WorldWideScience

Sample records for antiparkinsonian drug-induced sleepiness

  1. Excessive Daytime Sleepiness

    Directory of Open Access Journals (Sweden)

    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

  2. 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...

  3. Thrombocytopenia - drug induced

    Science.gov (United States)

    ... the condition is called drug-induced immune thrombocytopenia. Heparin, a blood thinner, is the most common cause ... bleeding Bleeding when you brush your teeth Easy bruising Pinpoint red spots on the skin ( petechiae )

  4. 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 ...

  5. 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 ...

  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. Drug-induced uveitis

    OpenAIRE

    London, Nikolas JS; Garg, Sunir J; Moorthy, Ramana S; Cunningham, Emmett T

    2013-01-01

    A number of medications have been associated with uveitis. This review highlights both well-established and recently reported systemic, topical, intraocular, and vaccine-associated causes of drug-induced uveitis, and assigns a quantitative score to each medication based upon criteria originally described by Naranjo and associates.

  8. 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....

  9. Drug-induced panniculitides.

    Science.gov (United States)

    Borroni, G; Torti, S; D'Ospina, R M; Pezzini, C

    2014-04-01

    A substantial number of all panniculitides fails to recognize a specific etiology, and that is true also for a relatively frequent type of panniculitis, such as erythema nodosum (EN). Between the recognized causative factors of panniculitides, infectious, physical agents, autoimmune mechanisms and neoplastic disorders are well known. On the contrary, the role of drugs as inducers of panniculitides is marginally considered, and their report limited to anecdotal observations, often without due histopathological support. Since the clinical and histopathological features of drug-induced panniculitides are indistinguishable from those caused by other agents, the causative relationship may be demonstrated by the history of previous drug intake and by clinical improvement after drug discontinuation. We reviewed the currently reported descriptions of drug-induced panniculitis, including a few exemplificative original observations. EN results as the most frequently reported drug-induced panniculitis. Among the causative drugs of EN a variety of medications, with disparate, or even opposite, mechanisms of action are reported, thus limiting the understanding of the pathogenesis. Common causative drugs include oral contraceptives, nonsteroidal anti-inflammatory drugs, antiobiotics and leukotriene-modifying agents. Unfortunately, in several cases, the diagnosis of drug-induced EN is done on clinical findings alone. In those cases, the lack of histopathological support does not allow to define a precise clinicopathological correlation on etiologic grounds. Drug-induced lobular and mixed panniculitides, including eosinophilic panniculitis, are even more rarely described. Reported causative agents are glatiramer acetate, interferon beta and heparin (at sites of injections), and systemic steroids, tyrosine kinase inhibitors and BRAF with subcutaneous fat involvement at distance. In view of the recent introduction of new classes of drugs, attention should be paid to disclose their

  10. Sleepiness in Parkinson's disease.

    OpenAIRE

    Arnulf, Isabelle; Leu-Semenescu, Smaranda

    2009-01-01

    Excessive daytime sleepiness is a disabling and vital problem in patients with PD. It affects around 33% patients and culminates in sleep attacks (without prodroma) in 1 to 4% of the patients. When monitored, short, narcolepsy-like naps with abnormal intrusion of REM sleep during daytime (and hypnagogic hallucinations as wakeful dreams) are observed in 33-41% patients, while other patients display naps with non REM sleep. Although insomnia, sleep apnea and periodic leg movements are common in...

  11. [Drug-induced dyschromatopsias].

    Science.gov (United States)

    Perdriel, G; Manent, P J

    1982-01-01

    Drug-induced dyschromatopsias are defined as functional or objective alterations of color sense following drug treatment. Drug induced chromatopsias are characterized by a perception of white surfaces as colored and occur following modifications of normally transparent structures or alterations of the chorioretina or higher centers. Digitalic intoxication is responsible for incorrect perception of yellow or blue; the retinal origin of the disorder is confirmed by electroretinograms and histologic modifications in the photoreceptor synapses. Santonin in doses exceeding 1 cg is associated with various color misperceptions due to injury to a peripheral neuron or problems of rhodopsin formation. Some sulfas and antibiotics may cause misperception of yellow, and the anticonvulsant drug Tridione may cause an almost complete disappearance of some colors. Chromotopsias of central origin due to direct action on cerebral neurons are rare but may follow use of phenacetine or atropine. Drug induced dyschromatopsias are more common and may be the initial symptoms of various kinds of drug intoxication. Various simple and reliable tests enable the practicing clinician to detect such disorders at an early stage. Synthetic antimalarial drugs derived from chloroquine and used in longterm treatment of rheumatism or during antimalarial prophylaxis, indomethacine, and the phenotiazins may cause dyschromatopsias due to retinal intoxication. Oral contraceptives diminish the chromatic perception in 20% of cases according to 1 author, and often cause deficits of blue-yellow perception. Disulfiram, certain antibiotics such as chloramphenicol, nystatin, isoniazide, and other drugs may cause dyschromatopsias due to alterations in the optical fibers. Ethambutol is the most harmful to color perception; its effects are usually but not always reversible on discontinuation of the drug. Systematic tests of color perception should be administered prior to and during treatment with any drug known to

  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. Examining signs of driver sleepiness, usage of sleepiness countermeasures and the associations with sleepy driving behaviours and individual factors.

    Science.gov (United States)

    Watling, Christopher N; Armstrong, Kerry A; Radun, Igor

    2015-12-01

    The impairing effect from sleepiness is a major contributor to road crashes. The ability of a sleepy driver to perceive their level of sleepiness is an important consideration for road safety as well as the type of sleepiness countermeasure used by drivers as some sleepiness countermeasures are more effective than others. The aims of the current study were to determine the extent that the signs of driver sleepiness were associated with sleepy driving behaviours, as well as determining which individual factors (demographic, work, driving, and sleep-related factors) were associated with using a roadside or in-vehicle sleepiness countermeasure. A sample of 1518 Australian drivers from the Australian State of New South Wales and the neighbouring Australian Capital Territory took part in the study. The participants' experiences with the signs of sleepiness were reasonably extensive. A number of the early signs of sleepiness (e.g., yawning, frequent eye blinks) were related with continuing to drive while sleepy, with the more advanced signs of sleepiness (e.g., difficulty keeping eyes open, dreamlike state of consciousness) associated with having a sleep-related close call. The individual factors associated with using a roadside sleepiness countermeasure included age (being older), education (tertiary level), difficulties getting to sleep, not continuing to drive while sleepy, and having experienced many signs of sleepiness. The results suggest that these participants have a reasonable awareness and experience with the signs of driver sleepiness. Factors related to previous experiences with sleepiness were associated with implementing a roadside countermeasure. Nonetheless, the high proportions of drivers performing sleepy driving behaviours suggest that concerted efforts are needed with road safety campaigns regarding the dangers of driving while sleepy. PMID:26364140

  14. Continuing to drive while sleepy: the influence of sleepiness countermeasures, motivation for driving sleepy, and risk perception.

    Science.gov (United States)

    Watling, Christopher N; Armstrong, Kerry A; Obst, Patricia L; Smith, Simon S

    2014-12-01

    Driver sleepiness is a major contributor to road crashes. The current study sought to examine the association between perceptions of effectiveness of six sleepiness countermeasures and their relationship with self-reports of continuing to drive while sleepy among 309 drivers after controlling for the influence of age, sex, motivation for driving sleepy, and risk perception of sleepy driving. The results demonstrate that the variables of age, sex, motivation, and risk perception were significantly associated with self-reports of continuing to drive while sleepy and only one countermeasure was associated with self-reports of continuing to drive while sleepy. Further, it was found that age differences in self-reports of continuing to drive while sleepy was mediated by participants' motivation and risk perception. These findings highlight modifiable factors that could be focused on with interventions that seek to modify drivers' attitudes and behaviours of driving while sleepy. PMID:25261619

  15. A hidden Markov model to assess drug-induced sleep fragmentation in the telemetered rat

    OpenAIRE

    Diack, C.; Ackaert, O.; Ploeger, B A; van der Graaf, P H; Gurrell, R.; Ivarsson, M.; Fairman, D.

    2011-01-01

    Drug-induced sleep fragmentation can cause sleep disturbances either via their intended pharmacological action or as a side effect. Examples of disturbances include excessive daytime sleepiness, insomnia and nightmares. Developing drugs without these side effects requires insight into the mechanisms leading to sleep disturbance. The characterization of the circadian sleep pattern by EEG following drug exposure has improved our understanding of these mechanisms and their translatability across...

  16. Drug-induced immune thrombocytopenia.

    Science.gov (United States)

    van den Bemt, Patricia M L A; Meyboom, Ronald H B; Egberts, Antoine C G

    2004-01-01

    Thrombocytopenia can have several causes, including the use of certain drugs. The mechanism behind drug-induced thrombocytopenia is either a decrease in platelet production (bone marrow toxicity) or an increased destruction (immune-mediated thrombocytopenia). In addition, pseudothrombocytopenia, an in vitro effect, has to be distinguished from true drug-induced thrombocytopenia. This article reviews literature on drug-induced immune thrombocytopenia, with the exception of thrombo-haemorrhagic disorders such as thrombotic thrombocytopenic purpura and heparin-induced thrombocytopenia and thrombosis. A literature search in PubMed combined with a check of the reference lists of all the retrieved articles resulted in 108 articles relevant to the subject. The drug classes that are most often associated with drug-induced immune thrombocytopenia are cinchona alkaloid derivatives (quinine, quinidine), sulfonamides, NSAIDs, anticonvulsants, disease modifying antirheumatic drugs and diuretics. Several other drugs are occasionally described in case reports of thrombocytopenia; an updated review of these case reports can be found on the internet. A small number of epidemiological studies, differing largely in the methodology used, describe incidences in the magnitude of 10 cases per 1 000 000 inhabitants per year. No clear risk factors could be identified from these studies. The underlying mechanism of drug-induced immune thrombocytopenia is not completely clarified, but at least three different types of antibodies appear to play a role (hapten-dependent antibodies, drug-induced, platelet-reactive auto-antibodies and drug-dependent antibodies). Targets for drug-dependent antibodies are glycoproteins on the cell membrane of the platelets, such as glycoprotein (GP) Ib/IX and GPIIb/IIIa. Diagnosis of drug-induced immune thrombocytopenia may consist of identifying clinical symptoms (bruising, petechiae, bleeding), a careful evaluation of the causal relationship of the suspected

  17. Drug-induced renal disorders.

    Science.gov (United States)

    Ghane Shahrbaf, Fatemeh; Assadi, Farahnak

    2015-01-01

    Drug-induced nephrotoxicity are more common among infants and young children and in certain clinical situations such as underlying renal dysfunction and cardiovascular disease. Drugs can cause acute renal injury, intrarenal obstruction, interstitial nephritis, nephrotic syndrome, and acid-base and fluid electrolytes disorders. Certain drugs can cause alteration in intraglomerular hemodynamics, inflammatory changes in renal tubular cells, leading to acute kidney injury (AKI), tubulointerstitial disease and renal scarring. Drug-induced nephrotoxicity tends to occur more frequently in patients with intravascular volume depletion, diabetes, congestive heart failure, chronic kidney disease, and sepsis. Therefore, early detection of drugs adverse effects is important to prevent progression to end-stage renal disease. Preventive measures requires knowledge of mechanisms of drug-induced nephrotoxicity, understanding patients and drug-related risk factors coupled with therapeutic intervention by correcting risk factors, assessing baseline renal function before initiation of therapy, adjusting the drug dosage and avoiding use of nephrotoxic drug combinations. PMID:26468475

  18. 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

  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 with...

  20. [Drug-induced Cognitive Impairment].

    Science.gov (United States)

    Shinohara, Moeko; Yamada, Masahito

    2016-04-01

    Elderly people are more likely than young people to develop cognitive impairments associated with medication use. One of the reasons for this is that renal and liver functions are often impaired in elderly people. Dementia and delirium (an acute confused state) are known to be associated with drug toxicity. Anticholinergic medications are common causes of both acute and chronic cognitive impairment. Psychoactive drugs, antidepressants and anticonvulsants can cause dementia and delirium. In addition, non-psychoactive drugs such as histamine H2 receptor antagonists, corticosteroids, NSAIDs (nonsteroidal anti-inflammatory agent), and cardiac medications, may cause acute or chronic cognitive impairment. Early diagnosis and withdrawal of the offending agent are essential for the prevention of drug-induced dementia and delirium. PMID:27056860

  1. The sleepy teenager - diagnostic challenges

    Directory of Open Access Journals (Sweden)

    Anne-MarieLandtblom

    2014-08-01

    Full Text Available The sleepy teenager is a diagnostic challenge because the problems may be physiological or pathological, with behavioural, social and pychological expressions. It is of great importance that health staff that encounter young people with sleep disturbance have good knowledge about the diseases that must be excluded. Narcolepsy, periodic hypersomnia like Kleine Levin syndrome, delayed sleep phase syndrome and obstructive sleep apnoea syndrome, depression and substance use as well as fatigue from chronic disease like multiple sclerosis should be investigated. Clinical assessment, neurophysiological and laboratory investigations constitute important support in these investigations. Functional methods, for example fMRI, are being developed. The role of computer gaming and use of social media in the night is discussed in relation to these diseases. Cognitive dysfunction may develop with several of the conditions. There is need for increased awareness of how to investigate sleep disturbance in children and young people.

  2. 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.

  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. Drug-induced weight gain.

    Science.gov (United States)

    Ness-Abramof, Rosane; Apovian, Caroline M

    2005-01-01

    Drug-induced weight gain is a serious side effect of many commonly used drugs leading to noncompliance with therapy and to exacerbation of comorbid conditions related to obesity. Improved glycemic control achieved by insulin, insulin secretagogues or thiazolidinedione therapy is generally accompanied by weight gain. It is a problematic side effect of therapy due to the known deleterious effect of weight gain on glucose control, increased blood pressure and worsening lipid profile. Weight gain may be lessened or prevented by adherence to diet and exercise or combination therapy with metformin. Weight gain is also common in psychotropic therapy. The atypical antipsychotic drugs (clozapine, olanzepine, risperidone and quetiapine) are known to cause marked weight gain. Antidepressants such as amitriptyline, mirtazapine and some serotonin reuptake inhibitors (SSRIs) also may promote appreciable weight gain that cannot be explained solely by improvement in depressive symptoms. The same phenomenon is observed with mood stabilizers such as lithium, valproic acid and carbamazepine. Antiepileptic drugs (AEDs) that promote weight gain include valproate, carbamazepine and gabapentin. Lamotrigine is an AED that is weight-neutral, while topiramate and zonisamide may induce weight loss. PMID:16341287

  5. 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

  6. Sleepiness and alertness in American industries

    International Nuclear Information System (INIS)

    Recent evidence that industrial accidents may be caused in part by shiftworkers' lack of alertness has caused growing concern at the US Nuclear Regulatory Commission and within the scientific community. The purpose of the study reported in this paper was threefold: (1) Is sleepiness on the job specific to utility plants? (2) Are performance and safety problems caused by sleepiness specific to utility plants? (3) Are specific shift schedules associated with a higher prevalence of sleepiness? Findings indicate sleepiness on the job among shiftworkers is a widespread problem, not limited to the nuclear power industry. The most common solution in American industry is to overstaff each shift and discipline sleeping employees. Results show this is not effective. A more proactive solution is recommended including some of the following: (1) Provide employees education to assist adjustment to shiftwork. (2) Design and implement shift schedules that are more compatible with human physiological capabilities. (3) Allow officially sanctioned napping on shift as is done in Japan. (4) Divide 6-, 8-, or 12-h shifts into smaller blocks of 2 to 3 h of primary duty. (5) make the environment where employees work more conductive to alertness. (6) Develop a firehouse type of schedule where some employees sleep throughout the night, but are awakened if operational problems arise. (7) Provide incentives to employees to adjust their life style to the night shift and reward them with time off

  7. Distributed neural actions of anti-parkinsonian therapies as revealed by PET

    International Nuclear Information System (INIS)

    There is a limited understanding of how different anti-parkinsonian treatments act at the neuronal systems level. Using positron emission tomography we examined the effects of levodopa and deep brain stimulation of the subthalamic nucleus on patterns of regional cerebral blood flow in patients with Parkinson's disease during a homogenous cognitive-behavioral state rather than during an unspecified resting state. We found that when medicated precuneus, frontal, parietal, cerebellar and midbrain areas were relatively more activated than when stimulated, whereas when stimulated the precentral gyrus, caudate and thalamus were relatively more activated than when medicated. Areas that were activated by both treatments included the temporal gyri, anterior thalamus, and midbrain. Regions of prefrontal cortex showed relatively greater activation in the 'off treatment' conditions of both the medicated and stimulated groups. Our findings suggest that the two treatment methods may lead to symptomatic relief via both common and different sites of action. (author)

  8. 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

  9. 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.

  10. 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-...

  11. Drug Induced Hypersensitivity and the HLA Complex

    OpenAIRE

    Munir Pirmohamed; Ana Alfirevic

    2010-01-01

    Drug-induced hypersensitivity reactions are of major concern and present a burden for national healthcare systems due to their often severe nature, high rate of hospital admissions and high mortality. They manifest with a wide range of symptoms and signs, and can be initiated by a wide range of structurally diverse chemical compounds. The pathophysiological mechanisms underlying hypersensitivity reactions are not well understood, but it is thought that they are immune mediated. MHC region on ...

  12. 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%.

  13. 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

  14. 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.

  15. 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 ...

  16. Drugs Induced Stevens-Johnson Syndrome

    Directory of Open Access Journals (Sweden)

    Elif ÖNDER

    2010-05-01

    Full Text Available Stevens Johnson Syndrome (SJS is a life threatening mucocutaneous skin disease that mostlydeveloped after using some drug. SJS mostly appear between 2-4th decades. Mucocutaneouslesions were seen between 1-14 days of drug intake. And these lesions spread diffusely all aroundthe body. First treatment choice is the stopping of drug that cause SJS and giving supportingtreatment. After understanding of underlying cytotoxic and immunological mechanism of SJS,new treatment approaches were developed and mortality of disease was reduced. We hereinreport a short review of drug induced SJS and its treatment.

  17. Drug-induced regulation of target expression

    DEFF Research Database (Denmark)

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

    2010-01-01

    -induced differential expression of drug target mRNA was examined in three cell lines using the Connectivity Map. To overcome various biases in this valuable resource, we have developed a computational normalization and scoring procedure that is applicable to gene expression recording upon heterogeneous drug treatments...... 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....

  18. [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

  19. 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.

  20. Biomarkers of drug-induced vascular injury

    International Nuclear Information System (INIS)

    In pre-clinical safety studies, drug-induced vascular injury is an issue of concern because there are no obvious diagnostic markers for pre-clinical or clinical monitoring and there is an intellectual gap in our understanding of the pathogenesis of this lesion. While vasodilatation and increased shear stress appear to play a role, the exact mechanism(s) of injury to the primary targets, smooth muscle and endothelial cells are unknown. However, evaluation of novel markers for potential clinical monitoring with a mechanistic underpinning would add value in risk assessment and management. This mini review focuses on the progress to identify diagnostic markers of drug-induced vascular injury. Von Willebrand factor (vWF), released upon perturbation of endothelial cells, is transiently increased in plasma prior to morphological evidence of damage in dogs or rats treated with vascular toxicants. Therefore, vWF might be a predictive biomarker of vascular injury. However, vWF is not an appropriate biomarker of lesion progression or severity since levels return to baseline values when there is morphological evidence of injury. A potential mechanistically linked biomarker of vascular injury is caveolin-1. Expression of this protein, localized primarily to smooth muscle and endothelial cells, decreases with the onset of vascular damage. Since vascular injury involves multiple mediators and cell types, evaluation of a panel rather than a single biomarker may be more useful in monitoring early and severe progressive vascular injury

  1. 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...

  2. 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

  3. 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

  4. 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

  5. Pharmacodynamics of drug-induced weight gain.

    Science.gov (United States)

    Kulkarni, S. K.; Kaur, Gurpreet

    2001-08-01

    Body weight gain during treatment with drugs for any kind of disease may represent improvement of the disease itself. However, sometimes these drug-induced alterations of the body's appetite-regulating mechanisms result in excessive weight gain, thus jeopardizing compliance with prescribed medication. A number of drugs are capable of changing body weight as an adverse consequence of their therapeutic effect. Included in this category are the psychotropic drugs such as antipsychotics, antidepressants and mood stabilizers. Antipsychotics are well-known culprits of weight gain. The low-potency (e.g., chlorpromazine and thioridazine) and atypical agents (e.g., clozapine, olanzapine, quetiapine and risperidone) are most often associated with weight gain. Antidepressants such as tricyclic antidepressants and monoamine oxidase (MAO) inhibitors are most often associated with significant weight gain. The tertiary tricyclic antidepressant amitriptyline is thought to induce the most weight gain. Mood stabilizers such as lithium carbonate, valproic acid and carbamazepine also induce weight gain in a considerable number of patients. Treatment with corticosteroids is associated with dose-dependent body weight gain in many patients and corticosteroid-induced obesity aggravates other corticosteroid-associated health risks. Insulin therapy in diabetic patients usually increases body weight. Finally, sulfonylurea derivatives, antineoplastic agents used for the treatment of breast cancer and several drugs used in migraine prophylaxis may cause body weight gain as well. (c) 2001 Prous Science. All rights reserved. PMID:12743638

  6. 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...

  7. 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...

  8. Ecological momentary assessment of fatigue, sleepiness, and exhaustion in ESKD

    OpenAIRE

    Abdel-Kader, Khaled; Jhamb, Manisha; Mandich, Lee Anne; Yabes, Jonathan; Keene, Robert M; Beach, Scott; Buysse, Daniel J.; Unruh, Mark L.

    2014-01-01

    Background Many patients on maintenance dialysis experience significant sleepiness and fatigue. However, the influence of the hemodialysis (HD) day and circadian rhythms on patients’ symptoms have not been well characterized. We sought to use ecological momentary assessment to evaluate day-to-day and diurnal variability of fatigue, sleepiness, exhaustion and related symptoms in thrice-weekly maintenance HD patients. Methods Subjects used a modified cellular phone to access an interactive voic...

  9. Pharmacotherapy of Excessive Sleepiness: Focus on Armodafinil

    Directory of Open Access Journals (Sweden)

    Michael Russo

    2009-01-01

    Full Text Available 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-modafinil has a longer half-life and is present at higher circulating concentrations than the S-enantiomer following chronic administration of modafinil and may therefore be the enantiomer predominantly responsible for the beneficial effects of the racemic compound. Armodafinil has been approved by the Food and Drug Administration for the improvement of ES associated with narcolepsy, shift-work disorder, and obstructive sleep apnea following a program of randomized, placebo-controlled clinical trials. This comprehensive medication review discusses the pharmacologic profile of armodafinil and the current evidence regarding its efficacy, safety, and tolerability; appraises patient-reported outcomes data; and suggests additional indications in which armodafinil may be of use.

  10. Drug-induced immune neutropenia/agranulocytosis.

    Science.gov (United States)

    Curtis, Brian R

    2014-01-01

    Neutrophils are the most abundant white blood cell in blood and play a critical role in preventing infections as part of the innate immune system. Reduction in neutrophils below an absolute count of 500 cells/pL is termed severe neutropenia or agranulocytosis. Drug-induced immune neutropenia (DIIN) occurs when drug-dependent antibodies form against neutrophil membrane glycoproteins and cause neutrophil destruction. Affected patients have fever, chills, and infections; severe infections left untreated can result in death. Treatment with granulocyte colony-stimulating factor can hasten neutrophil recovery. Cumulative data show that severe neutropenia or agranulocytosis associated with exposure to nonchemotherapy drugs ranges from approximately 1.6 to 15.4 cases per million population per year. Drugs most often associated with neutropenia or agranulocytosis include dipyrone, diclofenac, ticlopidine, calcium dobesilate, spironolactone, antithyroid drugs (e.g., propylthiouracil), carbamazepine, sulfamethoxazole- trimethoprim, [3-lactam antibiotics, clozapine, levamisole, and vancomycin. Assays used for detection of neutrophil drug-dependent antibodies (DDAbs) include flow cytometry, monoclonal antibody immobilization of granulocyte antigens, enzyme-linked immunosorbent assay, immunoblotting, granulocyte agglutination, and granulocytotoxicity. However, testing for neutrophil DDAbs is rarely performed owing to its complexity and lack of availability. Mechanisms proposed for DIIN have not been rigorously studied, but those that have been studied include drug- or hapten-induced antibody formation and autoantibody production against drug metabolite or protein adducts covalently attached to neutrophil membrane proteins. This review will address acute, severe neutropenia caused by neutrophil-reactive antibodies induced by nonchemotherapy drugs-DIIN PMID:25247619

  11. A hidden Markov model to assess drug-induced sleep fragmentation in the telemetered rat.

    Science.gov (United States)

    Diack, C; Ackaert, O; Ploeger, B A; van der Graaf, P H; Gurrell, R; Ivarsson, M; Fairman, D

    2011-12-01

    Drug-induced sleep fragmentation can cause sleep disturbances either via their intended pharmacological action or as a side effect. Examples of disturbances include excessive daytime sleepiness, insomnia and nightmares. Developing drugs without these side effects requires insight into the mechanisms leading to sleep disturbance. The characterization of the circadian sleep pattern by EEG following drug exposure has improved our understanding of these mechanisms and their translatability across species. The EEG shows frequent transitions between specific sleep states leading to multiple correlated sojourns in these states. We have developed a Markov model to consider the high correlation in the data and quantitatively compared sleep disturbance in telemetered rats induced by methylphenidate, which is known to disturb sleep, and of a new chemical entity (NCE). It was assumed that these drugs could either accelerate or decelerate the transitions between the sleep states. The difference in sleep disturbance of methylphenidate and the NCE were quantitated and different mechanisms of action on rebound sleep were identified. The estimated effect showed that both compounds induce sleep fragmentation with methylphenidate being fivefold more potent compared to the NCE. PMID:21909798

  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. Drug-Induced Hyperglycaemia and Diabetes.

    Science.gov (United States)

    Fathallah, Neila; Slim, Raoudha; Larif, Sofien; Hmouda, Houssem; Ben Salem, Chaker

    2015-12-01

    Drug-induced hyperglycaemia and diabetes is a global issue. It may be a serious problem, as it increases the risk of microvascular and macrovascular complications, infections, metabolic coma and even death. Drugs may induce hyperglycaemia through a variety of mechanisms, including alterations in insulin secretion and sensitivity, direct cytotoxic effects on pancreatic cells and increases in glucose production. Antihypertensive drugs are not equally implicated in increasing serum glucose levels. Glycaemic adverse events occur more frequently with thiazide diuretics and with certain beta-blocking agents than with calcium-channel blockers and inhibitors of the renin-angiotensin system. Lipid-modifying agents may also induce hyperglycaemia, and the diabetogenic effect seems to differ between the different types and daily doses of statins. Nicotinic acid may also alter glycaemic control. Among the anti-infectives, severe life-threatening events have been reported with fluoroquinolones, especially when high doses are used. Protease inhibitors and, to a lesser extent, nucleoside reverse transcriptase inhibitors have been reported to induce alterations in glucose metabolism. Pentamidine-induced hyperglycaemia seems to be related to direct dysfunction in pancreatic cells. Phenytoin and valproic acid may also induce hyperglycaemia. The mechanisms of second-generation antipsychotic-associated hyperglycaemia, diabetes mellitus and ketoacidosis are complex and are mainly due to insulin resistance. Antidepressant agents with high daily doses seem to be more frequently associated with an increased risk of diabetes. Ketoacidosis may occur in patients receiving beta-adrenergic stimulants, and theophylline may also induce hyperglycaemia. Steroid diabetes is more frequently associated with high doses of glucocorticoids. Some chemotherapeutic agents carry a higher risk of hyperglycaemia, and calcineurin inhibitor-induced hyperglycaemia is mainly due to a decrease in insulin secretion

  14. 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

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

    Science.gov (United States)

    Kaufman, Michele B

    2013-06-01

    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. PMID:23946630

  16. 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 ...

  17. 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

  18. 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.

  19. 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...

  20. 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

  1. 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

  2. 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

  3. Stop and revive? The effectiveness of nap and active rest breaks for reducing driver sleepiness.

    Science.gov (United States)

    Watling, Christopher N; Smith, Simon S; Horswill, Mark S

    2014-11-01

    The purpose of this study was to compare the effects of two commonly utilized sleepiness countermeasures: a nap break and an active rest break. The effects of the countermeasures were evaluated by physiological (EEG), subjective, and driving performance measures. Participants completed 2 h of simulated driving, followed by a 15-min nap break or a 15-min active rest break, then completed the final hour of simulated driving. The nap break reduced EEG and subjective sleepiness. The active rest break did not reduce EEG sleepiness, with sleepiness levels eventually increasing, and resulted in an immediate reduction of subjective sleepiness. No difference was found between the two breaks for the driving performance measure. The immediate reduction of subjective sleepiness after the active rest break could leave drivers with erroneous perceptions of their sleepiness, particularly with increases of physiological sleepiness after the break. PMID:24961384

  4. 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

  5. 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.

  6. Phenotype standardization for drug-induced kidney disease.

    Science.gov (United States)

    Mehta, Ravindra L; Awdishu, Linda; Davenport, Andrew; Murray, Patrick T; Macedo, Etienne; Cerda, Jorge; Chakaravarthi, Raj; Holden, Arthur L; Goldstein, Stuart L

    2015-08-01

    Drug-induced kidney disease is a frequent cause of renal dysfunction; however, there are no standards to identify and characterize the spectrum of these disorders. We convened a panel of international, adult and pediatric, nephrologists and pharmacists to develop standardized phenotypes for drug-induced kidney disease as part of the phenotype standardization project initiated by the International Serious Adverse Events Consortium. We propose four phenotypes of drug-induced kidney disease based on clinical presentation: acute kidney injury, glomerular, tubular, and nephrolithiasis, along with the primary and secondary clinical criteria to support the phenotype definition, and a time course based on the KDIGO/AKIN definitions of acute kidney injury, acute kidney disease, and chronic kidney disease. Establishing causality in drug-induced kidney disease is challenging and requires knowledge of the biological plausibility for the specific drug, mechanism of injury, time course, and assessment of competing risk factors. These phenotypes provide a consistent framework for clinicians, investigators, industry, and regulatory agencies to evaluate drug nephrotoxicity across various settings. We believe that this is the first step to recognizing drug-induced kidney disease and developing strategies to prevent and manage this condition. PMID:25853333

  7. 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

  8. 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.

  9. 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.

  10. 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

  11. Anti-TNF-α and hydralazine drug-induced lupus*

    Science.gov (United States)

    Quaresma, Maria Victória; Bernardes Filho, Fred; de Oliveira, Fernanda Brandão; Pockstaller, Mercedes Prates; Dias, Maria Fernanda Reis Gavazzoni; Azulay, David Rubem

    2015-01-01

    Drug-induced lupus is a rare drug reaction featuring the same symptoms as idiopathic lupus erythematosus. Recently, with the introduction of new medicines in clinical practice, an increase in the number of illness-triggering implicated drugs has been reported, with special emphasis on anti-TNF-α drugs. In the up-to-date list, almost one hundred medications have been associated with the occurrence of drug-induced lupus. The authors present two case reports of the illness induced respectively by hydralazine and infliximab, addressing the clinical and laboratorial characteristics, diagnosis, and treatment. PMID:26312694

  12. Anti-TNF-α and hydralazine drug-induced lupus.

    Science.gov (United States)

    Quaresma, Maria Victória; Bernardes Filho, Fred; Oliveira, Fernanda Brandão de; Pockstaller, Mercedes Prates; Dias, Maria Fernanda Reis Gavazzoni; Azulay, David Rubem

    2015-01-01

    Drug-induced lupus is a rare drug reaction featuring the same symptoms as idiopathic lupus erythematosus. Recently, with the introduction of new medicines in clinical practice, an increase in the number of illness-triggering implicated drugs has been reported, with special emphasis on anti-TNF-α drugs. In the up-to-date list, almost one hundred medications have been associated with the occurrence of drug-induced lupus. The authors present two case reports of the illness induced respectively by hydralazine and infliximab, addressing the clinical and laboratorial characteristics, diagnosis, and treatment. PMID:26312694

  13. Inferior phrenic artery pseudoaneurysm complicating drug-induced acute pancreatitis.

    Science.gov (United States)

    Salem, Jean F; Haydar, Ali; Hallal, Ali

    2014-01-01

    Inferior phrenic artery (IPA) pseudoaneurysm is an extremely rare complication of chronic pancreatitis with only three cases reported in the literature so far. It is a serious condition that can be life-threatening if not diagnosed promptly. Recent advances in endovascular interventions made angiography with embolisation the modality of choice for diagnosis and treatment. We presented the first report of a case of ruptured IPA pseudoaneurysm complicating a drug-induced acute pancreatitis that was successfully treated by transcatheter arterial embolisation. Despite its rarity, rupture of pseudoaneurysm due to drug-induced pancreatitis should be suspected and included in the differential diagnosis when associated with haemodynamic instability. PMID:24385392

  14. 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 in...

  15. 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

  16. 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)

  17. 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.

  18. [Narcolepsy in sleepy obese children. Two case reports].

    Science.gov (United States)

    Rives-Lange, C; Karsenty, A; Chantereau, H; Oderda, L; Dubern, B; Lecendreux, M; Tounian, P

    2016-06-01

    Narcolepsy is a disabling disorder, characterized by excessive daytime sleepiness, irresistible sleep attacks, and partial or complete cataplexy. Many cases of obesity and precocious puberty have been reported in narcoleptic children, suggesting that the deficiency of hypocretin in narcolepsy could also be implicated in appetite stimulation. We report the observations of two young girls, who were referred for obesity and who developed narcolepsy accompanied by an abrupt weight gain. In both cases, specific drugs promoted wakefulness and overweight stabilization. Narcolepsy has to be suspected in sleepy obese children and not misdiagnosed as obstructive apnea. A nocturnal polysomnography with multiple sleep latency tests should be performed to confirm the diagnosis and begin specific treatment that is effective for sleep disorders and weight gain. PMID:27133373

  19. 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...

  20. [The effects of self-awakening on daytime sleepiness].

    Science.gov (United States)

    Ikeda, Hiroki; Hayashi, Mitsuo

    2012-04-01

    This study investigated the effects of self-awakening on daytime sleepiness. Eleven undergraduate and graduate students without the habit of self-awakening participated. They were instructed to follow their usual sleep-wake schedule at home during the experimental weeks and were required to awaken at their usual time by themselves every morning for one week without the aid of an alarm (self-awakening condition) or in response to a telephone call from the experimenter every morning for another one week (forced-awakening condition). On the last day of each week, daytime tests were conducted in the laboratory. The participants would arrive at the laboratory 2 h after awakening, and 1 h later, they performed the auditory simple reaction time task, the digit-symbol substitution task, the letter cancellation test, and the multiple sleep latency test, and assessment of sleepiness, fatigue, comfort, and work motivation every 2 h. In the week when the participants underwent the self-awakening condition, self-awakening had a higher success rate (82%) than failure rate (18%) on the seventh day. In comparison with forced-awakening, self-awakening resulted in an improvement in subjective fatigue; however, sleepiness did not deteriorate. PMID:22715533

  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. 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

  3. 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

  4. Student Preferences Regarding Teaching Methods in a Drug-Induced Diseases and Clinical Toxicology Course

    OpenAIRE

    Rivkin, Anastasia; Gim, Suzanna

    2013-01-01

    Objectives. To determine which teaching method in a drug-induced diseases and clinical toxicology course was preferred by students and whether their preference correlated with their learning of drug-induced diseases.

  5. An Update on Drug-induced Liver Injury

    OpenAIRE

    Devarbhavi, Harshad

    2012-01-01

    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 ...

  6. 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...

  7. 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

  8. Prevalence and correlates of insomnia and excessive sleepiness in adults with obstructive sleep apnea symptoms.

    Science.gov (United States)

    Bjorvatn, Bjørn; Pallesen, Ståle; Grønli, Janne; Sivertsen, Børge; Lehmann, Sverre

    2014-04-01

    This study investigated the prevalence and correlates of insomnia and excessive sleepiness in adults presenting symptoms of obstructive sleep apnea (OSA) in the general population. Randomly selected participants (N = 1,502; 50.7% men, 49.3% women), ages 40 to 70 yr. (M = 53.6, SD = 8.5) were interviewed over the telephone. Insomnia and excessive sleepiness (hypersomnia) were assessed with the Bergen Insomnia Scale and the Epworth Sleepiness Scale, respectively. OSA symptoms were identified by self- or spouse reports on snoring, breathing cessations during sleep, and being tired or sleepy. The prevalence of OSA was 6.2%. Among these participants with OSA, 57.6% reported insomnia and 30.1% reported excessive sleepiness. Furthermore, OSA symptoms were associated with self-reported obesity, hypertension, diabetes, and depression, but only in participants with comorbid insomnia or excessive sleepiness. PMID:24897888

  9. Pupillographic Sleepiness Test and Polysomnography in Nondemented Patients with Ischemic White Matter Lesions

    OpenAIRE

    Ralf Landwehr; Robert Liszka

    2015-01-01

    Background. Patients with ischemic white matter lesions (WML) frequently report nonrestorative sleep or daytime sleepiness. However, subjective estimations of sleep and sleepiness can differ considerably from objective measures. The pupillographic sleepiness test (PST) could identify patients with sleep disorders requiring polysomnography (PSG) and further treatment. Methods. We performed a PST and a PSG of 35 nondemented patients with WML, who reported nonrestorative sleep or daytime sleepin...

  10. 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...

  11. 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

  12. 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

  13. 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 fidelity but the weakness that large inter- and intra-individual variability in sleep, combined with the small sample size, limited the power of the study to detect statistically significant differences between sleep at home and at sea. The clear preference for sleep at night during the 12 h on/6 h off schedule at sea is consistent with the expectation that this 18 h duty/rest cycle is outside the range of entrainment of the circadian pacemaker. High levels of acute sleep 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

  14. 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.

  15. Antituberculous drug-induced liver injury: current perspective.

    Science.gov (United States)

    Devarbhavi, Harshad

    2011-01-01

    Drug-induced liver injury (DILI) is a minor but significant cause of liver injury across all regions. Antituberculosis drug-induced liver injury (TB DILI) is a leading cause of DILI and drug-induced acute liver failure (DIALF) in India and much of the developing world. Single center registries of DILI continue to highlight the high incidence of DILI and DIALF, much of it due to diagnostic errors and inappropriate prescriptions. The clinical spectrum includes asymptomatic elevation in liver tests to acute hepatitis and acute liver failure. TB DILI can occur across all age groups including children with significant morbidity and mortality. Although TB DILI develops more commonly in males, ALF is noted to be commoner in females with a worse prognosis. Contrasting reports on the role of genetic and environmental factors continue to be published. Since DILI is a diagnosis of exclusion, acute viral hepatitis particularly hepatitis E needs to be excluded in such cases. The presence of jaundice, hypoalbuminemia, ascites, encephalopathy and high prothrombin time are poor prognostic markers. Recent reports of the beneficial role of N-acetylcysteine in DIALF and in preventing TB DILI in elderly individuals needs further investigation. Reintroduction of antitubercular therapy must be balanced with the knowledge of adaptation a common occurrence with antituberculosis drugs. Although monitoring and rechallenge practices vary greatly, the importance of early clinical symptoms cannot be underestimated. Simultaneous rechallenge with combination drugs or sequential treatment have similar incidence of DILI, although increasing reports about the role of pyrazinamide in DILI and on rechallenge warrants its careful use. The combined affliction of HIV or chronic hepatitis B or C and tuberculosis poses multiple challenges including the greatly increased risks of DILI. PMID:22332331

  16. 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...

  17. 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

  18. 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 ...

  19. 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.

  20. 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

  1. 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.

  2. Fatigue, Sleepiness and Driving Simulator Performance in Head-neck Trauma Patients

    OpenAIRE

    MacLeod, A; CHAUMET,G; SAGASPE,P; TAILLARD,JM; QUERA-SALVA,M; MAZAUX,J; BIOULAC,B; de Philip, P

    2006-01-01

    Head-neck trauma (HNT) patients often suffer from chronic fatigue. A previous study showed that sleepiness could account for fatigue in HNT patients. It is well-known that HNT patients have difficulties in daily life, in particular in automobile driving. In this new study, we wanted to test the relation between sleepiness, fatigue and driving impairment in HNT patients.

  3. 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....

  4. Clinical features, pathogenesis and management of drug-induced seizures.

    Science.gov (United States)

    Zaccara, G; Muscas, G C; Messori, A

    1990-01-01

    Many classes of pharmacological agents have been implicated in cases of drug-induced seizures. The list includes antidepressant drugs, lithium salts, neuroleptics, antihistamines (H1-receptor antagonists), anticonvulsants, central nervous system stimulants, general and local anaesthetics, antiarrhythmic drugs, narcotic and non-narcotic analgesics, non-steroidal anti-inflammatory drugs, antimicrobial agents, antifungal agents, antimalarial drugs, antineoplastic drugs, immunosuppressive drugs, radiological contrast agents and vaccines. For each of these classes of drugs, this article offers a revision of the literature and emphasises in particular the frequency of the adverse reaction, its clinical presentation, its presumed epileptogenic mechanism and the therapeutic strategy for the management of drug-induced seizures. An attempt is also made to distinguish seizures induced by standard dosages from those provoked by accidental or self-induced intoxication. For some classes of drugs such as antidepressants, neuroleptics, central nervous system stimulants (e.g. theophylline, cocaine, amphetamines) and beta-lactam antibiotics, seizures are a well recognised adverse reaction, and a large body of literature has been published discussing exhaustively the major aspects of the issue; sufficient data are available also for the other classes of pharmacological agents mentioned above. In contrast, several other drugs [e.g. allopurinol, digoxin, cimetidine, protirelin (thyrotrophin releasing hormone), bromocriptine, domperidone, insulin, fenformin, penicillamine, probenecid, verapamil, methyldopa] have not been studied thoroughly under this aspect, and the only source of information is the occasional case report. This review does not address the issue of seizures induced by drug withdrawal. PMID:2182049

  5. 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

  6. [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

  7. 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

  8. 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 ...

  9. Are drivers aware of sleepiness and increasing crash risk while driving?

    Science.gov (United States)

    Williamson, Ann; Friswell, Rena; Olivier, Jake; Grzebieta, Raphael

    2014-09-01

    Drivers are advised to take breaks when they feel too tired to drive, but there is question over whether they are able to detect increasing fatigue and sleepiness sufficiently to decide when to take a break. The aim of this study was to investigate the extent to which drivers have access to cognitive information about their current state of sleepiness, likelihood of falling asleep, and the implications for driving performance and the likelihood of crashing. Ninety drivers were recruited to do a 2h drive in a driving simulator. They were divided into three groups: one made ratings of their sleepiness, likelihood of falling asleep and likelihood of crashing over the next few minutes at prompts occurring at 200s intervals throughout the drive, the second rated sleepiness and likelihood of falling asleep at prompts but pressed a button on the steering wheel at any time if they felt they were near to crashing and the third made no ratings and only used a button-press if they felt a crash was likely. Fatigue and sleepiness was encouraged by monotonous driving conditions, an imposed shorter than usual sleep on the night before and by afternoon testing. Drivers who reported that they were possibly, likely or very likely to fall asleep in the next few minutes, were more than four times more likely to crash subsequently. Those who rated themselves as sleepy or likely to fall asleep had a more than 9-fold increase in the hazards of a centerline crossing compared to those who rated themselves as alert. The research shows clearly that drivers can detect changes in their levels of sleepiness sufficiently to make a safe decision to stop driving due to sleepiness. Therefore, road safety policy needs to move from reminding drivers of the signs of sleepiness and focus on encouraging drivers to respond to obvious indicators of fatigue and sleepiness and consequent increased crash risk. PMID:24803170

  10. 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)

  11. Occupational Injuries related to Sleepiness in Indian Traditional Industries

    Directory of Open Access Journals (Sweden)

    Ajeet Jaiswal

    2012-08-01

    Full Text Available A cross-sectional study was done to evaluate the rate of sleepiness and its relation to occupational injuries in Indian Traditional Industries. Data was collected using pretested and structured questionnaire about eight sleep habits, symptoms of depression, occupational injury due to fatigue, demographics, presence of diseases and lifestyle factors from 920 workers between the ages of 18-65 (mean 433.5 year in small scale industries. Occupational injury was assessed by asking subjects 'Have you ever been injured during your work, including minor scratches and cuts (Yes/ No? Both sleep and injury were assessed over the previous one year period. One-third of workers answered that they had experienced injury. Workers with sleep features of DIS, sleeping poorly at night, insufficient sleep, and insomnia had a significantly higher prevalence for injury after adjusting for multiple confounders. The findings suggest that poor nocturnal sleep habits are associated with self-reported occupational injury.

  12. 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

  13. 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.

  14. 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

  15. Normal lipase drug-induced pancreatitis: a novel finding.

    Science.gov (United States)

    Shafqet, Muhammad A; Brown, Teresa V; Sharma, Ranita

    2015-03-01

    Acute pancreatitis (AP) in the setting of a normal serum amylase has been previously reported in the literature. Serum lipase on the other hand has a negative predictive value approaching 100% and therefore is an excellent test to rule out AP in the emergency department. The occurrence of AP with a normal lipase is extremely rare and has never been reported in the setting of drug-induced pancreatitis. Thiazide diuretics have been implicated as a cause of pancreatic injury via a number of proposed mechanisms. However, all such cases have been in the setting of elevated serum amylase or lipase. We report the first case of radiographically proven hydrochlorothiazide-induced pancreatitis with a normal lipase. PMID:25227976

  16. 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.

  17. 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

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. The Effect of Low-Frequency Road Noise on Driver Sleepiness and Performance

    OpenAIRE

    Anund, Anna; Lahti, Eva; Fors, Carina; Genell, Anders

    2015-01-01

    It is a well-known fact today that driver sleepiness is a contributory factor in crashes. Factors considered as sleepiness contributor are mostly related to time of the day, hours being awake and hours slept. Factors contributing to active and passive fatigue are mostly focusing on the level of cognitive load. Less is known what role external factors, e.g. type of road, sound/noise, vibrations etc., have on the ability to stay awake both under conditions of sleepiness and under active or pass...

  5. "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...

  6. 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 ...

  7. 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

  8. Drug-induced interstitial lung diseases. Often forgotten

    International Nuclear Information System (INIS)

    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.)

  9. Drug-induced pancreatitis: A rare manifestation of doxycycline administration

    Directory of Open Access Journals (Sweden)

    Faisal Inayat

    2016-01-01

    Full Text Available Context: Drug-induced pancreatitis (DIP is rare, but as there are no systematic data on it, the true incidence is not known. Although numerous and varied drugs have been associated with DIP, the clinical evidence on doxycycline-induced pancreatitis is sparse. Case Report: We present the case of a 58-year-old female who presented with complaints of nausea and severe epigastric pain. Her medications included doxycycline which she had been on for only 2 days. Computed tomography of her abdomen showed mild enlargement of body of the pancreas with peripancreatic fatty infiltration, along with lipase level suggestive of acute pancreatitis. In the absence of classical risk factors for acute pancreatitis, a diagnosis of DIP secondary to doxycycline therapy was made. Immediate withdrawal of the drug was accompanied by relief of symptoms and resolution of pancreatitis. Conclusion: This report implicates doxycycline as an etiological factor for acute pancreatitis. Knowledge regarding doxycycline related pancreatitis is of paramount importance in order to diagnose cases early and institute effective treatment in patients who are undergoing therapy with this drug.

  10. 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

  11. 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.

  12. 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

  13. 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.

  14. 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.

  15. Excessive Daytime Sleepiness and Epilepsy: A Systematic Review

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    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.

  16. 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

  17. "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

  18. Hepatic necrosis associated with drug-induced hypersensitivity syndrome

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    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.

  19. 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.

  20. 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...

  1. 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.

  2. 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

  3. 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

  4. 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

  5. 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.

  6. The effect of low-frequency road noise on driver sleepiness and performance.

    Science.gov (United States)

    Anund, Anna; Lahti, Eva; Fors, Carina; Genell, Anders

    2015-01-01

    It is a well-known fact today that driver sleepiness is a contributory factor in crashes. Factors considered as sleepiness contributor are mostly related to time of the day, hours being awake and hours slept. Factors contributing to active and passive fatigue are mostly focusing on the level of cognitive load. Less is known what role external factors, e.g. type of road, sound/noise, vibrations etc., have on the ability to stay awake both under conditions of sleepiness and under active or passive fatigue. The aim of this moving base driving simulator study with 19 drivers participating in a random order day and night time, was to evaluate the effect of low-frequency road noise on driver sleepiness and performance, including both long-term and short-term effects. The results support to some extent the hypothesis that road-induced interior vehicle sound affects driving performance and driver sleepiness. Increased low-frequency noise helps to reduce speed during both day- and night time driving, but also contributes to increase the number of lane crossings during night time. PMID:25874883

  7. Sleepy driving on the real road and in the simulator--A comparison.

    Science.gov (United States)

    Hallvig, David; Anund, Anna; Fors, Carina; Kecklund, Göran; Karlsson, Johan G; Wahde, Mattias; Akerstedt, Torbjörn

    2013-01-01

    Sleepiness has been identified as one of the most important factors contributing to road crashes. However, almost all work on the detailed changes in behavior and physiology leading up to sleep related crashes has been carried out in driving simulators. It is not clear, however, to what extent simulator results can be generalized to real driving. This study compared real driving with driving in a high fidelity, moving base, driving simulator with respect to driving performance, sleep related physiology (using electroencephalography and electrooculography) and subjective sleepiness during night and day driving for 10 participants. The real road was emulated in the simulator. The results show that the simulator was associated with higher levels of subjective and physiological sleepiness than real driving. However, both for real and simulated driving, the response to night driving appears to be rather similar for subjective sleepiness and sleep physiology. Lateral variability was more responsive to night driving in the simulator, while real driving at night involved a movement to the left in the lane and a reduction of speed, both of which effects were absent in the simulator. It was concluded that the relative validity of simulators is acceptable for many variables, but that in absolute terms simulators cause higher sleepiness levels than real driving. Thus, generalizations from simulators to real driving must be made with great caution. PMID:23149323

  8. Acute Hepatocellular Drug-Induced Liver Injury From Bupropion and Doxycycline

    OpenAIRE

    Derek M Tang; Koh, Christopher; Twaddell, William S.; von Rosenvinge, Erik C; Han, Hyosun

    2015-01-01

    The management and diagnosis of drug-induced liver injury (DILI) is often challenging, particularly when patients are taking multiple medications. We present a 29-year-old African American man who presented with jaundice and malaise after starting bupropion and doxycycline 2 weeks prior. He was found to have acute hepatocellular drug-induced liver injury with autoimmune features, and made a complete recovery with prednisone. Although bupropion and doxycycline are both known to cause liver tox...

  9. 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...

  10. 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 ...

  11. 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

  12. Impact Of Nasal Continuous Positive Airway Pressure On Excessive Daytime Sleepiness In Obstructive Sleep Apnea Patients

    Directory of Open Access Journals (Sweden)

    Geetha Kandasamy

    2013-01-01

    Full Text Available Purpose: To study the impact of nasal continuous positive airway pressure (nCPAP on excessive daytime sleepiness in obstructive sleep apnea patients (OSA. Method: Patient’s data were collected through direct patient interview and polysomnographic reports. Excessive daytime sleepiness (EDS was assessed by using Epworth Sleepiness Scale (ESS at baseline and after six months of nCPAP treatment. Results: This prospective study was conducted from August 2008 to June 2012. A total of 141patients were diagnosed as OSA based on Apnea Hypopnea Index. The study group (n=141 was further categorized based on AHI as Mild, Moderate and Severe. AHI 17.71% (31 had mild OSA (AHI 5-14.9, 33.14% (24 had moderate (AHI 15-29.9 Events/hourand 49.14% (86 were found to have severe OSA (AHI≥30. Evaluation of demographic data revealed that among the 141 patients, 121 were male (85.81% and 20 were female (14.48% and the mean age was 51.82±11.77 years. The mean ESS Score for mild OSA, moderate OSA, and severe obstructive sleep apnea groups were 8.13±1.78, 13.45±3.14, 15.48±5.22 respectively. The ESS score was significantly higher in severe obstructive sleep apnea patients as compared to mild and moderate OSA. ESS scores at baseline were 12.48±3.12 and after nCPAP treatment were 6.42±2.92. Significantly improved after 6 months of nCPAP treatment. Conclusion: Nasal CPAP reduces daytime sleepiness, resulting in an increased daytime activity. Subjective sleepiness was also (Excessive daytime sleepiness significantly improved after 6 months of nCPAP treatment.

  13. Sleep disordered breathing, fatigue, and sleepiness in HIV-infected and -uninfected men.

    Directory of Open Access Journals (Sweden)

    Susheel P Patil

    Full Text Available We investigated the association of HIV infection and highly active antiretroviral therapy (HAART with sleep disordered breathing (SDB, fatigue, and sleepiness.HIV-uninfected men (HIV-; n = 60, HIV-infected men using HAART (HIV+/HAART+; n = 58, and HIV-infected men not using HAART (HIV+/HAART-; n = 41 recruited from two sites of the Multicenter AIDS cohort study (MACS underwent a nocturnal sleep study, anthropometric assessment, and questionnaires for fatigue and the Epworth Sleepiness Scale. The prevalence of SDB in HIV- men was compared to that in men matched from the Sleep Heart Health Study (SHHS.The prevalence of SDB was unexpectedly high in all groups: 86.7% for HIV-, 70.7% for HIV+/HAART+, and 73.2% for HIV+/HAART-, despite lower body-mass indices (BMI in HIV+ groups. The higher prevalence in the HIV- men was significant in univariate analyses but not after adjustment for BMI and other variables. SDB was significantly more common in HIV- men in this study than those in SHHS, and was common in participants with BMIs <25 kg/m2. HIV+ men reported fatigue more frequently than HIV- men (25.5% vs. 6.7%; p = 0.003, but self-reported sleepiness did not differ among the three groups. Sleepiness, but not fatigue, was significantly associated with SDB.SDB was highly prevalent in HIV- and HIV+ men, despite a normal or slightly elevated BMI. The high rate of SDB in men who have sex with men deserves further investigation. Sleepiness, but not fatigue, was related to the presence of SDB. Clinicians caring for HIV-infected patients should distinguish between fatigue and sleepiness when considering those at risk for SDB, especially in non-obese men.

  14. 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

  15. The effect of chewing gum on physiological and self-rated measures of alertness and daytime sleepiness.

    Science.gov (United States)

    Johnson, Andrew J; Miles, Christopher; Haddrell, Ben; Harrison, Emily; Osborne, Liam; Wilson, Nigel; Jenks, Rebecca

    2012-02-01

    The proposition that chewing gum can improve alertness was investigated via both physiological and self-rated measures. The Pupillographic Sleepiness Test (PST) provided a measure of pupillary unrest (PUI); a physiological index of daytime sleepiness. Chewing gum reduced the extent of sleepiness as measured by both PUI and self-rated sleepiness. Specifically, in comparison with sham chewing and no chewing controls, the chewing gum condition significantly limited the increase in pupillary unrest following the 11-minute PST within a darkened laboratory: a finding indicating moderation of the daytime sleepiness increase for the chewing gum condition. In addition, there was some evidence that chewing gum (relative to the no-chewing condition only) moderated the increase in a self-rated measure of sleepiness (Stanford Sleepiness Scale). However, there was no evidence that chewing gum moderated the decrease in self-rated alertness (Bond-Lader Visual Analogue Mood Scale). Although the precise mechanism underpinning the effect of chewing gum is unclear, the reduction in daytime sleepiness may be underpinned via heightened cerebral activity following the chewing of gum or the arousing effects of mint flavour. PMID:22061430

  16. 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

  17. "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

  18. 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

  19. 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…

  20. 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,…

  1. 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…

  2. The Psychosocial Problems of Children with Narcolepsy and Those with Excessive Daytime Sleepiness of Uncertain Origin

    Science.gov (United States)

    Stores, Gregory; Montgomery, Paul; Wiggs, Luci

    2007-01-01

    Background: Narcolepsy is a predominantly rapid eye movement sleep disorder with onset usually in the second decade but often in earlier childhood. Classically it is characterized by combinations of excessive sleepiness especially sleep attacks, cataplexy, hypnagogic hallucinations, and sleep paralysis. The psychosocial effects of this lifelong…

  3. The effects of Ramadan fasting on sleep patterns and daytime sleepiness: An objective assessment

    Directory of Open Access Journals (Sweden)

    Ahmed S BaHammam

    2013-01-01

    Full Text Available Background: Ramadan fasting and its associated lifestyle changes have been linked to changes in sleep and daytime sleepiness. This study was designed to assess the effects of Ramadan fasting on patterns of sleep and daytime sleepiness. Methods: The SenseWear Pro Armband™ was used to assess the duration and distribution of sleep in eight Muslim and eight non-Muslim volunteers during the last week of Shaaban [baseline (BL and the first (R1 and second (R2 weeks of Ramadan (1430 H]. OPTALERT™ was used to assess daytime drowsiness objectively using the John Drowsiness Scale (JDS to assess sleepiness, and a visual reaction time test was used to assess mean reaction time (MRT. Results: The mean ages of Muslims and non-Muslims were 36.25 ± 4.46 and 34.75 ± 3.33 years, respectively. Although the start of work was delayed for Muslims from 0730 to 1000 hours, there was no change in working hours for non-Muslims. During Ramadan, bedtime and wake-up time were delayed, and there was a significant reduction in total sleep time for Muslims (5.91 ± 1.36 hours, 4.95 ± 1.46 hours, and 4.78 ± 1.36 hours during BL, R1, and R2, respectively, P < 0.001, but not for non-Muslims. JDS values in both Muslims and non-Muslims were normal at BL (1.70 ± 1.16 and 1.68 ± 1.07, respectively, and no changes occurred during Ramadan (R1 or R2, indicating no increase in daytime sleepiness. There were no significant changes in MRT during R1 and R2 from BL in either group. Conclusion: Although the sleep cycle of the studied sample shifted during Ramadan among fast observers, there was no objective evidence for increased sleepiness during fasting.

  4. 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.

  5. 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

  6. Acute Hepatocellular Drug-Induced Liver Injury From Bupropion and Doxycycline.

    Science.gov (United States)

    Tang, Derek M; Koh, Christopher; Twaddell, William S; von Rosenvinge, Erik C; Han, Hyosun

    2015-10-01

    The management and diagnosis of drug-induced liver injury (DILI) is often challenging, particularly when patients are taking multiple medications. We present a 29-year-old African American man who presented with jaundice and malaise after starting bupropion and doxycycline 2 weeks prior. He was found to have acute hepatocellular drug-induced liver injury with autoimmune features, and made a complete recovery with prednisone. Although bupropion and doxycycline are both known to cause liver toxicity, a closer inspection of the signature of liver injury and a review of prior related DILI cases assigns causality more to bupropion than doxycycline. PMID:26504884

  7. 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

  8. Drug-Induced Hypothermia as Beneficial Treatment before and after Cerebral Ischemia

    DEFF Research Database (Denmark)

    Johansen, Flemming F; Hasseldam, Henrik; Rasmussen, Rune Skovgaard; Bisgård, Anne Sofie; Bonfils, Peter Kramshøj; Poulsen, Steen Seier; Hansen-Schwartz, Jacob

    2014-01-01

    Objectives: Hypothermia is still unproven as beneficial treatment in human stroke, although in animal models, conditioning the brain with hypothermia has induced tolerance to insults. Here, we delineate the feasibility of drug-induced mild hypothermia in reducing ischemic brain damage when...

  9. 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.

  10. 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

  11. 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.

  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. Drug-induced interstitial lung disease: mechanisms and best diagnostic approaches

    Directory of Open Access Journals (Sweden)

    Matsuno Osamu

    2012-05-01

    Full Text Available Abstract Drug-induced interstitial lung disease (DILD is not uncommon and has many clinical patterns, ranging from benign infiltrates to life-threatening acute respiratory distress syndrome. There are two mechanisms involved in DILD, which are probably interdependent: one is direct, dose-dependent toxicity and the other is immune-mediated. Cytotoxic lung injury may result from direct injury to pneumocytes or the alveolar capillary endothelium. Drugs can induce all types of immunological reactions described by Gell and Coombs; however, most reactions in immune-mediated DILD may be T cell-mediated. DILD can be difficult to diagnose; diagnosis is often possible by exclusion alone. Identifying the causative drug that induces an allergy or cytotoxicity is essential for preventing secondary reactions. One method to confirm the diagnosis of a drug-induced disease is re-exposure or re-test of the drug. However, clinicians are reluctant to place patients at further risk of illness, particularly in cases with severe drug-induced diseases. Assessment of cell-mediated immunity has recently increased, because verifying the presence or absence of drug-sensitized lymphocytes can aid in confirmation of drug-induced disease. Using peripheral blood samples from drug-allergic patients, the drug-induced lymphocyte stimulation test (DLST and the leukocyte migration test (LMT can detect the presence of drug-sensitized T cells. However, these tests do not have a definite role in the diagnosis of DILD. This study explores the potential of these new tests and other similar tests in the diagnosis of DILD and provides a review of the relevant literature on this topic.

  14. 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

  15. 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

  16. 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?''...

  17. 76 FR 4918 - Drug-Induced Liver Injury: Are We Ready to Look?; Public Conference; Request for Comments

    Science.gov (United States)

    2011-01-27

    ... for industry entitled ``Drug-Induced Liver Injury: Premarketing Clinical Evaluation'' (see 74 FR 38035... HUMAN SERVICES Food and Drug Administration Drug-Induced Liver Injury: Are We Ready to Look?; Public Conference; Request for Comments AGENCY: Food and Drug Administration, HHS. ACTION: Notice of...

  18. 75 FR 14602 - Guidance for Industry on Drug-Induced Liver Injury: Premarketing Clinical Evaluation; Opening of...

    Science.gov (United States)

    2010-03-26

    ... on Drug-Induced Liver Injury: Premarketing Clinical Evaluation; Opening of Comment Period for Future Revision of Guidance Dated July 2009; Public Conference AGENCY: Food and Drug Administration, HHS. ACTION... industry published in the Federal ] Register July 30, 2009, entitled ``Drug-Induced Liver...

  19. 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

  20. 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

  1. Prevalence of sleep apnea and excessive day time sleepiness in patients with end-stage renal disease on dialysis

    OpenAIRE

    Hamdan Al-Jahdali

    2012-01-01

    Sleep apnea (SA) and excessive daytime sleepiness (EDS) are common sleep disorders among patients with end-stage renal disease (ESRD). This cross-sectional study, carried out in two dialysis centers in Saudi Arabia, assessed the prevalence of sleep apnea and sleepiness in Saudi patients with ESRD who are on maintenance dialysis with either peritoneal or hemodialysis. We used questionnaires to assess the prevalence of SA and EDS. The association between sleep apnea, EDS, and other sleep disord...

  2. Sleepiness Versus Sleeplessness: Shift Work and Sleep Disorders in the Primary Care Setting

    OpenAIRE

    2004-01-01

    This Academic Highlights section of The Primary Care Companion to The Journal of Clinical Psychiatry presents the highlights of the teleconference series “Differential Diagnosis and Management of Excessive Sleepiness,” held April 5, 7, and 22, 2004. The teleconference and this ACADEMIC HIGHLIGHTS were supported by an unrestricted educational grant from Cephalon, Inc. This report was prepared by Physicians Postgraduate Press, Inc.

  3. 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

  4. 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...

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

    OpenAIRE

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

    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 ex...

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

    Directory of Open Access Journals (Sweden)

    Camila Astolphi Lima

    2015-09-01

    Full Text Available 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.

  7. 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

  8. 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.

  9. 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

  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. 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...

  12. 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...

  13. Effect of cimetidine and ranitidine on drug induced damage to gastric epithelial cell monolayers in vitro.

    OpenAIRE

    Romano, M.; Razandi, M; Ivey, K J

    1989-01-01

    The effect of the H2 blockers cimetidine and ranitidine on drug induced damage to gastric cell monolayers has been evaluated in conditions independent of systemic factors and their anti-acid properties. Monolayers of mucous cells from a human cell line MKN 28, obtained from a human gastric adenocarcinoma, have been studied. Cell damage has been assessed qualitatively by trypan blue dye exclusion test and quantitatively by 51Cr release assay. Cimetidine and ranitidine significantly protected c...

  14. 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...

  15. 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 ...

  16. 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.

  17. 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...

  18. 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...

  19. 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...

  20. 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...

  1. Caffeine administration at night during extended wakefulness effectively mitigates performance impairment but not subjective assessments of fatigue and sleepiness.

    Science.gov (United States)

    Paech, Gemma M; Banks, Siobhan; Pajcin, Maja; Grant, Crystal; Johnson, Kayla; Kamimori, Gary H; Vedova, Chris B Della

    2016-06-01

    The current study investigated the effects of repeated caffeine administration on performance and subjective reports of sleepiness and fatigue during 50h extended wakefulness. Twenty-four, non-smokers aged 22.5±2.9y (mean±SD) remained awake for two nights (50h) in a controlled laboratory environment. During this period, 200mg of caffeine or placebo gum was administered at 01:00, 03:00, 05:00 and 07:00 on both nights (total of 800mg/night). Neurobehavioral performance and subjective reports were assessed throughout the wake period. Caffeine improved performance compared to placebo, but did not affect overall ratings of subjective sleepiness and fatigue. Performance and sleepiness worsened with increasing time awake for both conditions. However, caffeine slowed performance impairments such that after 50h of wakefulness performance was better following caffeine administration compared to placebo. Caffeine also slowed the increase in subjective sleepiness and performance ratings, but only during the first night of wakefulness. After two nights of sleep deprivation, there was no difference in sleepiness ratings between the two conditions. These results demonstrate that strategic administration of caffeine effectively mitigates performance impairments associated with 50h wakefulness but does not improve overall subjective assessments of sleepiness, fatigue and performance. Results indicate that while performance impairment is alleviated, individuals may continue to report feelings of sleepiness. Individuals who use caffeine as a countermeasure in sustained operations may feel as though caffeine is not effective despite impairments in objective performance being largely mitigated. PMID:27061779

  2. 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.

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

    Science.gov (United States)

    Ganesh, P. R.

    2016-01-01

    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. PMID:27307657

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

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    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. 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

  7. 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

  8. Excessive daytime sleepiness assessed by the Epworth Sleepiness Scale and its association with health related quality of life: a population-based study in China

    Directory of Open Access Journals (Sweden)

    Wu Shunquan

    2012-10-01

    Full Text Available Abstract Background Excessive daytime sleepiness (EDS is a common condition worldwide that has many negative effects on people who were afflicted with it, especially on their health-related quality of life (HRQOL. The Epworth Sleepiness Scale (ESS is a commonly used method for evaluating EDS in English-speaking countries. This paper reported the prevalence of subjective EDS in China as assessed by the Mandarin version of the ESS; tested the scale’s response rate, reliability and validity; and investigated the relationship between ESS scores and HRQOL. Methods A population-based sample of 3600 residents was selected randomly in five cities in China. The demographic information was collected, subjective EDS was assessed by the Mandarin version of the ESS (ESS scores >10, and HRQOL was evaluated by the Mandarin version of the 36-item Short Form Health Survey (SF-36. Results The Mandarin version of ESS had very few missing responses, and the average response rate of its eight items was 97.92%. The split-half reliability coefficient and Cronbach’s α coefficient were 0.81 and 0.80, respectively. One factor was identified by factor analysis with an eigenvalue of 2.78. The ESS scores showed positive skewness in the selected sample, with a median (Q1, Q3 of 6 (3, 0. 644 (22.16% respondents reported subjective EDS, and all of the scores of the eight dimensions of the SF-36 were negatively correlated with ESS scores. Conclusions The Mandarin version of ESS is an acceptable, reliable, and valid tool for measuring EDS. In addition, subjective EDS is common in China, based on the ESS results, and impairs HRQOL.

  9. 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

  10. Clinical implications of daytime sleepiness for the academic performance of middle school-aged adolescents with attention deficit hyperactivity disorder.

    Science.gov (United States)

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

    2013-10-01

    This study investigated the relative impact of total time slept per night and daytime sleepiness on the academic functioning of 100 middle school-aged youth (mean age = 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 covariates, such as intelligence, achievement scores and parent education level. Self-reported daytime sleepiness but not self-reported total time slept per night was associated significantly with all academic outcomes. When examined in a hierarchical regression model, self-reported daytime sleepiness significantly predicted parent-rated homework problems and academic impairment and teacher-rated academic competence above and beyond symptoms of ADHD and relevant covariates, but did not predict grade point average or teacher-rated academic impairment. The implications of these findings for understanding more clearly the association between ADHD and sleep and the functional implications of this relationship are discussed. PMID:23509927

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

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    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

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

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    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.

  13. 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.

  14. 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...... sleep quality and daytime sleepiness are associated with cognition in middle-aged males. PARTICIPANTS: A total of 189 healthy males born in 1953 were considered as participants for the study. Based on previous cognitive assessments, the participants were selected for the study as cognitively improved (N...... = 97) 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...

  15. A survey study of the association between mobile phone use and daytime sleepiness in California high school students

    OpenAIRE

    Nathan, Nila; Zeitzer, Jamie

    2013-01-01

    Background Mobile phone use is near ubiquitous in teenagers. Paralleling the rise in mobile phone use is an equally rapid decline in the amount of time teenagers are spending asleep at night. Prior research indicates that there might be a relationship between daytime sleepiness and nocturnal mobile phone use in teenagers in a variety of countries. As such, the aim of this study was to see if there was an association between mobile phone use, especially at night, and sleepiness in a group of U...

  16. 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...

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

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    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. 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

  19. Evaluation of Protective Effect of Thymoquinone against Anti-tubercular Drug Induced Nephrotoxicity in Rats

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    Arvind Chansoria

    2013-01-01

    Full Text Available Present study was done to see the protective effect of thymoquinone against antitubercular drugs induced nephrotoxicity in rats. Thymoquinone significantly reduced serum urea, serum creatinine and K+ levels in ATT induced renal toxicity. No effect was seen in serum serum Na+ level. Higher dose was found to reduce serum urea to greater extent than 5 mg TQ dose. The nephroprotective effect of thymoquinone was found to be significant. Hence the present study throws light on usefulness of TQ in protection against ATT induced renal injury. This might prove useful for combating the serious renal adverse effects of ATT regimen without eliminating the use of standard first line drugs.

  20. 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

  1. 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...

  2. 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...

  3. Drug-induced acute pancreatitis: A rare manifestation of an incomplete "dapsone syndrome"

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    Anup K Das

    2014-01-01

    Full Text Available Drug-induced acute pancreatitis (AP is under-reported, and a large number of drugs are listed as offenders, but are often overlooked. Knowledge about the possible association of medications in causing AP is important, and needs a high index of suspicion, especially with drugs that have been reported to be the etiology only rarely. Dapsone, a commonly used drug, can cause various hypersensitivity reactions including AP collectively called "dapsone syndrome." Here, we report dapsone-induced AP in a young man. Our case shows certain dissimilarities like associated acute renal failure and acute hemolysis not previously described.

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

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    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

  5. Drug-induced acute tubulointerstitial nephritis: a case with elevated urinary cadmium.

    Science.gov (United States)

    Subat-Dezulović, Mirna; Slavić, Irena; Rozmanić, Vojko; Persić, Mladen; Medjimurec, Branka; Sćukanec-Spoljar, Mira

    2002-05-01

    Acute tubulointerstitial nephritis (ATIN) has many different causes, but is most frequently caused by drugs. We report a 13-year-old vegetarian girl with drug-induced ATIN, confirmed by renal biopsy, and simultaneous occurrence of elevated urinary cadmium. Four weeks prior to admission she had been treated with antibiotics and acetaminophen for respiratory infection, and remaining febrile, was treated with different "home-made" herbal mixtures. She presented with acute non-oliguric renal failure, tubular dysfunction, and sterile pyuria, but without skin rash or edema. Laboratory data showed a raised erythrocyte sedimentation rate, normal white blood count with eosinophilia, and a serum creatinine of 245 micromol/l. Urinalysis was remarkable for glycosuria, tubular proteinuria, and elevated beta(2)-microglobulin and N-acetyl-beta-D-glucosaminidase excretion. Immunoserological tests characteristic of acute glomerulonephritis and systemic diseases were negative. She was treated with steroids and her renal function improved. Follow-up analyses disclosed normal urinary cadmium and enzyme excretion within 6 months. Heavy metal analysis of herbal preparations that she had taken confirmed the presence of cadmium, but within approved concentrations. In conclusion, elevated urinary cadmium in the case of drug-induced ATIN may be assumed to be an accidental finding. However, consumption of different herbs containing cadmium and cadmium-induced nephro-toxicity could be the reason for such serious renal damage. PMID:12042900

  6. 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

  7. 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

  8. 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.

  9. 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

  10. 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

  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. 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

  13. 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

  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. 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

  16. 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

  17. 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

  18. Sleep and sleepiness during an ultra long-range flight operation between the Middle East and United States.

    Science.gov (United States)

    Holmes, Alexandra; Al-Bayat, Soha; Hilditch, Cassie; Bourgeois-Bougrine, Samira

    2012-03-01

    This study provides a practical example of fatigue risk management in aviation. The sleep and sleepiness of 44 pilots (11 trips × 4 pilot crew) working an ultra long-range (ULR; flight time >16 h) round-trip operation between Doha and Houston was assessed. Sleep was assessed using activity monitors and self-reported sleep diaries. Mean Karolinska Sleepiness Scores (KSS) for climb and descent did not exceed 5 ("neither alert nor sleepy"). Mean daily sleep duration was maintained above 6.3h throughout the operation. During in-flight rest periods, 98% of pilots obtained sleep and sleepiness was subsequently reduced. On layover (49.5h) crew were advised to sleep on Doha or Universal Co-ordinated Time (UTC), but 64% slept during the local (social) night time. Pilots originating from regions with a siesta culture were more likely to nap and made particularly effective use of their daytime in-flight rest periods. The results indicate that the operation is well designed from a fatigue management perspective. PMID:22239927

  19. 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.

  20. 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.

  1. 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

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

    International Nuclear Information System (INIS)

    Background: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (INa) may carry pro-arrhythmic risks. Due to the frequency-dependent block of INa, 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 (Emax 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 out of three

  3. 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

  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. Electrical stimulation of the frontal cortex enhances slow-frequency EEG activity and sleepiness.

    Science.gov (United States)

    D'Atri, A; De Simoni, E; Gorgoni, M; Ferrara, M; Ferlazzo, F; Rossini, P M; De Gennaro, L

    2016-06-01

    Our aim was to enhance the spontaneous slow-frequency EEG activity during the resting state using oscillating transcranial direct currents (tDCS) with a stimulation frequency that resembles the spontaneous oscillations of sleep onset. Accordingly, in this preliminary study, we assessed EEG after-effects of a frontal oscillatory tDCS with different frequency (0.8 vs. 5Hz) and polarity (anodal, cathodal, and sham). Two single-blind experiments compared the after effects on the resting EEG of oscillatory tDCS [Exp. 1=0.8Hz, 10 subjects (26.2±2.5years); Exp. 2=5Hz, 10 subjects (27.4±2.4years)] by manipulating its polarity. EEG signals recorded (28 scalp derivations) before and after stimulation [slow oscillations (0.5-1Hz), delta (1-4Hz), theta (5-7Hz), alpha (8-12Hz), beta 1 (13-15Hz) and beta 2 (16-24Hz)] were compared between conditions as a function of polarity (anodal vs. cathodal vs. sham) and frequency of stimulation (0.8 vs. 5Hz). We found a significant relative enhancement of the delta activity after the anodal tDCS at 5Hz compared to that at 0.8Hz. This increase, even though not reaching the statistical significance compared to sham, is concomitant to a significant increase of subjective sleepiness, as assessed by a visual analog scale. These two phenomena are linearly related with a regional specificity, correlations being restricted to cortical areas perifocal to the stimulation site. We have shown that a frontal oscillating anodal tDCS at 5Hz results in an effective change of both subjective sleepiness and spontaneous slow-frequency EEG activity. These changes are critically associated to both stimulation polarity (anodal) and frequency (5Hz). However, evidence of frequency-dependence seems more unequivocal than evidence of polarity-dependence. PMID:26964682

  6. 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)

  7. 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.

  8. 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

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

    Energy Technology Data Exchange (ETDEWEB)

    Pedersen, R A; Brandriff, B

    1979-01-01

    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.

  10. Lack of correlation between fecal blood loss and drug-induced gastric mucosal lesions

    Energy Technology Data Exchange (ETDEWEB)

    Hedenbro, J.L.; Wetterberg, P.; Vallgren, S.; Bergqvist, L.

    1988-05-01

    Increased fecal blood loss was produced in healthy volunteers by the administration of two nonsteroidal anti-inflammatory drugs (NSAID), naproxen or fenflumizole. Basal as well as drug-induced gastrointestinal blood loss was measured using /sup 51/Cr erythrocyte labeling. Median rise in daily fecal blood loss was 432%. All subjects were endoscoped at the initiation and at the completion of the study. Endoscopic findings were assessed quantitatively by two observers in two different ways. All subjects but three had gastric mucosal lesions at follow-up endoscopy. There was a good correlation between the endoscopic assessments but no statistical correlation between the endoscopic assessment and the increase in fecal blood loss. The data suggest that factors other than gastric mucosal lesions have to be taken into account when investigating NSAID-induced gastrointestinal bleeding.

  11. 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

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

    DEFF Research Database (Denmark)

    Johansen, Flemming Fryd; Hasseldam, Henrik; Nybro Smith, Matthias; Rasmussen, Rune Skovgaard

    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...... controls (P < .05). S14671 rats kept normothermic did not show infarct reduction (P > .05). The body temperature after stroke was reduced 1.0-3.0°C compared with controls for 20 hours with S14671 treatment and for 6 hours with ipsapirone treatment. In humans, ipsapirone reduced temperature in average with...... stroke model and in man by literature meta-analysis. METHODS: Rats had 60 minutes of middle cerebral artery occlusion (MCAO) and then 7 days of survival. Body temperatures were monitored for 22 hours. Thirty minutes after MCAO, 1 group (n = 9) received bolus of S14671 (.75 mg/kg) and continuous infusion...

  13. 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

  14. [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

  15. Lack of correlation between fecal blood loss and drug-induced gastric mucosal lesions

    International Nuclear Information System (INIS)

    Increased fecal blood loss was produced in healthy volunteers by the administration of two nonsteroidal anti-inflammatory drugs (NSAID), naproxen or fenflumizole. Basal as well as drug-induced gastrointestinal blood loss was measured using 51Cr erythrocyte labeling. Median rise in daily fecal blood loss was 432%. All subjects were endoscoped at the initiation and at the completion of the study. Endoscopic findings were assessed quantitatively by two observers in two different ways. All subjects but three had gastric mucosal lesions at follow-up endoscopy. There was a good correlation between the endoscopic assessments but no statistical correlation between the endoscopic assessment and the increase in fecal blood loss. The data suggest that factors other than gastric mucosal lesions have to be taken into account when investigating NSAID-induced gastrointestinal bleeding

  16. Bilateral macular hemorrhage as a complication of drug-induced anemia: a case report

    Directory of Open Access Journals (Sweden)

    Belfort Rubens N

    2009-01-01

    Full Text Available Abstract Introduction Bilateral macular hemorrhage is a rare ocular finding and to the best of our knowledge, this is the first report of such hemorrhages as a presentation of drug-induced anemia. Case presentation We describe the case of a 14-year-old Caucasian boy who presented with a toxoplasmic retinochoroiditis and was treated with sulfadiazine and pyrimethamine. Three months later, he presented with a bilateral macular hemorrhage as a complication of a toxic induced anemia. Conclusion Our patient presented with toxic anemia secondary to the treatment of a very common disease, ocular toxoplasmosis. Prophylactic use of folinic acid could prevent such complications but in many cases, it is not prescribed owing to its cost or is mistakenly substituted with folic acid, which does not present as a valid substitute.

  17. Oxytocinergic regulation of endogenous as well as drug-induced mood.

    Science.gov (United States)

    Broadbear, J H; Kabel, D; Tracy, L; Mak, P

    2014-04-01

    The interconnections between the serotonin and oxytocin pathways in the brain suggest that changes in oxytocin levels - arising from natural or drug-induced stimuli - lead to measureable changes in mood. In this paper, we review our findings in the context of what is known about the roles of oxytocin and vasopressin in the expression of a range of behaviours. In our first set of studies we investigated whether stimulation of oxytocin and vasopressin receptors, via central or systemic drug administration, would produce behavioural changes indicative of anti-depressant or anxiolytic activity. In our second study we investigated whether oxytocin receptor activation might be implicated in the interoceptive effects experienced with the popular party drug, MDMA ('ecstasy'). Our first study demonstrated that carbetocin, an oxytocin analogue, had anti-depressant actions following systemic and central administration, effects which were blocked by the oxytocin and vasopressin 1A receptor antagonist, atosiban. Carbetocin also had anxiolytic effects in the elevated plus maze. In an evaluation of the complementary nature of oxytocin and vasopressin, we found that systemic administration of desmopressin, a vasopressin analogue, was anxiogenic; its effects blocked by atosiban which on its own produced robust anxiolytic behavioural changes. In our second study, we evaluated MDMA's interoceptive effects using a drug discrimination paradigm. Carbetocin partially substituted for MDMA, while atosiban interfered with MDMA discrimination, suggesting that oxytocin receptor activation contributes to MDMA-related interoceptive cues. The results of these and other clinical and preclinical studies suggest that oxytocin, as well as its closely related counterpart vasopressin, may provide alternative therapeutic targets for the treatment of mood disorders such as anxiety and depression. The possibility that oxytocin release may contribute to the perception of and processes underlying natural

  18. 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

  19. Pharmacogenetic testing in idiosyncratic drug-induced liver injury: current role in clinical practice.

    Science.gov (United States)

    Aithal, Guruprasad P

    2015-07-01

    In contrast to the studies that have explored association of genetic variants with other complex traits, those investigating hepatotoxicity have identified risk alleles with substantially higher risk ratios for the susceptibility to drug-induced liver injury (DILI). In addition, a relatively small number of human leukocyte antigen (HLA) alleles have overlapping associations with a variety of adverse reactions including DILI, cutaneous hypersensitivity and drug-induced pancreatitis. However, if used as a test prior to prescription to prevent potential adverse reaction, genotyping would have a very high negative predictive value, yet a low positive predictive value based on the low incidence of DILI. One potential consideration is to treat all relevant HLA genotypes as one panel covering different forms of adverse drug reactions, thereby improving the positive predictive value of the panel and widen its application. The majority of HLA alleles associated with DILI have a very high negative predictive value; therefore, they can be used to rule out hepatotoxicity caused by particular drugs. A high negative predictive value of a genetic test can be used to identify the correct agent underlying DILI when the patient had been exposed to two concomitant medications with a potential to cause DILI. Inclusion of genetic tests in the causality assessment of an event, where DILI is suspected, may improve consistency and precision of causality assessment tools. A recent clinical trial used N-acetyltransferase 2 genotyping to determine the appropriate dose of isoniazid in an anti-tuberculosis therapeutic regimen and demonstrated that pharmacogenetic-based clinical algorithms have the potential to improve efficacy of a drug and to reduce DILI. PMID:25809692

  20. Update on Advances in Research on Idiosyncratic Drug-Induced Liver Injury.

    Science.gov (United States)

    Kim, Seung Hyun; Naisbitt, Dean J

    2016-01-01

    Drug-induced liver injury (DILI) is a major concern for public health, as well as for drug development in the pharmaceutical industry, since it can cause liver failure and lead to drug withdrawal from the market and black box warnings. Thus, it is important to identify biomarkers for early prediction to increase our understanding of mechanisms underlying DILI that will ultimately aid in the exploration of novel therapeutic strategies to prevent or manage DILI. DILI can be subdivided into 'intrinsic' and 'idiosyncratic' categories, although the validity of this classification remains controversial. Idiosyncratic DILI occurs in a minority of susceptible individuals with a prolonged latency, while intrinsic DILI results from drug-induced direct hepatotoxicity over the course of a few days. The rare occurrence of idiosyncratic DILI requires multicenter collaborative investigations and phenotype standardization. Recent progress in research on idiosyncratic DILI is based on key developments in 3 areas: (1) newly developed high-throughput genotyping across the whole genome allowing for the identification of genetic susceptibility markers, (2) new mechanistic concepts on the pathogenesis of DILI revealing a key role of drug-responsive T lymphocytes in the immunological response, and (3) broad multidisciplinary approaches using different platform "-omics" technologies that have identified novel biomarkers for the prediction of DILI. An association of a specific human leukocyte antigen (HLA) allele with DILI has been reported for several drugs. HLA-restricted T-cell immune responses have also been investigated using lymphocytes and T-cell clones isolated from patients. A microRNA, miR-122, has been discovered as a promising biomarker for the early prediction of DILI. In this review, we summarize recent advances in research on idiosyncratic DILI with an understanding of the key role of adaptive immune systems. PMID:26540496

  1. 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

  2. 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

  3. Advantageous use of HepaRG cells for the screening and mechanistic study of drug-induced steatosis.

    Science.gov (United States)

    Tolosa, Laia; Gómez-Lechón, M José; Jiménez, Nuria; Hervás, David; Jover, Ramiro; Donato, M Teresa

    2016-07-01

    Only a few in vitro assays have been proposed to evaluate the steatotic potential of new drugs. The present study examines the utility of HepaRG cells as a cell-based assay system for screening drug-induced liver steatosis. A high-content screening assay was run to evaluate multiple toxicity-related cell parameters in HepaRG cells exposed to 28 compounds, including drugs reported to cause steatosis through different mechanisms and non-steatotic compounds. Lipid content was the most sensitive parameter for all the steatotic drugs, whereas no effects on lipid levels were produced by non-steatotic compounds. Apart from fat accumulation, increased ROS production and altered mitochondrial membrane potential were also found in the cells exposed to steatotic drugs, which indicates that all these cellular events contributed to drug-induced hepatotoxicity. These findings are of clinical relevance as most effects were observed at drug concentrations under 100-fold of the therapeutic peak plasmatic concentration. HepaRG cells showed increased lipid overaccumulation vs. HepG2 cells, which suggests greater sensitivity to drug-induced steatosis. An altered expression profile of transcription factors and the genes that code key proteins in lipid metabolism was also found in the cells exposed to drugs capable of inducing liver steatosis. Our results generally indicate the value of HepaRG cells for assessing the risk of liver damage associated with steatogenic compounds and for investigating the molecular mechanisms involved in drug-induced steatosis. PMID:27089845

  4. Improvement in Fatigue during Natalizumab Treatment is Linked to Improvement in Depression and Day-Time Sleepiness

    DEFF Research Database (Denmark)

    Penner, Iris-Katharina; Sivertsdotter, Eva Catharina; Celius, Elisabeth G; Fuchs, Siegrid; Schreiber, Karen; Berkö, Sara; Svenningsson, Anders

    2015-01-01

    BACKGROUND: Fatigue is a frequent symptom in multiple sclerosis (MS) and often interrelated with depression and sleep disorders making symptomatic treatment decisions difficult. In the single-arm, observational phase IV TYNERGY study, relapsing-remitting MS patients showed a clinically meaningful...... decrease in fatigue over 1 year of treatment with natalizumab. OBJECTIVE: To evaluate whether fatigue improvement might be directly linked to improved depression and day-time sleepiness. METHODS: Patients were assessed regarding fatigue, depression, and day-time sleepiness. The relation between changes of...... the two latter symptoms and changes in fatigue was analyzed. RESULTS: After 1 year of natalizumab treatment, the majority of patients (>92%) remained stable or improved in total, motor, and cognitive fatigue. Proportion of patients without depression increased by 17% while proportions of mildly...

  5. Driver sleepiness and risk of motor vehicle crash injuries: A population-based case control study in Fiji (TRIP 12) ☆

    OpenAIRE

    Herman, Josephine; Kafoa, Berlin; Wainiqolo, Iris; Robinson, Elizabeth; McCaig, Eddie; Connor, Jennie; Jackson, Rod; Ameratunga, Shanthi

    2014-01-01

    Introduction Published studies investigating the role of driver sleepiness in road crashes in low and middle-income countries have largely focused on heavy vehicles. We investigated the contribution of driver sleepiness to four-wheel motor vehicle crashes in Fiji, a middle-income Pacific Island country. Method The population-based case control study included 131 motor vehicles involved in crashes where at least one person died or was hospitalised (cases) and 752 motor vehicles identified in r...

  6. Sleep Apnea Clinical Score, Berlin Questionnaire, or Epworth Sleepiness Scale: which is the best obstructive sleep apnea predictor in patients with COPD?

    OpenAIRE

    Faria AC; Costa CH; Rufino R

    2015-01-01

    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 illne...

  7. 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

  8. 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

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

    International Nuclear Information System (INIS)

    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

  10. 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

  11. 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...

  12. 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...

  13. 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

  14. 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

  15. Stress vulnerability and the effects of moderate daily stress on sleep polysomnography and subjective sleepiness.

    Science.gov (United States)

    Petersen, Helena; Kecklund, Göran; D'Onofrio, Paolo; Nilsson, Jens; Åkerstedt, Torbjörn

    2013-02-01

    The purpose of this study was to investigate if and how sleep physiology is affected by naturally occurring high work stress and identify individual differences in the response of sleep to stress. Probable upcoming stress levels were estimated through weekly web questionnaire ratings. Based on the modified FIRST-scale (Ford insomnia response to stress) participants were grouped into high (n = 9) or low (n = 19) sensitivity to stress related sleep disturbances (Drake et al., 2004). Sleep was recorded in 28 teachers with polysomnography, sleep diaries and actigraphs during one high stress and one low stress condition in the participants home. EEG showed a decrease in sleep efficiency during the high stress condition. Significant interactions between group and condition were seen for REM sleep, arousals and stage transitions. The sensitive group had an increase in arousals and stage transitions during the high stress condition and a decrease in REM, whereas the opposite was seen in the resilient group. Diary ratings during the high stress condition showed higher bedtime stress and lower ratings on the awakening index (insufficient sleep and difficulties awakening). Ratings also showed lower cognitive function and preoccupation with work thoughts in the evening. KSS ratings of sleepiness increased during stress for the sensitive group. Saliva samples of cortisol showed no effect of stress. It was concluded that moderate daily stress is associated with a moderate negative effect on sleep sleep efficiency and fragmentation. A slightly stronger effect was seen in the sensitive group. PMID:22835074

  16. 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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    Masayuki Miyazaki

    2011-01-01

    Full Text Available Drug-induced hypersensitivity syndrome (DIHS is a severe 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.

  20. A metabolomics cell-based approach for anticipating and investigating drug-induced liver injury.

    Science.gov (United States)

    García-Cañaveras, Juan Carlos; Castell, José V; Donato, M Teresa; Lahoz, Agustín

    2016-01-01

    In preclinical stages of drug development, anticipating potential adverse drug effects such as toxicity is an important issue for both saving resources and preventing public health risks. Current in vitro cytotoxicity tests are restricted by their predictive potential and their ability to provide mechanistic information. This study aimed to develop a metabolomic mass spectrometry-based approach for the detection and classification of drug-induced hepatotoxicity. To this end, the metabolite profiles of human derived hepatic cells (i.e., HepG2) exposed to different well-known hepatotoxic compounds acting through different mechanisms (i.e., oxidative stress, steatosis, phospholipidosis, and controls) were compared by multivariate data analysis, thus allowing us to decipher both common and mechanism-specific altered biochemical pathways. Briefly, oxidative stress damage markers were found in the three mechanisms, mainly showing altered levels of metabolites associated with glutathione and γ-glutamyl cycle. Phospholipidosis was characterized by a decreased lysophospholipids to phospholipids ratio, suggestive of phospholipid degradation inhibition. Whereas, steatosis led to impaired fatty acids β-oxidation and a subsequent increase in triacylglycerides synthesis. The characteristic metabolomic profiles were used to develop a predictive model aimed not only to discriminate between non-toxic and hepatotoxic drugs, but also to propose potential drug toxicity mechanism(s). PMID:27265840

  1. 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.

  2. 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

  3. Expression of TNF-α and RANTES in drug-induced human gingival overgrowth

    Directory of Open Access Journals (Sweden)

    Subramani Tamilselvan

    2010-01-01

    Full Text Available Objectives : Regulated on activation, normal T cell expressed and secreted (RANTES is a chemokine that is produced by fibroblasts, lymphoid and epithelial cells of the mucosa in response to various external stimuli. RANTES expression has been demonstrated in a variety of diseases characterized by inflammation, including asthma, transplantation-associated accelerated atherosclerosis, endometriosis and fibrosis. RANTES mRNA is quickly up-regulated by tumor necrosis factor (TNF-α stimulation. Cyclosporine A (CsA is widely used in organ transplant patients, often causing various side-effects including gingival overgrowth, which is fibrotic in nature. This study was carried out to assess the mRNA expression of TNF-α and RANTES in healthy individual, chronic periodontitis and CsA-induced gingival overgrowth tissues. Materials and Methods : Gingival tissue samples were collected from chronic periodontitis, CsA-induced gingival overgrowth patients and healthy individuals. Total RNA was isolated and reverse transcription polymerase chain reaction (RT-PCR was performed for TNF-α and RANTES expression. Results : The results suggest that CsA-induced gingival overgrowth tissues expressed significantly increased TNF-α and RANTES compared to control and chronic periodontitis. Conclusion : The findings of the present study suggest that CsA can modify the expression of TNF-α and RANTES in drug-induced human gingival overgrowth.

  4. 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

  5. Case Characterization, Clinical Features and Risk Factors in Drug-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Aida Ortega-Alonso

    2016-05-01

    Full Text Available Idiosyncratic drug-induced liver injury (DILI caused by xenobiotics (drugs, herbals and dietary supplements presents with a range of both phenotypes and severity, from acute hepatitis indistinguishable of viral hepatitis to autoimmune syndromes, steatosis or rare chronic vascular syndromes, and from asymptomatic liver test abnormalities to acute liver failure. DILI pathogenesis is complex, depending on the interaction of drug physicochemical properties and host factors. The awareness of risk factors for DILI is arising from the analysis of large databases of DILI cases included in Registries and Consortia networks around the world. These networks are also enabling in-depth phenotyping with the identification of predictors for severe outcome, including acute liver failure and mortality/liver transplantation. Genome wide association studies taking advantage of these large cohorts have identified several alleles from the major histocompatibility complex system indicating a fundamental role of the adaptive immune system in DILI pathogenesis. Correct case definition and characterization is crucial for appropriate phenotyping, which in turn will strengthen sample collection for genotypic and future biomarkers studies.

  6. [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

  7. 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.

  8. 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

  9. 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.

  10. 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.

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

    Directory of Open Access Journals (Sweden)

    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

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

    Science.gov (United States)

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

    2015-09-01

    : 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. PMID:26371029

  13. 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

  14. 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

  15. Protective effects of exogenous glutathione and related thiol compounds against drug-induced liver injury.

    Science.gov (United States)

    Masubuchi, Yasuhiro; Nakayama, Junpei; Sadakata, Yuka

    2011-01-01

    An overdose of acetaminophen (APAP) causes liver injury both in experimental animals and humans. N-acetylcysteine (NAC) is clinically used as an antidote for APAP intoxication, and it is thought to act by providing cysteine as a precursor of glutathione, which traps a reactive metabolite of APAP. Other hepatoprotective mechanisms of NAC have also been suggested. Here, we examined the effects of thiol compounds with different abilities to restore hepatic glutathione, on hepatotoxicity of APAP and furosemide in mice. Overnight-fasted male CD-1 mice were given APAP or furosemide intraperitoneally. NAC, cysteine, glutathione, or glutathione-monoethyl ester was administered concomitantly with APAP or furosemide. All thiol compounds used in this study effectively protected mice against APAP-induced liver injury. Only glutathione-monoethyl ester completely prevented APAP-induced early hepatic glutathione depletion. Cysteine also significantly restored hepatic glutathione levels. NAC partially restored glutathione levels. Exogenous glutathione had no effect on hepatic glutathione loss. NAC and glutathione highly stimulated the hepatic expression of cytokines, particularly interleukin-6, which might be involved in the alleviation of APAP hepatotoxicity. Furosemide-induced liver injury, which does not accompany hepatic glutathione depletion, was also attenuated by NAC and exogenous glutathione, supporting their protective mechanisms other than replenishment of glutathione. In conclusion, exogenous thiols could alleviate drug-induced liver injury. NAC and glutathione might exert their effects, at least partially, via mechanisms that are independent of increasing hepatic glutathione, but probably act through cytokine-mediated and anti-inflammatory mechanisms. PMID:21372386

  16. A rare cause of drug-induced hepatitis in an immunocompromised patient and the role of glutathione.

    Science.gov (United States)

    Senadhi, Viplove; Arora, Deepika; Arora, Manish; Marsh, Franklin

    2012-08-27

    The Food and Drug Administration (FDA) has issued a warning on numerous herbal drugs, including many popular products at General Nutrition Centers (GNC), regarding unstudied hepatotoxicity. There have been recent reports of GNC products such as hydroxycut and herbalife, causing drug-induced hepatitis. Herbal medications are over-the-counter products and are not investigated thoroughly by the FDA. Given that the most common outpatient laboratory abnormality is elevated liver transaminases, a sign of hepatocellular toxicity; it is not surprising that some of these products end up causing hepatic dysfunction, especially when taken in large volume. There are numerous herbal supplements that are hepatotoxic, however, these medications have a much more significant effect in human immunodeficiency virus (HIV)/ acquired immune deficiency syndrome patients, which is secondary to depleted glutathione. We present a rare case of drug induced hepatitis secondary to herbal medications used to treat HIV and elucidate the role of glutathione depletion in immunocompromised patients. PMID:22993667

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

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    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

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

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    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.

  19. [Case reports of drug-induced liver injury in a reference hospital of Zulia state, Venezuela].

    Science.gov (United States)

    Mengual-Moreno, Edgardo; Lizarzábal-García, Maribel; Ruiz-Soler, María; Silva-Suarez, Niniveth; Andrade-Bellido, Raúl; Lucena-González, Maribel; Bessone, Fernando; Hernández, Nelia; Sánchez, Adriana; Medina-Cáliz, Inmaculada

    2015-03-01

    Drug-induced liver injury (DILI) is an important cause of morbidity and mortality worldwide, with varied geographical differences. The aim of this prospective, descriptive, cross-sectional study was to identify and characterize cases of DILI in a hospital of Zulia state, Venezuela. Thirteen patients with a presumptive diagnosis of DILI attended by the Department of Gastroenterology, Hospital Universitario, Zulia state, Venezuela, from December-2012 to December-2013 were studied. Ibuprofen (n = 3; 23.1%), acetaminophen (n = 3; 23.1), isoniazid (n = 2; 15.4%) and Herbalife products (n = 2; 15.4%) were the main drugs involved with DILI. Acetaminophen and ibuprofen showed a mixed pattern of liver injury (n = 3; 23.1%) and isoniazid presented a hepatocellular pattern (n = 2; 15.4%). The CIOMS/RUCAMS allowed the identification of possible (n = 7; 53.9%), probable (n = 4; 30.8%) and highly-probable cases (n = 2; 15.4%) of DILI. Amoxicillin/clavulanate, isoniazid, isotretinoin, methotrexate and Herbalife nutritional products were implicated as highly-probable and probable agents. The highest percentage of DILI corresponded to mild cases that recovered after the discontinuation of the agent involved (n = 9; 69.3%). The consumption of Herbalife botanical products is associated with probable causality and fatality (n = 1; 7.7%). In conclusion, the frequency of DILI cases controlled by the Department of Gastroenterology of the Hospital Universitario of Maracaibo was low, being ibuprofen, acetaminophen, isoniazid and products Herbalife the products most commonly involved. It is recommended to continue with the prospective registration of cases, with an extended follow up monitoring period and to facilitate the incorporation of other hospitals in the Zulia State and Venezuela. PMID:25920181

  20. Chemotherapeutic Drug-Induced ABCG2 Promoter Demethylation as a Novel Mechanism of Acquired Multidrug Resistance

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    Eran E. Bram

    2009-12-01

    Full Text Available ABCG2 is an efflux transporter conferring multidrug resistance (MDR on cancer cells. However, the initial molecular events leading to its up-regulation in MDR tumor cells are poorly understood. Herein, we explored the impact of drug treatment on the methylation status of the ABCG2 promoter and consequent reactivation of ABCG2 gene expression in parental tumor cell lines and their MDR sublines. We demonstrate that ABCG2 promoter methylation is common in T-cell acute lymphoblastic leukemia (T-ALL lines, also present in primary T-ALL lymphoblast specimens. Furthermore, drug selection with sulfasalazine and topotecan induced a complete demethylation of the ABCG2 promoter in the T-ALL and ovarian carcinoma model cell lines CCRF-CEM and IGROV1, respectively. This resulted in a dramatic induction of ABCG2 messenger RNA levels (235- and 743-fold, respectively and consequent acquisition of an ABCG2-dependent MDR phenotype. Quantitative genomic polymerase chain reaction and ABCG2 promoter-luciferase reporter assay did not reveal ABCG2 gene amplification or differential transcriptional trans-activation, which could account for ABCG2 up-regulation in these MDR cells. Remarkably, mimicking cytotoxic bolus drug treatment through 12- to 24-hour pulse exposure of ABCG2-silenced leukemia cells, to clinically relevant concentrations of the chemotherapeutic agents daunorubicin and mitoxantrone, resulted in a marked transcriptional up-regulation of ABCG2. Our findings establish that antitumor drug-induced epigenetic reactivation of ABCG2 gene expression in cancer cells is an early molecular event leading to MDR. These findings have important implications for the emergence, clonal selection, and expansion of malignant cells with the MDR phenotype during chemotherapy.

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

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

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    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

  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. 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...

  5. 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...

  6. A rare cause of drug-induced hepatitis in an immunocompromised patient and the role of glutathione

    OpenAIRE

    Viplove Senadhi; Deepika Arora; Manish Arora; Franklin Marsh

    2012-01-01

    The Food and Drug Administration (FDA) has issued a warning on numerous herbal drugs, including many popular products at General Nutrition Centers (GNC), regarding unstudied hepatotoxicity. There have been recent reports of GNC products such as hydroxycut and herbalife, causing drug-induced hepatitis. Herbal medications are over-the-counter products and are not investigated thoroughly by the FDA. Given that the most common outpatient laboratory abnormality is elevated liver transaminases, a s...

  7. Identification of a novel and severe pattern of efavirenz drug-induced liver injury in South Africa.

    Science.gov (United States)

    Sonderup, Mark W; Maughan, Debbie; Gogela, Neliswa; Setshedi, Mashiko; Wainwright, Helen; Meintjes, Graeme; Spearman, Wendy

    2016-06-01

    Efavirenz now forms part of many antiretroviral regimens in low and middle-income countries. Efavirenz-related drug-induced liver injury is not well characterized but is thought to occur less frequently than with nevirapine. We describe our observation of three defined clinicopathological patterns of injury, one of which, submassive necrosis, is associated with significant morbidity and mortality. A high baseline CD4, younger age and possibly female gender, predicts for the injury. PMID:26959511

  8. 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.

  9. 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.

  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 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

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

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    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 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, 26.13y ± 4.46) participated in a 9-day laboratory study that included two baseline nights (BL, 10h time in bed (TIB), 2200h-0800h), 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 0300h-0800h and 1500h-20000h, or 6-h late: TIB 0900h-1400h and 2100h-0200h), and two recovery nights (10h TIB per night, 2200h-0800h). 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 night shift

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

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    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.

  14. 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

  15. 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...

  16. 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

  17. 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

  18. Effects of recovery sleep after one work week of mild sleep restriction on interleukin-6 and cortisol secretion and daytime sleepiness and performance

    OpenAIRE

    Pejovic, Slobodanka; Basta, Maria; Vgontzas, Alexandros N; Kritikou, Ilia; Shaffer, Michele L.; Tsaoussoglou, Marina; Stiffler, David; Stefanakis, Zacharias; Bixler, Edward O.; Chrousos, George P.

    2013-01-01

    One workweek of mild sleep restriction adversely impacts sleepiness, performance, and proinflammatory cytokines. Many individuals try to overcome these adverse effects by extending their sleep on weekends. To assess whether extended recovery sleep reverses the effects of mild sleep restriction on sleepiness/alertness, inflammation, and stress hormones, 30 healthy young men and women (mean age ± SD, 24.7 ± 3.5 yr; mean body mass index ± SD, 23.6 ± 2.4 kg/m2) participated in a sleep laboratory ...

  19. 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.

  20. 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

  1. 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.

  2. Antidepressive-drug-induced bodyweight gain is associated with polymorphisms in genes coding for COMT and TPH1

    DEFF Research Database (Denmark)

    Secher, Anna; Bukh, Jens; Bock, Camilla; Koefoed, Pernille; Rasmussen, Henrik Berg; Werge, Thomas; Kessing, Lars Vedel; Mellerup, Erling

    2009-01-01

    examine the association of antidepressive-drug-induced bodyweight gain with polymorphisms in genes within the serotonin or catecholamine systems. Participants (N = 165) were selected from the Danish Psychiatric Central Research Register from June 2005 through May 2007 as patients with a diagnosis of a...... single depressive episode and who were under antidepressive treatment. Weight gainers were identified based on rating with the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale. Polymorphisms in catechol-O-methyltransferase, tryptophan hydroxylase (TPH1), serotonin receptor 2C (HTR2C) and...

  3. 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

  4. Current and future directions in the treatment and prevention of drug-induced liver injury: a systematic review.

    Science.gov (United States)

    Stine, Jonathan G; Lewis, James H

    2016-04-01

    While the pace of discovery of new agents, mechanisms and risk factors involved in drug-induced liver injury (DILI) remains brisk, advances in the treatment of acute DILI seems slow by comparison. In general, the key to treating suspected DILI is to stop using the drug prior to developing irreversible liver failure. However, predicting when to stop is an inexact science, and commonly used ALT monitoring is an ineffective strategy outside of clinical trials. The only specific antidote for acute DILI remains N-acetylcysteine (NAC) for acetaminophen poisoning, although NAC is proving to be beneficial in some cases of non-acetaminophen DILI in adults. Corticosteroids can be effective for DILI associated with autoimmune or systemic hypersensitivity features. Ursodeoxycholic acid, silymarin and glycyrrhizin have been used to treat DILI for decades, but success remains anecdotal. Bile acid washout regimens using cholestyramine appear to be more evidenced based, in particular for leflunomide toxicity. For drug-induced acute liver failure, the use of liver support systems is still investigational in the United States and emergency liver transplant remains limited by its availability. Primary prevention appears to be the key to avoiding DILI and the need for acute treatment. Pharmacogenomics, including human leukocyte antigen genotyping and the discovery of specific DILI biomarkers offers significant promise for the future. This article describes and summarizes the numerous and diverse treatment and prevention modalities that are currently available to manage DILI. PMID:26633044

  5. 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. PMID:26026931

  6. 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

  7. 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.…

  8. 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.

  9. 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

  10. Prevalence of sleep apnea and excessive day time sleepiness in patients with end-stage renal disease on dialysis.

    Science.gov (United States)

    Al-Jahdali, Hamdan

    2012-03-01

    Sleep apnea (SA) and excessive daytime sleepiness (EDS) are common sleep disorders among patients with end-stage renal disease (ESRD). This cross-sectional study, carried out in two dialysis centers in Saudi Arabia, assessed the prevalence of sleep apnea and sleepiness in Saudi patients with ESRD who are on maintenance dialysis with either peritoneal or hemodialysis. We used questionnaires to assess the prevalence of SA and EDS. The association between sleep apnea, EDS, and other sleep disorders, the underlying causes of renal failure, and other demographic data were also examined. Among 227 enrolled patients, the mean patient age was 55.7 years ± 17.2 years; 53.7% were male, and 46.3% were female. The overall prevalence of SA as defined by the Berlin questionnaire (BQ) was 37% in males and 34% in females, which was not a statistically significant difference (P = 0.459). Sleep apnea was significantly associated with age, neck size, afternoon and evening hemodialysis shift, obesity, diabetes, and hypertension (P-values, 0.001, 0.029, < 0.0001, < 0.0001, < 0.008, 0.002, and < 0.001, respectively). Sleep apnea was also significantly associated with other sleep disorders such as restless leg syndrome, insomnia, habitual snoring, and EDS (P-values, < 0.001, < 0.001, < 0.001, and < 0.001, respectively). The prevalence of EDS was 44%, and EDS was significantly more prevalent in patients undergoing peritoneal dialysis (P < 0.001); it was also associated with older age, diabetes mellitus, and other sleep disorders. SA and EDS are common in dialysis patients and are significantly associated with other sleep disorders. PMID:22382215

  11. Prevalence of sleep apnea and excessive day time sleepiness in patients with end-stage renal disease on dialysis

    Directory of Open Access Journals (Sweden)

    Hamdan Al-Jahdali

    2012-01-01

    Full Text Available Sleep apnea (SA and excessive daytime sleepiness (EDS are common sleep disorders among patients with end-stage renal disease (ESRD. This cross-sectional study, carried out in two dialysis centers in Saudi Arabia, assessed the prevalence of sleep apnea and sleepiness in Saudi patients with ESRD who are on maintenance dialysis with either peritoneal or hemodialysis. We used questionnaires to assess the prevalence of SA and EDS. The association between sleep apnea, EDS, and other sleep disorders, the underlying causes of renal failure, and other demo-graphic data were also examined. Among 227 enrolled patients, the mean patient age was 55.7 years ΁ 17.2 years; 53.7% were male, and 46.3% were female. The overall prevalence of SA as defined by the Berlin questionnaire (BQ was 37% in males and 34% in females, which was not a statistically significant difference (P = 0.459. Sleep apnea was significantly associated with age, neck size, afternoon and evening hemodialysis shift, obesity, diabetes, and hypertension (P-values, 0.001, 0.029, < 0.0001, < 0.0001, < 0.008, 0.002, and < 0.001, respectively. Sleep apnea was also significantly associated with other sleep disorders such as restless leg syndrome, insomnia, habitual snoring, and EDS (P-values, < 0.001, < 0.001, < 0.001, and < 0.001, respectively. The prevalence of EDS was 44%, and EDS was significantly more prevalent in patients undergoing peritoneal dialysis (P < 0.001; it was also associated with older age, diabetes mellitus, and other sleep disorders. SA and EDS are common in dialysis patients and are significantly associated with other sleep disorders.

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

    International Nuclear Information System (INIS)

    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

  15. 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

  16. Biopsy-proven drug-induced tubulointerstitial nephritis in a patient with acute kidney injury and alcoholic severe acute pancreatitis.

    Science.gov (United States)

    Yoshioka, Wakako; Mori, Takayasu; Nagahama, Kiyotaka; Tamura, Teiichi

    2013-01-01

    We report a 49-year-old man with alcoholic severe acute pancreatitis (SAP) complicated by drug-induced acute tubulointerstitial nephritis (DI-AIN). Oliguria persisted and became anuric again on day 17 despite improvement of pancreatitis. He presented rash, fever and eosinophilia from day 20. Renal biopsy was performed for dialysis-dependent acute kidney injury (AKI), DI-AIN was revealed, and prompt use of corticosteroids fully restored his renal function. This diagnosis might be missed because it is difficult to perform renal biopsy in such a clinical situation. If the patient's general condition allows, renal biopsy should be performed and reversible AKI must be distinguished from many cases of irreversible AKI complicated by SAP. This is the first report of biopsy-proven DI-AIN associated with SAP, suggesting the importance of biopsy for distinguishing DI-AIN in persisting AKI of SAP. PMID:23645698

  17. Drug-induced mild therapeutic hypothermia obtained by administration of a transient receptor potential vanilloid type 1 agonist

    DEFF Research Database (Denmark)

    Fosgerau, Keld; Weber, Uno J; Gotfredsen, Jacob W;

    2010-01-01

    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......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...... 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...

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

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    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.

  19. Clinical features and 123I-FP-CIT SPECT imaging in drug-induced parkinsonism and Parkinson's disease

    International Nuclear Information System (INIS)

    To determine clinical predictors and accuracy of 123I-FP-CIT SPECT imaging in the differentiation of drug-induced parkinsonism (DIP) and Parkinson's disease (PD). Several clinical features and 123I-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%, p123I-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 123I-FP-CIT SPECT imaging. (orig.)

  20. 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

  1. 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

  2. Design of the Anti-tuberculosis Drugs induced Adverse Reactions in China National Tuberculosis Prevention and Control Scheme Study (ADACS

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    He Ping

    2010-05-01

    Full Text Available Abstract Background More than 1 million tuberculosis (TB patients are receiving the standard anti-TB treatment provided by China National Tuberculosis Prevention and Control Scheme (CNTS in China every year. Adverse reactions (ADRs induced by anti-TB drugs could both do harm to patients and lead to anti-TB treatment failure. The ADACS aimed to explore ADRs' incidences, prognoses, economical and public health impacts for TB patients and TB control, and build a DNA bank of TB patients. Methods/Design Multiple study designs were adopted. Firstly, a prospective cohort with 4488 sputum smears positive pulmonary tuberculosis patients was established. Patients were followed up for 6-9 months in 52 counties of four regions. Those suspected ADRs should be checked and confirmed by Chinese State Food and Drug Administration (SFDA. Secondly, if the suspected ADR was anti-TB drug induced liver injury (ATLI, a nested case-control study would be performed which comprised choosing a matched control and doing a plus questionnaire inquiry. Thirdly, health economical data of ADRs would be collected to analyze financial burdens brought by ADRs and cost-effectiveness of ADRs' treatments. Fourthly, a drop of intravenous blood for each patient was taken and saved in FTA card for DNA banking and genotyping. Finally, the demographic, clinical, environmental, administrative and genetic data would be merged for the comprehensive analysis. Discussion ADACS will give an overview of anti-TB drugs induced ADRs' incidences, risk factors, treatments, prognoses, and clinical, economical and public health impacts for TB patients applying CNTS regimen in China, and provide suggestions for individualized health care and TB control policy.

  3. Drug-induced QT interval prolongation and torsades de pointes: Role of the pharmacist in risk assessment, prevention and management.

    Science.gov (United States)

    Tisdale, James E

    2016-05-01

    Torsades de pointes (TdP) is a life-threatening arrhythmia associated with prolongation of the corrected QT (QTc) interval on the electrocardiogram. More than 100 drugs available in Canada, including widely used antibiotics, antidepressants, cardiovascular drugs and many others, may cause QTc interval prolongation and TdP. Risk factors for TdP include QTc interval >500 ms, increase in QTc interval ≥60 ms from the pretreatment value, advanced age, female sex, acute myocardial infarction, heart failure with reduced ejection fraction, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, treatment with diuretics and elevated plasma concentrations of QTc interval-prolonging drugs due to drug interactions, inadequate dose adjustment of renally eliminated drugs in patients with kidney disease and rapid intravenous administration. Pharmacokinetic drug interactions associated with the highest risk of TdP include antifungal agents, macrolide antibiotics (except azithromycin) and drugs to treat human immunodeficiency virus interacting with amiodarone, disopyramide, dofetilide or pimozide. Other important pharmacokinetic interactions include antidepressants (bupropion, duloxetine, fluoxetine, paroxetine) interacting with flecainide, quinidine or thioridazine. Pharmacists play an important role in minimizing the risk of drug-induced QTc interval prolongation and TdP through knowledge of drugs that are associated with a known or possible risk of TdP, individualized assessment of risk of drug-induced QTc interval prolongation, awareness of drug interactions most likely to result in TdP and attention to dose reduction of renally eliminated QTc interval-prolonging drugs in patients with kidney disease. Treatment of hemodynamically stable TdP consists of discontinuation of the offending drug(s), correction of electrolyte abnormalities and administration of intravenous magnesium sulfate 1 to 2 g. PMID:27212965

  4. 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.

  5. 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.

  6. 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

  7. 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.

  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. 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.

  10. 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.

  11. 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.

  12. 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.

  13. A Case of Sublingual Ranula That Responded Successfully to Localized Injection Treatment with OK-432 after Healing from Drug Induced Hypersensitivity Syndrome.

    Science.gov (United States)

    Yoshizawa, Kunio; Moroi, Akinori; Kawashiri, Shuichi; Ueki, Koichiro

    2016-01-01

    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. PMID:27144039

  14. Excessive daytime sleepiness in patients with depressive disorder Sonolência diurna excessiva em pacientes com transtorno depressivo

    Directory of Open Access Journals (Sweden)

    Sarah Laxhmi Chellappa

    2006-06-01

    Full Text Available OBJECTIVE: To evaluate excessive daytime sleepiness in patients with depressive disorder and to examine its association with the severity of depression and suicidal ideation. METHOD: Seventy patients were interviewed and assessed by the Epworth Sleepiness Scale (ESS, the Beck Depression Inventory (BDI and the Beck Scale for Suicidal Ideation (SSI. Descriptive analysis, Pearson correlations and Student's t-test were used for data analyses. RESULTS: Most of the patients (57.1% obtained high scores on the ESS. Correlation was positive and strongly significant between ESS scores and BDI scores, as well as between ESS scores and SSI scores. Patients with high ESS scores obtained higher mean BDI and SSI scores in comparison to patients with lower ESS scores. Significant differences (p 10 and lower (OBJETIVO: Avaliar a incidência de sonolência diurna excessiva em pacientes com transtorno depressivo e examinar sua associação com a gravidade do quadro depressivo e ideação suicida. MÉTODO: Setenta pacientes foram entrevistados e avaliados através da Escala de Sonolência de Epworth (ESE, da Escala de Depressão de Beck BD e da Escala de Ideação Suicida de Beck (EIS. Análises descritivas, análise de correlação de Pearson e teste-t de Student foram utilizados para a análise dos dados. RESULTADOS: A maioria dos paciente (57,1% apresentaram altas pontuações na ESE. Houve correlações positivas e fortes entre scores da ESE e BD e entre scores da ESE e EIS. Pacientes com altas pontuações na ESE obtiveram escores na BD e na EIS mais elevados do que os pacientes com baixos escores de ESE. Houve diferenças significativas (p 10 na ESE, em relação às pontuações totais das ESE, EDB e EIS. CONCLUSÕES: A sonolência diurna excessiva foi freqüente nos pacientes e significativamente associada a maior gravidade da depressão e ideação suicida. Desta maneira, é necessária uma cuidadosa investigação da sonolência diurna excessiva em

  15. Relationship between the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale in a sleep laboratory referral population

    Directory of Open Access Journals (Sweden)

    Mondal P

    2013-02-01

    Full Text Available Prosanta Mondal,1 John A Gjevre,2 Regina M Taylor-Gjevre,3 Hyun J Lim11Department of Community Health and Epidemiology, 2Division of Respiratory, Critical Care and Sleep Medicine, 3Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, CanadaBackground: Sleep health questionnaires are often employed as a first assessment step for sleep pathology. The Epworth Sleepiness Scale (ESS and the Pittsburgh Sleep Quality Index (PSQI are two commonly employed questionnaire instruments. Aspects of sleep health may be measured differently depending on choice of instrument.Objectives: In a patient population at high risk for sleep disorders, referred for polysomnography (PSG, we evaluated the level of association between results from these two instruments. Questionnaire results were also compared with measured PSG parameters.Methods: Records of patients undergoing overnight PSG in the sleep laboratory between February–June 2011 were retrospectively reviewed for eligibility. Inclusion criteria were met by 236 patients. PSQI and ESS scores, demographic information, and PSG data were extracted from each record for analysis. Four subgroups based on normal/abnormal values for ESS and PSQI were evaluated for between-group differences.Results: Of 236 adult participants, 72.5% were male, the mean age was 52.9 years (13.9, mean body mass index (BMI 34.4 kg/m2 (8.3, mean ESS 9.0 (4.8; range: 0–22, PSQI mean 8.6 (4.2; range: 2–19. The Pearson correlation coefficient was r = 0.13 (P = 0.05 for association between ESS and PSQI. Participants with an abnormal ESS were more likely to have an abnormal PSQI score (odds ratio 1.9 [1.1–3.6]; P = 0.03. Those with an abnormal ESS had higher BMI (P = 0.008 and higher apnea–hypopnea indexes (AHI (P = 0.05. Differences between the four subgroups were observed for BMI and sex proportions, but not for AHI.Conclusions: We observed limited association between these two commonly used questionnaire

  16. 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"...

  17. 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

  18. 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.

  19. Cortical and Subcortical Grey and White Matter Atrophy in Myotonic Dystrophies Type 1 and 2 Is Associated with Cognitive Impairment, Depression and Daytime Sleepiness

    OpenAIRE

    Schneider-Gold, Christiane; Bellenberg, Barabara; Prehn, Christian; Krogias, Christos; Schneider, Ruth; Klein, Jan; Gold, Ralf; Lukas, Carsten

    2015-01-01

    Objectives Central nervous system involvement is one important clinical aspect of myotonic dystrophy type 1 and 2 (DM1 and DM2). We assessed CNS involvement DM1 and DM2 by 3T MRI and correlated clinical and neuocognitive symptoms with brain volumetry and voxel-based morphometry (VBM). Methods 12 patients with juvenile or classical DM1 and 16 adult DM2 patients underwent 3T MRI, a thorough neurological and neuropsychological examination and scoring of depression and daytime sleepiness. Volumes...

  20. 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

  1. 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.

  2. 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

  3. Mitochondrial bioenergetics and drug-induced toxicity in a panel of mouse embryonic fibroblasts with mitochondrial DNA single nucleotide polymorphisms

    International Nuclear Information System (INIS)

    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.

  4. 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.

  5. When the going gets tough: behavioural type-dependent space use in the sleepy lizard changes as the season dries.

    Science.gov (United States)

    Spiegel, Orr; Leu, Stephan T; Sih, Andrew; Godfrey, Stephanie S; Bull, C Michael

    2015-11-22

    Understanding space use remains a major challenge for animal ecology, with implications for species interactions, disease spread, and conservation. Behavioural type (BT) may shape the space use of individuals within animal populations. Bolder or more aggressive individuals tend to be more exploratory and disperse further. Yet, to date we have limited knowledge on how space use other than dispersal depends on BT. To address this question we studied BT-dependent space-use patterns of sleepy lizards (Tiliqua rugosa) in southern Australia. We combined high-resolution global positioning system (GPS) tracking of 72 free-ranging lizards with repeated behavioural assays, and with a survey of the spatial distributions of their food and refuge resources. Bayesian generalized linear mixed models (GLMM) showed that lizards responded to the spatial distribution of resources at the neighbourhood scale and to the intensity of space use by other conspecifics (showing apparent conspecific avoidance). BT (especially aggressiveness) affected space use by lizards and their response to ecological and social factors, in a seasonally dependent manner. Many of these effects and interactions were stronger later in the season when food became scarce and environmental conditions got tougher. For example, refuge and food availability became more important later in the season and unaggressive lizards were more responsive to these predictors. These findings highlight a commonly overlooked source of heterogeneity in animal space use and improve our mechanistic understanding of processes leading to behaviourally driven disease dynamics and social structure. PMID:26609082

  6. Hopes and challenges in using miRNAs as translational biomarkers for drug-induced liver injury.

    Science.gov (United States)

    Shi, Qiang; Yang, Xi; Mendrick, Donna L

    2013-04-01

    There is a need for better biomarkers of drug-induced liver injury (DILI) to guide risk assessment and patient management. Over the past 3 years, both animal and clinical studies have provided proof-of-concept data showing that a subset of miRNAs appear to offer unique advantages over the conventional DILI biomarkers, such as enhanced sensitivity and specificity, reduced inter-individual variations, the potential to differentiate lethal and nonlethal liver injury, and the ability to reflect the patterns and even the etiology of liver injury. Notably, many studies have demonstrated that level of miR-122, a liver-enriched miRNA accounting for approximately 70% of total hepatic miRNAs, was increased many fold in the blood when DILI occurred. However, currently available data are predominantly based on animal models and not human samples. Due to the lack of a standard quantification method for miRNAs and confirmatory studies using a comprehensive list of drugs and patients, the true value of all reported miRNA biomarkers remains to be carefully assessed. An outstanding challenge is to examine if miRNAs are also useful for idiosyncratic DILI, which constitutes the major part of clinical DILI cases but generally cannot be recapitulated in traditional animal models or in clinical trials (the latter due to its relative rarity). PMID:23547824

  7. 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

  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. Alterations in primary motor cortex neurotransmission and gene expression in hemi-parkinsonian rats with drug-induced dyskinesia.

    Science.gov (United States)

    Lindenbach, D; Conti, M M; Ostock, C Y; Dupre, K B; Bishop, C

    2015-12-01

    Treatment of Parkinson's disease (PD) with dopamine replacement relieves symptoms of poverty of movement, but often causes drug-induced dyskinesias. Accumulating clinical and pre-clinical evidence suggests that the primary motor cortex (M1) is involved in the pathophysiology of PD and that modulating cortical activity may be a therapeutic target in PD and dyskinesia. However, surprisingly little is known about how M1 neurotransmitter tone or gene expression is altered in PD, dyskinesia or associated animal models. The present study utilized the rat unilateral 6-hydroxydopamine (6-OHDA) model of PD/dyskinesia to characterize structural and functional changes taking place in M1 monoamine innervation and gene expression. 6-OHDA caused dopamine pathology in M1, although the lesion was less severe than in the striatum. Rats with 6-OHDA lesions showed a PD motor impairment and developed dyskinesia when given L-DOPA or the D1 receptor agonist, SKF81297. M1 expression of two immediate-early genes (c-Fos and ARC) was strongly enhanced by either L-DOPA or SKF81297. At the same time, expression of genes specifically involved in glutamate and GABA signaling were either modestly affected or unchanged by lesion and/or treatment. We conclude that M1 neurotransmission and signal transduction in the rat 6-OHDA model of PD/dyskinesia mirror features of human PD, supporting the utility of the model to study M1 dysfunction in PD and the elucidation of novel pathophysiological mechanisms and therapeutic targets. PMID:26363150

  10. 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)

  11. 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

  12. Sonolência diurna excessiva em pré-vestibulandos Excessive daytime sleepiness in senior high school students

    Directory of Open Access Journals (Sweden)

    José Carlos Souza

    2007-01-01

    Full Text Available OBJETIVO: O sono é um fenômeno que interfere nos aspectos cognitivos. O objetivo deste estudo foi avaliar a prevalência da sonolência diurna excessiva (SDE em pré-vestibulandos de Campo Grande, MS. MÉTODOS: Foram entrevistados 378 alunos com a escala de sonolência Epworth (ESE. As variáveis foram: sexo, uso esporádico de bebidas alcoólicas e fumo, relato de sinais e sintomas depressivos, renda familiar total dos membros do lar e idade. Foram empregados os testes qui-quadrado e de análise de variância. RESULTADOS: Em relação ao gênero, 50,3% eram homens e 49,7% mulheres; 39,2% ingeriam álcool; 6,6% fumavam e 33% já tinham tido depressão na vida. Entre os alunos, 55,8% tinham SDE, 5,3% eram indicativos de ter distúrbio respiratório ou síndrome da apnéia do sono. Foram detectadas associações entre as variáveis consumo de álcool e tabagismo, em relação à ESE. CONCLUSÕES: Foi alta a prevalência de SDE, sendo detectadas associações entre as variáveis uso esporádico de álcool e fumo, em relação à ESE. Novos estudos devem ser realizados a fim de prevenir as alterações cognitivas entre os pré-vestibulandos que apresentam SDE ou outro distúrbio do sono.OBJETIVE: Sleep is a phenomenon that has influence on cognitive aspects. The purpose of the present study was to evaluate the excessive daytime sleepiness (EDS prevalence. METHODS: 378 senior high school students from a school of Campo Grande-MS, Brazil, were interview with the Epworth Sleepiness Scale. The variables that were crosSDE with the scale were: sex, alcohol use, smoking, symptoms of depression, family income and age. For the analysis it was uSDE the chi2 test and the variance analysis test. RESULTS: Our sample consisted of 50,3% boys and 49,7% girls, 39,2% were alcohol drinkers, 6,6% were smokers and 33% had already had depression. The overall prevalence of EDS was 55,8% and of respiratory disturbance or sleep apnea was 5,3%. We found relationships

  13. Drug-induced tremor

    Science.gov (United States)

    ... tremor include the following: Cancer medicines such as thalidomide and cytarabine Seizure medicines such as valproic acid ( ... eyelids. In rare cases, the lower body is affected. The tremor may not affect both sides of ...

  14. 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. ...

  15. Drug-induced pancreatitis.

    Science.gov (United States)

    Nitsche, Claudia; Maertin, Sandrina; Scheiber, Jonas; Ritter, Christoph A; Lerch, Markus M; Mayerle, Julia

    2012-04-01

    Drugs are thought to be a rare cause for acute pancreatitis; however 525 different drugs are listed in the World Health Organization (WHO) database suspected to cause acute pancreatitis as a side effect. Many of them are widely used to treat highly prevalent diseases. The true incidence is not entirely clear since only few systematic population based studies exist. The majority of the available data are derived from case reports or case control studies. Furthermore, the causality for many of these drugs remains elusive and for only 31 of these 525 dugs a definite causality was established. Definite proof for causality is defined by the WHO classification if symptoms reoccur upon rechallenge.In the actual algorithm the diagnosis is confirmed if no other cause of acute pancreatitis can be detected, and the patient is taking one of the suspected drugs. PMID:22314811

  16. 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. ...

  17. 精神药物致脱发的识别与处理%Identification and Treatment of Psychotropic Drug-induced Alopecia

    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 .

  18. 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

  19. 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

  20. 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

  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. 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

  4. 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

  5. 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.

  6. 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

  7. Human precision-cut liver slices as an ex vivo model to study idiosyncratic drug-induced liver injury.

    Science.gov (United States)

    Hadi, Mackenzie; Westra, Inge M; Starokozhko, Viktoriia; Dragovic, Sanja; Merema, Marjolijn T; Groothuis, Geny M M

    2013-05-20

    Idiosyncratic drug-induced liver injury (IDILI) is a major problem during drug development and has caused drug withdrawal and black-box warnings. Because of the low concordance of the hepatotoxicity of drugs in animals and humans, robust screening methods using human tissue are needed to predict IDILI in humans. According to the inflammatory stress hypothesis, the effects of inflammation interact with the effects of a drug or its reactive metabolite, precipitating toxic reactions in the liver. As a follow-up to our recently published mouse precision-cut liver slices model, an ex vivo model involving human precision-cut liver slices (hPCLS), co-incubated for 24 h with IDILI-related drugs and lipopolysaccharide (LPS), was developed to study IDILI mechanisms related to inflammatory stress in humans and to detect potential biomarkers. LPS exacerbated the effects of ketoconazole and clozapine toxicity but not those of their non-IDILI-related comparators, voriconazole and olanzapine. However, the IDILI-related drugs diclofenac, carbamazepine, and troglitazone did not show synergistic toxicity with LPS after incubation for 24 h. Co-incubation of ketoconazole and clozapine with LPS decreased the levels of glutathione in hPCLS, but this was not seen for the other drugs. All drugs affected LPS-induced cytokine release, but interestingly, only ketoconazole and clozapine increased the level of LPS-induced TNF release. Decreased levels of glutathione and cysteine conjugates of clozapine were detected in IDILI-responding livers following cotreatment with LPS. In conclusion, we identified ketoconazole and clozapine as drugs that exhibited synergistic toxicity with LPS, while glutathione and TNF were found to be potential biomarkers for IDILI-inducing drugs mediated by inflammatory stress. hPCLS appear to be suitable for further unraveling the mechanisms of inflammatory stress-associated IDILI. PMID:23565644

  8. Translating clinical findings into knowledge in drug safety evaluation--drug induced liver injury prediction system (DILIps.

    Directory of Open Access Journals (Sweden)

    Zhichao Liu

    2011-12-01

    Full Text Available Drug-induced liver injury (DILI is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps. The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91% when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

  9. 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...

  10. 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...

  11. 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...

  12. 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...

  13. 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 ...

  14. 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...

  15. 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.

  16. Anti-tuberculosis drug induced hepatotoxicity among TB/HIV co-infected patients at Jimma University Hospital, Ethiopia: nested case-control study.

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    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.

  17. Cortical and Subcortical Grey and White Matter Atrophy in Myotonic Dystrophies Type 1 and 2 Is Associated with Cognitive Impairment, Depression and Daytime Sleepiness.

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    Christiane Schneider-Gold

    Full Text Available Central nervous system involvement is one important clinical aspect of myotonic dystrophy type 1 and 2 (DM1 and DM2. We assessed CNS involvement DM1 and DM2 by 3T MRI and correlated clinical and neuocognitive symptoms with brain volumetry and voxel-based morphometry (VBM.12 patients with juvenile or classical DM1 and 16 adult DM2 patients underwent 3T MRI, a thorough neurological and neuropsychological examination and scoring of depression and daytime sleepiness. Volumes of brain, ventricles, cerebellum, brainstem, cervical cord, lesion load and VBM results of the patient groups were compared to 33 matched healthy subjects.Clinical symptoms were depression (more pronounced in DM2, excessive daytime sleepiness (more pronounced in DM1, reduced attention and flexibility of thinking, and deficits of short-term memory and visuo-spatial abilities in both patient groups. Both groups showed ventricular enlargement and supratentorial GM and WM atrophy, with prevalence for more GM atrophy and involvement of the motor system in DM1 and more WM reduction and affection of limbic structures in DM2. White matter was reduced in DM1 in the splenium of the corpus callosum and in left-hemispheric WM adjacent to the pre- and post-central gyrus. In DM2, the bilateral cingulate gyrus and subgyral medio-frontal and primary somato-sensory WM was affected. Significant structural-functional correlations of morphological MRI findings (global volumetry and VBM with clinical findings were found for reduced flexibility of thinking and atrophy of the left secondary visual cortex in DM1 and of distinct subcortical brain structures in DM2. In DM2, depression was associated with brainstem atrophy, Daytime sleepiness correlated with volume decrease in the middle cerebellar peduncles, pons/midbrain and the right medio-frontal cortex.GM and WM atrophy was significant in DM1 and DM2. Specific functional-structural associations related morphological changes to cognitive impairment

  18. 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

  19. 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

  20. 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

  1. Mouse precision-cut liver slices as an ex vivo model to study idiosyncratic drug-induced liver injury.

    Science.gov (United States)

    Hadi, Mackenzie; Chen, Yixi; Starokozhko, Viktoriia; Merema, Marjolijn T; Groothuis, Geny M M

    2012-09-17

    Idiosyncratic drug-induced liver injury (IDILI) has been the top reason for withdrawing drugs from the market or for black box warnings. IDILI may arise from the interaction of a drug's reactive metabolite with a mild inflammation that renders the liver more sensitive to injury resulting in increased toxicity (inflammatory stress hypothesis). Aiming to develop a robust ex vivo screening method to study inflammatory stress-related IDILI mechanisms and to find biomarkers that can detect or predict IDILI, mouse precision-cut liver slices (mPCLS) were coincubated for 24 h with IDILI-related drugs and lipopolysaccharide. Lipopolysaccharide exacerbated ketoconazole (15 μM) and clozapine (45 μM) toxicity but not their non-IDILI-related comparators, voriconazole (1500 μM) and olanzapine (45 μM). However, the other IDILI-related drugs tested [diclofenac (200 μM), carbamazepine (400 μM), and troglitazone (30 μM)] did not cause synergistic toxicity with lipopolysaccharide after 24 h of incubation. Lipopolysaccharide further decreased the reduced glutathione levels caused by ketoconazole or clozapine in mPCLS after 24 h of incubation, which was not the case for the other drugs. Lipopolysaccharide significantly increased nitric oxide (NO), cytokine, and chemokine release into the mPCLS media, while the treatment with the drugs alone did not cause any substantial change. All seven drugs drastically reduced lipopolysaccharide-induced NO production. Interestingly, only ketoconazole and clozapine increased the lipopolysaccharide-induced granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) release. Pilot experiments showed that diclofenac and troglitazone, but not carbamazepine, demonstrated synergistic toxicity with lipopolysaccharide after a longer incubation of 48 h in mPCLS. In conclusion, we have developed an ex vivo model to detect inflammatory stress-related liver toxicity and identified ketoconazole, clozapine

  2. Sleep habits, sleepiness and accidents among truck drivers Hábitos de sono, sonolência e acidentes em caminhoneiros

    Directory of Open Access Journals (Sweden)

    José Carlos Souza

    2005-12-01

    Full Text Available OBJECTIVE: To evaluate the quality of sleep, shift work, alcohol and psychostimulant drug use, and the prevalence of accidents among truck drivers. METHOD: Data were collected using a demographic questionnaire, the Epworth Sleepiness Scale (ESS and the Pittsburgh sleep quality index (PSQI. Statistical analysis was conducted using the Student t, chi-square, Pearson and Fisher tests. RESULTS: 43.2% of the drivers drove over 16 h a day, and 2.9% worked shifts. Mean number of sleep hours/day was 5.97±1.47; 23.8% slept 5; 23 subjects snored more than three times a week (11.1%. Mean ESS was 6.56±4.2; 21.7% had a score >10. In the preceding five years, 27 drivers (13.1% were involved in accidents, 5 of which resulted in injuries and 3 in deaths. CONCLUSION: Results showed a high prevalence of sleep disorders, use of alcohol and psychostimulant drugs, and accidents.OBETIVO: Avaliar a qualidade do sono, trabalho em turnos, consumo de álcool e psicoestimulantes, e a prevalência de acidentes, entre caminhoneiros. MÉTDO: Foram aplicados questionários demográficos, a Escala de Epworth e o Índice de Pittsburgh. A análise estatística foi feita com os testes t de Student, qui-quadrado, Pearson e Fisher. RESULTADOS: 43,2% dirigiam mais que 16 h/dia; 2,9% faziam trabalho por turnos. A média de horas de sono foi 5,97 +/- 1,47. 23,8% dormiam menos de 5 horas. 50,9% faziam uso de bebida alcoólica; usavam cafeína 95,6% e anfetaminas 11,1%. A média do PSQI foi 4,95 +/- 2,56; 35,4% tinham o PSQI maior que 5; 23 sujeitos ressonavam mais que 3 vezes por semana (11,1%. A ESE teve uma média de 6,56 +/- 4,2; 21.7% um escore superior a 10. Nos últimos cinco anos 27 motoristas (13,1% estiveram envolvidos em acidentes, 5 com feridos e 3 com mortos. CONCLUSÃO: Foi alta a prevalência de distúrbios do sono, uso de álcool e estimulantes, e de acidentes.

  3. 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

  4. Genetic polymorphisms of NAT2, CYP2E1 and GST enzymes and the occurrence of antituberculosis drug-induced hepatitis in Brazilian TB patients

    Directory of Open Access Journals (Sweden)

    Raquel Lima de Figueiredo Teixeira

    2011-09-01

    Full Text Available 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 unrelated active tuberculosis patients from the University Hospital of the Federal University of Rio de Janeiro, Brazil, were enrolled in this study. Patients with a history of anti-TB drug-induced acute hepatitis (cases with an increase to 3 times the upper limit of normal serum transaminases and symptoms of hepatitis and patients with no evidence of anti-TB hepatic side effects (controls were genotyped for NAT2, CYP2E1, GSTM1 and GSTT1 polymorphisms. Slow acetylators had a higher incidence of hepatitis than intermediate/rapid acetylators [22% (18/82 vs. 9.8% (6/61, odds ratio (OR, 2.86, 95% confidence interval (CI, 1.06-7.68, p = 0.04. Logistic regression showed that slow acetylation status was the only independent risk factor (OR 3.59, 95% CI, 2.53-4.64, p = 0.02 for the occurrence of anti-TB drug-induced hepatitis during anti-TB treatment with INH-containing schemes in Brazilian individuals.

  5. 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

  6. 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

  7. 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...

  8. 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...

  9. 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...

  10. 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. ...

  11. 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...

  12. 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...

  13. 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

  14. 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

  15. 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...... 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...... compared with QTcF, p < 0.001. In subjects receiving sotalol, T-wave morphology reached similarity to LQT2, whereas QTcF did not. CONCLUSION: Distinct ECG patterns in LQT2 carriers effectively quantified repolarization changes induced by sotalol. Further studies are needed to validate whether this measure...

  16. 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。

  17. 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

  18. 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

  19. 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.

  20. 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

  1. Real Time Identification of Drug-Induced Liver Injury (DILI) through Daily Screening of ALT Results: A Prospective Pilot Cohort Study

    Science.gov (United States)

    M'Kada, Helmi; Perazzo, Hugo; Munteanu, Mona; Ngo, Yen; Ramanujam, Nittia; Fautrel, Bruno; Imbert-Bismut, Françoise; Ratziu, Vlad; Schuppe-Koistinen, Ina; Leblond, Véronique; Delattre, Jean Yves; Samson, Yves; Caen, Olivier Lyon; Bricaire, François; Khayat, David; Pierrot-Deseilligny, Charles; Herson, Serge; Amoura, Zahir; Tilleul, Patrick; Deckmyn, Olivier; Coriat, Pierre; Delpech, Vincent Nicolas; Boulogne, Philippe; Bonnefont-Rousselot, Dominique; Poynard, Thierry

    2012-01-01

    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. PMID:22905129

  2. 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.

  3. 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.

  4. 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

  5. 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

  6. 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

  7. Excessive daytime sleepiness in Campo Grande general population, Brazil Sonolência diurna excessiva na população geral de Campo Grande, MS

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    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.

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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.

  15. 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

  16. 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

  17. Analysis of IL-6, STAT3 and HSPA1L gene polymorphisms in anti-tuberculosis drug-induced hepatitis in a nested case-control study.

    Directory of Open Access Journals (Sweden)

    Jing Wang

    Full Text Available To investigate the association of IL-6, STAT3 and HSPA1L polymorphisms with the risk of anti-tuberculosis drug-induced hepatitis (ATDH in Chinese Han population.The study was designed as a nested case-control study within a prospective cohort. Each case was matched with four controls by sex, age at baseline (±5 years, treatment history, disease severity, drug dosage and place of sample collection. Genetic polymorphisms of IL-6, STAT3 and HSPA1L were determined blindly by TaqMan single-nucleotide polymorphism (SNP genotyping assay. Odds ratio (OR with 95% confidence intervals (CIs was estimated by conditional logistic regression model to measure the association between selected SNPs and the risk of ATDH.A total of 89 incident ATDH cases and 356 ATDH-free controls were genotyped for IL-6 (rs2066992, rs2069837, rs1524107, STAT3 (rs1053004, rs1053023, rs1053005 and HSPA1L (rs2227956. In genotype analysis, no significant difference was observed in genotypes frequencies of the seven selected SNPs between case and control group after Bonferroni correction. In haplotype analysis, carriers with STAT3 GAT and AGC (rs1053023-rs1053005-rs1053004 haplotypes had a significantly higher risk of ATDH compared with wild-type haplotype (P<0.0001.This study suggested that genetic variants of STAT3 might contribute to ATDH susceptibility in Chinese Han population. Studies in larger, varied populations are required to confirm these findings.

  18. 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.)

  19. Assessment of 99mTc-DMSA renoscintigraphy and uptake compared with creatinine clearance in rats with drug-induced nephrotoxicity, 1

    International Nuclear Information System (INIS)

    For evaluation of technetium-99m dimercaptosuccinic acid (99mTc-DMSA) renal uptake as an absolute renal function, 99mTc-DMSA uptake was compared with endogenous creatinine clearance (Ccr) in gentamicin-induced nephrotoxicity. Gentamicin (40 mg/kg/day) was given subcutaneously to male Wistar rats for periods of 3, 6, 9 and 12 days. On the next day, the renoscintigraphy was performed 2 hours following intravenous injection of 99mTc-DMSA and Ccr was measured. On the 7th day, 99mTc-DMSA uptake was significantly lower in the treated rats than that in control (32.27±0.92 vs 39.84±2.24%; p99mTc-DMSA uptake was measured and the histological examination was done. On the 4th day, 99mTc-DMSA uptake was significantly lower than that on the 1st day (32.32±3.00 vs 38.91±1.95%; p99mTc-DMSA uptake reduces earlier than Ccr in gentamicin-induced nephrotoxicity and 99mTc-DMSA uptake is a reliable indicator in the evaluation of a renal function in drug-induced nephrotoxicity. (author)

  20. 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

  1. 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

  2. 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

  3. 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...

  4. [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

  5. 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

  6. 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...

  7. Drug-induced pulmonary disease

    Science.gov (United States)

    ... mediastinitis ) Abnormal buildup of fluid in the lungs ( pulmonary edema ) Buildup of fluid between the layers of tissue that line the lungs and chest cavity ( pleural effusion ) Many ... as bleomycin, cyclophosphamide, and methotrexate Illegal drugs

  8. [Drug-induced ventricular tachycardia].

    Science.gov (United States)

    Fauchier, J P; Fauchier, L; Babuty, D; Breuillac, J C; Cosnay, P; Rouesnel, P

    1993-05-01

    Certain drugs can induce ventricular tachycardia (VT) by creating reentry, ventricular after potentials or exaggerating the slope of phase 4. These may or may not be symptomatic, sustained or non-sustained and have variable ECG appearances: monomorphic or polymorphic, bidirectional, torsades de pointes. They risk degenerating into ventricular flutter of fibrillation and have been held responsible for the increased mortality observed unexpectedly in some long-term treatments. The drugs responsible are mainly those used in cardiology, probably due to predisposing circumstances (cardiomegaly, cardiac failure, previous severe ventricular arrhythmias, therapeutic associations, metabolic abnormalities). These include primarily the antiarrhythmic drugs (IA, IC, sotalol and bepridil), digitalis, sympathomimetics and phosphodiesterase inhibitors. These complications may be toxic or idiosyncratic, in patients with or without cardiac disease, and may also occur with other drugs: vasodilators and anti-anginal drugs (lidoflazine, vincamine, fenoxedil), psychotropic agents (phenothiazine and imipramine), antimitotics, antimalarials (chloroquine) or antibiotics (erythromycin, pentamidine). The prognosis is severe and the treatment is often difficult which makes prevention, helped by repeated surface ECG (or Holter monitoring), very important with careful assessment of patients at risk. PMID:8267504

  9. [Drug-induced thyroid dysfunctions].

    Science.gov (United States)

    Krysiak, Robert; Okopień, Bogusław

    2014-01-01

    latrogenic disorders are an important cause of morbidity, mortality, and admission to hospital in developed countries. Similarly to many other organs, the thyroid gland may be affected by various drugs, often used for the treatment of non-thyroid disorders. Drugs may affect thyroid function via different mechanisms, including thyroid hormone production, storage, secretion and metabolism offering numerous targets for drug interventions. Usually, the effect of pharmacotherapy is observed more frequently and is stronger in case of the presence of the concomitant disorder of this gland. An understanding of the proposed mechanisms of these drug interactions and their evaluation and differential diagnosis is helpful in the interpretation of the findings associated thyroid disorders and in establishing the correct treatment. The purpose of this article is to review the present state of knowledge on the influence of various drugs on the hypothalamic-pituitary-adrenal axis. We discuss pros and cons of the use of these agents in patients with concomitant thyroid disease and provide the reader with recommendations concerning the diagnosis and treatment of iatrogenic thyroid disorders. PMID:26030960

  10. 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.

  11. 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

  12. 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.

  13. 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

  14. 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.

  15. 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

  16. 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.

  17. 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

  18. 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

  19. 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

  20. Cansancio y somnolencia en conductores de ómnibus y accidentes de carretera en el Perú: estudio cuantitativo Tiredness and sleepiness in bus drivers and road accidents in Peru: a quantitative study

    Directory of Open Access Journals (Sweden)

    Jorge Rey de Castro

    2004-07-01

    Full Text Available OBJETIVO: Evaluar la relación del cansancio y la somnolencia en los conductores de ómnibus con los accidentes de carretera. La información obtenida de diversos países atribuye a la somnolencia del conductor una parte importante en la génesis de los accidentes de carretera. No obstante, la información al respecto es escasa en el caso del Perú. MÉTODOS: Se realizó un estudio transversal, de índole observacional y comparativa, basado en una encuesta prevalidada y de aplicación supervisada, entre 238 conductores de ómnibus que circulan por la carretera Panamericana Norte del Perú. Para determinar la relación entre variables se emplearon la prueba de ji al cuadrado y el índice de Pearson, con un valor de significación de P OBJECTIVE: To evaluate the relationship that tiredness and sleepiness in bus drivers have to road accidents in Peru. Information from various countries indicates that driver sleepiness plays an important role in road accidents. However, there is only limited information on this subject in Peru. METHODS: Using a supervised, pretested survey, a cross-sectional observational and comparative study was carried out with 238 bus drivers who drive on the Northern Pan American Highway of Peru. To determine the relationship between variables the chi-square test was used, along with the Pearson correlation coefficient. The level of significance was set at P < 0.05. The variables analyzed were: tiredness, sleepiness, hours of driving per day, daily hours of sleep, body mass index, snoring, sleep apnea, and either having had or almost having had an accident while driving. RESULTS: Of the 238 drivers, all of them were men, 45% said they had had or nearly had had an accident while driving, 55% slept less than 6 hours per day, 31% had slept less than 6 hours in the 24 hours before answering the survey, and 80% were in the habit of driving more than 5 hours without stopping. Of the drivers, 56% of them reported being tired at least

  1. 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

  2. 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

  3. 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

  4. 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.

  5. 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

  6. 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

  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. 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。

  9. 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.

  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. 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

  12. 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

  13. 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.

  14. 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.

  15. Adding 5-hydroxytryptamine receptor type 3 antagonists may reduce drug-induced nausea in poor insight obsessive-compulsive patients taking off-label doses of selective serotonin reuptake inhibitors: a 52-week follow-up case report

    Directory of Open Access Journals (Sweden)

    Martino Matteo

    2010-12-01

    Full Text Available Abstract Poor-insight obsessive-compulsive disorder (PI-OCD is a severe form of OCD where the 'typically obsessive' features of intrusive, 'egodystonic' feelings and thoughts are absent. PI-OCD is difficult to treat, often requiring very high doses of serotonergic drugs as well as antipsychotic augmentation. When this occurs, unpleasant side effects as nausea are common, eventually further reducing compliance to medication and increasing the need for pharmacological alternatives. We present the case of a PI-OCD patient who developed severe nausea after response to off-label doses of the selective serotonin reuptake inhibitor (SSRI, fluoxetine. Drug choices are discussed, providing pharmacodynamic rationales and hypotheses along with reports of rating scale scores, administered within a follow-up period of 52 weeks. A slight reduction of fluoxetine dose, augmentation with mirtazapine and a switch from amisulpride to olanzapine led to resolution of nausea while preserving the anti-OCD therapeutic effect. Mirtazapine and olanzapine have already been suggested for OCD treatment, although a lack of evidence exists about their role in the course of PI-OCD. Both mirtazapine and olanzapine also act as 5-hydroxytryptamine receptor type 3 (5-HT3 blockers, making them preferred choices especially in cases of drug-induced nausea.

  16. Polyarticular heterotopic ossification complicating drug induced coma

    OpenAIRE

    G.D. Sebastiani; S. Antonelli

    2011-01-01

    The Authors describe a case of generalised heterotopic ossification (HO) complicating the course of a 31 years old male patient, with a history of Hodgkin’s lymphoma and a of long staying in an intensive care unit, where he had been placed on artificial coma. The clinical features, as well as radiological findings and therapy, are discussed.

  17. Polyarticular heterotopic ossification complicating drug induced coma

    Directory of Open Access Journals (Sweden)

    G.D. Sebastiani

    2011-09-01

    Full Text Available The Authors describe a case of generalised heterotopic ossification (HO complicating the course of a 31 years old male patient, with a history of Hodgkin’s lymphoma and a of long staying in an intensive care unit, where he had been placed on artificial coma. The clinical features, as well as radiological findings and therapy, are discussed.

  18. Toxic and drug-induced liver disease

    Institute of Scientific and Technical Information of China (English)

    1997-01-01

    970353 Distribution and significance of endothelin-1and endothelin receptor a mRNA in liver after endo-toxemia. LIU Baohua(刘宝华), et al. Dept Surg, Dap-ing Hosp, 3rd Milit Med Univ, Chongqing, 630042.Natl Med J China 1997; 77(3): 171-173. Objective: To study the distribution and significance

  19. Drug-induced progressive multifocal leukoencephalopathy

    DEFF Research Database (Denmark)

    Vermeer, N S; Straus, S M J M; Mantel-Teeuwisse, A K;

    2015-01-01

    lifecycle: natalizumab (before reapproval) and rituximab (nine years postapproval). We found that, apart from the differences in clinical characteristics (age, gender, indication, time to event, fatality), which reflect the diversity in context of use, PML reports for natalizumab were more complete and were...... to such comparisons. Lumping uncharacterized PML reports together without taking these differences into account may result in biased comparisons and flawed conclusions about differential safety....

  20. Targeted drug induces responses in aggressive lymphomas

    Science.gov (United States)

    Preliminary results from clinical trials in a subtype of lymphoma show that for a number of patients whose disease was not cured by other treatments, the drug ibrutinib can provide significant anti-cancer responses with modest side effects.

  1. Drug-induced immune hemolytic anemia

    Science.gov (United States)

    Immune hemolytic anemia secondary to drugs; Anemia - immune hemolytic - secondary to drugs ... Drugs that can cause this type of hemolytic anemia include: Cephalosporins (a class of antibiotics), most common ...

  2. Enrofloxacin drug induced reactive oxygen species

    OpenAIRE

    Ishraga G. Ibrahim; Yarsan E

    2011-01-01

    Fluroquinolones drugs are known to have adverse effects including chondriotoxicity, however, the mechanism of this effect was not fully understood. To investigate the possibility of the involvement of oxidative stress in this mechanism, enrofloxacin was administered orally to 80 broiler chicks for 15 and 30 days at 100, 200 and 400 mg/kg body weight and the activities of some antioxidant enzymes and malondialdehide (MDA) blood levels were studied. An increase in MDA levels and decrease in the...

  3. Pharmacogenetics of drug-induced arrhythmias

    DEFF Research Database (Denmark)

    De Bruin, Marie L; van Puijenbroek, Eugene P; Bracke, Madelon;

    2006-01-01

    PURPOSE: The bottleneck in pharmacogenetic research on rare adverse drug reactions (ADR) is retrieval of patients. Spontaneous reports of ADRs may form a useful source of patients. We investigated the feasibility of a pharmacogenetic study, in which cases were selected from the database of a...... included in the study, giving an overall participation rate of 9% (4/45). The main reason for GPs not being willing to participate was lack of time. Variants were identified in KCNH2, SCN5A and KCNE1. CONCLUSIONS: Spontaneous reporting systems for ADRs may be used for pharmacogenetic research. The methods...

  4. Drug-Induced Rosacea-like Dermatitis.

    Science.gov (United States)

    Rezaković, Saida; Bukvić Mokos, Zrinka; Paštar, Zrinjka

    2016-04-01

    Rosacea is a common, chronic cutaneous disorder with a prevalence of 0.5-10%, predominantly affecting women. The disease presents with a heterogeneous clinical picture characterized by transient flushing, persistent facial redness, telangiectasias, and, in more severe clinical forms, the presence of inflammatory papules and pustules in the central third of the face. Although its pathophysiology is complex and still remains unknown, factors that exacerbate the disease are well defined. They include genetic predisposition as well as external factors such as exposure to UV light, high temperature, and diet. Besides these well-known factors, recent studies suggest that drugs and vitamins could also be possible factors inducing rosacea-like dermatitis or aggravating pre-existing rosacea. Although these are less common possible triggering factors, the aim of this article is to present the current knowledge on the association between use of certain drugs or vitamins and rosacea. PMID:27149131

  5. Drug-induced immune hemolytic anemia

    Science.gov (United States)

    Immune hemolytic anemia secondary to drugs; Anemia - immune hemolytic - secondary to drugs ... early. Drugs that can cause this type of hemolytic anemia include: Cephalosporins (a class of antibiotics), most common ...

  6. Drug induced acute pancreatitis: Does it exist?

    OpenAIRE

    Tenner, Scott

    2014-01-01

    As the incidence of acute pancreatitis continues to rise, establishing the etiology in order to prevent recurrence is important. Although the etiology of acute pancreatitis is not difficult in the majority of patients, almost a quarter of patients are initially labeled as having idiopathic acute pancreatitis. When confronted with a patient with acute pancreatitis and no clear etiology defined as an absence alcoholism, gallstones (ultrasound and/or MRI), a normal triglyceride level, and absenc...

  7. Non-chemotherapy drug-induced agranulocytosis.

    Science.gov (United States)

    Garbe, Edeltraut

    2007-05-01

    Acute agranulocytosis is a rare, potentially life-threatening condition, which is attributable to drugs in > 70% of cases. Agranulocytosis is characterised by a peripheral neutrophil count clozapine, ticlopidine, sulfasalazine, dipyrone, trimethoprim/sulfamethoxazole, carbamazepine and probably rituximab. Suspect drugs should be stopped immediately. In febrile patients, blood cultures and, where indicated, site-specific cultures should be obtained and treatment with empirical broad spectrum antibiotics started. Haematopoietic growth factors should be considered in patients with poor prognostic factors (e.g., a neutrophil count < 0.1 x 10(9)/l), severe clinical infection or severe underlying disease or comorbidity. Case fatality has decreased to ~ 5% in recent years, probably owing to improved intensive care treatment and increased alertness of physicians to this severe adverse reaction. PMID:17480181

  8. Toxic and drug-induced liver disease

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    2009211 Effects of curcumin solid dispersion on oxidative stress of alcoholic hepatic injury in rats.HAN Gang(韩刚),et al.Pharmac Sci,North China Coal Med Univ,Tangshan 063000.World Chin J Digestol,2009;17(5):500-503.

  9. Antithyroid drug-induced fetal goitrous hypothyroidism

    DEFF Research Database (Denmark)

    Rasmussen, Ase Krogh; Sundberg, Karin; Brocks, Vibeke;

    2011-01-01

    Maternal overtreatment with antithyroid drugs can induce fetal goitrous hypothyroidism. This condition can have a critical effect on pregnancy outcome, as well as on fetal growth and neurological development. The purpose of this Review is to clarify if and how fetal goitrous hypothyroidism can be...... prevented, and how to react when prevention has failed. Understanding the importance of pregnancy-related changes in maternal thyroid status when treating a pregnant woman is crucial to preventing fetal goitrous hypothyroidism. Maternal levels of free T(4) are the most consistent indication of maternal and...... fetal thyroid status. In patients with fetal goitrous hypothyroidism, intra-amniotic levothyroxine injections improve fetal outcome. The best way to avoid maternal overtreatment with antithyroid drugs is to monitor closely the maternal thyroid status, especially estimates of free T(4) levels....

  10. 药物诱导后胚胎胰腺干细胞胰岛素分泌研究%STUDY ON INSULIN SECRETION BY DRUG-INDUCED EMBRYONIC PANCREATIC STEM CELLS

    Institute of Scientific and Technical Information of China (English)

    孟娟; 吴春梅; 许评; 刘杰; 谭雪莹

    2013-01-01

    目的 探讨胚胎胰腺干细胞经药物诱导为胰岛素分泌细胞(IPCs)后的胰岛素分泌情况.方法 体外分离培养获得的胚胎胰腺干细胞,经药物诱导后,双硫腙(DTZ)染色鉴定IPCs的形成情况;分别采用高浓度(25.0 mmol/L)和低浓度(5.5 mmol/L)的葡萄糖溶液刺激诱导后的细胞,ELISA方法检测该细胞群2周内胰岛素的分泌情况.结果 经诱导后IPCs在两种浓度葡萄糖溶液刺激下均分泌胰岛素,且高浓度葡萄糖溶液刺激下胰岛素分泌量明显高于低浓度葡萄糖溶液(t=7.228,P<0.01).IPCs在糖溶液刺激下第7天与第9天的胰岛素分泌量明显高于其他各天(F=38.373,q =3.033~6.085,P<0.05);第7天与第9天比较差异无显著性(P>0.05).结论 离体条件下,胚胎胰腺干细胞经药物诱导成为IPCs后,2周内可持续分泌胰岛素,其胰岛素释放量在诱导后第7~9天达到最大值,可作为胰岛移植的最佳时期.%Objective To explore the insulin secretion of insulin-producing cells (IPCs) derived from drug-induced embryonic stem cells (ESCs).Methods Embryonic pancreatic stem cells were isolated and cultured in vitro,and induced by drug,the formation of IPCs was identified by dithizone (DTZ) staining.The induced cells were then stimulated by high-concentration (25.0 mmol/L) and low-concentration glucose solution (5.5 mmol/L),respectively.ELISA was applied to determine insulin production of the cells in two weeks.Results The induced IPCs secreted insulin after stimulation by low-or high-concentration glucose solution,and the cells stimulated by high-concentration one secreted much more insulin (t =7.228,P <0.01).The insulin secretion of IPCs on days 7-9 after glucose stimulation was higher than other days (F=38.373,q=3.033-6.085,P<0.05).Conclusion In vitro,IPCs derived from drug-induced ESCs can continuously secrete insulin for two weeks,and the highest level of insulin secretion was observed on days 7-9,which can be regarded

  11. 我院104例药物性肝损害临床分析Δ%Clinical Analysis of 104 Cases of Drug-induced Liver Injury in Our Hospital

    Institute of Scientific and Technical Information of China (English)

    刘露; 梁桂林; 刘占奎; 徐新

    2015-01-01

    OBJECTIVE:To explore the clinical features and regularity of drug-induced liver injury (DILI),and to provide reference for clinical rational drug use. METHODS:104 DILI cases in our hospital from 2005 to 2014 were selected and analyzed retrospectively in respects of patient’s gender,age,allergic history,medication history,drug type and clinical manifestations. RE-SULTS:DILI hospitalized cases increased year by year. There were 47 males and 57 females,and average age was(8.71±13.90). The clinical symptoms appeared within 12 weeks after using the drug. The symptoms were no specific,including weak,anorexia, jaundice,yellow urine,etc. and 10.57% of patients were asymptomatic. Most of the DILI cases were hepatocyte type(80.77%), followed by cholestasis type(12.50%)and hybrid type(6.73%). The most common cause of drug-induced liver injury were TCM, antimicrobial drugs and the nervous system drugs. CONCLUSIONS:The incidence of DILI in females is slightly higher than males. DILI often occurs after 40 years old. The clinical symptoms have no specificity and are similar to viral hepatitis. The hepatic lesions can be caused by most of drugs. DILI by TCM should concerned. Clinical physicians should pay more attention to DILI.%目的:探讨药物性肝损害(DILI)的临床特点及其发生规律,为临床合理用药提供参考。方法:对我院2005-2014年发生的104例药物性肝损害患者的性别、年龄、发病时间、药品品种、临床表现等临床资料进行回顾性分析。结果:DILI住院病例逐年增多,其中男性47例,女性57例,平均年龄(48.71±13.90)岁;开始用药后至开始出现临床症状时间绝大多数在12周以内;临床症状包括纳差、乏力、身目黄染、上腹不适等,均无特异性;10.57%患者为无症状,临床分型以肝细胞损伤型最多(80.77%),胆汁淤积型次之(12.50%),混合型最少(6.73%)。最常见的引起肝损害药物依次为中

  12. 抗癫痫药物等引发药疹与人类白细胞抗原基因的相关性研究%Drug-induced cADR and polymorphism of HLA genes:A correlational study

    Institute of Scientific and Technical Information of China (English)

    吴培培; 李奕; 杨飞; 乔海灵; 杨静

    2013-01-01

    目的 探讨抗癫痫药物等引发药疹与HLA基因多态性的相关性,以期为药疹的预防和治疗提供依据.方法 收集48例药疹患者,采用PCR-SSP方法检测HLA-B*1502、HLA-A*0206、HLA-A*3101、HLA-A*1101、HLA-B*5901、HLA-Cw*0704、HLA-Cw*0801、HLA-DRB1*1202等8个等位基因.采用RT-PCR检测HLA-B*1502基因阳性者中mRNA表达水平.结果 药物引发的药疹可能与HLA-B*1502、HLA-Cw*0801、HLA-A*0206和HLA-Cw*0704等位基因相关(P<0.05);其中抗癫痫药物引发的重症药疹与HLA-B*1502等位基因的相关性最强(P<0.01);且抗癫痫药物引发的重症药疹HLA-B*1502 mRNA的表达水平明显高于耐受组及对照组(P<0.01).结论 抗癫痫药物引发的重症药疹与HLA-B*1502等位基因密切相关.HLA-B*1502mRNA表达水平可以作为预测抗癫痫药物诱发重症药疹的重要指标.%Aim To explore the association between cutaneous adverse drug reactions( Cadr ) and HLA genetic polymorphisms in patients with drug eruption, in order to provide basis for guarding and treating drug e-ruptions. Methods Forty-eight patients with drug-induced Cadr were enrolled to detect HLA-B * 1502, HLA-A * 0206, HLA-A * 3101, HLA-A * 1101, HLA-B* 5901, HLA-Cw* 0704, HLA-Cw* 0801, HLA-DRB1 * 1202 alleles by polymerase chain reaction with sequence specific primers( PCR-SSP ). The changes of HLA-B * 1502 Mrna level were detected by relative fluorescence quantitative PCR( RT-PCR ). Results HLA-B* 1502, HLA-Cw* 0801, HLA-A* 0206 and HLA-Cw * 0704 alleles might be associated with drug-induced cADR ( P < 0. 05 ). Of which, HLA-B * 1502 allele showed the highest relative risk for bullous drug cADR with SJS/TEN ( P < 0. 01 ). Compared with control and AED-tolerant group respectively, the levels of HLA-B * 1502 mRNA in AED-induced SJS/TEN group indicated a marked increase ( P < 0. 01 ). Conclusions HLA-B * 1502 allele is strongly associated with AED-induced SJS/TEN. Detection of HLA-B* 1502 mRNA level can be the important

  13. Metabolomic analysis of glycerophospholipid signatures of inflammation treated with non-steroidal anti-inflammatory drugs-induced-RAW264.7 cells using (1)H NMR and U-HPLC/Q-TOF-MS.

    Science.gov (United States)

    Wu, Xia; Cao, Han; Zhao, Lifang; Song, Jianao; She, Yuqi; Feng, Yifan

    2016-08-15

    Non-destructive proton nuclear magnetic resonance ((1)H NMR) spectroscopy and highly sensitive ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (U-HPLC/Q-TOF-MS) coupled to data processing methods were applied to analyze the metabolic profiling changes of glycerophospholipids (GPLs) in RAW264.7 cells from inflammation to prognosis. Analysis of (1)H NMR was shown that the models were grouped successfully, illustrating that all of them had significant differences. Based on the highly simple, accurate, non-targeted and non-destructively advantages of (1)H NMR, it could be used as a new screening tool of anti-inflammatory drugs in the metabolic profiling of GPLs. 58 GPLs were identified by U-HPLC/Q-TOF-MS, and 19 components were firstly identified in this study compared with our previous results. In addition, ten potential biomarkers were proved, of which phosphatidylcholine (PC) (16:0/18:1) and (18:0/18:1) changed consistently in three drug-induced groups and might be the important biomarkers. Compared with (1)H NMR, U-HPLC/Q-TOF-MS showed higher sensitivity and specificity and was more suitable for the determination of biomarkers apart from the deficiency of time-consuming sample preparation steps and unambiguous metabolite identification. Therefore, it is feasible to analyze the changes of GPLs during inflammation by combining (1)H NMR spectroscopy with U-HPLC/Q-TOF-MS. The metabolic profiling of GPLs provides valuable evidence for inflammation diagnosis and prognosis, and might unravel the mechanisms involved in inflammation progression. PMID:27371817

  14. 牙周基础治疗对药物性牙龈增生的疗效观察%Effect of initial periodontal therapy on drug-induced gingival hyperplasia

    Institute of Scientific and Technical Information of China (English)

    马兆峰; 张建霞; 孙丽荣; 李石

    2011-01-01

    目的:评价牙周基础治疗对钙拮抗剂导致的药物性牙龈增生的治疗效果.方法:钙拮抗剂导致的牙龈增生患者7例,在治疗前和牙周基础治疗后1、3、6个月各时点分别记录菌斑指数(plaque index,PLI),出血指数(bleeding index,BI),探诊深度(probing depth,PD)和牙龈增生指数(gingival hyperplasia index,GHI),7例患者完成7至少6个月的观察.结果:在观察期间,牙龈炎症状态指标(PLI、BI、PD)持续减轻(P<0.01),牙龈增生状态(GHI)持续改善.结论:牙周基础治疗可改善钙拮抗剂药物引起牙龈增生的程度.%Objective The objective of this study is to evaluate the effect of initial periodontal therapy on gingival hyperplasia induced by calcium channel blocker. Methods Seven patients with gingival hyperplasia induced by calcium channel blocker were collected.The bleeding index (BI), plaque index (PI), probing depth (PD) and gingival hyperplasia index (GHI) were scored at time of first periodontal therapy, 1 month,3 months and 6 months. Results During the longitudinal survey,the extent of gingival hyperplasia and gingivitis gradually reduced. Conclusion Initial periodontal therapy may successfully decrease the severity of drug-induced gingival hyperplasia for at least 6 months.

  15. Analysis and Pharmaceutical Care Performed by Clinical Pharmacist for 2 Cases of Drug-induced Acute Kidney Injury%临床药师参与2例药物所致急性肾损伤的分析与药学监护

    Institute of Scientific and Technical Information of China (English)

    李丹; 韩静静; 吴杰; 郭咸希; 雷嘉川; 宋金春

    2015-01-01

    Objective: To provide some experience and help for the pharmaceutical care for drug-induced acute kidney injury through analysis and pharmaceutical care performed by clinical pharmacist for two cases of drug-induced acute kidney injury. Meth-ods:Clinical pharmacist analyzed the mechanism of drug-induced acute kidney injury, provided some suggestions for the medication, helped doctors select hormone drugs reasonably and performed medical education in the patients. Results:The kidney function of the two patients was recovered during the hospitalization after the reasonable treatment and care by doctors and pharmacists. Conclusion:The drug-induced acute kidney injury should be paid high attention, and the medical education should be strengthened in the patients.%目的:临床药师通过对2例药物所致急性肾损伤的分析总结及药学监护,期望为药物所致的急性肾损伤的药学监护提供一些经验和帮助. 方法:药师通过分析药物所致急性肾损伤的机制并给出用药建议,协助医师合理选用激素并对患者进行用药教育和指导. 结果:在医师的合理治疗和药师的悉心监护下,2例患者肾功能在住院期间恢复. 结论: 应加强患者的用药教育,药物所致的急性肾损伤应引起高度重视.

  16. Excessive daytime sleepiness of the Brazilian emperor Dom Pedro II probably due to sleep apnea syndrome Sonolência diurna excessiva de Dom Pedro II do Brasil devida provavelmente à síndrome de apnéia do sono

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    Rubens Reimão

    2008-01-01

    Full Text Available OBJECTIVE: To show that the obstructive sleep apnea syndrome (OSAS was the probable cause of D. Pedro II's excessive daytime sleepiness. METHOD: Research of historical documents and bibliographical. RESULTS: The excessive daytime sleepiness of D. Pedro II (1825-1891 was well known and bitterly criticized behavior by oppositionist magazines; it was also recognized by his peers. He would fall asleep in public places such as the theater and while attending lectures. As a youth, he was of normal complexion, putting on weight (obesity at middle years. CONCLUSION: The possibility of this diagnosis is particularly relevant in this case because it points to an organic cause for D. Pedro II daytime naps and excessive daytime sleepiness. It could be the result of OSAS and not "disinterest" as erroneously assumed at that time.OBJETIVO: Evidenciar a síndrome de apnéia do sono tipo obstrutivo (SASO como provável causa da sonolência diurna excessiva de D. Pedro II. MÉTODO: Pesquisa de documentos históricos e bibliográfica. RESULTADOS: A sonolência diurna excessiva de D. Pedro II (1825-1891 era bem conhecida e criticada enfaticamente pelas revistas oposicionistas, era também reconhecida pelos seus pares. Ele adormecia em lugares públicos como no teatro e ao assistir aulas. Como jovem ele tinha compleição normal, ganhando peso (obesidade na meia idade. CONCLUSÃO: A possibilidade deste diagnóstico é particularmente relevante neste caso porque aponta para uma causa orgânica para os cochilos diurnos e a sonolência diurna excessiva. Pode se dever à SASO e não ao "desinteresse" como erroneamente admitido naquela época.

  17. Rapid preparation process of antiparkinsonian drug Mucuna pruriens silver nanoparticle by bioreduction and their characterization

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    Subramanian Arulkumar

    2010-01-01

    Full Text Available Backgorund: Development of biologically inspired experimental processes for the synthesis of nanoparticles is evolving an important branch of nanotechnology. Methods: The bioreduction behavior of plant seed extract of Mucuna pruriens in the synthesis of silver nanoparticles was investigated employing UV/visible spectrophotometry, X-ray diffraction (XRD, and transmission electron microscopy (TEM, Fourier transform - infra red (FT- IR. Result: M. pruriens was found to exhibit strong potential for rapid reduction of silver ions. The formation of nanoparticles by this method is extremely rapid, requires no toxic chemicals, and the nanoparticles are stable for several months. Conclusion: The main conclusion is that the bioreduction method to produce nanoparticles is a good alternative to the electrochemical methods and it is expected to be biocompatible.

  18. Evaluation of anti-parkinsonian activity of Elaeocarpus ganitrus on haloperidol induced Parkinson's disease in mice

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    Harish G. Bagewadi

    2015-02-01

    Conclusions: Oxidative stress plays a vital role in the pathophysiology of PD. The results of this study conclusively show that E. ganitrus has anti-oxidant activity and neuroprotective activity in haloperidol experimental model of PD. [Int J Basic Clin Pharmacol 2015; 4(1.000: 102-106

  19. In vitro alternatives to safety assessment of drug-induced hypersensitivity reactions%药物超敏反应安全评价体外替代方法的研究进展

    Institute of Scientific and Technical Information of China (English)

    张瑞霞; 林海霞; 汤纳平; 马璟

    2012-01-01

    超敏反应是药物的严重不良反应之一,严重时可危及患者生命.目前超敏反应(Ⅰ,Ⅳ型)临床前评价方法多为整体动物实验方法,基于动物福利和3R原则的考虑,以及体外替代方法的迅速发展,目前已建立了数种药物致敏性评价的体外替代方法,包括根据肥大细胞和嗜碱性粒细胞在Ⅰ型超敏反应中发挥的关键作用,用实验室易获得的肥大细胞和嗜碱性粒细胞系如RBL-2H3和KU812研究药物的Ⅰ型超敏反应,另外鉴于树突状细胞在Ⅳ型超敏反应中抗原呈递作用,用THP-1细胞构建的h-CLAT试验体系和LC-SA试验体系在皮肤致敏性的评价方面都显示出较好的发展前景.本文综合近年的国内外文献,对超敏反应的体外替代方法进行了综合论述和评估.%As one of the most frequent adverse effects induced by drugs, hypersensitivity reactions may result in severe morbidity and fatalities. It's critical to evaluate the allergy potential of new drugs and other chemicals, and usually animal experiments are used in the preclinical assessment. Considering animal welfare and 3R principles, in vitro alternatives to animal experiments have been developed to predict the hypersensitivity potential by simulating the physiological and pathological mechanism of hypersensitivity. The available cell lines RBI.-2H3 and KL812 are used to study type I hypersensitivity because mast cells and basophils play a critical role in the process of type ] hypersensitivity. Similarly, because dendritic cells are important APC, h-CLAT (human cell line activation test) and LCSA (loose -fit coculture-based sensitization assay) are established to evaluate type IV hypersensitivity. Throuth reviewing the literature in recent years, this article makes a comprehensive introduction and evaluation of the alternatives to safety assessment of drug-induced hypersensitivity reactions.

  20. TV and Sex Make Americans Sleepy

    Institute of Scientific and Technical Information of China (English)

    朱吉利

    2001-01-01

    本文让我们窥见了美国的“隐私”一隅。在美国失眠者不在少数,他们有什么安然入梦之良策?似乎男女各有招数: For women, reading came in as the best way to fall asleep, followed by watching TV and prayer or meditation(冥想). Men favored TV viewing and sex——although women also acknowledged the sleep-inducing powers of sex. When asked if sex before bed helped them fall asleep, three quarters of respondents said it did.】