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Sample records for pob1 induce drug

  1. BTB-BACK Domain Protein POB1 Suppresses Immune Cell Death by Targeting Ubiquitin E3 ligase PUB17 for Degradation.

    Directory of Open Access Journals (Sweden)

    Beatriz Orosa

    2017-01-01

    Full Text Available Hypersensitive response programmed cell death (HR-PCD is a critical feature in plant immunity required for pathogen restriction and prevention of disease development. The precise control of this process is paramount to cell survival and an effective immune response. The discovery of new components that function to suppress HR-PCD will be instrumental in understanding the regulation of this fundamental mechanism. Here we report the identification and characterisation of a BTB domain E3 ligase protein, POB1, that functions to suppress HR-PCD triggered by evolutionarily diverse pathogens. Nicotiana benthamiana and tobacco plants with reduced POB1 activity show accelerated HR-PCD whilst those with increased POB1 levels show attenuated HR-PCD. We demonstrate that POB1 dimerization and nuclear localization are vital for its function in HR-PCD suppression. Using protein-protein interaction assays, we identify the Plant U-Box E3 ligase PUB17, a well established positive regulator of plant innate immunity, as a target for POB1-mediated proteasomal degradation. Using confocal imaging and in planta immunoprecipitation assays we show that POB1 interacts with PUB17 in the nucleus and stimulates its degradation. Mutated versions of POB1 that show reduced interaction with PUB17 fail to suppress HR-PCD, indicating that POB1-mediated degradation of PUB17 U-box E3 ligase is an important step for negative regulation of specific immune pathways in plants. Our data reveals a new mechanism for BTB domain proteins in suppressing HR-PCD in plant innate immune responses.

  2. Drug-induced thrombocytopenia

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, U; Andersen, M; Hansen, P B

    1997-01-01

    induced by non-cytotoxic drugs is characterised by heterogeneous clinical picture and recovery is generally rapid. Although corticosteroids seem inefficient, we still recommend that severe symptomatic cases of drug-induced thrombocytopenia are treated as idiopathic thrombocytopenic purpura due...

  3. [Drug induced diarrhea].

    Science.gov (United States)

    Morard, Isabelle; Hadengue, Antoine

    2008-09-03

    Diarrhea is a frequent adverse event involving the most frequently antibiotics, laxatives and NSAI. Drug induced diarrhea may be acute or chronic. It may be due to expected, dose dependant properties of the drug, to immuno-allergic or bio-genomic mechanisms. Several pathophysiological mechanisms have been described resulting in osmotic, secretory or inflammatory diarrhea, shortened transit time, or malabsorption. Histopathological lesions sometimes associated with drug induced diarrhea are usually non specific and include ulcerations, inflammatory or ischemic lesions, fibrous diaphragms, microscopic colitis and apoptosis. The diagnosis of drug induced diarrhea, sometimes difficult to assess, relies on the absence of other obvious causes and on the rapid disappearance of the symptoms after withdrawal of the suspected drug.

  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 and depigmented, but maintains the ...

  5. Drug induced aseptic meningitis

    African Journals Online (AJOL)

    PROF. EZECHUKWU

    2013-09-29

    Sep 29, 2013 ... Abstract. Drug-induced aseptic meningitis (DIAM) is a rare but important and often challenging diagnosis for the physician. Intake of antimicrobials, steroids, anal- gesics amongst others has been implicated. Signs and symptoms generally develop within 24-48 hours of drug ingestion. The pa- tient often ...

  6. Drug-induced apnea.

    Science.gov (United States)

    Boutroy, M J

    1994-01-01

    Drugs have been in the past and will in the future still be liable to induce apnea in neonates, infants and older children. At these different stages of development, the child may be abnormally vulnerable to respiratory disorders and apnea, and doses of drugs, without any abnormal side effects in adult patients, can be harmful in younger subjects. Drugs responsible for apnea during development are numerous, but more than half of the problems are induced by sedatives and hypnotics, among which phenothiazines, barbiturates, benzodiazepines (included transplacentally acquired) and general anesthetics are a few. Other pharmacological families are apnea inducers in the neonatal period and childhood: analgesics and opioid narcotics, agents acting at the levels of neuromuscular function and autonomic ganglia, and cardiovascular agents. The pathogenesis of these apneas depends on the disturbance of any mechanism responsible for the respiratory activity: medullary centers and brain stem structures, afferent influx to CNS, sleep stages, upper airways, lungs and respiratory muscles. At key stages such as birth and infancy, drugs may emphasize the particular sensitivity of the mechanisms responsible for inducing apnea. This might explain unexpected respiratory disorders during development.

  7. Drug-induced hair loss.

    Science.gov (United States)

    2016-05-01

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

  8. Drug induced lung disease

    International Nuclear Information System (INIS)

    Schaefer-Prokop, Cornelia; Eisenhuber, Edith

    2010-01-01

    There is an ever increasing number of drugs that can cause lung disease. Imaging plays an important role in the diagnosis, since the clinical symptoms are mostly nonspecific. Various HRCT patterns can be correlated - though with overlaps - to lung changes caused by certain groups of drugs. Alternative diagnosis such as infection, edema or underlying lung disease has to be excluded by clinical-radiological means. Herefore is profound knowledge of the correlations of drug effects and imaging findings essential. History of drug exposure, suitable radiological findings and response to treatment (corticosteroids and stop of medication) mostly provide the base for the diagnosis. (orig.)

  9. 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.

  10. Drug induced rhabdomyolysis

    Science.gov (United States)

    Hohenegger, Martin

    2012-01-01

    Rhabdomyolysis is a clinical condition of potential life threatening destruction of skeletal muscle caused by diverse mechanisms including drugs and toxins. Given the fact that structurally not related compounds cause an identical phenotype pinpoints to common targets or pathways, responsible for executing rhabdomyolysis. A drop in myoplasmic ATP paralleled with sustained elevations in cytosolic Ca2+ concentration represents a common signature of rhabdomyolysis. Interestingly, cardiac tissue is hardly affected or only secondary, as a consequence of imbalance in electrolytes or acid–base equilibrium. This dogma is now impaired by compounds, which show up with combined toxicity in heart and skeletal muscle. In this review, cases of rhabdomyolysis with novel recently approved drugs will be explored for new target mechanisms in the light of previously described pathomechanisms. PMID:22560920

  11. [Drug-induced oral ulcerations].

    Science.gov (United States)

    Madinier, I; Berry, N; Chichmanian, R M

    2000-06-01

    Different side effects of drugs have been described in the oral cavity, including oral ulcerations. Direct contact between drugs and oral mucosa may induce chemical burn or local hypersensitivity. Less frequently, these drug-induced oral ulcerations are part of a complex reaction with cutaneous or systemic manifestations. Sometimes, one or more oral ulcerations appear as the main side-effect of a drug, or exceptionally as solitary lesions. Solitary oral ulcerations usually appear after few weeks of treatment. In most of cases, these lesions resist to conventional treatments, with a rapid healing following the suppression of the responsible drug. This diagnosis is usually difficult, particularly with patients receiving multiple drug therapy. Besides, special attention must be paid to new drugs. Oral ulcerations following symptoms of burning mouth, metallic taste, dysgueusia or agueusia are strongly suggestive of a pharmacological origin. Most of the molecules able to induce solitary oral ulcerations are commonly prescribed in a) rheumatology: NSAI (diclofenac, flurbiprofen, indomethacin, naproxen), long-term rheumatoid arthritis therapy (azathioprine, methotrexate, penicillamine, gold compounds, tiopronin); b) cardiology: angiotensin-converting-enzyme inhibitors (captopril, enalapril), angiotensin 2-receptor antagonist (losartan), anti-angorous (nicorandil), c) psychiatry: antidepressants (fluoxetine, lithium), d) AIDS therapy (foscarnet, zalcitabine).

  12. 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...

  13. Drug-induced liver injury

    DEFF Research Database (Denmark)

    Nielsen, Mille Bækdal; Ytting, Henriette; Skalshøi Kjær, Mette

    2017-01-01

    OBJECTIVE: The idiosyncratic subtype of drug-induced liver injury (DILI) is a rare reaction to medical treatment that in severe cases can lead to acute liver failure and death. The aim of this study was to describe the presentation and outcome of DILI and to identify potential predictive factors...... that DILI may be severe and run a fatal course, and that bilirubin and INR levels may predict poor outcome....

  14. Drug-induced status epilepticus.

    Science.gov (United States)

    Cock, Hannah R

    2015-08-01

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

  15. 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...

  16. Antithyroid Drug-induced Agranulocytosis

    Directory of Open Access Journals (Sweden)

    Ming-Tsung Sun

    2009-08-01

    Full Text Available Antithyroid drugs are widely used to treat hyperthyroidism, especially Graves' disease, but they tend to cause agranulocytosis, which increases the mortality rate. Granulocyte colony-stimulating factor decreases the duration of recovery from agranulocytosis. We retrospectively studied cases of antithyroid drug-induced agranulocytosis over the past 10 years in a northern Taiwan medical center. A clinical evaluation was conducted, including a review of complete blood cell counts and differential counts. Four cases were included in this analysis. Agranulocytosis persisted in 2 cases despite a change in therapy from propylthiouracil to methimazole. Fever, sore throat, and diarrhea were common symptoms of agranulocytosis. Initial white blood cell counts ranged from 450 to 1,710/μL. Only 1 case had a positive result from a throat swab culture (Staphylococcus aureus. Three of 4 cases received granulocyte colony-stimulating factor therapy, and the recovery time ranged from 3 to 13 days. All of the patients recovered from agranulocytosis. We concluded that: (1 conducting a routine complete blood cell count is beneficial in alerting caregivers to the possibility of agranulocytosis; (2 educating patients about the common symptoms of agranulocytosis may contribute to an early diagnosis; (3 providing granulocyte colony-stimulating factor therapy to patients results in good prognosis; and (4 monitoring for cross-reactions between drugs should be performed to prevent further episodes of agranulocytosis.

  17. Drug-induced Pulmonary Fibrosis

    International Nuclear Information System (INIS)

    Daba, Mohammad H.; Al-Arifi, Mohammad N; Gubar, Othman A.; El-Tahir, Kamal E.

    2004-01-01

    Pulmonary fibrosis is characterized by the accumulation of excessive connective tissue in the lungs. Its causes include chronic administration of some drugs for example bleomycin, cyclophosphamide, amiodarone, procainamide, penicillamine, gold and nitrofurantoin; exposure to certain environmental factors such as gases, asbestos and silica and bacterial or fungal infections. Some systemic diseases also predispose to the disease for example rheumatoid arthritis and systemic lupus erythematosus. The disease is associated with release of oxygen radicals and some mediators such as tumor necrosis factor-alpha TNF-alpha, transforming growth factor-beta Tbgf-beta, PDGF, If-I, Et-I and interleukins 1, 4, 8 and 13. The symptoms of the disease include dyspne a, non-productive cough, fever and damage to the lung cells. It is diagnosed with the aid of chest radiography, high resolution computed tomographic scanning and the result of pulmonary function tests. Drug-induced pulmonary fibrosis may involve release of free oxygen radicals and various cytokines for example Il-I beta and TNF-alpha via activation of nuclear transcription factor Nf-beta as in the case of bleomycin and mitomycin or via release of TGF-beta as in case of tamoxifen or via inhibition of macrophages and lymphocytes phospholipases as in the case of amiodarone with the resultant accumulation of phospholipids and reduction of the immune system. (author)

  18. Terbinafine-induced lichenoid drug eruption.

    Science.gov (United States)

    Zheng, Yue; Zhang, Jie; Chen, Haiyan; Lai, Wei; Maibach, Howard I

    2017-03-01

    Drug-induced lichen planus has been induced by antibiotics, anticonvulsants, antidiabetics, antimalarials, antitubercular drugs, antihypertensives, psychiatric drugs, chemotherapeutic agents, diuretic, heavy metals, NSAIDs, etc. Terbinafine, an antifungal agent, is widely used for dermatophyte infections and onychomycosis. Cutaneous adverse effects of terbinafine are rarely reported. Here, we report a case of terbinafine-induced lichenoid drug eruption in a 22-year-old who presented with generalized lichenoid eruption 2 weeks after terbinafine initiation of. The body and lip cleared completely after 8 weeks of drug withdrawal; nail change cleared after 12 weeks.

  19. Mechanistic review of drug-induced steatohepatitis

    International Nuclear Information System (INIS)

    Schumacher, Justin D.; Guo, Grace L.

    2015-01-01

    Drug-induced steatohepatitis is a rare form of liver injury known to be caused by only a handful of compounds. These compounds stimulate the development of steatohepatitis through their toxicity to hepatocyte mitochondria; inhibition of beta-oxidation, mitochondrial respiration, and/or oxidative phosphorylation. Other mechanisms discussed include the disruption of phospholipid metabolism in lysosomes, prevention of lipid egress from hepatocytes, targeting mitochondrial DNA and topoisomerase, decreasing intestinal barrier function, activation of the adenosine pathway, increasing fatty acid synthesis, and sequestration of coenzyme A. It has been found that the majority of compounds that induce steatohepatitis have cationic amphiphilic structures; a lipophilic ring structure with a side chain containing a cationic secondary or tertiary amine. Within the last decade, the ability of many chemotherapeutics to cause steatohepatitis has become more evident coining the term chemotherapy-associated steatohepatitis (CASH). The mechanisms behind drug-induced steatohepatitis are discussed with a focus on cationic amphiphilic drugs and chemotherapeutic agents. - Highlights: • Reviewed the mechanisms underlying drug-induced steatohepatitis for many compounds • Mitochondrial dysfunction is critical in the development of drug-induced steatohepatitis. • Majority of drugs that induce steatohepatitis are cationic amphiphilic drugs. • Chemotherapeutics that induce CASH are cationic amphiphilic drugs. • Majority of drugs that induce steatohepatitis are carnitine palmitoyltransferase-I inhibitors.

  20. Mechanistic review of drug-induced steatohepatitis

    Energy Technology Data Exchange (ETDEWEB)

    Schumacher, Justin D., E-mail: Justin.d.schumacher@rutgers.edu; Guo, Grace L.

    2015-11-15

    Drug-induced steatohepatitis is a rare form of liver injury known to be caused by only a handful of compounds. These compounds stimulate the development of steatohepatitis through their toxicity to hepatocyte mitochondria; inhibition of beta-oxidation, mitochondrial respiration, and/or oxidative phosphorylation. Other mechanisms discussed include the disruption of phospholipid metabolism in lysosomes, prevention of lipid egress from hepatocytes, targeting mitochondrial DNA and topoisomerase, decreasing intestinal barrier function, activation of the adenosine pathway, increasing fatty acid synthesis, and sequestration of coenzyme A. It has been found that the majority of compounds that induce steatohepatitis have cationic amphiphilic structures; a lipophilic ring structure with a side chain containing a cationic secondary or tertiary amine. Within the last decade, the ability of many chemotherapeutics to cause steatohepatitis has become more evident coining the term chemotherapy-associated steatohepatitis (CASH). The mechanisms behind drug-induced steatohepatitis are discussed with a focus on cationic amphiphilic drugs and chemotherapeutic agents. - Highlights: • Reviewed the mechanisms underlying drug-induced steatohepatitis for many compounds • Mitochondrial dysfunction is critical in the development of drug-induced steatohepatitis. • Majority of drugs that induce steatohepatitis are cationic amphiphilic drugs. • Chemotherapeutics that induce CASH are cationic amphiphilic drugs. • Majority of drugs that induce steatohepatitis are carnitine palmitoyltransferase-I inhibitors.

  1. Drug-induced renal injury

    African Journals Online (AJOL)

    The kidney receives a rich blood flow of 25% of resting cardiac output ... Drugs can cause acute renal failure by causing pre-renal, intrinsic or .... tubular epithelial cells causing cell swelling ... the dose as required or prescribe alternative drugs.

  2. Drug-induced cutaneous lupus erythematosus

    DEFF Research Database (Denmark)

    Laurinaviciene, Rasa; Holm Sandholdt, Linda; Bygum, Anette

    2017-01-01

    BACKGROUND: An increasing number of drugs have been linked to drug-induced subacute cutaneous lupus erythematosus (DI-SCLE). The recognition and management of DI-SCLE can be challenging, as the condition may be triggered by different classes of drugs after variable lengths of time. OBJECTIVES......: To determine the proportion of patients with cutaneous lupus erythematosus (CLE) whose drugs are an inducing or aggravating factor. MATERIALS & METHODS: We conducted a retrospective chart review of patients diagnosed with CLE at a dermatological department over a 21-year period. We registered clinical......, serological, and histological data with a focus on drug intake. RESULTS: Of 775 consecutive patients with a diagnosis of lupus erythematosus (LE) or suspected LE, a diagnosis of CLE could be confirmed in 448 patients. A total of 130 patients had a drug intake that could suggest DI-SCLE. In 88 cases, a drug...

  3. Drug-induced urinary incontinence

    NARCIS (Netherlands)

    Tsakiris, Peter; Oelke, Matthias; Michel, Martin C.

    2008-01-01

    Physiological urinary continence depends on many factors that are potentially vulnerable to adverse drug effects, which may lead to incontinence. In principle, drugs could cause incontinence by lowering bladder outlet resistance and/or by increasing intravesical pressure, which disrupts the normal

  4. Adverse drug reactions induced by cardiovascular drugs in outpatients

    Directory of Open Access Journals (Sweden)

    Gholami K

    2008-03-01

    Full Text Available Considering increased use of cardiovascular drugs and limitations in pre-marketing trials for drug safety evaluation, post marketing evaluation of adverse drug reactions (ADRs induced by this class of medicinal products seems necessary.Objectives: To determine the rate and seriousness of adverse reactions induced by cardiovascular drugs in outpatients. To compare sex and different age groups in developing ADRs with cardiovascular agents. To assess the relationship between frequencies of ADRs and the number of drugs used. Methods: This cross-sectional study was done in cardiovascular clinic at a teaching hospital. All patients during an eight months period were evaluated for cardiovascular drugs induced ADRs. Patient and reaction factors were analyzed in detected ADRs. Patients with or without ADRs were compared in sex and age by using chi-square test. Assessing the relationship between frequencies of ADRs and the number of drugs used was done by using Pearson analysis. Results: The total number of 518 patients was visited at the clinic. ADRs were detected in 105 (20.3% patients. The most frequent ADRs were occurred in the age group of 51-60. The highest rate of ADRs was recorded to be induced by Diltiazem (23.5% and the lowest rate with Atenolol (3%. Headache was the most frequent detected ADR (23%. Assessing the severity and preventability of ADRs revealed that 1.1% of ADRs were detected as severe and 1.9% as preventable reactions. Women significantly developed more ADRs in this study (chi square = 3.978, P<0.05. ADRs more frequently occurred with increasing age in this study (chi square = 15.871, P<0.05. With increasing the number of drugs used, the frequency of ADRs increased (Pearson=0.259, P<0.05. Conclusion: Monitoring ADRs in patients using cardiovascular drugs is a matter of importance since this class of medicines is usually used by elderly patients with critical conditions and underlying diseases.

  5. Drug-induced regulation of target expression

    DEFF Research Database (Denmark)

    Iskar, Murat; Campillos, Monica; Kuhn, Michael

    2010-01-01

    Drug perturbations of human cells lead to complex responses upon target binding. One of the known mechanisms is a (positive or negative) feedback loop that adjusts the expression level of the respective target protein. To quantify this mechanism systems-wide in an unbiased way, drug......-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....... In 1290 drug-target relations, corresponding to 466 drugs acting on 167 drug targets studied, 8% of the targets are subject to regulation at the mRNA level. We confirmed systematically that in particular G-protein coupled receptors, when serving as known targets, are regulated upon drug treatment. We...

  6. Drug-induced liver injuries

    African Journals Online (AJOL)

    2011-06-02

    Jun 2, 2011 ... liver failure in the developed world and a prominent aetiological factor ... most drugs is not known and several epidemiological studies have had major ... eosinophilia, are also pointers towards the cause of the injury and are.

  7. Drug-induced low blood sugar

    Science.gov (United States)

    Drug-induced low blood sugar is low blood glucose that results from taking medicine. ... Low blood sugar (hypoglycemia) is common in people with diabetes who are taking insulin or other medicines to control their diabetes. ...

  8. Adverse drug reactions induced by cardiovascular drugs in outpatients.

    Science.gov (United States)

    Gholami, Kheirollah; Ziaie, Shadi; Shalviri, Gloria

    2008-01-01

    Considering increased use of cardiovascular drugs and limitations in pre-marketing trials for drug safety evaluation, post marketing evaluation of adverse drug reactions (ADRs) induced by this class of medicinal products seems necessary. To determine the rate and seriousness of adverse reactions induced by cardiovascular drugs in outpatients. To compare sex and different age groups in developing ADRs with cardiovascular agents. To assess the relationship between frequencies of ADRs and the number of drugs used. This cross-sectional study was done in cardiovascular clinic at a teaching hospital. All patients during an eight months period were evaluated for cardiovascular drugs induced ADRs. Patient and reaction factors were analyzed in detected ADRs. Patients with or without ADRs were compared in sex and age by using chi-square test. Assessing the relationship between frequencies of ADRs and the number of drugs used was done by using Pearson analysis. The total number of 518 patients was visited at the clinic. ADRs were detected in 105 (20.3%) patients. The most frequent ADRs were occurred in the age group of 51-60. The highest rate of ADRs was recorded to be induced by Diltiazem (23.5%) and the lowest rate with Atenolol (3%). Headache was the most frequent detected ADR (23%). Assessing the severity and preventability of ADRs revealed that 1.1% of ADRs were detected as severe and 1.9% as preventable reactions. Women significantly developed more ADRs in this study (chi square = 3.978, PPearson=0.259, P<0.05). Monitoring ADRs in patients using cardiovascular drugs is a matter of importance since this class of medicines is usually used by elderly patients with critical conditions and underlying diseases.

  9. [Drug-induced extrapyramidal disorders].

    Science.gov (United States)

    Horga, J F; Navarro, M; Peiró, V; Hernández, M

    1995-01-01

    We analyze 402 drug-adverse events consisting of movement disorders or aggravation of parkinsonisms, submitted to Sistema Español de Farmacovigilancia until 1994. Our aim is to know patient characteristics and the drugs related with these submissions. Most of them (64) belong to calcium-entry blocker group (31%) and benzamides (27%). Case age intervals more frequent were 11-30 and 60-80 years-old and the events affect predominantly females. The percentage of serious adverse events were near 80%. We think that drug-related parkinsonisms have high prevalence rate and that the role of calcium-entry blockers in these events should be considered at the moment to prescribe groups.

  10. The discovery of drug-induced illness.

    Science.gov (United States)

    Jick, H

    1977-03-03

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

  11. Drug-induced pseudolymphoma syndrome

    Directory of Open Access Journals (Sweden)

    Mittal R

    1995-01-01

    Full Text Available Five cases of pseudolymphoma syndrome (PS in children aged six to twelve years were observed after anticonvulsant drugs. In two cases PS was observed after ten days and in three after fifteen days of therapy with the offending drug. Three cases of PS were due to carbamazepine and had morbilliform rash and two cases due to phenobarbitone had erythroderma. All had fever, generalised lymphadenopathy and 4/5 had hepatosplenomegaly. Therapy with 15 mg prednisolone daily and withdrawal of the offending durg led to cure in 4/5 cases and one died due to congestive cardiac failure.

  12. Drug-induced acute pancreatitis

    NARCIS (Netherlands)

    I.A. Eland (Ingo)

    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

  13. Data-driven prediction of adverse drug reactions induced by drug-drug interactions.

    Science.gov (United States)

    Liu, Ruifeng; AbdulHameed, Mohamed Diwan M; Kumar, Kamal; Yu, Xueping; Wallqvist, Anders; Reifman, Jaques

    2017-06-08

    The expanded use of multiple drugs has increased the occurrence of adverse drug reactions (ADRs) induced by drug-drug interactions (DDIs). However, such reactions are typically not observed in clinical drug-development studies because most of them focus on single-drug therapies. ADR reporting systems collect information on adverse health effects caused by both single drugs and DDIs. A major challenge is to unambiguously identify the effects caused by DDIs and to attribute them to specific drug interactions. A computational method that provides prospective predictions of potential DDI-induced ADRs will help to identify and mitigate these adverse health effects. We hypothesize that drug-protein interactions can be used as independent variables in predicting ADRs. We constructed drug pair-protein interaction profiles for ~800 drugs using drug-protein interaction information in the public domain. We then constructed statistical models to score drug pairs for their potential to induce ADRs based on drug pair-protein interaction profiles. We used extensive clinical database information to construct categorical prediction models for drug pairs that are likely to induce ADRs via synergistic DDIs and showed that model performance deteriorated only slightly, with a moderate amount of false positives and false negatives in the training samples, as evaluated by our cross-validation analysis. The cross validation calculations showed an average prediction accuracy of 89% across 1,096 ADR models that captured the deleterious effects of synergistic DDIs. Because the models rely on drug-protein interactions, we made predictions for pairwise combinations of 764 drugs that are currently on the market and for which drug-protein interaction information is available. These predictions are publicly accessible at http://avoid-db.bhsai.org . We used the predictive models to analyze broader aspects of DDI-induced ADRs, showing that ~10% of all combinations have the potential to induce ADRs

  14. Drug-induced psoriasis: clinical perspectives

    Directory of Open Access Journals (Sweden)

    Balak DMW

    2017-12-01

    Full Text Available Deepak MW Balak, Enes Hajdarbegovic Department of Dermatology, Erasmus University Medical Center, Rotterdam, the Netherlands Abstract: Exposure to certain drugs can elicit an induction or exacerbation of psoriasis. Although well-conducted systematic studies on drug-related psoriasis are mostly lacking, traditionally strong associations have been documented for beta-blockers, lithium, antimalarial drugs such as (hydroxychloroquine, interferons, imiquimod, and terbinafine. More recently, new associations have been reported for monoclonal antibody- and small-molecule-based targeted therapies used for oncological and immunological indications, such as tumor necrosis factor-alpha antagonists and anti-programmed cell death protein 1 immune checkpoint inhibitors. Recognizing potential drug-related psoriasis is of clinical relevance to allow an optimal management of psoriasis. However, in clinical practice, identifying medication-related exacerbations and induction of psoriasis can be challenging. The clinical and histopathological features of drug-provoked psoriasis may differ little from that of “classical” nondrug-related forms of psoriasis. In addition, the latency period between start of the medication and onset of psoriasis can be significantly long for some drugs. Assessment of the Naranjo adverse drug reaction probability scale could be used as a practical tool to better differentiate drug-related psoriasis. The first step in the management of drug-related psoriasis is cessation and replacement of the offending drug when deemed clinically possible. However, the induced psoriasis skin lesions may persist after treatment withdrawal. Additional skin-directed treatment options for drug-related psoriasis follows the conventional psoriasis treatment guidelines and includes topical steroids and vitamin D analogs, ultraviolet phototherapy, systemic treatments, such as acitretin, methotrexate, and fumaric acid esters, and biological treatments

  15. 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 spontaneous reporting system for ADRs, using drug-induced arrhythmias as an example. METHODS: Reports of drug-induced arrhythmias to proarrhythmic drugs were selected from the database of the Netherlands Pharmacovigilance Centre (1996-2003). Information on the patient's general practitioner (GP) was obtained...... be 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...

  16. Recent Advances in Drug-Induced Angioedema

    Directory of Open Access Journals (Sweden)

    Naoko Inomata

    2012-01-01

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

  17. Sexual side effects induced by psychotropic drugs

    DEFF Research Database (Denmark)

    Kristensen, Ellids

    2002-01-01

    The majority of psychotropic drugs entail sexual side effects. The sexual side effects may reduce quality of life and may give rise to non-compliance. For example, 30-60 per cent of patients treated with antidepressants are known to develop a sexual dysfunction. However, some psychotropic drugs...... with no or very few sexual side effects have begun to emerge. The treatment of sexual side effects induced by psychotropic drugs may consist of: modified sexual habits, reduction in dosage, switching to another medication, possibly in combination with different psychotropic agents, other varieties...

  18. Thymus function in drug-induced lupus.

    Science.gov (United States)

    Rubin, R L; Salomon, D R; Guerrero, R S

    2001-01-01

    Autoimmunity develops when a lupus-inducing drug is introduced into the thymus of normal mice, but the relevance of this model to the human disorder is unclear in part because it is widely assumed that the thymus is non-functional in the adult. We compared thymus function in 10 patients with symptomatic procainamide-induced lupus to that in 13 asymptomatic patients who only developed drug-induced autoantibodies. T cell output from the thymus was quantified using a competitive polymerase chain reaction that detects T cell receptor DNA excision circles in peripheral blood lymphocytes. Despite the advanced age of the patient population under study, newly generated T cells were detected in all subjects. Although there was no overall quantitative difference between the symptomatic and asymptomatic patients, we found a positive correlation between the level of T cell receptor excision circles in peripheral lymphocytes and serum IgG anti-chromatin antibody activity in patients with drug-induced lupus. The association between autoantibodies and nascent peripheral T cells supports the requirement for T cells in autoantibody production. Our observations are consistent with findings in mice in which autoreactive T cells derived from drug-induced abnormalities in T cell development in the thymus.

  19. Antimalarial drug induced decrease in creatinine clearance

    NARCIS (Netherlands)

    Landewé, R. B.; Vergouwen, M. S.; Goeei The, S. G.; van Rijthoven, A. W.; Breedveld, F. C.; Dijkmans, B. A.

    1995-01-01

    To confirm the antimalarial drug induced increase of creatinine to determine the factors contributing to this effect. Patients with rheumatoid arthritis (RA) (n = 118) who have used or still use antimalarials (chloroquine or hydroxychloroquine). Serum creatinines prior to antimalarials and serum

  20. Tranexamic acid-induced fixed drug eruption

    Directory of Open Access Journals (Sweden)

    Natsuko Matsumura

    2015-01-01

    Full Text Available A 33-year-old male showed multiple pigmented patches on his trunk and extremities after he took tranexamic acid for common cold. He stated that similar eruptions appeared when he was treated with tranexamic acid for influenza 10 months before. Patch test showed positive results at 48 h and 72 h by 1% and 10% tranexamic acid at the lesional skin only. To our knowledge, nine cases of fixed drug eruption induced by tranexamic acid have been reported in Japan. Tranexamic acid is a safe drug and frequently used because of its anti-fibrinolytic and anti-inflammatory effects, but caution of inducing fixed drug eruption should be necessary.

  1. Nonacetaminophen Drug-Induced Acute Liver Failure.

    Science.gov (United States)

    Thomas, Arul M; Lewis, James H

    2018-05-01

    Acute liver failure of all causes is diagnosed in between 2000 and 2500 patients annually in the United States. Drug-induced acute liver failure is the leading cause of acute liver failure, accounting for more than 50% of cases. Nonacetaminophen drug injury represents 11% of all cases in the latest registry from the US Acute Liver Failure Study Group. Although rare, acute liver failure is clinically dramatic when it occurs, and requires a multidisciplinary approach to management. In contrast with acetaminophen-induced acute liver failure, non-acetaminophen-induced acute liver failure has a more ominous prognosis with a lower liver transplant-free survival. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Antithyroid drug-induced fetal goitrous hypothyroidism

    DEFF Research Database (Denmark)

    Bliddal, Sofie; Rasmussen, Ase Krogh; Sundberg, Karin

    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....

  3. Drug induced neutropenia manifesting as oral ulcerations

    Directory of Open Access Journals (Sweden)

    Rachna Kaul

    2009-01-01

    Full Text Available As dental practitioners, we often come across oral ulcerations of varied etiology. Among all the causes of oral ulcers, those due to neutropenia are significant. Neutropenia can occur in many systemic conditions and also in patients on long-term therapy of certain drugs like phenytoin. The diagnosis of neutropenia in time leads to early recognition of the cause of this fatal condition. Here, we report a case of a 50-year-old female patient who developed oral ulcerations secondary to phenytoin-induced neutropenia. Early diagnosis of the condition led to discontinuation of the offending drug and significant improvement in her blood picture and also prevented her from falling prey to many other systemic infections that neutropenia can cause.

  4. Brugada Phenocopy Induced by Recreational Drug Use

    Directory of Open Access Journals (Sweden)

    Adedoyin Akinlonu

    2018-01-01

    Full Text Available Recreational drugs are commonly abused in all age groups. Intoxication with these substances can induce silent but significant electrocardiographic signs which may lead to sudden death. In this case study, we present a 49-year-old male with no medical comorbidities who came to the emergency department requesting opioid detoxification. Toxicology screen was positive for cocaine, heroin, and cannabis. Initial electrocardiogram (EKG showed features of a Brugada pattern in the right precordial leads, which resolved within one day into admission. This presentation is consistent with the recently recognized clinical entity known as Brugada phenocopy.

  5. Drug-induced parkinsonism: diagnosis and management

    Directory of Open Access Journals (Sweden)

    Blanchet PJ

    2016-09-01

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

  6. Biomarkers of drug-induced vascular injury

    International Nuclear Information System (INIS)

    Brott, D.; Gould, S.; Jones, H.; Schofield, J.; Prior, H.; Valentin, J.P; Bjurstrom, S.; Kenne, K.; Schuppe-Koistinen, I.; Katein, A.; Foster-Brown, L.; Betton, G.; Richardson, R.; Evans, G.; Louden, C.

    2005-01-01

    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

  7. Melatonin modulates drug-induced acute porphyria

    Directory of Open Access Journals (Sweden)

    Sandra M. Lelli

    Full Text Available This work investigated the modulation by melatonin (Mel of the effects of the porphyrinogenic drugs 2-allyl-2-isopropylacetamide (AIA and 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-collidine (DDC on oxidative environment, glucose biosynthesis and heme pathway parameters. Administration of Mel before rat intoxication with AIA/DDC showed a clear beneficial effect in all cases. Mel induced decreases of 42% and 35% in the excretion of the hemeprecursors 5-aminolevulinic acid (ALA and porphobilinogen (PBG, respectively, and a 33% decrease in the induction of the heme regulatory enzyme 5-aminolevulinic acid-synthase (ALA-S. The activity of the glucose metabolism enzyme phosphoenolpyruvate carboxykinase (PEPCK, which had been diminished by the porphyrinogenic treatment, was restored by 45% when animals were pre-treated with Mel. Mel abolished the modest decrease in glucose 6-phospatase (G6Pase activity caused by AIA/DDC treatment. The oxidative status of lipids was attenuated by Mel treatment in homogenates by 47%, whereas no statistically significant AIA/DDC-induced increase in thiobarbituric acid reactive substances (TBARS was observed in microsomes after Mel pre-treatment. We hypothesize that Mel may be scavenging reactive species of oxygen (ROS that could be damaging lipids, PEPCK, G6Pase and ferrochelatase (FQ. Additionally, Mel administration resulted in the repression of the key enzyme ALA-S, and this could be due to an increase in glucose levels, which is known to inhibit ALA-S induction. The consequent decrease in levels of the heme precursors ALA and PBG had a beneficial effect on the drug-induced porphyria. The results obtained open the possibility of further research on the use of melatonin as a co-treatment option in acute porphyria. Keywords: Melatonin, Glucose synthesis, Heme pathway, Acute porphyria, Oxidative stress

  8. Drug-induced cholestasis: mechanisms, models, and markers.

    Science.gov (United States)

    Chatterjee, Sagnik; Annaert, Pieter

    2018-04-27

    Drug-induced cholestasis is a risk factor in progression of drug candidates, and poses serious health hazard if not detected before going into human. Intrahepatic accumulation of bile acids (BAs) represents a characteristic phenomenon associated with drug-induced cholestasis. The major challenges in obtaining a complete understanding of drug-induced cholestasis lies in the complexity of BA-mediated toxicity mechanisms and the impact of bile acids at different 'targets' such as transporters, enzymes and nuclear receptors. At the same time, it is not trivial to have a relevant in vitro system that recapitulates these features. In addition, lack of sensitive and early preclinical biomarkers, relevant to the clinical situation, complicates proper detection of drug-induced cholestasis. Significant overlap in biomarker signatures between different mechanisms of drug-induced liver injury (DILI) precludes identification of specific mechanisms. Over the last decade the knowledge gaps in drug-induced cholestasis are closing due to growing mechanistic understanding of BA-mediated toxicity at (patho)physiologically relevant BA concentrations. Significant progress has been made in the mechanistic understanding of drug-induced cholestasis and associated toxicity, biomarkers and susceptibility factors. In addition, novel in vitro models are evolving which provide a holistic understanding of processes underlying drug-induced cholestasis. This review summarizes the challenges and recent understandings about drug-induced cholestasis with a potential path forward. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. 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 ...

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

    Science.gov (United States)

    Ryu, JiHyeon; Lee, HeeYoung; Suh, JinUk; Yang, MyungSuk; Kang, WonKu; Kim, EunYoung

    2015-01-01

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

  11. Thrombocytopenia induced by noncytotoxic drugs in Denmark 1968-91

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, U; Andersen, M; Hansen, P B

    1996-01-01

    reporting system on adverse drug reactions. SUBJECTS: A total of 309 critically reviewed cases of drug-induced thrombocytopenia reported during the period from 1968 to the end of 1991. RESULTS: Sodiumaurothiomalate and the combination sulfamethoxazole with trimethoprim were the most commonly reported single...... numerously reported. The still-growing list of thrombocytopenia-inducing agents contained 110 different drugs. At present, 20% of reported cases concern drugs not previously registered as causing thrombocytopenia in Denmark. Twenty-five per cent of all cases were caused by drugs which appeared only...

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

    Directory of Open Access Journals (Sweden)

    Reza Heidari

    2014-09-01

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

  13. Ursodeoxycholic acid induced generalized fixed drug eruption.

    Science.gov (United States)

    Ozkol, Hatice Uce; Calka, Omer; Dulger, Ahmet Cumhur; Bulut, Gulay

    2014-09-01

    Fixed drug eruption (FDE) is a rare form of drug allergies that recur at the same cutaneous or mucosal site in every usage of drug. Single or multiple round, sharply demarcated and dusky red plaques appear soon after drug exposure. Ursodeoxycholic acid (UDCA: 3α,7β-dihydroxy-5β-cholanic acid) is used for the treatment of cholestatic liver diseases. Some side effects may be observed, such as diarrhea, dyspepsia, pruritus and headaches. We encountered only three cases of lichenoid reaction regarding the use of UDCA among previous studies. In this article, we reported a generalized FDE case related to UDCA intake in a 59-year-old male patient with cholestasis for the first time in the literature.

  14. 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

  15. HLA Association with Drug-Induced Adverse Reactions

    Directory of Open Access Journals (Sweden)

    Wen-Lang Fan

    2017-01-01

    Full Text Available Adverse drug reactions (ADRs remain a common and major problem in healthcare. Severe cutaneous adverse drug reactions (SCARs, such as Stevens–Johnson syndrome (SJS/toxic epidermal necrolysis (TEN with mortality rate ranges from 10% to more than 30%, can be life threatening. A number of recent studies demonstrated that ADRs possess strong genetic predisposition. ADRs induced by several drugs have been shown to have significant associations with specific alleles of human leukocyte antigen (HLA genes. For example, hypersensitivity to abacavir, a drug used for treating of human immunodeficiency virus (HIV infection, has been proposed to be associated with allele 57:01 of HLA-B gene (terms HLA-B∗57:01. The incidences of abacavir hypersensitivity are much higher in Caucasians compared to other populations due to various allele frequencies in different ethnic populations. The antithyroid drug- (ATDs- induced agranulocytosis are strongly associated with two alleles: HLA-B∗38:02 and HLA-DRB1∗08:03. In addition, HLA-B∗15:02 allele was reported to be related to carbamazepine-induced SJS/TEN, and HLA-B∗57:01 in abacavir hypersensitivity and flucloxacillin induced drug-induced liver injury (DILI. In this review, we summarized the alleles of HLA genes which have been proposed to have association with ADRs caused by different drugs.

  16. Drug-induced progressive multifocal leukoencephalopathy

    DEFF Research Database (Denmark)

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

    2015-01-01

    Progressive multifocal leukoencephalopathy (PML) has been identified as a serious adverse drug reaction (ADR) of several immunomodulatory biologicals. In this study, we contrasted the reporting patterns of PML for two biologicals for which the risk was identified at different points in their life......Progressive multifocal leukoencephalopathy (PML) has been identified as a serious adverse drug reaction (ADR) of several immunomodulatory biologicals. In this study, we contrasted the reporting patterns of PML for two biologicals for which the risk was identified at different points...

  17. Rhabdomyolysis induced by antiepileptic drugs: characteristics, treatment and prognosis.

    Science.gov (United States)

    Jiang, Wei; Wang, Xuefeng; Zhou, Shengnian

    2016-01-01

    Rhabdomyolysis syndrome refers to a variety of factors that affect the striated muscle cell membrane, the membrane channels and its energy supply. Most cases of rhabdomyolysis are due to direct trauma. However, infection, toxins, drugs, muscle ischemia, electrolyte imbalance, metabolic diseases, genetic diseases and abnormal body temperature can also lead to rhabdomyolysis. Epilepsy is one of the most common chronic neurological diseases. The primary long-term treatment is antiepileptic drugs (AEDs), which may cause rhabdomyolysis. This article summarizes the characteristics, treatment methods and prognosis of patients with rhabdomyolysis that is induced by antiepileptic drugs. This review is based on PubMed, EMBASE and MEDLINE searches of the literature using the keywords "epilepsy", "antiepileptic drugs","status epilepticus","rhabdomyolysis", and "antiepileptic drugs and rhabdomyolysis syndrome" as well as extensive personal clinical experience with various antiepileptic drugs. Potential relationships between antiepileptic drugs and rhabdomyolysis are discussed. Worldwide, there are approximately 50 million epilepsy patients, most of whom are treated with drugs. Reports have indicated that the majority of antiepileptic drugs on the market can cause rhabdomyolysis. Although rhabdomyolysis induced by antiepileptic drugs is a rare condition with a low incidence, this condition has serious consequences and merits attention from clinicians.

  18. Drug-induced gynecomastia in children and adolescents

    Science.gov (United States)

    Goldman, Ran D.

    2010-01-01

    ABSTRACT QUESTION I frequently see adolescent boys in my practice with transient gynecomastia. My management includes reassuring the boys and their families; however, I also understand that specific medication, alcohol, and drugs can cause gynecomastia. How common is this phenomenon, and what medications can induce gynecomastia? ANSWER While gynecomastia is a physiologic phenomenon in most newborns and adolescents, it is important to consider pathologic conditions and medications that can cause breast enlargement. Antibiotics, antiulcer drugs, growth hormones, and chemotherapy have been reported to induce gynecomastia. Adolescents who use anabolic steroids, or who abuse alcohol, marijuana, heroin, or amphetamines, should be alerted to the fact that gynecomastia might develop. Treatment of drug-induced gynecomastia includes discontinuation of the offending drug. Very rarely is surgical intervention required. PMID:20393092

  19. Drug Induced Steatohepatitis: An Uncommon Culprit of a Common Disease

    Directory of Open Access Journals (Sweden)

    Liane Rabinowich

    2015-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is a leading cause of liver disease in developed countries. Its frequency is increasing in the general population mostly due to the widespread occurrence of obesity and the metabolic syndrome. Although drugs and dietary supplements are viewed as a major cause of acute liver injury, drug induced steatosis and steatohepatitis are considered a rare form of drug induced liver injury (DILI. The complex mechanism leading to hepatic steatosis caused by commonly used drugs such as amiodarone, methotrexate, tamoxifen, valproic acid, glucocorticoids, and others is not fully understood. It relates not only to induction of the metabolic syndrome by some drugs but also to their impact on important molecular pathways including increased hepatocytes lipogenesis, decreased secretion of fatty acids, and interruption of mitochondrial β-oxidation as well as altered expression of genes responsible for drug metabolism. Better familiarity with this type of liver injury is important for early recognition of drug hepatotoxicity and crucial for preventing severe forms of liver injury and cirrhosis. Moreover, understanding the mechanisms leading to drug induced hepatic steatosis may provide much needed clues to the mechanism and potential prevention of the more common form of metabolic steatohepatitis.

  20. [Drug-induced fever: a diagnosis to remember].

    Science.gov (United States)

    Vodovar, D; Le Beller, C; Lillo-Le-Louet, A; Hanslik, T; Megarbane, B

    2014-03-01

    Drug fever (DF) is a febrile reaction induced by a drug without additional clinical features like skin eruption. This adverse drug reaction is probably common but under diagnosed. While its outcome is generally favourable, DF generates unnecessary diagnostic procedures as well as hospitalisations or hospitalisation prolongations. Clinical presentation and biological findings are not specific. Fever is generally well tolerated but may be accompanied by general symptoms mimicking sepsis. Moderate biological disorders could be expected, including elevation or decrease in white blood cell count, eosinophilia, liver cytolysis, and increased C-reactive protein. An infection should be systematically ruled out. Clinical or biological signs of severity should question DF diagnosis. When DF is suspected, the involved drug(s) should be stopped after a reliable assessment of imputability. Antibiotics represent the most often implicated drugs. Fever disappearance after discontinuing the suspected drug is the cornerstone of DF diagnosis. Before stopping the administration of the suspected drug(s), a risk/benefit ratio assessment is necessary. Consistently, it may be complicated to stop an antimicrobial drug when treating an infection or an immunosuppressive drug if required. Copyright © 2013. Published by Elsevier SAS.

  1. THE DRUG-INDUCED HEPATITIS IN CHILDREN

    Directory of Open Access Journals (Sweden)

    O. V. Molochkova

    2017-01-01

    Full Text Available Among toxic lesions of the liver, an important place belongs to medicinal hepatitis. Among patients with hepatitis, drug disease of the liver occurs in 0.7—1.4% of cases, and in the presence of jaundice — in 5%. A family case of sisters 9 and 4-year-old life development  of acute drug hepatitis caused by ibuprofen in a daily dose of 32 mg / kg (total 3.2 g and 25 mg / kg (total 2 g, respectively, was demonstrated in siblings. Hepatitis developed after an acute respiratory infection. Weakness, nausea, vomiting, jaundice of the skin and sclera, pruritus, multiple increase in serum transaminases and markers of cholestasis are revealed. Viral hepatitis and some hereditary liver diseases were excluded. The drug lesion of the liver was of a mixed nature: hepatocellular (cytotoxic and cholestatic. Timely administration of therapy (detoxification, glucocorticosteroids, ursodeoxycholic acid (Ursosan led to a regression of clinical symptoms of the disease and positive dynamics of laboratory indicators.

  2. Increased Risk of Drug-Induced Hyponatremia during High Temperatures

    Directory of Open Access Journals (Sweden)

    Anna K Jönsson

    2017-07-01

    Full Text Available Purpose: To investigate the relationship between outdoor temperature in Sweden and the reporting of drug-induced hyponatremia to the Medical Products Agency (MPA. Methods: All individual adverse drug reactions (ADR reported to MPA from 1 January 2010 to 31 October 2013 of suspected drug-induced hyponatremia and random controls were identified. Reports where the ADR had been assessed as having at least a possible relation to the suspected drug were included. Information on administered drugs, onset date, causality assessment, sodium levels, and the geographical origin of the reports was extracted. A case-crossover design was used to ascertain the association between heat exposure and drug-induced hyponatremia at the individual level, while linear regression was used to study its relationship to sodium concentration in blood. Temperature exposure data were obtained from the nearest observation station to the reported cases. Results: During the study period, 280 reports of hyponatremia were identified. More cases of drug-induced hyponatremia were reported in the warmer season, with a peak in June, while other ADRs showed an opposite annual pattern. The distributed lag non-linear model indicated an increasing odds ratio (OR with increasing temperature in the warm season with a highest odds ratio, with delays of 1–5 days after heat exposure. A cumulative OR for a lag time of 1 to 3 days was estimated at 2.21 at an average daily temperature of 20 °C. The change in sodium per 1 °C increase in temperature was estimated to be −0.37 mmol/L (95% CI: −0.02, −0.72. Conclusions: Warm weather appears to increase the risk of drug-induced hyponatremia

  3. Biomarkers to monitor drug-induced phospholipidosis

    International Nuclear Information System (INIS)

    Baronas, Elizabeth Tengstrand; Lee, Ju-Whei; Alden, Carl; Hsieh, Frank Y.

    2007-01-01

    Di-docosahexaenoyl (C22:6)-bis(monoacylglycerol) phosphate (BMP) was identified as a promising phospholipidosis (PL) biomarker in rats treated with either amiodarone, gentamicin, or azithromycin. Sprague-Dawley rats received either amiodarone (150 mg/kg), gentamicin (100 mg/kg) or azithromycin (30 mg/kg) once daily for ten consecutive days. Histopathological examination of tissues by transmission electron microscopy (TEM) indicated different degrees of accumulation of phospholipidosis in liver, lung, mesenteric lymph node, and kidney of drug-treated rats but not controls. Liquid chromatography coupled to mass spectrometry (LC/MS) was used to identify levels of endogenous biochemical profiles in rat urine. Urinary levels of di-docosahexaenoyl (C22:6)-bis(monoacylglycerol) phosphate (BMP) correlated with induction of phospholipidosis for amiodarone, gentamicin and azithromycin. Rats treated with gentamicin also had increased urinary levels of several phosphatidylinositol (PI), phosphatidylcholine (PC), and phosphatidylethanolamine (PE) species

  4. In silico modeling to predict drug-induced phospholipidosis

    International Nuclear Information System (INIS)

    Choi, Sydney S.; Kim, Jae S.; Valerio, Luis G.; Sadrieh, Nakissa

    2013-01-01

    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

  5. Cardiovascular drugs inducing QT prolongation: facts and evidence.

    Science.gov (United States)

    Taira, Carlos A; Opezzo, Javier A W; Mayer, Marcos A; Höcht, Christian

    2010-01-01

    Acquired QT syndrome is mainly caused by the administration of drugs that prolong ventricular repolarization. On the other hand, the risk of drug-induced torsades de pointes is increased by numerous predisposing factors, such as genetic predisposition, female sex, hypokalemia and cardiac dysfunction. This adverse reaction is induced by different chemical compounds used for the treatment of a variety of pathologies, including arrhythmias. As it is known, antiarrhythmic agents and other cardiovascular drugs can prolong the QT interval, causing this adverse reaction. Of the 20 most commonly reported drugs, 10 were cardiovascular agents and these appeared in 348 of the reports (46%). Class Ia antiarrhythmic agents have frequently been linked to inducing arrhythmia, including torsades de pointes. Sotalol and amiodarone, class III antiarrhythmics, are known to prolong the QT interval by blocking I(Kr). Due to the severity of events caused by the therapeutic use of these drugs, in this work of revision the cardiovascular drugs that present this property and the factors and evidence will be mentioned.

  6. 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

  7. 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 focal ischemia by pharmacological alteration of the central thermoregulatory set-point. We tested the hypothesis that the dopaminergic agonist Talipexole, which induces hypothermia, reduces infarct size. Body temperature was monitored by a radio-pill-implant. Rats had reversible occlusion of the middle...... that the core body temperature was reduced by 1.7 degrees C for 24 hours after MCAO in rats treated with Talipexole. This treatment induced a significant reduction of infarct volume at 7 days after focal ischemia by 47%. We suggest that the reduction in infarct volume is related to drug-induced hypothermia...

  8. Drug induced xerostomia in elderly individuals: An institutional study

    Directory of Open Access Journals (Sweden)

    Shishir Ram Shetty

    2012-01-01

    Full Text Available Introduction : With better health care facilities and nutritional levels the average life expectancy of Indian population has been on the rise over the years. Most of the geriatric population is under long-term medication. Aim : The aim of this study was to evaluate the synergistic effect of multiple xerostomia drugs. Materials and Methods : Unstimulated saliva was measured in 60 geriatric patients, and xerostomia questionnaire and quality-of-life scale were also administered. Results : There was a very highly significant reduction in the salivary flow rates of patients under multiple xerostomia-inducing drugs. Conclusion : The synergistic effect of the xerostomia inducing medication could be the possible factor responsible for reduced salivary flow in elderly individuals using such drugs

  9. MDM2 Antagonists Counteract Drug-Induced DNA Damage

    Directory of Open Access Journals (Sweden)

    Anna E. Vilgelm

    2017-10-01

    Full Text Available Antagonists of MDM2-p53 interaction are emerging anti-cancer drugs utilized in clinical trials for malignancies that rarely mutate p53, including melanoma. We discovered that MDM2-p53 antagonists protect DNA from drug-induced damage in melanoma cells and patient-derived xenografts. Among the tested DNA damaging drugs were various inhibitors of Aurora and Polo-like mitotic kinases, as well as traditional chemotherapy. Mitotic kinase inhibition causes mitotic slippage, DNA re-replication, and polyploidy. Here we show that re-replication of the polyploid genome generates replicative stress which leads to DNA damage. MDM2-p53 antagonists relieve replicative stress via the p53-dependent activation of p21 which inhibits DNA replication. Loss of p21 promoted drug-induced DNA damage in melanoma cells and enhanced anti-tumor activity of therapy combining MDM2 antagonist with mitotic kinase inhibitor in mice. In summary, MDM2 antagonists may reduce DNA damaging effects of anti-cancer drugs if they are administered together, while targeting p21 can improve the efficacy of such combinations.

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

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    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.

  11. PTTG1 attenuates drug-induced cellular senescence.

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    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.

  12. Effectiveness of hepatoprotective drugs for anti-tuberculosis drug-induced hepatotoxicity: a retrospective analysis

    Directory of Open Access Journals (Sweden)

    Zenya Saito

    2016-11-01

    Full Text Available Abstract Background The effectiveness of hepatoprotective drugs for DIH (drug induced hepatotoxicity during tuberculosis treatment is not clear. We evaluated the effectiveness of hepatoprotective drugs by comparing the period until the normalization of hepatic enzymes between patients who were prescribed with the hepatoprotective drugs after DIH was occurred and patients who were not prescribed with the hepatoprotective drugs. Methods During 2006–2010, 389 patients with active tuberculosis were included in this study. DIH was defined as elevation of peak serum aspartate aminotransferase (AST and/or alanine aminotransferase (ALT of more than twice the upper limit of normal (ULN. We divided the patients into the severe (peak serum AST and/or ALT elevation of >5 times the ULN, moderate (peak serum AST and/or ALT elevation of >3 to ≤5 times the ULN, and mild DIH groups (peak serum AST and/or ALT elevation of >2 to ≤3 times the ULN. We compared the average period until the normalization of hepatic enzymes between patient subgroups with and without hepatoprotective drugs (ursodeoxycholic acid: UDCA, stronger neo-minophagen C: SNMC, and glycyrrhizin. Results In the severe group, there was no significant difference in the average period until the normalization between subgroups with and without hepatoprotective drugs (21.4 ± 10.8 vs 21.5 ± 11.1 days, P = 0.97. In the mild group, the period was longer in the subgroup with hepatoprotective drugs than that without hepatoprotective drugs (15.7 ± 6.2 vs 12.4 ± 7.9 days, P = 0.046. Conclusion Regardless of the severity, hepatoprotective drugs did not shorten the period until the normalization of hepatic enzymes.

  13. A high content screening assay to predict human drug-induced liver injury during drug discovery.

    Science.gov (United States)

    Persson, Mikael; Løye, Anni F; Mow, Tomas; Hornberg, Jorrit J

    2013-01-01

    Adverse drug reactions are a major cause for failures of drug development programs, drug withdrawals and use restrictions. Early hazard identification and diligent risk avoidance strategies are therefore essential. For drug-induced liver injury (DILI), this is difficult using conventional safety testing. To reduce the risk for DILI, drug candidates with a high risk need to be identified and deselected. And, to produce drug candidates without that risk associated, risk factors need to be assessed early during drug discovery, such that lead series can be optimized on safety parameters. This requires methods that allow for medium-to-high throughput compound profiling and that generate quantitative results suitable to establish structure-activity-relationships during lead optimization programs. We present the validation of such a method, a novel high content screening assay based on six parameters (nuclei counts, nuclear area, plasma membrane integrity, lysosomal activity, mitochondrial membrane potential (MMP), and mitochondrial area) using ~100 drugs of which the clinical hepatotoxicity profile is known. We find that a 100-fold TI between the lowest toxic concentration and the therapeutic Cmax is optimal to classify compounds as hepatotoxic or non-hepatotoxic, based on the individual parameters. Most parameters have ~50% sensitivity and ~90% specificity. Drugs hitting ≥2 parameters at a concentration below 100-fold their Cmax are typically hepatotoxic, whereas non-hepatotoxic drugs typically hit based on nuclei count, MMP and human Cmax, we identified an area without a single false positive, while maintaining 45% sensitivity. Hierarchical clustering using the multi-parametric dataset roughly separates toxic from non-toxic compounds. We employ the assay in discovery projects to prioritize novel compound series during hit-to-lead, to steer away from a DILI risk during lead optimization, for risk assessment towards candidate selection and to provide guidance of safe

  14. Molecular Mechanisms of Antipsychotic Drug-Induced Diabetes

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    Jiezhong Chen

    2017-11-01

    Full Text Available Antipsychotic drugs (APDs are widely prescribed to control various mental disorders. As mental disorders are chronic diseases, these drugs are often used over a life-time. However, APDs can cause serious glucometabolic side-effects including type 2 diabetes and hyperglycaemic emergency, leading to medication non-compliance. At present, there is no effective approach to overcome these side-effects. Understanding the mechanisms for APD-induced diabetes should be helpful in prevention and treatment of these side-effects of APDs and thus improve the clinical outcomes of APDs. In this review, the potential mechanisms for APD-induced diabetes are summarized so that novel approaches can be considered to relieve APD-induced diabetes. APD-induced diabetes could be mediated by multiple mechanisms: (1 APDs can inhibit the insulin signaling pathway in the target cells such as muscle cells, hepatocytes and adipocytes to cause insulin resistance; (2 APD-induced obesity can result in high levels of free fatty acids (FFA and inflammation, which can also cause insulin resistance. (3 APDs can cause direct damage to β-cells, leading to dysfunction and apoptosis of β-cells. A recent theory considers that both β-cell damage and insulin resistance are necessary factors for the development of diabetes. In high-fat diet-induced diabetes, the compensatory ability of β-cells is gradually damaged, while APDs cause direct β-cell damage, accounting for the severe form of APD-induced diabetes. Based on these mechanisms, effective prevention of APD-induced diabetes may need an integrated approach to combat various effects of APDs on multiple pathways.

  15. Idiosyncratic Drug-Induced Liver Injury: Is Drug-Cytokine Interaction the Linchpin?

    Science.gov (United States)

    Roth, Robert A; Maiuri, Ashley R; Ganey, Patricia E

    2017-02-01

    Idiosyncratic drug-induced liver injury continues to be a human health problem in part because drugs that cause these reactions are not identified in current preclinical testing and because progress in prevention is hampered by incomplete knowledge of mechanisms that underlie these adverse responses. Several hypotheses involving adaptive immune responses, inflammatory stress, inability to adapt to stress, and multiple, concurrent factors have been proposed. Yet much remains unknown about how drugs interact with the liver to effect death of hepatocytes. Evidence supporting hypotheses implicating adaptive or innate immune responses in afflicted patients has begun to emerge and is bolstered by results obtained in experimental animal models and in vitro systems. A commonality in adaptive and innate immunity is the production of cytokines, including interferon-γ (IFNγ). IFNγ initiates cell signaling pathways that culminate in cell death or inhibition of proliferative repair. Tumor necrosis factor-α, another cytokine prominent in immune responses, can also promote cell death. Furthermore, tumor necrosis factor-α interacts with IFNγ, leading to enhanced cellular responses to each cytokine. In this short review, we propose that the interaction of drugs with these cytokines contributes to idiosyncratic drug-induced liver injury, and mechanisms by which this could occur are discussed. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  16. Modeling drug- and chemical- induced hepatotoxicity with systems biology approaches

    Directory of Open Access Journals (Sweden)

    Sudin eBhattacharya

    2012-12-01

    Full Text Available We provide an overview of computational systems biology approaches as applied to the study of chemical- and drug-induced toxicity. The concept of ‘toxicity pathways’ is described in the context of the 2007 US National Academies of Science report, Toxicity testing in the 21st Century: A Vision and A Strategy. Pathway mapping and modeling based on network biology concepts are a key component of the vision laid out in this report for a more biologically-based analysis of dose-response behavior and the safety of chemicals and drugs. We focus on toxicity of the liver (hepatotoxicity – a complex phenotypic response with contributions from a number of different cell types and biological processes. We describe three case studies of complementary multi-scale computational modeling approaches to understand perturbation of toxicity pathways in the human liver as a result of exposure to environmental contaminants and specific drugs. One approach involves development of a spatial, multicellular virtual tissue model of the liver lobule that combines molecular circuits in individual hepatocytes with cell-cell interactions and blood-mediated transport of toxicants through hepatic sinusoids, to enable quantitative, mechanistic prediction of hepatic dose-response for activation of the AhR toxicity pathway. Simultaneously, methods are being developing to extract quantitative maps of intracellular signaling and transcriptional regulatory networks perturbed by environmental contaminants, using a combination of gene expression and genome-wide protein-DNA interaction data. A predictive physiological model (DILIsymTM to understand drug-induced liver injury (DILI, the most common adverse event leading to termination of clinical development programs and regulatory actions on drugs, is also described. The model initially focuses on reactive metabolite-induced DILI in response to administration of acetaminophen, and spans multiple biological scales.

  17. Drug-induced Liver Disease in Patients with Diabetes Mellitus

    OpenAIRE

    Iryna, Klyarytskaya; Helen, Maksymova; Elena, Stilidi

    2016-01-01

    The study presented here was accomplished to assess the course of drug-induced liver diseases in patient’s rheumatoid arthritis receiving long-term methotrexate therapy. Diabetes mellitus was revealed as the most significant risk factor. The combination of diabetes mellitus with other risk factors (female sex) resulted in increased hepatic fibrosis, degree of hepatic encephalopathy and reduction of hepatic functions. The effectiveness and safety of ursodeoxycholic acid and cytolytic type-with...

  18. Antithyroid drug induced agranulocytosis: what still we need to learn ?

    Science.gov (United States)

    Chaudhry, Liaqat Ali; Mazen, Khalid Fouad; Ba-Essa, Ebtesam; Robert, Asirvatham Alwin

    2016-01-01

    Antithyroid drugs (ATDs) induced agranulocytosis is a rare but life threatening condition. We report a 29 years Filipino female diagnosed as having hyperthyroidism with normal base line blood counts, liver and renal profile. She was started on maximum 60mg (20mg TID) oral dose of carbimazole since one month by her treating physician. Exactly after one month of treatment she presented to emergency room (ER) with fever, sore throat and generalized weakness for several days. PMID:27200132

  19. Drug induced hypertension--An unappreciated cause of secondary hypertension.

    Science.gov (United States)

    Grossman, Alon; Messerli, Franz H; Grossman, Ehud

    2015-09-15

    Most patients with hypertension have essential hypertension or well-known forms of secondary hypertension, such as renal disease, renal artery stenosis, or common endocrine diseases (hyperaldosteronism or pheochromocytoma). Physicians are less aware of drug induced hypertension. A variety of therapeutic agents or chemical substances may increase blood pressure. When a patient with well controlled hypertension is presented with acute blood pressure elevation, use of drug or chemical substance which increases blood pressure should be suspected. Drug-induced blood pressure increases are usually minor and short-lived, although rare hypertensive emergencies associated with use of certain drugs have been reported. Careful evaluation of prescription and non-prescription medications is crucial in the evaluation of the hypertensive individual and may obviate the need for expensive and unnecessary evaluations. Discontinuation of the offending agent will usually achieve adequate blood pressure control. When use of a chemical agent which increases blood pressure is mandatory, anti-hypertensive therapy may facilitate continued use of this agent. We summarize the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Antituberculosis Drug-Induced Liver Injury with Autoimmune Features: Facing Diagnostic and Treatment Challenges

    Directory of Open Access Journals (Sweden)

    Maria Adriana Rangel

    2017-01-01

    Full Text Available The authors present a case report of antituberculosis drug-induced liver injury that offered diagnostic challenges (namely, the possibility of drug-induced autoimmune hepatitis and treatment difficulties.

  1. Gamma-sterilization-induced radicals in biodegradable drug delivery systems

    International Nuclear Information System (INIS)

    Maeder, K.; Swartz, H.M.; Domb, A.

    1996-01-01

    Electron paramagnetic resonance (EPR) spectroscopy (1.2 and 9.25 GHz, 25 o C) was used to characterize free radicals in gamma-ray sterilized biodegradable polymers of the type which are in clinical use. Free radicals were detected in all irradiated polymer samples. The temperature of irradiation (25 o vs dry ice temperature) had only a minor influence on the yield of radicals and the shape of the EPR spectra. In contrast, the composition of the polymers and the drugs incorporated in them did strongly influence the amount of radiation-induced free radicals and their reactivity. In general, polymers with high melting points and crystallinity had the highest yields of radicals observable at room temperature. We were able to use the free radicals induced by the usual sterilization procedures to follow the penetration of water and the degradation of the polymers in vitro and in vivo. The ability of in vivo EPR to follow drug delivery noninvasively and continuously in vivo, using the free radicals induced in the usual sterilization process indicates that this approach could be applied immediately for the characterization of these drug delivery systems in experimental animals and in the near future should be able to be used in human subjects. (author)

  2. DRUG REACTION WITH HERBAL SUPPLEMENT: A POSSIBLE CASE OF DRUG INDUCED LUPUS ERYTHEMATOSUS

    Directory of Open Access Journals (Sweden)

    AZIZ NA

    2010-01-01

    Full Text Available A 24-year-old lady presented with four days history of fever, non-pruritic rash, ankle pain and swelling. She had consumed herbal supplement five days before the onset of symptoms. Examinations revealed erythematous maculo-papular lesions of varying sizes on sun exposed areas. Patient was suspected to have Drug Induced Lupus Erythematosus (DILE and subsequently symptoms subsided rapidly on withholding the herbal medication.

  3. Drug-Induced Anaphylaxis in Latin American Countries.

    Science.gov (United States)

    Jares, Edgardo José; Baena-Cagnani, Carlos E; Sánchez-Borges, Mario; Ensina, Luis Felipe C; Arias-Cruz, Alfredo; Gómez, Maximiliano; Cuello, Mabel Noemi; Morfin-Maciel, Blanca María; De Falco, Alicia; Barayazarra, Susana; Bernstein, Jonathan A; Serrano, Carlos; Monsell, Silvana; Schuhl, Juan; Cardona-Villa, Ricardo

    2015-01-01

    Information regarding the clinical features and management of drug-induced anaphylaxis (DIA) in Latin America is lacking. The objective of this study was to assess implicated medications, demographics, and treatments received for DIA in Latin American patients referred to national specialty centers for evaluation. A database previously used to compile information on drug-induced allergic reactions in 11 Latin American countries was used to identify and characterize patients presenting specifically with a clinical diagnosis of DIA. Information regarding clinical presentation, causative agent(s), diagnostic studies performed, treatment, and contributing factors associated with increased reaction severity was analyzed. There were 1005 patients evaluated for possible drug hypersensitivity reactions during the study interval, and 264 (26.3%) met criteria for DIA. DIA was more frequent in adults and in elderly females (N = 129 [76.6%] and N = 30 [75%], respectively) compared with children and/or adolescents (N = 21 [42.9%], P asthma (N = 22 vs 35 [38.6% vs 61.4%], P Latin American patients referred for evaluation of DIA, NSAIDs and antibiotics were implicated in approximately 80% of cases. Most of these reactions were treated in the emergency department. Epinephrine was administered in only 27.6% of all cases, although more frequently for anaphylactic shock. Dissemination of anaphylaxis guidelines among emergency department physicians should be encouraged to improve management of DIA. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  4. Drug-induced liver injury due to antibiotics.

    Science.gov (United States)

    Björnsson, Einar S

    Drug-induced liver injury (DILI) is an important differential diagnosis in patients with abnormal liver tests and normal hepatobiliary imaging. Of all known liver diseases, the diagnosis of DILI is probably one of the most difficult one to be established. In all major studies on DILI, antibiotics are the most common type of drugs that have been reported. The clinical phenotype of different types of antibiotics associated with liver injury is highly variable. Some widely used antibiotics such as amoxicillin-clavulanate have been shown to have a delayed onset on liver injury and recently cefazolin has been found to lead to liver injury 1-3 weeks after exposure of a single infusion. The other extreme is the nature of nitrofurantoin-induced liver injury, which can occur after a few years of treatment and lead to acute liver failure (ALF) or autoimmune-like reaction. Most patients with liver injury associated with use of antibiotics have a favorable prognosis. However, patients with jaundice have approximately 10% risk of death from liver failure and/or require liver transplantation. In rare instances, the hepatoxicity can lead to chronic injury and vanishing bile duct syndrome. Given, sometimes very severe consequences of the adverse liver reactions, it cannot be over emphasized that the indication for the different antibiotics should be evidence-based and symptoms and signs of liver injury from the drugs should lead to prompt cessation of therapy.

  5. Drug-induced gingival enlargement: Series of cases

    Directory of Open Access Journals (Sweden)

    Isabella Manzur-Villalobos

    2018-01-01

    Full Text Available Introduction: Gingival enlargement (GA is a benign condition of the oral cavity that is characterized by the excessive growth of the gingiva in mass and volume. This lesion is not only caused by hereditary factors or poor oral hygiene, but also by the intake of medications, including antihypertensive, anticonvulsant and immunosuppressive drugs. Objective: To sensitize the prevention or early care in patients with pathologies that merit the use of antihypertensive and anticonvulsants in conjunction with the dentist, to treat or avoid the drug-induced gingival enlargement (DIGE. Materials and methods: A series of clinical cases of patients with gingival enlargement by various drugs are reported, including Phenytoin, Amlodipine and Nifedipine. Periodontal and gingivectomy hygienic phase measures were applied to obtain better effects. Results: Satisfactory results were obtained with a considerable decrease in DIGE. Conclusions: The integral management is important in conjunction with the treating physician to follow up the drug that can be generating gingival enlargement. It is necessary to employ an initial approach with strategies of periodontal hygiene, and in severe cases and, as last resort, the periodontal surgery with gingivectomy and gingivoplasty.

  6. 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.

  7. Acute nonsteroidal anti-inflammatory drug-induced colitis

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    Massimo Tonolini

    2013-01-01

    Full Text Available Resulting from direct toxicity on the bowel mucosa, nonsteroidal anti-inflammatory drug (NSAID-induced colitis is an underestimated although potentially serious condition. Plain abdominal radiographs and multidetector computed tomography allow to identify a right-sided acute colitis with associated pericolonic inflammation, progressively diminished changes along the descending and sigmoid colon, and rectal sparing, consistent with the hypothesized pathogenesis of NSAID colitis. Increased awareness of this condition should reduce morbidity through both prevention and early recognition. High clinical suspicion and appropriate patient questioning, together with consistent instrumental findings, negative biochemistry, and stool investigations should help physicians not to miss this important diagnosis.

  8. Associations of Drug Lipophilicity and Extent of Metabolism with Drug-Induced Liver Injury.

    Science.gov (United States)

    McEuen, Kristin; Borlak, Jürgen; Tong, Weida; Chen, Minjun

    2017-06-22

    Drug-induced liver injury (DILI), although rare, is a frequent cause of adverse drug reactions resulting in warnings and withdrawals of numerous medications. Despite the research community's best efforts, current testing strategies aimed at identifying hepatotoxic drugs prior to human trials are not sufficiently powered to predict the complex mechanisms leading to DILI. In our previous studies, we demonstrated lipophilicity and dose to be associated with increased DILI risk and, and in our latest work, we factored reactive metabolites into the algorithm to predict DILI. Given the inconsistency in determining the potential for drugs to cause DILI, the present study comprehensively assesses the relationship between DILI risk and lipophilicity and the extent of metabolism using a large published dataset of 1036 Food and Drug Administration (FDA)-approved drugs by considering five independent DILI annotations. We found that lipophilicity and the extent of metabolism alone were associated with increased risk for DILI. Moreover, when analyzed in combination with high daily dose (≥100 mg), lipophilicity was statistically significantly associated with the risk of DILI across all datasets ( p < 0.05). Similarly, the combination of extensive hepatic metabolism (≥50%) and high daily dose (≥100 mg) was also strongly associated with an increased risk of DILI among all datasets analyzed ( p < 0.05). Our results suggest that both lipophilicity and the extent of hepatic metabolism can be considered important risk factors for DILI in humans, and that this relationship to DILI risk is much stronger when considered in combination with dose. The proposed paradigm allows the convergence of different published annotations to a more uniform assessment.

  9. Drug induced exocytosis of glycogen in Pompe disease.

    Science.gov (United States)

    Turner, Christopher T; Fuller, Maria; Hopwood, John J; Meikle, Peter J; Brooks, Doug A

    2016-10-28

    Pompe disease is caused by a deficiency in the lysosomal enzyme α-glucosidase, and this leads to glycogen accumulation in the autolysosomes of patient cells. Glycogen storage material is exocytosed at a basal rate in cultured Pompe cells, with one study showing up to 80% is released under specific culture conditions. Critically, exocytosis induction may reduce glycogen storage in Pompe patients, providing the basis for a therapeutic strategy whereby stored glycogen is redirected to an extracellular location and subsequently degraded by circulating amylases. The focus of the current study was to identify compounds capable of inducing rapid glycogen exocytosis in cultured Pompe cells. Here, calcimycin, lysophosphatidylcholine and α-l-iduronidase each significantly increased glycogen exocytosis compared to vehicle-treated controls. The most effective compound, calcimycin, induced exocytosis through a Ca 2+ -dependent mechanism, although was unable to release a pool of vesicular glycogen larger than the calcimycin-induced exocytic pore. There was reduced glycogen release from Pompe compared to unaffected cells, primarily due to increased granule size in Pompe cells. Drug induced exocytosis therefore shows promise as a therapeutic approach for Pompe patients but strategies are required to enhance the release of large molecular weight glycogen granules. Copyright © 2016. Published by Elsevier Inc.

  10. Primary psychosis with comorbid drug abuse and drug-induced psychosis: Diagnostic and clinical evolution at follow up.

    Science.gov (United States)

    Mauri, M C; Di Pace, C; Reggiori, A; Paletta, S; Colasanti, A

    2017-10-01

    The study reports a follow-up assessment of 48 patients with concomitant drug abuse at the first admission for psychosis. We focused on the diagnostic distinction between primary psychosis with concomitant drug abuse and drug induced psychosis, to observe whether the diagnoses are stable over time and whether the clinical course significantly differs. The study examined 25 primary psychotic disorder with comorbid drug abuse and 23 drug-induced psychotic disorder patients. Diagnostic and psychopathological assessments were made at baseline and at follow-up. Mean follow-up period was 4.96 years. Patients with comorbid Drug Abuse exhibited higher scores in the item Unusual Content of Thought at baseline than drug-induced psychotic disorder patients: 5.48 vs 4.39 while the two patients groups did not differ in any of the BPRS items evaluated at follow-up. The primary psychosis with comorbid drug abuse and the substance induced psychosis groups were similar regarding diagnostic stability, and a diagnosis of schizophrenia at follow-up occurred similarly. There was no evidence that Drug Induced psychotic patients' symptoms tend to improve more after cessation of drug abuse. An earlier age of onset was found in primary psychotic patients, particularly for patients diagnosed as affected by schizophrenia at follow up. These results might reflect the uncertainty of the distinction between Primary and Drug Induced Psychosis and the difficulties in applying the DSM IV-TR criteria for diagnosing comorbid drug use disorders and psychotic disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Anti-topoisomerase drugs as potent inducers of chromosomal aberrations

    Directory of Open Access Journals (Sweden)

    Loredana Bassi

    2000-12-01

    Full Text Available DNA topoisomerases catalyze topological changes in DNA that are essential for normal cell cycle progression and therefore they are a preferential target for the development of anticancer drugs. Anti-topoisomerase drugs can be divided into two main classes: "cleavable complex" poisons and catalytic inhibitors. The "cleavable complex" poisons are very effective as anticancer drugs but are also potent inducers of chromosome aberrations so they can cause secondary malignancies. Catalytic inhibitors are cytotoxic but they do not induce chromosome aberrations. Knowledge about the mechanism of action of topoisomerase inhibitors is important to determine the best anti-topoisomerase combinations, with a reduced risk of induction of secondary malignancies.As topoisomerases de DNA catalisam alterações topológicas no DNA que são essenciais para a progressão do ciclo celular normal e, portanto, são um alvo preferencial para o desenvolvimento de drogas anticâncer. Drogas anti-topoisomerases podem ser divididas em duas classes principais: drogas anti-"complexos cliváveis" e inibidores catalíticos. As drogas anti-"complexos cliváveis" são muito eficazes como drogas anticancerígenas, mas são também potentes indutores de aberrações cromossômicas, podendo causar neoplasias malignas secundárias. Inibidores catalíticos são citotóxicos mas não induzem aberrações cromossômicas. Conhecimento a respeito do mecanismo de ação de inibidores de topoisomerases é importante para determinar as melhores combinações anti-topoisomerases, com um reduzido risco de indução de neoplasias malignas secundárias.

  12. RUCAM in Drug and Herb Induced Liver Injury: The Update

    Directory of Open Access Journals (Sweden)

    Gaby Danan

    2015-12-01

    Full Text Available RUCAM (Roussel Uclaf Causality Assessment Method or its previous synonym CIOMS (Council for International Organizations of Medical Sciences is a well established tool in common use to quantitatively assess causality in cases of suspected drug induced liver injury (DILI and herb induced liver injury (HILI. Historical background and the original work confirm the use of RUCAM as single term for future cases, dismissing now the term CIOMS for reasons of simplicity and clarity. RUCAM represents a structured, standardized, validated, and hepatotoxicity specific diagnostic approach that attributes scores to individual key items, providing final quantitative gradings of causality for each suspect drug/herb in a case report. Experts from Europe and the United States had previously established in consensus meetings the first criteria of RUCAM to meet the requirements of clinicians and practitioners in care for their patients with suspected DILI and HILI. RUCAM was completed by additional criteria and validated, assisting to establish the timely diagnosis with a high degree of certainty. In many countries and for more than two decades, physicians, regulatory agencies, case report authors, and pharmaceutical companies successfully applied RUCAM for suspected DILI and HILI. Their practical experience, emerging new data on DILI and HILI characteristics, and few ambiguous questions in domains such alcohol use and exclusions of non-drug causes led to the present update of RUCAM. The aim was to reduce interobserver and intraobserver variability, to provide accurately defined, objective core elements, and to simplify the handling of the items. We now present the update of the well accepted original RUCAM scale and recommend its use for clinical, regulatory, publication, and expert purposes to validly establish causality in cases of suspected DILI and HILI, facilitating a straightforward application and an internationally harmonized approach of causality

  13. Traditional Chinese Medicine and Herb-induced Liver Injury: Comparison with Drug-induced Liver Injury.

    Science.gov (United States)

    Jing, Jing; Teschke, Rolf

    2018-03-28

    Cases of suspected herb-induced liver injury (HILI) caused by herbal Traditional Chinese Medicines (TCMs) and of drug-induced liver injury (DILI) are commonly published in the scientific literature worldwide. As opposed to the multiplicity of botanical chemicals in herbal TCM products, which are often mixtures of several herbs, conventional Western drugs contain only a single synthetic chemical. It is therefore of interest to study how HILI by TCM and DILI compare with each other, and to what extent results from each liver injury type can be transferred to the other. China is among the few countries with a large population using synthetic Western drugs as well as herbal TCM. Therefore, China is well suited to studies of liver injury comparing drugs with TCM herbs. Despite some concordance, recent analyses of liver injury cases with verified causality, using the Roussel Uclaf Causality Assessment Method, revealed major differences in HILI caused by TCMs as compared to DILI with respect to the following features: HILI cases are less frequently observed as compared to DILI, have a smaller proportion of females and less unintentional rechallenge events, and present a higher rate of hepatocellular injury features. Since many results were obtained among Chinese residents who had access to and had used Western drugs and TCM herbs, such ethnic homogeneity supports the contention that the observed differences of HILI and DILI in the assessed population are well founded.

  14. Drug induced acute kidney injury: an experimental animal study

    International Nuclear Information System (INIS)

    Khan, M.W.A.; Khan, B.T.; Qazi, R.A.; Ashraf, M.; Waqar, M.

    2017-01-01

    Objective: To assess the extent of drug induced nephrotoxicity in laboratory animals for determining the role and extent of iatrogenic kidney damage in patients exposed to nephrotoxic drugs in various clinical setups. Study Design: Randomized control trail. Place and Duration of study: Pharmacology department and animal house of Army Medical College from Jan 2011 to Aug 2011. Material and Methods: Thirty six mixed breed rabbits were used in this study. Animals were randomly divided into six groups consisting of six rabbits in each. Groups were named A, B, C, D, E and F. Group A was control group. Group B was given 0.9% normal saline. Group C rabbits were given acute nephrotoxic single dose of amphotericin B deoxycholate. Group D received 0.9% normal saline 10ml/kg followed by amphotericin B infusion. Group E was injected acute nephrotoxic regimen of cyclosporine and amphotericin B infusion. Group F received saline loading along with acute nephrotoxic regimen of cyclosporine and amphotericin B infusion. Results: Biochemical and histopathological analysis showed significant kidney injury in rabbits exposed to acute nephrotoxic doses of amphotericin B and cyclosporine. Toxicity was additive when the two drugs were administered simultaneously. Group of rabbits with saline loading had significantly lesser kidney damage. Conclusion: Iatrogenic acute kidney damage is a major cause of morbidity in experimental animals exposed to such nephrotoxic drugs like amphotericin B and cyclosporine, used either alone or in combination. Clinical studies are recommended to assess the extent of iatrogenic renal damage in patients and its economic burden. Efficient and cost effective protective measure may be adopted in clinical setups against such adverse effects. (author)

  15. Diphenhydramine as a Cause of Drug-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Yunseok Namn

    2017-01-01

    Full Text Available Drug-induced liver injury (DILI is the most common cause of acute liver failure in the Unites States and accounts for 10% of acute hepatitis cases. We report the only known case of diphenhydramine-induced acute liver injury in the absence of concomitant medications. A 28-year-old man with history of 13/14-chromosomal translocation presented with fevers, vomiting, and jaundice. Aspartate-aminotransferase and alanine-aminotransferase levels peaked above 20,000 IU/L and 5,000 IU/L, respectively. He developed coagulopathy but without altered mental status. Patient reported taking up to 400 mg diphenhydramine nightly, without concomitant acetaminophen, for insomnia. He denied taking other medications, supplements, antibiotics, and herbals. A thorough workup of liver injury ruled out viral hepatitis (including A, B, C, and E, autoimmune, toxic, ischemic, and metabolic etiologies including Wilson’s disease. A liver biopsy was consistent with DILI without evidence of iron or copper deposition. Diphenhydramine was determined to be the likely culprit. This is the first reported case of diphenhydramine-induced liver injury without concomitant use of acetaminophen.

  16. Conditioned Place Preference Induced by Licit Drugs: Establishment, Extinction, and Reinstatement

    Directory of Open Access Journals (Sweden)

    Yu Liu

    2008-01-01

    Full Text Available The conditioned place preference (CPP model has been widely used to evaluate the rewarding effects of abused drugs, and recently, the extinction and reinstatement phases of this paradigm have been used to assess relapse to drug seeking. The vast majority of studies have focused on CPP induced by illicit drugs, such as psychostimulants and opioids. Although legal psychoactive drugs, such as ethanol, nicotine, and caffeine, are more widely used than illegal drugs, the establishment, extinction, and reinstatement of CPP produced by these licit drugs are less well understood. The present review discusses the extant research on CPP induced by legal drugs. We first describe the CPP model and discuss the behavioral procedures used to induce CPP for ethanol, nicotine, and caffeine. We then summarize the neuronal substrates that underlie CPP induced by these drugs from a genetic perspective. Finally, we draw on findings from pharmacological studies and discuss the neurotransmitters and neurohormones underlying CPP produced by ethanol, nicotine, and caffeine.

  17. Drug-sensing hydrogels for the inducible release of biopharmaceuticals

    Science.gov (United States)

    Ehrbar, Martin; Schoenmakers, Ronald; Christen, Erik H.; Fussenegger, Martin; Weber, Wilfried

    2008-10-01

    Drug-dependent dissociation or association of cellular receptors represents a potent pharmacologic mode of action for regulating cell fate and function. Transferring the knowledge of pharmacologically triggered protein-protein interactions to materials science will enable novel design concepts for stimuli-sensing smart hydrogels. Here, we show the design and validation of an antibiotic-sensing hydrogel for the trigger-inducible release of human vascular endothelial growth factor. Genetically engineered bacterial gyrase subunit B (GyrB) (ref. 4) coupled to polyacrylamide was dimerized by the addition of the aminocoumarin antibiotic coumermycin, resulting in hydrogel formation. Addition of increasing concentrations of clinically validated novobiocin (Albamycin) dissociated the GyrB subunits, thereby resulting in dissociation of the hydrogel and dose- and time-dependent liberation of the entrapped protein pharmaceutical VEGF121 for triggering proliferation of human umbilical vein endothelial cells. Pharmacologically controlled hydrogels have the potential to fulfil the promises of stimuli-sensing materials as smart devices for spatiotemporally controlled delivery of drugs within the patient.

  18. Intrinsic and Antipsychotic Drug-Induced Metabolic Dysfunction in Schizophrenia

    Directory of Open Access Journals (Sweden)

    Zachary Freyberg

    2017-07-01

    Full Text Available For decades, there have been observations demonstrating significant metabolic disturbances in people with schizophrenia including clinically relevant weight gain, hypertension, and disturbances in glucose and lipid homeostasis. Many of these findings pre-date the use of antipsychotic drugs (APDs which on their own are also strongly associated with metabolic side effects. The combination of APD-induced metabolic changes and common adverse environmental factors associated with schizophrenia have made it difficult to determine the specific contributions of each to the overall metabolic picture. Data from drug-naïve patients, both from the pre-APD era and more recently, suggest that there may be an intrinsic metabolic risk associated with schizophrenia. Nevertheless, these findings remain controversial due to significant clinical variability in both psychiatric and metabolic symptoms throughout patients' disease courses. Here, we provide an extensive review of classic and more recent literature describing the metabolic phenotype associated with schizophrenia. We also suggest potential mechanistic links between signaling pathways associated with schizophrenia and metabolic dysfunction. We propose that, beyond its symptomatology in the central nervous system, schizophrenia is also characterized by pathophysiology in other organ systems directly related to metabolic control.

  19. Drug-induced interstitial lung diseases. Often forgotten

    International Nuclear Information System (INIS)

    Poschenrieder, F.; Stroszczynski, C.; Hamer, O.W.

    2014-01-01

    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.) [de

  20. Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans.

    Science.gov (United States)

    Fujiwara, Ryoichi; Yoda, Emiko; Tukey, Robert H

    2018-02-01

    More than 20% of clinically used drugs are glucuronidated by a microsomal enzyme UDP-glucuronosyltransferase (UGT). Inhibition or induction of UGT can result in an increase or decrease in blood drug concentration. To avoid drug-drug interactions and adverse drug reactions in individuals, therefore, it is important to understand whether UGTs are involved in metabolism of drugs and drug candidates. While most of glucuronides are inactive metabolites, acyl-glucuronides that are formed from compounds with a carboxylic acid group can be highly toxic. Animals such as mice and rats are widely used to predict drug metabolism and drug-induced toxicity in humans. However, there are marked species differences in the expression and function of drug-metabolizing enzymes including UGTs. To overcome the species differences, mice in which certain drug-metabolizing enzymes are humanized have been recently developed. Humanized UGT1 (hUGT1) mice were created in 2010 by crossing Ugt1-null mice with human UGT1 transgenic mice in a C57BL/6 background. hUGT1 mice can be promising tools to predict human drug glucuronidation and acyl-glucuronide-associated toxicity. In this review article, studies of drug metabolism and toxicity in the hUGT1 mice are summarized. We further discuss research and strategic directions to advance the understanding of drug glucuronidation in humans. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  1. Comparison between two ovulation-inducing drugs in mares

    Directory of Open Access Journals (Sweden)

    Paula Cardoso de Almeida Silva

    2016-11-01

    Full Text Available ABSTRACT. Silva P.C.A., Oliveira J.P., Sá M.A.F., Paiva S.O., Caram D.F., Junqueira R.G.C. & Jacob J.C.F. [Comparison between two ovulation-inducing drugs in mares.] Comparação entre dois agentes indutores da ovulação em éguas. Revista Brasileira de Medicina Veterinária, 38(Supl.2:45-48, 2016. Departamento de Reprodução e Avaliação Animal, Instituto de Zootecnia, Universidade Federal Rural do Rio de Janeiro, BR-465, Km 7, Seropédica, RJ 23890-000, Brasil. E-mail: paulinha_calmeida@hotmail.com Hormonal control of the ovulation is an effective tool to improve reproductive performance and reduce costs in equine breeding programs. The aim of this study was to compare the efficiency of lower doses of hCG and Deslorelina than doses traditionally used, evaluating the follicular parameters and time between induction and ovulation. Induction of ovulation was performed according to the groups, 1000 IU of hCG (G1, 0.75mg of Deslorelin (G2, and 1.0ml of saline solution (G3. Twenty-four hours after administration, ovaries were evaluated by ultrasound every six hours until detection of ovulation.  The percentage of ovulation within 36 hours was 34.4%, 13.3% and 8.7%, and up to 42 hours was 96.9%, 70% and 17.4% for G1, G2 and G3, respectively, showing a significant increase (p ˂ 0.0001 in G1 compared to other groups. In G2 there was a significant increase (p ˂ 0.0001 of ovulation after 42 hours from the induction, and G3 after 48 hours. Until 48 hours the percentage of induction of ovulation was 96.8% (31/32 90% (27/30 and 30.4% (7/23, respectively, for G1, G2 and G3. Thus, the lower doses of ovulation-inducing drugs were effective in inducing ovulation within 48 hours, however hCG was faster than deslorelin, which might reduce costs and help the reproduction management.

  2. Functionalized nanoparticles for AMF-induced gene and drug delivery

    Science.gov (United States)

    Biswas, Souvik

    The properties and broad applications of nano-magnetic colloids have generated much interest in recent years. Specially, Fe3O4 nanoparticles have attracted a great deal of attention since their magnetic properties can be used for hyperthermia treatment or drug targeting. For example, enhanced levels of intracellular gene delivery can be achieved using Fe3O4 nano-vectors in the presence of an external magnetic field, a process known as 'magnetofection'. The low cytotoxicity, tunable particle size, ease of surface functionalization, and ability to generate thermal energy using an external alternating magnetic field (AMF) are properties have propelled Fe3O4 research to the forefront of nanoparticle research. The strategy of nanoparticle-mediated, AMF-induced heat generation has been used to effect intracellular hyperthermia. One application of this 'magnetic hyperthermia' is heat activated local delivery of a therapeutic effector (e.g.; drug or polynucleotide). This thesis describes the development of a magnetic nano-vector for AMF-induced, heat-activated pDNA and small molecule delivery. The use of heat-inducible vectors, such as heat shock protein ( hsp) genes, is a promising mode of gene therapy that would restrict gene expression to a local region by focusing a heat stimulus only at a target region. We thus aimed to design an Fe3O4 nanoparticle-mediated gene transfer vehicle for AMF-induced localized gene expression. We opted to use 'click' oximation techniques to assemble the magnetic gene transfer vector. Chapter 2 describes the synthesis, characterization, and transfection studies of the oxime ether lipid-based nano-magnetic vectors MLP and dMLP. The synthesis and characterization of a novel series of quaternary ammonium aminooxy reagents (2.1--2.4) is described. These cationic aminooxy compounds were loaded onto nanoparticles for ligation with carbonyl groups and also to impart a net positive charge on the nanoparticle surface. Our studies indicated that the

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

    DEFF Research Database (Denmark)

    Andersen, V; Sonne, J; Andersen, M

    2001-01-01

    valproate (two cases), clomipramine (one case) and azathioprine (one case). Definite relationship was stated for mesalazine (three cases), azathioprine (two cases) and simvastatin (one case) on the basis of re-challenge. A possible or probable causality was considered for a further 30 drugs including 5...... (measles" mumps/rubella) vaccination. CONCLUSION: Drug-induced pancreatitis is rarely reported. The incidence may be increasing and the course is often serious. This is the first report on definite simvastatin-induced pancreatitis. Further studies on the pancreotoxic potential of drugs are warranted.......OBJECTIVES: To present an update on drug-induced pancreatitis reported to the Danish Committee on Adverse Drug Reactions. DESIGN: Retrospective study of spontaneous case reports to the Danish reporting system on adverse drug reactions. METHODS: All cases of suspected drug-induced pancreatitis...

  4. Test systems in drug discovery for hazard identification and risk assessment of human drug-induced liver injury.

    Science.gov (United States)

    Weaver, Richard J; Betts, Catherine; Blomme, Eric A G; Gerets, Helga H J; Gjervig Jensen, Klaus; Hewitt, Philip G; Juhila, Satu; Labbe, Gilles; Liguori, Michael J; Mesens, Natalie; Ogese, Monday O; Persson, Mikael; Snoeys, Jan; Stevens, James L; Walker, Tracy; Park, B Kevin

    2017-07-01

    The liver is an important target for drug-induced toxicities. Early detection of hepatotoxic drugs requires use of well-characterized test systems, yet current knowledge, gaps and limitations of tests employed remains an important issue for drug development. Areas Covered: The current state of the science, understanding and application of test systems in use for the detection of drug-induced cytotoxicity, mitochondrial toxicity, cholestasis and inflammation is summarized. The test systems highlighted herein cover mostly in vitro and some in vivo models and endpoint measurements used in the assessment of small molecule toxic liabilities. Opportunities for research efforts in areas necessitating the development of specific tests and improved mechanistic understanding are highlighted. Expert Opinion: Use of in vitro test systems for safety optimization will remain a core activity in drug discovery. Substantial inroads have been made with a number of assays established for human Drug-induced Liver Injury. There nevertheless remain significant gaps with a need for improved in vitro tools and novel tests to address specific mechanisms of human Drug-Induced Liver Injury. Progress in these areas will necessitate not only models fit for application, but also mechanistic understanding of how chemical insult on the liver occurs in order to identify translational and quantifiable readouts for decision-making.

  5. The application of hematopoietic growth factors in drug-induced agranulocytosis: a review of 70 cases

    NARCIS (Netherlands)

    Sprikkelman, A.; de Wolf, J. T.; 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

  6. Drug Eruptions Induced by Allopurinol Associated with HLA-BFNx015801

    Directory of Open Access Journals (Sweden)

    Meihua Zeng

    2015-01-01

    Full Text Available Allopurinol, a drug commonly used for treating gout and hyperuricemia, is a frequent cause of drug eruptions. Recent investigations suggest that HLA-BFNx015801 allele is a very strong marker for allopurinol-induced cutaneous adverse drug reactions (cADRs. In this article we report two cases of allopurinol-induced drug eruptions in patients carrying the HLA-BFNx015801 allele and review the literature on the association between HLA-BFNx015801 and allopurinol-induced cADRs based on a MEDLINE and PubMed search

  7. Magnetically induced localized on-demand drug delivery

    NARCIS (Netherlands)

    Rovers, S.A.

    2010-01-01

    Externally triggered on-demand drug release from an implant can significantly improve the efficiency of the drug therapy since it enables the patient or physician to control the dosing to the patient’s needs and releases the drug only at the required location in the human body. Therefore, patient

  8. A Drug Combination Screen Identifies Drugs Active against Amoxicillin-Induced Round Bodies of In Vitro Borrelia burgdorferi Persisters from an FDA Drug Library.

    Science.gov (United States)

    Feng, Jie; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Auwaerter, Paul G; Zhang, Ying

    2016-01-01

    Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under experimental stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that appear resistant in vitro to customary first-line antibiotics for Lyme disease. To identify more effective drugs with activity against the round body form of B. burgdorferi, we established a round body persister model induced by exposure to amoxicillin (50 μg/ml) and then screened the Food and Drug Administration drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven individual drugs scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. In this amoxicillin-induced round body model, some drug candidates such as daptomycin and clofazimine also displayed enhanced activity which was similar to a previous screen against stationary phase B. burgdorferi persisters not exposure to amoxicillin. Additional candidate drugs active against round bodies identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against amoxicillin-induced round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi

  9. [Hydroxyurea (hydroxycarbamide)-induced hepatic dysfunction confirmed by drug-induced lymphocyte stimulation test].

    Science.gov (United States)

    Shimizu, Takayuki; Mori, Takehiko; Karigane, Daiki; Kikuchi, Taku; Koda, Yuya; Toyama, Takaaki; Nakajima, Hideaki; Okamoto, Shinichiro

    2014-01-01

    A 62-year-old man with refractory leukemia transformed from myelodysplastic syndrome was placed on hydroxyurea (hydroxycarbamide) at a daily dose of 500 mg. Because of insufficient cytoreductive efficacy, the dose was increased to 1,500 mg five days later. Eight days after the initiation of hydroxyurea, the patient started complaining of chills, fever, and vomiting. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were markedly elevated to 5,098 and 3,880 IU/l from 44 and 59 IU/l in one day, respectively. Tests for hepatitis viruses were all negative. With the discontinuation of hydroxyurea, AST and ALT returned to their former levels within two weeks. A drug-induced lymphocyte stimulation test for hydroxyurea was positive with a stimulating index of 2.0. Hepatic dysfunction has been recognized as one of the side effects of hydroxyurea. However, there have been only a limited number of reports demonstrating drug allergy to have a role in hepatic dysfunction accompanied by fever and gastrointestinal symptoms. The findings of our case strongly suggest that all presentations could be explained by drug allergy. Physicians should be mindful of the potential for acute and severe hepatic dysfunction due to allergic reaction against hydroxyurea.

  10. Drug-Induced Dental Caries: A Disproportionality Analysis Using Data from VigiBase.

    Science.gov (United States)

    de Campaigno, Emilie Patras; Kebir, Inès; Montastruc, Jean-Louis; Rueter, Manuela; Maret, Delphine; Lapeyre-Mestre, Maryse; Sallerin, Brigitte; Despas, Fabien

    2017-12-01

    Dental caries is defined as a pathological breakdown of the tooth. It is an infectious phenomenon involving a multifactorial aetiology. The impact of drugs on cariogenic risk has been poorly investigated. In this study, we identified drugs suspected to induce dental caries as adverse drug reactions (ADRs) and then studied a possible pathogenic mechanism for each drug that had a statistically significant disproportionality. We extracted individual case safety reports of dental caries associated with drugs from VigiBase ® (the World Health Organization global individual case safety report database). We calculated disproportionality for each drug with a reporting odds ratio (ROR) and 99% confidence interval. We analysed the pharmacodynamics of each drug that had a statistically significant disproportionality. In VigiBase ® , 5229 safety reports for dental caries concerning 733 drugs were identified. Among these drugs, 88 had a significant ROR, and for 65 of them (73.9%), no information about dental caries was found in the summaries of the product characteristics, the Micromedex ® DRUGDEX, or the Martindale databases. Regarding the pharmacological classes of drugs involved in dental caries, we identified bisphosphonates, atropinic drugs, antidepressants, corticoids, immunomodulating drugs, antipsychotics, antiepileptics, opioids and β 2 -adrenoreceptor agonist drugs. Regarding possible pathogenic mechanisms for these drugs, we identified changes in salivary flow/composition for 54 drugs (61.4%), bone metabolism changes for 31 drugs (35.2%), hyperglycaemia for 32 drugs (36.4%) and/or immunosuppression for 23 drugs (26.1%). For nine drugs (10.2%), the mechanism was unclear. We identified 88 drugs with a significant positive disproportionality for dental caries. Special attention has to be paid to bisphosphonates, atropinic drugs, immunosuppressants and drugs causing hyperglycaemia.

  11. Stress- and glucocorticoid-induced priming of neuroinflammatory responses: potential mechanisms of stress-induced vulnerability to drugs of abuse.

    Science.gov (United States)

    Frank, Matthew G; Watkins, Linda R; Maier, Steven F

    2011-06-01

    Stress and stress-induced glucocorticoids (GCs) sensitize drug abuse behavior as well as the neuroinflammatory response to a subsequent pro-inflammatory challenge. Stress also predisposes or sensitizes individuals to develop substance abuse. There is an emerging evidence that glia and glia-derived neuroinflammatory mediators play key roles in the development of drug abuse. Drugs of abuse such as opioids, psychostimulants, and alcohol induce neuroinflammatory mediators such as pro-inflammatory cytokines (e.g. interleukin (IL)-1β), which modulate drug reward, dependence, and tolerance as well as analgesic properties. Drugs of abuse may directly activate microglial and astroglial cells via ligation of Toll-like receptors (TLRs), which mediate the innate immune response to pathogens as well as xenobiotic agents (e.g. drugs of abuse). The present review focuses on understanding the immunologic mechanism(s) whereby stress primes or sensitizes the neuroinflammatory response to drugs of abuse and explores whether stress- and GC-induced sensitization of neuroimmune processes predisposes individuals to drug abuse liability and the role of neuroinflammatory mediators in the development of drug addiction. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. Stable and biocompatible genipin-inducing interlayer-crosslinked micelles for sustained drug release

    Energy Technology Data Exchange (ETDEWEB)

    Dai, Yu; Zhang, Xiaojin, E-mail: zhangxj@cug.edu.cn [China University of Geosciences, Faculty of Materials Science and Chemistry (China)

    2017-05-15

    To develop the sustained drug release system, here we describe genipin-inducing interlayer-crosslinked micelles crosslinked via Schiff bases between the amines of amphiphilic linear-hyperbranched polymer poly(ethylene glycol)-branched polyethylenimine-poly(ε-caprolactone) (PEG-PEI-PCL) and genipin. The generation of Schiff bases was confirmed by the color changes and UV-Vis absorption spectra of polymeric micelles after adding genipin. The particle size, morphology, stability, in vitro cytotoxicity, drug loading capacity, and in vitro drug release behavior of crosslinked micelles as well as non-crosslinked micelles were characterized. The results indicated that genipin-inducing interlayer-crosslinked micelles had better stability and biocompatibility than non-crosslinked micelles and glutaraldehyde-inducing interlayer-crosslinked micelles. In addition, genipin-inducing interlayer-crosslinked micelles were able to improve drug loading capacity, reduce the initial burst release, and achieve sustained drug release.

  13. Drug-induced conditioned place preference and aversion in mice.

    Science.gov (United States)

    Cunningham, Christopher L; Gremel, Christina M; Groblewski, Peter A

    2006-01-01

    This protocol describes the equipment and methods used to establish conditioned place preference (CPP) or aversion (CPA). Place conditioning is a form of Pavlovian conditioning routinely used to measure the rewarding or aversive motivational effects of objects or experiences (e.g., abused drugs). Here, we present a place conditioning procedure that has been used extensively to study the motivational effects of ethanol and other abused drugs in mice. This protocol involves three phases: (i) habituation (or a pretest), (ii) conditioning of an association between the drug and a tactile or visual stimulus and (iii) a test that offers a choice between the drug-associated cue and a neutral cue. If the drug has motivational significance, mice will spend significantly more time (CPP) or less time (CPA) in proximity to the drug-associated cue. Potential problems in the design and interpretation of place conditioning studies are discussed. A typical experiment lasts 2 weeks.

  14. Acute fulminant drug induced necrotizing pancreatitis in a patient with ankylosing spondylitis

    Directory of Open Access Journals (Sweden)

    Pablo Miramontes

    2015-03-01

    Full Text Available Drug-induced acute necrotizing pancreatitis is a rare adverse event, although it has been reported in association with different drugs, including non-steroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, and analgesic agents commonly used in rheumatology. In different reviews of the pancreotoxicity of drugs, infliximab and etanercept are mentioned among all medications implicated in drug-induced pancreatitis, but clinical cases of acute pancreatitis complicating treatment with these anti-TNF-α agents have been exceptionally reported. We describe a patient with ankylosing spondylitis treated with etanercept, who developed an acute fulminant necrotizing pancreatitis that resulted in death. Doctors should pay close attention to patients taking biologic drugs in which a complaint of abdominal pain lasting for several days with no apparent cause may require a prompt referral for medical consultation.

  15. Kidney-on-a-Chip: a New Technology for Predicting Drug Efficacy, Interactions, and Drug-induced Nephrotoxicity.

    Science.gov (United States)

    Lee, Jeonghwan; Kim, Sejoong

    2018-03-08

    The kidneys play a pivotal role in most drug-removal processes and are important when evaluating drug safety. Kidney dysfunction resulting from various drugs is an important issue in clinical practice and during the drug development process. Traditional in vivo animal experiments are limited with respect to evaluating drug efficacy and nephrotoxicity due to discrepancies in drug pharmacokinetics and pharmacodynamics between humans and animals, and static cell culture experiments cannot fully reflect the actual microphysiological environment in humans. A kidney-on-a-chip is a microfluidic device that allows the culture of living renal cells in 3-dimensional channels and mimics the human microphysiological environment, thus simulating the actual drug filtering, absorption, and secretion process.. In this review, we discuss recent developments in microfluidic culturing technique and describe current and future kidney-on-a-chip applications. We focus on pharmacological interactions and drug-induced nephrotoxicity, and additionally discuss the development of multi-organ chips and their possible applications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Wet Process Induced Phase Transited Drug Delivery System as a ...

    African Journals Online (AJOL)

    A non-disintegrating, asymmetric membrane capsular system for a poorly water soluble drug, flurbiprofen, was developed and evaluated in vitro and in vivo. Asymmetric membrane capsules were made by phase inversion. The effect of varying osmotic pressure of the dissolution medium on drug release was studied.

  17. Ocular changes induced by drugs commonly used in dermatology

    NARCIS (Netherlands)

    Turno-Kręcicka, Anna; Grzybowski, Andrzej; Misiuk-Hojło, Marta; Patryn, Eliza; Czajor, Karolina; Nita, Małgorzata

    2016-01-01

    The use of many drugs in dermatologic diseases may cause ocular side effects. Some may regress after discontinuation of the therapy, but others persist or progress even after the cessation of treatment. This review presents four groups of commonly prescribed drugs-antimalarial medicines,

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

    Science.gov (United States)

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

    2015-12-01

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

  19. Porous Polymer Drug-Eluting Coating Prepared by Radiation Induced Polymerization

    International Nuclear Information System (INIS)

    Veres, M.; Tóth, S.; Koós, M.; Beiler, B.

    2009-01-01

    Drug-eluting stents have several advantages over bare metal implants. They eliminate restenosis, the main drawback of bare metal stents. In addition the locally delivered drug is more effective and causes less side-effects. However in some cases dangerous stent thrombosis, inflammatory and allergy reactions were observed after their implantation, which first of all related to the drug-eluting coating. This project is aimed to develop a novel biocompatible nanoporous polymer layer by radiation induced polymerization that is capable of holding and eluting drugs and promotes endothelization after the release of the drug. (author)

  20. Porous Polymer Drug-Eluting Coating Prepared by Radiation Induced Polymerization

    Energy Technology Data Exchange (ETDEWEB)

    Veres, M.; Tóth, S.; Koós, M. [Research Institute for Solid State Physics and Optics, Budapest (Hungary); Beiler, B. [Institute of Isotopes, HAS, Budapest (Hungary)

    2009-07-01

    Drug-eluting stents have several advantages over bare metal implants. They eliminate restenosis, the main drawback of bare metal stents. In addition the locally delivered drug is more effective and causes less side-effects. However in some cases dangerous stent thrombosis, inflammatory and allergy reactions were observed after their implantation, which first of all related to the drug-eluting coating. This project is aimed to develop a novel biocompatible nanoporous polymer layer by radiation induced polymerization that is capable of holding and eluting drugs and promotes endothelization after the release of the drug. (author)

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

    Directory of Open Access Journals (Sweden)

    Reza Heidari

    2015-03-01

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

  2. Drug-induced liver injury associated with HIV medications.

    Science.gov (United States)

    Jain, Mamta K

    2007-08-01

    Antiretroviral therapy (ART) for HIV infection frequently has been associated with elevated liver enzyme levels. Determining the cause of elevated liver enzyme levels in patients who have HIV is difficult because ART usually consists of three different drugs, patients may be taking additional hepatotoxic medications and patients who have HIV often suffer from other liver diseases. Several agents, however, are recognized as having noteworthy and specific patterns of toxicity. This article reviews the different HIV drug classes, incidence of elevated liver enzyme values by class and by individual drug, risk factors, specific toxicities, and possible mechanisms of injury.

  3. Colloid electrochemistry of conducting polymer: towards potential-induced in-situ drug release

    International Nuclear Information System (INIS)

    Sankoh, Supannee; Vagin, Mikhail Yu.; Sekretaryova, Alina N.; Thavarungkul, Panote; Kanatharana, Proespichaya; Mak, Wing Cheung

    2017-01-01

    Highlights: • Pulsed electrode potential induced an in-situ drug release from dispersion of conducting polymer microcapsules. • Fast detection of the released drug within the colloid microenvironment. • Improved the efficiency of localized drug release at the electrode interface. - Abstract: Over the past decades, controlled drug delivery system remains as one of the most important area in medicine for various diseases. We have developed a new electrochemically controlled drug release system by combining colloid electrochemistry and electro-responsive microcapsules. The pulsed electrode potential modulation led to the appearance of two processes available for the time-resolved registration in colloid microenvironment: change of the electronic charge of microparticles (from 0.5 ms to 0.1 s) followed by the drug release associated with ionic equilibration (1–10 s). The dynamic electrochemical measurements allow the distinction of drug release associated with ionic relaxation and the change of electronic charge of conducting polymer colloid microparticles. The amount of released drug (methylene blue) could be controlled by modulating the applied potential. Our study demonstrated a surface-potential driven controlled drug release of dispersion of conducting polymer carrier at the electrode interfaces, while the bulk colloids dispersion away from the electrode remains as a reservoir to improve the efficiency of localized drug release. The developed new methodology creates a model platform for the investigations of surface potential-induced in-situ electrochemical drug release mechanism.

  4. Predictive typing of drug-induced neurological sufferings from studies of the distribution of labelled drugs

    International Nuclear Information System (INIS)

    Takasu, T.

    1980-01-01

    A drug given to an animal becomes widely distributed throughout the body, acting on the living mechanisms or structures, and is gradually excreted. Some drugs can remain in some parts of the body for a long period. For example, 14 C-chloramphenical was found to remain preferentially in the salivary gland, liver and bone marrow of mice 24 hours after its oral administration. If such a drug is given repeatedly, it could possibly accumulate gradually in these organs. Thus, when its accumulation in a particular part of the body exceeds a certain level, the living mechanism or structure may possibly be injured. The harmful effects of a drug in repeated administration are called its chronic toxicity. The author discusses whether it is possible to predict the toxicity of a drug by studying its distribution in relation to time, and, if possible, the points in time. This problem is studied especially in relation to the nervous system. (Auth.)

  5. 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...

  6. hERG trafficking inhibition in drug-induced lethal cardiac arrhythmia.

    Science.gov (United States)

    Nogawa, Hisashi; Kawai, Tomoyuki

    2014-10-15

    Acquired long QT syndrome induced by non-cardiovascular drugs can cause lethal cardiac arrhythmia called torsades de points and is a significant problem in drug development. The prolongation of QT interval and cardiac action potential duration are mainly due to reduced physiological function of the rapidly activating voltage-dependent potassium channels encoded by human ether-a-go-go-related gene (hERG). Structurally diverse groups of drugs are known to directly inhibit hERG channel conductance. Therefore, the ability of acute hERG inhibition is routinely assessed at the preclinical stages in pharmaceutical testing. Recent findings indicated that chronic treatment with various drugs not only inhibits hERG channels but also decreases hERG channel expression in the plasma membrane of cardiomyocytes, which has become another concern in safety pharmacology. The mechanisms involve the disruption of hERG trafficking to the surface membrane or the acceleration of hERG protein degradation. From this perspective, we present a brief overview of mechanisms of drug-induced trafficking inhibition and pathological regulation. Understanding of drug-induced hERG trafficking inhibition may provide new strategies for predicting drug-induced QT prolongation and lethal cardiac arrhythmia in pharmaceutical drug development. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Levofloxacin-Induced QTc Prolongation Depends on the Time of Drug Administration

    NARCIS (Netherlands)

    Kervezee, L; Gotta, V; Stevens, J; Birkhoff, W; Kamerling, Imc; Danhof, M; Meijer, J H; Burggraaf, J

    2016-01-01

    Understanding the factors influencing a drug's potential to prolong the QTc interval on an electrocardiogram is essential for the correct evaluation of its safety profile. To explore the effect of dosing time on drug-induced QTc prolongation, a randomized, crossover, clinical trial was conducted in

  8. Hypoxia-induced cytotoxic drug resistance in osteosarcoma is independent of HIF-1Alpha.

    Directory of Open Access Journals (Sweden)

    Jennifer Adamski

    Full Text Available Survival rates from childhood cancer have improved dramatically in the last 40 years, such that over 80% of children are now cured. However in certain subgroups, including metastatic osteosarcoma, survival has remained stubbornly poor, despite dose intensive multi-agent chemotherapy regimens, and new therapeutic approaches are needed. Hypoxia is common in adult solid tumours and is associated with treatment resistance and poorer outcome. Hypoxia induces chemotherapy resistance in paediatric tumours including neuroblastoma, rhabdomyosarcoma and Ewing's sarcoma, in vitro, and this drug resistance is dependent on the oxygen-regulated transcription factor hypoxia inducible factor-1 (HIF-1. In this study the effects of hypoxia on the response of the osteosarcoma cell lines 791T, HOS and U2OS to the clinically relevant cytotoxics cisplatin, doxorubicin and etoposide were evaluated. Significant hypoxia-induced resistance to all three agents was seen in all three cell lines and hypoxia significantly reduced drug-induced apoptosis. Hypoxia also attenuated drug-induced activation of p53 in the p53 wild-type U2OS osteosarcoma cells. Drug resistance was not induced by HIF-1α stabilisation in normoxia by cobalt chloride nor reversed by the suppression of HIF-1α in hypoxia by shRNAi, siRNA, dominant negative HIF or inhibition with the small molecule NSC-134754, strongly suggesting that hypoxia-induced drug resistance in osteosarcoma cells is independent of HIF-1α. Inhibition of the phosphoinositide 3-kinase (PI3K pathway using the inhibitor PI-103 did not reverse hypoxia-induced drug resistance, suggesting the hypoxic activation of Akt in osteosarcoma cells does not play a significant role in hypoxia-induced drug resistance. Targeting hypoxia is an exciting prospect to improve current anti-cancer therapy and combat drug resistance. Significant hypoxia-induced drug resistance in osteosarcoma cells highlights the potential importance of hypoxia as a target

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

    International Nuclear Information System (INIS)

    Chatterjee, Sagnik; Richert, Lysiane; Augustijns, Patrick; Annaert, Pieter

    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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-01-01

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

  11. 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

  12. Drug-Induced Morphology Switch in Drug Delivery Systems Based on Poly(2-oxazoline)s

    Science.gov (United States)

    2015-01-01

    Defined aggregates of polymers such as polymeric micelles are of great importance in the development of pharmaceutical formulations. The amount of drug that can be formulated by a drug delivery system is an important issue, and most drug delivery systems suffer from their relatively low drug-loading capacity. However, as the loading capacities increase, i.e., promoted by good drug–polymer interactions, the drug may affect the morphology and stability of the micellar system. We investigated this effect in a prominent system with very high capacity for hydrophobic drugs and found extraordinary stability as well as a profound morphology change upon incorporation of paclitaxel into micelles of amphiphilic ABA poly(2-oxazoline) triblock copolymers. The hydrophilic blocks A comprised poly(2-methyl-2-oxazoline), while the middle blocks B were either just barely hydrophobic poly(2-n-butyl-2-oxazoline) or highly hydrophobic poly(2-n-nonyl-2-oxazoline). The aggregation behavior of both polymers and their formulations with varying paclitaxel contents were investigated by means of dynamic light scattering, atomic force microscopy, (cryogenic) transmission electron microscopy, and small-angle neutron scattering. While without drug, wormlike micelles were present, after incorporation of small amounts of drugs only spherical morphologies remained. Furthermore, the much more hydrophobic poly(2-n-nonyl-2-oxazoline)-containing triblock copolymer exhibited only half the capacity for paclitaxel than the poly(2-n-butyl-2-oxazoline)-containing copolymer along with a lower stability. In the latter, contents of paclitaxel of 8 wt % or higher resulted in a raspberry-like micellar core. PMID:24548260

  13. A Drug Combination Screen Identifies Drugs Active against Amoxicillin-induced Round Bodies of Borrelia burgdorferi Persisters from an FDA Drug Library

    Directory of Open Access Journals (Sweden)

    Jie eFeng

    2016-05-01

    Full Text Available Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that are not killed by current Lyme antibiotics. To identify more effective drugs that are active against the round bodies of B. burgdorferi, we established a round body persister model induced by amoxicillin and screened the Food and Drug Administration (FDA drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide (PI viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven of these scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. While some drug candidates such as daptomycin and clofazimine overlapped with a previous screen against stationary phase B. burgdorferi persisters, additional drug candidates active against round bodies we identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi persisters in vitro, even if pre-treated with amoxicillin. These findings may have implications for improved treatment of Lyme disease.

  14. Novel monohydroxamate drugs attenuate myocardial reperfusion-induced arrhythmias

    DEFF Research Database (Denmark)

    Collis, C S; Rice-Evans, C; Davies, Michael Jonathan

    1996-01-01

    the first 5 min of reperfusion were quantified. Drugs (all at 150 microM) were introduced during the last 2 min of ischaemia and remained throughout reperfusion. Although the monohydroxamate- and desferrioxamine-treated hearts showed a reduction in the incidence of ventricular tachycardia and fibrillation...

  15. Dry Process Induced Phase Transited Drug Delivery System: A ...

    African Journals Online (AJOL)

    Effect of varying osmotic pressure (created by osmogen-sodium chloride) of the dissolution medium on drug release was studied. Acute toxicity studies and histomorphological analyses were conducted in rats. Membrane characterization by scanning electron microscopy showed an outer dense region with less pores

  16. Incidence of drug-induced torsades de pointes with intravenous amiodarone

    Directory of Open Access Journals (Sweden)

    Jayaprakash Shenthar

    2017-11-01

    Conclusion: The incidence of drug-induced TdP with IV amiodarone is about 1.5%. Risk factors include female sex, left ventricular dysfunction, electrolyte abnormalities, baseline prolonged QTc, concomitant beta-blocker, and digoxin therapy. Amiodarone induced TdP has favorable prognosis if recognized and treated promptly, and these patients should not receive amiodarone by any route in future.

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    BACKGROUND: Drug-induced hypothermia reduces brain damage in animal stroke models and is an undiscovered potential in human stroke treatment. We studied hypothermia induced by the serotonergic agonists S14671 (1-[2-(2-thenoylamino)ethyl]-4[1-(7- methoxynaphtyl)]piperazine) and ipsapirone in a rat...... therapeutic hypothermia....

  18. Drug-induced Fanconi syndrome associated with fumaric acid esters treatment for psoriasis: A case series

    NARCIS (Netherlands)

    D.M.W. Balak (Deepak); J.N.B. Bavinck (Jan Nico Bouwes); De Vries, A.P.J. (Aiko P. J.); Hartman, J. (Jenny); Martino Neumann, H.A. (Hendrik A.); R. Zietse (Bob); H.B. Thio (Bing)

    2016-01-01

    textabstractBackground: Fumaric acid esters (FAEs), an oral immunomodulating treatment for psoriasis and multiple sclerosis, have been anecdotally associated with proximal renal tubular dysfunction due to a drug-induced Fanconi syndrome. Few data are available on clinical outcomes of FAE-induced

  19. Machine learning-based prediction of adverse drug effects: An example of seizure-inducing compounds

    Directory of Open Access Journals (Sweden)

    Mengxuan Gao

    2017-02-01

    Full Text Available Various biological factors have been implicated in convulsive seizures, involving side effects of drugs. For the preclinical safety assessment of drug development, it is difficult to predict seizure-inducing side effects. Here, we introduced a machine learning-based in vitro system designed to detect seizure-inducing side effects. We recorded local field potentials from the CA1 alveus in acute mouse neocortico-hippocampal slices, while 14 drugs were bath-perfused at 5 different concentrations each. For each experimental condition, we collected seizure-like neuronal activity and merged their waveforms as one graphic image, which was further converted into a feature vector using Caffe, an open framework for deep learning. In the space of the first two principal components, the support vector machine completely separated the vectors (i.e., doses of individual drugs that induced seizure-like events and identified diphenhydramine, enoxacin, strychnine and theophylline as “seizure-inducing” drugs, which indeed were reported to induce seizures in clinical situations. Thus, this artificial intelligence-based classification may provide a new platform to detect the seizure-inducing side effects of preclinical drugs.

  20. Management of drug-induced hyperbilirubinaemia in early pregnancy

    African Journals Online (AJOL)

    perinatal outcomes because of the increased risks of preterm delivery and ... induced hepatotoxicity in early pregnancy. ... for threatened abortion since the 6th week. Her past and ... gene mutations, a disease complicated by unconjugated.

  1. Cell proliferation in dimethylhydrazine-induced colonic adenocarcinomata following cytotoxic drug treatment.

    Science.gov (United States)

    Tutton, P J; Barkla, D H

    1978-08-25

    A stathmokinetic technique was used to study cell proliferation in dimethylhydrazine-induced adenocarcinomata of rat colon following treatment with cytotoxic drugs. The rate of cell division was significantly increased three days after treatment with 5,7-dihydroxytryptamine and seven days after treatment with 5-fluorouracil. Acceleration of tumour cell proliferation following 5,7-dihydroxytryptamine treatment was inhibited by treating animals with the antiseritoninergic drug Xylamidine Tosylate. Acceleration of tumour cell proliferation following 5-fluorouracil treatment was inhibited by treating animals either with the antiseritoninergic drug BW501 or with the histamine H2-receptor blocking drug Cimetidine.

  2. Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity

    Science.gov (United States)

    Massart, Julie; Begriche, Karima; Moreau, Caroline; Fromenty, Bernard

    2017-01-01

    Background Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. Aim The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a data-mining analysis using different queries including drug-induced liver injury (or DILI), drug-induced hepatotoxicity, fatty liver, nonalcoholic fatty liver disease (or NAFLD), steatosis and obesity. The main data from the collected articles are reported in this review and when available, some pathophysiological hypotheses are put forward. Relevance for patients Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen, halothane, methotrexate, rosiglitazone, stavudine and tamoxifen. For some of these drugs, experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Other drugs such as pentoxifylline, phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not. Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes, hyperlipidemia and coronary heart disease, it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening

  3. Drug-Induced QTc Interval Prolongation: A Multicenter Study to Detect Drugs and Clinical Factors Involved in Every Day Practice.

    Science.gov (United States)

    Keller, Guillermo A; Alvarez, Paulino A; Ponte, Marcelo L; Belloso, Waldo H; Bagnes, Claudia; Sparanochia, Cecilia; Gonzalez, Claudio D; Villa Etchegoyen, M Cecilia; Diez, Roberto A; Di Girolamo, Guillermo

    2016-01-01

    The actual prevalence of drug induced QTc prolongation in clinical practice is unknown. Our objective was to determine the occurrence and characteristics of drug-induced QT prolongation in several common clinical practices. Additionally, a subgroup of patients treated with dextropropoxyphene of particular interest for the regulatory authority was analysed. Medical history and comorbidities predisposing to QT interval prolongation were registered for 1270 patient requiring medical assistance that involved drug administration. Three ionograms and ECGs were performed: baseline, intra- and after treatment; QT interval was corrected with Bazzet formula. Among patients, 9.9% presented QTc >450/470 ms, 3% QTc > 500 ms, 12.7% ΔQTc >30 ms and 5.2% ΔQTc >60 ms. QTc prolongation associated with congestive heart failure, ischemic cardiopathy, diabetes, renal failure, arrhythmias, hypothyroidism, and bradycardia. At univariate analysis, clarithromycin, haloperidol, tramadol, amiodarone, glyceryl trinitrate, amoxicillin + clavulanic acid, amoxicillin + sulbactam, ampicillin + sulbactam, fentanyl, piperacillin + tazobactam, and diazepam prolonged QTc. Prolongation remained significantly associated with furosemide, clarithromycin, glyceryl trinitrate and betalactamase inhibitors after multivariate analysis. QT interval prolongation in everyday practice is frequent, in association to clinical factors and drugs that can be easily identified for monitoring and prevention strategies.

  4. Drug-induced liver injury due to antimicrobials, central nervous system agents, and nonsteroidal anti-inflammatory drugs.

    Science.gov (United States)

    Devarbhavi, Harshad; Andrade, Raúl J

    2014-05-01

    Antimicrobial agents including antituberculosis (anti-TB) agents are the most common cause of idiosyncratic drug-induced liver injury (DILI) and drug-induced liver failure across the world. Better molecular and genetic biomarkers are acutely needed to help identify those at risk of liver injury particularly for those needing antituberculosis therapy. Some antibiotics such as amoxicillin-clavulanate and isoniazid consistently top the lists of agents in retrospective and prospective DILI databases. Central nervous system agents, particularly antiepileptics, account for the second most common class of agents implicated in DILI registries. Hepatotoxicity from older antiepileptics such as carbamazepine, phenytoin, and phenobarbital are often associated with hypersensitivity features, whereas newer antiepileptic drugs have a more favorable safety profile. Antidepressants and nonsteroidal anti-inflammatory drugs carry very low risk of significant liver injury, but their prolific use make them important causes of DILI. Early diagnosis and withdrawal of the offending agent remain the mainstays of minimizing hepatotoxicity. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  5. A case of adverse drug reaction induced by dispensing error.

    Science.gov (United States)

    Gallelli, L; Staltari, O; Palleria, C; Di Mizio, G; De Sarro, G; Caroleo, B

    2012-11-01

    To report about a case of acute renal failure due to absence of communication between physician and patient. A 78 year old man with human immunodeficiency virus (HIV) accessed our hospital and was brought to our attention in August 2011 for severe renal failure. Clinical history revealed that he had been taking highly active antiretroviral therapy with lamivudine/abacavir and fosamprenavir since 2006. In April 2011 due to an augmentation in creatinine plasma levels, a reduction in lamivudine dosage to 100 mg/day and the prescription of abacavir 300 mg/day became necessary. Unfortunately, the patient took both lamivudine and abacavir therefore the association of the two medications (lamivudine/abacavir) lead to asthenia and acute renal failure within a few days. This case emphasizes the importance about how physicians must pay very careful attention during drug prescription, most particularly, as far as elderly patients are concerned. In fact, communication improvement between physicians and patients can prevent increase of adverse drug reactions related to drug dispensing, with consequential reduction of costs in the healthcare system. Copyright © 2012 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

  6. Pharmacogenetics of drug-induced arrhythmias : a feasibility study using spontaneous adverse drug reactions reporting data

    NARCIS (Netherlands)

    De Bruin, Marie L; van Puijenbroek, Eugene P; Bracke, Madelon; Hoes, Arno W; Leufkens, Hubert G M

    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

  7. Redox-based Epigenetic status in Drug Addiction: Potential mediator of drug-induced gene priming phenomenon and use of metabolic intervention for symptomatic treatment in drug addiction.

    Directory of Open Access Journals (Sweden)

    Malav Suchin Trivedi

    2015-01-01

    Full Text Available Alcohol and other drugs of abuse, including psychostimulants and opioids, can induce epigenetic changes: a contributing factor for drug addiction, tolerance and associated withdrawal symptoms. DNA methylation is the major epigenetic mechanism and it is one of more than 200 methylation reactions supported by methyl donor S-adenosylmethionine (SAM. The levels of SAM are controlled by cellular redox status via the folate and vitamin B12-dependent enzyme methionine synthase (MS, for example; under oxidative conditions MS is inhibited, diverting its substrate homocysteine (HCY to the transsulfuration pathway. Alcohol, dopamine and morphine, can alter intracellular levels of glutathione (GSH-based cellular redox status, subsequently affecting S-adenosylmethionine (SAM levels and DNA methylation status. In this discussion, we compile this and other existing evidence in a coherent manner to present a novel hypothesis implicating the involvement of redox-based epigenetic changes in drug addiction. Next, we also discuss how gene priming phenomenon can contribute to maintenance of redox and methylation status homeostasis under various stimuli including drugs of abuse. Lastly, based on our hypothesis and some preliminary evidence, we discuss a mechanistic explanation for use of metabolic interventions / redox-replenishers as symptomatic treatment of alcohol addiction and associated withdrawal symptoms. Hence, the current review article strengthens the hypothesis that neuronal metabolism has a critical bidirectional coupling with epigenetic changes in drug addiction and we support this claim via exemplifying the link between redox-based metabolic changes and resultant epigenetic consequences under the effect of drugs of abuse.

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

    Directory of Open Access Journals (Sweden)

    Behnam Behnoush

    2012-05-01

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

  9. Metabolic activation of hepatotoxic drug (benzbromarone) induced mitochondrial membrane permeability transition

    Energy Technology Data Exchange (ETDEWEB)

    Shirakawa, Maho; Sekine, Shuichi; Tanaka, Ayaka [The Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba (Japan); Horie, Toshiharu [Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo (Japan); Ito, Kousei, E-mail: itokousei@chiba-u.jp [The Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba (Japan)

    2015-10-01

    The risk of drug-induced liver injury (DILI) is of great concern to the pharmaceutical industry. It is well-known that metabolic activation of drugs to form toxic metabolites (TMs) is strongly associated with DILI onset. Drug-induced mitochondrial dysfunction is also strongly associated with increased risk of DILI. However, it is difficult to determine the target of TMs associated with exacerbation of DILI because of difficulties in identifying and purifying TMs. In this study, we propose a sequential in vitro assay system to assess TM formation and their ability to induce mitochondrial permeability transition (MPT) in a one-pot process. In this assay system, freshly-isolated rat liver mitochondria were incubated with reaction solutions of 44 test drugs preincubated with liver microsomes in the presence or absence of NADPH; then, NADPH-dependent MPT pore opening was assessed as mitochondrial swelling. In this assay system, several hepatotoxic drugs, including benzbromarone (BBR), significantly induced MPT in a NADPH-dependent manner. We investigated the rationality of using BBR as a model drug, since it showed the most prominent MPT in our assay system. Both the production of a candidate toxic metabolite of BBR (1′,6-(OH){sub 2} BBR) and NADPH-dependent MPT were inhibited by several cytochrome P450 (CYP) inhibitors (clotrimazole and SKF-525A, 100 μM). In summary, this assay system can be used to evaluate comprehensive metabolite-dependent MPT without identification or purification of metabolites. - Highlights: • We constructed a sequential assay system for toxic metabolite induced MPT in one pot. • 14 drugs (e.g. benzbromarone (BBR)) induced toxic metabolite dependent MPT. • Both the production of toxic metabolite and MPT could be inhibited by CYP inhibitors. • This system could evaluate the comprehensive MPT without purification of metabolites.

  10. Structural changes on polymeric nanoparticles induced by hydrophobic drug entrapment

    Czech Academy of Sciences Publication Activity Database

    Jäger, Alessandro; Jäger, Eliezer; Giacomelli, F. C.; Nallet, F.; Steinhart, Miloš; Putaux, J.-L.; Konefal, Rafal; Spěváček, Jiří; Ulbrich, Karel; Štěpánek, Petr

    2018-01-01

    Roč. 538, 5 February (2018), s. 238-249 ISSN 0927-7757 R&D Projects: GA ČR(CZ) GA17-09998S; GA ČR(CZ) GA15-13853S Grant - others:AV ČR(CZ) MSM200501606 Program:Program na podporu mezinárodní spolupráce začínajících výzkumných pracovníků Institutional support: RVO:61389013 Keywords : polymer nanoparticles * drug delivery * paclitaxel Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Polymer science Impact factor: 2.714, year: 2016

  11. Human Precision-Cut Liver Slices as an ex Vivo Model to Study Idiosyncratic Drug-Induced Liver Injury

    NARCIS (Netherlands)

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

    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

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

    NARCIS (Netherlands)

    Hadi, Mackenzie; Westra, Inge; Starokozhko, Viktoriia; Dragovic, Sanja; Merema, Maja; Groothuis, Genoveva

    2013-01-01

    Idiosyncratic drug-induced liver injury (IDILI) is a major problem during drug development and has caused drug withdrawal and black-box warnings. Due to the low concordance of the hepatotoxicity of drugs in animals and humans, robust screening methods using human tissue are needed to predict and to

  13. mTOR complex 1: a key player in neuroadaptations induced by drugs of abuse.

    Science.gov (United States)

    Neasta, Jeremie; Barak, Segev; Hamida, Sami Ben; Ron, Dorit

    2014-07-01

    The mammalian (or mechanistic) target of rapamycin (mTOR) complex 1 (mTORC1) is a serine and threonine kinase that regulates cell growth, survival, and proliferation. mTORC1 is a master controller of the translation of a subset of mRNAs. In the central nervous system mTORC1 plays a crucial role in mechanisms underlying learning and memory by controlling synaptic protein synthesis. Here, we review recent evidence suggesting that the mTORC1 signaling pathway promotes neuroadaptations following exposure to a diverse group of drugs of abuse including stimulants, cannabinoids, opiates, and alcohol. We further describe potential molecular mechanisms by which drug-induced mTORC1 activation may alter brain functions. Finally, we propose that mTORC1 is a focal point shared by drugs of abuse to mediate drug-related behaviors such as reward seeking and excessive drug intake, and offer future directions to decipher the contribution of the kinase to mechanisms underlying addiction. Recent studies suggesting that exposure to diverse classes of drugs of abuse as well as exposure to drug-associated memories lead to mTORC1 kinase activation in the limbic system. In turn, mTORC1 controls the onset and the maintenance of pathological neuroadaptions that underlie several features of drug addiction such as drug seeking and relapse. Therefore, we propose that targeting mTORC1 and its effectors is a promising strategy to treat drug disorders. © 2014 International Society for Neurochemistry.

  14. Glucose hypermetabolism in the thalamus of patients with drug-induced blepharospasm.

    Science.gov (United States)

    Suzuki, Y; Kiyosawa, M; Wakakura, M; Mochizuki, M; Ishiwata, K; Oda, K; Ishii, K

    2014-03-28

    We examined the difference in cerebral function alterations between drug-induced blepharospasm patients and essential blepharospasm (EB) patients by using positron emission tomography with (18)F-fluorodeoxyglucose. Cerebral glucose metabolism was examined in 21 patients with drug-induced blepharospasm (5 men and 16 women; mean age, 53.1 [range, 29-78] years), 21 essential EB patients (5 men and 16 women; mean age, 53.0 [range, 33-72] years) and 24 healthy subjects (6 men and 18 women; mean age, 57.9 [range, 22-78] years) with long-term history of benzodiazepines use (drug healthy subjects). Drug-induced blepharospasm patients developed symptoms while taking benzodiazepines or thienodiazepines. Sixty-three normal volunteers (15 men and 48 women; mean age, 53.6 [range, 20-70] years) were examined as controls. Differences between the patient groups and control group were examined by statistical parametric mapping. Additionally, we defined regions of interests on both sides of the thalamus, caudate nucleus, anterior putamen, posterior putamen and primary somatosensory area. The differences between groups were tested using two-sample t-tests with Bonferroni correction for multiple comparisons. Cerebral glucose hypermetabolism on both side of the thalamus was detected in drug-induced blepharospasm, EB patients and drug healthy subjects by statistical parametric mapping. In the analysis of regions of interest, glucose metabolism in both sides of the thalamus in the drug-induced blepharospasm group was significantly lower than that in the EB group. Moreover, we observed glucose hypermetabolism in the anterior and posterior putamen bilaterally in EB group but not in drug-induced blepharospasm group and drug healthy subjects. Long-term regimens of benzodiazepines or thienodiazepines may cause down-regulation of benzodiazepine receptors in the brain. We suggest that the functional brain alteration in drug-induced blepharospasm patients is similar to that in EB patients, and

  15. Neural correlates of stress-induced and cue-induced drug craving: influences of sex and cocaine dependence.

    Science.gov (United States)

    Potenza, Marc N; Hong, Kwang-ik Adam; Lacadie, Cheryl M; Fulbright, Robert K; Tuit, Keri L; Sinha, Rajita

    2012-04-01

    Although stress and drug cue exposure each increase drug craving and contribute to relapse in cocaine dependence, no previous research has directly examined the neural correlates of stress-induced and drug cue-induced craving in cocaine-dependent women and men relative to comparison subjects. Functional MRI was used to assess responses to individualized scripts for stress, drug/alcohol cue and neutral-relaxing-imagery conditions in 30 abstinent cocaine-dependent individuals (16 women, 14 men) and 36 healthy recreational-drinking comparison subjects (18 women, 18 men). Significant three-way interactions between diagnostic group, sex, and script condition were observed in multiple brain regions including the striatum, insula, and anterior and posterior cingulate. Within women, group-by-condition interactions were observed involving these regions and were attributable to relatively increased regional activations in cocaine-dependent women during the stress and, to a lesser extent, neutral-relaxing conditions. Within men, group main effects were observed involving these same regions, with cocaine-dependent men demonstrating relatively increased activation across conditions, with the main contributions from the drug and neutral-relaxing conditions. In men and women, subjective drug-induced craving measures correlated positively with corticostriatal-limbic activations. In cocaine dependence, corticostriatal-limbic hyperactivity appears to be linked to stress cues in women, drug cues in men, and neutral-relaxing conditions in both. These findings suggest that sex should be taken into account in the selection of therapies in the treatment of addiction, particularly those targeting stress reduction.

  16. Drug-Induced Vasculitis: New Insights and a Changing Lineup of Suspects.

    Science.gov (United States)

    Grau, Rafael G

    2015-12-01

    An increasing number of therapeutic agents have been associated with a vasculitic syndrome. This usually involves small vessels, primarily capillaries, venules, and arterioles in leukocytoclastic vasculitis, small-vessel disease similar to an antineutrophil cytoplasmic antibody-related vasculitis, or mid-sized muscular arteries in a polyarteritis-like picture. Antineutrophil cytoplasmic antibodies are present in many cases of vasculitis regardless of the size of the vessel involved. Monoclonal antibodies used to treat many autoimmune disorders have become the most common agents associated with drug-induced vasculitis. Important advances in epigenetics, genetics, and neutrophil apoptosis are providing new insights into the pathogenesis of both drug-induced vasculitis and idiopathic vasculitis. Although management has not changed significantly in the past few years where withdrawal of the offending agent is the primary intervention, increasing awareness of drug-induced vasculitis can lead to earlier diagnosis and prevention of severe organ damage and fatalities.

  17. Antithyroid drug-induced agranulocytosis complicated by pneumococcal sepsis and upper airway obstruction.

    Science.gov (United States)

    Ishimaru, Naoto; Ohnishi, Hisashi; Nishiuma, Teruaki; Doukuni, Ryota; Umezawa, Kanoko; Oozone, Sachiko; Kuramoto, Emi; Yoshimura, Sho; Kinami, Saori

    2013-01-01

    Streptococcus pneumoniae is a rare pathogen of sepsis in patients with antithyroid drug-induced agranulocytosis. We herein describe a case of antithyroid drug-induced agranulocytosis complicated by pneumococcal sepsis and upper airway obstruction. A 27-year-old woman who was previously prescribed methimazole for nine months presented with a four-day history of a sore throat. She nearly choked and was diagnosed with febrile agranulocytosis. She was successfully treated with intubation, intravenous antibiotics and granulocyte colony-stimulating factor. Her blood cultures yielded S. pneumoniae. Emergency airway management, treatment of sepsis and the administration of granulocyte colony-stimulating factor can improve the clinical course of antithyroid drug-induced pneumococcal sepsis in patients with airway obstruction.

  18. ECG-Based Measurements of Drug-induced Repolarization Changes

    DEFF Research Database (Denmark)

    Bhuiyan, Tanveer Ahmed

    The purpose of this thesis is to investigate the abnormal repolarization both in the cellular and the surface ECG along with their relationship. It has been identified that the certain morphological changes of the monophasic action potential are predictor of TdP arrhythmia. Therefore the proporti......The purpose of this thesis is to investigate the abnormal repolarization both in the cellular and the surface ECG along with their relationship. It has been identified that the certain morphological changes of the monophasic action potential are predictor of TdP arrhythmia. Therefore...... the proportional changes of the surface ECG which corresponds to the arrhythmia-triggering MAP morphology is warranted to increase the confidence of determining cardiotoxicity of drugs....

  19. [Quetiapine and anticholinergic drugs induced ischaemic colitis: A case study].

    Science.gov (United States)

    Cuny, P; Houot, M; Ginisty, S; Horowicz, S; Plassart, F; Mentec, H; Eftekhari, P

    2017-02-01

    The aim of this paper is to underline the need for systematic monitoring of patients treated with anticholinergic antipsychotic drugs. We present the clinical history of a 34-year-old adult, treated with quetiapine in combination with other drugs with anticholinergic effects. A 34-year-old male adult had been suffering from bipolar disorder since 2001. He was treated with risperidone, but he was not compliant due to adverse effects, including decreased libido and erectile dysfunction. On June 5th 2012, it was decided to administrate 600mg per day of quetiapine in combination with tropatepine consequent to an episode of agitation and aggressiveness. On June 14th 2012, while the patient was receiving diazepam and valproic acid, loxapine oral solution was introduced. On June 23th, the patient started mentioning digestive disorders, such as diffuse abdominal pain with constipation but continued to pass gaz. On June 25th, at 6:30 am, he declared abdominal pain, which worsened at 8:15 am despite administration of analgesics, followed by malaise and onset of vomiting. His laboratory tests showed leukocytosis 11.2G/L with neutrophils 7.7G/L. The abdomen's radiograph without preparation showed small bowel and colonic air-fluid levels. The result of the CT scan confirmed an occlusive syndrome affecting the whole small gut and colon. At 1 pm, the patient's condition worsened. He received an intramuscular injection of 100mg of loxapine and an opioid treatment, including tramadol and morphine. At 2:30 pm, the clinical condition further deteriorated with an onset of generalized abdominal contracture, the absence of abdominal breathing, sweating, tachycardia at 104 beats per minute, and hypothermia of 34.5°C. He was transferred to an intensive care unit. Laboratory tests showed metabolic acidosis, elevated liver enzymes and acute renal failure. He received volume expansion and was treated by renal replacement therapy and antibiotics. He was intubated and transferred to the

  20. Adriamycin-radiation combinations: drug induced delayed gastrointestinal radiosensitivity

    International Nuclear Information System (INIS)

    Schenken, L.L.; Burholt, D.R.; Kovacs, C.J.

    1979-01-01

    The administration of Adriamycin (ADR) results in acute short-term reductions in cell production within the gastrointestinal mucosa. Interactions between ADR doses and radiation appear minimized as the inter-treatment time interval expands to five days. However, as the times between drug administration and abdominal radiation exposure are further lengthened (from 14 to 49 days), a progressively severe defect in post-irradiation mucosal cell production is noted. Although the mucosa appears abnormal histologically and crypt cell cellularity and cell production are normal, the proliferative response following radiation is reduced by as much as 50% if ADR is given 7 weeks prior to the radiation exposure. We postulate that this effect is a manifestation of latent damage to the stem cell compartment within the crypt or that secondary support systems such as mucosal vascularity have been compromised by ADR

  1. Prevention of nonsteroidal anti-inflammatory drug-induced gastropathy.

    Science.gov (United States)

    Schlansky, Barry; Hwang, Joo Ha

    2009-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their analgesic, antipyretic, and antiinflammatory properties, and aspirin is increasingly employed in the primary and secondary prevention of cardiovascular disease and ischemic stroke. Despite undisputed therapeutic efficacy for these indications, all NSAIDs impart a considerable risk of peptic ulcer disease and upper gastrointestinal hemorrhage. A growing body of evidence supports an association between non-aspirin NSAIDs and acute coronary syndromes, and an expanding understanding of the gastroduodenal effects of aspirin, COX-2 selective agents, clopidogrel, and Helicobacter pylori synergism fuel controversies in NSAID use. In this review, we discuss risk stratification of patients taking NSAIDs and the appropriate application of proven gastro-protective strategies to decrease the incidence of gastrointestinal hemorrhage based upon an individualized assessment of risk for potential toxicities. Prevention of NSAID-related gastropathy is an important clinical issue, and therapeutic strategies for both the primary and secondary prevention of adverse events are continually evolving.

  2. Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

    International Nuclear Information System (INIS)

    Florea, Ana-Maria; Büsselberg, Dietrich

    2011-01-01

    Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects

  3. Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

    Energy Technology Data Exchange (ETDEWEB)

    Florea, Ana-Maria [Department of Neuropathology, Heinrich-Heine University, Düsseldorf (Germany); Büsselberg, Dietrich, E-mail: dib2015@qatar-med.cornell.edu [Weil Cornell Medical College in Qatar, Qatar Foundation-Education City, P.O. Box 24144, Doha (Qatar)

    2011-03-15

    Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects.

  4. 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.

  5. Enhanced vaginal drug delivery through the use of hypotonic formulations that induce fluid uptake

    Science.gov (United States)

    Ensign, Laura M.; Hoen, Timothy; Maisel, Katharina; Cone, Richard; Hanes, Justin

    2013-01-01

    Mucosal epithelia use osmotic gradients for fluid absorption and secretion. We hypothesized that administration of hypotonic solutions would induce fluid uptake that could be advantageous for rapidly delivering drugs through mucus to the vaginal epithelium. We found that hypotonic formulations markedly increased the rate at which small molecule drugs and muco-inert nanoparticles (mucus-penetrating particles, or MPP), but not conventional mucoadhesive nanparticles (CP), reached the vaginal epithelial surface in vivo in mice. Additionally, hypotonic formulations greatly enhanced drug and MPP delivery to the entire epithelial surface, including deep into the vaginal folds (rugae) that drugs or MPP in isotonic formulations failed to reach efficiently. However, hypotonic formulations caused unencapsulated “free” drugs to be drawn through the epithelium, reducing vaginal retention. In contrast, hypotonic formulations caused MPP to accumulate rapidly and uniformly on vaginal surfaces, ideally positioned for localized sustained drug delivery. Using a mouse model of vaginal genital herpes (HSV-2) infection, we found that hypotonic delivery of free drug led to improved immediate protection, but diminished longer-term protection. In contrast, as we previously demonstrated, hypotonic delivery of drug via MPP led to better long-term retention and protection in the vagina. Importantly, we demonstrate that slightly hypotonic formulations provided rapid and uniform delivery of MPP to the entire vaginal surface, thus enabling formulations with minimal risk of epithelial toxicity. Hypotonic formulations for vaginal drug delivery via MPP may significantly improve prevention and treatment of reproductive tract diseases and disorders. PMID:23769419

  6. Eculizumab for drug-induced de novo posttransplantation thrombotic microangiopathy: A case report.

    Science.gov (United States)

    Safa, Kassem; Logan, Merranda S; Batal, Ibrahim; Gabardi, Steven; Rennke, Helmut G; Abdi, Reza

    2015-02-01

    De novo thrombotic microangiopathy (TMA) following renal transplantation is a severe complication associated with high rates of allograft failure. Several immunosuppressive agents are associated with TMA. Conventional approaches to managing this entity, such as withdrawal of the offending agent and/or plasmapheresis, often offer limited help, with high rates of treatment failure and graft loss. We herein report a case of drug induced de novo TMA successfully treated using the C5a inhibitor eculizumab in a renal transplant patient. This report highlights a potentially important role for eculizumab in settings where drug-induced de novo TMA is refractory to conventional therapies.

  7. Clarithromycine-Induced Ventricular Tachycardia in a Geriatric Patient Using Multiple Drugs

    Directory of Open Access Journals (Sweden)

    Gulsah Karaoren

    2016-07-01

    Full Text Available Long QT syndrome is a cardiac repolarization disorder, which can be either idiopathic or congenital, and cause sudden cardiac death. The iatrogenic form is generally associated with drugs or electrolyte imbalance. Although prolonged QT interval is frequently seen due to antiarrhythmic agents, it can also be seen with antibiotics or anti-epileptics. Adverse drug interaction can manifest in several clinicopathological forms in elder individuals. In such cases, potential adverse effects of drugs used should be taken into consideration before prescribing additional drugs. Here, we present a case of clarithromycine-induced ventricular arrhythmia accompanied by QT prolongation on the third day of therapy, and the subsequent therapeutic approach, in a 91-year-old man. The patient was taking multiple drugs due to comorbid conditions and was prescribed clarithromycine therapy in the intensive care unit.

  8. 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.

  9. Characterization of mercury based Indian herbomineral drug by radioisotope induced EDXRF and synchrotron based EXAFS

    International Nuclear Information System (INIS)

    Joseph, Daisy; Saxena, A.; Joseph, Rajeeta; Rajput, P.; Nayak, C.; Bhattacharya, D.; Jha, S.N.; Natrajan, V.

    2014-01-01

    An Indian herbomineral drug was characterized for its trace elements by radioisotope induced EDXRF. The drug contains minerals like mercury, sulfur and arsenic disulfide, along with herbs such as dhaturra, bhrami, vacha etc. All the above ingredients were processed together in a step wise manner (6 steps). Hence the motive was to expect some change in the drug molecule at every step of processing it. The 6 samples are the samples collected at every step of drug preparation. These 6 samples which are collected as intermediatary samples would be then evaluated for its role in various neuropsychological (psychosis, depression etc) disorders in experimental animals such as rats/mice. Hence it was required to find the elements/trace elements composition, details of chemical components present in the drug samples. It was seen that using EDXRF it was possible to determine As and Hg. The EXAFS results also showed the presence of As in their sulphide form. (author)

  10. Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND

    Science.gov (United States)

    Gaskill, Peter J.; Calderon, Tina M.; Coley, Jacqueline S.; Berman, Joan W.

    2013-01-01

    Central nervous system (CNS) complications resulting from HIV infection remain a major public health problem as individuals live longer due to the success of combined antiretroviral therapy (cART). As many as 70% of HIV infected people have HIV associated neurocognitive disorders (HAND). Many HIV infected individuals abuse drugs, such as cocaine, heroin or methamphetamine, that may be important cofactors in the development of HIV CNS disease. Despite different mechanisms of action, all drugs of abuse increase extracellular dopamine in the CNS. The effects of dopamine on HIV neuropathogenesis are not well understood, and drug induced increases in CNS dopamine may be a common mechanism by which different types of drugs of abuse impact the development of HAND. Monocytes and macrophages are central to HIV infection of the CNS and to HAND. While T cells have not been shown to be a major factor in HIV-associated neuropathogenesis, studies indicate that T cells may play a larger role in the development of HAND in HIV infected drug abusers. Drug induced increases in CNS dopamine may dysregulate functions of, or increase HIV infection in, monocytes, macrophages and T cells in the brain. Thus, characterizing the effects of dopamine on these cells is important for understanding the mechanisms that mediate the development of HAND in drug abusers. PMID:23456305

  11. 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

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

    International Nuclear Information System (INIS)

    Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori; Tsuneyama, Koichi; Endo, Shinya; Tsukui, Tohru; Toyoda, Yasuyuki; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

    2012-01-01

    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

  13. Glucose Modulation Induces Lysosome Formation and Increases Lysosomotropic Drug Sequestration via the P-Glycoprotein Drug Transporter.

    Science.gov (United States)

    Seebacher, Nicole A; Lane, Darius J R; Jansson, Patric J; Richardson, Des R

    2016-02-19

    Pgp is functional on the plasma membrane and lysosomal membrane. Lysosomal-Pgp can pump substrates into the organelle, thereby trapping certain chemotherapeutics (e.g. doxorubicin; DOX). This mechanism serves as a "safe house" to protect cells against cytotoxic drugs. Interestingly, in contrast to DOX, lysosomal sequestration of the novel anti-tumor agent and P-glycoprotein (Pgp) substrate, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), induces lysosomal membrane permeabilization. This mechanism of lysosomal-Pgp utilization enhances cytotoxicity to multidrug-resistant cells. Consequently, Dp44mT has greater anti-tumor activity in drug-resistant relative to non-Pgp-expressing tumors. Interestingly, stressors in the tumor microenvironment trigger endocytosis for cell signaling to assist cell survival. Hence, this investigation examined how glucose variation-induced stress regulated early endosome and lysosome formation via endocytosis of the plasma membrane. Furthermore, the impact of glucose variation-induced stress on resistance to DOX was compared with Dp44mT and its structurally related analogue, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC). These studies showed that glucose variation-induced stress-stimulated formation of early endosomes and lysosomes. In fact, through the process of fluid-phase endocytosis, Pgp was redistributed from the plasma membrane to the lysosomal membrane via early endosome formation. This lysosomal-Pgp actively transported the Pgp substrate, DOX, into the lysosome where it became trapped as a result of protonation at pH 5. Due to increased lysosomal DOX trapping, Pgp-expressing cells became more resistant to DOX. In contrast, cytotoxicity of Dp44mT and DpC was potentiated due to more lysosomes containing functional Pgp under glucose-induced stress. These thiosemicarbazones increased lysosomal membrane permeabilization and cell death. This mechanism has critical implications for drug-targeting in

  14. The effect of anti-parkinsonian drugs on chlorpromazine-induced depression of operant behaviour.

    Science.gov (United States)

    Székely, J I; Dunai-Kovács, Z; Borsy, J

    1976-01-01

    Rats were conditioned in automatic Skinner boxes on a discrete trial avoidance-escape schedule. The chlorpromazine-induced conditioned reflex inhibition could be reversed by apomorphine and amantadine, but not by atropine, trihexyphenidyl and diethazine. These findings seem to provide an additional tool for differentiating the atropine-like and dopaminergic anti-parkinsonian drugs.

  15. The Open Form Inducer Approach for Structure-Based Drug Design.

    Directory of Open Access Journals (Sweden)

    Daniel Ken Inaoka

    Full Text Available Many open form (OF structures of drug targets were obtained a posteriori by analysis of co-crystals with inhibitors. Therefore, obtaining the OF structure of a drug target a priori will accelerate development of potent inhibitors. In addition to its small active site, Trypanosoma cruzi dihydroorotate dehydrogenase (TcDHODH is fully functional in its monomeric form, making drug design approaches targeting the active site and protein-protein interactions unrealistic. Therefore, a novel a priori approach was developed to determination the TcDHODH active site in OF. This approach consists of generating an "OF inducer" (predicted in silico to bind the target and cause steric repulsion with flexible regions proximal to the active site that force it open. We provide the first proof-of-concept of this approach by predicting and crystallizing TcDHODH in complex with an OF inducer, thereby obtaining the OF a priori with its subsequent use in designing potent and selective inhibitors. Fourteen co-crystal structures of TcDHODH with the designed inhibitors are presented herein. This approach has potential to encourage drug design against diseases where the molecular targets are such difficult proteins possessing small AS volume. This approach can be extended to study open/close conformation of proteins in general, the identification of allosteric pockets and inhibitors for other drug targets where conventional drug design approaches are not applicable, as well as the effective exploitation of the increasing number of protein structures deposited in Protein Data Bank.

  16. Drug-drug interaction of microdose and regular-dose omeprazole with a CYP2C19 inhibitor and inducer.

    Science.gov (United States)

    Park, Gab-Jin; Bae, Soo Hyeon; Park, Wan-Su; Han, Seunghoon; Park, Min-Ho; Shin, Seok-Ho; Shin, Young G; Yim, Dong-Seok

    2017-01-01

    A microdose drug-drug interaction (DDI) study may be a valuable tool for anticipating drug interaction at therapeutic doses. This study aimed to compare the magnitude of DDIs at microdoses and regular doses to explore the applicability of a microdose DDI study. Six healthy male volunteer subjects were enrolled into each DDI study of omeprazole (victim) and known perpetrators: fluconazole (inhibitor) and rifampin (inducer). For both studies, the microdose (100 μg, cold compound) and the regular dose (20 mg) of omeprazole were given at days 0 and 1, respectively. On days 2-9, the inhibitor or inducer was given daily, and the microdose and regular dose of omeprazole were repeated at days 8 and 9, respectively. Full omeprazole pharmacokinetic samplings were performed at days 0, 1, 8, and 9 of both studies for noncompartmental analysis. The magnitude of the DDI, the geometric mean ratios (with perpetrator/omeprazole only) of maximum concentration (C max ) and area under the curve to the last measurement (AUC t ) of the microdose and the regular dose were compared. The geometric mean ratios in the inhibition study were: 2.17 (micro) and 2.68 (regular) for C max , and 4.07 (micro), 4.33 (regular) for AUC t . For the induction study, they were 0.26 (micro) and 0.21 (regular) for C max , and 0.16 (micro) and 0.15 (regular) for AUC t . There were no significant statistical differences in the magnitudes of DDIs between microdose and regular-dose conditions, regardless of induction or inhibition. Our results may be used as partial evidence that microdose DDI studies may replace regular-dose studies, or at least be used for DDI-screening purposes.

  17. Glucosylceramide and Lysophosphatidylcholines as Potential Blood Biomarkers for Drug-Induced Hepatic Phospholipidosis

    Science.gov (United States)

    Saito, Kosuke; Maekawa, Keiko; Ishikawa, Masaki; Senoo, Yuya; Urata, Masayo; Murayama, Mayumi; Nakatsu, Noriyuki; Yamada, Hiroshi; Saito, Yoshiro

    2014-01-01

    Drug-induced phospholipidosis is one of the major concerns in drug development and clinical treatment. The present study involved the use of a nontargeting lipidomic analysis with liquid chromatography-mass spectrometry to explore noninvasive blood biomarkers for hepatic phospholipidosis from rat plasma. We used three tricyclic antidepressants (clomipramine [CPM], imipramine [IMI], and amitriptyline [AMT]) for the model of phospholipidosis in hepatocytes and ketoconazole (KC) for the model of phospholipidosis in cholangiocytes and administered treatment for 3 and 28 days each. Total plasma lipids were extracted and measured. Lipid molecules contributing to the separation of control and drug-treated rat plasma in a multivariate orthogonal partial least squares discriminant analysis were identified. Four lysophosphatidylcholines (LPCs) (16:1, 18:1, 18:2, and 20:4) and 42:1 hexosylceramide (HexCer) were identified as molecules separating control and drug-treated rats in all models of phospholipidosis in hepatocytes. In addition, 16:1, 18:2, and 20:4 LPCs and 42:1 HexCer were identified in a model of hepatic phospholipidosis in cholangiocytes, although LPCs were identified only in the case of 3-day treatment with KC. The levels of LPCs were decreased by drug-induced phospholipidosis, whereas those of 42:1 HexCer were increased. The increase in 42:1 HexCer was much higher in the case of IMI and AMT than in the case of CPM; moreover, the increase induced by IMI was dose-dependent. Structural characterization determining long-chain base and hexose delineated that 42:1 HexCer was d18:1/24:0 glucosylceramide (GluCer). In summary, our study demonstrated that d18:1/24:0 GluCer and LPCs are potential novel biomarkers for drug-induced hepatic phospholipidosis. PMID:24980264

  18. 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.

  19. Drug-induced acute interstitial nephritis: A clinicopathological study and comparative trial of steroid regimens

    Directory of Open Access Journals (Sweden)

    R Ramachandran

    2015-01-01

    Full Text Available Steroids are used in the management of drug-induced acute interstitial nephritis (AIN. The present study was undertaken to compare the efficacy of pulse methyl prednisolone with oral prednisolone in the treatment of drug-induced AIN. Patients with biopsy-proven AIN with a history of drug intake were randomized to oral prednisolone (Group 1 1 mg/kg for 3 weeks or a pulse methyl prednisolone (Group II 30 mg/kg for 3 days followed by oral prednisolone 1 mg/kg for 2 weeks, tapered over 3 weeks. Kidney biopsy scoring was done for interstitial edema, infiltration and tubular damage. The response was reported as complete remission (CR (improvement in estimated glomerular filtration rate [eGFR] to ≥60 ml/min/1.73 m 2 , partial remission (PR (improvement but eGFR <60 ml/min/1.73 m 2 or resistance (no CR/PR. A total of 29 patients, Group I: 16 and Group II: 13 were studied. Offending drugs included nonsteroidal anti-inflammatory drugs, herbal drugs, antibiotics, diuretic, rifampicin and omeprazole. There was no difference in the baseline parameters between the two groups. The biopsy score in Groups I and II was 5.9 ΁ 1.1 and 5.1 ΁ 1.2, respectively. At 3 months in Group I, eight patients each (50% achieved CR and PR. In Group II, 8 (61% achieved CR and 5 (39% PR. This was not significantly different. Percentage fall in serum creatinine at 1 week (56% was higher in CR as compared to (42% those with PR. ( P = 0.14. Patients with neutrophil infiltration had higher CR compared to patients with no neutrophil infiltration ( P = 0.01. Early steroid therapy, both oral and pulse steroid, is equally effective in achieving remission in drug-induced AIN.

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

    International Nuclear Information System (INIS)

    Makin, Guy; Dive, Caroline

    2001-01-01

    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

  1. Drug-interaction-induced hemodynamically mediated acute renal failure in postsurgical patient

    Directory of Open Access Journals (Sweden)

    Arup K Misra

    2014-01-01

    Full Text Available Acute renal failure is a life threatening condition. Nonsteroidal antiinflammatory drugs (NSAIDs and cephalosporins are widely used postoperative drugs. NSAID-induced acute renal failure has been reported in the past. In this case, drug interaction and decompensated state of the patient precipitate the condition. NSAIDs inhibit prostaglandins synthesis and thus aggravate ischemia to the kidney that is already facing volume crisis due to surgery. Due to renal dysfunction, plasma ceftriaxone level increases due to decrease clearance and it also acts as nephrotoxic by unknown mechanism. On the other hand, ceftriaxone on its interaction with diclofenac for renal tubular clearance also increases the level of diclofenac and thus further aggravate the ischemia. It is a reversible condition with excluding diclofenac from the treatment regimen and giving adequate hydration to the patient. This highlights the importance of hydration and knowledge of drugs interactions in a postsurgical patient.

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

    DEFF Research Database (Denmark)

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

    2005-01-01

    AIMS: Drug-induced QTc-prolongation, resulting from inhibition of HERG potassium channels may lead to serious ventricular arrhythmias and sudden death. We studied the quantitative anti-HERG activity of pro-arrhythmic drugs as a risk factor for this outcome in day-to-day practice. METHODS...... defined as reports of cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia (n = 5591), and compared with non-cases regarding the anti-HERG activity, defined as the effective therapeutic plasma concentration (ETCPunbound) divided by the HERG IC50 value......, of suspected drugs. We identified a significant association of 1.93 (95% CI: 1.89-1.98) between the anti-HERG activity of drugs, measured as log10 (ETCPunbound/IC50), and reporting of serious ventricular arrhythmias and sudden death to the WHO-UMC database. CONCLUSION: Anti-HERG activity is associated...

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

    Directory of Open Access Journals (Sweden)

    Richard de Boer

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

  4. Synesthetic hallucinations induced by psychedelic drugs in a congenitally blind man.

    Science.gov (United States)

    Dell'Erba, Sara; Brown, David J; Proulx, Michael J

    2018-04-01

    This case report offers rare insights into crossmodal responses to psychedelic drug use in a congenitally blind (CB) individual as a form of synthetic synesthesia. BP's personal experience provides us with a unique report on the psychological and sensory alterations induced by hallucinogenic drugs, including an account of the absence of visual hallucinations, and a compelling look at the relationship between LSD induced synesthesia and crossmodal correspondences. The hallucinatory experiences reported by BP are of particular interest in light of the observation that rates of psychosis within the CB population are extremely low. The phenomenology of the induced hallucinations suggests that experiences acquired through other means, might not give rise to "visual" experiences in the phenomenological sense, but instead gives rise to novel experiences in the other functioning senses. Copyright © 2018 Elsevier Inc. All rights reserved.

  5. Radiation retinopathy caused by low dose irradiation and antithyroid drug-induced systemic vasculitis

    International Nuclear Information System (INIS)

    Sonoda, Koh-hei; Ishibashi, Tatsuro

    2005-01-01

    We report on a patient with Graves' disease with radiation retinopathy caused by low-dose irradiation and antithyroid drug-induced antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. A 38-year-old woman with Graves' disease presented with bilateral blurred vision, micro-aneurysms, telangiectasia, and macular edema. The patient was examined by ophthalmoscopy and fluorescein angiography, and radiation retinopathy was diagnosed. The patient had been treated with low-dose irradiation for her Graves' ophthalmopathy a few years earlier. She also had ANCA-positive vasculitis induced by the antithyroid drug (propylthiouracil, PTU) that had been prescribed for her at that time. Because of multiple avascular areas on both retinas, she was treated by intensive retinal photocoagulation to control progressive retinopathy. The radiation doses used to treat Graves' disease ophthalmopathy are low. Nevertheless, there is still a risk of radiation retinopathy developing in patients with PTU-induced ANCA-positive vasculitis. (author)

  6. Comparison of snoring sounds between natural and drug-induced sleep recorded using a smartphone.

    Science.gov (United States)

    Koo, Soo Kweon; Kwon, Soon Bok; Moon, Ji Seung; Lee, Sang Hoon; Lee, Ho Byung; Lee, Sang Jun

    2018-08-01

    Snoring is an important clinical feature of obstructive sleep apnea (OSA), and recent studies suggest that the acoustic quality of snoring sounds is markedly different in drug-induced sleep compared with natural sleep. However, considering differences in sound recording methods and analysis parameters, further studies are required. This study explored whether acoustic analysis of drug-induced sleep is useful as a screening test that reflects the characteristics of natural sleep in snoring patients. The snoring sounds of 30 male subjects (mean age=41.8years) were recorded using a smartphone during natural and induced sleep, with the site of vibration noted during drug-induced sleep endoscopy (DISE); then, we compared the sound intensity (dB), formant frequencies, and spectrograms of snoring sounds. Regarding the intensity of snoring sounds, there were minor differences within the retrolingual level obstruction group, but there was no significant difference between natural and induced sleep at either obstruction site. There was no significant difference in the F 1 and F 2 formant frequencies of snoring sounds between natural sleep and induced sleep at either obstruction site. Compared with natural sleep, induced sleep was slightly more irregular, with a stronger intensity on the spectrogram, but the spectrograms showed the same pattern at both obstruction sites. Although further studies are required, the spectrograms and formant frequencies of the snoring sounds of induced sleep did not differ significantly from those of natural sleep, and may be used as a screening test that reflects the characteristics of natural sleep according to the obstruction site. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Drug-Induced Endoplasmic Reticulum and Oxidative Stress Responses Independently Sensitize Toward TNF alpha-Mediated Hepatotoxicity

    NARCIS (Netherlands)

    Fredriksson, Lisa; Wink, Steven; Herpers, Bram; Benedetti, Giulia; Hadi, Mackenzie; de Bont, Hans; Groothuis, Geny; Luijten, Mirjam; Danen, Erik; de Graauw, Marjo; Meerman, John; van de Water, Bob

    Drug-induced liver injury (DILI) is an important clinical problem. Here, we used a genomics approach to in detail investigate the hypothesis that critical drug-induced toxicity pathways act in synergy with the pro-inflammatory cytokine tumor necrosis factor alpha (TNF alpha) to cause cell death of

  8. Systemic provocation in doxycycline induced fixed drug eruption: a case report

    Directory of Open Access Journals (Sweden)

    Anik Murwaningsih Rosmarini Estri Sih Hananti Niken Indrastuti

    2014-04-01

    Full Text Available Fixed drug eruption (FDE is recurrent lesions that upon repeated uptake of causative drug, always appears at the same skin and mucosal site. Determination of causal relationship in drug allergy is very important. In this case report, cases of doxycycline-induced FDE was reported. The subject of the research was a 29-year-old male, referred by dermatologist, with history of reccurent FDE. Physical examination revealed an oval well demarcated patch hyperpigmentation. Patch test was perfomed on previous involved and uninvolved site. The result of the patch test was irrelevant. Retesting patch test gave similar result. Systemic provocation test or drug provocation test (DPT  with doxcycline were done with suspected drug under ambulatory survelance and gave positive result. In this case, the DPT succeeded to identify doxycycline as the causal agent of FDE. The work-up of a suspected drug hypersensitivity includes a detailed clinical history, physical examination, skin tests, and provocation tests. The DPT is recommended to confirm drug’s hypersensitivity reactions. Systemic provocation test is considered as the gold standard for diagnosing FDE. Keywords:   fixed drug eruption - doxycycline - causal relationship - patch test - systemic provocation test

  9. Mouse Precision-Cut Liver Slices as an ex Vivo Model To Study Idiosyncratic Drug-Induced Liver Injury

    NARCIS (Netherlands)

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

    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

  10. Drug-Induced Apoptosis: Mechanism by which Alcohol and Many Other Drugs Can Disrupt Brain Development

    Directory of Open Access Journals (Sweden)

    John W. Olney

    2013-07-01

    Full Text Available Maternal ingestion of alcohol during pregnancy can cause a disability syndrome termed Fetal Alcohol Spectrum Disorder (FASD, which may include craniofacial malformations, structural pathology in the brain, and a variety of long-term neuropsychiatric disturbances. There is compelling evidence that exposure to alcohol during early embryogenesis (4th week of gestation can cause excessive death of cell populations that are essential for normal development of the face and brain. While this can explain craniofacial malformations and certain structural brain anomalies that sometimes accompany FASD, in many cases these features are absent, and the FASD syndrome manifests primarily as neurobehavioral disorders. It is not clear from the literature how alcohol causes these latter manifestations. In this review we will describe a growing body of evidence documenting that alcohol triggers widespread apoptotic death of neurons and oligodendroglia (OLs in the developing brain when administered to animals, including non-human primates, during a period equivalent to the human third trimester of gestation. This cell death reaction is associated with brain changes, including overall or regional reductions in brain mass, and long-term neurobehavioral disturbances. We will also review evidence that many drugs used in pediatric and obstetric medicine, including general anesthetics (GAs and anti-epileptics (AEDs, mimic alcohol in triggering widespread apoptotic death of neurons and OLs in the third trimester-equivalent animal brain, and that human children exposed to GAs during early infancy, or to AEDs during the third trimester of gestation, have a significantly increased incidence of FASD-like neurobehavioral disturbances. These findings provide evidence that exposure of the developing human brain to GAs in early infancy, or to alcohol or AEDs in late gestation, can cause FASD-like neurodevelopmental disability syndromes. We propose that the mechanism by which

  11. Morphologic categorization of cell death induced by mild hyperthermia and comparison with death induced by ionizing radiation and cytotoxic drugs

    International Nuclear Information System (INIS)

    Allan, D.J.; Harmon, B.V.

    1986-01-01

    This paper presents a summary of the morphological categorization of cell death, results of two in vivo studies on the cell death induced by mild hyperthermia in rat small intestine and mouse mastocytoma, and a comparison of the cell death induced by hyperthermia, radiation and cytotoxic drugs. Two distinct forms of cell death, apoptosis and necrosis, can be recognized on morphologic grounds. Apoptosis appears to be a process of active cellular self-destruction to which a biologically meaningful role can usually be attributed, whereas necrosis is a passive degenerative phenomenon that results from irreversible cellular injury. Light and transmission electron microscopic studies showed that lower body hyperthermia (43 degrees C for 30 min) induced only apoptosis of intestinal epithelial cells, and of lymphocytes, plasma cells, and eosinophils. In the mastocytoma, hyperthermia (43 degrees C for 15 min) produced widespread tumor necrosis and also enhanced apoptosis of tumor cells. Ionizing radiation and cytotoxic drugs are also known to induce apoptosis in a variety of tissues. It is attractive to speculate that DNA damage by each agent is the common event which triggers the same process of active cellular self-destruction that characteristically effects selective cell deletion in normal tissue homeostasis

  12. Adherence to drug label recommendations for avoiding drug interactions causing statin-induced myopathy--a nationwide register study.

    Directory of Open Access Journals (Sweden)

    Jennifer Settergren

    Full Text Available To investigate the extent to which clinicians avoid well-established drug-drug interactions that cause statin-induced myopathy. We hypothesised that clinicians would avoid combining erythromycin or verapamil/diltiazem respectively with atorvastatin or simvastatin. In patients with statin-fibrate combination therapy, we hypothesised that gemfibrozil was avoided to the preference of bezafibrate or fenofibrate. When combined with verapamil/diltiazem or fibrates, we hypothesized that the dispensed doses of atorvastatin/simvastatin would be decreased.Cross-sectional analysis of nationwide dispensing data. Odds ratios of interacting erythromycin, verapamil/diltiazem versus respective prevalence of comparator drugs doxycycline, amlodipine/felodipine in patients co-dispensed interacting statins simvastatin/atorvastatin versus patients unexposed (pravastatin/fluvastatin/rosuvastatin was calculated. For fibrates, OR of gemfibrozil versus fenofibrate/bezafibrate in patients co-dispensed any statin was assessed.OR of interacting erythromycin versus comparator doxycycline did not differ between patients on interacting and comparator statins either in patients dispensed high or low statin doses (adjusted OR 0.87; 95% CI 0.60-1.25 and 0.92; 95% CI 0.69-1.23. Interacting statins were less common among patients dispensed verapamil/diltiazem as compared to patients on amlodipine/felodipine (OR high dose 0.62; CI 0.56-0.68 and low dose 0.63; CI 0.58-0.68. Patients on any statin were to a lesser extent dispensed gemfibrozil compared to patients not dispensed a statin (OR high dose 0.65; CI 0.55-0.76 and low dose 0.70; CI 0.63-0.78. Mean DDD (SD for any statin was substantially higher in patients co-dispensed gemfibrozil 178 (149 compared to patients on statin monotherapy 127 (93, (p<0.001.Prescribers may to some extent avoid co-prescription of statins with calcium blockers and fibrates with an increased risk of myopathy. We found no evidence for avoiding co

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

    International Nuclear Information System (INIS)

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

    2002-01-01

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

  14. Serotonergic hyperactivity as a potential factor in developmental, acquired and drug-induced synesthesia.

    Science.gov (United States)

    Brogaard, Berit

    2013-01-01

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

  15. 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.

  16. Usefulness of zebrafish larvae to evaluate drug-induced functional and morphological renal tubular alterations.

    Science.gov (United States)

    Gorgulho, Rita; Jacinto, Raquel; Lopes, Susana S; Pereira, Sofia A; Tranfield, Erin M; Martins, Gabriel G; Gualda, Emilio J; Derks, Rico J E; Correia, Ana C; Steenvoorden, Evelyne; Pintado, Petra; Mayboroda, Oleg A; Monteiro, Emilia C; Morello, Judit

    2018-01-01

    Prediction and management of drug-induced renal injury (DIRI) rely on the knowledge of the mechanisms of drug insult and on the availability of appropriate animal models to explore it. Zebrafish (Danio rerio) offers unique advantages for assessing DIRI because the larval pronephric kidney has a high homology with its human counterpart and it is fully mature at 3.5 days post-fertilization. Herein, we aimed to evaluate the usefulness of zebrafish larvae as a model of renal tubular toxicity through a comprehensive analysis of the renal alterations induced by the lethal concentrations for 10% of the larvae for gentamicin, paracetamol and tenofovir. We evaluated drug metabolic profile by mass spectrometry, renal function with the inulin clearance assay, the 3D morphology of the proximal convoluted tubule by two-photon microscopy and the ultrastructure of proximal convoluted tubule mitochondria by transmission electron microscopy. Paracetamol was metabolized by conjugation and oxidation with further detoxification with glutathione. Renal clearance was reduced with gentamicin and paracetamol. Proximal tubules were enlarged with paracetamol and tenofovir. All drugs induced mitochondrial alterations including dysmorphic shapes ("donuts", "pancakes" and "rods"), mitochondrial swelling, cristae disruption and/or loss of matrix granules. These results are in agreement with the tubular effects of gentamicin, paracetamol and tenofovir in man and demonstrate that zebrafish larvae might be a good model to assess functional and structural damage associated with DIRI.

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

    International Nuclear Information System (INIS)

    Liu, Cong; Sekine, Shuichi; Ito, Kousei

    2016-01-01

    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. - Highlights: • Drug-induced mitochondrial toxicity was evaluated using primary rat hepatocytes. • Galactose and hyperoxia could activate OXPHOS in primary rat hepatocytes. • Cells with enhanced OXPHOS exhibit improved sensitivity to mitochondrial toxins. • Transferrin potentiate mitochondrial toxicity via increased ROS production.

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

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Cong; Sekine, Shuichi, E-mail: ssekine@faculty.chiba-u.jp; 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. - Highlights: • Drug-induced mitochondrial toxicity was evaluated using primary rat hepatocytes. • Galactose and hyperoxia could activate OXPHOS in primary rat hepatocytes. • Cells with enhanced OXPHOS exhibit improved sensitivity to mitochondrial toxins. • Transferrin potentiate mitochondrial toxicity via increased ROS production.

  19. A prediction model of drug-induced ototoxicity developed by an optimal support vector machine (SVM) method.

    Science.gov (United States)

    Zhou, Shu; Li, Guo-Bo; Huang, Lu-Yi; Xie, Huan-Zhang; Zhao, Ying-Lan; Chen, Yu-Zong; Li, Lin-Li; Yang, Sheng-Yong

    2014-08-01

    Drug-induced ototoxicity, as a toxic side effect, is an important issue needed to be considered in drug discovery. Nevertheless, current experimental methods used to evaluate drug-induced ototoxicity are often time-consuming and expensive, indicating that they are not suitable for a large-scale evaluation of drug-induced ototoxicity in the early stage of drug discovery. We thus, in this investigation, established an effective computational prediction model of drug-induced ototoxicity using an optimal support vector machine (SVM) method, GA-CG-SVM. Three GA-CG-SVM models were developed based on three training sets containing agents bearing different risk levels of drug-induced ototoxicity. For comparison, models based on naïve Bayesian (NB) and recursive partitioning (RP) methods were also used on the same training sets. Among all the prediction models, the GA-CG-SVM model II showed the best performance, which offered prediction accuracies of 85.33% and 83.05% for two independent test sets, respectively. Overall, the good performance of the GA-CG-SVM model II indicates that it could be used for the prediction of drug-induced ototoxicity in the early stage of drug discovery. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. 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.

  1. Serum drug level-related sodium valproate-induced hair loss.

    Science.gov (United States)

    Ramakrishnappa, Suresh K; Belhekar, Mahesh N

    2013-01-01

    Sodium valproate is a well-established treatment in epilepsy and mood disorders. Its utility is compromised by its adverse effects such as tremor, weight gain, hair loss, and liver dysfunction. Hair loss may occur when drug is used in higher dose. Drug-induced hair loss is diffused and non-scarring, which is reversible upon withdrawal. But there are no case reports showing relation between serum levels of valproate and occurrence of hair loss. So we took interest in reporting this case report.

  2. Levofloxacin?Induced QTc Prolongation Depends on the Time of Drug Administration

    OpenAIRE

    Kervezee, L; Gotta, V; Stevens, J; Birkhoff, W; Kamerling, IMC; Danhof, M; Meijer, JH; Burggraaf, J

    2016-01-01

    Understanding the factors influencing a drug's potential to prolong the QTc interval on an electrocardiogram is essential for the correct evaluation of its safety profile. To explore the effect of dosing time on drug-induced QTc prolongation, a randomized, crossover, clinical trial was conducted in which 12 healthy male subjects received levofloxacin at 02:00, 06:00, 10:00, 14:00, 18:00, and 22:00. Using a pharmacokinetic-pharmacodynamic (PK-PD) modeling approach to account for variations in ...

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

    Directory of Open Access Journals (Sweden)

    Bahareh Abbasi

    2015-11-01

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

  4. Reconstruction of Drug-induced Cleft Palate Using Bone Marrow Mesenchymal Stem Cell in Rodents.

    Science.gov (United States)

    Amalraj, Julie Christy; Gangothri, Manasa; Babu, Hari

    2017-01-01

    Triamcinolone acetonide (TAC) (Kenacort*) is a commonly used synthetic glucocorticoid in today's medical practice. The drug is also a potential agent in inducing cleft palates in rats. This drug has been used to induce cleft palate in the fetus of the pregnant rats to bring out a suitable animal model for human cleft lip and palate. The drug was given intraperitoneally to induce congenital cleft palate in pregnant mother rats. The aim of this study is to induce congenital cleft palate in pregnant Wister albino rats and reconstruct the defect with bone marrow mesenchymal stem cells (BMSCs) isolated from the same species along with PLGA (poly lactic co glycolic acid) scaffold. Twenty female animals were divided into two groups. Each group contains 10 animals. The animals were allowed to mate with male rat during the esterase period and the day, in hich vaginal plug was noticed was taken to be day 0. The pregnant rats were given triamcinolone acetonide (Kenacort* 10 mg/1 ml intramuscularly/intravenous [IM/IV] injections) injection intraperitoneally at two different dosages as the existing literature. The injection was given on the 10, 12, and 14 th day of gestation. The clinical changes observed were recorded, and the change in the body weight was noted carefully. Group 1 which received 0.5 mg/kg body weight of TAC had many drug toxic effects. Group 2 which received 0.05 mg/kg body weight produced cleft palate in rat pups. The pups were divided into three groups. Group A control group without cell transplant, the cleft was allowed to close by itself. Group B containing palate reconstructed with plain PLGA scaffold (Bioscaffold, Singapore) without BMSC, Group C containing BMSC and PLGA scaffold (Bioscaffold, Singapore), Group C operated for the cleft palate reconstruction using BMSCs and PLGA scaffold. There was faster and efficient reconstruction of bone in the cleft defect in Group C while there was no defect closure in Group A and B. There was complete

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

    Energy Technology Data Exchange (ETDEWEB)

    Tolosa, Laia [Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026 (Spain); Gómez-Lechón, M. José [Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026 (Spain); CIBERehd, FIS, Barcelona 08036 (Spain); Jiménez, Nuria [Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026 (Spain); Hervás, David [Biostatistics Unit, Instituto de Investigación Sanitaria La Fe, Valencia 46026 (Spain); Jover, Ramiro [Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026 (Spain); CIBERehd, FIS, Barcelona 08036 (Spain); Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia 46010 (Spain); Donato, M. Teresa, E-mail: donato_mte@gva.es [Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026 (Spain); CIBERehd, FIS, Barcelona 08036 (Spain); Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia 46010 (Spain)

    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. - Highlights: • HepaRG cells were explored as an in vitro model to detect steatogenic potential. • Multiple toxicity-related endpoints were analysed by HCS. • HepaRG showed a greater sensitivity to drug-induced steatosis than HepG2 cells. • Changes in the expression of genes related to lipid metabolism were revealed. • HepaRG allow mechanistic understanding of liver damage induced by steatogenic drugs.

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

    International Nuclear Information System (INIS)

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

    2016-01-01

    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. - Highlights: • HepaRG cells were explored as an in vitro model to detect steatogenic potential. • Multiple toxicity-related endpoints were analysed by HCS. • HepaRG showed a greater sensitivity to drug-induced steatosis than HepG2 cells. • Changes in the expression of genes related to lipid metabolism were revealed. • HepaRG allow mechanistic understanding of liver damage induced by steatogenic drugs.

  7. Age-Dependent Cellular and Behavioral Deficits Induced by Molecularly Targeted Drugs Are Reversible.

    Science.gov (United States)

    Scafidi, Joseph; Ritter, Jonathan; Talbot, Brooke M; Edwards, Jorge; Chew, Li-Jin; Gallo, Vittorio

    2018-04-15

    Newly developed targeted anticancer drugs inhibit signaling pathways commonly altered in adult and pediatric cancers. However, as these pathways are also essential for normal brain development, concerns have emerged of neurologic sequelae resulting specifically from their application in pediatric cancers. The neural substrates and age dependency of these drug-induced effects in vivo are unknown, and their long-term behavioral consequences have not been characterized. This study defines the age-dependent cellular and behavioral effects of these drugs on normally developing brains and determines their reversibility with post-drug intervention. Mice at different postnatal ages received short courses of molecularly targeted drugs in regimens analagous to clinical treatment. Analysis of rapidly developing brain structures important for sensorimotor and cognitive function showed that, while adult administration was without effect, earlier neonatal administration of targeted therapies attenuated white matter oligodendroglia and hippocampal neuronal development more profoundly than later administration, leading to long-lasting behavioral deficits. This functional impairment was reversed by rehabilitation with physical and cognitive enrichment. Our findings demonstrate age-dependent, reversible effects of these drugs on brain development, which are important considerations as treatment options expand for pediatric cancers. Significance: Targeted therapeutics elicit age-dependent long-term consequences on the developing brain that can be ameliorated with environmental enrichment. Cancer Res; 78(8); 2081-95. ©2018 AACR . ©2018 American Association for Cancer Research.

  8. Drug perfusion enhancement in tissue model by steady streaming induced by oscillating microbubbles.

    Science.gov (United States)

    Oh, Jin Sun; Kwon, Yong Seok; Lee, Kyung Ho; Jeong, Woowon; Chung, Sang Kug; Rhee, Kyehan

    2014-01-01

    Drug delivery into neurological tissue is challenging because of the low tissue permeability. Ultrasound incorporating microbubbles has been applied to enhance drug delivery into these tissues, but the effects of a streaming flow by microbubble oscillation on drug perfusion have not been elucidated. In order to clarify the physical effects of steady streaming on drug delivery, an experimental study on dye perfusion into a tissue model was performed using microbubbles excited by acoustic waves. The surface concentration and penetration length of the drug were increased by 12% and 13%, respectively, with streaming flow. The mass of dye perfused into a tissue phantom for 30s was increased by about 20% in the phantom with oscillating bubbles. A computational model that considers fluid structure interaction for streaming flow fields induced by oscillating bubbles was developed, and mass transfer of the drug into the porous tissue model was analyzed. The computed flow fields agreed with the theoretical solutions, and the dye concentration distribution in the tissue agreed well with the experimental data. The computational results showed that steady streaming with a streaming velocity of a few millimeters per second promotes mass transfer into a tissue. © 2013 Published by Elsevier Ltd.

  9. 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.

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

    DEFF Research Database (Denmark)

    Johansen, Flemming F; Hasseldam, Henrik; Rasmussen, Rune Skovgaard

    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...... conditioning before (preconditioning) and after (postconditioning) experimental stroke. Methods: Hypothermia was induced in rats with a bolus of 6 mg/kg talipexole followed by 20 h continuous talipexole infusion of 6 mg/kg in total. Controls received similar treatment with saline. The core body temperature...... was continuously monitored. In preconditioning, hypothermia was terminated before either reversible occlusion of the middle cerebral artery (MCAO) for 60 min or global ischemia for 10 min with 2-vessel occlusion and hypotension. In postconditioning, rats experienced 60 min of MCAO before hypothermia was induced...

  11. Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer.

    Science.gov (United States)

    Jarzabek, Monika A; Proctor, William R; Vogt, Jennifer; Desai, Rupal; Dicker, Patrick; Cain, Gary; Raja, Rajiv; Brodbeck, Jens; Stevens, Dale; van der Stok, Eric P; Martens, John W M; Verhoef, Cornelis; Hegde, Priti S; Byrne, Annette T; Tarrant, Jacqueline M

    2018-01-01

    Drug-related sinusoidal dilatation (SD) is a common form of hepatotoxicity associated with oxaliplatin-based chemotherapy used prior to resection of colorectal liver metastases (CRLM). Recently, hepatic SD has also been associated with anti-delta like 4 (DLL4) cancer therapies targeting the NOTCH pathway. To investigate the hypothesis that NOTCH signaling plays an important role in drug-induced SD, gene expression changes were examined in livers from anti-DLL4 and oxaliplatin-induced SD in non-human primate (NHP) and patients, respectively. Putative mechanistic biomarkers of bevacizumab (bev)-mediated protection against oxaliplatin-induced SD were also investigated. RNA was extracted from whole liver sections or centrilobular regions by laser-capture microdissection (LCM) obtained from NHP administered anti-DLL4 fragment antigen-binding (F(ab')2 or patients with CRLM receiving oxaliplatin-based chemotherapy with or without bev. mRNA expression was quantified using high-throughput real-time quantitative PCR. Significance analysis was used to identify genes with differential expression patterns (false discovery rate (FDR) < 0.05). Eleven (CCL2, CCND1, EFNB2, ERG, ICAM1, IL16, LFNG, NOTCH1, NOTCH4, PRDX1, and TGFB1) and six (CDH5, EFNB2, HES1, IL16, MIK67, HES1 and VWF) candidate genes were differentially expressed in the liver of anti-DLL4- and oxaliplatin-induced SD, respectively. Addition of bev to oxaliplatin-based chemotherapy resulted in differential changes in hepatic CDH5, HEY1, IL16, JAG1, MMP9, NOTCH4 and TIMP1 expression. This work implicates NOTCH and IL16 pathways in the pathogenesis of drug-induced SD and further explains the hepato-protective effect of bev in oxaliplatin-induced SD observed in CRLM patients.

  12. 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.

  13. Hibiscus vitifolius (Linn.) root extracts shows potent protective action against anti-tubercular drug induced hepatotoxicity.

    Science.gov (United States)

    Samuel, Anbu Jeba Sunilson John; Mohan, Syam; Chellappan, Dinesh Kumar; Kalusalingam, Anandarajagopal; Ariamuthu, Saraswathi

    2012-05-07

    The roots of Hibiscus vitifolius Linn. (Malvaceae) is used for the treatment of jaundice in the folklore system of medicine in India. This study is an attempt to evaluate the hepatoprotective activity of the roots of Hibiscus vitifolius against anti-tubercular drug induced hepatotoxicity. Hepatotoxicity was induced in albino rats of either sex by oral administration of a combination of three anti-tubercular drugs. Petroleum ether, chloroform, methanol and aqueous extracts of roots of Hibiscus vitifolius (400mg/kg/day) were evaluated for their possible hepatoprotective potential. All the extracts were found to be safe up to a dose of 2000mg/kg. Among the four extracts studied, oral administration of methanol extract of Hibiscus vitifolius at 400mg/kg showed significant difference in all the parameters when compared to control. There was a significant (PHibiscus vitifolius have potent hepatoprotective activity, thereby justifying its ethnopharmacological claim. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  14. Potential candidate genomic biomarkers of drug induced vascular injury in the rat

    International Nuclear Information System (INIS)

    Dalmas, Deidre A.; Scicchitano, Marshall S.; Mullins, David; Hughes-Earle, Angela; Tatsuoka, Kay; Magid-Slav, Michal; Frazier, Kendall S.; Thomas, Heath C.

    2011-01-01

    Drug-induced vascular injury is frequently observed in rats but the relevance and translation to humans present a hurdle for drug development. Numerous structurally diverse pharmacologic agents have been shown to induce mesenteric arterial medial necrosis in rats, but no consistent biomarkers have been identified. To address this need, a novel strategy was developed in rats to identify genes associated with the development of drug-induced mesenteric arterial medial necrosis. Separate groups (n = 6/group) of male rats were given 28 different toxicants (30 different treatments) for 1 or 4 days with each toxicant given at 3 different doses (low, mid and high) plus corresponding vehicle (912 total rats). Mesentery was collected, frozen and endothelial and vascular smooth muscle cells were microdissected from each artery. RNA was isolated, amplified and Affymetrix GeneChip® analysis was performed on selectively enriched samples and a novel panel of genes representing those which showed a dose responsive pattern for all treatments in which mesenteric arterial medial necrosis was histologically observed, was developed and verified in individual endothelial cell- and vascular smooth muscle cell-enriched samples. Data were confirmed in samples containing mesentery using quantitative real-time RT-PCR (TaqMan™) gene expression profiling. In addition, the performance of the panel was also confirmed using similarly collected samples obtained from a timecourse study in rats given a well established vascular toxicant (Fenoldopam). Although further validation is still required, a novel gene panel has been developed that represents a strategic opportunity that can potentially be used to help predict the occurrence of drug-induced mesenteric arterial medial necrosis in rats at an early stage in drug development. -- Highlights: ► A gene panel was developed to help predict rat drug-induced mesenteric MAN. ► A gene panel was identified following treatment of rats with 28

  15. In Silico Identification of Proteins Associated with Drug-induced Liver Injury Based on the Prediction of Drug-target Interactions.

    Science.gov (United States)

    Ivanov, Sergey; Semin, Maxim; Lagunin, Alexey; Filimonov, Dmitry; Poroikov, Vladimir

    2017-07-01

    Drug-induced liver injury (DILI) is the leading cause of acute liver failure as well as one of the major reasons for drug withdrawal from clinical trials and the market. Elucidation of molecular interactions associated with DILI may help to detect potentially hazardous pharmacological agents at the early stages of drug development. The purpose of our study is to investigate which interactions with specific human protein targets may cause DILI. Prediction of interactions with 1534 human proteins was performed for the dataset with information about 699 drugs, which were divided into three categories of DILI: severe (178 drugs), moderate (310 drugs) and without DILI (211 drugs). Based on the comparison of drug-target interactions predicted for different drugs' categories and interpretation of those results using clustering, Gene Ontology, pathway and gene expression analysis, we identified 61 protein targets associated with DILI. Most of the revealed proteins were linked with hepatocytes' death caused by disruption of vital cellular processes, as well as the emergence of inflammation in the liver. It was found that interaction of a drug with the identified targets is the essential molecular mechanism of the severe DILI for the most of the considered pharmaceuticals. Thus, pharmaceutical agents interacting with many of the identified targets may be considered as candidates for filtering out at the early stages of drug research. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Drug Release Profile from Calcium-Induced Alginate-Phosphate Composite Gel Beads

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    Yoshifumi Murata

    2009-01-01

    Full Text Available Calcium-induced alginate-phosphate composite gel beads were prepared, and model drug release profiles were investigated in vitro. The formation of calcium phosphate in the alginate gel matrix was observed and did not affect the rheological properties of the hydrogel beads. X-ray diffraction patterns showed that the calcium phosphate does not exist in crystalline form in the matrix. The initial release amount and release rate of a water-soluble drug, diclofenac, from the alginate gel beads could be controlled by modifying the composition of the matrix with calcium phosphate. In contrast, the release profile was not affected by the modification for hydrocortisone, a drug only slightly soluble in water.

  17. Effect of goat milk on hepatotoxicity induced by antitubercular drugs in rats

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    Sonam Miglani

    2016-10-01

    Full Text Available Aim of the present study was to assess the hepatoprotective activity of goat milk on antitubercular drug-induced hepatotoxicity in rats. Hepatotoxicity was induced in rats using a combination of isoniazid, rifampicin, and pyrazinamide given orally as a suspension for 30 days. Treatment groups received goat milk along with antitubercular drugs. Liver damage was assessed using biochemical and histological parameters. Administration of goat milk (20 mL/kg along with antitubercular drugs (Group III reversed the levels of serum alanine aminotransferase (82 ± 25.1 vs. 128.8 ± 8.9 units/L and aspartate aminotransferase (174.7 ± 31.5 vs. 296.4 ± 56.4 units/L, p<0.01 compared with antitubercular drug treatment Group II. There was a significant decrease in serum alanine aminotransferase (41.8 ± 4.1 vs. 128.8 ± 8.9 ​ units/L, p<0.01 and aspartate aminotransferase (128.8 ± 8.54 vs. 296.4 ± 56.4 units/L, p<0.001 levels in Group IV (goat milk 40 mL/kg compared with antitubercular drug treatment Group II. Goat milk (20 mL/kg and 40 mL/kg was effective in reversing the rise in malondialdehyde level compared with the antitubercular drug suspension groups (58.5 ± 2 vs. 89.88 ± 2.42 μmol/mL of tissue homogenate, p<0.001 and 69.7 ± 0.78 vs. 89.88 ± 2.42 μmol/mL of tissue homogenate, p<0.001, respectively. Similarly, both doses of milk significantly prevented a fall in superoxide dismutase level (6.23 ± 0.29 vs. 3.1 ± 0.288 units/mL, p<0.001 and 7.8 ± 0.392 vs. 3.1 ± 0.288 units/mL, p<0.001 compared with the group receiving antitubercular drugs alone. Histological examination indicated that goat milk reduced inflammation and necrotic changes in hepatocytes in the treatment groups. The results indicated that goat milk prevented the antitubercular drug-induced hepatotoxicity and is an effective hepatoprotective agent.

  18. Epidemiology of symptomatic drug-induced long QT syndrome and Torsade de Pointes in Germany.

    Science.gov (United States)

    Sarganas, Giselle; Garbe, Edeltraut; Klimpel, Andreas; Hering, Rolf C; Bronder, Elisabeth; Haverkamp, Wilhelm

    2014-01-01

    Drug-induced long QT syndrome (diLQTS) leading to Torsade de Pointes (TdP) is a potentially lethal condition, which has led to several post-marketing drug withdrawals in the past decade. The true incidence of diLQTS/TdP is largely unknown. One explanation is under-reporting of this potentially life-threatening adverse event by physicians and other medical staff to pharmacovigilance agencies. To gain more insight into the incidence of diLQTS and TdP, the Berlin Pharmacovigilance Center (PVZ-FAKOS) has actively and prospectively identified patients who developed this particular type of drug-induced adverse event. Here, the basic characteristics of the affected patients are summarized and suspected drugs are discussed. Furthermore, an extrapolation of the Berlin incidence rates to the German Standard Population is presented. Using a Berlin-wide network of 51 collaborating hospitals (>180 clinical departments), adult patients presenting with long QT syndrome (LQTS/TdP) between 2008 and 2011 were identified by active surveillance of these hospitals. Drug exposures as well as other possible risk factors were obtained from the patient's files and in a face-to-face interview with the patient. One-hundred and seventy patients of possible LQTS/TdP were reported to the Pharmacovigilance Center of whom 58 cases were confirmed in a thorough validation process. The majority (66%) of these cases were female and 60% had developed LQTS/TdP in the outpatient setting. Thirty-five (60%) of 58 confirmed cases were assessed as drug-related based on a standardized causality assessment applying the criteria of the World Health Organization. Drugs assessed as related in more than two cases were metoclopramide, amiodarone, melperone, citalopram, and levomethadone. The age-standardized incidence of diLQTS/TdP in Berlin was estimated to be 2.5 per million per year for males and 4.0 per million per year for females. While European annual reporting rates based on spontaneous reports suggest an

  19. Clinical Relevance and Predictive Value of Damage Biomarkers of Drug-Induced Kidney Injury.

    Science.gov (United States)

    Kane-Gill, Sandra L; Smithburger, Pamela L; Kashani, Kianoush; Kellum, John A; Frazee, Erin

    2017-11-01

    Nephrotoxin exposure accounts for up to one-fourth of acute kidney injury episodes in hospitalized patients, and the associated consequences are as severe as acute kidney injury due to other etiologies. As the use of nephrotoxic agents represents one of the few modifiable risk factors for acute kidney injury, clinicians must be able to identify patients at high risk for drug-induced kidney injury rapidly. Recently, significant advancements have been made in the field of biomarker utilization for the prediction and detection of acute kidney injury. Such biomarkers may have a role both for detection of drug-induced kidney disease and implementation of preventative and therapeutic strategies designed to mitigate injury. In this article, basic principles of renal biomarker use in practice are summarized, and the existing evidence for six markers specifically used to detect drug-induced kidney injury are outlined, including liver-type fatty acid binding protein, neutrophil gelatinase-associated lipocalin, tissue inhibitor of metalloproteinase-2 times insulin-like growth factor-binding protein 7 ([TIMP-2]·[IGFBP7]), kidney injury molecule-1 and N-acetyl-β-D-glucosaminidase. The results of the literature search for these six kidney damage biomarkers identified 29 unique articles with none detected for liver-type fatty acid binding protein and [TIMP-2]·[IGFBP7]. For three biomarkers, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin and N-acetyl-β-D-glucosaminidase, the majority of the studies suggest utility in clinical practice. While many questions need to be answered to clearly articulate the use of biomarkers to predict drug-induced kidney disease, current data are promising.

  20. Drug-Induced Liver Injury by Glatiramer Acetate Used for Treatment of Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Attila Onmez

    2013-12-01

    Full Text Available Glatiramer acetate (GA, Copaxone is an approved drug for the treatment of relapsing–remitting multiple sclerosis. Most common side effects observed with GA are local injection site reactions, which can include pain, swelling, or redness. However, systemic adverse event such as hepatotoxicity related to GA is rarely seen. In this report, we present a case of GA-induced toxic hepatitis associated with cholestatic and hepatocellular damage.

  1. Drug-induced Sweet's syndrome secondary to hepatitis C antiviral therapy.

    Science.gov (United States)

    Gheorghe, Liana; Cotruta, Bogdan; Trifu, Viorel; Cotruta, Cristina; Becheanu, Gabriel; Gheorghe, Cristian

    2008-09-01

    Pegylated interferon-alpha in combination with ribavirin currently represents the therapeutic standard for the hepatitis C virus infection. Interferon based therapy may be responsible for many cutaneous side effects. We report a case of drug-induced Sweet's syndrome secondary to hepatitis C antiviral therapy. To our knowledge, this is the first reported case of Sweet's syndrome in association with pegylated interferon-alpha therapy.

  2. Induced pluripotent stem cell-derived cardiomyocytes for cardiovascular disease modeling and drug screening

    OpenAIRE

    Sharma, Arun; Wu, Joseph C; Wu, Sean M

    2013-01-01

    Human induced pluripotent stem cells (hiPSCs) have emerged as a novel tool for drug discovery and therapy in cardiovascular medicine. hiPSCs are functionally similar to human embryonic stem cells (hESCs) and can be derived autologously without the ethical challenges associated with hESCs. Given the limited regenerative capacity of the human heart following myocardial injury, cardiomyocytes derived from hiPSCs (hiPSC-CMs) have garnered significant attention from basic and translational scienti...

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

    Science.gov (United States)

    Etxagibel, Aitziber; Julià, M Rosa; Brotons, Alvaro; Company, M Margarita; Dolz, Carlos

    2008-01-28

    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. 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. 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.

  4. 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.

  5. Calotropis procera Latex-Induced Inflammatory Hyperalgesia—Effect of Antiinflammatory Drugs

    Directory of Open Access Journals (Sweden)

    Raman Sehgal

    2005-01-01

    Full Text Available The milky white latex of plant Calotropis procera produces inflammation of the skin and mucous membranes on accidental exposure. It produces edema on local administration due to the release of histamine and prostaglandins and is associated with hyperalgesia. In the present study we have evaluated the antiedematous and analgesic activity of antiinflammatory drugs against inflammatory response induced by dried latex (DL of C procera in rat paw edema model. An aqueous extract of DL of C procera was injected into the subplantar surface of the rat paw and the paw volume was measured by a plethysmometer at 0, 1, 2, 6, 12, and 24 hours. Concomitantly the hyperalgesic response was also evaluated by motility test, stair climbing ability test, dorsal flexion pain test, compression test, and observing the grooming behavior. The inhibitory effect of diclofenac and rofecoxib on edema formation and hyperalgesic response was compared with cyproheptadine (CPH. DL-induced edema formation was maximum at 2 hours that was associated with decreased pain threshold, functional impairment, and grooming. Treatment with antiinflammatory drugs and CPH significantly attenuated the edematous response and grooming, increased the pain threshold, and improved functional parameters. Both antiinflammatory and antiserotonergic drugs significantly inhibited the hyperalgesia associated with DL-induced paw edema. Rofecoxib was found to be superior than diclofenac and was as effective as CPH in ameliorating the hyperalgesia. However, it was found to be less effective than CPH in attenuating edema formation.

  6. Effectiveness of malic acid 1% in patients with xerostomia induced by antihypertensive drugs

    Science.gov (United States)

    Guardia, Javier; Aguilar-Salvatierra, Antonio; Cabrera-Ayala, Maribel; Maté-Sánchez de-Val, José E.; Calvo-Guirado, José L.

    2013-01-01

    Objectives: Assessing the clinical effectiveness of a topical sialogogue on spray (malic acid, 1%) in the treatment of xerostomia induced by antihypertensive drugs. Study Design: This research has been carried out through a randomized double-blind clinical trial. 45 patients suffering from hypertensive drugs-induced xerostomia were divided into 2 groups: the first group (25 patients) received a topical sialogogue on spray (malic acid, 1%) whereas the second group (20 patients) received a placebo. Both of them were administered on demand for 2 weeks. Dry Mouth Questionnaire (DMQ) was used in order to evaluate xerostomia levels before and after product/placebo application. Unstimulated and stimulated salivary flows rates, before and after application, were measured. All the statistical analyses were performed by using SPSS software v17.0. Different DMQ scores at the earliest and final stage of the trial were analysed by using Mann-Whitney U test, whereas Student’s T-test was used to analyse salivary flows. Critical p-value was established at p0.05) after placebo application. After two weeks of treatment with malic acid, unstimulated salivary flow increased from 0.17 to 0.242 mL/min whereas the stimulated one increased from 0.66 to 0.92 mL/min (p0.05). Conclusions: Malic acid 1% spray improved antihypertensive-induced xerostomia and stimulated the production of saliva. Key words:Xerostomia, hyposialia, malic acid, antihypertensive drugs. PMID:22926481

  7. Reversion of pH-induced physiological drug resistance: a novel function of copolymeric nanoparticles.

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    Rutian Li

    Full Text Available AIMS: The extracellular pH of cancer cells is lower than the intracellular pH. Weakly basic anticancer drugs will be protonated extracellularly and display a decreased intracellular concentration. In this study, we show that copolymeric nanoparticles (NPs are able to overcome this "pH-induced physiological drug resistance" (PIPDR by delivering drugs to the cancer cells via endocytosis rather than passive diffussion. MATERIALS AND METHODS: As a model nanoparticle, Tetradrine (Tet, Pka 7.80 was incorporated into mPEG-PCL. The effectiveness of free Tet and Tet-NPs were compared at different extracellular pHs (pH values 6.8 and 7.4, respectively by MTT assay, morphological observation and apoptotic analysis in vitro and on a murine model by tumor volume measurement, PET-CT scanning and side effect evaluation in vivo. RESULTS: The cytotoxicity of free Tet decreased prominently (P<0.05 when the extracellular pH decreased from 7.4 to 6.8. Meanwhile, the cytotoxicity of Tet-NPs was not significantly influenced by reduced pH. In vivo experiment also revealed that Tet-NPs reversed PIPDR more effectively than other existing methods and with much less side effects. CONCLUSION: The reversion of PIPDR is a new discovered mechanism of copolymeric NPs. This study emphasized the importance of cancer microenvironmental factors in anticancer drug resistance and revealed the superiority of nanoscale drug carrier from a different aspect.

  8. MicroRNAs as Signaling Mediators and Biomarkers of Drug- and Chemical-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Mitchell R. McGill

    2015-05-01

    Full Text Available Drug-induced liver injury (DILI is major problem for both the drug industry and for clinicians. There are two basic categories of DILI: intrinsic and idiosyncratic. The former is the chief cause of acute liver failure in several developed countries, while the latter is the most common reason for post-marketing drug withdrawal and a major reason for failure to approve new drugs in the U.S. Although considerably more progress has been made in the study of intrinsic DILI, our understanding of both forms of drug hepatotoxicity remains incomplete. Recent work involving microRNAs (miRNAs has advanced our knowledge of DILI in two ways: (1 possible roles of miRNAs in the pathophysiological mechanisms of DILI have been identified, and (2 circulating miRNA profiles have shown promise for the detection and diagnosis of DILI in clinical settings. The purpose of this review is to summarize major findings in these two areas of research. Taken together, exciting progress has been made in the study of miRNAs in DILI. Possible mechanisms through which miRNA species contribute to the basic mechanisms of DILI are beginning to emerge, and new miRNA-based biomarkers have the potential to greatly improve diagnosis of liver injury and prediction of patient outcomes.

  9. Prophylaxis and management of antineoplastic drug induced nausea and vomiting in children with cancer

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    Sidharth Totadri

    2016-10-01

    Full Text Available Antineoplastic drug induced nausea and vomiting (AINV is a major adverse event which deeply impacts the quality of life of children with cancer. It additionally causes distress to parents and negatively impacts compliance to therapy. A robust AINV prophylaxis regimen is essential to achieve complete control; and prevent anticipatory, breakthrough and refractory AINV. With a wide array of available anti-emetics, standard guidelines for their use are crucial to ensure uniform and optimum prophylaxis. Chemotherapeutic agents are classified as having high, moderate, low or minimal emetic risk based on their potential to cause emesis in the absence of prophylaxis. Three drug regimen with aprepitant, ondansetron/granisetron and dexamethasone is recommended for protocols with high emetic risk. Although approved in children ≥12 years, there is mounting evidence for the use of aprepitant in younger children too. In protocols with moderate and low emetic risk, combination of ondansetron/granisetron and dexamethasone; and single agent ondansetron/granisetron are recommended, respectively. Metoclopramide is an alternative when steroids are contraindicated. Olanzapine and lorazepam are useful drugs for breakthrough AINV and anticipatory AINV. Knowledge of pediatric dosage, salient adverse events, drug interactions as well as cost of drugs is essential to prescribe anti-emetics accurately and safely in resource constrained settings. Non pharmacological interventions such as hypnosis, acupressure and psychological interventions can benefit a sub-group of patients without significant risk of adverse events.

  10. Microdose-Induced Drug-DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice.

    Science.gov (United States)

    Zimmermann, Maike; Wang, Si-Si; Zhang, Hongyong; Lin, Tzu-Yin; Malfatti, Michael; Haack, Kurt; Ognibene, Ted; Yang, Hongyuan; Airhart, Susan; Turteltaub, Kenneth W; Cimino, George D; Tepper, Clifford G; Drakaki, Alexandra; Chamie, Karim; de Vere White, Ralph; Pan, Chong-Xian; Henderson, Paul T

    2017-02-01

    We report progress on predicting tumor response to platinum-based chemotherapy with a novel mass spectrometry approach. Fourteen bladder cancer patients were administered one diagnostic microdose each of [ 14 C]carboplatin (1% of the therapeutic dose). Carboplatin-DNA adducts were quantified by accelerator mass spectrometry in blood and tumor samples collected within 24 hours, and compared with subsequent chemotherapy response. Patients with the highest adduct levels were responders, but not all responders had high adduct levels. Four patient-derived bladder cancer xenograft mouse models were used to test the possibility that another drug in the regimen could cause a response. The mice were dosed with [ 14 C]carboplatin or [ 14 C]gemcitabine and the resulting drug-DNA adduct levels were compared with tumor response to chemotherapy. At least one of the drugs had to induce high drug-DNA adduct levels or create a synergistic increase in overall adducts to prompt a corresponding therapeutic response, demonstrating proof-of-principle for drug-DNA adducts as predictive biomarkers. Mol Cancer Ther; 16(2); 376-87. ©2016 AACR. ©2016 American Association for Cancer Research.

  11. The Drug Release Profile from Calcium-induced Alginate Gel Beads Coated with an Alginate Hydrolysate

    Directory of Open Access Journals (Sweden)

    Susumu Kawashima

    2007-11-01

    Full Text Available Calcium-induced alginate gel bead (Alg-Ca coated with an alginate hydrolysate(Alg, e.g. the guluronic acid block (GB was prepared and the model drug, hydrocortisonerelease profiles were investigated under simulated gastrointestinal conditions. Theirmolecular weights were one sixth or one tenth that of Alg and the diffraction patterns of thehydrolysates resembled that of Alg. The drug release rate from Alg-Ca coated with GBapparently lowered than that of Alg-Ca (coating-free in the gastric juice (pH1.2. And thecoating did not resist the disintegration of Alg-Ca in the intestinal juice (pH 6.8 and thegel erosion accelerated the drug release. On the other hand, for the coated Alg-Cacontaining chitosan, the drug release showed zero-order kinetics without rapid erosion ofAlg-Ca. The drug release rate from Alg-Ca was able to be controlled by the coating andmodifying the composition of the gel matrix.

  12. Hiponatremia in the practice of a psychiatrist. Part 1: SIADH syndrome and drug-induced hyponatremia.

    Directory of Open Access Journals (Sweden)

    Stelmach Ewa

    2017-06-01

    Full Text Available Introduction. Hyponatremia is an important part of psychiatric practice. In order to analyze its causes and symptoms, the literature on hyponatremia in psychiatric patients has been reviewed. The work has been divided into two separate manuscripts. In the first one the authors discuss the syndrome of inappropriate antidiuretic hormone secretion (SIADH and hyponatremia occurring with the use of psychotropic drugs (antidepressants, antipsychotics, normotimics, while the second paper discusses research on psychogenic polydipsia. The causes of hyponatremia in patients treated in psychiatric wards include: water intoxication associated with polydipsia, somatic comorbidities, side effect of internal medicine and psychiatric drugs. The most common mechanism leading in these cases to hyponatremia is the syndrome of inappropriate secretion of vasopressin (SIADH. The SIADH syndrome is a group of symptoms, first described in 1967 by Schwartz and Bartter in The American Journal of Medicine, which results from the hypersecretion of antidiuretic hormone, also called vasopressin, which causes patients to develop normovolemic hyponatremia. The phenomenon of drug-induced hyponatremia in psychiatric practice is generally observed with the use of antidepressants, antipsychotics and anti-epileptic drugs (used in psychiatry as normotimic drugs.

  13. Solvent exchange-induced in situ forming gel comprising ethyl cellulose-antimicrobial drugs.

    Science.gov (United States)

    Phaechamud, Thawatchai; Mahadlek, Jongjan

    2015-10-15

    Solvent-exchanged in situ forming gel is a drug delivery system which is in sol form before administration. When it contacts with the body fluid, then the water miscible organic solvent dissipates and water penetrates into the system, leading the polymer precipitation as in situ gel at the site of injection. The aim of this research was to study the parameters affecting the gel properties, drug release and antimicrobial activities of the in situ forming gels prepared from ethyl cellulose (EC) dissolved in N-methyl pyrrolidone (NMP) to deliver the antimicrobial agents (doxycycline hyclate, metronidazole and benzyl peroxide) for periodontitis treatment. The gel appearance, pH, viscosity, rheology, syringeability, gel formation, rate of water diffusion into the gels, in vitro degradation, drug release behavior and antimicrobial activities against Staphylococcus aureus, Escherichia coli, Candida albicans, Streptococcus mutans and Porphyrommonas gingivalis were determined. Increasing the amount of EC increased the viscosity of system while still exhibiting Newtonian flow and increased the work of syringeability whereas decreased the releasing of drug. The system transformed into the rigid gel formation after being injected into the simulated gingival crevicular fluid. The developed systems containing 5% w/w antimicrobial agent showed the antimicrobial activities against all test bacteria. Thus the developed solvent exchange-induced in situ forming gels comprising EC-antimicrobial drugs exhibited potential use for periodontitis treatment. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Binding Mode and Induced Fit Predictions for Prospective Computational Drug Design.

    Science.gov (United States)

    Grebner, Christoph; Iegre, Jessica; Ulander, Johan; Edman, Karl; Hogner, Anders; Tyrchan, Christian

    2016-04-25

    Computer-aided drug design plays an important role in medicinal chemistry to obtain insights into molecular mechanisms and to prioritize design strategies. Although significant improvement has been made in structure based design, it still remains a key challenge to accurately model and predict induced fit mechanisms. Most of the current available techniques either do not provide sufficient protein conformational sampling or are too computationally demanding to fit an industrial setting. The current study presents a systematic and exhaustive investigation of predicting binding modes for a range of systems using PELE (Protein Energy Landscape Exploration), an efficient and fast protein-ligand sampling algorithm. The systems analyzed (cytochrome P, kinase, protease, and nuclear hormone receptor) exhibit different complexities of ligand induced fit mechanisms and protein dynamics. The results are compared with results from classical molecular dynamics simulations and (induced fit) docking. This study shows that ligand induced side chain rearrangements and smaller to medium backbone movements are captured well in PELE. Large secondary structure rearrangements, however, remain challenging for all employed techniques. Relevant binding modes (ligand heavy atom RMSD PELE method within a few hours of simulation, positioning PELE as a tool applicable for rapid drug design cycles.

  15. Drug-induced hypersensitivity syndrome associated with Epstein-Barr virus infection.

    Science.gov (United States)

    Descamps, V; Mahe, E; Houhou, N; Abramowitz, L; Rozenberg, F; Ranger-Rogez, S; Crickx, B

    2003-05-01

    Association of drug-induced hypersensitivity syndrome with viral infection is debated. Human herpesvirus 6 (HHV-6) reactivation has been the most frequently reported infection associated with this syndrome. However, a case of cytomegalovirus (CMV) infection was recently described associated with anticonvulsant-induced hypersensitivity syndrome. We report a case of severe allopurinol-induced hypersensitivity syndrome with pancreatitis associated with Epstein-Barr virus (EBV) infection. Active EBV infection was demonstrated in two consecutive serum samples by the presence of anti-EBV early antigen (EA) IgM antibodies and an increase in anti-EBV EA IgG antibodies, whereas no anti-EBV nuclear antigen IgG antibodies were detected. EBV DNA was detected by polymerase chain reaction (PCR) in peripheral blood mononuclear cells. Reactivation of HHV-6 was suggested only by the presence of anti-HHV-6 IgM antibodies, but HHV-6 DNA was not detected by PCR in the serum. Other viral investigations showed previous infection (CMV, rubella, measles, parvovirus B19), immunization after vaccination (hepatitis B virus), or absence of previous infection (hepatitis C virus, human immunodeficiency virus). We suggest that EBV infection may participate in some cases, as do the other herpesviruses HHV-6 or CMV, in the development of drug-induced hypersensitivity syndrome.

  16. Exposure to reactive intermediate-inducing drugs during pregnancy and the incident use of psychotropic medications among children.

    Science.gov (United States)

    Tran, Yen-Hao; Groen, Henk; Bergman, Jorieke E H; Hak, Eelko; Wilffert, Bob

    2017-03-01

    Our study aimed to investigate the association between prenatal exposure to reactive intermediate (RI)-inducing drugs and the initiation of psychotropic medications among children. We designed a cohort study using a pharmacy prescription database. Pregnant women were considered exposed when they received a prescription of RI-inducing drugs. These drugs could be either used alone (RI+/FAA-) or combined with drugs exhibiting folic acid antagonism (FAA, RI+/FAA+). The reference group included pregnant women who did not receive any RI-inducing drugs or FAA drugs. We analyzed 4116 exposed and 30 422 reference pregnancies. The hazard ratio (HR) with 95% confidence interval (CI) was 1.27 (95%CI 1.15-1.41) for pregnancies exposed to RI-inducing drugs as a whole. Considering subgroups of RI-inducing drugs, prenatal exposure to both RI+/FAA+ and RI+/FAA- was associated with the children's initiation of psychotropic medications, HRs being 1.35 (95%CI 1.10-1.66) and 1.26 (1.13-1.41), respectively. The HRs were increased with prolonged exposure to RI-inducing drugs, especially in the first and second trimesters. In a detailed examination of the psychotropics, the incidences of receiving antimigraine preparations and psychostimulants were significantly increased for the exposed children, compared with the reference children. The incidences of receiving antipsychotics and hypnotics were also higher for the exposed children; however, the HRs did not reach significance after adjustment. We found a significantly increased incident use of psychotropic medications among children prenatally exposed to RI-inducing drugs, especially during the first and second trimesters. This suggests a detrimental effect during critical periods of brain development. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  17. 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

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

    International Nuclear Information System (INIS)

    Cros, C.; Skinner, M.; Moors, J.; Lainee, P.; Valentin, J.P.

    2012-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Berit eBrogaard

    2013-10-01

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

  20. Intense pseudotransport of a cationic drug mediated by vacuolar ATPase: Procainamide-induced autophagic cell vacuolization

    International Nuclear Information System (INIS)

    Morissette, Guillaume; Lodge, Robert; Marceau, Francois

    2008-01-01

    Cationic drugs frequently exhibit large apparent volumes of distribution, consistent with various forms of cellular sequestration. The contributions of organelles and metabolic processes that may mimic drug transport were defined in human vascular smooth muscle cells. We hypothesized that procainamide-induced vacuolar cytopathology is driven by intense pseudotransport mediated by the vacuolar (V)-ATPase and pursued the characterization of vesicular trafficking alterations in this model. Large amounts of procainamide were taken up by intact cells (maximal in 2 h, reversible upon washout, apparent K M 4.69 mM; fluorometric determination of cell-associated drug). Procainamide uptake was extensively prevented or reversed by pharmacological inhibition of the V-ATPase with bafilomycin A1 or FR 167356, decreased at low extracellular pH and preceded vacuolar cell morphology. However, the uptake of procainamide was unaffected by mitochondrial poisons that reduced the uptake of rhodamine 6G. Large vacuoles induced by millimolar procainamide were labeled with the late endosome/lysosome markers Rab7 and CD63 and the autophagy effector LC3; their osmotic formation (but not procainamide uptake) was reduced by extracellular mannitol and parallel to LC3 II formation. Procainamide-induced vacuolization is associated with defective endocytosis of fluorophore-labeled bovine serum albumin, but not with induction of the unfolded protein response. The contents of a vacuole subset slowly (≥ 24 h) become positive for Nile red staining (phospholipidosis-like response). V-ATPase-driven ion trapping is a form of intense cation pseudotransport that concerns the uncharged form of the drugs, and is associated with a vacuolar, autophagic and evolutive cytopathology and profound effects on vesicular trafficking

  1. Inorganic Profiling of Amoxicillin Drugs in Ghana Using Proton Induced X-Ray Emission (Pixe) Analysis

    International Nuclear Information System (INIS)

    Abdul-Wahab, Zurika

    2017-07-01

    Induced X-ray Emission (PIXE) analysis of the amoxicillin standard reference material revealed ten (10 ) elements which include Al, S, K, Ca, V, Cr, Mn, Fe, Ni, and Zn. Sulphur was identified as the major element in the standard reference material and recorded concentration value of 396,805 ppm. Samples from Kwame Nkrumah Circle, a locally manufactured brand recorded the lowest sulphur concentrations of 251,745 ppm, compared to all drugs analysed using PIXE; imported amoxicillin (395,753 ppm) and Okaishi locally manufactured (384,710 ppm). Additionally, the elements Cr, Mn and Fe were found to be relatively higher in the Kwame Nkrumah Circle sample hence raising concerns over the quality of the Kwame Nkrumah Circle brand. When a physical parameter test was performed on all samples, all brands with the exception of Kwame Nkrumah Circle passed the disintegration and dissolution test deeming the Kwame Nkrumah Circle brand substandard. After an HPLC test was performed for all samples, it was discovered that all the drugs analysed passed the acceptance criteria (90-120%) for drugs set by the British Pharmacopoeia; with the Kwame Nkrumah Circle brand recording a value of 97% relatively lower than all the other samples which range from 113 to 117%. Sulphur as an active principle ingredient was correlated with the other identified elements. Strong correlations with correlation coefficients within the range 0.9936 – 0.9978 were found with the elements Cr, Mn, and Fe. Hence the elements S, Cr, Mn, and Fe lend themselves as element signature for amoxicillin medical drug. This was done to discover element signatures that will facilitate differentiating between genuine and counterfeit amoxicillin drugs. Considering the simplicity in sample preparation, the non-distractive nature of PIXE analysis, and also fast turn out in producing results. PIXE offers a considerable advantage when analysing antibiotic drugs on a large scale. (author)

  2. Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis

    Directory of Open Access Journals (Sweden)

    Andrea Iorga

    2017-05-01

    Full Text Available Drug-induced liver injury (DILI can broadly be divided into predictable and dose dependent such as acetaminophen (APAP and unpredictable or idiosyncratic DILI (IDILI. Liver injury from drug hepatotoxicity (whether idiosyncratic or predictable results in hepatocyte cell death and inflammation. The cascade of events leading to DILI and the cell death subroutine (apoptosis or necrosis of the cell depend largely on the culprit drug. Direct toxins to hepatocytes likely induce oxidative organelle stress (such as endoplasmic reticulum (ER and mitochondrial stress leading to necrosis or apoptosis, while cell death in idiosyncratic DILI (IDILI is usually the result of engagement of the innate and adaptive immune system (likely apoptotic, involving death receptors (DR. Here, we review the hepatocyte cell death pathways both in direct hepatotoxicity such as in APAP DILI as well as in IDILI. We examine the known signaling pathways in APAP toxicity, a model of necrotic liver cell death. We also explore what is known about the genetic basis of IDILI and the molecular pathways leading to immune activation and how these events can trigger hepatotoxicity and cell death.

  3. NMDA Receptors on Dopaminoceptive Neurons Are Essential for Drug-Induced Conditioned Place Preference.

    Science.gov (United States)

    Sikora, Magdalena; Tokarski, Krzysztof; Bobula, Bartosz; Zajdel, Joanna; Jastrzębska, Kamila; Cieślak, Przemysław Eligiusz; Zygmunt, Magdalena; Sowa, Joanna; Smutek, Magdalena; Kamińska, Katarzyna; Gołembiowska, Krystyna; Engblom, David; Hess, Grzegorz; Przewlocki, Ryszard; Rodriguez Parkitna, Jan

    2016-01-01

    Plasticity of the brain's dopamine system plays a crucial role in adaptive behavior by regulating appetitive motivation and the control of reinforcement learning. In this study, we investigated drug- and natural-reward conditioned behaviors in a mouse model in which the NMDA receptor-dependent plasticity of dopaminoceptive neurons was disrupted. We generated a transgenic mouse line with inducible selective inactivation of the NR1 subunit in neurons expressing dopamine D1 receptors (the NR1(D1CreERT2) mice). Whole-cell recordings of spontaneous EPSCs on neurons in the nucleus accumbens confirmed that a population of neurons lacked the NMDA receptor-dependent component of the current. This effect was accompanied by impaired long-term potentiation in the nucleus accumbens and in the CA1 area of the ventral, but not the dorsal, hippocampus. Mutant mice did not differ from control animals when tested for pavlovian or instrumental conditioning. However, NR1(D1CreERT2) mice acquired no preference for a context associated with administration of drugs of abuse. In the conditioned place preference paradigm, mutant mice did not spend more time in the context paired with cocaine, morphine, or ethanol, although these mice acquired a preference for sucrose jelly and an aversion to naloxone injections, as normal. Thus, we observed that the selective inducible ablation of the NMDA receptors specifically blocks drug-associated context memory with no effect on positive reinforcement in general.

  4. NMDA Receptors on Dopaminoceptive Neurons Are Essential for Drug-Induced Conditioned Place Preference123

    Science.gov (United States)

    Tokarski, Krzysztof; Bobula, Bartosz; Zygmunt, Magdalena; Smutek, Magdalena; Kamińska, Katarzyna; Gołembiowska, Krystyna; Hess, Grzegorz; Przewlocki, Ryszard

    2016-01-01

    Abstract Plasticity of the brain’s dopamine system plays a crucial role in adaptive behavior by regulating appetitive motivation and the control of reinforcement learning. In this study, we investigated drug- and natural-reward conditioned behaviors in a mouse model in which the NMDA receptor-dependent plasticity of dopaminoceptive neurons was disrupted. We generated a transgenic mouse line with inducible selective inactivation of the NR1 subunit in neurons expressing dopamine D1 receptors (the NR1D1CreERT2 mice). Whole-cell recordings of spontaneous EPSCs on neurons in the nucleus accumbens confirmed that a population of neurons lacked the NMDA receptor-dependent component of the current. This effect was accompanied by impaired long-term potentiation in the nucleus accumbens and in the CA1 area of the ventral, but not the dorsal, hippocampus. Mutant mice did not differ from control animals when tested for pavlovian or instrumental conditioning. However, NR1D1CreERT2 mice acquired no preference for a context associated with administration of drugs of abuse. In the conditioned place preference paradigm, mutant mice did not spend more time in the context paired with cocaine, morphine, or ethanol, although these mice acquired a preference for sucrose jelly and an aversion to naloxone injections, as normal. Thus, we observed that the selective inducible ablation of the NMDA receptors specifically blocks drug-associated context memory with no effect on positive reinforcement in general. PMID:27294197

  5. [Correction of bronchial obstructive syndrome and antituberculous drugs-induced eosinophilia in patients with pulmonary tuberculosis by using plasmapheresis].

    Science.gov (United States)

    Shmelev, E I; Stepanian, I E

    1996-01-01

    The paper provides the results of a follow-up of 70 patients with active pulmonary tuberculosis in whom the administration of antituberculous drugs induced eosinophilia and bronchial obstructive syndrome. To eliminate the side effects of antituberculous therapy, a plasmapheresis regimen was performed in 44 patients, the remaining patients were given only bronchodilators and antihistamine drugs. Plasmapheresis as a means for correcting drug-induced eosinophilia and bronchial obstructive syndrome was found to be more effective than drug therapy and, in some cases, enabled antituberculous therapy to be continued, without changing a combination of drugs. It is recommended that plasmapheresis should be used in cases of inadequate efficiency of conventional methods for correcting drug intolerance.

  6. L1000FWD: Fireworks visualization of drug-induced transcriptomic signatures.

    Science.gov (United States)

    Wang, Zichen; Lachmann, Alexander; Keenan, Alexandra B; Ma'ayan, Avi

    2018-02-06

    As part of the NIH Library of Integrated Network-based Cellular Signatures (LINCS) program, hundreds of thousands of transcriptomic signatures were generated with the L1000 technology, profiling the response of human cell lines to over 20,000 small molecule compounds. This effort is a promising approach toward revealing the mechanisms-of-action (MOA) for marketed drugs and other less studied potential therapeutic compounds. L1000 fireworks display (L1000FWD) is a web application that provides interactive visualization of over 16,000 drug and small-molecule induced gene expression signatures. L1000FWD enables coloring of signatures by different attributes such as cell type, time point, concentration, as well as drug attributes such as MOA and clinical phase. Signature similarity search is implemented to enable the search for mimicking or opposing signatures given as input of up and down gene sets. Each point on the L1000FWD interactive map is linked to a signature landing page, which provides multifaceted knowledge from various sources about the signature and the drug. Notably such information includes most frequent diagnoses, co-prescribed drugs and age distribution of prescriptions as extracted from the Mount Sinai Health System electronic medical records (EMR). Overall, L1000FWD serves as a platform for identifying functions for novel small molecules using unsupervised clustering, as well as for exploring drug MOA. L1000FWD is freely accessible at: http://amp.pharm.mssm.edu/L1000FWD. avi.maayan@mssm.edu. Supplementary data are available at Bioinformatics online. © The Author (2018). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  7. Use of Fall-Risk Inducing Drugs in Patients Using Anti-Parkinson Drugs (APD: A Swedish Register-Based Study.

    Directory of Open Access Journals (Sweden)

    Ylva Haasum

    Full Text Available Many drugs increase the risk of falls in old age. Although persons with Parkinson's disease (PD are at increased risk of experiencing falls and fractures, the use of fall-risk inducing drugs (FRIDs in this population has not previously been investigated. The objective of this study was to investigate the burden of use of FRIDs in older persons treated with anti-Parkinson drugs (APD; used as a proxy for PD, compared to persons without APD.We analyzed individual data on age, sex, type of housing and drug use in 1 346 709 persons aged ≥ 65 years in the Swedish Prescribed Drug Register on the date of 30 September 2008. Main outcome measure was the use of FRIDs.FRIDs were used by 79% of persons with APD and 75% of persons without APD. Persons with APD were more likely to use ≥ 1 FRIDs compared to persons without APD (adjusted OR: 1.09; 95% CI: 1.06-1-12. The association was stronger for concomitant use of ≥ 5 FRIDS (adjusted OR: 1.49; 95% CI: 1.44-1.55.The high use of FRIDs among persons with APD indicates that these patients may be at increased risk of drug-induced falls. Further studies are needed to investigate how these drugs affect the risk of falling in persons with PD.

  8. Drug-induced GABA transporter currents enhance GABA release to induce opioid withdrawal behaviors.

    Science.gov (United States)

    Bagley, Elena E; Hacker, Jennifer; Chefer, Vladimir I; Mallet, Christophe; McNally, Gavan P; Chieng, Billy C H; Perroud, Julie; Shippenberg, Toni S; Christie, MacDonald J

    2011-10-30

    Neurotransmitter transporters can affect neuronal excitability indirectly via modulation of neurotransmitter concentrations or directly via transporter currents. A physiological or pathophysiological role for transporter currents has not been described. We found that GABA transporter 1 (GAT-1) cation currents directly increased GABAergic neuronal excitability and synaptic GABA release in the periaqueductal gray (PAG) during opioid withdrawal in rodents. In contrast, GAT-1 did not indirectly alter GABA receptor responses via modulation of extracellular GABA concentrations. Notably, we found that GAT-1-induced increases in GABAergic activity contributed to many PAG-mediated signs of opioid withdrawal. Together, these data support the hypothesis that GAT-1 activity directly produces opioid withdrawal signs through direct hyperexcitation of GABAergic PAG neurons and nerve terminals, which presumably enhances GABAergic inhibition of PAG output neurons. These data provide, to the best of our knowledge, the first evidence that dysregulation of a neurotransmitter transporter current is important for the maladaptive plasticity that underlies opiate withdrawal.

  9. Prediction of phospholipidosis-inducing potential of drugs by in vitro biochemical and physicochemical assays followed by multivariate analysis.

    Science.gov (United States)

    Kuroda, Yukihiro; Saito, Madoka

    2010-03-01

    An in vitro method to predict phospholipidosis-inducing potential of cationic amphiphilic drugs (CADs) was developed using biochemical and physicochemical assays. The following parameters were applied to principal component analysis, as well as physicochemical parameters: pK(a) and clogP; dissociation constant of CADs from phospholipid, inhibition of enzymatic phospholipid degradation, and metabolic stability of CADs. In the score plot, phospholipidosis-inducing drugs (amiodarone, propranolol, imipramine, chloroquine) were plotted locally forming the subspace for positive CADs; while non-inducing drugs (chlorpromazine, chloramphenicol, disopyramide, lidocaine) were placed scattering out of the subspace, allowing a clear discrimination between both classes of CADs. CADs that often produce false results by conventional physicochemical or cell-based assay methods were accurately determined by our method. Basic and lipophilic disopyramide could be accurately predicted as a nonphospholipidogenic drug. Moreover, chlorpromazine, which is often falsely predicted as a phospholipidosis-inducing drug by in vitro methods, could be accurately determined. Because this method uses the pharmacokinetic parameters pK(a), clogP, and metabolic stability, which are usually obtained in the early stages of drug development, the method newly requires only the two parameters, binding to phospholipid, and inhibition of lipid degradation enzyme. Therefore, this method provides a cost-effective approach to predict phospholipidosis-inducing potential of a drug. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

  10. Drug-induced chest pain and myocardial infarction. Reports to a national centre and review of the literature

    NARCIS (Netherlands)

    J.P. Ottervanger (Jan Paul); J.H.P. Wilson (Paul); B.H.Ch. Stricker (Bruno)

    1997-01-01

    textabstractObjectives: To analyse reports of drug-induced myocardial infarction and chest pain sent to a national reporting centre. To review which drugs were suspected of exhibiting these adverse events and what mechanisms were involved. Methods: During the 20-year period 1975 through 1994, a

  11. Common Variation in the NOS1AP Gene Is Associated With Drug-Induced QT Prolongation and Ventricular Arrhythmia

    NARCIS (Netherlands)

    Jamshidi, Yalda; Nolte, Ilja M.; Dalageorgou, Chrysoula; Zheng, Dongling; Johnson, Toby; Bastiaenen, Rachel; Ruddy, Suzanne; Talbott, Daniel; Norris, Kris J.; Snieder, Harold; George, Alfred L.; Marshall, Vanessa; Shakir, Saad; Kannankeril, Prince J.; Munroe, Patricia B.; Camm, A. John; Jeffery, Steve; Roden, Dan M.; Behr, Elijah R.

    2012-01-01

    Objectives This study sought to determine whether variations in NOS1AP affect drug-induced long QT syndrome (LQTS). Background Use of antiarrhythmic drugs is limited by the high incidence of serious adverse events including QT prolongation and torsades de pointes. NOS1AP gene variants play a role in

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

    International Nuclear Information System (INIS)

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

    2010-01-01

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

  13. Induced pluripotent stem cell-derived cardiomyocytes for cardiovascular disease modeling and drug screening.

    Science.gov (United States)

    Sharma, Arun; Wu, Joseph C; Wu, Sean M

    2013-12-24

    Human induced pluripotent stem cells (hiPSCs) have emerged as a novel tool for drug discovery and therapy in cardiovascular medicine. hiPSCs are functionally similar to human embryonic stem cells (hESCs) and can be derived autologously without the ethical challenges associated with hESCs. Given the limited regenerative capacity of the human heart following myocardial injury, cardiomyocytes derived from hiPSCs (hiPSC-CMs) have garnered significant attention from basic and translational scientists as a promising cell source for replacement therapy. However, ongoing issues such as cell immaturity, scale of production, inter-line variability, and cell purity will need to be resolved before human clinical trials can begin. Meanwhile, the use of hiPSCs to explore cellular mechanisms of cardiovascular diseases in vitro has proven to be extremely valuable. For example, hiPSC-CMs have been shown to recapitulate disease phenotypes from patients with monogenic cardiovascular disorders. Furthermore, patient-derived hiPSC-CMs are now providing new insights regarding drug efficacy and toxicity. This review will highlight recent advances in utilizing hiPSC-CMs for cardiac disease modeling in vitro and as a platform for drug validation. The advantages and disadvantages of using hiPSC-CMs for drug screening purposes will be explored as well.

  14. Multimode drug inducible CRISPR/Cas9 devices for transcriptional activation and genome editing

    Science.gov (United States)

    Lu, Jia; Zhao, Chen; Zhao, Yingze; Zhang, Jingfang; Zhang, Yue; Chen, Li; Han, Qiyuan; Ying, Yue; Peng, Shuai; Ai, Runna; Wang, Yu

    2018-01-01

    Abstract Precise investigation and manipulation of dynamic biological processes often requires molecular modulation in a controlled inducible manner. The clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) has emerged as a versatile tool for targeted gene editing and transcriptional programming. Here, we designed and vigorously optimized a series of Hybrid drug Inducible CRISPR/Cas9 Technologies (HIT) for transcriptional activation by grafting a mutated human estrogen receptor (ERT2) to multiple CRISPR/Cas9 systems, which renders them 4-hydroxytamoxifen (4-OHT) inducible for the access of genome. Further, extra functionality of simultaneous genome editing was achieved with one device we named HIT2. Optimized terminal devices herein delivered advantageous performances in comparison with several existing designs. They exerted selective, titratable, rapid and reversible response to drug induction. In addition, these designs were successfully adapted to an orthogonal Cas9. HIT systems developed in this study can be applied for controlled modulation of potentially any genomic loci in multiple modes. PMID:29237052

  15. Gemfibrozil, a Lipid-lowering Drug, Induces Suppressor of Cytokine Signaling 3 in Glial Cells

    Science.gov (United States)

    Ghosh, Arunava; Pahan, Kalipada

    2012-01-01

    Glial inflammation is an important feature of several neurodegenerative disorders. Suppressor of cytokine signaling (SOCS) proteins play a crucial role in inhibiting cytokine signaling and inflammatory gene expression in various cell types, including glial cells. However, mechanisms by which SOCS genes could be up-regulated are poorly understood. This study underlines the importance of gemfibrozil, a Food and Drug Administration-approved lipid-lowering drug, in up-regulating the expression of SOCS3 in glial cells. Gemfibrozil increased the expression of Socs3 mRNA and protein in mouse astroglia and microglia in both a time- and dose-dependent manner. Interestingly, gemfibrozil induced the activation of type IA phosphatidylinositol (PI) 3-kinase and AKT. Accordingly, inhibition of PI 3-kinase and AKT by chemical inhibitors abrogated gemfibrozil-mediated up-regulation of SOCS3. Furthermore, we demonstrated that gemfibrozil induced the activation of Krüppel-like factor 4 (KLF4) via the PI 3-kinase-AKT pathway and that siRNA knockdown of KLF4 abrogated gemfibrozil-mediated up-regulation of SOCS3. Gemfibrozil also induced the recruitment of KLF4 to the distal, but not proximal, KLF4-binding site of the Socs3 promoter. This study delineates a novel property of gemfibrozil in up-regulating SOCS3 in glial cells via PI 3-kinase-AKT-mediated activation of KLF4 and suggests that gemfibrozil may find therapeutic application in neuroinflammatory and neurodegenerative disorders. PMID:22685291

  16. Influence of dietary iodine on drug-induced hypothyrodism in the rat.

    Science.gov (United States)

    Beyssen, M L; Lagorce, J F; Cledat, D; Buxeraud, J

    1999-06-01

    Several compounds of pharmaceutical importance from a variety of chemical families, for example chlorpromazine and clomipramine, have been found to form charge-transfer complexes with iodine. We have investigated the influence of dietary iodine on thyroid-gland dysfunction induced by clomipramine, chlorpromazine or 2-thiazoline-2-thiol. We suggest that iodine is partly diverted from its metabolic pathway by complexation with drugs, and so the urinary concentration of iodide is increased. Both chlorpromazine and clomipramine, at doses which do not inhibit thyroperoxidase, enhanced urinary iodine excretion when dietary iodine was restricted (3.944+/-0.96 microg/day for chlorpromazine-tested rats, 3.43+/-1.33 microg/day for clomipramine-tested rats, compared with 2.34+/-0.11 microg/day in control rats). Concurrently, these pharmaceutical compounds increased the level of free thyroid-stimulating hormone (TSH) in comparison with controls and induced histological modifications in, and enlargement of, the thyroid gland. We have demonstrated that drug-induced loss of iodine in the urine was associated with antithyroid action when iodine intake was limited.

  17. [Trends in drug-induced liver injury based on reports of adverse reactions to PMDA in Japan].

    Science.gov (United States)

    Sudo, Chie; Maekawa, Keiko; Segawa, Katsunori; Hanatani, Tadaaki; Sai, Kimie; Saito, Yoshiro

    2012-01-01

    Reports on drug-related adverse reactions from manufacturing/distributing pharmaceutical companies or medical institutions/pharmacies are regulated under the Pharmaceutical Affairs Law of Japan, and this system is important for post-marketing safety measures. Although association between the medicine and the adverse event has not been clearly evaluated, and an incidence may be redundantly reported, this information would be useful to roughly grasp the current status of drug-related adverse reactions. In the present study, we analyzed the incidence of drug-induced liver injury by screening the open-source data publicized by the homepage of Pharmaceutical and Medical Devices Agency from 2005 to 2011 fiscal years. Major drug-classes suspected to cause general drug-induced liver injury were antineoplastics, anti-inflammatory agents/common cold drugs, chemotherapeutics including antituberculous drugs, antidiabetics, antiulcers and antiepileptics. In addition, reported cases for fulminant hepatitis were also summarized. We found that antituberculous isoniazid and antineoplastic tegafur-uracil were the top two suspected drugs. These results might deepen understanding of current situations for the drug-induced liver injury in Japan.

  18. Successful Treatment of Antiepileptic Drug-Induced DRESS Syndrome with Pulse Methylprednisolone

    Directory of Open Access Journals (Sweden)

    Celebi Kocaoglu

    2013-01-01

    Full Text Available Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome is a rare but potentially life-threatening syndrome characterized by skin rash, fever, lymph node enlargement, and involvement of internal organs. It is most commonly induced by aromatic anticonvulsants and antibiotics. Nonaromatic anticonvulsants are rarely encountered as the causes of DRESS syndrome. In the present report, three discrete cases with DRESS syndrome developing due to three antiepileptic drugs, including valproic acid (nonaromatic, carbamazepine (aromatic, and lamotrigine (aromatic, and their treatment modalities were aimed to be discussed in light of the literature. To the best of our knowledge, our cases are the first children to be treated with pulse methylprednisolone in the literature.

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

    Directory of Open Access Journals (Sweden)

    Paul H. Hayashi

    2016-02-01

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

  20. The Ayurvedic drug, Ksheerabala, ameliorates quinolinic acid-induced oxidative stress in rat brain.

    Science.gov (United States)

    Swathy, S S; Indira, M

    2010-01-01

    One of the mechanisms of neurotoxicity is the induction of oxidative stress. There is hardly any cure for neurotoxicity in modern medicine, whereas many drugs in Ayurveda possess neuroprotective effects; however, there is no scientific validation for these drugs. Ksheerabala is an ayurvedic drug which is used to treat central nervous system disorders, arthritis, and insomnia. The aim of our study was to evaluate the effect of Ksheerabala on quinolinic acid-induced toxicity in rat brain. The optimal dose of Ksheerabala was found from a dose escalation study, wherein it was found that Ksheerabala showed maximum protection against quinolinic acid-induced neurotoxicity at a dose of 15 microL/100 g body weight/day, which was selected for further experiments. Four groups of female albino rats were maintained for 21 days as follows: 1. Control group, 2. Quinolinic acid (55 microg/100 g body weight), 3. Ksheerabala (15 microL/100 g body weight), 4. Ksheerabala (15 microL/100 g body weight) + Quinolinic acid (55 microg/100 g body weight). At the end of the experimental period, levels of lipid peroxidation products, protein carbonyls, and activities of scavenging enzymes were analyzed. The results revealed that quinolinic acid intake caused enhanced lipid and protein peroxidation as evidenced by increased levels of peroxidation products such as malondialdehyde, hydroperoxide, conjugated dienes, and protein carbonyls. On the other hand, the activities of scavenging enzymes such as catalase, superoxide dismutase (SOD), glutathione peroxidase, and glutathione reductase as well as the concentration of glutathione were reduced. On coadminstration of Ksheerabala along with quinolinic acid, the levels of all the biochemical parameters were restored to near-normal levels, indicating the protective effect of the drug. These results were reinforced by histopathological studies.

  1. Drug-induced premature chromosome condensation (PCC) protocols: cytogenetic approaches in mitotic chromosome and interphase chromatin.

    Science.gov (United States)

    Gotoh, Eisuke

    2015-01-01

    Chromosome analysis is a fundamental technique which is used in wide areas of cytogenetic study including karyotyping species, hereditary diseases diagnosis, or chromosome biology study. Chromosomes are usually prepared from mitotic cells arrested by colcemid block protocol. However, obtaining mitotic chromosomes is often hampered under several circumstances. As a result, cytogenetic analysis will be sometimes difficult or even impossible in such cases. Premature chromosome condensation (PCC) (see Note 1) is an alternative method that has proved to be a unique and useful way in chromosome analysis. Former, PCC has been achieved following cell fusion method (cell-fusion PCC) mediated either by fusogenic viruses (e.g., Sendai virus) or cell fusion chemicals (e.g., polyethylene glycol), but the cell fusion PCC has several drawbacks. The novel drug-induced PCC using protein phosphatase inhibitors was introduced about 20 years ago. This method is much simpler and easier even than the conventional mitotic chromosome preparation protocol use with colcemid block and furthermore obtained PCC index (equivalent to mitotic index for metaphase chromosome) is usually much higher than colcemid block method. Moreover, this method allows the interphase chromatin to be condensed to visualize like mitotic chromosomes. Therefore drug-induced PCC has opened the way for chromosome analysis not only in metaphase chromosomes but also in interphase chromatin. The drug-induced PCC has thus proven the usefulness in cytogenetics and other cell biology fields. For this second edition version, updated modifications/changes are supplemented in Subheadings 2, 3, and 4, and a new section describing the application of PCC in chromosome science fields is added with citation of updated references.

  2. Subtoxic Alterations in Hepatocyte-Derived Exosomes: An Early Step in Drug-Induced Liver Injury?

    Science.gov (United States)

    Holman, Natalie S; Mosedale, Merrie; Wolf, Kristina K; LeCluyse, Edward L; Watkins, Paul B

    2016-06-01

    Drug-induced liver injury (DILI) is a significant clinical and economic problem in the United States, yet the mechanisms that underlie DILI remain poorly understood. Recent evidence suggests that signaling molecules released by stressed hepatocytes can trigger immune responses that may be common across DILI mechanisms. Extracellular vesicles released by hepatocytes, principally hepatocyte-derived exosomes (HDEs), may constitute one such signal. To examine HDE alterations as a function of drug-induced stress, this work utilized prototypical hepatotoxicant acetaminophen (APAP) in male Sprague-Dawley (SD) rats, SD rat hepatocytes, and primary human hepatocytes. HDE were isolated using ExoQuick precipitation reagent and analyzed by quantification of the liver-specific RNAs albumin and microRNA-122 (miR-122). In vivo, significant elevations in circulating exosomal albumin mRNA were observed at subtoxic APAP exposures. Significant increases in exosomal albumin mRNA were also observed in primary rat hepatocytes at subtoxic APAP concentrations. In primary human hepatocytes, APAP elicited increases in both exosomal albumin mRNA and exosomal miR-122 without overt cytotoxicity. However, the number of HDE produced in vitro in response to APAP did not increase with exosomal RNA quantity. We conclude that significant drug-induced alterations in the liver-specific RNA content of HDE occur at subtoxic APAP exposures in vivo and in vitro, and that these changes appear to reflect selective packaging rather than changes in exosome number. The current findings demonstrate that translationally relevant HDE alterations occur in the absence of overt hepatocellular toxicity, and support the hypothesis that HDE released by stressed hepatocytes may mediate early immune responses in DILI. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  3. Tryptamine-Gallic Acid Hybrid Prevents Non-steroidal Anti-inflammatory Drug-induced Gastropathy

    Science.gov (United States)

    Pal, Chinmay; Bindu, Samik; Dey, Sumanta; Alam, Athar; Goyal, Manish; Iqbal, Mohd. Shameel; Sarkar, Souvik; Kumar, Rahul; Halder, Kamal Krishna; Debnath, Mita Chatterjee; Adhikari, Susanta; Bandyopadhyay, Uday

    2012-01-01

    We have investigated the gastroprotective effect of SEGA (3a), a newly synthesized tryptamine-gallic acid hybrid molecule against non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy with mechanistic details. SEGA (3a) prevents indomethacin (NSAID)-induced mitochondrial oxidative stress (MOS) and dysfunctions in gastric mucosal cells, which play a pathogenic role in inducing gastropathy. SEGA (3a) offers this mitoprotective effect by scavenging of mitochondrial superoxide anion (O2˙̄) and intramitochondrial free iron released as a result of MOS. SEGA (3a) in vivo blocks indomethacin-mediated MOS, as is evident from the inhibition of indomethacin-induced mitochondrial protein carbonyl formation, lipid peroxidation, and thiol depletion. SEGA (3a) corrects indomethacin-mediated mitochondrial dysfunction in vivo by restoring defective electron transport chain function, collapse of transmembrane potential, and loss of dehydrogenase activity. SEGA (3a) not only corrects mitochondrial dysfunction but also inhibits the activation of the mitochondrial pathway of apoptosis by indomethacin. SEGA (3a) inhibits indomethacin-induced down-regulation of bcl-2 and up-regulation of bax genes in gastric mucosa. SEGA (3a) also inhibits indometacin-induced activation of caspase-9 and caspase-3 in gastric mucosa. Besides the gastroprotective effect against NSAID, SEGA (3a) also expedites the healing of already damaged gastric mucosa. Radiolabeled (99mTc-labeled SEGA (3a)) tracer studies confirm that SEGA (3a) enters into mitochondria of gastric mucosal cell in vivo, and it is quite stable in serum. Thus, SEGA (3a) bears an immense potential to be a novel gastroprotective agent against NSAID-induced gastropathy. PMID:22157011

  4. [Diffuse large B-cell lymphoma complicated with drug-induced vasculitis during administration of pegfilgrastim].

    Science.gov (United States)

    Ito, Yuta; Noda, Kentaro; Aiba, Keisuke; Yano, Shingo; Fujii, Tsunehiro

    A 59-year-old female with diffuse large B-cell lymphoma was treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimen. In addition, we administered pegfilgrastim for treating chemotherapy-induced febrile neutropenia. She complained of fever and neck and chest pain a few days after pegfilgrastim administration during the third and fourth courses of R-CHOP. Radiological imaging revealed an inflammation of large vessels, which led to the diagnosis of drug-associated vasculitis. We confirmed that vasculitis observed in this case was caused by pegfilgrastim administration because similar symptoms appeared with both injections of pegfilgrastim.

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

    Science.gov (United States)

    Benoist, L B L; de Vries, N

    2015-09-01

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

  6. Sex-related differences in cadmium-induced alteration of drug action in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Schnell, R.C.; Pence, D.H.; Prosser, T.D.; Miya, T.S.

    1976-01-01

    Three days after pretreatment of rats of both sexes with cadmium (2 mg/kg, i.p.), the duration of hypnosis induced by hexobarbital (75 mg/kg, i.p.) was potentiated in males but not females. Likewise, similar treatment with cadmium leads to significant inhibition of the metabolism of hexobarbital by hepatic microsomal enzymes obtained from male but not female animals. These data suggest that there is a sex-related difference in the ability of cadmium to alter drug action in rats.

  7. Drug-Induced Liver Injury Associated with Complementary and Alternative Medicines

    Science.gov (United States)

    Takahashi, Koji; Kanda, Tatsuo; Yasui, Shin; Haga, Yuki; Kumagai, Junichiro; Sasaki, Reina; Wu, Shuang; Nakamoto, Shingo; Nakamura, Masato; Arai, Makoto; Yokosuka, Osamu

    2016-01-01

    A 24-year-old man was admitted due to acute hepatitis with unknown etiology. After his condition and laboratory data gradually improved with conservative therapy, he was discharged 1 month later. Two months after his discharge, however, liver dysfunction reappeared. After his mother accidentally revealed that he took complementary and alternative medicine, discontinuation of the therapy caused his condition to improve. Finally, he was diagnosed with a recurrent drug-induced liver injury associated with Japanese complementary and alternative medicine. It is important to take the medical history in detail and consider complementary and alternative medicine as a cause of liver disease. PMID:28100990

  8. Okadaic acid for radiation dose estimation using drug-induced premature chromosome condensation

    International Nuclear Information System (INIS)

    Wang Chunyan; Zhang Wei; Su Xu

    2005-01-01

    Objective: To establish simple biological method for high irradiation dose estimation using drug-induced prematurely condensed chromosomes (PCC) aberrations. Methods: Peripheral blood was taken from healthy adults and irradiated by 0, 1, 2, 5, 10, 15, 20 and 25 Gy 60 Co γ-rays. Then the blood samples were cultured for 48 hrs. One hr before the end of culture , okadaic acid was added into culture medium to induce PCC rings, which were counted for each dose point. Results: The yield of PCC rings was increased with the dose of radiation until 20 Gy. Within the range of 1 to 20 Gy, there was a good dose-response relationship between the yield of PCC rings and radiation dose. Conclusion: Compared with the analysis of frequency of dicentrics, the yield of PCC rings could be a good biodosimetry indicator for estimation of high dose irradiation. (authors)

  9. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

    International Nuclear Information System (INIS)

    Henninger, Christian; Huelsenbeck, Johannes; Huelsenbeck, Stefanie; Grösch, Sabine; Schad, Arno; Lackner, Karl J.; Kaina, Bernd; Fritz, Gerhard

    2012-01-01

    Liver is the main detoxifying organ and therefore the target of high concentrations of genotoxic compounds, such as environmental carcinogens and anticancer drugs. Here, we investigated the usefulness of lovastatin, which is nowadays widely used for lipid lowering purpose, as a hepatoprotective drug following the administration of the anthracycline derivative doxorubicin in vivo. To this end, BALB/c mice were exposed to either a single high dose or three consecutive low doses of doxorubicin. Acute and subacute hepatotoxicities were analyzed with or without lovastatin co-treatment. Lovastatin protected the liver against doxorubicin-induced acute pro-inflammatory and pro-fibrotic stress responses as indicated by an attenuated mRNA expression of tumor necrosis factor alpha (TNFα) and connective tissue growth factor (CTGF), respectively. Hepatoprotection by lovastatin was due to a reduced induction of DNA damage following doxorubicin treatment. The statin also mitigated subacute anthracycline-provoked hepatotoxicity as shown on the level of doxorubicin- and epirubicin-stimulated CTGF mRNA expression as well as histopathologically detectable fibrosis and serum concentration of marker enzymes of hepatotoxicity (GPT/GLDH). Kidney damage following doxorubicin exposure was not detectable under our experimental conditions. Moreover, lovastatin showed multiple inhibitory effects on doxorubicin-triggered hepatic expression of genes involved in oxidative stress response, drug transport, DNA repair, cell cycle progression and cell death. Doxorubicin also stimulated the formation of ceramides. Ceramide production, however, was not blocked by lovastatin, indicating that hepatoprotection by lovastatin is independent of the sphingolipid metabolism. Overall, the data show that lovastatin is hepatoprotective following genotoxic stress induced by anthracyclines. Based on the data, we hypothesize that statins might be suitable to lower hepatic injury following anthracycline

  10. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Henninger, Christian [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf (Germany); Huelsenbeck, Johannes; Huelsenbeck, Stefanie [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Grösch, Sabine [Institute of Clinical Pharmacology, Johann Wolfgang Goethe University Frankfurt, Theodor Stern Kai 7, D-60590 Frankfurt/Main (Germany); Schad, Arno [Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Lackner, Karl J. [Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Kaina, Bernd [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Fritz, Gerhard, E-mail: fritz@uni-duesseldorf.de [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf (Germany)

    2012-05-15

    Liver is the main detoxifying organ and therefore the target of high concentrations of genotoxic compounds, such as environmental carcinogens and anticancer drugs. Here, we investigated the usefulness of lovastatin, which is nowadays widely used for lipid lowering purpose, as a hepatoprotective drug following the administration of the anthracycline derivative doxorubicin in vivo. To this end, BALB/c mice were exposed to either a single high dose or three consecutive low doses of doxorubicin. Acute and subacute hepatotoxicities were analyzed with or without lovastatin co-treatment. Lovastatin protected the liver against doxorubicin-induced acute pro-inflammatory and pro-fibrotic stress responses as indicated by an attenuated mRNA expression of tumor necrosis factor alpha (TNFα) and connective tissue growth factor (CTGF), respectively. Hepatoprotection by lovastatin was due to a reduced induction of DNA damage following doxorubicin treatment. The statin also mitigated subacute anthracycline-provoked hepatotoxicity as shown on the level of doxorubicin- and epirubicin-stimulated CTGF mRNA expression as well as histopathologically detectable fibrosis and serum concentration of marker enzymes of hepatotoxicity (GPT/GLDH). Kidney damage following doxorubicin exposure was not detectable under our experimental conditions. Moreover, lovastatin showed multiple inhibitory effects on doxorubicin-triggered hepatic expression of genes involved in oxidative stress response, drug transport, DNA repair, cell cycle progression and cell death. Doxorubicin also stimulated the formation of ceramides. Ceramide production, however, was not blocked by lovastatin, indicating that hepatoprotection by lovastatin is independent of the sphingolipid metabolism. Overall, the data show that lovastatin is hepatoprotective following genotoxic stress induced by anthracyclines. Based on the data, we hypothesize that statins might be suitable to lower hepatic injury following anthracycline

  11. Reversible Lansoprazole-Induced Interstitial Lung Disease Showing Improvement after Drug Cessation

    International Nuclear Information System (INIS)

    Hwang, Kyu Won; Woo, Ok Hee; Yong, Hwan Seok; Shin, Bong Kyung; Shim, Jae Jeong; Kang, Eun Young

    2008-01-01

    Lansoprazole is an acid proton-pump inhibitor that is similar to omeprazole. It is used to treat duodenal or gastric ulcers, H. pylori infection, gastroesophageal reflux disease (GERD) or Zollinger-Ellison syndrome. Common adverse effects of lansoprazole are diarrhea, abdominal pain, skin rash and/or itching. Information from U.S. National Library of Medicine warns that this drug can on rare occasion cause cough or cold-like symptoms. The pathophysiological mechanisms of lansoprazole-related pulmonary symptoms are not yet understood. In particular, there are no known reports regarding lansoprazole-induced interstitial lung diseases. We report here a case of interstitial lung disease (ILD) induced by oral administration of lansoprazole, which showed a pattern of nonspecific interstitial pneumonia (NSIP) as detected from a video-assisted thoracoscopic lung biopsy. We believe that this is the first report of a case of pathologically proven lansoprazole-induced ILD for which a surgical lung biopsy was performed. To the best of our knowledge, this is the first description of DI-ILD caused by lansoprazole. The diagnosis was made by considering the radiological, histopathological and clinical findings, including the close temporal relationship between lansoprazole exposure and symptom severity. Other possible causes were excluded due to a lack of a temporal relationship between the symptoms and work history or prednisolone therapy, and no other history of specific allergen exposure. When there is diffuse interstitial lung disease with an unknown etiology, it is important to remember that drugs can be the cause of pulmonary symptoms and it is crucial to take a careful patient history. If there is a recent history of taking lansoprazole in a patient with clinical and radiological findings of diffuse interstitial lung disease, we recommend stopping the medication to see if there is clinical and radiological improvement. That way, one can avoid using invasive procedures to

  12. Reversible Lansoprazole-Induced Interstitial Lung Disease Showing Improvement after Drug Cessation

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, Kyu Won; Woo, Ok Hee; Yong, Hwan Seok; Shin, Bong Kyung; Shim, Jae Jeong; Kang, Eun Young [College of Medicine, Korea University, Guro Hospital, Seoul (Korea, Republic of)

    2008-04-15

    Lansoprazole is an acid proton-pump inhibitor that is similar to omeprazole. It is used to treat duodenal or gastric ulcers, H. pylori infection, gastroesophageal reflux disease (GERD) or Zollinger-Ellison syndrome. Common adverse effects of lansoprazole are diarrhea, abdominal pain, skin rash and/or itching. Information from U.S. National Library of Medicine warns that this drug can on rare occasion cause cough or cold-like symptoms. The pathophysiological mechanisms of lansoprazole-related pulmonary symptoms are not yet understood. In particular, there are no known reports regarding lansoprazole-induced interstitial lung diseases. We report here a case of interstitial lung disease (ILD) induced by oral administration of lansoprazole, which showed a pattern of nonspecific interstitial pneumonia (NSIP) as detected from a video-assisted thoracoscopic lung biopsy. We believe that this is the first report of a case of pathologically proven lansoprazole-induced ILD for which a surgical lung biopsy was performed. To the best of our knowledge, this is the first description of DI-ILD caused by lansoprazole. The diagnosis was made by considering the radiological, histopathological and clinical findings, including the close temporal relationship between lansoprazole exposure and symptom severity. Other possible causes were excluded due to a lack of a temporal relationship between the symptoms and work history or prednisolone therapy, and no other history of specific allergen exposure. When there is diffuse interstitial lung disease with an unknown etiology, it is important to remember that drugs can be the cause of pulmonary symptoms and it is crucial to take a careful patient history. If there is a recent history of taking lansoprazole in a patient with clinical and radiological findings of diffuse interstitial lung disease, we recommend stopping the medication to see if there is clinical and radiological improvement. That way, one can avoid using invasive procedures to

  13. Pressure ulcers induced by drug administration: A new concept and report of four cases in elderly patients.

    Science.gov (United States)

    Mizokami, Fumihiro; Takahashi, Yoshiko; Hasegawa, Keiko; Hattori, Hideyuki; Nishihara, Keiji; Endo, Hidetoshi; Furuta, Katsunori; Isogai, Zenzo

    2016-04-01

    Drug-induced akinesia is a potential cause of pressure ulcers. However, pressure ulcers that are caused by drug-induced akinesia are not considered an adverse drug reaction (ADR). We propose that drug-induced pressure ulcers (DIPU) are pressure ulcers that are caused by an external force that is experienced after drug administration, and we considered resolution of these ulcers after drug discontinuation to be a supportive finding. In this report, we reviewed the medical records of pressure ulcer cases from a 300-bed hospital. Among 148 patients, four patients with pressure ulcers met the criterion for DIPU. In these cases, the suspected DIPU were related to treatment with olanzapine, fluvoxamine, valproic acid, clotiazepam, triazolam and rilmazafone. These drugs were administrated to manage the patients' behavioral and psychological symptoms that accompanied dementia. The DIPU in these patients were categorized as stage IV according to the National Pressure Ulcer Advisory Panel criteria. Discontinuation of the causal drugs led to significant improvements or complete healing of the pressure ulcers, and the patients subsequently recovered their mobility. Therefore, we propose that DIPU are potential ADR that have been overlooked in clinical practice. Thus, recognition of DIPU as an ADR may be important in preventing and appropriately managing pressure ulcers among elderly patients. © 2015 Japanese Dermatological Association.

  14. ABC gene-ranking for prediction of drug-induced cholestasis in rats

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    Yauheniya Cherkas

    Full Text Available As legacy toxicogenomics databases have become available, improved data mining approaches are now key to extracting and visualizing subtle relationships between toxicants and gene expression. In the present study, a novel “aggregating bundles of clusters” (ABC procedure was applied to separate cholestatic from non-cholestatic drugs and model toxicants in the Johnson & Johnson (Janssen rat liver toxicogenomics database [3]. Drug-induced cholestasis is an important issue, particularly when a new compound enters the market with this liability, with standard preclinical models often mispredicting this toxicity. Three well-characterized cholestasis-responsive genes (Cyp7a1, Mrp3 and Bsep were chosen from a previous in-house Janssen gene expression signature; these three genes show differing, non-redundant responses across the 90+ paradigm compounds in our database. Using the ABC procedure, extraneous contributions were minimized in comparisons of compound gene responses. All genes were assigned weights proportional to their correlations with Cyp7a1, Mrp3 and Bsep, and a resampling technique was used to derive a stable measure of compound similarity. The compounds that were known to be associated with rat cholestasis generally had small values of this measure relative to each other but also had large values of this measure relative to non-cholestatic compounds. Visualization of the data with the ABC-derived signature showed a very tight, essentially identically behaving cluster of robust human cholestatic drugs and experimental cholestatic toxicants (ethinyl estradiol, LPS, ANIT and methylene dianiline, disulfiram, naltrexone, methapyrilene, phenacetin, alpha-methyl dopa, flutamide, the NSAIDs–—indomethacin, flurbiprofen, diclofenac, flufenamic acid, sulindac, and nimesulide, butylated hydroxytoluene, piperonyl butoxide, and bromobenzene, some slightly less active compounds (3′-acetamidofluorene, amsacrine, hydralazine, tannic acid, some

  15. The Efficacy of Dandelion Root Extract in Inducing Apoptosis in Drug-Resistant Human Melanoma Cells

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    S. J. Chatterjee

    2011-01-01

    Full Text Available Notoriously chemoresistant melanoma has become the most prevalent form of cancer for the 25–29 North American age demographic. Standard treatment after early detection involves surgical excision (recurrence is possible, and metastatic melanoma is refractory to immuno-, radio-, and most harmful chemotherapies. Various natural compounds have shown efficacy in killing different cancers, albeit not always specifically. In this study, we show that dandelion root extract (DRE specifically and effectively induces apoptosis in human melanoma cells without inducing toxicity in noncancerous cells. Characteristic apoptotic morphology of nuclear condensation and phosphatidylserine flipping to the outer leaflet of the plasma membrane of A375 human melanoma cells was observed within 48 hours. DRE-induced apoptosis activates caspase-8 in A375 cells early on, demonstrating employment of an extrinsic apoptotic pathway to kill A375 cells. Reactive Oxygen Species (ROS generated from DRE-treated isolated mitochondria indicates that natural compounds in DRE can also directly target mitochondria. Interestingly, the relatively resistant G361 human melanoma cell line responded to DRE when combined with the metabolism interfering antitype II diabetic drug metformin. Therefore, treatment with this common, yet potent extract of natural compounds has proven novel in specifically inducing apoptosis in chemoresistant melanoma, without toxicity to healthy cells.

  16. Sleep loss and acute drug abuse can induce DNA damage in multiple organs of mice.

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    Alvarenga, T A; Ribeiro, D A; Araujo, P; Hirotsu, C; Mazaro-Costa, R; Costa, J L; Battisti, M C; Tufik, S; Andersen, M L

    2011-09-01

    The purpose of the present study was to characterize the genetic damage induced by paradoxical sleep deprivation (PSD) in combination with cocaine or ecstasy (3,4-methylenedioxymethamphetamine; MDMA) in multiple organs of male mice using the single cell gel (comet) assay. C57BL/6J mice were submitted to PSD by the platform technique for 72 hours, followed by drug administration and evaluation of DNA damage in peripheral blood, liver and brain tissues. Cocaine was able to induce genetic damage in the blood, brain and liver cells of sleep-deprived mice at the majority of the doses evaluated. Ecstasy also induced increased DNA migration in peripheral blood cells for all concentrations tested. Analysis of damaged cells by the tail moment data suggests that ecstasy is a genotoxic chemical at the highest concentrations tested, inducing damage in liver or brain cells after sleep deprivation in mice. Taken together, our results suggest that cocaine and ecstasy/MDMA act as potent genotoxins in multiple organs of mice when associated with sleep loss.

  17. [Terbinafine : Drug-induced lupus erythematodes and triggering of psoriatic skin lesions].

    Science.gov (United States)

    Mayser, P

    2016-09-01

    Based on the technical information that oral terbinafine must be used with caution in patients with pre-existing psoriasis or lupus erythematosus, the literature was summarized. Terbinafine belongs to the drugs able to induce subcutaneous lupus erythematosus (SCLE)-with a relatively high risk. The clinical picture of terbinafine-induced SCLE may be highly variable and can also include erythema exsudativum multiforme-like or bullous lesions. Thus, differentiation of terbinafine-induced Stevens-Johnson syndrome or toxic epidermal necrolysis may be difficult. Therefore, terbinafine should be prescribed with caution in patients who show light sensitivity, arthralgias, positive antinuclear antibodies or have a history of SLE or SCLE. Case reports include wide-spread, but mostly nonlife-threatening courses, which did not require systemic therapy with steroids or antimalarials in every case. Terbinafine is also able to induce or to aggravate psoriasis. The latency period seems to be rather short (Terbinafine therefore is not first choice if a systemic therapy with antimycotics is indicated in a patient with psoriasis or psoriatic diathesis. Azole derivatives according to the guidelines may be used as an alternative.

  18. AMPK Activation Prevents and Reverses Drug-Induced Mitochondrial and Hepatocyte Injury by Promoting Mitochondrial Fusion and Function.

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    Sun Woo Sophie Kang

    Full Text Available Mitochondrial damage is the major factor underlying drug-induced liver disease but whether conditions that thwart mitochondrial injury can prevent or reverse drug-induced liver damage is unclear. A key molecule regulating mitochondria quality control is AMP activated kinase (AMPK. When activated, AMPK causes mitochondria to elongate/fuse and proliferate, with mitochondria now producing more ATP and less reactive oxygen species. Autophagy is also triggered, a process capable of removing damaged/defective mitochondria. To explore whether AMPK activation could potentially prevent or reverse the effects of drug-induced mitochondrial and hepatocellular damage, we added an AMPK activator to collagen sandwich cultures of rat and human hepatocytes exposed to the hepatotoxic drugs, acetaminophen or diclofenac. In the absence of AMPK activation, the drugs caused hepatocytes to lose polarized morphology and have significantly decreased ATP levels and viability. At the subcellular level, mitochondria underwent fragmentation and had decreased membrane potential due to decreased expression of the mitochondrial fusion proteins Mfn1, 2 and/or Opa1. Adding AICAR, a specific AMPK activator, at the time of drug exposure prevented and reversed these effects. The mitochondria became highly fused and ATP production increased, and hepatocytes maintained polarized morphology. In exploring the mechanism responsible for this preventive and reversal effect, we found that AMPK activation prevented drug-mediated decreases in Mfn1, 2 and Opa1. AMPK activation also stimulated autophagy/mitophagy, most significantly in acetaminophen-treated cells. These results suggest that activation of AMPK prevents/reverses drug-induced mitochondrial and hepatocellular damage through regulation of mitochondrial fusion and autophagy, making it a potentially valuable approach for treatment of drug-induced liver injury.

  19. AMPK Activation Prevents and Reverses Drug-Induced Mitochondrial and Hepatocyte Injury by Promoting Mitochondrial Fusion and Function

    Science.gov (United States)

    Taniane, Caitlin; Farrell, Geoffrey; Arias, Irwin M.; Lippincott-Schwartz, Jennifer; Fu, Dong

    2016-01-01

    Mitochondrial damage is the major factor underlying drug-induced liver disease but whether conditions that thwart mitochondrial injury can prevent or reverse drug-induced liver damage is unclear. A key molecule regulating mitochondria quality control is AMP activated kinase (AMPK). When activated, AMPK causes mitochondria to elongate/fuse and proliferate, with mitochondria now producing more ATP and less reactive oxygen species. Autophagy is also triggered, a process capable of removing damaged/defective mitochondria. To explore whether AMPK activation could potentially prevent or reverse the effects of drug-induced mitochondrial and hepatocellular damage, we added an AMPK activator to collagen sandwich cultures of rat and human hepatocytes exposed to the hepatotoxic drugs, acetaminophen or diclofenac. In the absence of AMPK activation, the drugs caused hepatocytes to lose polarized morphology and have significantly decreased ATP levels and viability. At the subcellular level, mitochondria underwent fragmentation and had decreased membrane potential due to decreased expression of the mitochondrial fusion proteins Mfn1, 2 and/or Opa1. Adding AICAR, a specific AMPK activator, at the time of drug exposure prevented and reversed these effects. The mitochondria became highly fused and ATP production increased, and hepatocytes maintained polarized morphology. In exploring the mechanism responsible for this preventive and reversal effect, we found that AMPK activation prevented drug-mediated decreases in Mfn1, 2 and Opa1. AMPK activation also stimulated autophagy/mitophagy, most significantly in acetaminophen-treated cells. These results suggest that activation of AMPK prevents/reverses drug-induced mitochondrial and hepatocellular damage through regulation of mitochondrial fusion and autophagy, making it a potentially valuable approach for treatment of drug-induced liver injury. PMID:27792760

  20. MDMA, Methylone, and MDPV: Drug-Induced Brain Hyperthermia and Its Modulation by Activity State and Environment.

    Science.gov (United States)

    Kiyatkin, Eugene A; Ren, Suelynn E

    2017-01-01

    Psychomotor stimulants are frequently used by humans to intensify the subjective experience of different types of social interactions. Since psychomotor stimulants enhance metabolism and increase body temperatures, their use under conditions of physiological activation and in warm humid environments could result in pathological hyperthermia, a life-threatening symptom of acute drug intoxication. Here, we will describe the brain hyperthermic effects of MDMA, MDPV, and methylone, three structurally related recreational drugs commonly used by young adults during raves and other forms of social gatherings. After a short introduction on brain temperature and basic mechanisms underlying its physiological fluctuations, we will consider how MDMA, MDPV, and methylone affect brain and body temperatures in awake freely moving rats. Here, we will discuss the role of drug-induced heat production in the brain due to metabolic brain activation and diminished heat dissipation due to peripheral vasoconstriction as two primary contributors to the hyperthermic effects of these drugs. Then, we will consider how the hyperthermic effects of these drugs are modulated under conditions that model human drug use (social interaction and warm ambient temperature). Since social interaction results in brain and body heat production, coupled with skin vasoconstriction that impairs heat loss to the external environment, these physiological changes interact with drug-induced changes in heat production and loss, resulting in distinct changes in the hyperthermic effects of each tested drug. Finally, we present our recent data, in which we compared the efficacy of different pharmacological strategies for reversing MDMA-induced hyperthermia in both the brain and body. Specifically, we demonstrate increased efficacy of the centrally acting atypical neuroleptic compound clozapine over the peripherally acting vasodilator drug, carvedilol. These data could be important for understanding the potential

  1. Tracking Drug-induced Changes in Receptor Post-internalization Trafficking by Colocalizational Analysis.

    Science.gov (United States)

    Ong, Edmund; Cahill, Catherine

    2015-07-03

    The intracellular trafficking of receptors is a collection of complex and highly controlled processes. Receptor trafficking modulates signaling and overall cell responsiveness to ligands and is, itself, influenced by intra- and extracellular conditions, including ligand-induced signaling. Optimized for use with monolayer-plated cultured cells, but extendable to free-floating tissue slices, this protocol uses immunolabelling and colocalizational analysis to track changes in intracellular receptor trafficking following both chronic/prolonged and acute interventions, including exogenous drug treatment. After drug treatment, cells are double-immunolabelled for the receptor and for markers for the intracellular compartments of interest. Sequential confocal microscopy is then used to capture two-channel photomicrographs of individual cells, which are subjected to computerized colocalizational analysis to yield quantitative colocalization scores. These scores are normalized to permit pooling of independent replicates prior to statistical analysis. Representative photomicrographs may also be processed to generate illustrative figures. Here, we describe a powerful and flexible technique for quantitatively assessing induced receptor trafficking.

  2. Tremor pattern differentiates drug-induced resting tremor from Parkinson disease.

    Science.gov (United States)

    Nisticò, R; Fratto, A; Vescio, B; Arabia, G; Sciacca, G; Morelli, M; Labate, A; Salsone, M; Novellino, F; Nicoletti, A; Petralia, A; Gambardella, A; Zappia, M; Quattrone, A

    2016-04-01

    DAT-SPECT, is a well-established procedure for distinguishing drug-induced parkinsonism from Parkinson's disease (PD). We investigated the usefulness of blink reflex recovery cycle (BRrc) and of electromyographic parameters of resting tremor for the differentiation of patients with drug-induced parkinsonism with resting tremor (rDIP) from those with resting tremor due to PD. This was a cross-sectional study. In 16 patients with rDIP and 18 patients with PD we analysed electrophysiological parameters (amplitude, duration, burst and pattern) of resting tremor. BRrc at interstimulus intervals (ISI) of 100, 150, 200, 300, 400, 500 and 750 msec was also analysed in patients with rDIP, patients with PD and healthy controls. All patients and controls underwent DAT-SPECT. Rest tremor amplitude was higher in PD patients than in rDIP patients (p tremor showed a synchronous pattern in all patients with rDIP, whereas it had an alternating pattern in all PD patients (p tremor can be considered a useful investigation for differentiating rDIP from PD. Copyright © 2016. Published by Elsevier Ltd.

  3. Clinical Features Indicating Nigrostriatal Dopaminergic Degeneration in Drug-Induced Parkinsonism

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    Seung Ha Lee

    2017-01-01

    Full Text Available Objective Patients with drug-induced parkinsonism (DIP may have nigrostriatal dopaminergic degeneration. We studied the clinical features that may indicate nigrostriatal dopaminergic degeneration in patients with DIP. Methods Forty-one DIP patients were classified into normal and abnormal [18F] FP-CIT scan groups. Differences in 32 clinical features and drug withdrawal effects were studied. Results Twenty-eight patients had normal (Group I and 13 patients had abnormal (Group II scans. Eight patients of Group I, but none of Group II, had taken calcium channel blockers (p = 0.040. Three patients of Group I and six of Group II had hyposmia (p = 0.018. After drug withdrawal, Group I showed greater improvement in Unified Parkinson’s Disease Rating Scale total motor scores and subscores for bradykinesia and tremors than Group II. Only hyposmia was an independent factor associated with abnormal scans, but it had suboptimal sensitivity. Conclusion None of the clinical features were practical indicators of nigrostriatal dopaminergic degeneration in patients with DIP.

  4. Prototypical antipsychotic drugs protect hippocampal neuronal cultures against cell death induced by growth medium deprivation

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    Williams Sylvain

    2006-03-01

    Full Text Available Abstract Background Several clinical studies suggested that antipsychotic-based medications could ameliorate cognitive functions impaired in certain schizophrenic patients. Accordingly, we investigated the effects of various dopaminergic receptor antagonists – including atypical antipsychotics that are prescribed for the treatment of schizophrenia – in a model of toxicity using cultured hippocampal neurons, the hippocampus being a region of particular relevance to cognition. Results Hippocampal cell death induced by deprivation of growth medium constituents was strongly blocked by drugs including antipsychotics (10-10-10-6 M that display nM affinities for D2 and/or D4 receptors (clozapine, haloperidol, (±-sulpiride, domperidone, clozapine, risperidone, chlorpromazine, (+-butaclamol and L-741,742. These effects were shared by some caspases inhibitors and were not accompanied by inhibition of reactive oxygen species. In contrast, (--raclopride and remoxipride, two drugs that preferentially bind D2 over D4 receptors were ineffective, as well as the selective D3 receptor antagonist U 99194. Interestingly, (--raclopride (10-6 M was able to block the neuroprotective effect of the atypical antipsychotic clozapine (10-6 M. Conclusion Taken together, these data suggest that D2-like receptors, particularly the D4 subtype, mediate the neuroprotective effects of antipsychotic drugs possibly through a ROS-independent, caspase-dependent mechanism.

  5. Valproic acid-induced hyperammonemic encephalopathy - a potentially fatal adverse drug reaction.

    Science.gov (United States)

    Sousa, Carla

    2013-12-01

    A patient with an early diagnosed epilepsy Valproic acid is one of the most widely used antiepileptic drugs. Hyperammonemic encephalopathy is a rare, but potentially fatal, adverse drug reaction to valproic acid. A patient with an early diagnosed epilepsy, treated with valproic acid, experienced an altered mental state after 10 days of treatment. Valproic acid serum levels were within limits, hepatic function tests were normal but ammonia levels were above the normal range. Valproic acid was stopped and the hyperammonemic encephalopathy was treated with lactulose 15 ml twice daily, metronidazole 250 mg four times daily and L-carnitine 1 g twice daily. Monitoring liver function and ammonia levels should be recommended in patients taking valproic acid. The constraints of the pharmaceutical market had to be taken into consideration and limited the pharmacological options for this patient's treatment. Idiosyncratic symptomatic hyperammonemic encephalopathy is completely reversible, but can induce coma and even death, if not timely detected. Clinical pharmacists can help detecting adverse drug reactions and provide evidence based information for the treatment.

  6. A check valve controlled laser-induced microjet for uniform transdermal drug delivery

    Science.gov (United States)

    Ham, Hwi-chan; Jang, Hun-jae; Yoh, Jack J.

    2017-12-01

    A narrow nozzle ejects a microjet of 150 μm in diameter with a velocity of 140 m/s a by the laser-induced bubble expansion in the designed injector. The pulsed form of the driving force at a period of 10 Hz from the connected Er:YAG laser makes it possible for multiple microjet ejections aimed at delivery of drugs into a skin target. The pulsed actuation of the microjet generation is however susceptible to the air leak which can cause the outside air to enter into the momentarily de-pressurized nozzle, leading to a significant reduction of the microjet speed during the pulsed administering of the drug. In the present study, we designed a ball-check valve injector which is less prone to an unwanted air build up inside the nozzle by controlling the nozzle pressure to remain above ambient pressure at all times. The new device is rigorously compared against the reported performance of the previous injector and has shown to maintain about 97% of the initial microjet speed regardless of the number of shots administered; likewise, the drug penetration depth into a porcine skin is improved to 1.5 to 2.25 times the previously reported penetration depths.

  7. A check valve controlled laser-induced microjet for uniform transdermal drug delivery

    Directory of Open Access Journals (Sweden)

    Hwi-chan Ham

    2017-12-01

    Full Text Available A narrow nozzle ejects a microjet of 150 μm in diameter with a velocity of 140 m/s a by the laser-induced bubble expansion in the designed injector. The pulsed form of the driving force at a period of 10 Hz from the connected Er:YAG laser makes it possible for multiple microjet ejections aimed at delivery of drugs into a skin target. The pulsed actuation of the microjet generation is however susceptible to the air leak which can cause the outside air to enter into the momentarily de-pressurized nozzle, leading to a significant reduction of the microjet speed during the pulsed administering of the drug. In the present study, we designed a ball-check valve injector which is less prone to an unwanted air build up inside the nozzle by controlling the nozzle pressure to remain above ambient pressure at all times. The new device is rigorously compared against the reported performance of the previous injector and has shown to maintain about 97% of the initial microjet speed regardless of the number of shots administered; likewise, the drug penetration depth into a porcine skin is improved to 1.5 to 2.25 times the previously reported penetration depths.

  8. Minoxidil is a potential neuroprotective drug for paclitaxel-induced peripheral neuropathy

    Science.gov (United States)

    Chen, Yi-Fan; Chen, Li-Hsien; Yeh, Yu-Min; Wu, Pei-Ying; Chen, Yih-Fung; Chang, Lian-Yun; Chang, Jang-Yang; Shen, Meng-Ru

    2017-01-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment. No medication has been shown to be effective in the treatment of CIPN. This study aims to integrate the image-based high-content screening, mouse behavior models and mechanistic cell-based assays to discover potential neuroprotective drugs. Among screened compounds, minoxidil showed the most potent neuroprotective effect against paclitaxel, with regard to neurite outgrowth of dorsal root ganglia (DRG). Minoxidil protected mice from thermal insensitivity and alleviated mechanical allodynia in paclitaxel-treated mice. The ultrastructure and quantified G-ratio of myelin integrity of sciatic nerve tissues supported the observations in mouse behavioral tests. The mechanistic study on DRG neurons suggested that minoxidil suppressed neuroinflammation and remodeled the dysregulation of intracellular calcium homeostasis provoked by paclitaxel. Importantly, minoxidil showed a synergistic anti-tumor effect with paclitaxel both in tumor xenograft models of cervical and breast cancer. Interestingly, the quantitative assays on hair length and hair growth both exhibited that minoxidil significantly improved the hair quality after chemotherapy. Since minoxidil is a drug approved by the Food and Drug Administration (FDA), the safety and biocompatibility are well documented. The immediate next step is to launch an early-stage clinical trial intending to prevent CIPN by minoxidil. PMID:28349969

  9. Genetic polymorphisms of N-acetyltransferase 2 & susceptibility to antituberculosis drug-induced hepatotoxicity

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    Surendra K Sharma

    2016-01-01

    Full Text Available Background & objectives: The N-acetyltransferase 2 (NAT2 gene encodes an enzyme which both activates and deactivates arylamine and other drugs and carcinogens. This study was aimed to investigate the role of NAT2 gene polymorphism in anti-tuberculosis drug-induced hepatotoxicity (DIH. Methods: In this prospective study, polymerase chain reaction-restriction fragment length polymorphism results for NAT2 gene were compared between 185 tuberculosis patients who did not develop DIH and 105 tuberculosis patients who developed DIH while on anti-tuberculosis drugs. Results: Frequency of slow-acetylator genotype was commonly encountered and was not significantly different between DIH (82.8% and non-DIH (77.2% patients. However, the genotypic distribution of variant NAT2FNx015/FNx017 amongst slow-acetylator genotypes was significantly higher in DIH (56% group as compared to non-DIH (39% group (odds ratio 2.02; P=0.006. Interpretation & conclusions: The present study demonstrated no association between NAT2 genotype and DIH in the north Indian patients with tuberculosis.

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

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    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.

  11. Drug-loaded nanoparticles induce gene expression in human pluripotent stem cell derivatives

    Science.gov (United States)

    Gajbhiye, Virendra; Escalante, Leah; Chen, Guojun; Laperle, Alex; Zheng, Qifeng; Steyer, Benjamin; Gong, Shaoqin; Saha, Krishanu

    2013-12-01

    Tissue engineering and advanced manufacturing of human stem cells requires a suite of tools to control gene expression spatiotemporally in culture. Inducible gene expression systems offer cell-extrinsic control, typically through addition of small molecules, but small molecule inducers typically contain few functional groups for further chemical modification. Doxycycline (DXC), a potent small molecule inducer of tetracycline (Tet) transgene systems, was conjugated to a hyperbranched dendritic polymer (Boltorn H40) and subsequently reacted with polyethylene glycol (PEG). The resulting PEG-H40-DXC nanoparticle exhibited pH-sensitive drug release behavior and successfully controlled gene expression in stem-cell-derived fibroblasts with a Tet-On system. While free DXC inhibited fibroblast proliferation and matrix metalloproteinase (MMP) activity, PEG-H40-DXC nanoparticles maintained higher fibroblast proliferation levels and MMP activity. The results demonstrate that the PEG-H40-DXC nanoparticle system provides an effective tool to controlling gene expression in human stem cell derivatives.Tissue engineering and advanced manufacturing of human stem cells requires a suite of tools to control gene expression spatiotemporally in culture. Inducible gene expression systems offer cell-extrinsic control, typically through addition of small molecules, but small molecule inducers typically contain few functional groups for further chemical modification. Doxycycline (DXC), a potent small molecule inducer of tetracycline (Tet) transgene systems, was conjugated to a hyperbranched dendritic polymer (Boltorn H40) and subsequently reacted with polyethylene glycol (PEG). The resulting PEG-H40-DXC nanoparticle exhibited pH-sensitive drug release behavior and successfully controlled gene expression in stem-cell-derived fibroblasts with a Tet-On system. While free DXC inhibited fibroblast proliferation and matrix metalloproteinase (MMP) activity, PEG-H40-DXC nanoparticles maintained

  12. Uninterrupted monitoring of drug effects in human-induced pluripotent stem cell-derived cardiomyocytes with bioluminescence Ca2+ microscopy.

    Science.gov (United States)

    Suzuki, Kazushi; Onishi, Takahito; Nakada, Chieko; Takei, Shunsuke; Daniels, Matthew J; Nakano, Masahiro; Matsuda, Tomoki; Nagai, Takeharu

    2018-05-18

    Cardiomyocytes derived from human-induced pluripotent stem cells are a powerful platform for high-throughput drug screening in vitro. However, current modalities for drug testing, such as electrophysiology and fluorescence imaging have inherent drawbacks. To circumvent these problems, we report the development of a bioluminescent Ca 2+ indicator GmNL(Ca 2+ ), and its application in a customized microscope for high-throughput drug screening. GmNL(Ca 2+ ) gives a 140% signal change with Ca 2+ , and can image drug-induced changes of Ca 2+ dynamics in cultured cells. Since bioluminescence requires application of a chemical substrate, which is consumed over ~ 30 min we made a dedicated microscope with automated drug dispensing inside a light-tight box, to control drug addition. To overcome thermal instability of the luminescent substrate, or small molecule, dual climate control enables distinct temperature settings in the drug reservoir and the biological sample. By combining GmNL(Ca 2+ ) with this adaptation, we could image spontaneous Ca 2+ transients in cultured cardiomyocytes and phenotype their response to well-known drugs without accessing the sample directly. In addition, the bioluminescent strategy demonstrates minimal perturbation of contractile parameters and long-term observation attributable to lack of phototoxicity and photobleaching. Overall, bioluminescence may enable more accurate drug screening in a high-throughput manner.

  13. Effect of nonsteroidal anti-inflammatory drugs on colorectal distension-induced visceral pain

    Science.gov (United States)

    Baskın, Veysel; Bilge, S. Sırrı; Bozkurt, Ayhan; Akyüz, Bahar; Ağrı, Arzu Erdal; Güzel, Hasan; İlkaya, Fatih

    2016-01-01

    Objectives: To investigate nonsteroidal anti-inflammatory drugs effectiveness in colorectal distension (CRD)-induced visceral pain model. Materials and Methods: Male Sprague–Dawley (250–300 g) rats were anesthetized with ketamine (50 mg/kg, intraperitoneally [i.p.]) and chlorpromazine (25 mg/kg, i.p.). Two bipolar Teflon-coated Ni/Cr wire electrodes (80-M diameter) were placed in the abdominal external oblique muscle for the recording of electromyography. Jugular vein catheter was placed for the administration of drugs. CRD method was applied to evaluate of visceral pain. All drugs (paracetamol, meloxicam, metamizole, and dexketoprofen) administered intravenously. Results: Paracetamol 200, 400, and 600 mg/kg did not change the visceromotor response (VMR) when compare with the control group. Meloxicam 2 and 4 mg/kg showed no effect but at doses of 6 mg/kg meloxicam significantly ([51.9 ± 6.4%] [P Dexketoprofen 2 and 4 mg/kg did not cause a change in VMR but 6 mg/kg dose significantly reduced response compared with the control group ([43.9 ± 3.9%, 36.8 ± 2.8%, 34.8 ± 2.5%, 42.1 ± 4.8%, 40.7 ± 3.5%, 36.4 ± 2.7%, and 26.1 ± 2.2%]; from 10 min to 70 min, respectively, [P dexketoprofen and meloxicam show antinociceptive effect with different duration of action on CRD-induced visceral pain model. This condition can be explained due to different chemical structures and different mechanisms which play a role in modulation of pain. PMID:27114637

  14. Porous Polymer Drug-Eluting Coating Prepared by Radiation Induced Polymerization

    International Nuclear Information System (INIS)

    Veres, M.; Beiler, B.; Himics, L.; Tóth, S.; Koós, M.

    2010-01-01

    Many areas of modern medicine are almost unimaginable without the use of different kinds of implants. They used as replacements, supports, auxiliary devices etc. for various parts or functions of the body. Their use has many advantages, however there could be some drawbacks too, like the possibility of rejection, inflammation and other side-effects. Many of these drawbacks are directly related to the materials used for the implant fabrication. Coatings are widely used to eliminate the unwanted effects appearing after the implantation. In addition to the protection and separation of tissues from the implant material they could also enhance the functionality and the acceptance of the artificial device and also promote the regeneration of the tissues after the intervention. Drug-eluting coatings are a good example for the latter. By delivery and controlled elution of drugs they could actively suppress inflammatory reactions, allergy and rejection of the implant, and their activity is localized to the place where these effects could mainly occur – to the region of the implant. This project is aimed to develop a drug-eluting porous polymer coating by radiation induced polymerization that can be used in different medical implants. The primary objects for this research are coronary stents however these porous layers could have perspective in other types of medical devices too. The main objectives are to develop a method for coating the surface of medical grade metallic alloy wires, plates and tubes with a porous polymer nanocomposite layer prepared by radiation induced polymerization and to characterize the obtained coatings

  15. Porous Polymer Drug-Eluting Coating Prepared by Radiation Induced Polymerization

    Energy Technology Data Exchange (ETDEWEB)

    Veres, M.; Beiler, B.; Himics, L.; Tóth, S.; Koós, M., E-mail: vm@szfki.hu [Hungarian Academy of Sciences, Research Institute for Solid State Physics and Optics, Department of Laser Applications, Konkoly Thege Miklós ut 29-33, 1121 Budapest, P.O. Box 49, 1525 Budapest (Hungary)

    2010-07-01

    Many areas of modern medicine are almost unimaginable without the use of different kinds of implants. They used as replacements, supports, auxiliary devices etc. for various parts or functions of the body. Their use has many advantages, however there could be some drawbacks too, like the possibility of rejection, inflammation and other side-effects. Many of these drawbacks are directly related to the materials used for the implant fabrication. Coatings are widely used to eliminate the unwanted effects appearing after the implantation. In addition to the protection and separation of tissues from the implant material they could also enhance the functionality and the acceptance of the artificial device and also promote the regeneration of the tissues after the intervention. Drug-eluting coatings are a good example for the latter. By delivery and controlled elution of drugs they could actively suppress inflammatory reactions, allergy and rejection of the implant, and their activity is localized to the place where these effects could mainly occur – to the region of the implant. This project is aimed to develop a drug-eluting porous polymer coating by radiation induced polymerization that can be used in different medical implants. The primary objects for this research are coronary stents however these porous layers could have perspective in other types of medical devices too. The main objectives are to develop a method for coating the surface of medical grade metallic alloy wires, plates and tubes with a porous polymer nanocomposite layer prepared by radiation induced polymerization and to characterize the obtained coatings.

  16. Proteomic profiling in incubation medium of mouse, rat and human precision-cut liver slices for biomarker detection regarding acute drug-induced liver injury

    NARCIS (Netherlands)

    van Swelm, Rachel P L; Hadi, Mackenzie; Laarakkers, Coby M M; Masereeuw, R.|info:eu-repo/dai/nl/155644033; Groothuis, Geny M M; Russel, Frans G M

    Drug-induced liver injury is one of the leading causes of drug withdrawal from the market. In this study, we investigated the applicability of protein profiling of the incubation medium of human, mouse and rat precision-cut liver slices (PCLS) exposed to liver injury-inducing drugs for biomarker

  17. Re-prescribing of causative drugs in persons discharged after serious drug-induced upper gastrointestinal bleeding

    DEFF Research Database (Denmark)

    Dall, M; Christensen, René dePont; Schaffalitzky de Muckadell, O B

    2012-01-01

    Several drug classes are known to be associated with serious upper gastrointestinal bleeding (UGIB), among others NSAID, low-dose acetylsalicylic acid (ASA), vitamin K antagonists (VKA), clopidogrel and selective serotonin reuptake inhibitors (SSRIs). There are few data on how and to what extent...... these drugs are reintroduced in patients who have been discharged after a bleeding episode related to any of them....

  18. Strategies to reduce the risk of drug-induced QT interval prolongation: a pharmaceutical company perspective.

    Science.gov (United States)

    Pollard, C E; Valentin, J-P; Hammond, T G

    2008-08-01

    Drug-induced prolongation of the QT interval is having a significant impact on the ability of the pharmaceutical industry to develop new drugs. The development implications for a compound causing a significant effect in the 'Thorough QT/QTc Study' -- as defined in the clinical regulatory guidance (ICH E14) -- are substantial. In view of this, and the fact that QT interval prolongation is linked to direct inhibition of the hERG channel, in the early stages of drug discovery the focus is on testing for and screening out hERG activity. This has led to understanding of how to produce low potency hERG blockers whilst retaining desirable properties. Despite this, a number of factors mean that when an integrated risk assessment is generated towards the end of the discovery phase (by conducting at least an in vivo QT assessment) a QT interval prolongation risk is still often apparent; inhibition of hERG channel trafficking and partitioning into cardiac tissue are just two confounding factors. However, emerging information suggests that hERG safety margins have high predictive value and that when hERG and in vivo non-clinical data are combined, their predictive value to man, whilst not perfect, is >80%. Although understanding the anomalies is important and is being addressed, of greater importance is developing a better understanding of TdP, with the aim of being able to predict TdP rather than using an imperfect surrogate marker (QT interval prolongation). Without an understanding of how to predict TdP risk, high-benefit drugs for serious indications may never be marketed.

  19. Hospitalized pediatric antituberculosis drug induced hepatotoxicity: Experience of an Indonesian referral hospital

    Directory of Open Access Journals (Sweden)

    Heda Melinda Nataprawira

    2017-05-01

    Full Text Available Objective: To determine the characteristics and risk factors of pediatric antituberculosis drug induced hepatotoxicity (ADIH in Dr. Hasan Sadikin Hospital, a referral hospital in West Java, Indonesia. Methods: Medical records of hospitalized pediatric ADIH from October 2010 to October 2015 were reviewed retrospectively through computer-based search. Descriptive data were presented as percentage. Analytical case-control study on characteristics of ADIH was conducted using Chi-square and Mann Whitney test. Results: Fifty (3.5% out of 1 424 pediatric TB patients developed ADIH; 20 (40% were boys and 30 (60% girls. More than half were under 5 years old and 33 (66% were malnourished. ADIH occured in 29 (58% cases treated for pulmonary TB, 15 (30% for extrapulmonary TB and 6 (12% for both; 34 cases (68% occured during the intensive phase. We identified hepatic comorbidities including CMV infection [1 (2%] and typhoid [1 (2%], and other diseases treated by hepatotoxic drugs such as chemotherapeutic drugs, antiepileptics, and antiretroviral drugs [9 (18%]. Case-control analysis of 50 ADIH cases and 100 TB controls without ADIH showed that the correlation between gender, age, type of TB, nutritional status and comorbidities to occurence of ADIH was statistically insignificant (P = 0.26, 0.765, 0.495, 0.534 9 and 0.336, respectively. Pediatric ADIH was treated using modified British Thoracic Society guidelines. Conclusions: Pediatric ADIH in our hospital is quite frequent, thus identifying risk factors and development of pediatric guideline is mandatory. Further study is needed to identify other risk factors such as genetic acetylator status.

  20. CYP2C9 polymorphism in non-steroidal anti-inflammatory drugs-induced gastropathy.

    Science.gov (United States)

    Ma, Juan; Yang, Xiu Yan; Qiao, Liang; Liang, Liu Qin; Chen, Min Hu

    2008-05-01

    Non-steroidal anti-inflammatory drugs (NSAID) induce gastroduodenal mucosal injury and are metabolized by cytochrome P450 2C9 (CYP2C9). It is postulated that CYP2C9 genotype is associated with NSAID-induced gastropathy. This study aims to determine whether individuals with a CYP2C9 allele mutation are susceptible to NSAID-induced gastropathy. A total of 109 patients diagnosed as having rheumatic diseases and taking NSAID were appraised as having gastropathy by endoscopy, stool occult blood test and questionnaire two weeks after entering the study. Their peripheral blood was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). A total of 47.7% gastropathy (33% erosions, 14.7% ulcers, 2.75% ulcer bleeding) and 56% dyspeptic symptoms were presented. Only one CYP2C9*2 heterozygote (*1/*2) was found in the group with gastropathy and two variant alleles (CYP2C9*2 and CYP2C9* 3) could not be found in the group without gastropathy. There was no significant difference in both CYP2C9 genotype (0.96%vs 0%) and CYP2C9 variant allele frequency (1.92%vs 0%) between patients with and without gastropathy. These results confirm the high prevalence of NSAID-induced gastropathy but do not support the postulation that CYP2C9*2 and CYP2C9*3 contribute to the development of NSAID-induced gastropathy. This may be due to the low frequency of the two alleles in the population studied.

  1. Genome-wide mutagenesis and multi-drug resistance in American trypanosomes induced by the front-line drug benznidazole

    KAUST Repository

    Campos, Mônica C.

    2017-10-25

    Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects 5–8 million people in Latin America. Although the nitroheterocyclic compound benznidazole has been the front-line drug for several decades, treatment failures are common. Benznidazole is a pro-drug and is bio-activated within the parasite by the mitochondrial nitroreductase TcNTR-1, leading to the generation of reactive metabolites that have trypanocidal activity. To better assess drug action and resistance, we sequenced the genomes of T. cruzi Y strain (35.5 Mb) and three benznidazole-resistant clones derived from a single drug-selected population. This revealed the genome-wide accumulation of mutations in the resistant parasites, in addition to variations in DNA copy-number. We observed mutations in DNA repair genes, linked with increased susceptibility to DNA alkylating and inter-strand cross-linking agents. Stop-codon-generating mutations in TcNTR-1 were associated with cross-resistance to other nitroheterocyclic drugs. Unexpectedly, the clones were also highly resistant to the ergosterol biosynthesis inhibitor posaconazole, a drug proposed for use against T. cruzi infections, in combination with benznidazole. Our findings therefore identify the highly mutagenic activity of benznidazole metabolites in T. cruzi, demonstrate that this can result in multi-drug resistance, and indicate that vigilance will be required if benznidazole is used in combination therapy.

  2. Hydrocortisone-induced embryotoxicity and embryonic drug disposition in H-2 congenic mice

    International Nuclear Information System (INIS)

    Roberts, L.S.G.

    1986-01-01

    Congenic mouse strains C57BL/10Sn (B10) and B10.A/SgSn(B10A), genetically different only at the H-2 complex, were compared for sensitivity to glucocorticoid-induced embryotoxicity and embryonic drug disposition. B10A mice dosed intramuscularly with 0, 100, 150 and 200 mg hydrocortisone/kg body weight on gestational day twelve, and B10 mice injected with 0, 200, 400, 600, and 800 mg/kg, were evaluated at dissection on gestational day eighteen for signs of toxicity. In both strains, probit analysis of cleft palate production demonstrated a linear dose response. The ED50 for cleft palate production demonstrates a linear dose response. The ED50 for cleft palate production in B10A mice was 143.6 mg/kg and 512.0 mg/kg for the B10 strain. Embryonic exposure was evaluated by administration of 3 H-hydrocortisone (5 uCi/mouse) to pregnant mice on day twelve of gestation, at the ED50 for cleft palate production in B10A strain. The purposes of the experiment were to quantify the difference in susceptibility to steroid-induced cleft palate, determine if a milder manifestation of embryotoxicity, fetal growth retardation, occurred at sub-clefting dosages, and determine if the difference in sensitivity to hydrocortisone-induced embryotoxicity was the result of an underlying difference in embryonic exposure to the teratogen

  3. Disease modeling and phenotypic drug screening for diabetic cardiomyopathy using human induced pluripotent stem cells.

    Science.gov (United States)

    Drawnel, Faye M; Boccardo, Stefano; Prummer, Michael; Delobel, Frédéric; Graff, Alexandra; Weber, Michael; Gérard, Régine; Badi, Laura; Kam-Thong, Tony; Bu, Lei; Jiang, Xin; Hoflack, Jean-Christophe; Kiialainen, Anna; Jeworutzki, Elena; Aoyama, Natsuyo; Carlson, Coby; Burcin, Mark; Gromo, Gianni; Boehringer, Markus; Stahlberg, Henning; Hall, Benjamin J; Magnone, Maria Chiara; Kolaja, Kyle; Chien, Kenneth R; Bailly, Jacques; Iacone, Roberto

    2014-11-06

    Diabetic cardiomyopathy is a complication of type 2 diabetes, with known contributions of lifestyle and genetics. We develop environmentally and genetically driven in vitro models of the condition using human-induced-pluripotent-stem-cell-derived cardiomyocytes. First, we mimic diabetic clinical chemistry to induce a phenotypic surrogate of diabetic cardiomyopathy, observing structural and functional disarray. Next, we consider genetic effects by deriving cardiomyocytes from two diabetic patients with variable disease progression. The cardiomyopathic phenotype is recapitulated in the patient-specific cells basally, with a severity dependent on their original clinical status. These models are incorporated into successive levels of a screening platform, identifying drugs that preserve cardiomyocyte phenotype in vitro during diabetic stress. In this work, we present a patient-specific induced pluripotent stem cell (iPSC) model of a complex metabolic condition, showing the power of this technique for discovery and testing of therapeutic strategies for a disease with ever-increasing clinical significance. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  4. Antibiotic drug tigecycline inhibited cell proliferation and induced autophagy in gastric cancer cells

    International Nuclear Information System (INIS)

    Tang, Chunling; Yang, Liqun; Jiang, Xiaolan; Xu, Chuan; Wang, Mei; Wang, Qinrui; Zhou, Zhansong; Xiang, Zhonghuai; Cui, Hongjuan

    2014-01-01

    Highlights: • Tigecycline inhibited cell growth and proliferation in human gastric cancer cells. • Tigecycline induced autophagy not apoptosis in human gastric cancer cells. • AMPK/mTOR/p70S6K pathway was activated after tigecycline treatment. • Tigecycline inhibited tumor growth in xenograft model of human gastric cancer cells. - Abstract: Tigecycline acts as a glycylcycline class bacteriostatic agent, and actively resists a series of bacteria, specifically drug fast bacteria. However, accumulating evidence showed that tetracycline and their derivatives such as doxycycline and minocycline have anti-cancer properties, which are out of their broader antimicrobial activity. We found that tigecycline dramatically inhibited gastric cancer cell proliferation and provided an evidence that tigecycline induced autophagy but not apoptosis in human gastric cancer cells. Further experiments demonstrated that AMPK pathway was activated accompanied with the suppression of its downstream targets including mTOR and p70S6K, and ultimately induced cell autophagy and inhibited cell growth. So our data suggested that tigecycline might act as a candidate agent for pre-clinical evaluation in treatment of patients suffering from gastric cancer

  5. Antibiotic drug tigecycline inhibited cell proliferation and induced autophagy in gastric cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Chunling; Yang, Liqun; Jiang, Xiaolan [State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716 (China); Xu, Chuan [Division of Scientific Research and Training, General Hospital of PLA Chengdu Military Area Command, Chengdu, Sichuan 610083 (China); Wang, Mei; Wang, Qinrui [State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716 (China); Zhou, Zhansong, E-mail: zhouzhans@sina.com [Institute of Urinary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Xiang, Zhonghuai [State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716 (China); Cui, Hongjuan, E-mail: hcui@swu.edu.cn [State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716 (China)

    2014-03-28

    Highlights: • Tigecycline inhibited cell growth and proliferation in human gastric cancer cells. • Tigecycline induced autophagy not apoptosis in human gastric cancer cells. • AMPK/mTOR/p70S6K pathway was activated after tigecycline treatment. • Tigecycline inhibited tumor growth in xenograft model of human gastric cancer cells. - Abstract: Tigecycline acts as a glycylcycline class bacteriostatic agent, and actively resists a series of bacteria, specifically drug fast bacteria. However, accumulating evidence showed that tetracycline and their derivatives such as doxycycline and minocycline have anti-cancer properties, which are out of their broader antimicrobial activity. We found that tigecycline dramatically inhibited gastric cancer cell proliferation and provided an evidence that tigecycline induced autophagy but not apoptosis in human gastric cancer cells. Further experiments demonstrated that AMPK pathway was activated accompanied with the suppression of its downstream targets including mTOR and p70S6K, and ultimately induced cell autophagy and inhibited cell growth. So our data suggested that tigecycline might act as a candidate agent for pre-clinical evaluation in treatment of patients suffering from gastric cancer.

  6. [Assessment of anti-tremorogenic drugs--nicotine-induced tail-tremor model].

    Science.gov (United States)

    Suemaru, K; Kawasaki, H; Gomita, Y

    1997-06-01

    The repeated administration of nicotine at small doses, which do not produce whole body tremor or convulsion, causes tremor only in the tail (tail-tremor) of rats. The tremor is accompanied by locomotor hyperactivity without rigidity and immobility of the whole body, suggesting that the nicotine-induced tail-tremor model is useful for studying the mechanism underlying tremor associated with movement. The tail-tremor induced by nicotine was suppressed by mecamylamine, a nicotinic antagonist, but not by atropine or scopolamine, muscalinic antagonists. Moreover, the tail-tremor was suppressed by the beta-blockers propranolol and pindolol, as well as the benzodiazepines diazepam and clonazepam. Tremor at rest is observed only in Parkinson's disease, which is improved with anti-muscalinic drugs. Essential tremor is one of the typical tremors connected with movement (postural and kinetic tremor) and is improved with beta-blocker. These findings and results suggest that nicotine-induced tail-tremor is useful for the study of essential tremor in animal models.

  7. Drug delivery strategies for chemoprevention of UVB-induced skin cancer: A review.

    Science.gov (United States)

    Bagde, Arvind; Mondal, Arindam; Singh, Mandip

    2018-01-01

    Annually, more skin cancer cases are diagnosed than the collective incidence of the colon, lung, breast, and prostate cancer. Persistent contact with sunlight is a primary cause for all the skin malignancies. UVB radiation induces reactive oxygen species (ROS) production in the skin which eventually leads to DNA damage and mutation. Various delivery approaches for the skin cancer treatment/prevention have been evolving and are directed toward improvements in terms of delivery modes, therapeutic agents, and site-specificity of therapeutics delivery. The effective chemoprevention activity achieved is based on the efficiency of the delivery system used and the amount of the therapeutic molecule deposited in the skin. In this article, we have discussed different studies performed specifically for the chemoprevention of UVB-induced skin cancer. Ultra-flexible nanocarriers, transethosomes nanocarriers, silica nanoparticles, silver nanoparticles, nanocapsule suspensions, microemulsion, nanoemulsion, and polymeric nanoparticles which have been used so far to deliver the desired drug molecule for preventing the UVB-induced skin cancer. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Disease Modeling and Phenotypic Drug Screening for Diabetic Cardiomyopathy using Human Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Faye M. Drawnel

    2014-11-01

    Full Text Available Diabetic cardiomyopathy is a complication of type 2 diabetes, with known contributions of lifestyle and genetics. We develop environmentally and genetically driven in vitro models of the condition using human-induced-pluripotent-stem-cell-derived cardiomyocytes. First, we mimic diabetic clinical chemistry to induce a phenotypic surrogate of diabetic cardiomyopathy, observing structural and functional disarray. Next, we consider genetic effects by deriving cardiomyocytes from two diabetic patients with variable disease progression. The cardiomyopathic phenotype is recapitulated in the patient-specific cells basally, with a severity dependent on their original clinical status. These models are incorporated into successive levels of a screening platform, identifying drugs that preserve cardiomyocyte phenotype in vitro during diabetic stress. In this work, we present a patient-specific induced pluripotent stem cell (iPSC model of a complex metabolic condition, showing the power of this technique for discovery and testing of therapeutic strategies for a disease with ever-increasing clinical significance.

  9. Precision-cut mouse liver slices as an ex vivo model to study the mechanism of inflammatory stress-related idiosyncratic drug-induced liver injury

    NARCIS (Netherlands)

    Hadi, Mackenzie; Chen, Y.; Starokozhko, Viktoriia; Merema, Maja; Groothuis, Genoveva

    2012-01-01

    Idiosyncratic drug reactions (IDRs) can be defined as adverse drug reactions that occur in a small minority of the patients taking clinically-relevant doses and do not involve the known pharmacological effects of the drug. IDR related to hepatotoxicity or idiosyncratic drug-induced liver injury

  10. IN VITRO MODELS TO EVALUATE DRUG-INDUCED HYPERSENSITIVITY: POTENTIAL TEST BASED ON ACTIVATION OF DENDRITIC CELLS

    Directory of Open Access Journals (Sweden)

    Valentina Galbiati

    2016-07-01

    Full Text Available Hypersensitivity drug reactions (HDRs are the adverse effect of pharmaceuticals that clinically resemble allergy. HDRs account for approximately 1/6 of drug-induced adverse effects, and include immune-mediated ('allergic' and non immune-mediated ('pseudo allergic' reactions. In recent years, the severe and unpredicted drug adverse events clearly indicate that the immune system can be a critical target of drugs. Enhanced prediction in preclinical safety evaluation is, therefore, crucial. Nowadays, there are no validated in vitro or in vivo methods to screen the sensitizing potential of drugs in the pre-clinical phase. The problem of non-predictability of immunologically-based hypersensitivity reactions is related to the lack of appropriate experimental models rather than to the lack of -understanding of the adverse phenomenon.We recently established experimental conditions and markers to correctly identify drug associated with in vivo hypersensitivity reactions using THP-1 cells and IL-8 production, CD86 and CD54 expression. The proposed in vitro method benefits from a rationalistic approach with the idea that allergenic drugs share with chemical allergens common mechanisms of cell activation. This assay can be easily incorporated into drug development for hazard identification of drugs, which may have the potential to cause in vivo hypersensitivity reactions. The purpose of this review is to assess the state of the art of in vitro models to assess the allergenic potential of drugs based on the activation of dendritic cells.

  11. Toxicidad hepática por medicamentos antituberculosos Hepatotoxicity induced by antituberculosis drugs

    Directory of Open Access Journals (Sweden)

    Isabel Eugenia Escobar Toledo

    2008-01-01

    Full Text Available

    El fenómeno de la toxicidad hepática inducida por medicamentos cobró relevancia hace algunos años con el estudio de las reacciones adversas a medicamentos. El daño producido en el hígado por un xenobiótico que altera su función es lo que se conoce como toxicidad hepática. La importancia de reconocer y diagnosticar la toxicidad hepática por medicamentos estriba en su gravedad potencial; no en vano es la causa más frecuente por la que la industria farmacéutica retira medicamentos. La tuberculosis es una pandemia que afecta a gran parte de la población mundial y junto con el VIH es una enfermedad cada vez más frecuente en Colombia. Esta enfermedad se puede considerar como una situación especial porque para su tratamiento es preciso suministrar, por largos períodos, medicamentos con potencial tóxico para el hígado.

     

    El objetivo de este artículo es revisar algunos aspectos relacionados con la toxicidad hepática secundaria a medicamentos antituberculosos, tales como: epidemiología, factores de riesgo, mecanismos de toxicidad, manifestaciones clínicas, diagnóstico, tratamiento y seguimiento.

    Hepatotoxicity is the alteration of liver structure and function induced by either drugs or other substances. The importance of its proper diagnosis rests on its potential severity. It is the most frequent reason by which the pharmaceutical industry withdraws its products. Tuberculosis is a pandemic infection affecting a large proportion of the world population. Together with HIV infection it is becoming ever more frequent in Colombia. Tuberculosis poses

  12. Genome-wide mutagenesis and multi-drug resistance in American trypanosomes induced by the front-line drug benznidazole

    KAUST Repository

    Campos, Mô nica C.; Phelan, Jody; Francisco, Amanda F.; Taylor, Martin C.; Lewis, Michael D.; Pain, Arnab; Clark, Taane G.; Kelly, John M.

    2017-01-01

    Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects 5–8 million people in Latin America. Although the nitroheterocyclic compound benznidazole has been the front-line drug for several decades, treatment failures

  13. The microculture-kinetic (MiCK) assay: the role of a drug-induced apoptosis assay in drug development and clinical care.

    Science.gov (United States)

    Bosserman, Linda; Prendergast, Franklyn; Herbst, Roy; Fleisher, Martin; Salom, Emery; Strickland, Steven; Raptis, Anastasios; Hallquist, Allan; Perree, Mathieu; Rajurkar, Swapnil; Karimi, Misagh; Rogers, Karl; Davidson, Dirk; Willis, Carl; Penalver, Manuel; Homesley, Howard; Burrell, Matthew; Garrett, Audrey; Rutledge, James; Chernick, Michael; Presant, Cary A

    2012-08-15

    A drug-induced apoptosis assay, termed the microculture-kinetic (MiCK) assay, has been developed. Blinded clinical trials have shown higher response rates and longer survival in groups of patients with acute myelocytic leukemia and epithelial ovarian cancer who have been treated with drugs that show high apoptosis in the MiCK assay. Unblinded clinical trials in multiple tumor types have shown that the assay will be used frequently by clinicians to determine treatment, and when used, results in higher response rates, longer times to relapse, and longer survivals. Model economic analyses suggest possible cost savings in clinical use based on increased generic drug use and single-agent substitution for combination therapies. Two initial studies with drugs in development are promising. The assay may help reduce costs and speed time to drug approval. Correlative studies with molecular biomarkers are planned. This assay may have a role both in personalized clinical therapy and in more efficient drug development. ©2012 AACR.

  14. Optimizing anticancer drug treatment in pregnant cancer patients : pharmacokinetic analysis of gestation-induced changes for doxorubicin, epirubicin, docetaxel and paclitaxel

    NARCIS (Netherlands)

    van Hasselt, J G C; van Calsteren, K; Heyns, L; Han, S; Mhallem Gziri, M; Schellens, J H M; Beijnen, J H; Huitema, A D R; Amant, F

    2014-01-01

    BACKGROUND: Pregnant patients with cancer are increasingly treated with anticancer drugs, although the specific impact of pregnancy-induced physiological changes on the pharmacokinetics (PK) of anticancer drugs and associated implications for optimal dose regimens remains unclear. Our objectives

  15. 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.

  16. Beat-to-beat variability of QT intervals is increased in patients with drug-induced long-QT syndrome

    DEFF Research Database (Denmark)

    Hinterseer, Martin; Thomsen, Morten Bækgaard; Beckmann, Britt-Maria

    2008-01-01

    Torsades de pointes arrhythmias (TdP) occur by definition in the setting of prolonged QT intervals. Animal models of drug induced Long-QT syndrome (dLQTS) have shown higher predictive value for proarrhythmia with beat-to-beat variability of repolarization duration (BVR) when compared with QT inte...... intervals. Here, we evaluate variability of QT intervals in patients with a history of drug-induced long QT syndrome (dLQTS) and TdP in absence of a mutation in any of the major LQTS genes.......Torsades de pointes arrhythmias (TdP) occur by definition in the setting of prolonged QT intervals. Animal models of drug induced Long-QT syndrome (dLQTS) have shown higher predictive value for proarrhythmia with beat-to-beat variability of repolarization duration (BVR) when compared with QT...

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

    International Nuclear Information System (INIS)

    Zhao Honggang; Dong Hua; Gu Yan; Zhang Zuncheng

    2009-01-01

    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 (t β-HCG =4.845, t E =7.655, t P =11.390, P E =9.089, P P =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)

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

    International Nuclear Information System (INIS)

    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

  19. [Experience of treatment of patients with gastropathy induced by non-steroid anti-inflammatory drugs].

    Science.gov (United States)

    Vakhrushev, Ia M; Loshchakova, O Iu

    2007-01-01

    A complex study of 147 patients who were taking non-steroid anti-inflammatory drugs (NSAIDs) revealed gastric lesions in 120 patients (81.6%). H2 blocker (ranitidine) was used for treating 40 patients with NSAID-induced gastropathy, proton pump inhibitor (omeprazole) was used for 40 patients, and Gastrozepin combined with Misoprostol--for 40 patients. Pain syndrome and dyspepsia were eliminated in most of the patients as a result of the treatment. Using Gastrozepin and Misoprostol produced an active effect on the trophic processes in the gastric mucous coat and caused erosion and ulcer healing. As compared to ranitidine and omeprazole, Gastrozepin used in combination with Cytotec produces a lower effect on the reduction of the acid-producing stomach function, yet it has a considerably greater effect on the normalization of the gastric mucus structure and restoration of metabolism of the gastric mucous coat collagen.

  20. temporomandibular joint cartilage in rabbits affected by drug-induced osteoarthritis

    Directory of Open Access Journals (Sweden)

    Krzysztof Kałużyński

    2016-02-01

    Full Text Available Background: The aims of this study were to assess the anti-degenerative effects of pioglitazone and to compare these effects with those of methylprednisolone and hyaluronic acid on drug-induced osteoarthritis in rabbits’ temporomandibular joint cartilage.Material and Methods: The experiment was conducted on 40 Californian white rabbits. Degenerative changes were induced by intra-articular injections of papain. Subsequently, all of the animals were randomly assigned to one of four groups:1 a control group that received no medications;2 a group treated with 4 intra-articular injections of 2 mg (0.2 ml of hyaluronic acid at weekly intervals;3 a group treated with 4 intra-articular injections of 2 mg (0.1 ml of methylprednisolone at weekly intervals;4 a group administered pioglitazone orally in daily doses of 2 mg/kg of body weight. Four weeks after the beginning of drug administration, the rabbits were sacrificed. Sagittal sections of the intra-articular cartilage (discs and mandibular condyles were stained with hematoxylin and eosin by the PAS technique and with van Gieson’s solution. Histologic examinations, as well as cartilage thickness and number of cell layers measurements, were performed.Results: Histologic assessment in cases of arthritis-associated pathologies revealed that changes occurred most frequently in the control group and least frequently in the pioglitazone group. There were no differences in the histological structures of the intra-articular discs. Cartilage thickness measurements demonstrated the thinnest cartilage in group 2 and the thickest in group 3. Analysis of cell layer numbers showed the most numerous layers in the pioglitazone group and the least in the control group.Conclusion: Pioglitazone and hyaluronic acid showed anti-degenerative properties compared to methylprednisolone in an animal model.

  1. Vitamin D3: A Role in Dopamine Circuit Regulation, Diet-Induced Obesity, and Drug Consumption.

    Science.gov (United States)

    Trinko, Joseph R; Land, Benjamin B; Solecki, Wojciech B; Wickham, Robert J; Tellez, Luis A; Maldonado-Aviles, Jaime; de Araujo, Ivan E; Addy, Nii A; DiLeone, Ralph J

    2016-01-01

    The influence of micronutrients on dopamine systems is not well defined. Using mice, we show a potential role for reduced dietary vitamin D3 (cholecalciferol) in promoting diet-induced obesity (DIO), food intake, and drug consumption while on a high fat diet. To complement these deficiency studies, treatments with exogenous fully active vitamin D3 (calcitriol, 10 µg/kg, i.p.) were performed. Nondeficient mice that were made leptin resistant with a high fat diet displayed reduced food intake and body weight after an acute treatment with exogenous calcitriol. Dopamine neurons in the midbrain and their target neurons in the striatum were found to express vitamin D3 receptor protein. Acute calcitriol treatment led to transcriptional changes of dopamine-related genes in these regions in naive mice, enhanced amphetamine-induced dopamine release in both naive mice and rats, and increased locomotor activity after acute amphetamine treatment (2.5 mg/kg, i.p.). Alternatively, mice that were chronically fed either the reduced D3 high fat or chow diets displayed less activity after acute amphetamine treatment compared with their respective controls. Finally, high fat deficient mice that were trained to orally consume liquid amphetamine (90 mg/L) displayed increased consumption, while nondeficient mice treated with calcitriol showed reduced consumption. Our findings suggest that reduced dietary D3 may be a contributing environmental factor enhancing DIO as well as drug intake while eating a high fat diet. Moreover, these data demonstrate that dopamine circuits are modulated by D3 signaling, and may serve as direct or indirect targets for exogenous calcitriol.

  2. Periodic lateralized epileptiform discharges can survive anesthesia and result in asymmetric drug-induced burst suppression

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    Edward C. Mader Jr.

    2017-02-01

    Full Text Available Drug-induced burst suppression (DIBS is bihemispheric and bisymmetric in adults and older children. However, asymmetric DIBS may occur if a pathological process is affecting one hemisphere only or both hemispheres disproportionately. The usual suspect is a destructive lesion; an irritative or epileptogenic lesion is usually not invoked to explain DIBS asymmetry. We report the case of a 66-year-old woman with new-onset seizures who was found to have a hemorrhagic cavernoma and periodic lateralized epileptiform discharges (PLEDs in the right temporal region. After levetiracetam and before anesthetic antiepileptic drugs (AEDs were administered, the electroencephalogram (EEG showed continuous PLEDs over the right hemisphere with maximum voltage in the posterior temporal region. Focal electrographic seizures also occurred occasionally in the same location. Propofol resulted in bihemispheric, but not in bisymmetric, DIBS. Remnants or fragments of PLEDs that survived anesthesia increased the amplitude and complexity of the bursts in the right hemisphere leading to asymmetric DIBS. Phenytoin, lacosamide, ketamine, midazolam, and topiramate were administered at various times in the course of EEG monitoring, resulting in suppression of seizures but not of PLEDs. Ketamine and midazolam reduced the rate, amplitude, and complexity of PLEDs but only after producing substantial attenuation of all burst components. When all anesthetics were discontinued, the EEG reverted to the original preanesthesia pattern with continuous non-fragmented PLEDs. The fact that PLEDs can survive anesthesia and affect DIBS symmetry is a testament to the robustness of the neurodynamic processes underlying PLEDs.

  3. Fungicidal Drugs Induce a Common Oxidative-Damage Cellular Death Pathway

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    Peter Belenky

    2013-02-01

    Full Text Available Amphotericin, miconazole, and ciclopirox are antifungal agents from three different drug classes that can effectively kill planktonic yeast, yet their complete fungicidal mechanisms are not fully understood. Here, we employ a systems biology approach to identify a common oxidative-damage cellular death pathway triggered by these representative fungicides in Candida albicans and Saccharomyces cerevisiae. This mechanism utilizes a signaling cascade involving the GTPases Ras1 and Ras2 and protein kinase A, and it culminates in death through the production of toxic reactive oxygen species in a tricarboxylic-acid-cycle- and respiratory-chain-dependent manner. We also show that the metabolome of C. albicans is altered by antifungal drug treatment, exhibiting a shift from fermentation to respiration, a jump in the AMP/ATP ratio, and elevated production of sugars; this coincides with elevated mitochondrial activity. Lastly, we demonstrate that DNA damage plays a critical role in antifungal-induced cellular death and that blocking DNA-repair mechanisms potentiates fungicidal activity.

  4. Nonclinical safety biomarkers of drug-induced vascular injury: current status and blueprint for the future.

    Science.gov (United States)

    Mikaelian, Igor; Cameron, Mark; Dalmas, Deidre A; Enerson, Bradley E; Gonzalez, Raymond J; Guionaud, Silvia; Hoffmann, Peter K; King, Nicholas M P; Lawton, Michael P; Scicchitano, Marshall S; Smith, Holly W; Thomas, Roberta A; Weaver, James L; Zabka, Tanja S

    2014-06-01

    Better biomarkers are needed to identify, characterize, and/or monitor drug-induced vascular injury (DIVI) in nonclinical species and patients. The Predictive Safety Testing Consortium (PSTC), a precompetitive collaboration of pharmaceutical companies and the U.S. Food and Drug Administration (FDA), formed the Vascular Injury Working Group (VIWG) to develop and qualify translatable biomarkers of DIVI. The VIWG focused its research on acute DIVI because early detection for clinical and nonclinical safety monitoring is desirable. The VIWG developed a strategy based on the premise that biomarkers of DIVI in rat would be translatable to humans due to the morphologic similarity of vascular injury between species regardless of mechanism. The histomorphologic lexicon for DIVI in rat defines degenerative and adaptive findings of the vascular endothelium and smooth muscles, and characterizes inflammatory components. We describe the mechanisms of these changes and their associations with candidate biomarkers for which advanced analytical method validation was completed. Further development is recommended for circulating microRNAs, endothelial microparticles, and imaging techniques. Recommendations for sample collection and processing, analytical methods, and confirmation of target localization using immunohistochemistry and in situ hybridization are described. The methods described are anticipated to aid in the identification and qualification of translational biomarkers for DIVI. © 2014 by The Author(s).

  5. Nephron segment specific microRNA biomarkers of pre-clinical drug-induced renal toxicity: Opportunities and challenges

    Energy Technology Data Exchange (ETDEWEB)

    Nassirpour, Rounak, E-mail: Rounak.nassirpour@pfizer.com [Drug Safety, Pfizer Worldwide Research and Development, 1 Burtt Rd, Andover, MA 01810 (United States); Ramaiah, Shashi K. [Drug Safety, Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, MA 02139 (United States); Whiteley, Laurence O. [Drug Safety, Pfizer Worldwide Research and Development, 1 Burtt Rd, Andover, MA 01810 (United States)

    2016-12-01

    Drug-induced nephrotoxicity is a common drug development complication for pharmaceutical companies. Sensitive, specific, translatable and non-invasive biomarkers of renal toxicity are urgently needed to diagnose nephron segment specific injury. The currently available gold standard biomarkers for nephrotoxicity are not kidney-specific, lack sensitivity for early detection, and are not suitable for renal damage localization (glomerular vs tubulointerstitial injury). MicroRNAs (miRNAs) are increasingly gaining momentum as promising biomarkers of various organ toxicities, including drug induced renal injury. This is mostly due to their stability in easily accessible biofluids, ease of developing nucleic acids detection compared to protein detection assays, as well as their interspecies translatability. Increasing concordance of miRNA findings by standardizing methodology most suitable for their detection and quantitation, as well as characterization of their expression pattern in a cell type specific manner, will accelerate progress toward validation of these miRNAs as biomarkers in pre-clinical, and clinical settings. This review aims to highlight the current pre-clinical findings surrounding miRNAs as biomarkers in two important segments of the nephron, the glomerulus and tubules. - Highlights: • miRNAs are promising biomarkers of drug-induced kidney injury. • Summarized pre-clinical miRNA biomarkers of drug-induced nephrotoxicity. • Described the strengths and challenges associated with miRNAs as biomarkers.

  6. Analysis of 90 cases of antithyroid drug-induced severe hepatotoxicity over 13 years in China.

    Science.gov (United States)

    Yang, Jun; Li, Lin-Fa; Xu, Qin; Zhang, Jun; Weng, Wan-Wen; Zhu, Yang-Jun; Dong, Meng-Jie

    2015-03-01

    Antithyroid drug (ATD)-induced severe hepatotoxicity is a rare but serious complication of ATD therapy. The characteristics of severe hepatotoxicity have been reported in only a small number of patients. Ninety patients with ATD-induced severe hepatotoxicity presenting during a 13 year period (2000-2013) who were about to undergo nuclear medicine therapy with (131)I from a sample of 8864 patients with hyperthyroidism were studied, and the outcomes were evaluated. The mean age of the patients with ATD-induced severe hepatotoxicity was 41.6±12.5 years (mean±standard deviation), and the female to male ratio was 2.2:1. The methimazole (MMI) dose given at the onset was 19.1±7.4 mg/day. The propylthiouracil (PTU) dose given at the onset was 212.8±105.0 mg/day. ATD-induced severe hepatotoxicity occurred in 63.3%, 75.6%, and 81.1% of patients within 4, 8, and 12 weeks of the onset of ATD therapy, respectively. The types of severe hepatotoxicity did not differ significantly between the MMI and PTU groups (p=0.188). The frequency of the cholestatic type in the MMI group (35.3%, 18/51) was higher than that in the PTU group (17.9%, 7/39), but these frequencies were not significantly different (p=0.069). The patients who were treated with (131)I received an average dose of 279.1±86.1 MBq (n=84). Therapy was successful in 60 of the 67 patients (89.6%). The success rate was equivalent (p=0.696) between the groups receiving MMI (91.7%, 33/36) and PTU (87.1%, 27/31). Severe hepatotoxicity tends to occur within the first three months after the onset of ATD therapy. The type of ATD-induced severe hepatotoxicity did not differ between the MMI and PTU groups. (131)I therapy is an effective treatment approach for patients with ATD-induced severe hepatotoxicity.

  7. Evidence connecting old, new and neglected glucose-lowering drugs to bile acid-induced GLP-1 secretion

    DEFF Research Database (Denmark)

    Kårhus, Martin L; Brønden, Andreas; Sonne, David P

    2017-01-01

    Bile acids are amphipathic water-soluble steroid-based molecules best known for their important lipid-solubilizing role in the assimilation of fat. Recently, bile acids have emerged as metabolic integrators with glucose-lowering potential. Among a variety of gluco-metabolic effects, bile acids have...... current evidence connecting established glucose-lowering drugs to bile acid-induced GLP-1 secretion and discusses whether bile acid-induced GLP-1 secretion may constitute a new basis for understanding how metformin, inhibitors of the apical sodium-dependent bile acids transporter, and bile acid...... sequestrants - old, new and neglected glucose-lowering drugs - improve glucose metabolism....

  8. Looking for the Self: Phenomenology, Neurophysiology and Philosophical Significance of Drug-induced Ego Dissolution

    Directory of Open Access Journals (Sweden)

    Raphaël Millière

    2017-05-01

    Full Text Available There is converging evidence that high doses of hallucinogenic drugs can produce significant alterations of self-experience, described as the dissolution of the sense of self and the loss of boundaries between self and world. This article discusses the relevance of this phenomenon, known as “drug-induced ego dissolution (DIED”, for cognitive neuroscience, psychology and philosophy of mind. Data from self-report questionnaires suggest that three neuropharmacological classes of drugs can induce ego dissolution: classical psychedelics, dissociative anesthetics and agonists of the kappa opioid receptor (KOR. While these substances act on different neurotransmitter receptors, they all produce strong subjective effects that can be compared to the symptoms of acute psychosis, including ego dissolution. It has been suggested that neuroimaging of DIED can indirectly shed light on the neural correlates of the self. While this line of inquiry is promising, its results must be interpreted with caution. First, neural correlates of ego dissolution might reveal the necessary neurophysiological conditions for the maintenance of the sense of self, but it is more doubtful that this method can reveal its minimally sufficient conditions. Second, it is necessary to define the relevant notion of self at play in the phenomenon of DIED. This article suggests that DIED consists in the disruption of subpersonal processes underlying the “minimal” or “embodied” self, i.e., the basic experience of being a self rooted in multimodal integration of self-related stimuli. This hypothesis is consistent with Bayesian models of phenomenal selfhood, according to which the subjective structure of conscious experience ultimately results from the optimization of predictions in perception and action. Finally, it is argued that DIED is also of particular interest for philosophy of mind. On the one hand, it challenges theories according to which consciousness always involves

  9. Looking for the Self: Phenomenology, Neurophysiology and Philosophical Significance of Drug-induced Ego Dissolution

    Science.gov (United States)

    Millière, Raphaël

    2017-01-01

    There is converging evidence that high doses of hallucinogenic drugs can produce significant alterations of self-experience, described as the dissolution of the sense of self and the loss of boundaries between self and world. This article discusses the relevance of this phenomenon, known as “drug-induced ego dissolution (DIED)”, for cognitive neuroscience, psychology and philosophy of mind. Data from self-report questionnaires suggest that three neuropharmacological classes of drugs can induce ego dissolution: classical psychedelics, dissociative anesthetics and agonists of the kappa opioid receptor (KOR). While these substances act on different neurotransmitter receptors, they all produce strong subjective effects that can be compared to the symptoms of acute psychosis, including ego dissolution. It has been suggested that neuroimaging of DIED can indirectly shed light on the neural correlates of the self. While this line of inquiry is promising, its results must be interpreted with caution. First, neural correlates of ego dissolution might reveal the necessary neurophysiological conditions for the maintenance of the sense of self, but it is more doubtful that this method can reveal its minimally sufficient conditions. Second, it is necessary to define the relevant notion of self at play in the phenomenon of DIED. This article suggests that DIED consists in the disruption of subpersonal processes underlying the “minimal” or “embodied” self, i.e., the basic experience of being a self rooted in multimodal integration of self-related stimuli. This hypothesis is consistent with Bayesian models of phenomenal selfhood, according to which the subjective structure of conscious experience ultimately results from the optimization of predictions in perception and action. Finally, it is argued that DIED is also of particular interest for philosophy of mind. On the one hand, it challenges theories according to which consciousness always involves self-awareness. On

  10. Liver Status Assessment by Spectrally and Time Resolved IR Detection of Drug Induced Breath Gas Changes

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    Tom Rubin

    2016-05-01

    Full Text Available The actual metabolic capacity of the liver is crucial for disease identification, liver therapy, and liver tumor resection. By combining induced drug metabolism and high sensitivity IR spectroscopy of exhaled air, we provide a method for quantitative liver assessment at bedside within 20 to 60 min. Fast administration of 13C-labelled methacetin induces a fast response of liver metabolism and is tracked in real-time by the increase of 13CO2 in exhaled air. The 13CO2 concentration increase in exhaled air allows the determination of the metabolic liver capacity (LiMAx-test. Fluctuations in CO2 concentration, pressure and temperature are minimized by special gas handling, and tracking of several spectrally resolved CO2 absorption bands with a quantum cascade laser. Absorption measurement of different 12CO2 and 13CO2 rotation-vibration transitions in the same time window allows for multiple referencing and reduction of systematic errors. This FLIP (Fast liver investigation package setup is being successfully used to plan operations and determine the liver status of patients.

  11. Effect of dicycloplatin, a novel platinum chemotherapeutical drug, on inhibiting cell growth and inducing cell apoptosis.

    Directory of Open Access Journals (Sweden)

    Guang-quan Li

    Full Text Available Dicycloplatin, a new supramolecular platinum-based antitumor drug, has been approved by the State Food and Administration (SFDA of China. In this study, we investigated the anticancer activity of dicycloplatin in cancer cells and signaling pathways involved in dicycloplatin-induced apoptosis. Dicycloplatin inhibited the proliferation of cancer cells and increased the percentage of apoptosis in a concentration-dependent manner. Besides, some apoptosis related events were observed after treatment with dicycloplatin, including increase of reactive oxygen species (ROS, collapse of mitochondrial membrane potential (Δψm, release of cytochrome c from the mitochondria to the cytosol, upregulation of p53, which were accompanied by activation of caspase-9, caspase-3, caspase-8, and poly (ADP-ribose polymerase cleavage in a concentration-dependent manner. The role of apoptosis in dicycloplatin-mediated cell death was further confirmed by the concomitant treatment with caspase-8 or caspase-9 inhibitors, which inhibited apoptosis and PARP cleavage. Intracellular glutathione (GSH was also found to inhibit the cytotoxic effect of dicycloplatin. In conclusion, these findings suggest that dicycloplatin induces apoptosis through ROS stress-mediated death receptor pathway and mitochondrial pathway which is similar to carboplatin.

  12. Toxicoproteomics: serum proteomic pattern diagnostics for early detection of drug induced cardiac toxicities and cardioprotection.

    Science.gov (United States)

    Petricoin, Emanuel F; Rajapaske, Vinodh; Herman, Eugene H; Arekani, Ali M; Ross, Sally; Johann, Donald; Knapton, Alan; Zhang, J; Hitt, Ben A; Conrads, Thomas P; Veenstra, Timothy D; Liotta, Lance A; Sistare, Frank D

    2004-01-01

    Proteomics is more than just generating lists of proteins that increase or decrease in expression as a cause or consequence of pathology. The goal should be to characterize the information flow through the intercellular protein circuitry which communicates with the extracellular microenvironment and then ultimately to the serum/plasma macroenvironment. The nature of this information can be a cause, or a consequence, of disease and toxicity based processes as cascades of reinforcing information percolate through the system and become reflected in changing proteomic information content of the circulation. Serum Proteomic Pattern Diagnostics is a new type of proteomic platform in which patterns of proteomic signatures from high dimensional mass spectrometry data are used as a diagnostic classifier. While this approach has shown tremendous promise in early detection of cancers, detection of drug-induced toxicity may also be possible with this same technology. Analysis of serum from rat models of anthracycline and anthracenedione induced cardiotoxicity indicate the potential clinical utility of diagnostic proteomic patterns where low molecular weight peptides and protein fragments may have higher accuracy than traditional biomarkers of cardiotoxicity such as troponins. These fragments may one day be harvested by circulating nanoparticles designed to absorb, enrich and amplify the diagnostic biomarker repertoire generated even at the critical initial stages of toxicity.

  13. Sedative choice in drug-induced sleep endoscopy: A neuropharmacology-based review.

    Science.gov (United States)

    Shteamer, Jack W; Dedhia, Raj C

    2017-01-01

    To examine the suitability of commonly used agents for drug-induced sleep endoscopy (DISE) based on agent-specific neuropharmacology. PubMed. A literature search of the PubMed database was performed on January 1, 2016. A two-layered search strategy was performed to identify relevant pharmacologic agents and articles related to neuropharmacology for these agents. The first search identified relevant pharmacologic agents; the second search examined agents with greater than five results from search 1, along with medical subject headings "respiration," "sleep," "pharmacology," and/or "[respective agent] (e.g., propofol)." Articles not in English were excluded. Bibliographies of pertinent articles were hand-searched for additional articles. Three agents were commonly identified from search 1: propofol, midazolam, and dexmedetomidine with 44, 13, and 6 results, respectively. Of note, 11 results utilized coinduction with midazolam and propofol. Search 2 for propofol, midazolam, and dexmedetomidine retrieved 219, 220, and 26 results, respectively. Eleven results for propofol, 4 for midazolam, and 9 for dexmedetomidine were found to be related to their neuropharmacology. The current review demonstrates relatively few investigations seeking to characterize the neuropharmacologic suitability of DISE agents. Compared to propofol and midazolam, dexmedetomidine's mechanism of action appears most likely to induce natural sleep pathways. Further study of its effect on upper airway collapsibility (critical closing pressure) and pharyngeal muscle tone (genioglossus electrode electromyography) are needed. Laryngoscope, 2016 Laryngoscope, 127:273-279, 2017. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

  14. S4. ASYMMETRIC DRUG-INDUCED PARKINSONISM IS RELATED TO PSYCHOPATHOLOGY

    Science.gov (United States)

    Pieters, Lydia; Bakker, P Roberto; Van Harten, Peter N

    2018-01-01

    Abstract Background Drug-Induced Parkinsonism (DIP) is the most common movement disorder induced by antipsychotics. The prevalence of DIP in chronic psychiatric populations ranges between 17 and 72% (1–3). Although, DIP is mostly symmetric, asymmetric DIP is reported in 18 to 54% of the patients. (4). There are no studies to the clinical relevance of asymmetric DIP. We investigated the prevalence of motor asymmetry in DIP and its relationship to the severity of psychopathology in a prospective study. Methods In a cohort study of 207 long-stay psychiatric inpatients the prevalence of DIP was assessed at least two times (mean follow-up 1.1 year) in each patient (5). DIP was assessed with the Unified Parkinson Disease Rating Scale (UPDRS) and the prevalence of persistent DIP was 56.2%. Patients with at least one time parkinsonism in the upper/lower limb(s) were included for analyses. Asymmetry of parkinsonism was calculated with the symmetry index (Figure 1). A cut-off value of ≥ 0,20 was used for the definition of asymmetric DIP. Multilevel mixed models were built to explore the relationship between asymmetry in DIP and the severity of psychopathology, measured on the Clinical Global Impression-Schizophrenia scale severity index (CGI-SCH SI). Results In a cohort study of 207 long-stay psychiatric inpatients the prevalence of DIP was assessed at least two times (mean follow-up 1.1 year) in each patient (5). DIP was assessed with the Unified Parkinson Disease Rating Scale (UPDRS) and the prevalence of persistent DIP was 56.2%. Patients with at least one time parkinsonism in the upper/lower limb(s) were included for analyses. Asymmetry of parkinsonism was calculated with the symmetry index (Figure 1). A cut-off value of ≥ 0,20 was used for the definition of asymmetric DIP. Multilevel mixed models were built to explore the relationship between asymmetry in DIP and the severity of psychopathology, measured on the Clinical Global Impression-Schizophrenia scale

  15. 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

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

    Directory of Open Access Journals (Sweden)

    Mauro Turrin

    2013-03-01

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

  17. Recapitulation of Clinical Individual Susceptibility to Drug-Induced QT Prolongation in Healthy Subjects Using iPSC-Derived Cardiomyocytes

    Directory of Open Access Journals (Sweden)

    Tadahiro Shinozawa

    2017-02-01

    Full Text Available To predict drug-induced serious adverse events (SAE in clinical trials, a model using a panel of cells derived from human induced pluripotent stem cells (hiPSCs of individuals with different susceptibilities could facilitate major advancements in translational research in terms of safety and pharmaco-economics. However, it is unclear whether hiPSC-derived cells can recapitulate interindividual differences in drug-induced SAE susceptibility in populations not having genetic disorders such as healthy subjects. Here, we evaluated individual differences in SAE susceptibility based on an in vitro model using hiPSC-derived cardiomyocytes (hiPSC-CMs as a pilot study. hiPSCs were generated from blood samples of ten healthy volunteers with different susceptibilities to moxifloxacin (Mox-induced QT prolongation. Different Mox-induced field potential duration (FPD prolongation values were observed in the hiPSC-CMs from each individual. Interestingly, the QT interval was significantly positively correlated with FPD at clinically relevant concentrations (r > 0.66 in multiple analyses including concentration-QT analysis. Genomic analysis showed no interindividual significant differences in known target-binding sites for Mox and other drugs such as the hERG channel subunit, and baseline QT ranges were normal. The results suggest that hiPSC-CMs from healthy subjects recapitulate susceptibility to Mox-induced QT prolongation and provide proof of concept for in vitro preclinical trials.

  18. Application of optical action potentials in human induced pluripotent stem cells-derived cardiomyocytes to predict drug-induced cardiac arrhythmias.

    Science.gov (United States)

    Lu, H R; Hortigon-Vinagre, M P; Zamora, V; Kopljar, I; De Bondt, A; Gallacher, D J; Smith, G

    2017-09-01

    Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are emerging as new and human-relevant source in vitro model for cardiac safety assessment that allow us to investigate a set of 20 reference drugs for predicting cardiac arrhythmogenic liability using optical action potential (oAP) assay. Here, we describe our examination of the oAP measurement using a voltage sensitive dye (Di-4-ANEPPS) to predict adverse compound effects using hiPS-CMs and 20 cardioactive reference compounds. Fluorescence signals were digitized at 10kHz and the records subsequently analyzed off-line. Cells were exposed to 30min incubation to vehicle or compound (n=5/dose, 4 doses/compound) that were blinded to the investigating laboratory. Action potential parameters were measured, including rise time (T rise ) of the optical action potential duration (oAPD). Significant effects on oAPD were sensitively detected with 11 QT-prolonging drugs, while oAPD shortening was observed with I Ca -antagonists, I Kr -activator or ATP-sensitive K + channel (K ATP )-opener. Additionally, the assay detected varied effects induced by 6 different sodium channel blockers. The detection threshold for these drug effects was at or below the published values of free effective therapeutic plasma levels or effective concentrations by other studies. The results of this blinded study indicate that OAP is a sensitive method to accurately detect drug-induced effects (i.e., duration/QT-prolongation, shortening, beat rate, and incidence of early after depolarizations) in hiPS-CMs; therefore, this technique will potentially be useful in predicting drug-induced arrhythmogenic liabilities in early de-risking within the drug discovery phase. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. 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 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.To describe a strategy that identifies potentially drug-induced acute myocardial infarction (AMI from a large international healthcare data network.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.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.Although global health status, co-morbidities, and time-invariant factors were adjusted for, residual confounding cannot be ruled out.A strategy to identify potentially drug-induced AMI from electronic healthcare data has been proposed that takes into account not only statistical

  20. 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.

  1. Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) induced by carbamazepine: a case report and literature review

    Science.gov (United States)

    EL Omairi, Nissrine; Abourazzak, Sanae; Chaouki, Sanae; Atmani, Samir; Hida, Moustapha

    2014-01-01

    Drug-induced hypersensitivity or Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) is a severe adverse drug-induced reaction. Diagnosing DRESS is challenging due to the diversity of cutaneous eruption and organs involved. Most of the aromatic anticonvulsants, such as phenytoin, phenobarbital, and carbamazepine, can induce DRESS. Culprit drug withdrawal and corticosteroids constituted the mainstay of DRESS treatment. We describe a 6 year-old boy who presented fever and rash 4 weeks after starting carbamazepine. Investigation revealed leukocytosis, atypical lymphocytosis, and elevated serum transaminases. The diagnosis of DREES syndrome was made, Carbamazepine was stopped and replaced initially by Clobazam and by Valproic acid after discharge, no systemic corticotherapy was prescribed. Symptoms began to resolve within two weeks, and by one month later her laboratory values had returned to normal. The aim of this work is to raise awareness general practitioner and pediatricians to suspect Dress syndrome in patients who present with unusual complaints and skin findings after starting any antiepileptic drug. PMID:25360193

  2. Role of cytochrome P450-mediated metabolism and involvement of reactive metabolite formations on antiepileptic drug-induced liver injuries.

    Science.gov (United States)

    Sasaki, Eita; Yokoi, Tsuyoshi

    2018-01-01

    Several drugs have been withdrawn from the market or restricted to avoid unexpected adverse outcomes. Drug-induced liver injury (DILI) is a serious issue for drug development. Among DILIs, idiosyncratic DILIs have been a serious problem in drug development and clinical uses. Idiosyncratic DILI is most often unrelated to pharmacological effects or the dosing amount of a drug. The number of drugs that cause idiosyncratic DILI continue to grow in part because no practical preclinical tests have emerged that can identify drug candidates with the potential for developing idiosyncratic DILIs. Nevertheless, the implications of drug metabolism-related factors and immune-related factors on idiosyncratic DILIs has not been fully clarified because this toxicity can not be reproduced in animals. Therefore, accumulated evidence for the mechanisms of the idiosyncratic toxicity has been limited to only in vitro studies. This review describes current knowledge of the effects of cytochrome P450 (CYP)-mediated metabolism and its detoxification abilities based on studies of idiosyncratic DILI animal models developed recently. This review also focused on antiepileptic drugs, phenytoin (diphenyl hydantoin, DPH) and carbamazepine (CBZ), which have rarely caused severe adverse reactions, such as fulminant hepatitis, and have been recognized as sources of idiosyncratic DILI. The studies of animal models of idiosyncratic DILIs have produced new knowledge of chronic administration, CYP inductions/inhibitions, glutathione contents, and immune-related factors for the initiation of idiosyncratic DILIs. Considering changes in the drug metabolic profile and detoxification abilities, idiosyncratic DILIs caused by antiepileptic drugs will lead to understanding the mechanisms of these DILIs.

  3. Drug ‘‘supersaturation’’ states induced by polymeric micelles and liposomes: A mechanistic investigation into permeability enhancements

    DEFF Research Database (Denmark)

    Di Cagno, Massimiliano; Luppi, Barbara

    2013-01-01

    The objective of this study was to investigate if the increase in apparent solubility induced by liposomalization or micellization of the poorly soluble drug hydrocortisone (HC) would lead to an enhancement of its permeability through biological membranes. For this purpose phosphatidylcholine...

  4. Disrupting the memory of places induced by drugs of abuse weakens motivational withdrawal in a context-dependent manner.

    Science.gov (United States)

    Taubenfeld, Stephen M; Muravieva, Elizaveta V; Garcia-Osta, Ana; Alberini, Cristina M

    2010-07-06

    Addicts repeatedly relapse to drug seeking even after years of abstinence, and this behavior is frequently induced by the recall of memories of the rewarding effects of the drug. Established memories, including those induced by drugs of abuse, can become transiently fragile if reactivated, and during this labile phase, known as reconsolidation, can be persistently disrupted. Here we show that, in rats, a morphine-induced place preference (mCPP) memory is linked to context-dependent withdrawal as disrupting the reconsolidation of the memory leads to a significant reduction of withdrawal evoked in the same context. Moreover, the hippocampus plays a critical role in linking the place preference memory with the context-conditioned withdrawal, as disrupting hippocampal protein synthesis and cAMP-dependent-protein kinase A after the reactivation of mCPP significantly weakens the withdrawal. Hence, targeting memories induced by drugs may represent an important strategy for attenuating context-conditioned withdrawal and therefore subsequent relapse in opiate addicts.

  5. T cell-dependent B-cell proliferation and activation induced by administration of the drug diphenylhydantoin to mice

    NARCIS (Netherlands)

    Gleichmann, H. I.; Pals, S. T.; Radaszkiewicz, T.

    1983-01-01

    We have postulated that binding of the hydrophobic anticonvulsant drug diphenylhydantoin (DPH) to lymphoid cells might induce graft-versus-host (GVH)-like cell reactions by T lymphocytes and thus trigger autoimmunization and lymphoma development observed in patients treated with DPH. This hypothesis

  6. Exposure to reactive intermediate-inducing drugs during pregnancy and the incident use of psychotropic medications among children

    NARCIS (Netherlands)

    Tran, Yen-Hao; Groen, Henk; Bergman, Jorieke E H; Hak, Eelko; Wilffert, Bob

    Purpose Our study aimed to investigate the association between prenatal exposure to reactive intermediate (RI)-inducing drugs and the initiation of psychotropic medications among children. Methods We designed a cohort study using a pharmacy prescription database. Pregnant women were considered

  7. Genotoxic effects induced by the exposure to an environmental mixture of illicit drugs to the zebra mussel.

    Science.gov (United States)

    Parolini, Marco; Magni, Stefano; Castiglioni, Sara; Binelli, Andrea

    2016-10-01

    Despite the growing interest on the presence of illicit drugs in freshwater ecosystems, just recently the attention has been focused on their potential toxicity towards non-target aquatic species. However, these studies largely neglected the effects induced by exposure to complex mixtures of illicit drugs, which could be different compared to those caused by single psychoactive molecules. This study was aimed at investigating the genetic damage induced by a 14-day exposure to a realistic mixture of the most common illicit drugs found in surface waters worldwide (cocaine, benzoylecgonine, amphetamine, morphine and 3,4-methylenedioxymethamphetamine) on the zebra mussel (Dreissena polymorpha). The mixture caused a significant increase of DNA fragmentation and triggered the apoptotic process and micronuclei formation in zebra mussel hemocytes, pointing out its potential genotoxicity towards this bivalve species. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. 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

  9. Correlation between drug–drug interaction-induced Stevens–Johnson syndrome and related deaths in Taiwan

    Directory of Open Access Journals (Sweden)

    Fu-Jen Cheng

    2016-04-01

    Full Text Available Concomitant use of some drugs can lead to interactions between them resulting in severe adverse effects. To date, there are few reports of incidences of Stevens-Johnson syndrome (SJS associated with combination drug administration. Therefore, we studied the relationship between drug combinations and SJS-related mortality, with the hope that a retrospective study of this nature would provide information crucial for the prevention of future drug-drug interaction related deaths attributable to SJS. This retrospective longitudinal study used mortality cases from 1999 to 2008 that were diagnosed as erythema multiforme (International Classification of Diseases, Ninth Revision, Clinical Modification 695.1 from the National Health Insurance database in Taiwan. Statistical comparisons of the results were performed using analysis of variance (ANOVA, independent sample t-tests, and odds ratio (OR. In this way, the relationship between combinations of SJS-inducing drugs and mortality could be determined. A total of 111 patients who had died, including 63 males and 48 females (66.0 ± 20 and 70.0 ± 17.7 years, respectively, were suspected of having experienced drug-drug interaction-related adverse effects. The associated drug combinations included allopurinol and ampicillin (p = 0.049, carbamazepine and sulfamethoxazole/trimethoprim (TMP (p < 0.0001, carbamazepine and phenytoin (p < 0.0001, sulfamethoxazole/TMP and phenytoin (p = 0.015, sulfadoxine and piroxicam (p = 0.045, phenobarbital and cephalexin (p < 0.0001, ampicillin and erythromycin (p < 0.0001, erythromycin and minocycline (p < 0.0001, and vancomycin and ethambutol (p < 0.0001 administered 1 month before the patients' deaths. Caution should be exercised when administering any drugs that may possibly induce SJS. In addition, attention should be paid to ensure prompt identification of possible drug-drug interactions, and patients should be closely monitored. Furthermore

  10. [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.

  11. Disease-specific induced pluripotent stem cells: a platform for human disease modeling and drug discovery.

    Science.gov (United States)

    Jang, Jiho; Yoo, Jeong-Eun; Lee, Jeong-Ah; Lee, Dongjin R; Kim, Ji Young; Huh, Yong Jun; Kim, Dae-Sung; Park, Chul-Yong; Hwang, Dong-Youn; Kim, Han-Soo; Kang, Hoon-Chul; Kim, Dong-Wook

    2012-03-31

    The generation of disease-specific induced pluripotent stem cell (iPSC) lines from patients with incurable diseases is a promising approach for studying disease mechanisms and drug screening. Such innovation enables to obtain autologous cell sources in regenerative medicine. Herein, we report the generation and characterization of iPSCs from fibroblasts of patients with sporadic or familial diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), juvenile-onset, type I diabetes mellitus (JDM), and Duchenne type muscular dystrophy (DMD), as well as from normal human fibroblasts (WT). As an example to modeling disease using disease-specific iPSCs, we also discuss the previously established childhood cerebral adrenoleukodystrophy (CCALD)- and adrenomyeloneuropathy (AMN)-iPSCs by our group. Through DNA fingerprinting analysis, the origins of generated disease-specific iPSC lines were identified. Each iPSC line exhibited an intense alkaline phosphatase activity, expression of pluripotent markers, and the potential to differentiate into all three embryonic germ layers: the ectoderm, endoderm, and mesoderm. Expression of endogenous pluripotent markers and downregulation of retrovirus-delivered transgenes [OCT4 (POU5F1), SOX2, KLF4, and c-MYC] were observed in the generated iPSCs. Collectively, our results demonstrated that disease-specific iPSC lines characteristically resembled hESC lines. Furthermore, we were able to differentiate PD-iPSCs, one of the disease-specific-iPSC lines we generated, into dopaminergic (DA) neurons, the cell type mostly affected by PD. These PD-specific DA neurons along with other examples of cell models derived from disease-specific iPSCs would provide a powerful platform for examining the pathophysiology of relevant diseases at the cellular and molecular levels and for developing new drugs and therapeutic regimens.

  12. A predictive ligand-based Bayesian model for human drug-induced liver injury.

    Science.gov (United States)

    Ekins, Sean; Williams, Antony J; Xu, Jinghai J

    2010-12-01

    Drug-induced liver injury (DILI) is one of the most important reasons for drug development failure at both preapproval and postapproval stages. There has been increased interest in developing predictive in vivo, in vitro, and in silico models to identify compounds that cause idiosyncratic hepatotoxicity. In the current study, we applied machine learning, a Bayesian modeling method with extended connectivity fingerprints and other interpretable descriptors. The model that was developed and internally validated (using a training set of 295 compounds) was then applied to a large test set relative to the training set (237 compounds) for external validation. The resulting concordance of 60%, sensitivity of 56%, and specificity of 67% were comparable to results for internal validation. The Bayesian model with extended connectivity functional class fingerprints of maximum diameter 6 (ECFC_6) and interpretable descriptors suggested several substructures that are chemically reactive and may also be important for DILI-causing compounds, e.g., ketones, diols, and α-methyl styrene type structures. Using Smiles Arbitrary Target Specification (SMARTS) filters published by several pharmaceutical companies, we evaluated whether such reactive substructures could be readily detected by any of the published filters. It was apparent that the most stringent filters used in this study, such as the Abbott alerts, which captures thiol traps and other compounds, may be of use in identifying DILI-causing compounds (sensitivity 67%). A significant outcome of the present study is that we provide predictions for many compounds that cause DILI by using the knowledge we have available from previous studies. These computational models may represent cost-effective selection criteria before in vitro or in vivo experimental studies.

  13. Proteomic candidate biomarkers of drug-induced nephrotoxicity in the rat.

    Directory of Open Access Journals (Sweden)

    Rodney Rouse

    Full Text Available Improved biomarkers of acute nephrotoxicity are coveted by the drug development industry, regulatory agencies, and clinicians. In an effort to identify such biomarkers, urinary peptide profiles of rats treated with two different nephrotoxins were investigated. 493 marker candidates were defined that showed a significant response to cis-platin comparing a cis-platin treated cohort to controls. Next, urine samples from rats that received three consecutive daily doses of 150 or 300 mg/kg gentamicin were examined. 557 potential biomarkers were initially identified; 108 of these gentamicin-response markers showed a clear temporal response to treatment. 39 of the cisplatin-response markers also displayed a clear response to gentamicin. Of the combined 147 peptides, 101 were similarly regulated by gentamicin or cis-platin and 54 could be identified by tandem mass spectrometry. Most were collagen type I and type III fragments up-regulated in response to gentamicin treatment. Based on these peptides, classification models were generated and validated in a longitudinal study. In agreement with histopathology, the observed changes in classification scores were transient, initiated after the first dose, and generally persistent over a period of 10-20 days before returning to control levels. The data support the hypothesis that gentamicin-induced renal toxicity up-regulates protease activity, resulting in an increase in several specific urinary collagen fragments. Urinary proteomic biomarkers identified here, especially those common to both nephrotoxins, may serve as a valuable tool to investigate potential new drug candidates for the risk of nephrotoxicity.

  14. Assessing Concordance of Drug-Induced Transcriptional Response in Rodent Liver and Cultured Hepatocytes.

    Directory of Open Access Journals (Sweden)

    Jeffrey J Sutherland

    2016-03-01

    Full Text Available The effect of drugs, disease and other perturbations on mRNA levels are studied using gene expression microarrays or RNA-seq, with the goal of understanding molecular effects arising from the perturbation. Previous comparisons of reproducibility across laboratories have been limited in scale and focused on a single model. The use of model systems, such as cultured primary cells or cancer cell lines, assumes that mechanistic insights derived from the models would have been observed via in vivo studies. We examined the concordance of compound-induced transcriptional changes using data from several sources: rat liver and rat primary hepatocytes (RPH from Drug Matrix (DM and open TG-GATEs (TG, human primary hepatocytes (HPH from TG, and mouse liver/HepG2 results from the Gene Expression Omnibus (GEO repository. Gene expression changes for treatments were normalized to controls and analyzed with three methods: 1 gene level for 9071 high expression genes in rat liver, 2 gene set analysis (GSA using canonical pathways and gene ontology sets, 3 weighted gene co-expression network analysis (WGCNA. Co-expression networks performed better than genes or GSA when comparing treatment effects within rat liver and rat vs. mouse liver. Genes and modules performed similarly at Connectivity Map-style analyses, where success at identifying similar treatments among a collection of reference profiles is the goal. Comparisons between rat liver and RPH, and those between RPH, HPH and HepG2 cells reveal lower concordance for all methods. We observe that the baseline state of untreated cultured cells relative to untreated rat liver shows striking similarity with toxicant-exposed cells in vivo, indicating that gross systems level perturbation in the underlying networks in culture may contribute to the low concordance.

  15. Development of optical neuroimaging to detect drug-induced brain functional changes in vivo

    Science.gov (United States)

    Du, Congwu; Pan, Yingtian

    2014-03-01

    Deficits in prefrontal function play a crucial role in compulsive cocaine use, which is a hallmark of addiction. Dysfunction of the prefrontal cortex might result from effects of cocaine on neurons as well as from disruption of cerebral blood vessels. However, the mechanisms underlying cocaine's neurotoxic effects are not fully understood, partially due to technical limitations of current imaging techniques (e.g., PET, fMRI) to differentiate vascular from neuronal effects at sufficiently high temporal and spatial resolutions. We have recently developed a multimodal imaging platform which can simultaneously characterize the changes in cerebrovascular hemodynamics, hemoglobin oxygenation and intracellular calcium fluorescence for monitoring the effects of cocaine on the brain. Such a multimodality imaging technique (OFI) provides several uniquely important merits, including: 1) a large field-of-view, 2) high spatiotemporal resolutions, 3) quantitative 3D imaging of the cerebral blood flow (CBF) networks, 4) label-free imaging of hemodynamic changes, 5) separation of vascular compartments (e.g., arterial and venous vessels) and monitoring of cortical brain metabolic changes, 6) discrimination of cellular (neuronal) from vascular responses. These imaging features have been further advanced in combination with microprobes to form micro-OFI that allows quantification of drug effects on subcortical brain. In addition, our ultrahigh-resolution ODT (μODT) enables 3D microangiography and quantitative imaging of capillary CBF networks. These optical strategies have been used to investigate the effects of cocaine on brain physiology to facilitate the studies of brain functional changes induced by addictive substance to provide new insights into neurobiological effects of the drug on the brain.

  16. Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells

    International Nuclear Information System (INIS)

    Taylor, David J; Parsons, Christine E; Han, Haiyong; Jayaraman, Arul; Rege, Kaushal

    2011-01-01

    Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL) and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis. FDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis. Fourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward malignant cells over normal pancreatic epithelial cells

  17. Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells

    Directory of Open Access Journals (Sweden)

    Taylor David J

    2011-11-01

    Full Text Available Abstract Background Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis. Methods FDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis. Results Fourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward

  18. Drug-related cue induced craving and the correlation between the activation in nucleus accumbens and drug craving: a fMRI study on heroin addicts

    International Nuclear Information System (INIS)

    Wang Yarong; Yang Lanying; Li Qiang; Yang Weichuan; Du Pang; Wang Wei

    2010-01-01

    Objective: To explore the neural mechanism underlying the craving of heroin addicts induced by picture-cue and the correlation between the brain activation degree in nucleus accumbens (NAc)/ the ventral striatum and the scores of patients self-report craving. Methods: Twelve active heroin addicts and 12 matched healthy controls underwent fMRI scan while viewing drug-related pictures and neutral pictures presented in a block design paradigm after anatomical scanning in GE 3.0 T scanner. The fMRI data were analyzed with SPM 5. The change of craving scores was tested by Wilcoxon signed rank test. The Pearson correlation between the activation of NAc/the ventral striatum and the heroin craving score was tested by SPSS 13.0. Results: The craving scores of heroin addicts ranged from 0 to 3.70 (median 0.15) before exposed to drug cue and 0 to 5.10 (median 3.25) after viewing drug-related pictures and showed statistical significance (Z=-2.666, P<0.05). There were 16 activated brain areas when heroin dependent patients exposed to visual drug-related cue vs. neutral visual stimuli. The activation brain regions belonged to two parts, one was limbic system (amygdale, hippocampus, putamen, anterior cingulate cortex and caudate), another was brain cortex (middle frontal cortex, inferior frontal cortex, precentral gyrus, middle temporal cortex, inferior temporal cortex, fusiform gyrus, precuneus and middle occipital gyrus). The MR signal activation magnitude of heroin addicts ranged from 0.19 to 3.50. The result displayed a significant positive correlation between the cue-induced fMRI activation in NAc/the ventral striatum and heroin craving severity (r=0.829, P<0.05). Conclusion: Heroin shared the same neural circuitry in part with other drugs of abuse for cue-induced craving, including brain reward circuitry, visualspatial attention circuit and working memory region. In addition, the dysfunction of NAc/the ventral striatum may attribute to heroin-related cue induced craving

  19. Strategies for the early detection of drug-induced hepatic steatosis in preclinical drug safety evaluation studies

    International Nuclear Information System (INIS)

    Amacher, David E.

    2011-01-01

    Hepatic steatosis is characterized by the accumulation of lipid droplets in the liver. Although relatively benign, simple steatosis can eventually lead to the development of steatohepatitis, a more serious condition characterized by fibrosis, cirrhosis, and eventual liver failure if the underlying cause is not eliminated. According to the 'two hit' theory of steatohepatitis, the initial hit involves fat accumulation in the liver, and a second hit leads to inflammation and subsequent tissue injury. Because some xenobiotics target liver fatty acid metabolism, especially mitochondrial β-oxidation, it is important to avoid potential drug candidates that can contribute to either the initiation of liver steatosis or progression to the more injurious steatohepatitis. The gold standard for the detection of these types of hepatic effects is histopathological examination of liver tissue. In animal studies, these examinations are slow, restricted to a single sampling time, and limited tissue sections. Recent literature suggests that rapid in vitro screening methods can be used early in the drug R and D process to identify compounds with steatotic potential. Further, progress in the identification of potential serum or plasma protein biomarkers for these liver changes may provide additional in vivo tools to the preclinical study toxicologist. This review summarizes recent developments for in vitro screening and in vivo biomarker detection for steatotic drug candidates.

  20. High-throughput identification of off-targets for the mechanistic study of severe adverse drug reactions induced by analgesics

    Energy Technology Data Exchange (ETDEWEB)

    Pan, Jian-Bo [Department of Chemical Biology, College of Chemistry and Chemical Engineering, The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, Fujian 361005 (China); Ji, Nan; Pan, Wen; Hong, Ru [State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102 (China); Wang, Hao [Department of Chemical Biology, College of Chemistry and Chemical Engineering, The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, Fujian 361005 (China); Ji, Zhi-Liang, E-mail: appo@xmu.edu.cn [State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102 (China); Department of Chemical Biology, College of Chemistry and Chemical Engineering, The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, Fujian 361005 (China)

    2014-01-01

    Drugs may induce adverse drug reactions (ADRs) when they unexpectedly bind to proteins other than their therapeutic targets. Identification of these undesired protein binding partners, called off-targets, can facilitate toxicity assessment in the early stages of drug development. In this study, a computational framework was introduced for the exploration of idiosyncratic mechanisms underlying analgesic-induced severe adverse drug reactions (SADRs). The putative analgesic-target interactions were predicted by performing reverse docking of analgesics or their active metabolites against human/mammal protein structures in a high-throughput manner. Subsequently, bioinformatics analyses were undertaken to identify ADR-associated proteins (ADRAPs) and pathways. Using the pathways and ADRAPs that this analysis identified, the mechanisms of SADRs such as cardiac disorders were explored. For instance, 53 putative ADRAPs and 24 pathways were linked with cardiac disorders, of which 10 ADRAPs were confirmed by previous experiments. Moreover, it was inferred that pathways such as base excision repair, glycolysis/glyconeogenesis, ErbB signaling, calcium signaling, and phosphatidyl inositol signaling likely play pivotal roles in drug-induced cardiac disorders. In conclusion, our framework offers an opportunity to globally understand SADRs at the molecular level, which has been difficult to realize through experiments. It also provides some valuable clues for drug repurposing. - Highlights: • A novel computational framework was developed for mechanistic study of SADRs. • Off-targets of drugs were identified in large scale and in a high-throughput manner. • SADRs like cardiac disorders were systematically explored in molecular networks. • A number of ADR-associated proteins were identified.

  1. High-throughput identification of off-targets for the mechanistic study of severe adverse drug reactions induced by analgesics

    International Nuclear Information System (INIS)

    Pan, Jian-Bo; Ji, Nan; Pan, Wen; Hong, Ru; Wang, Hao; Ji, Zhi-Liang

    2014-01-01

    Drugs may induce adverse drug reactions (ADRs) when they unexpectedly bind to proteins other than their therapeutic targets. Identification of these undesired protein binding partners, called off-targets, can facilitate toxicity assessment in the early stages of drug development. In this study, a computational framework was introduced for the exploration of idiosyncratic mechanisms underlying analgesic-induced severe adverse drug reactions (SADRs). The putative analgesic-target interactions were predicted by performing reverse docking of analgesics or their active metabolites against human/mammal protein structures in a high-throughput manner. Subsequently, bioinformatics analyses were undertaken to identify ADR-associated proteins (ADRAPs) and pathways. Using the pathways and ADRAPs that this analysis identified, the mechanisms of SADRs such as cardiac disorders were explored. For instance, 53 putative ADRAPs and 24 pathways were linked with cardiac disorders, of which 10 ADRAPs were confirmed by previous experiments. Moreover, it was inferred that pathways such as base excision repair, glycolysis/glyconeogenesis, ErbB signaling, calcium signaling, and phosphatidyl inositol signaling likely play pivotal roles in drug-induced cardiac disorders. In conclusion, our framework offers an opportunity to globally understand SADRs at the molecular level, which has been difficult to realize through experiments. It also provides some valuable clues for drug repurposing. - Highlights: • A novel computational framework was developed for mechanistic study of SADRs. • Off-targets of drugs were identified in large scale and in a high-throughput manner. • SADRs like cardiac disorders were systematically explored in molecular networks. • A number of ADR-associated proteins were identified

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

    International Nuclear Information System (INIS)

    Thomas, Roberta A.; Scicchitano, Marshall S.; Mirabile, Rosanna C.; Chau, Nancy T.; Frazier, Kendall S.; Thomas, Heath C.

    2012-01-01

    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

  3. 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.

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

    Directory of Open Access Journals (Sweden)

    Ruchi Banthia

    2014-01-01

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

  5. A Large Candidate Gene Survey Identifies the KCNE1 D85N Polymorphism as a Possible Modulator of Drug-Induced Torsades de Pointes

    NARCIS (Netherlands)

    Kaeaeb, Stefan; Crawford, Dana C.; Sinner, Moritz F.; Behr, Elijah R.; Kannankeril, Prince J.; Wilde, Arthur A. M.; Bezzina, Connie R.; Schulze-Bahr, Eric; Guicheney, Pascale; Bishopric, Nanette H.; Myerburg, Robert J.; Schott, Jean-Jacques; Pfeufer, Arne; Beckmann, Britt-Maria; Martens, Eimo; Zhang, Taifang; Stallmeyer, Birgit; Zumhagen, Sven; Denjoy, Isabelle; Bardai, Abdennasser; Van Gelder, Isabelle C.; Jamshidi, Yalda; Dalageorgou, Chrysoula; Marshall, Vanessa; Jeffery, Steve; Shakir, Saad; Camm, A. John; Steinbeck, Gerhard; Perz, Siegfried; Lichtner, Peter; Meitinger, Thomas; Peters, Annette; Wichmann, H. -Erich; Ingram, Christiana; Bradford, Yuki; Carter, Shannon; Norris, Kris; Ritchie, Marylyn D.; George, Alfred L.; Roden, Dan M.

    Background-Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS. Methods and Results-In a

  6. A Large Candidate Gene Survey Identifies the KCNE1 D85N Polymorphism as a Possible Modulator of Drug-Induced Torsades de Pointes

    NARCIS (Netherlands)

    Kääb, Stefan; Crawford, Dana C.; Sinner, Moritz F.; Behr, Elijah R.; Kannankeril, Prince J.; Wilde, Arthur A. M.; Bezzina, Connie R.; Schulze-Bahr, Eric; Guicheney, Pascale; Bishopric, Nanette H.; Myerburg, Robert J.; Schott, Jean-Jacques; Pfeufer, Arne; Beckmann, Britt-Maria; Martens, Eimo; Zhang, Taifang; Stallmeyer, Birgit; Zumhagen, Sven; Denjoy, Isabelle; Bardai, Abdennasser; van Gelder, Isabelle C.; Jamshidi, Yalda; Dalageorgou, Chrysoula; Marshall, Vanessa; Jeffery, Steve; Shakir, Saad; Camm, A. John; Steinbeck, Gerhard; Perz, Siegfried; Lichtner, Peter; Meitinger, Thomas; Peters, Annette; Wichmann, H.-Erich; Ingram, Christiana; Bradford, Yuki; Carter, Shannon; Norris, Kris; Ritchie, Marylyn D.; George, Alfred L.; Roden, Dan M.

    2012-01-01

    Background-Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS. Methods and Results-In a

  7. Successful management of drug-induced hypercapnic acidosis with naloxone and noninvasive positive pressure ventilation.

    Science.gov (United States)

    Agrafiotis, Michalis; Tryfon, Stavros; Siopi, Demetra; Chassapidou, Georgia; Galanou, Artemis; Tsara, Venetia

    2015-02-01

    A 74-year-old man was referred to our hospital due to deteriorating level of consciousness and desaturation. His Glasgow Coma Scale was 6, and his pupils were constricted but responded to light. Chest radiograph was negative for significant findings. Arterial blood gas evaluation on supplemental oxygen revealed severe acute on chronic respiratory acidosis: pH 7.15; PCO2, 133 mm Hg; PO2,64 mm Hg; and HCO3, 31 mmol/L. He regained full consciousness (Glasgow Coma Scale, 15) after receiving a 0.4 mg dose of naloxone, but because of persistent severe respiratory acidosis (pH 7.21; PCO2, 105 mm Hg), he was immediately commenced on noninvasive positive pressure ventilation (NIV) displaying a remarkable improvement in arterial blood gas values within the next few hours. However, in the days that followed, he remained dependent on NIV, and he was finally discharged on a home mechanical ventilation prescription. In cases of drug-induced respiratory depression, NIV should be regarded as an acceptable treatment, as it can provide ventilatory support without the increased risks associated with invasive mechanical ventilation.

  8. Gastrointestinal blood loss induced by three different non-steroidal anti-inflammatory drugs.

    Science.gov (United States)

    Bidlingmaier, A; Hammermaier, A; Nagyiványi, P; Pabst, G; Waitzinger, J

    1995-04-01

    A clinical study was performed on 18 healthy volunteers to compare the gastrointestinal daily blood loss induced by oral intake of three different non-steroidal anti-inflammatory drugs, lysine clonixinate (CAS 55837-30-4), ibuprofen (CAS 15687-27-1) and acetylsalicylic acid (CAS 50-78-2 ASA). For quantitative determination of gastrointestinal blood loss, autologous erythrocytes were radiolabelled in vitro with 51Cr and reinfused at study start. The amount of radioactivity excreted in faeces was measured during a placebo baseline phase of three days, a treatment phase of five days with thrice daily dosing of ASA, ibuprofen or lysine clonixinate and a subsequent wash-out phase of five days. The highest increase of mean daily blood loss over baseline was observed after treatment with ASA (+ 1.66 ml/d versus baseline). Treatment with ibuprofen led to an increase of mean daily blood loss by + 0.52 ml/d. During treatment with lysine clonixinate the mean increase of daily blood loss was +0.32 ml/d versus baseline. In the ibuprofen and lysine clonixinate treatment groups the values of mean daily blood loss decreased during the wash-out phase with respect to the verum phase, whereas the mean daily blood loss during the wash-out phase after treatment with ASA even increased in comparison to the verum phase (mean daily blood loss: +2.07 ml/d versus baseline.

  9. Persistent Drug-Induced Parkinsonism in Patients with Normal Dopamine Transporter Imaging.

    Directory of Open Access Journals (Sweden)

    Jin Yong Hong

    Full Text Available Functional neuroimaging for the dopamine transporter (DAT is used to distinguish drug-induced parkinsonism (DIP from subclinical Parkinson's disease (PD. Although DIP patients who show a normal DAT image are expected to recover completely, some do not. We investigated whether these patients showed changes in striatal DAT activity using semi-quantitative analysis of 18F-FP-CIT PET data. DIP patients with visually normal DAT images were selected from medical records. The subjects were classified as patients who recovered partially (PR or completely within 12 months (CR. The 18F-FP-CIT uptake in each striatal subregion was compared between the CR and the PR groups. In total, 41 and 9 patients of the CR and PR groups were assessed, respectively. The two patient groups were comparable in terms of clinical characteristics including age, sex, and severity of parkinsonism. From semi-quantitative analysis of the PET image, the PR patients showed a relatively lower ligand uptake in the ventral striatum, the anterior putamen and the posterior putamen compared with the CR patients. This result suggests that persistent DIP in patients with visually normal DAT imaging may be associated with subtle decrement of DAT activity.

  10. Thermoresponsive nanocomposite gel for local drug delivery to suppress the growth of glioma by inducing autophagy.

    Science.gov (United States)

    Ding, Li; Wang, Qi; Shen, Ming; Sun, Ying; Zhang, Xiangyu; Huang, Can; Chen, Jianhua; Li, Rongxin; Duan, Yourong

    2017-07-03

    Although the treatments of malignant glioma include surgery, radiotherapy and chemotherapy by oral drug administration, the prognosis of patients with glioma remains very poor. We developed a polyethylene glycol-dipalmitoylphosphatidyle- thanoiamine (mPEG-DPPE) calcium phosphate nanoparticles (NPs) injectable thermoresponsive hydrogel (nanocomposite gel) that could provide a sustained and local delivery of paclitaxel (PTX) and temozolomide (TMZ). In addition, the proportion of PTX and TMZ for the optimal synergistic antiglioma effect on C6 cells was determined to be 1:100 (w/w) by the Chou and Talalay method. Our results clearly indicated that the autophagy induced by PTX:TMZ NPs plays an important role in regulating tumor cell death, while autophagy inhibition dramatically reverses the antitumor effect of PTX:TMZ NPs, suggesting that antiproliferative autophagy occurs in response to PTX:TMZ NPs treatment. The antitumor efficacy of the PTX:TMZ NP-loaded gel was evaluated in situ using C6 tumor-bearing rats, and the PTX:TMZ NP-loaded gel exhibited superior antitumor performance. The antitumor effects of the nanocomposite gel in vivo were shown to correlate with autophagic cell death in this study. The in vivo results further confirmed the advantages of such a strategy. The present study may provide evidence supporting the development of nanomedicine for potential clinical application.

  11. Sodium Chloride Crystal-Induced SERS Platform for Controlled Highly Sensitive Detection of Illicit Drugs.

    Science.gov (United States)

    Yu, Borong; Li, Pan; Zhou, Binbin; Tang, Xianghu; Li, Shaofei; Yang, Liangbao

    2018-04-03

    A sodium chloride crystal-driven spontaneous 'hot spot' structure was demonstrated as a SERS-active platform, to get reproducible SERS signals, and eliminate the need for mapping large areas, in comparison with solution phase testing. During the process of solvent evaporation, the crystals produced induced silver aggregates to assemble around themselves. The micro-scale crystals can also act as a template to obtain an optical position, such that the assembled hot area is conveniently located during SERS measurements. More importantly, the chloride ions added in colloids can also replace the citrate and on the surface of the silver sol, and further decrease the background interference. High quality SERS spectra from heroin, methamphetamine (MAMP), and cocaine have been obtained on the crystal-driven hot spot structure with high sensitivity and credible reproducibility. This approach can not only bring the nanoparticles to form plasmonic hot spots in a controlled way, and thus provide high sensitivity, but also potentially be explored as an active substrate for label-free detection of other illicit drugs or additives. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. The predictive value of drug-induced sleep endoscopy for CPAP titration in OSA patients.

    Science.gov (United States)

    Lan, Ming-Chin; Hsu, Yen-Bin; Lan, Ming-Ying; Huang, Yun-Chen; Kao, Ming-Chang; Huang, Tung-Tsun; Chiu, Tsan-Jen; Yang, Mei-Chen

    2017-12-15

    The aim of this study was to identify possible upper airway obstructions causing a higher continuous positive airway pressure (CPAP) titration level, utilizing drug-induced sleep endoscopy (DISE). A total of 76 patients with obstructive sleep apnea (OSA) underwent CPAP titration and DISE. DISE findings were recorded using the VOTE classification system. Polysomnographic (PSG) data, anthropometric variables, and patterns of airway collapse during DISE were analyzed with CPAP titration levels. A significant association was found between the CPAP titration level and BMI, oxygen desaturation index (ODI), apnea-hypopnea index (AHI), and neck circumference (NC) (P CPAP titration level (P CPAP titration level and any other collapse at the tongue base or epiglottis. By analyzing PSG data, anthropometric variables, and DISE results with CPAP titration levels, we can better understand possible mechanisms resulting in a higher CPAP titration level. We believe that the role of DISE can be expanded as a tool to identify the possible anatomical structures that may be corrected by oral appliance therapy or surgical intervention to improve CPAP compliance.

  13. Drug-Induced Sleep Endoscopy Changes the Treatment Concept in Patients with Obstructive Sleep Apnoea

    Directory of Open Access Journals (Sweden)

    Jaroslava Hybášková

    2016-01-01

    Full Text Available The present study evaluated whether drug-induced sleep endoscopy (DISE helps identify the site of obstruction in patients with obstructive sleep apnoea (OSA. A total of 51 consecutive patients with polysomnography-confirmed OSA were enrolled in this prospective study. The presumed site of obstruction was determined according to history, otorhinolaryngologic examination, and polysomnography and a therapeutic plan designed before DISE. In 11 patients with severe OSA and/or previously failed continuous positive airway pressure (CPAP treatment, DISE with simultaneous CPAP was performed. Multilevel collapse was noted in 49 patients (96.1%. The most frequent multilevel collapse was palatal, oropharyngeal, and tongue base collapse (n=17, 33.3%, followed by palatal and oropharyngeal collapse (n=12, 23.5%. Pathology of the larynx (epiglottis was observed in 16 patients (31.4%. The laryngeal obstruction as a reason for intolerance of CPAP was observed in 3/11 (27.3% patients. After DISE, the surgical plan was changed in 31 patients (60.8%. The results indicate that DISE helps identify the site of obstruction in the upper airways in patients with OSA more accurately and that the larynx plays an important role in OSA.

  14. A patch test confirmed phenobarbital-induced fixed drug eruption in a child.

    Science.gov (United States)

    Chadly, Zohra; Aouam, Karim; Chaabane, Amel; Belhadjali, Hichem; Abderrazzak Boughattas, Naceur; Zili, Jamel Eddine

    2014-06-01

    A-10-year-old girl was referred to our department for multiple hyperpigmented plaques. One week previously, she had been given one suppository of acetylsalicylic acid - phenobarbital for fever. Twelve hours after the drug intake the child developed pruritic red plaques on the left thigh. Six weeks after resolution of the acute reaction, patch tests were performed separately, with phenobarbital and acetylsalicylic acid. On 48-hour reading, only the phenobarbital patch test on residual pigmented lesion was positive. Because of possible cross-reactions between aromatic anticonvulsants, subsequent patch tests using carbamazepine and phenytoin on residual pigmented lesions were performed. They were all negative at 48-hour reading. To our knowledge, only two isolated pediatric cases of Phenobarbital-induced FDE have been reported in the literature. In this case report, as it was difficult to determine whether phenobarbital or acetylsalicylic acid was responsible for this reaction, subsequent patch tests allowed the identification of the culprit component since it was positive to phenobarbital.

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

    Science.gov (United States)

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

    2014-01-01

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

  16. Drug-induced sedation endoscopy (DISE) classification systems: a systematic review and meta-analysis.

    Science.gov (United States)

    Dijemeni, Esuabom; D'Amone, Gabriele; Gbati, Israel

    2017-12-01

    Drug-induced sedation endoscopy (DISE) classification systems have been used to assess anatomical findings on upper airway obstruction, and decide and plan surgical treatments and act as a predictor for surgical treatment outcome for obstructive sleep apnoea management. The first objective is to identify if there is a universally accepted DISE grading and classification system for analysing DISE findings. The second objective is to identify if there is one DISE grading and classification treatment planning framework for deciding appropriate surgical treatment for obstructive sleep apnoea (OSA). The third objective is to identify if there is one DISE grading and classification treatment outcome framework for determining the likelihood of success for a given OSA surgical intervention. A systematic review was performed to identify new and significantly modified DISE classification systems: concept, advantages and disadvantages. Fourteen studies proposing a new DISE classification system and three studies proposing a significantly modified DISE classification were identified. None of the studies were based on randomised control trials. DISE is an objective method for visualising upper airway obstruction. The classification and assessment of clinical findings based on DISE is highly subjective due to the increasing number of DISE classification systems. Hence, this creates a growing divergence in surgical treatment planning and treatment outcome. Further research on a universally accepted objective DISE assessment is critically needed.

  17. Pharmacy Students' Learning and Satisfaction With High-Fidelity Simulation to Teach Drug-Induced Dyspepsia

    Science.gov (United States)

    2013-01-01

    Objective. To assess second-year pharmacy students’ acquisition of pharmacotherapy knowledge and clinical competence from participation in a high-fidelity simulation, and to determine the impact on the simulation experience of implementing feedback from previous students. Design. A high-fidelity simulation was used to present a patient case scenario of drug-induced dyspepsia with gastrointestinal bleeding. The simulation was revised based on feedback from a previous class of students to include a smaller group size, provision of session material to students in advance, and an improved learning environment. Assessment. Student performance on pre- and post-simulation knowledge and clinical competence tests documented significant improvements in students' knowledge of dyspepsia and associated symptoms, with the greatest improvement on questions relating to the hemodynamic effects of gastrointestinal bleeding. Students were more satisfied with the simulation experience compared to students in the earlier study. Conclusion. Participation in a high-fidelity simulation allowed pharmacy students to apply knowledge and skills learned in the classroom. Improved student satisfaction with the simulation suggests that implementing feedback obtained through student course evaluations can be an effective means of improving the curriculum. PMID:23519773

  18. Food and Drug Administration criteria for the diagnosis of drug-induced valvular heart disease in patients previously exposed to benfluorex: a prospective multicentre study.

    Science.gov (United States)

    Maréchaux, Sylvestre; Rusinaru, Dan; Jobic, Yannick; Ederhy, Stéphane; Donal, Erwan; Réant, Patricia; Arnalsteen, Elise; Boulanger, Jacques; Garban, Thierry; Ennezat, Pierre-Vladimir; Jeu, Antoine; Szymanski, Catherine; Tribouilloy, Christophe

    2015-02-01

    The Food and Drug Administration (FDA) criteria for diagnosis of drug-induced valvular heart disease (DIVHD) are only based on the observation of aortic regurgitation ≥ mild and/or mitral regurgitation ≥ moderate. We sought to evaluate the diagnostic value of FDA criteria in a cohort of control patients and in a cohort of patients exposed to a drug (benfluorex) known to induce VHD. This prospective, multicentre study included 376 diabetic control patients not exposed to valvulopathic drugs and 1000 subjects previously exposed to benfluorex. Diagnosis of mitral or aortic DIVHD was based on a combined functional and morphological echocardiographic analysis of cardiac valves. Patients were classified according to the FDA criteria [mitral or aortic-FDA(+) and mitral or aortic-FDA(-)]. Among the 376 control patients, 2 were wrongly classified as mitral-FDA(+) and 17 as aortic-FDA(+) (0.53 and 4.5% of false positives, respectively). Of those exposed to benfluorex, 48 of 58 with a diagnosis of mitral DIVHD (83%) were classified as mitral-FDA(-), and 901 of the 910 patients (99%) without a diagnosis of the mitral DIVHD group were classified as mitral-FDA(-). All 40 patients with a diagnosis of aortic DIVHD were classified as aortic-FDA(+), and 105 of the 910 patients without a diagnosis of aortic DIVHD (12%) were classified aortic-FDA(+). Older age and lower BMI were independent predictors of disagreement between FDA criteria and the diagnosis of DIVHD in patients exposed to benfluorex (both P ≤ 0.001). FDA criteria solely based on the Doppler detection of cardiac valve regurgitation underestimate for the mitral valve and overestimate for the aortic valve the frequency of DIVHD. Therefore, the diagnosis of DIVHD must be based on a combined echocardiographic and Doppler morphological and functional analysis of cardiac valves. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

  19. Evaluation of the Potential Risk of Drugs to Induce Hepatotoxicity in Human?Relationships between Hepatic Steatosis Observed in Non-Clinical Toxicity Study and Hepatotoxicity in Humans-

    OpenAIRE

    Goda, Keisuke; Kobayashi, Akio; Takahashi, Akemi; Takahashi, Tadakazu; Saito, Kosuke; Maekawa, Keiko; Saito, Yoshiro; Sugai, Shoichiro

    2017-01-01

    In the development of drugs, we sometimes encounter fatty change of the hepatocytes (steatosis) which is not accompanied by degenerative change in the liver in non-clinical toxicity studies. In this study, we investigated the relationships between fatty change of the hepatocytes noted in non-clinical toxicity studies of compound X, a candidate compound in drug development, and mitochondrial dysfunction in order to estimate the potential risk of the compound to induce drug-induced liver injury...

  20. Testosterone-induced benign prostatic hyperplasia rat and dog as facile models to assess drugs targeting lower urinary tract symptoms.

    Directory of Open Access Journals (Sweden)

    Jing Li

    Full Text Available Benign prostatic hyperplasia (BPH is an age-related disease, affecting a majority of elderly men worldwide. Medical management of BPH is an alternative to surgical treatment of this disease. Currently, α1-adrenergic receptor (α1-AR antagonists are among the first line drugs to treat BPH by reducing the tension of urinary track and thus the obstructive symptoms in voiding. In drug development, old male dogs with spontaneous BPH are considered the golden standard of the animal models. However, old dogs (>6 years are expensive and not all old dogs develop BPH. So it is necessary to develop more accessible animal models for drug efficacy evaluation. Here we describe the development of testosterone-induced BPH models in both rats and young adult dogs and their applications in the in vivo evaluation of α1-AR antagonist. The BPH rats and dogs induced by chronic testosterone treatment have significantly increased micturition frequency and reduced mean voided volume, very similar to the clinical symptoms of BPH patients. Silodosin, an α1-AR antagonist, significantly reduces the urinary frequency and increases the voided volume in BPH model animals in a dose-dependent manner. The results demonstrate that testosterone-induced BPH rat and dog models might provide a more efficient way to evaluate micturition behavior in anti-BPH drug studies.

  1. 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.

  2. Global Optimization of Ventricular Myocyte Model to Multi-Variable Objective Improves Predictions of Drug-Induced Torsades de Pointes

    Directory of Open Access Journals (Sweden)

    Trine Krogh-Madsen

    2017-12-01

    Full Text Available In silico cardiac myocyte models present powerful tools for drug safety testing and for predicting phenotypical consequences of ion channel mutations, but their accuracy is sometimes limited. For example, several models describing human ventricular electrophysiology perform poorly when simulating effects of long QT mutations. Model optimization represents one way of obtaining models with stronger predictive power. Using a recent human ventricular myocyte model, we demonstrate that model optimization to clinical long QT data, in conjunction with physiologically-based bounds on intracellular calcium and sodium concentrations, better constrains model parameters. To determine if the model optimized to congenital long QT data better predicts risk of drug-induced long QT arrhythmogenesis, in particular Torsades de Pointes risk, we tested the optimized model against a database of known arrhythmogenic and non-arrhythmogenic ion channel blockers. When doing so, the optimized model provided an improved risk assessment. In particular, we demonstrate an elimination of false-positive outcomes generated by the baseline model, in which simulations of non-torsadogenic drugs, in particular verapamil, predict action potential prolongation. Our results underscore the importance of currents beyond those directly impacted by a drug block in determining torsadogenic risk. Our study also highlights the need for rich data in cardiac myocyte model optimization and substantiates such optimization as a method to generate models with higher accuracy of predictions of drug-induced cardiotoxicity.

  3. Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro.

    Directory of Open Access Journals (Sweden)

    Deborah G Nguyen

    Full Text Available 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.

  4. The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model.

    Directory of Open Access Journals (Sweden)

    Qi-Liang Mao-Ying

    Full Text Available Chemotherapy-induced peripheral neuropathy (CIPN characterized by loss of sensory sensitivity and pain in hands and feet is the major dose-limiting toxicity of many chemotherapeutics. At present, there are no FDA-approved treatments for CIPN. The anti-diabetic drug metformin is the most widely used prescription drug in the world and improves glycemic control in diabetes patients. There is some evidence that metformin enhances the efficacy of cancer treatment. The aim of this study was to test the hypothesis that metformin protects against chemotherapy-induced neuropathic pain and sensory deficits. Mice were treated with cisplatin together with metformin or saline. Cisplatin induced increased sensitivity to mechanical stimulation (mechanical allodynia as measured using the von Frey test. Co-administration of metformin almost completely prevented the cisplatin-induced mechanical allodynia. Co-administration of metformin also prevented paclitaxel-induced mechanical allodynia. The capacity of the mice to detect an adhesive patch on their hind paw was used as a novel indicator of chemotherapy-induced sensory deficits. Co-administration of metformin prevented the cisplatin-induced increase in latency to detect the adhesive patch indicating that metformin prevents sensory deficits as well. Moreover, metformin prevented the reduction in density of intra-epidermal nerve fibers (IENFs in the paw that develops as a result of cisplatin treatment. We conclude that metformin protects against pain and loss of tactile function in a mouse model of CIPN. The finding that metformin reduces loss of peripheral nerve endings indicates that mechanism underlying the beneficial effects of metformin includes a neuroprotective activity. Because metformin is widely used for treatment of type II diabetes, has a broad safety profile, and is currently being tested as an adjuvant drug in cancer treatment, clinical translation of these findings could be rapidly achieved.

  5. Neurofeedback Effects on Evoked and Induced EEG Gamma Band Reactivity to Drug-related Cues in Cocaine Addiction

    Science.gov (United States)

    Horrell, Timothy; El-Baz, Ayman; Baruth, Joshua; Tasman, Allan; Sokhadze, Guela; Stewart, Christopher; Sokhadze, Estate

    2010-01-01

    Introduction Preoccupation with drug and drug-related items is a typical characteristic of cocaine addicted individuals. It has been shown in multiple accounts that prolonged drug use has a profound effect on the EEG recordings of drug addicts when compared to controls during cue reactivity tests. Cue reactivity refers to a phenomenon in which individuals with a history of drug abuse exhibit excessive psychophysiological responses to cues associated with their drug of choice. One of the aims of this pilot study was to determine the presence of an attentional bias to preferentially process drug-related cues using evoked and induced gamma reactivity measures in cocaine addicts before and after biobehavioral treatment based on neurofeedback. Another aim was to show that central SMR amplitude increase and frontal theta control is possible in an experimental outpatient drug users group over 12 neurofeedback sessions. Method Ten current cocaine abusers participated in this pilot research study using neurofeedback combined with Motivational Interviewing sessions. Eight of them completed all planned pre- and post –neurofeedback cue reactivity tests with event-related EEG recording and clinical evaluations. Cue reactivity test represented a visual oddball task with images from the International Affective Picture System and drug-related pictures. Evoked and induced gamma responses to target and non-target drug cues were analyzed using wavelet analysis. Results Outpatient subjects with cocaine addiction completed the biobehavioral intervention and successfully increased SMR while keeping theta practically unchanged in 12 sessions of neurofeedback training. The addition of Motivational Interviewing helped retain patients in the study. Clinical evaluations immediately after completion of the treatment showed decreased self-reports on depression and stress scores, and urine tests collaborated reports of decreased use of cocaine and marijuana. Effects of neurofeedback resulted

  6. Global mass spectrometry and transcriptomics array based drug profiling provides novel insight into glucosamine induced endoplasmic reticulum stress

    DEFF Research Database (Denmark)

    Carvalho, Ana Sofia; Ribeiro, Helena; Voabil, Paula

    2014-01-01

    We investigated the molecular effects of glucosamine supplements, a popular and safe alternative to nonsteroidal anti-inflammatory drugs, for decreasing pain, inflammation, and maintaining healthy joints. Numerous studies have reported an array of molecular effects after glucosamine treatment. We...... questioned whether the differences in the effects observed in previous studies were associated with the focus on a specific subproteome or with the use of specific cell lines or tissues. To address this question, global mass spectrometry- and transcription array-based glucosamine drug profiling was performed....... Further, we hypothesize that O-HexNAcylation induced by glucosamine treatment enhances protein trafficking....

  7. Modulating effect of the nootropic drug, piracetam on stress- and subsequent morphine-induced prolactin secretion in male rats.

    OpenAIRE

    Matton, A.; Engelborghs, S.; Bollengier, F.; Finné, E.; Vanhaeist, L.

    1996-01-01

    1. The effect of the nootropic drug, piracetam on stress- and subsequent morphine-induced prolactin (PRL) secretion was investigated in vivo in male rats, by use of a stress-free blood sampling and drug administration method by means of a permanent indwelling catheter in the right jugular vein. 2. Four doses of piracetam were tested (20, 100, 200 and 400 mg kg-1), being given intraperitoneally 1 h before blood sampling; control rats received saline instead. After a first blood sample, rats we...

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

    Directory of Open Access Journals (Sweden)

    Linda Bosserman

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

  9. Attenuation of radiation- and drug-induced conditioned taste aversions following area postrema lesions in the rat

    International Nuclear Information System (INIS)

    Rabin, B.M.; Hunt, W.A.; Lee, J.

    1983-01-01

    The effects of lesions of the area postrema on the acquisition of radiation- and drug-induced (histamine and lithium chloride) conditioned taste aversions were investigated. The results indicated that area postrema lesions caused a significant attenuation of the aversion produced by pairing a novel sucrose solution with radiation (100 rad) or drug injection. Further, the area postrema lesions produced a similar level of attenuation of the taste aversion in all three treatment conditions. The results are discussed in terms of the implications of this finding for defining the mechanisms by which exposure to ionizing radiation can lead to the acquisition of a conditioned taste aversion

  10. Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for QT prolongation

    International Nuclear Information System (INIS)

    Nozaki, Yumiko; Honda, Yayoi; Tsujimoto, Shinji; Watanabe, Hitoshi; Kunimatsu, Takeshi; Funabashi, Hitoshi

    2014-01-01

    Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in an electrocardiogram, is reported to be a useful tool to predict K + channel and Ca 2+ channel blocker effects on QT interval. However, there is no report showing that this technique can be used to predict multichannel blocker potential for QT prolongation. The aim of this study is to show that FPD from MEA (Multielectrode array) of hiPS-CMs can detect QT prolongation induced by multichannel blockers. hiPS-CMs were seeded onto MEA and FPD was measured for 2 min every 10 min for 30 min after drug exposure for the vehicle and each drug concentration. I Kr and I Ks blockers concentration-dependently prolonged corrected FPD (FPDc), whereas Ca 2+ channel blockers concentration-dependently shortened FPDc. Also, the multichannel blockers Amiodarone, Paroxetine, Terfenadine and Citalopram prolonged FPDc in a concentration dependent manner. Finally, the I Kr blockers, Terfenadine and Citalopram, which are reported to cause Torsade de Pointes (TdP) in clinical practice, produced early afterdepolarization (EAD). hiPS-CMs using MEA system and FPDc can predict the effects of drug candidates on QT interval. This study also shows that this assay can help detect EAD for drugs with TdP potential. - Highlights: • We focused on hiPS-CMs to replace in vitro assays in preclinical screening studies. • hiPS-CMs FPD is useful as an indicator to predict drug potential for QT prolongation. • MEA assay can help detect EAD for drugs with TdP potentials. • MEA assay in hiPS-CMs is useful for accurately predicting drug TdP risk in humans

  11. Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for QT prolongation

    Energy Technology Data Exchange (ETDEWEB)

    Nozaki, Yumiko, E-mail: yumiko-nozaki@ds-pharma.co.jp [Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053 (Japan); Honda, Yayoi, E-mail: yayoi-honda@ds-pharma.co.jp [Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053 (Japan); Tsujimoto, Shinji, E-mail: shinji-tsujimoto@ds-pharma.co.jp [Regenerative and Cellular Medicine Office, Dainippon Sumitomo Pharma. Co., Ltd., Chuo-ku, Tokyo 104-0031 (Japan); Watanabe, Hitoshi, E-mail: hitoshi-1-watanabe@ds-pharma.co.jp [Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053 (Japan); Kunimatsu, Takeshi, E-mail: takeshi-kunimatsu@ds-pharma.co.jp [Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053 (Japan); Funabashi, Hitoshi, E-mail: hitoshi-funabashi@ds-pharma.co.jp [Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053 (Japan)

    2014-07-01

    Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in an electrocardiogram, is reported to be a useful tool to predict K{sup +} channel and Ca{sup 2+} channel blocker effects on QT interval. However, there is no report showing that this technique can be used to predict multichannel blocker potential for QT prolongation. The aim of this study is to show that FPD from MEA (Multielectrode array) of hiPS-CMs can detect QT prolongation induced by multichannel blockers. hiPS-CMs were seeded onto MEA and FPD was measured for 2 min every 10 min for 30 min after drug exposure for the vehicle and each drug concentration. I{sub Kr} and I{sub Ks} blockers concentration-dependently prolonged corrected FPD (FPDc), whereas Ca{sup 2+} channel blockers concentration-dependently shortened FPDc. Also, the multichannel blockers Amiodarone, Paroxetine, Terfenadine and Citalopram prolonged FPDc in a concentration dependent manner. Finally, the I{sub Kr} blockers, Terfenadine and Citalopram, which are reported to cause Torsade de Pointes (TdP) in clinical practice, produced early afterdepolarization (EAD). hiPS-CMs using MEA system and FPDc can predict the effects of drug candidates on QT interval. This study also shows that this assay can help detect EAD for drugs with TdP potential. - Highlights: • We focused on hiPS-CMs to replace in vitro assays in preclinical screening studies. • hiPS-CMs FPD is useful as an indicator to predict drug potential for QT prolongation. • MEA assay can help detect EAD for drugs with TdP potentials. • MEA assay in hiPS-CMs is useful for accurately predicting drug TdP risk in humans.

  12. Incubation of extinction responding and cue-induced reinstatement, but not context- or drug priming-induced reinstatement, after withdrawal from methamphetamine.

    Science.gov (United States)

    Adhikary, Sweta; Caprioli, Daniele; Venniro, Marco; Kallenberger, Paige; Shaham, Yavin; Bossert, Jennifer M

    2017-07-01

    In rats trained to self-administer methamphetamine, extinction responding in the presence of drug-associated contextual and discrete cues progressively increases after withdrawal (incubation of methamphetamine craving). The conditioning factors underlying this incubation are unknown. Here, we studied incubation of methamphetamine craving under different experimental conditions to identify factors contributing to this incubation. We also determined whether the rats' response to methamphetamine priming incubates after withdrawal. We trained rats to self-administer methamphetamine in a distinct context (context A) for 14 days (6 hours/day). Lever presses were paired with a discrete light cue. We then tested groups of rats in context A or a different non-drug context (context B) after 1 day, 1 week or 1 month for extinction responding with or without the discrete cue. Subsequently, we tested the rats for reinstatement of drug seeking induced by exposure to contextual, discrete cue, or drug priming (0, 0.25 and 0.5 mg/kg). Operant responding in the extinction sessions in contexts A or B was higher after 1 week and 1 month of withdrawal than after 1 day; this effect was context-independent. Independent of the withdrawal period, operant responding in the extinction sessions was higher when responding led to contingent delivery of the discrete cue. After extinction, discrete cue-induced reinstatement, but not context- or drug priming-induced reinstatement, progressively increased after withdrawal. Together, incubation of methamphetamine craving, as assessed in extinction tests, is primarily mediated by time-dependent increases in non-reinforced operant responding, and this effect is potentiated by exposure to discrete, but not contextual, cues. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

  13. Incidence of antituberculosis-drug-induced hepatotoxicity and associated risk factors among tuberculosis patients in Dawro Zone, South Ethiopia: A cohort study

    OpenAIRE

    Wondwossen Abera,; Waqtola Cheneke,; Gemeda Abebe,

    2016-01-01

    Background: Antituberculosis drugs cause hepatotoxicity in some individuals leading to acute liver failure, which results in death. Such phenomena limit the clinical use of drugs, contributing to treatment failure that possibly causes drug resistance. Furthermore, associated risk factors for the development of antituberculosis-drug-induced hepatotoxicity (anti-TB-DIH) are found to be controversial among different study findings. Methods: A prospective cohort study was conducted from May 20...

  14. Cell-specific prediction and application of drug-induced gene expression profiles.

    Science.gov (United States)

    Hodos, Rachel; Zhang, Ping; Lee, Hao-Chih; Duan, Qiaonan; Wang, Zichen; Clark, Neil R; Ma'ayan, Avi; Wang, Fei; Kidd, Brian; Hu, Jianying; Sontag, David; Dudley, Joel

    2018-01-01

    Gene expression profiling of in vitro drug perturbations is useful for many biomedical discovery applications including drug repurposing and elucidation of drug mechanisms. However, limited data availability across cell types has hindered our capacity to leverage or explore the cell-specificity of these perturbations. While recent efforts have generated a large number of drug perturbation profiles across a variety of human cell types, many gaps remain in this combinatorial drug-cell space. Hence, we asked whether it is possible to fill these gaps by predicting cell-specific drug perturbation profiles using available expression data from related conditions--i.e. from other drugs and cell types. We developed a computational framework that first arranges existing profiles into a three-dimensional array (or tensor) indexed by drugs, genes, and cell types, and then uses either local (nearest-neighbors) or global (tensor completion) information to predict unmeasured profiles. We evaluate prediction accuracy using a variety of metrics, and find that the two methods have complementary performance, each superior in different regions in the drug-cell space. Predictions achieve correlations of 0.68 with true values, and maintain accurate differentially expressed genes (AUC 0.81). Finally, we demonstrate that the predicted profiles add value for making downstream associations with drug targets and therapeutic classes.

  15. Preventive efficacy and safety of rebamipide in nonsteroidal anti-inflammatory drug-induced mucosal toxicity.

    Science.gov (United States)

    Kim, Jeong Ho; Park, Soo-Heon; Cho, Chul-Soo; Lee, Soo Teik; Yoo, Wan-Hee; Kim, Sung Kook; Kang, Young Mo; Rew, Jong Sun; Park, Yong-Wook; Lee, Soo Kon; Lee, Yong Chan; Park, Won; Lee, Don-Haeng

    2014-07-01

    The use of proton pump inhibitors or misoprostol is known to prevent the gastrointestinal complications of nonsteroidal anti-inflammatory drugs (NSAIDs). Rebamipide is known to increase the mucosal generation of prostaglandins and to eliminate free oxygen radicals, thus enhancing the protective function of the gastric mucosa. However, it is unknown whether rebamipide plays a role in preventing NSAID-induced gastropathy. The aim of this study was to determine the effectiveness of rebamipide compared to misoprostol in preventing NSAID-induced gastrointestinal complications in patients requiring continuous NSAID treatment. We studied 479 patients who required continuous NSAID treatment. The patients were randomly assigned to groups that received 100 mg of rebamipide three times per day or 200 μg of misoprostol three times per day for 12 weeks. The primary endpoint of the analysis was the occurrence rate of gastric ulcers, as determined by endoscopy after 12 weeks of therapy. Of the 479 patients in the study, 242 received rebamipide, and 237 received misoprostol. Ultimately, 44 patients (18.6%) withdrew from the misoprostol group and 25 patients (10.3%) withdrew from the rebamipide group. There was a significant difference in withdrawal rate between the two groups (p=0.0103). The per protocol analysis set was not valid because of the dropout rate of the misoprostol group; thus, the intention to treat (ITT) analysis set is the main set for the efficacy analysis in this study. After 12 weeks, the occurrence rate of gastric ulcers was similar in the rebamipide and misoprostol groups (20.3% vs 21.9%, p=0.6497) according to ITT analysis. In addition, the therapeutic failure rate was similar in the rebamipide and misoprostol groups (13.6% vs 13.1%, p=0.8580). The total severity score of the gastrointestinal symptoms was significantly lower in the rebamipide group than in the misoprostol group (p=0.0002). The amount of antacid used was significantly lower in the rebamipide

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

    Directory of Open Access Journals (Sweden)

    Jeffrey L Woodhead

    2014-11-01

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

  17. The Nonsteroidal Anti-inflammatory Drug Diclofenac Reduces Acid-Induced Heartburn Symptoms in Healthy Volunteers.

    Science.gov (United States)

    Kondo, Takashi; Oshima, Tadayuki; Tomita, Toshihiko; Fukui, Hirokazu; Okada, Hiroki; Watari, Jiro; Miwa, Hiroto

    2015-07-01

    We investigated the effects of diclofenac, a nonsteroidal anti-inflammatory drug that inhibits prostaglandin production, on induction of esophageal sensation by acid perfusion in healthy men. We performed a prospective, double-blind, placebo-controlled, 2-period, cross-over study over 3 visits in 12 healthy men. Diclofenac was given 6 hours and 2 hours before an acid perfusion test. During the test, hydrochloric acid (0.15 mol/L) was perfused into the lower esophagus for 30 minutes; we evaluated upper gastrointestinal symptoms using a validated categoric rating scale. Then, we calculated and assessed the acid perfusion sensitivity score (APSS). Biopsy specimens were collected by endoscopy of the distal esophagus before and after acid perfusion; levels of prostaglandin E2 (PGE2) (pg/mg) were measured in the samples using an enzyme-linked immunosorbent assay. Compared with placebo, diclofenac significantly reduced the APSS for heartburn (82.2 ± 12.2 for placebo and 47.5 ± 8.9 for diclofenac; P heartburn was reduced significantly by diclofenac. Compared with placebo, diclofenac reduced the overproduction of PGE2 by esophageal tissues after acid perfusion (23.3 ± 5.2 for placebo and 11.4 ± 3.5 for diclofenac; P heartburn and esophageal levels of PGE2 (r = 0.53; P heartburn vs PGE2). Diclofenac attenuated acid-induced heartburn by inhibiting PGE2 overproduction in the esophagus. Esophageal PGE2 might be involved in producing heartburn symptoms. Clinical Trials Registry no: UMIN000014595. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

  18. Diagnostic performance of traditional hepatobiliary biomarkers of drug-induced liver injury in the rat.

    Science.gov (United States)

    Ennulat, Daniela; Magid-Slav, Michal; Rehm, Sabine; Tatsuoka, Kay S

    2010-08-01

    Nonclinical studies provide the opportunity to anchor biochemical with morphologic findings; however, liver injury is often complex and heterogeneous, confounding the ability to relate biochemical changes with specific patterns of injury. The aim of the current study was to compare diagnostic performance of hepatobiliary markers for specific manifestations of drug-induced liver injury in rat using data collected in a recent hepatic toxicogenomics initiative in which rats (n = 3205) were given 182 different treatments for 4 or 14 days. Diagnostic accuracy of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (Tbili), serum bile acids (SBA), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total cholesterol (Chol), and triglycerides (Trig) was evaluated for specific types of liver histopathology by Receiver Operating Characteristic (ROC) analysis. To assess the relationship between biochemical and morphologic changes in the absence of hepatocellular necrosis, a second ROC analysis was performed on a subset of rats (n = 2504) given treatments (n = 152) that did not cause hepatocellular necrosis. In the initial analysis, ALT, AST, Tbili, and SBA had the greatest diagnostic utility for manifestations of hepatocellular necrosis and biliary injury, with comparable magnitude of area under the ROC curve and serum hepatobiliary marker changes for both. In the absence of hepatocellular necrosis, ALT increases were observed with biochemical or morphologic evidence of cholestasis. In both analyses, diagnostic utility of ALP and GGT for biliary injury was limited; however, ALP had modest diagnostic value for peroxisome proliferation, and ALT, AST, and total Chol had moderate diagnostic utility for phospholipidosis. None of the eight markers evaluated had diagnostic value for manifestations of hypertrophy, cytoplasmic rarefaction, inflammation, or lipidosis.

  19. Characteristics of Korean Patients with Antithyroid Drug-Induced Agranulocytosis: A Multicenter Study in Korea

    Science.gov (United States)

    Kim, Hee Kyung; Yoon, Jee Hee; Jeon, Min Ji; Kim, Tae Yong; Shong, Young Kee; Lee, Min Jin; Kim, Bo Hyun; Kim, In Joo; Joung, Ji Young; Kim, Sun Wook; Chung, Jae Hoon

    2015-01-01

    Background Antithyroid drugs (ATDs) can lead to the development of agranulocytosis, which is the most serious adverse effect. Characteristics of ATD-induced agranulocytosis (AIA) have seldom been reported due to the rarity. In this study, we characterized the clinical features for AIA in Korean patients. Methods We retrospectively reviewed data from patients with AIA diagnosed between 1997 and 2014 at four tertiary hospitals. Agranulocytosis was defined as an absolute neutrophil count (ANC) below 500/mm3. Results The mean age of the patients (11 males, 43 females) was 38.2±14.9 years. Forty-eight patients (88.9%) with AIA had fever and sore throat on initial presentation, 20.4% of patients developed AIA during the second course of treatment, and 75.9% of patients suffered AIA within 3 months after initiation of ATD. The patients taking methimazole (n=39) showed lower levels of ANC and more frequent use of granulocyte-macrophage colony-stimulating factor than propylthiouracil (n=15) users. The median duration of agranulocytosis was 5.5 days (range, 1 to 20). No differences were observed between the long (≥6 days) and short recovery time (≤5 days) groups in terms of age, gender, ATDs, duration of ATDs, or initial ANC levels. Four patients (7.4%) who were taking ATDs for less than 2 months died of sepsis on the first or second day of hospitalization. Conclusion The majority of AIA incidents occur in the early treatment period. Considering the high fatality rate of AIA, an early aggressive therapeutic approach is critical and patients should be well informed regarding the warning symptoms of the disease. PMID:26394729

  20. Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment

    International Nuclear Information System (INIS)

    Liu, Nanjun; Tengstrand, Elizabeth A.; Chourb, Lisa; Hsieh, Frank Y.

    2014-01-01

    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

  1. 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

  2. Drug-induced psychosis: how to avoid star gazing in schizophrenia research by looking at more obvious sources of light

    Directory of Open Access Journals (Sweden)

    Alessandra Paparelli

    2011-01-01

    Full Text Available The prevalent view today is that schizophrenia is a syndrome rather than a specific disease. Liability to schizophrenia is highly heritable. It appears that multiple genetic and environmental factors operate together to push individuals over a threshold into expressing the characteristic clinical picture. One environmental factor which has been curiously neglected is the evidence that certain drugs can induce schizophrenia-like psychosis. In the last 60 years, improved understanding of the relationship between drug abuse and psychosis has contributed substantially to our modern view of the disorder suggesting that liability to psychosis in general, and to schizophrenia in particular, is distributed trough the general population in a similar continuous way to liability to medical disorders such as hypertension and diabetes. In this review we examine the main hypotheses resulting from the link observed between the most common psychomimetic drugs (LSD, amphetamines, cannabis, PCP and schizophrenia.

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

    Directory of Open Access Journals (Sweden)

    E Jong

    2013-09-01

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

  4. Cytotoxicity and cell death mechanisms induced by the polyamine-vectorized anti-cancer drug F14512 targeting topoisomerase II.

    Science.gov (United States)

    Brel, Viviane; Annereau, Jean-Philippe; Vispé, Stéphane; Kruczynski, Anna; Bailly, Christian; Guilbaud, Nicolas

    2011-12-15

    The polyamines transport system (PTS) is usually enhanced in cancer cells and can be exploited to deliver anticancer drugs. The spermine-conjugated epipodophyllotoxin derivative F14512 is a topoisomerase II poison that exploits the PTS to target preferentially tumor cells. F14512 has been characterized as a potent anticancer drug candidate and is currently in phase 1 clinical trials. Here we have analyzed the mechanisms of cell death induced by F14512, compared to the parent drug etoposide lacking the polyamine tail. F14512 proved to be >30-fold more cytotoxic than etoposide against A549 non-small cell lung cancer cells and triggers less but unrecoverable DNA damages. The cytotoxic action of F14512 is extremely rapid (within 3 h) and does not lead to a marked accumulation in the S-phase of the cell cycle, unlike etoposide. Interestingly, A549 cells treated with F14512 were less prone to undergo apoptosis (neither caspases-dependent nor caspases-independent pathways) or autophagy but preferentially entered into senescence. Drug-induced senescence was characterized qualitatively and quantitatively by an increased β-galactosidase activity, both by cytochemical staining and by flow cytometry. A morphological analysis by electron microscopy revealed the presence of numerous multi-lamellar and vesicular bodies and large electron-lucent (methuosis-like) vacuoles in F14512-treated cell samples. The mechanism of drug-induced cell death is thus distinct for F14512 compared to etoposide, and this difference may account for their distinct pharmacological profiles and the markedly superior activity of F14512 in vivo. This study suggests that senescence markers should be considered as potential pharmacodynamic biomarkers of F14512 antitumor activity. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. Effects of Social Interaction and Warm Ambient Temperature on Brain Hyperthermia Induced by the Designer Drugs Methylone and MDPV

    Science.gov (United States)

    Kiyatkin, Eugene A; Kim, Albert H; Wakabayashi, Ken T; Baumann, Michael H; Shaham, Yavin

    2015-01-01

    3,4-Methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV) are new drugs of abuse that have gained worldwide popularity. These drugs are structurally similar to 3,4-methylenedioxymethamphetamine (MDMA) and share many of its physiological and behavioral effects in humans, including the development of hyperthermia during acute intoxication. Here, we examined the effects of methylone (1–9 mg/kg, s.c.) or MDPV (0.1–1.0 mg/kg, s.c.) on brain temperature homeostasis in rats maintained in a standard laboratory environment (single-housed in a quiet rest at 22 °C) and under conditions that model human drug use (social interaction and 29 °C ambient temperature). By simultaneously monitoring temperatures in the nucleus accumbens, temporal muscle, and facial skin, we assessed the effects of methylone and MDPV on intra-brain heat production and cutaneous vascular tone, two critical factors that control brain temperature responses. Both methylone and MDPV dose-dependently increased brain temperature, but even at high doses that induced robust locomotor activation, hyperthermia was modest in magnitude (up to ∼2 °C). Both drugs also induced dose-dependent peripheral vasoconstriction, which appears to be a primary mechanism determining the brain hyperthermic responses. In contrast to the powerful potentiation of MDMA-induced hyperthermia by social interaction and warm ambient temperature, such potentiation was absent for methylone and minimal for MDPV. Taken together, despite structural similarities to MDMA, exposure to methylone or MDPV under conditions commonly associated with human drug use does not lead to profound elevations in brain temperature and sustained vasoconstriction, two critical factors associated with MDMA toxicity. PMID:25074640

  6. Contribution of a mesocorticolimbic subcircuit to drug context-induced reinstatement of cocaine-seeking behavior in rats.

    Science.gov (United States)

    Lasseter, Heather C; Xie, Xiaohu; Arguello, Amy A; Wells, Audrey M; Hodges, Matthew A; Fuchs, Rita A

    2014-02-01

    Cocaine-seeking behavior triggered by drug-paired environmental context exposure is dependent on orbitofrontal cortex (OFC)-basolateral amygdala (BLA) interactions. Here, we present evidence supporting the hypothesis that dopaminergic input from the ventral tegmental area (VTA) to the OFC critically regulates these interactions. In experiment 1, we employed site-specific pharmacological manipulations to show that dopamine D1-like receptor stimulation in the OFC is required for drug context-induced reinstatement of cocaine-seeking behavior following extinction training in an alternate context. Intra-OFC pretreatment with the dopamine D1-like receptor antagonist, SCH23390, dose-dependently attenuated cocaine-seeking behavior in an anatomically selective manner, without altering motor performance. Furthermore, the effects of SCH23390 could be surmounted by co-administration of a sub-threshold dose of the D1-like receptor agonist, SKF81297. In experiment 2, we examined effects of D1-like receptor antagonism in the OFC on OFC-BLA interactions using a functional disconnection manipulation. Unilateral SCH23390 administration into the OFC plus GABA agonist-induced neural inactivation of the contralateral or ipsilateral BLA disrupted drug context-induced cocaine-seeking behavior relative to vehicle, while independent unilateral manipulations of these brain regions were without effect. Finally, in experiment 3, we used fluorescent retrograde tracers to demonstrate that the VTA, but not the substantia nigra, sends dense intra- and interhemispheric projections to the OFC, which in turn has reciprocal bi-hemispheric connections with the BLA. These findings support that dopaminergic input from the VTA, via dopamine D1-like receptor stimulation in the OFC, is required for OFC-BLA functional interactions. Thus, a VTA-OFC-BLA neural circuit promotes drug context-induced motivated behavior.

  7. Drug-induced lung injury associated with sorafenib: analysis of all-patient post-marketing surveillance in Japan.

    Science.gov (United States)

    Horiuchi-Yamamoto, Yuka; Gemma, Akihiko; Taniguchi, Hiroyuki; Inoue, Yoshikazu; Sakai, Fumikazu; Johkoh, Takeshi; Fujimoto, Kiminori; Kudoh, Shoji

    2013-08-01

    Sorafenib is a multi-kinase inhibitor currently approved in Japan for unresectable and/or metastatic renal cell carcinoma and unresectable hepatocellular carcinoma. Although drug-induced lung injury has recently been the focus of interest in Japanese patients treated with molecular targeting agents, the clinical features of patients receiving sorafenib remain to be completely investigated. All-patient post-marketing surveillance data was obtained within the frame of Special Drug Use Investigation; between April 2008 and March 2011, we summarized the clinical information of 62 cases with drug-induced lung injury among approximately 13,600 sorafenib-treated patients in Japan. In addition, we summarized the results of evaluation by a safety board of Japanese experts in 34 patients in whom pulmonary images were available. For the calculation of reporting frequency, interim results of Special Drug Use Investigation were used. In the sets of completed reports (2,407 in renal cell carcinoma and 647 in hepatocellular carcinoma), the reporting frequency was 0.33 % (8 patients; fatal, 4/8) and 0.62 % (4 patients; fatal, 2/4), respectively. Major clinical symptoms included dyspnea, cough, and fever. Evaluation of the images showed that 18 cases out of 34 patients had a pattern of diffuse alveolar damage. The patients with hepatocellular carcinoma showed a greater incidence and earlier onset of lung injury than those with renal cell carcinoma. Although the overall reporting frequency of sorafenib-induced lung injury is not considered high, the radiological diffuse alveolar damage pattern led to a fatal outcome. Therefore, early recognition of sorafenib-induced lung injury is crucial for physicians and patients.

  8. Drug-Induced Psychosis: How to Avoid Star Gazing in Schizophrenia Research by Looking at More Obvious Sources of Light

    OpenAIRE

    Paparelli, Alessandra; Di Forti, Marta; Morrison, Paul D.; Murray, Robin M.

    2011-01-01

    The prevalent view today is that schizophrenia is a syndrome rather than a specific disease. Liability to schizophrenia is highly heritable. It appears that multiple genetic and environmental factors operate together to push individuals over a threshold into expressing the characteristic clinical picture. One environmental factor which has been curiously neglected is the evidence that certain drugs can induce schizophrenia-like psychosis. In the last 60 years, improved understanding of the re...

  9. Genipin-induced inhibition of uncoupling protein-2 sensitizes drug-resistant cancer cells to cytotoxic agents.

    Directory of Open Access Journals (Sweden)

    Ryan J Mailloux

    2010-10-01

    Full Text Available Uncoupling protein-2 (UCP2 is known to suppress mitochondrial reactive oxygen species (ROS production and is employed by drug-resistant cancer cells to mitigate oxidative stress. Using the drug-sensitive HL-60 cells and the drug-resistant MX2 subline as model systems, we show that genipin, a UCP2 inhibitor, sensitizes drug-resistant cells to cytotoxic agents. Increased MX2 cell death was observed upon co-treatment with genipin and different doses of menadione, doxorubicin, and epirubicin. DCFH-DA fluorimetry revealed that the increase in MX2 cell death was accompanied by enhanced cellular ROS levels. The drug-induced increase in ROS was linked to genipin-mediated inhibition of mitochondrial proton leak. State 4 and resting cellular respiratory rates were higher in the MX2 cells in comparison to the HL-60 cells, and the increased respiration was readily suppressed by genipin in the MX2 cells. UCP2 accounted for a remarkable 37% of the resting cellular oxygen consumption indicating that the MX2 cells are functionally reliant on this protein. Higher amounts of UCP2 protein were detected in the MX2 versus the HL-60 mitochondria. The observed effects of genipin were absent in the HL-60 cells pointing to the selectivity of this natural product for drug-resistant cells. The specificity of genipin for UCP2 was confirmed using CHO cells stably expressing UCP2 in which genipin induced an ∼22% decrease in state 4 respiration. These effects were absent in empty vector CHO cells expressing no UCP2. Thus, the chemical inhibition of UCP2 with genipin sensitizes multidrug-resistant cancer cells to cytotoxic agents.

  10. Direct-to-consumer prescription drug advertising, 1989-1998. A content analysis of conditions, targets, inducements, and appeals.

    Science.gov (United States)

    Bell, R A; Kravitz, R L; Wilkes, M S

    2000-04-01

    We conducted a content analysis of consumer-targeted prescription drug advertisements to explore trends in prevalence, shifts in the medical conditions for which drugs are promoted, reliance on financial and nonmonetary inducements, and appeals used to attract public interest. We collected the drug advertisements appearing in 18 consumer magazines from 1989 through 1998. Two judges independently coded each advertisement and placed it in a category pertaining to the target audience, use of inducements, and product benefits (mean kappa=0.93). We employed descriptive statistics, cross-tabulations, and curve estimation procedures. A total of 320 distinct advertisements were identified, representing 101 brands and 14 medical conditions. New advertisement and brand introductions increased dramatically during this decade. Advertisements for drugs used for dermatologic, human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), and obstetric/gynecologic conditions were most common. Almost all of the advertisements were aimed at the potential user of the drug, not third-party intermediaries such as parents and spouses. Although most advertisements were gender-neutral, women were more likely to be exclusively targeted. One eighth of the advertisements offered a monetary incentive (eg, a rebate or money-back guarantee), and one third made an offer of additional information in printed or audio/video form. The most common appeals used were effectiveness, symptom control, innovativeness, and convenience. Consumer-directed prescription drug advertising has increased dramatically during the past decade. The pharmaceutical industry is turning to this type of advertising to generate interest in its products. Our data may be useful to physicians who want to stay abreast of the treatments that are being directly marketed to their patients.

  11. Effect of micropatterning induced surface hydrophobicity on drug release from electrospun cellulose acetate nanofibers

    Science.gov (United States)

    Adepu, Shivakalyani; Gaydhane, Mrunalini K.; Kakunuri, Manohar; Sharma, Chandra S.; Khandelwal, Mudrika; Eichhorn, Stephen J.

    2017-12-01

    Sustained release and prevention of burst release for low half-life drugs like Diclofenac sodium is crucial to prevent drug related toxicity. Electrospun nanofibers have emerged recently as potential carrier materials for controlled and sustained drug release. Here, we present a facile method to prevent burst release by tuning the surface wettability through template assisted micropatterning of drug loaded electrospun cellulose acetate (CA) nanofibers. A known amount of drug (Diclofenac sodium) was first mixed with CA and then electrospun in the form of a nanofabric. This as-spun network was hydrophilic in nature. However, when electrospinning was carried out through non-conducting templates, viz nylon meshes with 50 and 100 μm size openings, two kinds of hydrophobic micro-patterned CA nanofabrics were produced. In vitro transdermal testing of our nanofibrous mats was carried out; these tests were able to show that it would be possible to create a patch for transdermal drug release. Further, our results show that with optimized micro-patterned dimensions, a zero order sustained drug release of up to 12 h may be achieved for the transdermal system when compared to non-patterned samples. This patterning caused a change in the surface wettability, to a hydrophobic surface, resulting in a controlled diffusion of the hydrophilic drug. Patterning assisted in controlling the initial burst release, which is a significant finding especially for low half-life drugs.

  12. Correlation of oxidative stress in patients with HBV-induced liver disease with HBV genotypes and drug resistance mutations.

    Science.gov (United States)

    Xianyu, Jianbo; Feng, Jiafu; Yang, Yuwei; Tang, Jie; Xie, Gang; Fan, Lingying

    2018-05-01

    This study aims to explore the correlation of oxidative stress (OxS) in patients with chronic hepatitis B (CHB) and the disease severity with HBV genotypes and drug resistance mutations. A total of 296 patients with CHB were enrolled into the study. PCR-reverse dot-blot hybridization was used to detect the HBV genotypes (B, C, and D) and the drug resistance-causing HBV mutant genes. In addition, the total oxidative stress (TOS) and total antioxidant status (TAS) were determined, and oxidative stress index (OSI) was calculated and compared. Serum levels of TOS and OSI, the B/C ratio, and drug resistance mutation rate were increased along with the elevated disease severity degree (CHBHBV mutation had higher serum TOS and OSI levels, while lower serum TAS levels (P HBV-induced liver disease, and the damage degree is correlated with the HBV genotype and drug resistance mutation. Oxidative stress might be a useful indicator of the progression of HBV-induced liver disease in patients. Copyright © 2018. Published by Elsevier Inc.

  13. An Automated Platform for Assessment of Congenital and Drug-Induced Arrhythmia with hiPSC-Derived Cardiomyocytes

    Directory of Open Access Journals (Sweden)

    Wesley L. McKeithan

    2017-10-01

    Full Text Available The ability to produce unlimited numbers of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs harboring disease and patient-specific gene variants creates a new paradigm for modeling congenital heart diseases (CHDs and predicting proarrhythmic liabilities of drug candidates. However, a major roadblock to implementing hiPSC-CM technology in drug discovery is that conventional methods for monitoring action potential (AP kinetics and arrhythmia phenotypes in vitro have been too costly or technically challenging to execute in high throughput. Herein, we describe the first large-scale, fully automated and statistically robust analysis of AP kinetics and drug-induced proarrhythmia in hiPSC-CMs. The platform combines the optical recording of a small molecule fluorescent voltage sensing probe (VoltageFluor2.1.Cl, an automated high throughput microscope and automated image analysis to rapidly generate physiological measurements of cardiomyocytes (CMs. The technique can be readily adapted on any high content imager to study hiPSC-CM physiology and predict the proarrhythmic effects of drug candidates.

  14. Drug- and herb-induced liver injury: Progress, current challenges and emerging signals of post-marketing risk.

    Science.gov (United States)

    Raschi, Emanuel; De Ponti, Fabrizio

    2015-07-08

    Drug-induced liver injury (DILI) and herb-induced liver injury is a hot topic for clinicians, academia, drug companies and regulators, as shown by the steadily increasing number of publications in the past 15 years. This review will first provide clues for clinicians to suspect idiosyncratic (unpredictable) DILI and succeed in diagnosis. Causality assessment remains challenging and requires careful medical history as well as awareness of multifaceted aspects, especially for herbs. Drug discontinuation and therapy reconciliation remain the mainstay in patent's management to minimize occurrence of acute liver failure. The second section will address novel agents associated with liver injury in 2014 (referred to as "signals"), especially in terms of clinical, research and drug development implications. Insights will be provided into recent trends by highlighting the contribution of different post-marketing data, especially registries and spontaneous reporting systems. This literature scrutiny suggests: (1) the importance of post-marketing databases as tools of clinical evidence to detect signals of DILI risk; and (2) the need for joining efforts in improving predictivity of pre-clinical assays, continuing post-marketing surveillance and design ad hoc post-authorization safety studies. In this context, ongoing European/United States research consortia and novel pharmaco-epidemiological tools (e.g., specialist prescription event monitoring) will support innovation in this field. Direct oral anticoagulants and herbal/dietary supplements appear as key research priorities.

  15. Study on the Antiradiation role of Melatonin: An investigation on Induced Oxidative Stress Mice by Radiomimetic Drug Cyclophosphamide

    Energy Technology Data Exchange (ETDEWEB)

    Manda, K.; Bhatia, A. L.

    2004-07-01

    Clinical studies have demonstrated an altered pineal function in cancer patients. Owing to the document antineoplastic activity of the pineal gland, these anomalies could have a prognostic significance. This study was carried out to monitor the effect of higher blood levels of melatonin, the most important pineal hormone, which could be applied in relation to the response to chemotherapy in human neoplasms. Cyclophosphamide is a commonly used chemotherapeutic drug and well-known mutagen and clastogen. It is an alkylating agent, producing highly active carbonium ion, which the extremely electron-rich area of the nucleic acids and proteins. The present study aimed to investigate the protective effect of melatonin against cyclophosphamide induced oxidative stress in mice tissues. Lipid perioxidation. Reduced glutathione (GSH), Glutathione disulphide (GSSG), Glutathione peroxidase (GSH-Px) and serum phosphatase level taken as endpoints. Twenty days oral administration with melatonin (0.25 mg/Kg body weight) followed by an acute treatment with cyclophosphamide (75 mg/kg b. w.) inhibited the radiomimetic drug-induced augmented level of lipid peroxidation, Blood GSSG and acid phosphatase. Cyclophosphamide induced depletion in the level of GSH, GSH-Px and alkaline phosphatase is ameliorated significantly by melatonin administration. The findings support the results showing melatonin as a free radical scavenger, and singlet oxygen quencher. Results clearly indicate the antioxidative properties of melatonin against the radiomimetic drug which could be effectively used selectively for the protection of normal tissue during chemotherapy. (Author) 34 refs.

  16. Study on the Antiradiation role of Melatonin: An investigation on Induced Oxidative Stress Mice by Radiomimetic Drug Cyclophosphamide

    International Nuclear Information System (INIS)

    Manda, K.; Bhatia, A. L.

    2004-01-01

    Clinical studies have demonstrated an altered pineal function in cancer patients. Owing to the document antineoplastic activity of the pineal gland, these anomalies could have a prognostic significance. This study was carried out to monitor the effect of higher blood levels of melatonin, the most important pineal hormone, which could be applied in relation to the response to chemotherapy in human neoplasms. Cyclophosphamide is a commonly used chemotherapeutic drug and well-known mutagen and clastogen. It is an alkylating agent, producing highly active carbonium ion, which the extremely electron-rich area of the nucleic acids and proteins. The present study aimed to investigate the protective effect of melatonin against cyclophosphamide induced oxidative stress in mice tissues. Lipid perioxidation. Reduced glutathione (GSH), Glutathione disulphide (GSSG), Glutathione peroxidase (GSH-Px) and serum phosphatase level taken as endpoints. Twenty days oral administration with melatonin (0.25 mg/Kg body weight) followed by an acute treatment with cyclophosphamide (75 mg/kg b. w.) inhibited the radiomimetic drug-induced augmented level of lipid peroxidation, Blood GSSG and acid phosphatase. Cyclophosphamide induced depletion in the level of GSH, GSH-Px and alkaline phosphatase is ameliorated significantly by melatonin administration. The findings support the results showing melatonin as a free radical scavenger, and singlet oxygen quencher. Results clearly indicate the antioxidative properties of melatonin against the radiomimetic drug which could be effectively used selectively for the protection of normal tissue during chemotherapy. (Author) 34 refs

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

    Directory of Open Access Journals (Sweden)

    Yifeng Guo

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

  18. Synchrotron radiation induced X-ray emission studies of the antioxidant mechanism of the organoselenium drug ebselen.

    Science.gov (United States)

    Aitken, Jade B; Lay, Peter A; Duong, T T Hong; Aran, Roshanak; Witting, Paul K; Harris, Hugh H; Lai, Barry; Vogt, Stefan; Giles, Gregory I

    2012-04-01

    Synchrotron radiation induced X-ray emission (SRIXE) spectroscopy was used to map the cellular uptake of the organoselenium-based antioxidant drug ebselen using differentiated ND15 cells as a neuronal model. The cellular SRIXE spectra, acquired using a hard X-ray microprobe beam (12.8-keV), showed a large enhancement of fluorescence at the K(α) line for Se (11.2-keV) following treatment with ebselen (10 μM) at time periods from 60 to 240 min. Drug uptake was quantified and ebselen was shown to induce time-dependent changes in cellular elemental content that were characteristic of oxidative stress with the efflux of K, Cl, and Ca species. The SRIXE cellular Se distribution map revealed that ebselen was predominantly localized to a discreet region of the cell which, by comparison with the K and P elemental maps, is postulated to correspond to the endoplasmic reticulum. On the basis of these findings, it is hypothesized that a major outcome of ebselen redox catalysis is the induction of cellular stress. A mechanism of action of ebselen is proposed that involves the cell responding to drug-induced stress by increasing the expression of antioxidant genes. This hypothesis is supported by the observation that ebselen also regulated the homeostasis of the transition metals Mn, Cu, Fe, and Zn, with increases in transition metal uptake paralleling known induction times for the expression of antioxidant metalloenzymes. © SBIC 2012

  19. Targeted drug delivery with focused ultrasound-induced blood-brain barrier opening using acoustically-activated nanodroplets.

    Science.gov (United States)

    Chen, Cherry C; Sheeran, Paul S; Wu, Shih-Ying; Olumolade, Oluyemi O; Dayton, Paul A; Konofagou, Elisa E

    2013-12-28

    Focused ultrasound (FUS) in the presence of systemically administered microbubbles has been shown to locally, transiently and reversibly increase the permeability of the blood-brain barrier (BBB), thus allowing targeted delivery of therapeutic agents in the brain for the treatment of central nervous system diseases. Currently, microbubbles are the only agents that have been used to facilitate the FUS-induced BBB opening. However, they are constrained within the intravascular space due to their micron-size diameters, limiting the delivery effect at or near the microvessels. In the present study, acoustically-activated nanodroplets were used as a new class of contrast agents to mediate FUS-induced BBB opening in order to study the feasibility of utilizing these nanoscale phase-shift particles for targeted drug delivery in the brain. Significant dextran delivery was achieved in the mouse hippocampus using nanodroplets at clinically relevant pressures. Passive cavitation detection was used in the attempt to establish a correlation between the amount of dextran delivered in the brain and the acoustic emission recorded during sonication. Conventional microbubbles with the same lipid shell composition and perfluorobutane core as the nanodroplets were also used to compare the efficiency of an FUS-induced dextran delivery. It was found that nanodroplets had a higher BBB opening pressure threshold but a lower stable cavitation threshold than microbubbles, suggesting that contrast agent-dependent acoustic emission monitoring was needed. A more homogeneous dextran delivery within the targeted hippocampus was achieved using nanodroplets without inducing inertial cavitation or compromising safety. Our results offered a new means of developing the FUS-induced BBB opening technology for potential extravascular targeted drug delivery in the brain, extending the potential drug delivery region beyond the cerebral vasculature. © 2013.

  20. Preparation of microspheres for slow release drug by radiation-induced suspension polymerization and their properties

    International Nuclear Information System (INIS)

    Yoshida, Masaru; Asano, Masaharu; Kaetsu, Isao

    1982-01-01

    The polymer microspheres containing drugs as drug delivery system were made by means of suspension-polymerization by radiation at low temperature by using glass-forming monomers which have stable supercooling properties and large polymerizability at low temperature. The particle distribution depended on the kind of monomer. It was found that the entrapping yield of drug in polymer microspheres increased with increasing viscosity of monomer and that the maximum value on the particle size distribution curve was also shifted to large particle diameter side. In the case of trimethylolpropane trimethacrylate monomer (43 cps), TMPT, the entrapping yield of drug reached 74% and the maximum value in particle size distribution curve appeared in the neighborhood of 105 to 210 mu m ranges. On the other hand, those values in neopentyl glycol dimethacrylate monomer (4 cps) were 12% in former and 44 -- 105 mu m in the latter. The release phenomenon of drugs from polymer microspheres was investigated. for example, the cumulative amount of mitomycin C (water soluble drug) released from TMPT polymer microsphere was about 90% after 30-day dissolution, while in the case of water-insoluble drug such as testosterone the amount of release was about 49% after 40-day dissolution. In all cases, the release rate is constant during the experimental period. Therefore, it was concluded that the release of drugs from polymer microspheres obtained in this study is possible over the long periods. (author)

  1. Near-infrared induced release for localized on-demand drug delivery

    NARCIS (Netherlands)

    Vertommen, M.A.M.E.

    2009-01-01

    By non-invasive external triggering of drug release from an implant, pulsewise administration can be realized according to the patient’s needs and at specific locations in the human body. In comparison to more traditional delivery forms (e.g. oral or by injection), externally triggered drug release

  2. Novel High-Throughput Drug Screening Platform for Chemotherapy-Induced Axonal Neuropathy

    Science.gov (United States)

    2014-05-01

    from anti-cancer drug therapy [1,2]. Platinum drugs, taxanes, proteasome inhibitors, vinca alkaloids, epothilones, and immunomodulators are the...and immunomodulators are the standard of anti-cancer therapies for the six most cancers. An estimated 2010 incidence of 994, 680 cases for these

  3. DILI (drug induced liver injury in a 9-month-old infant: a rare case of phenobarbital-induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Anna Paola Pinna

    2013-04-01

    Full Text Available Phenobarbital is one of the most commonly prescribed antiepileptic drugs in childhood, but it can rarely cause serious adverse effects, such as hepatotoxicity that includes a broad clinical spectrum (from isolate hypertransaminasemia to acute liver failure. We describe a case of DILI in a 9-month-old infant caused by chronic therapy with phenobarbital.

  4. Mechanism-based risk assessment strategy for drug-induced cholestasis using the transcriptional benchmark dose derived by toxicogenomics.

    Science.gov (United States)

    Kawamoto, Taisuke; Ito, Yuichi; Morita, Osamu; Honda, Hiroshi

    2017-01-01

    Cholestasis is one of the major causes of drug-induced liver injury (DILI), which can result in withdrawal of approved drugs from the market. Early identification of cholestatic drugs is difficult due to the complex mechanisms involved. In order to develop a strategy for mechanism-based risk assessment of cholestatic drugs, we analyzed gene expression data obtained from the livers of rats that had been orally administered with 12 known cholestatic compounds repeatedly for 28 days at three dose levels. Qualitative analyses were performed using two statistical approaches (hierarchical clustering and principle component analysis), in addition to pathway analysis. The transcriptional benchmark dose (tBMD) and tBMD 95% lower limit (tBMDL) were used for quantitative analyses, which revealed three compound sub-groups that produced different types of differential gene expression; these groups of genes were mainly involved in inflammation, cholesterol biosynthesis, and oxidative stress. Furthermore, the tBMDL values for each test compound were in good agreement with the relevant no observed adverse effect level. These results indicate that our novel strategy for drug safety evaluation using mechanism-based classification and tBMDL would facilitate the application of toxicogenomics for risk assessment of cholestatic DILI.

  5. Alterations in endo-lysosomal function induce similar hepatic lipid profiles in rodent models of drug-induced phospholipidosis and Sandhoff disease.

    Science.gov (United States)

    Lecommandeur, Emmanuelle; Baker, David; Cox, Timothy M; Nicholls, Andrew W; Griffin, Julian L

    2017-07-01

    Drug-induced phospholipidosis (DIPL) is characterized by an increase in the phospholipid content of the cell and the accumulation of drugs and lipids inside the lysosomes of affected tissues, including in the liver. Although of uncertain pathological significance for patients, the condition remains a major impediment for the clinical development of new drugs. Human Sandhoff disease (SD) is caused by inherited defects of the β subunit of lysosomal β-hexosaminidases (Hex) A and B, leading to a large array of symptoms, including neurodegeneration and ultimately death by the age of 4 in its most common form. The substrates of Hex A and B, gangliosides GM2 and GA2, accumulate inside the lysosomes of the CNS and in peripheral organs. Given that both DIPL and SD are associated with lysosomes and lipid metabolism in general, we measured the hepatic lipid profiles in rodent models of these two conditions using untargeted LC/MS to examine potential commonalities. Both model systems shared a number of perturbed lipid pathways, notably those involving metabolism of cholesteryl esters, lysophosphatidylcholines, bis(monoacylglycero)phosphates, and ceramides. We report here profound alterations in lipid metabolism in the SD liver. In addition, DIPL induced a wide range of lipid changes not previously observed in the liver, highlighting similarities with those detected in the model of SD and raising concerns that these lipid changes may be associated with underlying pathology associated with lysosomal storage disorders. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  6. β1-Adrenoceptor in the Central Amygdala Is Required for Unconditioned Stimulus-Induced Drug Memory Reconsolidation

    Science.gov (United States)

    Zhu, Huiwen; Zhou, Yiming; Liu, Zhiyuan; Chen, Xi; Li, Yanqing; Liu, Xing; Ma, Lan

    2018-01-01

    Abstract Background Drug memories become labile and reconsolidated after retrieval by presentation of environmental cues (conditioned stimulus) or drugs (unconditioned stimulus). Whether conditioned stimulus and unconditioned stimulus retrieval trigger different memory reconsolidation processes is not clear. Methods Protein synthesis inhibitor or β-adrenergic receptor (β-AR) antagonist was systemically administrated or intra-central amygdala infused immediately after cocaine reexposure in cocaine-conditioned place preference or self-administration mice models. β-ARs were selectively knocked out in the central amygdala to further confirm the role of β-adrenergic receptor in cocaine reexposure-induced memory reconsolidation of cocaine-conditioned place preference. Results Cocaine reexposure triggered de novo protein synthesis dependent memory reconsolidation of cocaine-conditioned place preference. Cocaine-priming-induced reinstatement was also impaired with post cocaine retrieval manipulation, in contrast to the relapse behavior with post context retrieval manipulation. Cocaine retrieval, but not context retrieval, induced central amygdala activation. Protein synthesis inhibitor or β1-adrenergic receptor antagonist infused in the central amygdala after cocaine retrieval, but not context retrieval, inhibited memory reconsolidation and reinstatement. β1-adrenergic receptor knockout in the central amygdala suppressed cocaine retrieval-triggered memory reconsolidation and reinstatement of cocaine conditioned place preference. β1-adrenergic receptor antagonism after cocaine retrieval also impaired reconsolidation and reinstatement of cocaine self-administration. Conclusions Cocaine reward memory triggered by unconditioned stimulus retrieval is distinct from conditioned stimulus retrieval. Unconditioned stimulus retrieval induced reconsolidation of cocaine reward memory depends on β1-adrenergic signaling in the central amygdala. Post unconditioned stimulus

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    2010-01-01

    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. PMID:20492672

  9. Drug Loading and Release Behavior Depending on the Induced Porosity of Chitosan/Cellulose Multilayer Nanofilms.

    Science.gov (United States)

    Park, Sohyeon; Choi, Daheui; Jeong, Hyejoong; Heo, Jiwoong; Hong, Jinkee

    2017-10-02

    The ability to control drug loading and release is the most important feature in the development of medical devices. In this research, we prepared a functional nanocoating technology to incorporate a drug-release layer onto a desired substrate. The multilayer films were prepared using chitosan (CHI) and carboxymethyl cellulose (CMC) polysaccharides by the layer-by-layer (LbL) method. By using chemical cross-linking to change the inner structure of the assembled multilayer, we could control the extent of drug loading and release. The cross-linked multilayer film had a porous structure and enhanced water wettability. Interestingly, more of the small-molecule drug was loaded into and released from the non-cross-linked multilayer film, whereas more of the macromolecular drug was loaded into and released from the cross-linked multilayer film. These results indicate that drug loading and release can be easily controlled according to the molecular weight of the desired drug by changing the structure of the film.

  10. Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes.

    Directory of Open Access Journals (Sweden)

    Elijah R Behr

    Full Text Available Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP, treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p  =  3×10(-7, odds ratio = 2, 95% confidence intervals: 1.5-2.6. The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p  =  3×10(-9. Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs.

  11. NMDA Receptor Signaling Is Important for Neural Tube Formation and for Preventing Antiepileptic Drug-Induced Neural Tube Defects.

    Science.gov (United States)

    Sequerra, Eduardo B; Goyal, Raman; Castro, Patricio A; Levin, Jacqueline B; Borodinsky, Laura N

    2018-05-16

    Failure of neural tube closure leads to neural tube defects (NTDs), which can have serious neurological consequences or be lethal. Use of antiepileptic drugs (AEDs) during pregnancy increases the incidence of NTDs in offspring by unknown mechanisms. Here we show that during Xenopus laevis neural tube formation, neural plate cells exhibit spontaneous calcium dynamics that are partially mediated by glutamate signaling. We demonstrate that NMDA receptors are important for the formation of the neural tube and that the loss of their function induces an increase in neural plate cell proliferation and impairs neural cell migration, which result in NTDs. We present evidence that the AED valproic acid perturbs glutamate signaling, leading to NTDs that are rescued with varied efficacy by preventing DNA synthesis, activating NMDA receptors, or recruiting the NMDA receptor target ERK1/2. These findings may prompt mechanistic identification of AEDs that do not interfere with neural tube formation. SIGNIFICANCE STATEMENT Neural tube defects are one of the most common birth defects. Clinical investigations have determined that the use of antiepileptic drugs during pregnancy increases the incidence of these defects in the offspring by unknown mechanisms. This study discovers that glutamate signaling regulates neural plate cell proliferation and oriented migration and is necessary for neural tube formation. We demonstrate that the widely used antiepileptic drug valproic acid interferes with glutamate signaling and consequently induces neural tube defects, challenging the current hypotheses arguing that they are side effects of this antiepileptic drug that cause the increased incidence of these defects. Understanding the mechanisms of neurotransmitter signaling during neural tube formation may contribute to the identification and development of antiepileptic drugs that are safer during pregnancy. Copyright © 2018 the authors 0270-6474/18/384762-12$15.00/0.

  12. Gallic acid prevents nonsteroidal anti-inflammatory drug-induced gastropathy in rat by blocking oxidative stress and apoptosis.

    Science.gov (United States)

    Pal, Chinmay; Bindu, Samik; Dey, Sumanta; Alam, Athar; Goyal, Manish; Iqbal, Mohd Shameel; Maity, Pallab; Adhikari, Susanta S; Bandyopadhyay, Uday

    2010-07-15

    Nonsteroidal anti-inflammatory drug (NSAID)-induced oxidative stress plays a critical role in gastric mucosal cell apoptosis and gastropathy. NSAIDs induce the generation of hydroxyl radical ((*)OH) through the release of free iron, which plays an important role in developing gastropathy. Thus, molecules having both iron-chelating and antiapoptotic properties will be beneficial in preventing NSAID-induced gastropathy. Gallic acid (GA), a polyphenolic natural product, has the capacity to chelate free iron. Here, we report that GA significantly prevents, as well as heals, NSAID-induced gastropathy. In vivo, GA blocks NSAID-mediated mitochondrial oxidative stress by preventing mitochondrial protein carbonyl formation, lipid peroxidation, and thiol depletion. In vitro, GA scavenges free radicals and blocks (*)OH-mediated oxidative damage. GA also attenuates gastric mucosal cell apoptosis in vivo as well as in vitro in cultured gastric mucosal cells as evident from the TUNEL assay. GA prevents NSAID-induced activation of caspase-9, a marker for the mitochondrial pathway of apoptosis, and restores NSAID-mediated collapse of the mitochondrial transmembrane potential and dehydrogenase activity. Thus, the inhibition of mitochondrial oxidative stress by GA is associated with the inhibition of NSAID-induced mitochondrial dysfunction and activation of apoptosis in gastric mucosal cells, which are responsible for gastric injury or gastropathy. Copyright 2010 Elsevier Inc. All rights reserved.

  13. Learning and memory deficits in male adult mice treated with a benzodiazepine sleep-inducing drug during the juvenile period

    Directory of Open Access Journals (Sweden)

    Yusuke Furukawa

    2016-07-01

    Full Text Available Gamma-aminobutyric acid (GABA, the major inhibitory neurotransmitter in the mammalian central nervous system, is also known to be important for brain development. Therefore, disturbances of GABA receptor (GABA-R mediated signaling (GABA-R signal during brain development may influence normal brain maturation and cause late-onset brain malfunctions. In this study, we examined whether the temporal stimulation of the GABA-R signal during brain development induces late-onset adverse effects on the brain in adult male mice. To stimulate the GABA-R signal, we used either the benzodiazepine sleep-inducing drug triazolam (TZ or the non-benzodiazepine drug zolpidem (ZP. We detected deficits in learning and memory in mice treated with TZ during the juvenile period, as seen in the fear conditioning test. On the other hand, ZP administration during the juvenile period had little effect. In addition, decreased protein expression of GluR1 and GluR4, which are excitatory neurotransmitter receptors, was detected in the hippocampi of mice treated with TZ during the juvenile period. We measured mRNA expression of the immediate early genes (IEGs, which are neuronal activity markers, in the hippocampus shortly after the administration of TZ or ZP to juvenile mice. Decreased IEG expression was detected in mice with juvenile TZ administration, but not in mice with juvenile ZP administration. Our findings demonstrate that TZ administration during the juvenile period can induce irreversible brain dysfunction in adult mice. It may need to take an extra care for the prescription of benzodiazepine sleep-inducing drugs to juveniles because it might cause late onset learning and memory defects.

  14. Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia

    DEFF Research Database (Denmark)

    Göllner, Stefanie; Oellerich, Thomas; Agrawal-Singh, Shuchi

    2017-01-01

    In acute myeloid leukemia (AML), therapy resistance frequently occurs, leading to high mortality among patients. However, the mechanisms that render leukemic cells drug resistant remain largely undefined. Here, we identified loss of the histone methyltransferase EZH2 and subsequent reduction...

  15. Association between P-glycoprotein polymorphisms and antipsychotic drug-induced hyperprolactinemia

    NARCIS (Netherlands)

    Geers, Lisanne; Pozhidaev, Ivan V; Ivanova, Svetlana A.; Freidin, Maxim B.; Cohen, Dan; Boiko, Anastasia S; Osmanova, Diana Z; Fedorenko, Olga Yu; Touw, Daniël; Semke, Arkadiy V.; Wilffert, Berend; Bokhan, Nikolay A.; Loonen, Antonius

    2017-01-01

    Background: Regular therapy for schizophrenia includes maintenance antipsychotic treatment. Unfortunately, antipsychotics also have a spectrum of side effects, including metabolic, endocrine, cardiovascular, and movement disorders. One of the common side effects of these drugs is hyperprolactinemia

  16. Pharmacogenetics of drug-induced birth defects : What is known so far?

    NARCIS (Netherlands)

    Wilffert, Bob; Altena, Judith; Tijink, Laurien; van Gelder, Marleen M. H. J.; de Jong-van den Berg, Lolkje T. W.

    A literature review was performed to collect information on the role of pharmacogenetics in six proposed teratogenic mechanisms associated with drug use during pregnancy: folate antagonism, oxidative stress, angiotensin-converting enzyme inhibition and angiotensin II receptor antagonism,

  17. Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans

    International Nuclear Information System (INIS)

    Tamura, Akitoshi; Miyawaki, Izuru; Yamada, Toru; Kimura, Juki; Funabashi, Hitoshi

    2013-01-01

    It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28 days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination of serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence. - Highlights: • We tested Brown Norway rats as a candidate model for predicting drug hypersensitivity. • The allergic drugs did not induce skin rash, whereas D-penicillamine did so in the rats. • Some of allergic drugs increased

  18. Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans

    Energy Technology Data Exchange (ETDEWEB)

    Tamura, Akitoshi, E-mail: akitoshi-tamura@ds-pharma.co.jp; Miyawaki, Izuru; Yamada, Toru; Kimura, Juki; Funabashi, Hitoshi

    2013-08-15

    It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28 days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination of serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence. - Highlights: • We tested Brown Norway rats as a candidate model for predicting drug hypersensitivity. • The allergic drugs did not induce skin rash, whereas D-penicillamine did so in the rats. • Some of allergic drugs increased

  19. Yohimbine-induced cutaneous drug eruption, progressive renal failure, and lupus-like syndrome.

    Science.gov (United States)

    Sandler, B; Aronson, P

    1993-04-01

    Yohimbine is an indole alkaloid obtained from the yohimbe tree, a common tree in West Africa. We describe a forty-two-year black man in whom a generalized erythrodermic skin eruption, progressive renal failure, and lupus-like syndrome developed following treatment with the drug, yohimbine. A literature review failed to reveal any reported association of these side effects. We review current information on yohimbine's use in male impotence, reported side effects, and its role as a drug allergen.

  20. Computational chemistry approach for the early detection of drug-induced idiosyncratic liver toxicity.

    Science.gov (United States)

    Cruz-Monteagudo, Maykel; Cordeiro, M Natália D S; Borges, Fernanda

    2008-03-01

    Idiosyncratic drug toxicity (IDT), considered as a toxic host-dependent event, with an apparent lack of dose response relationship, is usually not predictable from early phases of clinical trials, representing a particularly confounding complication in drug development. Albeit a rare event (usually approach proposed in the present study, can play an important role in addressing IDT in early drug discovery. We report for the first time a systematic evaluation of classification models to predict idiosyncratic hepatotoxicity based on linear discriminant analysis (LDA), artificial neural networks (ANN), and machine learning algorithms (OneR) in conjunction with a 3D molecular structure representation and feature selection methods. These modeling techniques (LDA, feature selection to prevent over-fitting and multicollinearity, ANN to capture nonlinear relationships in the data, as well as the simple OneR classifier) were found to produce QSTR models with satisfactory internal cross-validation statistics and predictivity on an external subset of chemicals. More specifically, the models reached values of accuracy/sensitivity/specificity over 84%/78%/90%, respectively in the training series along with predictivity values ranging from ca. 78 to 86% of correctly classified drugs. An LDA-based desirability analysis was carried out in order to select the levels of the predictor variables needed to trigger the more desirable drug, i.e. the drug with lower potential for idiosyncratic hepatotoxicity. Finally, two external test sets were used to evaluate the ability of the models in discriminating toxic from nontoxic structurally and pharmacologically related drugs and the ability of the best model (LDA) in detecting potential idiosyncratic hepatotoxic drugs, respectively. The computational approach proposed here can be considered as a useful tool in early IDT prognosis.

  1. Toward an understanding of antipsychotic drug induced weight gain - use of a rodent model

    OpenAIRE

    Stefanidis, Aneta

    2017-01-01

    Antipsychotic drug therapy is a fundamental tool in the treatment of schizophrenia and other psychoses. Recent years have seen the development of new antipsychotic compounds with an improved acute adverse effect profile; however these are often associated with weight gain and increased risk of metabolic disturbances. Olanzapine, despite its considerable adverse impact on weight gain and associated pathologies, has been recognized as the most efficacious antipsychotic drug in the treatment of ...

  2. Do the Drugs Used to Treat Rheumatic Disorders Induce Bone Fragility? A Review

    DEFF Research Database (Denmark)

    Thomsen, Súsanna við Streym; Vestergaard, Peter

    2009-01-01

    Rheumatic disorders are linked to immuno-logical processes in the body; therefore, drugs used to treat these disorders may interfere with the immune system. The immune system shares several signaling mechanisms with bone cells, both directly via cytokines and prostaglandins, and indirectly via...... vitamin D, which is also an active immunological substance. As a result, drugs used to modulate the immune response may interfere with bone mineral density (BMD), bone biomechanical competence, and the risk of fractures [1–3]....

  3. Early detection of drug-induced pneumonitis by gallium-67 lung scan in six patients with normal chest radiographs

    Energy Technology Data Exchange (ETDEWEB)

    Nakajima, H; Sawa, H; Takashima, S [Osaka City Univ. (Japan). Hospital

    1981-06-01

    Increased pulmonary accumulation of Gallium-67-citrate was observed in 6 patients (4 with malignant lymphoma, 1 with uterine cancer and 1 with acute myelocytic leukemia) preceding the appearance of any abnormal findings in both chest X-ray and blood gas data. All of them had received multiple courses of chemotherapy. In these patients, the anticancer drugs were administered for 13 to 22 weeks (mean 15 weeks). One patient with malignant lymphoma showed abnormal /sup 67/Ga lung uptake greater than hepatic activity, 3 patients (malignant lymphoma, 2 and uterine cancer, 1) visualized abnormal /sup 67/Ga lung uptake equal to hepatic activity and 2 cases (malignant lymphoma, 1 and acute myelocytic leukemia, 1) demonstrated abnormal accumulation of /sup 67/Ga in the lung greater than background activity. In 4 patients (3 with malignant lymphoma and 1 with uterine cancer) out of 6, transbronchial lung biopsy obtained after the /sup 67/Ga scans showed non-specific interstitial pneumonitis with infiltration of lymphocytes and macrophages compatible with drug-induced pneumonitis. In the other 2 patients, cytology and cultures were negative and follow up /sup 67/Ga lung scans revealed a reduction in intensity of uptake after treatment with corticosteroid. Therefore, we considered that the /sup 67/Ga lung scan was useful for early detection of drug-induced pneumonitis.

  4. Efficacy and safety of rabeprazole in non-steroidal anti-inflammatory drug-induced ulcer in Japan.

    Science.gov (United States)

    Mizokami, Yuji

    2009-10-28

    To investigate the efficacy and safety of rabeprazole under continuous non-steroidal anti-inflammatory drug (NSAID) administration for NSAID-induced ulcer in Japan. Subjects comprised patients undergoing NSAID treatment in whom upper gastrointestinal endoscopy revealed an ulcerous lesion (open ulcer) with diameter > or = 3 mm, who required continuous NSAID treatment. Endoscopies were performed at the start of treatment, during the treatment period, and at the conclusion (or discontinuation) of treatment. Findings were evaluated as size (maximum diameter) and stage based on the Sakita-Miwa classification. An ulcer was regarded as cured when the "white coating" was seen to have disappeared under endoscopy. As criteria for evaluating safety, all medically untoward symptoms and signs (adverse events, laboratory abnormalities, accidental symptoms, etc.) occurring after the start of rabeprazole treatment were handled as adverse events. Endoscopic cure rate in 38 patients in the efficacy analysis (endoscopic evaluation) was 71.1% (27/38). Among those 38 patients, 35 had gastric ulcer with a cure rate of 71.4% (25/35), and 3 had duodenal ulcer with a cure rate of 66.7% (2/3). Three adverse drug reactions were reported from 64 patients in the safety analysis (interstitial pneumonia, low white blood cell count and pruritus); thus, the incidence rate for adverse drug reactions was 4.7% (3/64). The treatment efficacy of rabeprazole for NSAID-induced ulcer under continuous NSAID administration was confirmed.

  5. Establishment of a drug-induced rhabdomyolysis mouse model by co-administration of ciprofloxacin and atorvastatin.

    Science.gov (United States)

    Matsubara, Akiko; Oda, Shingo; Akai, Sho; Tsuneyama, Koichi; Yokoi, Tsuyoshi

    2018-07-01

    Rhabdomyolysis is one of the serious side effects of ciprofloxacin (CPFX), a widely used antibacterial drug; and occasionally, acute kidney injury (AKI) occurs. Often, rhabdomyolysis has occurred in patients taking CPFX co-administered with statins. The purpose of this study is to establish a mouse model of drug-induced rhabdomyolysis by co-administration of CPFX and atorvastatin (ATV) and to clarify the mechanisms of its pathogenesis. C57BL/6J mice treated with L-buthionine-(S,R)-sulfoximine (BSO), a glutathione synthesis inhibitor, were orally administered with CPFX and ATV for 4 days. Plasma levels of creatinine phosphokinase (CPK) and aspartate aminotransferase (AST) were significantly increased in the CPFX and ATV-co-administered group. Histopathological examination of skeletal muscle observed degeneration in gastrocnemius muscle and an increased number of the satellite cells. Expressions of skeletal muscle-specific microRNA and mRNA in plasma and skeletal muscle, respectively, were significantly increased. The area under the curve (AUC) of plasma CPFX was significantly increased in the CPFX and ATV-co-administered group. Furthermore, cytoplasmic vacuolization and a positively myoglobin-stained region in kidney tissue and high content of myoglobin in urine were observed. These results indicated that AKI was induced by myoglobin that leaked from skeletal muscle. The established mouse model in the present study would be useful for predicting potential rhabdomyolysis risks in preclinical drug development. Copyright © 2018 Elsevier B.V. All rights reserved.

  6. Interaction between the Basolateral Amygdala and Dorsal Hippocampus Is Critical for Cocaine Memory Reconsolidation and Subsequent Drug Context-Induced Cocaine-Seeking Behaviorin Rats

    Science.gov (United States)

    Wells, Audrey M.; Lasseter, Heather C.; Xie, Xiaohu; Cowhey, Kate E.; Reittinger, Andrew M.; Fuchs, Rita A.

    2011-01-01

    Contextual stimulus control over instrumental drug-seeking behavior relies on the reconsolidation of context-response-drug associative memories into long-term memory storage following retrieval-induced destabilization. According to previous studies, the basolateral amygdala (BLA) and dorsal hippocampus (DH) regulate cocaine-related memory…

  7. High-resolution sub-cellular imaging by correlative NanoSIMS and electron microscopy of amiodarone internalisation by lung macrophages as evidence for drug-induced phospholipidosis.

    Science.gov (United States)

    Jiang, Haibo; Passarelli, Melissa K; Munro, Peter M G; Kilburn, Matt R; West, Andrew; Dollery, Colin T; Gilmore, Ian S; Rakowska, Paulina D

    2017-01-26

    Correlative NanoSIMS and EM imaging of amiodarone-treated macrophages shows the internalisation of the drug at a sub-cellular level and reveals its accumulation within the lysosomes, providing direct evidence for amiodarone-induced phospholipidosis. Chemical fixation using tannic acid effectively seals cellular membranes aiding intracellular retention of diffusible drugs.

  8. The contribution of oxidative stress to drug-induced organ toxicity and its detection in vitro and in vivo.

    Science.gov (United States)

    Pereira, Claudia V; Nadanaciva, Sashi; Oliveira, Paulo J; Will, Yvonne

    2012-02-01

    Nowadays the 'redox hypothesis' is based on the fact that thiol/disulfide couples such as glutathione (GSH/GSSG), cysteine (Cys/CySS) and thioredoxin ((Trx-(SH)2/Trx-SS)) are functionally organized in redox circuits controlled by glutathione pools, thioredoxins and other control nodes, and they are not in equilibrium relative to each other. Although ROS can be important intermediates of cellular signaling pathways, disturbances in the normal cellular redox can result in widespread damage to several cell components. Moreover, oxidative stress has been linked to a variety of age-related diseases. In recent years, oxidative stress has also been identified to contribute to drug-induced liver, heart, renal and brain toxicity. This review provides an overview of current in vitro and in vivo methods that can be deployed throughout the drug discovery process. In addition, animal models and noninvasive biomarkers are described. Reducing post-market drug withdrawals is essential for all pharmaceutical companies in a time of increased patient welfare and tight budgets. Predictive screens positioned early in the drug discovery process will help to reduce such liabilities. Although new and more efficient assays and models are being developed, the hunt for biomarkers and noninvasive techniques is still in progress.

  9. Impulsion of nanoparticles as a drug carrier for the theoretical investigation of stenosed arteries with induced magnetic effects

    Energy Technology Data Exchange (ETDEWEB)

    Nadeem, S.; Ijaz, S., E-mail: shagufta.me2011@yahoo.com

    2016-07-15

    In this paper hemodynamics of stenosis are discussed to predict effect of atherosclerosis by means of mathematical models in the presence of uniform transverse magnetic field. The analysis is carried out using silver and copper nanoparticles as a drug carrier. Exact solution for the fluid temperature, velocity, axial induced magnetic field and current density distribution are obtained under mild stenosis approximation. The results indicate that with an increase in the concentration of nanoparticle hemodynamics effects of stenosis reduces throughout the inclined composite stenosed arteries. The considered analysis also summarizes that the drug silver nanoparticles is more efficient to reduce hemodynamics of stenosis when compare to the drug copper nanoparticle. In future this model could be helpful to predict important properties in some biomedical applications. - Highlights: • The contribution of copper and silver nanoparticles as drug carrier reveals that they are important to reduce hemodynamic of stenosis. • The heat is dissipated throughout the considered inclined artery with an increase in the nanoparticle volume fraction. • The stress on the wall of inclined arteries decreases with an increase in the magnetic Reynolds number and Strommers number.

  10. Lipid microbubbles as a vehicle for targeted drug delivery using focused ultrasound-induced blood-brain barrier opening.

    Science.gov (United States)

    Sierra, Carlos; Acosta, Camilo; Chen, Cherry; Wu, Shih-Ying; Karakatsani, Maria E; Bernal, Manuel; Konofagou, Elisa E

    2017-04-01

    Focused ultrasound in conjunction with lipid microbubbles has fully demonstrated its ability to induce non-invasive, transient, and reversible blood-brain barrier opening. This study was aimed at testing the feasibility of our lipid-coated microbubbles as a vector for targeted drug delivery in the treatment of central nervous system diseases. These microbubbles were labeled with the fluorophore 5-dodecanoylaminfluorescein. Focused ultrasound targeted mouse brains in vivo in the presence of these microbubbles for trans-blood-brain barrier delivery of 5-dodecanoylaminfluorescein. This new approach, compared to previously studies of our group, where fluorescently labeled dextrans and microbubbles were co-administered, represents an appreciable improvement in safety outcome and targeted drug delivery. This novel technique allows the delivery of 5-dodecanoylaminfluorescein at the region of interest unlike the alternative of systemic exposure. 5-dodecanoylaminfluorescein delivery was assessed by ex vivo fluorescence imaging and by in vivo transcranial passive cavitation detection. Stable and inertial cavitation doses were quantified. The cavitation dose thresholds for estimating, a priori, successful targeted drug delivery were, for the first time, identified with inertial cavitation were concluded to be necessary for successful delivery. The findings presented herein indicate the feasibility and safety of the proposed microbubble-based targeted drug delivery and that, if successful, can be predicted by cavitation detection in vivo.

  11. Lipid microbubbles as a vehicle for targeted drug delivery using focused ultrasound-induced blood–brain barrier opening

    Science.gov (United States)

    Sierra, Carlos; Acosta, Camilo; Chen, Cherry; Wu, Shih-Ying; Karakatsani, Maria E; Bernal, Manuel

    2016-01-01

    Focused ultrasound in conjunction with lipid microbubbles has fully demonstrated its ability to induce non-invasive, transient, and reversible blood–brain barrier opening. This study was aimed at testing the feasibility of our lipid-coated microbubbles as a vector for targeted drug delivery in the treatment of central nervous system diseases. These microbubbles were labeled with the fluorophore 5-dodecanoylaminfluorescein. Focused ultrasound targeted mouse brains in vivo in the presence of these microbubbles for trans-blood–brain barrier delivery of 5-dodecanoylaminfluorescein. This new approach, compared to previously studies of our group, where fluorescently labeled dextrans and microbubbles were co-administered, represents an appreciable improvement in safety outcome and targeted drug delivery. This novel technique allows the delivery of 5-dodecanoylaminfluorescein at the region of interest unlike the alternative of systemic exposure. 5-dodecanoylaminfluorescein delivery was assessed by ex vivo fluorescence imaging and by in vivo transcranial passive cavitation detection. Stable and inertial cavitation doses were quantified. The cavitation dose thresholds for estimating, a priori, successful targeted drug delivery were, for the first time, identified with inertial cavitation were concluded to be necessary for successful delivery. The findings presented herein indicate the feasibility and safety of the proposed microbubble-based targeted drug delivery and that, if successful, can be predicted by cavitation detection in vivo. PMID:27278929

  12. Vinpocetine inhibits glutamate release induced by the convulsive agent 4-aminopyridine more potently than several antiepileptic drugs.

    Science.gov (United States)

    Sitges, M; Sanchez-Tafolla, B M; Chiu, L M; Aldana, B I; Guarneros, A

    2011-10-01

    4-Aminopyridine (4-AP) is a convulsing agent that in vivo preferentially releases Glu, the most important excitatory amino acid neurotransmitter in the brain. Here the ionic dependence of 4-AP-induced Glu release and the effects of several of the most common antiepileptic drugs (AEDs) and of the new potential AED, vinpocetine on 4-AP-induced Glu release were characterized in hippocampus isolated nerve endings pre-loaded with labelled Glu ([3H]Glu). 4-AP-induced [3H]Glu release was composed by a tetrodotoxin (TTX) sensitive and external Ca2+ dependent fraction and a TTX insensitive fraction that was sensitive to the excitatory amino acid transporter inhibitor, TBOA. The AEDs: carbamazepine, phenytoin, lamotrigine and oxcarbazepine at the highest dose tested only reduced [3H]Glu release to 4-AP between 50-60%, and topiramate was ineffective. Vinpocetine at a much lower concentration than the above AEDs, abolished [3H]Glu release to 4-AP. We conclude that the decrease in [3H]Glu release linked to the direct blockade of presynaptic Na+ channels, may importantly contribute to the anticonvulsant actions of all the drugs tested here (except topiramate); and that the significantly greater vinpocetine effect in magnitude and potency on [3H]Glu release when excitability is exacerbated like during seizures, may involve the increase additionally exerted by vinpocetine in some K+ channels permeability. Copyright © 2011 Elsevier B.V. All rights reserved.

  13. Gemfibrozil, a lipid-lowering drug, induces suppressor of cytokine signaling 3 in glial cells: implications for neurodegenerative disorders.

    Science.gov (United States)

    Ghosh, Arunava; Pahan, Kalipada

    2012-08-03

    Glial inflammation is an important feature of several neurodegenerative disorders. Suppressor of cytokine signaling (SOCS) proteins play a crucial role in inhibiting cytokine signaling and inflammatory gene expression in various cell types, including glial cells. However, mechanisms by which SOCS genes could be up-regulated are poorly understood. This study underlines the importance of gemfibrozil, a Food and Drug Administration-approved lipid-lowering drug, in up-regulating the expression of SOCS3 in glial cells. Gemfibrozil increased the expression of Socs3 mRNA and protein in mouse astroglia and microglia in both a time- and dose-dependent manner. Interestingly, gemfibrozil induced the activation of type IA phosphatidylinositol (PI) 3-kinase and AKT. Accordingly, inhibition of PI 3-kinase and AKT by chemical inhibitors abrogated gemfibrozil-mediated up-regulation of SOCS3. Furthermore, we demonstrated that gemfibrozil induced the activation of Krüppel-like factor 4 (KLF4) via the PI 3-kinase-AKT pathway and that siRNA knockdown of KLF4 abrogated gemfibrozil-mediated up-regulation of SOCS3. Gemfibrozil also induced the recruitment of KLF4 to the distal, but not proximal, KLF4-binding site of the Socs3 promoter. This study delineates a novel property of gemfibrozil in up-regulating SOCS3 in glial cells via PI 3-kinase-AKT-mediated activation of KLF4 and suggests that gemfibrozil may find therapeutic application in neuroinflammatory and neurodegenerative disorders.

  14. High fat diet and GLP-1 drugs induce pancreatic injury in mice

    Energy Technology Data Exchange (ETDEWEB)

    Rouse, Rodney, E-mail: rodney.rouse@fda.hhs.gov; Xu, Lin; Stewart, Sharron; Zhang, Jun

    2014-04-15

    Glucagon Like Peptide-1 (GLP-1) drugs are currently used to treat type-2 diabetes. Safety concerns for increased risk of pancreatitis and pancreatic ductal metaplasia have accompanied these drugs. High fat diet (HFD) is a type-2 diabetes risk factor that may affect the response to GLP-1 drug treatment. The objective of the present study was to investigate the effects of diet and GLP-1 based drugs on the exocrine pancreas in mice. Experiments were designed in a mouse model of insulin resistance created by feeding a HFD or standard diet (STD) for 6 weeks. The GLP-1 drugs, sitagliptin (SIT) and exenatide (EXE) were administered once daily for additional 6 weeks in both mice fed HFD or STD. The results showed that body weight, blood glucose levels, and serum levels of pro-inflammatory cytokines (TNFα, IL-1β, and KC) were significantly greater in HFD mice than in STD mice regardless of GLP-1 drug treatment. The semi-quantitative grading showed that pancreatic changes were significantly greater in EXE and SIT-treated mice compared to control and that HFD exacerbated spontaneous exocrine pancreatic changes seen in saline-treated mice on a standard diet. Exocrine pancreatic changes identified in this study included acinar cell injury (hypertrophy, autophagy, apoptosis, necrosis, and atrophy), vascular injury, interstitial edema and inflammation, fat necrosis, and duct changes. These findings support HFD as a risk factor to increased susceptibility/severity for acute pancreatitis and indicate that GLP-1 drugs cause pancreatic injury that can be exacerbated in a HFD environment.

  15. SIMulation of Medication Error induced by Clinical Trial drug labeling: the SIMME-CT study.

    Science.gov (United States)

    Dollinger, Cecile; Schwiertz, Vérane; Sarfati, Laura; Gourc-Berthod, Chloé; Guédat, Marie-Gabrielle; Alloux, Céline; Vantard, Nicolas; Gauthier, Noémie; He, Sophie; Kiouris, Elena; Caffin, Anne-Gaelle; Bernard, Delphine; Ranchon, Florence; Rioufol, Catherine

    2016-06-01

    To assess the impact of investigational drug labels on the risk of medication error in drug dispensing. A simulation-based learning program focusing on investigational drug dispensing was conducted. The study was undertaken in an Investigational Drugs Dispensing Unit of a University Hospital of Lyon, France. Sixty-three pharmacy workers (pharmacists, residents, technicians or students) were enrolled. Ten risk factors were selected concerning label information or the risk of confusion with another clinical trial. Each risk factor was scored independently out of 5: the higher the score, the greater the risk of error. From 400 labels analyzed, two groups were selected for the dispensing simulation: 27 labels with high risk (score ≥3) and 27 with low risk (score ≤2). Each question in the learning program was displayed as a simulated clinical trial prescription. Medication error was defined as at least one erroneous answer (i.e. error in drug dispensing). For each question, response times were collected. High-risk investigational drug labels correlated with medication error and slower response time. Error rates were significantly 5.5-fold higher for high-risk series. Error frequency was not significantly affected by occupational category or experience in clinical trials. SIMME-CT is the first simulation-based learning tool to focus on investigational drug labels as a risk factor for medication error. SIMME-CT was also used as a training tool for staff involved in clinical research, to develop medication error risk awareness and to validate competence in continuing medical education. © The Author 2016. Published by Oxford University Press in association with the International Society for Quality in Health Care; all rights reserved.

  16. High fat diet and GLP-1 drugs induce pancreatic injury in mice

    International Nuclear Information System (INIS)

    Rouse, Rodney; Xu, Lin; Stewart, Sharron; Zhang, Jun

    2014-01-01

    Glucagon Like Peptide-1 (GLP-1) drugs are currently used to treat type-2 diabetes. Safety concerns for increased risk of pancreatitis and pancreatic ductal metaplasia have accompanied these drugs. High fat diet (HFD) is a type-2 diabetes risk factor that may affect the response to GLP-1 drug treatment. The objective of the present study was to investigate the effects of diet and GLP-1 based drugs on the exocrine pancreas in mice. Experiments were designed in a mouse model of insulin resistance created by feeding a HFD or standard diet (STD) for 6 weeks. The GLP-1 drugs, sitagliptin (SIT) and exenatide (EXE) were administered once daily for additional 6 weeks in both mice fed HFD or STD. The results showed that body weight, blood glucose levels, and serum levels of pro-inflammatory cytokines (TNFα, IL-1β, and KC) were significantly greater in HFD mice than in STD mice regardless of GLP-1 drug treatment. The semi-quantitative grading showed that pancreatic changes were significantly greater in EXE and SIT-treated mice compared to control and that HFD exacerbated spontaneous exocrine pancreatic changes seen in saline-treated mice on a standard diet. Exocrine pancreatic changes identified in this study included acinar cell injury (hypertrophy, autophagy, apoptosis, necrosis, and atrophy), vascular injury, interstitial edema and inflammation, fat necrosis, and duct changes. These findings support HFD as a risk factor to increased susceptibility/severity for acute pancreatitis and indicate that GLP-1 drugs cause pancreatic injury that can be exacerbated in a HFD environment

  17. Repercussion of mitochondria deformity induced by anti-Hsp90 drug 17AAG in human tumor cells

    KAUST Repository

    Vishal, Chaturvedi

    2011-06-07

    Inhibiting Hsp90 chaperone roles using 17AAG induces cytostasis or apoptosis in tumor cells through destabilization of several mutated cancer promoting proteins. Although mitochondria are central in deciding the fate of cells, 17AAG induced effects on tumor cell mitochondria were largely unknown. Here, we show that Hsp90 inhibition with 17AAG first affects mitochondrial integrity in different human tumor cells, neuroblastoma, cervical cancer and glial cells. Using human neuroblastoma tumor cells, we found the early effects associated with a change in mitochondrial membrane potential, elongation and engorgement of mitochondria because of an increased matrix vacuolization. These effects are specific to Hsp90 inhibition as other chemotherapeutic drugs did not induce similar mitochondrial deformity. Further, the effects are independent of oxidative damage and cytoarchitecture destabilization since cytoskeletal disruptors and mitochondrial metabolic inhibitors also do not induce similar deformity induced by 17AAG. The 1D PAGE LC MS/ MS mitochondrial proteome analysis of 17AAG treated human neuroblastoma cells showed a loss of 61% proteins from membrane, metabolic, chaperone and ribonucleoprotein families. About 31 unmapped protein IDs were identified from proteolytic processing map using Swiss-Prot accession number, and converted to the matching gene name searching the ExPASy proteomics server. Our studies display that Hsp90 inhibition effects at first embark on mitochondria of tumor cells and compromise mitochondrial integrity. the author(s), publisher and licensee Libertas Academica Ltd.

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

    International Nuclear Information System (INIS)

    Diaz-Corrales, Francisco J.; Escobar-Delgado, Teresa; Sanz-Viedma, Salome; Garcia-Solis, David; Mir, Pablo

    2010-01-01

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

  19. [Clinical investigation on treatment of integrated traditional and Western medicine in hyperthyroidism with leukocytopenia induced by sulfourea drugs].

    Science.gov (United States)

    Lu, W

    1998-01-01

    To seek for a safe and effective drug to treat hyperthyroidism. Sixty cases of hyperthyroidism with leukocytopenia induced by sulfourea drugs were divided into treatment and control groups by 31 cases who were treated by traditional medicine Syndrome Differentiation and 29 cases who were treated by conventional western medicine alone respectively at random. They were estimated by total effective rate, major symptoms, WBC and immunological tests after four weeks. The total effective rate in the treatment group (96.8%) was more effective than that in the control group (86.2%, P symptom recovery rate in the treatment group was better than that in the control group. The WBC in both were all increased, but in the treatment group, it was better than that in the control group (P symptoms and immune function, but also increase WBC by using western medicine in combination with traditional medicine in treating hyperthyroidism.

  20. Etanercept overcomes P-glycoprotein-induced drug resistance in lymphocytes of patients with intractable rheumatoid arthritis.

    Science.gov (United States)

    Tsujimura, Shizuyo; Saito, Kazuyoshi; Nakayamada, Shingo; Tanaka, Yoshiya

    2010-04-01

    P-glycoprotein (P-gp) on activated lymphocytes is an adenosine triphosphate (ATP)-binding cassette transporter that causes drug resistance by exclusion of intracellular drugs in patients with active rheumatoid arthritis (RA). However, infliximab with methotrexate (MTX) can overcome P-gp-mediated drug resistance. We encounter patients who cannot continue infliximab or MTX. Here we tested how etanercept affected P-gp-mediated drug resistance in such intractable RA patients. Peripheral lymphocytes of 11 RA patients (3 switched from infliximab and 8 who could not be treated with MTX) were analyzed for P-gp expression by flow cytometry and for drug exclusion using radioisotope-labeled dexamethasone. Activated lymphocytes of RA patients overexpressed P-gp and coexpressed CD69. Incubation of these lymphocytes with dexamethasone in vitro reduced intracellular dexamethasone levels. Two-week etanercept therapy significantly reduced P-gp expression and eliminated such P-gp- and CD69-high-expressing subgroup. The reduction in P-gp resulted in recovery of intracellular dexamethasone levels in lymphocytes and improvement of disease activity, thus allowing tapering of corticosteroids. None of the patients experienced any severe adverse effects. Etanercept is useful for overcoming P-gp-mediated treatment resistance in intractable RA patients who have to discontinue infliximab or are intolerant to MTX.

  1. Noninvasive cardiac activation imaging of ventricular arrhythmias during drug-induced QT prolongation in the rabbit heart.

    Science.gov (United States)

    Han, Chengzong; Pogwizd, Steven M; Killingsworth, Cheryl R; Zhou, Zhaoye; He, Bin

    2013-10-01

    Imaging myocardial activation from noninvasive body surface potentials promises to aid in both cardiovascular research and clinical medicine. To investigate the ability of a noninvasive 3-dimensional cardiac electrical imaging technique for characterizing the activation patterns of dynamically changing ventricular arrhythmias during drug-induced QT prolongation in rabbits. Simultaneous body surface potential mapping and 3-dimensional intracardiac mapping were performed in a closed-chest condition in 8 rabbits. Data analysis was performed on premature ventricular complexes, couplets, and torsades de pointes (TdP) induced during intravenous administration of clofilium and phenylephrine with combinations of various infusion rates. The drug infusion led to a significant increase in the QT interval (from 175 ± 7 to 274 ± 31 ms) and rate-corrected QT interval (from 183 ± 5 to 262 ± 21 ms) during the first dose cycle. All the ectopic beats initiated by a focal activation pattern. The initial beat of TdPs arose at the focal site, whereas the subsequent beats were due to focal activity from different sites or 2 competing focal sites. The imaged results captured the dynamic shift of activation patterns and were in good correlation with the simultaneous measurements, with a correlation coefficient of 0.65 ± 0.02 averaged over 111 ectopic beats. Sites of initial activation were localized to be ~5 mm from the directly measured initiation sites. The 3-dimensional cardiac electrical imaging technique could localize the origin of activation and image activation sequence of TdP during QT prolongation induced by clofilium and phenylephrine in rabbits. It offers the potential to noninvasively investigate the proarrhythmic effects of drug infusion and assess the mechanisms of arrhythmias on a beat-to-beat basis. © 2013 Heart Rhythm Society. All rights reserved.

  2. Critical Role of Peripheral Vasoconstriction in Fatal Brain Hyperthermia Induced by MDMA (Ecstasy) under Conditions That Mimic Human Drug Use

    Science.gov (United States)

    Kim, Albert H.; Wakabayashi, Ken T.; Baumann, Michael H.; Shaham, Yavin

    2014-01-01

    MDMA (Ecstasy) is an illicit drug used by young adults at hot, crowed “rave” parties, yet the data on potential health hazards of its abuse remain controversial. Here, we examined the effect of MDMA on temperature homeostasis in male rats under standard laboratory conditions and under conditions that simulate drug use in humans. We chronically implanted thermocouple microsensors in the nucleus accumbens (a brain reward area), temporal muscle, and facial skin to measure temperature continuously from freely moving rats. While focusing on brain hyperthermia, temperature monitoring from the two peripheral locations allowed us to evaluate the physiological mechanisms (i.e., intracerebral heat production and heat loss via skin surfaces) that underlie MDMA-induced brain temperature responses. Our data confirm previous reports on high individual variability and relatively weak brain hyperthermic effects of MDMA under standard control conditions (quiet rest, 22−23°C), but demonstrate dramatic enhancements of drug-induced brain hyperthermia during social interaction (exposure to male conspecific) and in warm environments (29°C). Importantly, we identified peripheral vasoconstriction as a critical mechanism underlying the activity- and state-dependent potentiation of MDMA-induced brain hyperthermia. Through this mechanism, which prevents proper heat dissipation to the external environment, MDMA at a moderate nontoxic dose (9 mg/kg or ∼1/5 of LD50 in rats) can cause fatal hyperthermia under environmental conditions commonly encountered by humans. Our results demonstrate that doses of MDMA that are nontoxic under cool, quiet conditions can become highly dangerous under conditions that mimic recreational use of MDMA at rave parties or other hot, crowded venues. PMID:24899699

  3. Overexpression of IL-38 protein in anticancer drug-induced lung injury and acute exacerbation of idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Tominaga, Masaki; Okamoto, Masaki; Kawayama, Tomotaka; Matsuoka, Masanobu; Kaieda, Shinjiro; Sakazaki, Yuki; Kinoshita, Takashi; Mori, Daisuke; Inoue, Akira; Hoshino, Tomoaki

    2017-09-01

    Interleukin (IL)-38, a member of the IL-1 family, shows high homology to IL-1 receptor antagonist (IL-1Ra) and