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Sample records for abnormalities drug-induced

  1. 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.

  2. Drug-induced liver injuries

    African Journals Online (AJOL)

    2011-06-02

    Jun 2, 2011 ... Drug-induced liver injury (DILI) is a term increasingly being used by most clinicians and is synonymous with drug-induced hepatotoxicity. A succinct definition of a DILI is 'a liver injury induced by a drug or herbal medicine resulting in liver test abnormalities or liver dysfunction with a reasonable exclusion of ...

  3. Identifying drug-induced repolarization abnormalities from distinct ECG patterns in congenital long QT syndrome: a study of sotalol effects on T-wave morphology

    DEFF Research Database (Denmark)

    Graff, Claus; Andersen, Mads P; Xue, Joel Q

    2009-01-01

    repolarization is therefore warranted. Most drugs associated with risk are inhibitors of the rapidly activating delayed rectifier potassium current (I(Kr)). This current is also inhibited in the congenital type 2 form of the long QT syndrome (LQT2). It is therefore possible that electrocardiographic LQT2......BACKGROUND: The electrocardiographic QT interval is used to identify drugs with potential harmful effects on cardiac repolarization in drug trials, but the variability of the measurement can mask drug-induced ECG changes. The use of complementary electrocardiographic indices of abnormal......-induced prolongation of the heart rate corrected QT interval (QTcF) was compared with changes in the computerized measure for T-wave morphology. Effect sizes for QTcF and MCS were calculated at the time of maximum plasma concentrations and for maximum change from baseline. Accuracy for separating baseline from sotalol...

  4. Drug-Induced Hematologic Syndromes

    Directory of Open Access Journals (Sweden)

    David M. Mintzer

    2009-01-01

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

  5. Thrombocytopenia - drug induced

    Science.gov (United States)

    Drug-induced thrombocytopenia; Immune thrombocytopenia - drug ... Drug-induced thrombocytopenia occurs when certain medicines destroy platelets or interfere with the body's ability to make enough of them. There ...

  6. Drug induced aseptic meningitis

    African Journals Online (AJOL)

    PROF. EZECHUKWU

    2013-09-29

    Sep 29, 2013 ... Drug induced aseptic meningitis can mimic an infectious process as well as meningitis secondary to systemic disorders for which treatment of these drugs were used. 6,9,10. Drug-induced aseptic meningitis may develop in a pa- tient who initially was able to tolerate the causative drug. The patients in our ...

  7. 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 ...

  8. Drug-induced uveitis

    Science.gov (United States)

    2013-01-01

    A number of medications have been associated with uveitis. This review highlights both well-established and recently reported systemic, topical, intraocular, and vaccine-associated causes of drug-induced uveitis, and assigns a quantitative score to each medication based upon criteria originally described by Naranjo and associates. PMID:23522744

  9. Drug-induced nail disorders.

    Science.gov (United States)

    2014-07-01

    Nail disorders are defined according to their appearance and the part of the nail affected: the nail plate, the tissues that support or hold the nail plate in place, or the lunula. The consequences of most nail disorders are purely cosmetic. Other disorders, such as ingrown nails, inflammation, erythema, abscesses or tumours, cause functional impairment or pain. The appearance of the lesions is rarely indicative of their cause. Possible causes include physiological changes, local disorders or trauma, systemic conditions, toxic substances and drugs. Most drug-induced nail disorders resolve after discontinuation of the drug, although complete resolution sometimes takes several years. Drugs appear to induce nail disorders through a variety of mechanisms. Some drugs affect the nail matrix epithelium, the nail bed or the nail folds. Some alter nail colour. Other drugs induce photosensitivity. Yet others affect the blood supply to the nail unit. Nail abnormalities are common during treatment with certain cytotoxic drugs: taxanes, anthracyclines, fluorouracil, EGFR, tyrosine kinase inhibitors, etc. Some drugs are associated with a risk of serious and painful lesions, such as abscesses. When these disorders affect quality of life, the benefits of withdrawing the drug must be weighed against the severity of the condition being treated and the drug's efficacy, taking into account the harm-benefit balance of other options. Various anti-infective drugs, including tetracyclines, quinolones, clofazimine and zidovudine, cause the nail plate to detach from the nail bed after exposure to light, or cause nail discoloration. Psoralens and retinoids can also have the same effects.

  10. Drug-induced thrombocytopenia

    DEFF Research Database (Denmark)

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

    1997-01-01

    OBJECTIVE: To analyse the clinical picture and the course of thrombocytopenia induced by non-cytotoxic drugs, and to evaluate a possible therapeutic effect of corticosteroids. METHODS: A retrospective analysis of 309 well-documented cases of drug-induced thrombocytopenia was performed. Data sources...... were reports from the files of the Danish Committee on Adverse Drug Reactions and discharge summaries. RESULTS: The median length of exposure to the offending drug, before development of thrombocytopenia, was 21 days. The median nadir platelet count was 11 x 10(9).l-1, and 74% of the patients had...... treatment was corticosteroids, which were administered in 53% of the cases. No difference in recovery between corticosteroid-treated and untreated patients was observed. No other clinical parameter affected the recovery rate. The mortality rate due to haemorrhage was 3.6%. CONCLUSION: Thrombocytopenia...

  11. Management of drug-induced hyperbilirubinaemia in early pregnancy

    African Journals Online (AJOL)

    abdominal ultrasound scan revealed no abnormalities. As soon as the patient stopped taking aspirin, the hyperbilirubinaemia and abnormal liver enzymes began to normalise. Drug-lymphocyte stimulation tests for aspirin were positive. We therefore diagnosed drug-induced hepatotoxicity caused by aspirin. From the 15th.

  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 Brugada syndrome: Clinical characteristics and risk factors.

    Science.gov (United States)

    Konigstein, Maayan; Rosso, Raphael; Topaz, Guy; Postema, Pieter G; Friedensohn, Limor; Heller, Karin; Zeltser, David; Belhassen, Bernard; Adler, Arnon; Viskin, Sami

    2016-05-01

    Cardiac arrest may result from seemingly innocuous medications that do not necessarily have cardiac indications. The best-known example is the drug-induced long QT syndrome. A less known but not necessarily less important form of drug-induced proarrhythmia is the drug-induced Brugada syndrome. The purpose of this study was to identify clinical and ECG risk markers for drug-induced Brugada syndrome. Reports of drug-induced Brugada syndrome recounted by an international database (http://www.brugadadrugs.org) were reviewed to define characteristics that identify patients prone to developing this complication. For each patient with drug-induced Brugada syndrome who had an ECG recorded in the absence of drugs, we included 5 healthy controls matched by gender and age. All ECGs were evaluated for Brugada-like abnormalities. Seventy-four cases of drug-induced Brugada syndrome from noncardiac medications were identified: 77% were male, and drug toxicity was involved in 46%. Drug-induced Brugada syndrome from oral medications generally occurred weeks after the initiation of therapy. Mortality was 13%. By definition, all cases had a type I Brugada pattern during drug therapy. Nevertheless, their ECG in the absence of drugs was more frequently abnormal than the ECG of controls (56% vs 33%, P = .04). Drug-induced Brugada syndrome from noncardiac drugs occurs predominantly in adult males, is frequently due to drug toxicity, and occurs late after the onset of therapy. Minor changes are frequently noticeable on baseline ECG, but screening is impractical because of a prohibitive false-positive rate. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  14. Drug-Induced Metabolic Acidosis

    Science.gov (United States)

    Pham, Amy Quynh Trang; Xu, Li Hao Richie; Moe, Orson W.

    2015-01-01

    Metabolic acidosis could emerge from diseases disrupting acid-base equilibrium or from drugs that induce similar derangements. Occurrences are usually accompanied by comorbid conditions of drug-induced metabolic acidosis, and clinical outcomes may range from mild to fatal. It is imperative that clinicians not only are fully aware of the list of drugs that may lead to metabolic acidosis but also understand the underlying pathogenic mechanisms. In this review, we categorized drug-induced metabolic acidosis in terms of pathophysiological mechanisms, as well as individual drugs’ characteristics. PMID:26918138

  15. 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.

  16. Drug-induced Brugada syndrome

    Directory of Open Access Journals (Sweden)

    Yoshino Minoura

    2013-04-01

    Full Text Available Brugada syndrome (BrS is an inherited cardiac disorder that is associated with an electrocardiogram pattern of ST segment elevation on right precordial leads and a high incidence of sudden death. Diagnosis requires documentation of a coved-type ST segment that occurs spontaneously or in the presence of a class IA or IC antiarrhythmic agent. A wide variety of other drugs, including antianginals, antidepressants, antipsychotics, and antihistamines, have been reported to unmask or induce the electrocardiographic and arrhythmic manifestations of BrS. This review focuses on drug-induced BrS phenotypes, prevalence, and underlying mechanisms.

  17. 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...

  18. Drug induced interstitial lung disease.

    Science.gov (United States)

    Schwaiblmair, Martin; Behr, Werner; Haeckel, Thomas; Märkl, Bruno; Foerg, Wolfgang; Berghaus, Thomas

    2012-01-01

    With an increasing number of therapeutic drugs, the list of drugs that is responsible for severe pulmonary disease also grows. Many drugs have been associated with pulmonary complications of various types, including interstitial inflammation and fibrosis, bronchospasm, pulmonary edema, and pleural effusions. Drug-induced interstitial lung disease (DILD) can be caused by chemotherapeutic agents, antibiotics, antiarrhythmic drugs, and immunosuppressive agents. There are no distinct physiologic, radiographic or pathologic patterns of DILD, and the diagnosis is usually made when a patient with interstitial lung disease (ILD) is exposed to a medication known to result in lung disease. Other causes of ILD must be excluded. Treatment is avoidance of further exposure and systemic corticosteroids in patients with progressive or disabling disease.

  19. 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...... biochemical findings included bilirubin elevated to above 3.2 × ULN, ALT elevated to above 9 × ULN in 86%, INR above 1.4 in 70%. Twenty two patients needed treatment in the liver intensive care unit. Fifteen patients developed acute liver failure with a severe outcome. Six patients were liver transplanted...... and nine patients died. Jaundice, a moderately elevated bilirubin level or INR at presentation was predictive of severe outcome. CONCLUSION: In this retrospective study, 35% of patients with DILI developed severe acute liver failure and were either liver transplanted or died. Our results underline...

  20. Drug-induced black hairy tongue.

    Science.gov (United States)

    Thompson, Dennis F; Kessler, Tiffany L

    2010-06-01

    Black hairy tongue (BHT) is a benign, self-limiting disorder characterized by abnormally hypertrophied and elongated filiform papillae on the surface of the tongue. The prevalence of BHT is quite variable, ranging from 0-53.8% depending on the population. Many predisposing factors to BHT exist, and several drugs and drug classes have been implicated in causing this disorder. A modified Naranjo adverse drug reaction probability nomogram specific for BHT was used to rate causality for the available published case reports of drug-induced BHT. From the available data, antibiotics and drugs capable of inducing xerostomia are the drug classes that have modest evidence of causality and a rational mechanism. The presence of underlying predisposing factors in these cases along with the variable prevalence of BHT make drawing firm conclusions difficult. Treatment for BHT involves eliminating any predisposing issues and practicing scrupulous oral hygiene. Drug therapy and physical removal of the elongated filiform papillae are available for resistant cases. Clinicians should be aware of the prevalence, the predisposing factors and drug classes that may play a role in the development, and the treatment of BHT.

  1. 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.

  2. Drug-induced immune thrombocytopenia

    Directory of Open Access Journals (Sweden)

    Janković Slobodan

    2015-01-01

    Full Text Available Drug-induced immune thrombocytopenia (DIIT is a consequence of destruction or inadequate activation of platelets by immune system provoked by current or previous presence of a drug in human organism. Annual incidence of DIIT is around 1-2 cases on 100,000 inhabitants. There are four proposed mechanisms behind the DIIT: (1 binding of drug-dependent antibodies for platelets; (2 blocking of fibrinogen binding for glycoprotein receptors IIb/IIIa; (3 drug-independent antibodies against platelets; and (4 creation of drug-antibody immune complexes which further activate platelets and lead to thromboses. Regardless of the DIIT mechanism, it is of paramount importance that physicians think of drugs as possible causes when they encounter low platelet count in a patient. Key therapeutic measure is discontinuation of the offending drug, while platelet transfusion is used only after extreme drop of platelet count. Heparin-induced thrombocytopenia is an exception, because it also requires treatment of thromboses with direct thrombin inhibitors.

  3. 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. ...

  4. Drug Induced Hearing Loss: What Is Ototoxicity?

    Science.gov (United States)

    ... page please turn JavaScript on. Feature: Drug-Induced Hearing Loss What Is Ototoxicity? Past Issues / Spring 2016 Table ... of patients taking these drugs." "Antibiotics Caused My Hearing Loss..." Gulab Lalwani Photo Courtesy of: Gulab Lalwani When ...

  5. Drug-induced hyperthermia in Huntington's disease

    NARCIS (Netherlands)

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

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

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

    NARCIS (Netherlands)

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

    2004-01-01

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

  7. Drug-induced gingival overgrowth: The nemesis of gingiva unravelled

    Directory of Open Access Journals (Sweden)

    Vipin Bharti

    2013-01-01

    Full Text Available Drug-induced gingival overgrowth or enlargement manifests as abnormal growth of the gingiva due to an adverse drug reaction (ADR in patients treated with anticonvulsants, immunosuppressants, and calcium channel blockers. As gingival enlargement develops, it affects the normal oral hygiene practice and may interfere with masticatory functions. It gradually becomes a source of pain and the condition often leads to disfiguration. Within the group of patients that develop this unwanted effect, there appears to be variability in the extent and severity of the gingival changes. It would seem pertinent to identify and explore possible risk factors and relating them with the treatment plan. This article throws light on respective drugs and their association with gingival overgrowth and approaches to treatment based on current knowledge and investigative observations.

  8. Drug-induced gingival overgrowth: The nemesis of gingiva unravelled.

    Science.gov (United States)

    Bharti, Vipin; Bansal, Chhaya

    2013-03-01

    Drug-induced gingival overgrowth or enlargement manifests as abnormal growth of the gingiva due to an adverse drug reaction (ADR) in patients treated with anticonvulsants, immunosuppressants, and calcium channel blockers. As gingival enlargement develops, it affects the normal oral hygiene practice and may interfere with masticatory functions. It gradually becomes a source of pain and the condition often leads to disfiguration. Within the group of patients that develop this unwanted effect, there appears to be variability in the extent and severity of the gingival changes. It would seem pertinent to identify and explore possible risk factors and relating them with the treatment plan. This article throws light on respective drugs and their association with gingival overgrowth and approaches to treatment based on current knowledge and investigative observations.

  9. Computational approaches to predicting drug induced toxicity

    OpenAIRE

    Marchese Robinson, Richard Liam

    2013-01-01

    Errors and issues requiring clarification are included as a separate document (January 2016). Novel approaches and models for predicting drug induced toxicity in silico are presented. Typically, these were based on Quantitative Structure-Activity Relationships (QSAR). The following endpoints were modelled: mutagenicity, carcinogenicity, inhibition of the hERG ion channel and the associated arrhythmia - Torsades de Pointes. A consensus model was developed based on Derek for Window...

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

    Science.gov (United States)

    ... JavaScript on. Feature: Drug-Induced Hearing Loss Researchers Study Strategies to Preserve Hearing Past Issues / Spring 2016 Table ... Read More "Drug Induced Hearing Loss" Articles Researchers Study Strategies to Preserve Hearing / What Is Ototoxicity? Spring 2016 ...

  11. 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.

  12. Drug-induced Brugada syndrome: Clinical characteristics and risk factors

    NARCIS (Netherlands)

    Konigstein, Maayan; Rosso, Raphael; Topaz, Guy; Postema, Pieter G.; Friedensohn, Limor; Heller, Karin; Zeltser, David; Belhassen, Bernard; Adler, Arnon; Viskin, Sami

    2016-01-01

    Cardiac arrest may result from seemingly innocuous medications that do not necessarily have cardiac indications. The best-known example is the drug-induced long QT syndrome. A less known but not necessarily less important form of drug-induced proarrhythmia is the drug-induced Brugada syndrome. The

  13. Non-drug induced gingival enlargement.

    Science.gov (United States)

    Moffitt, Michelle L; Cohen, Robert E

    2013-08-01

    Gingival enlargement refers to an increase in the size of the gingival tissue. The etiology varies, and often is multifactorial; however, local and systemic conditions, disease, and idiopathic factors may contribute to gingival enlargement. Tissue consistency can vary from soft and spongy to dense, typically appearing darker in shade compared to the drug-induced gingival enlargement. Treatment modalities usually involve surgical removal of excess tissue, non-surgical debridement, use of chemotherapeutic agents, and/or elimination or mitigation of contributing factors and conditions.

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

  15. Drugs Induced Stevens-Johnson Syndrome

    Directory of Open Access Journals (Sweden)

    Elif ÖNDER

    2010-05-01

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

  16. Drug induced acute pancreatitis: Does it exist?

    Science.gov (United States)

    Tenner, Scott

    2014-01-01

    As the incidence of acute pancreatitis continues to rise, establishing the etiology in order to prevent recurrence is important. Although the etiology of acute pancreatitis is not difficult in the majority of patients, almost a quarter of patients are initially labeled as having idiopathic acute pancreatitis. When confronted with a patient with acute pancreatitis and no clear etiology defined as an absence alcoholism, gallstones (ultrasound and/or MRI), a normal triglyceride level, and absence of tumor, it often appears reasonable to consider a drug as the cause of acute pancreatitis. Over 100 drugs have been implicated by case reports as causing acute pancreatitis. While some of these case reports are well written, many case reports represent poorly written experiences of the clinician simply implicating a drug without a careful evaluation. Over-reliance on case reports while ignoring randomized clinical trials and large pharmacoepidemiologic surveys has led to confusion about drug induced acute pancreatitis. This review will explain that drug induced acute pancreatitis does occur, but it is rare, and over diagnosis leads to misconceptions about the disease resulting in inappropriate patient care, increased litigation and a failure to address the true entity: idiopathic acute pancreatitis. PMID:25469020

  17. Spectrum of Drug-induced Chronic Diarrhea.

    Science.gov (United States)

    Philip, Nissy A; Ahmed, Nazir; Pitchumoni, Capecomorin S

    2017-02-01

    The evaluation of a patient with chronic diarrhea can be quite frustrating, as it is expensive and involves multiple diagnostic studies. Moreover, identification of a drug as a cause of chronic diarrhea is a challenge in patients taking multiple medications. The disease may either be associated with intestinal mucosal changes, mimicking diseases such as celiac disease, or purely functional, with no histopathologic change. Drug-induced diarrhea may or may not be associated with malabsorption of nutrients, and a clinical improvement may occur within days of discontinuation of the drug, or may take longer when associated with mucosal injury. Diarrhea in diabetics, often attributed to poor management and lack of control, may be due to oral hypoglycaemic agents. Chemotherapy can result in diffuse or segmental colitis, whereas olmesartan and a few other medications infrequently induce a disease that mimics celiac disease, but is not associated with gluten intolerance. In short, increased awareness of a drug, as a cause for diarrhea and a clear understanding of the clinical manifestations will help clinicians to solve this challenging problem. This article aims to review drug-induced diarrhea to (a) understand known pathophysiological mechanisms; (b) assess the risk associated with frequently prescribed medications, and discuss the pathogenesis; and (c) provide easily retrievable data in tables to help identify known offending medication/s and a list of top 100 prescribed medications in the United States as a useful comprehensive reference.

  18. Drug-induced bile duct injury.

    Science.gov (United States)

    Visentin, Michele; Lenggenhager, Daniela; Gai, Zhibo; Kullak-Ublick, Gerd A

    2017-09-04

    Drug-induced liver injury includes a spectrum of pathologies, some related to the mode of injury, some to the cell type primarily damaged. Among these, drug-induced bile duct injury is characterized by the destruction of the biliary epithelium following exposure to a drug. Most of the drugs associated with bile duct injury cause immune-mediated lesions to the epithelium of interlobular ducts. These share common histopathological features with primary biliary cholangitis, such as inflammation and necrosis at the expense of cholangiocytes and, if the insult persists, bile duct loss and biliary cirrhosis. Some drugs selectively target larger ducts. Such injury is often dose-dependent and thought to be the result of intrinsic drug toxicity. The histological changes resemble those seen in primary sclerosing cholangitis. This overview focuses on the clinical and pathological features of bile duct injury associated with drug treatment and on the immunological and biochemical effects that drugs exert on the biliary epithelium. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Drug-Induced Long QT Syndrome

    Science.gov (United States)

    Kannankeril, Prince; Darbar, Dawood

    2010-01-01

    The drug-induced long QT syndrome is a distinct clinical entity that has evolved from an electrophysiologic curiosity to a centerpiece in drug regulation and development. This evolution reflects an increasing recognition that a rare adverse drug effect can profoundly upset the balance between benefit and risk that goes into the prescription of a drug by an individual practitioner as well as the approval of a new drug entity by a regulatory agency. This review will outline how defining the central mechanism, block of the cardiac delayed-rectifier potassium current IKr, has contributed to defining risk in patients and in populations. Models for studying risk, and understanding the way in which clinical risk factors modulate cardiac repolarization at the molecular level are discussed. Finally, the role of genetic variants in modulating risk is described. PMID:21079043

  20. 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...

  1. Drug induced QT prolongation: the measurement and assessment of the QT interval in clinical practice

    Science.gov (United States)

    Isbister, Geoffrey K; Page, Colin B

    2013-01-01

    There has been an increasing focus on drug induced QT prolongation including research on drug development and QT prolongation, following the removal of drugs due to torsades de pointes (TdP). Although this has improved our understanding of drug-induced QT prolongation there has been much less research aimed at helping clinicians assess risk in individual patients with drug induced QT prolongation. This review will focus on assessment of drug-induced QT prolongation in clinical practice using a simple risk assessment approach. Accurate measurement of the QT interval is best done manually, and not using the measurement of standard ECG machines. Correction for heart rate (HR) using correction formulae such as Bazett's is often inaccurate. These formulae underestimate and overestimate the duration of cardiac repolarization at low and high heart rates, respectively. Numerous cut-offs have been suggested as an indicator of an abnormal QT, but are problematic in clinical practice. An alternative approach is the QT nomogram which is a plot of QT vs. HR. The nomogram has an ‘at risk’ line and QT-HR pairs above this line have been shown in a systematic study to be associated with TdP and the line is more sensitive and specific than Bazett's QTc of 440 ms or 500 ms. Plotting the QT-HR pair for patients on drugs suspected or known to cause QT prolongation allows assessment of the QT interval based on normal population QT variability. This risk assessment then allows the safer commencement of drugs therapeutically or management of drug induced effects in overdose. PMID:23167578

  2. 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.

  3. Melatonin modulates drug-induced acute porphyria

    Directory of Open Access Journals (Sweden)

    Sandra M. Lelli

    2016-01-01

    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.

  4. The VCS parameters: Potential hematological indicators for predicting antituberculosis drug-induced neutropenia.

    Science.gov (United States)

    Shen, Tian; Gu, Delin; Zhu, Yihua; Shi, Junwei; Xu, Dongsheng; Cao, Xingjian

    2016-08-01

    The morphological changes in activated neutrophils associated with antituberculosis drugs can be measured by volume, conductivity, and scatter (VCS) technology on the Coulter LH750 hematology analyzer. We conducted the current study to further validate the clinical usefulness of the neutrophil VCS parameters in predicting drug-induced neutropenia. Peripheral blood samples were collected from 52 patients with drug-induced neutropenia, 309 patients without any abnormal CBC, and 237 healthy controls. The mean neutrophil volume (MNV) with its distribution width (NDW) and the mean neutrophil scatter (MNS) were studied. We observed a significant increase in the MNV and NDW as well as a significant decrease in the MNS in neutropenia patients approximately one week prior to development of neutropenia compared to healthy controls as well as to case controls. In addition, the delta MNV and delta MNS were respectively correlated well with delta absolute neutrophil counts when neutropenia occurred. The ROC curve analyses showed that the MNV、NDW and MNS had larger areas under curves compared to conventional parameters. With a cutoff of 150.15 for the MNV, a sensitivity of 84.4% and specificity of 75.7% were achieved prior to neutropenia. The neutrophil VCS parameters may be clinically useful as potential hematological indicators for predicting antituberculosis drug-induced neutropenia. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Stavudine, an anti‑retroviral drug induces reactive astrocytes in ...

    African Journals Online (AJOL)

    Stavudine, an anti‑retroviral drug induces reactive astrocytes in motor cortex of albino mice. Agnes A. Nwakanma, Theresa B. Ekanem, Moses B. Ekong, Mokutima A. Eluwa, Eme E. Osim, Terkula Kpela ...

  6. Drug-Induced QT Prolongation And Torsades de Pointes

    OpenAIRE

    Li, Matthew; Ramos, Liz G.

    2017-01-01

    Torsades de pointes (TdP)—an uncommon but life-threatening polymorphic ventricular tachycardia—is almost always drug induced. The authors describe the causes, risk factors, symptoms, diagnosis, and treatment of TdP.

  7. 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.

  8. Phenotypes and Pathology of Drug-Induced Liver Disease.

    Science.gov (United States)

    Goodman, Zachary D

    2017-02-01

    Drug hepatotoxicity can simulate nearly any clinical syndrome or pathologic lesion that may occur in the liver, so clinical and histopathologic diagnosis of drug-induced liver injury may be difficult. Nevertheless, most drugs that are known to idiosyncratic liver injury tend to cause patterns of injury that produce characteristic phenotypes. Recognition of these patterns or phenotypes in liver biopsy material is helpful in evaluation of clinical cases of suspected drug-induced liver injury. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Genuine and drug-induced synesthesia: a comparison.

    Science.gov (United States)

    Sinke, Christopher; Halpern, John H; Zedler, Markus; Neufeld, Janina; Emrich, Hinderk M; Passie, Torsten

    2012-09-01

    Despite some principal similarities, there is no systematic comparison between the different types of synesthesia (genuine, acquired and drug-induced). This comprehensive review compares the three principal types of synesthesia and focuses on their phenomenological features and their relation to different etiological models. Implications of this comparison for the validity of the different etiological models are discussed. Comparison of the three forms of synesthesia show many more differences than similarities. This is in contrast to their representation in the literature, where they are discussed in many respects as being virtually similar. Noteworthy is the much broader spectrum and intensity with the typical drug-induced synesthesias compared to genuine and acquired synesthesias. A major implication of the phenomenological comparison in regard to the etiological models is that genuine and acquired synesthesias point to morphological substrates, while drug-induced synesthesia appears to be based on functional changes of brain activity. Copyright © 2012 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2014-01-02

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

  11. Prevalence and management out comes of anti TB drugs induced ...

    African Journals Online (AJOL)

    WHO designed a strategy of treatment under direct observation (DOTS), but most of the anti TB drugs affect the liver and causes drug-induced hepatitis. This side effect was usually observed in St. Peter TB Specialized Hospital and there was a debate weather to discontinue all anti TB drugs so that drug resistance could be ...

  12. Drug induced aseptic meningitis: A diagnostic challenge | Frank ...

    African Journals Online (AJOL)

    Drug-induced aseptic meningitis (DIAM) is a rare but important and often challenging diagnosis for the physician. Intake of antimicrobials, steroids, analgesics amongst others has been implicated. Signs and symptoms generally develop within 24-48 hours of drug ingestion. The patient often exhibits the classic symptoms of ...

  13. Assessment of drug induced genotoxicity in gastric cancer patients ...

    African Journals Online (AJOL)

    Assessment of drug induced genotoxicity in gastric cancer patients. ... African Journal of Biotechnology ... Blood samples were collected from gastric cancer patients receiving chemotherapy with the cytotoxic drugs epirubicin, cisplatin and 5-fluorouracil, and 100 controls from recognized cancer hospitals under the ...

  14. Pharmacogenetics of Drug-Induced QT Interval Prolongation: An Update

    NARCIS (Netherlands)

    M.N. Niemeijer (Maartje); M.E. van den Berg (Marten); M. Eijgelsheim (Mark); P.R. Rijnbeek (Peter); B.H.Ch. Stricker (Bruno)

    2015-01-01

    textabstractA prolonged QT interval is an important risk factor for ventricular arrhythmias and sudden cardiac death. QT prolongation can be caused by drugs. There are multiple risk factors for drug-induced QT prolongation, including genetic variation. QT prolongation is one of the most common

  15. The prevalence of drug induced hepatotoxicity among HIV positive ...

    African Journals Online (AJOL)

    Introduction: Drug induced hepatotoxicity is a recognized problem associated with the anti-tuberculosis (anti-TB) chemotherapy and is of great concern especially in this era of HIV infection. Objectives: To obtain the prevalence of hepatotoxicity due to anti-TB medications in HIV positive and negative patients with pulmonary ...

  16. 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

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

    Science.gov (United States)

    Jönsson, Anna K.; Lövborg, Henrik; Lohr, Wolfgang; Ekman, Bertil; Rocklöv, Joacim

    2017-01-01

    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. PMID:28737683

  18. 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.

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

    Science.gov (United States)

    Shenthar, Jayaprakash; Rachaiah, Jayasheelan Mambally; Pillai, Vivek; Chakali, Siva Sankara; Balasubramanian, Vidhyakar; Chollenhalli Nanjappa, Manjunath

    To define the incidence, presentation, and outcomes of drug-induced Torsades de Pointes (TdP) with intravenous (IV) amiodarone. From January 2014 to August 2016 a total of 268 patients received IV amiodarone, 142 for ventricular tachycardia, 104 for atrial flutter/fibrillation, and 22 for incessant atrial tachycardia. A uniform dosing of amiodarone to yield 1gm/day was used in all patients. Four of the 268 patients (M:F 1:3) with mean age of 51.25+9.17years developed pause dependent TdP degenerating to VF, after a mean dose of 690+176.63mg, infused over 12+5.88h. The QTc that was 505+9.02ms at the time of TdP normalized to 433.75+6.13ms 48-72h after stopping amiodarone. There was no immediate or late mortality, and patients are well at 5-10 months of follow-up. None of the patients tested positive for LQTS genes. 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. Copyright © 2017 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.

  20. Drug-Induced Kidney Injury in the Elderly.

    Science.gov (United States)

    Khan, Sana; Loi, Valentina; Rosner, Mitchell H

    2017-10-01

    The incidence of acute kidney injury in the elderly has grown over the past decade. One of the primary drivers is drug-induced nephrotoxicity, which is the result of a combination of the unique susceptibilities to kidney injury and the increased use of medications in the elderly population. Specific drug classes are associated with increased rates of kidney injury including agents that block the renin angiotensin system, antimicrobials, and chemotherapeutic agents. Mechanistically, injury may be due to hemodynamic effects, tubular or glomerular toxicity, and interstitial nephritis. Early recognition of nephrotoxicity is critical, as are preventative steps when applicable. Unfortunately, treatment for established drug-induced kidney injury is limited and supportive care is required. Limiting exposure to nephrotoxic drugs is critical in decreasing the incidence of acute kidney injury in the elderly patient.

  1. Drug-induced leukocytoclastic vasculitis: tigecycline a rare cause

    Directory of Open Access Journals (Sweden)

    Kalpana Bhairavarasu

    2015-01-01

    Full Text Available Drug-induced leukocytoclastic vasculitis is an inflammation of blood vessels triggered by various drugs. It presents with a localized skin rash but may involve the internal organ systems, including the gastrointestinal tract, kidneys, lungs, central nervous system, and joints. The clinical recognition of drug-induced vasculitis is very important because continued use of the culprit drug can be organ or life threatening. The prognosis is excellent if the disease is limited to the skin and diagnosed promptly. The use of tigecycline has recently increased due to resistance patterns of bacteria, and it is important to recognize this potential adverse effect of this drug and to diagnose and treat the patient early to achieve a favorable outcome. To best of our knowledge, we report the first case of tigecycline-induced leukocytoclastic vasculitis.

  2. Drug-induced QT interval prolongation: mechanisms and clinical management

    Science.gov (United States)

    Nachimuthu, Senthil; Assar, Manish D.

    2012-01-01

    The prolonged QT interval is both widely seen and associated with the potentially deadly rhythm, Torsades de Pointes (TdP). While it can occur spontaneously in the congenital form, there is a wide array of drugs that have been implicated in the prolongation of the QT interval. Some of these drugs have either been restricted or withdrawn from the market due to the increased incidence of fatal polymorphic ventricular tachycardia. The list of drugs that cause QT prolongation continues to grow, and an updated list of specific drugs that prolong the QT interval can be found at www.qtdrugs.org. This review focuses on the mechanism of drug-induced QT prolongation, risk factors for TdP, culprit drugs, prevention and monitoring of prolonged drug-induced QT prolongation and treatment strategies. PMID:25083239

  3. [Drug-induced discoloration of the teeth and gingiva].

    Science.gov (United States)

    Mosimann, P; Hartmann, K; Kuhn, M

    1998-03-18

    For this article all cases of suspected drug-induced discolouration of teeth and gingiva reported between 1.1.1989 and 31.5.1997 have been collected. As far as documented all discolourations were reversible and represented exclusively undesired but not serious adverse drug effects. In the literature such events are usually not mentioned. Thus, sense and intention of this work is to draw attention to certain adverse effects that are hitherto not well known.

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

    Directory of Open Access Journals (Sweden)

    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.

  5. Drug-induced nephrotoxicity: pathogenic mechanisms, biomarkers and prevention strategies.

    Science.gov (United States)

    Huang, Jiaguo; Wu, Huizi

    2017-11-08

    Overdosing of the drugs, drug-drug interaction or drug related adverse effects are the risk factors of drug-induced nephrotoxicity. Since the use of some nephrotoxic drugs is still unavoidable in clinic, to understand the pathogenic mechanisms of nephrotoxicity of these drugs is critical to decrease the incidence of kidney injury. Early detection of drug-induced nephrotoxicity and reduce the therapeutic side effects are still accessible approaches to avoid the end stage of renal failure. Therefore, the discovery or development of the early and accurate diagnostic biomarkers is an effective prevention strategy for drug-induced kidney impairment. In the present review, we summarized the mechanisms and prevention strategies for some common used drugs in clinic that induced acute and chronic kidney injury. We discussed the pros and cons of the biomarkers available nowadays. In addition, the in vitro and pre-clinical in vivo models to assess the nephrotoxicity during the drug development stages are also discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

    LENUS (Irish Health Repository)

    Rowley, D

    2014-03-01

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

  7. Epidemiology, Mechanisms, and Diagnosis of Drug-Induced Anaphylaxis

    Directory of Open Access Journals (Sweden)

    Maria Isabel Montañez

    2017-05-01

    Full Text Available Anaphylaxis is an acute, life-threatening, multisystem syndrome resulting from the sudden release of mediators by mast cells and basophils. Although anaphylaxis is often under-communicated and thus underestimated, its incidence appears to have risen over recent decades. Drugs are among the most common triggers in adults, being analgesics and antibiotics the most common causal agents. Anaphylaxis can be caused by immunologic or non-immunologic mechanisms. Immunologic anaphylaxis can be mediated by IgE-dependent or -independent pathways. The former involves activation of Th2 cells and the cross-linking of two or more specific IgE (sIgE antibodies on the surface of mast cells or basophils. The IgE-independent mechanism can be mediated by IgG, involving the release of platelet-activating factor, and/or complement activation. Non-immunological anaphylaxis can occur through the direct stimulation of mast cell degranulation by some drugs, inducing histamine release and leading to anaphylactic symptoms. Work-up of a suspected drug-induced anaphylaxis should include clinical history; however, this can be unreliable, and skin tests should also be used if available and validated. Drug provocation testing is not recommended due to the risk of inducing a harmful reaction. In vitro testing can help to confirm anaphylaxis by analyzing the release of mediators such as tryptase or histamine by mast cells. When immunologic mechanisms are suspected, serum-sIgE quantification or the use of the basophil activation test can help confirm the culprit drug. In this review, we will discuss multiple aspects of drug-induced anaphylaxis, including epidemiology, mechanisms, and diagnosis.

  8. Drug-induced angioedema: experience of Italian emergency departments.

    Science.gov (United States)

    Bertazzoni, G; Spina, M T; Scarpellini, M G; Buccelletti, F; De Simone, M; Gregori, M; Valeriano, V; Pugliese, F R; Ruggieri, M P; Magnanti, M; Susi, B; Minetola, L; Zulli, L; D'Ambrogio, F

    2014-06-01

    Acute angioedema represents a cause of admission to the emergency department requiring rapid diagnosis and appropriate management to prevent airway obstruction. Several drugs, including angiotensin-converting enzyme inhibitors (ACE-I), nonsteroidal anti-inflammatory drugs (NSAIDs) and oral antidiabetics, have been reported to induce angioedema. The aim of this prospective observational study conducted in a setting of routine emergency care was to evaluate the incidence and extent of drug-induced non-histaminergic angioedema in this specific clinical setting, and to identify the class of drugs possibly associated with angioedema. Patients admitted to seven different emergency departments (EDs) in Rome with the diagnosis of angioedema and urticaria were enrolled during a 6-month period. Of the 120,000 patients admitted at the EDs, 447 (0.37 %) were coded as having angioedema and 655 (0.5 %) as having urticaria. After accurate clinical review, 62 cases were defined as drug-induced, non-histaminergic angioedema. NSAIDs were the most frequent drugs (taken by 22 out of 62 patients) associated with the angioedema attack. Of the remaining patients, 15 received antibiotic treatment and 10 antihypertensive treatment. In addition, we observed in our series some cases of angioedema associated with drugs (such as antiasthmatics, antidiarrheal and antiepileptics) of which there are few descriptions in the literature. The present data, which add much needed information to the existing limited literature on drug-induced angioedema in the clinical emergency department setting, will provide more appropriate diagnosis and management of this potentially life-threatening adverse event.

  9. Basic Cardiac Electrophysiology and Common Drug-induced Arrhythmias.

    Science.gov (United States)

    Lee, Aimee; Pickham, David

    2016-09-01

    Drugs can be a double-edged sword, providing the benefit of symptom alleviation and disease modification but potentially causing harm from adverse cardiac arrhythmic events. Proarrhythmia is the ability of a drug to cause an arrhythmia, the number one reason for drugs to be withdrawn from the patient. Drug-induced arrhythmias are defined as the production of de novo arrhythmias or aggravation of existing arrhythmias, as a result of previous or concomitant pharmacologic treatment. This review summarizes normal cardiac cell and tissue functioning and provides an overview of drugs that effect cardiac repolarization and the adverse effects of commonly administered antiarrhythmics. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Drug-induced discoloration of teeth: an updated review.

    Science.gov (United States)

    Kumar, Arun; Kumar, Vijay; Singh, Janardhan; Hooda, Anita; Dutta, Samir

    2012-02-01

    The problem of tooth discoloration is emerging in our society because of the poor oral hygiene, physical agents, environmental chemicals, mouth rinses, some dental procedures, general systemic conditions, and drugs. Other common causes of tooth discoloration include excessive use of tea, coffee, tobacco smoking and chewing, chewing of betel morsel (piper betel, paan), and so on. Drug-induced tooth discoloration can be prevented by avoiding prescriptions of well-known offender drugs known to cause tooth discoloration during pregnancy and in young children. This review describes some important groups of drugs that cause tooth discoloration.

  11. Prolonged drug-induced myoclonus: is it related to palonosetron?

    Science.gov (United States)

    Chaw, Sook Hui; Chan, Lucy; Lee, Pui Kuan; Bakar, Jaseemuddeen A; Rasiah, Raveenthiran; Foo, Li Lian

    2016-12-01

    We report a case of drug-induced myoclonus possibly related to palonosetron, a second-generation 5-hydroxytryptamine-3 receptor antagonist which was administered as a prophylaxis for postoperative nausea and vomiting in a 28-year-old female. The recurrent episodes of myoclonus jerk involving the head, neck and shoulder persisted for a period of 4 days. The patient also exhibited an episode of severe bradycardia leading to hypotension 7 h after surgery. To our knowledge, this is the first report presenting these adverse events potentially associated with the use of palonosetron.

  12. 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 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.

  13. Recovering Drug-Induced Apoptosis Subnetwork from Connectivity Map Data

    Directory of Open Access Journals (Sweden)

    Jiyang Yu

    2015-01-01

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

  14. Drug-Induced Ocular Hypertension and Angle-Closure Glaucoma.

    Science.gov (United States)

    Badhu, Badri P; Bhattarai, Balkrishna; Sangraula, Himal P

    2013-01-01

    The objective of this study was to review the available literature on the drugs causing ocular hypertension and glaucoma. Electronic literature search was carried out using the Web sites www.pubmed.gov and www.google.com published through the year 2011. The search words were "drug induced ocular hypertension" and "drug induced glaucoma" used in combination. The articles published or translated into English were studied. Quite a significant number of drugs commonly prescribed by various physicians of different specialties can induce ocular hypertension or glaucoma. A brief account of various drugs that can induce ocular hypertension has been given in this article. Those drugs are parasympatholytics; steroids; anticholinergics, adrenergics, and antidepressants; cholinomimetics; antineoplastic agents; antipsychotic and antiparkinsonism agents; H1 and H2 receptor blockers; botulinum toxin, cardiac agents, and anticoagulants; silicone oil; sulfa drugs; and anesthetic agents. Rational use of these drugs and knowledge of their potential adverse effects can help prevent the devastating complications resulting in loss of vision and compromised quality of life.

  15. The mechanobiology of drug-induced cardiac valve disease.

    Science.gov (United States)

    Lam, Ngoc Thien; Balachandran, Kartik

    2015-01-01

    Drug-related adverse reactions leading to valve disease or valvulopathy were first identified in the 1960s. These were associated with patients taking anti-migraine ergot-derivative drugs, anti-anorectics, anti-Parkinson's drugs, or other anti-depressant drugs. In general, these drugs have serotonergic, dopaminergic, or β-adrenergic activity, being either agonists or reuptake inhibitors of the aforementioned neurotransmitter pathways. Recent work has focused on several possible mechanisms for valvulopathy, specifically highlighting the serotonin or 5-hydroxy-trypta-mine-2B (5-HT2B) receptor subtype and the 5-HT transporter as mediators that cause expression of myofibroblast phenotype, excessive cell proliferation, leading to valve fibrosis. Most of these studies and reviews, however, were not reported in the context of the mechanical environment of the valve, which by itself is an important factor in the initiation and progression of valve disease. It is also not known whether patients who have altered mechanical environments in their cardiovascular system, such as those who are hypertensive or have functional cardiac disease, such as ischemic ventricular dilation, or those who have an increased propensity for developing drug-induced valvulopathy. In the present review, we highlight the potential role of hemodynamics and the mechanical environment in influencing these drug-induced valvulopathies, focusing on serotonin-mediated disease and the need for further study of this topic.

  16. 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.

  17. Prolonged drug-induced hypothermia in experimental stroke

    DEFF Research Database (Denmark)

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

    2007-01-01

    regimen with saline only. All rats were killed 7 days after MCAO. Infarct volume was quantified stereologically. The mean body temperature (35.6 + 1.0 degrees C) during 24 hours after bolus injection of Talipexole was significantly lower than in control rats (37.3 +/- 0.5 degrees C), P ... 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...... 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...

  18. PTTG1 attenuates drug-induced cellular senescence.

    Directory of Open Access Journals (Sweden)

    Yunguang Tong

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

  19. An Update on Drug-induced Liver Injury.

    Science.gov (United States)

    Devarbhavi, Harshad

    2012-09-01

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

  20. Identification of drugs inducing phospholipidosis by novel in vitro data.

    Science.gov (United States)

    Muehlbacher, Markus; Tripal, Philipp; Roas, Florian; Kornhuber, Johannes

    2012-11-01

    Drug-induced phospholipidosis (PLD) is a lysosomal storage disorder characterized by the accumulation of phospholipids within the lysosome. This adverse drug effect can occur in various tissues and is suspected to impact cellular viability. Therefore, it is important to test chemical compounds for their potential to induce PLD during the drug design process. PLD has been reported to be a side effect of many commonly used drugs, especially those with cationic amphiphilic properties. To predict drug-induced PLD in silico, we established a high-throughput cell-culture-based method to quantitatively determine the induction of PLD by chemical compounds. Using this assay, we tested 297 drug-like compounds at two different concentrations (2.5 μM and 5.0 μM). We were able to identify 28 previously unknown PLD-inducing agents. Furthermore, our experimental results enabled the development of a binary classification model to predict PLD-inducing agents based on their molecular properties. This random forest prediction system yields a bootstrapped validated accuracy of 86 %. PLD-inducing agents overlap with those that target similar biological processes; a high degree of concordance with PLD-inducing agents was identified for cationic amphiphilic compounds, small molecules that inhibit acid sphingomyelinase, compounds that cross the blood-brain barrier, and compounds that violate Lipinski's rule of five. Furthermore, we were able to show that PLD-inducing compounds applied in combination additively induce PLD. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Meiotic abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  2. 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.

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

    Directory of Open Access Journals (Sweden)

    Aida Ortega-Alonso

    2016-05-01

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

  4. Congenital Abnormalities

    Science.gov (United States)

    ... Ribbon Commands Skip to main content Turn off Animations Turn on Animations Our Sponsors Log in | Register Menu Log in | ... course of action. Additional Information Your Family Health History & Genetics Detecting Genetic Abnormalities Prenatal Genetic Counseling Children ...

  5. Walking abnormalities

    Science.gov (United States)

    ... with short-term or long-term gait disorders. Therapy will reduce the risk of falls and other injuries. For an abnormal gait that occurs with conversion disorder, counseling and support from family members are ...

  6. Integrated TK-TD modeling for drug-induced concurrent tachycardia and QT changes in beagle dogs.

    Science.gov (United States)

    Wu, Fan; Heimbach, Tycho; Hatsis, Panos; Tang, Hai-Ming; Dugyala, Raviprakash; Yue, Qin; Wang, Tao; He, Handan

    2017-10-01

    Drug-induced cardiotoxicity, including tachycardia and QT prolongation, remains a major safety concern that needs to be identified and its risk mitigated in early stages of drug development. In the present study, an integrated toxicokinetic-toxicodynamic (TK-TD) modeling approach within a nonlinear mixed-effect modeling framework is applied to investigate concurrent abnormal heart rate and QT changes in three beagle dogs, using a Novartis internal compound (NVS001) as the case example. By accounting for saturable drug absorption, circadian rhythms, drug-effect tolerance, and nonlinear rate-dependency of QT interval, the dynamic TK-TD model captures the experimentally observed drug effects on heart rate and QT interval across a wide dosing range of NVS001 in beagle dogs. Further analyses reveal that the NVS001-induced QT prolongation observed in the low-dose groups is potentially caused by direct drug inhibition on the hERG channel, while the apparent QT shortening in the high-dose groups may be due to strong rate-dependency of QT at high heart rates. This study also suggests that the TK-TD model can be used to identify direct drug effects on the non-rate-dependent QT component by dissociating QT changes from tachycardia and deriving a new QT correction method. The integrated TK-TD model presented here may serve as a novel quantitative framework for evaluating drug-induced concurrent changes in heart rate and QT to potentially facilitate preclinical and clinical safety studies.

  7. Herbal medicine treatment for drug-induced parkinsonism.

    Science.gov (United States)

    Shim, Young-Ho; Park, Joo-Young; Choi, Won-Woo; Min, In-Kyu; Park, Seong-Uk; Jung, Woo-Sang; Moon, Sang-Kwan; Park, Jung-Mi; Ko, Chang-Nam; Cho, Ki-Ho; Cho, Seung-Yeon

    2015-05-01

    To evaluate the role of herbal medicine in drug-induced parkinsonism (DIP) and identify an optimal treatment approach. Retrospective review of DIP cases treated with herbal medicine. The Parkinson's clinic at Kyung Hee Traditional Korean Medicine Hospital, Korea. Twenty-one patients whose clinical outcome and offending drug could be identified. Clinical features, treatments, and outcomes and summarized the clinical course and treatment in each case. Twelve patients had levosulpiride-induced parkinsonism and 9 had parkinsonism induced by another drug. The offending drugs were discontinued in all patients, and all patients received herbal medications during treatment. Nine of 12 patients with parkinsonism from levosulpiride and 4 of 9 patients with parkinsonism from other drugs had complete reversal of symptoms. The most frequently used herbal formula was Ukgansan (Yigansan). DIP in the levosulpiride group tended to improve faster with herbal medicine, and the percentage of improvement was higher. Optimal herbal medicine treatments chosen after a careful history and evaluation for risk factors may be helpful in reversing DIP.

  8. 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.

  9. Drug-induced QT-interval prolongation: considerations for clinicians.

    Science.gov (United States)

    Li, Edward C; Esterly, John S; Pohl, Shaunte; Scott, Shane D; McBride, Brian F

    2010-07-01

    Drug-induced proarrhythmia is a frequently encountered clinical problem and a leading cause for withdrawal or relabeling of prescription drugs. Suppression of the rapid component of the delayed rectifier potassium current, I(Kr), represents the principal pharmacodynamic mechanism leading to heterogeneous prolongation of the ventricular action potential and prolongation of the QT interval clinically. However, the risk of proarrhythmia by QT-interval-prolonging drugs is variable and critically dependent on several factors leading to multiple reductions in the cardiac repolarization reserve. As antiarrhythmic drugs that prolong the QT interval are usually aggressively managed with continuous electrocardiogram monitoring and screening for drug interactions when administered to patients who have a high risk of sudden cardiac death, their risk of mortality is not increased. However, noncardiovascular QT-interval-prolonging drugs, which often produce less QT-interval prolongation compared with antiarrhythmic drugs, are found to be associated with increased rates of death in patients who have a markedly lower de novo risk of sudden cardiac death. Thus, it is important for clinicians, particularly pharmacists, to be cognizant of the levels of risk associated with varying degrees of QT-interval prolongation caused by drugs so that they can develop strategies to either prevent or reduce the risk of proarrhythmias.

  10. Drug-induced photosensitivity: culprit drugs, management and prevention.

    Science.gov (United States)

    Drucker, Aaron M; Rosen, Cheryl F

    2011-10-01

    Photo-induced drug eruptions are cutaneous adverse events due to exposure to a drug and either ultraviolet or visible radiation. Based on their pathogenesis, they can be classified as phototoxic or photoallergic drug eruptions, although in many cases it is not possible to determine whether a particular eruption is due to a phototoxic or photoallergic mechanism. In this review, the diagnosis, prevention and management of drug-induced photosensitivity are discussed. Diagnosis is based primarily on the history of drug intake and the clinical appearance of the eruption, primarily affecting sun-exposed areas of the skin. Phototesting and photopatch testing can be useful adjuncts in making a diagnosis. The mainstay of management is prevention, including informing patients of the possibility of increased sun sensitivity and the use of sun protective measures. However, once the eruption has occurred, it may be necessary to discontinue the culprit medication and treat the eruption with a potent topical corticosteroid. Drugs that have been implicated in causing photosensitive eruptions are reviewed. Tetracycline, doxycycline, nalidixic acid, voriconazole, amiodarone, hydrochlorothiazide, naproxen, piroxicam, chlorpromazine and thioridazine are among the most commonly implicated medications. We review the medical literature regarding evidence for the culpability of each drug, including the results of phototesting, photopatch testing and rechallenge testing.

  11. 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.

  12. 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.

  13. Cellular imaging predictions of clinical drug-induced liver injury.

    Science.gov (United States)

    Xu, Jinghai J; Henstock, Peter V; Dunn, Margaret C; Smith, Arthur R; Chabot, Jeffrey R; de Graaf, David

    2008-09-01

    Drug-induced liver injury (DILI) is the most common adverse event causing drug nonapprovals and drug withdrawals. Using drugs as test agents and measuring a panel of cellular phenotypes that are directly linked to key mechanisms of hepatotoxicity, we have developed an in vitro testing strategy that is predictive of many clinical outcomes of DILI. Mitochondrial damage, oxidative stress, and intracellular glutathione, all measured by high content cellular imaging in primary human hepatocyte cultures, are the three most important features contributing to the hepatotoxicity prediction. When applied to over 300 drugs and chemicals including many that caused rare and idiosyncratic liver toxicity in humans, our testing strategy has a true-positive rate of 50-60% and an exceptionally low false-positive rate of 0-5%. These in vitro predictions can augment the performance of the combined traditional preclinical animal tests by identifying idiosyncratic human hepatotoxicants such as nimesulide, telithromycin, nefazodone, troglitazone, tetracycline, sulindac, zileuton, labetalol, diclofenac, chlorzoxazone, dantrolene, and many others. Our findings provide insight to key DILI mechanisms, and suggest a new approach in hepatotoxicity testing of pharmaceuticals.

  14. [Clinicopathologic features of drug-induced vanishing bile duct syndrome].

    Science.gov (United States)

    Ye, L H; Wang, C K; Zhang, H C; Liu, Z Q; Zheng, H W

    2017-04-20

    Vanishing bile duct syndrome (VBDS) manifests as progressive destruction and disappearance of the intrahepatic bile duct caused by various factors and cholestasis. VBDS associated with drug-induced liver injury (D-VBDS) is an important etiology of VBDS, and immune disorder or immune imbalance may be the main pathogenesis. According to its clinical symptoms, serological markers, and course of the disease, D-VBDS is classified into major form and minor form, and its clinical features are based on various pathomorphological findings. Its prognosis is associated various factors including regeneration of bile duct cells, number of bile duct injuries, level and range of bile duct injury, bile duct proliferation, and compensatory shunt of bile duct branches. This disease has various clinical outcomes; most patients have good prognosis after drug withdrawal, and some patients may experience cholestatic cirrhosis, liver failure, and even death. Due to the clinical manifestation and biochemical changes are similar to the primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), it need to identify by clinical physician.

  15. 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...

  16. Predicting Drug-induced Hepatotoxicity Using QSAR and Toxicogenomics Approaches

    Science.gov (United States)

    Low, Yen; Uehara, Takeki; Minowa, Yohsuke; Yamada, Hiroshi; Ohno, Yasuo; Urushidani, Tetsuro; Sedykh, Alexander; Muratov, Eugene; Fourches, Denis; Zhu, Hao; Rusyn, Ivan; Tropsha, Alexander

    2014-01-01

    Quantitative Structure-Activity Relationship (QSAR) modeling and toxicogenomics are used independently as predictive tools in toxicology. In this study, we evaluated the power of several statistical models for predicting drug hepatotoxicity in rats using different descriptors of drug molecules, namely their chemical descriptors and toxicogenomic profiles. The records were taken from the Toxicogenomics Project rat liver microarray database containing information on 127 drugs (http://toxico.nibio.go.jp/datalist.html). The model endpoint was hepatotoxicity in the rat following 28 days of exposure, established by liver histopathology and serum chemistry. First, we developed multiple conventional QSAR classification models using a comprehensive set of chemical descriptors and several classification methods (k nearest neighbor, support vector machines, random forests, and distance weighted discrimination). With chemical descriptors alone, external predictivity (Correct Classification Rate, CCR) from 5-fold external cross-validation was 61%. Next, the same classification methods were employed to build models using only toxicogenomic data (24h after a single exposure) treated as biological descriptors. The optimized models used only 85 selected toxicogenomic descriptors and had CCR as high as 76%. Finally, hybrid models combining both chemical descriptors and transcripts were developed; their CCRs were between 68 and 77%. Although the accuracy of hybrid models did not exceed that of the models based on toxicogenomic data alone, the use of both chemical and biological descriptors enriched the interpretation of the models. In addition to finding 85 transcripts that were predictive and highly relevant to the mechanisms of drug-induced liver injury, chemical structural alerts for hepatotoxicity were also identified. These results suggest that concurrent exploration of the chemical features and acute treatment-induced changes in transcript levels will both enrich the

  17. Clinical Characteristics of Patients with Drug-induced Liver Injury.

    Science.gov (United States)

    Yang, Li-Xia; Liu, Cheng-Yuan; Zhang, Lun-Li; Lai, Ling-Ling; Fang, Ming; Zhang, Chong

    2017-01-20

    Drug is an important cause of liver injury and accounts for up to 40% of instances of fulminant hepatic failure. Drug-induced liver injury (DILI) is increasing while the diagnosis becomes more difficult. Though many drugs may cause DILI, Chinese herbal medicines have recently emerged as a major cause due to their extensive use in China. We aimed to provide drug safety information to patients and health carers by analyzing the clinical and pathological characteristics of the DILI and the associated drug types. A retrospective analysis was conducted in 287 patients diagnosed with DILI enrolled in our hospital from January 2011 to December 2015. The categories of causative drugs, clinical and pathological characteristics were reviewed. Western medicines ranked as the top cause of DILI, accounting for 163 out of the 287 DILI patients (56.79%) in our study. Among the Western medicine, antituberculosis drugs were the highest cause (18.47%, 53 patients) of DILI.   Antibiotics (18 patients, 6.27%) and antithyroid (18 patients, 6.27%) drugs also ranked among the major causes of DILI. Chinese herbal medicines are another major cause of DILI, accounting for 36.59% of cases (105 patients). Most of the causative Chinese herbal medicines were those used to treat osteopathy, arthropathy, dermatosis, gastropathy, leukotrichia, alopecia, and gynecologic diseases. Hepatocellular hepatitis was prevalent in DILI, regardless of Chinese herbal medicine or Western medicine-induced DILI. Risks and the rational use of medicines should be made clear to reduce the occurrence of DILI. For patients with liver injury of unknown origin, liver tissue pathological examination is recommended for further diagnosis.

  18. Identification of MHC Haplotypes Associated with Drug-induced Hypersensitivity Reactions in Cynomolgus Monkeys.

    Science.gov (United States)

    Wu, Hong; Whritenour, Jessica; Sanford, Jonathan C; Houle, Christopher; Adkins, Karissa K

    2017-01-01

    Drug-induced hypersensitivity reactions can significantly impact drug development and use. Studies to understand risk factors for drug-induced hypersensitivity reactions have identified genetic association with specific human leukocyte antigen (HLA) alleles. Interestingly, drug-induced hypersensitivity reactions can occur in nonhuman primates; however, association between drug-induced hypersensitivity reactions and major histocompatibility complex (MHC) alleles has not been described. In this study, tissue samples were collected from 62 cynomolgus monkeys from preclinical studies in which 9 animals had evidence of drug-induced hypersensitivity reactions. Microsatellite analysis was used to determine MHC haplotypes for each animal. A total of 7 haplotypes and recombinant MHC haplotypes were observed, with distribution frequency comparable to known MHC I allele frequency in cynomolgus monkeys. Genetic association analysis identified alleles from the M3 haplotype of the MHC I B region (B*011:01, B*075:01, B*079:01, B*070:02, B*098:05, and B*165:01) to be significantly associated (χ2 test for trend, p reactions. Sequence similarity from alignment of alleles in the M3 haplotype B region and HLA alleles associated with drug-induced hypersensitivity reactions in humans was 86% to 93%. These data demonstrate that MHC alleles in cynomolgus monkeys are associated with drug-induced hypersensitivity reactions, similar to HLA alleles in humans.

  19. 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.

  20. Effect of Bicyclol tablets on drug induced liver injuries after kidney transplantation

    National Research Council Canada - National Science Library

    Wenjun Shang; Yonghua Feng; Jinfeng Li; Xinzhou Wang; Hongchang Xie; Guiwen Feng

    2017-01-01

    .... Bicyclol tablets possess obvious anti-inflammatory and liver-protective functions. This study aimed to explore the clinical effect of preventive application of Bicyclol on drug induced liver injuries at an early stage after kidney transplantation...

  1. Use of Arotinolol Pharmacotherapy to Treat Drug-induced Tremor: A Report of Three Cases.

    Science.gov (United States)

    Lee, D B; Woo, Y S; Bahk, W M

    2015-07-01

    The aim of the present study is to demonstrate the effect of arotinolol on drug-induced tremor in psychiatric patients. This is a case study of three psychiatric patients with the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) diagnosis of major depressive disorder who were treated in inpatient or outpatient psychiatric settings with antidepressant or antipsychotics. Patients developed tremor. Arotinolol was started to treat the tremor. Drug-induced tremor almost resolved completely. No adverse effects were observed. We have presented a case series of drug-induced tremors that responded well to treatment with arotinolol, which appears to be a safe and well-tolerated drug in the dose ranges used. The possible utility of arotinolol to treat drug-induced tremor deserves attention and further investigation. © Georg Thieme Verlag KG Stuttgart · New York.

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

    National Research Council Canada - National Science Library

    Balak, Deepak; Bavinck, Jan Nico Bouwes; De Vries, A.P.J; Hartman, J; Martino Neumann, H.A; Zietse, Bob; 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...

  3. Severe drug-induced repetitive behaviors and striatal overexpression of VAChT in ChAT-ChR2-EYFP BAC transgenic mice

    Directory of Open Access Journals (Sweden)

    Jill R Crittenden

    2014-05-01

    Full Text Available In drug users, drug-related cues alone can induce dopamine release in the dorsal striatum. Instructive cues activate inputs to the striatum from both dopaminergic and cholinergic neurons, which are thought to work together to support motor learning and motivated behaviors. Imbalances in these neuromodulatory influences can impair normal action selection and might thus contribute to pathologically repetitive and compulsive behaviors such as drug addiction. Dopamine and acetylcholine can have either antagonistic or synergistic effects on behavior, depending on the state of the animal and the receptor signaling systems at play. Semi-synchronized activation of cholinergic interneurons in the dorsal striatum drives dopamine release via presynaptic nicotinic acetylcholine receptors located on dopamine terminals. Nicotinic receptor blockade is known to diminish abnormal repetitive behaviors (stereotypies induced by psychomotor stimulants. By contrast, blockade of postsynaptic acetylcholine muscarinic receptors in the dorsomedial striatum exacerbates drug-induced stereotypy, exemplifying how different acetylcholine receptors can also have opposing effects. Although acetylcholine release is known to be altered in animal models of drug addiction, predicting whether these changes will augment or diminish drug-induced behaviors thus remains a challenge. Here, we measured amphetamine-induced stereotypy in BAC transgenic mice that have been shown to overexpress the vesicular acetylcholine transporter (VAChT with consequent increased acetylcholine release. We found that drug-induced stereotypies, consisting of confined sniffing and licking behaviors, were greatly increased in the transgenic mice relative to sibling controls, as was striatal VAChT protein. These findings suggest that VAChT-mediated increases in acetylcholine could be critical in exacerbating drug-induced stereotypic behaviors and promoting exaggerated behavioral fixity.

  4. Severe drug-induced repetitive behaviors and striatal overexpression of VAChT in ChAT-ChR2-EYFP BAC transgenic mice.

    Science.gov (United States)

    Crittenden, Jill R; Lacey, Carolyn J; Lee, Tyrone; Bowden, Hilary A; Graybiel, Ann M

    2014-01-01

    In drug users, drug-related cues alone can induce dopamine release in the dorsal striatum. Instructive cues activate inputs to the striatum from both dopaminergic and cholinergic neurons, which are thought to work together to support motor learning and motivated behaviors. Imbalances in these neuromodulatory influences can impair normal action selection and might thus contribute to pathologically repetitive and compulsive behaviors such as drug addiction. Dopamine and acetylcholine can have either antagonistic or synergistic effects on behavior, depending on the state of the animal and the receptor signaling systems at play. Semi-synchronized activation of cholinergic interneurons in the dorsal striatum drives dopamine release via presynaptic nicotinic acetylcholine receptors located on dopamine terminals. Nicotinic receptor blockade is known to diminish abnormal repetitive behaviors (stereotypies) induced by psychomotor stimulants. By contrast, blockade of postsynaptic acetylcholine muscarinic receptors in the dorsomedial striatum exacerbates drug-induced stereotypy, exemplifying how different acetylcholine receptors can also have opposing effects. Although acetylcholine release is known to be altered in animal models of drug addiction, predicting whether these changes will augment or diminish drug-induced behaviors thus remains a challenge. Here, we measured amphetamine-induced stereotypy in BAC transgenic mice that have been shown to overexpress the vesicular acetylcholine transporter (VAChT) with consequent increased acetylcholine release. We found that drug-induced stereotypies, consisting of confined sniffing and licking behaviors, were greatly increased in the transgenic mice relative to sibling controls, as was striatal VAChT protein. These findings suggest that VAChT-mediated increases in acetylcholine could be critical in exacerbating drug-induced stereotypic behaviors and promoting exaggerated behavioral fixity.

  5. Effective Infusion Therapy of Drug-Induced Liver and Pancreas Injuries in Patients with Pulmonary Tuberculosis

    Directory of Open Access Journals (Sweden)

    N.B. Gubergrits

    2013-08-01

    Full Text Available The authors examined 328 patients with pulmonary tuberculosis who had drug-induced hepatitis and drug-induced pancreatitis due to polychemotherapy. Patients had metabolic intoxication syndrome associated with increasing level of «average molecules» in the blood. Not only reliable decrease of this indicator but also its normalization was achieved under the influence of treatment with a usage of succinic acid preparation for infusion therapy.

  6. Drug induced pseudoporphyria in CKD: A case report

    Directory of Open Access Journals (Sweden)

    S Quaiser

    2015-01-01

    Full Text Available Pseudoporphyria (PP is used to describe a photodistributed bullous disorder with clinical and histologic features of porphyria cutanea tarda (PCT but without accompanying biochemical porphyrin abnormalities. Medications, excessive sun and ultraviolet radiation exposure, have all been reported to develop PP. We report a case of PP in a 49-year-old man with CKD stage 3a, caused due to torsemide intake. This is probably the first reported case of PP developing in a dialysis naive patient CKD due to torsemide intake from India.

  7. 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

  8. A long-term trend of drug-induced deaths in European countries

    Directory of Open Access Journals (Sweden)

    WenJun Zhang

    2017-12-01

    Full Text Available In present study, data of drug-induced deaths in 29 European countries were used to analyze the profile and trend of drug-induced deaths recorded for total population, males and females in order to provide some basic information on adverse effects and misuse of drugs. The results showed that Germany (28501 deaths and United Kindom (22537 deaths have the greatest accumalted number (1995-2014 of drug-induced deaths, followed by Italy (14134 deaths and Spain (11133 deaths. Germany (23% and United Kingdom (18% held the highest percentage of drug-induced deaths in Europe, followed by Italy (12%, Spain (9%, Sweden (4%, and Norway (4%, etc. For males, United Kindom (24% and Germany (20% held the highest percentage, followed by Poland (8%, Italy (6%, etc. Similarly, Germany (25% and United Kingdom (18% are the highest in death percentage of males, followed by Italy (13%, etc. Not less than 1 death/yr, the European countries with the highest linear growth of drug-induced deaths for total population (p<0.05 are Turkey (33.2 deaths/yr and Sweden (21.6 deaths/yr, followed by Ireland (8.9 deaths/yr, Estonia (7.3 deaths/yr, Finland (6.5 deaths/yr, Lithuania (2.6 deaths/yr, and Romania (2.3 deaths/yr. Not less than 1 death/yr, the European countries with the highest linear decline of drug-induced deaths for total population (p<0.05 are Italy (-53.9 deaths/yr and Germany (-42.1 deaths/yr, followed by Spain (-21.6 deaths/yr, Portugal (-9.8 deaths/yr, Czech Republic (-2.9 deaths/yr, and Hungry (-1.5 deaths/yr. In average, the number of drug-induced deaths for both total population and males in Europe declined at the annual rate of 2 deaths, and that for females grew at the annual rate of 0.1 death. Generally the continuous growth of drug-induced deaths was mostly attributed to the growth of drug uses, the deteriorated medical service, or the promotion of diagnostic levels, etc. However, the continuous decline of drug-induced deaths was mostly attributed to the

  9. A history of drug-induced Torsades de Pointes is associated with T-wave morphological abnormalities

    DEFF Research Database (Denmark)

    Bhuiyan, Tanveer Ahmed; Graff, Claus; Kanters, Jørgen K.

    2018-01-01

    The hypothesis of the study is that Torsades de pointes (TdP) history can be better identified using T-wave morphology compared to Fridericia-corrected QT interval (QTcF) at baseline. ECGs were recorded at baseline and during sotalol challenge in 20 patients with a history of TdP (+TdP) and 16...... the groups at baseline (+TdP: MCS = 1.07 ± 0.095; -TdP: MCS = 0.74 ± 0.07, P = 0.012). Both QTcF and MCS could be used to discriminate between +TdP and -TdP after sotalol but only MCS reached statistical significance at baseline. Combining QTcF with MCS provided a significantly larger difference between...

  10. The T-peak–T-end Interval as a Marker of Repolarization Abnormality

    DEFF Research Database (Denmark)

    Bhuiyan, Tanveer A.; Graff, Claus; Kanters, Jørgen K.

    2015-01-01

    BACKGROUND AND OBJECTIVE: The T-peak to T-end (TpTe) interval has been suggested as an index of transmural dispersion and as a marker of drug-induced abnormal repolarization. In this study, we investigate the relation between TpTe and the QT interval. METHODS: Electrocardiograms (ECGs) from five ...

  11. Prevalence and risk factors of liver biochemical abnormalities in patients with systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Reem Ismail El Shazly

    2014-01-01

    Conclusion The prevalence of elevated liver enzymes among SLE patients attending the Rheumatology and Rehabilitation Department during the time of the study was 6.5%. The most common liver abnormality was found to be fatty liver, affecting 38.5% of the patients, followed by drug-induced hepatotoxicity (30.8%, and then HCV infection, AIH, and SLE (each 15.4%.

  12. DRUG-INDUCED NEPHROPATHY IN PULMONARY TUBERCULOSIS PATIENTS WITH BURDENED ALLERGIC HISTORY

    Directory of Open Access Journals (Sweden)

    T. A. Kolpakova

    2016-01-01

    Full Text Available 112 tuberculosis patients with burdened allergic history were examined with the purpose to study clinical and laboratory manifestations of drug-induced nephropathy, they made main group and 157 patients without allergy made control group. Drug-induced renal lesion in tuberculosis patients with multiple allergies can be manifested in various ways: from microhematuria, minor eosinophilia and cutaneous allergic syndrome to major disorders of nitrogenous excretion, filtration and resorption function of kidneys leading to the development of acute and in some cases chronic renal failure. Laboratory rates reflecting renal function returned to normal later after recovery from other drug-induced complications not related to kidneys. Rifampicin was responsible for the development of nephropathy in the majority of patients, and in single cases it was streptomycin.

  13. 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

  14. Drug-Induced Thrombocytopenia following a Transvaginal Oocyte Retrieval for In Vitro Fertilization

    Directory of Open Access Journals (Sweden)

    Ioanna A. Comstock

    2015-01-01

    Full Text Available Drug-induced immune thrombocytopenia has been associated with hundreds of medications and can lead to devastating consequences for the patient. We present a case of a healthy 33-year-old female undergoing in vitro fertilization who developed a severe drug-induced thrombocytopenia, petechiae, and a large hemoperitoneum after receiving Cefazolin antibiotic prophylaxis for a transvaginal oocyte retrieval. The patient was admitted to the intensive care unit for resuscitation with blood products. The presence of drug-dependent platelet antibodies to Cefazolin was confirmed serologically.

  15. Drug-Induced Thrombocytopenia following a Transvaginal Oocyte Retrieval for In Vitro Fertilization.

    Science.gov (United States)

    Comstock, Ioanna A; Longmire, Michelle; Aster, Richard H; Milki, Amin A

    2015-01-01

    Drug-induced immune thrombocytopenia has been associated with hundreds of medications and can lead to devastating consequences for the patient. We present a case of a healthy 33-year-old female undergoing in vitro fertilization who developed a severe drug-induced thrombocytopenia, petechiae, and a large hemoperitoneum after receiving Cefazolin antibiotic prophylaxis for a transvaginal oocyte retrieval. The patient was admitted to the intensive care unit for resuscitation with blood products. The presence of drug-dependent platelet antibodies to Cefazolin was confirmed serologically.

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

    OpenAIRE

    Haeseung Lee; Seungmin Kang; Wankyu Kim

    2016-01-01

    An in silico chemical genomics approach is developed to predict drug repositioning (DR) candidates for three types of cancer: glioblastoma, lung cancer, and breast cancer. It is based on a recent large-scale dataset of ~20,000 drug-induced expression profiles in multiple cancer cell lines, which provides i) a global impact of transcriptional perturbation of both known targets and unknown off-targets, and ii) rich information on drug's mode-of-action. First, the drug-induced expression profile...

  17. Termination of drug-induced torsades de pointes with overdrive pacing.

    Science.gov (United States)

    Charlton, Nathan P; Lawrence, David T; Brady, William J; Kirk, Mark A; Holstege, Christopher P

    2010-01-01

    Drug-induced prolongation of the QT interval is frequently encountered after medication overdose. Such toxicity can result in degeneration to torsades de pointes (TdP) and require overdrive pacing. We present 3 cases in which intentional medication overdose resulted in QTc prolongation with subsequent degeneration to TdP. Despite appropriate care, including magnesium therapy, each case required overdrive pacing for resolution of TdP. Although rarely encountered, patients with drug-induced TdP can be successfully managed with overdrive pacing.

  18. In silico prediction of drug-induced myelotoxicity by using Naïve Bayes method.

    Science.gov (United States)

    Zhang, Hui; Yu, Peng; Zhang, Teng-Guo; Kang, Yan-Li; Zhao, Xiao; Li, Yuan-Yuan; He, Jia-Hui; Zhang, Ji

    2015-11-01

    Drug-induced myelotoxicity usually leads to decrease the production of platelets, red cells, and white cells. Thus, early identification and characterization of myelotoxicity hazard in drug development is very necessary. The purpose of this investigation was to develop a prediction model of drug-induced myelotoxicity by using a Naïve Bayes classifier. For comparison, other prediction models based on support vector machine and single-hidden-layer feed-forward neural network  methods were also established. Among all the prediction models, the Naïve Bayes classification model showed the best prediction performance, which offered an average overall prediction accuracy of [Formula: see text] for the training set and [Formula: see text] for the external test set. The significant contributions of this study are that we first developed a Naïve Bayes classification model of drug-induced myelotoxicity adverse effect using a larger scale dataset, which could be employed for the prediction of drug-induced myelotoxicity. In addition, several important molecular descriptors and substructures of myelotoxic compounds have been identified, which should be taken into consideration in the design of new candidate compounds to produce safer and more effective drugs, ultimately reducing the attrition rate in later stages of drug development.

  19. Troxis necrosis, a novel mechanism for drug-induced hepatitis secondary to immunomodulatory therapy.

    Science.gov (United States)

    Wei, Christina H; Penunuri, Andrew; Karpouzas, George; Fleishman, Wayne; Datta, Anuj; French, Samuel W

    2015-10-01

    A case of drug-induced hepatitis mediated by troxis necrosis, a form of autoimmune hepatitis, is described. Clinical data, light and electron microscopy of an ultrasound-guided core needle liver biopsy specimen, were examined to investigate the cause of transaminitis in a 26year old male patient on Cellcept and Plaquenil for the treatment of lupus erythematosus. A systematic PUBMED review of troxis necrosis as the underlying mechanism for drug-induced hepatitis was performed. Liver function tests (LFTs) were significant for elevated AST (305) and ALT (174); the autoimmune workup was significant for anti-ANA positivity and α-SMA negativity. On light microscopy, the liver biopsy shows focal areas of lymphocytic infiltrates surrounding and forming immunologic synapses with lobular hepatocytes, indicating lobular hepatitis of autoimmune nature. Electron microscopy confirmed the presence of immunologic synapses. Upon cessation of the offending medications, the LFTs returned to baseline with no further intervention. Literature search yielded 7 previously reported cases of drug-induced hepatitis mediated by troxis necrosis. Troxis necrosis is a novel mechanism for drug-induced hepatitis, including immunomodulatory medications including a monoclonal anti-TWEAK antibody and Cellcept and Plaquenil, two widely used immunosuppression/anti-rejection medications. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. 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.

  1. Application of urine proteomics for biomarker discovery in drug-induced liver injury

    NARCIS (Netherlands)

    van Swelm, Rachel P L; Kramers, Cornelis; Masereeuw, R.|info:eu-repo/dai/nl/155644033; Russel, Frans G M

    2014-01-01

    Abstract The leading cause of hepatic damage is drug-induced liver injury (DILI), for which currently no adequate predictive biomarkers are available. Moreover, for most drugs related to DILI, the mechanisms underlying the adverse reaction have not yet been elucidated. Urinary protein biomarker

  2. 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

  3. Brd4 Is Required for Recovery from Antimicrotubule Drug-induced Mitotic Arrest: Preservation of Acetylated ChromatinD⃞

    Science.gov (United States)

    Nishiyama, Akira; Dey, Anup; Miyazaki, Jun-ichi; Ozato, Keiko

    2006-01-01

    The mammalian bromodomain protein Brd4 interacts with mitotic chromosomes by binding to acetylated histone H3 and H4 and is thought to play a role in epigenetic memory. Mitotic cells are susceptible to antimicrotubule drugs. These drugs activate multiple response pathways and arrest cells at mitosis. We found that Brd4 was rapidly released from chromosomes upon treatment with antimicrotubule drugs, including the reversible agent nocodazole. Yet, when nocodazole was withdrawn, Brd4 was reloaded onto chromosomes, and cells proceeded to complete cell division. However, cells in which a Brd4 allele was disrupted (Brd4+/-), and expressing only half of the normal Brd4 levels, were defective in reloading Brd4 onto chromosomes. Consequently, Brd4+/- cells were impaired in their ability to recover from nocodazole-induced mitotic arrest: a large fraction of +/- cells failed to reach anaphase after drug withdrawal, and those that entered anaphase showed an increased frequency of abnormal chromosomal segregation. The reloading defect observed in Brd4+/- cells coincided with selective hypoacetylation of lysine residues on H3 and H4. The histone deacetylase inhibitor trichostatin A increased global histone acetylation and perturbed nocodazole-induced Brd4 unloading. Brd4 plays an integral part in a cellular response to drug-induced mitotic stress by preserving a properly acetylated chromatin status. PMID:16339075

  4. Drug reaction with eosinophilia and systemic symptoms: A drug-induced hypersensitivity syndrome with variable clinical features

    Directory of Open Access Journals (Sweden)

    Yi-Chun Chen

    2013-12-01

    Full Text Available Drug reaction with eosinophilia and systemic symptoms (DRESS or drug-induced hypersensitivity syndrome (DIHS involves a unique and severe adverse drug reaction. Patients present with fever, rash, lymphadenopathy, hematological abnormalities, systemic illness, and may suffer from prolonged courses. Although the precise pathogenesis of DRESS/DIHS is not fully understood, it is widely considered to be an immunological reaction to a drug or drug metabolites. In this review article, we discuss the historical aspects of nosology, variable clinical and histopathological features, advantages and disadvantages of using an international Registry of Severe Cutaneous Adverse Reactions (RegiSCAR and Japanese DIHS criteria, pathogenesis, treatment, and long-term sequelae of DRESS/DIHS. Early recognition of this syndrome, withdrawal of suspected culprit drugs, and adequate supportive care are mainstays of improving patient prognosis and reducing morbidities and mortality. Moreover, some DRESS/DIHS patients may develop long-term sequelae, especially autoimmune diseases and end organ failure. Physicians should be aware of these possibilities in patients after DRESS/DIHS and cautiously follow-up symptoms and laboratory tests for early detection of these sequelae.

  5. Drug-induced seizures in children and adolescents presenting for emergency care: current and emerging trends.

    Science.gov (United States)

    Finkelstein, Y; Hutson, J R; Freedman, S B; Wax, P; Brent, J

    2013-01-01

    Seizures may be the presenting manifestation of acute poisoning in children. Knowledge of the etiologic agent, or likely drug-class exposure, is crucial to minimize morbidity and optimize care. To describe the agents most commonly responsible for pediatric drug-induced seizures, whose evaluation included a medical toxicology consultation in the United States. Using the 37 participating sites of the Toxicology Investigators Consortium (ToxIC) Case Registry, a cross-country surveillance tool, we conducted an observational study of a prospectively collected cohort. We identified all pediatric (younger than 18 years) reports originating from an Emergency Department (ED) which included a chemical or drug-induced seizure, and required a medical toxicology consultation between April 1, 2010 and March 31, 2012. Results. We identified 142 pediatric drug-induced seizure cases (56% male), which represent nearly 5% of pediatric cases requiring bedside consultation by medical toxicologists. One-hundred and seven cases (75%) occurred in children aged 13-18 years, and 86 (61%) resulted from intentional ingestions. Antidepressants were the most commonly identified agents ingested (n = 61; 42%), of which bupropion was the leading drug (n = 30; 50% of antidepressants), followed by anticholinergics/antihistamines (n = 31; 22%). All antidepressant-induced seizures in teenagers were intentional and represented self-harm behavior. Sympathomimetic agents, including street drugs, represent the most common agents in children younger than 2 years (n = 4/19). Antidepressants, and specifically bupropion, are presently the most common medications responsible for pediatric drug-induced seizures requiring medical toxicology consultation in the United States. In teenagers presenting with new-onset seizures of unknown etiology, the possibility of deliberate self-poisoning should be explored, since most drug-induced seizures in this age group resulted from intentional ingestion.

  6. Prevalence, drug-induced hepatotoxicity, and mortality among patients multi-infected with HIV, tuberculosis, and hepatitis virus.

    Science.gov (United States)

    Mo, Pingzheng; Zhu, Qi; Teter, Caroline; Yang, Rongrong; Deng, Liping; Yan, Yajun; Chen, Jun; Zeng, Jie; Gui, Xi-en

    2014-11-01

    To investigate the prevalence, incidence of abnormal liver function tests (LFTs), and mortality during anti-TB treatment in patients multi-infected with HIV, tuberculosis (TB), and hepatitis virus (hepatitis B virus (HBV) and hepatitis C virus (HCV)). Three hundred and sixty-one HIV-positive TB patients were enrolled and divided into an HIV/TB group, HIV/TB/HBV group, and HIV/TB/HCV group; 1013 HIV-negative TB patients were selected randomly as controls. One hundred and seventeen (32.4%) HIV-positive TB patients were infected with HBV and/or HCV, compared with 90 (8.9%) HIV-negative TB patients (p=0.000). HIV-positive TB patients had a higher incidence of anti-TB drug-induced hepatotoxicity than HIV-negative TB patients (4.2% vs. 1.0%, odds ratio (OR) 4.348, 95% confidence interval (CI) 1.935-9.769, p=0.000). The incidence of abnormal LFTs in the HIV/TB/HBV group and HIV/TB/HCV group were significantly higher than in the HIV/TB group (40.7% vs. 11.1%, OR 5.525, 95% CI 2.325-13.131, p=0.000; 20.0% vs. 11.1%, OR 2.009, 95% CI 1.057-3.820, p=0.031). A total of 68.4% of patients with HBV-DNA >1.0×10(5) copies/ml and 42.9% of patients with HCV-RNA >1.0×10(5) copies/ml had abnormal LFTs. Twenty-three (19.7%) patients multi-infected with HIV, TB, and hepatitis virus died during anti-TB treatment. HIV, HBV, and HCV are risk factors for the development of abnormal LFTs and mortality during anti-TB treatment. TB patients co-infected with HIV and hepatitis virus need close follow-up.

  7. Drug-induced hypochlorhydria causes high duodenal bacterial counts in the elderly.

    Science.gov (United States)

    Pereira, S P; Gainsborough, N; Dowling, R H

    1998-01-01

    Small bowel bacterial overgrowth secondary to drug-induced hypochlorhydria may be of particular importance in the elderly, in whom anti-ulcer drugs are commonly prescribed and the consequences of malabsorption may be severe. Duodenal aspirates were obtained from elderly individuals before (n = 24) and during a 2-month treatment course with either omeprazole (20 mg daily; n = 8) or ranitidine (300 mg b.d.; n = 6), and from six patients with small bowel bacterial overgrowth who had diarrhoea and malabsorption. Before treatment, duodenal bacterial counts were normal ( 10(5) cfu/mL. All remained asymptomatic and had normal lactulose breath H2 profiles during treatment. Drug-induced hypochlorhydria causes high duodenal bacterial counts in the elderly but, in the short term, this bacterial overgrowth is not associated with malabsorption.

  8. [Advances in clinical differentiation between immunological and drug-induced liver injury].

    Science.gov (United States)

    Wang, Y; Li, Y N; Zhang, J; Wang, B M; Zhou, L

    2017-09-20

    The differentiation between autoimmune hepatitis (AIH) and drug-induced liver injury (DILI) is a difficult task in clinical practice. Some AIH patients had a medication history before disease onset, and some DILI patients may have positive serum antibody. In addition, these two groups of patients have similar clinical symptoms, serological examination results, and liver histopathology, which lead to the difficulties in differentiation. However, correct differential diagnosis is of great significance in making clinical treatment decisions and preventing liver cirrhosis. Therefore, it is necessary to investigate the association between immunological and drug-induced liver injury from the perspectives of pathogenesis, similarities and differences in clinical features, serological examination results, and histological changes, prospects of new biomarkers in differentiation, and the significance of hormone therapy and clinical follow-up in differential diagnosis and treatment, in order to provide a reference for clinical decision-making and research in future.

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

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    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.

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

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    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.

  11. Drug-Induced by Systemic Lupus Erythematosus Presenting as Recurrent Pericardial Effusion After Mitral Valve Repair

    OpenAIRE

    Aghigh Haydari; Feridoun Sabzi; Samsam Dabiri; Alireza Poormotaabed

    2017-01-01

    We report a patient presented with recurrent pericardial effusion caused by drug-induced systemic lupus Erythematosus (SLE) following mitral valve repair. The surgery was complicated by hemiparesis and convulsion in early postoperative period. The patient had been received carbamazepine for a paroxysmal seizure that occurred following mitral valve repair. The post operative computed tomography showed embolic stroke and its sequel (seizure) that treated with carbamazepine. In the 3rd month of ...

  12. Sjögren-like pluriglandular exocrine insufficiency after drug-induced toxic epidermal necrolysis.

    Science.gov (United States)

    Sabán, J.; Pais, J. R.; Rodríguez, J. L.; Boixeda, D.

    1991-01-01

    We present the case of a patient that progressively developed xerophthalmia, xerostomia, cutaneous xerosis and exocrine pancreatic insufficiency 3 months after metamizole-induced toxic epidermal necrolysis. Though the association of Sjögren's syndrome and exocrine pancreatic impairment is well established, the Sjögren-like syndrome after drug-induced toxic epidermal necrolysis in association with such a wide exocrine glandular insufficiency has not been previously described, to our knowledge. PMID:2041854

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

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    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.

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

    OpenAIRE

    Balak, Deepak; Bavinck, Jan Nico Bouwes; De Vries, A.P.J. (Aiko P. J.); Hartman, J.; Martino Neumann, H.A.; Zietse, Bob; 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 Fanconi syndrome. Methods: Descriptive case series with two cases of Fanconi syndrome associated with FAE treatment diagnosed at two Dutch university nephrology departments, three cases reported at th...

  15. Relationship between drug-induced interstitial lung diseases and cytochrome P450 polymorphisms.

    Science.gov (United States)

    Wijnen, Petal A H M; Bekers, Otto; Drent, Marjolein

    2010-09-01

    Interstitial lung disease and especially drug-induced interstitial lung disease can occur as a cause of drug(s) or drug-drug interactions. In this review we summarize the possible role of cytochrome P450 (CYP) enzymes in drug-induced interstitial lung disease. The CYP enzyme family plays an important role in the metabolism of all sorts of ingested, injected or inhaled xenobiotic substances. Although the liver is considered to be the major metabolism site of CYP enzymes, in recent years more CYP isoforms have been detected in lung tissue. Polymorphisms in these CYP genes can influence the metabolic activity of the subsequent enzymes, which in turn may lead to localized (toxic) reactions and tissue damage. Drug toxicity can be the consequence of no or very poor enzyme activity, especially if no other metabolic route is available. In the case of reduced enzyme activity, dose reduction or prescribing an alternative drug metabolized by a different, unaffected CYP enzyme is recommended to prevent toxic side effects. Therefore, knowing a patient's CYP profile before drug prescription could be a way to prevent drug-induced interstitial lung disease. Moreover, it might be helpful in explaining serious adverse effects from inhaled, injected or ingested xenobiotic substances.

  16. Protective Effect of Bicyclol on Anti-Tuberculosis Drug Induced Liver Injury in Rats

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    Xin Liu

    2017-04-01

    Full Text Available The present study was performed to investigate the effect of bicyclol, a synthetic anti-hepatitis drug with anti-oxidative and anti-inflammatory properties, on anti-tuberculosis (anti-TB drug-induced liver injury and related mechanisms in rats. Bicyclol was given to rats by gavage 2 h before the oral administration of an anti-TB drug once a day for 30 days. Liver injury was evaluated by biochemical and histopathological examinations. Lipid peroxidation, mitochondrial function, and the activity of antioxidants were measured by spectrophotometric methods. Cytokines expression and CYP2E1 activity were determined by ELISA assay and liquid chromatography–tandem mass spectrometry (LC–MS/MS analysis. The expressions of hepatic CYP2E1 and hepatocyte growth factor (HGF were assessed by Western blotting. As a result, bicyclol significantly protected against anti-TB drug-induced liver injury by reducing the elevated serum aminotransferases levels and accumulation of hepatic lipids. Meanwhile, the histopathological changes were also attenuated in rats. The protective effect of bicyclol on anti-TB drug-induced hepatotoxicity was mainly due to its ability to attenuate oxidative stress, suppress the inflammatory cytokines and CYP2E1 expression, up-regulate the expression of HGF, and improve mitochondrial function. Furthermore, administration of bicyclol had no significant effect on the plasma pharmacokinetics of the anti-TB drug in rats.

  17. 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.

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

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    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.

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

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    P R Ganesh

    2016-01-01

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

  20. Antimalarial Drugs-Induced Hepatic Injury in Rats and the Protective Role of Carnosine

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    Akram Jamshidzadeh, Reza Heidari, Farzaneh Abazari, Maral Ramezani, Forouzan Khodaei, Mohammad Mehdi Ommati, Maryam Ayarzadeh, Roya Firuzi, Arastoo Saeedi, Negar Azarpira, Asma Najibi

    2016-09-01

    Full Text Available Background: Chloroquine and amodiaquine are used in the prophylaxis and treatment of malaria. However, hepatic injury is associated with malaria drug therapy. On the other hand, there is no promising hepatoprotective agent for prophylaxis or treatment of antimalarial drugs‑induced liver injury. Carnosine is a naturally occurring peptide with pleiotropic protective properties in different tissues. This investigation aimed to evaluate the effect of carnosine administration in antimalarial drugs-induced hepatic injury in rats. Methods: Animals were treated with amodiaquine (180 mg/kg, oral or chloroquine (970 mg/kg, oral. Carnosine (250, 500 and 1000 mg/kg, i.p was administered as the hepatoprotective agent against antimalarial drugs liver injury. Results: Liver injury was manifested biochemically by a significant increase in serum level of ALT, LDH, and AST. In addition, hepatic tissue from antimalarial drugs‐treated rats showed a significant increase in reactive oxygen species (ROS, lipid peroxidation and protein carbonylation along with a decrease in hepatic glutathione reservoirs and total antioxidant capacity. Moreover, the liver histopathologic evaluation revealed significant congestion, inflammation, and necrosis in amodiaquine and/or chloroquine-treated animals. Carnosine administration significantly alleviated antimalarial drugs-induced pathologic changes in serum biochemistry and liver tissue. Conclusion: Our data suggest that carnosine possesses protective properties against amodiaquine and/or chloroquine‑induced liver injury possibly through mitigation of drug-induced oxidative stress and its consequent events.

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

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    Erkan eSukuroglu

    2015-12-01

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

  2. Prediction Model of Drug-Induced Liver Injury in Patients with Pulmonary Tuberculosis: Evaluation of the Incidence and Risk Factors

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    Farzaneh Dastan

    2017-03-01

    Full Text Available Introduction and objectives:Tuberculosis (TB still remains a major health concern both in developing and developed countries. The rate of the liver injury due to anti-TB drugs in developed countries has been reported up to 4%. The goal of this study is to assess the rate and risk factors for anti-tuberculosis drug-induced liver injury (DILI. Also, a model has been designed to predict DILI in patients with pulmonary tuberculosis.Methods:We conducted an observational study. The investigation was carried out in the National Research Institute of Tuberculosis and Lung Disease, Tehran, Iran. Anti-tuberculosis drug treatment course and patients’ demographic data, medical and drug history, and social habits were extracted from their medical records. DILI was defined as an increase in serum alanine aminotransfrase (ALT or aspartate aminotransfrase (AST greater than three times of the upper limit of normal (ULN, with symptoms of liver injury, or five times of the ULN without symptoms.Results:In this study, 87 patients (33 male, 54 female, mean age 54.29±21.79 years with tuberculosis diagnosis were followed. Anti-tuberculosis induced liver injury was detected in 14 (16.1% patients. Concomitant use of hepatotoxic drugs (Isoniazid, Rifampin and Pyrazinamide and the abnormal baseline serum liver enzyme levels before the initiation of therapy were found as risk factors for anti-tuberculosis induced liver injury.Conclusion:Anti-tuberculosis induced liver injury is a major problem in tuberculosis patients which lead to treatment interruption in 14 (16.1% patients. Due to the lack of evidence regarding the mechanism of this side effect, we recommend to monitor anti-tuberculosis drug levels in order to study their probable correlations with DILI.   

  3. Phospholipid specificity of autoimmune and drug induced lupus anticoagulants; association of phosphatidylethanolamine reactivity with thrombosis in autoimmune disease.

    Science.gov (United States)

    Drouvalakis, K A; Buchanan, R R

    1998-02-01

    To assess the phospholipid specificity of lupus anticoagulants (LAC) in autoimmune and drug induced LAC positive patients, and to determine their relevance with the clinical feature thrombosis. Thirty-five plasma samples with LAC were tested. Of these, 22 samples were from patients with autoimmune disease: 12 had systemic lupus erythematosus (SLE) and 10 primary antiphospholipid syndrome (APS). These were compared with 13 patients with drug induced LAC. Antiphospholipid (aPL) activity was tested by inhibition of LAC activity in a modified coagulation assay using the phospholipids: egg phosphatidylethanolamine (PE), 20% phosphatidylserine/80% phosphatidylcholine (PS/PC), and 15% PS/65%PC/20%PE mixture. Anticardiolipin antibodies (aCL) were measured in all samples by ELISA. In the autoimmune group, 95% were positive for reactivity to PE, 68% for PS/PC, 68% for PS/PC/PE, and 77% aCL. Of the drug induced group, 69% were positive for reactivity to PE, but only 23% for PS/PC, 46% PS/PC/PE, and 23% aCL positive. In the autoimmune patient group, 64% had thrombotic episodes, all of which had anti-PE activity, and 64% had associated anti-PS activity. No drug induced patient had episodes of thrombosis. Autoimmune induced LAC may contain a broader range of phospholipid specificities than those from drug induced patients. These data thus identify another potential reason why patients with drug induced LAC appear to be at less risk of developing APS than those with autoimmune LAC.

  4. The clinical features of drug-induced liver injury observed through liver biopsy: focus on relevancy to autoimmune hepatitis

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    Hye Young Ju

    2012-06-01

    Full Text Available Background/AimsAccurate diagnosis of drug-induced liver injury (DILI is difficult without considering the possibility of underlying diseases, especially autoimmune hepatitis (AIH. We investigated the clinical patterns in patients with a history of medication, liver-function abnormalities, and in whom liver biopsy was conducted, focusing on accompaniment by AIH.MethodsThe clinical, serologic, and histologic findings of 29 patients were compared and analyzed. The patients were aged 46.2±12.8 years (mean±SD, and 72.4% of patient were female. The most common symptom and causal drug were jaundice (58.6% and herbal medications (55.2%, respectively.ResultsAspartate aminotransferase (AST, alanine aminotransferase, total bilirubin, alkaline phosphatase, and γ-glutamyl transpeptidase levels were 662.2±574.8 U/L, 905.4±794.9 U/L, 12.9±10.8 mg/dL, 195.8±123.3 U/L, and 255.3±280.8 U/L, respectively. According to serologic and histologic findings, 21 cases were diagnosed with DILI and 8 with AIH. The AIH group exhibited significantly higher AST levels (537.1±519.1 vs. 1043.3±600.5 U/L, globulin levels (2.7±0.4 vs. 3.3±0.5 g/dL, and prothrombin time (12.9±2.4 vs. 15.2±3.9 s; P<0.05. Antinuclear antibody was positive in 7 of 21 cases of DILI and all 8 cases of AIH (P=0.002. The simplified AIH score was 3.7±0.9 in the DILI group and 6.5±0.9 in the AIH group (P<0.001.ConclusionsAccurate diagnosis is necessary for patients with a history of medication and visits for liver-function abnormalities; in particular, the possibility of AIH should be considered.

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

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    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.

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

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    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.

  7. Drug-induced acute pancreatitis: A rare manifestation of an incomplete “dapsone syndrome”

    Science.gov (United States)

    Das, Anup K.; Jawed, Qaiser

    2014-01-01

    Drug-induced acute pancreatitis (AP) is under-reported, and a large number of drugs are listed as offenders, but are often overlooked. Knowledge about the possible association of medications in causing AP is important, and needs a high index of suspicion, especially with drugs that have been reported to be the etiology only rarely. Dapsone, a commonly used drug, can cause various hypersensitivity reactions including AP collectively called “dapsone syndrome.” Here, we report dapsone-induced AP in a young man. Our case shows certain dissimilarities like associated acute renal failure and acute hemolysis not previously described. PMID:25097293

  8. Drug-induced acute pancreatitis: a rare manifestation of an incomplete "dapsone syndrome".

    Science.gov (United States)

    Das, Anup K; Jawed, Qaiser

    2014-01-01

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

  9. Episcleritis Related to Drug-Induced Lupus Erythematosus following Infliximab Therapy: A Case Report

    Directory of Open Access Journals (Sweden)

    Irini P. Chatziralli

    2011-01-01

    Full Text Available Drug-induced lupus erythematosus is defined as a lupus-like syndrome temporally related to continuous drug exposure which resolves after discontinuation of the offending drug. Herein, we describe a patient with distinct clinical manifestations of anti-TNF-associated DILE related to infliximab therapy. The patient exhibited clinical and laboratory findings of lupus-like illnesses as well as ocular disorders, such as episcleritis. The main message is that the symptoms of DILE should not be overlooked, although sometimes other systematic conditions may underlie them. As a result, it is very important for the clinicians to evaluate the symptoms of DILE and manage appropriately these cases.

  10. 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...... controls of the S14761 effect in MCAO were performed as previously mentioned (n = 10) but with rats kept normothermic by a heating lamp for 22 hours. Finally, a meta-analysis of ipsapirone-induced hypothermia in man was included. RESULTS: Infarct volumes were reduced by 50% in hypothermic rats versus...... therapeutic hypothermia....

  11. Drug Induced Liver Injury: Review with a Focus on Genetic Factors, Tissue Diagnosis, and Treatment Options

    Science.gov (United States)

    Khoury, Tawfik; Rmeileh, Ayman Abu; Yosha, Liron; Benson, Ariel A.; Daher, Saleh; Mizrahi, Meir

    2015-01-01

    Drug-induced liver injury (DILI) is a rare but potentially life threatening adverse drug reaction. DILI may mimic any morphologic characteristic of acute or chronic liver disease, and the histopathologic features of DILI may be indistinguishable from those of other causes of liver injury, such as acute viral hepatitis. In this review article, we provide an update on causative agents, clinical features, pathogenesis, diagnosis modalities, and outcomes of DILI. In addition, we review results of recently reported genetic studies and updates on pharmacological and invasive treatments. PMID:26356634

  12. A Case Report of Drug-Induced Thrombocytopenia after Living Donor Liver Transplantation.

    Science.gov (United States)

    Arai, Keisuke; Kuramitsu, Kaori; Fukumoto, Takumi; Kido, Masahiro; Takebe, Atsushi; Tanaka, Motofumi; Kinoshita, Hisoka; Ajiki, Tetsuo; Toyama, Hirochika; Asari, Sadaki; Goto, Tadahiro; Ku, Yonson

    2016-06-16

    There are few descriptions of severe thrombocytopenia during the early postoperative period after liver transplantation, and these have not been fully documented in the literature. Here, we report a case of drug-induced thrombocytopenia requiring transfusion of blood products after living donor liver transplantation. We determined that this was not caused by the interferon-free anti-viral therapy but by tacrolimus A 61-year-old woman with hepatitis C-related cirrhosis and hepatorenal syndrome underwent living donor liver transplantation using a left lobe graft from her son. After transplantation, immunosuppression consisted of tacrolimus and steroid. Seven weeks after transplantation, interferon-free therapy with daclatasvir and asunaprevir was started. Thirteen days thereafter, hepatitis C virus tested negative. However, the platelet count had begun to gradually decrease just before starting anti-viral therapy. Daclatasvir and asunaprevir were stopped because this was suspected to be a side-effect of these drugs, but the patient nonetheless went on to develop severe thrombocytopenia (platelet count 17,000/μL), which needed transfusions. Now suspecting tacrolimus as the inducer of this side effect, we changed to cyclosporin, after which the platelet count gradually recovered. Viral markers were still not detectable up to 2 months after discontinuation of the antiviral drugs. We conclude that when severe thrombocytopenia occurs, possible drug-induced thrombocytopenia as well as other disorders must be investigated.

  13. The epidemiology of drug-induced akathisia: Part I. Acute akathisia.

    Science.gov (United States)

    Sachdev, P

    1995-01-01

    This article reviews the epidemiological data on drug-induced acute akathisia, examining studies in which akathisia was the primary focus as well as those in which it was one of a number of drug side effects studied. The studies are diverse in methodology and suffer from many limitations. Incidence rates for acute akathisia with conventional neuroleptics vary from 8 to 76 percent, with 20 to 30 percent being a conservative estimate; preliminary evidence suggests that the newer atypical antipsychotic drugs are less likely to produce acute akathisia. A number of nonneuroleptic drugs--in particular the serotonin-specific reuptake inhibitors--have been implicated in the development of akathisia, but the epidemiological data are limited. Risk factors for neuroleptic-induced akathisia are not completely understood. Drug dose, rate of increment of dose, and drug potency seem to be important, but the role of sociodemographic factors and other treatment-related variables is modest. Drug-induced parkinsonism is significantly correlated with akathisia. Evidence for iron deficiency as a risk factor is conflicting, and its contribution is likely to be minor.

  14. Possible drug-induced hepatopathy in a dog receiving zonisamide monotherapy for treatment of cryptogenic epilepsy.

    Science.gov (United States)

    Schwartz, Malte; Muñana, Karen R; Olby, Natasha J

    2011-11-01

    A 9-year old female spayed Rottweiler was diagnosed with cryptogenic epilepsy and started on zonisamide monotherapy (8.3 mg/kg, PO, q 12 hr). Three weeks after the 1st dose of zonisamide the dog presented for vomiting, inappetence and icterus. Serum biochemistry showed marked elevation of liver enzymes, consistent with hepatocellular damage and cholestasis. No underlying cause for liver disease was identified and a drug-induced hepatopathy was suspected. Zonisamide was discontinued and replaced by potassium bromide. Supportive therapy consisted of intravenous fluids, antiemetics, antibiotics and hepatoprotectants. The dog made a complete recovery and serial serum biochemical examinations showed complete normalisation of liver parameters 8 weeks after discontinuation of zonisamide. Based on a human Drug-induced Liver Injury Diagnostic Scale, the likelihood for zonisamide-induced hepatopathy was classified as "possible". Veterinary practitioners and owners should be educated about the potential for an idiosyncratic drug reaction to zonisamide. If signs of hepatotoxicity are recognised early and zonisamide is discontinued, complete recovery is possible.

  15. Uni- or bi-ventricular hypertrophy and susceptibility to drug-induced torsades de pointes.

    Science.gov (United States)

    Panyasing, Yaowalak; Kijtawornrat, Anusak; Del Rio, Carlos; Carnes, Cynthia; Hamlin, Robert L

    2010-01-01

    Cardiac hypertrophy is an independent risk factor for torsades de pointes (TdP), a polymorphic ventricular tachycardia that is often drug-induced, that may evolve into ventricular fibrillation and sudden death. Therefore this study was designed to determine if right (RVH), left (LVH), or biventricular (BVH) hypertrophy increases susceptibility to drug-induced TdP. Rabbits were separated into 4 groups: control or RVH, LVH, BVH (studied 8weeks after banding of one or both great arteries). ECGs were recorded continuously under anesthesia after baseline and after rabbits received escalating doses of torsadogens (dofetilide, clofilium and terfenadine) or non-torsadogens (cilobradine, diltiazem and vehicle). The following parameters were measured [RR, PQ, QRS and QT] or calculated [QTc (F), short term variability of QT interval]. Generally, torsadogenicity for the compounds tested was dofetilide>clofilium>terfenadine, and there was no TdP following cilobradine, diltiazem or vehicle. In general the susceptibility to TdP was RVH>BVH>LVH>control. Rabbits with RVH developed TdP much more prevalently than for those with either LVH or BVH (p<0.05). At the low dose of dofetilide, LVH was actually protective. Rabbits with any form of hypertrophy develop prolongation of QT, QTc and increased QT instability. Rabbits with any form of hypertrophy are more prone to arrhythmia than normals in response to known torsadogens. 2010 Elsevier Inc. All rights reserved.

  16. Case of drug-induced acute pancreatitis produced by horsetail infusions

    Directory of Open Access Journals (Sweden)

    María del Carmen García-Gavilán

    Full Text Available Introduction: The most frequent causes of acute pancreatitis are biliary stones, alcohol consumption, smoking and tumors. Some of them do not have any established cause, and they are catalogued as idiopathic pancreatitis. Case report: We report the case of a 56-year-old woman with a history of bilateral adrenalectomy on hormone replacement therapy with corticosteroids, who has recurrent episodes of mild acute pancreatitis with an etiologic study (laboratory and imaging tests without significant findings. A drug-induced etiology was suspected, so corticosteroids were removed and antihypertensive treatment was modified, but the clinical manifestations persisted. Later regular consumption of horsetail infusions was detected, and after their suspension the patient became asymptomatic and has not presented new episodes. Discussion: The drug-induced acute pancreatitis is a strange cause of pancreatitis that is frequently underdiagnosed because of the difficulty to establish a relationship between the drugs and the pancreatitis. Lots of drugs have been related with acute pancreatitis, while the information available for herbal products is limited. They usually present like mild and recurrent episodes, without significant findings in both laboratory and imaging tests (abdominal ultrasound, abdominal computed tomography [CT], cholangiography and endoscopic ultrasound. It is important to detect the origin of this type of pancreatitis to prevent recurrence.

  17. 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.

  18. High Content Analysis of Human Pluripotent Stem Cell Derived Hepatocytes Reveals Drug Induced Steatosis and Phospholipidosis

    Directory of Open Access Journals (Sweden)

    Arvind Pradip

    2016-01-01

    Full Text Available Hepatotoxicity is one of the most cited reasons for withdrawal of approved drugs from the market. The use of nonclinically relevant in vitro and in vivo testing systems contributes to the high attrition rates. Recent advances in differentiating human induced pluripotent stem cells (hiPSCs into pure cultures of hepatocyte-like cells expressing functional drug metabolizing enzymes open up possibilities for novel, more relevant human cell based toxicity models. The present study aimed to investigate the use of hiPSC derived hepatocytes for conducting mechanistic toxicity testing by image based high content analysis (HCA. The hiPSC derived hepatocytes were exposed to drugs known to cause hepatotoxicity through steatosis and phospholipidosis, measuring several endpoints representing different mechanisms involved in drug induced hepatotoxicity. The hiPSC derived hepatocytes were benchmarked to the HepG2 cell line and generated robust HCA data with low imprecision between plates and batches. The different parameters measured were detected at subcytotoxic concentrations and the order of which the compounds were categorized (as severe, moderate, mild, or nontoxic based on the degree of injury at isomolar concentration corresponded to previously published data. Taken together, the present study shows how hiPSC derived hepatocytes can be used as a platform for screening drug induced hepatotoxicity by HCA.

  19. Drug-induced cholestasis risk assessment in sandwich-cultured human hepatocytes.

    Science.gov (United States)

    Oorts, Marlies; Baze, Audrey; Bachellier, Philippe; Heyd, Bruno; Zacharias, Thomas; Annaert, Pieter; Richert, Lysiane

    2016-08-01

    Drug-induced cholestasis (DIC) is recognized as one of the prime mechanisms for DILI. Hence, earlier detection of drug candidates with cholestatic signature is crucial. Recently, we introduced an in vitro model for DIC and evaluated its performance with several cholestatic drugs. We presently expand on the validation of this model by 14 training compounds (TCs) of the EU-EFPIA IMI project MIP-DILI. Several batches of human hepatocytes in sandwich-culture were qualified for DIC assessment by verifying the bile acid-dependent increase in sensitivity to the toxic effects of cyclosporin A. The cholestatic potential of the TCs was expressed by determining the drug-induced cholestasis index (DICI). A safety margin (SM) was calculated as the ratio of the lowest TC concentration with a DICI≤0.80 to the Cmax,total. Nefazodone, bosentan, perhexiline and troglitazone were flagged for cholestasis (SMdrug candidates with cholestasis risk. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Case of drug-induced acute pancreatitis produced by horsetail infusions.

    Science.gov (United States)

    García Gavilán, María Del Carmen; Moreno García, Antonio Miguel; Rosales Zabal, José Miguel; Navarro Jarabo, José María; Sánchez Cantos, Andrés

    2017-04-01

    The most frequent causes of acute pancreatitis are biliary stones, alcohol consumption, smoking and tumors. Some of them do not have any established cause, and they are catalogued as idiopathic pancreatitis. We report the case of a 56-year-old woman with a history of bilateral adrenalectomy on hormone replacement therapy with corticosteroids, who has recurrent episodes of mild acute pancreatitis with an etiologic study (laboratory and imaging tests) without significant findings. A drug-induced etiology was suspected, so corticosteroids were removed and antihypertensive treatment was modified, but the clinical manifestations persisted. Later regular consumption of horsetail infusions was detected, and after their suspension the patient became asymptomatic and has not presented new episodes. The drug-induced acute pancreatitis is a strange cause of pancreatitis that is frequently underdiagnosed because of the difficulty to establish a relationship between the drugs and the pancreatitis. Lots of drugs have been related with acute pancreatitis, while the information available for herbal products is limited. They usually present like mild and recurrent episodes, without significant findings in both laboratory and imaging tests (abdominal ultrasound, abdominal computed tomography [CT], cholangiography and endoscopic ultrasound). It is important to detect the origin of this type of pancreatitis to prevent recurrence.

  1. Drug-Induced by Systemic Lupus Erythematosus Presenting as Recurrent Pericardial Effusion After Mitral Valve Repair

    Directory of Open Access Journals (Sweden)

    Aghigh Haydari

    2017-10-01

    Full Text Available We report a patient presented with recurrent pericardial effusion caused by drug-induced systemic lupus Erythematosus (SLE following mitral valve repair. The surgery was complicated by hemiparesis and convulsion in early postoperative period. The patient had been received carbamazepine for a paroxysmal seizure that occurred following mitral valve repair. The post operative computed tomography showed embolic stroke and its sequel (seizure that treated with carbamazepine. In the 3rd month of follow-up, however, hemiparesis recovered by physiotherapy but carbamazepine was not discontinued as by request of neurologist. In the 6th month of surgery, the patient admitted by dyspnea and massive pericardial effusion that treated by subxiphoid drainage. This event was re occurred in two times in a short time frame and each event treated by surgical approach. The serologic exam in the last admission revealed drug-induced lupus erythematosus. The carbamazepine as an anti convulsive drug has been described to cause LE like disease in multiple case reports. Laboratory exam exhibited the possibility of carbamazepine-induced lupus in our case, with the extremely rare presentation of recurrent massive pericardial effusion.

  2. Drug-Induced by Systemic Lupus Erythematosus Presenting as Recurrent Pericardial Effusion After Mitral Valve Repair.

    Science.gov (United States)

    Haydari, Aghigh; Sabzi, Feridoun; Dabiri, Samsam; Poormotaabed, Alireza

    2017-09-01

    We report a patient presented with recurrent pericardial effusion caused by drug-induced systemic lupus Erythematosus (SLE) following mitral valve repair. The surgery was complicated by hemiparesis and convulsion in early postoperative period. The patient had been received carbamazepine for a paroxysmal seizure that occurred following mitral valve repair. The post operative computed tomography showed embolic stroke and its sequel (seizure) that treated with carbamazepine. In the 3rd month of follow-up, however, hemiparesis recovered by physiotherapy but carbamazepine was not discontinued as by request of neurologist. In the 6th month of surgery, the patient admitted by dyspnea and massive pericardial effusion that treated by subxiphoid drainage. This event was re occurred in two times in a short time frame and each event treated by surgical approach. The serologic exam in the last admission revealed drug-induced lupus erythematosus. The carbamazepine as an anti convulsive drug has been described to cause LE like disease in multiple case reports. Laboratory exam exhibited the possibility of carbamazepine-induced lupus in our case, with the extremely rare presentation of recurrent massive pericardial effusion.

  3. 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.

  4. Role of Serotoninergic Pathways in Drug-induced Valvular Heart Disease and Diagnostic Features by Echocardiography

    Science.gov (United States)

    Smith, Sakima A.; Waggoner, Alan D.; de las Fuentes, Lisa; Davila-Roman, Victor G.

    2013-01-01

    Serotonin plays a significant role in the development of carcinoid heart disease, which primarily leads to fibrosis and contraction of right-sided heart valves. Recently, strong evidence has emerged that the use of specific drug classes such as ergot alkaloids (for migraine headaches), 5-hydroxytryptamine (5-HT or serotonin) uptake regulators/inhibitors (for weight reduction), and ergot-derived dopamine agonists (for Parkinson’s disease) can result in left-sided heart valve damage that resembles carcinoid heart disease. Recent studies suggest that both right- and left-sided drug-induced heart valve disease involves increased serotoninergic activity and in particular activation of the 5-HT receptors, including the 5-HT2B receptor subtype, which mediate many of the central and peripheral functions of serotonin. G-proteins that inhibit adenylate cyclase activity mediate the activity of the 5-HT2B receptor subunit which is widely expressed in a variety of tissues including liver, lung, heart, and coronary and pulmonary arteries; and it has also been reported in embryonic mouse heart, particularly on mouse heart valve leaflets. In this review we discuss the salient features of serotoninergic manifestations of both carcinoid heart disease and drug-induced cardiac valvulopathy with an emphasis on echocardiographic diagnosis. PMID:19553085

  5. A combined approach to early detect in vitro drug-induced hemostatic changes in preclinical safety.

    Science.gov (United States)

    Defontis, Myriam; Côté, Serge; Ledieu, David

    2017-06-14

    Early detection of drug-induced alterations of hemostasis is challenging. Drugs can affect different components of the Virchow's triad and measurement of plasmatic coagulation times lacks sensitivity. New techniques for a more global assessment of the hemostasis are now available: the impedance platelet aggregometry, the thromboelastography and the thrombin generation measurement. The aim of this study was to evaluate three techniques (i.e.: Multiplate®, TEG® and CAT) for the in vitro detection of the effect of a drug known to induce hemostatic alterations in a preclinical safety environment. Cyclosporine A was chosen and tested at 4 concentrations after solubilization in DMSO in Wistar rats and Beagle dogs. The results obtained were comparable between both species except for the thrombin generation in platelet rich plasma. Enhanced platelet aggregability was observed after ADP stimulation and alterations of the thromboelastograms consisted in decreased maximum amplitude and increased LY30. A dual effect on thrombin generation was observed and suggested that CsA may interact with platelets in rat platelet rich plasma and speed up thrombin generation. The results of this study indicate that using a combined approach on hemostasis testing in preclinical safety it is possible to detect in vitro drug-induced alterations of hemostasis. Copyright © 2017. Published by Elsevier GmbH.

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

    Science.gov (United States)

    Balak, Deepak M W; Bouwes Bavinck, Jan Nico; de Vries, Aiko P J; Hartman, Jenny; Neumann, Hendrik A Martino; Zietse, Robert; Thio, Hok Bing

    2016-02-01

    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 Fanconi syndrome. Descriptive case series with two cases of Fanconi syndrome associated with FAE treatment diagnosed at two Dutch university nephrology departments, three cases reported at the Dutch and German national pharmacovigilance databases and six previously reported cases. All 11 cases involved female patients with psoriasis. The median age at the time of onset was 38 years [interquartile range (IQR) 37-46]. Patients received long-term FAEs treatment with a median treatment duration of 60 months (IQR 28-111). Laboratory tests were typically significant for low serum levels of phosphate and uric acid, while urinalysis showed glycosuria and proteinuria. Eight (73%) patients had developed a hypophosphataemic osteomalacia and three (27%) had pathological bone fractures. All patients discontinued FAEs, while four (36%) patients were treated with supplementation of phosphate and/or vitamin D. Five (45%) patients had persisting symptoms despite FAEs discontinuation. FAEs treatment can cause drug-induced Fanconi syndrome, but the association has been reported infrequently. Female patients with psoriasis treated long term with FAEs seem to be particularly at risk. Physicians treating patients with FAEs should be vigilant and monitor for the potential occurrence of Fanconi syndrome. Measurement of the urinary albumin:total protein ratio is a suggested screening tool for tubular proteinuria in Fanconi syndrome.

  7. 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

  8. Clinical efficacy of glucocorticoid therapy in treatment of drug-induced cholestatic liver disease

    Directory of Open Access Journals (Sweden)

    GE Hongyan

    2015-10-01

    Full Text Available ObjectiveTo analyze the clinical efficacy of glucocorticoid therapy in addition to conventional treatment for patients with drug-induced cholestatic liver disease. MethodsA total of 115 patients with drug-induced cholestatic liver disease who were admitted to Affiliated Hospital of Inner Mongolia University for the Nationalities from January 2010 to December 2014 were collected and divided into glucocorticoid treatment group and non-glucocorticoid treatment group. The glucocorticoid treatment group was given methylprednisolone sodium succinate 120 mg once daily by intravenous injection in addition to conventional treatment. The indicator for glucocorticoid response was defined as 10% decrease of total bilirubin (TBil on the third day or 30% decrease on the seventh day. Then the patients were orally given prednisone tablets 10 mg three times daily based on the level of TBil, and the administration of prednisone tablets was adjusted to twice daily a week later. The course of treatment was less than three weeks. Comparison of continuous data in normal distribution between the two groups was made by t test, and comparison of continuous data not in normal distribution between the two groups was made by rank sum test. ResultsThe levels of gamma-glutamyl transpeptidase (GGT, alanine aminotransferase (ALT, and TBil in the glucocorticoid treatment group decreased significantly on days 3, 7, and 14 of treatment compared with those before treatment (tGGT=3.64, 13.08, 16.22; tALT=2.39, 4.73, 8.36; tTBil=3.46, 7.41, 13.17; all P<0.05. Compared with the non-glucocorticoid treatment group, the glucocorticoid treatment group had significantly lower AST and ALT levels before treatment and on days 3 and 7 of treatment (all P>0.05. The GGT, AST, and TBil levels in the glucocorticoid treatment group were significantly lower than those in the non-glucocorticoid treatment group on day 14 of treatment (t=7.074, 2.929, 2.018; all P<0.05. The average decreasing

  9. A Multiplatform Approach for the Discovery of Novel Drug-Induced Kidney Injury Biomarkers.

    Science.gov (United States)

    Chen, Liuxi; Smith, James; Mikl, Jaromir; Fryer, Ryan; Pack, Frank; Williams, Brad J; Phillips, Jonathan A; Papov, Vladimir V

    2017-10-16

    Drug-induced kidney injury (DIKI) is a common toxicity observed in pharmaceutical development. We demonstrated the use of label-free liquid chromatography-mass spectrometry (LC-MS) and multiplex liquid chromatography-single reaction monitoring (LC-SRM) as practical extensions of standard immunoassay based safety biomarker assessments for identification of new toxicity marker candidates and for improved mechanistic understanding. Two different anticancer drugs, doxorubicin (DOX) and cisplatin (cis-diamminedichloridoplatinum, CDDP), were chosen as the toxicants due to their different modes of nephrotoxicity. Analyses of urine samples from toxicant treated and untreated rats were compared to identify biochemical analytes that changed in response to toxicant exposure. A discovery (label-free LC-MS) and targeted proteomics (multiplex LC-SRM) approach was used in combination with well established immunoassay experiments for the identification of a panel of urinary protein markers related to drug induced nephrotoxicity in rats. The initial generation of an expanded set of markers was accomplished using the label-free LC-MS discovery screen and ELISA based analysis of six nephrotoxicity biomarker proteins. Diagnostic performance of the expanded analyte set was statistically compared to conventional nephrotoxicity biomarkers. False discovery rate (FDR) analysis revealed 18 and 28 proteins from the CDDP and DOX groups, respectively, exhibiting significant differences between the vehicle and treated groups. Multiplex SRM assays were constructed to more precisely quantify candidate markers selected from the discovery screen and immunoassay experiments. To evaluate the sensitivity and specificity for each of the candidate biomarkers, histopathology severity scores were used as a benchmark for renal injury followed by receiver-operating characteristic (ROC) curve analysis on selected biomarkers. Further examination of the best performing analytes revealed relevant biological

  10. DRUG-INDUCED LIVER LESIONS AND THEIR MANAGEMENT IN THE MANIFESTATIONS OF TUBERCULOSIS

    Directory of Open Access Journals (Sweden)

    A. V. Mordyk

    2015-01-01

    Full Text Available The e`ciency of medication of remaxol for the management of liver lesions induced by anti-tuberculosis drugs was studied in 177 respiratory tuberculosis patients, divided into 3 groups: 1st group included 68 patients with no history of viral hepatitis and HIV infection; 2nd group included 52 patients with tuberculosis and HIV co-infection (patients from the 1st and 2nd groups received 10 day treatment with remaxol in case of drug-induced liver lesions and 3rd control group included 57 patients (who received adamethioninum – heptor for management of the drug-induced liver lesions. 4.4% of patients from the 1st group, 7.6% from the 2nd group and 5.3% of control group manifested the improvement of the functional liver tests by the 18-20th days of the follow-up. In case of expressed concurrent conditions (viral hepatitis, diabetes etc. and low improvement of aminotransferase level the duration of treatment of remaxol was extended up to 15 injections. Given the obtained results remaxol can be recommended for treatment of drug-induced liver lesions caused by the intake of anti-tuberculosis drugs. Tuberculosis patients with concurrent chronic alcohol addiction, HIV-infection, decompensated diabetes with low improvement of functional liver tests can be recommended to have longer treatment courses with remaxol: 15 infusions and more.

  11. 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...

  12. 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.

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

    Directory of Open Access Journals (Sweden)

    Belfort Rubens N

    2009-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Pedersen, R A; Brandriff, B

    1979-01-01

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

  15. Improvement in Hemodynamics After Methylene Blue Administration in Drug-Induced Vasodilatory Shock: A Case Report.

    Science.gov (United States)

    Laes, JoAn R; Williams, David M; Cole, Jon B

    2015-12-01

    The purpose of this study is to describe a case where methylene blue improved hemodynamics in a poisoned patient. This is a single case report where a poisoned patient developed vasodilatory shock following ingestion of atenolol, amlodipine, and valsartan. Shock persisted after multiple therapies including vasopressors, high-dose insulin, hemodialysis, and 20% intravenous fat emulsion. Methylene blue (2 mg/kg IV over 30 min) was administered in the ICU with temporal improvement as measured by pulmonary artery catheter hemodynamic data pre- and post-methylene blue administration. Within 1 h of methylene blue administration, systemic vascular resistance improved (240 dyn s/cm5 increased to 1204 dyn s/cm5), and vasopressor requirements decreased with maintenance of mean arterial pressure 60 mmHg. Methylene blue may improve hemodynamics in drug-induced vasodilatory shock and should be considered in critically ill patients poisoned with vasodilatory medications refractory to standard therapies.

  16. Drug-induced thyroiditis and papillary carcinoma in a minocycline-pigmented black thyroid gland.

    Science.gov (United States)

    Tacon, Lyndal; Tan, Charles T K; Alvarado, Raul; Gill, Anthony J; Sywak, Mark; Fulcher, Greg

    2008-07-01

    We describe a 31-year-old woman who had ingested minocycline for 18 months prior to presenting with hyperthyroidism and a palpable thyroid nodule. There was no evidence of Graves' disease or autonomous nodule on thyroid scintigraphy, and a clinical diagnosis of thyroiditis was made. Fine-needle aspiration biopsy of the palpable lesion suggested papillary carcinoma, and the patient underwent a total thyroidectomy. Intraoperatively, the thyroid gland was found to have a striking black discoloration. Subsequent histological examination revealed the accumulation of pigment globules within the apical cytoplasm of the follicular cells, and associated findings of a drug-induced thyroiditis. The tumor nodule showed features of infarction and was felt to represent a necrotic papillary microcarcinoma. We postulate that in addition to causing black thyroid pigmentation, chronic minocycline use in our patient resulted in thyroiditis and subsequent hyperthyroidism. The papillary microcarcinoma was probably a coincidental finding.

  17. 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......-acetylsalicylic acid agents, angiotensin-converting enzyme inhibitors, estrogen preparations, didanosine, valproate, codeine, antiviral agents used in acquired immunodeficiency syndrome therapy, various lipid-reducing agents, interferon, paracetamol, griseofulvin, ticlopine, allopurinol, lithium and the MMR...... (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....

  18. Recurrent optic disc and retinal vasculitis in a patient with drug-induced urticarial vasculitis.

    Science.gov (United States)

    Batioğlu, Figen; Taner, Pelin; Aydintuğ, Olcay Tiryaki; Heper, Aylin Okçu; Ozmert, Emin

    2006-01-01

    The purpose of this study was to report recurrent optic disc and retinal vasculitis in a patient with drug-induced urticarial vasculitis. Complete ophthalmological examination including fluorescein angiography and visual field examination were done. A 53-year-old woman with recurrent painful urticarial skin lesions following trimethoprim sulfamethoxazole usage had the clinical and histopathological diagnosis of urticarial vasculitis. Two years after cutaneous manifestations, she began to notice visual disturbances in both eyes that recurred at 1-year intervals. Her ophthalmological findings were consistent with recurrent vasculitis of the optic nerve and retina. Treatment with high-dose corticosteroids and hydroxychloroquine resulted in the resolution of cutaneous and ocular manifestations. This patient demonstrates that recurrent occlusive vasculitis of the optic nerve and retina can occur in this rare disease. These patients should be examined periodically by ophthalmologists.

  19. The drug-induced degradation of oncoproteins: an unexpected Achilles' heel of cancer cells?

    Science.gov (United States)

    Ablain, Julien; Nasr, Rihab; Bazarbachi, Ali; de Thé, Hugues

    2011-07-01

    Many targeted therapies against cancer are aimed at inhibiting the enzymatic activity of kinases. Thus far, this approach has undoubtedly yielded significant clinical improvements, but has only rarely achieved cures. Other drugs, which selectively elicit proteasome-dependent degradation of oncoproteins, induce the loss of cancer cell self-renewal and promote cell differentiation and/or apoptosis. In acute promyelocytic leukemia, the cooperative degradation of PML/RARA by arsenic and retinoic acid cures most patients. In this condition and others, drug-induced proteolysis of oncoproteins is feasible and underlies improved clinical outcome. Several transcription factors, nuclear receptors, or fusion proteins driving cancer growth could be candidates for proteolysis-based drug-discovery programs.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1988-05-01

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

  1. A Patient with Nafcillin-Associated Drug-Induced Liver Failure

    Directory of Open Access Journals (Sweden)

    Qin Rao

    2017-09-01

    Full Text Available Nafcillin-induced acute liver injury is a rare and potentially fatal complication that has been known since the 1960s but inadequately studied. At this time, the only proven treatment is early discontinuation of the drug. Because of the high prevalence of nafcillin class antibiotic use in the United States, it is important for clinicians to have a high clinical suspicion for this diagnosis. We present a case of liver failure attributable to nafcillin use in a 68-year-old male with a history methicillin-sensitive Staphylococcus and L3/L4 osteomyelitis. After starting long-term antibiotic therapy, he presented with painless jaundice which necessitated discontinuation of the drug. At the time of presentation, the patient’s lab work exhibited a bilirubin/direct bilirubin of 9.4/8.2 mg/dL, alkaline phosphatase of 311 IU/L, and aspartate transaminase/alanine transaminase of 109/127 IU/L. The patient was switched to i.v. vancomycin given the concern for drug-induced liver injury. Imaging did not show obstruction of the hepatobiliary or pancreaticobiliary trees. Serology was unremarkable for viral etiology, autoimmune processes, Wilson disease, and hemochromatosis. A liver biopsy showed findings consistent with drug-induced liver injury. The patient’s liver function tests peaked at day 7 of admission and trended towards normal levels with cessation of nafcillin therapy. The patient was discharged with a diagnosis of nafcillin-induced acute liver injury. Our case highlights the importance of early recognition of the diagnosis and careful monitoring of liver function when nafcillin is employed in the clinical setting.

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

    Science.gov (United States)

    Andrade, Raúl J; Robles, Mercedes; Fernández-Castañer, Alejandra; López-Ortega, Susana; López-Vega, M Carmen; Lucena, M Isabel

    2007-01-01

    Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and post-commercialization regulatory decisions. The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice. To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug’s hepatotoxic potential, the exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology. This process is time-consuming and the final result is frequently inaccurate. Diagnostic algorithms may add consistency to the diagnostic process by translating the suspicion into a quantitative score. Such scales are useful since they provide a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction as well. Current efforts in collecting bona fide cases of drug-induced hepatotoxicity will make refinements of existing scales feasible. It is now relatively easy to accommodate relevant data within the scoring system and to delete low-impact items. Efforts should also be directed toward the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be made. The instrument chosen would enable a confident diagnosis to be made on admission of the patient and treatment to be fine-tuned as further information is collected. PMID:17230599

  3. Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus: a reasoned and updated guide.

    Science.gov (United States)

    Cianfrone, G; Pentangelo, D; Cianfrone, F; Mazzei, F; Turchetta, R; Orlando, M P; Altissimi, G

    2011-06-01

    The present work on drug-induced ototoxicity, tinnitus and vertigo represents the update and revision of a previous guide to adverse drug reactions for italian physicians (2005). The panorama of drug-induced side effects causing ototoxicity or symptoms such as tinnitus or dizziness and vertigo has enlarged in recent years, thanks to a better knowledge and a more specific attention of pharmaceutical firms and drug-control institutions. In daily clinical practice, there is a need for the family physician and the ENT specialist or audiologist (also in consideration of the possible medico-legal implications) to focus the attention on the possible risk of otological side effects. This would allow a clinical risk-benefit evaluation, weighing the possible clinical advantage in their field of competence against possible otological side-effects. The list of active ingredients and drugs is subdivided in categories based on their audiological and otoneurological side-effects, that have been signaled by the drug companies and/or ministerial notes. Drugs have also been subcategorized with regards to the field in which they are applied, the therapeutic indications and the clinical behaviour. They have also been organized in alphabetical order, for an easier consultation. The guide above, even if initially conceived for being used in Italy, also presents a more general and international interest, expecially as for as the concepts of pharmacology and the features of the active ingredients are concerned. The guide is, therefore, useful as for as we are concerned to any physician, regardless of the country he/she operates in.

  4. 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.

  5. 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. PMID:24155703

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

    Science.gov (United States)

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

    2014-04-01

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

  7. Drug-induced fatal arrhythmias: Acquired long QT and Brugada syndromes.

    Science.gov (United States)

    Turker, Isik; Ai, Tomohiko; Itoh, Hideki; Horie, Minoru

    2017-08-01

    Since the early 1990s, the concept of primary "inherited" arrhythmia syndromes or ion channelopathies has evolved rapidly as a result of revolutionary progresses made in molecular genetics. Alterations in genes coding for membrane proteins such as ion channels or their associated proteins responsible for the generation of cardiac action potentials (AP) have been shown to cause specific malfunctions which eventually lead to cardiac arrhythmias. These arrhythmic disorders include congenital long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, progressive cardiac conduction disease, etc. Among these, long QT and Brugada syndromes are the most extensively studied, and drugs cause a phenocopy of these two diseases. To date, more than 10 different genes have been reported to be responsible for each syndrome. More recently, it was recognized that long QT syndrome can be latent, even in the presence of an unequivocally pathogenic mutation (silent mutation carrier). Co-existence of other pathological conditions in these silent mutation carriers may trigger a malignant form of ventricular arrhythmia, the so called torsade de pointes (TdP) that is most commonly brought about by drugs. In analogy to the drug-induced long QT syndrome, Brugada type 1 ECG can also be induced or unmasked by a wide variety of drugs and pathological conditions; so physicians may encounter patients with a latent form of Brugada syndrome. Of particular note, Brugada syndrome is frequently associated with atrial fibrillation whose therapeutic agents such as Vaughan Williams class IC drugs can unmask the dormant and asymptomatic Brugada syndrome. This review describes two types of drug-induced arrhythmias: the long QT and Brugada syndromes. Copyright © 2017. Published by Elsevier Inc.

  8. Profiles of serum cytokines in acute drug-induced liver injury and their prognostic significance.

    Directory of Open Access Journals (Sweden)

    Nury M Steuerwald

    Full Text Available Drug-induced liver injury (DILI is the most common cause of acute liver failure in the United-States. The aim of the study was to describe serum immune profiles associated with acute DILI, to investigate whether there are profiles associated with clinical features or types of DILI and/or with prognosis, and to assess temporal changes in levels. Twenty-seven immune analytes were measured in the sera of 78 DILI subjects in the Drug-Induced Liver Injury Network (DILIN and compared with 40 healthy controls. Immune analytes (14 cytokines, 7 chemokines and 6 growth factors were measured by BioPlex multiplex ELISA at DILI onset and after 6 months. A modeling process utilizing immune principles was used to select a final set of variables among 27 immune analytes and several additional clinical lab values for prediction of early death (within 6 months of DILI onset. Nineteen of the 27 immune analytes were differentially expressed among healthy control, DILI onset and 6-month cohorts. Disparate patterns of immune responses, especially innate and adaptive cellular (mostly TH17 immunity were evident. Low values of four immune analytes (IL-9, IL-17, PDGF-bb and RANTES and serum albumin are predictive of early death [PPV = 88% (95% CI, 65%-100%, NPV = 97% (95% CI, 93%-100%, accuracy = 96% (95% CI, 92%-100%].Acute DILI is associated with robust and varying immune responses. High levels of expression of cytokines associated with innate immunity are associated with a poor prognosis, whereas high levels of expression of adaptive cytokines are associated with good long-term prognosis and eventual recovery. Serum immune analyte profiles at DILI onset appear to be of prognostic, and perhaps, diagnostic significance.

  9. Structurally abnormal human autosomes

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1993-12-31

    Chapter 25, discusses structurally abnormal human autosomes. This discussion includes: structurally abnormal chromosomes, chromosomal polymorphisms, pericentric inversions, paracentric inversions, deletions or partial monosomies, cri du chat (cat cry) syndrome, ring chromosomes, insertions, duplication or pure partial trisomy and mosaicism. 71 refs., 8 figs.

  10. 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...... 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....

  11. 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.

  12. Two drug-induced dermatological syndromes among employees of a Polish construction site in a tropical country.

    Science.gov (United States)

    Jaremin, B

    1987-01-01

    The two rare cases of exudative multiform erythema were described in its heavier alterations of Fiessinger-Rendu-Leroy as well as of Stevens-Johnson syndrome, most likely of drug-induced origin, at the employees of a Polish construction site in a tropical country, taking under consideration the causing reasons, diagnostic features as well as conditions of course and principles of treatment.

  13. 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

  14. 76 FR 4918 - Drug-Induced Liver Injury: Are We Ready to Look?; Public Conference; Request for Comments

    Science.gov (United States)

    2011-01-27

    ... Research Manufacturers of America to discuss and debate issues regarding drug-induced liver injury (DILI... to http://www.regulations.gov . Submit written comments to the Division of Dockets Management (HFA... of both basic science and clinical experts, and selecting for specific debate and discussion issues...

  15. Clinical features and {sup 123}I-FP-CIT SPECT imaging in drug-induced parkinsonism and Parkinson's disease

    Energy Technology Data Exchange (ETDEWEB)

    Diaz-Corrales, Francisco J.; Escobar-Delgado, Teresa [Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Unidad de Trastornos del Movimiento, Servicio de Neurologia, Instituto de Biomedicina de Sevilla, Seville (Spain); Sanz-Viedma, Salome [Hospital Universitario Virgen del Rocio, Unidad Diagnostica de Medicina Nuclear, Seville (Spain); Garcia-Solis, David [Hospital Universitario Virgen del Rocio, Unidad Diagnostica de Medicina Nuclear, Seville (Spain); Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Seville (Spain); Mir, Pablo [Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Unidad de Trastornos del Movimiento, Servicio de Neurologia, Instituto de Biomedicina de Sevilla, Seville (Spain); Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Seville (Spain); Hospital Universitario Virgen del Rocio, Unidad de Trastornos del Movimiento. Servicio de Neurologia, Seville (Spain)

    2010-03-15

    To determine clinical predictors and accuracy of {sup 123}I-FP-CIT SPECT imaging in the differentiation of drug-induced parkinsonism (DIP) and Parkinson's disease (PD). Several clinical features and {sup 123}I-FP-CIT SPECT images in 32 patients with DIP, 25 patients with PD unmasked by antidopaminergic drugs (PDu) and 22 patients with PD without a previous history of antidopaminergic treatment (PDc) were retrospectively evaluated. DIP and PD shared all clinical features except symmetry of parkinsonian signs which was more frequently observed in patients with DIP (46.9%) than in patients with PDu (16.0%, p<0.05) or PDc (4.5%, p<0.01). Qualitatively {sup 123}I-FP-CIT SPECT images were normal in 29 patients with DIP (90.6%) and abnormal in all patients with PD, and this imaging technique showed high levels of accuracy. DIP and PD are difficult to differentiate based on clinical signs. The precision of clinical diagnosis could be reliably enhanced by {sup 123}I-FP-CIT SPECT imaging. (orig.)

  16. Chromosomal Abnormalities in ADHD

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2002-07-01

    Full Text Available The prevalence of fragile X syndrome, velocardiofacial syndrome (VCFS, and other cytogenetic abnormalities among 100 children (64 boys with combined type ADHD and normal intelligence was assessed at the NIMH and Georgetown University Medical Center.

  17. Chromosomal abnormalities and autism

    Directory of Open Access Journals (Sweden)

    Farida El-Baz

    2016-01-01

    Conclusion: Chromosomal abnormalities were not detected in the studied autistic children, and so the relation between the genetics and autism still needs further work up with different study methods and techniques.

  18. Liver Function Test Abnormalities in Patients with Inflammatory Bowel Diseases: A Hospital-based Survey

    Directory of Open Access Journals (Sweden)

    Maria Cappello

    2014-07-01

    Full Text Available Background and Aims Inflammatory bowel diseases (IBD are frequently associated with altered liver function tests (LFTs. The causal relationship between abnormal LFTs and IBD is unclear. The aim of our study was to evaluate the prevalence and etiology of LFTs abnormalities and their association with clinical variables in a cohort of IBD patients followed up in a single center. Materials and Methods A retrospective review was undertaken of all consecutive IBD in- and outpatients routinely followed up at a single referral center. Clinical and demographic parameters were recorded. Subjects were excluded if they had a previous diagnosis of chronic liver disease. LFT abnormality was defined as an increase in aspartate aminotransferase, (AST, alanine aminotransferase (ALT, alkaline phosphatase (ALP, gamma-glutamyl transpeptidase (GGT, or total bilirubin. Results A cohort of 335 patients (179 males, mean age 46.0 ± 15.6 years was analyzed. Abnormal LFTs were detected in 70 patients (20.9%. In most cases, the alterations were mild and spontaneously returned to normal values in about 60% of patients. Patients with abnormal LFTs were less frequently on treatment with aminosalicylates (22.8 vs. 36.6%, P = 0.04. The most frequent cause for transient abnormal LFTs was drug-induced cholestasis (34.1%, whereas fatty liver was the most frequent cause of persistent liver damage (65.4%. A cholestatic pattern was found in 60.0% of patients and was mainly related to older age, longer duration of disease, and hypertension. Conclusions The prevalence of LFT abnormalities is relatively high in IBD patients, but the development of severe liver injury is exceptional. Moreover, most alterations of LFTs are mild and spontaneously return to normal values. Drug-induced hepatotoxicity and fatty liver are the most relevant causes of abnormal LFTs in patients with IBD.

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

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    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

  20. 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.

  1. Ginger for prevention or treatment of drug-induced nausea and vomiting.

    Science.gov (United States)

    Dabaghzadeh, Fatemeh; Khalili, Hossein; Dashti-Khavidaki, Simin

    2014-01-01

    In this review, potential benefits of oral ginger for prevention or management of drug- induced nausea and vomiting were evaluated based on the available evidences. By searching medical resources including Scopus, PubMed, Medline, Cochrane central register of controlled trials and Cochrane database systematic reviews, available evidences were collected. Ginger, zingiber, nausea and vomiting were considered as keywords. Various studies have evaluated effects of ginger in prevention and management of nausea and vomiting in different conditions such as pregnancy, chemotherapy, and post-operation. Evidences regarding anti-emetic effect of ginger in prevention and treatment of chemotherapy induced nausea and vomiting are limited and results are conflicting. More randomized clinical trials should be conducted to confirm efficacy of ginger in this regards. Ginger showed promising and attractive effects in preventing post-operative nausea and vomiting at least as add-on therapy. The exact role of ginger as anti-emetic in prevention of post- operative nausea and vomiting can be elucidated by future randomized clinical trials.

  2. GRPR antagonist protects from drug-induced liver injury by impairing neutrophil chemotaxis and motility.

    Science.gov (United States)

    Czepielewski, Rafael S; Jaeger, Natália; Marques, Pedro E; Antunes, Maísa M; Rigo, Maurício M; Alvarenga, Débora M; Pereira, Rafaela V; da Silva, Rodrigo D; Lopes, Tiago G; da Silva, Vinícius D; Porto, Bárbara N; Menezes, Gustavo B; Bonorino, Cristina

    2017-04-01

    Drug-induced liver injury (DILI) is a major cause of acute liver failure (ALF), where hepatocyte necrotic products trigger liver inflammation, release of CXC chemokine receptor 2 (CXCR2) ligands (IL-8) and other neutrophil chemotactic molecules. Liver infiltration by neutrophils is a major cause of the life-threatening tissue damage that ensues. A GRPR (gastrin-releasing peptide receptor) antagonist impairs IL-8-induced neutrophil chemotaxis in vitro. We investigated its potential to reduce acetaminophen-induced ALF, neutrophil migration, and mechanisms underlying this phenomenon. We found that acetaminophen-overdosed mice treated with GRPR antagonist had reduced DILI and neutrophil infiltration in the liver. Intravital imaging and cell tracking analysis revealed reduced neutrophil mobility within the liver. Surprisingly, GRPR antagonist inhibited CXCL2-induced migration in vivo, decreasing neutrophil activation through CD11b and CD62L modulation. Additionally, this compound decreased CXCL8-driven neutrophil chemotaxis in vitro independently of CXCR2 internalization, induced activation of MAPKs (p38 and ERK1/2) and downregulation of neutrophil adhesion molecules CD11b and CD66b. In silico analysis revealed direct binding of GRPR antagonist and CXCL8 to the same binding spot in CXCR2. These findings indicate a new potential use for GRPR antagonist for treatment of DILI through a mechanism involving adhesion molecule modulation and possible direct binding to CXCR2. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Outcome from molecular adsorbent recycling system (MARS) liver dialysis following drug-induced liver failure.

    Science.gov (United States)

    Lee, Kang-Hoe; Lee, Margaret Kwee-Hiang; Sutedja, Dede Selamat; Lim, Seng-Gee

    2005-10-01

    Fulminant liver failure from drug ingestion is associated with a high mortality, and the introduction of liver transplantation has improved the mortality significantly if done in a timely fashion. Recently, molecular adsorbent recycling system (MARS) liver dialysis has been introduced as a support for liver failure with varying results. We review our experience with drug-induced liver failure and the impact of MARS liver dialysis on the outcome, in a setting where cadaveric liver transplantation is rarely available. A total of 13 patients were treated, and 40 sessions of MARS liver dialysis were conducted in the intensive care unit. The majority of cases were because of herbal medicine toxicity. Total bilirubin, conjugated bilirubin, and delta bilirubin were significantly reduced, with no change in unconjugated bilirubin. All patients satisfied the criteria for urgent liver transplantation with an average Model End Stage Liver Disease (MELD) score of 35. Only one patient received a liver transplantation from a live donor (right lobe). Overall mortality was 85%. Median time-to-death from the start of MARS was 8 days. MARS liver dialysis in a setting without timely liver transplantation is associated with a poor outcome. It does, however, provide a window of time for consideration of living donors in the setting of limited cadaveric donors.

  4. Metabolomic approaches in the discovery of potential urinary biomarkers of drug-induced liver injury (DILI).

    Science.gov (United States)

    Araújo, Ana Margarida; Carvalho, Márcia; Carvalho, Félix; Bastos, Maria de Lourdes; Guedes de Pinho, Paula

    2017-09-01

    Drug-induced liver injury (DILI) is a major safety issue during drug development, as well as the most common cause for the withdrawal of drugs from the pharmaceutical market. The identification of DILI biomarkers is a labor-intensive area. Conventional biomarkers are not specific and often only appear at significant levels when liver damage is substantial. Therefore, new biomarkers for early identification of hepatotoxicity during the drug discovery process are needed, thus resulting in lower development costs and safer drugs. In this sense, metabolomics has been increasingly playing an important role in the discovery of biomarkers of liver damage, although the characterization of the mechanisms of toxicity induced by xenobiotics remains a huge challenge. These new-generation biomarkers will offer obvious benefits for the pharmaceutical industry, regulatory agencies, as well as a personalized clinical follow-up of patients, upon validation and translation into clinical practice or approval for routine use. This review describes the current status of the metabolomics applied to the early diagnosis and prognosis of DILI and in the discovery of new potential urinary biomarkers of liver injury.

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

    Directory of Open Access Journals (Sweden)

    Joseph J Babcock

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

  6. 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.

  7. Disease-related and drug-induced skin manifestations in inflammatory bowel disease.

    Science.gov (United States)

    Hindryckx, Pieter; Novak, Gregor; Costanzo, Antonio; Danese, Silvio

    2017-03-01

    Skin manifestations are common in patients with inflammatory bowel diseases (IBD) and can be part of a concomitant illness with a shared genetic background, an extra-intestinal manifestation of the disease, or a drug side-effect. Areas covered: We provide a practical overview of the epidemiology, pathogenesis, diagnosis, therapeutic approach and prognosis of the most frequent disease-related and drug-induced cutaneous manifestations in IBD, illustrated by cases encountered in our clinical practice. Among the most frequently encountered IBD-related lesions are erythema nodosum, pyoderma gangrenosum and Sweet's syndrome. Common skin manifestations with a strong association to TNF antagonists are local injection site reactions, psoriasiform lesions, cutaneous infections, vasculitides and lupus-like syndromes. In addition, we discuss the relation of thiopurines and TNF antagonists with the risk of skin cancer. Expert commentary: We hope this review will help caretakers involved in the management of IBD patients to recognize the lesions and to manage them in close collaboration with a dedicated dermatologist.

  8. [Drug-induced sedation endoscopy-quo vadis? : Review and outlook].

    Science.gov (United States)

    Herzog, M; Maurer, J T

    2017-02-01

    Drug-induced sedation endoscopy (DISE) is a diagnostic procedure which allows evaluation of the collapsibility of the upper airway. According to expert opinion, it is possible to imitate nocturnal collapsibility and perform a realistic investigation of the site of obstruction and vibration. This should enable sufficient and precise therapeutic advice to be given solely on the basis of clinical assessment. The current publication critically evaluates the present state of development of DISE and its potential indications. A PubMed literature research was performed using "sleep" and "endoscopy" or "DISE" as keywords. Relevant publications were evaluated. The present publication provides a historical summary of the available publications and relates these to other methods for examining obstructive sleep apnea. The present state of DISE in terms of drugs applied, grading systems, and validity is evaluated. Indications for DISE are described and critically discussed on the basis of literature data. DISE provides deep insights into the genesis of obstructions of the upper airway and snoring. Although its value for diagnosis and treatment of sleep-disordered breathing could not yet be demonstrated for all non-CPAP (continuous positive airway pressure) therapies, DISE could identify predictive parameters some methods. Further potential indications for DISE might be predictive examinations for mandibular advancement devices and respiration-synchronous neurostimulation of the hypoglossal nerve. DISE will thus remain a valuable diagnostic tool for obstructive sleep apnea and rhonchopathy.

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

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    Renumathy Dhanasekaran

    2013-01-01

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

  10. Establishing a comprehensive questionnaire for detecting drug-induced extrapyramidal symptoms.

    Science.gov (United States)

    Ohno, Keiko; Miyazawa, Shinsuke; Hashiguchi, Masayuki; Unemoto, Tamao; Itoh, Atsuo; Echizen, Hirotoshi; Rikihisa, Tadaaki; Ogata, Hiroyasu; Murata, Masahiro

    2003-10-01

    Drug-induced extrapyramidal symptoms (DIEPS) often substantially compromise quality of life (QOL) of patients receiving drugs with central antidopaminergic activities. A lack of comprehensive screening method based upon patients' subjective symptoms for detecting DIEPS appears to have prevented pharmacists from delivering satisfactory pharmaceutical care for these patients. Thus, we have attempted to develop a comprehensive questionnaire for screening patients having higher risks of developing DIEPS. One hundred fourteen outpatients taking gastroprokinetic drugs (itopride, cisapride, trimebutine, domperidone and metoclopramide) at least 2 weeks participated in the study. One patient with familial Parkinson disease served as a positive reference. They undertook a questionnaire consisting of 9 comprehensive questions written in non-technical words that were aimed to detect typical symptoms of Parkinsonism including akathisia and dyskinesia. Each symptom was scored in a semiquantitative scale [i.e., from 1 (not at all) to 5 (very much)] by the patients. Of the 108 subjects who successfully completed the questionnaires, 43 gave scores 2 or greater indicating the presence of DIEPS. However, no statistically significant correlations were observed between the scores of any possible pairs of the questionnaire items. Five subjects had a mean questionnaire score of equal to or greater than 1.6, and the patient with familiar Parkinsonism had the highest mean score of 1.9. The questionnaire presented herein detected 4 patients with suspected DIEPS. Further studies should be warranted to assess whether it would be useful for pharmacists as a screening tool for DIEPS in patients having higher risks of DIEPS.

  11. Development of novel tools for the in vitro investigation of drug-induced liver injury.

    Science.gov (United States)

    Jiang, Jian; Wolters, Jarno E J; van Breda, Simone G; Kleinjans, Jos C; de Kok, Theo M

    2015-01-01

    Due to its complex mechanisms and unpredictable occurrence, drug-induced liver injury (DILI) complicates drug identification and classification. Since species-specific differences in metabolism and pharmacokinetics exist, data obtained from animal studies may not be sufficient to predict DILI in humans. Over the last few decades, numerous in vitro models have been developed to replace animal testing. The advantages and disadvantages of commonly used liver-derived in vitro models (e.g., cell lines, hepatocyte models, liver slices, three-dimensional (3D) hepatospheres, etc.) are discussed. Toxicogenomics-based methodologies (genomics, epigenomics, transcriptomics, proteomics and metabolomics) and next-generation sequencing have also been used to enhance the reliability of DILI prediction. This review presents an overview of the currently used alternative toxicological models and of the most advanced approaches in the field of DILI research. It seems unlikely that a single in vitro system will be able to mimic the complex interactions in the human liver. Three-dimensional multicellular systems may bridge the gap between conventional 2D models and in vivo clinical studies in humans and provide a reliable basis for hepatic toxicity assay development. Next-generation sequencing technologies, in comparison to microarray-based technologies, may overcome the current limitations and are promising for the development of predictive models in the near future.

  12. Drug-induced blood pressure increase - recommendations for assessment in clinical and non-clinical studies.

    Science.gov (United States)

    Gottfridsson, Christer; Panfilov, Seva; Ebrahimi, Ahmad; Gigger, Emery; Pollard, Chris; Henderson, Simon; Ambery, Philip; Raichlen, Joel S

    2017-02-01

    Changes in blood pressure (BP) are now proactively examined throughout the drug development process as an integral aspect of safety monitoring. This is because hypertension is a very strong risk factor for cardiovascular events and drug-induced increases in BP have attracted increased regulatory attention. However, there is currently no guidance from regulatory agencies on the minimum BP data required for submissions, and there are no specific criteria for what constitutes a safety signal for increased BP in non clinical studies. Areas covered: Evaluation of BP increases through the drug discovery and development process. Expert opinion: Research into the effects of drugs should begin before clinical development is initiated and continue throughout the clinical trial program. Non clinical studies should inform a benefit-risk analysis that will aid decision-making of whether to enter the drug into Phase I development. The degree of acceptable risk will vary according to the therapy area, treatment indication and intended population for the new drug, and the approach to BP assessment and risk mitigation should be tailored accordingly. However, BP monitoring should always be included in clinical trials, and data collected from multiple studies, to convincingly prove or refute a suspicion of BP effects.

  13. 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.

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

    Science.gov (United States)

    Vijayakumar, Dhanya; Jankovic, Joseph

    2016-05-01

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

  15. Drug induced liver injury: do we still need a routine liver biopsy for diagnosis today?

    Science.gov (United States)

    Teschke, Rolf; Frenzel, Christian

    For the pathologist, the diagnosis of drug induced liver injury (DILI) is challenging, because histopathological features mimic all primary hepatic and biliary diseases, lacking changes that are specific for DILI. Therefore, in any patient of suspected DILI who underwent liver biopsy, the pathologist will assure the clinician that the observed hepatic changes are compatible with DILI, but this information is less helpful due to lack of specificity. Rather, the pathologist should assess liver biopsies blindly, without knowledge of prior treatment by drugs. This will result in a detailed description of the histological findings, associated with suggestions for potential causes of these hepatic changes. Then, it is up to the physician to reassess carefully the differential diagnoses, if not done before. At present, liver histology is of little impact establishing the diagnosis of DILI with the required degree of certainty, and this shortcoming also applies to herb induced liver injury (HILI). To reach at the correct diagnoses of DILI and HILI, clinical and structured causality assessments are therefore better approaches than liver histology results obtained through liver biopsy, an invasive procedure with a low complication rate.

  16. 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.

  17. Predicting drug-induced liver injury: The importance of data curation.

    Science.gov (United States)

    Kotsampasakou, Eleni; Montanari, Floriane; Ecker, Gerhard F

    2017-08-15

    Drug-induced liver injury (DILI) is a major issue for both patients and pharmaceutical industry due to insufficient means of prevention/prediction. In the current work we present a 2-class classification model for DILI, generated with Random Forest and 2D molecular descriptors on a dataset of 966 compounds. In addition, predicted transporter inhibition profiles were also included into the models. The initially compiled dataset of 1773 compounds was reduced via a 2-step approach to 966 compounds, resulting in a significant increase (p-value<0.05) in model performance. The models have been validated via 10-fold cross-validation and against three external test sets of 921, 341 and 96 compounds, respectively. The final model showed an accuracy of 64% (AUC 68%) for 10-fold cross-validation (average of 50 iterations) and comparable values for two test sets (AUC 59%, 71% and 66%, respectively). In the study we also examined whether the predictions of our in-house transporter inhibition models for BSEP, BCRP, P-glycoprotein, and OATP1B1 and 1B3 contributed in improvement of the DILI mode. Finally, the model was implemented with open-source 2D RDKit descriptors in order to be provided to the community as a Python script. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2015-01-01

    Hospitalized patients require the use of a variety of drugs, many of which individually or in combination have the potential to cause kidney damage. The use of potentially nephrotoxic drugs is often unavoidable, and the need for dose adjustment should be evaluated. This study is aimed at assessing concordance in information on drug-induced nephrotoxicity and dose adjustment recommendations by comparing four drug information sources (DRUGDEX®, UpToDate®, Medscape® and the Brazilian Therapeutic Formulary) using the formulary of a Brazilian public hospital. A total of 218 drugs were investigated. The global Fleiss’ kappa coefficient was 0.265 for nephrotoxicity (p < 0.001; CI 95%, 0.211–0.319) and 0.346 for recommendations (p < 0.001; CI 95%, 0.292–0.401), indicating fair concordance among the sources. Anti-infectives and anti-hypertensives were the main drugs cited as nephrotoxic by the different sources. There were no clear definitions for qualitative data or quantitative values for dose adjustments among the four information sources. There was no advice for dosing for a large number of the drugs in the international databases. The National Therapeutic Formulary offered imprecise dose adjustment recommendations for many nephrotoxic drugs. Discrepancies among information sources may have a clinical impact on patient care and contribute to drug-related morbidity and mortality. PMID:26371029

  19. Toxicogenomics of drug-induced hemolytic anemia by analyzing gene expression profiles in the spleen.

    Science.gov (United States)

    Rokushima, Masatomo; Omi, Kazuo; Imura, Kae; Araki, Akiko; Furukawa, Naoko; Itoh, Fumio; Miyazaki, Masako; Yamamoto, Junko; Rokushima, Makiko; Okada, Manabu; Torii, Mikinori; Kato, Ikuo; Ishizaki, Jun

    2007-11-01

    Hemolytic anemia is a serious adverse effect of therapeutic drugs that is caused by increased destruction of drug-damaged erythrocytes by macrophages in the spleen and liver. We previously applied a toxicogenomic approach to the toxicity by analyzing microarray data of the liver of rats dosed with two hemolytic agents: phenylhydrazine and phenacetin. In the present study, we analyzed gene expression profiles in the spleen, the primary organ for destruction of damaged erythrocytes, of the same models in order to identify splenic gene expression alterations that could be used to predict the hematotoxicity. Microarray analyses revealed hundreds of genes commonly deregulated under all severe hemolytic conditions, which included genes related to splenic events characteristic of the hematotoxicity, such as proteolysis and iron metabolism. Eleven upregulated genes were selected as biomarker candidates, and their expression changes were validated by quantitative real-time PCR. The transcript levels of most of these genes showed strong correlation with the results of classical toxicological assays (e.g., histopathology and hematology). Furthermore, hierarchical clustering analysis suggested that altered expression patterns of the 11 genes sensitively reflected the erythrocyte damage even under a condition that caused no decrease in erythrocyte counts. Among the selected genes, heme oxygenase 1 was one of the most promising biomarker candidates, the upregulation of which on the protein level was confirmed by immunohistochemistry. These results indicate that altered splenic expression of a subset of genes may allow detection of drug-induced hemolytic anemia, with better sensitivity than that of erythrocyte counts in the blood.

  20. [Clinical Analysis of Drug-induced Liver Injury Caused by Polygonum multiflorum and its Preparations].

    Science.gov (United States)

    Zhu, Yun; Liu, Shu-hong; Wang, Jia-bo; Song, Hai-bo; Li, Yong-gang; He, Ting-ting; Ma, Xiao; Wang, Zhong-xia; Wang-Li-ping; Zhou, Kun; Bai, Yun-feng; Zou, Zheng-sheng; Xiao, Xiao-he

    2015-12-01

    To analyze hepatotoxicity of Polygonum multiflorum and clinical character- istics of drug-induced liver injury (DILI) caused by Polygonum multiflorum and its preparations. A retrospective study was performed in 158 patients treated at 302 Military Hospital between January 2009 and January 2014. All of them had used Polygonum multiflorum and its preparations before the onset of DILI, and their clinical characteristics and prognoses were analyzed. Of the 158 DILI patients who used Polygonum multiflorum or its preparations, 92 (58.2%) combined with Western medicine or Chinese herbal preparations without Polygonum multiflorum; 66 patients (41.8%) used Polygonum mult florum and its preparations alone. In 66 DILI patients induced by Polygonum multiflorum or its preparations alone, 51 cases (77.3%) were induced by Polygonum multiflorum compounds and 22.7% by single Po- lygonum multiflorum; 4 cases (6.1%) were caused by crude Polygonum multiflorum and 62 (93.9%) by processed Polygonum multiflorum and its preparations. Clinical injury patterns were hepatocellular 92.4% (61 cases), cholestatic 1.5% (1 case), and mixed 6.1% (4 cases). Pathological examination was per- formed by liver biopsy in 32 cases (48.15%), manifested as hepatocellular degeneration and necrosis, fibroplasia, Kupffer cells with pigment granule, and a large number of eosinophil infiltration, were ob- served. Four patients were developed into liver failure, 4 into cirrhosis, and 1 died. Polygo- num multiflorum and its preparations could induce DILI, but clinical diagnosis of Polygonum multiflorum induced hepatotoxicity should be cautious.

  1. Preoperative Drug Induced Sleep Endoscopy Improves the Surgical Approach to Treatment of Obstructive Sleep Apnea.

    Science.gov (United States)

    Huntley, Colin; Chou, David; Doghramji, Karl; Boon, Maurits

    2017-06-01

    Drug induced sleep endoscopy (DISE) allows for preoperative evaluation of the specific site and character of upper airway obstruction in obstructive sleep apnea (OSA). We aim to assess the impact DISE has on customizing the surgical plan and evaluate its role in surgical success. We retrospectively reviewed patients undergoing surgery for OSA. We compared those patients undergoing preoperative DISE to those that did not to assess procedures performed and surgical outcomes. We found 87 patients undergoing surgery for OSA who had postoperative polysomnogram results. Of the group undergoing preoperative DISE, 8% had multilevel surgery. This compared to 59.5% in those not undergoing DISE ( p = .0004). The success rate of patients who had preoperative DISE was 86% compared to 51.4% in those who did not have preoperative DISE ( p BMI) and postoperative oxygen nadir, ESS, or BMI in the DISE and no DISE cohorts. The addition of DISE to our preoperative workup has contributed to a decreased rate of multilevel surgery and increased rate of surgical success through identification of the individual patient's OSA architecture and customization of the surgical plan.

  2. 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

  3. 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.

  4. The value of penile duplex in the prediction of intracavernous drug-induced priapism.

    Science.gov (United States)

    Shamloul, R; Ghanem, H M; Salem, A; Kamel, I I; Mousa, A A

    2004-02-01

    The aim of this work is to assess the value of penile duplex in the prediction of intracavernous drug-induced ischemic priapism. A total of 400 patients with erectile dysfunction were evaluated before and after diagnostic intracavernous injection of a trimix solution (papaverine+phentolamine+PGE1) using color Doppler sonography. In all, 29 patients experienced sustained rigid erections for more than an hour. Patients were further divided into two groups. Group A included patients with spontaneous resolution of their rigid erection within 3 h (10/29) and group B included patients with priapism (19/29) that did not resolve within 3 h. In group A, patients had minimal cavernous artery blood flow within the first hour postinjection, that increased with relief of their erection. Group B patients had no blood flow in their cavernous artery an hour after intracavernous injection and for 6 h later. The disappearance of blood flow in the cavernous artery after an hour of sustained rigid erection predicted priapism with 100% specificity and sensitivity. The persistent absence of cavernous artery blood flow for more than an hour, as detected by color Doppler ultrasound, is an objective predictor of priapism. This may guide early intervention to resolve the prolonged erection.

  5. Evaluation of hepatoprotective potential of Erythrina indica leaves against antitubercular drugs induced hepatotoxicity in experimental rats.

    Science.gov (United States)

    Mujahid, Mohd; Hussain, Talib; Siddiqui, Hefazat Hussain; Hussain, Arshad

    Erythrina indica Lam. traditionally used in the treatment of laxative, diuretic, worm infestation, liver ailment and joints pain. To evaluate the antihepatotoxic potential of Erythrina indica against isoniazid (INH) and rifampicin (RIF) induced hepatotoxicity in rats. Liver toxicity was induced by antitubercular drugs (INH+ RIF) at dose level of 50 mg/kg each, p.o for 28 days. 50% methanolic extract of Erythrina indica (100 and 200 mg/kg) were administered orally once daily for 28 days. The hepatoprotective activity was assessed using various biochemical parameters SGOT, SGPT, ALP, bilirubin, total protein, albumin and LDH. Meanwhile, in vivo antioxidant activities as SOD, CAT, GSH and, LPO were measured in liver homogenate also histological examinations were carried out to assess hepatoprotective activity. The values were subjected to one way analysis of variance (ANOVA) followed by Tukey multiple compare test. Results were considered statistically significant when P indica (E. indica) significantly prevented drug induced increase in serum levels of hepatic enzymes. Furthermore, Erythrina indica significantly reduced the lipid peroxidation (P indica attenuated the hepatocellular necrosis, regeneration and repair of cells toward normal. The results of this study strongly indicate the protective effect of Erythrina indica against liver injury which may be attributed to its hepatoprotective activity, and there by scientifically support its traditional use. Copyright © 2016 Transdisciplinary University, Bangalore and World Ayurveda Foundation. Published by Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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.

  7. 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 titration level (P 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.

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

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    Nasser M

    2013-09-01

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

  9. Mechanisms of cell death pathway activation following drug-induced inhibition of mitochondrial complex I.

    Science.gov (United States)

    Imaizumi, Naoki; Kwang Lee, Kang; Zhang, Carmen; Boelsterli, Urs A

    2015-01-01

    Respiratory complex I inhibition by drugs and other chemicals has been implicated as a frequent mode of mitochondria-mediated cell injury. However, the exact mechanisms leading to the activation of cell death pathways are incompletely understood. This study was designed to explore the relative contributions to cell injury of three distinct consequences of complex I inhibition, i.e., impairment of ATP biosynthesis, increased formation of superoxide and, hence, peroxynitrite, and inhibition of the mitochondrial protein deacetylase, Sirt3, due to imbalance of the NADH/NAD(+) ratio. We used the antiviral drug efavirenz (EFV) to model drug-induced complex I inhibition. Exposure of cultured mouse hepatocytes to EFV resulted in a rapid onset of cell injury, featuring a no-effect level at 30µM EFV and submaximal effects at 50µM EFV. EFV caused a concentration-dependent decrease in cellular ATP levels. Furthermore, EFV resulted in increased formation of peroxynitrite and oxidation of mitochondrial protein thiols, including cyclophilin D (CypD). This was prevented by the superoxide scavenger, Fe-TCP, or the peroxynitrite decomposition catalyst, Fe-TMPyP. Both ferroporphyrins completely protected from EFV-induced cell injury, suggesting that peroxynitrite contributed to the cell injury. Finally, EFV increased the NADH/NAD(+) ratio, inhibited Sirt3 activity, and led to hyperacetylated lysine residues, including those in CypD. However, hepatocytes isolated from Sirt3-null mice were protected against 40µM EFV as compared to their wild-type controls. In conclusion, these data are compatible with the concept that chemical inhibition of complex I activates multiple pathways leading to cell injury; among these, peroxynitrite formation may be the most critical. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  10. Mechanisms of cell death pathway activation following drug-induced inhibition of mitochondrial complex I

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    Naoki Imaizumi

    2015-04-01

    Full Text Available Respiratory complex I inhibition by drugs and other chemicals has been implicated as a frequent mode of mitochondria-mediated cell injury. However, the exact mechanisms leading to the activation of cell death pathways are incompletely understood. This study was designed to explore the relative contributions to cell injury of three distinct consequences of complex I inhibition, i.e., impairment of ATP biosynthesis, increased formation of superoxide and, hence, peroxynitrite, and inhibition of the mitochondrial protein deacetylase, Sirt3, due to imbalance of the NADH/NAD+ ratio. We used the antiviral drug efavirenz (EFV to model drug-induced complex I inhibition. Exposure of cultured mouse hepatocytes to EFV resulted in a rapid onset of cell injury, featuring a no-effect level at 30 µM EFV and submaximal effects at 50 µM EFV. EFV caused a concentration-dependent decrease in cellular ATP levels. Furthermore, EFV resulted in increased formation of peroxynitrite and oxidation of mitochondrial protein thiols, including cyclophilin D (CypD. This was prevented by the superoxide scavenger, Fe-TCP, or the peroxynitrite decomposition catalyst, Fe-TMPyP. Both ferroporphyrins completely protected from EFV-induced cell injury, suggesting that peroxynitrite contributed to the cell injury. Finally, EFV increased the NADH/NAD+ ratio, inhibited Sirt3 activity, and led to hyperacetylated lysine residues, including those in CypD. However, hepatocytes isolated from Sirt3-null mice were protected against 40 µM EFV as compared to their wild-type controls. In conclusion, these data are compatible with the concept that chemical inhibition of complex I activates multiple pathways leading to cell injury; among these, peroxynitrite formation may be the most critical.

  11. Approach to the Diagnosis and Management of Drug-Induced Immune Thrombocytopenia

    Science.gov (United States)

    Arnold, Donald M.; Nazi, Ishac; Warkentin, Theodore E.; Smith, James W.; Toltl, Lisa J.; George, James N.; Kelton, John G.

    2013-01-01

    Drug-induced immune thrombocytopenia (DITP) is a challenging clinical problem that is under-recognized, difficult to diagnose and associated with severe bleeding complications. DITP may be caused by classic drug-dependent platelet antibodies (eg, quinine); haptens (eg, penicillin); fiban-dependent antibodies (eg, tirofiban); monoclonal antibodies (eg, abciximab); autoantibody formation (eg, gold); and immune complex formation (eg, heparin). A thorough clinical history is essential in establishing the diagnosis of DITP and should include exposures to prescription medications, herbal preparations and even certain foods and beverages. Clinical and laboratory criteria have been established to determine the likelihood of a drug being the cause of thrombocytopenia, but these criteria can only be applied retrospectively. The most commonly implicated drugs include quinine, quinidine, trimethoprim/sulfamethoxazole and vancomycin. We propose a practical approach to the diagnosis of the patient with suspected DITP. Key features are: the presence of severe thrombocytopenia (platelet nadir <20 × 109/L); bleeding complications; onset 5 to 10 days after first drug exposure, or within hours of subsequent exposures or after first exposure to fibans or abciximab; and exposure to drugs that have been previously implicated in DITP reactions. Treatment involves stopping the drug(s), administering platelet transfusions or other therapies if bleeding is present and counselling on future drug avoidance. The diagnosis can be confirmed by a positive drug re-challenge, which is often impractical, or by demonstrating drug-dependent platelet reactive antibodies in vitro. Current test methods, which are mostly flow cytometry-based, must show drug-dependence, immunoglobulin binding, platelet specificity and ideally should be reproducible across laboratories. Improved standardization and accessibility of laboratory testing should be a focus of future research. PMID:23845922

  12. Drug-induced panic attacks: Analysis of cases registered in the French pharmacovigilance database.

    Science.gov (United States)

    Abadie, Delphine; Essilini, Anaïs; Fulda, Virginie; Gouraud, Aurore; Yéléhé-Okouma, Mélissa; Micallef, Joëlle; Montastruc, François; Montastruc, Jean Louis

    2017-07-01

    The potential role of drugs in the onset of panic attacks (PAs) is poorly understood. The objective of our study was to characterize drug-induced PAs. We performed an analysis of PAs registered in the French pharmacovigilance database between 01/01/1985 and 05/11/2014. Among the 163 recorded cases, 136 (83.4%) were directly related to drugs, mainly antidepressants (11.3%, mainly serotonin reuptake inhibitors), mefloquine (7.2%), isotretinoin (5.2%), rimonabant (3.6%) and corticosteroids (4.7%). PAs are labelled in the Summary of Product Characteristics (SmPC) for a minority (8.6%) of these drugs. In 31.4% of these cases, withdrawal of the suspected drug was performed more than a week after the onset of PAs. PAs could also be secondary to another adverse drug reaction (ADR; n = 14, 8.6%), mainly an allergy to antineoplastic or immunomodulating agents. In 13 cases (8.0%), PAs occurred during a drug-withdrawal syndrome, mainly after benzodiazepines or opioids. Most cases (73%) involved patients without any previous psychiatric disorder. This is the first pharmacoepidemiological study about iatrogenic PAs. Beside antidepressants, the most often encountered drugs are not indicated for psychiatric diseases. This study also reveals that iatrogenic PAs mostly occur in patients without any psychiatric medical history and that PAs can be triggered by another ADR. Lastly, the many cases with delayed management underline the need to raise awareness of this relatively unknown ADR among physicians, especially since PAs are generally not labelled in SmPCs of the suspected drugs. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

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    Kristin McEuen

    2017-06-01

    Full Text Available 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.

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

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    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.

  15. [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.

  16. Drug-induced QT interval prolongation: does ethnicity of the thorough QT study population matter?

    Science.gov (United States)

    Shah, Rashmi R

    2013-01-01

    Inter-ethnic differences in drug responses have been well documented. Drug-induced QT interval prolongation is a major safety concern and therefore, regulatory authorities recommend a clinical thorough QT study (TQT) to investigate new drugs for their QT-prolonging potential. A positive study, determined by breach of a preset regulatory threshold, significantly influences late phase clinical trials by requiring intense ECG monitoring. A few studies that are currently available, although not statistically conclusive at present, question the assumption that ethnicity of the study population may not influence the outcome of a TQT study. Collective consideration of available pharmacogenetic and clinical information suggests that there may be inter-ethnic differences in QT-prolonging effects of drugs and that Caucasians may be more sensitive than other populations. The information also suggest s that (a) these differences may depend on the QT-prolonging potency of the drug and (b) exposure–response (E–R) analysis may be more sensitive than simple changes in QTc interval in unmasking this difference. If the QT response in Caucasians is generally found to be more intense than in non-Caucasians, there may be significant regulatory implications for domestic acceptance of data from a TQT study conducted in foreign populations. However, each drug will warrant an individual consideration when extrapolating the results of a TQT studyfrom one ethnic population to another and the ultimate clinical relevance of any difference. Further adequately designed and powered studies, investigating the pharmacologic properties and E–R relationships of additional drugs with different potencies, are needed in Caucasians, Oriental/Asian and African populations before firm conclusions can be drawn. PMID:22882246

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

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    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.

  18. Customised in vitro model to detect human metabolism-dependent idiosyncratic drug-induced liver injury.

    Science.gov (United States)

    Tolosa, Laia; Jiménez, Nuria; Pérez, Gabriela; Castell, José V; Gómez-Lechón, M José; Donato, M Teresa

    2017-07-31

    Drug-induced liver injury (DILI) has a considerable impact on human health and is a major challenge in drug safety assessments. DILI is a frequent cause of liver injury and a leading reason for post-approval drug regulatory actions. Considerable variations in the expression levels of both cytochrome P450 (CYP) and conjugating enzymes have been described in humans, which could be responsible for increased susceptibility to DILI in some individuals. We herein explored the feasibility of the combined use of HepG2 cells co-transduced with multiple adenoviruses that encode drug-metabolising enzymes, and a high-content screening assay to evaluate metabolism-dependent drug toxicity and to identify metabolic phenotypes with increased susceptibility to DILI. To this end, HepG2 cells with different expression levels of specific drug-metabolism enzymes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, GSTM1 and UGT2B7) were exposed to nine drugs with reported hepatotoxicity. A panel of pre-lethal mechanistic parameters (mitochondrial superoxide production, mitochondrial membrane potential, ROS production, intracellular calcium concentration, apoptotic nuclei) was used. Significant differences were observed according to the level of expression and/or the combination of several drug-metabolism enzymes in the cells created ad hoc according to the enzymes implicated in drug toxicity. Additionally, the main mechanisms implicated in the toxicity of the compounds were also determined showing also differences between the different types of cells employed. This screening tool allowed to mimic the variability in drug metabolism in the population and showed a highly efficient system for predicting human DILI, identifying the metabolic phenotypes associated with increased DILI risk, and indicating the mechanisms implicated in their toxicity.

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

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    Ruchi Banthia

    2014-01-01

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

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

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    Francesco Grippo

    2015-04-01

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

  2. 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 the other

  3. The role of ultrahigh-frequency audiometry in the early detection of systemic drug-induced hearing loss.

    Science.gov (United States)

    Singh Chauhan, Rajeev; Saxena, Ravinder Kumar; Varshey, Saurabh

    2011-05-01

    In monitoring patients for drug-induced hearing loss, most audiometric evaluations are limited to the range of frequencies from 0.25 to 8 kHz. However, such testing would fail to detect ototoxicity in patients who have already experienced hearing loss in the ultrahigh frequencies from 10 to 20 kHz. Awareness of ultrahigh-frequency ototoxicity could lead to changes in a drug regimen to prevent further damage. We conducted a prospective study of 105 patients who were receiving a potentially ototoxic drug-either gentamicin, amikacin, or cisplatin-to assess the value of ultrahigh-frequency audiometry in detecting systemic drug-induced hearing loss. We found that expanding audiometry into the ultrahigh-frequency range led to the detection of a substantial number of cases of hearing loss that would have otherwise been missed.

  4. Abnormal Head Position

    Science.gov (United States)

    ... non-ocular causes of an abnormal head position? Congenital shortening of the neck muscles (sternocleidomastoid) can cause a head tilt. This is ... amblyopia) are other treatment alternatives. Physical therapy helps congenital torticollis from tight neck muscles. Updated ... Terms & Conditions Most Common ...

  5. 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.

  6. 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.

  7. [Connective tissue growth factors, CTGF and Cyr61 in drug-induced gingival overgrowth--an animal model].

    Science.gov (United States)

    Ciobanică, Mihaela; Cianga, Corina; Căruntu, Irina-Draga; Grigore, Georgiana; Cianga, P

    2008-01-01

    Human gingival overgrowth may occur as a side effect of chronic administration of some therapeutic agents. The mechanisms responsible for the gingival tissues lesions, fibrosis and inflamation, involve an impaired balance between the production and the degradation of type I collagen. It has been demonstrated that CCN2/CTGF, a connective tissue growth factor, is highly expressed in the gingival tissues and positively correlated with the degree of fibrosis in the drug-induced gingival overgrowth. The aim of this study was to identify the presence and localization of CCN2/CTGF and CCN1/Cyr61, members of the same molecular family, in gingival tissues of cyclosporin A- and nifedipine-treated rats, by immunohistochemistry. Staining was evaluated with light microscope and the results show cellular and extracellular CTGF in nifedipin gingival overgrowth tissues with intensity of labeling higher compared to the CsA gingival overgrowth tissues or the controls. The staining for Cyr61 shows its intracellular localization with no diference of labeling intensity between drug-induced gingival overgrowth and normal tissues. Also, we were interested in the gingival TGF-â expression in those animals. We didn't find any commercial anti-rat TGF antibody and our anti-human antibody shows no cross-reactivity with rat tissues. The data from our study sustain the involvement of CTGF and Cyr61 as growth factors in the gingival tissues and the CTGF association with drug-induced gingival overgrowth.

  8. Prevention and treatment of vaginal bleeding after drug-induced abortion by Yaoliuan capsule and its effects on menses recovery.

    Science.gov (United States)

    Jin, Zhichun; Huang, Guangying

    2005-01-01

    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 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.

  9. Activation of JNK triggers release of Brd4 from mitotic chromosomes and mediates protection from drug-induced mitotic stress.

    Science.gov (United States)

    Nishiyama, Akira; Dey, Anup; Tamura, Tomohiko; Ko, Minoru; Ozato, Keiko

    2012-01-01

    Some anti-cancer drugs, including those that alter microtubule dynamics target mitotic cells and induce apoptosis in some cell types. However, such drugs elicit protective responses in other cell types allowing cells to escape from drug-induced mitotic inhibition. Cells with a faulty protective mechanism undergo defective mitosis, leading to genome instability. Brd4 is a double bromodomain protein that remains on chromosomes during mitosis. However, Brd4 is released from mitotic chromosomes when cells are exposed to anti-mitotic drugs including nocodazole. Neither the mechanisms, nor the biological significance of drug-induced Brd4 release has been fully understood. We found that deletion of the internal C-terminal region abolished nocodazole induced Brd4 release from mouse P19 cells. Furthermore, cells expressing truncated Brd4, unable to dissociate from chromosomes were blocked from mitotic progression and failed to complete cell division. We also found that pharmacological and peptide inhibitors of the c-jun-N-terminal kinases (JNK) pathway, but not inhibitors of other MAP kinases, prevented release of Brd4 from chromosomes. The JNK inhibitor that blocked Brd4 release also blocked mitotic progression. Further supporting the role of JNK in Brd4 release, JNK2-/- embryonic fibroblasts were defective in Brd4 release and sustained greater inhibition of cell growth after nocodazole treatment. In sum, activation of JNK pathway triggers release of Brd4 from chromosomes upon nocodazole treatment, which mediates a protective response designed to minimize drug-induced mitotic stress.

  10. Activation of JNK triggers release of Brd4 from mitotic chromosomes and mediates protection from drug-induced mitotic stress.

    Directory of Open Access Journals (Sweden)

    Akira Nishiyama

    Full Text Available Some anti-cancer drugs, including those that alter microtubule dynamics target mitotic cells and induce apoptosis in some cell types. However, such drugs elicit protective responses in other cell types allowing cells to escape from drug-induced mitotic inhibition. Cells with a faulty protective mechanism undergo defective mitosis, leading to genome instability. Brd4 is a double bromodomain protein that remains on chromosomes during mitosis. However, Brd4 is released from mitotic chromosomes when cells are exposed to anti-mitotic drugs including nocodazole. Neither the mechanisms, nor the biological significance of drug-induced Brd4 release has been fully understood. We found that deletion of the internal C-terminal region abolished nocodazole induced Brd4 release from mouse P19 cells. Furthermore, cells expressing truncated Brd4, unable to dissociate from chromosomes were blocked from mitotic progression and failed to complete cell division. We also found that pharmacological and peptide inhibitors of the c-jun-N-terminal kinases (JNK pathway, but not inhibitors of other MAP kinases, prevented release of Brd4 from chromosomes. The JNK inhibitor that blocked Brd4 release also blocked mitotic progression. Further supporting the role of JNK in Brd4 release, JNK2-/- embryonic fibroblasts were defective in Brd4 release and sustained greater inhibition of cell growth after nocodazole treatment. In sum, activation of JNK pathway triggers release of Brd4 from chromosomes upon nocodazole treatment, which mediates a protective response designed to minimize drug-induced mitotic stress.

  11. Activation of JNK Triggers Release of Brd4 from Mitotic Chromosomes and Mediates Protection from Drug-Induced Mitotic Stress

    Science.gov (United States)

    Nishiyama, Akira; Dey, Anup; Tamura, Tomohiko; Ko, Minoru; Ozato, Keiko

    2012-01-01

    Some anti-cancer drugs, including those that alter microtubule dynamics target mitotic cells and induce apoptosis in some cell types. However, such drugs elicit protective responses in other cell types allowing cells to escape from drug-induced mitotic inhibition. Cells with a faulty protective mechanism undergo defective mitosis, leading to genome instability. Brd4 is a double bromodomain protein that remains on chromosomes during mitosis. However, Brd4 is released from mitotic chromosomes when cells are exposed to anti-mitotic drugs including nocodazole. Neither the mechanisms, nor the biological significance of drug-induced Brd4 release has been fully understood. We found that deletion of the internal C-terminal region abolished nocodazole induced Brd4 release from mouse P19 cells. Furthermore, cells expressing truncated Brd4, unable to dissociate from chromosomes were blocked from mitotic progression and failed to complete cell division. We also found that pharmacological and peptide inhibitors of the c-jun-N-terminal kinases (JNK) pathway, but not inhibitors of other MAP kinases, prevented release of Brd4 from chromosomes. The JNK inhibitor that blocked Brd4 release also blocked mitotic progression. Further supporting the role of JNK in Brd4 release, JNK2–/– embryonic fibroblasts were defective in Brd4 release and sustained greater inhibition of cell growth after nocodazole treatment. In sum, activation of JNK pathway triggers release of Brd4 from chromosomes upon nocodazole treatment, which mediates a protective response designed to minimize drug-induced mitotic stress. PMID:22567088

  12. Up-regulation of CCL17, CCL22 and CCR4 in drug-induced maculopapular exanthema.

    Science.gov (United States)

    Tapia, B; Morel, E; Martín-Díaz, M-A; Díaz, R; Alves-Ferreira, J; Rubio, P; Padial, A; Bellón, T

    2007-05-01

    Maculopapular exanthema has been reported to be the most frequently drug-induced cutaneous reaction. Although T lymphocytes are involved in the pathomechanism of this disease, little is know about the recruitment of these cells to the skin. The aim of this work is to study the role of the chemokines TARC/CCL17 and MDC/CCL22 in the lymphocyte trafficking to affected skin in drug-induced exanthemas. Real-time PCR was performed to quantify gene expression levels of CCL17, CCL22 and their receptor CCR4 in lesional skin biopsies and in peripheral blood mononuclear cells from patients. CCL27 and CCL22 proteins were detected in the skin by immunochemistry. Protein expression of CCR4 was determined by flow cytometry in peripheral blood lymphocytes. Functional migration assays to CCL17 and CCL22 were assessed to compare the migratory responses of peripheral blood lymphocytes from patients and healthy subjects. CCL17 and CCL22 were up-regulated in maculopapular exanthema-affected skin. CCR4 mRNA levels and protein expression were increased in peripheral blood mononuclear cells during the acute phase of the disease. The increased expression of the receptor was consistent with a higher response of peripheral blood lymphocytes to CCL17 and CCL22 compared with the migratory response in healthy donors. TARC/CCL17 and MDC/CCL22 might cooperate in attracting T lymphocytes to skin in drug-induced maculopapular exanthemas.

  13. DIGEP-Pred: web service for in silico prediction of drug-induced gene expression profiles based on structural formula.

    Science.gov (United States)

    Lagunin, Alexey; Ivanov, Sergey; Rudik, Anastasia; Filimonov, Dmitry; Poroikov, Vladimir

    2013-08-15

    Experimentally found gene expression profiles are used to solve different problems in pharmaceutical studies, such as drug repositioning, resistance, toxicity and drug-drug interactions. A special web service, DIGEP-Pred, for prediction of drug-induced changes of gene expression profiles based on structural formulae of chemicals has been developed. Structure-activity relationships for prediction of drug-induced gene expression profiles were determined by Prediction of Activity Spectra for Substances (PASS) software. Comparative Toxicogenomics Database with data on the known drug-induced gene expression profiles of chemicals was used to create mRNA- and protein-based training sets. An average prediction accuracy for the training sets (ROC AUC) calculated by leave-one-out cross-validation on the basis of mRNA data (1385 compounds, 952 genes, 500 up- and 475 down-regulations) and protein data (1451 compounds, 139 genes, 93 up- and 55 down-regulations) exceeded 0.85. Freely available on the web at http://www.way2drug.com/GE.

  14. Neurological abnormalities predict disability

    DEFF Research Database (Denmark)

    Poggesi, Anna; Gouw, Alida; van der Flier, Wiesje

    2014-01-01

    To investigate the role of neurological abnormalities and magnetic resonance imaging (MRI) lesions in predicting global functional decline in a cohort of initially independent-living elderly subjects. The Leukoaraiosis And DISability (LADIS) Study, involving 11 European centres, was primarily aimed...... at evaluating age-related white matter changes (ARWMC) as an independent predictor of the transition to disability (according to Instrumental Activities of Daily Living scale) or death in independent elderly subjects that were followed up for 3 years. At baseline, a standardized neurological examination.......0 years, 45 % males), 327 (51.7 %) presented at the initial visit with ≥1 neurological abnormality and 242 (38 %) reached the main study outcome. Cox regression analyses, adjusting for MRI features and other determinants of functional decline, showed that the baseline presence of any neurological...

  15. 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

  16. 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

  17. Drug-induced sedation endoscopy in surgically naive children with Down syndrome and obstructive sleep apnea.

    Science.gov (United States)

    Maris, Mieke; Verhulst, Stijn; Saldien, Vera; Van de Heyning, Paul; Wojciechowski, Marek; Boudewyns, An

    2016-08-01

    To describe the pattern of upper airway (UA) obstruction in surgically naive children with Down syndrome and obstructive sleep apnea (OSA), and to evaluate the outcome of drug-induced sedation endoscopy (DISE)-directed treatment. A prospective study of DISE in surgically naive children with Down syndrome and OSA was performed. Treatment was individually tailored based on the DISE findings and was evaluated by control polysomnography (PGS). Results are presented as median (lower-upper quartile) unless otherwise stated. In 41 children, aged 4.2 years (range, 2.8-6.0) with a body mass z score of 1.04 (-0.55 to 1.82) and obstructive apnea-hypopnea index (oAHI) of 10.1/h (range, 6.3-23.0), DISE was performed. Adeno-/tonsillar obstruction was found in 75.6% of the patients, and these patients subsequently underwent UA surgery. Seven patients were non-surgically treated, and three received a combined treatment. A multilevel collapse was present in 85.4%. Tongue base obstruction was present in ten patients (24.4%) and epiglottic collapse in 48.8%. Pre- and postoperative PSG data were available for 25 children (adenotonsillectomy, n = 16; tonsillectomy, n = 7; adenoidectomy, n = 2). A significant improvement in oAHI from 11.4/h (range, 7.7-27.0) to 5.5/h (range, 2.1-7.6) was found. Persistent OSA was present in 52% of the children. No significant association between different DISE findings and persistent OSA could be found. Most patients with Down syndrome and OSA present with multilevel collapse on DISE. Adenotonsillectomy results in a significant improvement of the oAHI; however more than half of the patients had persistent OSA, probably due to multilevel collapse. Upper airway evaluation may provide more insights into the pattern of UA obstruction in patients with persistent OSA. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Abnormal Uterine Bleeding

    OpenAIRE

    Benetti-Pinto, Cristina Laguna; Rosa-e-Silva, Ana Carolina Japur de Sá; Yela, Daniela Angerame; Soares Júnior,José Maria

    2017-01-01

    Abstract Abnormal uterine bleeding is a frequent condition in Gynecology. It may impact physical, emotional sexual and professional aspects of the lives of women, impairing their quality of life. In cases of acute and severe bleeding, women may need urgent treatment with volumetric replacement and prescription of hemostatic substances. In some specific cases with more intense and prolonged bleeding, surgical treatment may be necessary. The objective of this chapter is to describe the main evi...

  19. Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: Marked differences between various antipsychotic drugs

    Directory of Open Access Journals (Sweden)

    Vik-Mo Audun O

    2006-10-01

    Full Text Available Abstract Background The etiology of schizophrenia is unknown, but neurodevelopmental disturbances, myelin- and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder. Cholesterol is an essential component of myelin and has proved important for synapse formation. Recently, we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element-binding protein (SREBP transcription factors. We here compare the action of chlorpromazine, haloperidol, clozapine, olanzapine, risperidone and ziprasidone on SREBP activation and SREBP-controlled gene expression (ACAT2, HMGCR, HMGCS1, FDPS, SC5DL, DHCR7, LDLR, FASN and SCD1 in four CNS-relevant human cell lines. Results There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes, with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations. Glial-like cells (GaMg glioma and CCF-STTG1 astrocytoma cell lines displayed more pronounced drug-induced SREBP activation compared to the response in HCN2 human cortical neurons and SH-SY5Y neuroblastoma cells, indicating that antipsychotic-induced activation of lipogenesis is most prominent in glial cells. Conclusion Our present data show a marked variation in the ability of different antipsychotics to induce SREBP-controlled transcriptional activation of lipogenesis in cultured human CNS-relevant cells. We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs.

  20. Stereoselective Blockage of Quinidine and Quinine in the hERG Channel and the Effect of Their Rescue Potency on Drug-Induced hERG Trafficking Defect.

    Science.gov (United States)

    Yan, Meng; Fan, Pan; Shi, Yanhui; Feng, Lifang; Wang, Junnan; Zhan, Ge; Li, Baoxin

    2016-09-28

    Diastereoisomers of quinidine and quinine are used to treat arrhythmia and malaria, respectively. It has been reported that both drugs block the hERG (human ether-a-go-go-related gene) potassium channel which is essential for myocardium repolarization. Abnormality of repolarization increases risk of arrhythmia. The aim of our research is to study and compare the impacts of quinidine and quinine on hERG. Results show that both drugs block the hERG channel, with quinine 14-fold less potent than quinidine. In addition, they presented distinct impacts on channel dynamics. The results imply their stereospecific block effect on the hERG channel. However, F656C-hERG reversed this stereoselectivity. The mutation decreases affinity of the two drugs with hERG, and quinine was more potent than quinidine in F656C-hERG blockage. These data suggest that F656 residue contributes to the stereoselective pocket for quinidine and quinine. Further study demonstrates that both drugs do not change hERG protein levels. In rescue experiments, we found that they exert no reverse effect on pentamidine- or desipramine-induced hERG trafficking defect, although quinidine has been reported to rescue trafficking-deficient pore mutation hERG G601S based on the interaction with F656. Our research demonstrated stereoselective effects of quinidine and quinine on the hERG channel, and this is the first study to explore their reversal potency on drug-induced hERG deficiency.

  1. Cicatrizing Conjunctivitis in a Patient Diagnosed With Drug Reaction With Eosinophilia and Systemic Symptoms/Drug-Induced Hypersensitivity Syndrome but With Features of Stevens-Johnson Syndrome.

    Science.gov (United States)

    Bohm, Kelley J; Ciralsky, Jessica B; Harp, Joanna L; Bajaj, Shirin; Sippel, Kimberly C

    2016-06-01

    Severe cutaneous adverse reactions to drugs (SCARs) such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS) serve as one of the main reasons for inpatient ophthalmic consultation. Although it is well-recognized that SJS/TEN is associated with severe ocular mucosal inflammation and cicatrizing, potentially blinding, sequelae, this association has not been described in relation to other SCARs. We present a patient fulfilling the diagnostic criteria for probable DRESS/DIHS but not for SJS/TEN, yet exhibiting the severe ocular surface involvement characteristic of SJS/TEN. Case report. A 64-year-old man presented with bilateral pseudomembranous conjunctivitis and conjunctival denudation (sloughing) in the setting of a maculopapular rash, fever, liver dysfunction, and hematologic abnormalities 1 month after initiating several medications. A skin biopsy was not consistent with SJS/TEN. The patient was diagnosed with probable DRESS/DIHS and treated with high-dose systemic corticosteroids. The ocular surface inflammation was addressed with intensive topical corticosteroid ointment. The pseudomembranes resolved over a 6-week period, but the patient exhibited residual conjunctival scarring of all palpebral surfaces. The development of severe ocular surface mucosal inflammation and denudation with cicatrizing sequelae in a patient carrying a diagnosis of DRESS/DIHS has diagnostic and therapeutic implications for the ophthalmologist. Careful ophthalmic assessment is indicated in any SCAR patient with ophthalmic symptoms, regardless of formal diagnosis. Furthermore, the early therapeutic interventions recently recommended in SJS/TEN to limit the ophthalmic cicatricial sequelae, such as systemic or topical corticosteroids, may be indicated.

  2. Early alterations of bile canaliculi dynamics and the rho kinase/myosin light chain kinase pathway are characteristics of drug-induced intrahepatic cholestasis

    OpenAIRE

    Burbank, M.G.; Burban, Audrey; Sharanek, Ahmad; Weaver, R J; Guguen-Guillouzo, Christiane; Guillouzo, André

    2016-01-01

    International audience; Intrahepatic cholestasis represents 20%-40%of drug-induced injuries from which a large proportion remains unpredictable. We aimed to investigate mechanisms underlying drug-induced cholestasis and improve its early detection using human HepaRG cells and a set of 12 cholestatic drugs and six noncholestatic drugs. In this study, we analyzed bile canaliculi dynamics, Rho kinase (ROCK)/myosin light chain kinase (MLCK) pathway implication, efflux inhibition of taurocholate [...

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

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    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. Influence of war on quantitative and qualitative changes in drug-induced mortality in Split-Dalmatia County, Croatia.

    Science.gov (United States)

    Marasovic Susnjara, Ivana; Definis Gojanovic, Marija; Vodopija, Davor; Capkun, Vesna; Smoljanovic, Ankica

    2011-10-15

    To study drug-induced mortality and characteristics of overdose deaths in the war (1991-1995), pre-war (1986-1990), and post-war period (1996-2000) in Split-Dalmatia County. We retrospectively searched through Databases of the Department of Forensic Medicine, University Hospital Split, the national register of death records, the archives of the Split-Dalmatia County Police, and the Register of Treated Drug Addicts of the Croatian National Institute of Public Health, covering the period from 1986 to 2000, according to drug poisoning codes IX and X of the International Classification of Diseases. The indicators were statistically analyzed. There were 146 registered drug-induced deaths, with 136 (93%) deceased being men. The median age of all cases was 27 years (interquartile range 8). Most of them were single (70.6%), unemployed (44.6%), and secondary school graduates (69.2%). In the war period, there were 4.8 times more deaths than in the pre-war period (P=0.014), and in the post-war period there were 5.2 times more deaths than in the pre-war period (P=0.008). The most common site of death was the deceased person's home. The toxicological analyses showed that 59 (61%) deaths were heroin related, alcohol use was found in 62 cases (42.5%), and multi-substance use was found in more than a half of the cases. In 133 (91.1%) cases, deaths were classified as unintentional, whereas 13 (8.9%) were classified as suicides. CONCLUSION; The war, along with other risk factors, contributed to unfavorable developments related to drug abuse in Split-Dalmatia County, including the increase in the drug-induced mortality rate.

  5. 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 IL-36 receptor antagonist (IL-36Ra). Its function in interstitial lung disease (ILD) is still unknown. To determine the expression pattern of IL-38 mRNA, a panel of cDNAs derived from various tissues was analyzed by quantitative real-time PCR. Immunohistochemical reactivity with anti-human IL-38 monoclonal antibody (clone H127C) was evaluated semi-quantitatively in lung tissue samples from 12 patients with idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), 5 with acute exacerbation of IPF, and 10 with anticancer drug-induced ILD (bleomycin in 5 and epidermal growth factor receptor-tyrosine kinase inhibitor in 5). Control lung tissues were obtained from areas of normal lung in 22 lung cancer patients who underwent extirpation surgery. IL-38 transcripts were strongly expressed in the lung, spleen, synoviocytes, and peripheral blood mononuclear cells, and at a lower level in pancreas and muscle. IL-38 protein was not strongly expressed in normal pulmonary alveolar tissues in all 22 control lungs. In contrast, IL-38 was overexpressed in the lungs of 4 of 5 (80%) patients with acute IPF exacerbation and 100% (10/10) of the patients with drug-induced ILD. IL-38 overexpression was limited to hyperplastic type II pneumocytes, which are considered to reflect regenerative change following diffuse alveolar damage in ILD. IL-38 may play an important role in acute and/or chronic inflammation in anticancer drug-induced lung injury and acute exacerbation of IPF. Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

  6. 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

  7. 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.

  8. Drug-induced hypersensitivity syndrome caused by valproic acid as a monotherapy for epilepsy: First case report in Asian population.

    Science.gov (United States)

    Wu, X T; Hong, P W; Suolang, D J; Zhou, D; Stefan, H

    2017-01-01

    Valproic acid (VPA) is a broad-spectrum antiseizure drug used for a variety of clinical conditions, such as epilepsy and mood disorders. Drug-induced hypersensitivity syndrome (DRESS) accompanied by hyponatremia, thrombocytopenia, hypoalbuminemia and elevated aminotransferase has never been reported as an adverse effect of VPA monotherapy during titration for epilepsy in Asian population. Hereby, we present the case of a 73-year-old Chinese male who suffered from DRESS and other complications two weeks after initiating VPA treatment for epilepsy. Understanding the risk associated with VPA-induced DRESS, and taking effective measures to avoid the severe side effects are necessary.

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

    Science.gov (United States)

    Nassirpour, Rounak; Ramaiah, Shashi K; Whiteley, Laurence O

    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. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. 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.

  11. Use of a mail-out continuing education article to teach health professionals about drug-induced disease.

    Science.gov (United States)

    Goldman, S A

    1999-11-01

    A U.S. Food and Drug Administration (FDA)/Georgetown University Medical Center conference was the basis for "Clinical Therapeutics and the Recognition of Drug-Induced Disease," the first MEDWATCH continuing education (CE) mail-out article. Developed as a major component of FDA MEDWATCH post-marketing surveillance outreach, the article used a clinical therapeutic approach to discuss topics including adverse drug events (ADEs) pharmacology and ADE reporting. Distributed nationwide through the MEDWATCH Partners, health professionals applied for CE credit by completing a self-assessment examination. With the overall response rate slightly more than 2%, 15,260 health professionals (55% physicians and 37% pharmacists) received CE credit. Evaluation of the initial approximately two-thirds (N = 10,021) of successfully completed exams found 99% agreement that stated learning objectives were met, and the article relevant to their clinical practice; spontaneous comments/letters were also very positive. The highest percentage responding specialists were internists (28%) and psychiatrists (17%), with notable differences found among specialties for response rate versus relative article distribution (such as relatively low response rates among surgeons and radiology/radiation physics specialists). The number of health professionals receiving CE credit, coupled with examination performance and overall response, indicates that "Clinical Therapeutics and the Recognition of Drug-Induced Disease" was well received and fulfilled learning objectives. The results provide encouragement for this continuing educational approach.

  12. 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.

  13. Protecting effect of caffeine against vinblastine (an anticancer drug) induced genotoxicity in mice.

    Science.gov (United States)

    Geriyol, Prakash; Basavanneppa, Hosetti Basaling; Dhananjaya, Bhadrapura Lakkappa

    2015-04-01

    Vinblastine a DNA non-intercalating agent has wide application against several human neoplasms, and found to cause cytogenotoxicity. In this study, clastogenotoxicity of vinblastine (1.5 mg/kg b w) and its prevention by caffeine at different doses (25, 50 and 100 mg/kg b w) administered intraperitoneally was assessed in in vivo mice. It was found that micronucleus level had decreased significantly (up to 28.8%) in 100 mg caffeine treated group at 30 h post treatment. However, it did not exhibit protective effect against chromosomal aberration in spaermatogonial cells at 24 h post treatment. The frequencies of aberrant primary spermatocytes had decreased significantly in 25 and 100 mg caffeine at 4th week of post treatment. Similarly, in 100 mg of caffeine administered, abnormal sperm level had reduced (4.01%) significantly at 8th week post treatment. Thus, caffeine decreased the vinblastine induced chromosomal aberrations and mitotic index in bone marrow cells. In conclusion, this study shows that caffeine exerts protective effect against vinblastin induced cytogenotoxicity. Further studies on molecular mechanism are interesting in order to develop it as an effective drug in cancer chemotherapy.

  14. VITAMINE E IN THE MANAGEMENT OF DRUG INDUCED TARDIVE DYSKINESIA: A DOUBLE BLIND RANDOMIZED CLINICAL TRIAL

    Directory of Open Access Journals (Sweden)

    M KAR AHMADI

    2002-12-01

    Full Text Available Introduction. Expresssion of tardive dyskinesia as one of the side effects of antipsychotic drugs causes various problems in psychotic patients. It is the main cause of patient"s drug incompliance.Vitamine E with it"s antioxidants properties might be an effective treatment for tardive dyskinesia. Methods. In a randomized double blind clinical trial, thirty inpatients of the psychiatric hospital in Isfahan were studied. Patients were stratified according to their age, psychiatric disorder and duration, intensity of tardive dyskinesia and antipsychotic dosage. Then they were asssigned randomly into two groups. Vitamine E (600 mg/day was administered to interventional group (15 patients. Another group received placebo (15 patients. Treatment durated for 6 weeks. Abnormal Involuntary Movment Scale (AIMS was used to measure tardive dyskinesia intensity. Results. Average of disorder intensity in those who received vit. E, dropped down from 8.33/10 (befor treatment to 6.13/10 (after treatment. It means 26.3 percent reduction of tardive dyskinesia intensity. This difference was only 7.3 percent in control group. There were no statistical diffrence between two groups after treatment (P>0.05. Discussion. There is no statistical efficacy for vitamine E in the management of tardive dyskinesia. But it is recommended to make another study with more samples.

  15. Anticancer drugs induce hypomethylation of the acetylcholinesterase promoter via a phosphorylated-p38-DNMT1-AChE pathway in apoptotic hepatocellular carcinoma cells.

    Science.gov (United States)

    Xi, Qiliang; Gao, Ning; Yang, Yang; Ye, Weiyuan; Zhang, Bo; Wu, Jun; Jiang, Gening; Zhang, Xuejun

    2015-11-01

    Apoptosis, also known as programmed cell death, plays an essential role in eliminating excessive, damaged or harmful cells. Previous work has demonstrated that anticancer drugs induce cell apoptosis by inducing cytotoxicity. In recent years, several reports demonstrated modulated expression of DNA methyltransferases 1 (DNMT1) and acetylcholinesterase (AChE) in a variety of tumors. In this study, we showed that the expression of DNMT1 was decreased and the methylation of CpGs in the promoter of AChE was reduced in anticancer drugs-induced apoptotic hepatocellular carcinoma cells. Silencing of DNMT1 expression by AZA or RNA interference (RNAi) restored AChE production and inhibition of AChE expression by RNAi protected HCC cells from anticancer drugs-induced apoptosis. Furthermore, we demonstrated that the regulation of AChE by DNMT1 was involved in the phosphorylated p38 pathway in anticancer drugs-induced apoptosis. In addition, immunohistochemical staining showed that P-p38, DNMT1 and AChE were aberrantly expressed in a subset of HCC tumors. Taken together, we demonstrated the regulation of AChE by DNMT1 and further, we found that this regulation was involved in the phosphorylated p38 pathway in anticancer drugs-induced apoptosis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Abnormal uterine bleeding.

    Science.gov (United States)

    Whitaker, Lucy; Critchley, Hilary O D

    2016-07-01

    Abnormal uterine bleeding (AUB) is a common and debilitating condition with high direct and indirect costs. AUB frequently co-exists with fibroids, but the relationship between the two remains incompletely understood and in many women the identification of fibroids may be incidental to a menstrual bleeding complaint. A structured approach for establishing the cause using the Fédération International de Gynécologie et d'Obstétrique (FIGO) PALM-COEIN (Polyp, Adenomyosis, Leiomyoma, Malignancy (and hyperplasia), Coagulopathy, Ovulatory disorders, Endometrial, Iatrogenic and Not otherwise classified) classification system will facilitate accurate diagnosis and inform treatment options. Office hysteroscopy and increasing sophisticated imaging will assist provision of robust evidence for the underlying cause. Increased availability of medical options has expanded the choice for women and many will no longer need to recourse to potentially complicated surgery. Treatment must remain individualised and encompass the impact of pressure symptoms, desire for retention of fertility and contraceptive needs, as well as address the management of AUB in order to achieve improved quality of life. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  17. Evaluation of nail abnormalities.

    Science.gov (United States)

    Tully, Amber S; Trayes, Kathryn P; Studdiford, James S

    2012-04-15

    Knowledge of the anatomy and function of the nail apparatus is essential when performing the physical examination. Inspection may reveal localized nail abnormalities that should be treated, or may provide clues to an underlying systemic disease that requires further workup. Excessive keratinaceous material under the nail bed in a distal and lateral distribution should prompt an evaluation for onychomycosis. Onychomycosis may be diagnosed through potassium hydroxide examination of scrapings. If potassium hydroxide testing is negative for the condition, a nail culture or nail plate biopsy should be performed. A proliferating, erythematous, disruptive mass in the nail bed should be carefully evaluated for underlying squamous cell carcinoma. Longitudinal melanonychia (vertical nail bands) must be differentiated from subungual melanomas, which account for 50 percent of melanomas in persons with dark skin. Dystrophic longitudinal ridges and subungual hematomas are local conditions caused by trauma. Edema and erythema of the proximal and lateral nail folds are hallmark features of acute and chronic paronychia. Clubbing may suggest an underlying disease such as cirrhosis, chronic obstructive pulmonary disease, or celiac sprue. Koilonychia (spoon nail) is commonly associated with iron deficiency anemia. Splinter hemorrhages may herald endocarditis, although other causes should be considered. Beau lines can mark the onset of a severe underlying illness, whereas Muehrcke lines are associated with hypoalbuminemia. A pincer nail deformity is inherited or acquired and can be associated with beta-blocker use, psoriasis, onychomycosis, tumors of the nail apparatus, systemic lupus erythematosus, Kawasaki disease, and malignancy.

  18. Communication and abnormal behaviour.

    Science.gov (United States)

    Crown, S

    1979-01-01

    In this paper the similarities between normal and abnormal behaviour are emphasized and selected aspects of communication, normal and aberrant, between persons are explored. Communication in a social system may be verbal or non-verbal: one person's actions cause a response in another person. This response may be cognitive, behavioural or physiological. Communication may be approached through the individual, the social situation or social interaction. Psychoanalysis approaches the individual in terms of the coded communications of psychoneurotic symptoms or psychotic behaviour; the humanist-existential approach is concerned more with emotional expression. Both approaches emphasize the development of individual identity. The interaction between persons and their social background is stressed. Relevant are sociological concepts such as illness behaviour, stigma, labelling, institutionalization and compliance. Two approaches to social interactions are considered: the gamesplaying metaphor, e.g. back pain as a psychosocial manipulation--the 'pain game'; and the 'spiral of reciprocal perspectives' which emphasizes the interactional complexities of social perceptions. Communicatory aspects of psychological treatments are noted: learning a particular metaphor such as 'resolution' of the problem (psychotherapy), learning more 'rewarding' behaviour (learning theory) or learning authenticity or self-actualization (humanist-existential).

  19. 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

  20. Mis-trafficking of endosomal urokinase proteins triggers drug-induced glioma nonapoptotic cell death.

    Science.gov (United States)

    Pasupuleti, Nagarekha; Grodzki, Ana Cristina; Gorin, Fredric

    2015-04-01

    5-Benzylglycinyl-amiloride (UCD38B) is the parent molecule of a class of anticancer small molecules that kill proliferative and nonproliferative high-grade glioma cells by programmed necrosis. UCD38B intracellularly triggers endocytosis, causing 40-50% of endosomes containing proteins of the urokinase plasminogen activator system (uPAS) to relocate to perinuclear mitochondrial regions. Endosomal "mis-trafficking" caused by UCD38B in human glioma cells corresponds to mitochondrial depolarization with the release and nuclear translocation of apoptotis-inducing factor (AIF) followed by irreversible caspase-independent cell demise. High-content quantification of immunocytochemical colocalization studies identified that UCD38B treatment increased endocytosis of the urokinase plasminogen activator (uPA), its receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1) into the early and late endosomes by 4- to 5-fold prior to AIF nuclear translocation and subsequent glioma demise. PAI-1 was found to comparably relocate with a subset of early and late endosomes in four different human glioma cell lines after UCD38B treatment, followed by caspase-independent, nonapoptotic cell death. Following UCD38B treatment, the receptor guidance protein LRP-1, which is required for endosomal recycling of the uPA receptor to the plasmalemma, remained abnormally associated with PAI-1 in early and late endosomes. The resultant aberrant endosomal recycling increased the total cellular content of the uPA-PAI-1 protein complex. Reversible inhibition of cellular endocytosis demonstrated that UCD38B bypasses the plasmalemmal uPAS complex and directly acts intracellularly to alter uPAS endocytotic trafficking. UCD38B represents a class of small molecules whose anticancer cytotoxicity is a consequence of causing the mis-trafficking of early and late endosomes containing uPAS cargo and leading to AIF-mediated necrotic cell death. Copyright © 2015 by The American Society for Pharmacology and

  1. A systematic analysis of the application of diagnostic criteria for drug-induced liver injury in China based on the literature

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    ZHANG Dong

    2017-05-01

    Full Text Available ObjectiveTo investigate the application of diagnostic criteria for drug-induced liver injury in China. MethodsCNKI, VIP, and Wanfang Data were searched for articles published from 1990 to 2015, and the diagnostic criteria in the articles were recorded to investigate the current application of diagnostic criteria for drug-induced liver injury. ResultsA total of 609 articles were included, with 410 articles of case studies and 199 case reports. A total of 15 types of diagnostic criteria were used in China, and only 13.4% of these articles used the causality assessment method recommended by the international community. In 46% of the cases reported in the articles, a diagnosis was made based on clinical symptoms and exclusion of common causes of liver injury. ConclusionThere are many diagnostic criteria for drug-induced liver injury in China, and the diagnosis is subjective and lacks rigor.

  2. Drug-induced lung injury associated with combination therapy of daclatasvir and asunaprevir: The first case report.

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    Kamada, Takahiro; Furuta, Kenjiro; Tomioka, Hiromi

    2016-05-01

    Combination therapy with direct acting antiviral agents (DAAs) without interferon (IFN) has emerged as a treatment for chronic hepatitis C because of its high overall sustained virologic response rates and favorable side effect profile as compared to that with interferon. We report the first case of drug-induced lung injury (DLI) associated with IFN-free therapy with the DAAs, daclatasvir (NS5A inhibitor) and asunaprevir (NS3/4A protease inhibitor). Although this combination therapy of DAAs has been considered to have fewer side effects than IFN, more attention should be paid to DLI as an important side effect. Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

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

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    E Jong

    2013-09-01

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

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

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    Tupili Muralikrishna

    2013-01-01

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

  5. Life-threatening cardiac arrhythmias due to drug-induced QT prolongation : A retrospective study over 6 years from a medical intensive care unit.

    Science.gov (United States)

    Michels, G; Kochanek, M; Pfister, R

    2016-05-01

    Long QT syndrome (LQTS) can lead to ventricular arrhythmia, especially torsade de pointes (TdP) tachycardia and/or ventricular tachycardia (VT). The aim of this study is to characterize patients with life-threatening cardiac arrhythmias associated with drug-induced LQTS and to identify risk factors of distinct presenting arrhythmias. In this retrospective study, we present 33 consecutive cases of life-threatening cardiac arrhythmias associated with drug-induced long QT, which were direct admitted as emergency to a medical intensive care unit (MICU) during an observational time of 6 years. Of 33 identified cases, 55 % presented with TdP with the need of resuscitation and 45 % showed nonsustained VT, respectively. In the total cohort the mean corrected QT interval (QTc) was 532 ± 29 ms, with 530 ± 31 ms (n = 14) in men and 533 ± 28 ms (n = 19) in women (p = 0.80), respectively. Cardiac drugs with QTc interval prolonging effect were reported in 24 % of cases, and the other 76 % involved noncardiac medications. Although hypokalemia is the most common risk factor for drug-induced malignant arrhythmias, a QTc interval of at least 500 ms seems to be the major determinant of the risk of drug-induced proarrhythmias. Interestingly, patients with TdP exhibit more bradycardia as such with VT. This is the first study of patients with drug-induced life-threatening cardiac arrhythmias who were admitted as a case of emergency to a MICU. Physicians should be aware of drug-induced LQTS and be able to identify patients at risk and avoid specific drugs in such patients.

  6. Drug-induced MR urography: the effects of furosemide and intravenous saline injection on MR urography of obstructed and non-obstructed urinary tract

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    Park, Jeong Ha; Lee, Myung Jun; Lee, Chang Joon [National Medical Center, Seoul (Korea, Republic of)

    2001-10-01

    To determine the usefulness of MR urography technique for the evaluation of urinary systems in patients with obstructed urinary tract and normal volunteers with non-obstructed urinary tract after intravenous normal saline and diuretic injection. Three normal volunteers and 12 patients with urinary tract obstruction [ureteral calculi (n=8), extraurinary mass (n=1), ureteral tumor invasion (n=3)] underwent MR urography using a 1.0T scanner and a 2D non-breath-hold heavily T2-weighted fast spin-cho sequence. These acquisition were post-processed with a maximum intensity projection (MIP) algorithm. Two acquisitions were performed, the first prior to saline solution infusion following standard MR urography procedures, and the second, within 2-3 minutes of the infusion of 250 ml saline solution followed by 20 mg of Lasix administered intravenously. For this latter, drug-induced MR urography procedures were followed. In healthy volunteer (n=3) and those experiencing partial obstruction (n=4) by a urinary stone, drug-induced MR urography provided better images of the urinary tract than did standard MR urography. In those in whom a urinary stone or tumor had caused complete obstruction (n=8), standard MR urography provided good images, as did drug-induced MR urography. In patients with a partially or non-obstructed urinary tract, drug-induced MR urography provided better anatomic and functional details of the kidney and urinary tract than did standard MR urography. In those experiencing complete obstruction of the urinary tract, however, standard or drug-induced MR urography permitted very adequate evaluation of the tract, and drug-induced MR urography was unnecessary.

  7. Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro.

    Science.gov (United States)

    Nguyen, Deborah G; Funk, Juergen; Robbins, Justin B; Crogan-Grundy, Candace; Presnell, Sharon C; Singer, Thomas; Roth, Adrian B

    2016-01-01

    Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI). This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM). Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level.

  8. 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.

  9. Metformin Represses Drug-Induced Expression of CYP2B6 by Modulating the Constitutive Androstane Receptor Signaling

    Science.gov (United States)

    Yang, Hui; Garzel, Brandy; Heyward, Scott; Moeller, Timothy; Shapiro, Paul

    2014-01-01

    Metformin is currently the most widely used drug for the treatment of type 2 diabetes. Mechanistically, metformin interacts with many protein kinases and transcription factors that alter the expression of numerous downstream target genes governing lipid metabolism, cell proliferation, and drug metabolism. The constitutive androstane receptor (CAR, NR1i3), a known xenobiotic sensor, has recently been recognized as a novel signaling molecule, in that its activation could be regulated by protein kinases in addition to the traditional ligand binding. We show that metformin could suppress drug-induced expression of CYP2B6 (a typical target gene of CAR) by modulating the phosphorylation status of CAR. In human hepatocytes, metformin robustly suppressed the expression of CYP2B6 induced by both indirect (phenobarbital) and direct CITCO [6-(4-chlorophenyl)imidazo[2,1-b]1,3thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime] activators of human CAR. Mechanistic investigation revealed that metformin specifically enhanced the phosphorylation of threonine-38 of CAR, which blocks CAR nuclear translocation and activation. Moreover, we showed that phosphorylation of CAR by metformin was primarily an AMP-activated protein kinase– and extracellular signal-regulated kinase 1/2–dependent event. Additional two-hybrid and coimmunoprecipitation assays demonstrated that metformin could also disrupt CITCO-mediated interaction between CAR and the steroid receptor coactivator 1 or the glucocorticoid receptor-interacting protein 1. Our results suggest that metformin is a potent repressor of drug-induced CYP2B6 expression through specific inhibition of human CAR activation. Thus, metformin may affect the metabolism and clearance of drugs that are CYP2B6 substrates. PMID:24252946

  10. Inhibin beta E is upregulated by drug-induced endoplasmic reticulum stress as a transcriptional target gene of ATF4

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    Brüning, Ansgar, E-mail: ansgar.bruening@med.uni-muenchen.de; Matsingou, Christina; Brem, German Johannes; Rahmeh, Martina; Mylonas, Ioannis

    2012-10-15

    Inhibins and activins are gonadal peptide hormones of the transforming growth factor-β super family with important functions in the reproductive system. By contrast, the recently identified inhibin βE subunit, primarily expressed in liver cells, appears to exert functions unrelated to the reproductive system. Previously shown downregulation of inhibin βE in hepatoma cells and anti-proliferative effects of ectopic inhibin βE overexpression indicated growth-regulatory effects of inhibin βE. We observed a selective re-expression of the inhibin βE subunit in HepG2 hepatoblastoma cells, MCF7 breast cancer cells, and HeLa cervical cancer cells under endoplasmic reticulum stress conditions induced by tunicamycin, thapsigargin, and nelfinavir. Analysis of XPB1 splicing and ATF4 activation revealed that inhibin βE re-expression was associated with induction of the endoplasmic reticulum stress reaction by these drugs. Transfection of an ATF4 expression plasmid specifically induced inhibin βE expression in HeLa cells and indicates inhibin βE as a hitherto unidentified target gene of ATF4, a key transcription factor of the endoplasmic reticulum stress response. Therefore, the inhibin βE subunit defines not only a new player but also a possible new marker for drug-induced endoplasmic reticulum stress. -- Highlights: ► Endoplasmic reticulum stress induces inhibin beta E expression. ► Inhibin beta E is regulated by the transcription factor ATF4. ► Inhibin beta E expression can be used as a marker for drug-induced ER stress.

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

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    Kunio Yoshizawa

    2016-01-01

    Full Text Available A ranula is a mucus retention cyst or pseudocyst caused by leakage of mucus from the sublingual gland and generally occurs in the oral floor. In addition, drug induced hypersensitivity syndrome (DIHS is a rare but well-recognized serious adverse effect characterized by fever, skin rashes, generalized lymphadenopathy, hepatitis, and hepatosplenomegaly and oral stomatitis. This paper presents the first case of successfully treated sublingual ranula with localized injection of OK-432 after healing from drug induced hypersensitivity syndrome, which has previously been unreported in the literature. We present the case of a 38-year-old Japanese woman with sublingual ranula that responded successfully to localized injection treatment with OK-432 after healing from drug induced hypersensitivity syndrome. She was affected with cutaneous myositis and interstitial lung disease when she was 26 years old. At the age 34 years, she received additional oral treatment of diaminodiphenyl-sulfone due to deterioration of the cutaneous myositis, which resulted in drug induced hypersensitivity syndrome (DIHS with severe oral stomatitis. Local injection of OK-432 to the ranula may be a very safe and useful treatment method even if the patient has a history of drug allergy and has connective tissue disease such as cutaneous myositis.

  12. A case report of fulminant type 1 diabetes mellitus associated with drug-induced hypersensitivity syndrome in an elderly patient with coxsackie B4 virus infection and human leukocyte antigen-A24 haplotype.

    Science.gov (United States)

    Takeno, Ayumu; Kanazawa, Ippei; Morita, Miwa; Takedani, Kai; Miyake, Hitomi; Yamamoto, Masahiro; Nogami, Kyoko; Kaneko, Sakae; Sugimoto, Toshitsugu

    2017-09-29

    Drug-induced hypersensitivity syndrome (DIHS) is a severe systemic adverse drug reaction. Previous studies showed that DIHS is associated with the onset of fulminant type 1 diabetes mellitus (FT1D). Although genetic background and abnormalities in immune response or viral infection are considered to be associated with pathogenesis of FT1D, it remains unclear whether virus infection and specific human leukocyte antigen (HLA) typing are involved in DIHS-associated FT1D. Here, we report a case of a 78-year-old female patient with FT1D after DIHS treatment. She was diagnosed as DIHS caused by carbamazepine, and treatment with predonisolone was initiated. After 46 days from the occurrence of DIHS, she was admitted to our hospital because of type 1 diabetes mellitus and diabetic ketoacidosis. Although her Hemoglobin A1c (HbA1c) was elevated by predonisolone treatment (HbA1c: 9.2%), we diagnosed her as fulminant type 1 diabetes mellitus considering the abrupt onset of the ketoacidosis. Her general condition was improved by treatment with fluid infusion and insulin administration. During her clinical course, the infection of coxsackie B4 virus was observed. In addition, the examination of HLA typing showed HLA-A24 haplotype. These findings suggest that the coxsackie B4 virus infection may be involved in the pathogenesis of DIHS-induced FT1D, and that HLA-A24 haplotype might relate to DIHS-associated FT1D.

  13. Common Genetic Variant Risk Score Is Associated With Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study.

    Science.gov (United States)

    Strauss, David G; Vicente, Jose; Johannesen, Lars; Blinova, Ksenia; Mason, Jay W; Weeke, Peter; Behr, Elijah R; Roden, Dan M; Woosley, Ray; Kosova, Gulum; Rosenberg, Michael A; Newton-Cheh, Christopher

    2017-04-04

    Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known. We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, crossover trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine, and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject's drug-induced increase in heart rate-corrected QT (QTc) versus drug concentration. The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide (r=0.55; 95% confidence interval, 0.09-0.81; P=0.02), 23% in response to quinidine (r=0.48; 95% confidence interval, -0.03 to 0.79; P=0.06), and 27% in response to ranolazine (r=0.52; 95% confidence interval, 0.05-0.80; P=0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared with 771 controls (r2=12%, P=1×10-7). We demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to improve

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

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    Yamazaki, Makoto; Miyake, Manami; Sato, Hiroko; Masutomi, Naoya; Tsutsui, Naohisa [Mitsubishi Tanabe Pharma Corporation, Kisarazu, Chiba 292-0818 (Japan); Adam, Klaus-Peter; Alexander, Danny C.; Lawton, Kay A.; Milburn, Michael V.; Ryals, John A.; Wulff, Jacob E. [Metabolon Inc., 617 Davis Drive, Suite 400, Durham, NC 27713 (United States); Guo, Lining, E-mail: lguo@metabolon.com [Metabolon Inc., 617 Davis Drive, Suite 400, Durham, NC 27713 (United States)

    2013-04-01

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

  15. Drug-Induced Acute Myocardial Infarction: Identifying ‘Prime Suspects’ from Electronic Healthcare Records-Based Surveillance System

    Science.gov (United States)

    Coloma, Preciosa M.; Schuemie, Martijn J.; Trifirò, Gianluca; Furlong, Laura; van Mulligen, Erik; Bauer-Mehren, Anna; Avillach, Paul; Kors, Jan; Sanz, Ferran; Mestres, Jordi; Oliveira, José Luis; Boyer, Scott; Helgee, Ernst Ahlberg; Molokhia, Mariam; Matthews, Justin; Prieto-Merino, David; Gini, Rosa; Herings, Ron; Mazzaglia, Giampiero; Picelli, Gino; Scotti, Lorenza; Pedersen, Lars; van der Lei, Johan; Sturkenboom, Miriam

    2013-01-01

    Background Drug-related adverse events remain an important cause of morbidity and mortality and impose huge burden on healthcare costs. Routinely collected electronic healthcare data give a good snapshot of how drugs are being used in ‘real-world’ settings. Objective To describe a strategy that identifies potentially drug-induced acute myocardial infarction (AMI) from a large international healthcare data network. Methods Post-marketing safety surveillance was conducted in seven population-based healthcare databases in three countries (Denmark, Italy, and the Netherlands) using anonymised demographic, clinical, and prescription/dispensing data representing 21,171,291 individuals with 154,474,063 person-years of follow-up in the period 1996–2010. Primary care physicians’ medical records and administrative claims containing reimbursements for filled prescriptions, laboratory tests, and hospitalisations were evaluated using a three-tier triage system of detection, filtering, and substantiation that generated a list of drugs potentially associated with AMI. Outcome of interest was statistically significant increased risk of AMI during drug exposure that has not been previously described in current literature and is biologically plausible. Results Overall, 163 drugs were identified to be associated with increased risk of AMI during preliminary screening. Of these, 124 drugs were eliminated after adjustment for possible bias and confounding. With subsequent application of criteria for novelty and biological plausibility, association with AMI remained for nine drugs (‘prime suspects’): azithromycin; erythromycin; roxithromycin; metoclopramide; cisapride; domperidone; betamethasone; fluconazole; and megestrol acetate. Limitations Although global health status, co-morbidities, and time-invariant factors were adjusted for, residual confounding cannot be ruled out. Conclusion A strategy to identify potentially drug-induced AMI from electronic healthcare data has

  16. Genome-Wide Association Studies for Idiosyncratic Drug-Induced Hepatotoxicity: Looking Back-Looking Forward to Next-Generation Innovation.

    Science.gov (United States)

    Petros, Zelalem; Makonnen, Eyasu; Aklillu, Eleni

    2017-03-01

    Idiosyncratic drug-induced hepatotoxicity is a formidable challenge for rational drug discovery and development, as well as the science of personalized medicine. There is evidence that hereditary factors, in part, contribute to drug toxicity. This expert analysis and review offer the insights gained, and the challenges ahead, for genome-wide association studies (GWASs) of idiosyncratic drug-induced hepatotoxicity. Published articles on genome-wide and subsequent replication studies were systematically searched in the PubMed electronic database. We found that the genetic risk variants that were identified genome-wide, and replication confirmed, are mainly related to polymorphisms in the human leukocyte antigen (HLA) region that include HLA-DQB1*06:02 for amoxicillin-clavulanate, HLA-B*57:01 for flucloxacillin, HLA-DRB1*15:01 for lumiracoxib, and HLA-DRB1*07:01 for lapatinib and ximelagatran-induced hepatotoxicity. Additionally, polymorphisms in ST6 β-galactosamide α-2, 6-sialyltranferase-1 (ST6GAL1), which plays a role in systemic inflammatory response, and variants in intron of family with sequence similarity-65 member-B (FAM65B) that play roles in liver inflammation displayed association with flucloxacillin and antituberculosis drug-induced hepatotoxicity, respectively. Taken together, these GWAS findings offer molecular leads on the central role that the immune system plays in idiosyncratic drug-induced hepatotoxicity. We conclude the expert review with a brief discussion of the salient challenges ahead. These include, for example, the need for discursive discovery paradigms that incorporate alternating GWASs and candidate gene studies, as well as the study of the environtome, the entire complement of environmental factors, including science and innovation policies that enact on global society and the human host, and by extension, on susceptibility for idiosyncratic drug-induced hepatotoxicity.

  17. Reprogramming of sheep fibroblasts into pluripotency under a drug-inducible expression of mouse-derived defined factors.

    Directory of Open Access Journals (Sweden)

    Yang Li

    Full Text Available Animal embryonic stem cells (ESCs provide powerful tool for studies of early embryonic development, gene targeting, cloning, and regenerative medicine. However, the majority of attempts to establish ESC lines from large animals, especially ungulate mammals have failed. Recently, another type of pluripotent stem cells, known as induced pluripotent stem cells (iPSCs, have been successfully generated from mouse, human, monkey, rat and pig. In this study we show sheep fibroblasts can be reprogrammed to pluripotency by defined factors using a drug-inducible system. Sheep iPSCs derived in this fashion have a normal karyotype, exhibit morphological features similar to those of human ESCs and express AP, Oct4, Sox2, Nanog and the cell surface marker SSEA-4. Pluripotency of these cells was further confirmed by embryoid body (EB and teratoma formation assays which generated derivatives of all three germ layers. Our results also show that the substitution of knockout serum replacement (KSR with fetal bovine serum in culture improves the reprogramming efficiency of sheep iPSCs. Generation of sheep iPSCs places sheep on the front lines of large animal preclinical trials and experiments involving modification of animal genomes.

  18. Change of obstruction level during drug-induced sleep endoscopy according to sedation depth in obstructive sleep apnea.

    Science.gov (United States)

    Hong, Sang Duk; Dhong, Hun-Jong; Kim, Hyo Yeol; Sohn, Jung Hyeob; Jung, Yong Gi; Chung, Seung-Kyu; Park, Ju Yeon; Kim, Jin Kyoung

    2013-11-01

    We evaluated the change in upper airway collapse according to the depth of sedation during drug-induced sleep endoscopy (DISE), as well as characteristics possibly associated with that change. Prospective, single center, observational study. Twenty-nine patients with upper airway collapse were twice evaluated using DISE according to the depth of sedation, as confirmed by the bispectral index (BIS), which is a measure of the level of consciousness. Changes in the site and degree of obstruction according to the change in sedation depth at the retropalatal and the retroglossal levels were evaluated. The possible contributing factors of this change were explored. As DISE sedation deepened, the upper airway became narrower in 37% of patients at the retropalatal level and in 44.8% of patients at the retroglossal level. No clinical, polysomnographic, or cephalometric variables showed any association with the change in the degree of retroglossal airway narrowing, with the exception of mouth breathing during DISE. The degree of upper airway narrowing can be aggravated according to the sedation depth. The monitoring of sedation depth during DISE is critical, especially in patients with mouth breathing. Copyright © 2013 The American Laryngological, Rhinological and Otological Society, Inc.

  19. Drug-Induced Self-Assembly of Modified Albumins as Nano-theranostics for Tumor-Targeted Combination Therapy.

    Science.gov (United States)

    Chen, Qian; Wang, Xin; Wang, Chao; Feng, Liangzhu; Li, Yonggang; Liu, Zhuang

    2015-05-26

    Paclitaxel (PTX) can bind to human serum albumin (HSA) via hydrophobic interaction, forming Abraxane, which is a U.S. Food and Drug Administration (FDA) approved effective antitumor nanomedicine drug. Herein, the effective antitumor drug PTX is used to induce the self-assembly of HSA modified with either a photosensitizer chlorin e6 (Ce6), which at the same time serves as a chelating agent for Mn(2+) to enable magnetic resonance imaging, or acyclic Arg-Gly-Asp (cRGDyK) peptide that targets αvβ3-integrin overexpressed on tumor angiogenic endothelium. Two types of tumor-targeting theranostic nanoparticles are constructed, either by coassembly of both HSA-Ce6 and HSA-RGD simultaneously or by forming an HSA-Ce6@HSA-RGD core-shell structure, with the assistance of PTX-induced albumin aggregation. Such albumin-based nanoparticles on one hand could targetαvβ3-integrin, as evidenced by both in vitro and in vivo experiments, and on the other hand enable combined photodynamic/chemotherapy, which offers remarkably improved therapeutic efficacy to kill cancer in comparison to the respective monotherapies. Our work presents a new type of tumor-targeted multifunctional albumin-based nanoparticles by drug-induced self-assembly, which is a rather simple method without any sophisticated chemistry or materials engineering and is promising for multimodel imaging-guided combination therapy of cancer.

  20. Does drug-induced sleep endoscopy predict surgical success of limited palatal muscle resection in patients with obstructive sleep apnea?

    Science.gov (United States)

    Kim, Jae-Wook; Kim, Deok Soo; Kim, Sung-Dong; Mun, Sue Jean; Koo, Soo-Kweon; Cho, Kyu-Sup

    2018-01-30

    The aims of this study were to determine the associated factors affecting the success rate of limited palatal muscle resection (LPMR), and to investigate whether drug-induced sleep endoscopy (DISE) could predict the therapeutic response to LPMR in patients with obstructive sleep apnea obstructive sleep apnea (OSA). Twenty-one consecutive OSA patients underwent LPMR were enrolled. All patients received routine ENT examination, preoperative DISE, and polysomnography (PSG). Clinical, polysomnographic, cephalometric variables, and DISE findings were evaluated. The measurements were related to the success or failure of LPMR based on the results of preoperative and postoperative PSG. The overall success rate of LPMR was 66.6%. Postoperative AHI and minimal oxygen saturation were significantly decreased after LPMR (psuccess and failure groups revealed no significant differences in BMI, Friedman stage, preoperative AHI, minimal oxygen saturation, and all cephalometric parameters. However, the success of LPMR was significantly correlated with site, degree, and configuration of obstruction in DISE. In the velopharynx, complete obstruction (p=0.006) with anterolateral or concentric pattern (p=0.044) had significantly better success rate than partial obstruction with lateral pattern. DISE was only predictive method for identifying the success in OSA patients undergoing LPMR. Patients with anteroposterior or concentric total obstruction in the velopharynx might be suitable candidate for LPMR. Copyright © 2018 Elsevier B.V. All rights reserved.

  1. Does drug-induced sleep endoscopy predict surgical success in transoral robotic multilevel surgery in obstructive sleep apnea?

    Science.gov (United States)

    Meraj, Taha S; Muenz, Daniel G; Glazer, Tiffany A; Harvey, Rebecca S; Spector, Matthew E; Hoff, Paul T

    2017-04-01

    The aim of this study was to determine if drug-induced sleep endoscopy (DISE) was predictive of success for patients undergoing transoral robotic surgery (TORS) and multilevel procedures for sleep apnea. Retrospective case series of patients who underwent TORS surgery for sleep apnea METHODS: Before and after polysomnograms were analyzed to assess improvement, success, and cure. Improvement was defined as any decrease in apnea-hypopnea index (AHI), success as an AHI 50%, and cure as an AHI success, whereas 17% were cured. The degree of collapse at individual NOHL and VOTE subsites as well as total additive scores did not predict improvement, success, or cure. Patients with no oropharyngeal lateral collapse in the VOTE classification system were more likely to improve following surgery (P = .001); however, this effect did not hold for success or cure. Multivariate analysis of DISE variables was not predictive of success. In obstructive sleep apnea patients, there is a 51% success rate and a 17% cure rate. DISE, as scored by the NOHL and VOTE system, did not readily identify patients who would benefit most from surgery. Patients with lateral oropharyngeal collapse may be poorer candidates. Prospective, larger studies are required to further evaluate the use of DISE in predicting success following TORS. 4 Laryngoscope, 127:971-976, 2017. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

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

    DEFF Research Database (Denmark)

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

    2010-01-01

    Background  The use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment for survivors of out of hospital cardiac arrest. However, this type of therapy is cumbersome and associated with several side-effects. We investigated the feas......Background  The use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment for survivors of out of hospital cardiac arrest. However, this type of therapy is cumbersome and associated with several side-effects. We investigated...... the feasibility of using a transient receptor potential vanilloid type 1 (TRPV1) agonist for obtaining drug-induced sustainable mild hypothermia. Methods First, we screened a heterogeneous group of TRPV1 agonists and secondly we tested the hypothermic properties of a selected candidate by dose-response studies......). The investigated TRPV1 agonists were administered by continuous intravenous infusion. Results  Screening: Dihydrocapsaicin (DHC), a component of chili pepper, displayed a desirable hypothermic profile with regards to the duration, depth and control in conscious rats. Dose-response experiments: In both rats...

  3. OXIDANT STRESS, MITOCHONDRIA AND CELL DEATH MECHANISMS IN DRUG-INDUCED LIVER INJURY: LESSONS LEARNED FROM ACETAMINOPHEN HEPATOTOXICITY

    Science.gov (United States)

    Jaeschke, Hartmut; McGill, Mitchell R.; Ramachandran, Anup

    2017-01-01

    Hepatotoxicity is a serious problem during drug development and for the use of many established drugs. For example, acetaminophen overdose is currently the most frequent cause of acute liver failure in the United States and Great Britain. Evaluation of the mechanisms of drug-induced liver injury indicates that mitochondria are critical targets for drug toxicity, either directly or indirectly through formation of reactive metabolites. The consequence of these modifications is generally a mitochondrial oxidant stress and peroxynitrite formation, which leads to structural alterations of proteins and mitochondrial DNA and eventually to the opening of mitochondrial membrane permeability transition (MPT) pores. MPT pore formation results in collapse of the mitochondrial membrane potential and cessation of ATP synthesis. In addition, the release of intermembrane proteins such as apoptosis-inducing factor and endonuclease G and their translocation to the nucleus leads to nuclear DNA fragmentation. Together these events trigger necrotic cell death. Alternatively, release of cytochrome c and other pro-apoptotic factors from mitochondria can promote caspase activation and apoptotic cell death. Drug toxicity can also induce an inflammatory response with formation of reactive oxygen species by Kupffer cells and neutrophils. If not properly detoxified, these extracellularly generated oxidants can diffuse into hepatocytes and trigger mitochondrial dysfunction and oxidant stress, which then induces the MPT and necrotic cell death. This review addresses the formation of oxidants and the defense mechanisms available for the cells and applies this knowledge to better understand mechanisms of drug hepatotoxicity, especially acetaminophen-induced liver injury. PMID:22229890

  4. 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.

  5. Liver injury from herbals and dietary supplements in the U.S. 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

    2014-10-01

    The Drug-Induced Liver Injury Network (DILIN) studies hepatotoxicity caused by conventional medications as well as herbals and dietary supplements (HDS). 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 U.S. 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 caused by HDS. Hepatotoxicity caused by HDS was evaluated by expert opinion. Demographic and clinical characteristics and outcome assessments, including death and liver transplantation (LT), were ascertained. Cases were stratified and compared according to the type of agent implicated in liver injury; 45 had injury caused by bodybuilding HDS, 85 by nonbodybuilding HDS, and 709 by medications. Liver injury caused by 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 LT. 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 or medications, as evidenced by differences in unfavorable outcomes (death and transplantation). (Hepatology 2014;60:1399-1408). © 2014 by the American Association for the Study of Liver Diseases.

  6. Application of data mining and visualization techniques for the prediction of drug-induced nausea in man.

    Science.gov (United States)

    Parkinson, Joanna; Muthas, Daniel; Clark, Matthew; Boyer, Scott; Valentin, Jean-Pierre; Ewart, Lorna

    2012-03-01

    The therapeutic value of many drugs can be limited by gastrointestinal (GI) adverse effects such as nausea and vomiting. Nausea is a subjective human sensation, hence little is known about preclinical biomarkers that may accurately and effectively predict its presence in man. The aim of this analysis was to use informatics and data-mining tools to identify plausible preclinical GI effects that may be associated with nausea and that could be of potential use in its prediction. A total of 86 marketed drugs were used in this analysis, and the main outcome was a confirmation that nausogenic and non-nausogenic drugs can be clearly separated based on their preclinical GI observations. Specifically, combinations of common preclinical GI effects (vomiting, diarrhea, and salivary hypersecretion) proved to be strong predictors. The model was subsequently validated with a subset of 20 blinded proprietary small molecules and successfully predicted clinical outcome in 90% of cases. This investigation demonstrated the feasibility of data-mining approaches to facilitate discovery of novel, plausible associations that can be used to understand drug-induced adverse effects.

  7. Drug-Induced QT Prolongation and Torsades de Pointes: An All-Exclusive Relationship or Time for an Amicable Separation?

    Science.gov (United States)

    Hondeghem, Luc M

    2017-08-29

    QT prolongation was perceived as a major antiarrhythmic mechanism, but soon became a surrogate for torsades de pointes (TdP) instead. Drugs that prolong the QT interval range from having potent torsadogenic activity to no proarrhythmic action and even antiarrhythmic effects. Blockade of hERG channels is the primary cause of TdP, but blockade/activation of other channels can also be torsadogenic. TdP is primarily caused by disturbances of TRIaD, but disturbance of wavelength can also contribute to TdP (where TRIaD is triangulation, reverse use dependence, instability and dispersion, and wavelength equals conduction velocity times effective refractory period). The above proarrhythmic parameters do not only result in TdP, but can also lead to ventricular tachycardia (VT) and ventricular fibrillation (VF). Note that QT prolongation (not listed as a causal factor) yields many false positives (potentially depriving patients from much needed drugs) and false negatives (potentially exposing patients to lethal arrhythmias). Thus, drug-induced QT prolongation is a bad surrogate for TdP, VT or VF; it is high time to move away from an oversimplified and erroneous surrogate.

  8. Systems Analysis of Drug-Induced Receptor Tyrosine Kinase Reprogramming Following Targeted Mono- and Combination Anti-Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Alexey Goltsov

    2014-06-01

    Full Text Available The receptor tyrosine kinases (RTKs are key drivers of cancer progression and targets for drug therapy. A major challenge in anti-RTK treatment is the dependence of drug effectiveness on co-expression of multiple RTKs which defines resistance to single drug therapy. Reprogramming of the RTK network leading to alteration in RTK co-expression in response to drug intervention is a dynamic mechanism of acquired resistance to single drug therapy in many cancers. One route to overcome this resistance is combination therapy. We describe the results of a joint in silico, in vitro, and in vivo investigations on the efficacy of trastuzumab, pertuzumab and their combination to target the HER2 receptors. Computational modelling revealed that these two drugs alone and in combination differentially suppressed RTK network activation depending on RTK co-expression. Analyses of mRNA expression in SKOV3 ovarian tumour xenograft showed up-regulation of HER3 following treatment. Considering this in a computational model revealed that HER3 up-regulation reprograms RTK kinetics from HER2 homodimerisation to HER3/HER2 heterodimerisation. The results showed synergy of the trastuzumab and pertuzumab combination treatment of the HER2 overexpressing tumour can be due to an independence of the combination effect on HER3/HER2 composition when it changes due to drug-induced RTK reprogramming.

  9. Nenatal drug induced nephrotoxicity : old and next generation biomarkers for early detection and management of neonatal drug-induced nephrotoxicity, with special emphasis on uNGAL and on metabolomics.

    Science.gov (United States)

    Fanos, V; Antonucci, R; Zaffanello, M; Mussap, M

    2012-01-01

    For a long time, nephrotoxicity has been definitively defined as renal injury or dysfunction that arises as a direct or indirect result of exposure to drugs and industrial or environmental chemicals. There are a number of inherent difficulties in diagnostic procedures for toxic nephropathy, which include the absence of standard diagnostic criteria and the inability to relate exposure to a given agent and the observed effect. Critically ill newborns represent a high risk population for developing toxic nephropathy because of incomplete maturation of the kidney; furthermore, they are often treated with a combination of various therapeutic agents, each of them potentially inducing renal tissue injury. Antibiotics, antifungals, and non-steroidal antiiflammatory drugs (NSAIDs) can induce nephrotoxic damage by several, concomitant mechanisms of action on different segments of the nephron. The most common clinical feature following a nephrotoxic effect is acute kidney injury (AKI) which, in turn, comprises a spectrum of severe tissue damages along the nephron, leading to an abrupt decline in renal function. Because early stages of toxic nephropathy are characterized by very few specific clinical signs and symptoms, there is the urgent need to investigate new biomarkers for predicting nephrotoxicity and localizing the injury to a specific nephron site, in order to reduce the risk of acute renal injury and/or acute tubular necrosis. The most promising biomarker for the early assessment of kidney injury and damage is neutrophil gelatinase-associated lipocalin (NGAL). NGAL can be easily measured in urine by an automated analytical method, allowing its clinical use in emergency likewise creatinine. Considerable expectations in terms of improvement of the management of newborns developing drug-induced nephropaties derive from the clinical application of metabolomics.

  10. Abnormal glucose tolerance and lipid abnormalities in Indian ...

    African Journals Online (AJOL)

    quency of abnormal glucose tolerance (impaired glucose tole- rance and diabetes mellitus) in Indian patients with CAD is similar to that in White patients.9 However, with respect to the lipid profile there have been conflicting reports; hypercholeste- rolaemia was present in 37% ofthe series described by McKech- nie' and ...

  11. Assessing common classification methods for the identification of abnormal repolarization using indicators of T-wave morphology and QT interval

    DEFF Research Database (Denmark)

    Shakibfar, Saeed; Graff, Claus; Ehlers, Lars Holger

    2012-01-01

    Various parameters based on QTc and T-wave morphology have been shown to be useful discriminators for drug induced I(Kr)-blocking. Using different classification methods this study compares the potential of these two features for identifying abnormal repolarization on the ECG. A group of healthy...... volunteers and LQT2 carriers were used to train classification algorithms using measures of T-wave morphology and QTc. The ability to correctly classify a third group of test subjects before and after receiving d,l-sotalol was evaluated using classification rules derived from training. As a single...... electrocardiographic feature, T-wave morphology separates normal from abnormal repolarization better than QTc. It is further indicated that nonlinear boundaries can provide stronger classifiers than a linear boundaries. Whether this is true in general with other ECG markers and other data sets is uncertain because...

  12. Drug-induced diarrhea

    Science.gov (United States)

    ... Zantac), and nizatidine (Axid) Medicines that suppress the immune system (such as mycophenolate) Nonsteroidal anti-iflammatory drugs (NSAIDs) ... care provider about taking supplements containing healthy bacteria (probiotics). Some of these products may reduce the risk of diarrhea. Keep taking these ... References Schiller LR, Sellin JH. Diarrhea. In: ...

  13. Chemotherapeutic drug induced pneumonitis

    Energy Technology Data Exchange (ETDEWEB)

    Schmidt, M.; Brugger, E.

    1981-09-01

    A series of chemotherapeutic drugs is known to induce interstitial lung disease of letal outcome. Diffuse fibrosing interstitial pneumonias are more frequently observed due to Busulfan, Bleomycin, BCNU or Methotrexat therapy. As well literature as our own investigations demonstrate low sensitivity of X-ray controlls in diagnosing beginning changes. Lung function tests including diffusion capacity analysis are more practicable to recognize early phases of disease. Nevertheless, clinical practice shows patients being moust sensitive in decovering beginning decreases of lung function. Exercise induced dyspnea, raw cough and often fever, dyspnea at rest and finally pulmonary insufficiency will be the climax of symptoms. All patients treated with Busulfan, Bleomycin, BCNU and probably Methotrexat should regulary be controlled by lung function analysis.

  14. Drug-induced tremor

    Science.gov (United States)

    ... include: Alcohol withdrawal Cigarette smoking Overactive thyroid ( hyperthyroidism ) Parkinson disease Adrenal gland tumor ( pheochromocytoma ) Too much caffeine Disorder in which there is too much copper in the body ( Wilson disease ) Blood tests and ...

  15. The role of cigarette smoking and liver enzymes polymorphisms in anti-tuberculosis drug-induced hepatotoxicity in Brazilian patients.

    Science.gov (United States)

    Zaverucha-do-Valle, Camila; Monteiro, Sérgio P; El-Jaick, Kênia B; Rosadas, Leonardo A; Costa, Marli J M; Quintana, Marcel S B; de Castro, Liane

    2014-05-01

    Tuberculosis (TB) is still a major health concern and side-effects related to the treatment, especially drug-induced hepatotoxicity (DIH), should be better investigated. In the present study, a possible association between anti-TB DIH and cigarette smoking, N-acetyltransferase 2 (NAT2), Cytochrome P450 2E1 (CYP2E1) and Cytochrome P450 3A4 (CYP3A4) genotypes was studied in 131 TB Brazilian patients. The NAT2 and CYP3A4 genetic polymorphisms were determined using a polymerase chain reaction (PCR) direct sequencing approach and genetic polymorphisms of CYP2E1 gene were determined by restriction fragment length polymorphism (RFLP). The risk of anti-TB DIH was lower in rapid/intermediate acetylators when compared to slow acetylators (OR: 0.34, CI 95: 0.16-0.71; p < 0.01). A decreased risk of developing anti-TB DIH was also observed in active smokers when compared to non-smokers (OR: 0.28, 95 CI: 0.11-0.64; p < 0.01). Significant association between CYP3A4 genotypes and hepatotoxicity was not observed, as well as between CYP2E1 genotype and hepatotoxicity, whose frequency of patients with wild homozygous was more prevalent. The anti-TB drugs interactions with smoking on hepatotoxicity, as well as the NAT2 phenotype, may require to adjust therapeutic regimen dosages or alarm in case of adverse event developments. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Drug-induced immune hemolytic anemia associated with anti-carboplatin and the first example of anti-paclitaxel.

    Science.gov (United States)

    Leger, Regina M; Jain, Shweta; Nester, Theresa A; Kaplan, Henry

    2015-12-01

    Combined chemotherapy with carboplatin and paclitaxel is first-line treatment for lung and ovarian cancer. Drug-induced antibodies to carboplatin are rare but can cause severe, even fatal, hemolysis. Paclitaxel-induced immune hemolysis has not been reported. We describe a case of immune-mediated hemolysis associated with antibodies to carboplatin and paclitaxel in a woman with ovarian cancer who had received multiple chemotherapeutic agents over 7 years, including several courses of these two drugs. She required many transfusions. During a chemotherapy infusion the patient became hypotensive, was pale, and had rigors and red urine. The nadir hematocrit was 12.4%; peak bilirubin and lactate dehydrogenase were 16.3 mg/dL and 1188 units/L, respectively. Blood samples collected within hours after chemotherapy and 2 days later were tested for antibodies to carboplatin and paclitaxel. The direct antiglobulin test was positive with anti-IgG (3+) and anti-C3 (2+). The plasma collected shortly after chemotherapy agglutinated carboplatin-treated red blood cells (RBCs); untreated and paclitaxel-treated RBCs both reacted at the antiglobulin test most likely due to circulating carboplatin, paclitaxel, or both drugs. Serum collected 2 days later agglutinated (titer 2) and sensitized (titer 128) carboplatin-treated RBCs; untreated and paclitaxel-treated RBCs were nonreactive. An acid eluate reacted weakly in the presence of polyethylene glycol with carboplatin-treated RBCs. The serum reacted with untreated and enzyme-treated RBCs in the presence of soluble carboplatin and paclitaxel. Anti-carboplatin and the first example of anti-paclitaxel were detected in this patient's sample. © 2015 AABB.

  17. A systematic assessment of mitochondrial function identified novel signatures for drug-induced mitochondrial disruption in cells.

    Science.gov (United States)

    Li, Nianyu; Oquendo, Elisa; Capaldi, Roderick A; Robinson, J Paul; He, Yudong D; Hamadeh, Hisham K; Afshari, Cynthia A; Lightfoot-Dunn, Ruth; Narayanan, Padma Kumar

    2014-11-01

    Mitochondrial perturbation has been recognized as a contributing factor to various drug-induced organ toxicities. To address this issue, we developed a high-throughput flow cytometry-based mitochondrial signaling assay to systematically investigate mitochondrial/cellular parameters known to be directly impacted by mitochondrial dysfunction: mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (ROS), intracellular reduced glutathione (GSH) level, and cell viability. Modulation of these parameters by a training set of compounds, comprised of established mitochondrial poisons and 60 marketed drugs (30 nM to 1mM), was tested in HL-60 cells (a human pro-myelocytic leukemia cell line) cultured in either glucose-supplemented (GSM) or glucose-free (containing galactose/glutamine; GFM) RPMI-1640 media. Post-hoc bio-informatic analyses of IC50 or EC50 values for all parameters tested revealed that MMP depolarization in HL-60 cells cultured in GSM was the most reliable parameter for determining mitochondrial dysfunction in these cells. Disruptors of mitochondrial function depolarized MMP at concentrations lower than those that caused loss of cell viability, especially in cells cultured in GSM; cellular GSH levels correlated more closely to loss of viability in vitro. Some mitochondrial respiratory chain inhibitors increased mitochondrial ROS generation; however, measuring an increase in ROS alone was not sufficient to identify mitochondrial disruptors. Furthermore, hierarchical cluster analysis of all measured parameters provided confirmation that MMP depletion, without loss of cell viability, was the key signature for identifying mitochondrial disruptors. Subsequent classification of compounds based on ratios of IC50s of cell viability:MMP determined that this parameter is the most critical indicator of mitochondrial health in cells and provides a powerful tool to predict whether novel small molecule entities possess this liability. © The Author

  18. Tuberculous drug-induced liver injury and treatment re-challenge in Human Immunodeficiency Virus co-infection

    Directory of Open Access Journals (Sweden)

    Cecilia T Costiniuk

    2015-01-01

    Full Text Available Background: Tuberculosis drug-induced liver injury (TB-DILI is the most common adverse event necessitating therapy interruption. The optimal re-challenge strategy for antituberculous therapy (ATT remains unclear, especially in human immunodeficiency virus (HIV co-infected individuals in high-prevalence settings such as South Africa. Objective: To determine the incidence of and risk factors for the recurrence of TB-DILI with different ATT re-challenge strategies. Materials and Methods: We conducted a retrospective chart review of patients managed for TB-DILI from 2005 to 2013 at King Edward VIII Hospital in Durban, South Africa. Relevant clinical and laboratory data at the presentation of TB-DILI, time to recovery of liver function, method of ATT re-challenge and outcome of re-challenge were documented. Results: 1016 charts were reviewed, and 53 individuals with TB-DILI (48 HIV-co-infected were identified. Following discontinuation of ATT, the median time to alanine aminotransferase normalization was 28 days (interquartile range 13-43. Forty-two subjects were re-challenged (30 regimen re-challenges and 12 step-wise re-challenges. 5 (12% cases of recurrent TB-DILI were noted. Recurrences were not associated with the method of re-challenge. Conclusion: Based on the data available, it appears that full ATT can be safely restarted in the majority of subjects with a recurrence of DILI occurring in about 12% of subjects. The method of re-challenge did not appear to impact on the risk of recurrence. Ideally, a prospective randomized trial is needed to determine the best method of re-challenge.

  19. Optimized Methods to Explore the Mechanistic and Biomarker Potential of Hepatocyte-Derived Exosomes in Drug-Induced Liver Injury.

    Science.gov (United States)

    Thacker, Sarah E; Nautiyal, Manisha; Otieno, Monicah A; Watkins, Paul B; Mosedale, Merrie

    2018-01-27

    Recent evidence supports that alterations in hepatocyte-derived exosomes (HDE) may play a role in the pathogenesis of drug-induced liver injury (DILI). HDE-based biomarkers also hold promise to improve the sensitivity of existing in vitro assays for predicting DILI liability. Primary human hepatocytes (PHH) provide a physiologically relevant in vitro model to explore the mechanistic and biomarker potential of HDE in DILI. However, optimal methods to study exosomes in this culture system have not been defined. Here we use HepG2 and HepaRG cells along with PHH to optimize methods for in vitro HDE research. We compared the quantity and purity of HDE enriched from HepG2 cell culture medium by three widely used methods: ultracentrifugation (UC), OptiPrep density gradient ultracentrifugation (ODG), and ExoQuick (EQ) - a commercially available exosome precipitation reagent. While EQ resulted in the highest number of particles, UC resulted in more exosomes as indicated by the relative abundance of exosomal CD63 to cellular prohibitin-1 as well as the comparative absence of contaminating extravesicular material. To determine culture conditions that best supported exosome release, we also assessed the effect of Matrigel matrix overlay at concentrations ranging from 0-0.25 mg/ml in HepaRG cells and compared exosome release from fresh and cryopreserved PHH from same donor. Sandwich culture did not impair exosome release, and freshly prepared PHH yielded a higher number of HDE overall. Taken together, our data support the use of UC-based enrichment from fresh preparations of sandwich-cultured PHH for future studies of HDE in DILI. © The Author 2018. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  20. In vitro to in vivo extrapolation for drug-induced liver injury using a pair ranking method.

    Science.gov (United States)

    Liu, Zhichao; Fang, Hong; Borlak, Jürgen; Roberts, Ruth; Tong, Weida

    2017-01-01

    Preclinical animal toxicity studies may not accurately predict human toxicity. In light of this, in vitro systems have been developed that have the potential to supplement or even replace animal use. We examined in vitro to in vivo extrapolation (IVIVE) of gene expression data obtained from The Open Japanese Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (Open TG-GATEs) for 131 compounds given to rats for 28 days, and to human or rat hepatocytes for 24 hours. Notably, a pair ranking (PRank) method was developed to assess IVIVE potential with a PRank score based on the preservation of the order of similarity rankings of compound pairs between the platforms using a receiver operating characteristic (ROC) curve analysis to measure area under the curve (AUC). A high IVIVE potential was noted for rat primary hepatocytes when compared to rat 28-day studies (PRank score = 0.71) whereas the IVIVE potential for human primary hepatocytes compared to rat 28-day studies was lower (PRank score = 0.58), indicating that species difference plays a critical role in IVIVE. When limiting the analysis to only those drugs causing drug-induced liver injury, the IVIVE potential was slightly improved both for rats (from 0.71 to 0.76) and for humans (from 0.58 to 0.62). Similarly, PRank scores were improved when the analysis focused on specific hepatotoxic endpoints such as hepatocellular injury, or cholestatic injury. In conclusion, toxicogenomic data generated in vitro yields a ranking of drugs regarding their potential to cause toxicity which is comparable to that generated by in vivo analyses.

  1. The Effectiveness of Low-Level Laser Therapy in Patients with Drug-Induced Hyposalivation: A Pilot Study.

    Science.gov (United States)

    Terlević Dabić, Diana; Jurišić, Sanja; Vučićević Boras, Vanja; Gabrić, Dragana; Bago, Ivona; Vrdoljak, Danko Velimir

    2016-09-01

    The aim of this study was to compare switched on and switched off (sham) low-level laser therapy (LLLT) in the treatment of drug-induced hyposalivation. Hyposalivation is decreased salivary flow rate most frequently present in patients who take a lot of medication, suffer from Sjögren's syndrome, or were irradiated. Available therapies provide only short-term relief. Forty-three participants (40 females and 3 males, average age 72.3 ± 8.9) participated in the study. Before therapy or after therapy, every participant fulfilled quality-of-life assessment scale (OHIP-CRO14). Unstimulated and stimulated salivary flow rates were measured before and after treatment. The LLLT was performed by the use of gallium-aluminum-arsenide (GaAlAs) laser (830 nm) on parotid, submandibular, and sublingual glands every day except during weekends for 14 days. Significant difference in unstimulated salivary flow rate after the treatment was found in the study group (p = 0.002) compared with the sham group. No significant difference in stimulated salivary flow rate after treatment was found in the laser group (p = 0.626) nor in the sham laser group (p = 0.233). No significant difference in patient's quality-of-life score was found after both treatments. The results of this study showed that the LLLT increased unstimulated salivary flow rate significantly. However, stimulated salivary flow rate did not increase significantly after the LLLT. In patients who underwent sham laser therapy, neither unstimulated nor stimulated salivary flow rate increased significantly.

  2. Drug-Induced Liver Injury: Twenty Five Cases of Acute Hepatitis Following Ingestion of Polygonum multiflorum Thunb

    Science.gov (United States)

    Jung, Kyoung Ah; Yoo, Seung Suk; Kim, Hong Jun; Choi, Su Nyoung; Ha, Chang Yoon; Kim, Hyun Jin; Kim, Tae Hyo; Jung, Woon Tae; Lee, Ok Jae; Lee, Jong Sil; Shim, Sang Goon

    2011-01-01

    Background/Aims Complementary medicines, including herbal preparations and nutritional supplements, are widely used without prescriptions. As a result, there has been growing interest in the risk of hepatotoxicity with these agents. It is difficult to determine causal relationships between these herbal preparations and hepatotoxicity. We report on 25 patients diagnosed with toxic hepatitis following ingestion of Polygonum multiflorum Thunb. Methods Twenty-five patients (median age, 48 years [24 to 65 years]; M:F=18:7) with suspected P. multiflorum Thunb-induced liver injury were admitted to our hospital between 2007 and 2009. We analyzed clinical and histological data, including the types and the duration of P. multiflorum Thunb intake and the duration of hospital care. We also determined the type of liver injury using the R ratio (serum activity of ALT/serum activity of ALP). Results The types of complementary medicine used included tea (n=16), liquor (n=5), tea and liquor (n=2), powder (n=1), and honeyed pudding (n=1). The most common presenting sign was jaundice (76%), and 18 patients (72%) had evidence of hepatocellular liver injury. Histological findings were consistent with acute hepatitis in all cases (n=10) for which liver biopsy was performed. Twenty-three patients (91.6%) recovered with conservative management, 1 patient (4%) had a liver transplant, and 1 patient (4%) died of hepatic failure. Conclusions In our cases, we found that P. multiflorum Thunb could be hepatotoxic and could lead to severe drug-induced liver injury, and even death. PMID:22195249

  3. Serum apolipoprotein A1 and haptoglobin, in patients with suspected drug-induced liver injury (DILI as biomarkers of recovery.

    Directory of Open Access Journals (Sweden)

    Valentina Peta

    Full Text Available There is a clear need for better biomarkers of drug-induced-liver-injury (DILI.We aimed to evaluate the possible prognostic value of ActiTest and FibroTest proteins apoliprotein-A1, haptoglobin and alpha-2-macroglobulin, in patients with DILI.We analyzed cases and controls included in the IMI-SAFE-T-DILI European project, from which serum samples had been stored in a dedicated biobank. The analyses of ActiTest and FibroTest had been prospectively scheduled. The primary objective was to analyze the performance (AUROC of ActiTest components as predictors of recovery outcome defined as an ALT <2x the upper limit of normal (ULN, and BILI <2x ULN.After adjudication, 154 patients were considered to have DILI and 22 were considered to have acute liver injury without DILI. A multivariate regression analysis (ActiTest-DILI patent pending combining the ActiTest components without BILI and ALT (used as references, apolipoprotein-A1, haptoglobin, alpha-2-macroglobulin and GGT, age and gender, resulted in a significant prediction of recovery with 67.0% accuracy (77/115 and an AUROC of 0.724 (P<0.001 vs. no prediction 0.500. Repeated apolipoprotein-A1 and haptoglobin remained significantly higher in the DILI cases that recovered (n = 65 versus those that did not (n = 16, at inclusion, at 4-8 weeks and at 8-12 weeks. The same results were observed after stratification on APAP cases and non-APAP cases.We identified that apolipoprotein-A1 and haptoglobin had significant predictive values for the prediction of recovery at 12 weeks in DILI, enabling the construction of a new prognostic panel, the DILI-ActiTest, which needs to be independently validated.

  4. High frequency of HLA B62 in fulminant type 1 diabetes with the drug-induced hypersensitivity syndrome.

    Science.gov (United States)

    Onuma, Hiroshi; Tohyama, Mikiko; Imagawa, Akihisa; Hanafusa, Toshiaki; Kobayashi, Tetsuro; Kano, Yoko; Ohashi, Jun; Hashimoto, Koji; Osawa, Haruhiko; Makino, Hideichi

    2012-12-01

    Fulminant type 1 diabetes (FT1D) is a subtype of type 1 diabetes characterized by an extremely abrupt onset. FT1D cases associated with the drug-induced hypersensitivity syndrome (DIHS) have recently been reported. The clinical characteristics of FT1D associated with DIHS were investigated in this study. Case reports of FT1D associated with DIHS in Japanese subjects were collected and analyzed by means of a questionnaire to the authors. A nationwide questionnaire survey was administered to dermatology specialists, concerning the frequency of FT1D associated with DIHS. In 15 case reports, the mean age at onset of FT1D was 53.4 yr and the mean time for its development from the onset of DIHS was 39.9 d. A higher frequency of human leukocyte antigen (HLA) B62, but not of HLA DR was found in FT1D with DIHS than that for cases without DIHS (P < 0.001). The reactivation of herpes virus 6 and cytomegalovirus was detected in 11 and four cases, respectively. Among 746 patients with DIHS in the nationwide survey, four developed FT1D during a 3-yr period. The frequency of FT1D in DIHS (0.54%) was much higher than that in the general Japanese population (0.010%). The clinical characteristics of FT1D with DIHS were similar to those without DIHS except for the high frequency of HLA B62, which may be involved in the pathogenesis of FT1D with DIHS. Because the frequency was much higher than that in the general Japanese population, FT1D should be kept in mind when DIHS develops.

  5. Soluble thrombomodulin in bronchoalveolar lavage fluid is an independent predictor of severe drug-induced lung injury.

    Science.gov (United States)

    Suzuki, Atsushi; Taniguchi, Hiroyuki; Kondoh, Yasuhiro; Ando, Masahiko; Watanabe, Naohiro; Kimura, Tomoki; Kataoka, Kensuke; Yokoyama, Toshiki; Sakamoto, Koji; Hasegawa, Yoshinori

    2017-05-01

    Drug-induced lung injury (DLI) can result from a vast number of agents, and sometimes presents findings similar to those of acute respiratory distress syndrome (ARDS). Previous studies have reported that circulating levels of soluble thrombomodulin (TM) reflect endothelial injuries, which play key roles in the development of ARDS. We hypothesized that endothelial injuries are an important aspect of pathogenesis in severe DLI. The primary aim of this study was to examine the associations between soluble TM and disease severity in DLI patients. Of the 2580 patients who underwent a bronchoalveolar lavage (BAL) procedure at Tosei General Hospital between May 2007 and February 2015, we retrospectively analysed the data of 68 DLI patients. Soluble TM in plasma and BAL fluid (BALF), and other biomarkers were included in our analysis. At the time of diagnosis, 39 patients (57%) had respiratory failure (partial pressure of oxygen/inspiratory oxygen fraction ratio, PaO2 /FiO2 ratio soluble TM in BALF (r = -0.448, P soluble TM in BALF and surfactant protein D (SP-D) were the only independent determinants of the PaO2 /FiO2 ratio. Additionally, in a multivariate logistic regression model, soluble TM in BALF (adjusted OR (aOR): 7.48, 95% CI: 1.60-34.98) and SP-D (aOR: 5.31, 95% CI: 1.40-20.15) was an independent predictor of respiratory failure (PaO2 /FiO2 ratio Soluble TM in BALF is an independent predictor of severe DLI. These findings underscore the importance of pulmonary endothelial injuries in the pathogenesis of severe DLI. © 2016 Asian Pacific Society of Respirology.

  6. Lentiginosis, Deafness and Cardiac Abnormalities*

    African Journals Online (AJOL)

    1973-01-06

    Jan 6, 1973 ... The familia:l form is milder. The cardiac lesion commonly consists of hypertrophic obstructive cardiomyopathy of either ventricle or abnor- malities of the ECG.' The obstructive lesion may be pro- gressive and cause cardiac failure. The ECG features include conduction abnormalities, such as left hemiblock,.

  7. Chromosomal Abnormalities Associated With Omphalocele

    Directory of Open Access Journals (Sweden)

    Chih-Ping Chen

    2007-03-01

    Full Text Available Fetuses with omphalocele have an increased risk for chromosomal abnormalities. The risk varies with maternal age, gestational age at diagnosis, association with umbilical cord cysts, complexity of associated anomalies, and the contents of omphalocele. There is considerable evidence that genetics contributes to the etiology of omphalocele. This article provides an overview of chromosomal abnormalities associated with omphalocele and a comprehensive review of associated full aneuploidy such as trisomy 18, trisomy 13, triploidy, trisomy 21, 45,X, 47,XXY, and 47,XXX, partial aneuploidy such as dup(3q, dup(11p, inv(11, dup(1q, del(1q, dup(4q, dup(5p, dup(6q, del(9p, dup(15q, dup(17q, Pallister-Killian syndrome with mosaic tetrasomy 12p and Miller-Dieker lissencephaly syndrome with deletion of 17p13.3, and uniparental disomy (UPD such as UPD 11 and UPD 14. Omphalocele is a prominent marker for chromosomal abnormalities. Perinatal identification of omphalocele should alert chromosomal abnormalities and familial unbalanced translocations, and prompt thorough cytogenetic investigations and genetic counseling.

  8. Interpreting chromosomal abnormalities using Prolog.

    Science.gov (United States)

    Cooper, G; Friedman, J M

    1990-04-01

    This paper describes an expert system for interpreting the standard notation used to represent human chromosomal abnormalities, namely, the International System for Human Cytogenetic Nomenclature. Written in Prolog, this program is very powerful, easy to maintain, and portable. The system can be used as a front end to any database that employs cytogenetic notation, such as a patient registry.

  9. Admission haematological abnormalities and postoperative ...

    African Journals Online (AJOL)

    Admission haematological abnormalities and postoperative outcomes in neonates with acute surgical conditions in Alexandria, Egypt. HL Wella, SMM Farahat. Abstract. No Abstract. Full Text: EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT · AJOL African Journals ...

  10. Frontal decortication eliminates drug-induced ascorbic acid release in the striatum but not the nucleus accumbens of freely moving rats.

    Science.gov (United States)

    Gu, Pei Fei; Yang, Jing Yu; Wu, Chun Fu; Li, Wei; Shang, Yu

    2005-02-08

    The mechanism of morphine-, methamphetamine-, and nicotine-induced ascorbic acid (AA) release in the striatum and nucleus accumbens (NAc) is not well understood. In the present study, the roles of the corticostriatal and corticoaccumbens pathways in drug-induced AA release were studied by using microdialysis coupled to high performance liquid chromatography with electrochemical detection (HPLC-ECD). The results showed that morphine (20 mg/kg), methamphetamine (3.0 mg/kg), or nicotine (1.5 mg/kg) intraperitoneally (i.p.) significantly stimulated AA release in the striatum to more than 180%, 190%, and 140% compared with saline groups, respectively. These effects could be completely eliminated by frontal decortication, or antagonized by MK-801 (1.0 mg/kg). Moreover, methamphetamine or nicotine also significantly induced AA release in the NAc to more than 180% and 150% compared with saline groups, respectively. However, these effects could not be eliminated by frontal decortication. Although the effects of methamphetamine or nicotine in the NAc could be antagonized by MK-801, two-way ANOVA analysis did not show a significantly interaction between MK-801 and methamphetamine, or nicotine. The results indicates that the corticostriatal glutamatergic pathway may be a common and necessary pathway in drug-induced AA release in the striatum, but the corticoaccumbens glutamatergic pathway may not be crucial in drug-induced AA release in the NAc. The present study implies that different mechanisms might be involved in drug-induced AA release in the striatum and the NAc in rats.

  11. Risk Factors for Development of Cholestatic Drug-Induced Liver Injury: Inhibition of Hepatic Basolateral Bile Acid Transporters Multidrug Resistance-Associated Proteins 3 and 4

    OpenAIRE

    Köck, Kathleen; Ferslew, Brian C.; Netterberg, Ida; Yang, Kyunghee; Urban, Thomas J.; Swaan, Peter W.; Stewart, Paul W.; Brouwer, Kim L. R.

    2014-01-01

    Impaired hepatic bile acid export may contribute to development of cholestatic drug-induced liver injury (DILI). The multidrug resistance-associated proteins (MRP) 3 and 4 are postulated to be compensatory hepatic basolateral bile acid efflux transporters when biliary excretion by the bile salt export pump (BSEP) is impaired. BSEP inhibition is a risk factor for cholestatic DILI. This study aimed to characterize the relationship between MRP3, MRP4, and BSEP inhibition and cholestatic potentia...

  12. The Hepatoprotection Provided by Taurine and Glycine against Antineoplastic Drugs Induced Liver Injury in an Ex Vivo Model of Normothermic Recirculating Isolated Perfused Rat Liver

    Directory of Open Access Journals (Sweden)

    Reza Heidari

    2016-03-01

    Full Text Available Taurine (2-aminoethane sulfonic acid is a non-protein amino acid found in high concentration in different tissues. Glycine (Amino acetic acid is the simplest amino acid incorporated in the structure of proteins. Several investigations indicate the hepatoprotective properties of these amino acids. On the other hand, antineoplastic agents-induced serum transaminase elevation and liver injury is a clinical complication. The current investigation was designed to screen the possible hepatoprotective properties of taurine and glycine against antineoplastic drugs-induced hepatic injury in an ex vivo model of isolated perfused rat liver. Rat liver was perfused with different concentration (10 μM, 100 μM and 1000 μM of antineoplastic drugs (Mitoxantrone, Cyclophosphamide, Cisplatin, 5 Fluorouracil, Doxorubicin and Dacarbazine via portal vein. Taurine and glycine were administered to drug-treated livers and liver perfusate samples were collected for biochemical measurements (ALT, LDH, AST, and K+. Markers of oxidative stress (reactive oxygen species formation, lipid peroxidation, total antioxidant capacity and glutathione were also assessed in liver tissue. Antineoplastic drugs caused significant pathological changes in perfusate biochemistry. Furthermore, markers of oxidative stress were significantly elevated in drug treated livers. It was found that taurine (5 and 10 mM and glycine (5 and 10 mM administration significantly mitigated the biomarkers of liver injury and attenuated drug induced oxidative stress. Our data indicate that taurine and glycine supplementation might help as potential therapeutic options to encounter anticancer drugs-induced liver injury.

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

    Directory of Open Access Journals (Sweden)

    Alima Hassen Ali

    Full Text Available BACKGROUND: This study was carried out to determine the incidence and predictors of anti-tuberculosis drug induced hepatotoxicity among TB/HIV co-infected patients at Jimma University Hospital, Ethiopia. METHODS/PRINCIPAL FINDINGS: A nested case-control study was conducted by reviewing charts of all TB/HIV co-infected patients who commenced anti-TB treatment from January 2008 to December 2011 at Jimma University Hospital. Patients who had developed hepatotoxicity after at least 5 days of standard doses of anti-TB drug therapy were labeled as "cases" and those without hepatotoxicity were "controls". Each case with anti-TB drug induced hepatotoxicity was compared with 3 controls selected randomly from the cohort. From a cohort of 296 TB/HIV co-infected patients 8 were excluded from the study as the causality between anti-TB drugs and hepatotoxicity was not confirmed, 33 had developed hepatotoxicity. On bivariate logistic regression analysis, body mass index (BMI <18.5 Kg/m(2 [P = 0.01; OR (95%CI: 3.6 (1.4-9.5], disseminated pulmonary TB [P = 0.00; OR (95%CI: 5.6 (2.2-14.6], CD4 count ≤50 [P = 0.016; OR (95%CI: 3.6(1.27-10.23] and WHO stage 4 [P = 0.004, OR (95%CI: 3.8 (1.68-8.77] were significantly associated with anti-TB drug induced hepatotoxicity. Predictor variables with p-value <0.05 by bivariate analysis were analyzed using multivariable logistic regression analysis and identified disseminated pulmonary TB [P = 0.001; AOR (95%CI = 5.6 (2.1-15.0] and BMI <18.5 [P = 0.014; AOR (95%CI= 3.6 (1.3-10.1] as independent predictors of anti-TB drug induced hepatotoxicity. CONCLUSIONS: The incidence of anti-TB drug induced hepatotoxicity was 11.5%. The results suggest that in the presence of disseminated pulmonary TB and/or BMI <18.5 Kg/m(2, TB/HIV co-infected patients should be closely followed for the occurrence of hepatotoxicity during the intensive phase of TB treatment to prevent morbidity and mortality.

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

    Science.gov (United States)

    Hassen Ali, Alima; Belachew, Tefera; Yami, Alemeshet; Ayen, Wubeante Yenet

    2013-01-01

    This study was carried out to determine the incidence and predictors of anti-tuberculosis drug induced hepatotoxicity among TB/HIV co-infected patients at Jimma University Hospital, Ethiopia. A nested case-control study was conducted by reviewing charts of all TB/HIV co-infected patients who commenced anti-TB treatment from January 2008 to December 2011 at Jimma University Hospital. Patients who had developed hepatotoxicity after at least 5 days of standard doses of anti-TB drug therapy were labeled as "cases" and those without hepatotoxicity were "controls". Each case with anti-TB drug induced hepatotoxicity was compared with 3 controls selected randomly from the cohort. From a cohort of 296 TB/HIV co-infected patients 8 were excluded from the study as the causality between anti-TB drugs and hepatotoxicity was not confirmed, 33 had developed hepatotoxicity. On bivariate logistic regression analysis, body mass index (BMI) <18.5 Kg/m(2) [P = 0.01; OR (95%CI): 3.6 (1.4-9.5)], disseminated pulmonary TB [P = 0.00; OR (95%CI): 5.6 (2.2-14.6)], CD4 count ≤50 [P = 0.016; OR (95%CI): 3.6(1.27-10.23)] and WHO stage 4 [P = 0.004, OR (95%CI): 3.8 (1.68-8.77)] were significantly associated with anti-TB drug induced hepatotoxicity. Predictor variables with p-value <0.05 by bivariate analysis were analyzed using multivariable logistic regression analysis and identified disseminated pulmonary TB [P = 0.001; AOR (95%CI) = 5.6 (2.1-15.0)] and BMI <18.5 [P = 0.014; AOR (95%CI)= 3.6 (1.3-10.1)] as independent predictors of anti-TB drug induced hepatotoxicity. The incidence of anti-TB drug induced hepatotoxicity was 11.5%. The results suggest that in the presence of disseminated pulmonary TB and/or BMI <18.5 Kg/m(2), TB/HIV co-infected patients should be closely followed for the occurrence of hepatotoxicity during the intensive phase of TB treatment to prevent morbidity and mortality.

  15. Mastoid abnormalities in Down syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Glass, R.B.J.; Yousefzadeh, D.K.; Roizen, N.J.

    1989-06-01

    Hearing loss and otitis media are commonly associated with Down syndrome. Hypoplasia of the mastoids is seen in many affected children and sclerosis of mastoid bones is not uncommon in Down syndrome. Awareness and early recognition of mastoid abnormality may lead to appropriate and timely therapy, thereby preserving the child's hearing or compensating for hearing loss; factors which are important for learning and maximum development.

  16. Normal and abnormal skin color.

    Science.gov (United States)

    Ortonne, J P

    2012-12-01

    The varieties of normal skin color in humans range from people of "no color" (pale white) to "people of color" (light brown, dark brown, and black). Skin color is a blend resulting from the skin chromophores red (oxyhaemoglobin), blue (deoxygenated haemoglobin), yellow-orange (carotene, an exogenous pigment), and brown (melanin). Melanin, however, is the major component of skin color ; it is the presence or absence of melanin in the melanosomes in melanocytes and melanin in keratinocytes that is responsible for epidermal pigmentation, and the presence of melanin in macrophages or melanocytes in the dermis that is responsible for dermal pigmentation. Two groups of pigmentary disorders are commonly distinguished: the disorders of the quantitative and qualitative distribution of normal pigment and the abnormal presence of exogenous or endogenous pigments in the skin. The first group includes hyperpigmentations, which clinically manifest by darkening of the skin color, and leukodermia, which is characterized by lightening of the skin. Hypermelanosis corresponds to an overload of melanin or an abnormal distribution of melanin in the skin. Depending on the color, melanodermia (brown/black) and ceruloderma (blue/grey) are distinguished. Melanodermia correspond to epidermal hypermelanocytosis (an increased number of melanocytes) or epidermal hypermelanosis (an increase in the quantity of melanin in the epidermis with no modification of the number of melanocytes). Ceruloderma corresponds to dermal hypermelanocytosis (abnormal presence in the dermis of cells synthesizing melanins) ; leakage in the dermis of epidermal melanin also exists, a form of dermal hypermelanosis called pigmentary incontinence. Finally, dyschromia can be related to the abnormal presence in the skin of a pigment of exogenous or endogenous origin. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  17. [Normal and abnormal skin color].

    Science.gov (United States)

    Ortonne, J-P

    2012-11-01

    The varieties of normal skin color in humans range from people of "no color" (pale white) to "people of color" (light brown, dark brown, and black). Skin color is a blend resulting from the skin chromophores red (oxyhaemoglobin), blue (deoxygenated haemoglobin), yellow-orange (carotene, an exogenous pigment), and brown (melanin). Melanin, however, is the major component of skin color ; it is the presence or absence of melanin in the melanosomes in melanocytes and melanin in keratinocytes that is responsible for epidermal pigmentation, and the presence of melanin in macrophages or melanocytes in the dermis that is responsible for dermal pigmentation. Two groups of pigmentary disorders are commonly distinguished: the disorders of the quantitative and qualitative distribution of normal pigment and the abnormal presence of exogenous or endogenous pigments in the skin. The first group includes hyperpigmentations, which clinically manifest by darkening of the skin color, and leukodermia, which is characterized by lightening of the skin. Hypermelanosis corresponds to an overload of melanin or an abnormal distribution of melanin in the skin. Depending on the color, melanodermia (brown/black) and ceruloderma (blue/grey) are distinguished. Melanodermia correspond to epidermal hypermelanocytosis (an increased number of melanocytes) or epidermal hypermelanosis (an increase in the quantity of melanin in the epidermis with no modification of the number of melanocytes). Ceruloderma correspond to dermal hypermelanocytosis (abnormal presence in the dermis of cells synthesizing melanins) ; leakage in the dermis of epidermal melanin also exists, a form of dermal hypermelanosis called pigmentary incontinence. Finally, dyschromia can be related to the abnormal presence in the skin of a pigment of exogenous or endogenous origin. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  18. Goldenhar syndrome and urogenital abnormalities

    Directory of Open Access Journals (Sweden)

    Mohan Marulaiah

    2003-01-01

    Full Text Available The Goldenhar syndrome (oculo-auriculo-vertebral syn-drome or 1st and 2nd branchial arch syndrome is a com-plex of craniofacial anomalies. It has been associated with anomalies in other systems and with abnormalities of the urogenital system. We present a case of Goldenhar syn-drome with multiple renal anomalies and a urogenital si-nus, which has not been reported before.

  19. Spatial correlation of action potential duration and diastolic dysfunction in transgenic and drug-induced LQT2 rabbits.

    Science.gov (United States)

    Odening, Katja E; Jung, Bernd A; Lang, Corinna N; Cabrera Lozoya, Rocio; Ziupa, David; Menza, Marius; Relan, Jatin; Franke, Gerlind; Perez Feliz, Stefanie; Koren, Gideon; Zehender, Manfred; Bode, Christoph; Brunner, Michael; Sermesant, Maxime; Föll, Daniela

    2013-10-01

    Enhanced dispersion of action potential duration (APD) is a major contributor to long QT syndrome (LQTS)-related arrhythmias. To investigate spatial correlations of regional heterogeneities in cardiac repolarization and mechanical function in LQTS. Female transgenic LQTS type 2 (LQT2; n = 11) and wild-type littermate control (LMC) rabbits (n = 9 without E4031 and n = 10 with E4031) were subjected to phase contrast magnetic resonance imaging to assess regional myocardial velocities. In the same rabbits' hearts, monophasic APDs were assessed in corresponding segments. In LQT2 and E4031-treated rabbits, APD was longer in all left ventricular segments (P < .01) and APD dispersion was greater than that in LMC rabbits (P < .01). In diastole, peak radial velocities (Vr) were reduced in LQT2 and E4031-treated compared to LMC rabbits in LV base and mid (LQT2: -3.36 ± 0.4 cm/s, P < .01; E4031-treated: -3.24 ± 0.6 cm/s, P < .0001; LMC: -4.42 ± 0.5 cm/s), indicating an impaired diastolic function. Regionally heterogeneous diastolic Vr correlated with APD (LQT2: correlation coefficient [CC] 0.38, P = .01; E4031-treated: CC 0.42, P < .05). Time-to-diastolic peak Vr were prolonged in LQT2 rabbits (LQT2: 196.8 ± 2.9 ms, P < .001; E4031-treated: 199.5 ± 2.2 ms, P < .0001, LMC 183.1 ± 1.5), indicating a prolonged contraction duration. Moreover, in transgenic LQT2 rabbits, diastolic time-to-diastolic peak Vr correlated with APD (CC 0.47, P = .001). In systole, peak Vr were reduced in LQT2 and E4031-treated rabbits (P < .01) but longitudinal velocities or ejection fraction did not differ. Finally, random forest machine learning algorithms enabled a differentiation between LQT2, E4031-treated, and LMC rabbits solely based on "mechanical" magnetic resonance imaging data. The prolongation of APD led to impaired diastolic and systolic function in transgenic and drug-induced LQT2 rabbits. APD correlated with regional diastolic dysfunction, indicating that LQTS is not purely an

  20. Drug-induced and postnatal hypothyroidism impairs the accumulation of diacylglycerol in liver and liver cell plasma membranes

    Directory of Open Access Journals (Sweden)

    Kavok Nataliya S

    2002-08-01

    sharply differed from PL. DAG was relatively enriched in [14C]oleic acid whereas PL were enriched in [3H]arachidonic acid. Conclusions The above data have indicated that thyroid hormones are important physiological modulators of DAG level in rat liver and cell plasma membranes. Age- and drug-induced malfunction of thyroid gland resulted in a prominent decrease of glycerolipid synthesis which may promote DAG accumulation in liver.

  1. Effect of gene-gene and gene-environment interactions associated with antituberculosis drug-induced hepatotoxicity.

    Science.gov (United States)

    Chamorro, Julián G; Castagnino, Jorge P; Aidar, Omar; Musella, Rosa M; Frías, Ana; Visca, Mabel; Nogueras, Mabel; Costa, Lucas; Perez, Alessandro; Caradonna, Fabio; de Larrañaga, Gabriela F

    2017-10-01

    This study evaluated the association between environmental factors and genetic variations in enzymes that metabolize antituberculosis (anti-TB) drugs [arylamine N-acetyltransferase 2, cytochrome P450 2E1 (CYP2E1), glutathione S-transferase theta 1 (GSTT1), and glutathione S-transferase mu 1] with antituberculosis drug-induced hepatotoxicity (ATDH). We also investigated the potential gene-gene and gene-environment interactions as well as their association with ATDH development in a population of hospitalized TB patients from Buenos Aires. We investigated 364 TB patients who received anti-TB drugs. Physicians collected demographic and clinical data to identify environmental risk factors for ATDH development. Polymorphisms were detected using gene sequencing, PCR, and PCR-restriction fragment length polymorphisms. A binary logistic regression analysis was carried out to compare the results of TB patients with and without the development of hepatotoxicity. The multifactor dimensionality reduction method was used to examine genetic and environmental interactions in association with ATDH. This study suggests that the slow acetylator profile [odds ratio (OR): 3.02; 95% confidence interval (CI): 1.82-5.00; P<0.001], genotypes carrying the c2 variant (OR: 2.16; 95% CI: 1.33-3.51; P=0.002) or the A4 variant of CYP2E1 (OR: 2.13; 95% CI: 1.06-4.29; P=0.050), and female sex (OR: 1.94; 95% CI: 1.20-3.14; P=0.006) were independent predictor variables for ATDH. Patients carrying the slow acetylator profile and the c2 variant showed an increased risk (OR: 7.068; 95% CI: 3.34-14.95; P<0.001). We also identified a synergic interaction (epistasis) between GSTT1 and CYP2E1 associated with an increased risk for ATDH. A meaningful gene-environment interaction was associated with an increased risk of ATDH [testing balance accuracy=0.675 (P=0.001) and cross-validation consistency=10/10]. ATDH is a severe and prevalent adverse drug reaction and leads to drug discontinuation in 11% of TB

  2. Conduction velocity depression and drug-induced ventricular tachyarrhythmias. Effects of lidocaine in the intact canine heart.

    Science.gov (United States)

    Anderson, K P; Walker, R; Lux, R L; Ershler, P R; Menlove, R; Williams, M R; Krall, R; Moddrelle, D

    1990-03-01

    Depression of myocardial conduction velocity can be an important mechanism of action of antiarrhythmic drugs but it can also facilitate arrhythmogenesis. We used lidocaine in an anesthetized canine preparation to address the hypothesis that drug-induced rate-dependent conduction velocity depression causes ventricular tachyarrhythmias. A closely spaced square array of 64 electrodes was used to determine conduction velocity longitudinal and transverse to epicardial ventricular fiber direction. Lidocaine caused rate-dependent decreases in conduction velocity that were proportionately greater in the longitudinal direction at the shortest pacing cycle lengths. Conduction velocity depression developed rapidly in the presence of lidocaine with a new steady state present by the second beat of the rapid train. Recovery from rate-dependent depression of conduction velocity was exponential with a time constant of 122 +/- 20 msec (mean +/- SD) in the longitudinal direction and 114 +/- 30 msec in the transverse direction; this difference was not significant. The relation between conduction velocity depression and ventricular arrhythmias was assessed by pacing for 3 minutes at cycle lengths of 1,000, 500, 300, and 250 msec, and for 1 minute at a cycle length of 200 msec. Arrhythmias did not occur in the baseline period in the dogs that received lidocaine, nor in 12 control dogs that were subjected to the same stimulation protocol except that saline was administered in place of lidocaine. Sustained polymorphic ventricular tachycardia (VT) occurred in six of 16 dogs given lidocaine. VT occurred in the presence of relatively high plasma lidocaine concentrations (8.4 +/- 2.3 micrograms/ml) and only at pacing cycle lengths of 300 msec or shorter. The dogs that developed VT demonstrated greater rate-dependent depression of conduction velocity than the other dogs, and activation patterns obtained just before the onset of VT showed marked conduction disturbances. Furthermore, QRS

  3. Inhibition of Human Hepatic Bile Acid Transporters by Tolvaptan and Metabolites: Contributing Factors to Drug-Induced Liver Injury?

    Science.gov (United States)

    Slizgi, Jason R; Lu, Yang; Brouwer, Kenneth R; St Claire, Robert L; Freeman, Kimberly M; Pan, Maxwell; Brock, William J; Brouwer, Kim L R

    2016-01-01

    Tolvaptan is a vasopressin V(2)-receptor antagonist that has shown promise in treating Autosomal Dominant Polycystic Kidney Disease (ADPKD). Tolvaptan was, however, associated with liver injury in some ADPKD patients. Inhibition of bile acid transporters may be contributing factors to drug-induced liver injury. In this study, the ability of tolvaptan and two metabolites, DM-4103 and DM-4107, to inhibit human hepatic transporters (NTCP, BSEP, MRP2, MRP3, and MRP4) and bile acid transport in sandwich-cultured human hepatocytes (SCHH) was explored. IC(50) values were determined for tolvaptan, DM-4103 and DM-4107 inhibition of NTCP (∼41.5, 16.3, and 95.6 μM, respectively), BSEP (31.6, 4.15, and 119 μM, respectively), MRP2 (>50, ∼51.0, and >200 μM, respectively), MRP3 (>50, ∼44.6, and 61.2 μM, respectively), and MRP4 (>50, 4.26, and 37.9 μM, respectively). At the therapeutic dose of tolvaptan (90 mg), DM-4103 exhibited a C(max)/IC(50) value >0.1 for NTCP, BSEP, MRP2, MRP3, and MRP4. Tolvaptan accumulation in SCHH was extensive and not sodium-dependent; intracellular concentrations were ∼500 μM after a 10-min incubation duration with tolvaptan (15 μM). The biliary clearance of taurocholic acid (TCA) decreased by 43% when SCHH were co-incubated with tolvaptan (15 μM) and TCA (2.5 μM). When tolvaptan (15 μM) was co-incubated with 2.5 μM of chenodeoxycholic acid, taurochenodeoxycholic acid, or glycochenodeoxycholic acid in separate studies, the cellular accumulation of these bile acids increased by 1.30-, 1.68-, and 2.16-fold, respectively. Based on these data, inhibition of hepatic bile acid transport may be one of the biological mechanisms underlying tolvaptan-associated liver injury in patients with ADPKD. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  4. Abnormal thermography in Parkinson's disease.

    Science.gov (United States)

    Antonio-Rubio, I; Madrid-Navarro, C J; Salazar-López, E; Pérez-Navarro, M J; Sáez-Zea, C; Gómez-Milán, E; Mínguez-Castellanos, A; Escamilla-Sevilla, F

    2015-08-01

    An autonomic denervation and abnormal vasomotor reflex in the skin have been described in Parkinson's disease (PD) and might be evaluable using thermography with cold stress test. A cross-sectional pilot study was undertaken in 35 adults: 15 patients with PD and abnormal [(123)I]-metaiodobenzylguanidine cardiac scintigraphy and 20 healthy controls. Baseline thermography of both hands was obtained before immersing one in cold water (3 ± 1 °C) for 2 min. Continuous thermography was performed in: non-immersed hand (right or with lesser motor involvement) during immersion of the contralateral hand and for 6 min afterward; and contralateral immersed hand for 6 min post-immersion. The region of interest was the dorsal skin of the third finger, distal phalanx. PD patients showed a lower mean baseline hand temperature (p = 0.037) and greater thermal difference between dorsum of wrist and third finger (p = 0.036) and between hands (p = 0.0001) versus controls, regardless of the motor laterality. Both tests evidenced an adequate capacity to differentiate between groups: in the non-immersed hand, the PD patients did not show the normal cooling pattern or final thermal overshoot observed in controls (F = 5.29; p = 0.001), and there was an AUC of 0.897 (95%CI 0.796-0.998) for this cooling; in the immersed hand, thermal recovery at 6 min post-immersion was lesser in patients (29 ± 17% vs. 55 ± 28%, p = 0.002), with an AUC of 0.810 (95%CI 0.662-0.958). PD patients reveal abnormal skin thermal responses in thermography with cold stress test, suggesting cutaneous autonomic dysfunction. This simple technique may be useful to evaluate autonomic dysfunction in PD. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. The Electrogenic Na+/K+ Pump Is a Key Determinant of Repolarization Abnormality Susceptibility in Human Ventricular Cardiomyocytes: A Population-Based Simulation Study

    Directory of Open Access Journals (Sweden)

    Oliver J. Britton

    2017-05-01

    Full Text Available Background: Cellular repolarization abnormalities occur unpredictably due to disease and drug effects, and can occur even in cardiomyocytes that exhibit normal action potentials (AP under control conditions. Variability in ion channel densities may explain differences in this susceptibility to repolarization abnormalities. Here, we quantify the importance of key ionic mechanisms determining repolarization abnormalities following ionic block in human cardiomyocytes yielding normal APs under control conditions.Methods and Results: Sixty two AP recordings from non-diseased human heart preparations were used to construct a population of human ventricular models with normal APs and a wide range of ion channel densities. Multichannel ionic block was applied to investigate susceptibility to repolarization abnormalities. IKr block was necessary for the development of repolarization abnormalities. Models that developed repolarization abnormalities over the widest range of blocks possessed low Na+/K+ pump conductance below 50% of baseline, and ICaL conductance above 70% of baseline. Furthermore, INaK made the second largest contribution to repolarizing current in control simulations and the largest contribution under 75% IKr block. Reversing intracellular Na+ overload caused by reduced INaK was not sufficient to prevent abnormalities in models with low Na+/K+ pump conductance, while returning Na+/K+ pump conductance to normal substantially reduced abnormality occurrence, indicating INaK is an important repolarization current.Conclusions: INaK is an important determinant of repolarization abnormality susceptibility in human ventricular cardiomyocytes, through its contribution to repolarization current rather than homeostasis. While we found IKr block to be necessary for repolarization abnormalities to occur, INaK decrease, as in disease, may amplify the pro-arrhythmic risk of drug-induced IKr block in humans.

  6. A long-term three dimensional liver co-culture system for improved prediction of clinically relevant drug-induced hepatotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Kostadinova, Radina; Boess, Franziska [Non-Clinical Safety, Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Building 73 / Room 117b, 4070 Basel (Switzerland); Applegate, Dawn [RegeneMed, 9855 Towne Centre Drive Suite 200, San Diego, CA 92121 (United States); Suter, Laura; Weiser, Thomas; Singer, Thomas [Non-Clinical Safety, Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Building 73 / Room 117b, 4070 Basel (Switzerland); Naughton, Brian [RegeneMed, 9855 Towne Centre Drive Suite 200, San Diego, CA 92121 (United States); Roth, Adrian, E-mail: adrian_b.roth@roche.com [Non-Clinical Safety, Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Building 73 / Room 117b, 4070 Basel (Switzerland)

    2013-04-01

    Drug-induced liver injury (DILI) is the major cause for liver failure and post-marketing drug withdrawals. Due to species-specific differences in hepatocellular function, animal experiments to assess potential liabilities of drug candidates can predict hepatotoxicity in humans only to a certain extent. In addition to animal experimentation, primary hepatocytes from rat or human are widely used for pre-clinical safety assessment. However, as many toxic responses in vivo are mediated by a complex interplay among different cell types and often require chronic drug exposures, the predictive performance of hepatocytes is very limited. Here, we established and characterized human and rat in vitro three-dimensional (3D) liver co-culture systems containing primary parenchymal and non-parenchymal hepatic cells. Our data demonstrate that cells cultured on a 3D scaffold have a preserved composition of hepatocytes, stellate, Kupffer and endothelial cells and maintain liver function for up to 3 months, as measured by the production of albumin, fibrinogen, transferrin and urea. Additionally, 3D liver co-cultures maintain cytochrome P450 inducibility, form bile canaliculi-like structures and respond to inflammatory stimuli. Upon incubation with selected hepatotoxicants including drugs which have been shown to induce idiosyncratic toxicity, we demonstrated that this model better detected in vivo drug-induced toxicity, including species-specific drug effects, when compared to monolayer hepatocyte cultures. In conclusion, our results underline the importance of more complex and long lasting in vitro cell culture models that contain all liver cell types and allow repeated drug-treatments for detection of in vivo-relevant adverse drug effects. - Highlights: ► 3D liver co-cultures maintain liver specific functions for up to three months. ► Activities of Cytochrome P450s remain drug- inducible accross three months. ► 3D liver co-cultures recapitulate drug-induced liver toxicity

  7. Abnormal visuomotor processing in schizophrenia

    Directory of Open Access Journals (Sweden)

    Siân E. Robson

    2016-01-01

    Full Text Available Subtle disturbances of visual and motor function are known features of schizophrenia and can greatly impact quality of life; however, few studies investigate these abnormalities using simple visuomotor stimuli. In healthy people, electrophysiological data show that beta band oscillations in sensorimotor cortex decrease during movement execution (event-related beta desynchronisation (ERBD, then increase above baseline for a short time after the movement (post-movement beta rebound (PMBR; whilst in visual cortex, gamma oscillations are increased throughout stimulus presentation. In this study, we used a self-paced visuomotor paradigm and magnetoencephalography (MEG to contrast these responses in patients with schizophrenia and control volunteers. We found significant reductions in the peak-to-peak change in amplitude from ERBD to PMBR in schizophrenia compared with controls. This effect was strongest in patients who made fewer movements, whereas beta was not modulated by movement in controls. There was no significant difference in the amplitude of visual gamma between patients and controls. These data demonstrate that clear abnormalities in basic sensorimotor processing in schizophrenia can be observed using a very simple MEG paradigm.

  8. Lower Extremity Abnormalities in Children.

    Science.gov (United States)

    Rerucha, Caitlyn M; Dickison, Caleb; Baird, Drew C

    2017-08-15

    Leg and foot problems in childhood are common causes of parental concern. Rotational problems include intoeing and out-toeing. Intoeing is most common in infants and young children. Intoeing is caused by metatarsus adductus, internal tibial torsion, and femoral anteversion. Out-toeing is less common than intoeing and occurs more often in older children. Out-toeing is caused by external tibial torsion and femoral retroversion. Angular problems include genu varum (bowleg) and genu valgum (knock knee). With pes planus (flatfoot), the arch of the foot is usually flexible rather than rigid. A history and physical examination that include torsional profile tests and angular measurements are usually sufficient to evaluate patients with lower extremity abnormalities. Most children who present with lower extremity problems have normal rotational and angular findings (i.e., within two standard deviations of the mean). Lower extremity abnormalities that are within normal measurements resolve spontaneously as the child grows. Radiologic studies are not routinely required, except to exclude pathologic conditions. Orthotics are not beneficial. Orthopedic referral is often not necessary. Rarely, surgery is required in patients older than eight years who have severe deformities that cause dysfunction.

  9. Identification of thymus and activation-regulated chemokine (TARC/CCL17) as a potential marker for early indication of disease and prediction of disease activity in drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS).

    Science.gov (United States)

    Ogawa, Kohei; Morito, Hironori; Hasegawa, Ayako; Daikoku, Natsuko; Miyagawa, Fumi; Okazaki, Aiko; Fukumoto, Takaya; Kobayashi, Nobuhiko; Kasai, Takahiko; Watanabe, Hideaki; Sueki, Hirohiko; Iijima, Masafumi; Tohyama, Mikiko; Hashimoto, Koji; Asada, Hideo

    2013-01-01

    Drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS) is a serious acute drug reaction with fever, cutaneous eruption, lymphadenopathy, and several visceral dysfunctions. Eosinophilia is a common hematological abnormality in DIHS/DRESS suggesting that the Th2-type immune response is involved. Thymus and activation-regulated chemokine (TARC/CCL17) is a family of CC chemokines known to play an important role in Th2-mediated immune-inflammatory processes. We investigated the pathogenic role of TARC in patients with DIHS. Sera were obtained from 8 patients with DIHS, 7 patients with Stevens-Johnson syndrome/Toxic epidermal necrolysis (SJS/TEN), and 14 patients with drug-induced maculopapular exanthema (MPE). Serum TARC levels were measured by ELISA. TARC levels were then compared with clinical symptoms and various hematological parameters. In addition, a biopsy was taken from the lesional skin of patients with DIHS and stained with anti-TARC Ab and anti-CD11c Ab. Serum TARC levels in patients with DIHS were significantly higher than those in patients with SJS/TEN and MPE during the acute phase. Serum TARC levels in DIHS patients correlated with skin eruptions, serum sIL-2R levels, eosinophil counts, and serum IL-5 levels. Immunohistochemical staining revealed that TARC was mainly expressed on CD11c+ dermal dendritic cells in patients with DIHS. Serum TARC levels may be associated with the initial presentation of DIHS as well as disease activity during the course. Thus, they could be useful as an indicator for early diagnosis and assessment of disease activity in DIHS. CD11c+ dendritic cells may be the main source of TARC in patients with DIHS. Copyright © 2012 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  10. CHROMOSOMAL ABNORMALITIES IN PATIENTS WITH RECURRENT MISCARRIAGE

    Directory of Open Access Journals (Sweden)

    Daniela Mierla

    2012-06-01

    Full Text Available Chromosomal abnormalities are involved in the etiology of recurrent spontaneous pregnancy loss and sub-fertility. The purpose of this study was to determine the frequency and contribution of chromosomal abnormalities in recurrent miscarriages. The results obtained and literature review are helpful in understanding the importance of cytogenetics analysis of female infertility. To investigate the distribution of chromosomal abnormalities in the Romanian population with recurrent miscarriage, karyotype analysis by G-banding was performed from peripheral blood in 967 women infertility. Results: Chromosomal abnormalities were found to 79 women (8,17%. The percentage of chromosomal abnormalities in the studied population correlates with the data in the literature. Chromosomal abnormalities could play the important role in etiology of infertility and are more frequently detected in this group of patients compared to general population. In the infertile couples balanced chromosomal abnormalities are the main cause of spontaneous abortions.

  11. Prediction of drug-induced nephrotoxicity and injury mechanisms with human induced pluripotent stem cell-derived cells and machine learning methods.

    Science.gov (United States)

    Kandasamy, Karthikeyan; Chuah, Jacqueline Kai Chin; Su, Ran; Huang, Peng; Eng, Kim Guan; Xiong, Sijing; Li, Yao; Chia, Chun Siang; Loo, Lit-Hsin; Zink, Daniele

    2015-07-27

    The renal proximal tubule is a main target for drug-induced toxicity. The prediction of proximal tubular toxicity during drug development remains difficult. Any in vitro methods based on induced pluripotent stem cell-derived renal cells had not been developed, so far. Here, we developed a rapid 1-step protocol for the differentiation of human induced pluripotent stem cells (hiPSC) into proximal tubular-like cells. These proximal tubular-like cells had a purity of >90% after 8 days of differentiation and could be directly applied for compound screening. The nephrotoxicity prediction performance of the cells was determined by evaluating their responses to 30 compounds. The results were automatically determined using a machine learning algorithm called random forest. In this way, proximal tubular toxicity in humans could be predicted with 99.8% training accuracy and 87.0% test accuracy. Further, we studied the underlying mechanisms of injury and drug-induced cellular pathways in these hiPSC-derived renal cells, and the results were in agreement with human and animal data. Our methods will enable the development of personalized or disease-specific hiPSC-based renal in vitro models for compound screening and nephrotoxicity prediction.

  12. Early detection of interstitial pneumonia by WXGa-citrate scintigraphy. Cases of abnormal pulmonary WXGa uptake with normal chest radiographs

    Energy Technology Data Exchange (ETDEWEB)

    Ito, Shinsaku; Mikami, Riichiro; Ryujin, Yoshitada

    1985-04-01

    In this paper we report our recent experience indicating usefulness of WXGa-citrate scintigraphy in 4 cases with inflammatory pulmonary diseases. These cases showed abnormal pulmonary WXGa uptake with normal chest radiographs. The first case with malignant lymphoma and the second one with lung cancer suffered from pulmonary infection following secondary immuno-insufficiency due to radiotherapy and chemotherapy. Pneumocystis carinii was suspected as causative agent in the first case, and gram negative bacilli in the second case. The third case with lung cancer developed radiation pneumonia after radiotherapy. The fourth case with acute bronchitis developed drug induced interstitial pneumonia presumably due to minocycline administration. It is concluded that WXGa-citrate scintigraphy is more sensitive for early detection of interstitial pneumonia than routine chest radiography.

  13. Chromosomal abnormalities in child psychiatric patients.

    OpenAIRE

    Hong, K. E.; Kim, J. H.; Moon, S. Y.; Oh, S. K.

    1999-01-01

    To determine the frequency of chromosomal abnormalities in a child psychiatric population, and to evaluate possible associations between types of abnormalities and patient's clinical characteristics, cytogenetic examination was performed on 604 patients. Demographic data, reasons for karyotyping, clinical signs, and other patient characteristics were assessed and correlated with the results from karyotyping. Chromosomal abnormalities were found in 69 patients (11.3%); these were structural in...

  14. Semen abnormalities with SSRI antidepressants.

    Science.gov (United States)

    2015-01-01

    Despite decades of widespread use, the adverse effect profile of "selective" serotonin reuptake inhibitor (SSRI) antidepressants has still not been fully elucidated. Studies in male animals have shown delayed sexual development and reduced fertility. Three prospective cohort studies conducted in over one hundred patients exposed to an SSRI for periods ranging from 5 weeks to 24 months found altered semen param-eters after as little as 3 months of exposure: reduced sperm concentration, reduced sperm motility, a higher percentage of abnormal spermatozoa, and increased levels of sperm DNA fragmentation. One clinical trial showed growth retardation in children considered depressed who were exposed to SSRls. SSRls may have endocrine disrupting properties. Dapoxetine is a short-acting serotonin reuptake inhibitor that is chemically related to fluoxetine and marketed in the European Union for men complaining of premature ejaculation. But the corresponding European summary of product characteristics does not mention any effects on fertility. In practice, based on the data available as of mid-2014, the effects of SSRI exposure on male fertility are unclear. However, it is a risk that should be taken into account and pointed out to male patients who would like to father a child or who are experiencing fertility problems.

  15. [Cognitive abnormalities and cannabis use].

    Science.gov (United States)

    Solowij, Nadia; Pesa, Nicole

    2010-05-01

    Evidence that cannabis use impairs cognitive function in humans has been accumulating in recent decades. The purpose of this overview is to update knowledge in this area with new findings from the most recent literature. Literature searches were conducted using the Web of Science database up to February 2010. The terms searched were: "cannabi*" or "marijuana", and "cogniti*" or "memory" or "attention" or "executive function", and human studies were reviewed preferentially over the animal literature. Cannabis use impairs memory, attention, inhibitory control, executive functions and decision making, both during the period of acute intoxication and beyond, persisting for hours, days, weeks or more after the last use of cannabis. Pharmacological challenge studies in humans are elucidating the nature and neural substrates of cognitive changes associated with various cannabinoids. Long-term or heavy cannabis use appears to result in longer-lasting cognitive abnormalities and possibly structural brain alterations. Greater adverse cognitive effects are associated with cannabis use commencing in early adolescence. The endogenous cannabinoid system is involved in regulatory neural mechanisms that modulate processes underlying a range of cognitive functions that are impaired by cannabis. Deficits in human users most likely therefore reflect neuroadaptations and altered functioning of the endogenous cannabinoid system.

  16. Red cell membrane transport abnormalities.

    Science.gov (United States)

    Bruce, Lesley J

    2008-05-01

    The present review describes the red cell transport abnormalities of proteins of the band 3 macrocomplex. The macrocomplex is involved in red cell gas exchange and recent findings have furthered our understanding of this process. Study of a novel band 3 hereditary spherocytosis variant suggests that expression of mutant band 3 protein can be rescued by wild-type band 3. Other studies show that some mutant band 3 protein can mediate a cation conductance. Recent work suggests both Rh-associated glycoprotein and aquaporin act as gas channels confirming the integrated function of the macrocomplex and the importance of its role in red cell gas transport. The most recent studies on band 3-induced hereditary spherocytosis are reviewed and an explanation for the mild phenotype of heterozygous hereditary spherocytosis is discussed. A number of red cell conditions (hereditary stomatocytosis, south-east Asian ovalocytosis, distal renal tubular acidosis, Rhnull), associated with both stomatocytosis and a cation leak, are described. The evidence that Rh-associated glycoprotein forms a gas channel that transports CO2 and/or NH3 is reviewed and discussed, together with recent studies that show that aquaporin 1 transports both CO2 and O2.

  17. Drug-induced trafficking of p-glycoprotein in human brain capillary endothelial cells as demonstrated by exposure to mitomycin C.

    Science.gov (United States)

    Noack, Andreas; Noack, Sandra; Hoffmann, Andrea; Maalouf, Katia; Buettner, Manuela; Couraud, Pierre-Olivier; Romero, Ignacio A; Weksler, Babette; Alms, Dana; Römermann, Kerstin; Naim, Hassan Y; Löscher, Wolfgang

    2014-01-01

    P-glycoprotein (Pgp; ABCB1/MDR1) is a major efflux transporter at the blood-brain barrier (BBB), restricting the penetration of various compounds. In other tissues, trafficking of Pgp from subcellular stores to the cell surface has been demonstrated and may constitute a rapid way of the cell to respond to toxic compounds by functional membrane insertion of the transporter. It is not known whether drug-induced Pgp trafficking also occurs in brain capillary endothelial cells that form the BBB. In this study, trafficking of Pgp was investigated in human brain capillary endothelial cells (hCMEC/D3) that were stably transfected with a doxycycline-inducible MDR1-EGFP fusion plasmid. In the presence of doxycycline, these cells exhibited a 15-fold increase in Pgp-EGFP fusion protein expression, which was associated with an increased efflux of the Pgp substrate rhodamine 123 (Rho123). The chemotherapeutic agent mitomycin C (MMC) was used to study drug-induced trafficking of Pgp. Confocal fluorescence microscopy of single hCMEC/D3-MDR1-EGFP cells revealed that Pgp redistribution from intracellular pools to the cell surface occurred within 2 h of MMC exposure. Pgp-EGFP exhibited a punctuate pattern at the cell surface compatible with concentrated regions of the fusion protein in membrane microdomains, i.e., lipid rafts, which was confirmed by Western blot analysis of biotinylated cell surface proteins in Lubrol-resistant membranes. MMC exposure also increased the functionality of Pgp as assessed in three functional assays with Pgp substrates (Rho123, eFluxx-ID Gold, calcein-AM). However, this increase occurred with some delay after the increased Pgp expression and coincided with the release of Pgp from the Lubrol-resistant membrane complexes. Disrupting rafts by depleting the membrane of cholesterol increased the functionality of Pgp. Our data present the first direct evidence of drug-induced Pgp trafficking at the human BBB and indicate that Pgp has to be released from lipid

  18. Pharmaka mit negativer Auswirkung auf den Knochen – durch Medikamente induzierte Osteoporose // Medications with Negative Effect on Bone – Drug-Induced Osteoporosis

    Directory of Open Access Journals (Sweden)

    Gasser RW

    2016-01-01

    Full Text Available Drug-induced osteoporosis may occur as a side effect of many commonly prescribed drugs. This leads to a disturbance of bone remodelling, which ultimately results in a preponderance of bone loss and – as a consequence – in an increased incidence of bone fractures. Also, a drug-induced disturbance of the calcium metabolism may contribute to bone mineral loss. Glucocorticoids, thyroxine, depot-medroxyprogesterone acetate, aromatase inhibitors, GnRH agonists, thiazolidinediones, proton pump inhibitors, antiepileptic drugs, selective serotonin (and norepinephrine reuptake inhibitors, anticoagulants, loop diuretics, calcineurin inhibitors and antiretroviral active substances can lead to significant bone mineral loss in long-term use. A combination of several bone-toxic substances can potentially amplify the negative effect on bone. When applying the above mentioned drugs over a prolonged period, a possible effect on bone should always be taken into account, especially in older people. An osteological investigation with laboratory and bone densitometry or fracture risk assessment by FRAX is required. For prevention and therapy of drug-induced osteoporosis lifestyle measures, an adequate supply of calcium and vitamin D and optionally a specific osteoporosis treatment with bisphosphonates, denosumab or teriparatide are appropriate. p bKurzfassung/b: Eine durch Medikamente induzierte Osteoporose kann als Nebenwirkung bei vielen häufig verschriebenen Pharmaka auftreten. Dabei kommt es zu einer Störung des Knochenumbaus, wobei letztendlich ein Überwiegen des Knochenabbaus vorliegt. Ein vermehrtes Auftreten von Knochenbrüchen ist die Folge. Auch eine durch Medikamente bedingte Störung des Kalziumstoffwechsels kann zum Knochenmineralverlust beitragen. Glukokortikoide, Thyroxin, Depot-Medroxyprogesteron-Acetat, Aromataseinhibitoren, GnRH-Agonisten, Thiazolidindione, Protonenpumpenhemmer, Antiepileptika, selektive Serotonin- (und Noradrenalin- Reuptake

  19. Chronic drug-induced effects on contractile motion properties and cardiac biomarkers in human induced pluripotent stem cell-derived cardiomyocytes.

    Science.gov (United States)

    Kopljar, Ivan; De Bondt, An; Vinken, Petra; Teisman, Ard; Damiano, Bruce; Goeminne, Nick; Van den Wyngaert, Ilse; Gallacher, David J; Lu, Hua Rong

    2017-11-01

    In the pharmaceutical industry risk assessments of chronic cardiac safety liabilities are mostly performed during late stages of preclinical drug development using in vivo animal models. Here, we explored the potential of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) to detect chronic cardiac risks such as drug-induced cardiomyocyte toxicity. Video microscopy-based motion field imaging was applied to evaluate the chronic effect (over 72 h) of cardiotoxic drugs on the contractile motion of hiPS-CMs. In parallel, the release of cardiac troponin I (cTnI), heart fatty acid binding protein (FABP3) and N-terminal pro-brain natriuretic peptide (NT-proBNP) was analysed from cell medium, and transcriptional profiling of hiPS-CMs was done at the end of the experiment. Different cardiotoxic drugs altered the contractile motion properties of hiPS-CMs together with increasing the release of cardiac biomarkers. FABP3 and cTnI were shown to be potential surrogates to predict cardiotoxicity in hiPS-CMs, whereas NT-proBNP seemed to be a less valuable biomarker. Furthermore, drug-induced cardiotoxicity produced by chronic exposure of hiPS-CMs to arsenic trioxide, doxorubicin or panobinostat was associated with different profiles of changes in contractile parameters, biomarker release and transcriptional expression. We have shown that a parallel assessment of motion field imaging-derived contractile properties, release of biomarkers and transcriptional changes can detect diverse mechanisms of chronic drug-induced cardiac liabilities in hiPS-CMs. Hence, hiPS-CMs could potentially improve and accelerate cardiovascular de-risking of compounds at earlier stages of drug discovery. This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc. © 2017 The British Pharmacological Society.

  20. Characterization of electroencephalographic and biochemical responses at 5-HT promoting drug-induced onset of serotonin syndrome in rats

    Science.gov (United States)

    Ma, Zhiyuan; Rudacille, Mary; Prentice, Howard M.; Tao, Rui

    2014-01-01

    Many psychotropic substances used either for medications or illicit recreational purposes are able to produce an increase in extracellular serotonin (5HT) in the CNS. 5HT is well known to improve mood, however, only when the levels of its release are in an appropriate range. Excessive 5HT is harmful, and will generally result in serotonin syndrome. To date, clinical diagnosis of serotonin syndrome relies exclusively on observation of symptoms because of a lack of available laboratory tests. The goal of the present study was to characterize the onset of the syndrome using laboratory settings to determine excessive 5HT-evoked neurological abnormalities. Experiments were carried out in rats with the syndrome being elicited by three groups of 5HT-promoting drugs: 1) (±)-3,4-methylenedioxymethamphetamine (MDMA); 2) a combination of the monoamine oxidase inhibitor clorgyline with the 5HT precursor 5-hydroxytryptophan; 3) clorgyline combined with the serotonin-selective reuptake inhibitor paroxetine. The onset of the syndrome was characterized by electroencephalography (EEG), tremor and brain/plasma 5HT tests. We found that a mild syndrome was associated with reduced EEG amplitudes while a severe syndrome strongly with seizure-like EEG activity and increased tremor activity. The occurrence of the syndrome was confirmed with microdialysis, showing excessive 5HT efflux in brain dialysate and the increased concentration of unbound 5HT in the plasma. Our findings suggest that the syndrome onset can be revealed with EEG recording, measurements of tremor activity and changes of unbound 5HT concentration in the plasma. PMID:23286698

  1. The importance of drug-induced sedation endoscopy (D.I.S.E.) techniques in surgical decision making: conventional versus target controlled infusion techniques-a prospective randomized controlled study and a retrospective surgical outcomes analysis.

    Science.gov (United States)

    De Vito, Andrea; Agnoletti, Vanni; Zani, Gianluca; Corso, Ruggero Massimo; D'Agostino, Giovanni; Firinu, Elisabetta; Marchi, Chiara; Hsu, Ying-Shuo; Maitan, Stefano; Vicini, Claudio

    2017-05-01

    Drug-Induced Sedation Endoscopy (DISE) consists of the direct observation of the upper airways during sedative-induced sleep, allowing the identification of the sites of pharyngeal collapse, which is the main pathological event in Obstructive Sleep Apnea (OSA). The Authors have compared Target Controlled Infusion (TCI) sedation endoscopy (TCI-DISE) technique to conventional DISE (CDISE), performed by a manual bolus injection of sedative agent, to recreate accurately and safely snoring and apnea patterns comparable to natural sleep. The authors conducted a prospective, randomized, long-term study and a retrospective analysis of surgical outcomes. The apnea-event observation and its correlation with pharyngeal collapse patterns is the primary endpoint; secondary endpoints are defined as stability and safety of sedation plan of DISE-TCI technique. From January 2009 to January 2011, OSA patients were included in the study and randomly allocated into two groups: the bolus injection conventional DISE group and the TCI-DISE group. Third endpoint is to compare the surgical outcomes enrolling OSA patients from January 2009 to June 2015. We recorded the complete apnea-event at oropharynx and hypopharynx levels in 15/50 pts in conventional DISE group (30%) and in 99/123 pts in TCI-DISE group (81%) (p surgical patients we reported a significant reduction of postoperative AHI (from 42.7 ± 20.2 to 11.4 ± 10.3) in comparison with postoperative AHI in 15 C-DISE group surgical patients (from 41.3 ± 23.4 to 20.4 ± 15.5) (p = 0.05). Our results suggest the DISE-TCI technique as first choice in performing sleep-endoscopy because of its increased accuracy, stability and safety. However, it is mandatory an accurate assessment of PSG/PM, which allows us to differentiate OSA patients in whom UA anatomical abnormalities are predominant in comparison with not-anatomical pathophysiologic factors, achieving good surgical patient's selection and outcomes as a

  2. Altered fetal growth, placental abnormalities, and stillbirth.

    Science.gov (United States)

    Bukowski, Radek; Hansen, Nellie I; Pinar, Halit; Willinger, Marian; Reddy, Uma M; Parker, Corette B; Silver, Robert M; Dudley, Donald J; Stoll, Barbara J; Saade, George R; Koch, Matthew A; Hogue, Carol; Varner, Michael W; Conway, Deborah L; Coustan, Donald; Goldenberg, Robert L

    2017-01-01

    Worldwide, stillbirth is one of the leading causes of death. Altered fetal growth and placental abnormalities are the strongest and most prevalent known risk factors for stillbirth. The aim of this study was to identify patterns of association between placental abnormalities, fetal growth, and stillbirth. Population-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in 5 geographic areas in the U.S. Fetal growth abnormalities were categorized as small (90th percentile) for gestational age at death (stillbirth) or delivery (live birth) using a published algorithm. Placental examination by perinatal pathologists was performed using a standardized protocol. Data were weighted to account for the sampling design. Among 319 singleton stillbirths and 1119 singleton live births at ≥24 weeks at death or delivery respectively, 25 placental findings were investigated. Fifteen findings were significantly associated with stillbirth. Ten of the 15 were also associated with fetal growth abnormalities (single umbilical artery; velamentous insertion; terminal villous immaturity; retroplacental hematoma; parenchymal infarction; intraparenchymal thrombus; avascular villi; placental edema; placental weight; ratio birth weight/placental weight) while 5 of the 15 associated with stillbirth were not associated with fetal growth abnormalities (acute chorioamnionitis of placental membranes; acute chorioamionitis of chorionic plate; chorionic plate vascular degenerative changes; perivillous, intervillous fibrin, fibrinoid deposition; fetal vascular thrombi in the chorionic plate). Five patterns were observed: placental findings associated with (1) stillbirth but not fetal growth abnormalities; (2) fetal growth abnormalities in stillbirths only; (3) fetal growth abnormalities in live births only; (4) fetal growth abnormalities in stillbirths and live births in a similar manner; (5) a different pattern of fetal growth abnormalities in

  3. Altered fetal growth, placental abnormalities, and stillbirth.

    Directory of Open Access Journals (Sweden)

    Radek Bukowski

    Full Text Available Worldwide, stillbirth is one of the leading causes of death. Altered fetal growth and placental abnormalities are the strongest and most prevalent known risk factors for stillbirth. The aim of this study was to identify patterns of association between placental abnormalities, fetal growth, and stillbirth.Population-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in 5 geographic areas in the U.S. Fetal growth abnormalities were categorized as small (90th percentile for gestational age at death (stillbirth or delivery (live birth using a published algorithm. Placental examination by perinatal pathologists was performed using a standardized protocol. Data were weighted to account for the sampling design. Among 319 singleton stillbirths and 1119 singleton live births at ≥24 weeks at death or delivery respectively, 25 placental findings were investigated. Fifteen findings were significantly associated with stillbirth. Ten of the 15 were also associated with fetal growth abnormalities (single umbilical artery; velamentous insertion; terminal villous immaturity; retroplacental hematoma; parenchymal infarction; intraparenchymal thrombus; avascular villi; placental edema; placental weight; ratio birth weight/placental weight while 5 of the 15 associated with stillbirth were not associated with fetal growth abnormalities (acute chorioamnionitis of placental membranes; acute chorioamionitis of chorionic plate; chorionic plate vascular degenerative changes; perivillous, intervillous fibrin, fibrinoid deposition; fetal vascular thrombi in the chorionic plate. Five patterns were observed: placental findings associated with (1 stillbirth but not fetal growth abnormalities; (2 fetal growth abnormalities in stillbirths only; (3 fetal growth abnormalities in live births only; (4 fetal growth abnormalities in stillbirths and live births in a similar manner; (5 a different pattern of fetal growth

  4. [Renal abnormalities in ankylosing spondylitis].

    Science.gov (United States)

    Samia, Barbouch; Hazgui, Faiçal; Abdelghani, Khaoula Ben; Hamida, Fethi Ben; Goucha, Rym; Hedri, Hafedh; Taarit, Chokri Ben; Maiz, Hedi Ben; Kheder, Adel

    2012-07-01

    We will study the epidemiologic, clinical, biological, therapeutic, prognostic characteristics and predictive factors of development of nephropathy in ankylosing spondylitis patients. We retrospectively reviewed the medical record of 32 cases with renal involvement among 212 cases of ankylosing spondylitis followed in our service during the period spread out between 1978 and 2006. The renal involvement occurred in all patients a mean of 12 years after the clinical onset of the rheumatic disease. Thirty-two patients presented one or more signs of renal involvement: microscopic hematuria in 22 patients, proteinuria in 23 patients, nephrotic syndrome in 11 patients and decreased renal function in 24 patients (75%). Secondary renal amyloidosis (13 patients), which corresponds to a prevalence of 6,1% and tubulointerstitial nephropathy (7 patients) were the most common cause of renal involvement in ankylosing spondylitis followed by IgA nephropathy (4 patients). Seventeen patients evolved to the end stage renal disease after an average time of 29.8 ± 46 months. The average follow-up of the patients was 4,4 years. By comparing the 32 patients presenting a SPA and renal disease to 88 with SPA and without nephropathy, we detected the predictive factors of occurred of nephropathy: tobacco, intense inflammatory syndrome, sacroileite stage 3 or 4 and presence of column bamboo. The finding of 75% of the patients presented a renal failure at the time of the diagnosis of renal involvement suggests that evidence of renal abnormality involvement should be actively sought in this disease. Copyright © 2011 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.

  5. Technique and Preliminary Analysis of Drug-Induced Sleep Endoscopy With Online Polygraphic Cardiorespiratory Monitoring in Patients With Obstructive Sleep Apnea Syndrome.

    Science.gov (United States)

    Gobbi, Riccardo; Baiardi, Simone; Mondini, Susanna; Cerritelli, Luca; Piccin, Ottavio; Scaramuzzino, Giuseppe; Milano, Francesca; Melotti, Maria Rita; Mordini, Francesco; Pirodda, Antonio; Cirignotta, Fabio; Sorrenti, Giovanni

    2017-05-01

    Drug-induced sleep endoscopy is a diagnostic technique that allows dynamic evaluation of the upper airway during artificial sleep. The lack of a standardized procedure and the difficulties associated with direct visual detection of obstructive events result in poor intraobserver and interobserver reliability, especially when otolaryngology surgeons not experienced in the technique are involved. To describe a drug-induced sleep endoscopy technique implemented with simultaneous polygraphic monitoring of cardiorespiratory parameters (DISE-PG) in patients with a diagnosis of obstructive sleep apnea syndrome and discuss the technique's possible advantages compared with the standard procedure. This prospective cohort study included 50 consecutive patients with obstructive sleep apnea syndrome who underwent DISE-PG from March 1, 2013, to June 30, 2014. A standard protocol was adopted, and all the procedures were carried out in an operation room by an experienced otolaryngology surgeon under the supervision of an anesthesiologist. Endoscopic and polygraphic obstructive respiratory events were analyzed offline in a double-blind setting and randomized order. The feasibility and safety of the DISE-PG technique, as well as its sensitivity in detecting respiratory events compared with that of the standard drug-induced sleep endoscopy procedure. All 50 patients (43 men and 7 women; mean [SD] age, 51.1 [12.1] years) underwent DISE-PG without technical problems or patient difficulties regarding the procedure. As expected, polygraphic scoring was more sensitive than endoscopic scoring in identifying obstructive events (mean [SD] total events, 13.3 [6.8] vs 5.3 [3.6]; mean [SD] difference, 8.8 [5.6]; 95% CI, 7.3 to 10.4; Cohen d, -1.5). This difference was most pronounced in patients with a higher apnea-hypopnea index (AHI) at baseline (mean [SD] difference for AHI >30, 27.1% [31.0%]; 95% CI, -36.2% to 90.4%; Cohen d, 0.2; for AH I >40, 76.0% [35.5%]; 95% CI, 4.6% to 147.4%; Cohen d

  6. Drug-Induced QT Prolongation as a Result of an Escitalopram Overdose in a Patient with Previously Undiagnosed Congenital Long QT Syndrome

    Directory of Open Access Journals (Sweden)

    Paul Singh

    2014-01-01

    Full Text Available We present a case of drug-induced QT prolongation caused by an escitalopram overdose in a patient with previously undiagnosed congenital LQTS. A 15-year-old Caucasian female presented following a suicide attempt via an escitalopram overdose. The patient was found to have a prolonged QT interval with episodes of torsades de pointes. The patient was admitted to the telemetry unit and treated. Despite the resolution of the torsades de pointes, she continued to demonstrate a persistently prolonged QT interval. She was seen by the cardiology service and diagnosed with congenital long QT syndrome. This case illustrates the potential for an escitalopram overdose to cause an acute QT prolongation in a patient with congenital LQTS and suggests the importance of a screening electrocardiogram prior to the initiation of SSRIs, especially in patients at high risk for QT prolongation.

  7. Combined hERG channel inhibition and disruption of trafficking in drug-induced long QT syndrome by fluoxetine: a case-study in cardiac safety pharmacology.

    Science.gov (United States)

    Hancox, J C; Mitcheson, J S

    2006-11-01

    Drug-induced prolongation of the rate-corrected QT interval (QTCI) on the electrocardiogram occurs as an unwanted effect of diverse clinical and investigational drugs and carries a risk of potentially fatal cardiac arrhythmias. hERG (human ether-à-go-go-related gene) is the gene encoding the alpha-subunit of channels mediating the rapid delayed rectifier K+ current, which plays a vital role in repolarising the ventricles of the heart. Most QTCI prolonging drugs can inhibit the function of recombinant hERG K+ channels, consequently in vitro hERG assays are used widely as front-line screens in cardiac safety-testing of novel chemical entities. In this issue, Rajamani and colleagues report a case of QTCI prolongation with the antidepressant fluoxetine and correlate this with a dual effect of the drug and of its major metabolite norfluoxetine on hERG channels. Both compounds were found to produce an acute inhibition of the hERG channel by pharmacological blockade, but in addition they also were able to disrupt the normal trafficking of hERG protein to the cell membrane. Mutations to a key component of the drug binding site in the S6 region of the channel greatly attenuated channel block, but did not impair disruption of trafficking; this suggests that channel block and drug effects on trafficking were mediated by different mechanisms. These findings add to growing evidence for disruption of hERG channel trafficking as a mechanism for drug-induced long QT syndrome and raise questions as to possible limitations of acute screening methods in the assessment of QTcI prolonging liability of drugs in development.

  8. Early-life experience decreases drug-induced reinstatement of morphine CPP in adulthood via microglial-specific epigenetic programming of anti-inflammatory IL-10 expression.

    Science.gov (United States)

    Schwarz, Jaclyn M; Hutchinson, Mark R; Bilbo, Staci D

    2011-12-07

    A critical component of drug addiction research involves identifying novel biological mechanisms and environmental predictors of risk or resilience to drug addiction and associated relapse. Increasing evidence suggests microglia and astrocytes can profoundly affect the physiological and addictive properties of drugs of abuse, including morphine. We report that glia within the rat nucleus accumbens (NAcc) respond to morphine with an increase in cytokine/chemokine expression, which predicts future reinstatement of morphine conditioned place preference (CPP) following a priming dose of morphine. This glial response to morphine is influenced by early-life experience. A neonatal handling paradigm that increases the quantity and quality of maternal care significantly increases baseline expression of the anti-inflammatory cytokine IL-10 within the NAcc, attenuates morphine-induced glial activation, and prevents the subsequent reinstatement of morphine CPP in adulthood. IL-10 expression within the NAcc and reinstatement of CPP are negatively correlated, suggesting a protective role for this specific cytokine against morphine-induced glial reactivity and drug-induced reinstatement of morphine CPP. Neonatal handling programs the expression of IL-10 within the NAcc early in development, and this is maintained into adulthood via decreased methylation of the IL-10 gene specifically within microglia. The effect of neonatal handling is mimicked by pharmacological modulation of glia in adulthood with ibudilast, which increases IL-10 expression, inhibits morphine-induced glial activation within the NAcc, and prevents reinstatement of morphine CPP. Taken together, we have identified a novel gene × early-life environment interaction on morphine-induced glial activation and a specific role for glial activation in drug-induced reinstatement of drug-seeking behavior.

  9. Metabolically active extracellular vesicles released from hepatocytes under drug-induced liver-damaging conditions modify serum metabolome and might affect different pathophysiological processes.

    Science.gov (United States)

    Royo, Felix; Palomo, Laura; Mleczko, Justyna; Gonzalez, Esperanza; Alonso, Cristina; Martínez, Ibon; Pérez-Cormenzana, Miriam; Castro, Azucena; Falcon-Perez, Juan M

    2017-02-15

    Hepatocytes are involved in the endogenous and drug metabolism; many of the enzymes involved in those processes are incorporated into extracellular vesicles and secreted into the bloodstream. Liver-damaging conditions modify the molecular cargo of those vesicles significantly. However, no information about the effect of these hepatic vesicles on the extracellular environment is available. Drug-induced liver damage increases the number of circulating extracellular vesicles and affects the release and content of hepatocyte-derived vesicles. In this work, we evaluated the metabolic effect of these vesicles on the composition of the serum. We performed a targeted ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) metabolomics analysis of serum samples. The samples had been first incubated with hepatic extracellular vesicles from hepatocytes challenged with acetaminophen or diclofenac. The incubation affected the serum levels of 67 metabolites, such as amino acids and different species of lipids. The metabolites included various species of phosphatidylcholines and phosphatidylethanolamines. These compounds are the components of biological membranes; our observations suggest that the vesicles might take part in remodelling and maintenance of the membranes. Alterations in the levels of some other serum metabolites might have deleterious consequences, for example, the tetracosanoic acid with its cardiovascular effects. However, some of the metabolites whose levels were increased, including alpha-linoleic and tauroursodeoxycholic acids, have been reported to have a protective effect. Our targeted metabolomics analysis indicated that the hepatic extracellular vesicles act as nano-metabolic machines supplying the extracellular environment with the means to integrate diverse tissue responses. In conclusion, we show that the hepatic extracellular vesicles are metabolically active and might play a role in the physiopathological response to hepatic insults

  10. Is the drug-induced hypersensitivity syndrome (DIHS due to human herpesvirus 6 infection or to allergy-mediated viral reactivation? Report of a case and literature review

    Directory of Open Access Journals (Sweden)

    Borgia Guglielmo

    2010-03-01

    Full Text Available Abstract Background Drug-Induced Hypersensitivity Syndrome (DIHS is a severe and rare systemic reaction triggered by a drug (usually an antiepileptic drug. We present a case of DISH and we review studies on the clinical features and treatment of DIHS, and on its pathogenesis in which two elements (Herpesvirus infection and the drug interact with the immune system to trigger such a syndrome that can lead to death in about 20% of cases. Case presentation We report the case of a 26-year old woman with fever, systemic maculopapular rash, lymphadenopathy, hepatitis and eosinophilic leukocytosis. She had been treated with antibiotics that gave no benefit. She was taking escitalopram and lamotrigine for a bipolar disease 30 days before fever onset. Because the patient's general condition deteriorated, betamethasone and acyclovir were started. This treatment resulted in a mild improvement of symptoms. Steroids were rapidly tapered and this was followed with a relapse of fever and a worsening of laboratory parameters. Human herpesvirus 6 (HHV-6 DNA was positive as shown by PCR. Drug-Induced Hypersensitivity Syndrome (DIHS was diagnosed. Symptoms regressed on prednisone (at a dose of 50 mg/die that was tapered very slowly. The patient recovered completely. Conclusions The search for rare causes of fever led to complete resolution of a very difficult case. As DIHS is a rare disease the most relevant issue is to suspect and include it in differential diagnosis of fevers of unknown origin. Once diagnosed, the therapy is easy (steroidal administration and often successful. However our case strongly confirms that attention should be paid on the steroidal tapering that should be very slow to avoid a relapse.

  11. Prevalence of biochemical and immunological abnormalities in ...

    African Journals Online (AJOL)

    Tile prevalence of biochemical and immunological abnormalities was studied in a group of 256 patients with rheumatoid arthritis (104 coloureds, 100 whites and 52 blacks). The most common biochemical abnormalities detected were a reduction in the serum creatinine value (43,4%), raised globulins (39,7%), raised serum ...

  12. The prevalence of electroencephalographic abnormalities and ...

    African Journals Online (AJOL)

    Adele

    2004-05-20

    May 20, 2004 ... premorbid organic insult. Both would likely have increased the probability of an abnormal EEG. The high prevalence of abnormal EEGs, particularly of EEGs supporting a diagnosis of epilepsy may reflect a high prevalence in the study popula- tion, but more likely reflects the careful selection of patients.

  13. Relationship among sera lipoprotein abnormalities in healthy ...

    African Journals Online (AJOL)

    As the prevalence of lipoprotein abnormalities in adolescents is increasing dramatically, the identification of relevant risk factors is a major public health challenge. The aim of this study was to investigate whether a family history of diabetes could be a risk factor for lipid abnormalities in healthy individuals. This study is a ...

  14. Sex chromosomes and sex chromosome abnormalities.

    Science.gov (United States)

    Li, Xu

    2011-12-01

    This article focuses on constitutional sex chromosome abnormalities detected by conventional cytogenetics and fluorescence in situ hybridization. The author discusses the two general classifications of abnormalities: numerical and structural. Also included are descriptions of unique aspects of X and Y chromosomes, technological advances in detection, and future perspectives.

  15. [CHROMOSOMAL ABNORMALITIES IN PATIENTS WITH INFERTILITY].

    Science.gov (United States)

    Pylyp, L Y; Spinenko, L O; Verhoglyad, N V; Kashevarova, O O; Zukin, V D

    2015-01-01

    To assess the frequency and structure of chromosomal abnormalities in patients with infertility, a retrospective analysis of cytogenetic studies of 3414 patients (1741 females and 1673 males), referred to the Clinic of reproductive medicine "Nadiya" from 2007 to 2012, was performed. Chromosomal abnormalities were detected in 2.37% patients: 2.79% in males and 1.95% in females. Balanced structural chromosomal abnormalities prevailed over numerical abnormalities and corresponded to 80.2% of all chromosomal abnormalities detected in the studied group. Sex chromosome abnormalities made up 23.5% of chromosomal pathology (19/81) and included gonosomal aneuploidies in 84% of cases (16/19) and structural abnormalities of chromosome Y in 16% of cases (3/19). The low level sex chromosome mosaicism was detected with the frequency of 0.55%. Our results highlight the importance of cytogenetic studies in patients seeking infertility treatment by assisted reproductive technologies, since an abnormal finding not only provide a firm diagnosis to couples with infertility, but also influences significantly the approach to infertility treatment in such patients.

  16. Multiparametric tissue abnormality characterization using manifold regularization

    Science.gov (United States)

    Batmanghelich, Kayhan; Wu, Xiaoying; Zacharaki, Evangelia; Markowitz, Clyde E.; Davatzikos, Christos; Verma, Ragini

    2008-03-01

    Tissue abnormality characterization is a generalized segmentation problem which aims at determining a continuous score that can be assigned to the tissue which characterizes the extent of tissue deterioration, with completely healthy tissue being one end of the spectrum and fully abnormal tissue such as lesions, being on the other end. Our method is based on the assumptions that there is some tissue that is neither fully healthy or nor completely abnormal but lies in between the two in terms of abnormality; and that the voxel-wise score of tissue abnormality lies on a spatially and temporally smooth manifold of abnormality. Unlike in a pure classification problem which associates an independent label with each voxel without considering correlation with neighbors, or an absolute clustering problem which does not consider a priori knowledge of tissue type, we assume that diseased and healthy tissue lie on a manifold that encompasses the healthy tissue and diseased tissue, stretching from one to the other. We propose a semi-supervised method for determining such as abnormality manifold, using multi-parametric features incorporated into a support vector machine framework in combination with manifold regularization. We apply the framework towards the characterization of tissue abnormality to brains of multiple sclerosis patients.

  17. Effects of theophylline administration and intracranial abnormalities ...

    African Journals Online (AJOL)

    Objective: To determine effects of theophylline therapy for recurrent apnoea of prematurity and abnormal early (within the first 24 hours) cranial ultrasound abnormalities on protective neck turning response in preterm infants. Design: A cross sectional descriptive study. Setting: The Neonatal Unit of Hammersmith Hospital, ...

  18. Relationship among sera lipoprotein abnormalities in healthy ...

    African Journals Online (AJOL)

    Jane

    2011-08-29

    Aug 29, 2011 ... As the prevalence of lipoprotein abnormalities in adolescents is increasing dramatically, the identification of relevant ... investigate whether a family history of diabetes could be a risk factor for lipid abnormalities in healthy individuals. This study is a ..... thickness in children with type 1 diabetes. Diabetes, 51: ...

  19. Common echocardiographic abnormalities in Nigerians of different ...

    African Journals Online (AJOL)

    Conclusion: This study has reaffirmed rheumatic heart disease (predominantly mitral valve regurgitation) as the commonest cardiac abnormality in adolescents and young adults. Degenerative valvular diseases, left ventricular diastolic dysfunction, and atrial septal defects were the commonest abnormalities in the elderly, ...

  20. Common echocardiographic abnormalities in Nigerians of different ...

    African Journals Online (AJOL)

    2012-09-17

    Sep 17, 2012 ... Degenerative valvular diseases, left ventricular diastolic dysfunction, and atrial septal defects were the commonest abnormalities in the elderly, middle-aged population and children, respectively. Key words: Different age groups, echocardiographic abnormalities, Nigerians. Date of Acceptance: 17-Sep- ...

  1. First Trimester Ultrasound Screening for Congenital Abnormalities ...

    African Journals Online (AJOL)

    approach used, especially with the introduction of first trimester ultrasound as a reliable screening method. Objective: To give a comprehensive review of the basis for first trimester ultrasound screening for congenital abnormalities, it's utilization in the prenatal screening for chromosomal, structural and genetic abnormalities ...

  2. Abnormal fat distribution in PMM2-CDG

    NARCIS (Netherlands)

    Wolthuis, D.F.; Asbeck, E.V. van; Kozicz, T.L.; Morava, E.

    2013-01-01

    We hypothesize that abnormal fat distribution, a common feature of PMM2-CDG, is associated with abnormal perinatal hormone regulation. We assessed 32 cases with PMM2-CDG, for the comorbidity of hypoglycemia/hyperinsulinism and fat pads. Ninety percent of patients with hypoketotic hypoglycemia and/or

  3. Chromosomal abnormalities in patients with sperm disorders

    Directory of Open Access Journals (Sweden)

    L. Y. Pylyp

    2013-02-01

    Full Text Available Chromosomal abnormalities are among the most common genetic causes of spermatogenic disruptions. Carriers of chromosomal abnormalities are at increased risk of infertility, miscarriage or birth of a child with unbalanced karyotype due to the production of unbalanced gametes. The natural selection against chromosomally abnormal sperm usually prevents fertilization with sperm barring in cases of serious chromosomal abnormalities. However, assisted reproductive technologies in general and intracytoplasmic sperm injection in particular, enable the transmission of chromosomal abnormalities to the progeny. Therefore, cytogenetic studies are important in patients with male factor infertility before assisted reproduction treatment. The purpose of the current study was to investigate the types and frequencies of chromosomal abnormalities in 724 patients with infertility and to estimate the risk of chromosomal abnormalities detection in subgroups of patients depending on the severity of spermatogenic disruption, aiming at identifying groups of patients in need of cytogenetic studies. Karyotype analysis was performed in 724 blood samples of men attending infertility clinic. Chromosomal preparation was performed by standard techniques. At least 20 GTG-banded metaphase plates with the resolution from 450 to 750 bands per haploid set were analysed in each case. When chromosomal mosaicism was suspected, this number was increased to 50. Abnormal karyotypes were observed in 48 (6.6% patients, including 67% of autosomal abnormalities and 33% of gonosomal abnormalities. Autosomal abnormalities were represented by structural rearrangements. Reciprocal translocations were the most common type of structural chromosomal abnormalities in the studied group, detected with the frequency of 2.6% (n = 19, followed by Robertsonian translocation, observed with the frequency of 1.2% (n = 9. The frequency of inversions was 0.6% (n = 4. Gonosomal abnormalities included 14 cases

  4. Rare cytogenetic abnormalities in myelodysplastic syndromes.

    Science.gov (United States)

    Bacher, Ulrike; Schanz, Julie; Braulke, Friederike; Haase, Detlef

    2015-01-01

    The karyotype represents one of the main cornerstones for the International Prognostic Scoring System (IPSS) and the revised IPSS-R (IPSS-R) that are most widely used for prognostication in patients with myelodysplastic syndromes (MDS). The most frequent cytogenetic abnormalities in MDS, i.e. del(5q), -7/del(7q), +8, complex karyotypes, or -Y have been extensively explored for their prognostic impact. The IPSS-R also considers some less frequent abnormalities such as del(11q), isochromosome 17, +19, or 3q abnormalities. However, more than 600 different cytogenetic categories had been identified in a previous MDS study. This review aims to focus interest on selected rare cytogenetic abnormalities in patients with MDS. Examples are numerical gains of the chromosomes 11 (indicating rapid progression), of chromosome 14 or 14q (prognostically intermediate to favorable), -X (in females, with an intermediate prognosis), or numerical abnormalities of chromosome 21. Structural abnormalities are also considered, e.g. del(13q) that is associated with bone marrow failure syndromes and favorable response to immunosuppressive therapy. These and other rare cytogenetic abnormalities should be integrated into existing prognostication systems such as the IPSS-R. However, due to the very low number of cases, this is clearly dependent on international collaboration. Hopefully, this article will help to inaugurate this process.

  5. RARE CYTOGENETIC ABNORMALITIES IN MYELODYSPLASTIC SYNDROMES

    Directory of Open Access Journals (Sweden)

    Julie Schanz

    2015-04-01

    Full Text Available The karyotype represents one of the main cornerstones for the International Prognostic Scoring System (IPSS and the revised IPSS-R (IPSS-R that are most widely used for prognostication in patients with myelodysplastic syndromes (MDS. The most frequent cytogenetic abnormalities in MDS, i.e. del(5q, -7/del(7q, +8, complex karyotypes, or –Y have been extensively explored for their prognostic impact. The IPSS-R considers also some less frequent abnormalities such as del(11q, isochromosome 17, +19, or 3q abnormalities. However, more than 600 different cytogenetic categories had been identified in a previous MDS study. This review aims to focus interest on selected rare cytogenetic abnormalities in patients with MDS. Examples are numerical gains of the chromosomes 11 (indicating rapid progression, of chromosome 14 or 14q (prognostically intermediate to favorable, -X (in females, with an intermediate prognosis, or numerical abnormalities of chromosome 21. Structural abnormalities are also considered, e.g. del(13q that is associated with bone marrow failure syndromes and favorable response to immunosuppressive therapy. These and other rare cytogenetic abnormalities should be integrated into existing prognostication systems such as the IPSS-R. However, due to the very low number of cases, this is clearly dependent on international collaboration. Hopefully, this article will help to inaugurate this process.

  6. Nail abnormalities in patients with vitiligo.

    Science.gov (United States)

    Topal, Ilteris Oguz; Gungor, Sule; Kocaturk, Ozgur Emek; Duman, Hatice; Durmuscan, Mustafa

    2016-01-01

    Vitiligo is an acquired pigmentary skin disorder affecting 0.1-4% of the general population. The nails may be affected in patients with an autoimmune disease such as psoriasis, and in those with alopecia areata. It has been suggested that nail abnormalities should be apparent in vitiligo patients. We sought to document the frequency and clinical presentation of nail abnormalities in vitiligo patients compared to healthy volunteers. We also examined the correlations between nail abnormalities and various clinical parameters. This study included 100 vitiligo patients and 100 healthy subjects. Full medical histories were collected from the subjects, who underwent thorough general and nail examinations. All nail changes were noted. In the event of clinical suspicion of a fungal infection, additional mycological investigations were performed. Nail abnormalities were more prevalent in the patients (78%) than in the controls (55%) (p=0.001). Longitudinal ridging was the most common finding (42%), followed by (in descending order): leukonychia, an absent lunula, onycholysis, nail bed pallor, onychomycosis, splinter hemorrhage and nail plate thinning. The frequency of longitudinal ridging was significantly higher in patients than in controls (pvitiligo patients than in controls. Systematic examination of the nails in such patients is useful because nail abnormalities are frequent. However, the causes of such abnormalities require further study. Longitudinal ridging and leukonychia were the most common abnormalities observed in this study.

  7. [Fetal abnormalities and prognosis associated with increased nuchal translucency and abnormal karyotype].

    Science.gov (United States)

    Saldanha, Fátima Aparecida Targino; Brizot, Maria de Lourdes; Lopes, Lilian M; Liao, Adolfo Wenjaw; Zugaib, Marcelo

    2009-01-01

    This study aimed to evaluate the incidence of chromosomal abnormalities in fetuses with increased nuchal translucency (NT) measurement. Incidence of structural abnormalities and pregnancy outcome was also described in fetuses with increased NT and abnormal karyotype. This was a retrospective study involving 246 fetuses with increased NT and known karyotype followed at the Fetal Medicine Unit, Hospital das Clínicas, São Paulo University Medical School. Fetal karyotype was abnormal in 14.2% of the cases. Ultrasound anomaly scan and specialized echocardiographic studies in these cases showed fetal structural abnormalities in 80.8% and cardiac defects were found in 61.5% of the fetuses. Pregnancy outcome was abnormal in 76.5% of these women. Increased NT measurement at 11 to 13 weeks and 6 days is an important marker for fetal chromosomal and structural abnormalities, mainly fetal cardiac defects. This finding also indicates increased risk of spontaneous fetal and neonatal death.

  8. Numerically abnormal chromosome constitutions in humans

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1993-12-31

    Chapter 24, discusses numerically abnormal chromosome constitutions in humans. This involves abnormalities of human chromosome number, including polyploidy (when the number of sets of chromosomes increases) and aneuploidy (when the number of individual normal chromosomes changes). Chapter sections discuss the following chromosomal abnormalities: human triploids, imprinting and uniparental disomy, human tetraploids, hydatidiform moles, anomalies caused by chromosomal imbalance, 13 trisomy (D{sub 1} trisomy, Patau syndrome), 21 trisomy (Down syndrome), 18 trisomy syndrome (Edwards syndrome), other autosomal aneuploidy syndromes, and spontaneous abortions. The chapter concludes with remarks on the nonrandom participation of chromosomes in trisomy. 69 refs., 3 figs., 4 tabs.

  9. Characterisation of liver chemistry abnormalities associated with pazopanib monotherapy: a systematic review and meta-analysis of clinical trials in advanced cancer patients.

    Science.gov (United States)

    Powles, Thomas; Bracarda, Sergio; Chen, Mei; Norry, Elliot; Compton, Natalie; Heise, Mark; Hutson, Thomas; Harter, Philipp; Carpenter, Christopher; Pandite, Lini; Kaplowitz, Neil

    2015-07-01

    Drug-induced liver chemistry abnormalities, primarily transaminase elevations, are commonly observed in pazopanib-treated patients. This meta-analysis characterises liver chemistry abnormalities associated with pazopanib. Data of pazopanib-treated patients from nine prospective trials were integrated (N=2080). Laboratory datasets were used to characterise the incidence, timing, recovery and patterns of liver events, and subsequent rechallenge with pazopanib. Severe cases of liver chemistry abnormalities were clinically reviewed. Multivariate analyses identified predisposing factors. Twenty percent of patients developed elevated alanine aminotransferase (ALT) >3×ULN. Incidence of peak ALT >3-5×ULN, >5-8×ULN, >8-20×ULN and >20×ULN was 8%, 5%, 5% and 1%, respectively. Median time to onset for all events was 42days; 91% of events were observed within 18weeks. Recovery rates based on peak ALT >3-5×ULN, >5-8×ULN, >8-20×ULN and >20×ULN were 91%, 90%, 90% and 64%, respectively. Median time from onset to recovery was 30days, but longer in patients without dose interruption. Based on clinical review, no deaths were associated with drug-induced liver injury. Overall, 38% of rechallenged patients had ALT elevation recurrence, with 9-day median time to recurrence. Multivariate analysis showed that older age was associated with development of ALT >8×ULN. There was no correlation between hypertension and transaminitis. Our data support the current guidelines on regular liver chemistry tests after initiation of pazopanib, especially during the first 9 or 10weeks, and also demonstrate the safety of rechallenge with pazopanib. Copyright © 2015. Published by Elsevier Ltd.

  10. On two abnormal sharks from Gujarat

    Digital Repository Service at National Institute of Oceanography (India)

    Gopalan, U.K.

    The description of the two abnormal sharks, Carchariaswalbeehmi and Eulamia dussumieri collected from Gujarat, India, is given Of these C walbeehmi was double-headed The other shark E dussumieri had thumb snouted albino...

  11. Low-set ears and pinna abnormalities

    Science.gov (United States)

    ... because they do not affect hearing. However, sometimes cosmetic surgery is recommended. Skin tags may be tied off, ... 5 years old. More severe abnormalities may require surgery for cosmetic reasons as well as for function. Surgery to ...

  12. Morphological abnormality among regenerated shoots of banana ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-11-02

    AAA), 'Rastali',. 'Nangka' (AAB) and 'Baka Baling' (ABB) were chosen to compare the effect of benzylaminopurine (BAP) and thidiazuron (TDZ) on multiplication efficiency in relation with frequency of abnormal shoot.

  13. Prevalence of asymptomatic urinary abnormalities among adolescents

    Directory of Open Access Journals (Sweden)

    Mohamed Fouad

    2016-01-01

    Full Text Available To determine the prevalence of asymptomatic urinary abnormalities in adolescents, first morning clean mid-stream urine specimens were obtained from 2500 individuals and examined by dipstick and light microscopy. Adolescents with abnormal screening results were reexamined after two weeks and those who had abnormal results twice were subjected to systemic clinical examination and further clinical and laboratory investigations. Eight hundred and three (32.1% individuals had urinary abnormalities at the first screening, which significantly decreased to 345 (13.8% at the second screening, (P <0.001. Hematuria was the most common urinary abnormalities detected in 245 (9.8% adolescents who had persistent urine abnormalities; 228 (9.1% individuals had non glomerular hematuria. The hematuria was isolated in 150 (6% individuals, combined with leukocyturia in 83 (3.3% individuals, and combined with proteinuria in 12 (0.5% individuals. Leukocyturia was detected in 150 (6% of all studied adolescents; it was isolated in 39 (1.6% individuals and combined with proteinuria in 28 (1.1% of them. Asymp- tomatic bacteriuria was detected in 23 (0.9% of all studied adolescents; all the cases were females. Proteinuria was detected in 65 (2.6% of all the studied adolescents; 45 (1.8% indivi- duals had <0.5 g/day and twenty (0.8% individuals had 0.5-3 g/day. Asymptomatic urinary abnormalities were more common in males than females and adolescents from rural than urban areas (P <0.01 and (P <0.001, respectively. The present study found a high prevalence of asymptomatic urinary abnormalities among adolescents in our population.

  14. Heterotaxy syndromes and abnormal bowel rotation

    Energy Technology Data Exchange (ETDEWEB)

    Newman, Beverley [Stanford University, Lucile Packard Children' s Hospital, Department of Radiology, Stanford, CA (United States); Koppolu, Raji; Sylvester, Karl [Lucile Packard Children' s Hospital at Stanford, Department of Surgery, Stanford, CA (United States); Murphy, Daniel [Lucile Packard Children' s Hospital at Stanford, Department of Cardiology, Stanford, CA (United States)

    2014-05-15

    Bowel rotation abnormalities in heterotaxy are common. As more children survive cardiac surgery, the management of gastrointestinal abnormalities has become controversial. To evaluate imaging of malrotation in heterotaxy with surgical correlation and provide an algorithm for management. Imaging reports of heterotaxic children with upper gastrointestinal (UGI) and/or small bowel follow-through (SBFT) were reviewed. Subsequently, fluoroscopic images were re-reviewed in conjunction with CT/MR studies. The original reports and re-reviewed images were compared and correlated with surgical findings. Nineteen of 34 children with heterotaxy underwent UGI, 13/19 also had SBFT. In 15/19 reports, bowel rotation was called abnormal: 11 malrotation, 4 non-rotation, no cases of volvulus. Re-review, including CT (10/19) and MR (2/19), designated 17/19 (90%) as abnormal, 10 malrotation (abnormal bowel arrangement, narrow or uncertain length of mesentery) and 7 non-rotation (small bowel and colon on opposite sides plus low cecum with probable broad mesentery). The most useful CT/MR findings were absence of retroperitoneal duodenum in most abnormal cases and location of bowel, especially cecum. Abnormal orientation of mesenteric vessels suggested malrotation but was not universal. Nine children had elective bowel surgery; non-rotation was found in 4/9 and malrotation was found in 5/9, with discrepancies (non-rotation at surgery, malrotation on imaging) with 4 original interpretations and 1 re-review. We recommend routine, early UGI and SBFT studies once other, urgent clinical concerns have been stabilized, with elective laparoscopic surgery in abnormal or equivocal cases. Cross-sectional imaging, usually obtained for other reasons, can contribute diagnostically. Attempting to assess mesenteric width is important in differentiating non-rotation from malrotation and more accurately identifies appropriate surgical candidates. (orig.)

  15. Diagnosis and treatment of abnormal dental pain

    OpenAIRE

    Fukuda, Ken-ichi

    2016-01-01

    Most dental pain is caused by an organic problem such as dental caries, periodontitis, pulpitis, or trauma. Diagnosis and treatment of these symptoms are relatively straightforward. However, patients often also complain of abnormal dental pain that has a non-dental origin, whose diagnosis is challenging. Such abnormal dental pain can be categorized on the basis of its cause as referred pain, neuromodulatory pain, and neuropathic pain. When it is difficult to diagnose a patient's dental pain, ...

  16. Familial eccrine syringofibroadenomatosis with associated ophthalmologic abnormalities.

    Science.gov (United States)

    Chen, S; Palay, D; Templeton, S F

    1998-08-01

    Eccrine syringofibroadenoma (ESFA) is a rare benign adnexal tumor, generally with sporadic occurrence and not linked to other diseases. Only one familial occurrence of ESFA has been reported. We describe the familial occurrence of multiple ESFAs in a father and his two sons, all of whom also had similar eyelid abnormalities and progressive corneal scarring. This description of hereditary ESFA is the first to link ESFA with periocular and ocular abnormalities.

  17. Adult Human Primary Cardiomyocyte-Based Model for the Simultaneous Prediction of Drug-Induced Inotropic and Pro-arrhythmia Risk

    Directory of Open Access Journals (Sweden)

    Nathalie Nguyen

    2017-12-01

    Full Text Available Cardiac safety remains the leading cause of drug development discontinuation. We developed a human cardiomyocyte-based model that has the potential to provide a predictive preclinical approach for simultaneously predicting drug-induced inotropic and pro-arrhythmia risk.Methods: Adult human primary cardiomyocytes from ethically consented organ donors were used to measure contractility transients. We used measures of changes in contractility parameters as markers to infer both drug-induced inotropic effect (sarcomere shortening and pro-arrhythmia (aftercontraction, AC; contractility escape (CE; time to 90% relaxation (TR90. We addressed the clinical relevance of this approach by evaluating the effects of 23 torsadogenic and 10 non-torsadogenic drugs. Each drug was tested separately at four multiples of the free effective therapeutic plasma concentration (fETPC.Results: Human cardiomyocyte-based model differentiated between torsadogenic and non-torsadogenic drugs. For example, dofetilide, a torsadogenic drug, caused ACs and increased TR90 starting at 10-fold the fETPC, while CE events were observed at the highest multiple of fETPC (100-fold. Verapamil, a non-torsadogenic drug, did not change TR90 and induced no AC or CE up to the highest multiple of fETPCs tested in this study (222-fold. When drug pro-arrhythmic activity was evaluated at 10-fold of the fETPC, AC parameter had excellent assay sensitivity and specificity values of 96 and 100%, respectively. This high predictivity supports the translational safety potential of this preparation and of the selected marker. The data demonstrate that human cardiomyocytes could also identify drugs associated with inotropic effects. hERG channel blockers, like dofetilide, had no effects on sarcomere shortening, while multi-ion channel blockers, like verapamil, inhibited sarcomere shortening.Conclusions: Isolated adult human primary cardiomyocytes can simultaneously predict risks associated with inotropic

  18. Action potential-based MEA platform for in vitro screening of drug-induced cardiotoxicity using human iPSCs and rat neonatal myocytes.

    Science.gov (United States)

    Jans, Danny; Callewaert, Geert; Krylychkina, Olga; Hoffman, Luis; Gullo, Francesco; Prodanov, Dimiter; Braeken, Dries

    2017-09-01

    Drug-induced cardiotoxicity poses a negative impact on public health and drug development. Cardiac safety pharmacology issues urged for the preclinical assessment of drug-induced ventricular arrhythmia leading to the design of several in vitro electrophysiological screening assays. In general, patch clamp systems allow for intracellular recordings, while multi-electrode array (MEA) technology detect extracellular activity. Here, we demonstrate a complementary metal oxide semiconductor (CMOS)-based MEA system as a reliable platform for non-invasive, long-term intracellular recording of cardiac action potentials at high resolution. Quinidine (8 concentrations from 10 -7 to 2.10 -5 M) and verapamil (7 concentrations from 10 -11 to 10 -5 M) were tested for dose-dependent responses in a network of cardiomyocytes. Electrophysiological parameters, such as the action potential duration (APD), rates of depolarization and repolarization and beating frequency were assessed. In hiPSC, quinidine prolonged APD with EC 50 of 2.2·10 -6 M. Further analysis indicated a multifactorial action potential prolongation by quinidine: (1) decreasing fast repolarization with IC 50 of 1.1·10 -6 M; (2) reducing maximum upstroke velocity with IC 50 of 2.6·10 -6 M; and (3) suppressing spontaneous activity with EC 50 of 3.8·10 -6 M. In rat neonatal cardiomyocytes, verapamil blocked spontaneous activity with EC 50 of 5.3·10 -8 M and prolonged the APD with EC 50 of 2.5·10 -8 M. Verapamil reduced rates of fast depolarization and repolarization with IC 50 s of 1.8 and 2.2·10 -7 M, respectively. In conclusion, the proposed action potential-based MEA platform offers high quality and stable long-term recordings with high information content allowing to characterize multi-ion channel blocking drugs. We anticipate application of the system as a screening platform to efficiently and cost-effectively test drugs for cardiac safety. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. 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

  20. Is drug-induced toxicity a good predictor of response to neo-adjuvant chemotherapy in patients with breast cancer? -A prospective clinical study

    Directory of Open Access Journals (Sweden)

    Singh JP

    2004-08-01

    Full Text Available Abstract Background Neo-adjuvant chemotherapy is an integral part of multi-modality approach in the management of locally advanced breast cancer and it is vital to predict the response in order to tailor the regime for a patient. The common final pathway in the tumor cell death is believed to be apoptosis or programmed cell death and chemotherapeutic drugs like other DNA-damaging agents act on rapidly multiplying cells including both the tumor and the normal cells by following the same common final pathway. This could account for both the toxic effects and the response. Absence or decreased apoptosis has been found to be associated with chemo resistance. The change in expression of apoptotic markers (Bcl-2 and Bax proteins brought about by various chemotherapeutic regimens is being used to identify drug resistance in the tumor cells. A prospective clinical study was conducted to assess whether chemotherapy induced toxic effects could serve as reliable predictors of apoptosis or response to neo-adjuvant chemotherapy in patients with locally advanced breast cancer. Methods 50 cases of locally advanced breast cancer after complete routine and metastatic work up were subjected to trucut biopsy and the tissue evaluated immunohistochemically for apoptotic markers (bcl-2/bax ratio. Three cycles of Neoadjuvant Chemotherapy using FAC regime (5-fluorouracil, adriamycin, cyclophosphamide were given at three weekly intervals and patients assessed for clinical response as well as toxicity after each cycle. Modified radical mastectomy was performed in all patients three weeks after the last cycle and the specimen were re-evaluated for any change in the bcl-2/bax ratio. The clinical response, immunohistochemical response and the drug-induced toxicity were correlated and compared. Descriptive studies were performed with SPSS version 10 and the significance of response was assessed using paired t-test. Significance of correlation between various variables was

  1. [Changes in biomechanical properties of the ocular fibrous tunic in patients with primary open-angle glaucoma in response to drug-induced stress-relief tests].

    Science.gov (United States)

    Makashova, N V; Vasilyeva, A E

    2017-01-01

    To determine the effect of drug-induced stress-relief tests on biomechanical properties of the ocular fibrous tunic in eyes with early, moderate, or advanced primary open-angle glaucoma (POAG). A total of 202 eyes of 150 patients with POAG of different severity (early, moderate, or advanced) and 36 eyes of 30 healthy controls were examined. The mean patient age was 62±8.2 years. All groups were standardized by age, sex, and the range of corneal-compensated intraocular pressure (IOP) at baseline (21-30 mmHg). All patients underwent a standard ophthalmic examination, including visometry, biomicroscopy, gonioscopy, ophthalmoscopy, and Humphrey visual field assessment. Corneal hysteresis (CH), corneal resistance factor (CRF), CH-CRF difference, corneal-compensated IOP (IOPcc), and Goldmann-related IOP (IOPg) were measured with Ocular Response Analyzer (ORA, Reichert, USA). The axial eye length was measured on an ultrasonic A-scan (Ocuscan RxP, Alcon, USA) in the 10 MHz mode. CH and CRF variability analysis was conducted to assess changes in biomechanical properties of the fibrous tunic due to an IOP decrease and a tendency toward compensation. For the first time, the ratio between CH and CRF changes (ΔCH/ΔCRF) was used to evaluate biomechanical properties of the fibrous tunic. This ratio provides understanding of the significance of CH and CRF changes after reduction of IOP. In early glaucoma patients, it differed inconsiderably from the control group (p>0.05) and averaged 1.62±0.9. In moderate glaucoma, CH changes were more pronounced than those of CRF: ΔCH/ΔCRF - 2.03±2.41 (under conservative treatment) and 2.12±1.07 (without treatment). In advanced glaucoma an opposite pattern was observed: the CH/CRF ratio got closer to 1.0 largely due to CRF changes, while CH changes became much less pronounced (or even negative, in some cases): ΔCH/ΔCRF - 0.27±0.32 (under conservative treatment), 0.16±1.29 (without treatment). While the IOP decreased as a result of

  2. Ocular abnormalities in healthy Standardbred foals.

    Science.gov (United States)

    Barsotti, Giovanni; Sgorbini, Micaela; Marmorini, Paola; Corazza, Michele

    2013-07-01

    To determine the prevalence and describe ocular abnormalities in healthy Standardbred foals within 48 h of birth. One hundred and two neonatal foals. All foals had an unassisted delivery. On the basis of physical examination and the results of hematological and biochemical parameters, all foals were unaffected by systemic diseases. A complete ophthalmic examination was performed within 48 h of birth. Foals with ocular hemorrhages were re-examined weekly until the abnormalities were resolved. 65/102 (63.7%) foals did not show ocular abnormalities, while in 37/102 (36.3%) cases, ocular abnormalities were present. Retinal and subconjunctival hemorrhages were recorded in 19/102 (18.6%), and in 13/102 (12.7%), respectively. In 4/102 (3.9%) animals, an entropion of the lower eyelid was present. Only one foal (1%) showed a congenital nuclear unilateral cataract. No other ocular abnormalities were detected. However, all foals showed various degrees of remnants of hyaloid system. One week after the first ocular examination, retinal hemorrhages had resolved in 100% of the eyes, whereas subconjunctival hemorrhages had disappeared in all eyes by the second week following the first examination. The acquired ocular lesions observed with relatively high frequency in the examined healthy Standardbred foals were ocular hemorrhages, which always showed a good outcome. Although these abnormalities were present at birth, they were not considered strictly congenital but likely acquired during parturition. Instead, congenital ocular abnormalities were rarely diagnosed, and the entropion of the lower eyelid was the most common disease in the breed. © 2012 American College of Veterinary Ophthalmologists.

  3. Comparison of Liver Biopsy Findings with the Digestive Disease Week Japan 2004 Scale for Diagnosis of Drug-Induced Liver Injury.

    Science.gov (United States)

    Tsutsui, Akemi; Nakanuma, Yasuni; Takaguchi, Kouichi; Nakamura, Satoko; Shibata, Hiroshi; Baba, Nobuyuki; Senoh, Tomonori; Nagano, Takuya; Ikeda, Hiroko

    2015-01-01

    The liver biopsy remains a valuable tool in the diagnosis of drug-induced liver injury (DILI). The Digestive Disease Week Japan 2004 (DDW-J) scale proposed as an objective tool for the diagnosis of DILI has been widely used in Japan. So far, the histological features have not been compared with DDW-J scale in detail. Herein, we examined the correlation between liver biopsy findings and clinical features, particularly DDW-J scales. A total of 80 patients with liver injuries of unknown cause were enrolled. Based on the histological findings, these cases were categorized into 3 groups: A (DILI was strongly suspected), B (DILI was suspected), and C (DILI should be considered in the differential diagnosis). Histological groups and DDW-J scale were moderately correlated (κ = 0.60). The mean total DDW-J scale scores were as follows: 4.89 for A, 3.26 for B, and 0.75 for C (p biopsy findings and DDW-J scale were well correlated, and the hepatocellular type of liver injuries was well coincided by both evaluations, though there were several discrepant cases, particularly in cholestatic type.

  4. Depth-dependent changes of obstruction patterns under increasing sedation during drug-induced sedation endoscopy: results of a German monocentric clinical trial.

    Science.gov (United States)

    Kellner, Patrick; Herzog, Beatrice; Plößl, Sebastian; Rohrmeier, Christian; Kühnel, Thomas; Wanzek, Ramona; Plontke, Stefan; Herzog, Michael

    2016-09-01

    Drug-induced sedation endoscopy (DISE) and simulated snoring (SimS) can locate the site of obstruction in patients with sleep-disordered breathing (SDB). There is clinical evidence for a change in collapsibility of the upper airway depending on the depth of sedation. So far, a dose-response relationship between sedation and collapsibility has not been demonstrated. DISE and SimS were performed in 60 consecutive patients with SDB under monitoring of depth of sedation by BiSpectral Index® (BIS). Initially, SimS was conducted followed by DISE using bolus application of propofol. Sedation was performed up to a sedation level representing slow wave sleep (BIS = 40). The collapsibility of the upper airway was documented at decreasing sedation levels by an identical pictogram classification. For all levels and patterns of obstruction, a dose-dependent increase in the collapsibility of the upper airway was detected. A maximum collapsibility was achieved at sedation levels representing slow wave sleep. The collapsibility during SimS corresponded to light sleep stages and did not cover slow wave sleep. A dose-dependent change of patterns of obstructions can be observed during DISE under BIS monitoring indicating sedation depth. The obtained patterns of obstruction during DISE and SimS should thus be interpreted with regard to the sedation depth.

  5. 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

    2017-10-07

    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.

  6. The Promise of New Technologies to Reduce, Refine, or Replace Animal Use while Reducing Risks of Drug Induced Liver Injury in Pharmaceutical Development.

    Science.gov (United States)

    Sistare, Frank D; Mattes, William B; LeCluyse, Edward L

    2016-12-01

    Drug induced liver injury (DILI) has contributed more to marketed pharmaceutical withdrawals and clinical development failures than any other human organ toxicity. DILI seen in animal studies also frequently leads to the discontinuation of promising drug candidates very early in the pipeline. This manuscript reviews and critically assesses the current regulatory expectations; the current drug development approaches, strategies, and gaps; and the numerous exciting opportunities becoming available to address these gaps through technological advances. Emerging integrated pharmaceutical development strategies, while far from uniform, have generally evolved to currently inform early DILI risk potential using supplemental assays for reactive metabolite formation, mitochondrial toxicity, inhibition of bile salt transport, and cellular imaging endpoints including cytotoxicity. Despite these approaches and robust animal testing, significant gaps in addressing human DILI remain. Increasingly sophisticated in vitro humanized test systems, new animal models, emerging computational models, and novel translational biomarkers are being introduced to improve our ability to more accurately predict DILI. Expectations are high for a future state with more predictive tools and problem solving strategies that will improve pharmaceutical discovery and development in relation to understanding human DILI risk potential and make it less dependent on animal studies for successfully developing safer drug candidates. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  7. Higher Risk of Severe Drug-Induced Liver Injury among Hispanic HIV-Infected Patients after Initiation of Highly Active Antiretroviral Therapy.

    Science.gov (United States)

    Lamar, Zanetta S; Núnez, Marina

    2011-01-01

    Little is known about differences across ethnicities in the development of drug-induced liver injury (DILI) after highly active antiretroviral therapy (HAART) initiation. This is a retrospective, longitudinal, comparative, pilot study. DILI within the first year of HAART was evaluated in 50 HIV-infected Hispanics without viral hepatitis who initiated HAART between 2000 and 2009. It was compared to white and black patients (1:1:1) matched by age and CD4 counts. HAART-related DILI of any grade occurred in 30 of 150 (20%) patients and was associated with nonnucleoside reverse transcriptase inhibitor (NNRTI) use (OR 4.49 [95%CI 1.5-13.8]). Severe DILI was significantly more frequent among Hispanics compared to other groups (6% vs. 0%; P = .04). Of the 3 patients with severe DILI, 2 underwent liver imaging and had hepatic steatosis. Severe DILI within the first year of HAART initiation was infrequent and restricted to Hispanics. Additional studies are needed to determine if fatty liver is involved in the excess of severe DILI observed in this group.

  8. Comparison of Liver Biopsy Findings with the Digestive Disease Week Japan 2004 Scale for Diagnosis of Drug-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Akemi Tsutsui

    2015-01-01

    Full Text Available The liver biopsy remains a valuable tool in the diagnosis of drug-induced liver injury (DILI. The Digestive Disease Week Japan 2004 (DDW-J scale proposed as an objective tool for the diagnosis of DILI has been widely used in Japan. So far, the histological features have not been compared with DDW-J scale in detail. Herein, we examined the correlation between liver biopsy findings and clinical features, particularly DDW-J scales. A total of 80 patients with liver injuries of unknown cause were enrolled. Based on the histological findings, these cases were categorized into 3 groups: A (DILI was strongly suspected, B (DILI was suspected, and C (DILI should be considered in the differential diagnosis. Histological groups and DDW-J scale were moderately correlated (κ=0.60. The mean total DDW-J scale scores were as follows: 4.89 for A, 3.26 for B, and 0.75 for C (p<0.05. While hepatocellular type was coincided in a majority of cases by histological and DDW-J scale evaluation, cholestatic type was not well coincided. In conclusion, biopsy findings and DDW-J scale were well correlated, and the hepatocellular type of liver injuries was well coincided by both evaluations, though there were several discrepant cases, particularly in cholestatic type.

  9. High-power diode laser on management of drug-induced gingival overgrowth: Report of two cases and long-term follow-up.

    Science.gov (United States)

    Campos, Luana; Gallottini, Marina; Pallos, Débora; Simões, Alyne; Martins, Fabiana

    2018-01-19

    Drug-induced gingival overgrowth (DIGO) is attributed mainly to the prolonged use of calcium channel blocking agents, anticonvulsants, and anti-calcineurin inhibitors . The management of DIGO depends on the severity of the disease and includes surgical intervention and plaque control. Compared to conventional surgical treatment, the recent literature data have shown that gingivectomy using a high-power laser (HPL) is a short and easy procedure, which results in minimal postoperative discomfort and greater patient accep- tance. The purpose of this study was to report two cases of recurrent DIGO treated surgically using HPL (λ 808nm, 1.5W). Minimal bleeding and discomfort were observed during surgery, and patients reported no pain or bleeding after the procedure. After 1 year of follow-up, patients presented a minimal increase of gingival volume, indicating that laser technology can improve the efficiency and prognosis of DIGO. The HPL was able to preventing hemorrhage and improving the patient's collaboration with the treatment and quality of life.

  10. Drug-induced QT prolongation when QT interval is measured in each of the 12 ECG leads in men and women in a thorough QT study.

    Science.gov (United States)

    Panicker, Gopi Krishna; Salvi, Vaibhav; Karnad, Dilip R; Chakraborty, Saikat; Manohar, Deepak; Lokhandwala, Yash; Kothari, Snehal

    2014-01-01

    Lead II is commonly used to study drug-induced QT prolongation. Whether other ECG leads too show comparable QT prolongation is not known. We studied moxifloxacin-induced QT prolongation in a thorough QT study in healthy subjects (54 males, 43 females). Placebo-subtracted change from baseline in QTc corrected by Fridericia's method (ΔΔQTcF) at 1, 1.5, 2 and 4 hours after moxifloxacin was studied in all 12 leads. Unacceptably wide 90% confidence interval (CI) for ΔΔQTcF was seen in three leads; these leads also had maximum ECGs with flat T waves (60% in aVL, 45% in lead III and 42% in V1). After excluding ECGs with flat T waves, 90% lower CI of ΔΔQTcF was ≥ 5 ms in all leads except leads III, aVL and V1 in men. The 90% lower CI exceeded 5 ms in these leads in women despite wide 90% CIs because of greater mean ΔΔQTcF. Leads III, aVL and V1 should be avoided when measuring QT interval in thorough QT studies. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Abnormal Magnetic Field Effects on Electrogenerated Chemiluminescence

    Science.gov (United States)

    Pan, Haiping; Shen, Yan; Wang, Hongfeng; He, Lei; Hu, Bin

    2015-03-01

    We report abnormal magnetic field effects on electrogenerated chemiluminescence (MFEECL) based on triplet emission from the Ru(bpy)3Cl2-TPrA electrochemical system: the appearance of MFEECL after magnetic field ceases. In early studies the normal MFEECL have been observed from electrochemical systems during the application of magnetic field. Here, the abnormal MFEECL suggest that the activated charge-transfer [Ru(bpy)33+ … TPrA•] complexes may become magnetized in magnetic field and experience a long magnetic relaxation after removing magnetic field. Our analysis indicates that the magnetic relaxation can gradually increase the density of charge-transfer complexes within reaction region due to decayed magnetic interactions, leading to a positive component in the abnormal MFEECL. On the other hand, the magnetic relaxation facilitates an inverse conversion from triplets to singlets within charge-transfer complexes. The inverse triplet --> singlet conversion reduces the density of triplet light-emitting states through charge-transfer complexes and gives rise to a negative component in the abnormal MFEECL. The combination of positive and negative components can essentially lead to a non-monotonic profile in the abnormal MFEECL after ceasing magnetic field. Nevertheless, our experimental studies may reveal un-usual magnetic behaviors with long magnetic relaxation from the activated charge-transfer [Ru(bpy)33+ … TPrA•] complexes in solution at room temperature.

  12. [Liver enzyme abnormalities among oil refinery workers].

    Science.gov (United States)

    Carvalho, Fernando Martins; Silvany Neto, Annibal Muniz; Mendes, João Luiz Barberino; Cotrim, Helma Pinchemel; Nascimento, Ana Lísia Cunha; Lima Júnior, Alberto Soares; Cunha, Tatiana Oliveira Bernardo da

    2006-02-01

    Occupational exposure typical of an oil refinery may alter liver function among the workers. Thus, the objective of the study was to identify risk factors for liver enzyme abnormalities among oil refinery workers. The workers at an oil refinery in Northeastern Brazil underwent routine annual medical examination from 1982 to 1998. This case-control study investigated all the 150 cases of individuals with simultaneous gamma-glutamyltransferase and alanine aminotransferase abnormalities of at least 10% above reference levels. As controls, 150 workers without any liver enzyme or bilirubin abnormalities since starting to work there were selected. Odds ratios and the respective 95% confidence intervals were calculated from logistic regression models. In all the production sectors, the risk of liver enzyme abnormalities was significantly higher than in the administrative sector (OR=5.7; 95% CI: 1.7-18.4), even when the effects of alcohol, obesity and medical history of hepatitis were controlled for. During the period from 1992 to 1994, 88 out of the 89 cases occurred among workers from the various production sectors. Occupational exposure plays an important role in causing liver enzyme abnormalities among oil refinery workers. This is in addition to the specifically biological and/or behavioral risk factors such as obesity and alcohol consumption.

  13. Abnormal Grain Growth Suppression in Aluminum Alloys

    Science.gov (United States)

    Hales, Stephen J. (Inventor); Claytor, Harold Dale (Inventor); Alexa, Joel A. (Inventor)

    2015-01-01

    The present invention provides a process for suppressing abnormal grain growth in friction stir welded aluminum alloys by inserting an intermediate annealing treatment ("IAT") after the welding step on the article. The IAT may be followed by a solution heat treatment (SHT) on the article under effectively high solution heat treatment conditions. In at least some embodiments, a deformation step is conducted on the article under effective spin-forming deformation conditions or under effective superplastic deformation conditions. The invention further provides a welded article having suppressed abnormal grain growth, prepared by the process above. Preferably the article is characterized with greater than about 90% reduction in area fraction abnormal grain growth in any friction-stir-welded nugget.

  14. Neurological abnormalities associated with CDMA exposure.

    Science.gov (United States)

    Hocking, B; Westerman, R

    2001-09-01

    Dysaesthesiae of the scalp and neurological abnormality after mobile phone use have been reported previously, but the roles of the phone per se or the radiations in causing these findings have been questioned. We report finding a neurological abnormality in a patient after accidental exposure of the left side of the face to mobile phone radiation [code division multiple access (CDMA)] from a down-powered mobile phone base station antenna. He had headaches, unilateral left blurred vision and pupil constriction, unilateral altered sensation on the forehead, and abnormalities of current perception thresholds on testing the left trigeminal ophthalmic nerve. His nerve function recovered during 6 months follow-up. His exposure was 0.015-0.06 mW/cm(2) over 1-2 h. The implications regarding health effects of radiofrequency radiation are discussed.

  15. Enhanced monitoring of abnormal emergency department demands

    KAUST Repository

    Harrou, Fouzi

    2016-06-13

    This paper presents a statistical technique for detecting signs of abnormal situation generated by the influx of patients at emergency department (ED). The monitoring strategy developed was able to provide early alert mechanisms in the event of abnormal situations caused by abnormal patient arrivals to the ED. More specifically, This work proposed the application of autoregressive moving average (ARMA) models combined with the generalized likelihood ratio (GLR) test for anomaly-detection. ARMA was used as the modelling framework of the ARMA-based GLR anomaly-detection methodology. The GLR test was applied to the uncorrelated residuals obtained from the ARMA model to detect anomalies when the data did not fit the reference ARMA model. The ARMA-based GLR hypothesis testing scheme was successfully applied to the practical data collected from the database of the pediatric emergency department (PED) at Lille regional hospital center, France. © 2015 IEEE.

  16. Advances in understanding paternally transmitted Chromosomal Abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    Marchetti, F; Sloter, E; Wyrobek, A J

    2001-03-01

    Multicolor FISH has been adapted for detecting the major types of chromosomal abnormalities in human sperm including aneuploidies for clinically-relevant chromosomes, chromosomal aberrations including breaks and rearrangements, and other numerical abnormalities. The various sperm FISH assays have been used to evaluate healthy men, men of advanced age, and men who have received mutagenic cancer therapy. The mouse has also been used as a model to investigate the mechanism of paternally transmitted genetic damage. Sperm FISH for the mouse has been used to detect chromosomally abnormal mouse sperm, while the PAINT/DAPI analysis of mouse zygotes has been used to evaluate the types of chromosomal defects that can be paternally transmitted to the embryo and their effects on embryonic development.

  17. Conduction abnormalities during dipyridamole stress testing.

    Science.gov (United States)

    Massalha, Samia; Reizberg, Ilya; Israel, Ora; Kapeliovich, Michael; Sholy, Haitham; Koskosi, Amjad; Keidar, Zohar; Marai, Ibrahim

    2017-04-01

    Pharmacological stress tests using dipyridamole are considered to be safe. However, cases of atrioventricular (AV) block have been reported. We retrospectively analyzed ECG at baseline and during dipyridamole stress tests of 2010 consecutive patients (patients with second or third degree AV block were excluded). At baseline, 350 (17.4%) patients had conduction abnormalities. Following dipyridamole infusion 16 patients (0.8%) developed a transient change in AV conduction (15 patients) and or sinus arrest (1 patient). Compared to patients without baseline conduction abnormalities, patients with any conduction abnormalities at baseline were at a higher risk for the development of AV block after dipyridamole infusion [0.3% vs 3.14%, respectively; P < .0001].

  18. Abnormal sperm count and motility on semen analysis are not sufficiently predictive of abnormal Kruger morphology.

    Science.gov (United States)

    Morelli, Sara S; Seungdamrong, Aimee; McCulloh, David H; McGovern, Peter G

    2010-12-01

    Abnormal morphology by Kruger's strict criteria cannot be predicted reliably by the presence of other abnormal parameters on semen analysis. Assessment of Kruger morphology therefore remains a necessary component of a complete semen analysis in the workup of the infertile couple. Copyright © 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  19. Abnormal vibration induced illusion of movement in essential tremor: evidence for abnormal muscle spindle afferent function

    OpenAIRE

    Frima, N; Grunewald, R

    2005-01-01

    Objectives: Vibration induced illusion of movement (VIIM) is abnormal in patients with idiopathic focal dystonia, an abnormality which corrects with fatigue of the vibrated muscle. Since dystonia and essential tremor sometimes coexist in families, we investigated the perception of VIIM and the effect of fatigue on VIIM in patients with essential tremor.

  20. Abnormal Event Detection Using Local Sparse Representation

    DEFF Research Database (Denmark)

    Ren, Huamin; Moeslund, Thomas B.

    2014-01-01

    measurement based on the difference between the normal space and local space. Specifically, we provide a reasonable normal bases through repeated K spectral clustering. Then for each testing feature we first use temporal neighbors to form a local space. An abnormal event is found if any abnormal feature...... is found that satisfies: the distance between its local space and the normal space is large. We evaluate our method on two public benchmark datasets: UCSD and Subway Entrance datasets. The comparison to the state-of-the-art methods validate our method's effectiveness....

  1. RARE CYTOGENETIC ABNORMALITIES IN MYELODYSPLASTIC SYNDROMES

    OpenAIRE

    Julie Schanz; Friederike Braulke; Detlef Haase

    2015-01-01

    The karyotype represents one of the main cornerstones for the International Prognostic Scoring System (IPSS) and the revised IPSS-R (IPSS-R) that are most widely used for prognostication in patients with myelodysplastic syndromes (MDS). The most frequent cytogenetic abnormalities in MDS, i.e. del(5q), -7/del(7q), +8, complex karyotypes, or -Y have been extensively explored for their prognostic impact. The IPSS-R also considers some less frequent abnormalities such as del(11q), isochromosome 1...

  2. Regional Articular Cartilage Abnormalities of the Hip.

    Science.gov (United States)

    Link, Thomas M; Schwaiger, Benedikt J; Zhang, Alan L

    2015-09-01

    Imaging of hip cartilage is challenging because of its limited thickness and complex geometry and therefore requires advanced MRI techniques. However, cartilage abnormalities are found in a number of disease entities, and their diagnosis may impact patient management. This article will provide pertinent information about the motivation to image hip cartilage, which imaging techniques to use, and how to analyze cartilage; finally, we will discuss disease entities with regional cartilage lesions, including the typical MRI findings. Because the detection and quantification of regional cartilage abnormalities are critical for guidance of operative and nonoperative management of hip disorders, radiologists should be familiar with imaging and analysis techniques for assessing hip cartilage.

  3. Abnormal Taenia saginata tapeworms in Thailand.

    Science.gov (United States)

    Maipanich, Wanna; Sato, Megumi; Pubampen, Somchit; Sanguankiat, Surapol; Kusolsuk, Teera; Thaenkham, Urusa; Waikagul, Jitra

    2011-09-01

    Sixty-eight residents of Ban Luang and Ban Pang Kae villages, in Nan Province, northern Thailand, visited our mobile field station in September 2006 and March 2007, seeking treatment for taeniasis. After treatment, 22 cases discharged tapeworm strobila in their fecal samples and 17 scolices were recovered. Among these, 3 were morphologically abnormal, with six suckers on the scolex. To confirm the species of these tapeworms, the mitochondrial cytochrome c oxidase subunit I (COI) gene was used as a molecular marker. The partial COI sequences (800 bp) of the abnormal tapeworms were identical to the sequences of Taenia saginata deposited in Genbank.

  4. Hemorheological abnormalities in human arterial hypertension

    Science.gov (United States)

    Lo Presti, Rosalia; Hopps, Eugenia; Caimi, Gregorio

    2014-05-01

    Blood rheology is impaired in hypertensive patients. The alteration involves blood and plasma viscosity, and the erythrocyte behaviour is often abnormal. The hemorheological pattern appears to be related to some pathophysiological mechanisms of hypertension and to organ damage, in particular left ventricular hypertrophy and myocardial ischemia. Abnormalities have been observed in erythrocyte membrane fluidity, explored by fluorescence spectroscopy and electron spin resonance. This may be relevant for red cell flow in microvessels and oxygen delivery to tissues. Although blood viscosity is not a direct target of antihypertensive therapy, the rheological properties of blood play a role in the pathophysiology of arterial hypertension and its vascular complications.

  5. Temporal abnormalities in children with developmental dyscalculia.

    Science.gov (United States)

    Vicario, Carmelo Mario; Rappo, Gaetano; Pepi, Annamaria; Pavan, Andrea; Martino, Davide

    2012-01-01

    Recent imaging studies have associated Developmental dyscalculia (DD) to structural and functional alterations corresponding Parietal and the Prefrontal cortex (PFC). Since these areas were shown also to be involved in timing abilities, we hypothesized that time processing is abnormal in DD. We compared time processing abilities between 10 children with pure DD (8 years old) and 11 age-matched healthy children. Results show that the DD group underestimated duration of a sub-second scale when asked to perform a time comparison task. The timing abnormality observed in our DD participants is consistent with evidence of a shared fronto-parietal neural network for representing time and quantity.

  6. Drug-induced extrapyramidal syndromes

    NARCIS (Netherlands)

    Schillevoort, Igor Ernesto Rudolf Maurice

    2002-01-01

    Extrapyramidal syndromes (EPS) are a group of movement disorders that result from damage in the basal ganglia and certain related thalamic and brainstem nuclei. EPS are either primary, i.e. due to a neurodegenerative disease, or secondary. Secondary forms can have different causes, the most

  7. Drug-induced renal injury

    African Journals Online (AJOL)

    induced renal toxicity into four major renal syndromes: • acute renal failure. • chronic renal failure. • glomerulonephritis. • tubulopathies. These major renal syndromes are discussed in further detail below (see summary in Table I). Acute renal failure. Drugs can cause acute renal failure by causing pre-renal, intrinsic or.

  8. 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

  9. 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.

  10. Drug-induced lupus erythematosus

    Science.gov (United States)

    ... Tsokos GC, ed. Systemic Lupus Erythematosus . Philadelphia, PA: Elsevier; 2016:chap 54. Habif TP. Connective tissue diseases. ... TP, ed. Clinical Dermatology . 6th ed. Philadelphia, PA: Elsevier; 2016:chap 17. Kumar V, Abbas AK, Aster ...

  11. TOXIC AND DRUG INDUCED MYOPATHIES

    OpenAIRE

    2009-01-01

    Abstract Although the ?do no harm? dogma of Hippocrates is faithfully followed by all practitioners, drugs used for therapeutic interventions either alone or in combination, may sometimes cause unexpected toxicity to the muscles, resulting in a varying degree of symptomatology, from mild discomfort and inconvenience to permanent damage and disability. The clinician should suspect a toxic myopathy when a patient without a pre-existing muscle disease develops myalgia, fatigue, weakn...

  12. Lúpus induzido por drogas: da imunologia básica à aplicada Drug-induced lupus: from basic to spplied immunology

    Directory of Open Access Journals (Sweden)

    Licia Maria Henrique da Mota

    2007-12-01

    Full Text Available O lúpus induzido por drogas (LID é descrito como o desenvolvimento de sintomas semelhantes ao do lúpus eritematoso sistêmico idiopático, temporalmente relacionado à exposição a drogas, havendo, comumente, a resolução do quadro com a suspensão do medicamento desencadeante. A associação mais clássica é feita com a procainamida e a hidralazina. Recentemente, com a introdução de novas drogas na prática clínica, tem sido relatado um aumento no número de medicamentos implicados como causadores da doença, e a lista atual inclui quase uma centena de drogas relacionadas à ocorrência de LID. Embora descrito há mais de 60 anos, o mecanismo imunológico básico do LID ainda não está totalmente compreendido. Há várias hipóteses para o processo de indução de auto-imunidade pelas drogas, e o fenômeno geralmente é interpretado como uma inapropriada ativação do sistema imunitário. Entre as diversas teorias propostas, as mais aceitas são: a inibição da metilação do ácido desoxirribonucléico (DNA por algumas drogas, o que permitiria a ativação das células T; a oxidação de certas substâncias pelos monócitos, gerando metabólitos ativos que ocasionariam ativação das células apresentadoras de antígenos e/ou a interferência dos metabólitos de determinadas drogas com a tolerância do sistema imune. Novos estudos são necessários para a melhor compreensão da imunopatogenia do LID, objetivando desenvolver tratamentos específicos com base no melhor conhecimento dos mecanismos patogênicos.Drug-induced lupus (DIL has been described as the development of idiopathic systemic lupus erythematous-like symptoms, temporarily associated to the exposition to drugs, and as a rule, the condition is improved with the suspension of the triggering medication. The most classical association is with procainamide and hydralazine. Recently, with the introduction of new drugs in the clinical practice, an increase on the number of

  13. Outcome of liver transplantation for drug-induced acute liver failure in the United States: analysis of the United Network for Organ Sharing database.

    Science.gov (United States)

    Mindikoglu, Ayse L; Magder, Laurence S; Regev, Arie

    2009-07-01

    Acute liver failure (ALF) is an uncommon but potentially lethal drug-related adverse effect that often leads to liver transplantation (LT) or death. A retrospective cohort study was performed with the United Network for Organ Sharing Standard Transplant Analysis and Research files. Recipients who underwent LT for drug-induced acute liver failure (DIALF) from 1987 through 2006 were analyzed. A total of 661 patients transplanted for DIALF were included in the analysis. The 4 leading implicated drug groups were acetaminophen (n = 265; 40%), antituberculosis drugs (n = 50; 8%), antiepileptics (n = 46; 7%), and antibiotics (n = 39; 6%). One-year estimated survival probabilities were 76%, 82%, 52%, 82%, and 79% for acetaminophen, antituberculosis drugs, antiepileptics, antibiotics, and others, respectively. The lower rate of survival among those exposed to antiepileptics was observed mainly in children. Of the 22 patients less than 18 years old who had ALF due to antiepileptics, 73% died within the first year. The difference in overall survival between acetaminophen-related and non-acetaminophen-related ALF was not statistically significant. Patients with acetaminophen-related ALF required dialysis prior to LT at a significantly higher rate than all other drug groups (27% versus 3%-10%, P < 0.0001). According to Cox proportional hazards regression analysis, the independent pretransplant predictors of death after LT were being on life support, DIALF due to antiepileptic drugs at age less than 18, and elevated serum creatinine. In conclusion, the leading drug groups causing LT due to DIALF in the United States were acetaminophen, antituberculosis drugs, antiepileptics, and antibiotics. Children who had ALF due to antiepileptics had a substantially higher risk of death after LT in comparison with other drugs. Patients transplanted for acetaminophen-related ALF required dialysis at a significantly higher rate. Being on life support, DIALF due to antiepileptics (at age less

  14. Evaluation of the rabbit Purkinje fibre assay as an in vitro tool for assessing the risk of drug-induced torsades de pointes in humans.

    Science.gov (United States)

    Aubert, Marion; Osterwalder, Rolf; Wagner, Björn; Parrilla, Isabelle; Cavero, Icilio; Doessegger, Lucette; Ertel, Eric A

    2006-01-01

    The issue of drug-induced QT interval prolongation and torsades de pointes represents a major concern for pharmaceutical development. In this investigation, we examined the value of the isolated rabbit Purkinje fibre as an in vitro action potential (AP) assay to predict the potential of drugs to induce these undesirable adverse effects. First, we categorised the proarrhythmic risk of 26 medicinal products based on proportional reporting ratios for these two adverse events recorded in a US FDA database (Spontaneous Reporting System/Adverse Event Reporting System). Second, we measured drug effects on AP in rabbit Purkinje fibres. Finally, the results of the two analyses were compared to evaluate the predictive value of the in vitro assay. Analysis of the clinical data classified the drugs into 14 positive, 7 negative and 5 questionable for proarrhythmic risk. Based on in vitro electrophysiological profiles, the drugs were grouped into four categories: (i) profile 1 drugs prolong repolarisation without slowing depolarisation; (ii) profile 2 drugs prolong repolarisation and also slow depolarisation; (iii) profile 3 drugs shorten repolarisation; and (iv) profile 4 drugs are without effects. All 14 clinical-positive drugs fell into profiles 1 or 2 (prolongers) with low safety margins (except probucol, which showed no effect, probably because of its low solubility). Clinical-negative drugs belonged mostly to profiles 3 or 4 (non-prolongers) [except clemastine and amlodipine, which were prolongers but had large safety margins]. Clinical-questionable drugs either did not prolong or prolonged slightly but produced additional electrophysiological effects opposing prolongation. The rabbit Purkinje fibre is a valuable assay for evaluating the proarrhythmic liability of pharmaceuticals as it can reveal complex electrophysiological profiles that modulate repolarisation delay.

  15. Evaluation of HepaRG cells for the assessment of indirect drug-induced hepatotoxicity using INH as a model substance.

    Science.gov (United States)

    Mann, Anika; Pelz, Thomas; Rennert, Knut; Mosig, Alexander; Decker, Michael; Lupp, Amelie

    2017-10-01

    HepaRG cells are widely used as an in vitro model to assess drug-induced hepatotoxicity. However, only few studies exist so far regarding their suitability to detect the effects of drugs requiring a preceding activation via the cytochrome P450 (CYP) system. A prototypic substance is the anti-tuberculosis agent INH, which is metabolized into N-acetylhydrazine, which then triggers hepatotoxicity. Therefore, the aim of the present study was to test if this effect can also be detected in HepaRG cells and if it can be counteracted by the known hepatoprotectant silibinin. For this purpose, differentiated HepaRG cells were treated with increasing concentrations of INH (0.1-100 mM) or 10 mM INH plus escalating concentrations of silibinin (1-100 µM). After 48 h of treatment, cell morphology and parameters indicating cell vitality, oxidative stress, and liver cell function were assessed. High concentrations of INH led to severe histopathological changes, reduced cell vitality and glutathione content, increased LDH and ASAT release into the medium, enhanced lipid peroxidation, and elevated cleaved caspase-3 expression. Additionally, glycogen depletion and reduced biotransformation capacity were seen at high INH concentrations, whereas at low concentrations an induction of biotransformation enzymes was noticed. Silibinin caused clear-cut protective effects, but with few parameters INH toxicity was even aggravated, most probably due to increased metabolization of INH into its toxic metabolite. In conclusion, HepaRG cells are excellently suited to evaluate the effects of substances requiring prior toxification via the CYP system, such as INH. They additionally enable the identification of complex substance interactions.

  16. Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case-control study in Italy.

    Science.gov (United States)

    Donati, Monia; Conforti, Anita; Lenti, Maria Carmela; Capuano, Annalisa; Bortolami, Oscar; Motola, Domenico; Moretti, Ugo; Vannacci, Alfredo; Rafaniello, Concetta; Vaccheri, Alberto; Arzenton, Elena; Bonaiuti, Roberto; Sportiello, Liberata; Leone, Roberto

    2016-07-01

    Drug-induced liver injury is one of the most serious adverse drug reactions and the most frequent reason for restriction of indications or withdrawal of drugs. Some nonsteroidal anti-inflammatory drugs (NSAIDs) were withdrawn from the market because of serious hepatotoxicity. We estimated the risk of acute and serious liver injury associated with the use of nimesulide and other NSAIDs, with a prevalence of use greater than or equal to 5%. This is a multicentre case-control study carried out in nine Italian hospitals from October 2010 to January 2014. Cases were adults, with a diagnosis of acute liver injury. Controls presented acute clinical disorders not related to chronic conditions, not involving the liver. Adjusted odds ratio (ORs) with 95% confidence interval (CI) were calculated initially with a bivariate and then multivariate analysis. We included 179 cases matched to 1770 controls. Adjusted OR for acute serious liver injury associated with all NSAIDs was 1.69, 95% CI 1.21-2.37. Thirty cases were exposed to nimesulide (adjusted OR 2.10, 95% CI 1.28-3.47); the risk increased according to the length of exposure (OR > 30 days: 12.55, 95% CI 1.73-90.88) and to higher doses (OR 10.69, 95% CI 4.02-28.44). Risk of hepatotoxicity was increased also for ibuprofen, used both at recommended dosages (OR 1.92, 95% CI 1.13-3.26) and at higher doses (OR 3.73, 95% CI 1.11-12.46) and for ketoprofen ≥ 150 mg (OR 4.65, 95% CI 1.33-10.00). Among all NSAIDs, nimesulide is associated with the higher risk, ibuprofen and high doses of ketoprofen are also associated with a modestly increased risk of hepatotoxicity. © 2016 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

  17. Risk factors for development of cholestatic drug-induced liver injury: inhibition of hepatic basolateral bile acid transporters multidrug resistance-associated proteins 3 and 4.

    Science.gov (United States)

    Köck, Kathleen; Ferslew, Brian C; Netterberg, Ida; Yang, Kyunghee; Urban, Thomas J; Swaan, Peter W; Stewart, Paul W; Brouwer, Kim L R

    2014-04-01

    Impaired hepatic bile acid export may contribute to development of cholestatic drug-induced liver injury (DILI). The multidrug resistance-associated proteins (MRP) 3 and 4 are postulated to be compensatory hepatic basolateral bile acid efflux transporters when biliary excretion by the bile salt export pump (BSEP) is impaired. BSEP inhibition is a risk factor for cholestatic DILI. This study aimed to characterize the relationship between MRP3, MRP4, and BSEP inhibition and cholestatic potential of drugs. The inhibitory effect of 88 drugs (100 μM) on MRP3- and MRP4-mediated substrate transport was measured in membrane vesicles. Drugs selected for investigation included 50 BSEP non-inhibitors (24 non-cholestatic; 26 cholestatic) and 38 BSEP inhibitors (16 non-cholestatic; 22 cholestatic). MRP4 inhibition was associated with an increased risk of cholestatic potential among BSEP non-inhibitors. In this group, for each 1% increase in MRP4 inhibition, the odds of the drug being cholestatic increased by 3.1%. Using an inhibition cutoff of 21%, which predicted a 50% chance of cholestasis, 62% of cholestatic drugs inhibited MRP4 (P drugs were MRP4 inhibitors. Among BSEP inhibitors, MRP4 inhibition did not provide additional predictive value of cholestatic potential; almost all BSEP inhibitors were also MRP4 inhibitors. Inclusion of pharmacokinetic predictor variables (e.g., maximal unbound concentration in plasma) in addition to percent MRP4 inhibition in logistic regression models did not improve cholestasis prediction. Association of cholestasis with percent MRP3 inhibition was not statistically significant, regardless of BSEP-inhibition status. Inhibition of MRP4, in addition to BSEP, may be a risk factor for the development of cholestatic DILI.

  18. Serum microRNA profiles in patients with chronic hepatitis B, chronic hepatitis C, primary biliary cirrhosis, autoimmune hepatitis, nonalcoholic steatohepatitis, or drug-induced liver injury.

    Science.gov (United States)

    Yamaura, Yu; Tatsumi, Naoyuki; Takagi, Shingo; Tokumitsu, Shinsaku; Fukami, Tatsuki; Tajiri, Kazuto; Minemura, Masami; Yokoi, Tsuyoshi; Nakajima, Miki

    2017-12-01

    Some blood biomarkers or histological examination by liver biopsy are used for the diagnosis of liver diseases in clinics. However, conventional blood biomarkers show poor specificity and sensitivity, and liver biopsy is highly invasiveness. Therefore, to overcome such disadvantages, specific/sensitive and noninvasive options are desirable. In recent years, circulating microRNAs (miRNAs) have been acknowledged for their potential as disease markers. Actually, several miRNAs have been reported to be biomarker candidates of liver diseases. However, these earlier studies were performed for one disease. Therefore, the specificity as biomarkers was not guaranteed, because they didn't study for the other types of liver injury. In this study, we examined if circulating miRNA could distinguish different types of liver diseases. Serum miRNA profiles in 28 patients with chronic hepatitis B, chronic hepatitis C, primary biliary cirrhosis, autoimmune hepatitis, nonalcoholic steatohepatitis or drug-induced liver injury as well as 4 control subjects were determined by TaqMan MicroRNA Array analysis. Principal component analysis (PCA) of selected miRNAs was performed. We identified 37 miRNAs whose levels were significantly different between any of the groups. Although individual miRNAs could not distinguish different types of liver diseases, probably because of similar liver pathology, their profiling by PCA could classify different liver disease groups. The profiling of the selected miRNAs can be useful to distinguish different types of liver diseases. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  19. Bid participates in genotoxic drug-induced apoptosis of HeLa cells and is essential for death receptor ligands' apoptotic and synergistic effects.

    Science.gov (United States)

    Köhler, Barbara; Anguissola, Sergio; Concannon, Caoimhin G; Rehm, Markus; Kögel, Donat; Prehn, Jochen H M

    2008-07-30

    The BH3-only protein Bid is an important component of death receptor-mediated caspase activation. Bid is cleaved by caspase-8 or -10 into t-Bid, which translocates to mitochondria and triggers the release of caspase-activating factors. Bid has also been reported to be cleaved by other proteases. To test the hypothesis that Bid is a central mediator of stress-induced apoptosis, we investigated the effects of a small molecule Bid inhibitor on stress-induced apoptosis, and generated HeLa cells deficient for Bid. Stable knockdown of bid lead to a pronounced resistance to Fas/CD95- and TRAIL-induced caspase activation and apoptosis, and significantly increased clonogenic survival. While Bid-deficient cells were equally sensitive to ER stress-induced apoptosis, they showed moderate, but significantly reduced levels of apoptosis, as well as increased clonogenic survival in response to the genotoxic drugs Etoposide, Oxaliplatin, and Doxorubicin. Similar effects were observed using the Bid inhibitor BI6C9. Interestingly, Bid-deficient cells were dramatically protected from apoptosis when subtoxic concentrations of ER stressors, Etoposide or Oxaliplatin were combined with subtoxic TRAIL concentrations. Our data demonstrate that Bid is central for death receptor-induced cell death and participates in anti-cancer drug-induced apoptosis in human cervical cancer HeLa cells. They also show that the synergistic effects of TRAIL in combination with either ER stressors or genotoxic anti-cancer drugs are nearly exclusively mediated via an increased activation of Bid-induced apoptosis signalling.

  20. Developmental abnormalities of mid and hindbrain

    African Journals Online (AJOL)

    Complete clinical evaluation, cytogenetic analysis and neuroradiological study were done for each patient. Patients' .... measurements (weight, height and head circumference) were assessed. Magnetic resonance imaging ..... developed abnormal kidneys or liver functions; however, regular monitor- ing of these functions is ...

  1. Schizophrenogenic Parenting in Abnormal Psychology Textbooks.

    Science.gov (United States)

    Wahl, Otto F.

    1989-01-01

    Considers the treatment of family causation of schizophrenia in undergraduate abnormal psychology textbooks. Reviews texts published only after 1986. Points out a number of implications for psychologists which arise from the inclusion in these texts of the idea that parents cause schizophrenia, not the least of which is the potential for…

  2. Psychology Faculty Perceptions of Abnormal Psychology Textbooks

    Science.gov (United States)

    Rapport, Zachary

    2011-01-01

    The problem. The purpose of the current study was to investigate the perceptions and opinions of psychology professors regarding the accuracy and inclusiveness of abnormal psychology textbooks. It sought answers from psychology professors to the following questions: (1) What are the expectations of the psychology faculty at a private university of…

  3. Prevalence Of Dental Abnormalities Among Handicapped Children ...

    African Journals Online (AJOL)

    Efforts to improve the quality of life of handicapped people are on the increase world wide, their oral health inclusive. Relevant data is required for adequate planning for this purpose. A survey of 579 handicapped children was carried out in Lagos to assess the various dental abnormalities among them. Over 34% of them ...

  4. Specificity of haemostasis abnormalities for vascular phenotypes.

    Science.gov (United States)

    Lowe, G D; Haverkate, F

    1998-01-01

    Atherothrombosis is a systemic disease, hence it is difficult to prove the specificity of haemostasis abnormality for any single vascular phenotype. Associations between haemostatic variables and any given phenotype, e.g. (vascular) dementia, should be interpreted with caution, given the overlaps of vascular disease phenotypes, risk factors, and haemostatic variables.

  5. Pattern Analysis: The Question of Abnormality.

    Science.gov (United States)

    Silverstein, A. B.

    1984-01-01

    Addresses the question of abnormality when comparing a subject's score on each subtest with that subject's average subtest score on one of Weschler's scales. Suggests comparing each subtest score with the Verbal or Performance average rather than with the overall average. Provides tables estimating differences of standardization samples. (BH)

  6. A Universally Abnormality-Adaptive Logic

    OpenAIRE

    BATENS D.

    2001-01-01

    The present paper presents a logic that allows for the abnormal behaviour of any logical constant and for the ambiguous behaviour of any non-logical constant, but nevertheless offers an interpretation of the premises that is as normal as possible.

  7. immunological arthritis Prevalence of biochemical and abnormalities ...

    African Journals Online (AJOL)

    1991-02-02

    Feb 2, 1991 ... Tile prevalence of biochemical and immunological abnormali- ties was studied in a group of 256 patients with rheumatoid arthritis (104 coloureds, 100 whites and 52 blacks). The most common biochemical abnormalities detected were a reduction in the serum creatinine value (43,4%), raised globulins (39 ...

  8. [A young man with extensive skin abnormalities].

    Science.gov (United States)

    van der Weijden, C P; Joore, I K

    2018-01-01

    A 26-year-old man who has sex with men visited the STI clinic because of increasing skin abnormalities since four months. The patient had macular skin lesions on his penis and scrotum, condylomata lata in the anal region, cutaneous lesions on the feet, and a widespread papular rash. A secondary stage of syphilis was diagnosed.

  9. [Renal abnormalities in Down syndrome: A review].

    Science.gov (United States)

    Niamien-Attai, C; Bacchetta, J; Ranchin, B; Sanlaville, D; Cochat, P

    2017-10-01

    Down syndrome (DS) is often associated with cardiac malformations, so that kidney damage is little known. The objective of this study was to present the diversity of renal abnormalities and their potential progression to chronic renal failure. Among congenital abnormalities of the kidney and urinary tract (CAKUT) abnormalities appear to be frequent: pyelectasis, megaureters, posterior urethra valves, as well as renal malformations such as renal hypoplasia, horseshoe kidney, or renal ectopia. Contributing factors to acute kidney failure have been described in patients with DS: bilateral lesions and minor renal injury, such as glomerular microcysts, tubular dilation, and immature glomeruli. Histological lesions can be found, albeit nonspecific; they occur earlier than in the general population. Two metabolic specificities have also been described: decreased clearance of uric acid and a hypercalciuria by passive hyperabsorption. End-stage renal disease can occur, thus raising the problem of the best choice of management. In conclusion, renal abnormalities in patients in DS should be known so as to preserve a good renal functional prognosis: systematic screening with renal ultrasound can be proposed. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  10. ORIGINAL ARTICLE EEG changes and neuroimaging abnormalities ...

    African Journals Online (AJOL)

    salah

    Background:Autism is currently viewed as a genetically determined neurode- velopmental disorder although its definite underlying etiology remains to be established. Aim of the Study: Our purpose was to assess autism related morphological neuroimaging changes of the brain and EEG abnormalities in correlation to the.

  11. Correcting abnormal speaking through communication partners ...

    African Journals Online (AJOL)

    The listed characteristics are called speech disorders. Abnormal speaking attracts some penalties to the speaker. The penalties are usually very disturbing to the speaker that undertaking some therapeutic measures becomes inevitable. Communication partners strategy is a speech correction approach which makes use of ...

  12. [Y chromosome structural abnormalities and Turner's syndrome].

    Science.gov (United States)

    Ravel, C; Siffroi, J-P

    2009-06-01

    Although specifically male, the human Y chromosome may be observed in female karyotypes, mostly in women with Turner syndrome stigmata. In women with isolated gonadal dysgenesis but otherwise normal stature, the testis determining factor or SRY gene may have been removed from the Y chromosome or may be mutated. In other women with Turner syndrome, the karyotype is usually abnormal and shows a frequent 45,X/46,XY mosaicism. In these cases, the phenotype depends on the ratio between Y positive and 45,X cell lines in the body. When in mosaicism, Y chromosomes are likely to carry structural abnormalities which explain mitotic instability, such as the existence of two centromeres. Dicentric Y isochromosomes for the short arm (idic[Yp]) or ring Y chromosomes (r[Y]) are the most frequent abnormal Y chromosomes found in infertile patients and in Turner syndrome in mosaic with 45,X cells. Although monocentric, deleted Y chromosomes for the long arm and those carrying microdeletions in the AZF region are also instable and are frequently associated with a 45,X cell line. Management of infertile patients carrying such abnormal Y chromosomes must take into account the risk and the consequences of a mosaicism in the offspring.

  13. Evaluation of Chromosomal Abnormalities and Common ...

    African Journals Online (AJOL)

    Its' pathophysiology is poorly understood. Infections, genetic, endocrine, anatomic and immunologic problems have been suggested as causes for RM. Objective: To evaluate the frequency of chromosomal abnormalities and 3 common thrombophilic mutations in couples with RM. Methods: A retrospective data collection ...

  14. Craniocervical junction abnormalities with atlantoaxial subluxation ...

    African Journals Online (AJOL)

    Craniocervical junction abnormalities with atlantoaxial subluxation caused by ventral subluxation of C2 were diagnosed in a 6-month-old female Pomeranian with tetraplegia as a clinical sign. Lateral survey radiography of the neck with flexion revealed atlantoaxial subluxation with ventral subluxation of C2. Computed ...

  15. Fetal chromosome abnormalities and congenital malformations: an ...

    African Journals Online (AJOL)

    Objective: Our objective were to determine and evaluate the role of genetic counseling and amniocentesis in early detection of chromosomal abnormalities or congenital malformations among women at risk. Patients and Methods: The study was performed on 784 pregnant women. Results: The cause for seeking genetic ...

  16. Prevelence and Pattern of Electrocardiographic Abnormalities Seen ...

    African Journals Online (AJOL)

    Objective: There is paucity of published data on the prevalence and pattern of electrocardiographic abnormalities (ECGA) seen in adult Nigerians referred for this investigation. This study determined the prevalence and pattern of some ECGA in Nigerian adults. Methods: This is a hospital based audit to determine the ...

  17. Ophthalmological abnormalities in wild European hedgehogs ...

    African Journals Online (AJOL)

    The predominant finding was bilateral nuclear cataract seen particularly in young poorly growing animals. Investigation into the potential causation of cataracts by poor nutrition or poor feeding ability by lens opacification requires further study. Keywords: Cataract, Conservation, Eye abnormality, Hedgehog, Rehabilitation ...

  18. Systemic abnormalities in migraine: what comes first?

    Science.gov (United States)

    Marmura, Michael J

    2009-03-01

    Recent research suggests that migraine results from the interplay of multiple factors, and many studies have considered the relationship of migraine to systemic abnormalities. This editorial comments on recent findings relating to migraine and metabolic syndrome, and suggests some possible causes.

  19. ORIGINAL ARTICLE EEG changes and neuroimaging abnormalities ...

    African Journals Online (AJOL)

    salah

    Ghada El-Kamah. E-mail: ghadaelkamah@hotmail.com. Key Words: Autism, MRI, EEG, brain develop- ment. INTRODUCTION. Autism is a neuropsychiatric disorder of social, cognitive and language development. Autism. Spectrum Disorders (ASDs). (OMIM 608638)1 are diagnosed on the basis of qualitative abnormalities ...

  20. Craniofacial abnormalities among patients with Edwards Syndrome

    Directory of Open Access Journals (Sweden)

    Rafael Fabiano M. Rosa

    2013-09-01

    Full Text Available OBJECTIVE To determine the frequency and types of craniofacial abnormalities observed in patients with trisomy 18 or Edwards syndrome (ES. METHODS This descriptive and retrospective study of a case series included all patients diagnosed with ES in a Clinical Genetics Service of a reference hospital in Southern Brazil from 1975 to 2008. The results of the karyotypic analysis, along with clinical data, were collected from medical records. RESULTS: The sample consisted of 50 patients, of which 66% were female. The median age at first evaluation was 14 days. Regarding the karyotypes, full trisomy of chromosome 18 was the main alteration (90%. Mosaicism was observed in 10%. The main craniofacial abnormalities were: microretrognathia (76%, abnormalities of the ear helix/dysplastic ears (70%, prominent occiput (52%, posteriorly rotated (46% and low set ears (44%, and short palpebral fissures/blepharophimosis (46%. Other uncommon - but relevant - abnormalities included: microtia (18%, orofacial clefts (12%, preauricular tags (10%, facial palsy (4%, encephalocele (4%, absence of external auditory canal (2% and asymmetric face (2%. One patient had an initial suspicion of oculo-auriculo-vertebral spectrum (OAVS or Goldenhar syndrome. CONCLUSIONS: Despite the literature description of a characteristic clinical presentation for ES, craniofacial alterations may be variable among these patients. The OAVS findings in this sample are noteworthy. The association of ES with OAVS has been reported once in the literature.

  1. Craniofacial abnormalities among patients with Edwards Syndrome

    Science.gov (United States)

    Rosa, Rafael Fabiano M.; Rosa, Rosana Cardoso M.; Lorenzen, Marina Boff; Zen, Paulo Ricardo G.; Graziadio, Carla; Paskulin, Giorgio Adriano

    2013-01-01

    OBJECTIVE To determine the frequency and types of craniofacial abnormalities observed in patients with trisomy 18 or Edwards syndrome (ES). METHODS This descriptive and retrospective study of a case series included all patients diagnosed with ES in a Clinical Genetics Service of a reference hospital in Southern Brazil from 1975 to 2008. The results of the karyotypic analysis, along with clinical data, were collected from medical records. RESULTS: The sample consisted of 50 patients, of which 66% were female. The median age at first evaluation was 14 days. Regarding the karyotypes, full trisomy of chromosome 18 was the main alteration (90%). Mosaicism was observed in 10%. The main craniofacial abnormalities were: microretrognathia (76%), abnormalities of the ear helix/dysplastic ears (70%), prominent occiput (52%), posteriorly rotated (46%) and low set ears (44%), and short palpebral fissures/blepharophimosis (46%). Other uncommon - but relevant - abnormalities included: microtia (18%), orofacial clefts (12%), preauricular tags (10%), facial palsy (4%), encephalocele (4%), absence of external auditory canal (2%) and asymmetric face (2%). One patient had an initial suspicion of oculo-auriculo-vertebral spectrum (OAVS) or Goldenhar syndrome. CONCLUSIONS: Despite the literature description of a characteristic clinical presentation for ES, craniofacial alterations may be variable among these patients. The OAVS findings in this sample are noteworthy. The association of ES with OAVS has been reported once in the literature. PMID:24142310

  2. Abnormal interhemispheric connectivity in male psychopathic offenders.

    Science.gov (United States)

    Hoppenbrouwers, Sylco S; De Jesus, Danilo R; Sun, Yinming; Stirpe, Tania; Hofman, Dennis; McMaster, Jeff; Hughes, Ginny; Daskalakis, Zafiris J; Schutter, Dennis J L G

    2014-01-01

    Psychopathic offenders inevitably violate interpersonal norms and frequently resort to aggressive and criminal behaviour. The affective and cognitive deficits underlying these behaviours have been linked to abnormalities in functional interhemispheric connectivity. However, direct neurophysiological evidence for dysfunctional connectivity in psychopathic offenders is lacking. We used transcranial magnetic stimulation combined with electroencephalography to examine interhemispheric connectivity in the dorsolateral and motor cortex in a sample of psychopathic offenders and healthy controls. We also measured intracortical inhibition and facilitation over the left and right motor cortex to investigate the effects of local cortical processes on interhemispheric connectivity. We enrolled 17 psychopathic offenders and 14 controls in our study. Global abnormalities in right to left functional connectivity were observed in psychopathic offenders compared with controls. Furthermore, in contrast to controls, psychopathic offenders showed increased intracortical inhibition in the right, but not the left, hemisphere. The relatively small sample size limited the sensitivity to show that the abnormalities in interhemispheric connectivity were specifically related to the dorsolateral prefrontal cortex in psychopathic offenders. To our knowledge, this study provides the first neurophysiological evidence for abnormal interhemispheric connectivity in psychopathic offenders and may further our understanding of the disruptive antisocial behaviour of these offenders.

  3. Syringomyelia and Craniocervical Junction Abnormalities in Chihuahuas.

    Science.gov (United States)

    Kiviranta, A-M; Rusbridge, C; Laitinen-Vapaavuori, O; Hielm-Björkman, A; Lappalainen, A K; Knowler, S P; Jokinen, T S

    2017-11-01

    Chiari-like malformation (CM) and syringomyelia (SM) are widely reported in Cavalier King Charles Spaniels and Griffon Bruxellois dogs. Increasing evidence indicates that CM and SM also occur in other small and toy breed dogs, such as Chihuahuas. To describe the presence of SM and craniocervical junction (CCJ) abnormalities in Chihuahuas and to evaluate the possible association of CCJ abnormalities with SM. To describe CM/SM-related clinical signs and neurologic deficits and to investigate the association of CM/SM-related clinical signs with signalment, SM, or CCJ abnormalities. Fifty-three client-owned Chihuahuas. Prospective study. Questionnaire analyses and physical and neurologic examinations were obtained before magnetic resonance and computed tomography imaging. Images were evaluated for the presence of SM, CM, and atlantooccipital overlapping. Additionally, medullary kinking, dorsal spinal cord compression, and their sum indices were calculated. Scratching was the most common CM/SM-related clinical sign and decreased postural reaction the most common neurologic deficit in 73 and 87% of dogs, respectively. Chiari-like malformation and SM were present in 100 and 38% of dogs, respectively. Syringomyelia was associated with the presence of CM/SM-related clinical signs (P = 0.034), and medullary kinking and sum indices were higher in dogs with clinical signs (P = 0.016 and P = 0.007, respectively). Syringomyelia and CCJ abnormalities are prevalent in Chihuahuas. Syringomyelia was an important factor for the presence of CM/SM-related clinical signs, but many dogs suffered from similar clinical signs without being affected by SM, highlighting the clinical importance of CCJ abnormalities in Chihuahuas. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  4. Parenchymal abnormalities associated with developmental venous anomalies

    Energy Technology Data Exchange (ETDEWEB)

    San Millan Ruiz, Diego; Gailloud, Philippe [Johns Hopkins Hospital, Division of Interventional Neuroradiology, Baltimore, MD (United States); Delavelle, Jacqueline [Geneva University Hospital, Neuroradiology Section, Department of Radiology and Medical Informatics, Geneva (Switzerland); Yilmaz, Hasan; Ruefenacht, Daniel A. [Geneva University Hospital, Section of Interventional Neuroradiology, Department of Clinical Neurosciences, Geneva (Switzerland); Piovan, Enrico; Bertramello, Alberto; Pizzini, Francesca [Verona City Hospital, Service of Neuroradiology, Verona (Italy)

    2007-12-15

    To report a retrospective series of 84 cerebral developmental venous anomalies (DVAs), focusing on associated parenchymal abnormalities within the drainage territory of the DVA. DVAs were identified during routine diagnostic radiological work-up based on magnetic resonance imaging (MRI) (60 cases), computed tomography (CT) (62 cases) or both (36 cases). Regional parenchymal modifications within the drainage territory of the DVA, such as cortical or subcortical atrophy, white matter density or signal alterations, dystrophic calcifications, presence of haemorrhage or a cavernous-like vascular malformation (CVM), were noted. A stenosis of the collecting vein of the DVA was also sought for. Brain abnormalities within the drainage territory of a DVA were encountered in 65.4% of the cases. Locoregional brain atrophy occurred in 29.7% of the cases, followed by white matter lesions in 28.3% of MRI investigations and 19.3% of CT investigations, CVMs in 13.3% of MRI investigations and dystrophic calcification in 9.6% of CT investigations. An intracranial haemorrhage possibly related to a DVA occurred in 2.4% cases, and a stenosis on the collecting vein was documented in 13.1% of cases. Parenchymal abnormalities were identified for all DVA sizes. Brain parenchymal abnormalities were associated with DVAs in close to two thirds of the cases evaluated. These abnormalities are thought to occur secondarily, likely during post-natal life, as a result of chronic venous hypertension. Outflow obstruction, progressive thickening of the walls of the DVA and their morphological organization into a venous convergence zone are thought to contribute to the development of venous hypertension in DVA. (orig.)

  5. Morphological Abnormalities of Thalamic Subnuclei in Migraine

    DEFF Research Database (Denmark)

    Magon, Stefano; May, Arne; Stankewitz, Anne

    2015-01-01

    . SIGNIFICANCE STATEMENT: This multicenter imaging study shows morphological thalamic abnormalities in a large cohort of patients with episodic migraine compared with healthy subjects using state-of-the-art MRI and advanced, fully automated multiatlas segmentation techniques. The results stress that migraine...... is a disorder of the CNS in which not only is brain function abnormal, but also brain structure is undergoing significant remodeling....... techniques in substantial patient populations are lacking. In the present study, we investigated changes of thalamic volume and shape in a large multicenter cohort of patients with migraine. High-resolution T1-weighted MRI data acquired at 3 tesla in 131 patients with migraine (38 with aura; 30.8 ± 9 years...

  6. Reproductive abnormalities in aged female Macaca fascicularis.

    Science.gov (United States)

    Wilkinson, Michele; Walters, Sherry; Smith, Taryn; Wilkinson, Andrew

    2008-02-01

    Spontaneous reproductive tract abnormalities occurred in six female wild-caught, Philippine-origin, Macaca fascicularis. These animals were between 19 and 22 years of age and maintained in captivity for approximately 15 years. Clinical presentations ranged from asymptomatic to painful menses manifested as cyclical recumbency and lethargy. All animals had masses in the caudal ventral abdomen. Diagnostics included physical examination, complete blood counts, clinical chemistries, radiography, and ultrasonography. All animals had an ovariosalpingohysterectomy. Histologic diagnoses included ovarian granulosa cell tumor, ovarian pseudocystic cavitation with encapsulating fibrosis, uterine smooth muscle hyperplasia, uterine leiomysarcoma, and uterine leiomyoma with possible adenomyosis. The abnormalities discovered in these animals present novel insight into the reproductive diseases prevalent in geriatric female M. fascicularis, which vary from that previously reported in other non-human primate species.

  7. Chromosomal abnormalities in a psychiatric population

    Energy Technology Data Exchange (ETDEWEB)

    Lewis, K.E.; Lubetsky, M.J.; Wenger, S.L.; Steele, M.W. [Univ. of Pittsburgh Medical Center, PA (United States)

    1995-02-27

    Over a 3.5 year period of time, 345 patients hospitalized for psychiatric problems were evaluated cytogenetically. The patient population included 76% males and 94% children with a mean age of 12 years. The criteria for testing was an undiagnosed etiology for mental retardation and/or autism. Cytogenetic studies identified 11, or 3%, with abnormal karyotypes, including 4 fragile X positive individuals (2 males, 2 females), and 8 with chromosomal aneuploidy, rearrangements, or deletions. While individuals with chromosomal abnormalities do not demonstrate specific behavioral, psychiatric, or developmental problems relative to other psychiatric patients, our results demonstrate the need for an increased awareness to order chromosomal analysis and fragile X testing in those individuals who have combinations of behavioral/psychiatric, learning, communication, or cognitive disturbance. 5 refs., 1 fig., 2 tabs.

  8. Migraine and structural abnormalities in the brain

    DEFF Research Database (Denmark)

    Hougaard, Anders; Amin, Faisal Mohammad; Ashina, Messoud

    2014-01-01

    PURPOSE OF REVIEW: The aim is to provide an overview of recent studies of structural brain abnormalities in migraine and to discuss the potential clinical significance of their findings. RECENT FINDINGS: Brain structure continues to be a topic of extensive research in migraine. Despite advances...... in neuroimaging techniques, it is not yet clear if migraine is associated with grey matter changes. Recent large population-based studies sustain the notion of increased prevalence of white matter abnormalities in migraine, and possibly of silent infarct-like lesions. The clinical relevance of this association...... is not clear. Structural changes are not related to cognitive decline, but a link to an increased risk of stroke, especially in patients with aura, cannot be ruled out. SUMMARY: Migraine may be a risk factor for structural changes in the brain. It is not yet clear how factors such as migraine sub-type, attack...

  9. Behavioral correlates of epileptiform abnormalities in autism.

    Science.gov (United States)

    Trauner, Doris A

    2015-06-01

    There is a high incidence of epileptiform abnormalities in children with autism even in the absence of clinical seizures. These findings are most prominent during sleep recordings. The significance of these abnormalities is unclear. Although studies do not all agree, there may be some association between cognitive function, behavior, and the presence or absence of epileptiform discharges. Small studies of anticonvulsant treatment mostly suggest an improvement in certain aspects of cognitive or behavioral functioning in these children, but larger and more comprehensive studies are needed to determine the potential relationship between epileptiform discharges on EEG, cognitive and behavioral functioning, and treatment effects in the population with autism. This article is part of a Special Issue entitled "Autism and Epilepsy". Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Abnormal cervical cytology and health care use

    DEFF Research Database (Denmark)

    Frederiksen, Maria Eiholm; Baillet, Miguel Vázquez-Prada; Dugué, Pierre-Antoine

    2015-01-01

    OBJECTIVE: This study aimed to assess the long-term use of health care services in women with abnormal cytology results compared to women with normal cytology results. METHODS: We did a nationwide population-based study, using women aged 23 to 59years participating in the national organized...... cervical cancer screening program. We included a study population of 40,153 women with abnormal cytology (exposed) and 752,627 women with normal cytology (non-exposed). We retrieved data from the Danish Civil Registration System, the Danish Pathology Data Bank, the National Health Service, the National......" the cytology result and for the 5-year period "after" the result. RESULTS: During the "before" period exposed women had more contacts to GPs, more contacts to psychologists/psychiatrist, and more hospital admissions than non-exposed women. In both exposed and non-exposed women, health care use increased from...

  11. Chorionic villus sampling for abnormal screening compared to historical indications: prevalence of abnormal karyotypes.

    Science.gov (United States)

    Marshall, Nicole E; Fraley, Gwen; Feist, Cori; Burns, Michael J; Pereira, Leonardo

    2012-08-01

    To determine the prevalence of abnormal karyotype results in women undergoing chorionic villus sampling (CVS) for abnormal first trimester screening compared to CVS for historical indications (advanced maternal age (AMA) or prior aneuploidy). Retrospective cohort of all patients undergoing CVS at Oregon Health & Science University from January 2006 to June 2010. Patients were separated based on CVS indication: (1) positive ultrasound (U/S) or serum screening; or (2) AMA or prior aneuploidy with normal or no screening. Prevalence of abnormal karyotype results were compared between groups. Fetal karyotyping was successful in 500 of 506 CVS procedures performed. 203 CVS were performed for positive screening with 69 abnormal karyotypes (34.0%). 264 CVS were performed for historical indications with 11 abnormal karyotypes (4.2%). This difference was statistically significant (χ(2) 71.9, p abnormal U/S and/or serum screening (35 U/S, 4 serum, 3 U/S and serum). Combined ultrasound and serum screening should be recommended to all women, including AMA women, prior to undergoing invasive testing to improve risk-based counseling and minimize morbidity.

  12. Abnormal eating behaviors in military women.

    Science.gov (United States)

    Lauder, T D; Williams, M V; Campbell, C S; Davis, G D; Sherman, R A

    1999-09-01

    The purpose of this study was to evaluate the prevalence of abnormal eating behaviors in women on active duty in the Army. A total of 423 female soldiers from the general population on active duty volunteered to participate in this study. They completed the Eating Disorder Inventory (EDI) questionnaire. Each questionnaire was screened and any woman on active duty practicing abnormal eating behaviors (criteria set up by the authors) underwent an interview. A diagnosis, using DSM IV criteria, of one of the following was determined from the interview: 1) No eating disorder, (2) Anorexia nervosa, 3) Bulimia nervosa, 4) binge eating disorder, 5a) Eating disorder NOS, and 5b) Situational eating disorder. A situational eating disorder was defined as any abnormal eating behaviors consistent with an eating disorder NOS that was practiced intermittently and in response to external pressures associated with significant distress, such as military weigh-ins or army physical fitness testing (APFT). Of the 423 women on active duty who participated, 33.6% (N = 142) met the questionnaire screening criteria for being "at risk" for abnormal eating behaviors and underwent an interview. Of the 142 women interviewed, 33 (8%) women were diagnosed with an eating disorder. The women with eating disorders exercised, felt dissatisfied with their weight, and felt significantly more pressure about their weight than the women without eating disorders. In addition, they also had significantly greater scores on the Drive for Thinness (DT), Bulemia (B), and Body Dissatisfaction (BD) subscales, and the total EDI scores for both the 8 and 11 subscales. In the women on active duty in the Army studied, there was an 8% prevalence of eating disorders.

  13. Dysglycemia induces abnormal circadian blood pressure variability

    Directory of Open Access Journals (Sweden)

    Kumarasamy Sivarajan

    2011-11-01

    Full Text Available Abstract Background Prediabetes (PreDM in asymptomatic adults is associated with abnormal circadian blood pressure variability (abnormal CBPV. Hypothesis Systemic inflammation and glycemia influence circadian blood pressure variability. Methods Dahl salt-sensitive (S rats (n = 19 after weaning were fed either an American (AD or a standard (SD diet. The AD (high-glycemic-index, high-fat simulated customary human diet, provided daily overabundant calories which over time lead to body weight gain. The SD (low-glycemic-index, low-fat mirrored desirable balanced human diet for maintaining body weight. Body weight and serum concentrations for fasting glucose (FG, adipokines (leptin and adiponectin, and proinflammatory cytokines [monocyte chemoattractant protein-1 (MCP-1 and tumor necrosis factor-α (TNF-α] were measured. Rats were surgically implanted with C40 transmitters and blood pressure (BP-both systolic; SBP and diastolic; DBP and heart rate (HR were recorded by telemetry every 5 minutes during both sleep (day and active (night periods. Pulse pressure (PP was calculated (PP = SBP-DBP. Results [mean(SEM]: The AD fed group displayed significant increase in body weight (after 90 days; p Conclusion These data validate our stated hypothesis that systemic inflammation and glycemia influence circadian blood pressure variability. This study, for the first time, demonstrates a cause and effect relationship between caloric excess, enhanced systemic inflammation, dysglycemia, loss of blood pressure control and abnormal CBPV. Our results provide the fundamental basis for examining the relationship between dysglycemia and perturbation of the underlying mechanisms (adipose tissue dysfunction induced local and systemic inflammation, insulin resistance and alteration of adipose tissue precursors for the renin-aldosterone-angiotensin system which generate abnormal CBPV.

  14. Binocular combination in abnormal binocular vision

    Science.gov (United States)

    Ding, Jian; Klein, Stanley A.; Levi, Dennis M.

    2013-01-01

    We investigated suprathreshold binocular combination in humans with abnormal binocular visual experience early in life. In the first experiment we presented the two eyes with equal but opposite phase shifted sine waves and measured the perceived phase of the cyclopean sine wave. Normal observers have balanced vision between the two eyes when the two eyes' images have equal contrast (i.e., both eyes contribute equally to the perceived image and perceived phase = 0°). However, in observers with strabismus and/or amblyopia, balanced vision requires a higher contrast image in the nondominant eye (NDE) than the dominant eye (DE). This asymmetry between the two eyes is larger than predicted from the contrast sensitivities or monocular perceived contrast of the two eyes and is dependent on contrast and spatial frequency: more asymmetric with higher contrast and/or spatial frequency. Our results also revealed a surprising NDE-to-DE enhancement in some of our abnormal observers. This enhancement is not evident in normal vision because it is normally masked by interocular suppression. However, in these abnormal observers the NDE-to-DE suppression was weak or absent. In the second experiment, we used the identical stimuli to measure the perceived contrast of a cyclopean grating by matching the binocular combined contrast to a standard contrast presented to the DE. These measures provide strong constraints for model fitting. We found asymmetric interocular interactions in binocular contrast perception, which was dependent on both contrast and spatial frequency in the same way as in phase perception. By introducing asymmetric parameters to the modified Ding-Sperling model including interocular contrast gain enhancement, we succeeded in accounting for both binocular combined phase and contrast simultaneously. Adding binocular contrast gain control to the modified Ding-Sperling model enabled us to predict the results of dichoptic and binocular contrast discrimination experiments

  15. Spatial ontologies for detecting abnormal maritime behaviour

    OpenAIRE

    Vandecasteele, Arnaud; Napoli, Aldo

    2012-01-01

    International audience; The upsurge in piracy and the impact of recent environmental disasters have highlighted the need to improve maritime surveillance. Governmental and private initiatives have developed monitoring systems with improved acquisition and analysis capabilities. These systems rely on one major component, namely the detection of abnormal ship behaviour. This implies a detailed formalisation of expert knowledge. However, the quantity of data, the complexity of situations, the fa...

  16. Skeleton-Based Abnormal Gait Detection

    OpenAIRE

    Trong-Nguyen Nguyen; Huu-Hung Huynh; Jean Meunier

    2016-01-01

    Human gait analysis plays an important role in musculoskeletal disorder diagnosis. Detecting anomalies in human walking, such as shuffling gait, stiff leg or unsteady gait, can be difficult if the prior knowledge of such a gait pattern is not available. We propose an approach for detecting abnormal human gait based on a normal gait model. Instead of employing the color image, silhouette, or spatio-temporal volume, our model is created based on human joint positions (skeleton) in time series. ...

  17. Additional chromosome abnormalities in chronic myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Hui-Hua Hsiao

    2011-02-01

    Full Text Available The Philadelphia (Ph chromosome and/or Breakpoint cluster region-Abelson leukemia virus oncogene transcript are unique markers for chronic myeloid leukemia (CML. However, CML demonstrates heterogeneous presentations and outcomes. We analyzed the cytogenetic and molecular results of CML patients to evaluate their correlation with clinical presentations and outcome. A total of 84 newly diagnosed CML patients were enrolled in the study. Patients were treated according to disease status. Bone marrow samples were obtained to perform cytogenetic and molecular studies. Clinical presentations, treatment courses, and survival were reviewed retrospectively. Among 84 patients, 72 had chronic phase and 12 had accelerated phase CML. Cytogenetic study showed 69 (82.1% with the classic Ph chromosome, 6 (7.2% with a variant Ph chromosome, and 9 (10.7% with additional chromosome abnormalities. Fifty-four (64.3% cases harbored b3a2 transcripts, 29 (34.5% had b2a2 transcript, and 1 had e19a2 transcript. There was no difference in clinical presentations between different cytogenetic and molecular groups; however, additional chromosome abnormalities were significantly associated with the accelerated phase. Imatinib therapy was an effective treatment, as measured by cytogenetic response, when administered as first- and second-line therapy in chronic phase patients. Survival analysis showed that old age, additional chromosome abnormalities, high Sokal score, and no cytogenetic response in second-line therapy had a significant poor impact (p<0.05. In conclusion, we presented the cytogenetic and molecular pattern of CML patients and demonstrated that the additional chromosome abnormality was associated with poor outcome.

  18. Computed tomography in abnormalities of the hip

    Energy Technology Data Exchange (ETDEWEB)

    Visser, J.D.; Jonkers, A.; Klasen, H.J. (Rijksuniversiteit Groningen (Netherlands). Academisch Ziekenhuis); Hillen, B. (Rijksuniversiteit Groningen (Netherlands). Lab. voor Anatomie en Embryologie)

    1982-06-26

    The value of computed tomography in the assessment of abnormalities of the hip is demonstrated with the aid of an anatomical preparation and in patients with, respectively, congenital dislocation of a hip, dislocation of the hip in spina bifida, an acetabular fracture and a Ewing tumour. The anteversion of the acetabulum and femur and the instability index of the hip joint can be measured by means of computed tomography.

  19. Chromosomal Abnormality in Men with Impaired Spermatogenesis

    OpenAIRE

    Dana Mierla; Dumitru Jardan; Veronica Stoian

    2014-01-01

    Background: Chromosomal abnormalities and Y chromosome microdeletions are regarded as two most frequent genetic causes associated with failure of spermatogenesis in the Caucasian population. Materials and Methods: To investigate the distribution of genetic defects in the Romanian population with azoospermia or severe oligozoospermia, karyotype analysis by G-banding was carried out in 850 idiopathic infertile men and in 49 fertile men with one or more children. Screening for microdeletions in ...

  20. Sex bias in experimental immune-mediated, drug-induced liver injury in BALB/c mice: suggested roles for Tregs, estrogen, and IL-6.

    Directory of Open Access Journals (Sweden)

    Joonhee Cho

    Full Text Available Immune-mediated, drug-induced liver injury (DILI triggered by drug haptens is more prevalent in women than in men. However, mechanisms responsible for this sex bias are not clear. Immune regulation by CD4+CD25+FoxP3+ regulatory T-cells (Tregs and 17β-estradiol is crucial in the pathogenesis of sex bias in cancer and autoimmunity. Therefore, we investigated their role in a mouse model of immune-mediated DILI.To model DILI, we immunized BALB/c, BALB/cBy, IL-6-deficient, and castrated BALB/c mice with trifluoroacetyl chloride-haptenated liver proteins. We then measured degree of hepatitis, cytokines, antibodies, and Treg and splenocyte function.BALB/c females developed more severe hepatitis (p<0.01 and produced more pro-inflammatory hepatic cytokines and antibodies (p<0.05 than did males. Castrated males developed more severe hepatitis than did intact males (p<0.001 and females (p<0.05. Splenocytes cultured from female mice exhibited fewer Tregs (p<0.01 and higher IL-1β (p<0.01 and IL-6 (p<0.05 than did those from males. However, Treg function did not differ by sex, as evidenced by absence of sex bias in programmed death receptor-1 and responses to IL-6, anti-IL-10, anti-CD3, and anti-CD28. Diminished hepatitis in IL-6-deficient, anti-IL-6 receptor α-treated, ovariectomized, or male mice; undetectable IL-6 levels in splenocyte supernatants from ovariectomized and male mice; elevated splenic IL-6 and serum estrogen levels in castrated male mice, and IL-6 induction by 17β-estradiol in splenocytes from naïve female mice (p<0.05 suggested that 17β-estradiol may enhance sex bias through IL-6 induction, which subsequently discourages Treg survival. Treg transfer from naïve female mice to those with DILI reduced hepatitis severity and hepatic IL-6.17β-estradiol and IL-6 may act synergistically to promote sex bias in experimental DILI by reducing Tregs. Modulating Treg numbers may provide a therapeutic approach to DILI.

  1. Efficacy of Jian'ganle () versus Hugan Pian (), glucuronolactone and reduced glutathione in prevention of antituberculosis drug-induced liver injury.

    Science.gov (United States)

    Zhang, Quan; Zhong, Fang-ying; Wu, Meng; Zhang, Xin-ping

    2014-06-01

    Evidence-based medicine is advocated by WHO and adopted by developed countries for many years. In China, however, the selection of essential medicine and various medical insurance reimbursement schemes medicine is usually based on experts' experience of prescription practice which is under heavy critics resulting from the lack of related comparative efficacy and evidence-based research. The efficacy of Jian'ganle in prevention of drug-induced liver injury (DILI) caused by antituberculotics was evaluated in this study by comparison with Hugan Pian, glucuronolactone and reduced glutathione. Evidence was provided for relevant sectors such as Ministry for Human Resources and Social Security of the People's Republic of China and National Health and Family Planning Commission of the People's Republic of China to select and renew the Essential Medicine List (EML), the new rural cooperative medical scheme in China (NRCMS) list or the reimbursement list of industrial injury insurance. A total of 189 patients with initial pulmonary tuberculosis were divided into four groups who took antituberculotics combined with Jian'ganle, Hugan Pian, glucuronolactone and reduced glutathione respectively. Their liver function profile including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), total protein (TP), albumin (A) and globulin (G) were detected at admission as baseline and after treatment. The Jian'ganle group was compared with the three others by chi-square tests. In an aspect of maintaining bilirubin indexes normal, Jian'ganle was more efficacious than glucuronolactone. And Jian'ganle had a little more efficacy than reduced glutathione to maintain protein indexes normal as well. And the therapeutic regimen of antituberculotics combined with Jian'ganle was the best in treating tuberculosis and preventing DILI at the same time. The study showed that among the four hepatinicas which demonstrated similar prevention

  2. Medical toxicologists' practice patterns regarding drug-induced QT prolongation in overdose patients: a survey in the United States of America, Europe, and Asia Pacific region.

    Science.gov (United States)

    Othong, Rittirak; Devlin, John J; Kazzi, Ziad N

    2015-05-01

    To describe practice patterns of medical toxicologists in the United States of America (USA), Europe, and Asia Pacific Region regarding management of drug induced QT prolongation and torsades de pointes in overdose. A survey was developed to assess current practice patterns and consistency with guidelines published by the American Heart Association (AHA), American College of Cardiology (ACC), and European Society of Cardiology (ESC). It was reviewed by our department research committee and the American College of Medical Toxicology (ACMT). The ACMT, European Association of Poisons Centres and Clinical Toxicologists, and Asia Pacific Association of Medical Toxicology electronically disseminated the survey to their physician members in the USA, Europe and Asia Pacific Region. The overall response rate was 37% (229/617) (36% USA; 32% Europe; 52% Asia Pacific Region). Twelve toxicologists from Asia Pacific Region and Europe used the QT nomogram (Australia-5, New Zealand-1, United Kingdom-1) or QT alone (France-1, Russia-1, Romania-1, Germany-1, Philippines-1), in lieu of the corrected QT (QTc) to determine risks of developing torsades de pointes. Because only those who used QTc could proceed through the remainder of the survey, only 217 could do so. Approximately half of the respondents (52%) did not calculate QTc manually and based decisions on the electrocardiogram machines automated measurement. For those who corrected the QT interval themselves, the most common formula used was Bazett's (40%). There is great variation in the QTc value considered prolonged. Most responders considered QTc greater than 450 ms in men (28%) and 460 ms in women (25%) to be prolonged. Interestingly, approximately 15% of participants did not consider the QTc prolonged until it exceeded 500 ms in both men and women. Given an overdose scenario of a male patient with a QTc of 560 ms, heart rate of 90 beats/minute, 59% would not recommend administering intravenous magnesium sulfate. Forty

  3. Synthesis, in vitro and in vivo evaluation of 3β-[18F]fluorocholic acid for the detection of drug-induced cholestasis in mice

    Science.gov (United States)

    Neyt, Sara; Kersemans, Ken; Verhoeven, Jeroen; Devisscher, Lindsey; Van Vlierberghe, Hans; Vanhove, Christian; De Vos, Filip

    2017-01-01

    Introduction Drug-induced cholestasis is a liver disorder that might be caused by interference of drugs with the hepatobiliary bile acid transporters. It is important to identify this interference early on in drug development. In this work, Positron Emission Tomography (PET)-imaging with a 18F labeled bile acid analogue was introduced to detect disturbed hepatobiliary transport of bile acids. Methods 3β-[18F]fluorocholic acid ([18F]FCA) was prepared by nucleophilic substitution of a mesylated precursor with [18F]fluoride, followed by deprotection with sodium hydroxide. Transport of [18F]FCA was assessed in vitro using CHO-NTCP, HEK-OATP1B1, HEK-OATP1B3 transfected cells and BSEP & MRP2 membrane vesicles. Investigation of [18F]FCA metabolites was performed with primary mouse hepatocytes. Hepatobiliary transport of [18F]FCA was evaluated in vivo in wild-type, rifampicin and bosentan pretreated FVB-mice by dynamic μPET scanning. Results Radiosynthesis of [18F]FCA was achieved in a moderate radiochemical yield (8.11 ± 1.94%; non-decay corrected; n = 10) and high radiochemical purity (>99%). FCA was transported by the basolateral bile acid uptake transporters NTCP, OATP1B1 and OATP1B3. For canalicular efflux, BSEP and MRP2 are the relevant bile acid transporters. [18F]FCA was found to be metabolically stable. In vivo, [18F]FCA showed fast hepatic uptake (4.5 ± 0.5 min to reach 71.8 ± 1.2% maximum % ID) and subsequent efflux to the gallbladder and intestines (93.3 ± 6.0% ID after 1 hour). Hepatobiliary transport of [18F]FCA was significantly inhibited by both rifampicin and bosentan. Conclusion A 18F labeled bile acid analogue, [18F]FCA, has been developed that shows transport by NTCP, OATP, MRP2 and BSEP. [18F]FCA can be used as a probe to monitor disturbed hepatobiliary transport in vivo and accumulation of bile acids in blood and liver during drug development. PMID:28273180

  4. [Nutritional abnormalities in chronic obstructive pulmonary disease].

    Science.gov (United States)

    Gea, Joaquim; Martínez-Llorens, Juana; Barreiro, Esther

    2014-07-22

    Nutritional abnormalities are associated with chronic obstructive pulmonary disease with a frequency ranging from 2 to 50%, depending on the geographical area and the study design. Diagnostic tools include anthropometry, bioelectrical impedance, dual energy radioabsortiometry and deuterium dilution, being the body mass and the lean mass indices the most frequently used parameters. While the most important consequences of nutritional abnormalities are muscle dysfunction and exercise limitation, factors implicated include an imbalance between caloric intake and consumption, and between anabolic and catabolic hormones, inflammation, tobacco smoking, poor physical activity, hypoxemia, some drugs and aging/comorbidities. The most important molecular mechanism for malnutrition associated with chronic obstructive pulmonary disease appears to be the mismatching between protein synthesis and breakdown. Among the therapeutic measures proposed for these nutritional abnormalities are improvements in lifestyle and nutritional support, although the use of anabolic drugs (such as secretagogues of the growth hormone) offers a new therapeutic strategy. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  5. Recurrent Cytogenetic Abnormalities in Acute Myeloid Leukemia.

    Science.gov (United States)

    Yang, John J; Park, Tae Sung; Wan, Thomas S K

    2017-01-01

    The spectrum of chromosomal abnormality associated with leukemogenesis of acute myeloid leukemia (AML) is broad and heterogeneous when compared to chronic myeloid leukemia and other myeloid neoplasms. Recurrent chromosomal translocations such as t(8;21), t(15;17), and inv(16) are frequently detected, but hundreds of other uncommon chromosomal aberrations from AML also exist. This chapter discusses 22 chromosomal abnormalities that are common structural, numerical aberrations, and other important but infrequent (less than 1 %) translocations emphasized in the WHO classification. Brief morphologic, cytogenetic, and clinical characteristics are summarized, so as to provide a concise reference to cancer cytogenetic laboratories. Morphology based on FAB classification is used together with the current WHO classification due to frequent mentioning in a vast number of reference literatures. Characteristic chromosomal aberrations of other myeloid neoplasms such as myelodysplastic syndrome and myeloproliferative neoplasm will be discussed in separate chapters-except for certain abnormalities such as t(9;22) in de novo AML. Gene mutations detected in normal karyotype AML by cutting edge next generation sequencing technology are also briefly mentioned.

  6. Chromosomal Abnormality in Men with Impaired Spermatogenesis

    Directory of Open Access Journals (Sweden)

    Dana Mierla

    2014-03-01

    Full Text Available Background: Chromosomal abnormalities and Y chromosome microdeletions are regarded as two most frequent genetic causes associated with failure of spermatogenesis in the Caucasian population. Materials and Methods: To investigate the distribution of genetic defects in the Romanian population with azoospermia or severe oligozoospermia, karyotype analysis by G-banding was carried out in 850 idiopathic infertile men and in 49 fertile men with one or more children. Screening for microdeletions in the azoospermia factor (AZF region of Y chromosome was performed by multiplex polymerase chain reaction (PCR on a group of 67 patients with no detectable chromosomal abnormality. The results of the two groups were compared by a two-tailed Fisher’s exact test. Results: In our study chromosomal abnormalities were observed in 12.70% and 8.16% of infertile and fertile individuals respectively. Conclusion: Our data suggests that infertile men with severe azoospermia have higher incidences of genetic defects than fertile men and also patients from any other group. Infertile men with normal sperm present a higher rate of polymorphic variants. It is important to know whether there is a genetic cause of male infertility before patients are subjected to intracytoplasmic sperm injection (ICSI or testicular sperm extraction (TESE/ICSI treatment.

  7. Electrocardiographic abnormalities in centenarians: impact on survival

    Directory of Open Access Journals (Sweden)

    Rabuñal-Rey Ramón

    2012-04-01

    Full Text Available Abstract Background The centenarian population is gradually increasing, so it is becoming more common to see centenarians in clinical practice. Electrocardiogram abnormalities in the elderly have been reported, but several methodological biases have been detected that limit the validity of their results. The aim of this study is to analyse the ECG abnormalities in a prospective study of the centenarian population and to assess their impact on survival. Method We performed a domiciliary visit, where a medical history, an ECG and blood analysis were obtained. Barthel index (BI, cognitive mini-exam (CME and Charlson index (ChI were all determined. Patients were followed up by telephone up until their death. Results A total of 80 centenarians were studied, 26 men and 64 women, mean age 100.8 (SD 1.3. Of these, 81% had been admitted to the hospital at least once in the past, 81.3% were taking drugs (mean 3.3, rank 0–11. ChI was 1.21 (SD 1.19. Men had higher scores both for BI (70 -SD 34.4- vs. 50.4 -SD 36.6-, P = .005 and CME (16.5 -SD 9.1- vs. 9.1 –SD 11.6-, P = .008; 40.3% of the centenarians had anaemia, 67.5% renal failure, 13% hyperglycaemia, 22.1% hypoalbuminaemia and 10.7% dyslipidaemia, without statistically significant differences regarding sex. Only 7% had a normal ECG; 21 (26.3% had atrial fibrillation (AF, 30 (37.5% conduction defects and 31 (38.8% abnormalities suggestive of ischemia, without sex-related differences. A history of heart disease was significantly associated with the presence of AF (P = .002, OR 5.2, CI 95% 1.8 to 15.2 and changes suggestive of ischemia (P = .019, OR 3.2, CI 95% 1.2-8.7. Mean survival was 628 days (SD 578.5, median 481 days. Mortality risk was independently associated with the presence of AF (RR 2.0, P = .011, hyperglycaemia (RR 2.2, P = .032, hypoalbuminaemia (RR 3.5, P P = .024. Conclusion Although ECG abnormalities are common in centenarians, they are not related to

  8. Abnormality of Auricular Muscles in Congenital Auricular Deformities.

    Science.gov (United States)

    Yotsuyanagi, Takatoshi; Yamauchi, Makoto; Yamashita, Ken; Sugai, Asuka; Gonda, Ayako; Kitada, Ayaka; Saito, Tamotsu; Urushidate, Satoshi

    2015-07-01

    It has been suggested that there is a close association of abnormality in auricular muscles with various congenital auricular deformities. However, there has been no investigation to determine what muscles are involved and how they affect the deformity. The authors examined abnormalities of auricular muscles for patients with various auricular deformities. The authors examined 77 auricles of 62 patients with congenital auricular deformities, including cryptotia, Stahl's ear, prominent ear, lop ear, and others. The superior and posterior auricular muscles from the extrinsic auricular muscle group and the auricular oblique and transverse muscles from the auricular intrinsic muscle group were investigated. The authors found characteristic features of the abnormality of the muscle for each auricular deformity. In nearly all cases of cryptotia, abnormality was found in the superior auricular, auricular oblique, and auricular transverse muscles. Abnormal insertion was found mainly in the superior auricular muscle and was the main cause of cryptotia. In Stahl's ear, the major abnormality was abnormal insertion of the auricular transverse muscle, which creates an abnormal cartilaginous prominence in the scapha. The abnormality in cases of prominent ear was clearly limited mostly to the auricular transverse muscle and, in some cases, to the posterior auricular muscle. In lop ear, abnormality was mostly found in the auricular transverse muscle, with elongation, and in the superior auricular or auricular oblique muscle in some cases. There is a tendency for a specific muscle abnormality to be found in each deformity. It is important to identify the abnormal muscle and correct the abnormality during the operation.

  9. Phenotype abnormality: 41 [Arabidopsis Phenome Database[Archive

    Lifescience Database Archive (English)

    Full Text Available 41 http://metadb.riken.jp/db/SciNetS_ria224i/cria224u1ria224u547i abnormal for trait of behavioral...ganelle ... abnormal ... anatomical structure arrangement ... behavioral quality

  10. Phenotype abnormality: 36 [Arabidopsis Phenome Database[Archive

    Lifescience Database Archive (English)

    Full Text Available 36 http://metadb.riken.jp/db/SciNetS_ria224i/cria224u1ria224u542i abnormal for trait of behavioral...tyledon ... abnormal ... anatomical structure arrangement ... behavioral quality

  11. Phenotype abnormality: 38 [Arabidopsis Phenome Database[Archive

    Lifescience Database Archive (English)

    Full Text Available 38 http://metadb.riken.jp/db/SciNetS_ria224i/cria224u1ria224u544i abnormal for trait of behavioral...idermis ... abnormal ... anatomical structure arrangement ... behavioral quality

  12. Sperm chromosomal abnormalities in patients with unexplained recurrent abortions.

    Science.gov (United States)

    Al-Hassan, S; Hellani, A; Al-Shahrani, A; Al-Deery, M; Jaroudi, K; Coskun, S

    2005-01-01

    Cytogenetic studies showed that about half of concepti were chromosomally abnormal in first trimester abortions. Sperm chromosomal abnormalities in men with normal karyotype could occur during spermatogenesis. The objective of this study was to evaluate sperm chromosomal abnormalities in patients with unexplained recurrent abortions. A total of 14 couples with normal karyotype, and negative workup for endocrine, immune and anatomical causes of recurrent abortion was investigated. Semen analysis was performed and chromosomal abnormalities were assessed by fluorescent in situ hybridization for chromosomes 13, 18, 21, X and Y. The average number of abortions was 5.8. The incidence of chromosomal abnormalities was 16.5% that was higher when compared to baseline (4.6%). In conclusion, a high rate of sperm chromosomal abnormalities was observed in recurrent abortion patients. These abnormalities might form during spermatogenesis since all patients had normal karyotype. Sperm chromosomal abnormality analysis can be included into recurrent abortion workup when no other cause is detected.

  13. Phenotype abnormality: 73 [Arabidopsis Phenome Database[Archive

    Lifescience Database Archive (English)

    Full Text Available 73 http://metadb.riken.jp/db/SciNetS_ria224i/cria224u1ria224u579i abnormal for trait of morphology... in organ named vascular system ... vascular system ... abnormal ... morphology

  14. Phenotype abnormality: 61 [Arabidopsis Phenome Database[Archive

    Lifescience Database Archive (English)

    Full Text Available 61 http://metadb.riken.jp/db/SciNetS_ria224i/cria224u1ria224u567i abnormal for trait of morphology... in organ named obsolete microgametophyte ... obsolete microgametophyte ... abnormal ... morphology

  15. Detecting Kidney and Urinary Tract Abnormalities Before Birth

    Science.gov (United States)

    ... A to Z Health Guide Detecting Kidney and Urinary Tract Abnormalities Before Birth Print Email Ultrasound examinations are ... impact on the child's overall health. What causes urinary tract abnormalities to occur before birth? In about one ...

  16. Acute Radiological Abnormalities after Bronchial Thermoplasty: A Prospective Cohort Trial

    NARCIS (Netherlands)

    d'Hooghe, Julia N. S.; van den Berk, Inge A. H.; Annema, Jouke T.; Bonta, Peter I.

    2017-01-01

    Background: Bronchial thermoplasty (BT) is a novel treatment for severe asthma based on radiofrequency energy delivery to the larger airways. Although impressive radiological abnormalities have been reported, the incidence, pattern, and behavior over time of acute radiological abnormalities

  17. Comparisons of stomatal parameters between normal and abnormal ...

    African Journals Online (AJOL)

    ED), guard cell length (GCL) and guard cell width (GCW) of normal and abnormal leaf of Bougainvillea spectabilis Willd were studied. This can be useful for further research of physical mechanism of abnormal leaf. Epidermal cells were ...

  18. Chromosome abnormalities in primary ovarian cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yonescu, R.; Currie, J.; Griffin, C.A. [John Hopkins Univ., Baltimore, MD (United States)

    1994-09-01

    Chromosome abnormalities that are specific and recurrent may occur in regions of the genome that are involved in the conversion of normal cells to those with tumorigenic potential. Ovarian cancer is the primary cause of death among patients with gynecological malignancies. We have performed cytogenetic analysis of 16 ovarian tumors from women age 28-82. Three tumors of low malignant potential and three granulosa cell tumors had normal karyotypes. To look for the presence of trisomy 12, which has been suggested to be a common aberration in this group of tumors, interphase fluorescence in situ hybridization was performed on direct preparations from three of these tumors using a probe for alpha satellite sequences of chromosome 12. In the 3 preparations, 92-98 percent of the cells contained two copies of chromosome 12, indicating that trisomy 12 is not a universal finding in low grade ovarian tumors. Endometrioid carcinoma of the ovary is histologically indistinguishable from endometial carcinoma of the uterus. We studied 10 endometrioid tumors to determine the degree of genetic similarity between these two carcinomas. Six out of ten endometrioid tumors showed a near-triploid modal number, and one presented with a tetraploid modal number. Eight of the ten contained structural chromosome abnormalities, of which the most frequent were 1p- (5 tumors), 19q+ (3 tumors), 6q- or ins(6) (4 tumors), 3q- or 3q+ (4 tumors). These cytogenetic results resemble those reported for papillary ovarian tumors and differ from those of endometrial carcinoma of the uterus. We conclude that despite the histologic similarities between the endometrioid and endometrial carcinomas, the genetic abnormalities in the genesis of these tumors differ significantly.

  19. Haematological abnormalities in systemic lupus erythematosus.

    Science.gov (United States)

    Aleem, Aamer; Al Arfaj, Abdurahman Saud; khalil, Najma; Alarfaj, Husain

    2014-01-01

    This study was conducted to evaluate the frequency and pattern of haematological abnormalities (HA) in SLE patients at the time of diagnosis and last follow-up, and their relationship with organ involvement. This retrospective study included patients who were diagnosed and treated for SLE from 1982 to 2008 at King Khalid University hospital, Riyadh. Demographic and haematological parameters at diagnosis and the last follow-up, disease manifestations, organ involvement and clinical hematological complications were recorded. Association of HA with organ involvement was explored by multivariate analysis. A total of 624 patients (90.7% females, mean age 34.3±11.9 years) were studied. HA were present in 516 (82.7 %) patients at the time of diagnosis. Anemia was the most frequent HA in 63.0% patients followed by lymphopenia in 40.3%, leukopenia in 30.0%, thrombocytopenia in 10.9% and autoimmune hemolytic anemia (AIHA) in 4.6% patients. Deep vein thrombosis and pulmonary embolism were diagnosed in 7.4% and 2.6% patients respectively. After a mean follow-up of 9.3±5.3 years, 329/491 (67%) patients still had some HA present. Anemia remained the most common abnormality (51.7% patients) followed by lymphopenia in 33.1%, and thrombocytopenia in 4.8% patients. Leucopenia was associated with oral ulcers (p=0.021) and alopecia (p=0.031), anemia with renal disease (p=0.017), AIHA with neurological involvement (p=0.003), elevated IgG with malar rash (p=0.027), and low C3 with serositis (p=0.026). HA are very common at the time of diagnosis and during follow-up in SLE, and some of these abnormalities are associated with organ damage. This information may help in better management planning of SLE patients.

  20. Skeletal abnormalities of acrogeria, a progeroid syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Ho, A.; White, S.J.; Rasmussen, J.E.

    1987-08-01

    We report the skeletal abnormalities in a 4 1/2-year-old boy with acrogeria, a progeroid syndrome of premature aging of the skin without the involvement of internal organs seen in Hutchinson-Gilford progeria syndrome. Acro-osteolysis of the distal phalanges, delayed cranial suture closure with wormian bones, linear lucent defects of the metaphyses, and antegonial notching of the mandible are the predominant skeletal features of the disorder. The skeletal features described in 21 other reported cases of acrogeria are summarized.