ultra-short sleep/wake protocol remains underutilized in circadian rhythm research. The purpose of this study was to examine circadian rhythms of psychomotor vigilance (PVT), mood, and sleepiness in a sample (n = 25) of healthy young adults while they adhered to a 3-h ultra-short sleep/wake protocol. The protocol involved 1-h sleep intervals in darkness followed by 2-h wake intervals in dim light, repeated for 50–55 h. A 5-min PVT te...

  19. The utility of a rodent model in detecting pediatric drug-induced nephrotoxicity.

    Science.gov (United States)

    Espandiari, Parvaneh; Zhang, Jun; Rosenzweig, Barry A; Vaidya, Vishal S; Sun, Jinchun; Schnackenberg, Laura; Herman, Eugene H; Knapton, Alan; Bonventre, Joseph V; Beger, Richard D; Thompson, Karol L; Hanig, Joseph

    2007-10-01

    A multi-age rat model was used to identify potential age-related differences in renal injury following exposure to gentamicin (GM). In this study, 10-, 25-, 40-, and 80-day-old Sprague-Dawley rats were dosed with GM at 0, 50, or 100 mg kg(-1) body weight per day (mkd) sc for 6 or 14 days. Urine samples were collected up to 72 h after initial dosing. The maximum tolerated dose was lower in 10-day-old rats than for other ages (none survived 11 days of treatment). Eighty-day-old rats given the highest dose showed a diminished rate of growth and an increase in serum creatinine, blood urea nitrogen (BUN), urinary kidney injury molecule-1 (Kim-1), and renal pathology. Ten- and 40-day-old rats given 100 mkd of GM for 6- or 14 days also had increased levels of serum BUN and Cr and renal pathology, whereas only mild renal alterations were found in 25-day-old rats. After 6 days of treatment with 100 mkd GM, significant increases in Havcr-1 (Kim-1) gene expression were detected only in 10- and 80-day-old rats. In urine samples, nuclear magnetic resonance and ultra performance liquid chromatography/mass spectrometry analysis detected changes related to GM efficacy (e.g., hippurate) and increases in metabolites related to antioxidant activity, which was greatest in the 80-day-old rats. The magnitude of the genomic, metabonomic, and serum chemistry changes appeared to correlate with the degree of nephropathy. These findings indicate that an experimental animal model that includes several developmental stages can detect age-related differences in drug-induced organ toxicities and may be a useful predictor of pediatric drug safety in preclinical studies.

  20. Drug induced sleep endoscopy in the decision-making process of children with obstructive sleep apnea.

    Science.gov (United States)

    Galluzzi, Francesca; Pignataro, Lorenzo; Gaini, Renato Maria; Garavello, Werner

    2015-03-01

    Tonsillectomy and adenoidectomy (T&A) is currently recommended in children with Obstructive Sleep Apnea (OSA). However, the condition persists after surgery in about one third of cases. It has been suggested that Drug Induced Sleep Endoscopy (DISE) may be of help for planning a more targeted and effective surgical treatment but evidence is yet weak. The aim of this review is to draw recommendation on the use of DISE in children with OSA. More specifically, we aimed at determine the proportion of cases whose treatment may be influenced by DISE findings. A comprehensive search of articles published from February 1983 to January 2014 listed in the PubMed/MEDLINE databases was performed. The search terms used were: "endoscopy" or "nasoendoscopy" or "DISE" and "obstructive sleep apnea" and "children" or "child" or "pediatric." The main outcome was the rate of naive children with hypertrophic tonsils and/or adenoids. The assumptions are that clinical diagnosis of hypertrophic tonsils and/or adenoids is reliable and does not require DISE, and that exclusive T&A may solve OSA in the vast majority of cases even in the presence of other concomitant sites of obstruction. Five studies were ultimately selected and all were case series. The median (range) number of studied children was 39 (15-82). Mean age varied from 3.2 to 7.8 years. The combined estimate rate of OSA consequent to hypertrophic tonsils and/or adenoids was 71% (95%CI: 64-77%). In children with Down Syndrome, the combined estimated rate of hypertrophic tonsils and/or adenoids was 62% (95%CI: 44-79%). Our findings show that DISE may be of benefit in a minority of children with OSA since up to two thirds of naive cases presents with hypertrophic tonsils and/or adenoids. Its use should be limited to those whose clinical evaluation is unremarkable or when OSA persists after T&A.

  1. Drug induced mortality: a multiple cause approach on Italian causes of death Register

    Directory of Open Access Journals (Sweden)

    Francesco Grippo

    2015-04-01

    Full Text Available Background: Drug-related mortality is a complex phenomenon that has several health, social and economic effects. In this paper trends of drug-induced mortality in Italy are analysed. Two approaches have been followed: the traditional analysis of the underlying cause of death (UC (data refers to the Istat mortality database from 1980 to 2011, and the multiple cause (MCanalysis, that is the analysis of all conditions reported on the death certificate (data for 2003-2011 period.Methods: Data presented in this paper are based on the Italian mortality register. The selection of Icd codes used for the analysis follows the definition of the European Monitoring Centre for Drugs and Drug Addiction. Using different indicators (crude and standardized rates, ratio multiple to underlying, the results obtained from the two approaches (UC and MC have been compared. Moreover, as a measure of association between drug-related causes and specific conditions on the death certificate, an estimation of the age-standardized relative risk (RR has been used.Results: In the years 2009-2011, the total number of certificates whit mention of drug use was 1,293, 60% higher than the number UC based. The groups of conditions more strongly associated with drug-related causes are the mental and behavioral disorders (especially alcohol consumption, viral hepatitis, cirrhosis and fibrosis of liver, AIDS and endocarditis.Conclusions : The analysis based on multiple cause approach shows, for the first time, a more detailed picture of the drug related death; it allows to better describe the mortality profiles and to re-evaluate  the contribution of a specific cause to death.

  2. Assessment of time interval between tramadol intake and seizure and second drug-induced attack

    Directory of Open Access Journals (Sweden)

    Bahareh Abbasi

    2015-11-01

    Full Text Available Background: Tramadol is a synthetic drug which is prescribed in moderate and severe pain. Tramadol overdose can induce severe complications such as consciousness impairment and convulsions. This study was done to determine the convulsions incidence after tramadol use until one week after hospital discharge. Methods: This prospective study was done in tramadol overdose patients without uncontrolled epilepsy and head injury history. All cases admitted in Loghman and Rasol Akram Hospitals, Tehran, Iran from 1, April 2011 to 1, April 2012 were included and observed for at least 12 hours. Time interval between tramadol intake and first seizure were record. Then, patients with second drug-induced seizure were recognized and log time between the first and second seizure was analyzed. The patients were transferred to the intensive care unit (ICU if clinical worsening status observed. One week after hospital discharge, telephone follow-up was conducted. Results: A total of 150 patients with a history of tramadol induced seizures (141 men, 9 women, age: 23.23±5.94 years were enrolled in this study. Convulsion was seen in 104 patients (69.3%. In 8 out of 104 patients (7.6% two or more convulsion was seen. Time interval between tramadol use and the onset of the first and second seizure were 0.93±0.17 and 2.5±0.75 hours, respectively. Tramadol induced seizures are more likely to occur in males and patients with a history of drug abuse. Finally, one hundred forty nine patients (99.3% were discharged with good condition and the only one patient died from tramadol overdose. Conclusion: The results of the study showed tramadol induced seizure most frequently occurred within the first 4 hours of tramadol intake. The chance of experiencing a second seizure exists in the susceptible population. Thus, 4 hours after drug intake is the best time for patients to be hospital discharged.

  3. Mechanism of exacerbative effect of progesterone on drug-induced liver injury.

    Science.gov (United States)

    Toyoda, Yasuyuki; Endo, Shinya; Tsuneyama, Koichi; Miyashita, Taishi; Yano, Azusa; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

    2012-03-01

    Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical drug therapy. However, the underlying mechanism of DILI is little known. It is generally believed that women exhibit worse outcomes from DILI than men. Recently, we found that pretreatment of mice with estradiol attenuated halothane (HAL)-induced liver injury, whereas pretreatment with progesterone exacerbated it in female mice. To investigate the mechanism of sex difference of DILI, we focused on progesterone in this study. We found the exacerbating effect of progesterone in thioacetamide (TA), α-naphthylisothiocyanate, and dicloxacillin-induced liver injury only in female mice. Higher number of myeloperoxidase-positive mononuclear cells infiltrated into the liver and increased levels of Chemokine (C-X-C motif) ligand 1 and 2 (CXCL1 and CXCL2) and intercellular adhesion molecule-1 in the liver were observed. Interestingly, CXCL1 was slightly increased by progesterone pretreatment alone. Progesterone pretreatment increased the extracellular signal-regulated kinase (ERK) phosphorylation in HAL-induced liver injury. Pretreatment with U0126 (ERK inhibitor) significantly suppressed the exacerbating effect of progesterone and the expression of inflammatory mediators. In addition, pretreatment with gadolinium chloride (GdCl(3): inhibitor of Kupffer cells) significantly suppressed the exacerbating effect of progesterone pretreatment and the expression of inflammatory mediators. Moreover, posttreatment of RU486 (progesterone receptor antagonist) 1 h after the HAL or TA administration ameliorated the HAL- or TA-induced liver injury, respectively, in female mice. In conclusion, progesterone exacerbated the immune-mediated hepatotoxic responses in DILI via Kupffer cells and ERK pathway. The inhibition of progesterone receptor and decrease of the immune response may have important therapeutic implications in DILI. PMID:22157104

  4. Is periodontal health a predictor of drug-induced gingival overgrowth? A cross-sectional study

    Directory of Open Access Journals (Sweden)

    Ruchi Banthia

    2014-01-01

    Full Text Available Background: Gingival overgrowth is a common side-effect of amlodipine regimen on the oral cavity. There is controversy regarding the cause and effect relationship of periodontal health and drug induced gingival overgrowth. Therefore, this study was conducted to investigate and to assess the relationship between the periodontal health and the onset and severity of gingival overgrowth in hypertensive patients receiving amlodipine. Materials and Methods: A total of 99 known hypertensive patients on amlodipine regimen were included in this study. Probing pocket depth (PPD and clinical attachment loss (CAL were noted on four sites of maxillary and mandibular anterior teeth. Gingival enlargement scores were assessed for each patient by employing the hyperplastic index. Oral hygiene status was evaluated using the calculus index (CI. Patients were divided into H, E and L groups based on their periodontal status and responders and non-responders based on their hyperplastic index scores. Differences in means of different periodontal variables in different groups were tested for significance by using ANOVA and unpaired Student t-test. Pearson′s correlation coefficient was calculated to assess the correlation between different variables. For all analyses, P < 0.05 was considered to be significant. Results: All the periodontal parameters were statistically highly significant (P = 0.00 amongst H, E and L groups and between responders and non-responders. Statistically highly significant Pearson correlation coefficients were found between mean PPD and mean hyperplastic score, mean CAL and mean hyperplastic score and mean calculus and mean hyperplastic score. Conclusion: The results of this study indicated a definite association between periodontal health and development and severity of amlodipine-induced gingival overgrowth

  5. Exploring BSEP Inhibition-Mediated Toxicity with a Mechanistic Model of Drug-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Jeffrey L Woodhead

    2014-11-01

    Full Text Available Inhibition of the bile salt export pump (BSEP has been linked to incidence of drug-induced liver injury (DILI, presumably by the accumulation of toxic bile acids in the liver. We have previously constructed and validated a model of bile acid disposition within DILIsym®, a mechanistic model of DILI. In this paper, we use DILIsym® to simulate the DILI response of the hepatotoxic BSEP inhibitors bosentan and CP-724,714 and the non-hepatotoxic BSEP inhibitor telmisartan in humans in order to explore whether we can predict that hepatotoxic BSEP inhibitors can cause bile acid accumulation to reach toxic levels. We also simulate bosentan in rats in order to illuminate potential reasons behind the lack of toxicity in rats compared to the toxicity observed in humans. DILIsym® predicts that bosentan, but not telmisartan, will cause mild hepatocellular ATP decline and serum ALT elevation in a simulated population of humans. The difference in hepatotoxic potential between bosentan and telmisartan is consistent with clinical observations. However, DILIsym® underpredicts the incidence of bosentan toxicity. DILIsym® also predicts that bosentan will not cause toxicity in a simulated population of rats, and that the difference between the response to bosentan in rats and in humans is primarily due to the less toxic bile acid pool in rats. Our simulations also suggest a potential synergistic role for bile acid accumulation and mitochondrial electron transport chain inhibition in producing the observed toxicity in CP-724,714, and suggest that CP-724,714 metabolites may also play a role in the observed toxicity. Our work also compares the impact of competitive and noncompetitive BSEP inhibition for CP-724,714 and demonstrates that noncompetitive inhibition leads to much greater bile acid accumulation and potential toxicity. Our research demonstrates the potential for mechanistic modeling to contribute to the understanding of how bile acid transport inhibitors

  6. Drug-induced lupus: simvastatin or amiodarone? A case report in elderly

    Directory of Open Access Journals (Sweden)

    Mauro Turrin

    2013-03-01

    Full Text Available Reports of systemic lupus erythematosus (SLE seen during treatment with amiodarone are rare in the literature. SLE or immunological abnormalities induced by treatment with statins are more frequent. In this issue we report a case of a 81-year-old male who, after a 2-year therapy with amiodarone, developed a clinical and serologic picture of drug-induced SLE (DILE. He was admitted for congestive heart failure in mechanical aortic valve prosthesis, permanent atrial fibrillation (anticoagulation with warfarin, hypercholesterolaemia, and hypothyroidism. Amiodarone was started two years earlier for polymorphic ventricular tachycardia, statin and L-thyroxine the following year. At admission he presented pleuro-pericardical effusion detected by CT-scan (also indicative of interstitial lung involvement and echocardiography. Serological main indicative findings were: elevation of inflammatory markers, ANA (Anti-Nuclear Antibodies titers = 1:320 (indirect immune-fluorescence – IIF – assay on HEp-2, homogeneous/fine speckled pattern, anti-dsDNA titers = 1:80 (IIF on Crithidia luciliae, negative ENA (Extractable Nuclear Antigens and antibodies anti-citrulline, rheumatoid factor = 253 KU/l, normal C3-C4, negative HbsAg and anti-HCV, negative anticardiolipin antibodies IgG and IgM, negative anti-beta2GPI IgG and IgM. Amiodarone was discontinued and methylprednisolone was started, since the patient was severely ill. At discharge, after a month, the patient was better and pleuro-pericardical effusion was reduced. Readmitted few weeks later for bradyarithmia and worsening of dyspnoea, pericardial effusion was further reduced but he died for refractory congestive heart failure and pneumonia. Clinical picture (sierositis, neither skin nor kidney involvement, other typical side effects of amiodarone (hypothyroidism and lung interstitial pathology and serological findings are suggestive of amiodarone-induced SLE.

  7. Biomarkers for metabolic drug activation : towards an integrated risk assessment for drug-induced liver injury (DILI)

    OpenAIRE

    Teppner, Marieke

    2014-01-01

    The term drug-induced liver injury (DILI) describes adverse effects upon therapeutic drug treatment. They are relatively rare, affecting only 1 of 10000 - 1000000 patients, and remain mostly unpredictable. Due to development of severe hepatotoxicity or death, drugs causing DILI display a high risk for patients and have been withdrawn from the market or severely restricted in use. For the pharmaceutical industry late stage attrition due to DILI represents a big burden stretching development ti...

  8. Drug-Induced Acute Myocardial Infarction: Identifying 'Prime Suspects' from Electronic Healthcare Records-Based Surveillance System

    OpenAIRE

    Coloma, Preciosa M; Schuemie, Martijn J; Gianluca Trifirò; Laura Furlong; Erik van Mulligen; Anna Bauer-Mehren; Paul Avillach; Jan Kors; Ferran Sanz; Jordi Mestres; José Luis Oliveira; Scott Boyer; Ernst Ahlberg Helgee; Mariam Molokhia; Justin Matthews

    2013-01-01

    Background: Drug-related adverse events remain an important cause of morbidity and mortality and impose huge burden on healthcare costs. Routinely collected electronic healthcare data give a good snapshot of how drugs are being used in ???real-world??? settings. Objective: To describe a strategy that identifies potentially drug-induced acute myocardial infarction (AMI) from a large international healthcare data network. Methods: Post-marketing safety surveillance was conducted in seven popula...

  9. Laser-Assisted Periodontal Management of Drug-Induced Gingival Overgrowth under General Anesthesia: A Viable Option

    OpenAIRE

    Tupili Muralikrishna; Butchibabu Kalakonda; Sumanth Gunupati; Pradeep Koppolu

    2013-01-01

    Gingival overgrowth/hyperplasia can be attributed to several causes, but drug-induced gingival overgrowth/hyperplasia arises secondarily to prolonged use of antihypertensive drugs, anticonvulsants and immunosuppressants. The management is complex in nature considering the multitude of factors involved such as substitution of drug strict plaque control along with excision of the tissue to be performed under local anesthesia as outpatient. In the recent times, the patient’s psychological fear o...

  10. The Art and Science of Diagnosing and Managing Drug-induced Liver Injury in 2015 and Beyond.

    Science.gov (United States)

    Lewis, James H

    2015-11-01

    Drug-induced liver injury (DILI) remains a leading reason why new compounds are dropped from further study or are the subject of product warnings and regulatory actions. Hy's Law of drug-induced hepatocellular jaundice causing a case-fatality rate or need for transplant of 10% or higher has been validated in several large national registries, including the ongoing, prospective U.S. Drug-Induced Liver Injury Network. It serves as the basis for stopping rules in clinical trials and in clinical practice. Because DILI can mimic all known causes of acute and chronic liver disease, establishing causality can be difficult. Histopathologic findings are often nonspecific and rarely, if ever, considered pathognomonic. A daily drug dose >50-100 mg is more likely to be hepatotoxic than does management of DILI have recently been published, although specific therapies remain limited. The LiverTox Web site has been introduced as an interactive online virtual textbook that makes the latest information on more than 650 agents available to clinicians, regulators, and drug developers alike.

  11. Polymorphisms in CTLA4 influence incidence of drug-induced liver injury after renal transplantation in Chinese recipients.

    Directory of Open Access Journals (Sweden)

    Yifeng Guo

    Full Text Available Genetic polymorphisms in cytotoxic T lymphocyte-associated antigen 4 (CTLA4 play an influential role in graft rejection and the long-term clinical outcome of organ transplantation. We investigated the association of 5 CTLA4 single-nucleotide polymorphisms (SNPs (rs733618 C/T, rs4553808 A/G, rs5742909 C/T, rs231775 A/G, and rs3087243 G/A with drug-induced liver injury (DILI in Chinese renal transplantation (RT recipients. Each recipient underwent a 24-month follow-up observation for drug-induced liver damage. The CTLA4 SNPs were genotyped in 864 renal transplantation recipients. A significant association was found between the rs231775 genotype and an early onset of DILI in the recipients. Multivariate analyses revealed that a risk factor, recipient rs231775 genotype (p = 0.040, was associated with DILI. Five haplotypes were estimated for 4 SNPs (excluding rs733618; the frequency of haplotype ACGG was significantly higher in the DILI group (68.9% than in the non-DILI group (61.1% (p = 0.041. In conclusion, CTLA4 haplotype ACGG was partially associated with the development of DILI in Chinese kidney transplant recipients. The rs231775 GG genotype may be a risk factor for immunosuppressive drug-induced liver damage.

  12. The Art and Science of Diagnosing and Managing Drug-induced Liver Injury in 2015 and Beyond.

    Science.gov (United States)

    Lewis, James H

    2015-11-01

    Drug-induced liver injury (DILI) remains a leading reason why new compounds are dropped from further study or are the subject of product warnings and regulatory actions. Hy's Law of drug-induced hepatocellular jaundice causing a case-fatality rate or need for transplant of 10% or higher has been validated in several large national registries, including the ongoing, prospective U.S. Drug-Induced Liver Injury Network. It serves as the basis for stopping rules in clinical trials and in clinical practice. Because DILI can mimic all known causes of acute and chronic liver disease, establishing causality can be difficult. Histopathologic findings are often nonspecific and rarely, if ever, considered pathognomonic. A daily drug dose >50-100 mg is more likely to be hepatotoxic than does acetaminophen overdose. Although a number of drugs causing idiosyncratic DILI have HLA associations that may allow for pre-prescription testing to prevent hepatotoxicity, the cost and relatively low frequency of injury among affected patients limit the current usefulness of such genome-wide association studies. Alanine aminotransferase monitoring is often recommended but has rarely been shown to be an effective method to prevent serious DILI. Guidelines on the diagnosis and management of DILI have recently been published, although specific therapies remain limited. The LiverTox Web site has been introduced as an interactive online virtual textbook that makes the latest information on more than 650 agents available to clinicians, regulators, and drug developers alike. PMID:26116527

  13. Prevention and Treatment of Vaginal Bleeding after Drug-induced Abortion by Yaoliuan Capsule and Its Effects on Menses Recovery

    Institute of Scientific and Technical Information of China (English)

    JIN Zhichun; HUANG Guangying

    2005-01-01

    Summary: In order to explore the effect of Yaoliuan capsule in the prevention and treatment of vaginal bleeding after drug-induced abortion and menses recovery after drug-induced abortion, 323 cases of gestation period ≤ 49 days and without contraindication, were divided randomly into study group (168 cases, taking Yaoliuan capsule) and control group (155 cases, taking placebo capsule). The results showed that in the study group, there were 161 cases (95.8 %) of complete abortion, 7 cases (4.2 %) of incomplete abortion; In the control group, there were 146 cases (94.2 %) of complete abortion, 6 cases (3.9 %) of incomplete abortion, 3 cases (1.9 %) of abortion failure. The vaginal bleeding time was 5-25 days (mean 10.8 days) in study group, while that was 6-62 days (mean 19.1 days) in control group. The menstrual cycle was 30.5±5.2 days and 33.8 d±8.6 days respectively in study and control groups. The menstrual period was 6.1±3.5 days and 9.9±5.1 days respectively in study and control groups. Yaoliuan capsule is an effective drug to prevent and treat vaginal bleeding following drug-induced abortion, promote menstruation recovery and prevent pelvic infection.

  14. The association between use of electronic media in bed before going to sleep and insomnia symptoms, daytime sleepiness, morningness, and chronotype.

    Science.gov (United States)

    Fossum, Ingrid Nesdal; Nordnes, Linn Tinnesand; Storemark, Sunniva Straume; Bjorvatn, Bjørn; Pallesen, Ståle

    2014-09-01

    This study investigated whether the use of a television, computer, gaming console, tablet, mobile phone, or audio player in bed before going to sleep was associated with insomnia, daytime sleepiness, morningness, or chronotype. 532 students aged 18-39 were recruited from lectures or via e-mail. Respondents reported the frequency and average duration of their in-bed media use, as well as insomnia symptoms, daytime sleepiness, morningness-eveningness preference and bedtime/rise time on days off. Mean time of media use per night was 46.6 minutes. The results showed that computer usage for playing/surfing/reading was positively associated with insomnia, and negatively associated with morningness. Mobile phone usage for playing/surfing/texting was positively associated with insomnia and chronotype, and negatively associated with morningness. None of the other media devices were related to either of these variables, and no type of media use was related to daytime sleepiness. PMID:24156294

  15. Quality of life in patients with obstructive sleep apnea: Relationship with daytime sleepiness, sleep quality, depression, and apnea severity.

    Science.gov (United States)

    Lee, Wonhee; Lee, Sang-Ahm; Ryu, Han Uk; Chung, Yoo-Sam; Kim, Woo Sung

    2016-02-01

    The aim of this study was to investigate the relative contributions of daytime sleepiness, sleep quality, depression, and apnea severity to mental and physical quality of life (QoL) in obstructive sleep apnea (OSA) patients. This was a cross-sectional study. Participants were adults diagnosed with OSA. Medical Outcomes Study-Short Form 36 (SF-36), Epworth Sleepiness Scale (ESS), Medical Outcomes Study-Sleep Scale, and Beck Depression Inventory (BDI) were used. The factors predicting the physical and mental QoL were evaluated using multiple linear regression analysis. Seven hundred ninety three OSA patients participated in the study. The average age was 48.9 years (SD = 11.7 years). The mean apnea-hypopnea index (AHI) was 29.5 hour(-1) (SD = 20.6 hour(-1)). The SF-36 scores were 72.6 (SD = 18.5). The BDI, sleep quality, and age were related to both mental and physical QoL. However, ESS, minimal arterial oxygen saturation, gender, and body mass index were associated with the physical but not mental QoL. The BDI was the strongest predictor of both physical and mental QoL. AHI was related to neither physical nor mental QoL. The potential factors affecting QoL are different between physical and mental dimensions of QoL. Depressive mood was the strongest predictor of both the physical and mental QoL.

  16. Quality of life in patients with obstructive sleep apnea: Relationship with daytime sleepiness, sleep quality, depression, and apnea severity.

    Science.gov (United States)

    Lee, Wonhee; Lee, Sang-Ahm; Ryu, Han Uk; Chung, Yoo-Sam; Kim, Woo Sung

    2016-02-01

    The aim of this study was to investigate the relative contributions of daytime sleepiness, sleep quality, depression, and apnea severity to mental and physical quality of life (QoL) in obstructive sleep apnea (OSA) patients. This was a cross-sectional study. Participants were adults diagnosed with OSA. Medical Outcomes Study-Short Form 36 (SF-36), Epworth Sleepiness Scale (ESS), Medical Outcomes Study-Sleep Scale, and Beck Depression Inventory (BDI) were used. The factors predicting the physical and mental QoL were evaluated using multiple linear regression analysis. Seven hundred ninety three OSA patients participated in the study. The average age was 48.9 years (SD = 11.7 years). The mean apnea-hypopnea index (AHI) was 29.5 hour(-1) (SD = 20.6 hour(-1)). The SF-36 scores were 72.6 (SD = 18.5). The BDI, sleep quality, and age were related to both mental and physical QoL. However, ESS, minimal arterial oxygen saturation, gender, and body mass index were associated with the physical but not mental QoL. The BDI was the strongest predictor of both physical and mental QoL. AHI was related to neither physical nor mental QoL. The potential factors affecting QoL are different between physical and mental dimensions of QoL. Depressive mood was the strongest predictor of both the physical and mental QoL. PMID:26396158

  17. Differences between Drug-Induced and Contrast Media-Induced Adverse Reactions Based on Spontaneously Reported Adverse Drug Reactions.

    Directory of Open Access Journals (Sweden)

    JiHyeon Ryu

    Full Text Available We analyzed differences between spontaneously reported drug-induced (not including contrast media and contrast media-induced adverse reactions.Adverse drug reactions reported by an in-hospital pharmacovigilance center (St. Mary's teaching hospital, Daejeon, Korea from 2010-2012 were classified as drug-induced or contrast media-induced. Clinical patterns, frequency, causality, severity, Schumock and Thornton's preventability, and type A/B reactions were recorded. The trends among causality tools measuring drug and contrast-induced adverse reactions were analyzed.Of 1,335 reports, 636 drug-induced and contrast media-induced adverse reactions were identified. The prevalence of spontaneously reported adverse drug reaction-related admissions revealed a suspected adverse drug reaction-reporting rate of 20.9/100,000 (inpatient, 0.021% and 3.9/100,000 (outpatients, 0.004%. The most common adverse drug reaction-associated drug classes included nervous system agents and anti-infectives. Dermatological and gastrointestinal adverse drug reactions were most frequently and similarly reported between drug and contrast media-induced adverse reactions. Compared to contrast media-induced adverse reactions, drug-induced adverse reactions were milder, more likely to be preventable (9.8% vs. 1.1%, p < 0.001, and more likely to be type A reactions (73.5% vs. 18.8%, p < 0.001. Females were over-represented among drug-induced adverse reactions (68.1%, p < 0.001 but not among contrast media-induced adverse reactions (56.6%, p = 0.066. Causality patterns differed between the two adverse reaction classes. The World Health Organization-Uppsala Monitoring Centre causality evaluation and Naranjo algorithm results significantly differed from those of the Korean algorithm version II (p < 0.001.We found differences in sex, preventability, severity, and type A/B reactions between spontaneously reported drug and contrast media-induced adverse reactions. The World Health

  18. Evaluation of prognostic markers in severe drug-induced liver disease

    Institute of Scientific and Technical Information of China (English)

    Bo Li; Zhi Wang; Jian-Jiang Fang; Ci-Yi Xu; Wei-Xing Chen

    2007-01-01

    AIM: To analyze the outcome of patients with severe drug-induced liver disease (DILD) associated with jaundice classified as hepatocellular, cholestatic or mixed liver injury and to evaluate the validity of Hy's rule and the most important predictors for outcome.METHODS: The Adverse Drug Reaction Advisory Committee was set up in 1997 in our hospital to identify all suspicions of DILD following a structured prospective report form. Liver damage was divided into hepatocellular, cholestatic, and mixed types according to laboratory and histologic criteria when available. Further evaluation of causality assessment was performed.RESULTS: From January 1997 to December 2004, 265 patients were diagnosed with DILD, and 140 (52.8%) of them were female. Hepatocellular damage was the most common (72.1%), the incidence of death was 9.9% in patients with hepatocellular damage and 9.5% in patients with cholestatic/mixed damage (P < 0.05). There was no difference in age of dead and recovered patients. The proportion of females and males was similar in recovered and dead patients, no difference was observed in duration of treatment between the two groups. The serum total bilirubin (P < 0.001), direct bilirubin (P < 0.001) and aspartate transaminase (AST) (P = 0.013) values were higher in dead patients than in recovered patients. Chinese herbal medicine was the most frequently prescribed, accounting for 24.2% of the whole series. However, antitubercular drugs (3.4%) were found to be the primary etiological factor for fetal DILD. Factors associated with the development of fulminant hepatic failure were hepatic encephalopathy (OR = 43.66, 95% CI = 8.47-224.95, P < 0.0001), ascite (OR = 28.48, 95% CI = 9.26-87.58, P < 0.0001), jaundice (OR = 11.43, 95% CI = 1.52-85.96, P = 0.003), alcohol abuse (OR = 3.83, 95% CI = 1.26-11.67, P = 0.035) and direct bilirubin (OR = 1.93, 95% CI = 1.25-2.58, P = 0.012).CONCLUSION: Death occurs in 9.8% of patients with DILD. Chinese herbal

  19. Night sleep electroencephalogram power spectral analysis in excessive daytime sleepiness disorders

    Directory of Open Access Journals (Sweden)

    Rubens Reimão

    1991-06-01

    Full Text Available A group of 53 patients (40 míales, 13 females with mean age of 49 years, ranging from 30 to 70 years, was evaluated in the. following excessive daytime sleepiness (EDS disorders : obstructive sleep apnea syndrome (B4a, periodic movements in sleep (B5a, affective disorder (B2a, functional psychiatric non affective disorder (B2b. We considered all adult patients referred to the Center sequentially with no other distinctions but these three criteria: (a EDS was the main complaint; (b right handed ; (c not using psychotropic drugs for two weeks prior to the all-night polysomnography. EEG (C3/A1, C4/A2 samples from 2 to 10 minutes of each stage of the first REM cycle were chosen. The data was recorded simultaneously in magnetic tape and then fed into a computer for power spectral analysis. The percentage of power (PP in each band calculated in relation to the total EEG power was determined of subsequent sections of 20.4 s for the following frequency bands: delta, theta, alpha and beta. The PP in all EOS patients sample had a tendency to decrease progressively from the slowest to the fastest frequency bands, in every sleep stage. PP distribution in the delta range increased progressively from stage 1 to stage 4; stage REM levels were close to stage 2 levels. In an EDS patients interhemispheric coherence was high in every band and sleep stage. B4a patients sample PP had a tendency to decrease progressively from the slowest to the fastest frequency bands, in¡ every sleep stage; PP distribution in the delta range increased progressively from stage 1 to stage 4; stage REM levels were between stage 1 and stage 2 levels. B2a patients sample PP had a tendency to decrease progressively from the slowest to the fastest frequency bands, in every sleep stage; PP distribution in the delta range increased progressively from stage 1 to stage 4; stage REM levels were close to stage 2 levels. B2b patients sample PP had a tendency to decrease progressively from the

  20. Parent Report and Actigraphically Defined Sleep in Children with and without Developmental Coordination Disorder; Links with Fatigue and Sleepiness

    Directory of Open Access Journals (Sweden)

    Luci Wiggs

    2016-08-01

    Full Text Available Background: Impaired sleep is associated with negative effects on quality of life and daytime functioning. Higher rates of sleep disturbance are reported in children with various developmental disorders. However, little is known about sleep in children with Developmental Coordination Disorder (DCD, a condition characterized by everyday movement difficulties. Previously, in a preliminary study, we found higher rates of parent-reported sleep disturbance in children with DCD compared to controls. Aims: To examine sleep in DCD using objective measures and to examine links with daytime fatigue and sleepiness. Methods: Two groups (primary and secondary school-aged of 15 children with DCD, plus matched controls, participated. Parent reported child sleep was assessed using the Children’s Sleep Habits Questionnaire and actigraphy provided an objective measure of sleep-wake patterns over one week (including weekdays and weekend. Pediatric Restless Legs Syndrome (RLS Semi-Structured Diagnostic Interview was conducted with each child and parent to capture symptoms of RLS. Aspects of self-rated child functioning were assessed with questionnaires (Pre-sleep Arousal Scale, Pediatric Daytime Sleepiness Scale, PedsQL Multidimensional Fatigue Scale and mothers’ reported thoughts about child sleep with the Maternal Cognitions about Infant Sleep Questionnaire.Results: The DCD groups had greater parent-reported sleep disturbance. Actigraphy results suggested that for secondary aged children with DCD their sleep quality was impaired and there were differences in the timing of sleep compared to controls (including some differences in the variation between weekday and weekend sleep times. The actigraphy of the primary age group with DCD was unremarkable compared to controls. No child in the study met the criteria for RLS. Exploratory analyses suggested that daytime fatigue, aspects of pre-sleep arousal and daytime sleepiness were reported as greater in the DCD

  1. Fonoaudiologia e apneia do sono: uma revisão Speech therapy and sleepy apnae: a review

    Directory of Open Access Journals (Sweden)

    Erilucia Pereira Santa Rosa

    2010-10-01

    Full Text Available TEMA: a Síndrome da Apneia/Hipopneia Obstrutiva do Sono (SAHOS é definida pela Academia Americana do Sono como a presença de episódios recorrentes de obstrução parcial ou total das vias aéreas superiores durante o sono e manifesta-se como uma redução (hipopneia ou cessação completa (apneia do fluxo aéreo, apesar da manutenção dos esforços inspiratórios. A SAHOS motiva o chamado ronco crônico, sonolência e caracteriza-se pela parada do fluxo aéreo respiratório por pelo menos, 10 segundos. O diagnóstico é realizado através do exame polissonográfico, que consiste no registro simultâneo de atividades do organismo durante a noite, indicando a quantidade de apneias e hipopneias ocorridos e a gravidade da SAHOS. Para sucesso no tratamento desta desordem é fundamental o diagnóstico preciso e correto e a atuação de uma equipe multidisciplinar, estando inserido nela o fonoaudiólogo. OBJETIVO: analisar, através da literatura a interrrelação da Fonoaudiologia e a SAHOS. CONCLUSÃO: aom o referente estudo, podemos identificar a complexidade da SAHOS e mostrar a importância da atuação fonoaudiológica na terapêutica desses pacientes, para uma melhor qualidade de vida.BACKGROUND: the Apnea syndrome / Obstructive Sleepy Hypopnea (SOHAS is define by the American Academy of Sleep with recurrent presence of episodes of partial or total obstruction in the superior airways during sleep, in addition to showing a reduction (hypopnea or complete stoppage (apnea of airflow, although there is an ongoing maintenance of inspiratory efforts. SOHAS motivates the so-called sleepy chronic snoring and sleepiness to dress up by the stop of airflow by at least 10 seconds. The diagnosis is carried out through polysomnographic examination, which consists of the simultaneous recording of body activities during the night, indicating the number of occurring apneas and hypopneas and SOHAS severity. For the successful of disorder treatment it is

  2. Evaluation of the usefulness of novel biomarkers for drug-induced acute kidney injury in beagle dogs

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Xiaobing [National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing 100176 (China); Graduate School of Peking Union Medical College, Dongcheng District, Beijing, 100730 (China); Ma, Ben; Lin, Zhi; Qu, Zhe; Huo, Yan; Wang, Jufeng [National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing 100176 (China); Li, Bo, E-mail: libo@nifdc.org.cn [National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing 100176 (China); Graduate School of Peking Union Medical College, Dongcheng District, Beijing, 100730 (China)

    2014-10-01

    As kidney is a major target organ affected by drug toxicity, early detection of renal injury is critical in preclinical drug development. In past decades, a series of novel biomarkers of drug-induced nephrotoxicity were discovered and verified in rats. However, limited data regarding the performance of novel biomarkers in non-rodent species are publicly available. To increase the applicability of these biomarkers, we evaluated the performance of 4 urinary biomarkers including neutrophil gelatinase-associated lipocalin (NGAL), clusterin, total protein, and N-acetyl-β-D-glucosaminidase (NAG), relative to histopathology and traditional clinical chemistry in beagle dogs with acute kidney injury (AKI) induced by gentamicin. The results showed that urinary NGAL and clusterin levels were significantly elevated in dogs on days 1 and 3 after administration of gentamicin, respectively. Gene expression analysis further provided mechanistic evidence to support that NGAL and clusterin are potential biomarkers for the early assessment of drug-induced renal damage. Furthermore, the high area (both AUCs = 1.000) under receiver operator characteristics (ROC) curve also indicated that NGAL and clusterin were the most sensitive biomarkers for detection of gentamicin-induced renal proximal tubular toxicity. Our results also suggested that NAG may be used in routine toxicity testing due to its sensitivity and robustness for detection of tissue injury. The present data will provide insights into the preclinical use of these biomarkers for detection of drug-induced AKI in non-rodent species. - Highlights: • Urinary NGAL, clusterin and NAG levels were significantly elevated in canine AKI. • NGAL and clusterin gene expression were increased following treatment with gentamicin. • NGAL and clusterin have high specificity and sensitivity for detection of AKI.

  3. Evaluation of the usefulness of novel biomarkers for drug-induced acute kidney injury in beagle dogs

    International Nuclear Information System (INIS)

    As kidney is a major target organ affected by drug toxicity, early detection of renal injury is critical in preclinical drug development. In past decades, a series of novel biomarkers of drug-induced nephrotoxicity were discovered and verified in rats. However, limited data regarding the performance of novel biomarkers in non-rodent species are publicly available. To increase the applicability of these biomarkers, we evaluated the performance of 4 urinary biomarkers including neutrophil gelatinase-associated lipocalin (NGAL), clusterin, total protein, and N-acetyl-β-D-glucosaminidase (NAG), relative to histopathology and traditional clinical chemistry in beagle dogs with acute kidney injury (AKI) induced by gentamicin. The results showed that urinary NGAL and clusterin levels were significantly elevated in dogs on days 1 and 3 after administration of gentamicin, respectively. Gene expression analysis further provided mechanistic evidence to support that NGAL and clusterin are potential biomarkers for the early assessment of drug-induced renal damage. Furthermore, the high area (both AUCs = 1.000) under receiver operator characteristics (ROC) curve also indicated that NGAL and clusterin were the most sensitive biomarkers for detection of gentamicin-induced renal proximal tubular toxicity. Our results also suggested that NAG may be used in routine toxicity testing due to its sensitivity and robustness for detection of tissue injury. The present data will provide insights into the preclinical use of these biomarkers for detection of drug-induced AKI in non-rodent species. - Highlights: • Urinary NGAL, clusterin and NAG levels were significantly elevated in canine AKI. • NGAL and clusterin gene expression were increased following treatment with gentamicin. • NGAL and clusterin have high specificity and sensitivity for detection of AKI

  4. Improvement in Fatigue, Sleepiness, and Health-Related Quality of Life with Bright Light Treatment in Persons with Seasonal Affective Disorder and Subsyndromal SAD

    Directory of Open Access Journals (Sweden)

    Cecilia Rastad

    2011-01-01

    Full Text Available Objective. To investigate the effects of bright light treatment for secondary outcome measures and to explore and validate empirically derived subgroups and treatment effects in subgroups. Methods. A descriptive design. A sample of forty-nine persons (mean age of 45.8 with clinically assessed seasonal affective disorder (SAD or subsyndromal SAD (S-SAD participated in a two-group clinical trial evaluating the effects of treatment with bright light therapy. A person-oriented cluster analysis was applied to study treatment effects in subgroups. Results. For the merged group, sleepiness (Epworth Sleepiness Scale, fatigue (fatigue questionnaire, and health-related quality of life (SF-36 were improved at posttreatment, and results were maintained at the one-month followup. Three distinct subgroups had a high level of fatigue in common, while the level of excessive daytime sleepiness and depressed mood differed between the subgroups. Over time, all subgroups improved following ten days treatment in a light room. Conclusion. Fatigue, excessive daytime sleepiness, and health-related quality of life improve in a similar way as depressed mood following treatment with bright light. The treatment was effective irrespective of the severity of the disorder, that is, for persons with SAD and subsyndromal SAD.

  5. Scatter Plot Analysis of Excessive Daytime Sleepiness and Severe Disruptive Behavior in Adults with Prader-Willi Syndrome: A Pilot Study

    Science.gov (United States)

    Maas, Anneke P. H. M.; Didden, Robert; Bouts, Lex; Smits, Marcel G.; Curfs, Leopold M. G.

    2009-01-01

    Individuals with Prader-Willi syndrome (PWS) are at risk for excessive daytime sleepiness (EDS) and disruptive behavior. This pilot study explores temporal characteristics of EDS and severe disruptive behavior across time of day and day of week in seven individuals with PWS (aged between 33 and 49 years) of whom five were matched to controls.…

  6. A pilot study exploring the relationship between internists' self-reported sleepiness, performance on multiple-choice exam items and prefrontal cortex activity

    NARCIS (Netherlands)

    Durning, S.J.; Capaldi, V.F., 2nd; Artino, A.R.; Graner, J.; Vleuten, C.P.M. van der; Beckman, T.J.; Costanzo, M.; Holmboe, E.; Schuwirth, L.

    2014-01-01

    BACKGROUND: Studies of resident fatigue and performance have shown mixed results. However, research has not examined daytime sleepiness and performance among attending physicians. The purpose of this study was to explore the relationship between sleep, performance and prefrontal cortex (PFC) activit

  7. Experimental investigation of the effects of the car driver`s postures on sleepiness; Chakuza shisei ga nemuke ni oyobosu eikyo ni kansuru kenkyu

    Energy Technology Data Exchange (ETDEWEB)

    Komatsudani, M.; Okamura, C. [Toyo Seat Co. Ltd., Hiroshima (Japan); Nishiyama, S. [Hiroshima City Industrial Technology Institute, Hiroshima (Japan); Nozawa, T.; Nishikawa, K. [Matsuda Motor Corp., Hiroshima (Japan); Hori, T.; Hayashi, M. [Hiroshima University, Hiroshima (Japan)

    1998-05-01

    Effects of car driver`s postures on sleepiness were experimentally investigated. For the measurement method of EEG (electroencephalogram), bipolar induction was adopted, to record Cz and Pz using those at left ear as standard by international 10-20 electrode method. In addition, differential potential was recorded between locations of Cz and Pz. The time constant of EEG was set in 0.3 sec. Brain waves were measured for one minute under open and close eye conditions before and after each test as EEG at the rest. For the measurement of EOG (electro-oculograph), vertical and horizontal eye motions were observed. Induced potential change was measured by attaching silver-silver chloride electrode at the time constant 1.5 sec. For the measurement of SPL (skin potential level), the palm of left hand was used as a measuring point and the left front arm was used as a reference point for attaching electrodes. The danger of sleepiness was provided by the boring driving conditions independent of driver`s postures. There was a difference of relaxation time due to the driver`s postures. It was difficult to avoid sleepiness by adjusting the relative angle between seat and seat back. However, it was found that the angle 110deg was most suitable for avoiding sleepiness. 7 refs., 5 figs., 2 tabs.

  8. A diagnostic dilemma: drug-induced aseptic meningitis in a 45-year-old HIV-positive man.

    LENUS (Irish Health Repository)

    Rowley, D

    2014-03-01

    We describe a case of aseptic meningitis following the administration of moxifloxacin in a 45-year-old man with human immunodeficiency virus (HIV). At presentation he was receiving tuberculosis treatment on a modified regimen following severe hepatotoxicity; this included moxifloxacin, started 8 days previously. Initial cerebrospinal fluid (CSF) analysis was grossly abnormal. Anti-viral and -bacterial treatments were started. All microbiological tests proved negative and his moxifloxacin was withheld resulting in a complete normalisation of CSF. Drug-induced aseptic meningitis is a diagnosis of exclusion and presents a serious diagnostic dilemma. The decision to withhold medication cannot be taken lightly.

  9. Laser-Assisted Periodontal Management of Drug-Induced Gingival Overgrowth under General Anesthesia: A Viable Option.

    Science.gov (United States)

    Muralikrishna, Tupili; Kalakonda, Butchibabu; Gunupati, Sumanth; Koppolu, Pradeep

    2013-01-01

    Gingival overgrowth/hyperplasia can be attributed to several causes, but drug-induced gingival overgrowth/hyperplasia arises secondarily to prolonged use of antihypertensive drugs, anticonvulsants and immunosuppressants. The management is complex in nature considering the multitude of factors involved such as substitution of drug strict plaque control along with excision of the tissue to be performed under local anesthesia as outpatient. In the recent times, the patient's psychological fear of the treatment with the use of surgical blade and multiple visits has developed the concept of single visit treatment under general anesthesia incorporating a laser as viable option. The present case highlights the new method of management of gingival overgrowth.

  10. Application of a drug-induced apoptosis assay to identify treatment strategies in recurrent or metastatic breast cancer.

    Directory of Open Access Journals (Sweden)

    Linda Bosserman

    Full Text Available A drug-induced apoptosis assay has been developed to determine which chemotherapy drugs or regimens can produce higher cell killing in vitro. This study was done to determine if this assay could be performed in patients with recurrent or metastatic breast cancer patients, to characterize the patterns of drug-induced apoptosis, and to evaluate the clinical utility of the assay. A secondary goal was to correlate assay use with clinical outcomes.In a prospective, non-blinded, multi institutional controlled trial, 30 evaluable patients with recurrent or metastatic breast cancer who were treated with chemotherapy had tumor samples submitted for the MiCK drug-induced apoptosis assay. After receiving results within 72 hours after biopsy, physicians could use the test to determine therapy (users, or elect to not use the test (non-users.The assay was able to characterize drug-induced apoptosis in tumor specimens from breast cancer patients and identified which drugs or combinations gave highest levels of apoptosis. Patterns of drug activity were also analyzed in triple negative breast cancer. Different drugs from a single class of agents often produced significantly different amounts of apoptosis. Physician frequently (73% used the assay to help select chemotherapy treatments in patients, Patients whose physicians were users had a higher response (CR+PR rate compared to non-users (38.1% vs 0%, p = 0.04 and a higher disease control (CR+PR+Stable rate (81% vs 25%, p<0.01. Time to relapse was longer in users 7.4 mo compared to non-users 2.2 mo (p<0.01.The MiCK assay can be performed in breast cancer specimens, and results are often used by physicians in breast cancer patients with recurrent or metastatic disease. These results from a good laboratory phase II study can be the basis for a future larger prospective multicenter study to more definitively establish the value of the assay.Clinicaltrials.gov NCT00901264.

  11. Application of a Drug-Induced Apoptosis Assay to Identify Treatment Strategies in Recurrent or Metastatic Breast Cancer

    Science.gov (United States)

    Bosserman, Linda; Rogers, Karl; Willis, Carl; Davidson, Dirk; Whitworth, Pat; Karimi, Misagh; Upadhyaya, Gargi; Rutledge, James; Hallquist, Allan; Perree, Mathieu; Presant, Cary A.

    2015-01-01

    Background A drug-induced apoptosis assay has been developed to determine which chemotherapy drugs or regimens can produce higher cell killing in vitro. This study was done to determine if this assay could be performed in patients with recurrent or metastatic breast cancer patients, to characterize the patterns of drug-induced apoptosis, and to evaluate the clinical utility of the assay. A secondary goal was to correlate assay use with clinical outcomes. Methods In a prospective, non-blinded, multi institutional controlled trial, 30 evaluable patients with recurrent or metastatic breast cancer who were treated with chemotherapy had tumor samples submitted for the MiCK drug-induced apoptosis assay. After receiving results within 72 hours after biopsy, physicians could use the test to determine therapy (users), or elect to not use the test (non-users). Results The assay was able to characterize drug-induced apoptosis in tumor specimens from breast cancer patients and identified which drugs or combinations gave highest levels of apoptosis. Patterns of drug activity were also analyzed in triple negative breast cancer. Different drugs from a single class of agents often produced significantly different amounts of apoptosis. Physician frequently (73%) used the assay to help select chemotherapy treatments in patients, Patients whose physicians were users had a higher response (CR+PR) rate compared to non-users (38.1% vs 0%, p = 0.04) and a higher disease control (CR+PR+Stable) rate (81% vs 25%, p<0.01). Time to relapse was longer in users 7.4 mo compared to non-users 2.2 mo (p<0.01). Conclusions The MiCK assay can be performed in breast cancer specimens, and results are often used by physicians in breast cancer patients with recurrent or metastatic disease. These results from a good laboratory phase II study can be the basis for a future larger prospective multicenter study to more definitively establish the value of the assay. Trial Registration Clinicaltrials.gov NCT

  12. Melatonin treatment effects on adolescent students' sleep timing and sleepiness in a placebo-controlled crossover study.

    Science.gov (United States)

    Eckerberg, Berndt; Lowden, Arne; Nagai, Roberta; Akerstedt, Torbjörn

    2012-11-01

    During the last few decades, the incidence of sleep-onset insomnia, due to delay of circadian phase, has increased substantially among adolescents all over the world. We wanted to investigate whether a small dose of melatonin given daily, administered in the afternoon, could advance the sleep timing in teenagers. Twenty-one students, aged 14-19 yrs, with sleep-onset difficulties during school weeks were recruited. The study was a randomized, double blind, placebo (PL)-controlled crossover trial, lasting 5 wks. During the first 6 d in wks 2 and 4, the students received either PL or melatonin (1 mg) capsules between 16:30 and 18:00 h. During the first 6 d of wk 5, all students received melatonin. Wks 1 and 3 were capsule-free. In the last evening of each week and the following morning, the students produced saliva samples at home for later melatonin analysis. The samples were produced the same time each week, as late as possible in the evening and as early as possible in the morning. Both the student and one parent received automatic mobile text messages 15 min before saliva sampling times and capsule intake at agreed times. Diaries with registration of presumed sleep, subjective sleepiness during the day (Karolinska Sleepiness Scale, KSS) and times for capsule intake and saliva samplings were completed each day. Primary analysis over 5 wks gave significant results for melatonin, sleep and KSS. Post hoc analysis showed that reported sleep-onset times were advanced after melatonin school weeks compared with PL school weeks (p students fell asleep 68 min earlier and slept 62 min longer each night compared with the baseline week. Morning melatonin values in saliva diminished compared with PL (p students reported less wake up (p students more alert during school days even if they continued their often irregular sleep habits during weekends. PMID:23005039

  13. High-risk of obstructive sleep apnea and excessive daytime sleepiness among commercial intra-city drivers in Lagos metropolis

    Directory of Open Access Journals (Sweden)

    Obianuju B Ozoh

    2013-01-01

    Full Text Available Background: The burden of obstructive sleep apnea among commercial drivers in Nigeria is not known. Aim: To assess the prevalence of high risk of obstructive sleep apnea (OSA and excessive daytime sleepiness (EDS among intra-city commercial drivers. Setting and Design: A descriptive cross-sectional study in three major motor parks in Lagos metropolis. Materials and Methods: Demographic, anthropometric and historical data was obtained. The risk of OSA and EDS was assessed using the STOP BANG questionnaire and the Epworth Sleepiness Scale, respectively. Statistical Analysis: The relationship between the OSA risk, EDS risk and past road traffic accident (RTA was explored using the Pearson′s chi square. Independent determinants of OSA risk, EDS risk and past RTA, respectively, were assessed by multiple logistic regression models. Result: Five hundred male commercial drivers (mean age (years ±SD = 42.36 ± 11.17 and mean BMI (kg/m 2 ±SD = 25.68 ± 3.79 were recruited. OSA risk was high in 244 (48.8% drivers and 72 (14.4% had EDS. There was a positive relationship between OSA risk and the risk of EDS (Pearson′s X 2 = 28.2, P < 0.001. Sixty-one (12.2% drivers had a past history of RTA but there was no significant relationship between a past RTA and either OSA risk (X 2 = 2.05, P = 0.15 or EDS risk (X 2 = 2.7, P = 0.1, respectively. Abdominal adiposity, regular alcohol use and EDS were independent determinants of OSA risk while the use of cannabis and OSA risk were independent determinants of EDS. No independent risk factor for past RTA was identified. Conclusion: A significant proportion of commercial drivers in Lagos metropolis are at high risk of OSA and EDS.

  14. Efficacy of herbal coded Hepcon on drug induced hepatitis in experimental animals through histopathological and biochemical analysis.

    Science.gov (United States)

    Jamil, Muhammad Saim; Mahmood, Zahid; Saeed, Aftab; Jamil, Amir; Usmanghani, Khan; Asif, Hafiz Muhammad; Sajjad-al-Hassan; Roohi, Mahira

    2013-09-01

    Drug-induced liver injury is the leading cause for more than 50 percent of cases of acute liver failure. This study was conducted on herbo-mineral formulation "Hepcon" to evaluate its hepatoprotective effects in drug induced hepatitis in experimental animals. The liver injury was introduced with over dosage of non steroidal anti-inflammatory drugs (NSAIDs) and carbon tetrachloride (CCl4). The herbo-mineral formulations "Hepcon" consist of Zingiber officinale, Piprum nigrum, Ammonium chloride and Arsenic trioxide (Hartal warqi). The aqueous extraction was administered to experimental animals. Thereafter their LFTs, IgG, and tissue pathology was studied. It was observed on the basis of biochemical and histopathological analysis that animals which were subjected to Hepcon became normal in 60 days whereas those as control group did not showed improvements and most of them died. It was concluded that the efficacy of Hepcon to treat liver injury caused by CCl4 and NSAIDs is very effective, and no side effects were noticed. PMID:24035958

  15. A new system for profiling drug-induced calcium signal perturbation in human embryonic stem cell-derived cardiomyocytes.

    Science.gov (United States)

    Lewis, Kimberley J; Silvester, Nicole C; Barberini-Jammaers, Steven; Mason, Sammy A; Marsh, Sarah A; Lipka, Magdalena; George, Christopher H

    2015-03-01

    The emergence of human stem cell-derived cardiomyocyte (hSCCM)-based assays in the cardiovascular (CV) drug discovery sphere requires the development of improved systems for interrogating the rich information that these cell models have the potential to yield. We developed a new analytical framework termed SALVO (synchronization, amplitude, length, and variability of oscillation) to profile the amplitude and temporal patterning of intra- and intercellular calcium signals in hSCCM. SALVO quantified drug-induced perturbations in the calcium signaling "fingerprint" in spontaneously contractile hSCCM. Multiparametric SALVO outputs were integrated into a single index of in vitro cytotoxicity that confirmed the rank order of perturbation as astemizole > thioridazine > cisapride > flecainide > valdecoxib > sotalol > nadolol ≈ control. This rank order of drug-induced Ca(2+) signal disruption is in close agreement with the known arrhythmogenic liabilities of these compounds in humans. Validation of the system using a second set of compounds and hierarchical cluster analysis demonstrated the utility of SALVO to discriminate drugs based on their mechanisms of action. We discuss the utility of this new mechanistically agnostic system for the evaluation of in vitro drug cytotoxicity in hSCCM syncytia and the potential placement of SALVO in the early stage drug screening framework. PMID:25367900

  16. A New System for Profiling Drug-Induced Calcium Signal Perturbation in Human Embryonic Stem Cell–Derived Cardiomyocytes

    Science.gov (United States)

    Lewis, Kimberley J.; Silvester, Nicole C.; Barberini-Jammaers, Steven; Mason, Sammy A.; Marsh, Sarah A.; Lipka, Magdalena

    2015-01-01

    The emergence of human stem cell–derived cardiomyocyte (hSCCM)–based assays in the cardiovascular (CV) drug discovery sphere requires the development of improved systems for interrogating the rich information that these cell models have the potential to yield. We developed a new analytical framework termed SALVO (synchronization, amplitude, length, and variability of oscillation) to profile the amplitude and temporal patterning of intra- and intercellular calcium signals in hSCCM. SALVO quantified drug-induced perturbations in the calcium signaling “fingerprint” in spontaneously contractile hSCCM. Multiparametric SALVO outputs were integrated into a single index of in vitro cytotoxicity that confirmed the rank order of perturbation as astemizole > thioridazine > cisapride > flecainide > valdecoxib > sotalol > nadolol ≈ control. This rank order of drug-induced Ca2+ signal disruption is in close agreement with the known arrhythmogenic liabilities of these compounds in humans. Validation of the system using a second set of compounds and hierarchical cluster analysis demonstrated the utility of SALVO to discriminate drugs based on their mechanisms of action. We discuss the utility of this new mechanistically agnostic system for the evaluation of in vitro drug cytotoxicity in hSCCM syncytia and the potential placement of SALVO in the early stage drug screening framework. PMID:25367900

  17. Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post-chemotherapy tissues.

    Science.gov (United States)

    Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

    2015-12-01

    Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens.

  18. Evaluation of drug-induced neurotoxicity based on metabolomics, proteomics and electrical activity measurements in complementary CNS in vitro models.

    Science.gov (United States)

    Schultz, Luise; Zurich, Marie-Gabrielle; Culot, Maxime; da Costa, Anaelle; Landry, Christophe; Bellwon, Patricia; Kristl, Theresa; Hörmann, Katrin; Ruzek, Silke; Aiche, Stephan; Reinert, Knut; Bielow, Chris; Gosselet, Fabien; Cecchelli, Romeo; Huber, Christian G; Schroeder, Olaf H-U; Gramowski-Voss, Alexandra; Weiss, Dieter G; Bal-Price, Anna

    2015-12-25

    The present study was performed in an attempt to develop an in vitro integrated testing strategy (ITS) to evaluate drug-induced neurotoxicity. A number of endpoints were analyzed using two complementary brain cell culture models and an in vitro blood-brain barrier (BBB) model after single and repeated exposure treatments with selected drugs that covered the major biological, pharmacological and neuro-toxicological responses. Furthermore, four drugs (diazepam, cyclosporine A, chlorpromazine and amiodarone) were tested more in depth as representatives of different classes of neurotoxicants, inducing toxicity through different pathways of toxicity. The developed in vitro BBB model allowed detection of toxic effects at the level of BBB and evaluation of drug transport through the barrier for predicting free brain concentrations of the studied drugs. The measurement of neuronal electrical activity was found to be a sensitive tool to predict the neuroactivity and neurotoxicity of drugs after acute exposure. The histotypic 3D re-aggregating brain cell cultures, containing all brain cell types, were found to be well suited for OMICs analyses after both acute and long term treatment. The obtained data suggest that an in vitro ITS based on the information obtained from BBB studies and combined with metabolomics, proteomics and neuronal electrical activity measurements performed in stable in vitro neuronal cell culture systems, has high potential to improve current in vitro drug-induced neurotoxicity evaluation.

  19. Sleep Disruption and Daytime Sleepiness Correlating with Disease Severity and Insulin Resistance in Non-Alcoholic Fatty Liver Disease: A Comparison with Healthy Controls.

    Directory of Open Access Journals (Sweden)

    Christine Bernsmeier

    Full Text Available Sleep disturbance is associated with the development of obesity, diabetes and hepatic steatosis in murine models. Hepatic triglyceride accumulation oscillates in a circadian rhythm regulated by clock genes, light-dark cycle and feeding time in mice. The role of the sleep-wake cycle in the pathogenesis of human non-alcoholic fatty liver disease (NAFLD is indeterminate. We sought to detail sleep characteristics, daytime sleepiness and meal times in relation to disease severity in patients with NAFLD.Basic Sleep duration and latency, daytime sleepiness (Epworth sleepiness scale, Pittsburgh sleep quality index, positive and negative affect scale, Munich Chronotype Questionnaire and an eating habit questionnaire were assessed in 46 patients with biopsy-proven NAFLD and 22 healthy controls, and correlated with biochemical and histological parameters.In NAFLD compared to healthy controls, time to fall asleep was vastly prolonged (26.9 vs. 9.8 min., p = 0.0176 and sleep duration was shortened (6.3 vs. 7.2 hours, p = 0.0149. Sleep quality was poor (Pittsburgh sleep quality index 8.2 vs. 4.7, p = 0.0074 and correlated with changes in affect. Meal frequency was shifted towards night-times (p = 0.001. In NAFLD but not controls, daytime sleepiness significantly correlated with liver enzymes (ALAT [r = 0.44, p = 0.0029], ASAT [r = 0.46, p = 0.0017] and insulin resistance (HOMA-IR [r = 0.5, p = 0.0009] independent of cirrhosis. In patients with fibrosis, daytime sleepiness correlated with the degree of fibrosis (r = 0.364, p = 0.019.In NAFLD sleep duration was shortened, sleep onset was delayed and sleep quality poor. Food-intake was shifted towards the night. Daytime sleepiness was positively linked to biochemical and histologic surrogates of disease severity. The data may indicate a role for sleep-wake cycle regulation and timing of food-intake in the pathogenesis of human NAFLD as suggested from murine models.

  20. Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries

    Energy Technology Data Exchange (ETDEWEB)

    Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Tsuneyama, Koichi [Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Sugitani, Toyama 930‐0194 (Japan); Endo, Shinya [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Tsukui, Tohru [Research Center for Genomic Medicine, Saitama Medical University, Yamane, Hidaka 350‐1241 (Japan); Toyoda, Yasuyuki; Fukami, Tatsuki; Nakajima, Miki [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Yokoi, Tsuyoshi, E-mail: tyokoi@p.kanazawa-u.ac.jp [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan)

    2012-10-01

    Although estrogen receptor (ER)α agonists, such as estradiol and ethinylestradiol (EE2), cause cholestasis in mice, they also reduce the degree of liver injury caused by hepatotoxicants as well as ischemia–reperfusion. The functional mechanisms of ERα have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ERα agonist, selective ER modulators (SERMs) and an ER antagonist on drug-induced and chemical-induced liver injuries caused by acetaminophen, bromobenzene, diclofenac, and thioacetamide (TA). We observed hepatoprotective effects of EE2, tamoxifen (TAM) and raloxifene pretreatment in female mice that were exposed to a variety of hepatotoxic compounds. In contrast, the ER antagonist did not show any hepatoprotective effects. DNA microarray analyses suggested that monocyte to macrophage differentiation-associated 2 (Mmd2) protein, which has an unknown function, is commonly increased by TAM and RAL pretreatment, but not by pretreatment with the ER antagonist. In ERα-knockout mice, the hepatoprotective effects of TAM and the increased expression of Mmd2 mRNA were not observed in TA-induced liver injury. To investigate the function of Mmd2, the expression level of Mmd2 mRNA was significantly knocked down to approximately 30% in mice by injection of siRNA for Mmd2 (siMmd2). Mmd2 knockdown resulted in a reduction of the protective effects of TAM on TA-induced liver injury in mice. This is the first report of the involvement of ERα in drug-induced or chemical-induced liver injury. Upregulation of Mmd2 protein in the liver was suggested as the mechanism of the hepatoprotective effects of EE2 and SERMs. -- Highlights: ► Liver injury induced by drugs or chemicals was investigated in mice. ► Liver injury was suppressed by pretreatment with tamoxifen in female mice. ► Mmd2, whose function was unknown, could be a candidate gene for liver protection. ► Tamoxifen up-regulated Mmd2 mRNA expression

  1. Consensus statement: Management of drug-induced liver injury in HIV-positive patients treated for TB

    Directory of Open Access Journals (Sweden)

    E Jong

    2013-09-01

    Full Text Available Drug-induced liver injury (DILI in HIV/tuberculosis (TB co-infected patients is a common problem in the South African setting, and re-introduction of anti-TB drugs can be challenging for the healthcare worker. Although international guidelines on the re-introduction of TB treatment are available, the definition of DILI is not uniform, management of antiretroviral therapy (ART in HIV co-infection is not mentioned, and the guidance on management is not uniform and lacks a practical approach. In this consensus statement, we summarise important aspects of DILI and provide practical guidance for healthcare workers for different patient groups and healthcare settings on the re-introduction of anti-TB drugs and ART in HIV/TB co-infected individuals presenting with DILI.

  2. Laser-Assisted Periodontal Management of Drug-Induced Gingival Overgrowth under General Anesthesia: A Viable Option

    Directory of Open Access Journals (Sweden)

    Tupili Muralikrishna

    2013-01-01

    Full Text Available Gingival overgrowth/hyperplasia can be attributed to several causes, but drug-induced gingival overgrowth/hyperplasia arises secondarily to prolonged use of antihypertensive drugs, anticonvulsants and immunosuppressants. The management is complex in nature considering the multitude of factors involved such as substitution of drug strict plaque control along with excision of the tissue to be performed under local anesthesia as outpatient. In the recent times, the patient’s psychological fear of the treatment with the use of surgical blade and multiple visits has developed the concept of single visit treatment under general anesthesia incorporating a laser as viable option. The present case highlights the new method of management of gingival overgrowth.

  3. Investigation of parameters highlighting drug induced small changes of the T-wave's morphology for drug safety studies.

    Science.gov (United States)

    Baas, Tobias; Gräfe, Ksenija; Khawaja, Antoun; Dössel, Olaf

    2011-01-01

    In guideline E14, the American Food and Drug Administration (FDA) requests for clinical studies to investigate the prolongation of the heart rate corrected QT-interval (QTc) of the ECG. As drug induced QT-prolongation can be caused by changes in the repolarisation of the ventricles, it is so far a thorough ECG biomarker of risk for ventricular tachyarrhythmias and Torsade de Pointes (TdP). Ventricular repolarisation changes not only change QT but also influence the morphology of the T-wave. In a (400 mg single dose) Moxifloxacin positive control study both, QTc and several descriptors describing the T-wave morphology have been measured. Moxifloxacin is changing two shape dependent descriptors significantly (P<0.05) about 3 to 4 hours after a 400 mg oral single dose of Moxifloxacin.

  4. Late-Onset Drug-Induced Cholestasis in a Living-Related Liver Transplant Donor With Progressive Familial Intrahepatic Cholestasis.

    Science.gov (United States)

    Harmancı, Özgür; Ensaroğlu, Fatih; Özçay, Figen; Öcal, Serkan; Korkmaz, Murat; Özdemir, B Handan; Selçuk, Haldun; Moray, Gökhan; Haberal, Mehmet

    2015-11-01

    We present a rare case of progressive familial intrahepatic cholestasis within a family. A 34-yearold female became a living-related liver transplant donor for her son, who had the disease. Nine years after the transplant, the mother developed severe intrahepatic cholestasis, for which she was evaluated after using an oral contraceptive drug. She presented with jaundice, pruritus, and increased bilirubin levels, together with elevated gamma glutamyl transferase and alkaline phosphatase levels. A liver biopsy revealed findings consistent with intrahepatic cholestasis. However, despite follow-up management and cessation of the insulting drug, her total bilirubin count continuously increased to 20 mg/dL and was accompanied by intractable pruritus. A total of 9 plasmapheresis sessions were performed, and she was started on a regimen of ursodeoxycholic acid (13 mg/kg/d) and cholestyramine (4 g, 3 times daily). The clinical and laboratory picture dramatically improved following cessation of the oral contraceptive, plasmapheresis sessions, and drug treatment. The patient's cholestasis normalized within 3 months, and she recovered uneventfully. A genetic analysis of the whole family revealed that both parents were heterozygous for the mutation c.124G>A in ABCB11, and the son was homozygous for this mutation. These findings supported varying degrees of bile salt export pump deficiency in the family members. Defective bile salt excretory system function can result in a wide spectrum of clinical presentations, ranging from progressive familial intrahepatic cholestasis requiring liver transplant to late-onset drug-induced cholestasis. Our findings suggest that, in a heterozygous carrier of a progressive familial intrahepatic cholestasis mutation, drug-induced cholestasis is responsive to treatment, after which the clinical picture can normalize within 3 months.

  5. Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats

    International Nuclear Information System (INIS)

    Drug-induced liver injury (DILI) is a significant consideration for drug development. Current preclinical DILI assessment relying on histopathology and clinical chemistry has limitations in sensitivity and discordance with human. To gain insights on DILI pathogenesis and identify potential biomarkers for improved DILI detection, we performed untargeted metabolomic analyses on rats treated with thirteen known hepatotoxins causing various types of DILI: necrosis (acetaminophen, bendazac, cyclosporine A, carbon tetrachloride, ethionine), cholestasis (methapyrilene and naphthylisothiocyanate), steatosis (tetracycline and ticlopidine), and idiosyncratic (carbamazepine, chlorzoxasone, flutamide, and nimesulide) at two doses and two time points. Statistical analysis and pathway mapping of the nearly 1900 metabolites profiled in the plasma, urine, and liver revealed diverse time and dose dependent metabolic cascades leading to DILI by the hepatotoxins. The most consistent change induced by the hepatotoxins, detectable even at the early time point/low dose, was the significant elevations of a panel of bile acids in the plasma and urine, suggesting that DILI impaired hepatic bile acid uptake from the circulation. Furthermore, bile acid amidation in the hepatocytes was altered depending on the severity of the hepatotoxin-induced oxidative stress. The alteration of the bile acids was most evident by the necrosis and cholestasis hepatotoxins, with more subtle effects by the steatosis and idiosyncratic hepatotoxins. Taking together, our data suggest that the perturbation of bile acid homeostasis is an early event of DILI. Upon further validation, selected bile acids in the circulation could be potentially used as sensitive and early DILI preclinical biomarkers. - Highlights: ► We used metabolomics to gain insights on drug induced liver injury (DILI) in rats. ► We profiled rats treated with thirteen hepatotoxins at two doses and two time points. ► The toxins decreased the

  6. Late-Onset Drug-Induced Cholestasis in a Living-Related Liver Transplant Donor With Progressive Familial Intrahepatic Cholestasis.

    Science.gov (United States)

    Harmancı, Özgür; Ensaroğlu, Fatih; Özçay, Figen; Öcal, Serkan; Korkmaz, Murat; Özdemir, B Handan; Selçuk, Haldun; Moray, Gökhan; Haberal, Mehmet

    2015-11-01

    We present a rare case of progressive familial intrahepatic cholestasis within a family. A 34-yearold female became a living-related liver transplant donor for her son, who had the disease. Nine years after the transplant, the mother developed severe intrahepatic cholestasis, for which she was evaluated after using an oral contraceptive drug. She presented with jaundice, pruritus, and increased bilirubin levels, together with elevated gamma glutamyl transferase and alkaline phosphatase levels. A liver biopsy revealed findings consistent with intrahepatic cholestasis. However, despite follow-up management and cessation of the insulting drug, her total bilirubin count continuously increased to 20 mg/dL and was accompanied by intractable pruritus. A total of 9 plasmapheresis sessions were performed, and she was started on a regimen of ursodeoxycholic acid (13 mg/kg/d) and cholestyramine (4 g, 3 times daily). The clinical and laboratory picture dramatically improved following cessation of the oral contraceptive, plasmapheresis sessions, and drug treatment. The patient's cholestasis normalized within 3 months, and she recovered uneventfully. A genetic analysis of the whole family revealed that both parents were heterozygous for the mutation c.124G>A in ABCB11, and the son was homozygous for this mutation. These findings supported varying degrees of bile salt export pump deficiency in the family members. Defective bile salt excretory system function can result in a wide spectrum of clinical presentations, ranging from progressive familial intrahepatic cholestasis requiring liver transplant to late-onset drug-induced cholestasis. Our findings suggest that, in a heterozygous carrier of a progressive familial intrahepatic cholestasis mutation, drug-induced cholestasis is responsive to treatment, after which the clinical picture can normalize within 3 months. PMID:26640927

  7. Evaluation of antihepatotoxic potential of Solanum xanthocarpum fruit extract against antitubercular drugs induced hepatopathy in experimental rodents

    Institute of Scientific and Technical Information of China (English)

    Talib Hussain; Ramesh K Gupta; Sweety K; Mohd Sajid Khan; Md Sarfaraj Hussain; Md Arif; Arshad Hussain; Md Faiyazuddin; Chandana Venkateswara Rao

    2012-01-01

    Objective:To assess the hepatoprotective effect of Solanum xanthocarpum (S. xanthocarpum) fruit extract against antitubercular drug-induced liver toxicity in experimental animals. Methods:Ethanolic (50%) fruit extract of S. xanthocarpum (100, 200 and 400 mg/kg bw) was administered daily for 35 days in experimental animals. Liver toxicity was induced by combination of three antitubercular drugs [isoniazid (I) 7.5 mg/kg, rifampicin (R) 10 mg/kg and pyrazinamide (P) 35 mg/kg] given orally as suspension for 35 days in rats. The hepatoprotective activity was assessed using various biochemical parameters like aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatise (ALP), total bilirubin (TBL), albumin (ALB), total protein (TP), lactate dehydroginase (LDH), and serum cholesterol (CHL). Meanwhile, in vivo antioxidant activities as lipid peroxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were measured in rat liver homogenate. The biochemical observations were supplemented by histopathological examination. Results: The results demonstrated that treatment with S. xanthocarpum significantly (P<0.05-P<0.001) and dose-dependently prevented drug induced increase in serum levels of hepatic enzymes. Furthermore, S. xanthocarpum significantly (up to P<0.001) reduced the LPO in the liver tissue and restored activities of defence antioxidant enzymes GSH, SOD and CAT towards normal levels. Histopathology of the liver tissue showed that S. xanthocarpum attenuated the hepatocellular necrosis and led to reduction in inflammatory cells infiltration. Conclusions:The results of this study strongly indicate the protective effect of S. xanthocarpum against liver injury which may be attributed to its hepatoprotective activity, and thereby scientifically support its traditional use.

  8. Drug-Induced Acute Pancreatitis in a Cohort of 328 Patients. A Single-Centre Experience from Australia

    Directory of Open Access Journals (Sweden)

    Savio G Barreto

    2011-11-01

    Full Text Available Context Acute pancreatitis is associated with risk of morbidity and even mortality. Routine prescription drugs have been linked to the causation of acute pancreatitis. Objective To determine the incidence, presentation, course and outcome of drug-induced acute pancreatitis amongst patients admitted to a public hospital. Design/setting A retrospective analysis of patients presenting with acute pancreatitis to the Modbury Hospital, South Australia from January 2006 to April 2011. Main outcome measure Each admission was reviewed within the electronic database for patient details as well as to determine the aetiological factor. In patients with druginduced acute pancreatitis, the WHO Probability Scale was used to evaluate causality relationship. Results Three-hundreds and 28 patients were treated for acute pancreatitis during the study period. Biliary and alcohol-induced acute pancreatitis accounted for 80.8% of cases. Eleven patients (2 male and 9 female patients; median age: 59 years were diagnosed with drug-induced acute pancreatitis. These included 5 cases of codeine-, 2 cases of azathioprine-, and 1 case each of chlorothiazide-, valproic acid-, oestradiol- and rosuvastatin-induced acute pancreatitis. Nine patients had a mild disease while 2 patients had severe acute pancreatitis with a median hospital stay of 4 days. Withdrawal of the drug resulted in cessation of the attacks in all patients over a median follow-up of 24 months. Conclusions Routine prescription drugs, as an aetiological factor, accounted for 3.4% of cases of acute pancreatitis. The disease appeared to be more common in middle-aged women. It is likely that the overall incidence of this entity is under-reported owing to the stringent criteria needed to conclusively determine a causal relationship.

  9. Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro

    Science.gov (United States)

    Funk, Juergen; Robbins, Justin B.; Crogan-Grundy, Candace; Presnell, Sharon C.; Singer, Thomas; Roth, Adrian B.

    2016-01-01

    Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI). This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM). Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level. PMID:27387377

  10. Inhibin beta E is upregulated by drug-induced endoplasmic reticulum stress as a transcriptional target gene of ATF4

    International Nuclear Information System (INIS)

    Inhibins and activins are gonadal peptide hormones of the transforming growth factor-β super family with important functions in the reproductive system. By contrast, the recently identified inhibin βE subunit, primarily expressed in liver cells, appears to exert functions unrelated to the reproductive system. Previously shown downregulation of inhibin βE in hepatoma cells and anti-proliferative effects of ectopic inhibin βE overexpression indicated growth-regulatory effects of inhibin βE. We observed a selective re-expression of the inhibin βE subunit in HepG2 hepatoblastoma cells, MCF7 breast cancer cells, and HeLa cervical cancer cells under endoplasmic reticulum stress conditions induced by tunicamycin, thapsigargin, and nelfinavir. Analysis of XPB1 splicing and ATF4 activation revealed that inhibin βE re-expression was associated with induction of the endoplasmic reticulum stress reaction by these drugs. Transfection of an ATF4 expression plasmid specifically induced inhibin βE expression in HeLa cells and indicates inhibin βE as a hitherto unidentified target gene of ATF4, a key transcription factor of the endoplasmic reticulum stress response. Therefore, the inhibin βE subunit defines not only a new player but also a possible new marker for drug-induced endoplasmic reticulum stress. -- Highlights: ► Endoplasmic reticulum stress induces inhibin beta E expression. ► Inhibin beta E is regulated by the transcription factor ATF4. ► Inhibin beta E expression can be used as a marker for drug-induced ER stress.

  11. Expression patterns and action analysis of genes associated with drug-induced liver diseases during rat liver regeneration

    Institute of Scientific and Technical Information of China (English)

    Qian-Ji Ning; Shao-Wei Qin; Cun-Shuan Xu

    2006-01-01

    AIM: To study the action of the genes associated with drug-induced liver diseases at the gene transcriptional level during liver regeneration (LR) in rats.METHODS: The genes associated with drug-induced liver diseases were obtained by collecting the data from databases and literature, and the gene expression changes in the regenerating liver were checked by the Rat Genome 230 2.0 array.RESULTS: The initial and total expression numbers of genes occurring in phases of 0.5-4 h after partial hepatectomy (PH), 4-6 h after PH (G0/G1 transition),6-66 h after PH (cell proliferation), 66-168 h after PH (cell differentiation and structure-function reconstruction) were 21, 3, 9, 2 and 21, 9, 19, 18, respectively. It is illustrated that the associated genes were mainly triggered at the initial stage of LR and worked at different phases. According to their expression similarity,these genes were classified into 5 types: only upregulated (12 genes), predominantly up-regulated (4genes), only down-regulated (11 genes), predominantly down-regulated (3 genes), and approximately up-/down-regulated (2 genes). The total times of their upand down-expression were 130 and 79, respectively,demonstrating that expression of most of the genes was increased during LR, while a few decreased. The cell physiological and biochemical activities during LR were staggered according to the time relevance and were diverse and complicated in gene expression patterns.CONCLUSION: Drug metabolic capacity in regenerating liver was enhanced. Thirty-two genes play important roles during liver regeneration in rats.

  12. Anti-hepatotoxic and antioxidant influence of Ipomoea carnea against anti-tubercular drugs induced acute hepatopathy in experimental rodents

    Institute of Scientific and Technical Information of China (English)

    Ramesh Kumar Gupta; Ashok Kumar Gupta; Sudhansu Ranjan Swain; Vaishali; Gaurav Gupta; Saifuddin Khalid; Didagi Kulkarni Suresh; Rajnish Kumar Singh

    2013-01-01

    Objective: To assess the hepatoprotective effect of Ipomoea carnea (I. carnea) extract against antitubercular drug-induced liver toxicity in experimental animals. Methods: I. carnea extracts (125, 250 and 500 mg/kg, p.o. body weight) were administered daily for 3d5r udg sin experimental animals. Liver toxicity was induced by combination of three antitubercular suspen(siisoonn ifaozr id 7.5 mg/kg, rifampicin 10 mg/kg and pyrazinamide 35 mg/kg) given orally as drugs. 35 d in rats. Treatment groups received I. carnea extracts along with antitubercular aspartaTteh ea mhienpoattroapnrsofeteracstiev,e a alacntiivniet ya mwainso atrsasnessfseerda sues, ianlgk avlainrieo upsh obsipochhaetimsei caanl dp atortaaml ebtielirrsu bliikne. dMiesmanuwtahsiele a, nind- cvaivtaol aasnet iwoxeirdea mnte aascutirveidti eisn aras t lliipviedr pheormoxoigdeantaioten ,a rloendgu cweidth g lutathione, superoxide ATPase and G-6-Pase. The biochemical observations were supplemented by histopathological examination. Results: Obtained results demonstrated that treatment with I. carnea extracts significantly h(Pedrug induced increase in serum levels of peroxidation in theF ulrivtheer rtmisosruee, Ia.n cda rrnesetao reexdt raaccttisv istiigens ifoifc adnetfleyn c(uep atnot iPox

  13. Inhibin beta E is upregulated by drug-induced endoplasmic reticulum stress as a transcriptional target gene of ATF4

    Energy Technology Data Exchange (ETDEWEB)

    Brüning, Ansgar, E-mail: ansgar.bruening@med.uni-muenchen.de; Matsingou, Christina; Brem, German Johannes; Rahmeh, Martina; Mylonas, Ioannis

    2012-10-15

    Inhibins and activins are gonadal peptide hormones of the transforming growth factor-β super family with important functions in the reproductive system. By contrast, the recently identified inhibin βE subunit, primarily expressed in liver cells, appears to exert functions unrelated to the reproductive system. Previously shown downregulation of inhibin βE in hepatoma cells and anti-proliferative effects of ectopic inhibin βE overexpression indicated growth-regulatory effects of inhibin βE. We observed a selective re-expression of the inhibin βE subunit in HepG2 hepatoblastoma cells, MCF7 breast cancer cells, and HeLa cervical cancer cells under endoplasmic reticulum stress conditions induced by tunicamycin, thapsigargin, and nelfinavir. Analysis of XPB1 splicing and ATF4 activation revealed that inhibin βE re-expression was associated with induction of the endoplasmic reticulum stress reaction by these drugs. Transfection of an ATF4 expression plasmid specifically induced inhibin βE expression in HeLa cells and indicates inhibin βE as a hitherto unidentified target gene of ATF4, a key transcription factor of the endoplasmic reticulum stress response. Therefore, the inhibin βE subunit defines not only a new player but also a possible new marker for drug-induced endoplasmic reticulum stress. -- Highlights: ► Endoplasmic reticulum stress induces inhibin beta E expression. ► Inhibin beta E is regulated by the transcription factor ATF4. ► Inhibin beta E expression can be used as a marker for drug-induced ER stress.

  14. Sleep architecture of consolidated and split sleep due to the dawn (Fajr prayer among Muslims and its impact on daytime sleepiness

    Directory of Open Access Journals (Sweden)

    Ahmed S BaHammam

    2012-01-01

    Full Text Available Background: Muslims are required to wake up early to pray (Fajr at dawn (approximately one and one-half hours before sunrise. Some Muslims wake up to pray Fajr and then sleep until it is time to work (split sleep, whereas others sleep continuously (consolidated sleep until work time and pray Fajr upon awakening. Aim: To objectively assess sleep architecture and daytime sleepiness in consolidated and split sleep due to the Fajr prayer. Setting and Design: A cross-sectional, single-center observational study in eight healthy male subjects with a mean age of 32.0 ± 2.4 years. Methods: The participants spent three nights in the Sleep Disorders Center (SDC at King Khalid University Hospital, where they participated in the study, which included (1 a medical checkup and an adaptation night, (2 a consolidated sleep night, and (3 a split-sleep night. Polysomnography (PSG was conducted in the SDC following the standard protocol. Participants went to bed at 11:30 PM and woke up at 7:00 AM in the consolidated sleep protocol. In the split-sleep protocol, participants went to bed at 11:30 PM, woke up at 3:30 AM for 45 minutes, went back to bed at 4:15 AM, and finally woke up at 7:45 AM. PSG was followed by a multiple sleep latency test to assess the daytime sleepiness of the participants. Results: There were no differences in sleep efficiency, the distribution of sleep stages, or daytime sleepiness between the two protocols. Conclusion: No differences were detected in sleep architecture or daytime sleepiness in the consolidated and split-sleep schedules when the total sleep duration was maintained.

  15. Fremlæggelse af projekt med Epworth søvnighedsskema, opgørelse af data fra 2009-2014: "Prevalence of excessive daytime sleepiness in patients treated with orthognathic surgery"

    DEFF Research Database (Denmark)

    Linderup, Mette Werner

    Fremlæggelse af projekt med Epworth søvnighedsskema, opgørelse af data fra 2009-2014: "Prevalence of excessive daytime sleepiness in patients treated with orthognathic surgery"......Fremlæggelse af projekt med Epworth søvnighedsskema, opgørelse af data fra 2009-2014: "Prevalence of excessive daytime sleepiness in patients treated with orthognathic surgery"...

  16. Effects of long working hours and the night shift on severe sleepiness among workers with 12-hour shift systems for 5 to 7 consecutive days in the automobile factories of Korea.

    Science.gov (United States)

    Son, Mia; Kong, Jeong-Ok; Koh, Sang-Baek; Kim, Jaeyoung; Härmä, Mikko

    2008-12-01

    We investigated the effects of 12-hour shift work for five to seven consecutive days and overtime on the prevalence of severe sleepiness in the automobile industry in Korea. [Correction added after online publication 28 Nov: Opening sentence of the summary has been rephrased for better clarity.] A total of 288 randomly selected male workers from two automobile factories were selected and investigated using questionnaires and sleep-wake diaries in South Korea. The prevalence of severe sleepiness at work [i.e. Karolinska Sleepiness Scale (KSS) score of 7 or higher] was modeled using marginal logistic regression and included theoretical risk factors related to working hours and potential confounding factors related to socio-economic status, work demands, and health behaviors. Factors related to working hours increased the risk for severe sleepiness at the end of the shift in the following order: the night shift [odds ratio (OR): 4.7; 95% confidence interval (CI): 3.6-6.0)], daily overtime (OR: 2.2; 95% CI: 1.7-2.9), weekly overtime (OR: 1.6; 95% CI: 1.0-2.6), and night overtime (OR: 1.6; 95% CI: 0.8-3.0). Long working hours and shift work had a significant interactive effect for severe sleepiness at work. Night shift workers who worked for 12 h or more a day were exposed to a risk of severe sleepiness that was 7.5 times greater than day shift workers who worked less than 11 h. Night shifts and long working hours were the main risk factors for severe sleepiness among automobile factory workers in Korea. Night shifts and long working hours have a high degree of interactive effects resulting in severe sleepiness at work, which highlight the need for immediate measures to address these characteristics among South Korean labor force patterns. PMID:19021859

  17. The impact of daytime sleepiness on the school performance of college students with attention deficit hyperactivity disorder (ADHD): a prospective longitudinal study.

    Science.gov (United States)

    Langberg, Joshua M; Dvorsky, Melissa R; Becker, Stephen P; Molitor, Stephen J

    2014-06-01

    This prospective longitudinal study evaluated the impact of daytime sleepiness on the school performance of 62 college students diagnosed comprehensively with attention deficit hyperactivity disorder. The primary goal of the study was to determine if self-reported daytime sleepiness rated at the beginning of the academic year could predict academic and overall functioning at the end of the academic year while also considering potentially important covariates, including symptoms of inattention, hyperactivity and impulsivity, medication status and whether or not students lived at home or on-campus. Self-reported daytime sleepiness predicted longitudinally school maladjustment, overall functional impairment and the number of D and F grades (i.e. poor and failing) students received in courses above and beyond both self- and parent-report of symptoms, but did not predict overall grade point average. Living at home served as a protective factor and was associated with less school maladjustment and overall impairment. Gender was the only significant predictor in the overall grade point average model, with female gender associated with higher overall grades. The implications of these findings for monitoring and treatment of sleep disturbances in college students with attention deficit hyperactivity disorder are discussed.

  18. Risk of obstructive sleep apnea with daytime sleepiness is associated with liver damage in non-morbidly obese patients with nonalcoholic fatty liver disease.

    Directory of Open Access Journals (Sweden)

    Edoardo Alessandro Pulixi

    Full Text Available BACKGROUND: A high prevalence of obstructive sleep apnea syndrome (OSAS has been reported in severely obese patients with nonalcoholic fatty liver disease (NAFLD, but few studies have evaluated OSAS in non-morbidly obese NAFLD patients. AIMS: To determine the prevalence of risk for OSAS with or without daytime sleepiness in non-morbidly obese patients with NAFLD and evaluate the association with the severity of liver damage. METHODS: We considered 159 consecutive patients with histological NAFLD and body mass index (BMI 1; 9/13, 69% vs. 39/146, 27%; p = 0.003. At multivariate logistic regression analysis, OSAS with sleepiness was strongly associated with NASH and fibrosis>1 independently of known clinical risk factors such as age, gender, BMI, diabetes, and ALT levels (OR 7.1, 95% c.i. 1.7-51, p = 0.005 and OR 14.0, 95% c.i. 3.5-70, p = 0.0002, respectively. CONCLUSIONS: A proportion of NAFLD patients without severe obesity is at risk for OSAS with daytime sleepiness, which is associated with the severity of liver damage independently of body mass and other cofactors.

  19. A Case of Sublingual Ranula That Responded Successfully to Localized Injection Treatment with OK-432 after Healing from Drug Induced Hypersensitivity Syndrome

    Directory of Open Access Journals (Sweden)

    Kunio Yoshizawa

    2016-01-01

    Full Text Available A ranula is a mucus retention cyst or pseudocyst caused by leakage of mucus from the sublingual gland and generally occurs in the oral floor. In addition, drug induced hypersensitivity syndrome (DIHS is a rare but well-recognized serious adverse effect characterized by fever, skin rashes, generalized lymphadenopathy, hepatitis, and hepatosplenomegaly and oral stomatitis. This paper presents the first case of successfully treated sublingual ranula with localized injection of OK-432 after healing from drug induced hypersensitivity syndrome, which has previously been unreported in the literature. We present the case of a 38-year-old Japanese woman with sublingual ranula that responded successfully to localized injection treatment with OK-432 after healing from drug induced hypersensitivity syndrome. She was affected with cutaneous myositis and interstitial lung disease when she was 26 years old. At the age 34 years, she received additional oral treatment of diaminodiphenyl-sulfone due to deterioration of the cutaneous myositis, which resulted in drug induced hypersensitivity syndrome (DIHS with severe oral stomatitis. Local injection of OK-432 to the ranula may be a very safe and useful treatment method even if the patient has a history of drug allergy and has connective tissue disease such as cutaneous myositis.

  20. Hepatitis C virus co-infection increases the risk of anti-tuberculosis drug-induced hepatotoxicity among patients with pulmonary tuberculosis.

    Directory of Open Access Journals (Sweden)

    Nino Lomtadze

    Full Text Available BACKGROUND: The country of Georgia has a high prevalence of tuberculosis (TB and hepatitis C virus (HCV infection. PURPOSE: To determine whether HCV co-infection increases the risk of incident drug-induced hepatitis among patients on first-line anti-TB drug therapy. METHODS: Prospective cohort study; HCV serology was obtained on all study subjects at the time of TB diagnosis; hepatic enzyme tests (serum alanine aminotransferase [ALT] activity were obtained at baseline and monthly during treatment. RESULTS: Among 326 study patients with culture-confirmed TB, 68 (21% were HCV co-infected, 14 (4.3% had chronic hepatitis B virus (HBV infection (hepatitis B virus surface antigen positive [HBsAg+], and 6 (1.8% were HIV co-infected. Overall, 19% of TB patients developed mild to moderate incident hepatotoxicity. In multi-variable analysis, HCV co-infection (adjusted Hazards Ratio [aHR]=3.2, 95% CI=1.6-6.5 was found to be an independent risk factor for incident anti-TB drug-induced hepatotoxicity. Survival analysis showed that HCV co-infected patients developed hepatitis more quickly compared to HCV seronegative patients with TB. CONCLUSION: A high prevalence of HCV co-infection was found among patients with TB in Georgia. Drug-induced hepatotoxicity was significantly associated with HCV co-infection but severe drug-induced hepatotoxicity (WHO grade III or IV was rare.

  1. Proteomic profiling in incubation medium of mouse, rat and human precision-cut liver slices for biomarker detection regarding acute drug-induced liver injury

    NARCIS (Netherlands)

    van Swelm, Rachel P. L.; Hadi, Mackenzie; Laarakkers, Coby M. M.; Masereeuw, Rosalinde; Groothuis, Geny M. M.; Russel, Frans G. M.

    2014-01-01

    Drug-induced liver injury is one of the leading causes of drug withdrawal from the market. In this study, we investigated the applicability of protein profiling of the incubation medium of human, mouse and rat precision-cut liver slices (PCLS) exposed to liver injury-inducing drugs for biomarker ide

  2. Mitochondrial bioenergetics and drug-induced toxicity in a panel of mouse embryonic fibroblasts with mitochondrial DNA single nucleotide polymorphisms

    Energy Technology Data Exchange (ETDEWEB)

    Pereira, Claudia V.; Oliveira, Paulo J. [CNC—Center for Neuroscience and Cell Biology, University of Coimbra (Portugal); Will, Yvonne [Compound Safety Prediction, Pfizer Global Research and Development, Groton, CT (United States); Nadanaciva, Sashi, E-mail: sashi.nadanaciva@pfizer.com [Compound Safety Prediction, Pfizer Global Research and Development, Groton, CT (United States)

    2012-10-15

    Mitochondrial DNA (mtDNA) variations including single nucleotide polymorphisms (SNPs) have been proposed to be involved in idiosyncratic drug reactions. However, current in vitro and in vivo models lack the genetic diversity seen in the human population. Our hypothesis is that different cell strains with distinct mtDNA SNPs may have different mitochondrial bioenergetic profiles and may therefore vary in their response to drug-induced toxicity. Therefore, we used an in vitro system composed of four strains of mouse embryonic fibroblasts (MEFs) with mtDNA polymorphisms. We sequenced mtDNA from embryonic fibroblasts isolated from four mouse strains, C57BL/6J, MOLF/EiJ, CZECHII/EiJ and PERA/EiJ, with the latter two being sequenced for the first time. The bioenergetic profile of the four strains of MEFs was investigated at both passages 3 and 10. Our results showed that there were clear differences among the four strains of MEFs at both passages, with CZECHII/EiJ having a lower mitochondrial robustness when compared to C57BL/6J, followed by MOLF/EiJ and PERA/EiJ. Seven drugs known to impair mitochondrial function were tested for their effect on the ATP content of the four strains of MEFs in both glucose- and galactose-containing media. Our results showed that there were strain-dependent differences in the response to some of the drugs. We propose that this model is a useful starting point to study compounds that may cause mitochondrial off-target toxicity in early stages of drug development, thus decreasing the number of experimental animals used. -- Highlights: ► mtDNA SNPs may be linked to individual predisposition to drug-induced toxicity. ► CZECHII/EiJ and PERA/EiJ mtDNA was sequenced for the first time in this study. ► Strain-dependent mitochondrial capacity differences were measured. ► Strain-dependent differences in response to mitochondrial toxicants were observed.

  3. Drug-induced acute myocardial infarction: identifying 'prime suspects' from electronic healthcare records-based surveillance system.

    Directory of Open Access Journals (Sweden)

    Preciosa M Coloma

    Full Text Available BACKGROUND: Drug-related adverse events remain an important cause of morbidity and mortality and impose huge burden on healthcare costs. Routinely collected electronic healthcare data give a good snapshot of how drugs are being used in 'real-world' settings. OBJECTIVE: To describe a strategy that identifies potentially drug-induced acute myocardial infarction (AMI from a large international healthcare data network. METHODS: Post-marketing safety surveillance was conducted in seven population-based healthcare databases in three countries (Denmark, Italy, and the Netherlands using anonymised demographic, clinical, and prescription/dispensing data representing 21,171,291 individuals with 154,474,063 person-years of follow-up in the period 1996-2010. Primary care physicians' medical records and administrative claims containing reimbursements for filled prescriptions, laboratory tests, and hospitalisations were evaluated using a three-tier triage system of detection, filtering, and substantiation that generated a list of drugs potentially associated with AMI. Outcome of interest was statistically significant increased risk of AMI during drug exposure that has not been previously described in current literature and is biologically plausible. RESULTS: Overall, 163 drugs were identified to be associated with increased risk of AMI during preliminary screening. Of these, 124 drugs were eliminated after adjustment for possible bias and confounding. With subsequent application of criteria for novelty and biological plausibility, association with AMI remained for nine drugs ('prime suspects': azithromycin; erythromycin; roxithromycin; metoclopramide; cisapride; domperidone; betamethasone; fluconazole; and megestrol acetate. LIMITATIONS: Although global health status, co-morbidities, and time-invariant factors were adjusted for, residual confounding cannot be ruled out. CONCLUSION: A strategy to identify potentially drug-induced AMI from electronic healthcare

  4. Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats

    Energy Technology Data Exchange (ETDEWEB)

    Yamazaki, Makoto; Miyake, Manami; Sato, Hiroko; Masutomi, Naoya; Tsutsui, Naohisa [Mitsubishi Tanabe Pharma Corporation, Kisarazu, Chiba 292-0818 (Japan); Adam, Klaus-Peter; Alexander, Danny C.; Lawton, Kay A.; Milburn, Michael V.; Ryals, John A.; Wulff, Jacob E. [Metabolon Inc., 617 Davis Drive, Suite 400, Durham, NC 27713 (United States); Guo, Lining, E-mail: lguo@metabolon.com [Metabolon Inc., 617 Davis Drive, Suite 400, Durham, NC 27713 (United States)

    2013-04-01

    Drug-induced liver injury (DILI) is a significant consideration for drug development. Current preclinical DILI assessment relying on histopathology and clinical chemistry has limitations in sensitivity and discordance with human. To gain insights on DILI pathogenesis and identify potential biomarkers for improved DILI detection, we performed untargeted metabolomic analyses on rats treated with thirteen known hepatotoxins causing various types of DILI: necrosis (acetaminophen, bendazac, cyclosporine A, carbon tetrachloride, ethionine), cholestasis (methapyrilene and naphthylisothiocyanate), steatosis (tetracycline and ticlopidine), and idiosyncratic (carbamazepine, chlorzoxasone, flutamide, and nimesulide) at two doses and two time points. Statistical analysis and pathway mapping of the nearly 1900 metabolites profiled in the plasma, urine, and liver revealed diverse time and dose dependent metabolic cascades leading to DILI by the hepatotoxins. The most consistent change induced by the hepatotoxins, detectable even at the early time point/low dose, was the significant elevations of a panel of bile acids in the plasma and urine, suggesting that DILI impaired hepatic bile acid uptake from the circulation. Furthermore, bile acid amidation in the hepatocytes was altered depending on the severity of the hepatotoxin-induced oxidative stress. The alteration of the bile acids was most evident by the necrosis and cholestasis hepatotoxins, with more subtle effects by the steatosis and idiosyncratic hepatotoxins. Taking together, our data suggest that the perturbation of bile acid homeostasis is an early event of DILI. Upon further validation, selected bile acids in the circulation could be potentially used as sensitive and early DILI preclinical biomarkers. - Highlights: ► We used metabolomics to gain insights on drug induced liver injury (DILI) in rats. ► We profiled rats treated with thirteen hepatotoxins at two doses and two time points. ► The toxins decreased the

  5. Diagnosis and Management of Drug-Induced Liver Injury (DILI) in Patients with Pre-Existing Liver Disease.

    Science.gov (United States)

    Teschke, Rolf; Danan, Gaby

    2016-08-01

    The relationship between drugs and pre-existing liver disease is complex, particularly when increased liver tests (LTs) or new symptoms emerge in patients with pre-existing liver disease during drug therapy. This requires two strategies to assess whether these changes are due to drug-induced liver injury (DILI) as a new event or due to flares of the underlying liver disease. Lacking a valid diagnostic biomarker, DILI is a diagnosis of exclusion and requires causality assessment by RUCAM, the Roussel Uclaf Causality Assessment Method, to establish an individual causality grading of the suspected drug(s). Flares of pre-existing liver disease can reliably be assessed in some hepatotropic virus infections by polymerase chain reaction (PCR) and antibody titers at the beginning and in the clinical course to ascertain flares during the natural course of the disease. Unfortunately, flares cannot be verified in many other liver diseases such as alcoholic liver disease, since specific tests are unavailable. However, such a diagnostic approach using RUCAM applied to suspected DILI cases includes clinical and biological markers of pre-existing liver diseases and would determine whether drugs or underlying liver diseases caused the LT abnormalities or the new symptoms. More importantly, a clear diagnosis is essential to ensure effective disease management by drug cessation or specific treatment of the flare up due to the underlying disease. PMID:27091053

  6. Waveform analysis of tremor may help to differentiate Parkinson's disease from drug-induced parkinsonism

    International Nuclear Information System (INIS)

    In this study, we analyzed the waveform characteristics of resting tremor by accelerometer recordings in patients with drug-induced parkinsonism (DIP) and Parkinson's disease (PD). We prospectively recruited 12 patients with tremulous PD and 12 patients with DIP presenting with resting tremor. Tremor was recorded from the more affected side and was recorded twice for a 60 s period in each patient. Peak frequency, amplitude and all harmonic peaks were obtained, and the asymmetry of the decay of the autocorrelation function, third momentum and time-reversal invariance were also computed using a mathematical algorithm. Among the parameters used in the waveform analysis, the harmonic ratio, time-reversal invariance and asymmetric decay of the autocorrelation function were different between PD and DIP at a statistically significant level (all p < 0.01). The total harmonic peak power and third momentum in the time series were not significantly different. The clinical characteristics of DIP patients may be similar to those of PD patients in some cases, which makes the clinical differentiation between DIP and PD challenging. Our study shows that the identification of parameters reflecting waveform asymmetry might be helpful in differentiating between DIP and PD. (note)

  7. CLINICAL EVALUATION OF KODIPAVALA CHUNNAM IN THE TREATMENT OF INFECTIVE HEPATITIS, DRUG INDUCED HEPATITIS AND ALCOHOLIC HEPATITIS

    Directory of Open Access Journals (Sweden)

    V.Velpandian

    2013-04-01

    Full Text Available The present clinical study was carried out to validate the efficacy and safety of Siddha Herbo- mineral formulation ‘Kodipavala Chunnam’ in the treatment of Infective hepatitis, Drug induced hepatitis and Alcoholic hepatitis. Open clinical trial was conducted in 40 patients with these three categories of hepatitis in Arignar Anna Govt.Hospital of Indian Medicine and Homeopathy, Chennai. The trial drug Kodipavala Chunnam was administered in all the patients at the dose of 100 mg to 200 mg thrice a day with honey depending on severity. The clinical improvement shown by cases treated with Kodipavala Chunnam was more quick and significant. Before drug administration to patients it was observed that a significant increase in the levels of serum bilirubin ALT, AST, SAP, GGT and globulin. Elevated levels of these parameters are indicative of functional impairment of liver. Administration of KPC remarkably (P<0.001 restored elevated serum bilirubin ALT, AST, SAP, GGT and globulin towards normal value. Overall results revealed that out of 40 patients 10 patients had excellent relief, 26 had good relief, 3 cases showed satisfactory result and only one case showed fair response. The results clearly have shown that the Kodipavala Chunnam treatment to the jaundice therapy helped in cutting down the course of the disease and relieving jaundice earlier. There were no new or unexpected safety events noticed during the course of the treatment.

  8. A new method for identifying causal genes of schizophrenia and anti-tuberculosis drug-induced hepatotoxicity.

    Science.gov (United States)

    Huang, Tao; Liu, Cheng-Lin; Li, Lin-Lin; Cai, Mei-Hong; Chen, Wen-Zhong; Xu, Yi-Feng; O'Reilly, Paul F; Cai, Lei; He, Lin

    2016-01-01

    Schizophrenia (SCZ) may cause tuberculosis, the treatments for which can induce anti-tuberculosis drug-induced hepatotoxicity (ATDH) and SCZ-like disorders. To date, the causal genes of both SCZ and ATDH are unknown. To identify them, we proposed a new network-based method by integrating network random walk with restart algorithm, gene set enrichment analysis, and hypergeometric test; using this method, we identified 500 common causal genes. For gene validation, we created a regularly updated online database ATDH-SCZgenes and conducted a systematic meta-analysis of the association of each gene with either disease. Till now, only GSTM1 and GSTT1 have been well studied with respect to both diseases; and a total of 23 high-quality association studies were collected for the current meta-analysis validation. Finally, the GSTM1 present genotype was confirmed to be significantly associated with both ATDH [Odds Ratio (OR): 0.71, 95% confidence interval (CI): 0.56-0.90, P = 0.005] and SCZ (OR: 0.78, 95% CI: 0.66-0.92, P = 0.004) according to the random-effect model. Furthermore, these significant results were supported by "moderate" evidence according to the Venice criteria. Our findings indicate that GSTM1 may be a causal gene of both ATDH and SCZ, although further validation pertaining to other genes, such as CYP2E1 or DRD2, is necessary. PMID:27580934

  9. Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats.

    Science.gov (United States)

    Yamazaki, Makoto; Miyake, Manami; Sato, Hiroko; Masutomi, Naoya; Tsutsui, Naohisa; Adam, Klaus-Peter; Alexander, Danny C; Lawton, Kay A; Milburn, Michael V; Ryals, John A; Wulff, Jacob E; Guo, Lining

    2013-04-01

    Drug-induced liver injury (DILI) is a significant consideration for drug development. Current preclinical DILI assessment relying on histopathology and clinical chemistry has limitations in sensitivity and discordance with human. To gain insights on DILI pathogenesis and identify potential biomarkers for improved DILI detection, we performed untargeted metabolomic analyses on rats treated with thirteen known hepatotoxins causing various types of DILI: necrosis (acetaminophen, bendazac, cyclosporine A, carbon tetrachloride, ethionine), cholestasis (methapyrilene and naphthylisothiocyanate), steatosis (tetracycline and ticlopidine), and idiosyncratic (carbamazepine, chlorzoxasone, flutamide, and nimesulide) at two doses and two time points. Statistical analysis and pathway mapping of the nearly 1900 metabolites profiled in the plasma, urine, and liver revealed diverse time and dose dependent metabolic cascades leading to DILI by the hepatotoxins. The most consistent change induced by the hepatotoxins, detectable even at the early time point/low dose, was the significant elevations of a panel of bile acids in the plasma and urine, suggesting that DILI impaired hepatic bile acid uptake from the circulation. Furthermore, bile acid amidation in the hepatocytes was altered depending on the severity of the hepatotoxin-induced oxidative stress. The alteration of the bile acids was most evident by the necrosis and cholestasis hepatotoxins, with more subtle effects by the steatosis and idiosyncratic hepatotoxins. Taking together, our data suggest that the perturbation of bile acid homeostasis is an early event of DILI. Upon further validation, selected bile acids in the circulation could be potentially used as sensitive and early DILI preclinical biomarkers. PMID:23360887

  10. Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial.

    Science.gov (United States)

    Johannesen, L; Vicente, J; Mason, J W; Erato, C; Sanabria, C; Waite-Labott, K; Hong, M; Lin, J; Guo, P; Mutlib, A; Wang, J; Crumb, W J; Blinova, K; Chan, D; Stohlman, J; Florian, J; Ugander, M; Stockbridge, N; Strauss, D G

    2016-02-01

    Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market. At the same time, the current regulatory paradigm for screening new drugs causing long QT syndrome is preventing drugs from reaching the market, sometimes inappropriately. In this study, we report the results of a first-of-a-kind clinical trial studying late sodium (mexiletine and lidocaine) and calcium (diltiazem) current blocking drugs to counteract the effects of hERG potassium channel blocking drugs (dofetilide and moxifloxacin). We demonstrate that both mexiletine and lidocaine substantially reduce heart-rate corrected QT (QTc) prolongation from dofetilide by 20 ms. Furthermore, all QTc shortening occurs in the heart-rate corrected J-Tpeak (J-Tpeak c) interval, the biomarker we identified as a sign of late sodium current block. This clinical trial demonstrates that late sodium blocking drugs can substantially reduce QTc prolongation from hERG potassium channel block and assessment of J-Tpeak c may add value beyond only assessing QTc. PMID:26259627

  11. Drug-induced tremor

    Science.gov (United States)

    ... 417. Read More Caffeine in the diet Stimulants Update Date 7/27/2014 Updated by: Joseph V. Campellone, MD, Department of Medicine, Cooper University Hospital, Camden, NJ. Review provided by VeriMed Healthcare Network. ...

  12. Drug-induced diarrhea

    Science.gov (United States)

    Diarrhea associated with medicines ... Nearly all medicines may cause diarrhea as a side effect. The drugs listed below, however, are more likely to cause diarrhea. Laxatives are meant to cause diarrhea. ...

  13. Identification and Treatment of Psychotropic Drug-induced Alopecia%精神药物致脱发的识别与处理

    Institute of Scientific and Technical Information of China (English)

    孙振晓; 于相芬

    2014-01-01

    多种精神药物可引起脱发,本文对脱发的概念、精神药物所致脱发的诊断、鉴别诊断、发病机制及处理等作一综述,以提高临床对精神药物所致脱发的认识。%A variety of psychotropic drugs can cause alopecia . In order to make a better understanding of psy-chotropic drug-induced alopecia , this article made a review on the definition of alopecia , diagnosis , differential diag-nosis , pathomechanism and the treatment of psychotropic drug-induced alopecia .

  14. Upper airway collapse during drug induced sleep endoscopy: head rotation in supine position compared with lateral head and trunk position.

    Science.gov (United States)

    Safiruddin, Faiza; Koutsourelakis, Ioannis; de Vries, Nico

    2015-02-01

    Drug induced sedated sleep endoscopy (DISE) is often employed to determine the site, severity and pattern of obstruction in patients with sleep apnea. DISE is usually performed in supine position. We recently showed that the obstruction pattern is different when DISE is performed in lateral position. In this study, we compared the outcomes of DISE performed in supine position with head rotated, with the outcomes of DISE performed with head and trunk in lateral position. The Prospective study design was used in the present study. Sixty patients with OSA (44 male; mean apnea hypopnea index (AHI) 20.8 ± 17.5 events/h) underwent DISE under propofol sedation. Patients were placed in lateral position, and the upper airway collapse was evaluated. The patients were then placed in supine position with the head rotated to the right side. DISE outcomes were scored using the VOTE classification system. In lateral position, nine patients (15.0%) had a complete antero-posterior (A-P) collapse at the level of the velum, nine had a partial A-P collapse. During head rotation and trunk in supine position, at the level of the velum, four patients (6.7%) had a complete A-P collapse, while two patients (3.3%) had a partial A-P collapse. For all other sites, the patterns of collapse were not significantly different between head rotation and lateral position. During DISE, rotation of the head in supine position, and lateral head and trunk position present similar sites, severity and patterns of upper airway collapse, with the exception of collapse at the level of the velum. Here the severity of A-P collapse is less severe during head rotation than in lateral head and trunk position.

  15. Rat Urinary Osteopontin and Neutrophil Gelatinase-Associated Lipocalin Improve Certainty of Detecting Drug-Induced Kidney Injury.

    Science.gov (United States)

    Phillips, Jonathan A; Holder, Daniel J; Ennulat, Daniela; Gautier, Jean-Charles; Sauer, John-Michael; Yang, Yi; McDuffie, Eric; Sonee, Manisha; Gu, Yi-Zhong; Troth, Sean P; Lynch, Karen; Hamlin, Diane; Peters, David G; Brees, Dominique; Walker, Elizabeth G

    2016-06-01

    Traditional kidney biomarkers are insensitive indicators of acute kidney injury, with meaningful changes occurring late in the course of injury. The aim of this work was to demonstrate the diagnostic potential of urinary osteopontin (OPN) and neutrophil gelatinase-associated lipocalin (NGAL) for drug-induced kidney injury (DIKI) in rats using data from a recent regulatory qualification submission of translational DIKI biomarkers and to compare performance of NGAL and OPN to five previously qualified DIKI urinary biomarkers. Data were compiled from 15 studies of 11 different pharmaceuticals contributed by Critical Path Institute's Predictive Safety Testing Consortium (PSTC) Nephrotoxicity Working Group (NWG). Rats were given doses known to cause DIKI or other target organ toxicity, and urinary levels of the candidate biomarkers were assessed relative to kidney histopathology and serum creatinine (sCr) and blood urea nitrogen (BUN).OPN and NGAL outperformed sCr and BUN in identifying DIKI manifested as renal tubular epithelial degeneration or necrosis. In addition, urinary OPN and NGAL, when used with sCr and BUN, increased the ability to detect renal tubular epithelial degeneration or necrosis. NGAL and OPN had comparable or improved performance relative to Kim-1, clusterin, albumin, total protein, and beta-2 microglobulin. Given these data, both urinary OPN and NGAL are appropriate for use with current methods for assessing nephrotoxicity to identify and monitor DIKI in regulatory toxicology studies in rats. These data also support exploratory use of urinary OPN and NGAL in safety monitoring strategies of early clinical trials to aid in the assurance of patient safety. PMID:27026710

  16. Tuberculous Drug-induced Liver Injury and Treatment Re-challenge in Human Immunodeficiency Virus Co-infection

    Science.gov (United States)

    Costiniuk, Cecilia T.; Gosnell, Bernadett I.; Manzini, Thandekile C.; Du Plessis, Camille N.; Moosa, Mahomed Yunus S.

    2015-01-01

    Background: Tuberculosis drug-induced liver injury (TB-DILI) is the most common adverse event necessitating therapy interruption. The optimal re-challenge strategy for antituberculous therapy (ATT) remains unclear, especially in human immunodeficiency virus (HIV) co-infected individuals in high-prevalence settings such as South Africa. Objective: To determine the incidence of and risk factors for the recurrence of TB-DILI with different ATT re-challenge strategies. Materials and Methods: We conducted a retrospective chart review of patients managed for TB-DILI from 2005 to 2013 at King Edward VIII Hospital in Durban, South Africa. Relevant clinical and laboratory data at the presentation of TB-DILI, time to recovery of liver function, method of ATT re-challenge and outcome of re-challenge were documented. Results: 1016 charts were reviewed, and 53 individuals with TB-DILI (48 HIV-co-infected) were identified. Following discontinuation of ATT, the median time to alanine aminotransferase normalization was 28 days (interquartile range 13-43). Forty-two subjects were re-challenged (30 regimen re-challenges and 12 step-wise re-challenges). 5 (12%) cases of recurrent TB-DILI were noted. Recurrences were not associated with the method of re-challenge. Conclusion: Based on the data available, it appears that full ATT can be safely restarted in the majority of subjects with a recurrence of DILI occurring in about 12% of subjects. The method of re-challenge did not appear to impact on the risk of recurrence. Ideally, a prospective randomized trial is needed to determine the best method of re-challenge. PMID:26752869

  17. A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen.

    Science.gov (United States)

    Michaut, Anaïs; Le Guillou, Dounia; Moreau, Caroline; Bucher, Simon; McGill, Mitchell R; Martinais, Sophie; Gicquel, Thomas; Morel, Isabelle; Robin, Marie-Anne; Jaeschke, Hartmut; Fromenty, Bernard

    2016-02-01

    Obesity and nonalcoholic fatty liver disease (NAFLD) can increase susceptibility to hepatotoxicity induced by some xenobiotics including drugs, but the involved mechanisms are poorly understood. For acetaminophen (APAP), a role of hepatic cytochrome P450 2E1 (CYP2E1) is suspected since the activity of this enzyme is consistently enhanced during NAFLD. The first aim of our study was to set up a cellular model of NAFLD characterized not only by triglyceride accumulation but also by higher CYP2E1 activity. To this end, human HepaRG cells were incubated for one week with stearic acid or oleic acid, in the presence of different concentrations of insulin. Although cellular triglycerides and the expression of lipid-responsive genes were similar with both fatty acids, CYP2E1 activity was significantly increased only by stearic acid. CYP2E1 activity was reduced by insulin and this effect was reproduced in cultured primary human hepatocytes. Next, APAP cytotoxicity was assessed in HepaRG cells with or without lipid accretion and CYP2E1 induction. Experiments with a large range of APAP concentrations showed that the loss of ATP and glutathione was almost always greater in the presence of stearic acid. In cells pretreated with the CYP2E1 inhibitor chlormethiazole, recovery of ATP was significantly higher in the presence of stearate with low (2.5mM) or high (20mM) concentrations of APAP. Levels of APAP-glucuronide were significantly enhanced by insulin. Hence, HepaRG cells can be used as a valuable model of NAFLD to unveil important metabolic and hormonal factors which can increase susceptibility to drug-induced hepatotoxicity. PMID:26739624

  18. In vitro assessment of drug-induced liver steatosis based on human dermal stem cell-derived hepatic cells.

    Science.gov (United States)

    Rodrigues, Robim M; Branson, Steven; De Boe, Veerle; Sachinidis, Agapios; Rogiers, Vera; De Kock, Joery; Vanhaecke, Tamara

    2016-03-01

    Steatosis, also known as fatty liver disease (FLD), is a disorder in which the lipid metabolism of the liver is disturbed, leading to the abnormal retention of lipids in hepatocytes. FLD can be induced by several drugs, and although it is mostly asymptomatic, it can lead to steatohepatitis, which is associated with liver inflammation and damage. Drug-induced liver injury is currently the major cause of postmarketing withdrawal of pharmaceuticals and discontinuation of the development of new chemical entities. Therefore, the potential induction of steatosis must be evaluated during preclinical drug development. However, robust human-relevant in vitro models are lacking. In the present study, we explore the applicability of hepatic cells (hSKP-HPCs) derived from postnatal skin precursors, a stem cell population residing in human dermis, to investigate the steatosis-inducing effects of sodium valproate (Na-VPA). Exposure of hSKP-HPC to sub-cytotoxic concentrations of this reference steatogenic compound showed an increased intracellular accumulation of lipid droplets, and the modulation of key factors involved in lipid metabolism. Using a toxicogenomics approach, we further compared Na-VPA-treated hSKP-HPC and Na-VPA-treated primary human hepatocytes to liver samples from patients suffering from mild and advanced steatosis. Our data show that in hSKP-HPC exposed to Na-VPA and liver samples of patients suffering from mild steatosis, but not in primary human hepatocytes, "liver steatosis" was efficiently identified as a toxicological response. These findings illustrate the potential of hSKP-HPC as a human-relevant in vitro model to identify hepatosteatotic effects of chemical compounds. PMID:25716160

  19. Drug-induced liver injury: results from the hospital-based Berlin Case–Control Surveillance Study

    Science.gov (United States)

    Douros, Antonios; Bronder, Elisabeth; Andersohn, Frank; Klimpel, Andreas; Thomae, Michael; Sarganas, Giselle; Kreutz, Reinhold; Garbe, Edeltraut

    2015-01-01

    Aim Drug-induced liver injury (DILI) is often responsible for acute liver failure, drug withdrawal, boxed warnings or drug non-approval. Therefore, we conducted a case–control study to determine the hepatotoxic risk of a wide range of drugs. Methods The Berlin Case–Control Surveillance Study FAKOS included all 51 Berlin hospitals in a hospital network. Between 2002 and 2011, 198 patients with acute idiopathic hepatitis, 377 inpatient controls and 708 outpatient controls were ascertained. Case patients were thoroughly validated using anamnestic, clinical, laboratory and histological data. Drug exposure was obtained in a face-to-face interview. A possible drug aetiology was assessed in individual patients by applying the updated Council for International Organizations of Medical Sciences (CIOMS) scale. Drug risks were further quantified [odds ratios (OR) with 95% confidence intervals (CI)] in a case–control design with unconditional logistic regression analysis. Drug intake in the last 28 days before index date was considered for the analysis. Results The study corroborated hepatotoxic risks for a number of drugs, including phenprocoumon (OR 3.3, 95% CI 1.5, 6.7), amiodarone (OR 5.5, 95% CI 1.3, 21.2), clozapine (OR 34.6, 95% CI 2.8, 824.9) and flupirtine (OR 40.2, 95% CI 5.5, 856.9). Increased risks were also suggested for less commonly reported substances such as angiotensin II receptor blockers, atypical antipsychotics and for biperiden, a drug never before reported to be hepatotoxic. Conclusions Our study identified a large number of drugs as possible causes of hepatotoxicity. The observed risk for seldom reported substances highlights the need for further post-authorization safety studies not exclusively focusing on drugs already labelled as potentially hepatotoxic. PMID:25444550

  20. Development of a prediction system for anti-tuberculosis drug-induced liver injury in Japanese patients

    Science.gov (United States)

    Mushiroda, Taisei; Yanai, Hideki; Yoshiyama, Takashi; Sasaki, Yuka; Okumura, Masao; Ogata, Hideo; Tokunaga, Katsushi

    2016-01-01

    Drug-induced liver injury (DILI) is a common adverse drug reaction in patients receiving antituberculosis (anti-TB) treatment. Among the anti-TB agents, isoniazid (INH) is the primary drug that causes hepatotoxicity in TB patients with DILI. Previous reports in several populations have consistently demonstrated an association between polymorphisms in the N-acetyltransferase 2 (NAT2) gene, which is responsible for INH hepatic metabolism, and a risk of DILI in TB patients. In this study, the genetic and baseline clinical data from 366 Japanese patients with TB (73 patients with DILI and 293 without DILI) were used to develop a system to predict DILI risk due to anti-TB agents. The distribution of the NAT2 acetylator status among the TB patients with DILI was 31 (42.5%), 29 (39.7%), and 13 (17.8%) for rapid, intermediate, and slow acetylators, respectively. A significant association was observed between NAT2 slow acetylators and DILI risk (odds ratio 4.32, 95% confidence interval 1.93–9.66, P value=5.56×10−4). A logistic regression model based on age and NAT2 genotype revealed that the area under the curve for the receiver-operating characteristic curve was 0.717. The findings demonstrated that slow NAT2 acetylator status is a significant predictor of the risk of DILI by anti-TB agents, and a personalized anti-TB treatment approach may aid in making treatment decisions and reducing the incidence of DILI. PMID:27340556

  1. The characteristics and clinical outcome of drug-induced liver injury in a Chinese hospital: A retrospective cohort study.

    Science.gov (United States)

    Chen, Sheng-Sen; Yu, Kang-Kang; Huang, Chong; Li, Ning; Zheng, Jian-Ming; Bao, Su-Xia; Chen, Ming-Quan; Zhang, Wen-Hong

    2016-08-01

    The aim of this cohort study was to determine the characteristics and clinical outcome of 287 patients with drug-induced liver injury (DILI) in a Chinese hospital.Between January 2008 and January 2013, individuals who were diagnosed with DILI were selected. The complete medical records of each case were reviewed, and factors for the outcome of patients with DILI were extracted and analyzed using univariate and multivariate analysis.Two hundred eighty-seven cases identified as DILI were included in the study. A total of 105 different drugs were considered to be related to the hepatotoxicity. The main causative group of drugs was Chinese herb (n = 111). Liver failure developed in 9 (3.1%) patients, and 2 died (0.7%). Overall, complete recovery occurred in 92 (32.1%) patients. Univariate analysis and binary logistic regression analysis identified the digestive symptoms, jaundice, total bilirubin (TBIL), and direct bilirubin (DBIL) as independent factors for the non-recovery of DILI. Then the prediction model, including digestive symptoms, jaundice, TBIL, and DBIL, was built by using binary logistic regression analysis again. Receiver operating characteristic curve validated the strong power (area under the curve (AUC) = 0.907) of prediction model for predicting the DILI non-recovery.DILI is an important cause of liver test abnormalities, and Chinese herb represented the most common drug group. The factors such as digestive symptoms, jaundice, TBIL, and DBIL have effect on DILI outcomes. The prediction model, including digestive symptoms, jaundice, TBIL, and DBIL, established in this study is really an excellent predictive tool for non-recovery of DILI patients. PMID:27559976

  2. Development of a prediction system for anti-tuberculosis drug-induced liver injury in Japanese patients.

    Science.gov (United States)

    Mushiroda, Taisei; Yanai, Hideki; Yoshiyama, Takashi; Sasaki, Yuka; Okumura, Masao; Ogata, Hideo; Tokunaga, Katsushi

    2016-01-01

    Drug-induced liver injury (DILI) is a common adverse drug reaction in patients receiving antituberculosis (anti-TB) treatment. Among the anti-TB agents, isoniazid (INH) is the primary drug that causes hepatotoxicity in TB patients with DILI. Previous reports in several populations have consistently demonstrated an association between polymorphisms in the N-acetyltransferase 2 (NAT2) gene, which is responsible for INH hepatic metabolism, and a risk of DILI in TB patients. In this study, the genetic and baseline clinical data from 366 Japanese patients with TB (73 patients with DILI and 293 without DILI) were used to develop a system to predict DILI risk due to anti-TB agents. The distribution of the NAT2 acetylator status among the TB patients with DILI was 31 (42.5%), 29 (39.7%), and 13 (17.8%) for rapid, intermediate, and slow acetylators, respectively. A significant association was observed between NAT2 slow acetylators and DILI risk (odds ratio 4.32, 95% confidence interval 1.93-9.66, P value=5.56×10(-4)). A logistic regression model based on age and NAT2 genotype revealed that the area under the curve for the receiver-operating characteristic curve was 0.717. The findings demonstrated that slow NAT2 acetylator status is a significant predictor of the risk of DILI by anti-TB agents, and a personalized anti-TB treatment approach may aid in making treatment decisions and reducing the incidence of DILI. PMID:27340556

  3. Drug-induced mild therapeutic hypothermia obtained by administration of a transient receptor potential vanilloid type 1 agonist

    Directory of Open Access Journals (Sweden)

    Schneider Andreas

    2010-10-01

    Full Text Available Abstract Background The use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment for survivors of out of hospital cardiac arrest. However, this type of therapy is cumbersome and associated with several side-effects. We investigated the feasibility of using a transient receptor potential vanilloid type 1 (TRPV1 agonist for obtaining drug-induced sustainable mild hypothermia. Methods First, we screened a heterogeneous group of TRPV1 agonists and secondly we tested the hypothermic properties of a selected candidate by dose-response studies. Finally we tested the hypothermic properties in a large animal. The screening was in conscious rats, the dose-response experiments in conscious rats and in cynomologus monkeys, and the finally we tested the hypothermic properties in conscious young cattle (calves with a body weight as an adult human. The investigated TRPV1 agonists were administered by continuous intravenous infusion. Results Screening: Dihydrocapsaicin (DHC, a component of chili pepper, displayed a desirable hypothermic profile with regards to the duration, depth and control in conscious rats. Dose-response experiments: In both rats and cynomologus monkeys DHC caused a dose-dependent and immediate decrease in body temperature. Thus in rats, infusion of DHC at doses of 0.125, 0.25, 0.50, and 0.75 mg/kg/h caused a maximal ΔT (°C as compared to vehicle control of -0.9, -1.5, -2.0, and -4.2 within approximately 1 hour until the 6 hour infusion was stopped. Finally, in calves the intravenous infusion of DHC was able to maintain mild hypothermia with ΔT > -3°C for more than 12 hours. Conclusions Our data support the hypothesis that infusion of dihydrocapsaicin is a candidate for testing as a primary or adjunct method of inducing and maintaining therapeutic hypothermia.

  4. Literature Analysis of 66 Cases of Drug-induced Hyperkalemia%66例药源性高钾血症文献分析

    Institute of Scientific and Technical Information of China (English)

    任晓蕾; 詹轶秋; 张春燕; 张海英; 冯婉玉

    2015-01-01

    目的:探讨药源性高钾血症的特点及相关因素,为临床合理用药提供依据。方法:检索1979-2014年国内医药期刊公开报道的药源性高钾血症的个案和群案文献46篇,共计病例66例,并进行统计分析。结果:66例药源性高钾血症病例中主要涉及心血管药物和免疫抑制剂。大部分停药及对症治疗后好转,其中2例患者死亡。结论:药物诱发高钾血症具有潜在的危险性,需提高警惕,重视防治。%OBJECTIVE:To investigate the characteristics and related factors of drug-induced hyperkalemia,present preven-tive measures and provide reference for the rational drug use. METHODS:46 literatures of individual cases and group cases of drug-induced hyperkalemia publicly reported in domestic medical journals from 1979 to 2014 were collected and analyzed statistical-ly,including 66 cases. RESULTS:66 cases with drug-induced hyperkalemia were mainly involved in cardiovascular drugs and im-munosuppressants. Most of them were improved after drug withdrawal and symptomatic treatment,and 2 cases died. CONCLU-SIONS:Drug-induced hyperkalemia are potentially dangerous. It is necessary to be vigilant,prevent and control timely and reduce the incidence of severe adverse reactions.

  5. Hepatitis C Virus Co-Infection Increases the Risk of Anti-Tuberculosis Drug-Induced Hepatotoxicity among Patients with Pulmonary Tuberculosis

    OpenAIRE

    Nino Lomtadze; Lali Kupreishvili; Archil Salakaia; Sergo Vashakidze; Lali Sharvadze; Kempker, Russell R.; Matthew J Magee; Carlos del Rio; Blumberg, Henry M.

    2013-01-01

    BACKGROUND: The country of Georgia has a high prevalence of tuberculosis (TB) and hepatitis C virus (HCV) infection. PURPOSE: To determine whether HCV co-infection increases the risk of incident drug-induced hepatitis among patients on first-line anti-TB drug therapy. METHODS: Prospective cohort study; HCV serology was obtained on all study subjects at the time of TB diagnosis; hepatic enzyme tests (serum alanine aminotransferase [ALT] activity) were obtained at baseline and monthly during tr...

  6. International Life Sciences Institute (Health and Environmental Sciences Institute, HESI) initiative on moving towards better predictors of drug-induced torsades de pointes

    OpenAIRE

    Bass, A S; Darpo, B; Breidenbach, A; Bruse, K; Feldman, H S; Garnes, D; Hammond, T.; Haverkamp, W; January, C; Koerner, J.; Lawrence, C; Leishman, D; Roden, D.; Valentin, J P; Vos, M A

    2008-01-01

    Knowledge of the cardiac safety of emerging new drugs is an important aspect of assuring the expeditious advancement of the best candidates targeted at unmet medical needs while also assuring the safety of clinical trial subjects or patients. Present methodologies for assessing drug-induced torsades de pointes (TdP) are woefully inadequate in terms of their specificity to select pharmaceutical agents, which are human arrhythmia toxicants. Thus, the critical challenge in the pharmaceutical ind...

  7. Risk Factors for Development of Cholestatic Drug-Induced Liver Injury: Inhibition of Hepatic Basolateral Bile Acid Transporters Multidrug Resistance-Associated Proteins 3 and 4

    OpenAIRE

    Köck, Kathleen; Ferslew, Brian C.; Netterberg, Ida; Yang, Kyunghee; Urban, Thomas J.; Swaan, Peter W.; Stewart, Paul W.; Brouwer, Kim L.R.

    2014-01-01

    Impaired hepatic bile acid export may contribute to development of cholestatic drug-induced liver injury (DILI). The multidrug resistance-associated proteins (MRP) 3 and 4 are postulated to be compensatory hepatic basolateral bile acid efflux transporters when biliary excretion by the bile salt export pump (BSEP) is impaired. BSEP inhibition is a risk factor for cholestatic DILI. This study aimed to characterize the relationship between MRP3, MRP4, and BSEP inhibition and cholestatic potentia...

  8. Genetic variations of bile salt transporters as predisposing factors for drug-induced cholestasis, intrahepatic cholestasis of pregnancy and therapeutic response of viral hepatitis

    OpenAIRE

    Stieger, B; Geier, A.

    2011-01-01

    INTRODUCTION: Drug-induced cholestasis, intrahepatic cholestasis of pregnancy and viral hepatitis are acquired forms of liver disease. Cholestasis is a pathophysiologic state with impaired bile formation and subsequent accumulation of bile salts in hepatocytes. The bile salt export pump (BSEP) (ABCB11) is the key export system for bile salts from hepatocytes. AREAS COVERED: This article provides an introduction into the physiology of bile formation followed by a summary of the current knowled...

  9. Toward Predicting Drug-Induced Liver Injury: Parallel Computational Approaches to Identify Multidrug Resistance Protein 4 and Bile Salt Export Pump Inhibitors

    OpenAIRE

    Welch, Matthew A.; Köck, Kathleen; Urban, Thomas J.; Brouwer, Kim L.R.; Swaan, Peter W.

    2015-01-01

    Drug-induced liver injury (DILI) is an important cause of drug toxicity. Inhibition of multidrug resistance protein 4 (MRP4), in addition to bile salt export pump (BSEP), might be a risk factor for the development of cholestatic DILI. Recently, we demonstrated that inhibition of MRP4, in addition to BSEP, may be a risk factor for the development of cholestatic DILI. Here, we aimed to develop computational models to delineate molecular features underlying MRP4 and BSEP inhibition. Models were ...

  10. Drug-induced retroperitoneal fibrosis: short aetiopathogenetic note, from the past times of ergot-derivatives large use to currently applied bio-pharmacology

    OpenAIRE

    Alberti, C

    2015-01-01

    Among the secondary forms of retroperitoneal fibrosis (RPF), that drug-induced shows very intriguing aspects given both the broad range of involved pharmaceuticals and the considerable interest arisen from the related pathogenetic mechanisms. The particular incidence, in the last four decades past century, of the RPF due to long-term use of ergot alkaloid derivatives (ergotamine, methysergide, pergolide, bromocriptine, cabergoline) and specific L-dopa derived agents, such as methyldopa, as we...

  11. The Hepatoprotection Provided by Taurine and Glycine against Antineoplastic Drugs Induced Liver Injury in an Ex Vivo Model of Normothermic Recirculating Isolated Perfused Rat Liver

    Directory of Open Access Journals (Sweden)

    Reza Heidari

    2016-03-01

    Full Text Available Taurine (2-aminoethane sulfonic acid is a non-protein amino acid found in high concentration in different tissues. Glycine (Amino acetic acid is the simplest amino acid incorporated in the structure of proteins. Several investigations indicate the hepatoprotective properties of these amino acids. On the other hand, antineoplastic agents-induced serum transaminase elevation and liver injury is a clinical complication. The current investigation was designed to screen the possible hepatoprotective properties of taurine and glycine against antineoplastic drugs-induced hepatic injury in an ex vivo model of isolated perfused rat liver. Rat liver was perfused with different concentration (10 μM, 100 μM and 1000 μM of antineoplastic drugs (Mitoxantrone, Cyclophosphamide, Cisplatin, 5 Fluorouracil, Doxorubicin and Dacarbazine via portal vein. Taurine and glycine were administered to drug-treated livers and liver perfusate samples were collected for biochemical measurements (ALT, LDH, AST, and K+. Markers of oxidative stress (reactive oxygen species formation, lipid peroxidation, total antioxidant capacity and glutathione were also assessed in liver tissue. Antineoplastic drugs caused significant pathological changes in perfusate biochemistry. Furthermore, markers of oxidative stress were significantly elevated in drug treated livers. It was found that taurine (5 and 10 mM and glycine (5 and 10 mM administration significantly mitigated the biomarkers of liver injury and attenuated drug induced oxidative stress. Our data indicate that taurine and glycine supplementation might help as potential therapeutic options to encounter anticancer drugs-induced liver injury.

  12. Anti-tuberculosis drug induced hepatotoxicity among TB/HIV co-infected patients at Jimma University Hospital, Ethiopia: nested case-control study.

    Directory of Open Access Journals (Sweden)

    Alima Hassen Ali

    Full Text Available BACKGROUND: This study was carried out to determine the incidence and predictors of anti-tuberculosis drug induced hepatotoxicity among TB/HIV co-infected patients at Jimma University Hospital, Ethiopia. METHODS/PRINCIPAL FINDINGS: A nested case-control study was conducted by reviewing charts of all TB/HIV co-infected patients who commenced anti-TB treatment from January 2008 to December 2011 at Jimma University Hospital. Patients who had developed hepatotoxicity after at least 5 days of standard doses of anti-TB drug therapy were labeled as "cases" and those without hepatotoxicity were "controls". Each case with anti-TB drug induced hepatotoxicity was compared with 3 controls selected randomly from the cohort. From a cohort of 296 TB/HIV co-infected patients 8 were excluded from the study as the causality between anti-TB drugs and hepatotoxicity was not confirmed, 33 had developed hepatotoxicity. On bivariate logistic regression analysis, body mass index (BMI <18.5 Kg/m(2 [P = 0.01; OR (95%CI: 3.6 (1.4-9.5], disseminated pulmonary TB [P = 0.00; OR (95%CI: 5.6 (2.2-14.6], CD4 count ≤50 [P = 0.016; OR (95%CI: 3.6(1.27-10.23] and WHO stage 4 [P = 0.004, OR (95%CI: 3.8 (1.68-8.77] were significantly associated with anti-TB drug induced hepatotoxicity. Predictor variables with p-value <0.05 by bivariate analysis were analyzed using multivariable logistic regression analysis and identified disseminated pulmonary TB [P = 0.001; AOR (95%CI = 5.6 (2.1-15.0] and BMI <18.5 [P = 0.014; AOR (95%CI= 3.6 (1.3-10.1] as independent predictors of anti-TB drug induced hepatotoxicity. CONCLUSIONS: The incidence of anti-TB drug induced hepatotoxicity was 11.5%. The results suggest that in the presence of disseminated pulmonary TB and/or BMI <18.5 Kg/m(2, TB/HIV co-infected patients should be closely followed for the occurrence of hepatotoxicity during the intensive phase of TB treatment to prevent morbidity and mortality.

  13. Effects of a selective educational system on fatigue, sleep problems, daytime sleepiness, and depression among senior high school adolescents in Taiwan

    Directory of Open Access Journals (Sweden)

    Chen TY

    2015-03-01

    Full Text Available Tien-Yu Chen,1,2 Yu-Ching Chou,3 Nian-Sheng Tzeng,1,2,4 Hsin-An Chang,1,2,4 Shin-Chang Kuo,1,2,5 Pei-Yin Pan,1,2 Yi-Wei Yeh,1,2,5 Chin-Bin Yeh,1,2 Wei-Chung Mao1,2,6 1Department of Psychiatry, Tri-Service General Hospital, 2School of Medicine, National Defense Medical Center, 3School of Public Health, National Defense Medical Center, 4Student Counseling Center, National Defense Medical Center, 5Graduate Institute of Medical Sciences, National Defense Medical Center, 6Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan, Republic of China Objective: The aim of the study reported here was to clarify the effects of academic pressure on fatigue, sleep problems, daytime sleepiness, and depression among senior high school adolescents in Taiwan. Methods: This cross-sectional study enrolled 757 senior high school adolescents who were classified into four groups: Grade 1 (n=261, Grade 2 (n=228, Grade 3T (n=199; Grade 3 students who had another college entrance test to take, and Grade 3S (n=69; Grade 3 students who had succeeded in their college application. Fatigue, sleep quality, daytime sleepiness, and depression were assessed using the Chinese version of the Multidimensional Fatigue Symptom Inventory – Short Form, Pittsburgh Sleep Quality Index-Taiwan Form, the Chinese version of the Epworth Sleepiness Scale, and the Chinese version of the Beck Depression Inventory®-II (BDI-II, respectively. Results: Physical, emotional, and mental fatigue scores were all higher in higher-grade groups. The Grade 3T (test students had the worst fatigue severity, and the Grade 3S (success students had the least fatigue severity. More than half of the students (60.9% went to bed after 12 am, and they had on average 6.0 hours of sleep per night. More than 30% of the students in Grade 2 (37.3% and Grades 3T/S (30.2%/30.4% possibly had daily sleepiness problems. The students in Grade 3T had the worst BDI-II score (13.27±9.24, and the Grade 3S

  14. The innovative use of a large-scale industry biomedical consortium to research the genetic basis of drug induced serious adverse events.

    Science.gov (United States)

    Holden, Arthur L

    2007-01-01

    The International Serious Adverse Event Consortium (SAEC) is a pharmaceutical industry and FDA led international (501 c3 non-profit) consortium, focused on identifying and validating DNA-variants useful in predicting the risk of drug induced, rare serious adverse events (SAEs). As such, it functions with the explicit purpose of enhancing the 'public good'. Its members are (i) organizations engaged principally in the business of discovering, developing and marketing pharmaceutical products, or (ii) a charitable, governmental, or other non-profit organization with an interest in researching the molecular basis of drug response.Drug-induced, rare SAEs present significant health issues for patients; and pose challenges for the safe use of approved drugs and the development of new drugs. Examples of drug-induced, rare SAEs include hepatotoxicity, QT prolongation, rhabdomyolosis, serious skin rashes (e.g. SJS), edema, acute renal failure, acute hypersensitivity, anemias/neutropenias, excessive weigh gain, retinopathy, vasculitis, among others. The rarity of such drug induced SAEs and the absence of effective government surveillance/research networks, makes it extremely difficult for any one company or research entity to accrue enough SAE cases and controls to conduct effective whole genome studies. Central to the notion of the SAEC is industry, government and health care providers can join forces to make use of a variety of sample and data resources in researching the genetic basis of these events.The purpose of the SAEC is threefold:•To carry out research directed toward the discovery of DNA-variants clinically useful in understanding and predicting the risk of drug induced serious adverse events and similar scientific research.•To ensure the widespread availability of the results of such research to the scientific research community and the public at large for no charge through publication and web-based methods; and•To educate the scientific research and medical

  15. Transcriptional profiling suggests that Nevirapine and Ritonavir cause drug induced liver injury through distinct mechanisms in primary human hepatocytes.

    Science.gov (United States)

    Terelius, Ylva; Figler, Robert A; Marukian, Svetlana; Collado, Maria S; Lawson, Mark J; Mackey, Aaron J; Manka, David; Qualls, Charles W; Blackman, Brett R; Wamhoff, Brian R; Dash, Ajit

    2016-08-01

    Drug induced liver injury (DILI), a major cause of pre- and post-approval failure, is challenging to predict pre-clinically due to varied underlying direct and indirect mechanisms. Nevirapine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) and Ritonavir, a protease inhibitor, are antiviral drugs that cause clinical DILI with different phenotypes via different mechanisms. Assessing DILI in vitro in hepatocyte cultures typically requires drug exposures significantly higher than clinical plasma Cmax concentrations, making clinical interpretations of mechanistic pathway changes challenging. We previously described a system that uses liver-derived hemodynamic blood flow and transport parameters to restore primary human hepatocyte biology, and drug responses at concentrations relevant to in vivo or clinical exposure levels. Using this system, primary hepatocytes from 5 human donors were exposed to concentrations approximating clinical therapeutic and supra-therapeutic levels of Nevirapine (11.3 and 175.0 μM) and Ritonavir (3.5 and 62.4 μM) for 48 h. Whole genome transcriptomics was performed by RNAseq along with functional assays for metabolic activity and function. We observed effects at both doses, but a greater number of genes were differentially expressed with higher probability at the toxic concentrations. At the toxic doses, both drugs showed direct cholestatic potential with Nevirapine increasing bile synthesis and Ritonavir inhibiting bile acid transport. Clear differences in antigen presentation were noted, with marked activation of MHC Class I by Nevirapine and suppression by Ritonavir. This suggests CD8+ T cell involvement for Nevirapine and possibly NK Killer cells for Ritonavir. Both compounds induced several drug metabolizing genes (including CYP2B6, CYP3A4 and UGT1A1), mediated by CAR activation in Nevirapine and PXR in Ritonavir. Unlike Ritonavir, Nevirapine did not increase fatty acid synthesis or activate the respiratory electron chain

  16. Inhibition of Human Hepatic Bile Acid Transporters by Tolvaptan and Metabolites: Contributing Factors to Drug-Induced Liver Injury?

    Science.gov (United States)

    Slizgi, Jason R; Lu, Yang; Brouwer, Kenneth R; St Claire, Robert L; Freeman, Kimberly M; Pan, Maxwell; Brock, William J; Brouwer, Kim L R

    2016-01-01

    Tolvaptan is a vasopressin V(2)-receptor antagonist that has shown promise in treating Autosomal Dominant Polycystic Kidney Disease (ADPKD). Tolvaptan was, however, associated with liver injury in some ADPKD patients. Inhibition of bile acid transporters may be contributing factors to drug-induced liver injury. In this study, the ability of tolvaptan and two metabolites, DM-4103 and DM-4107, to inhibit human hepatic transporters (NTCP, BSEP, MRP2, MRP3, and MRP4) and bile acid transport in sandwich-cultured human hepatocytes (SCHH) was explored. IC(50) values were determined for tolvaptan, DM-4103 and DM-4107 inhibition of NTCP (∼41.5, 16.3, and 95.6 μM, respectively), BSEP (31.6, 4.15, and 119 μM, respectively), MRP2 (>50, ∼51.0, and >200 μM, respectively), MRP3 (>50, ∼44.6, and 61.2 μM, respectively), and MRP4 (>50, 4.26, and 37.9 μM, respectively). At the therapeutic dose of tolvaptan (90 mg), DM-4103 exhibited a C(max)/IC(50) value >0.1 for NTCP, BSEP, MRP2, MRP3, and MRP4. Tolvaptan accumulation in SCHH was extensive and not sodium-dependent; intracellular concentrations were ∼500 μM after a 10-min incubation duration with tolvaptan (15 μM). The biliary clearance of taurocholic acid (TCA) decreased by 43% when SCHH were co-incubated with tolvaptan (15 μM) and TCA (2.5 μM). When tolvaptan (15 μM) was co-incubated with 2.5 μM of chenodeoxycholic acid, taurochenodeoxycholic acid, or glycochenodeoxycholic acid in separate studies, the cellular accumulation of these bile acids increased by 1.30-, 1.68-, and 2.16-fold, respectively. Based on these data, inhibition of hepatic bile acid transport may be one of the biological mechanisms underlying tolvaptan-associated liver injury in patients with ADPKD. PMID:26507107

  17. Excessive daytime sleepiness and adherence to antihypertensive medications among Blacks: analysis of the counseling African Americans to control hypertension (CAATCH trial

    Directory of Open Access Journals (Sweden)

    Williams NJ

    2014-03-01

    Full Text Available Natasha J Williams,1 Girardin Jean-Louis,1 Abhishek Pandey,2 Joseph Ravenell,1 Carla Boutin-Foster,3 Gbenga Ogedegbe1 1Center for Healthful Behavior Change, Division of Internal Medicine, NYU Medical Center, New York, 2Department of Family Medicine, SUNY Downstate Medical Center, Brooklyn, 3Center of Excellence in Disparities Research, Weill Cornell Medical College, New York, NY, USA Background: Excessive daytime sleepiness (EDS often occurs as a result of insufficient sleep, sleep apnea, illicit substance use, and other medical and psychiatric conditions. This study tested the hypothesis that blacks exhibiting EDS would have poorer self-reported adherence to hypertensive medication using cross-sectional data from the Counseling African-Americans to Control Hypertension (CAATCH trial. Methods: A total of 1,058 hypertensive blacks (average age 57±12 years participated in CAATCH, a randomized controlled trial evaluating the effectiveness of a multilevel intervention for participants who receive care from community health centers in New York City. Data analyzed in this study included baseline sociodemographics, medical history, EDS, and medication adherence. We used the Epworth Sleepiness Scale, with a cutoff score of ≥10, to define EDS. Medication adherence was measured using an abbreviated Morisky Medication Adherence scale, with a score >0 indicating nonadherence. Results: Of the sample, 71% were female, 72% received at least a high school education, 51% reported a history of smoking, and 33% had a history of alcohol consumption. Overall, 27% of the participants exhibited EDS, and 44% of those who exhibited EDS were classified as adherent to prescribed antihypertensive medications. Multivariable logistic regression analysis, adjusting for effects of age, body mass index, sex, education, and smoking and drinking history indicated that participants who exhibited EDS were more than twice as likely to be nonadherent (odds ratio 2.28, 95

  18. Protective effect of geranylgeranylacetone, an inducer of heat shock protein 70, against drug-induced lung injury/fibrosis in an animal model

    Directory of Open Access Journals (Sweden)

    Hasegawa Yoshinori

    2009-09-01

    Full Text Available Abstract Background To determine whether oral administration of geranylgeranylacetone (GGA, a nontoxic anti-ulcer drug that is an inducer of heat shock protein (HSP 70, protects against drug-induced lung injury/fibrosis in vivo. Methods We used a bleomycin (BLM-induced lung fibrosis model in which mice were treated with oral 600 mg/kg of GGA before and after BLM administration. Inflammation and fibrosis were evaluated by histological scoring, hydroxyproline content in the lung and inflammatory cell count, and quantification by ELISA of macrophage inflammatory protein-2 (MIP-2 in bronchoalveolar lavage fluid. Apoptosis was evaluated by the TUNEL method. The induction of HSP70 in the lung was examined with western blot analysis and its localization was determined by immunohistochemistry. Results We confirmed the presence of inflammation and fibrosis in the BLM-induced lung injury model and induction of HSP70 by oral administration of GGA. GGA prevented apoptosis of cellular constituents of lung tissue, such as epithelial cells, most likely related to the de novo induction of HSP70 in the lungs. GGA-treated mice also showed less fibrosis of the lungs, associated with the findings of suppression of both production of MIP-2 and inflammatory cell accumulation in the injured lung, compared with vehicle-treated mice. Conclusion GGA had a protective effect on drug-induced lung injury/fibrosis. Disease-modifying antirheumatic drugs such as methotrexate, which are indispensable for the treatment of rheumatoid arthritis, often cause interstitial lung diseases, an adverse event that currently cannot be prevented. Clinical use of GGA for drug-induced pulmonary fibrosis might be considered in the future.

  19. Disruption of BSEP Function in HepaRG Cells Alters Bile Acid Disposition and Is a Susceptive Factor to Drug-Induced Cholestatic Injury.

    Science.gov (United States)

    Qiu, Xi; Zhang, Yueping; Liu, Tongtong; Shen, Hong; Xiao, Yongling; Bourner, Maureen J; Pratt, Jennifer R; Thompson, David C; Marathe, Punit; Humphreys, W Griffith; Lai, Yurong

    2016-04-01

    In the present study, we characterized in vitro biosynthesis and disposition of bile acids (BAs) as well as hepatic transporter expression followed by ABCB11 (BSEP) gene knockout in HepaRG cells (HepaRG-KO cells). BSEP KO in HepaRG cells led to time-dependent BA accumulation, resulting in reduced biosynthesis of BAs and altered BA disposition. In HepaRG-KO cells, the expression of NTCP, OATP1B1, OATP2B1, BCRP, P-gp, and MRP2 were reduced, whereas MRP3 and OCT1 were up-regulated. As a result, BSEP KO altered the disposition of BAs and subsequently underwent adaptive regulations of BA synthesis and homeostasis to enable healthy growth of the cells. Although BSEP inhibitors caused no or slight increase of BAs in HepaRG wild type cells (HepaRG-WT cells), excessive intracellular accumulation of BAs was observed in HepaRG-KO cells exposed to bosentan and troglitazone, but not dipyridamole. LDH release in the medium was remarkably increased in HepaRG-KO cultures exposed to troglitazone (50 μM), suggesting drug-induced cellular injury. The results revealed that functional impairment of BSEP predisposes the cells to altered BA disposition and is a susceptive factor to drug-induced cholestatic injury. In total, BSEP inhibition might trigger the processes but is not a sole determinant of cholestatic cellular injury. As intracellular BA accumulation is determined by BSEP function and the subsequent adaptive gene regulation, assessment of intracellular BA accumulation in HepaRG-KO cells could be a useful approach to evaluate drug-induced liver injury (DILI) potentials of drugs that could disrupt other BA homeostasis pathways beyond BSEP inhibition. PMID:26910619

  20. Genetic polymorphisms of NAT2, CYP2E1 and GST enzymes and the occurrence of antituberculosis drug-induced hepatitis in Brazilian TB patients

    OpenAIRE

    Raquel Lima de Figueiredo Teixeira; Renata Gomes Morato; Pedro Hernan Cabello; Ligia Mayumi Kitada Muniz; Adriana da Silva Rezende Moreira; Afrânio Lineu Kritski; Fernanda Carvalho Queiroz Mello; Philip Noel Suffys; Antonio Basilio de Miranda; Adalberto Rezende Santos

    2011-01-01

    Isoniazid (INH), one of the most important drugs used in antituberculosis (anti-TB) treatment, is also the major drug involved in hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, such as NAT2, CYP2E1, GSTM1 and GSTT1, that code for drug-metabolising enzymes. Our goal was to examine the polymorphisms in these enzymes as susceptibility factors to anti-TB drug-induced hepatitis in Brazilian individuals. In a case-control design, 167...

  1. Association of the CYP2B6 gene with anti-tuberculosis drug-induced hepatotoxicity in a Brazilian Amazon population

    OpenAIRE

    Débora Christina Ricardo Oliveira Fernandes; Ney Pereira Carneiro Santos; Milene Raiol Moraes; Ana Cristina Oliveira Braga; Cleonardo Augusto Silva; Andrea Ribeiro-dos-Santos; Sidney Santos

    2015-01-01

    Objectives: The treatment of tuberculosis (TB) remains a challenge owing to the high incidence of drug-induced hepatotoxicity. The aim of this study was to examine the effect of two gene polymorphisms, one in the CYP2B6 (rs3745274) gene and one in the CYP3A5 (rs776746) gene, on the development of hepatotoxicity in patients treated with anti-TB drugs in a Brazilian Amazon population. Methods: TB patients who were treated with anti-TB drugs were examined for hepatotoxicity, an adverse effect...

  2. Anti-Tuberculosis Drug Induced Hepatotoxicity among TB/HIV Co-Infected Patients at Jimma University Hospital, Ethiopia: Nested Case-Control Study

    OpenAIRE

    Alima Hassen Ali; Tefera Belachew; Alemeshet Yami; Wubeante Yenet Ayen

    2013-01-01

    BACKGROUND: This study was carried out to determine the incidence and predictors of anti-tuberculosis drug induced hepatotoxicity among TB/HIV co-infected patients at Jimma University Hospital, Ethiopia. METHODS/PRINCIPAL FINDINGS: A nested case-control study was conducted by reviewing charts of all TB/HIV co-infected patients who commenced anti-TB treatment from January 2008 to December 2011 at Jimma University Hospital. Patients who had developed hepatotoxicity after at least 5 days of stan...

  3. A long-term three dimensional liver co-culture system for improved prediction of clinically relevant drug-induced hepatotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Kostadinova, Radina; Boess, Franziska [Non-Clinical Safety, Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Building 73 / Room 117b, 4070 Basel (Switzerland); Applegate, Dawn [RegeneMed, 9855 Towne Centre Drive Suite 200, San Diego, CA 92121 (United States); Suter, Laura; Weiser, Thomas; Singer, Thomas [Non-Clinical Safety, Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Building 73 / Room 117b, 4070 Basel (Switzerland); Naughton, Brian [RegeneMed, 9855 Towne Centre Drive Suite 200, San Diego, CA 92121 (United States); Roth, Adrian, E-mail: adrian_b.roth@roche.com [Non-Clinical Safety, Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Building 73 / Room 117b, 4070 Basel (Switzerland)

    2013-04-01

    Drug-induced liver injury (DILI) is the major cause for liver failure and post-marketing drug withdrawals. Due to species-specific differences in hepatocellular function, animal experiments to assess potential liabilities of drug candidates can predict hepatotoxicity in humans only to a certain extent. In addition to animal experimentation, primary hepatocytes from rat or human are widely used for pre-clinical safety assessment. However, as many toxic responses in vivo are mediated by a complex interplay among different cell types and often require chronic drug exposures, the predictive performance of hepatocytes is very limited. Here, we established and characterized human and rat in vitro three-dimensional (3D) liver co-culture systems containing primary parenchymal and non-parenchymal hepatic cells. Our data demonstrate that cells cultured on a 3D scaffold have a preserved composition of hepatocytes, stellate, Kupffer and endothelial cells and maintain liver function for up to 3 months, as measured by the production of albumin, fibrinogen, transferrin and urea. Additionally, 3D liver co-cultures maintain cytochrome P450 inducibility, form bile canaliculi-like structures and respond to inflammatory stimuli. Upon incubation with selected hepatotoxicants including drugs which have been shown to induce idiosyncratic toxicity, we demonstrated that this model better detected in vivo drug-induced toxicity, including species-specific drug effects, when compared to monolayer hepatocyte cultures. In conclusion, our results underline the importance of more complex and long lasting in vitro cell culture models that contain all liver cell types and allow repeated drug-treatments for detection of in vivo-relevant adverse drug effects. - Highlights: ► 3D liver co-cultures maintain liver specific functions for up to three months. ► Activities of Cytochrome P450s remain drug- inducible accross three months. ► 3D liver co-cultures recapitulate drug-induced liver toxicity

  4. Clinical observation of 60 cases of drug induced liver disease%药物性肝病60例临床观察

    Institute of Scientific and Technical Information of China (English)

    马志敏

    2016-01-01

    目的:观察分析药物性肝病患者的疾病类型、预后情况以及影响因素。方法:收治药物性肝病患者60例,对其进行回顾性分析。结果:60例患者临床症状、体征表现与临床分型各有不同;HBsAg呈阴性影响相关性大,阳性相关性小;患者长期饮酒习惯相关性大;不同类型药物长期服用相关性大;采用有效治疗措施可对药物性肝病患者起到良好的治疗效果。结论:药物性肝病的发病因素与患者饮酒习惯、用药史、病症史等具有较大的相关性,在停药采取积极治疗后,可取得较好的治疗效果。%Objective:To observe and analyze the disease type,prognosis and influencing factors of drug induced liver disease. Methods:60 cases of drug induced liver disease were selected.We analyzed the data of them retrospectively.Results:The clinical manifestation,signs expression and clinical types of 60 patients were different;HBsAg showed negative correlation was big,and the positive correlation was small;long term drinking habits of patients with large correlation;long-term use of different types of drugs related to large;the effective treatment can had good therapeutic effect when used to treat patients with drug-induced liver disease. Conclusion:The factors of drug induced liver disease are related to drinking habits,history of drug use,history of disease and so on. Stopping the medicine to take the active treatment can obtain the good treatment effect.

  5. Drug-induced trafficking of p-glycoprotein in human brain capillary endothelial cells as demonstrated by exposure to mitomycin C.

    OpenAIRE

    Noack, Andreas; Noack, Sandra; Hoffmann, Andrea; Maalouf, Katia; Buettner, Manuela; Couraud, Pierre-Olivier; Romero, Ignacio A.; Weksler, Babette; Alms, Dana; Römermann, Kerstin; Naim, Hassan Y; Löscher, Wolfgang

    2014-01-01

    P-glycoprotein (Pgp; ABCB1/MDR1) is a major efflux transporter at the blood-brain barrier (BBB), restricting the penetration of various compounds. In other tissues, trafficking of Pgp from subcellular stores to the cell surface has been demonstrated and may constitute a rapid way of the cell to respond to toxic compounds by functional membrane insertion of the transporter. It is not known whether drug-induced Pgp trafficking also occurs in brain capillary endothelial cells that form the BBB. ...

  6. Combined hERG channel inhibition and disruption of trafficking in drug-induced long QT syndrome by fluoxetine: a case-study in cardiac safety pharmacology

    OpenAIRE

    Hancox, J. C.; Mitcheson, J S

    2006-01-01

    Drug-induced prolongation of the rate-corrected QT interval (QTCI) on the electrocardiogram occurs as an unwanted effect of diverse clinical and investigational drugs and carries a risk of potentially fatal cardiac arrhythmias. hERG (human ether-à-go-go-related gene) is the gene encoding the α-subunit of channels mediating the rapid delayed rectifier K+ current, which plays a vital role in repolarising the ventricles of the heart. Most QTCI prolonging drugs can inhibit the function of recombi...

  7. Role of polymorphic bile salt export pump (BSEP, ABCB11) transporters in anti-tuberculosis drug-induced liver injury in a Chinese cohort

    OpenAIRE

    Ru Chen; Jing Wang; Shaowen Tang; Yuan Zhang; Xiaozhen Lv; Shanshan Wu; Zhirong Yang; Yinyin Xia; Dafang Chen; Siyan Zhan

    2016-01-01

    Evidence indicates that the polymorphisms in bile salt export pump (BSEP, encoded by ABCB11) may play an important role in the development of anti-tuberculosis drug-induced liver injury (ATDILI) and we aim to investigate the association between genetic variants of ABCB11 and the risk of ATDILI in a Chinese cohort. A total of 89 tuberculosis patients with ATDILI and 356 matched ATDILI -free patients constituted cases and controls. Genetic polymorphisms of ABCB11 were determined by TaqMan singl...

  8. Reaserch progress of anti-tuberculosis drugs induced hepatotoxicity%抗结核药致肝损害的研究进展

    Institute of Scientific and Technical Information of China (English)

    周应初; 刘斌

    2011-01-01

    Drug induced hepatotoxicity (DIH), especially the anti-tuberculosis (anti-TB) drugs induced hepatotoxicity(ATDH) , impacts greatly on hunman body, and is one of the most common causes of stoping chemotherapy in tuberculosis patients. The pathogenesis of ATDH is not very clear, but the toxicity and idiosyncratic reaction have been widely studied. Its risk factors are as follows: old age, female, slow acetylation status, malnutrition, human immunodeficiency virus infection, liver diseases, excessive intake of alcohol, combination therapy, and so on. Of ATDH, the early prevention, detection, diagnosis, and treatment will be helpful to successfully complete the tuberculosis chemodierapy. Therefore , it is crucial to understand the pathogenesis and risk factors of ATDH and it is urgent to strengthen the prevention of ATDH.%tuberculosis药物性肝痛(drug induced hepatotoxicity,DIH)以抗结核药诱导的肝毒性(anti-tuberculosis drugs induced hepatotoxicity,ATDH)较常见,其对人体影响最大,是导致结核病人停止化学治疗最常见的原因之一.ATDH的发病机制尚不十分清楚,但目前以毒性反应及特异质反应研究较多,其危险因素包括高龄、女性、慢乙酰化状态、营养不良、人类免疫缺陷病毒(human immunodeficiency virus,HIV)感染、肝疾病、过多撮入酒精,联合用药等.对ATDH的早预防、早发现、早诊断、早治疗是顺利完成结核化疗的保障.因此,了解ATDH的发病机制及危险因素显得至关重要,加强ATDH的防治是一个亟需解决的临床问题.

  9. A long-term three dimensional liver co-culture system for improved prediction of clinically relevant drug-induced hepatotoxicity

    International Nuclear Information System (INIS)

    Drug-induced liver injury (DILI) is the major cause for liver failure and post-marketing drug withdrawals. Due to species-specific differences in hepatocellular function, animal experiments to assess potential liabilities of drug candidates can predict hepatotoxicity in humans only to a certain extent. In addition to animal experimentation, primary hepatocytes from rat or human are widely used for pre-clinical safety assessment. However, as many toxic responses in vivo are mediated by a complex interplay among different cell types and often require chronic drug exposures, the predictive performance of hepatocytes is very limited. Here, we established and characterized human and rat in vitro three-dimensional (3D) liver co-culture systems containing primary parenchymal and non-parenchymal hepatic cells. Our data demonstrate that cells cultured on a 3D scaffold have a preserved composition of hepatocytes, stellate, Kupffer and endothelial cells and maintain liver function for up to 3 months, as measured by the production of albumin, fibrinogen, transferrin and urea. Additionally, 3D liver co-cultures maintain cytochrome P450 inducibility, form bile canaliculi-like structures and respond to inflammatory stimuli. Upon incubation with selected hepatotoxicants including drugs which have been shown to induce idiosyncratic toxicity, we demonstrated that this model better detected in vivo drug-induced toxicity, including species-specific drug effects, when compared to monolayer hepatocyte cultures. In conclusion, our results underline the importance of more complex and long lasting in vitro cell culture models that contain all liver cell types and allow repeated drug-treatments for detection of in vivo-relevant adverse drug effects. - Highlights: ► 3D liver co-cultures maintain liver specific functions for up to three months. ► Activities of Cytochrome P450s remain drug- inducible accross three months. ► 3D liver co-cultures recapitulate drug-induced liver toxicity

  10. Identifying drug-induced repolarization abnormalities from distinct ECG patterns in congenital long QT syndrome: a study of sotalol effects on T-wave morphology

    DEFF Research Database (Denmark)

    Graff, Claus; Andersen, Mads P; Xue, Joel Q;

    2009-01-01

    BACKGROUND: The electrocardiographic QT interval is used to identify drugs with potential harmful effects on cardiac repolarization in drug trials, but the variability of the measurement can mask drug-induced ECG changes. The use of complementary electrocardiographic indices of abnormal repolariz......BACKGROUND: The electrocardiographic QT interval is used to identify drugs with potential harmful effects on cardiac repolarization in drug trials, but the variability of the measurement can mask drug-induced ECG changes. The use of complementary electrocardiographic indices of abnormal...... are typical ECG patterns in LQT2. Blinded to labels, the new morphology measures were tested in a third group of 39 healthy subjects receiving sotalol. Over 3 days the sotalol group received 0, 160 and 320 mg doses, respectively, and a 12-lead Holter ECG was recorded for 22.5 hours each day. Drug...... with QTcF, p ECG patterns in LQT2 carriers effectively quantified repolarization changes induced by sotalol. Further studies are needed to validate whether this measure has...

  11. Establishment of a novel experimental protocol for drug-induced seizure liability screening based on a locomotor activity assay in zebrafish.

    Science.gov (United States)

    Koseki, Naoteru; Deguchi, Jiro; Yamashita, Akihito; Miyawaki, Izuru; Funabashi, Hitoshi

    2014-08-01

    As drug-induced seizures have severe impact on drug development, evaluating seizure induction potential of candidate drugs at the early stages of drug discovery is important. A novel assay system using zebrafish has attracted interest as a high throughput toxicological in vivo assay system, and we tried to establish an experimental method for drug-induced seizure liability on the basis of locomotor activity in zebrafish. We monitored locomotor activity at high-speed movement (> 20 mm/sec) for 60 min immediately after exposure, and assessed seizure liability potential in some drugs using locomotor activity. However this experimental procedure was not sufficient for predicting seizures because the potential of several drugs with demonstrated seizure potential in mammals was not detected. We, therefore, added other parameters for locomotor activity such as extending exposure time or conducting flashlight stimulation (10 Hz) which is a known seizure induction stimulus, and these additional parameters improved seizure potential detection in some drugs. The validation study using the improved methodology was used to assess 52 commercially available drugs, and the prediction rate was approximately 70%. The experimental protocol established in this present study is considered useful for seizure potential screening during early stages of drug discovery. PMID:25056783

  12. A two-photon fluorescent sensor revealing drug-induced liver injury via tracking γ-glutamyltranspeptidase (GGT) level in vivo.

    Science.gov (United States)

    Zhang, Peisheng; Jiang, Xiao-Fang; Nie, Xuezheng; Huang, Yong; Zeng, Fang; Xia, Xitao; Wu, Shuizhu

    2016-02-01

    Currently drug-induced liver injury (DILI) has become a major and challenging public health issue in terms of medicine development and clinical therapy. The level of γ-glutamyl transpeptidase (GGT) has long been regarded as a preclinical/clinical biomarker for prediction of DILI. Herein, we report a two-photon fluorescent sensor for tracking GGT level changes resulted from DILI in vivo. The sensor was prepared by linking a glutamic acid to a dicyanomethylene-4H-pyran (DCM) derivative; and the presence of GGT cleaves γ-glutamyl amide group from the sensor and thereby restores the fluorescence emission (at 635 nm) of DCM moiety under femtosecond pulses at 800 nm. This two-photon sensor exhibits superior sensing performance such as red emission, high photostability and low detection limit (∼0.057 U/L). On a two-photon microscope, the sensor shows a bright red fluorescence in GGT-overexpressing A2780 cells; and it can fluorescently respond to the GGT generated in the liver of zebrafishes as a result of clinical drug (phenytoin) treatment. These findings demonstrate that a commonly-used clinical drug phenytoin can cause remarkable elevation in GGT level in liver, and this sensor may be useful as a marker to detect clinical drug-induced organ damages. PMID:26706475

  13. 精神药物所致咳嗽的识别与处理%Identification and Treatment of Psychotropic Drug-induced Cough

    Institute of Scientific and Technical Information of China (English)

    于相芬; 孙振晓

    2014-01-01

    Many psychotropic drugs could cause cough which may have no typical symptoms and is difficult to distinguish at an early stage. In order to make a better understanding of psychotropic drug-induced cough, this article made a review on the definition and causes of cough, and the diagnosis, differential diagnosis, pathomechanism and management of psychotropic drug-induced cough. Clinicians should strengthen the ability of discrimination and treatment of cough induced by psychotropic drugs.%多种精神药物可引起咳嗽,且表现无典型特征,早期难以发现。本文对咳嗽的定义及原因、精神药物所致咳嗽的诊断、鉴别诊断、发病机制及处理等作一综述。临床应加强对精神药物引起的咳嗽进行识别和处理。

  14. Data mining reveals a network of early-response genes as a consensus signature of drug-induced in vitro and in vivo toxicity.

    Science.gov (United States)

    Zhang, J D; Berntenis, N; Roth, A; Ebeling, M

    2014-06-01

    Gene signatures of drug-induced toxicity are of broad interest, but they are often identified from small-scale, single-time point experiments, and are therefore of limited applicability. To address this issue, we performed multivariate analysis of gene expression, cell-based assays, and histopathological data in the TG-GATEs (Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system) database. Data mining highlights four genes-EGR1, ATF3, GDF15 and FGF21-that are induced 2 h after drug administration in human and rat primary hepatocytes poised to eventually undergo cytotoxicity-induced cell death. Modelling and simulation reveals that these early stress-response genes form a functional network with evolutionarily conserved structure and intrinsic dynamics. This is underlined by the fact that early induction of this network in vivo predicts drug-induced liver and kidney pathology with high accuracy. Our findings demonstrate the value of early gene-expression signatures in predicting and understanding compound-induced toxicity. The identified network can empower first-line tests that reduce animal use and costs of safety evaluation.

  15. Drug-induced hypotension SEP test and acetazolamide test using sup 133 Xe SPECT in patients with occlusive carotid disease; Selection of candidates for extracranial-intracranial bypass

    Energy Technology Data Exchange (ETDEWEB)

    Kuroda, Satoshi; Kamiyama, Hiroyasu; Abe, Hiroshi; Takigawa, Shugo (Hokkaido Univ., Sapporo (Japan). School of Medicine); Mitsumori, Kenji; Nomura, Mikio; Saitoh, Hisatoshi

    1991-01-01

    The correlation between the drug-induced hypotension somatosensory evoked potential (SEP) test and regional cerebral blood flow changes after acetazolamide administration was studied. Fourteen patients presenting with transient ischemic attack, reversible ischemic neurological deficits, or minor completed stroke were evaluated. All patients had no or only localized low-density areas on computed tomographic scans, and unilateral occlusion or severe stenosis of the internal carotid or middle cerebral artery on cerebral angiograms. The Diamox asymmetry enhancement (DAE) was studied to detect reduced cerebral perfusion reserve in the affected hemispheres. The DAE was 7.9+-5.8% in seven patients positive in the SEP test, significantly higher than -1.5+-2.9% in patients negative in the SEP test. Postoperative SEP tests were negative in all five patients who underwent extracranial-intracranial (EC-IC) bypass surgery, suggesting that the EC-IC bypass improved the cerebral perfusion reserve in the affected hemispheres. The DAE decreased significantly in four of these patients. This study disclosed a significant correlation between the drug-induced hypotension SEP test and DAE. These parameters are considered important for evaluating patients with hemodynamic compromise and/or suitable candidates for EC-IC bypass. (author).

  16. Role of polymorphic bile salt export pump (BSEP, ABCB11) transporters in anti-tuberculosis drug-induced liver injury in a Chinese cohort.

    Science.gov (United States)

    Chen, Ru; Wang, Jing; Tang, Shaowen; Zhang, Yuan; Lv, Xiaozhen; Wu, Shanshan; Yang, Zhirong; Xia, Yinyin; Chen, Dafang; Zhan, Siyan

    2016-01-01

    Evidence indicates that the polymorphisms in bile salt export pump (BSEP, encoded by ABCB11) may play an important role in the development of anti-tuberculosis drug-induced liver injury (ATDILI) and we aim to investigate the association between genetic variants of ABCB11 and the risk of ATDILI in a Chinese cohort. A total of 89 tuberculosis patients with ATDILI and 356 matched ATDILI -free patients constituted cases and controls. Genetic polymorphisms of ABCB11 were determined by TaqMan single-nucleotide polymorphism (SNP) genotyping assay. Odds ratio (OR) with 95% confidence intervals (CIs) was estimated by conditional logistic regression model. There were no significant differences in genotype frequencies of ABCB11 between cases and controls. In the subgroup analysis, polymorphisms of rs2287616 were found to be associated with cholestatic/mixed pattern of liver injury under dominant and addictive model (OR = 3.84, 95% CI:1.16-12.75, P = 0.028 and OR = 2.51, 95% CI:1.12-5.62, P = 0.025, respectively), however the significance disappeared after Bonferroni correction. This study suggested that genetic variants of ABCB11 gene might contribute to anti-tuberculosis drug-induced cholestatic liver injury in Chinese patients. Studies in larger, varied populations are required to confirm these findings. PMID:27293027

  17. Correlation of the microculture-kinetic drug-induced apoptosis assay with patient outcomes in initial treatment of adult acute myelocytic leukemia.

    Science.gov (United States)

    Strickland, Stephen A; Raptis, Anastasios; Hallquist, Allan; Rutledge, James; Chernick, Michael; Perree, Mathieu; Talbott, Mahsa S; Presant, Cary A

    2013-03-01

    Overall survival (OS) with acute myeloid leukemia (AML) remains poor. Determining prognostic factors will help in selecting patients for appropriate treatments. Our aim was to determine whether the level of drug-induced apoptosis (chemosensitivity) demonstrated by the microculture-kinetic drug-induced apoptosis (MiCK) assay significantly predicted outcomes after standard AML induction therapy. A total of 109 patients with untreated AML had blood and/or bone marrow aspirate samples analyzed for anthracycline-induced apoptosis using the MiCK assay. The amount of apoptosis observed over 48 h was determined and expressed as kinetic units of apoptosis (KU). Complete remission (CR) was significantly higher (72%) in patients with high idarubicin-induced apoptosis >3 KU compared to patients with apoptosis ≤ 3 KU (p = 0.01). Multivariate analysis showed the only significant variables to be idarubicin-induced apoptosis and karyotype. Median overall survival of patients with idarubicin-induced apoptosis >3 KU was 16.1 months compared to 4.5 months in patients with apoptosis ≤ 3 KU (p = 0.004). Multivariate analysis showed the only significant variable to be idarubicin-induced apoptosis. Chemotherapy-induced apoptosis measured by the MiCK assay demonstrated significant correlation with outcomes and appears predictive of complete remission and overall survival for patients receiving standard induction chemotherapy. PMID:22924433

  18. Drug-induced trafficking of p-glycoprotein in human brain capillary endothelial cells as demonstrated by exposure to mitomycin C.

    Science.gov (United States)

    Noack, Andreas; Noack, Sandra; Hoffmann, Andrea; Maalouf, Katia; Buettner, Manuela; Couraud, Pierre-Olivier; Romero, Ignacio A; Weksler, Babette; Alms, Dana; Römermann, Kerstin; Naim, Hassan Y; Löscher, Wolfgang

    2014-01-01

    P-glycoprotein (Pgp; ABCB1/MDR1) is a major efflux transporter at the blood-brain barrier (BBB), restricting the penetration of various compounds. In other tissues, trafficking of Pgp from subcellular stores to the cell surface has been demonstrated and may constitute a rapid way of the cell to respond to toxic compounds by functional membrane insertion of the transporter. It is not known whether drug-induced Pgp trafficking also occurs in brain capillary endothelial cells that form the BBB. In this study, trafficking of Pgp was investigated in human brain capillary endothelial cells (hCMEC/D3) that were stably transfected with a doxycycline-inducible MDR1-EGFP fusion plasmid. In the presence of doxycycline, these cells exhibited a 15-fold increase in Pgp-EGFP fusion protein expression, which was associated with an increased efflux of the Pgp substrate rhodamine 123 (Rho123). The chemotherapeutic agent mitomycin C (MMC) was used to study drug-induced trafficking of Pgp. Confocal fluorescence microscopy of single hCMEC/D3-MDR1-EGFP cells revealed that Pgp redistribution from intracellular pools to the cell surface occurred within 2 h of MMC exposure. Pgp-EGFP exhibited a punctuate pattern at the cell surface compatible with concentrated regions of the fusion protein in membrane microdomains, i.e., lipid rafts, which was confirmed by Western blot analysis of biotinylated cell surface proteins in Lubrol-resistant membranes. MMC exposure also increased the functionality of Pgp as assessed in three functional assays with Pgp substrates (Rho123, eFluxx-ID Gold, calcein-AM). However, this increase occurred with some delay after the increased Pgp expression and coincided with the release of Pgp from the Lubrol-resistant membrane complexes. Disrupting rafts by depleting the membrane of cholesterol increased the functionality of Pgp. Our data present the first direct evidence of drug-induced Pgp trafficking at the human BBB and indicate that Pgp has to be released from lipid

  19. Excessive daytime sleepiness in Campo Grande general population, Brazil Sonolência diurna excessiva na população geral de Campo Grande, MS

    Directory of Open Access Journals (Sweden)

    José Carlos Souza

    2002-09-01

    Full Text Available The prevalence of excessive daytime sleepiness (EDS in general population was determined by means of 408 home interviews of adults, in a representative sample of Campo Grande city, Brazil. The random sample was stratified by sex, age and economic social status. EDS was considered in those with indexes 11 or more in the Epworth Sleepiness Scale. Statistics used chi-square, Fisher and Pearson tests; and inferences based on binomial distribution parameters; the significance level was 5% and confidence interval (CI was 95%. The prevalence of EDS was 18.9% of the general population ( SD=1.9%; CI 15.1% to 22.7%. No significant association was found between EDS and the use of hypnotics, nor with insomnia, body mass index, sex, age, years of schooling, economic social status, marital status, occupation and the use of alternative means to improve sleep. When the sample was separated according to sex, only the male group showed significant association between EDS and actual insomnia (p=0.005.Buscou-se a prevalência da sonolência diurna excessiva (SDE com 408 entrevistas domiciliares de adultos, em amostra representativa da população geral da cidade de Campo Grande, MS. A amostragem aleatória foi estratificada por sexo, idade e classe social. Tinham SDE as pessoas com 11 ou mais pontos na Escala de Sonolência Epworth. Usaram-se os testes de qui-quadrado, Fisher, Pearson e inferências com base nos parâmetros da distribuição binomial; nível de significância 5% e intervalo de confiança (IC 95%. Tinham SDE 18,9% da população (dp=1,9%; IC 15,1% a 22,7%; não houve associação significativa entre SDE e uso de hipnóticos, nem insônia, índice de massa corporal, sexo, idade, escolaridade, classe sócio-econômica, estado civil, ocupação e uso de meios alternativos para dormir melhor. Ao serem separados de acordo com sexo, apenas no sexo masculino houve associação significativa entre SDE e presença de insônia (p=0,005.

  20. Sleep Apnea Clinical Score, Berlin Questionnaire, or Epworth Sleepiness Scale: which is the best obstructive sleep apnea predictor in patients with COPD?

    Directory of Open Access Journals (Sweden)

    Faria AC

    2015-08-01

    Full Text Available Anamelia Costa Faria, Cláudia Henrique da Costa, Rogério Rufino Cardiopulmonology Department, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil Introduction: The Sleep Apnea Clinical Score (SACS and the Berlin Questionnaire (BQ are used to predict the likelihood of obstructive sleep apnea (OSA. The Epworth Sleepiness Scale (ESS is used to assess daytime sleepiness, a common OSA symptom. These clinical tools help prioritize individuals with the most severe illness regarding on whom polysomnography (PSG should be performed. It is necessary to check the applicability of these tools in patients with chronic obstructive pulmonary disease (COPD. The aim of this study is to compare SACS, BQ, and ESS performance in patients with COPD. Methods: The SACS, BQ, and ESS were applied to 91 patients with COPD. From this group, 24 underwent PSG. In this transversal study, these three tests were compared regarding their likelihood to predict OSA in patients with COPD using receiver-operating characteristic curve statistics. Results: In this sample, 58 (63.7% patients were men, and their mean age was 69.4±9.6 years. Fourteen patients (15.4% had a high probability of OSA by SACS, 32 (32.5% had a high probability by BQ, and 37 (40.7% had excessive diurnal somnolence according to the ESS. From the 24 patients who underwent PSG, OSA diagnosis was confirmed in five (20.8%, according to the American Academy of Sleep Medicine criteria. BQ and ESS did not accurately predict OSA in this group of patients with COPD, with a receiver-operating characteristic curve area under the curves of 0.54 (95% CI: 0.329–0.745, P=0.75 and 0.69 (95% CI: 0.47–0.860, P=0.10, respectively. SACS performance was significantly better, with an area under the curve of 0.82 (95% CI: 0.606–0.943, P=0.02. Conclusion: SACS was better than BQ and ESS in predicting OSA in this group of patients with COPD. Keywords: overlap syndrome, COPD, emphysema, questionnaire, polysomnography

  1. Compartmentalized accumulation of cAMP near complexes of multidrug resistance protein 4 (MRP4) and cystic fibrosis transmembrane conductance regulator (CFTR) contributes to drug-induced diarrhea.

    Science.gov (United States)

    Moon, Changsuk; Zhang, Weiqiang; Ren, Aixia; Arora, Kavisha; Sinha, Chandrima; Yarlagadda, Sunitha; Woodrooffe, Koryse; Schuetz, John D; Valasani, Koteswara Rao; de Jonge, Hugo R; Shanmukhappa, Shiva Kumar; Shata, Mohamed Tarek M; Buddington, Randal K; Parthasarathi, Kaushik; Naren, Anjaparavanda P

    2015-05-01

    Diarrhea is one of the most common adverse side effects observed in ∼7% of individuals consuming Food and Drug Administration (FDA)-approved drugs. The mechanism of how these drugs alter fluid secretion in the gut and induce diarrhea is not clearly understood. Several drugs are either substrates or inhibitors of multidrug resistance protein 4 (MRP4), such as the anti-colon cancer drug irinotecan and an anti-retroviral used to treat HIV infection, 3'-azido-3'-deoxythymidine (AZT). These drugs activate cystic fibrosis transmembrane conductance regulator (CFTR)-mediated fluid secretion by inhibiting MRP4-mediated cAMP efflux. Binding of drugs to MRP4 augments the formation of MRP4-CFTR-containing macromolecular complexes that is mediated via scaffolding protein PDZK1. Importantly, HIV patients on AZT treatment demonstrate augmented MRP4-CFTR complex formation in the colon, which defines a novel paradigm of drug-induced diarrhea.

  2. Drug-Induced QT Prolongation as a Result of an Escitalopram Overdose in a Patient with Previously Undiagnosed Congenital Long QT Syndrome

    Directory of Open Access Journals (Sweden)

    Paul Singh

    2014-01-01

    Full Text Available We present a case of drug-induced QT prolongation caused by an escitalopram overdose in a patient with previously undiagnosed congenital LQTS. A 15-year-old Caucasian female presented following a suicide attempt via an escitalopram overdose. The patient was found to have a prolonged QT interval with episodes of torsades de pointes. The patient was admitted to the telemetry unit and treated. Despite the resolution of the torsades de pointes, she continued to demonstrate a persistently prolonged QT interval. She was seen by the cardiology service and diagnosed with congenital long QT syndrome. This case illustrates the potential for an escitalopram overdose to cause an acute QT prolongation in a patient with congenital LQTS and suggests the importance of a screening electrocardiogram prior to the initiation of SSRIs, especially in patients at high risk for QT prolongation.

  3. A Framework of Knowledge Integration and Discovery for Supporting Pharmacogenomics Target Predication of Adverse Drug Events: A Case Study of Drug-Induced Long QT Syndrome.

    Science.gov (United States)

    Jiang, Guoqian; Wang, Chen; Zhu, Qian; Chute, Christopher G

    2013-01-01

    Knowledge-driven text mining is becoming an important research area for identifying pharmacogenomics target genes. However, few of such studies have been focused on the pharmacogenomics targets of adverse drug events (ADEs). The objective of the present study is to build a framework of knowledge integration and discovery that aims to support pharmacogenomics target predication of ADEs. We integrate a semantically annotated literature corpus Semantic MEDLINE with a semantically coded ADE knowledgebase known as ADEpedia using a semantic web based framework. We developed a knowledge discovery approach combining a network analysis of a protein-protein interaction (PPI) network and a gene functional classification approach. We performed a case study of drug-induced long QT syndrome for demonstrating the usefulness of the framework in predicting potential pharmacogenomics targets of ADEs.

  4. CYP1A2 and CYP2D6 Gene Polymorphisms in Schizophrenic Patients with Neuroleptic Drug-Induced Side Effects.

    Science.gov (United States)

    Ivanova, S A; Filipenko, M L; Vyalova, N M; Voronina, E N; Pozhidaev, I V; Osmanova, D Z; Ivanov, M V; Fedorenko, O Yu; Semke, A V; Bokhan, N A

    2016-03-01

    Polymorphic variants of CYP1A2 and CYP2D6 genes of the cytochrome P450 system were studied in patients with schizophrenia with drug-induced motor disorders and hyperprolactinemia against the background of long-term neuroleptic therapy. We revealed an association of polymorphic variant C-163A CYP1A2*1F of CYP1A2 gene with tardive dyskinesia and association of polymorphic variant 1846G>A CY2D6*4 and genotype A/A of CYP2D6 gene (responsible for debrisoquin-4-hydroxylase synthesis) with limbotruncal tardive dyskinesia in patients with schizophrenia receiving neuroleptics for a long time. PMID:27021090

  5. Is the drug-induced hypersensitivity syndrome (DIHS due to human herpesvirus 6 infection or to allergy-mediated viral reactivation? Report of a case and literature review

    Directory of Open Access Journals (Sweden)

    Borgia Guglielmo

    2010-03-01

    Full Text Available Abstract Background Drug-Induced Hypersensitivity Syndrome (DIHS is a severe and rare systemic reaction triggered by a drug (usually an antiepileptic drug. We present a case of DISH and we review studies on the clinical features and treatment of DIHS, and on its pathogenesis in which two elements (Herpesvirus infection and the drug interact with the immune system to trigger such a syndrome that can lead to death in about 20% of cases. Case presentation We report the case of a 26-year old woman with fever, systemic maculopapular rash, lymphadenopathy, hepatitis and eosinophilic leukocytosis. She had been treated with antibiotics that gave no benefit. She was taking escitalopram and lamotrigine for a bipolar disease 30 days before fever onset. Because the patient's general condition deteriorated, betamethasone and acyclovir were started. This treatment resulted in a mild improvement of symptoms. Steroids were rapidly tapered and this was followed with a relapse of fever and a worsening of laboratory parameters. Human herpesvirus 6 (HHV-6 DNA was positive as shown by PCR. Drug-Induced Hypersensitivity Syndrome (DIHS was diagnosed. Symptoms regressed on prednisone (at a dose of 50 mg/die that was tapered very slowly. The patient recovered completely. Conclusions The search for rare causes of fever led to complete resolution of a very difficult case. As DIHS is a rare disease the most relevant issue is to suspect and include it in differential diagnosis of fevers of unknown origin. Once diagnosed, the therapy is easy (steroidal administration and often successful. However our case strongly confirms that attention should be paid on the steroidal tapering that should be very slow to avoid a relapse.

  6. In vitro screening of 50 highly prescribed drugs for thiol adduct formation--comparison of potential for drug-induced toxicity and extent of adduct formation.

    Science.gov (United States)

    Gan, Jinping; Ruan, Qian; He, Bing; Zhu, Mingshe; Shyu, Wen C; Humphreys, W Griffith

    2009-04-01

    Reactive metabolite formation has been associated with drug-induced liver, skin, and hematopoietic toxicity of many drugs that has resulted in serious clinical toxicity, leading to clinical development failure, black box warnings, or, in some cases, withdrawal from the market. In vitro and in vivo screening for reactive metabolite formation has been proposed and widely adopted in the pharmaceutical industry with the aim of minimizing the property and thus the risk of drug-induced toxicity (DIT). One of the most common screening methods is in vitro thiol trapping of reactive metabolites. Although it is well-documented that many hepatotoxins form thiol adducts, there is no literature describing the adduct formation potential of safer drugs that are widely used. The objective of this study was to quantitatively assess the thiol adduct formation potential of 50 drugs (10 associated with DIT and 40 not associated) and document apparent differences in adduct formation between toxic and safer drugs. Dansyl glutathione was used as a trapping agent to aid the quantitation of adducts following in vitro incubation of drugs with human liver microsomes in the presence and absence of NADPH. Metabolic turnover of these drugs was also monitored by LC/UV. Overall, 15 out of the 50 drugs screened formed detectable levels of thiol adducts. There were general trends toward more positive findings in the DIT group vs the non-DIT group. These trends became more marked when the relative amount of thiol adducts was taken into account and improved further when dose and total daily reactive metabolite burdens were considered. In conclusion, there appears to be a general trend between the extent of thiol adduct formation and the potential for DIT, which would support the preclinical measurement and minimization of the property through screening of thiol adduct formation as part of an overall discovery optimization paradigm. PMID:19253935

  7. Development of HepG2-derived cells expressing cytochrome P450s for assessing metabolism-associated drug-induced liver toxicity.

    Science.gov (United States)

    Xuan, Jiekun; Chen, Si; Ning, Baitang; Tolleson, William H; Guo, Lei

    2016-08-01

    The generation of reactive metabolites from therapeutic agents is one of the major mechanisms of drug-induced liver injury (DILI). In order to evaluate metabolism-related toxicity and improve drug efficacy and safety, we generated a battery of HepG2-derived cell lines that express 14 cytochrome P450s (CYPs) (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5 and 3A7) individually using a lentiviral expression system. The expression/production of a specific CYP in each cell line was confirmed by an increased abundance of the CYP at both mRNA and protein levels. Moreover, the enzymatic activities of representative CYPs in the corresponding cell lines were also measured. Using our CYP-expressed HepG2 cells, the toxicity of three drugs that could induce DILI (amiodarone, chlorpromazine and primaquine) was assessed, and all of them showed altered (increased or decreased) toxicity compared to the toxicity in drug-treated wild-type HepG2 cells. CYP-mediated drug toxicity examined in our cell system is consistent with previous reports, demonstrating the potential of these cells for assessing metabolism-related drug toxicity. This cell system provides a practical in vitro approach for drug metabolism screening and for early detection of drug toxicity. It is also a surrogate enzyme source for the enzymatic characterization of a particular CYP that contributes to drug-induced liver toxicity. PMID:26477383

  8. Detection of Drug-Induced Acute Kidney Injury in Humans Using Urinary KIM-1, miR-21, -200c, and -423.

    Science.gov (United States)

    Pavkovic, Mira; Robinson-Cohen, Cassianne; Chua, Alicia S; Nicoara, Oana; Cárdenas-González, Mariana; Bijol, Vanesa; Ramachandran, Krithika; Hampson, Lucy; Pirmohamed, Munir; Antoine, Daniel J; Frendl, Gyorgy; Himmelfarb, Jonathan; Waikar, Sushrut S; Vaidya, Vishal S

    2016-07-01

    Drug-induced acute kidney injury (AKI) is often encountered in hospitalized patients. Although serum creatinine (SCr) is still routinely used for assessing AKI, it is known to be insensitive and nonspecific. Therefore, our objective was to evaluate kidney injury molecule 1 (KIM-1) in conjunction with microRNA (miR)-21, -200c, and -423 as urinary biomarkers for drug-induced AKI in humans. In a cross-sectional cohort of patients (n = 135) with acetaminophen (APAP) overdose, all 4 biomarkers were significantly (P SCr increase) but also in APAP-OD patients without clinical diagnosis of AKI compared with healthy volunteers. In a longitudinal cohort of patients with malignant mesothelioma receiving intraoperative cisplatin (Cp) therapy (n = 108) the 4 biomarkers increased significantly (P < .0014) over time after Cp administration, but could not be used to distinguish patients with or without AKI. Evidence for human proximal tubular epithelial cells (HPTECs) being the source of miRNAs in urine was obtained first, by in situ hybridization based confirmation of increase in miR-21 expression in the kidney sections of AKI patients and second, by increased levels of miR-21, -200c, and -423 in the medium of cultured HPTECs treated with Cp and 4-aminophenol (APAP degradation product). Target prediction analysis revealed 1102 mRNA targets of miR-21, -200c, and -423 that are associated with pathways perturbed in diverse pathological kidney conditions. In summary, we report noninvasive detection of AKI in humans by combining the sensitivity of KIM-1 along with mechanistic potentials of miR-21, -200c, and -423. PMID:27122240

  9. Real time identification of drug-induced liver injury (DILI through daily screening of ALT results: a prospective pilot cohort study.

    Directory of Open Access Journals (Sweden)

    Helmi M'Kada

    Full Text Available OBJECTIVE: Identification of drug-induced liver disease (DILI is difficult, even among hospitalized patients. The aim of this pilot study was to assess the impact of a specific strategy for DILI screening. DESIGN: We prospectively compared the number of acute DILI cases identified in one week of a proactive strategy based on centralized elevated ALT values to those identified with a standard of care strategy for 24-week period based on referral cases to the hepatology unit. In the centralized strategy, a designated study biochemist identified patients with ALT greater than 3 times the upper limit of normal values (ULN and notified the designated hepatologists, who then went to the patients' wards, analyzed the charts, and if necessary, interviewed the identified patients. During these two periods, patients with possible DILI were included after signing an informed consent in an ongoing European diagnostic study (SAFE-T consortium. RESULTS: During the 24-week period of the standard strategy, 12 (0.04% patients out of a total of 28,145 were identified as having possible DILI, and 11 of these accepted to be included in the protocol. During the one-week proactive period, 7 patients out of a total of 1407 inpatients (0.498% [odds ratio vs. standard = 12.1 (95% CI, 3.9-32.3; P3 ULN by designated biochemists and hepatologists identified 12 times more acute cases of drug-induced liver disease than the standard strategy. This pilot cohort is registered on the number AP-HP P110201/1/08-03-2011 and AFSSAPS B110346-70.

  10. The effectiveness of the epworth sleepiness scale as an auxiliary resource in the diagnosis of obstructive sleep apnea syndrome - doi:10.5020/18061230.2013.p56

    Directory of Open Access Journals (Sweden)

    Ingrid Correia Nogueira

    2013-08-01

    Full Text Available Objective: To analyze the effectiveness of the Epworth Sleepiness Scale (ESS as an auxiliary resource in the diagnosis of the Obstructive Sleep Apnea Syndrome (OSAS. Methods: Observational study, with a retrospective phase and a prospective one, comprising 475 patients who sought the Sleep Study Center in Fortaleza (Centro de Estudo do Sono de Fortaleza - CESF. Data was collected from medical records, which comprises ESS, amidst some questionnaires prepared by CESF professionals and answered by the patients. The study compared the results raised by the ESS to the polysomnography data. Data analysis was performed on SPSS, using Pearson chi-square test, considering as statistically significant p-value 30 kg/m2 were the most affected by OSAS, with 38.9%, 41% and 45.1%, respectively. A significant relationship was found between ESS score and OSAS (p = 0,001, showing that 25.9% (n = 123 of patients, who had values higher than 10 in the ESS, were diagnosed with OSAS. Conclusions: Data on this study shows that ESS fits as an auxiliary resource in the diagnosis of OSAS and it may be applied by any health professional while taking the clinical history. However, clinical signs are not sufficient to diagnose it, so that polysomnography is still required.

  11. Clinical utility of LC3 and p62 immunohistochemistry in diagnosis of drug-induced autophagic vacuolar myopathies: a case-control study.

    Directory of Open Access Journals (Sweden)

    Han S Lee

    Full Text Available BACKGROUND: Some patients treated with chloroquine, hydroxychloroquine, or colchicine develop autophagic vacuolar myopathy, the diagnosis of which currently requires electron microscopy. The goal of the current study was to develop an immunohistochemical diagnostic marker for this pathologic entity. METHODOLOGY: Microtubule-associated protein light chain 3 (LC3 has emerged as a robust marker of autophagosomes. LC3 binds p62/SQSTM1, an adapter protein that is selectively degraded via autophagy. In this study, we evaluated the utility of immunohistochemical stains for LC3 and p62 as diagnostic markers of drug-induced autophagic vacuolar myopathy. The staining was performed on archival muscle biopsy material, with subject assignment to normal control, drug-treated control, and autophagic myopathy groups based on history of drug use and morphologic criteria. PRINCIPAL FINDINGS: In all drug-treated subjects, but not in normal controls, LC3 and p62 showed punctate staining characteristic of autophagosome buildup. In the autophagic myopathy subjects, puncta were coarser and tended to coalesce into linear structures aligned with the longitudinal axis of the fiber, often in the vicinity of vacuoles. The percentage of LC3- and p62-positive fibers was significantly higher in the autophagic myopathy group compared to either the normal control (p<0.001 or the drug-treated control group (p<0.05. With the diagnostic threshold set between 8% and 15% positive fibers (depending on the desired level of sensitivity and specificity, immunohistochemical staining for either LC3 or p62 could be used to identify subjects with autophagic vacuolar myopathy within the drug-treated subject group (p ≤ 0.001. SIGNIFICANCE: Immunohistochemistry for LC3 and p62 can facilitate tissue-based diagnosis of drug-induced autophagic vacuolar myopathies. By limiting the need for electron microscopy (a time consuming and costly technique with high specificity, but low sensitivity

  12. Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Nanjun; Tengstrand, Elizabeth A.; Chourb, Lisa; Hsieh, Frank Y., E-mail: frank.hsieh@nextcea.com

    2014-09-15

    The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann–Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ≤ 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings. - Highlights: • A reliable biomarker of drug-induced phospholipidosis (DIPL) is needed for humans. • Di-22:6-BMP is specific/sensitive for DIPL in animals as published in literatures. • The di-22:6-BMP biomarker can be validated for humans via NPC patients. • DIPL

  13. Effect of increase in orientational order of lipid chains and head group spacing on non steroidal anti-inflammatory drug induced membrane fusion.

    Science.gov (United States)

    Roy, Sutapa Mondal; Bansode, Amol S; Sarkar, Munna

    2010-12-21

    Membrane fusion is a key event in many biological processes. The fusion process, both in vivo and in vitro, is induced by different agents which include mainly proteins and peptides. For protein- and peptide-mediated membrane fusion, conformational reorganization serves as a driving force. Small drug molecules do not share this advantage; hence, drug induced membrane fusion occurring in absence of any other fusogenic agent and at physiologically relevant concentration of the drugs is a very rare event. To date, only three drugs, namely, meloxicam (Mx), piroxicam (Px), and tenoxicam (Tx), belonging to the oxicam group of non steroidal anti-inflammatory drugs (NSAIDs), have been shown by us to induce fusion at very low drug to lipid ratio without the aid of any other fusogenic agent. In our continued effort to understand the interplay of different physical and chemical parameters of both the participating drugs and the membrane on the mechanism of this drug induced membrane fusion, we present here the effect of increase in orientational order of the lipid chains and increase in head group spacing. This is achieved by studying the effect of low concentration cholesterol (gel to fluid transition temperature, is mainly known to increase orientational order of the lipid chains and increase head group spacing. To isolate the effect of these parameters, small unilameller vesicles (SUVs) formed by dimyristoylphosphatidylcholine (DMPC) with an average diameter of 50-60 nm were used as simple model membranes. Fluorescence assays were used to probe the time dependence of lipid mixing, content mixing, and leakage and also used to determine the partitioning of the drugs in the membrane bilayer. Differential scanning calorimetry (DSC) was used to study the effect of drugs in the presence of cholesterol on the chain-melting temperature which reflects the fluidization effect of the hydrophobic tail region of the bilayer. Our results show contradictory effect of low concentration

  14. Is drug-induced toxicity a good predictor of response to neo-adjuvant chemotherapy in patients with breast cancer? -A prospective clinical study

    Directory of Open Access Journals (Sweden)

    Singh JP

    2004-08-01

    Full Text Available Abstract Background Neo-adjuvant chemotherapy is an integral part of multi-modality approach in the management of locally advanced breast cancer and it is vital to predict the response in order to tailor the regime for a patient. The common final pathway in the tumor cell death is believed to be apoptosis or programmed cell death and chemotherapeutic drugs like other DNA-damaging agents act on rapidly multiplying cells including both the tumor and the normal cells by following the same common final pathway. This could account for both the toxic effects and the response. Absence or decreased apoptosis has been found to be associated with chemo resistance. The change in expression of apoptotic markers (Bcl-2 and Bax proteins brought about by various chemotherapeutic regimens is being used to identify drug resistance in the tumor cells. A prospective clinical study was conducted to assess whether chemotherapy induced toxic effects could serve as reliable predictors of apoptosis or response to neo-adjuvant chemotherapy in patients with locally advanced breast cancer. Methods 50 cases of locally advanced breast cancer after complete routine and metastatic work up were subjected to trucut biopsy and the tissue evaluated immunohistochemically for apoptotic markers (bcl-2/bax ratio. Three cycles of Neoadjuvant Chemotherapy using FAC regime (5-fluorouracil, adriamycin, cyclophosphamide were given at three weekly intervals and patients assessed for clinical response as well as toxicity after each cycle. Modified radical mastectomy was performed in all patients three weeks after the last cycle and the specimen were re-evaluated for any change in the bcl-2/bax ratio. The clinical response, immunohistochemical response and the drug-induced toxicity were correlated and compared. Descriptive studies were performed with SPSS version 10 and the significance of response was assessed using paired t-test. Significance of correlation between various variables was

  15. Is drug-induced toxicity a good predictor of response to neo-adjuvant chemotherapy in patients with breast cancer? -A prospective clinical study

    International Nuclear Information System (INIS)

    Neo-adjuvant chemotherapy is an integral part of multi-modality approach in the management of locally advanced breast cancer and it is vital to predict the response in order to tailor the regime for a patient. The common final pathway in the tumor cell death is believed to be apoptosis or programmed cell death and chemotherapeutic drugs like other DNA-damaging agents act on rapidly multiplying cells including both the tumor and the normal cells by following the same common final pathway. This could account for both the toxic effects and the response. Absence or decreased apoptosis has been found to be associated with chemo resistance. The change in expression of apoptotic markers (Bcl-2 and Bax proteins) brought about by various chemotherapeutic regimens is being used to identify drug resistance in the tumor cells. A prospective clinical study was conducted to assess whether chemotherapy induced toxic effects could serve as reliable predictors of apoptosis or response to neo-adjuvant chemotherapy in patients with locally advanced breast cancer. 50 cases of locally advanced breast cancer after complete routine and metastatic work up were subjected to trucut biopsy and the tissue evaluated immunohistochemically for apoptotic markers (bcl-2/bax ratio). Three cycles of Neoadjuvant Chemotherapy using FAC regime (5-fluorouracil, adriamycin, cyclophosphamide) were given at three weekly intervals and patients assessed for clinical response as well as toxicity after each cycle. Modified radical mastectomy was performed in all patients three weeks after the last cycle and the specimen were re-evaluated for any change in the bcl-2/bax ratio. The clinical response, immunohistochemical response and the drug-induced toxicity were correlated and compared. Descriptive studies were performed with SPSS version 10 and the significance of response was assessed using paired t-test. Significance of correlation between various variables was assessed using chi-square test and coefficient

  16. Potentials and pitfalls using high affinity radioligands in PET and SPET determinations on regional drug induced D2 receptor occupancy--a simulation study based on experimental data.

    Science.gov (United States)

    Olsson, H; Farde, L

    2001-10-01

    The D2 dopamine receptor density ranges from 0.2 to 40 nM among human brain regions. For high density regions radioligands like [(11)C]raclopride provide accurate and reliable estimates of the receptor density. In research on neuropsychiatric disorders there is, however, a growing need for quantitative approaches that accurately measure D2 dopamine receptor occupancy induced by drugs or endogenous dopamine in regions with low receptor density. The new high affinity radioligands [(11)C]FLB 457 and [(123)I]epidepride have been shown to provide a signal for extrasriatal D2 dopamine receptor populations in the human brain in vivo. Initial observations indicate, however, that the time required to reach equilibrium is dependent on receptor density. Ratio analyses may thus not be readily used for comparisons among different brain regions. The aim of the present simulation study was to examine commonly used approaches for calculation of drug induced D2 dopamine receptor occupancy among regions with widely different receptor density. The input functions and the rate constants of [(11)C]FLB 457 and the reference ligand [(11)C]raclopride were first used in a simulation estimating the effect of receptor density on equilibrium time. In a second step we examined how errors produced by inaccurate determination of the binding potential parameter propagate to calculations of drug induced receptor occupancy. The simulations showed a marked effect of receptor density on equilibrium time for [(11)C]FLB 457, but not for [(11)C]raclopride. For [(11)C]FLB 457, a receptor density above about 7 nM caused the time of equilibrium to fall beyond time of data acquisition (1 h). The use of preequilibrium data caused the peak equilibrium and the end time ratio approaches but not the simplified reference tissue model (SRTM) approach to underestimate the binding potential and thus also the drug occupancy calculated for high-density regions. The study supports the use of ratio and SRTM analyses in

  17. Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment

    International Nuclear Information System (INIS)

    The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann–Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ≤ 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings. - Highlights: • A reliable biomarker of drug-induced phospholipidosis (DIPL) is needed for humans. • Di-22:6-BMP is specific/sensitive for DIPL in animals as published in literatures. • The di-22:6-BMP biomarker can be validated for humans via NPC patients. • DIPL

  18. Drug-induced retroperitoneal fibrosis: short aetiopathogenetic note, from the past times of ergot-derivatives large use to currently applied bio-pharmacology

    Science.gov (United States)

    ALBERTI, C.

    2015-01-01

    Among the secondary forms of retroperitoneal fibrosis (RPF), that drug-induced shows very intriguing aspects given both the broad range of involved pharmaceuticals and the considerable interest arisen from the related pathogenetic mechanisms. The particular incidence, in the last four decades past century, of the RPF due to long-term use of ergot alkaloid derivatives (ergotamine, methysergide, pergolide, bromocriptine, cabergoline) and specific L-dopa derived agents, such as methyldopa, as well as to different analgesics, came progressively down given that their long-term use for either the prevention of migraine attacks or the therapy of chronic pathologies (Parkinson’s disease, prolactinoma, pain management, etc) has been, year after year, supplanted or even made unavailable in many countries. More recently, instead, the occurrence of the RPF has been sometimes identified with the use of antitumoral chemotherapeutics, such as carboplatin and methotrexate, and, just lately, as an unusual side-effect of certain biological agents, about which it is timely to go into specific pathogenetic problems in more depth. PMID:26712075

  19. Drug-induced retroperitoneal fibrosis: short aetiopathogenetic note, from the past times of ergot-derivatives large use to currently applied bio-pharmacology.

    Science.gov (United States)

    Alberti, C

    2015-01-01

    Among the secondary forms of retroperitoneal fibrosis (RPF), that drug-induced shows very intriguing aspects given both the broad range of involved pharmaceuticals and the considerable interest arisen from the related pathogenetic mechanisms. The particular incidence, in the last four decades past century, of the RPF due to long-term use of ergot alkaloid derivatives (ergotamine, methysergide, pergolide, bromocriptine, cabergoline) and specific L-dopa derived agents, such as methyldopa, as well as to different analgesics, came progressively down given that their long-term use for either the prevention of migraine attacks or the therapy of chronic pathologies (Parkinson's disease, prolactinoma, pain management, etc) has been, year after year, supplanted or even made unavailable in many countries. More recently, instead, the occurrence of the RPF has been sometimes identified with the use of antitumoral chemotherapeutics, such as carboplatin and methotrexate, and, just lately, as an unusual side-effect of certain biological agents, about which it is timely to go into specific pathogenetic problems in more depth. PMID:26712075

  20. Integrated analysis of miRNA and mRNA gene expression microarrays: Influence on platelet reactivity, clopidogrel response and drug-induced toxicity.

    Science.gov (United States)

    Freitas, Renata Caroline Costa de; Bortolin, Raul Hernandes; Lopes, Mariana Borges; Hirata, Mario Hiroyuki; Hirata, Rosario Dominguez Crespo; Silbiger, Vivian Nogueira; Luchessi, André Ducati

    2016-11-15

    Genetic and epigenetic variability may influence the efficacy and safety of antiplatelet therapies, including clopidogrel. Therefore, the miRNA-mRNA interactions and drug toxicity were investigated in silico using available microarray data. Expressions profiles of platelet miRNA (GSE59488) from acute coronary syndrome and mRNA in peripheral blood cells (GSE32226) from coronary artery disease patients were used to miRNA-target mRNA integrated analysis by Ingenuity Pathways Analysis 6 software (IPA). Results showed that ST13 mRNA is regulated by hsa-miR-107 (miR-103-3p); BTNL3 and CFD mRNAs are regulated by hsa-miR-4701-3p (miR-1262); SLC7A8 is regulated by hsa-miR-145-5p (miR-145-5p); and SENP5 mRNA is regulated by hsa-miR-15b-5p (miR-16-5p) and hsa-miR-26a-5p (miR-26a-5p). Drug toxicity IPA tool showed that these miRNAs/mRNAs are associated with clopidogrel-related liver and renal injury. In conclusion, these results demonstrate that differential expression of miRNAs in platelets and interactions with their target mRNAs are associated with variability in platelet reactivity, clopidogrel response and drug-induced toxicity. PMID:27543010

  1. Experimental evaluation of prophylactic and curative effect of a herbal drug Hemidesmus indicus R.Br. in drug induced ulcers in wistar albino rats

    Directory of Open Access Journals (Sweden)

    Shishira Bharadwaj

    2013-06-01

    Full Text Available Peptic Ulcers are the most common condition experienced by most of the people due to urbanized lifestyle. Hemidesmus indicus R.Br. is a herbal drug mentioned for its treatment in the ancient Indian traditional medicine. To compare the Prophylactic and Curative effects of aqueous and Alcoholic extracts of Hemidesmus indicus in Drug induced ulcers. Aqueous and Alcoholic extracts of the drug were studied for their ulcer healing activity in Wistar Albino rats. Ninety Wistar albino rats were divided into nine groups with one control, four prophylactic and four curative groups. Ulcers were induced with Indomethacin in a dose of 20 mg/kg body weight twice in a gap of 15 hours. Aqueous extract was given in a dose of 500 mg/kg body weight and alcohol in a dose of 100 mg/kg body weight. It was found that both have potential ulcer healing activity with alcoholic extract marginally better than aqueous extract. It can thus be concluded that Hemidesmus indicus R. Br is a effective drug in peptic ulcers. [Int J Res Med Sci 2013; 1(3.000: 243-247

  2. NAT2 variants are associated with drug-induced liver injury caused by anti-tuberculosis drugs in Indonesian patients with tuberculosis.

    Science.gov (United States)

    Yuliwulandari, Rika; Susilowati, Retno Wilujeng; Wicaksono, Britanto Dani; Viyati, Kencono; Prayuni, Kinasih; Razari, Intan; Kristin, Erna; Syafrizal; Subagyo; Sri Diana, Eva; Setiawati, Suci; Ariyani, Aziza; Mahasirimongkol, Surakameth; Yanai, Hideki; Mushiroda, Taisei; Tokunaga, Katsushi

    2016-06-01

    Drug-induced liver injury (DILI) is the most common adverse drug reaction in the treatment of tuberculosis (TB). Several studies showed that patients with TB and the slow-acetylator phenotype caused by NAT2 variants are highly susceptible to DILI caused by anti-TB drugs, hereafter designated AT-DILI. However, the role of NAT2 variants in AT-DILI has never been assessed for an Indonesian population. We recruited 50 patients with TB and AT-DILI and 191 patients with TB but without AT-DILI; we then used direct DNA sequencing to assess single-nucleotide polymorphisms in the coding region of NAT2. NAT2*6A was significantly associated with susceptibility to AT-DILI (P=7.7 × 10(-4), odds ratio (OR)=4.75 (1.8-12.55)). Moreover, patients with TB and the NAT2-associated slow-acetylator phenotype showed higher risk of AT-DILI than patients with the rapid- or intermediate-acetylator phenotypes (P=1.7 × 10(-4), OR=3.45 (1.79-6.67)). In conclusion, this study confirms the significance of the association between slow-acetylator NAT2 variants and susceptibility to AT-DILI in an Indonesian population.

  3. Clinical features and {sup 123}I-FP-CIT SPECT imaging in drug-induced parkinsonism and Parkinson's disease

    Energy Technology Data Exchange (ETDEWEB)

    Diaz-Corrales, Francisco J.; Escobar-Delgado, Teresa [Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Unidad de Trastornos del Movimiento, Servicio de Neurologia, Instituto de Biomedicina de Sevilla, Seville (Spain); Sanz-Viedma, Salome [Hospital Universitario Virgen del Rocio, Unidad Diagnostica de Medicina Nuclear, Seville (Spain); Garcia-Solis, David [Hospital Universitario Virgen del Rocio, Unidad Diagnostica de Medicina Nuclear, Seville (Spain); Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Seville (Spain); Mir, Pablo [Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Unidad de Trastornos del Movimiento, Servicio de Neurologia, Instituto de Biomedicina de Sevilla, Seville (Spain); Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Seville (Spain); Hospital Universitario Virgen del Rocio, Unidad de Trastornos del Movimiento. Servicio de Neurologia, Seville (Spain)

    2010-03-15

    To determine clinical predictors and accuracy of {sup 123}I-FP-CIT SPECT imaging in the differentiation of drug-induced parkinsonism (DIP) and Parkinson's disease (PD). Several clinical features and {sup 123}I-FP-CIT SPECT images in 32 patients with DIP, 25 patients with PD unmasked by antidopaminergic drugs (PDu) and 22 patients with PD without a previous history of antidopaminergic treatment (PDc) were retrospectively evaluated. DIP and PD shared all clinical features except symmetry of parkinsonian signs which was more frequently observed in patients with DIP (46.9%) than in patients with PDu (16.0%, p<0.05) or PDc (4.5%, p<0.01). Qualitatively {sup 123}I-FP-CIT SPECT images were normal in 29 patients with DIP (90.6%) and abnormal in all patients with PD, and this imaging technique showed high levels of accuracy. DIP and PD are difficult to differentiate based on clinical signs. The precision of clinical diagnosis could be reliably enhanced by {sup 123}I-FP-CIT SPECT imaging. (orig.)

  4. Basal efflux of bile acids contributes to drug-induced bile acid-dependent hepatocyte toxicity in rat sandwich-cultured hepatocytes.

    Science.gov (United States)

    Susukida, Takeshi; Sekine, Shuichi; Ogimura, Eiichiro; Aoki, Shigeki; Oizumi, Kumiko; Horie, Toshiharu; Ito, Kousei

    2015-10-01

    The bile salt export pump (BSEP or Bsep) functions as an apical transporter to eliminate bile acids (BAs) from hepatocytes into the bile. BSEP or Bsep inhibitors engender BA retention, suggested as an underlying mechanism of cholestatic drug-induced liver injury. We previously reported a method to evaluate BSEP-mediated BA-dependent hepatocyte toxicity by using sandwich-cultured hepatocytes (SCHs). However, basal efflux transporters, including multidrug resistance-associated proteins (MRP or Mrp) 3 and 4, also participate in BA efflux. This study examined the contribution of basal efflux transporters to BA-dependent hepatocyte toxicity in rat SCHs. The apical efflux of [(3)H]taurocholic acid (TC) was potently inhibited by 10 μM cyclosporine A (CsA), with later inhibition of basal [(3)H]TC efflux, while MK571 simultaneously inhibited both apical and basal [(3)H]TC efflux. CsA-induced BA-dependent hepatocyte toxicity was 30% at most at 10 μM CsA and ∼60% at 50 μM, while MK571 exacerbated hepatocyte toxicity at concentrations of ≥50 μM. Quinidine inhibited only basal [(3)H]TC efflux and showed BA-dependent hepatocyte toxicity in rat SCHs. Hence, inhibition of basal efflux transporters as well as Bsep may precipitate BA-dependent hepatocyte toxicity in rat SCHs. PMID:26055650

  5. Quantification of Drug-Induced Inhibition of Canalicular Cholyl-l-Lysyl-Fluorescein Excretion From Hepatocytes by High Content Cell Imaging.

    Science.gov (United States)

    Barber, Jane A; Stahl, Simone H; Summers, Claire; Barrett, Gillian; Park, B Kevin; Foster, John R; Kenna, J Gerald

    2015-11-01

    We describe the use of a commercially available high content cell imaging algorithm (Cellomics Arrayscan Spot Detector) to quantify biliary excretion of the fluorescent probe substrate cholyl-l-lysyl-fluorescein (CLF) from rat hepatocytes cultured in collagen/matrigel sandwich configuration and to explore inhibition of this process by a variety of test compounds. The method provided robust, reproducible data. Twenty-nine pharmaceuticals inhibited biliary CLF efflux from hepatocytes and a broad range of potencies of inhibition were observed (IC50 values ranged between Bsep), which suggests that the tested drugs inhibit both Bsep and Mrp2. Calculation of the ratios between the maximum human plasma concentrations of the drugs and their CLF efflux inhibition IC50 values raised the possibility that for many, but not all, of them the in vitro effects may be functionally significant in vivo and that Mrp2 inhibition might be a drug-induced liver injury (DILI) risk factor. These data indicate that imaging hepatocyte CLF inhibition is a promising new method for quantification of biliary efflux inhibition by drugs, which could aid assessment of compound-related DILI risk. PMID:26220638

  6. The microculture-kinetic (MiCK) assay: the role of a drug-induced apoptosis assay in drug development and clinical care.

    Science.gov (United States)

    Bosserman, Linda; Prendergast, Franklyn; Herbst, Roy; Fleisher, Martin; Salom, Emery; Strickland, Steven; Raptis, Anastasios; Hallquist, Allan; Perree, Mathieu; Rajurkar, Swapnil; Karimi, Misagh; Rogers, Karl; Davidson, Dirk; Willis, Carl; Penalver, Manuel; Homesley, Howard; Burrell, Matthew; Garrett, Audrey; Rutledge, James; Chernick, Michael; Presant, Cary A

    2012-08-15

    A drug-induced apoptosis assay, termed the microculture-kinetic (MiCK) assay, has been developed. Blinded clinical trials have shown higher response rates and longer survival in groups of patients with acute myelocytic leukemia and epithelial ovarian cancer who have been treated with drugs that show high apoptosis in the MiCK assay. Unblinded clinical trials in multiple tumor types have shown that the assay will be used frequently by clinicians to determine treatment, and when used, results in higher response rates, longer times to relapse, and longer survivals. Model economic analyses suggest possible cost savings in clinical use based on increased generic drug use and single-agent substitution for combination therapies. Two initial studies with drugs in development are promising. The assay may help reduce costs and speed time to drug approval. Correlative studies with molecular biomarkers are planned. This assay may have a role both in personalized clinical therapy and in more efficient drug development. PMID:22865459

  7. Avaliação da sonolência em estudantes universitários de turnos distintos Evaluación de la somnolencia en estudiantes universitarios de turnos distintos Evaluation of sleepiness in college students from different shifts

    Directory of Open Access Journals (Sweden)

    Danilo de Freitas Araújo

    2012-08-01

    Full Text Available Estudantes de graduação possuem altas chances de apresentar Sonolência Diurna Excessiva, devido aos horários escolares e às demandas acadêmicas. Por isso, pretendeu-se analisar níveis de sonolência de estudantes de turnos distintos. O universo foi constituído por 109 graduandos do turno matutino e 125 do noturno. Utilizou-se a Escala de Sonolência de Epworth. A amostra apresentou média total de 9,38 (DP=4,03, sendo 9,03 (DP=4,01 para o turno matutino e 9,7 (DP=3,93 para o noturno. Foram detectadas diferenças significativas nos níveis de sonolência entre turnos (η² =0,10;p Estudiantes de graduación poseen altas posibilidades de presentar Somnolencia Diurna Excesiva, debido a los horarios escolares y a las demandas académicas. Por eso, se pretendió analizar niveles de somnolencia de estudiantes de turnos distintos. El universo fue constituido por 109 graduandos del turno matutino y 125 del nocturno. Se utilizó la Escala de Somnolencia de Epworth. La muestra presentó promedio total de 9,38 (DP=4,03, siendo 9,03 (DP=4,01 para el turno matutino y 9,7 (DP=3,93 para el nocturno. Fueron detectadas diferencias significativas en los niveles de somnolencia entre turnos (η²=0,10; pUndergraduate students are a population with high chances of developing Excessive Daytime Sleepiness, due to school schedules and academic demands. Our aim was to examine the levels of sleepiness of students belonging to morning and night classes. The universe has consisted of 109 undergraduate students of the morning shift and 125 of the night shift. We have used the Epworth Sleepiness Scale. The sample had an average of 9.38 (SD=4.03, and 9.03 (SD=4.01 for the morning shift and 9.7 (SD=3.93 for the night shift. Statistical analysis showed significant differences in sleepiness between shifts (η²=0,10; p<0,00, and among male subjects and female in the two shifts (η²=0,45; p<0,00. It should therefore be considered the role of academic demands, since they

  8. Drug-induced lupus erythematosus

    Science.gov (United States)

    ... that caused the condition. Treatment may include: Nonsteroidal anti-inflammatory drugs (NSAIDs) to treat arthritis and pleurisy Corticosteroid creams to treat skin rashes Antimalarial drugs (hydroxychloroquine) to ...

  9. Drug-induced acute pancreatitis

    NARCIS (Netherlands)

    I.A. Eland

    2003-01-01

    textabstractAcute pancreatitis is an inflammatory disease of the pancreas with sudden onset. The severity of acute pancreatitis may vary from mild to life threatening. There are many risk factors for acute pancreatitis, among which gallstones and alcohol abuse are most widely known. Drugs are consid

  10. Drug-induced acute pancreatitis

    OpenAIRE

    Eland, I.A.

    2008-01-01

    textabstractAcute pancreatitis is an inflammatory disease of the pancreas with sudden onset. The severity of acute pancreatitis may vary from mild to life threatening. There are many risk factors for acute pancreatitis, among which gallstones and alcohol abuse are most widely known. Drugs are considered as potential risk factors for acute pancreatitis, but have received relatively little attention in the medical literature. In this thesis, several epidemiological studies were performed to ass...

  11. [Drug induced eosinophilic pleural effusion].

    Science.gov (United States)

    Vasilescu, Raluca

    2014-01-01

    The hypersensitivity reactions induced by drugs, some widely used, like central nervous system medication, can have various presentations. The lung is a frequent target for such events. We present the case of 40-year-old male patient, non-smoker, with infant encephalopaty, seizures since age of 6 with polimorphic crisis (mainly absences), with anticonvulsivant treatment since 2011 (carbamazepine, sodium valproate, levetiracetam), with no respiratory medical history. Current symptoms started two weeks before, with chest pain, dry cough. He received no antibiotics. Chest X-ray and thoracic CT scan (27 June 2013) showed a left pleral effusion. Left exploratory thoracocentesis extracted 20 ml reddish pleural fluid: eosinophilic exsudate (60%) with normal adenosin deaminase. He also presents moderate blood eosinophilia (13.7%-1780/mm3). Pulmonary infarction with secondary pleurisy, thoracic trauma, acute pancreatitis with secondary pleurisy were excluded. No Loeffler transient infiltrates were documented, serology for Toxocara is IgG positive (historical) and not significant for current episode, no symptoms suggestive for toxocarosis (characteristic to young children, patient had no liver enlargement etc.), no hidatidosis or trichinelosis were found. As an exclusion diagnosis, a hypersensitivity reaction to anticonvulsivant medication was considered (mentioned in literature) carbamazepine and sodium valproate (even if medication was taken for a longer time), with blood and pleural eosinophilia. Together with the neurologist, the mentioned drugs were stopped and he was started on lamotrigine 2 tb/day and levetiracetam 1 tb/day, well tolerated, no absences were noticed. Total remission of blood eosinophilia and partial remission of pleural effusion were noticed. Subsequent follow-ups confirm favourable evolution, with healing of pleurisy and normal blood cell count, which are stable at 7 months after changing anticonvulsivant treatment. PMID:25241560

  12. TOXIC AND DRUG INDUCED MYOPATHIES

    OpenAIRE

    Dalakas, Marinos C.

    2009-01-01

    Abstract Although the ?do no harm? dogma of Hippocrates is faithfully followed by all practitioners, drugs used for therapeutic interventions either alone or in combination, may sometimes cause unexpected toxicity to the muscles, resulting in a varying degree of symptomatology, from mild discomfort and inconvenience to permanent damage and disability. The clinician should suspect a toxic myopathy when a patient without a pre-existing muscle disease develops myalgia, fatigue, weakn...

  13. Drug-Induced Urinary Calculi

    Science.gov (United States)

    Matlaga, Brian R; Shah, Ojas D; Assimos, Dean G

    2003-01-01

    Urinary calculi may be induced by a number of medications used to treat a variety of conditions. These medications may lead to metabolic abnormalities that facilitate the formation of stones. Drugs that induce metabolic calculi include loop diuretics; carbonic anhydrase inhibitors; and laxatives, when abused. Correcting the metabolic abnormality may eliminate or dramatically attenuate stone activity. Urinary calculi can also be induced by medications when the drugs crystallize and become the primary component of the stones. In this case, urinary supersaturation of the agent may promote formation of the calculi. Drugs that induce calculi via this process include magnesium trisilicate; ciprofloxacin; sulfa medications; triamterene; indinavir; and ephedrine, alone or in combination with guaifenesin. When this situation occurs, discontinuation of the medication is usually necessary. PMID:16985842

  14. STOP-Bang questionnaire is superior to Epworth sleepiness scales,Berlin questionnaire, and STOP questionnaire in screening obstructive sleep apnea hypopnea syndrome patients

    Institute of Scientific and Technical Information of China (English)

    Luo Jinmei; Huang Rong; Zhong Xu; Xiao Yi; Zhou Jiong

    2014-01-01

    Background Obstructive sleep apnea hypopnea syndrome (OSAHS) is underdiagnosed.Screening patients at high risk of OSAHS is extremely important.Using the standard questionnaire to screen OSAHS is a practical method.This study aimed to evaluate the value of the STOP-Bang questionnaire (SBQ) in screening OSAHS in sleep-disordered breathing clinic by comparing it with the Epworth sleepiness scales (ESS),Berlin questionnaire,and STOP questionnaire.Methods In this study,212 patients at the sleep-disordered breathing clinic of the Peking Union Medical College Hospital between May 2011 and January 2012 were prospectively included.They were asked to fill in the SBQ,ESS,Berlin questionnaire,and STOP questionnaire before overnight polysomnography (PSG).Using PSG as gold standard,the sensitivities and specificities of SBQ were compared with those of ESS,Berlin questionnaire,and STOP questionnaire.Results There was no significance in applying ESS score ≥11 to screen OSAHS and detect moderate and severe OSAHS (P >0.05).SBQ was superior to Berlin questionnaire and STOP questionnaire in screening OSAHS and detecting the severity of OSAHS patients.The sensitivities of SBQ score ≥3 with apnea hypopnea index (AHI) ≥5/h,AHI ≥15/h,and AHI ≥30/h as gold standards were 94.9%,96.5%,and 97.7%,respectively.The specificities were 50.0%,28.6%,and 17.9%,respectively.The area upper curves were 0.815 (0.706-0.925,P <0.01),0.746 (0.665-0.828,P <0.01),and 0.751 (0.686-0.817,P <0.01),respectively.According to SBQ,the population was classified into high-risk group and low-risk group.The gender,BMI,neck circumference,AHI,LSpO2,and number of subjects ofAHI ≥5/h,AHI ≥15/h,and AHI ≥30/h of these two groups were significantly different.Conclusions The SBQ has superior predictive value compared with ESS,Berlin questionnaire,and STOP questionnaire.It should be used further in screening for OSAHS in the general population.

  15. Selected ABCB1, ABCB4 and ABCC2 Polymorphisms Do Not Enhance the Risk of Drug-Induced Hepatotoxicity in a Spanish Cohort

    Science.gov (United States)

    Ulzurrun, Eugenia; Stephens, Camilla; Ruiz-Cabello, Francisco; Robles-Diaz, Mercedes; Saenz-López, Pablo; Hallal, Hacibe; Soriano, German; Roman, Eva; Fernandez, M. Carmen; Lucena, M. Isabel; Andrade, Raúl J.

    2014-01-01

    Background and Aims Flawed ABC transporter functions may contribute to increased risk of drug-induced liver injury (DILI). We aimed to analyse the influence of genetic variations in ABC transporters on the risk of DILI development and clinical presentations in a large Spanish DILI cohort. Methods A total of ten polymorphisms in ABCB1 (1236T>C, 2677G>T,A, 3435T>C), ABCB4 (1954A>G) and ABCC2 (−1774G>del, −1549A>G, −24C>T, 1249G>A, 3972C>T and 4544G>A) were genotyped using Taqman 5′ allelic discrimination assays or sequencing in 141 Spanish DILI patients and 161 controls. The influence of specific genotypes, alleles and haplotypes on the risk of DILI development and clinical presentations was analysed. Results None of the individual polymorphisms or haplotypes was found to be associated with DILI development. Carriers homozygous for the ABCC2 −1774del allele were however only found in DILI patients. Hence, this genotype could potentially be associated with increased risk, though its low frequency in our Spanish cohort prevented a final conclusion. Furthermore, carriers homozygous for the ABCC2 −1774G/−1549A/−24T/1249G/3972T/4544G haplotype were found to have a higher propensity for total bilirubin elevations when developing DILI. Conclusions Our findings do not support a role for the analysed polymorphisms in the ABCB1, ABCB4 and ABCC2 transporter genes in DILI development in Spanish patients. The ABCC2 −1774deldel genotype was however restricted to DILI cases and could potentially contribute to enhanced DILI susceptibility. PMID:24732756

  16. Drug-Induced Liver Injury Associated With Antidepressive Psychopharmacotherapy: An Explorative Assessment Based on Quantitative Signal Detection Using Different MedDRA Terms.

    Science.gov (United States)

    Gahr, Maximilian; Zeiss, René; Lang, Dirk; Connemann, Bernhard J; Hiemke, Christoph; Schönfeldt-Lecuona, Carlos

    2016-06-01

    Drug-induced liver injury is a major problem of pharmacotherapy and is also frequent with antidepressive psychopharmacotherapy. However, there are only few studies using a consistent methodologic approach to study hepatotoxicity of a larger group of antidepress ants. We performed a quantitative signal detection analysis using data from the Uppsala Monitoring Centre from the WHO that records adverse drug reaction (ADR) data from worldwide sources; we retrieved substance- and country-specific (Australia, France, Germany, Italy, Spain, the United Kingdom, and the United States) ADR data and calculated reporting odds ratios as measures for disproportionality within a case/noncase approach. To allow for identification of agents that cause severe forms of hepatotoxic ADRs, we used 2 terms of the MedDRA ("drug-related hepatic disorders-comprehensive search" [DRHD-CS] and "… -severe events only" [DRHD-SEO]). Distribution of signals was heterogeneous throughout the different data sets, and consistent findings were present for only a few substances: agomelatine (AGM) and tianeptine as well as both positive control agents (amineptine, nefazodone) generated signals related to DRHD-CS and DRHD-SEO in all analyzed data sets. Tri- and tetracyclic antidepressants (here amitriptyline, clomipramine, mianserin, mirtazapine, trimipramine) were associated with hepatotoxicity in several data sets. Using 2 MedDRA terms did not allow for detection of agents that cause severe hepatotoxic ADR. Our results support the findings of previous, primarily literature-based, systematic analyses of hepatotoxicity related to antidepressive psychopharmacotherapy. No new safety information could be generated. Application of 2 MedDRA terms did not increase the substance-specific safety information.

  17. 柳氮磺吡啶致药物超敏反应综合征%Drug-induced hypersensitivity syndrome induced by sulfasalazine:a case report

    Institute of Scientific and Technical Information of China (English)

    李兴天; 刘莉萍; 李遇梅

    2014-01-01

    A case of sulfasalazine-induced hypersensitivity syndrome was reported. A 34-year-old male, presented macu-lopapular rash with fever, alterations of white cell populations and dysfunction of the liver after one-month treatment with sul-fasalazine for ulcerative colitis. Dermatological examination showed scarlet and partly confluent maculopapules over the entire body. The rash blanches on pressure. According to the history of treatment with sulfasalazine, clinical manifestation and labo-ratory examination, drug-induced hypersensitivity syndrome was diagnosed. The treatment produced a marked improvement af-ter the initiation of systemic corticosteroids, immunoglobulin and supportive therapy.%报告1例柳氮磺吡啶致药物超敏反应综合征。患者男,34岁。因溃疡性结肠炎使用柳氮磺吡啶1个月后出现皮疹,伴发热、白细胞及肝功能异常。皮肤科检查:全身可见泛发鲜红色斑丘疹,部分融合成片,触压皮肤可褪色。结合用药史、临床表现及实验室检查诊断为药物超敏反应综合征,给予系统应用糖皮质激素、静脉注射用人免疫球蛋白、保肝及护胃等治疗后病情好转。

  18. Longitudinal study of a human drug-induced model of autoantibody to cytoplasmic rods/rings following HCV therapy with ribavirin and interferon-α.

    Directory of Open Access Journals (Sweden)

    Gerson Dierley Keppeke

    Full Text Available BACKGROUND: A novel pattern in the indirect immunofluorescence antinuclear antibody assay on HEp-2 cells (IIF-HEp-2 characterized by cytoplasmic rods and rings (RR was reported in HCV patients, but stringent disease specificity studies and longitudinal analysis are lacking. We investigated the clinical significance of anti-RR in an HCV cohort with up to a 12-month treatment follow up. METHODOLOGY/RESULTS: 597 patients (342 HCV, 55 HCV/HIV, 200 non-HCV were screened and titered for anti-RR. Serial samples were available from 78 of 176 treated and 27 of 166 untreated patients. Anti-RR was detected in 14.1% of 342 HCV patients, 9.1% of 55 HCV/HIV, 3.4% of 29 Hepatitis B, and none of 171 non-HCV (p47% tested positive for anti-RR. The anti-RR titer generally increased with sustained treatment and remained high in 53% of patients. After treatment, anti-RR titer was negative in 41%. Non-responders to HCV therapy were 77% in anti-RR-positive versus 64% in anti-RR-negative patients. Response to treatment was not associated with anti-RR titer or the dynamics of anti-RR reactivity during and after treatment. CONCLUSIONS: The exquisite association of anti-RR reactivity with combined interferon-α/ribavirin therapy in HCV patients represents a unique model for drug-induced autoantibody generation in humans as demonstrated by the fact that a significant fraction of patients who have anti-RR during therapy becomes anti-RR-negative after completion of therapy.

  19. Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: Marked differences between various antipsychotic drugs

    Directory of Open Access Journals (Sweden)

    Vik-Mo Audun O

    2006-10-01

    Full Text Available Abstract Background The etiology of schizophrenia is unknown, but neurodevelopmental disturbances, myelin- and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder. Cholesterol is an essential component of myelin and has proved important for synapse formation. Recently, we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element-binding protein (SREBP transcription factors. We here compare the action of chlorpromazine, haloperidol, clozapine, olanzapine, risperidone and ziprasidone on SREBP activation and SREBP-controlled gene expression (ACAT2, HMGCR, HMGCS1, FDPS, SC5DL, DHCR7, LDLR, FASN and SCD1 in four CNS-relevant human cell lines. Results There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes, with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations. Glial-like cells (GaMg glioma and CCF-STTG1 astrocytoma cell lines displayed more pronounced drug-induced SREBP activation compared to the response in HCN2 human cortical neurons and SH-SY5Y neuroblastoma cells, indicating that antipsychotic-induced activation of lipogenesis is most prominent in glial cells. Conclusion Our present data show a marked variation in the ability of different antipsychotics to induce SREBP-controlled transcriptional activation of lipogenesis in cultured human CNS-relevant cells. We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs.

  20. Drug-Induced Liver Injury Associated With Antidepressive Psychopharmacotherapy: An Explorative Assessment Based on Quantitative Signal Detection Using Different MedDRA Terms.

    Science.gov (United States)

    Gahr, Maximilian; Zeiss, René; Lang, Dirk; Connemann, Bernhard J; Hiemke, Christoph; Schönfeldt-Lecuona, Carlos

    2016-06-01

    Drug-induced liver injury is a major problem of pharmacotherapy and is also frequent with antidepressive psychopharmacotherapy. However, there are only few studies using a consistent methodologic approach to study hepatotoxicity of a larger group of antidepress ants. We performed a quantitative signal detection analysis using data from the Uppsala Monitoring Centre from the WHO that records adverse drug reaction (ADR) data from worldwide sources; we retrieved substance- and country-specific (Australia, France, Germany, Italy, Spain, the United Kingdom, and the United States) ADR data and calculated reporting odds ratios as measures for disproportionality within a case/noncase approach. To allow for identification of agents that cause severe forms of hepatotoxic ADRs, we used 2 terms of the MedDRA ("drug-related hepatic disorders-comprehensive search" [DRHD-CS] and "… -severe events only" [DRHD-SEO]). Distribution of signals was heterogeneous throughout the different data sets, and consistent findings were present for only a few substances: agomelatine (AGM) and tianeptine as well as both positive control agents (amineptine, nefazodone) generated signals related to DRHD-CS and DRHD-SEO in all analyzed data sets. Tri- and tetracyclic antidepressants (here amitriptyline, clomipramine, mianserin, mirtazapine, trimipramine) were associated with hepatotoxicity in several data sets. Using 2 MedDRA terms did not allow for detection of agents that cause severe hepatotoxic ADR. Our results support the findings of previous, primarily literature-based, systematic analyses of hepatotoxicity related to antidepressive psychopharmacotherapy. No new safety information could be generated. Application of 2 MedDRA terms did not increase the substance-specific safety information. PMID:26470856

  1. Impact of glutathione S-transferase M1 and T1 on anti-tuberculosis drug-induced hepatotoxicity in Chinese pediatric patients.

    Directory of Open Access Journals (Sweden)

    Fang Liu

    Full Text Available Anti-tuberculosis drug induced hepatotoxicity (ATDH is a major adverse drug reaction associated for anti-tuberculosis therapy. The glutathione S-transferases (GST plays a crucial role in the detoxification of hepatotoxic metabolites of anti-tuberculosis drugs.An association between GSTM1/GSTT1 null mutations and increased risk of ATDH has been demonstrated in adults. Given the ethnic differences and developmental changes, our study aims to investigate the potential impacts of GSTM1/GSTT1 genotypes on the development of ATDH in Han Chinese children treated with anti-tuberculosis therapy.Children receiving anti-tuberculosis therapy with or without evidence of ATDH were considered as the cases or controls, respectively. The GSTM1 and GSTT1 genotyping were performed using the polymerase chain reaction.One hundred sixty-three children (20 cases and 143 controls with a mean age of 4.7 years (range: 2 months-14.1 years were included. For the GSTM1, 14 (70.0% cases and 96 (67.1% controls had homozygous null mutations. For the GSTT1, 13 (65.0% cases and 97 (67.8% controls had homozygous null mutations. Neither the GSTM1, nor the GSTT1 polymorphism was significantly correlated with the occurrence of ATHD.Our results did not support the GSTM1 and GSTT1 polymorphisms as the predictors of ADTH in Chinese Han children treated with anti-tuberculosis drugs. An age-related association between pharmacogenetics and ATHD need to be confirmed in the further study.

  2. Mitochondrial toxicity of diclofenac and its metabolites via inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria: Possible role in drug induced liver injury (DILI).

    Science.gov (United States)

    Syed, Muzeeb; Skonberg, Christian; Hansen, Steen Honoré

    2016-03-01

    Diclofenac is a widely prescribed NSAID, which by itself and its reactive metabolites (Phase-I and Phase-II) may be involved in serious idiosyncratic hepatotoxicity. Mitochondrial injury is one of the mechanisms of drug induced liver injury (DILI). In the present work, an investigation of the inhibitory effects of diclofenac (Dic) and its phase I [4-hydroxy diclofenac (4'-OH-Dic) and 5-hydroxy diclofenac (5-OH-dic)] and Phase-II [diclofenac acyl glucuronide (DicGluA) and diclofenac glutathione thioester (DicSG)] metabolites, on ATP synthesis in rat liver mitochondria was carried out. A mechanism based inhibition of ATP synthesis is exerted by diclofenac and its metabolites. Phase-I metabolite (4'-OH-Dic) and Phase-II metabolites (DicGluA and DicSG) showed potent inhibition (2-5 fold) of ATP synthesis, where as 5-OH-Dic, one of the Phase-I metabolite, was a less potent inhibitor as compared to Dic. The calculated kinetic constants of mechanism based inhibition of ATP synthesis by Dic showed maximal rate of inactivation (Kinact) of 2.64 ± 0.15 min(-1) and half maximal rate of inactivation (KI) of 7.69 ± 2.48 μM with Kinact/KI ratio of 0.343 min(-1) μM(-1). Co-incubation of mitochondria with Dic and reduced GSH exhibited a protective effect on Dic mediated inhibition of ATP synthesis. Our data from this study strongly indicate that Dic as well as its metabolites could be involved in the hepato-toxic action through inhibition of ATP synthesis.

  3. Identification of genomic biomarkers for concurrent diagnosis of drug-induced renal tubular injury using a large-scale toxicogenomics database

    International Nuclear Information System (INIS)

    Drug-induced renal tubular injury is one of the major concerns in preclinical safety evaluations. Toxicogenomics is becoming a generally accepted approach for identifying chemicals with potential safety problems. In the present study, we analyzed 33 nephrotoxicants and 8 non-nephrotoxic hepatotoxicants to elucidate time- and dose-dependent global gene expression changes associated with proximal tubular toxicity. The compounds were administered orally or intravenously once daily to male Sprague-Dawley rats. The animals were exposed to four different doses of the compounds, and kidney tissues were collected on days 4, 8, 15, and 29. Gene expression profiles were generated from kidney RNA by using Affymetrix GeneChips and analyzed in conjunction with the histopathological changes. We used the filter-type gene selection algorithm based on t-statistics conjugated with the SVM classifier, and achieved a sensitivity of 90% with a selectivity of 90%. Then, 92 genes were extracted as the genomic biomarker candidates that were used to construct the classifier. The gene list contains well-known biomarkers, such as Kidney injury molecule 1, Ceruloplasmin, Clusterin, Tissue inhibitor of metallopeptidase 1, and also novel biomarker candidates. Most of the genes involved in tissue remodeling, the immune/inflammatory response, cell adhesion/proliferation/migration, and metabolism were predominantly up-regulated. Down-regulated genes participated in cell adhesion/proliferation/migration, membrane transport, and signal transduction. Our classifier has better prediction accuracy than any of the well-known biomarkers. Therefore, the toxicogenomics approach would be useful for concurrent diagnosis of renal tubular injury.

  4. Toward predicting drug-induced liver injury: parallel computational approaches to identify multidrug resistance protein 4 and bile salt export pump inhibitors.

    Science.gov (United States)

    Welch, Matthew A; Köck, Kathleen; Urban, Thomas J; Brouwer, Kim L R; Swaan, Peter W

    2015-05-01

    Drug-induced liver injury (DILI) is an important cause of drug toxicity. Inhibition of multidrug resistance protein 4 (MRP4), in addition to bile salt export pump (BSEP), might be a risk factor for the development of cholestatic DILI. Recently, we demonstrated that inhibition of MRP4, in addition to BSEP, may be a risk factor for the development of cholestatic DILI. Here, we aimed to develop computational models to delineate molecular features underlying MRP4 and BSEP inhibition. Models were developed using 257 BSEP and 86 MRP4 inhibitors and noninhibitors in the training set. Models were externally validated and used to predict the affinity of compounds toward BSEP and MRP4 in the DrugBank database. Compounds with a score above the median fingerprint threshold were considered to have significant inhibitory effects on MRP4 and BSEP. Common feature pharmacophore models were developed for MRP4 and BSEP with LigandScout software using a training set of nine well characterized MRP4 inhibitors and nine potent BSEP inhibitors. Bayesian models for BSEP and MRP4 inhibition/noninhibition were developed with cross-validated receiver operator curve values greater than 0.8 for the test sets, indicating robust models with acceptable false positive and false negative prediction rates. Both MRP4 and BSEP inhibitor pharmacophore models were characterized by hydrophobic and hydrogen-bond acceptor features, albeit in distinct spatial arrangements. Similar molecular features between MRP4 and BSEP inhibitors may partially explain why various drugs have affinity for both transporters. The Bayesian (BSEP, MRP4) and pharmacophore (MRP4, BSEP) models demonstrated significant classification accuracy and predictability. PMID:25735837

  5. Persistence of autoreactive T cell drive is required to elicit anti-chromatin antibodies in a murine model of drug-induced lupus.

    Science.gov (United States)

    Kretz-Rommel, A; Rubin, R L

    1999-01-15

    Long-term treatment with procainamide and numerous other medications is occasionally associated with the development of drug-induced lupus. We recently established a murine model for this syndrome by disrupting central T cell tolerance. Two intrathymic injections of procainamide-hydroxylamine (PAHA), a reactive metabolite of procainamide, into (C57BL/6 x DBA/2)F1 mice resulted in the appearance of chromatin-reactive T cells and anti-chromatin autoantibodies. The current study explores in this model the role of autoreactive T cells in autoantibody production and examines why autoantibodies after a single intrathymic drug injection were much more limited in isotype and specificity. Injection of as few as 5000 chromatin-reactive T cells into naive, syngeneic mice induced a rapid IgM anti-denatured DNA response, while injection of at least 100-fold greater number of activated T cells was required for induction of IgG anti-chromatin Abs, suggesting that small numbers of autoreactive T cells can be homeostatically controlled. Mice subjected to a single intrathymic PAHA injection after receiving splenic B cells from an intrathymic PAHA-injected syngeneic donor also developed anti-chromatin Abs, but adoptive transfer of similarly primed T cells or of B cells without intrathymic PAHA injection of the recipient failed to produce an anti-chromatin response. However, anti-chromatin Abs developed after a single intrathymic PAHA injection in Fas-deficient C57BL/6-lpr/lpr mice, suggesting that activation-induced cell death limited autoimmunity in normal mice. Taken together, these results imply that chromatin-reactive T cells produced by intrathymic PAHA created a B cell population primed to somatically mutate and Ig class switch when subjected to a heavy load or second wave of autoreactive T cells.

  6. 药源性高血压的发病机制、致病药物及其防治%Drug-induced hypertension: mechanism, causative durgs, prevention, and management

    Institute of Scientific and Technical Information of China (English)

    刘琛; 王育琴

    2012-01-01

    Drug-induced hypertension is one of the common adverse drug reactions. The mechanism of drug-induced hypertension may involve stimulation of sympathetic nervous system activity, sodium and water retention, renin-angiotensin-aldosterone system activation, and changes in function and structure of arterial elasticity. Clinical presentations are increased blood pressure, rebound phenomenon, and even hypertensive crisis. The risk factors for drug-induced hypertension are advanced age, sex, genetic causes, previous history of hypertension, overweight, susceptibity to sodium, and underlying diseases. The drugs known to cause hypertension should be avoided in high-risk patients; if drug treatment is necessary, the treatment should start with a minimum dosage and blood pressure should be monitored during treatment. Once drug-induced hypertension occurs, the drug should be discontinued immediately or the dosage should be reduced, and symptomatic treatment should be given.%药源性高血压为常见药物不良反应之一,其发病机制包括交感神经活动亢进,肾性水钠潴留,肾素-血管紧张素-醛固酮系统激活,以及动脉弹性功能和结构改变.临床表现为血压升高、反跳现象,甚至出现高血压危象.高危因素包括高龄、性别、遗传原因、既往高血压病史、超重、钠敏感、基础疾病.高危人群应避免使用可致血压升高的药物;必须使用时,应从最小剂量开始并应监测血压水平.一旦出现高血压应立即停药或减少剂量,并予对症治疗.

  7. Drug-induced liver injury caused by anti-tuberculosis drugs%抗结核药所致药物性肝损害

    Institute of Scientific and Technical Information of China (English)

    李锋; 卢水华

    2014-01-01

    Incidence of antituberculosis drug-induced liver injury (DILI) is different according to reports of various areas, and different anti-TB drugs have different chances to cause liver injury. Pyrazinamide and rifampicin are the most common drugs resulted in DILI in our country. The related risk factors of DILI includes gender, age, lifestyle, genetic factors and complications. The main mechanism of anti-TB DILI includes liver toxicity and allergic liver damage. The patients with DILI require closely observation and have enough rest. The anti-TB regiment should stop if necessary, and protective therapy should be given. Most patients with DILI could recover gradually after proper medication. After liver functional improvement, the anti-TB regiment should be chosen carefully according to the patient's case history. Prophylactic treatment for hepatic injury is currently not conclusive. Therefore, the patients’ liver function should be paid attention to during the overall anti-TB process, and the factors that could cause hepatic damage other than anti-TB drugs should be avoided comprehensively.%不同国家、地区报道的抗结核药物性肝损伤(DILI)发生率不同,不同抗结核药物引起DILI的概率也不相同。在我国吡嗪酰胺与利福平是最常见的导致DILI的药物。DILI的相关危险因素包括:性别和年龄、生活方式、遗传因素、并发症等。抗结核药物发生DILI的主要机制包括中毒性肝损害和变态反应性肝损害。发生DILI后需密切观察,可给予停药,充分的休息,积极保肝治疗,大部分患者可逐渐恢复。应当根据患者的具体情况酌情选择抗结核方案。预防性保肝治疗目前正在研究中。抗结核过程中应当关注导致患者的肝功能指标,避免导致肝损伤的其他因素,更全面地保护肝脏。

  8. Focus on drug-induced liver injury%药物性肝损伤的临床热点问题探讨

    Institute of Scientific and Technical Information of China (English)

    董旭旸; 周新民

    2015-01-01

    随着处方药及中草药的应用增多,药物性肝损伤越来越受到重视。中草药和抗结核药物是目前我国药物性肝损伤的主要原因。药物诱导的自身免疫性肝炎与免疫介导的药物性肝损伤较难鉴别。肝脏组织学特征及对激素治疗的反应有助于其鉴别诊断。糖皮质激素对于胆汁淤积表现明显、免疫反应强烈的药物性肝损伤具有治疗作用,应注意早期应用,把握好适应证。人工肝支持系统对重症药物性肝损伤具有较好的疗效,根据具体临床病例,可采用多种模式联合,进行个体化治疗。%With a widely using of prescription medication and herbal supplement,it has been increasingly pay attention to drug-induced liver injury (DILI).Herbal remedies and tuberculostatics are the most common causes of DILI in China.To differentiate between true autoimmune hepatitis triggered by drugs (DI-AIH)and immune mediated DILI still remains a challenge.Histological features and the response to corticosteroid therapy support the diagnosis.Glucocorticoid therapy may be an effective treatment for DILI with obvious cholestasis or strong immune response.Early application should be paid attention to,and indications should be strictly controlled.For severe DILI,the artificial liver support system has been proved to be valuable.Individualized therapy and comprehensive patterns should be advocated according to the specific clinical cases.

  9. Comparative gene and protein expression analyses of a panel of cytokines in acute and chronic drug-induced liver injury in rats

    International Nuclear Information System (INIS)

    Drug-induced liver injury (DILI) is a significant safety issue associated with medication use, and is the major cause of failures in drug development and withdrawal in post marketing. Cytokines are signaling molecules produced and secreted by immune cells and play crucial roles in the progression of DILI. Although there are numerous reports of cytokine changes in several DILI models, a comprehensive analysis of cytokine expression changes in rat liver injury induced by various compounds has, to the best of our knowledge, not been performed. In the past several years, we have built a public, free, large-scale toxicogenomics database, called Open TG-GATEs, containing microarray data and toxicity data of the liver of rats treated with various hepatotoxic compounds. In this study, we measured the protein expression levels of a panel of 24 cytokines in frozen liver of rats treated with a total of 20 compounds, obtained in the original study that formed the basis of the Open TG-GATEs database and analyzed protein expression profiles combined with mRNA expression profiles to investigate the correlation between mRNA and protein expression levels. As a result, we demonstrated significant correlations between mRNA and protein expression changes for interleukin (IL)-1β, IL-1α, monocyte chemo-attractant protein (MCP)-1/CC-chemokine ligand (Ccl)2, vascular endothelial growth factor A (VEGF-A), and regulated upon activation normal T cell expressed and secreted (RANTES)/Ccl5 in several different types of DILI. We also demonstrated that IL-1β protein and MCP-1/Ccl2 mRNA were commonly up-regulated in the liver of rats treated with different classes of hepatotoxicants and exhibited the highest accuracy in the detection of hepatotoxicity. The results also demonstrate that hepatic mRNA changes do not always correlate with protein changes of cytokines in the liver. This is the first study to provide a comprehensive analysis of mRNA–protein correlations of factors involved in

  10. Sex bias in experimental immune-mediated, drug-induced liver injury in BALB/c mice: suggested roles for Tregs, estrogen, and IL-6.

    Directory of Open Access Journals (Sweden)

    Joonhee Cho

    Full Text Available BACKGROUND AND AIMS: Immune-mediated, drug-induced liver injury (DILI triggered by drug haptens is more prevalent in women than in men. However, mechanisms responsible for this sex bias are not clear. Immune regulation by CD4+CD25+FoxP3+ regulatory T-cells (Tregs and 17β-estradiol is crucial in the pathogenesis of sex bias in cancer and autoimmunity. Therefore, we investigated their role in a mouse model of immune-mediated DILI. METHODS: To model DILI, we immunized BALB/c, BALB/cBy, IL-6-deficient, and castrated BALB/c mice with trifluoroacetyl chloride-haptenated liver proteins. We then measured degree of hepatitis, cytokines, antibodies, and Treg and splenocyte function. RESULTS: BALB/c females developed more severe hepatitis (p<0.01 and produced more pro-inflammatory hepatic cytokines and antibodies (p<0.05 than did males. Castrated males developed more severe hepatitis than did intact males (p<0.001 and females (p<0.05. Splenocytes cultured from female mice exhibited fewer Tregs (p<0.01 and higher IL-1β (p<0.01 and IL-6 (p<0.05 than did those from males. However, Treg function did not differ by sex, as evidenced by absence of sex bias in programmed death receptor-1 and responses to IL-6, anti-IL-10, anti-CD3, and anti-CD28. Diminished hepatitis in IL-6-deficient, anti-IL-6 receptor α-treated, ovariectomized, or male mice; undetectable IL-6 levels in splenocyte supernatants from ovariectomized and male mice; elevated splenic IL-6 and serum estrogen levels in castrated male mice, and IL-6 induction by 17β-estradiol in splenocytes from naïve female mice (p<0.05 suggested that 17β-estradiol may enhance sex bias through IL-6 induction, which subsequently discourages Treg survival. Treg transfer from naïve female mice to those with DILI reduced hepatitis severity and hepatic IL-6. CONCLUSIONS: 17β-estradiol and IL-6 may act synergistically to promote sex bias in experimental DILI by reducing Tregs. Modulating Treg numbers may provide a

  11. 药物性肝病248例临床分析%Clinical analysis of 248 cases of drug induced liver diseases

    Institute of Scientific and Technical Information of China (English)

    杨立新

    2012-01-01

    Objective To explore the etiology, clinical features and prognosis of drug-induced liver disease (DILD). Methods A retrospective analysis was taken of DILD in hospitalized for medication history, clinical manifestations. Results The causes of DILD were mainly antibiotics (12. 1% ), medicine (23.0% ), anti-TB drugs (8.0% ), anti-cancer drugs (7. 2%), immunosuppressive agents (14..5%). The clinical manifestations were mainly anorexia (62.5%), fatigue (55. 1%), nausea (51.3%), jaundice (37.2%), abdominal pain (18.3%), pruritus (12.9% ), rash (4.6% ). Conclusion Clinicians should pay attention to and strengthen the DILD prevention, diagnosis and treatment.%目的 分析药物性肝病( DILD)的病因、临床特点及预后,提高临床医生对DILD的诊疗水平.方法 采用回顾性分析的方法对248例DILD住院患者的用药史、临床表现以及预后等进行研究.结果 引起DILD的药物以抗生素类药物(12.1%)、中药(23.0%)、抗结核药物(8.0%)、抗肿瘤药物(7.2%)、免疫抑制剂(14.5%)为常见.临床表现以纳差(62.5%)、乏力(55.1%)、恶心(51.3%)、黄疸(37.2%)、腹痛(18.3%)、瘙痒(12.9%)、皮疹(4.6%)等多见;肝性脑病、腹水、凝血酶原时间、黄疸等因素与患者死亡相关.结论 临床医生应重视和加强DILD的预防、诊断和治疗.

  12. 茵栀黄颗粒致药物性肝炎2例%Two cases of drug-induced hepatitis caused by Yinzhihuang granules

    Institute of Scientific and Technical Information of China (English)

    蒋杰; 劳国琴; 张谊芳

    2014-01-01

    Case 1:one 46-year-old male patient developed vomiting, lack of power, yellow urine with chill and fever after receiving Yinzhihuang granules for the treatment of abnormal liver function. The highest body temperature was 39.0℃. All the above symptoms alleviated after discontinuation of the drug. Two months later, Yinzhihuang granules were taken again and the symptoms of chill, fever, lack of power and yellow urine reappeared. Laboratory examinations were as follows:TBIL 65.7 µmol·L-1, DBIL 34.8 µmol·L-1, ALT 939.2 IU·L-1, AST 489.9 IU·L-1,γ-GT 785.0 IU·L-1. Drug-induced hepatitis was diagnosed and Yinzhihuang granules were stopped. Treatments of protecting liver function, depressing transaminase and abating jaundice were given to the patient. After 45 days, the patient discharged with normal liver function. Case 2:one 51-year-old female patient was admitted to hospital because of acute hepatitis E. The liver function of the patient recovered after 2-month treatment, and then the patient discharged with Yinzhihuang granules. Ten days later, the patient developed fever, vomiting, abdominal distention and anorexia. Laboratory ifndings were:TBIL 22.8 µmol·L-1, DBIL 16.0 µmol·L-1, ALT 308.0 IU·L-1, AST 309.0 IU·L-1,γ-GT 237.0 IU·L-1, AKP 258.0 IU·L-1. The patient was hospitalized again and the clinical diagnosis was drug-induced hepatitis. Yinzhihuang granules were stopped, and the symptomatic treatments of protecting liver function, depressing transaminase and abating jaundice were given immediately. About 35 days later, hepatic function of the patient recovered to normal.%病例1:患者,男性,46岁,因肝功能异常服用茵栀黄颗粒降酶退黄治疗,后出现呕吐、乏力,小便颜色进行性加深,并伴有畏寒、发热,体温最高达39.0℃。自行停药后体温降至正常,症状缓解。2个月后再次服用茵栀黄颗粒,畏寒、发热、乏力、尿黄症状再次出现。于外院查肝功能示:TBIL 65

  13. 夜尿对飞行人员夜间睡眠时间和白天嗜睡的影响%Influences of nocturia on sleep duration and excessive daytime sleepiness in flying personnel

    Institute of Scientific and Technical Information of China (English)

    王莞尔; 崔丽; 洪泉; 陈同欣; 段莹; 王建昌

    2013-01-01

    目的 探讨夜尿对飞行人员夜间睡眠时间、嗜睡评分以及白天精神状态的影响. 方法 采取整群抽样方法对1397名男性飞行人员进行问卷调查,回收1392份问卷.排除慢性疾病和其他可能导致睡眠时间变化和嗜睡的因素,研究对象510名飞行人员.根据“每夜因排尿必须醒来≥1次”的夜尿标准,对170名夜尿飞行人员(夜尿组)和340名非夜尿飞行人员(非夜尿组)的夜间睡眠时间和爱泼沃斯嗜睡量表(Epworth sleepiness scale,ESS)评分进行分析,并对夜尿与非夜尿组睡眠质量不良、白天困倦、精力不足和焦虑或抑郁的发生率进行比较. 结果 夜尿组夜间睡眠时间较非夜尿组更短(t=2.745,P<0.01);夜尿组ESS评分(6.23±4.62)明显高于非夜尿组(4.01±3.87),差异具有统计学意义(t=5.377,P<0.01).夜尿组睡眠质量不良、白天困倦、精力不足和焦虑或抑郁的发生率(23.53%、37.65%、12.35%和40.00%)均高于非夜尿组(10.88%、20.59%、5.59%和25.59%),差异具有统计学意义(x2=7.175~17.026,P<0.01). 结论 夜尿可导致飞行人员夜间睡眠时间减少,白天嗜睡增加,可能对飞行操作和安全产生一定影响.建议航空卫生部门加强卫生宣教,重视其对飞行操作的影响,积极防治.%Objective To investigate the influences of nocturia on nocturnal sleep duration,sleepiness score and daytime mental status in flying personnel.Methods A cluster sampling survey was performed in 1397 male flying personnel and 1392 questionnaires were received.When excluding the personnel with chronic diseases and other factors that might influence the sleep duration and cause sleepiness,510 flying personnel were analyzed in this research.According to the "awake at night one or more times to viod" standard,subjects were separated into two groups:nocturia group (≥1 voids/night) (n=170) and non-nocturia group (n=340).The differences on nocturnal sleep duration

  14. 53例药源性间质性肺炎的文献分析%Literature Analysis of 53 Reports of Drug-induced Interstitial Pneumonia

    Institute of Scientific and Technical Information of China (English)

    胡美绘; 孙安修

    2014-01-01

    目的:探讨引起间质性肺炎的药品种类及其临床表现特点。方法检索中国医院数字图书馆、中国知网、万方数据库中1994~2013年,关键词为“间质性肺炎”的相关文献,进行归纳总结。结果共检索出相关文献74篇,报道53例药源性间质性肺炎,涉及15种药物,包括吉非替尼(15例)、利妥西单抗(9例)、来氟米特(8例)、胺碘酮(8例)、厄洛替尼(5例)、干扰素(2例)、5-氟尿嘧啶(1例)、粒细胞集落刺激因子(1例)、吉西他滨(1例)、卡莫司汀(1例)、麻疹疫苗(1例)、百草枯(1例)等。53例患者中,2例治疗结果不详;治愈17例(33.33%),好转19例(37.26%),死亡15例(29.41%)。结论各药品引起间质性肺炎发病机制尚不明确,临床表现相似。发病率较高的药物有吉非替尼、利妥西单抗、来氟米特、胺碘酮、厄洛替尼。%Objective To study the drugs leading to interstitial pneumonia and analyze their clinical characteristics. Methods We searched the literatures from 1994 to 2013 by key words of "interstitial pneumonia" in China Digital Library, China National Knowledge Infrastructure, Wanfang Database, and summarized them. Results A total of 74 relevant articles were identified, which reported 53 cases of drug-induced interstitial neumonia, involving 15 kinds of drugs. The drugs included gefitinib(15), rituximab(9), leflunomide(8), amiodarone(8), erlotinib(5), interferon(2), 5-fluorouracil(1), granulocyte colony-stimulating factor(1), gemcitabine(1), carmustine (1), measles vaccine (1), paraquat(1), et al.The result showed that 53 cases contained 17 cases(33.33%) cured, 19 cases(37.26%) improved , 15 cases(29.41%) died and 2 cases unclear. Conclusion The clinical manifestations of interstitial pneumonia induced by drugs were similar, but the pathogenesis was unknown. The drugs leading to higher incidence were gefitinib, rituximab

  15. 药物性狼疮六例临床分析%Clinical analysis of 6 patients with drug-induced lupus

    Institute of Scientific and Technical Information of China (English)

    张楠; 冷晓梅; 田新平; 赵岩; 曾小峰

    2016-01-01

    目的 通过分析药物性狼疮(DIL)的临床特点、诊断与治疗,提高临床医生的认识及诊治水平.方法 回顾性分析2003年1月-2014年9月北京协和医院诊断明确、资料详细的6例DIL患者的临床资料.结果 6例DIL患者中,男性2例,女性4例,年龄17~ 72岁,平均39.3岁,药物诱发时间最短6d,最长3年,平均1.4年,其中使用干扰素后引起DIL者2例,使用重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白后引起DIL者1例,服用丙基硫氧嘧啶后引起DIL者1例,服用青霉胺引起DIL者1例,服用左氧氟沙星引起DIL者l例.6例患者均出现了高滴度的抗核抗体,3例患者抗双链DNA抗体阳性,1例患者抗Sm抗体阳性,1例患者抗核糖核蛋白抗体阳性,l例患者抗核小体抗体阳性,1例患者抗组蛋白抗体阳性,1例患者抗线粒体抗体M2阳性,1例患者抗心磷脂抗体阳性.患者停用诱发DIL药物,规范治疗后病情缓解,预后良好.结论 DIL比系统性红斑狼疮患者临床病情轻,患者及早停用诱发DIL的药物后规范治疗,预后较好.%Objective To improve the understanding of drug-induced lupus (DIL) and the differences from systemic lupus erythematosus (SLE).Methods Clinical manifestation and treatment of patients with definite DIL were retrospectively analyzed.Results Six patients with DIL were enrolled in this study,including 4 females and 2 males.Two patients were diagnosed after receiving interferon,one after soluble tumor necrosis factor receptor fusion protein,one after propylthiouracil,one after penicillamine,and one after levofloxacin.High titer of antinuclear antibody was identified in all six patients,including 3 with positive anti-dsDNA antibody.One patient had positive anti-Sm antibody.One patient had positive anti-RNP antibody.One patient had anti-nucleosome antibody.One patient had anti-histone antibody.One patient had antimitochondrial antibodies-M2,and one patient had anticardiolipin antibodies

  16. Study on the Effect of Anti Tuberculosis Drug Induced Liver Injury on the Length of Stay in Hospital%抗结核药物性肝损伤对住院天数的影响的研究

    Institute of Scientific and Technical Information of China (English)

    张宏; 覃红娟; 汪敏; 冯治宇

    2016-01-01

    Objective To evaluate the anti-tuberculosis drug-induced liver injury (DILI)impact on the the length of hospital stay.Methods According to the diagnostic criteria of drug-induced liver injury,there were 141 tuberculosis(TB)patients with DILI screened as the observation group,anther 143 TB patients without DILI screened as control group.Cinical data was recorded and studyed on the method of retrospective analysis.Results In the observation group,the median of length of hospital stay was 20.While it was 14 in the control group.The difference on the length of hospital stay between two groups was 6.Conclusion Anti-tuberculosis drug-induced liver injury will extend the length of hospital stay,resulting in a negative impact on anti-TB treatment.The DILI treatment time and the length of hospital stay have a positive corelation.%目的:探讨抗结核药物性肝损伤(drug induced liver injury,DILI)对结核病患者的住院天数影响。方法依照药物性肝损伤的诊断标准,筛选出结核药物性肝损伤病例141例作为观察组,同时筛选143例结核病作为对照组。记录两组的临床资料,从而研究抗结核药物性肝损伤对结核病患者住院天数影响。结果观察组住院天数的中位数是20,对照组住院时间的中位数是14,两者相差6。结论抗结核药物性肝损伤会延长患者的住院天数,从而对抗结核治疗产生负面的影响。

  17. Comparative observation of primiparae undergone drug-induced abortion or artificial abortion on subsequent pregnancy%初产妇药物流产与人工流产术后对再妊娠影响的对比观察

    Institute of Scientific and Technical Information of China (English)

    丘东海; 叶娉婷

    2013-01-01

    目的:比较初产妇药物流产后和人工流产术后对再妊娠的影响,为选择合适、安全的流产方式提供临床参考.方法:采用回顾性调查方法对135例有人工流产术史、126例有药物流产史及130例无流产史的初产妇进行比较,观察其妊娠期和分娩期并发症的发生情况以及妊娠结局.结果:妊娠期人流组先兆流产发生率明显高于药流组和无流产组,差异有统计学意义(χ2=14.993,P0.05).分娩期人流组产后出血、胎盘粘连和胎盘残留的发生率明显高于药流组和无流产组,χ2分别为22.146、12.211、9.387,P值均0.05).结论:初产妇药物流产后对再次妊娠影响小于人工流产术后,可考虑作为临床终止早孕的首先选择.%Objective :To observe the efforts of drug-induced aboition or aitifirial aboition for primiparous women on their subsequent pregnancies for cliniral evidence to determine a safe and adequate means for termination of pregnancy. Methods: Retrospective comparative study was performed in 135 primiparae undergone artificial aboition, 126 with drug-induced aboition history and 130 primiparity without aboition to examine outcomes of subsequent pregnancy and complications associated with gestation and delivery. Results : Higher incidence of threatened aboition during the gestation period was found in women undergone artificial aboition as compared with those with drug-induced aboition or without aboition history. The difference was significant ( x2 = 14. 993 , P 0. 05 ). Similarly, Mothers with a history of artificial aboition had significantly higher incidence of postpaitum hemorrhage, placenta! adherence and residual placenta in labor than those experienced drug-induced aboition or no aboition ( x2 - 22. 146, x2 -12.211, x2 - 9. 387 , respectively ,P 0. 05 ). Conclusion-. Ding-induced aboition for prhnigravidas seem to produce less effects on their subsequent pregnancies than artificial intervention, and may be recommended as

  18. Cansancio y somnolencia en conductores de ómnibus interprovinciales: estudio comparativo entre formalidad e informalidad Fatigue and sleepiness in interprovincial road bus drivers: comparative study between formality and informality

    Directory of Open Access Journals (Sweden)

    Gustavo R. Liendo

    2010-06-01

    Full Text Available Objetivos. Comparar los niveles de cansancio, somnolencia y sus repercusiones entre conductores formales e informales de ómnibus interprovinciales. Evaluar las condiciones laborales en ambos grupos de estudio. Materiales y métodos. Se realizó un estudio transversal comparativo con muestreo no probabilístico. Se incluyó 100 empresas de transporte terrestre, de las cuales 17 fueron formales según registros oficiales del Ministerio de Transportes y Comunicaciones (MTC, asimismo, los conductores se catalogaron como formales o informales. La encuesta incluía un cuestionario y la versión peruana validada de la escala de somnolencia de Epworth. Resultados. Participaron 71 conductores formales y 274 informales, todos fueron varones. De 134 conductores que pertenecían a las empresas formales de acuerdo al MTC, sólo 43 (32% pertenecen al grupo formal en base a los criterios propuestos. El 48% (34 de los conductores formales y el 43% (118 de los informales duermen menos de siete horas al día. Admitieron haberse accidentado o "casi accidentado" el 48% (34 de los formales y 135 (49% informales; el horario más frecuente fue entre la 01.00 y 04.00 horas. La madrugada es el período en que ambos grupos sienten más cansancio. El 44% (30 de los conductores formales y el 54% (144 de informales realizan cinco o más turnos nocturnos por semana. Del total de los entrevistados, el 16% (56 presentaron somnolencia. La asociación con accidentes de tránsito fue similar. Conclusiones. Los niveles de cansancio y somnolencia fueron similares entre conductores formales e informales. Aquellas empresas catalogadas como formales, presentan alto porcentaje de informalidad entre sus conductores.Objectives. To compare the levels of fatigue, sleepiness and their consequences between formal and informal drivers of interprovincial buses. To evaluate labor conditions between both study groups. Materials and methods. A comparative cross-sectional study was performed with

  19. NAT2*6A,a haplotype of the N-acetyltransferase 2 gene, is an important biomarker for risk of anti-tuberculosis drug-induced hepatotoxicity in Japanese patients with tuberculosis

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To investigate an association between N-acetyltransferase 2 (NAT2)-haplotypes/diplotypes and adverse effects in apanese pulmonary tuberculosis patients.METHODS: We studied 100 patients with pulmonary TB treated with anti-TB drugs including INH. The frequencies and distributions of single nucleotide polymorphisms, haplotypes, and diplotypes of NAT2 were determined by the PCR-restriction fragment length polymorphism method, and the results were compared between TB patients with and without adverse effect,using multivariate logistic regression analysis.RESULTS: Statistical analysis revealed that the frequency of a variant haplotype, NAT2*6A, was significantly increased in TB patients with hepatotoxicity,compared with those without hepatotoxicity [P = 0.001,odds ratio (OR) = 3.535]. By contrast, the frequency of a wild-type (major) haplotype,"NAT2*4″, was significantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P < 0.001, OR = 0.265).There was no association between NAT2-haplotypes and skin rash or eosinophilia.CONCLUSION: The present study shows that NAT2 is one of the determinants of anti-TB drug-induced hepatotoxicity. Moreover, the haplotypes, NAT2*4 and NAT2*6A, are useful new biomarkers for predicting antiTB drug-induced hepatotoxicity.

  20. miR-140-5p attenuates chemotherapeutic drug-induced cell death by regulating autophagy through inositol 1,4,5-trisphosphate kinase 2 (IP3k2) in human osteosarcoma cells

    Science.gov (United States)

    Wei, Renxiong; Cao, Gang; Deng, Zhouming; Su, Jiajia; Cai, Lin

    2016-01-01

    Acquisition of drug-resistant phenotypes is often associated with chemotherapy in osteosarcoma. A number of studies have demonstrated a critical role for autophagy in osteosarcoma development, therapy and drug resistance. However, the molecular mechanisms underlying the autophagy-mediated chemotherapy resistance of osteosarcoma cells remain largely unknown. In the present study, we determined the autophagy and microRNA-140 (miR-140-5p, miRBase ID: MIMAT0000431) expression induced by chemotherapeutic drugs in osteosarcoma cells. Then we determined the promotory role of miR-140-5p to the chemotherapy-induced autophagy. Our results demonstrated that miR-140-5p expression was highly induced during chemotherapy of osteosarcoma cells, and this was accompanied by up-regulated autophagy. The increased miR-140-5p expression levels up-regulated anticancer drug-induced autophagy in osteosarcoma cells and ameliorated the anticancer drug-induced cell proliferation and viability decrease. Importantly, miR-140-5p regulates this context-specific autophagy through its target, inositol 1,4,5-trisphosphate kinase 2 (IP3k2). Therefore, the results of the present study demonstrated that miR-140-5p mediated drug-resistance in osteosarcoma cells by inducing autophagy. The present study provides evidence of miRNA regulation of autophagy through modulation of IP3 signalling. The present study recognized a novel mechanism of chemoresistance in osteosarcoma cancers. PMID:27582507

  1. 药物性肝损害的多层螺旋CT影像表现%Drug-induced liver injury: spectrum of multi-detector spiral CT findings

    Institute of Scientific and Technical Information of China (English)

    宋文艳; 赵大伟; 陈煜; 刘旭华; 孟欣; 陈枫

    2010-01-01

    目的 探讨药物性肝损伤的MSCT表现.方法 回顾性分析2008年5月至2010年1月间经临床及病理证实的40例药物性肝损伤患者的MSCT影像及临床资料,总结其影像表现特征.结果 药物性肝损伤的MSCT影像表现主要有3种类型.(1)弥漫性肝脏损害2例:平扫肝脏密度均匀性减低,增强扫描肝实质轻度均匀强化.病理表现为肝细胞脂肪变性;混合炎性细胞浸润,点状坏死,毛细胆管淤胆.(2)灶性肝脏损害6例:肝内大片或多发小片状坏死灶5例.平扫肝脏密度不均匀,病变区为低密度改变;增强后病变区强化,特别是静脉期与平扫图像比较呈反转表现.另1例病程20 d的移植肝显示肝内弥漫的结节样再生.CT平扫可见肝内弥漫分布的稍高密度结节灶,增强后动脉期病灶强化,静脉期及延迟期近似于肝实质密度.5例患者病理表现为肝细胞片状及桥接坏死,大量混合炎性细胞浸润;1例重度淤胆,假小叶形成,肝细胞羽毛变性.(3)肝硬化表现2例:平扫肝脏表面呈结节状,肝叶比例失调,肝裂增宽.增强后肝脏强化一致,同时伴有脾大、腹水、侧支循环.病理为纤维组织增生,点状坏死和毛细胆管淤胆.结论 药物性肝损伤的MSCT影像表现具有一定的特征性,对临床诊断具有重要的参考价值.%Objective To demonstrate the spectrum of multi-detector spiral CT (MSCT) findings of drug-induced liver injury (DILI). Methods From May 2008 to January 2010, DILI was identified in 10 cases based on their clinical and pathological results. The spectrum of CT findings was analyzed retrospectively. Results According to the CT features, DILI were divided into three types. ( 1 ) Two cases presented diffuse hepatic injury, which appeared as homogeneous hypo-attenuation in precontrast CT scan and mild enhancement after contrast injection. The histopathological findings of the involved 1ivers include hepatocellular steatosis, neutrophil and

  2. 老年药物性肝损伤139例临床分析%Drug-induced liver injury: clinical analysis of 139 elderly cases

    Institute of Scientific and Technical Information of China (English)

    范振平; 张义敏; 刘毅; 张文瑾; 蔡少平; 高峰; 史雪敏

    2012-01-01

    Objective To retrospectively investigate the clinical characteristics of drug-induced liver injury(DILI) in the elderly patients admitted to Chinese PLA 302nd hospital during 2003-2010. Methods DILI patients were divided into aged group (age > 60 years, n=139) and non-aged group(age < 60 years, n=105). Clinical features and biochemical indexes were compared between the two groups. Results Among 14 species causative agents which can induce DILI, the frequency ranging top five in aged group were Chinese herbal drugs(31.7%), antibiotics(13.7%), analgesics/antipyretics(12.2%), cardiovascular drugs(11.5%) and antitubercular drugs(6.5%), which were significantly different from non-aged group (Chinese herbal drugs: 43.8%, analgesics/antipyretics: 18.1%, antibiotics: 13.3%, antitubercular drugs: 6.7%, hyperthyroidism drugs: 4.8%). There were no statistical differences in incidence of jaundice and liver failure between aged and non-aged groups(77.1% vs 82.0% and 2.9% vs 4.8% ). However, the level of glutamyl transpeptidase and hospitalization time were higher and longer in aged group than in non-aged group. Liver injury types in aged group were cholestetic(45.9%), hepatocelluar(28.6%) and mixed(25.5%) DILD. In non-aged group, the percentage of above types was 39.3%, 34.8% and 25.8% respectively, with no significant difference with aged group. Conclusion Due to highly cholestetic icteric occurrence and sporadic liver failure of DILI in the elderly, it is necessary to prevent drug hepatotoxicity. We recommand to increase vigilance during pre-clinical drug option, especially for Chinese herbs, antibiotics and analgesics/antipyretics. Regular monitoring liver functions during administration is one of the effective preventive measures.%目的 回顾性分析解放军302医院2003年~2010年间老年药物性肝损伤的临床特点.方法 将患者分为老年组(139例)和中青年组(105例),比较二者之间的临床特征和生化学指标.结果 导致

  3. Sleep quality, fatigue and daytime sleepiness in chronic subjective dizziness%慢性主观性头晕患者睡眠质量、疲劳严重度及日间嗜睡情况调查

    Institute of Scientific and Technical Information of China (English)

    陈健华; 黄颜; 刘秀琴; 孙鹤阳; 孟琼

    2011-01-01

    目的 对无前庭功能障碍的慢性头晕既慢性主观性头晕(CSD)患者睡眠质量、疲劳严重度、日间嗜睡以及焦虑抑郁情况进行调查.方法被调查者181例,其中CSD患者103例和对照者78例.所有参加者均完成了匹茨堡睡眠量表(PSQI)、疲劳严重度量表(FSS)、爱泼沃斯嗜睡量表(ESS)、抑郁自评量表(SDS)、焦虑自评量表(SAS)测评.同时进行了汉密尔顿抑郁量表(HAMD)及焦虑量表(HAMA)测定.采用非参数检验及x2检验进行统计分析.运用Spearman相关分析和逻辑回归法对CSD与PSQI、ESS、FSS以及焦虑抑郁之间的关系进行研究.结果CSD患者睡眠障碍、疲劳、日间过度嗜睡的患病率分别为90.3% (93/103)、70.9% (73/103)和46.6% (48/103).46.6%~48.5%的CSD患者存在焦虑,51.5%~55.3%存在抑郁.CSD患者与对照组相比,睡眠质量、疲劳严重度、日间嗜睡及焦虑抑郁发生率明显高于对照组(均P <0.05或<0.01).逻辑回归分析显示焦虑抑郁(P<0.01,OR=35.732,95% CI =7.690~166.023)、睡眠质量(P<0.01,OR=7.053,95% CI =2.675~18.595)和疲劳严重度(P<0.05,OR =2.910,95% CI =1.186~7.140)与CSD之间有显著相关性.结论 焦虑抑郁、睡眠质量差、疲劳与CSD相关.CSD患者睡眠质量下降,疲劳严重,存在日间过度嗜睡,焦虑抑郁情况突出.%Objective Chronic dizziness without identifiable vestibular impairments is described as chronic subjective dizziness(CSD). The objective of this study was to evaluate sleep quality, fatigue, daytime sleepiness and psychiatric comorbidity in CSD. Methods We investigated 181 subjects including 103 CSD patients and 78 controls. All participants completed the Pittsburgh Sleep Quality Index (PSQI), the Fatigue Severity Scale (FSS). The Epworth Sleepiness Scale (ESS), the Zung Self-rating Depression Scale (SDS). The Zung Self-rating Anxiety Scale(SAS). The Hamilton Depression Rating Scale (HAMD) and the Hamilton

  4. In vitro evaluation of hepatotoxic drugs in human hepatocytes from multiple donors: Identification of P450 activity as a potential risk factor for drug-induced liver injuries.

    Science.gov (United States)

    Utkarsh, Doshi; Loretz, Carol; Li, Albert P

    2016-08-01

    A possible risk factor for drug-induced hepatotoxicity is drug metabolizing enzyme activity, which is known to vary among individuals due to genetic (genetic polymorphism) and environmental factors (environmental pollutants, foods, and medications that are inhibitors or inducers of drug metabolizing enzymes). We hypothesize that hepatic cytochrome P450-dependent monooxygenase (CYP) activity is one of the key risk factors for drug induced liver injuries (DILI) in the human population, especially for drugs that are metabolically activated to cytotoxic/reactive metabolites. Human hepatocytes from 19 donors were evaluated for the activities of 8 major P450 isoforms: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Extensive individual variations were observed, consistent with what is known to be in the human population. As CYP3A4 is known to be one of the most important P450 isoforms for drug metabolism, studies were performed to evaluate the relationship between the in vitro cytotoxicity of hepatotoxic drugs and CYP3A4 activity. In a proof of concept study, hepatocytes from six donors (lots) representing the observed range of CYP3A4 activities were chosen for the evaluation of in vitro hepatotoxicity of four drugs known to be associated with acute liver failure: acetaminophen, cyclophosphamide, ketoconazole, and tamoxifen. The hepatocytes were cultured in collagen-coated plates and treated with the hepatotoxicants for approximately 24 h, followed by viability determination based on cellular adenosine triphosphate (ATP) contents. HH1023, the lot of hepatocytes with the highest CYP3A4 activity, was found to be the most sensitive to the cytotoxicity of all 4 hepatotoxic drugs, thereby suggesting that high CYP3A4 activity may be a risk factor. To further validate the relationship, a second study was performed with hepatocytes from 16 donors. In this study, the hepatocytes were quantified for CYP3A4 activity at the time of treatment. Results of the

  5. 牙周基础治疗对药物性牙龈增生的疗效观察%To Observe the Effect of Initial Periodontal Therapy on Drug-induced Gingival Hyperplasia

    Institute of Scientific and Technical Information of China (English)

    金晓丽

    2015-01-01

    目的:研究探讨牙周基础治疗对药物性牙龈增生的治疗效果。方法随机抽取我院2011年4月-2013年4月收治的因药物治疗引起牙龈增生患者300例为研究对象。给予所有的研究对象牙周基础治疗,观察其临床效果。结果在患者治疗一段时间后显示,患者的牙龈增生指数、牙周探诊深度、菌斑指数以及出血指数具有显著的变化,随着患者治疗时间的持续以及后续口腔卫生的维持,其治疗效果显著优于牙周基础治疗之前,数据符合统计学差异(P<0.05)。结论针对药物性牙龈增生的患者,基于牙周基础治疗能够改善患者临床症状,为药物性牙龈增生提供新的治疗方案,值得在临床上推广使用。%Objective To study the effects of periodontal therapy on drug-induced gingival hyperplasia therapeutic effect.Methods Randomly selected in our hospital in 2011 April~2013 year in April were caused due to drug treatment in patients with gingival hyperplasia 300 cases as the research object. Given al of the research on ivory periodontal treatment, and to observe its clinical effect. Results The display in the treatment for a period of time after the index, gingival hyperplasia patients, patients with periodontal probing depth, plaque index and bleeding index has significant changes, with the duration of folow-up treatment of patients, oral hygiene maintenance, before its therapeutic effect is significantly better than that of periodontal basic treatment, data in accordance with statistical difference (P<0.05).Conclusion For patients with drug-induced gingival hyperplasia, periodontal therapy can improve the clinical symptoms of patients based on, provide new treatment for drug-induced gingival hyperplasia, worthy of promotion in clinical use.

  6. To Observe the Effect of Initial Periodontal Therapy on Drug-induced Gingival Hyperplasia%牙周基础治疗对药物性牙龈增生的疗效观察

    Institute of Scientific and Technical Information of China (English)

    金晓丽

    2015-01-01

    Objective To study the effects of periodontal therapy on drug-induced gingival hyperplasia therapeutic effect.Methods Randomly selected in our hospital in 2011 April~2013 year in April were caused due to drug treatment in patients with gingival hyperplasia 300 cases as the research object. Given al of the research on ivory periodontal treatment, and to observe its clinical effect. Results The display in the treatment for a period of time after the index, gingival hyperplasia patients, patients with periodontal probing depth, plaque index and bleeding index has significant changes, with the duration of folow-up treatment of patients, oral hygiene maintenance, before its therapeutic effect is significantly better than that of periodontal basic treatment, data in accordance with statistical difference (P<0.05).Conclusion For patients with drug-induced gingival hyperplasia, periodontal therapy can improve the clinical symptoms of patients based on, provide new treatment for drug-induced gingival hyperplasia, worthy of promotion in clinical use.%目的:研究探讨牙周基础治疗对药物性牙龈增生的治疗效果。方法随机抽取我院2011年4月-2013年4月收治的因药物治疗引起牙龈增生患者300例为研究对象。给予所有的研究对象牙周基础治疗,观察其临床效果。结果在患者治疗一段时间后显示,患者的牙龈增生指数、牙周探诊深度、菌斑指数以及出血指数具有显著的变化,随着患者治疗时间的持续以及后续口腔卫生的维持,其治疗效果显著优于牙周基础治疗之前,数据符合统计学差异(P<0.05)。结论针对药物性牙龈增生的患者,基于牙周基础治疗能够改善患者临床症状,为药物性牙龈增生提供新的治疗方案,值得在临床上推广使用。

  7. In vitro evaluation of hepatotoxic drugs in human hepatocytes from multiple donors: Identification of P450 activity as a potential risk factor for drug-induced liver injuries.

    Science.gov (United States)

    Utkarsh, Doshi; Loretz, Carol; Li, Albert P

    2016-08-01

    A possible risk factor for drug-induced hepatotoxicity is drug metabolizing enzyme activity, which is known to vary among individuals due to genetic (genetic polymorphism) and environmental factors (environmental pollutants, foods, and medications that are inhibitors or inducers of drug metabolizing enzymes). We hypothesize that hepatic cytochrome P450-dependent monooxygenase (CYP) activity is one of the key risk factors for drug induced liver injuries (DILI) in the human population, especially for drugs that are metabolically activated to cytotoxic/reactive metabolites. Human hepatocytes from 19 donors were evaluated for the activities of 8 major P450 isoforms: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Extensive individual variations were observed, consistent with what is known to be in the human population. As CYP3A4 is known to be one of the most important P450 isoforms for drug metabolism, studies were performed to evaluate the relationship between the in vitro cytotoxicity of hepatotoxic drugs and CYP3A4 activity. In a proof of concept study, hepatocytes from six donors (lots) representing the observed range of CYP3A4 activities were chosen for the evaluation of in vitro hepatotoxicity of four drugs known to be associated with acute liver failure: acetaminophen, cyclophosphamide, ketoconazole, and tamoxifen. The hepatocytes were cultured in collagen-coated plates and treated with the hepatotoxicants for approximately 24 h, followed by viability determination based on cellular adenosine triphosphate (ATP) contents. HH1023, the lot of hepatocytes with the highest CYP3A4 activity, was found to be the most sensitive to the cytotoxicity of all 4 hepatotoxic drugs, thereby suggesting that high CYP3A4 activity may be a risk factor. To further validate the relationship, a second study was performed with hepatocytes from 16 donors. In this study, the hepatocytes were quantified for CYP3A4 activity at the time of treatment. Results of the

  8. Sonolência excessiva diurna na população geral de um município brasileiro Excessive daytime sleepiness in the general population of Brazilian city

    Directory of Open Access Journals (Sweden)

    José Carlos Souza

    2008-01-01

    Full Text Available OBJETIVO: Buscou-se avaliar a prevalência da sonolência excessiva diurna (SED na população geral de um município brasileiro. MÉTODO: Foram feitas 198 entrevistas domiciliares entre os adultos, em amostra representativa da população geral de Ribeirão do Largo, BA. A amostragem foi aleatória simples. Tinham SED as pessoas com 11 ou mais pontos na Escala de Sonolência de Epworth (ESE. Usaram-se os testes de qui-quadrado, Fisher e ANOVA; nível de significância 5%. RESULTADOS: Tinham SED 21,5% da população (DP = 2,9%; IC 15,8% a 27,2%; não houve associação significativa entre SED e idade (p = 0,924, nem IMC (p = 0,197, sexo (p = 0,095, instrução (p = 0,700, estado civil (p = 0,414 e uso de hipnóticos (p = 0,176. Houve associação com o despertar precoce (p = 0,046. CONCLUSÃO: Foi alta a prevalência de SED na população estudada.OBJECTIVE: To assess the prevalence of excessive daytime sleepiness (ESD in general population of a Brazilian city. METHODS: It was determined by means of 198 home interviews of adults, in a representative sample of Ribeirão do Largo city, Brazil. The random sample was simple. ESD was considered in those with index 11 or more in the Epworth Sleepiness Scale (ESS. Statistics used chi-square, Fisher and ANOVA; the significance level was 5%. RESULTS: The prevalence of ESD was 21.5% of population (SD = 2.9%; CI 15.8%-27.2%. No significant association was found between ESD and age (p=0.924, nor with body mass index (p=0.197, sex (p=0.095, schooling (p=0,700, marital status (p=0.414 and the use of hypnotics (p=0.176. There was significant association with early awakening (p=0.046. CONCLUSION: There was a high prevalence of ESD in the population.

  9. Reactivation of Human Herpes Virus-6 in the Renal Tissue of a Patient with Drug-induced Hypersensitivity Syndrome/Drug Rash with Eosinophilia and Systemic Symptoms (DIHS/DRESS).

    Science.gov (United States)

    Hagiya, Hideharu; Iwamuro, Masaya; Tanaka, Takehiro; Hasegawa, Kou; Hanayama, Yoshihisa; Kimura, Maya; Otsuka, Fumio

    2016-01-01

    A 74-year-old man who had been administered trimethoprim-sulfamethoxazole for three weeks suffered from drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms (DIHS/DRESS). In the early stage of the clinical course, he developed renal dysfunction. A renal biopsy showed granulomatous tubulointerstitial nephritis accompanying the proliferation of human herpes virus (HHV)-6 in tubular epithelial cells. With corticosteroid therapy, the systemic rash and renal function gradually improved. The present patient is the second case of DIHS/DRESS demonstrating a possible reactivation of HHV-6 in the renal tissue. The clinical role of viral reactivation in DIHS/DRESS must be further elucidated. PMID:27374681

  10. The Ratio KL-6 to SLX in Serum for Prediction of the Occurrence of Drug-Induced Interstitial Lung Disease in Lung Cancer Patients with Idiopathic Interstitial Pneumonias Receiving Chemotherapy.

    Science.gov (United States)

    Kashiwabara, Kosuke; Semba, Hiroshi; Fujii, Shinji; Tsumura, Shinsuke; Aoki, Ryota

    2015-01-01

    We retrospectively evaluated whether the ratio KL-6 to SLX in serum (K/S ratio) before chemotherapy was a predictor for the occurrence of drug-induced interstitial lung disease (D-ILD) in lung cancer patients with idiopathic interstitial pneumonias (IIPs). D-ILD occurred in 8 of 20 IIPs-positive cases and in 14 of 100 IIPs-negative cases (40 vs. 14%, p = .015). In IIPs-positive cases, the high K/S ratio (>20) before first-line chemotherapy had a tendency to increase the risk of D-ILD (p = .085). Serum K/S ratio may be a useful predictor for the occurrence of D-ILD in lung cancer patients with IIPs. PMID:26305851

  11. Research progress in pathogenesis,prevention and treatment of drug-induced dry eye disorders%药源性干眼症发生发展机制及防治研究进展

    Institute of Scientific and Technical Information of China (English)

    白芳; 陶海; 王朋

    2016-01-01

    药源性干眼症可致眼表潜在损伤,主要临床表现为眼部干涩、烧灼感、异物感、眼痒、眼红、畏光、视物模糊等,影响患者生活质量。引起药源性干眼症的药物包括全身使用的抗胆碱能药物如抗精神病药、抗组胺和减充血剂、激素、化疗药、抗病毒药、抗疟疾药、抗风湿药、螯合剂、神经毒素;眼周及眼局部使用的含或不含防腐剂的滴眼液及肉毒素等。药源性干眼症的发病机制与上述药物导致腺体分泌减少、影响水液层和黏蛋白层分泌、干扰泪膜脂质层使脂质分泌量减少、泪膜不稳定,诱发炎性反应损伤结膜杯状细胞、眼睑腺体、结膜及角膜,以及降低角膜感觉程度、减少传入神经冲动使泪液生成减少等有关。应避免不必要的全身或局部多重用药,确诊药源性干眼症后应停用有关药物或换用致干眼症不良反应程度较低的药物。%Drug-induced dry eye disorders may cause potential damage to the ocular surface which can seriously decrease the quality of life of patients. The main clinical manifestations include eye dryness, burning-like feeling,foreign body sensation,itching,redness,photophobia,and blurred vision. The common drugs causing drug-induced dry eye disorders include systemic anticholinergic drugs such as psychotropic drugs,antihistamines and decongestant,steroids,chemotherapeutic drugs,antiviral drug,anti-malarial,antirheumatic agents,chelating agent,and neurotoxin. The drug for local application around the eye include eye drops and botox with or without preservative. The main mechanisms of drug-induced dry eye disorders may involve decrease of glandular secretion,affecting the aqueous layer and mucin layer;disturbing the stabilization of tear lipid layer and decreasing the lipid secretory volume;inducing the inflammatory reaction which damages the conjunctival goblet cells,eyelid glands,conjunctiva and cornea;reducing the

  12. Curative effect analysis of senile drug-induced diabetes with hypoglycemic coma%老年性药源性糖尿病低血糖昏迷的临床疗效分析

    Institute of Scientific and Technical Information of China (English)

    姜涛

    2015-01-01

    目的:探讨老年性药源性糖尿病低血糖昏迷的临床诊治方法及安全性,意在提高老年性药源性糖尿病低血糖昏迷患者的临床疗效。方法:2012年8月-2014年8月收治老年性药源性糖尿病低血糖昏迷患者80例,回顾性分析临床资料。结果:经过治疗后,60例患者治疗20 min~2 h后意识清醒。20例患者在给予血糖纠正30 min后仍然处于昏迷状态,给予含量20%的甘露醇、脑细胞营养剂以及氢化可的松静脉滴注后,有显著好转。12例患者出现明显反应迟钝及记忆力减退的情况。1例患者自身伴发肾功能不全,经抢救无效后死亡。结论:老年性糖尿病患者非常容易诱发药源性低血糖昏迷等并发症,医护人员应当加强患者的生命体征监测与预防措施,以此降低并发症发生率,提高临床治愈率。%Objective:To explore the clinical diagnosis and treatment methods and security of senile drug-induced diabetes with hypoglycemic coma to improve the clinical curative effect of senile patients with drug-induced diabetes combined hypoglycemic coma.Methods:The clinical data of 80 senile patients with drug-induced diabetes combined low blood sugar coma from August 2012 to August 2014 were analyzed retrospectively.Results:After treatment,60 patients had conscious after the treatment for 20 min~2 h.20 patients were still in coma after correcting blood sugar for 30 min and had improved significantly after intravenous drip of 20% mannitol,brain cells nutrients and hydrocortisone.12 patients had unresponsive and memory loss.1 patient had renal insufficiency and died after invalid rescue.Conclusion:Senile diabetes patients had the complications such as drug-induced hypoglycemia coma easily and the medical personnel should strengthen the monitoring of patient's vital signs and preventive measures in order to reduce the incidence of complications,improving the clinical cure rate.

  13. 广东省乡镇青少年学生白日过度思睡状况及相关因素%Prevalence and risk factors of Excessive Daytime Sleepiness in middle school Adolescents

    Institute of Scientific and Technical Information of China (English)

    骆春柳; 陈伟菊; 卢婉娴; 廖继武; 黄俏庭; 刘亚平; 潘集阳

    2012-01-01

    Objectives To understand the prevalence and risk factors of excessive daytime sleepiness (EDS) in adolescents living in rural area. Methods A cross-sectional survey with cluster sampling was used to sampling a total of 5003 adolescents aged from 11 to 18 years old from 5 middle schools from Longmen County. These adolescents were assessed by using a series of questionnaires, including Epworth Sleepiness Scale (ESS), Insomnia Severity Index (ISI), Beck Depression Inventory (BDI), and Zung Self-Rating Anxiety Scale (SAS). Results EDS was common in adolescent with a rate of 11.1%(95%CI: 10.2%-12.0%; 12.0% for males and 10.1% for females, P < 0.05). Adolescents with EDS had higher ISI, BDI, and SAS scores than those without EDS (P < 0.01). Logistic regression analysis revealed that there were significant associations of EDS with male (OR = 1.25,95%CI: 1.03-1.52) , habitual napping(OR = 1.35,95%67: 1.11-1.64), smoking (OR = 2.02,95%CI: 1.23-3.33), high study stress(OR = 1.28, 95%CI: 1.07-1.54), low study interest(OR = 1.38, 95%CI: 1.10-1.73), poor health condition(OR = 1.69, 95%CI: 1.22-2.34), insomnia(OR = 3.37, 95%CI: 2.60-4.37), anxiety(OR = 1.95, 95% CI: 1.57-2.42)and depression (OR = 1.65 ,95%CI: 1.30-2.09). Conclusions EDS is a common problem in middle school students living in rural area. Adolescents with EDS have poor mental health and poor sleep quality.%目的 了解广东乡镇地区11 ~ 18岁青少年学生白日过度思睡(Excessive Daytime Sleepiness,EDS)的发生情况及探讨其影响因素.方法 整群抽取广东省龙门县5所中学的5003名学生,采用一般情况调查表、爱泼沃斯嗜睡量表(Epworth Sleepiness Scale,ESS)、失眠严重指数量表(Insomnia Severity Index,ISI)、贝克抑郁量表(Beck Depression Inventory,BDI)和焦虑自评量表(Self-rating Anxiety Scale,SAS)等进行问卷调查.结果 青少年学生EDS(ESS>10)发生率为11.1%(95%CI:10.2% ~ 12.0%),男性高于女性(12.0% vs.10.1%,P<0.05),并且

  14. Case-control study on the influence factors of drug-induced liver injury%药物性肝损害影响因素的病例对照研究

    Institute of Scientific and Technical Information of China (English)

    徐厚明; 施成骏; 魏建香

    2012-01-01

    目的:研究探讨引起药物性肝损害的常见药物及影响因素,为临床预防提供参考.方法:从江苏省药品不良反应中心的报表数据库中选取644例药物性肝损害病例与644例对照病例.应用1∶1匹配病例对照研究方法,对样本病例进行单因素及多因素条件Logistic回归分析,进而探讨药物性肝损害发生的影响因素.结果:经单因素分析共初步筛选12个具有统计学意义的影响因素,对该12个因素进行多因素条件Logistic回归分析,结果显示其中有9个因素易导致药物性肝损害的发生,其OR值(95%CI)分别为合并用药3.089(2.038~4.683),抗结核药37.496(10.873 ~ 129.302),抗真菌药8.197(2.876~23.364),抗病毒药8.687(1.831 ~41.214),抗精神病药2.789(1.081 ~7.194),抗癫痫药5.674(1.116~ 28.844),抗肿瘤药7.103(3.796 ~ 13.292),主要作用于心血管系统的药物2.314(1.237 ~4.330),激素及其有关药物3.954(1.921 ~8.139).结论:临床治疗中应警惕抗结核药物、抗真菌药、抗病毒药、抗精神病药、抗癫痫药、抗肿瘤药、主要作用于心血管系统药物、激素及其相关药物的使用,合并使用药物时要注意药物之间的相互作用,必要时可对患者的肝功能进行监测,避免或减少药物性肝损害的发生.%Objective: To investigate the common drugs and influence factors of the drug-induced liver injury for providing references of clinical prevention. Methods: A total of 644 patients with drug-induced liver injury and 644 control patients were selected from the date base of the Adverse Drug Reaction Monitoring Center of Jiangsu Province. With the application of 1:1 matched case-control study, the single factor analysis and conditional logistic regression analysis to the data were performed to find the influence factors of the occurrence of drug-induced liver injury. Results: Through the single factor analysis, 12 statistically significant influence factors were

  15. Immunoelectron microscopy study of superficial skin nerves in drug-induced acute urticaria Estudo de microscopia imunoeletrônica dos nervos superficiais da pele na urticária aguda induzida por medicamentos

    Directory of Open Access Journals (Sweden)

    Paulo Ricardo Criado

    2012-06-01

    Full Text Available BACKGROUND: Few studies have evaluated the ultrastructure of the superficial skin nerves in urticaria. OBJECTIVE: The objective of this study was to describe findings in superficial skin nerves in cases of drug-induced acute urticaria. METHODS: Seven patients with drug-induced acute urticaria were included in the study. Skin biopsies were obtained from the urticarial lesion and from the apparently normal skin. The 14 fragments collected were processed for immunogold electron microscopy using single stains for antitryptase and anti-FXIIIa antibodies, as well as double immunogold labeling for both. RESULTS: Some sections showed mast cells in the process of degranulation. Following double immunogold staining, 10 nm (FXIIIa and 15 nm (Tryptase gold particles were found together throughout the granules in mast cells, indicating that tryptase and FXIIIa are located inside each one of the granules of these cells. Interestingly, we found strong evidence of the presence of tryptase and factor XIIIa in the superficial skin nerves of these patients, both in cases of urticarial lesions (wheals and in the apparently normal skin. CONCLUSIONS: Tryptase and FXIIIa are present in the superficial nerves of the skin in drug-induced acute urticaria. This is the first report of tryptase and FXIIIa expression in the superficial skin nerves of patients with urticaria. Tryptase may be participating in neural activation in these patients, while FXIIIa may be present in the nerves to guarantee the functional integrity of structures.FUNDAMENTOS: Poucos autores têm estudado a ultraestrutura dos nervos superficiais na urticária. OBJETIVO: Descrever os achados nos nervos cutâneos superficiais em casos de urticária aguda induzida por medicamentos. MÉTODOS: Sete pacientes com urticária aguda induzida por medicamentos foram incluídos no estudo. Foram obtidas biopsias da pele da lesão urticariforme e da pele aparentemente normal. Os 14 fragmentos coletados foram

  16. Drug-induced osteoporosis: mechanisms, causative drug, prevention and treatment%药源性骨质疏松的发病原因、致病药物及防治

    Institute of Scientific and Technical Information of China (English)

    刘琛; 王育琴

    2011-01-01

    Osteoporosis is a skeletal disorder characterized by compromised bone strength that may predispose to an increased risk of fracture, which can seriously decrease the patient's quality of life and healthy status. The common drugs causing osteoporosis are oral anticoagulants, calcineurin inhibitors, potent diuretics, proton pump inhibitors, thiazolidinediones, aromatase inhibitors, protease inhibitors, glucocorticoids, antiepileptic drugs, etc. The main mechanisms may involve promoting bone resorption, inhibition of bone formation and bone mineralization. Drug-induced osteoporosis is diagnosed by a bone mineral density test. The effective measures for preventing and treating drug-induced osteoporosis include rational drug use, regularly monitoring of bone mineral density, shortening the duration of therapy, and patients should be administered calcium, vitamin D supplementation, bisphosphonate, calcitonin, selective estrogen receptor modulator, and so on.%骨质疏松是骨强度受到损害而致骨折风险增加的骨骼疾病,可严重降低患者的生活质量与健康状况.导致药源性骨质疏松的常见药物包括口服抗凝药、钙调磷酸酶抑制剂、强效利尿药、质子泵抑制剂、噻唑烷二酮类降糖药、芳香酶抑制剂、蛋白酶抑制剂、糖皮质激素和抗癫痫药等.致病机制为药物通过促进骨吸收、抑制骨形成、抑制骨矿化影响正常骨代谢.骨密度测定可用于诊断药源性骨质疏松.防治药源性骨质疏松的有效措施包括合理用药,定期监测骨密度,缩短用药疗程,给予患者钙剂、维生素D制剂、双膦酸盐类药物、降钙素、选择性雌激素受体调节剂等药物治疗.

  17. FibroScan对慢性药物性肝损害肝纤维化的诊断价值研究%Diagnostic value of FibroScan for liver fibrosis in patients with chronic drug-induced liver injury

    Institute of Scientific and Technical Information of China (English)

    李梵; 闫涛; 周燕萍; 张健; 邵清; 李忠斌; 李冰; 陈国凤

    2013-01-01

    目的 探讨FibroScan对于慢性药物性肝损害(drug-induced liver injury,DILI)肝纤维化的诊断准确性.方法 选择2009年4月-2011年1月在我院住院的经肝脏穿刺病理诊断的慢性DILI患者49例,进行FibroScan检测得到肝脏硬度测量(liver stiffness measurement,LSM)值.以肝脏活体组织检查病理结果为“金标准”绘制受试者工作特征(receiver operating characteristic,ROC)曲线,计算ROC曲线下面积(area under the receiver operating characteristic curve,AUROC),以评价FibroScan对慢性DILI肝纤维化的诊断价值.结果 LSM值与肝脏病理分期呈正相关,Kendall相关系数为0.607,P<0.001.FibroScan诊断慢性DILI肝纤维化≥S2期、≥S3期、S4期的AUROC分别为0.878、0.944、0.993.结论 FibroScan对诊断慢性DILI肝纤维化程度有较好的准确性.%Objective To investigate the diagnostic accuracy of FibroScan for liver fibrosis in patients with chronic drug-induced liver injury (DILI).Methods Forty-nine inpatients with chronic DILI,who were treated in our hospital and underwent liver biopsy from Apr.2009 to Jan.2011,were enrolled in this study.The values of liver stiffness measurement (LSM) were obtained using FibroScan.With liver biopsy as the gold standard,the receiver operating characteristic (ROC) curves were drawn,and the areas under the receiver operating characteristic curves (AUROC) were calculated to evaluate the diagnostic accuracy of FibroScan for liver fibrosis in patients with chronic DILI.Results Liver stiffness was positively correlated with liver fibrosis stage with a Kendall coefficient of 0.607 (P<0.001).Using FibroScan for the assessment of liver fibrosis in patients with chronic DILI,the AUROCs were 0.878 for the patients with ≥ S2,0.944 for those with ≥ S3 and 0.993 for those with S4.Conclusion FibroScan can assess liver fibrosis in patients with chronic DILI with a high accuracy.

  18. 早期帕金森病患者日间过度思睡的相关因素分析%Analysis of excessive daytime sleepiness of patients with Parkinson disease at early stage

    Institute of Scientific and Technical Information of China (English)

    娄凡; 李明; 任艳

    2012-01-01

    Objective To evaluate the excessive daylime sleepiness ( EDS) and total quality of nocturnal sleep of palienls with Parkinson's disease ( PD) at early slage and analyse their clinical characlerlics and relaled factors. Methods 76 conseculive palienls with idiopalhic PD in our palient-clinic and 70 age and sex matched healthy controls were participated in subjective evaluation. Trough face-to-face inlerview assessmenls were performed by using Pittsburgh Sleep Qualily Index(PQSI)& Epworth sleepiness scale(ESS) , unified Parkinson's disease raling scale Part Ⅲ ( UPDRS- Ⅲ ) , Hamilton Depression Rating Scale ( HAMD ) , and mino-mental state examination( MMSE ) to respectively evaluate the sleep quality,movement function,depression and cognition state. The relationship between EDS and age,sex,duration of disease,MMSE score,UPDRS-Ⅲ ,HAMD score,dopaminergic agonists,daily dose of L dopa, Restless leg syndrome ( RLS) and REM behavior disorder ( RBD) was evaluated by Multi-factor togistic. Results The total ESS score in the patients with PD at early stage (6. 14 ± 1.02) was significantly higher than healthy group(4. 14 ± 1. 13 ) ( P = 0. 003 ) . Multi-factor togistic showed that EDS of patients with PD at early stage was related to dopaminergic agonists, RBD, PQSI score and RLS, but not related to age, sex, duration of disease, MMSE sore, UPDRS Ⅲ , HAMD score or daily dose of L-dopa. Conclusions EDS are more common in patients with PD at early stage, and this may be related to the usage of dopaminergic agonists, the quality of nocturnal sleep, parasomnias and pathological changes of PD itself.%目的 评价早期帕金森病患者(PD)日间过度思睡(EDS)情况,分析其相关影响因素.方法 选取我院PD患者72例及年龄与之相匹配的正常对照组68例,采用爱泼沃斯思睡量表(ESS)、匹兹堡睡眠指数量表(PQSI)对其日间及夜间睡眠情况进行评价.对PD患者采用统一PD评定量表--运动检查(UPDRS-Ⅲ)、汉密尔顿抑

  19. Adding 5-hydroxytryptamine receptor type 3 antagonis