Sample records for abnormalities drug-induced

  1. Drug-induced abnormalities of potassium metabolism.

    PubMed

    Kokot, Franciszek; Hyla-Klekot, Lidia

    2008-01-01

    Pharmacotherapy has progressed rapidly over the last 20 years with the result that general practioners more and more often use drugs which may influence potassium metabolism at the kidney or gastrointestinal level, or the transmembrane transport of potassium at the cellular level. Potassium abnormalities may result in life-theatening clinical conditions. Hypokalemia is most frequently caused by renal loss of this electrolyte (thiazide, thiazide-like and loop diuretics, glucocorticoids) and the gastrointestinal tract (laxatives, diarrhea, vomiting, external fistula), and may be the result of an increased intracellular potassium influx induced by sympathicomimetics used mostly by patients with asthma, or by insulin overdosage in diabetic subjects. The leading symptoms of hypokalemia are skeletal and smooth muscle weakness and cardiac arrhythmias. Hyperkalemia may be caused by acute or end-stage renal failure, impaired tubular excretion of potassium (blockers of the renin-angiotensin-aldosterone system, nonsteroidal anti-inflammatory drugs, cyclosporine, antifungal drugs, potassium sparing diuretics), acidemia, and severe cellular injury (tumor lysis syndrome). Hyperkalemia may be the cause of severe injury of both skeletal and smooth muscle cells. The specific treatment counteracting hyperkalemia is a bolus injection of calcium salts and, when necessary, hemodialysis.

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

    PubMed Central

    Cubeddu, Luigi X.

    2016-01-01

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

  3. Drug-Induced Urinary Calculi

    PubMed Central

    Matlaga, Brian R; Shah, Ojas D; Assimos, Dean G

    2003-01-01

    Urinary calculi may be induced by a number of medications used to treat a variety of conditions. These medications may lead to metabolic abnormalities that facilitate the formation of stones. Drugs that induce metabolic calculi include loop diuretics; carbonic anhydrase inhibitors; and laxatives, when abused. Correcting the metabolic abnormality may eliminate or dramatically attenuate stone activity. Urinary calculi can also be induced by medications when the drugs crystallize and become the primary component of the stones. In this case, urinary supersaturation of the agent may promote formation of the calculi. Drugs that induce calculi via this process include magnesium trisilicate; ciprofloxacin; sulfa medications; triamterene; indinavir; and ephedrine, alone or in combination with guaifenesin. When this situation occurs, discontinuation of the medication is usually necessary. PMID:16985842

  4. Drug-induced apnea.

    PubMed

    Boutroy, M J

    1994-01-01

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

  5. Drug-Induced Hematologic Syndromes

    PubMed Central

    Mintzer, David M.; Billet, Shira N.; Chmielewski, Lauren

    2009-01-01

    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. PMID:19960059

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

    PubMed

    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.

  7. Thymus function in drug-induced lupus.

    PubMed

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

    2001-01-01

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

  8. Risperidone and aripiprazole alleviate prenatal valproic acid-induced abnormalities in behaviors and dendritic spine density in mice.

    PubMed

    Hara, Yuta; Ago, Yukio; Taruta, Atsuki; Hasebe, Shigeru; Kawase, Haruki; Tanabe, Wataru; Tsukada, Shinji; Nakazawa, Takanobu; Hashimoto, Hitoshi; Matsuda, Toshio; Takuma, Kazuhiro

    2017-11-01

    Rodents exposed prenatally to valproic acid (VPA) exhibit autism spectrum disorder (ASD)-like behavioral abnormalities. We recently found that prenatal VPA exposure causes hypofunction of the prefrontal dopaminergic system in mice. This suggests that the dopaminergic system may be a potential pharmacological target for treatment of behavioral abnormalities in ASD patients. In the present study, we examined the effects of antipsychotic drugs, which affect the dopaminergic system, on the social interaction deficits, recognition memory impairment, and reduction in dendritic spine density in the VPA mouse model of ASD. Both acute and chronic administrations of the atypical antipsychotic drugs risperidone and aripiprazole increased prefrontal dopamine (DA) release, while the typical antipsychotic drug haloperidol did not. Chronic risperidone and aripiprazole, but not haloperidol, increased the expression of c-Fos in the prefrontal cortex, although they all increased c-Fos expression in the striatum. Chronic, but not acute, administrations of risperidone and aripiprazole improved the VPA-induced social interaction deficits and recognition memory impairment, as well as the reduction in dendritic spine density in the prefrontal cortex and hippocampus. In contrast, chronic administration of haloperidol did not ameliorate VPA-induced abnormalities in behaviors and dendritic spine density. These findings indicate that chronic risperidone and aripiprazole treatments improve VPA-induced abnormalities in behaviors and prefrontal dendritic spine density, which may be mediated by repeated elevation of extracellular DA in the prefrontal cortex. Our results also imply that loss of prefrontal dendritic spines may be involved in the abnormal behaviors in the VPA mouse model of ASD.

  9. Abnormal brain structure implicated in stimulant drug addiction.

    PubMed

    Ersche, Karen D; Jones, P Simon; Williams, Guy B; Turton, Abigail J; Robbins, Trevor W; Bullmore, Edward T

    2012-02-03

    Addiction to drugs is a major contemporary public health issue, characterized by maladaptive behavior to obtain and consume an increasing amount of drugs at the expense of the individual's health and social and personal life. We discovered abnormalities in fronto-striatal brain systems implicated in self-control in both stimulant-dependent individuals and their biological siblings who have no history of chronic drug abuse; these findings support the idea of an underlying neurocognitive endophenotype for stimulant drug addiction.

  10. The hidden side of drug action: Brain temperature changes induced by neuroactive drugs

    PubMed Central

    Kiyatkin, Eugene A.

    2013-01-01

    Rationale Most neuroactive drugs affect brain metabolism as well as systemic and cerebral blood flow, thus altering brain temperature. Although this aspect of drug action usually remains in the shadows, drug-induced alterations in brain temperature reflect their metabolic neural effects and affect neural activity and neural functions. Objectives Here, I review brain temperature changes induced by neuroactive drugs, which are used therapeutically (general anesthetics), as a research tool (dopamine agonists and antagonists), and self-administered to induce desired psychic effects (cocaine, methamphetamine, ecstasy). I consider the mechanisms underlying these temperature fluctuations and their influence on neural, physiological, and behavioral effects of these drugs. Results By interacting with neural mechanisms regulating metabolic activity and heat exchange between the brain and the rest of the body, neuroactive drugs either increase or decrease brain temperatures both within (35-39°C) and exceeding the range of physiological fluctuations. These temperature effects differ drastically depending upon the environmental conditions and activity state during drug administration. This state-dependence is especially important for drugs of abuse that are usually taken by humans during psycho-physiological activation and in environments that prevent proper heat dissipation from the brain. Under these conditions, amphetamine-like stimulants induce pathological brain hyperthermia (>40°C) associated with leakage of the blood-brain barrier and structural abnormalities of brain cells. Conclusions The knowledge on brain temperature fluctuations induced by neuroactive drugs provides new information to understand how they influence metabolic neural activity, why their effects depend upon the behavioral context of administration, and the mechanisms underlying adverse drug effects including neurotoxicity PMID:23274506

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

    PubMed

    Jiang, Wei; Wang, Xuefeng; Zhou, Shengnian

    2016-01-01

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

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

    PubMed

    Agrawal, Poonam; Chopra, Deepti; Patra, Surajeet K; Madaan, Himanshu

    2014-01-01

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

  13. Cocaine Self-Administration Experience Induces Pathological Phasic Accumbens Dopamine Signals and Abnormal Incentive Behaviors in Drug-Abstinent Rats.

    PubMed

    Saddoris, Michael P; Wang, Xuefei; Sugam, Jonathan A; Carelli, Regina M

    2016-01-06

    Chronic exposure to drugs of abuse is linked to long-lasting alterations in the function of limbic system structures, including the nucleus accumbens (NAc). Although cocaine acts via dopaminergic mechanisms within the NAc, less is known about whether phasic dopamine (DA) signaling in the NAc is altered in animals with cocaine self-administration experience or if these animals learn and interact normally with stimuli in their environment. Here, separate groups of rats self-administered either intravenous cocaine or water to a receptacle (controls), followed by 30 d of enforced abstinence. Next, all rats learned an appetitive Pavlovian discrimination and voltammetric recordings of real-time DA release were taken in either the NAc core or shell of cocaine and control subjects. Cocaine experience differentially impaired DA signaling in the core and shell relative to controls. Although phasic DA signals in the shell were essentially abolished for all stimuli, in the core, DA did not distinguish between cues and was abnormally biased toward reward delivery. Further, cocaine rats were unable to learn higher-order associations and even altered simple conditioned approach behaviors, displaying enhanced preoccupation with cue-associated stimuli (sign-tracking; ST) but diminished time at the food cup awaiting reward delivery (goal-tracking). Critically, whereas control DA signaling correlated with ST behaviors, cocaine experience abolished this relationship. These findings show that cocaine has persistent, differential, and pathological effects on both DA signaling and DA-dependent behaviors and suggest that psychostimulant experience may remodel the very circuits that bias organisms toward repeated relapse. Relapsing to drug abuse despite periods of abstinence and sincere attempts to quit is one of the most pernicious facets of addiction. Unfortunately, little is known about how the dopamine (DA) system functions after periods of drug abstinence, particularly its role in

  14. Cocaine Self-Administration Experience Induces Pathological Phasic Accumbens Dopamine Signals and Abnormal Incentive Behaviors in Drug-Abstinent Rats

    PubMed Central

    Wang, Xuefei; Sugam, Jonathan A.; Carelli, Regina M.

    2016-01-01

    Chronic exposure to drugs of abuse is linked to long-lasting alterations in the function of limbic system structures, including the nucleus accumbens (NAc). Although cocaine acts via dopaminergic mechanisms within the NAc, less is known about whether phasic dopamine (DA) signaling in the NAc is altered in animals with cocaine self-administration experience or if these animals learn and interact normally with stimuli in their environment. Here, separate groups of rats self-administered either intravenous cocaine or water to a receptacle (controls), followed by 30 d of enforced abstinence. Next, all rats learned an appetitive Pavlovian discrimination and voltammetric recordings of real-time DA release were taken in either the NAc core or shell of cocaine and control subjects. Cocaine experience differentially impaired DA signaling in the core and shell relative to controls. Although phasic DA signals in the shell were essentially abolished for all stimuli, in the core, DA did not distinguish between cues and was abnormally biased toward reward delivery. Further, cocaine rats were unable to learn higher-order associations and even altered simple conditioned approach behaviors, displaying enhanced preoccupation with cue-associated stimuli (sign-tracking; ST) but diminished time at the food cup awaiting reward delivery (goal-tracking). Critically, whereas control DA signaling correlated with ST behaviors, cocaine experience abolished this relationship. These findings show that cocaine has persistent, differential, and pathological effects on both DA signaling and DA-dependent behaviors and suggest that psychostimulant experience may remodel the very circuits that bias organisms toward repeated relapse. SIGNIFICANCE STATEMENT Relapsing to drug abuse despite periods of abstinence and sincere attempts to quit is one of the most pernicious facets of addiction. Unfortunately, little is known about how the dopamine (DA) system functions after periods of drug abstinence

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

    PubMed Central

    Zeng, Hui; Cui, Qinghua

    2015-01-01

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

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

    PubMed

    Zeng, Hui; Qiu, Chengxiang; Cui, Qinghua

    2015-01-01

    Some databases for drug-associated pathways have been built and are publicly available. However, the pathways curated in most of these databases are drug-action or drug-metabolism pathways. In recent years, high-throughput technologies such as microarray and RNA-sequencing have produced lots of drug-induced gene expression profiles. Interestingly, drug-induced gene expression profile frequently show distinct patterns, indicating that drugs normally induce the activation or repression of distinct pathways. Therefore, these pathways contribute to study the mechanisms of drugs and drug-repurposing. Here, we present Drug-Path, a database of drug-induced pathways, which was generated by KEGG pathway enrichment analysis for drug-induced upregulated genes and downregulated genes based on drug-induced gene expression datasets in Connectivity Map. Drug-Path provides user-friendly interfaces to retrieve, visualize and download the drug-induced pathway data in the database. In addition, the genes deregulated by a given drug are highlighted in the pathways. All data were organized using SQLite. The web site was implemented using Django, a Python web framework. Finally, we believe that this database will be useful for related researches. © The Author(s) 2015. Published by Oxford University Press.

  17. Clozapine-induced EEG abnormalities and clinical response to clozapine.

    PubMed

    Risby, E D; Epstein, C M; Jewart, R D; Nguyen, B V; Morgan, W N; Risch, S C; Thrivikraman, K V; Lewine, R L

    1995-01-01

    The authors hypothesized that patients who develop gross EEG abnormalities during clozapine treatment would have a less favorable outcome than patients who did not develop abnormal EEGs. The clinical EEGs and the Brief Psychiatric Rating Scale (BPRS) scores of 12 patients with schizophrenia and 4 patients with schizoaffective disorder were compared before and during treatment with clozapine. Eight patients developed significant EEG abnormalities on clozapine; 1 showed worsening of an abnormal pre-clozapine EEG; none of these subjects had clinical seizures. BPRS scores improved significantly in the group of patients who developed abnormal EEGs but not in the group who did not. Findings are consistent with previous reports of a high incidence of clozapine-induced EEG abnormalities and a positive association between these abnormalities and clinical improvement.

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

    PubMed

    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.

  19. [Drug induced diarrhea].

    PubMed

    Morard, Isabelle; Hadengue, Antoine

    2008-09-03

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

  20. Drug-Induced Metabolic Acidosis

    PubMed Central

    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

  1. Drug-induced gynecomastia.

    PubMed

    Bowman, John D; Kim, Hyunah; Bustamante, Juan J

    2012-12-01

    Drugs account for about 20% of gynecomastia cases in men. As a number of factors can alter the estrogen:androgen ratio, several pathophysiologic mechanisms are associated with drugs causing this disorder. Antiandrogens, protease inhibitors, and nucleoside reverse transcriptase inhibitors are the most common drug causes of gynecomastia, whereas first-generation antipsychotics, spironolactone, verapamil, and cimetidine are less common causes. Other drugs have been reported rarely as causes. Treatment may involve switching to an alternative agent or may require surgery or irradiation if the causative agent cannot be discontinued. We reviewed the literature on drug-induced gynecomastia and provided another perspective by reviewing data from the United States Food and Drug Administration's Adverse Event Reporting System. Epidemiologic studies are needed to provide a more accurate description of the frequency of drug-induced gynecomastia. © 2012 Pharmacotherapy Publications, Inc.

  2. The pharmacology of neuroplasticity induced by non-invasive brain stimulation: building models for the clinical use of CNS active drugs

    PubMed Central

    Nitsche, Michael A; Müller-Dahlhaus, Florian; Paulus, Walter; Ziemann, Ulf

    2012-01-01

    The term neuroplasticity encompasses structural and functional modifications of neuronal connectivity. Abnormal neuroplasticity is involved in various neuropsychiatric diseases, such as dystonia, epilepsy, migraine, Alzheimer's disease, fronto-temporal degeneration, schizophrenia, and post cerebral stroke. Drugs affecting neuroplasticity are increasingly used as therapeutics in these conditions. Neuroplasticity was first discovered and explored in animal experimentation. However, non-invasive brain stimulation (NIBS) has enabled researchers recently to induce and study similar processes in the intact human brain. Plasticity induced by NIBS can be modulated by pharmacological interventions, targeting ion channels, or neurotransmitters. Importantly, abnormalities of plasticity as studied by NIBS are directly related to clinical symptoms in neuropsychiatric diseases. Therefore, a core theme of this review is the hypothesis that NIBS-induced plasticity can explore and potentially predict the therapeutic efficacy of CNS-acting drugs in neuropsychiatric diseases. We will (a) review the basics of neuroplasticity, as explored in animal experimentation, and relate these to our knowledge about neuroplasticity induced in humans by NIBS techniques. We will then (b) discuss pharmacological modulation of plasticity in animals and humans. Finally, we will (c) review abnormalities of plasticity in neuropsychiatric diseases, and discuss how the combination of NIBS with pharmacological intervention may improve our understanding of the pathophysiology of abnormal plasticity in these diseases and their purposeful pharmacological treatment. PMID:22869014

  3. Drug-induced liver injury due to antibiotics.

    PubMed

    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.

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

    PubMed

    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 < 0.001), and more likely to be type A reactions (73.5% vs. 18.8%, p < 0.001). Females were over-represented among drug-induced adverse reactions (68.1%, p < 0.001) but not among contrast media-induced adverse reactions (56.6%, p = 0.066). Causality patterns differed between the two adverse reaction classes. The World Health Organization-Uppsala Monitoring Centre causality evaluation and Naranjo algorithm results significantly differed from those of the Korean algorithm version II (p < 0.001). We found differences in sex, preventability, severity, and type A/B reactions between spontaneously reported drug and contrast media-induced adverse reactions. The World Health Organization

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

    PubMed Central

    Suh, JinUk; Yang, MyungSuk; Kang, WonKu; Kim, EunYoung

    2015-01-01

    Objective We analyzed differences between spontaneously reported drug-induced (not including contrast media) and contrast media-induced adverse reactions. Methods 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. Results Of 1,335 reports, 636 drug-induced and contrast media-induced adverse reactions were identified. The prevalence of spontaneously reported adverse drug reaction-related admissions revealed a suspected adverse drug reaction-reporting rate of 20.9/100,000 (inpatient, 0.021%) and 3.9/100,000 (outpatients, 0.004%). The most common adverse drug reaction-associated drug classes included nervous system agents and anti-infectives. Dermatological and gastrointestinal adverse drug reactions were most frequently and similarly reported between drug and contrast media-induced adverse reactions. Compared to contrast media-induced adverse reactions, drug-induced adverse reactions were milder, more likely to be preventable (9.8% vs. 1.1%, p < 0.001), and more likely to be type A reactions (73.5% vs. 18.8%, p < 0.001). Females were over-represented among drug-induced adverse reactions (68.1%, p < 0.001) but not among contrast media-induced adverse reactions (56.6%, p = 0.066). Causality patterns differed between the two adverse reaction classes. The World Health Organization–Uppsala Monitoring Centre causality evaluation and Naranjo algorithm results significantly differed from those of the Korean algorithm version II (p < 0.001). Conclusions We found differences in sex, preventability, severity, and type A/B reactions between spontaneously reported drug and contrast media-induced adverse

  6. Drug-induced life-threatening arrhythmias and sudden cardiac death: A clinical perspective of long QT, short QT and Brugada syndromes.

    PubMed

    Ramalho, Diogo; Freitas, João

    2018-05-01

    Sudden cardiac death is a major public health challenge, which can be caused by genetic or acquired structural or electrophysiological abnormalities. These abnormalities include hereditary channelopathies: long QT, short QT and Brugada syndromes. These syndromes are a notable concern, particularly in young people, due to their high propensity for severe ventricular arrhythmias and sudden cardiac death. Current evidence suggests the involvement of an increasing number of drugs in acquired forms of long QT and Brugada syndromes. However, drug-induced short QT syndrome is still a rarely reported condition. Therefore, there has been speculation on its clinical significance, since few fatal arrhythmias and sudden cardiac death cases have been described so far. Drug-induced proarrhythmia is a growing challenge for physicians, regulatory agencies and the pharmaceutical industry. Physicians should weigh the risks of potentially fatal outcomes against the therapeutic benefits, when making decisions about drug prescriptions. Growing concerns about its safety and the need for more accurate predictive models for drug-induced fatal outcomes justify further research in these fields. The aim of this article is to comprehensively and critically review the recently published evidence with regard to drug-induced life-threatening arrhythmias and sudden cardiac death. This article will take into account the provision of data to physicians that are useful in the identification of the culprit drugs, and thus, contribute to the prompt recognition and management of these serious clinical conditions. Copyright © 2018 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

  7. Terbinafine-induced lichenoid drug eruption.

    PubMed

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

    2017-03-01

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

  8. Drug-induced sexual dysfunction.

    PubMed

    Aldridge, S A

    1982-01-01

    Commonly used drugs that may cause sexual dysfunction are reviewed. The anatomy and physiology of the normal sexual response are reviewed. The influence of drugs on neurogenic, hormonal, and vascular mechanisms may result in diminished libido, impotence, ejaculatory and orgasmic difficulties, inhibited vaginal lubrication, menstrual irregularities, and gynecomastia in men or painful breast enlargement in women. Parasympatholytic agents, which interfere with cholinergic transmission, may affect erectile potency, while adrenergic inhibiting agents may interfere with ejaculatory control. Central nervous system depressants or sedating drugs, drugs producing hyperprolactinemia, and antiandrogenic drugs also may affect the normal sexual response. Drugs such as antihypertensive and antipsychotic agents may induce sexual dysfunction that can result in patient noncompliance. Usually, drug-induced side effects are reversible with discontinuation of the offending agent.

  9. Mechanistic review of drug-induced steatohepatitis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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

  10. Drug-Induced Acute Pancreatitis: A Review

    PubMed Central

    Jones, Mark R.; Hall, Oliver Morgan; Kaye, Adam M.; Kaye, Alan David

    2015-01-01

    Background The majority of drug-induced pancreatitis cases are mild to moderate in severity, but severe and even fatal cases can occur. Management of drug-induced pancreatitis requires withdrawal of the offending agent and supportive care. Methods This review focuses on differential diagnosis, clinical presentation, drug-mediated effects, treatments, and mechanisms of pancreatitis, with an emphasis on drug-induced pancreatitis. Results Although only a minority of cases associated with acute pancreatitis are linked to drugs, clinical presentation and mechanisms of injury to the pancreas are not well understood by clinicians in terms of individual drug effects in the mediation or modulation of injury to the pancreas. In recent years, a large number of commonly prescribed medications has been linked to drug-induced pancreatitis pathogenesis. Although mechanisms are proposed, the exact cause of injury is either not well understood or controversial. Conclusion Future investigation into the mechanisms of pancreatitis and an appreciation by clinicians of the drugs commonly linked to the condition will help establish earlier diagnosis and quicker cessation of offending drugs in the treatment of drug-induced acute pancreatitis. PMID:25829880

  11. [Drug-induced oral ulcerations].

    PubMed

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

    2000-06-01

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

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

    PubMed

    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.

  13. Microtubule Abnormalities Underlying Gulf War Illness in Neurons from Human-Induced Pluripotent Cells

    DTIC Science & Technology

    2016-09-01

    AWARD NUMBER: W81XWH-15-1-0433 TITLE: Microtubule Abnormalities Underlying Gulf War Illness in Neurons from Human -Induced Pluripotent Cells...2015 - 31 Aug 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Microtubule Abnormalities Underlying Gulf War Illness in Neurons from Human -Induced...functions to normal in neurons derived from human pluripotent cells exposed to Gulf War toxins. 15. SUBJECT TERMS microtubule, neuron, Gulf War Illness

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

    PubMed

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

    2008-01-28

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

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

    PubMed Central

    Niknahad, Hossein; Jamshidzadeh, Akram; Abdoli, Narges

    2014-01-01

    Methimazole and propylthiouracil have been used in the management of hyperthyroidism for more than half a century. However, hepatotoxicity is one of the most deleterious side effects associated with these medications. The mechanism(s) of hepatic injury induced by antithyroid agents is not fully recognized yet. Furthermore, there are no specific tools for predicting the occurrence of hepatotoxicity induced by these drugs. The purpose of this article is to give an overview on possible susceptibility factors in liver injury induced by antithyroid agents. Age, gender, metabolism characteristics, alcohol consumption, underlying diseases, immunologic mechanisms, and drug interactions are involved in enhancing antithyroid drugs-induced hepatic damage. An outline on the clinically used treatments for antithyroid drugs-induced hepatotoxicity and the potential therapeutic strategies found to be effective against this complication are also discussed. PMID:25320726

  16. [Drug-induced gynecomastia].

    PubMed

    Schirren, U; Hinz, B; Schirren, C

    1986-01-01

    Concerning four own observations by men in the age of 41-69 years it has been reported about the drug-induced gynecomastia. It can be demonstrated that the spironolactone induced gynecomastia disappeared after stopping this drug. The knowledge of such side effects is the condition for a pre-information of the patient at the beginning of therapy. The mode of action of spironolactone is discussed. It is referred about the important role of the disturbance of the relation androgen: estrogens under spironolactone as well as the peripheral antiandrogen effect of this substance.

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

    PubMed

    Chatterjee, Sagnik; Annaert, Pieter

    2018-04-27

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

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

    PubMed

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

    PubMed Central

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

    2012-01-01

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

  20. Abnormal experimentally- and behaviorally-induced LTP-like plasticity in focal hand dystonia.

    PubMed

    Belvisi, Daniele; Suppa, Antonio; Marsili, Luca; Di Stasio, Flavio; Parvez, Ahmad Khandker; Agostino, Rocco; Fabbrini, Giovanni; Berardelli, Alfredo

    2013-02-01

    Idiopathic focal hand dystonia (FHD) arises from abnormal plasticity in the primary motor cortex (M1) possibly reflecting abnormal sensori-motor integration processes. In this transcranial magnetic stimulation (TMS) study in FHD, we evaluated changes in motor evoked potentials (MEPs) after intermittent theta burst stimulation (iTBS) and paired associative stimulation (PAS), techniques that elicit different forms of experimentally-induced long-term potentiation (LTP)-like plasticity in M1. We also examined behaviorally-induced LTP-like plasticity as reflected by early motor learning of a simple motor task. We studied 14 patients with FHD and 14 healthy subjects. MEPs were recorded before and after iTBS and PAS at the 25 ms interstimulus interval (PAS(25)) in separate sessions. Subjects did a simple motor task entailing repetitive index finger abductions. To measure early motor learning we tested practice-related improvement in peak velocity and peak acceleration. In FHD patients iTBS failed to elicit the expected MEP changes and PAS(25) induced abnormally increased MEPs in target and non-target muscles. In the experiment testing early motor learning, patients lacked the expected practice-related changes in kinematic variables. In FHD, the degree of early motor learning correlated with patients' clinical features. We conclude that experimentally-induced (iTBS and PAS) and behaviorally-induced LTP-like plasticity are both altered in FHD. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Drug-induced Liver Injury

    PubMed Central

    David, Stefan; Hamilton, James P

    2011-01-01

    Drug-induced liver injury (DILI) is common and nearly all classes of medications can cause liver disease. Most cases of DILI are benign, and improve after drug withdrawal. It is important to recognize and remove the offending agent as quickly as possible to prevent the progression to chronic liver disease and/or acute liver failure. There are no definite risk factors for DILI, but pre-existing liver disease and genetic susceptibility may predispose certain individuals. Although most patients have clinical symptoms that are identical to other liver diseases, some patients may present with symptoms of systemic hypersensitivity. Treatment of drug and herbal-induced liver injury consists of rapid drug discontinuation and supportive care targeted to alleviate unwanted symptoms. PMID:21874146

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

    PubMed Central

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

    2008-01-01

    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. PMID:18226219

  3. Doxycycline-induced drug fever: a case report.

    PubMed

    Yuan, Hai-Ling; Lu, Ning-Wei; Xie, Hua; Zheng, Yuan-Yuan; Wang, Qiu-Hong

    2016-01-01

    Drug fever is a febrile reaction induced by a drug without additional clinical symptoms. This adverse reaction is not rare but under diagnosed and under reported. Doxycycline is a tetracycline compound with broad-spectrum antibiotic activity. Drug fever induced by doxycycline is rarely reported. In this study, we describe a patient in whom doxycycline induced drug fever after 17 days of therapy for brucellosis.

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

    PubMed

    Gholami, Kheirollah; Ziaie, Shadi; Shalviri, Gloria

    2008-01-01

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

  5. Investigation of defect-induced abnormal body current in fin field-effect-transistors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Liu, Kuan-Ju; Tsai, Jyun-Yu; Lu, Ying-Hsin

    2015-08-24

    This letter investigates the mechanism of abnormal body current at the linear region in n-channel high-k/metal gate stack fin field effect transistors. Unlike body current, which is generated by impact ionization at high drain voltages, abnormal body current was found to increase with decreasing drain voltages. Notably, the unusual body leakage only occurs in three-dimensional structure devices. Based on measurements under different operation conditions, the abnormal body current can be attributed to fin surface defect-induced leakage current, and the mechanism is electron tunneling to the fin via the defects, resulting in holes left at the body terminal.

  6. Drug-induced gynecomastia.

    PubMed

    Eckman, Ari; Dobs, Adrian

    2008-11-01

    Gynecomastia is caused by drugs in 10 - 25% of all cases. The pathophysiologic mechanism for some drugs includes exogenous estrogens exposure, medications that cause hypogonadism, anti-androgenic effects and hyperprolactinemia. This manuscript reviews common examples of drug-induced gynecomastia, discussing the mechanisms and possible treatments. Discontinuing the medication is always the best choice; however, if this is not possible, then testosterone replacement therapy may be needed for hypogonadism. When a man is euogonadal, a trial of the anti-estrogen, tamoxifen or an aromatase inhibitor may be an option.

  7. DITOP: drug-induced toxicity related protein database.

    PubMed

    Zhang, Jing-Xian; Huang, Wei-Juan; Zeng, Jing-Hua; Huang, Wen-Hui; Wang, Yi; Zhao, Rui; Han, Bu-Cong; Liu, Qing-Feng; Chen, Yu-Zong; Ji, Zhi-Liang

    2007-07-01

    Drug-induced toxicity related proteins (DITRPs) are proteins that mediate adverse drug reactions (ADRs) or toxicities through their binding to drugs or reactive metabolites. Collection of these proteins facilitates better understanding of the molecular mechanisms of drug-induced toxicity and the rational drug discovery. Drug-induced toxicity related protein database (DITOP) is such a database that is intending to provide comprehensive information of DITRPs. Currently, DITOP contains 1501 records, covering 618 distinct literature-reported DITRPs, 529 drugs/ligands and 418 distinct toxicity terms. These proteins were confirmed experimentally to interact with drugs or their reactive metabolites, thus directly or indirectly cause adverse effects or toxicities. Five major types of drug-induced toxicities or ADRs are included in DITOP, which are the idiosyncratic adverse drug reactions, the dose-dependent toxicities, the drug-drug interactions, the immune-mediated adverse drug effects (IMADEs) and the toxicities caused by genetic susceptibility. Molecular mechanisms underlying the toxicity and cross-links to related resources are also provided while available. Moreover, a series of user-friendly interfaces were designed for flexible retrieval of DITRPs-related information. The DITOP can be accessed freely at http://bioinf.xmu.edu.cn/databases/ADR/index.html. Supplementary data are available at Bioinformatics online.

  8. Pseudoephedrine induces sperm abnormalities, lower sperm counts and increased apoptosis in rat testis.

    PubMed

    Nudmamud-Thanoi, Sutisa; Thanoi, Samur

    2012-08-01

    Pseudoephedrine, an over-the-counter drug, is commonly used for the treatments of asthma, nasal congestion, and obesity. Furthermore, it can be used as a psychostimulant drug if taken in large doses; however, there have been no reports on its effects on reproduction. The aim of this study was therefore to investigate the effects of pseudoephedrine administration on sperm morphology, sperm concentration and apoptotic activity in the rat testis. Rats were administered intraperitoneally (IP) with pseudoephedrine at 120 mg/kg for the acute group and 80 mg/kg, IP, once daily for 15 days for the chronic group, while a control group was treated with vehicle. The percentages of normal sperm morphology were significantly decreased in both acute and chronic groups when compared with controls while the total sperm count was significantly decreased in the acute group. Apoptotic activities were increased significantly in both pseudoephedrine-treated groups. The results indicate that pseudoephedrine can induce sperm abnormalities, decrease sperm numbers and increase apoptotic activity in the testis of rats if taken at high doses. The results of this study suggest that the users of pseudoephedrine in medical treatments need to be aware of its potential toxicity involving spermatogenesis.

  9. A review and assessment of drug-induced parotitis.

    PubMed

    Brooks, Krista G; Thompson, Dennis F

    2012-12-01

    To review the current literature on drug-induced parotitis. Literature was accessed through MEDLINE/PubMed (1980-May 2012), using the search terms sialadenitis/chemically induced and parotitis/chemically induced. EMBASE (1980-May 2012) was searched using the terms parotitis/diagnosis, sialadenitis/side effect, and parotitis/side effect. International Pharmaceutical Abstracts (1970-May 2012) was searched using the search terms parotitis and sialadenitis. All searches were limited to articles on humans written in English. Inclusion criteria were published letters, case reports, reviews, and clinical trials involving drugs that may be associated with parotitis. Articles pertaining to parotitis induced by iodine-containing drugs were excluded. References of all relevant articles were reviewed for additional citations. Review articles, clinical trials, background data, and case reports of drug-induced parotitis were collected and case reports were assessed for causality. Parotitis is an uncommon adverse effect; however, signs and symptoms of parotitis have been noted in case reports as an adverse drug reaction related to various medications. Assessing causality of an adverse drug reaction such as parotitis is challenging. To help determine the probability of causality for these events, algorithms such as the Naranjo probability scale have been developed. Eighty-four case reports of drug-induced parotitis from 40 different drugs were reviewed using a modified Naranjo probability scale that included criteria specific for parotitis. Medications that met the criteria for establishing causality included l-asparaginase with 7 case reports, clozapine with 13 case reports, and phenylbutazone with 13 case reports. Drug-induced parotitis is a rare adverse drug reaction. Based on the quantitative and qualitative evidence collected from the case reports, medications that are associated with drug-induced parotitis include l-asparaginase, clozapine, and phenylbutazone. Many other

  10. Drug-Induced Hyperglycaemia and Diabetes.

    PubMed

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

    2015-12-01

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

  11. HLA Association with Drug-Induced Adverse Reactions

    PubMed Central

    Fan, Wen-Lang; Shiao, Meng-Shin; Hui, Rosaline Chung-Yee; Wang, Chuang-Wei; Chang, Ya-Ching

    2017-01-01

    Adverse drug reactions (ADRs) remain a common and major problem in healthcare. Severe cutaneous adverse drug reactions (SCARs), such as Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) with mortality rate ranges from 10% to more than 30%, can be life threatening. A number of recent studies demonstrated that ADRs possess strong genetic predisposition. ADRs induced by several drugs have been shown to have significant associations with specific alleles of human leukocyte antigen (HLA) genes. For example, hypersensitivity to abacavir, a drug used for treating of human immunodeficiency virus (HIV) infection, has been proposed to be associated with allele 57:01 of HLA-B gene (terms HLA-B∗57:01). The incidences of abacavir hypersensitivity are much higher in Caucasians compared to other populations due to various allele frequencies in different ethnic populations. The antithyroid drug- (ATDs- ) induced agranulocytosis are strongly associated with two alleles: HLA-B∗38:02 and HLA-DRB1∗08:03. In addition, HLA-B∗15:02 allele was reported to be related to carbamazepine-induced SJS/TEN, and HLA-B∗57:01 in abacavir hypersensitivity and flucloxacillin induced drug-induced liver injury (DILI). In this review, we summarized the alleles of HLA genes which have been proposed to have association with ADRs caused by different drugs. PMID:29333460

  12. [Posterior reversible encephalopathy syndrome induced by a cough and cold drug containing pseudoephedrine].

    PubMed

    Ebbo, M; Benarous, L; Thomas, G; Jourde, N; Genot, S; Bernit, E; Veit, V; Harlé, J-R; Schleinitz, N

    2010-06-01

    Posterior reversible encephalopathy syndrome is a clinico-radiological entity characterized by neurologic symptoms in association with usually reversible bilateral posterior hemispheric oedema on neuroimaging. Many pathological conditions and treatments have been associated with this syndrome. We report a 19-year-old woman, followed-up for hypocomplementemic urticarial vasculitis, who presented with a posterior reversible encephalopathy syndrome induced by the intake of an over-the-counter cold remedy containing pseudoephedrine. Clinical manifestations and radiological abnormalities resolved after anti-hypertensive therapy and withdrawal of sympathomimetic drug. The diagnosis of posterior reversible encephalopathy syndrome should be considered in patients with compatible clinical and radiological presentation because of its potential reversibility with an appropriate management. Intake of drugs, including over-the-counter cough and cold drugs, should be looked for in the history as well as autoimmune disorders. Copyright 2010 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

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

    PubMed Central

    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. PMID:24904300

  14. Mechanisms of Adaptation and Progression in Idiosyncratic Drug Induced Liver Injury, Clinical Implications

    PubMed Central

    Dara, Lily; Liu, Zhang-Xu; Kaplowitz, Neil

    2015-01-01

    In the past decade our understanding of idiosyncratic drug induced liver injury (IDILI) and the contribution of genetic susceptibility and the adaptive immune system to the pathogenesis of this disease process has grown tremendously. One of the characteristics of IDILI is that it occurs rarely and only in a subset of individuals with a presumed susceptibility to the drug. Despite a clear association between single nucleotide polymorphisms in human leukocyte antigen (HLA) genes and certain drugs that cause IDILI, not all individuals with susceptible HLA genotypes develop clinically significant liver injury when exposed to drugs. The adaptation hypothesis has been put forth as an explanation for why only a small percentage of susceptible individuals develop overt IDILI and severe injury, while the majority with susceptible genotypes develop only mild abnormalities that resolve spontaneously upon continuation of the drug. This spontaneous resolution is referred to as clinical adaptation. Failure to adapt or defective adaptation leads to clinically significant liver injury. In this review we explore the immuno-tolerant microenvironment of the liver and the mechanisms of clinical adaptation in IDILI with a focus on the role of immune-tolerance and cellular adaptive responses. PMID:26484420

  15. 21 CFR 864.7415 - Abnormal hemoglobin assay.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Abnormal hemoglobin assay. 864.7415 Section 864.7415 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Hematology Kits and Packages § 864.7415 Abnormal...

  16. 21 CFR 864.7415 - Abnormal hemoglobin assay.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Abnormal hemoglobin assay. 864.7415 Section 864.7415 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Hematology Kits and Packages § 864.7415 Abnormal...

  17. 21 CFR 864.7415 - Abnormal hemoglobin assay.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Abnormal hemoglobin assay. 864.7415 Section 864.7415 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Hematology Kits and Packages § 864.7415 Abnormal...

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

    PubMed

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

    2016-04-01

    DAT-SPECT, is a well-established procedure for distinguishing drug-induced parkinsonism from Parkinson's disease (PD). We investigated the usefulness of blink reflex recovery cycle (BRrc) and of electromyographic parameters of resting tremor for the differentiation of patients with drug-induced parkinsonism with resting tremor (rDIP) from those with resting tremor due to PD. This was a cross-sectional study. In 16 patients with rDIP and 18 patients with PD we analysed electrophysiological parameters (amplitude, duration, burst and pattern) of resting tremor. BRrc at interstimulus intervals (ISI) of 100, 150, 200, 300, 400, 500 and 750 msec was also analysed in patients with rDIP, patients with PD and healthy controls. All patients and controls underwent DAT-SPECT. Rest tremor amplitude was higher in PD patients than in rDIP patients (p < 0.001), while frequency and burst duration were higher in rDIP than in PD (p < 0.001, p < 0.003, respectively). Resting tremor showed a synchronous pattern in all patients with rDIP, whereas it had an alternating pattern in all PD patients (p < 0.001). DAT-SPECT was normal in rDIP patients while it was markedly abnormal in patients with PD. In the absence of DAT-SPECT, the pattern of resting tremor can be considered a useful investigation for differentiating rDIP from PD. Copyright © 2016. Published by Elsevier Ltd.

  19. [Prospective study of drug-induced interstitial nephritis in eleven French nephrology units].

    PubMed

    Leven, Cyril; Hudier, Laurent; Picard, Sylvie; Longuet, Hélène; Lorcy, Nolwenn; Cam, Gérard; Boukerroucha, Zakaria; Dolley-Hitze, Thibault; Le Cacheux, Philippe; Halimi, Jean-Michel; Cornec Le Gall, Emilie; Hanrotel-Saliou, Catherine; Arreule, Audrey; Massad, Michel; Duveau, Agnès; Couvrat-Desvergnes, Grégoire; Renaudineau, Eric

    2014-11-01

    Certain medications have been associated with drug-induced acute interstitial nephritis (AIN), but few prospective studies have been published. This prospective observational study aims to record and assess incidents of drug-induced AIN observed over a period of one year in nephrology units in France. The goal is to determine which medications are involved in AIN and to expound the clinical and biological presentation, management, and evolution of AIN. Between April 2012 and April 2013, drug-associated cases of AIN were prospectively recorded in 24 patients registered in 11 nephrology units that belong to the Société de Néphrologie de l'Ouest (SNO). Data sheets, including suspected and concomitant drug(s), kidney function assessment, biological disturbances, clinical signs, histological data, management, and evolution, were collected by the Rennes Regional Pharmacovigilance Center and recorded in the French pharmacovigilance database. In order, the most frequently involved medications in the AIN cases were: vitamin K antagonists (33.3% of the cases, almost exclusively fluindione), antibiotics (20.8% of cases) non-steroidal anti-inflammatory drugs (20.8% of cases), and proton pump inhibitors (16.7% of cases). The mean delay of onset to AIN was 8.3 weeks. At the time of diagnosis, mean serum creatinine was 366 μM, higher for vitamin K antagonists (VKAs), except in the case of warfarin. During the course of an AIN event, 70% of patients had complete blood count and/or urine analysis abnormalities, 55% had clinical signs of systemic hypersensitivity, and 13% of patients had hepatic disorders. Renal biopsies were performed in 54% of patients; however, only 37% of patients requiring therapeutic anticoagulation underwent a biopsy. Suspected drugs were discontinued in all patients and the majority was treated with oral corticosteroids. Renal function often continued to be impaired after an AIN event. At baseline, 25% of patients had chronic kidney disease (CKD); after

  20. Abnormal Neural Progenitor Cells Differentiated from Induced Pluripotent Stem Cells Partially Mimicked Development of TSC2 Neurological Abnormalities.

    PubMed

    Li, Yaqin; Cao, Jiqing; Chen, Menglong; Li, Jing; Sun, Yiming; Zhang, Yu; Zhu, Yuling; Wang, Liang; Zhang, Cheng

    2017-04-11

    Tuberous sclerosis complex (TSC) is a disease featuring devastating and therapeutically challenging neurological abnormalities. However, there is a lack of specific neural progenitor cell models for TSC. Here, the pathology of TSC was studied using primitive neural stem cells (pNSCs) from a patient presenting a c.1444-2A>C mutation in TSC2. We found that TSC2 pNSCs had higher proliferative activity and increased PAX6 expression compared with those of control pNSCs. Neurons differentiated from TSC2 pNSCs showed enlargement of the soma, perturbed neurite outgrowth, and abnormal connections among cells. TSC2 astrocytes had increased saturation density and higher proliferative activity. Moreover, the activity of the mTOR pathway was enhanced in pNSCs and induced in neurons and astrocytes. Thus, our results suggested that TSC2 heterozygosity caused neurological malformations in pNSCs, indicating that its heterozygosity might be sufficient for the development of neurological abnormalities in patients. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  1. Drug-induced gynecomastia in children and adolescents

    PubMed Central

    Goldman, Ran D.

    2010-01-01

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

  2. Drug-induced gynecomastia in children and adolescents.

    PubMed

    Goldman, Ran D

    2010-04-01

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

  3. Environmentally toxicant exposures induced intragenerational transmission of liver abnormalities in mice

    PubMed Central

    Al-Griw, Mohamed A.; Treesh, Soad A.; Alghazeer, Rabia O.; Regeai, Sassia O.

    2017-01-01

    Environmental toxicants such as chemicals, heavy metals, and pesticides have been shown to promote transgenerational inheritance of abnormal phenotypes and/or diseases to multiple subsequent generations following parental and/or ancestral exposures. This study was designed to examine the potential transgenerational action of the environmental toxicant trichloroethane (TCE) on transmission of liver abnormality, and to elucidate the molecular etiology of hepatocyte cell damage. A total of thirty two healthy immature female albino mice were randomly divided into three equal groups as follows: a sham group, which did not receive any treatment; a vehicle group, which received corn oil alone, and TCE treated group (3 weeks, 100 μg/kg i.p., every 4th day). The F0 and F1 generation control and TCE populations were sacrificed at the age of four months, and various abnormalities histpathologically investigated. Cell death and oxidative stress indices were also measured. The present study provides experimental evidence for the inheritance of environmentally induced liver abnormalities in mice. The results of this study show that exposure to the TCE promoted adult onset liver abnormalities in F0 female mice as well as unexposed F1 generation offspring. It is the first study to report a transgenerational liver abnormalities in the F1 generation mice through maternal line prior to gestation. This finding was based on careful evaluation of liver histopathological abnormalities, apoptosis of hepatocytes, and measurements of oxidative stress biomarkers (lipid peroxidation, protein carbonylation, and nitric oxide) in control and TCE populations. There was an increase in liver histopathological abnormalities, cell death, and oxidative lipid damage in F0 and F1 hepatic tissues of TCE treated group. In conclusion, this study showed that the biological and health impacts of environmental toxicant TCE do not end in maternal adults, but are passed on to offspring generations. Hence

  4. Human In Silico Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical Pro-Arrhythmic Cardiotoxicity.

    PubMed

    Passini, Elisa; Britton, Oliver J; Lu, Hua Rong; Rohrbacher, Jutta; Hermans, An N; Gallacher, David J; Greig, Robert J H; Bueno-Orovio, Alfonso; Rodriguez, Blanca

    2017-01-01

    Early prediction of cardiotoxicity is critical for drug development. Current animal models raise ethical and translational questions, and have limited accuracy in clinical risk prediction. Human-based computer models constitute a fast, cheap and potentially effective alternative to experimental assays, also facilitating translation to human. Key challenges include consideration of inter-cellular variability in drug responses and integration of computational and experimental methods in safety pharmacology. Our aim is to evaluate the ability of in silico drug trials in populations of human action potential (AP) models to predict clinical risk of drug-induced arrhythmias based on ion channel information, and to compare simulation results against experimental assays commonly used for drug testing. A control population of 1,213 human ventricular AP models in agreement with experimental recordings was constructed. In silico drug trials were performed for 62 reference compounds at multiple concentrations, using pore-block drug models (IC 50 /Hill coefficient). Drug-induced changes in AP biomarkers were quantified, together with occurrence of repolarization/depolarization abnormalities. Simulation results were used to predict clinical risk based on reports of Torsade de Pointes arrhythmias, and further evaluated in a subset of compounds through comparison with electrocardiograms from rabbit wedge preparations and Ca 2+ -transient recordings in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). Drug-induced changes in silico vary in magnitude depending on the specific ionic profile of each model in the population, thus allowing to identify cell sub-populations at higher risk of developing abnormal AP phenotypes. Models with low repolarization reserve (increased Ca 2+ /late Na + currents and Na + /Ca 2+ -exchanger, reduced Na + /K + -pump) are highly vulnerable to drug-induced repolarization abnormalities, while those with reduced inward current density

  5. Drug-induced uveitis

    PubMed Central

    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

  6. Mechanism of gastrointestinal abnormal motor activity induced by cisplatin in conscious dogs.

    PubMed

    Ando, Hiroyuki; Mochiki, Erito; Ohno, Tetsuro; Yanai, Mitsuhiro; Toyomasu, Yoshitaka; Ogata, Kyoichi; Tabe, Yuichi; Aihara, Ryuusuke; Nakabayashi, Toshihiro; Asao, Takayuki; Kuwano, Hiroyuki

    2014-11-14

    To investigate whether 5-hydroxytryptamine (serotonin; 5-HT) is involved in mediating abnormal motor activity in dogs after cisplatin administration. After the dogs had been given a 2-wk recovery period, all of them were administered cisplatin, and the motor activity was recorded using strain gauge force transducers. Blood and intestinal fluid samples were collected to measure 5-HT for 24 h. To determine whether 5-HT in plasma or that in intestinal fluids is more closely related to abnormal motor activity we injected 5-HT into the bloodstream and the intestinal tract of the dogs. Cisplatin given intravenously produced abnormal motor activity that lasted up to 5 h. From 3 to 4 h after cisplatin administration, normal intact dogs exhibited retropropagation of motor activity accompanied by emesis. The concentration of 5-HT in plasma reached the peak at 4 h, and that in intestinal fluids reached the peak at 3 h. In normal intact dogs with resection of the vagus nerve that were administered kytril, cisplatin given intravenously did not produce abnormal motor activity. Intestinal serotonin administration did not produce abnormal motor activity, but intravenous serotonin administration did. After the intravenous administration of cisplatin, abnormal motor activity was produced in the involved vagus nerve and in the involved serotonergic neurons via another pathway. This study was the first to determine the relationship between 5-HT and emesis-induced motor activity.

  7. Drug-induced corneal damage.

    PubMed

    2014-04-01

    Corneal damage can have a variety of causes, including infections, chemical splashes, environmental factors (radiation, trauma, contact lenses, etc.), and systemic diseases (genetic, autoimmune, inflammatory, metabolic, etc.). A wide range of drugs can also damage the cornea. The severity of drug-induced corneal changes can range from simple asymptomatic deposits to irreversible, sight-threatening damage. Several factors can influence the onset of corneal lesions. Some factors, such as the dose, are treatment-related, while others such as contact lenses, are patient-related. A variety of mechanisms may be involved, including corneal dryness, changes in the corneal epithelium, impaired wound healing and deposits. Many drugs can damage the cornea through direct contact, after intraocular injection or instillation, including VEGF inhibitors, anti-inflammatory drugs, local anaesthetics, glaucoma drugs, fluoroquinolones, and preservatives. Some systemically administered drugs can also damage the cornea, notably cancer drugs, amiodarone and isotretinoin. Vulnerable patients should be informed of this risk if they are prescribed a drug with the potential to damage the cornea so that they can identify problems in a timely manner. It may be necessary to discontinue the suspect drug when signs and symptoms of corneal damage occur.

  8. Specific limb abnormalities induced by hydrogen peroxide in tadpoles of Indian jumping frog, Polypedates maculatus.

    PubMed

    Mahapatra, P K; Mohanty-Hejmadi, P; Chainy, G B

    2001-11-01

    Hydrogen peroxide (H2O2), one of the reactive oxygen intermediates (ROI) and a potential inducer of nuclear transcription factors induces consistent type of abnormal limb development (truncated with bent skeletal elements) in the tadpoles of Indian jumping frog, Polypedates maculatus.

  9. Vitiligo, drug induced (image)

    MedlinePlus

    ... 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 ...

  10. The nature of neuroendocrine abnormalities in depression: a controversial issue in contemporary psychiatry.

    PubMed

    von Zerssen, D; Berger, M; Dose, M; Doerr, P; Krieg, C; Bossert, S; Riemann, D; Pirke, K M; Dolhofer, R; Müller, O A

    1986-01-01

    Neuroendocrine abnormalities in depression have been regarded, by many authors, as relatively specific markers of nosological subtypes of the disorder, e.g. primary vs. secondary, endogenous vs. non-endogenous or unipolar vs. bipolar depression. They should reflect the same changes in central neurotransmitters (e.g. noradrenergic insufficiency and/or cholinergic hyperactivity) that were hypothesized as the cause of clinical symptoms. This view is challenged on the basis of our own neuroendocrine investigations in 317 psychiatric patients and 103 normal controls. According to these studies the abnormalities are nosologically rather unspecific. They are induced by a large variety of factors, e.g. emotional stress associated with the clinical symptomatology, weight loss due to malnutrition as a consequence of reduced appetite, medication and drug withdrawal. Stress-induced hypercortisolism appears to be the most common abnormality that may trigger other neuroendocrine dysfunctions, such as a blunted TSH response to TRH. Differences in neuroendocrine abnormalities of depressives are probably due to variations in the manifold factors influencing the hormonal axes involved, to temporal changes in hormonal patterns (e.g. one abnormality triggering another) and to individual differences in the basic activity and the responsiveness of the various axes.

  11. One patient with schizophrenia showed reduced drug-induced extrapyramidal symptoms as a result of an alternative regimen of treatment with paliperidone 3 and 6 mg every other day.

    PubMed

    Suzuki, Hidenobu; Hibino, Hiroyuki; Inoue, Yuichi; Matsumoto, Hideo; Mikami, Katsunaka

    2017-01-01

    Schizophrenia is a chronic disease that requires long-term management with antipsychotics. Antipsychotic drugs are given by tapering their dose, extending the dosing interval, and so on, as part of a treatment strategy to minimize the adverse effects while at the same time maintaining efficacy. We report the case of one patient with schizophrenia in whom the clinical symptoms were alleviated after treatment with 6 mg paliperidone. However, the patient developed extrapyramidal syndrome, for which 3 and 6 mg paliperidone were administered alternately every other day. Extrapyramidal syndrome was assessed using the Drug-Induced Extrapyramidal Symptoms Scale, Abnormal Involuntary Movement Scale, or Barnes Akathisia Scale. There was improvement in Drug-Induced Extrapyramidal Symptoms Scale score and Abnormal Involuntary Movement Scale score. However, there was almost no change in the Positive and Negative Syndrome Scale total score, positive score, negative score, or general score. The results indicate the possibility of lessened adverse effects as a result of an alternative regimen of treatment with paliperidone 3 and 6 mg every other day in the maintenance phase.

  12. Drug-induced sarcoidosis-like reactions (DISR).

    PubMed

    Chopra, Amit; Nautiyal, Amit; Kalkanis, Alexander; Judson, Marc A

    2018-04-23

    A drug-induced sarcoidosis-like reaction (DISR) is a systemic granulomatous reaction that is indistinguishable from sarcoidosis and occurs in temporal relationship with initiation of an offending drug. DISRs typically improve or resolve after the withdrawal of offending drug. Four common categories of drugs that have been associated with the development of a DISR are immune checkpoint inhibitors (ICIs), highly active anti-retroviral therapy (HAART), interferons (IFNs) and tumor necrosis factor alpha antagonists (TNF-alpha antagonists). Similar to sarcoidosis, DISRs do not necessarily require treatment, as they may cause no significant symptoms, quality of life impairment or organ dysfunction. When treatment of a DISR is required, standard anti-sarcoidosis regimens seem to be effective. As a DISR tends to improve or resolve when the offending drug is discontinued, this is another effective treatment for a DISR. However, the offending drug need not be discontinued if it is useful, and anti-granulomatous therapy can be added. In some situations, the development of a DISR may suggest a beneficial effect of the inducing drug. Understanding the mechanisms leading to DISRs may yield important insights into the immunopathogenesis of sarcoidosis. Copyright © 2018. Published by Elsevier Inc.

  13. Mechanism of gastrointestinal abnormal motor activity induced by cisplatin in conscious dogs

    PubMed Central

    Ando, Hiroyuki; Mochiki, Erito; Ohno, Tetsuro; Yanai, Mitsuhiro; Toyomasu, Yoshitaka; Ogata, Kyoichi; Tabe, Yuichi; Aihara, Ryuusuke; Nakabayashi, Toshihiro; Asao, Takayuki; Kuwano, Hiroyuki

    2014-01-01

    AIM: To investigate whether 5-hydroxytryptamine (serotonin; 5-HT) is involved in mediating abnormal motor activity in dogs after cisplatin administration. METHODS: After the dogs had been given a 2-wk recovery period, all of them were administered cisplatin, and the motor activity was recorded using strain gauge force transducers. Blood and intestinal fluid samples were collected to measure 5-HT for 24 h. To determine whether 5-HT in plasma or that in intestinal fluids is more closely related to abnormal motor activity we injected 5-HT into the bloodstream and the intestinal tract of the dogs. RESULTS: Cisplatin given intravenously produced abnormal motor activity that lasted up to 5 h. From 3 to 4 h after cisplatin administration, normal intact dogs exhibited retropropagation of motor activity accompanied by emesis. The concentration of 5-HT in plasma reached the peak at 4 h, and that in intestinal fluids reached the peak at 3 h. In normal intact dogs with resection of the vagus nerve that were administered kytril, cisplatin given intravenously did not produce abnormal motor activity. Intestinal serotonin administration did not produce abnormal motor activity, but intravenous serotonin administration did. CONCLUSION: After the intravenous administration of cisplatin, abnormal motor activity was produced in the involved vagus nerve and in the involved serotonergic neurons via another pathway. This study was the first to determine the relationship between 5-HT and emesis-induced motor activity. PMID:25400453

  14. Drug-induced Epistaxis: An Often-Neglected Adverse Effect.

    PubMed

    Meirinho, Sara; Relvas, Ricardo; Alves, Gilberto

    2018-02-12

    Epistaxis is an active nose bleeding with a population occurrence of approximately 60%. Although epistaxis is a common clinical complaint, the majority of the cases are benign and caused by local induced factors (e.g., trauma and local inflammation). Nevertheless, it is also recognised that epistaxis can be induced after some drugs intake. Due to the increasing use of drugs or drug combinations that potentially may induce epistaxis, this review aims to alert healthcare professionals for this often neglected adverse drug effect and its possible complications. A comprehensive literature search was performed on PubMed and Google Scholar databases, considering the literature published from January 1985 to December 2015, using medical terms related to the scope of drug-induced epistaxis, nosebleeds and nasal blood supply. As expected, anticoagulant and antiplatelet drugs are the main pharmacotherapeutic agents associated with epistaxis, particularly warfarin, dabigatran, rivaroxaban and aspirin. However, it was reported that some selective serotonin reuptake inhibitors, intranasal corticosteroids, certain antibiotics and other drugs or drug associations can also be responsible by nosebleeds. Although most of these epistaxis episodes are mild to moderate, being spontaneously reversed or requiring only minor medical approaches to control it, there are also several case reports, as well as retrospective and prospective studies, documenting severe epistaxis episodes after specific medicines intake. In these cases some invasive medical interventions are demanded to manage the bleeding and avoid life-threatening consequences. This work provides an integrated and comprehensive review on drug-induced epistaxis bridging the gap in the current scientific literature addressing this topic. Therefore, the scientific information gathered and discussed will be valuable to raise awareness of doctors and pharmacists for this drug-related problem, as well as to promote their active

  15. Nonacetaminophen Drug-Induced Acute Liver Failure.

    PubMed

    Thomas, Arul M; Lewis, James H

    2018-05-01

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

  16. Drug induced acute pancreatitis: incidence and severity.

    PubMed Central

    Lankisch, P G; Dröge, M; Gottesleben, F

    1995-01-01

    To determine the incidence and severity of drug induced acute pancreatitis, data from 45 German centres of gastroenterology were evaluated. Among 1613 patients treated for acute pancreatitis in 1993, drug induced acute pancreatitis was diagnosed in 22 patients (incidence 1.4%). Drugs held responsible were azathioprine, mesalazine/sulfasalazine, 2',3'-dideoxyinosine (ddI), oestrogens, frusemide, hydrochlorothiazide, and rifampicin. Pancreatic necrosis not exceeding 33% of the organ was found on ultrasonography or computed tomography, or both, in three patients (14%). Pancreatic pseudocysts did not occur. A decrease of arterial PO2 reflecting respiratory insufficiency, and an increase of serum creatinine, reflecting renal insufficiency as complications of acute pancreatitis were seen in two (9%) and four (18%) patients, respectively. Artificial ventilation was not needed, and dialysis was necessary in only one (5%) case. Two patients (9%) died of AIDS and tuberculosis, respectively; pancreatitis did not seem to have contributed materially to their death. In conclusion, drugs rarely cause acute pancreatitis, and drug induced acute pancreatitis usually runs a benign course. PMID:7489946

  17. Electrocardiographic abnormalities in opiate addicts.

    PubMed

    Wallner, Christina; Stöllberger, Claudia; Hlavin, Anton; Finsterer, Josef; Hager, Isabella; Hermann, Peter

    2008-12-01

    To determine in a cross-sectional study the prevalence of electrocardiographic (ECG) abnormalities in opiate addicts who were therapy-seeking and its association with demographic, clinical and drug-specific parameters. In consecutive therapy-seeking opiate addicts, a 12-lead ECG was registered within 24 hours after admission and evaluated according to a pre-set protocol between October 2004 and August 2006. Additionally, demographic, clinical and drug-specific parameters were recorded. Included were 511 opiate-addicts, 25% female, with a mean age of 29 years (range 17-59 years). One or more ECG abnormalities were found in 314 patients (61%). In the 511 patients we found most commonly ST abnormalities (19%), QTc prolongation (13%), tall R- and/or S-waves (11%) and missing R progression (10%). ECG abnormalities were more common in males than in females (64 versus 54%, P < 0.05), and in patients with positive than negative urine findings for cannabis (68 versus 57%, P < 0.05). Patients with ST abnormalities were more often males than females (21 versus 11%, P < 0.05), had a history of seizures less often (16 versus 27%, P < 0.05), had positive than negative urine findings for cannabis more often (26 versus 15%, P < 0.01) and had negative than positive urine findings for methadone more often (21 versus 11%, P < 0.05). QTc prolongation was more frequent in patients with high dosages of maintenance drugs than in patients with medium or low dosages (27 versus 12 versus 10%, P < 0.05) and in patients whose urine findings were positive than negative for methadone (23 versus 11%, P < 0.001) as well as for benzodiazepines (17 versus 9%, P < 0.05). Limitations of the data are that in most cases other risk factors for the cardiac abnormalities were not known. ECG abnormalities are frequent in opiate addicts. The most frequent ECG abnormalities are ST abnormalities, QTc prolongation and tall R- and/or S-waves. ST abnormalities are associated with cannabis, and QTc prolongation

  18. Flecainide-induced proarrhythmia is attributed to abnormal changes in repolarization and refractoriness in perfused guinea-pig heart.

    PubMed

    Osadchii, Oleg E

    2012-11-01

    Flecainide is nonselective Na(+) channel blocker which may also inhibit I(Kr), the rapid component of the delayed rectifier. This study was designed to explore if proarrhythmic responses to flecainide noted in cardiac patients may be partly attributed to abnormal changes in repolarization and refractoriness. Monophasic action potential duration (APD) and effective refractory periods (ERP) were assessed at distinct epicardial and endocardial sites along with volume-conducted ECG recordings in isolated perfused guinea-pig heart preparations. Flecainide was found to prolong ventricular repolarization, with effect being greater at the left ventricular compared with the right ventricular epicardium. This change translated to reversal of the normal right ventricular-to-left ventricular transepicardial APD difference determined before drug infusion. An inverse correlation between local epicardial APD and corresponding activation time values seen at baseline was eliminated in flecainide-treated hearts, indicating the activation-to-repolarization uncoupling. Over transmural plane, flecainide produced a greater ERP lengthening at endocardium than epicardium, thus markedly increasing ERP dispersion across ventricular wall. Spontaneous short-lasting episodes of monomorphic ventricular tachycardia were observed in 45% of heart preparations upon flecainide infusion. In conclusion, in nonischemic guinea-pig heart, flecainide-induced proarrhythmia may be partly attributed to abnormal spatial gradients in repolarization and refractoriness and impaired transepicardial activation-to-repolarization coupling.

  19. Thrombin impairs human endometrial endothelial angiogenesis; implications for progestin-only contraceptive-induced abnormal uterine bleeding.

    PubMed

    Shapiro, John P; Guzeloglu-Kayisli, Ozlem; Kayisli, Umit A; Semerci, Nihan; Huang, S Joseph; Arlier, Sefa; Larsen, Kellie; Fadda, Paolo; Schatz, Frederick; Lockwood, Charles J

    2017-06-01

    Progestin-only contraceptives induce abnormal uterine bleeding, accompanied by prothrombin leakage from dilated endometrial microvessels and increased thrombin generation by human endometrial stromal cell (HESC)-expressed tissue factor. Initial studies of the thrombin-treated HESC secretome identified elevated levels of cleaved chondroitin sulfate proteoglycan 4 (CSPG4), impairing pericyte-endothelial interactions. Thus, we investigated direct and CSPG4-mediated effects of thrombin in eliciting abnormal uterine bleeding by disrupting endometrial angiogenesis. Liquid chromatography/tandem mass spectrometry, enzyme-linked immunosorbent assay (ELISA) and quantitative real-time-polymerase chain reaction (PCR) evaluated conditioned medium supernatant and cell lysates from control versus thrombin-treated HESCs. Pre- and post-Depo medroxyprogesterone acetate (DMPA)-administered endometria were immunostained for CSPG4. Proliferation, apoptosis and tube formation were assessed in human endometrial endothelial cells (HEECs) incubated with recombinant human (rh)-CSPG4 or thrombin or both. Thrombin induced CSPG4 protein expression in cultured HESCs as detected by mass spectrometry and ELISA (p<.02, n=3). Compared to pre-DMPA endometria (n=5), stromal cells in post-DMPA endometria (n=5) displayed stronger CSPG4 immunostaining. In HEEC cultures (n=3), total tube-formed mesh area was significantly higher in rh-CSPG4 versus control (p<.05). However, thrombin disrupted HEEC tube formation by a concentration- and time-dependent reduction of angiogenic parameters (p<.05), whereas CSPG4 co-treatment did not reverse these thrombin-mediated effects. These results suggest that disruption of HEEC tube formation by thrombin induces aberrant angiogenesis and abnormal uterine bleeding in DMPA users. Mass spectrometry analysis identified several HESC-secreted proteins regulated by thrombin. Therapeutic agents blocking angiogenic effects of thrombin in HESCs can prevent or minimize progestin

  20. 5-Mehtyltetrahydrofolate rescues alcohol-induced neural crest cell migration abnormalities.

    PubMed

    Shi, Yu; Li, Jiejing; Chen, Chunjiang; Gong, Manzi; Chen, Yuan; Liu, Youxue; Chen, Jie; Li, Tingyu; Song, Weihong

    2014-09-16

    Alcohol is detrimental to early development. Fetal alcohol spectrum disorders (FASD) due to maternal alcohol abuse results in a series of developmental abnormalities including cranial facial dysmorphology, ocular anomalies, congenital heart defects, microcephaly and intellectual disabilities. Previous studies have been shown that ethanol exposure causes neural crest (NC) apoptosis and perturbation of neural crest migration. However, the underlying mechanism remains elusive. In this report we investigated the fetal effect of alcohol on the process of neural crest development in the Xenopus leavis. Pre-gastrulation exposure of 2-4% alcohol induces apoptosis in Xenopus embryo whereas 1% alcohol specifically impairs neural crest migration without observing discernible apoptosis. Additionally, 1% alcohol treatment considerably increased the phenotype of small head (43.4% ± 4.4%, total embryo n = 234), and 1.5% and 2.0% dramatically augment the deformation to 81.2% ± 6.5% (n = 205) and 91.6% ± 3.0% (n = 235), respectively (P < 0.05). Significant accumulation of Homocysteine was caused by alcohol treatment in embryos and 5-mehtyltetrahydrofolate restores neural crest migration and alleviates homocysteine accumulation, resulting in inhibition of the alcohol-induced neurocristopathies. Our study demonstrates that prenatal alcohol exposure causes neural crest cell migration abnormality and 5-mehtyltetrahydrofolate could be beneficial for treating FASD.

  1. Idiosyncratic drug-induced agranulocytosis or acute neutropenia.

    PubMed

    Andrès, Emmanuel; Maloisel, Frédéric

    2008-01-01

    Idiosyncratic drug-induced agranulocytosis or acute neutropenia is an adverse event resulting in a neutrophil count of under 0.5 x 10/l. Patients with such severe neutropenia are likely to experience life-threatening and sometimes fatal infections. Over the last 20 years, the incidence of idiosyncratic drug-induced agranulocytosis or acute neutropenia has remained stable at 2.4-15.4 cases per million, despite the emergence of new causative drugs: antibiotics (beta-lactam and cotrimoxazole), antiplatelet agents (ticlopidine), antithyroid drugs, sulfasalazine, neuroleptics (clozapine), antiepileptic agents (carbamazepine), nonsteroidal anti-inflammatory agents and dipyrone. Drug-induced agranulocytosis remains a serious adverse event due to the occurrence of severe sepsis with severe deep infections (such as pneumonia), septicemia and septic shock in around two thirds of patients. In this setting, old age (>65 years), septicemia or shock, metabolic disorders such as renal failure, and a neutrophil count under 0.1 x 10/l are poor prognostic factors. Nevertheless with appropriate management using preestablished procedures, with intravenous broad-spectrum antibiotic therapy and hematopoietic growth factors, the mortality rate is currently around 5%. Given the increased life expectancy and subsequent longer exposure to drugs, as well as the development of new agents, healthcare professionals should be aware of this adverse event and its management.

  2. Drug-induced lupus erythematosus.

    PubMed

    Marzano, A V; Tavecchio, S; Menicanti, C; Crosti, C

    2014-06-01

    Drug-induced lupus erythematosus (DI-LE) is defined as an entity characterized by clinical manifestations and immunopathological serum findings similar to those of idiopathic lupus but which is temporally related to drug exposure and resolves after withdrawal of the implicated drug. Similarly to idiopathic lupus, DI-LE can be divided into systemic LE, subacute cutaneous LE (SCLE), chronic cutaneous LE (CCLE) and cutaneous LE tumidus. DI-SCLE is the most frequent variant of drug-induced cutaneous LE and presents mainly with annular-polycyclic lesions; the clinical picture is often widespread, with involvement of the lower legs that are usually spared in idiopathic SCLE. ANA and anti-Ro/SSA antibodies are typically present, whereas antihistone antibodies are uncommonly found. We have recently addressed the question whether DI-SCLE differs significantly from its idiopathic counterpart by virtue of clinical features and, based on our findings, we have suggested that the frequent occurrence of malar rash and bullous, erythema multiforme-like and vasculitic manifestations can be regarded as the hallmark of DI-SCLE. In contrast, the histology is not a useful diagnostic criterion for DI-SCLE, considering that the typical pattern of lichenoid interface dermatitis is seen only in the early stage of disease and tissue eosinophilia does not represent a differentiating histopathological feature. DI-CCLE and DI-LE tumidus, albeit possibly misdiagnosed, are rarely observed and are characterized by classic discoid lesions and erythematous-oedematous plaques on sun exposed areas, respectively. Management of DI-LE is based on the discontinuation of the offending drug; topical and/or systemic corticosteroids and other immunomodulating/immunosuppressive agents should be reserved for resistant cases.

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

    PubMed Central

    Hung, Whitney Y; Abreu Lanfranco, Odaliz

    2014-01-01

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

  4. Genetic risk factors associated with lipid-lowering drug-induced myopathies.

    PubMed

    Vladutiu, Georgirene D; Simmons, Zachary; Isackson, Paul J; Tarnopolsky, Mark; Peltier, Wendy L; Barboi, Alexandru C; Sripathi, Naganand; Wortmann, Robert L; Phillips, Paul S

    2006-08-01

    Lipid-lowering drugs produce myopathic side effects in up to 7% of treated patients, with severe rhabdomyolysis occurring in as many as 0.5%. Underlying metabolic muscle diseases have not been evaluated extensively. In a cross-sectional study of 136 patients with drug-induced myopathies, we report a higher prevalence of underlying metabolic muscle diseases than expected in the general population. Control groups included 116 patients on therapy with no myopathic symptoms, 100 asymptomatic individuals from the general population never exposed to statins, and 106 patients with non-statin-induced myopathies. Of 110 patients who underwent mutation testing, 10% were heterozygous or homozygous for mutations causing three metabolic myopathies, compared to 3% testing positive among asymptomatic patients on therapy (P = 0.04). The actual number of mutant alleles found in the test group patients was increased fourfold over the control group (P < 0.0001) due to an increased presence of mutation homozygotes. The number of carriers for carnitine palmitoyltransferase II deficiency and for McArdle disease was increased 13- and 20-fold, respectively, over expected general population frequencies. Homozygotes for myoadenylate deaminase deficiency were increased 3.25-fold with no increase in carrier status. In 52% of muscle biopsies from patients, significant biochemical abnormalities were found in mitochondrial or fatty acid metabolism, with 31% having multiple defects. Variable persistent symptoms occurred in 68% of patients despite cessation of therapy. The effect of statins on energy metabolism combined with a genetic susceptibility to triggering of muscle symptoms may account for myopathic outcomes in certain high-risk groups.

  5. Acquired granulocyte abnormality during drug allergic reactions: possible role of complement activation.

    PubMed

    Bowers, T K; Craddock, P R; Jacob, H S

    1977-01-01

    A profound defect in granulocyte chemotaxis was documented in an otherwise healthy 21-yr-old man who failed to localize granulocytes to an area of cellulitis during an allergic reaction to cephalothin. During the period of drug allergy, characterized by urticaria, eosinophilia, and profound hypocomplementemia, in vitro migration of the patient's granulocytes in the Boyden chamber was markedly impaired. Although devoid of hemolytic complement activity, the patient's serum possessed supranormal chemotactic activity, even following heat inactivation, suggesting the presence of chemotactically active complement split products. Chemotactic function improved concomitantly with steroid therapy and normalization of serum complement levels, and was entirely normal following clinical recovery and cessation of steroid therapy. The chemotactic abnormality noted in the patient's cells was reproduced in normal granulocytes by preincubation either with patient serum or with cobra venom-activated fresh (but not heated) normal serum, suggesting that in vivo exposure of granulocytes to activated complement was responsible for the patient's abnormal chemotactic response. This mechanism may contribute to the increased infection propensity noted in other conditions characterized by in vivo complement activation, such as rheumatoid arthritis and systemic lupus erythematosis.

  6. Characterization of drug-induced transcriptional modules: towards drug repositioning and functional understanding

    PubMed Central

    Iskar, Murat; Zeller, Georg; Blattmann, Peter; Campillos, Monica; Kuhn, Michael; Kaminska, Katarzyna H; Runz, Heiko; Gavin, Anne-Claude; Pepperkok, Rainer; van Noort, Vera; Bork, Peer

    2013-01-01

    In pharmacology, it is crucial to understand the complex biological responses that drugs elicit in the human organism and how well they can be inferred from model organisms. We therefore identified a large set of drug-induced transcriptional modules from genome-wide microarray data of drug-treated human cell lines and rat liver, and first characterized their conservation. Over 70% of these modules were common for multiple cell lines and 15% were conserved between the human in vitro and the rat in vivo system. We then illustrate the utility of conserved and cell-type-specific drug-induced modules by predicting and experimentally validating (i) gene functions, e.g., 10 novel regulators of cellular cholesterol homeostasis and (ii) new mechanisms of action for existing drugs, thereby providing a starting point for drug repositioning, e.g., novel cell cycle inhibitors and new modulators of α-adrenergic receptor, peroxisome proliferator-activated receptor and estrogen receptor. Taken together, the identified modules reveal the conservation of transcriptional responses towards drugs across cell types and organisms, and improve our understanding of both the molecular basis of drug action and human biology. PMID:23632384

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

    PubMed

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

    2010-01-01

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

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

    PubMed

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

    2017-10-01

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

  9. [INDIVIDUAL EVALUATION OF LORETA ABNORMALITIES IN IDIOPATHIC GENERALIZED EPILEPSY].

    PubMed

    Clemens, Béla; Puskás, Szilvia; Besenyei, Mónika; Kondákor, István; Hollódy, Katalin; Fogarasi, Andrós; Bense, Katalin; Emri, Miklós; Opposits Gábor; Kovács, Noémi Zsuzsanna; Fekete, István

    2016-03-30

    Contemporary neuroimaging methods disclosed structural and functional cerebral abnormalities in idiopathic generalized epilepsies (IGEs). However, individual electrical (EEG) abnormalities have not been evaluated yet in IGE patients. IGE patients were investigated in the drug-free condition and after 3-6 month of antiepileptic treatment. To estimate the reproducibility of qEEG variables a retrospective recruited cohort of IGE patients was investigated. 19-channel resting state EEG activity was recorded. For each patient a total of 2 minutes EEG activity was analyzed by LORETA (Low Resolution Electromagnetic Tomography). Raw LORETA values were Z-transformed and projected to a MRI template. Z-values outside within the [+3Z] to [-3Z] range were labelled as statistically abnormal. 1. In drug-free condition, 41-50% of IGE patients showed abnormal LORETA values. 2. Abnormal LORETA findings showed great inter-individual variability. 3. Most abnormal LORETA-findings were symmetrical. 4. Most maximum Z-values were localized to frontal or temporal cortex. 5. Succesfull treatment was mostly coupled with disappearence of LORETA-abnormality, persistent seizures were accompanied by persistent LORETA abnormality. 1. LORETA abnormalities detected in the untreated condition reflect seizure-generating property of the cortex in IGE patients. 2. Maximum LORETA-Z abnormalities were topographically congruent with structural abnormalities reported by other research groups. 3. LORETA might help to investigate drug effects at the whole-brain level.

  10. Drug Induced Hearing Loss: What Is Ototoxicity?

    MedlinePlus

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

  11. Identification of Drugs Inducing Phospholipidosis by Novel in vitro Data

    PubMed Central

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

    2012-01-01

    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. PMID:22945602

  12. Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

    PubMed Central

    Mantsch, John R; Baker, David A; Funk, Douglas; Lê, Anh D; Shaham, Yavin

    2016-01-01

    In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse. PMID:25976297

  13. Drug-induced low blood sugar

    MedlinePlus

    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. ...

  14. Pharmacogenetic aspects of drug-induced torsade de pointes: potential tool for improving clinical drug development and prescribing.

    PubMed

    Shah, Rashmi R

    2004-01-01

    Drug-induced torsade de pointes (TdP) has proved to be a significant iatro-genic cause of morbidity and mortality and a major reason for the withdrawal of a number of drugs from the market in recent times. Enzymes that metabolise many of these drugs and the potassium channels that are responsible for cardiac repolarisation display genetic polymorphisms. Anecdotal reports have suggested that in many cases of drug-induced TdP, there may be a concealed genetic defect of either these enzymes or the potassium channels, giving rise to either high plasma drug concentrations or diminished cardiac repolarisation reserve, respectively. The presence of either of these genetic defects may predispose a patient to TdP, a potentially fatal adverse reaction, even at therapeutic dosages of QT-prolonging drugs and in the absence of other risk factors. Advances in pharmacogenetics of drug metabolising enzymes and pharmacological targets, together with the prospects of rapid and inexpensive genotyping procedures, promise to individualise and improve the benefit/risk ratio of therapy with drugs that have the potential to cause TdP. The qualitative and the quantitative contributions of these genetic defects in clinical cases of TdP are unclear because not all of the patients with TdP are routinely genotyped and some relevant genetic mutations still remain to be discovered. There are regulatory guidelines that recommend strategies aimed at uncovering the risk of TdP associated with new chemical entities during their development. There are also a number of guidelines that recommend integrating pharmacogenetics in this process. This paper proposes a strategy for integrating pharmacogenetics into drug development programmes to optimise association studies correlating genetic traits and endpoints of clinical interest, namely failure of efficacy or development of repolarisation abnormalities. Until pharmacogenetics is carefully integrated into all phases of development of QT-prolonging drugs

  15. Right lateralized white matter abnormalities in first-episode, drug-naive paranoid schizophrenia.

    PubMed

    Guo, Wenbin; Liu, Feng; Liu, Zhening; Gao, Keming; Xiao, Changqing; Chen, Huafu; Zhao, Jingping

    2012-11-30

    Numerous studies in first-episode schizophrenia suggest the involvement of white matter (WM) abnormalities in multiple regions underlying the pathogenesis of this condition. However, there has never been a neuroimaging study in patients with first-episode, drug-naive paranoid schizophrenia by using tract-based spatial statistics (TBSS) method. Here, we used diffusion tensor imaging (DTI) with TBSS method to investigate the brain WM integrity in patients with first-episode, drug-naive paranoid schizophrenia. Twenty patients with first-episode, drug-naive paranoid schizophrenia and 26 healthy subjects matched with age, gender, and education level were scanned with DTI. An automated TBSS approach was employed to analyze the data. Voxel-wise statistics revealed that patients with paranoid schizophrenia had decreased fractional anisotropy (FA) values in the right superior longitudinal fasciculus (SLF) II, the right fornix, the right internal capsule, and the right external capsule compared to healthy subjects. Patients did not have increased FA values in any brain regions compared to healthy subjects. There was no correlation between the FA values in any brain regions and patient demographics and the severity of illness. Our findings suggest right-sided alterations of WM integrity in the WM tracts of cortical and subcortical regions may play an important role in the pathogenesis of paranoid schizophrenia. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  16. Gestational lead exposure induces developmental abnormalities and up-regulates apoptosis of fetal cerebellar cells in rats.

    PubMed

    Mousa, Alyaa M; Al-Fadhli, Ameera S; Rao, Muddanna S; Kilarkaje, Narayana

    2015-01-01

    Lead (Pb), a known environmental toxicant, adversely affects almost all organ systems. In this study, we investigated the effects of maternal lead exposure on fetal rat cerebellum. Female Sprague-Dawley rats were given lead nitrate in drinking water (0, 0.5, and 1%) for two weeks before conception, and during pregnancy. Fetuses were collected by caesarian section on gestational day 21 and observed for developmental abnormalities. The fetal cerebellar sections from control and 1% lead group were stained with cresyl violet. Immunohistochemical expressions of p53, Bax, Bcl-2, and caspase 3 were quantified by AnalySIS image analyzer (Life Science, Germany). Lead exposure induced developmental abnormalities of eyes, ear, limbs, neck and ventral abdominal wall; however, these abnormalities were commonly seen in the 1% lead-treated group. In addition, lead also caused fetal mortality and reduced body growth in both dose groups and reduced brain weight in the 1% lead-treated group. The fetal cerebella from the 1% lead-treated group showed unorganized cerebellar cortical layers, and degenerative changes in granule and Purkinje cells such as the formation of clumps of Nissl granules. An increase in Bax and caspase 3, and a decrease in Bcl-2 (p < 0.05), but not in p53, showed apoptosis of the neurons. In conclusion, gestational lead exposure in rats induces fetal toxicity and developmental abnormalities. The lead exposure also impairs development of cerebellar layers, induces structural changes, and apoptosis in the fetal cerebellar cortex. These results suggest that lead exposure during gestation is extremely toxic to developing cerebellum in rats.

  17. Glucuronidation of Drugs and Drug-Induced Toxicity in Humanized UDP-Glucuronosyltransferase 1 Mice

    PubMed Central

    Kutsuno, Yuki; Itoh, Tomoo; Tukey, Robert H.

    2014-01-01

    UDP-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that catalyze glucuronidation of various drugs. Although experimental rodents are used in preclinical studies to predict glucuronidation and toxicity of drugs in humans, species differences in glucuronidation and drug-induced toxicity have been reported. Humanized UGT1 mice in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus (hUGT1 mice) were recently developed. In this study, acyl-glucuronidations of etodolac, diclofenac, and ibuprofen in liver microsomes of hUGT1 mice were examined and compared with those of humans and regular mice. The kinetics of etodolac, diclofenac, and ibuprofen acyl-glucuronidation in hUGT1 mice were almost comparable to those in humans, rather than in mice. We further investigated the hepatotoxicity of ibuprofen in hUGT1 mice and regular mice by measuring serum alanine amino transferase (ALT) levels. Because ALT levels were increased at 6 hours after dosing in hUGT1 mice and at 24 hours after dosing in regular mice, the onset pattern of ibuprofen-induced liver toxicity in hUGT1 mice was different from that in regular mice. These data suggest that hUGT1 mice can be valuable tools for understanding glucuronidations of drugs and drug-induced toxicity in humans. PMID:24764149

  18. A review of drug-induced liver injury databases.

    PubMed

    Luo, Guangwen; Shen, Yiting; Yang, Lizhu; Lu, Aiping; Xiang, Zheng

    2017-09-01

    Drug-induced liver injuries have been a major focus of current research in drug development, and are also one of the major reasons for the failure and withdrawal of drugs in development. Drug-induced liver injuries have been systematically recorded in many public databases, which have become valuable resources in this field. In this study, we provide an overview of these databases, including the liver injury-specific databases LiverTox, LTKB, Open TG-GATEs, LTMap and Hepatox, and the general databases, T3DB, DrugBank, DITOP, DART, CTD and HSDB. The features and limitations of these databases are summarized and discussed in detail. Apart from their powerful functions, we believe that these databases can be improved in several ways: by providing the data about the molecular targets involved in liver toxicity, by incorporating information regarding liver injuries caused by drug interactions, and by regularly updating the data.

  19. In silico modeling to predict drug-induced phospholipidosis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

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

    2013-06-01

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

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

    PubMed Central

    Liu, Yu; Le Foll, Bernard; Liu, Yanli; Wang, Xi; Lu, Lin

    2008-01-01

    The conditioned place preference (CPP) model has been widely used to evaluate the rewarding effects of abused drugs, and recently, the extinction and reinstatement phases of this paradigm have been used to assess relapse to drug seeking. The vast majority of studies have focused on CPP induced by illicit drugs, such as psychostimulants and opioids. Although legal psychoactive drugs, such as ethanol, nicotine, and caffeine, are more widely used than illegal drugs, the establishment, extinction, and reinstatement of CPP produced by these licit drugs are less well understood. The present review discusses the extant research on CPP induced by legal drugs. We first describe the CPP model and discuss the behavioral procedures used to induce CPP for ethanol, nicotine, and caffeine. We then summarize the neuronal substrates that underlie CPP induced by these drugs from a genetic perspective. Finally, we draw on findings from pharmacological studies and discuss the neurotransmitters and neurohormones underlying CPP produced by ethanol, nicotine, and caffeine. PMID:19082419

  1. Conditioned place preference induced by licit drugs: establishment, extinction, and reinstatement.

    PubMed

    Liu, Yu; Le Foll, Bernard; Liu, Yanli; Wang, Xi; Lu, Lin

    2008-12-14

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

  2. PTTG1 Attenuates Drug-Induced Cellular Senescence

    PubMed Central

    Tong, Yunguang; Zhao, Weijiang; Zhou, Cuiqi; Wawrowsky, Kolja; Melmed, Shlomo

    2011-01-01

    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. PMID:21858218

  3. Abnormal splenic artery diameter/hepatic artery diameter ratio in cirrhosis-induced portal hypertension

    PubMed Central

    Zeng, Dao-Bing; Dai, Chuan-Zhou; Lu, Shi-Chun; He, Ning; Wang, Wei; Li, Hong-Jun

    2013-01-01

    AIM: To determine an optimal cutoff value for abnormal splenic artery diameter/proper hepatic artery diameter (S/P) ratio in cirrhosis-induced portal hypertension. METHODS: Patients with cirrhosis and portal hypertension (n = 770) and healthy volunteers (n = 31) underwent volumetric computed tomography three-dimensional vascular reconstruction to measure the internal diameters of the splenic artery and proper hepatic artery to calculate the S/P ratio. The cutoff value for abnormal S/P ratio was determined using receiver operating characteristic curve analysis, and the prevalence of abnormal S/P ratio and associations between abnormal S/P ratio and major complications of portal hypertension were studied using logistic regression. RESULTS: The receiver operating characteristic analysis showed that the cutoff points for abnormal splenic artery internal diameter and S/P ratio were > 5.19 mm and > 1.40, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value were 74.2%, 45.2%, 97.1%, and 6.6%, respectively. The prevalence of an abnormal S/P ratio in the patients with cirrhosis and portal hypertension was 83.4%. Patients with a higher S/P ratio had a lower risk of developing ascites [odds ratio (OR) = 0.708, 95%CI: 0.508-0.986, P = 0.041] and a higher risk of developing esophageal and gastric varices (OR = 1.483, 95%CI: 1.010-2.175, P = 0.044) and forming collateral circulation (OR = 1.518, 95%CI: 1.033-2.230, P = 0.034). After splenectomy, the portal venous pressure and maximum and mean portal venous flow velocities were reduced, while the flow rate and maximum and minimum flow velocities of the hepatic artery were increased (P < 0.05). CONCLUSION: The prevalence of an abnormal S/P ratio is high in patients with cirrhosis and portal hypertension, and it can be used as an important marker of splanchnic hemodynamic disturbances. PMID:23483462

  4. Markers of bone turnover in patients with epilepsy and their relationship to management of bone diseases induced by antiepileptic drugs.

    PubMed

    Hamed, Sherifa A

    2016-01-01

    Data from cross-sectional and prospective studies revealed that patients with epilepsy and on long-term treatment with antiepileptic drugs (AEDs) are at increased risk for metabolic bone diseases. Bone diseases were reported in about 50% of patients on AEDs. Low bone mineral density, osteopenia/osteoporosis, osteomalacia, rickets, altered concentration of bone turnover markers and fractures were reported with phenobarbital, phenytoin, carbamazepine, valproate, oxcarbazepine and lamotrigine. The mechanisms for AEDs-induced bone diseases are heterogeneous and include hypovitaminosis D, hypocalcemia and direct acceleration of bone loss and/or reduction of bone formation. This article reviews the evidence, predictors and mechanisms of AEDs-induced bone abnormalities and its clinical implications. For patients on AEDs, regular monitoring of bone health is recommended. Prophylactic administration of calcium and vitamin D is recommended for all patients. Treatment doses of calcium and vitamin D and even anti-resorptive drug therapy are reserved for patients at high risk of pathological fracture.

  5. Abnormal default-mode network homogeneity and its correlations with personality in drug-naive somatization disorder at rest.

    PubMed

    Wei, Shubao; Su, Qinji; Jiang, Muliang; Liu, Feng; Yao, Dapeng; Dai, Yi; Long, Liling; Song, Yan; Yu, Miaoyu; Zhang, Zhikun; Zhao, Jingping; Guo, Wenbin

    2016-03-15

    While the default-mode network (DMN) appears to play a crucial role in patients suffering from somatization disorder (SD), the abnormalities of the network homogeneity (NH) of the DMN in SD patients have been poorly explored. The aim of this study is to examine DMN NH using an NH approach in patients suffering from SD at rest and determine its correlations with personality as measured by the Eysenck Personality Questionnaire (EPQ). A total of 25 drug-naive patients with SD and 28 sex-, age-, and education-matched healthy controls underwent functional magnetic resonance imaging scans at rest. The data were analyzed by an automated NH method. Patients showed increased NH in the left superior frontal gyrus and decreased NH in the bilateral precuneus. Moreover, a significantly negative correlation was observed between the NH values in the bilateral precuneus and the EPQ--Neuroticism scores. The present study should be considered preliminary due to a lenient, uncorrected threshold of p<0.01. The results suggest that abnormal DMN NH exists in drug-naive SD and further highlight the importance of the DMN in the pathophysiology of SD. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. The discovery of drug-induced illness.

    PubMed

    Jick, H

    1977-03-03

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

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

    PubMed

    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.

  8. Drug-induced status epilepticus.

    PubMed

    Cock, Hannah R

    2015-08-01

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

  9. Swimming attenuates d-galactose-induced brain aging via suppressing miR-34a-mediated autophagy impairment and abnormal mitochondrial dynamics.

    PubMed

    Kou, Xianjuan; Li, Jie; Liu, Xingran; Chang, Jingru; Zhao, Qingxia; Jia, Shaohui; Fan, Jingjing; Chen, Ning

    2017-06-01

    microRNAs (miRNAs) have been reported to be involved in many neurodegenerative diseases. To explore the regulatory role of miR-34a in aging-related diseases such as Alzheimer's disease (AD) during exercise intervention, we constructed a rat model with d-galactose (d-gal)-induced oxidative stress and cognitive impairment coupled with dysfunctional autophagy and abnormal mitochondrial dynamics, determined the mitigation of cognitive impairment of d-gal-induced aging rats during swimming intervention, and evaluated miR-34a-mediated functional status of autophagy and abnormal mitochondrial dynamics. Meanwhile, whether the upregulation of miR-34a can lead to dysfunctional autophagy and abnormal mitochondrial dynamics was confirmed in human SH-SY5Y cells with silenced miR-34a by the transfection of a miR-34a inhibitor. Results indicated that swimming intervention could significantly attenuate cognitive impairment, prevent the upregulation of miR-34a, mitigate the dysfunctional autophagy, and inhibit the increase of dynamin-related protein 1 (DRP1) in d-gal-induced aging model rats. In contrast, the miR-34a inhibitor in cell model not only attenuated D-gal-induced the impairment of autophagy but also decreased the expression of DRP1 and mitofusin 2 (MFN2). Therefore, swimming training can delay brain aging of d-gal-induced aging rats through attenuating the impairment of miR-34a-mediated autophagy and abnormal mitochondrial dynamics, and miR-34a could be the novel therapeutic target for aging-related diseases such as AD. NEW & NOTEWORTHY In the present study, we have found that the upregulation of miR-34a is the hallmark of aging or aging-related diseases, which can result in dysfunctional autophagy and abnormal mitochondrial dynamics. In contrast, swimming intervention can delay the aging process by rescuing the impaired functional status of autophagy and abnormal mitochondrial dynamics via the suppression of miR-34a. Copyright © 2017 the American Physiological Society.

  10. Prime-, Stress- and Cue-Induced Reinstatement of Extinguished Drug-Reinforced Responding in Rats: Cocaine as the Prototypical Drug of Abuse

    PubMed Central

    Beardsley, Patrick M.; Shelton, Keith L.

    2012-01-01

    This unit describes the testing of rats in prime-, footshock- and cue-induced reinstatement procedures. Evaluating rats in these procedures enables the assessment of treatments on behavior thought to model drug relapse precipitated by re-contact with an abused drug (prime-induced), induced by stress (footshock-induced), or by stimuli previously associated with drug administration (cue-induced). For instance, levels of reinstatement under the effects of test compound administration could be compared to levels under vehicle administration to help identify potential treatments for drug relapse, or reinstatement levels of different rat strains could be compared to identify potential genetic determinants of perseverative drug-seeking behavior. Cocaine is used as a prototypical drug of abuse, and relapse to its use serves as the model in this unit, but other self-administered drugs could readily be substituted with little modification to the procedures. PMID:23093352

  11. Prenatal ethanol exposure-induced adrenal developmental abnormality of male offspring rats and its possible intrauterine programming mechanisms

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Huang, Hegui; He, Zheng; Zhu, Chunyan

    Fetal adrenal developmental status is the major determinant of fetal tissue maturation and offspring growth. We have previously proposed that prenatal ethanol exposure (PEE) suppresses fetal adrenal corticosterone (CORT) synthesis. Here, we focused on PEE-induced adrenal developmental abnormalities of male offspring rats before and after birth, and aimed to explore its intrauterine programming mechanisms. A rat model of intrauterine growth retardation (IUGR) was established by PEE (4 g/kg·d). In PEE fetus, increased serum CORT concentration and decreased insulin-like growth factor 1 (IGF1) concentration, with lower bodyweight and structural abnormalities as well as a decreased Ki67 expression (proliferative marker), were observedmore » in the male fetal adrenal cortex. Adrenal glucocorticoid (GC)-metabolic activation system was enhanced while gene expression of IGF1 signaling pathway with steroidogenic acute regulatory protein (StAR), 3β-hydroxysteroid dehydrogenase (3β-HSD) was decreased. Furthermore, in the male adult offspring of PEE, serum CORT level was decreased but IGF1 was increased with partial catch-up growth, and Ki67 expression demonstrated no obvious change. Adrenal GC-metabolic activation system was inhibited, while IGF1 signaling pathway and 3β-HSD was enhanced with the steroidogenic factor 1 (SF1), and StAR was down-regulated in the adult adrenal. Based on these findings, we propose a “two-programming” mechanism for PEE-induced adrenal developmental toxicity: “the first programming” is a lower functional programming of adrenal steroidogenesis, and “the second programming” is GC-metabolic activation system-related GC-IGF1 axis programming. - Highlights: • Prenatal ethanol exposure induces adrenal developmental abnormality in offspring rats. • Prenatal ethanol exposure induces intrauterine programming of adrenal steroidogenesis. • Intrauterine GC-IGF1 axis programming might mediate adrenal developmental abnormality.« less

  12. The onset and evolution of fatigue-induced abnormal grain growth in nanocrystalline Ni–Fe

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Furnish, T. A.; Mehta, A.; Van Campen, D.

    Conventional structural metals suffer from fatigue-crack initiation through dislocation activity which forms persistent slip bands leading to notch-like extrusions and intrusions. Ultrafine-grained and nanocrystalline metals can potentially exhibit superior fatigue-crack initiation resistance by suppressing these cumulative dislocation activities. Prior studies on these metals have confirmed improved high-cycle fatigue performance. In the case of nano-grained metals, analyses of subsurface crack initiation sites have indicated that the crack nucleation is associated with abnormally large grains. But, these post-mortem analyses have led to only speculation about when abnormal grain growth occurs (e.g., during fatigue, after crack initiation, or during crack growth). In thismore » study, a recently developed synchrotron X-ray diffraction technique was used to detect the onset and progression of abnormal grain growth during stress-controlled fatigue loading. Our study provides the first direct evidence that the grain coarsening is cyclically induced and occurs well before final fatigue failure—our results indicate that the first half of the fatigue life was spent prior to the detectable onset of abnormal grain growth, while the second half was spent coarsening the nanocrystalline structure and cyclically deforming the abnormally large grains until crack initiation. Post-mortem fractography, coupled with cycle-dependent diffraction data, provides the first details regarding the kinetics of this abnormal grain growth process during high-cycle fatigue testing. Finally, precession electron diffraction images collected in a transmission electron microscope after the in situ fatigue experiment also confirm the X-ray evidence that the abnormally large grains contain substantial misorientation gradients and sub-grain boundaries.« less

  13. The onset and evolution of fatigue-induced abnormal grain growth in nanocrystalline Ni–Fe

    DOE PAGES

    Furnish, T. A.; Mehta, A.; Van Campen, D.; ...

    2016-10-11

    Conventional structural metals suffer from fatigue-crack initiation through dislocation activity which forms persistent slip bands leading to notch-like extrusions and intrusions. Ultrafine-grained and nanocrystalline metals can potentially exhibit superior fatigue-crack initiation resistance by suppressing these cumulative dislocation activities. Prior studies on these metals have confirmed improved high-cycle fatigue performance. In the case of nano-grained metals, analyses of subsurface crack initiation sites have indicated that the crack nucleation is associated with abnormally large grains. But, these post-mortem analyses have led to only speculation about when abnormal grain growth occurs (e.g., during fatigue, after crack initiation, or during crack growth). In thismore » study, a recently developed synchrotron X-ray diffraction technique was used to detect the onset and progression of abnormal grain growth during stress-controlled fatigue loading. Our study provides the first direct evidence that the grain coarsening is cyclically induced and occurs well before final fatigue failure—our results indicate that the first half of the fatigue life was spent prior to the detectable onset of abnormal grain growth, while the second half was spent coarsening the nanocrystalline structure and cyclically deforming the abnormally large grains until crack initiation. Post-mortem fractography, coupled with cycle-dependent diffraction data, provides the first details regarding the kinetics of this abnormal grain growth process during high-cycle fatigue testing. Finally, precession electron diffraction images collected in a transmission electron microscope after the in situ fatigue experiment also confirm the X-ray evidence that the abnormally large grains contain substantial misorientation gradients and sub-grain boundaries.« less

  14. Hypothalamic mitochondrial abnormalities occur downstream of inflammation in diet-induced obesity.

    PubMed

    Carraro, Rodrigo S; Souza, Gabriela F; Solon, Carina; Razolli, Daniela S; Chausse, Bruno; Barbizan, Roberta; Victorio, Sheila C; Velloso, Licio A

    2018-01-15

    Hypothalamic dysfunction is a common feature of experimental obesity. Studies have identified at least three mechanisms involved in the development of hypothalamic neuronal defects in diet-induced obesity: i, inflammation; ii, endoplasmic reticulum stress; and iii, mitochondrial abnormalities. However, which of these mechanisms is activated earliest in response to the consumption of large portions of dietary fats is currently unknown. Here, we used immunoblot, real-time PCR, mitochondrial respiration assays and transmission electron microscopy to evaluate markers of inflammation, endoplasmic reticulum stress and mitochondrial abnormalities in the hypothalamus of Swiss mice fed a high-fat diet for up to seven days. In the present study we show that the expression of the inflammatory chemokine fractalkine was the earliest event detected. Its hypothalamic expression increased as early as 3 h after the introduction of a high-fat diet and was followed by the increase of cytokines. GPR78, an endoplasmic reticulum chaperone, was increased 6 h after the introduction of a high-fat diet, however the actual triggering of endoplasmic reticulum stress was only detected three days later, when IRE-1α was increased. Mitofusin-2, a protein involved in mitochondrial fusion and tethering of mitochondria to the endoplasmic reticulum, underwent a transient reduction 24 h after the introduction of a high-fat diet and then increased after seven days. There were no changes in hypothalamic mitochondrial respiration during the experimental period, however there were reductions in mitochondria/endoplasmic reticulum contact sites, beginning three days after the introduction of a high-fat diet. The inhibition of TNF-α with infliximab resulted in the normalization of mitofusin-2 levels 24 h after the introduction of the diet. Thus, inflammation is the earliest mechanism activated in the hypothalamus after the introduction of a high-fat diet and may play a mechanistic role in the

  15. Drug-induced psoriasis: clinical perspectives.

    PubMed

    Balak, Deepak Mw; Hajdarbegovic, Enes

    2017-01-01

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

  16. Von Willebrand's disease with spontaneous platelet aggregation induced by an abnormal plasma von Willebrand factor.

    PubMed Central

    Grainick, H R; Williams, S B; McKeown, L P; Rick, M E; Maisonneuve, P; Jenneau, C; Sultan, Y

    1985-01-01

    We have investigated and characterized the abnormalities in four unrelated patients with von Willebrand's disease (vWd) who have (a) enhanced ristocetin-induced platelet aggregation (RIPA) at low ristocetin concentrations, (b) absence of the largest plasma von Willebrand factor (vWf) multimers, and (c) thrombocytopenia. The platelet-rich plasma of these patients aggregates spontaneously without the addition of any agonists. When isolated normal platelets are resuspended in patient plasma spontaneous aggregation occurs; however, the patients' plasmas did not induce platelet aggregation of normal washed formalinized platelets. When the patients' platelets are suspended in normal plasma, spontaneous aggregation is not observed. The spontaneous platelet aggregation (SPA) is associated with dense granule secretion as measured by ATP release and alpha granule release as measured by beta-thromboglobulin and platelet factor 4 release. The SPA is totally inhibited by 5 mM EDTA, prostaglandin I2, and dibutryl cyclic AMP, while it is only partially inhibited by 1 mM EDTA, acetylsalicylic acid, or apyrase. A monoclonal antibody directed against glycoprotein Ib (GPIb) and/or a monoclonal antibody against the glycoprotein IIb/IIIa (GPIIb/IIIa) complex totally inhibits the SPA. The vWf was isolated from the plasma of one of these patients. The purified vWf induced platelet aggregation of normal platelets resuspended in either normal or severe vWd plasma, but the vWf did not induce platelet aggregation of normal platelets resuspended in afibrinognemic plasma. Sialic acid and galactose quantification of the patient's vWf revealed approximately a 50% reduction compared with normal vWf. These studies indicate that a form of vWd exists, which is characterized by SPA that is induced by the abnormal plasma vWf. The SPA is dependent on the presence of plasma fibrinogen, and the availability of the GPIb and the GPIIb/IIIa complex. In this variant form of vWd the abnormal vWf causes

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

    PubMed

    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.

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

    PubMed

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

    2014-03-28

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

  19. Neuroprotective Effects of Drug-Induced Therapeutic Hypothermia in Central Nervous System Diseases.

    PubMed

    Ma, Junwei; Wang, Yibin; Wang, Zhong; Li, Haiying; Wang, Zhimin; Chen, Gang

    2017-01-01

    This review article focuses on the neuroprotective effect of drug-induced hypothermia in cerebrovascular diseases and discusses its related side effects. A systematic literature search was performed using Pubmed and Embase electronic databases for a retrospective analysis. Experimental studies have shown that drug-induced hypothermia alleviates brain damage and plays a neuroprotective role, thereby reducing mortality and ameliorating neurological deficits. Therefore, drug-induced hypothermia has an important research value and is worth further consideration in the clinical setting. However, drug-induced hypothermia is also associated with side effects, such as ventricular tachycardia, ventricular fibrillation, suppressed immune function, infection, electrolyte imbalance, glucose metabolism disorders, and skeletal muscle tremor. Existing drugs with cooling effects belong to the following categories: (1) dopamine receptor agonists; (2) cannabis; (3) opioid receptors; (4) vanilloid receptors; (5) vasopressins (potent neurotensin receptor agonists); (6) thyroid drugs; (7) adenosine drugs; and (8) purine drugs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  20. An Update on Drug-induced Liver Injury.

    PubMed

    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

  1. Clinical presentation and management of drug-induced agranulocytosis.

    PubMed

    Andrès, Emmanuel; Zimmer, Jacques; Mecili, Mustapha; Weitten, Thierry; Alt, Martine; Maloisel, Frédéric

    2011-04-01

    In this article, we report and discuss the clinical presentation and management of idiosyncratic drug-induced agranulocytosis (neutrophil count <0.5 × 10(9)/l). Idiosyncratic drug-induced agranulocytosis remains a potentially serious adverse event owing to the frequency of severe sepsis with severe deep tissue infections (e.g., pneumonia), septicemia and septic shock in approximately two-thirds of all hospitalized patients. However, several prognostic factors have recently been identified that may be helpful in practice to identify 'susceptible' patients. Old age (>65 years), septicemia or shock, metabolic disorders such as renal failure and a neutrophil count below 0.1 × 10(9)/l are currently consensually accepted as poor prognostic factors. In this potentially life-threatening disorder, modern management with broad-spectrum antibiotics and hematopoietic growth factors (particularly granulocyte colony-stimulating factor) is likely to improve prognosis. Thus, with appropriate management, the mortality rate from idiosyncratic drug-induced agranulocytosis is currently approximately 5%.

  2. Drug-inducing gynaecomastia--a critical review.

    PubMed

    Krause, W

    2012-05-01

    Gynaecomastia has been associated with a large variety of drugs in the literature. However, a causal relation of the incidence of gynaecomastia to a certain drug should be considered only if sufficient and significant evidence can be obtained from the studies published. In this review, studies quoted in Medline were evaluated according to the Scottish Intercollegiate Guidelines Network (SIGN) grading system for clinical studies. Reports on 92 drugs were found in Medline in combination with gynaecomastia. An imbalance of the oestrogen/androgen ratio causes gynaecomastia. Also, prolactin has gynaecomastia-inducing properties. In 14 of the drugs quoted, the studies lead to a level of recommendation 'A'. All these drugs have been designed to interfere with the production and action of sexual hormones or of prolactin. In 25 of the drugs, the level of recommendation was 'B'. Besides those drugs in this group that have been designed for interference with the metabolism of steroid hormones or of prolactin, in drugs for acid-related disorders, diuretics, antiretroviral drugs, antimycotics, psychoanaleptics, alcohol gynaecomastia was described as an unexpected adverse effect. Studies on the association of drugs and gynaecomastia do not share a generally accepted definition of gynaecomastia; in this way, the informational value is limited. © 2011 Blackwell Verlag GmbH.

  3. Vessel abnormalization: another hallmark of cancer? Molecular mechanisms and therapeutic implications.

    PubMed

    De Bock, Katrien; Cauwenberghs, Sandra; Carmeliet, Peter

    2011-02-01

    As a result of excessive production of angiogenic molecules, tumor vessels become abnormal in structure and function. By impairing oxygen delivery, abnormal vessels fuel a vicious cycle of non-productive angiogenesis, which creates a hostile microenvironment from where tumor cells escape through leaky vessels and which renders tumors less responsive to chemoradiation. While anti-angiogenic strategies focused on inhibiting new vessel growth and destroying pre-existing vessels, clinical studies showed modest anti-tumor effects. For many solid tumors, anti-VEGF treatment offers greater clinical benefit when combined with chemotherapy. This is partly due to a normalization of the tumor vasculature, which improves cytotoxic drug delivery and efficacy and offers unprecedented opportunities for anti-cancer treatment. Here, we overview key novel molecular players that induce vessel normalization. Copyright © 2010 Elsevier Ltd. All rights reserved.

  4. On the Cellular and Molecular Mechanisms of Drug-Induced Gingival Overgrowth

    PubMed Central

    Ramírez-Rámiz, Albert; Brunet-LLobet, Lluís; Lahor-Soler, Eduard; Miranda-Rius, Jaume

    2017-01-01

    Introduction: Gingival overgrowth has been linked to multiple factors such as adverse drug effects, inflammation, neoplastic processes, and hereditary gingival fibromatosis. Drug-induced gingival overgrowth is a well-established adverse event. In early stages, this gingival enlargement is usually located in the area of the interdental papilla. Histologically, there is an increase in the different components of the extracellular matrix. Objective: The aim of this manuscript is to describe and analyze the different cellular and molecular agents involved in the pathogenesis of Drug-induced gingival overgrowth. Method: A literature search of the MEDLINE/PubMed database was conducted to identify the mechanisms involved in the process of drug-induced gingival overgrowth, with the assistance of a research librarian. We present several causal hypotheses and discuss the advances in the understanding of the mechanisms that trigger this gingival alteration. Results: In vitro studies have revealed phenotypic cellular changes in keratinocytes and fibroblasts and an increase of the extracellular matrix with collagen and glycosaminoglycans. Drug-induced gingival overgrowth confirms the key role of collagenase and integrins, membrane receptors present in the fibroblasts, due to their involvement in the catabolism of collagen. The three drug categories implicated: calcineuron inhibitors (immunosuppressant drugs), calcium channel blocking agents and anticonvulsant drugs appear to present a multifactorial pathogenesis with a common molecular action: the blockage of the cell membrane in the Ca2+/Na+ ion flow. The alteration of the uptake of cellular folic acid, which depends on the regulated channels of active cationic transport and on passive diffusion, results in a dysfunctional degradation of the connective tissue. Certain intermediate molecules such as cytokines and prostaglandins play a role in this pathological mechanism. The concomitant inflammatory factor encourages the

  5. Ontology-based literature mining and class effect analysis of adverse drug reactions associated with neuropathy-inducing drugs.

    PubMed

    Hur, Junguk; Özgür, Arzucan; He, Yongqun

    2018-06-07

    Adverse drug reactions (ADRs), also called as drug adverse events (AEs), are reported in the FDA drug labels; however, it is a big challenge to properly retrieve and analyze the ADRs and their potential relationships from textual data. Previously, we identified and ontologically modeled over 240 drugs that can induce peripheral neuropathy through mining public drug-related databases and drug labels. However, the ADR mechanisms of these drugs are still unclear. In this study, we aimed to develop an ontology-based literature mining system to identify ADRs from drug labels and to elucidate potential mechanisms of the neuropathy-inducing drugs (NIDs). We developed and applied an ontology-based SciMiner literature mining strategy to mine ADRs from the drug labels provided in the Text Analysis Conference (TAC) 2017, which included drug labels for 53 neuropathy-inducing drugs (NIDs). We identified an average of 243 ADRs per NID and constructed an ADR-ADR network, which consists of 29 ADR nodes and 149 edges, including only those ADR-ADR pairs found in at least 50% of NIDs. Comparison to the ADR-ADR network of non-NIDs revealed that the ADRs such as pruritus, pyrexia, thrombocytopenia, nervousness, asthenia, acute lymphocytic leukaemia were highly enriched in the NID network. Our ChEBI-based ontology analysis identified three benzimidazole NIDs (i.e., lansoprazole, omeprazole, and pantoprazole), which were associated with 43 ADRs. Based on ontology-based drug class effect definition, the benzimidazole drug group has a drug class effect on all of these 43 ADRs. Many of these 43 ADRs also exist in the enriched NID ADR network. Our Ontology of Adverse Events (OAE) classification further found that these 43 benzimidazole-related ADRs were distributed in many systems, primarily in behavioral and neurological, digestive, skin, and immune systems. Our study demonstrates that ontology-based literature mining and network analysis can efficiently identify and study specific group of

  6. Retinal abnormalities in β-thalassemia major

    PubMed Central

    Bhoiwala, Devang L.; Dunaief, Joshua L.

    2015-01-01

    Patients with beta (β)-thalassemia (β-TM: thalassemia major, β-TI: thalassemia intermedia) have a variety of complications that may affect all organs, including the eye. Ocular abnormalities include retinal pigment epithelium degeneration, angioid streaks, venous tortuosity, night blindness, visual field defects, decreased visual acuity, color vision abnormalities, and acute visual loss. Patients with β-TM are transfusion dependent and require iron chelation therapy (ICT) in order to survive. Retinal degeneration may result from either retinal iron accumulation from transfusion-induced iron overload or retinal toxicity induced by ICT. Some who were never treated with ICT exhibited retinopathy, and others receiving ICT had chelator-induced retinopathy. We will focus on retinal abnormalities present in individuals with β-TM viewed in light of new findings on the mechanisms and manifestations of retinal iron toxicity. PMID:26325202

  7. Antipsychotics reverse abnormal EEG complexity in drug-naïve schizophrenia: A multiscale entropy analysis

    PubMed Central

    Takahashi, Tetsuya; Cho, Raymond Y.; Mizuno, Tomoyuki; Kikuchi, Mitsuru; Murata, Tetsuhito; Takahashi, Koichi; Wada, Yuji

    2010-01-01

    Multiscale entropy (MSE) analysis is a novel entropy-based approach for measuring dynamical complexity in physiological systems over a range of temporal scales. To evaluate this analytic approach as an aid to elucidating the pathophysiologic mechanisms in schizophrenia, we examined MSE in EEG activity in drug-naïve schizophrenia subjects pre- and post-treatment with antipsychotics in comparison with traditional EEG analysis. We recorded eyes-closed resting state EEG from frontal, temporal, parietal and occipital regions in drug-naïve 22 schizophrenia and 24 age-matched healthy control subjects. Fifteen patients were re-evaluated within 2–8 weeks after the initiation of antipsychotic treatment. For each participant, MSE was calculated on one continuous 60 second epoch for each experimental session. Schizophrenia subjects showed significantly higher complexity at higher time scales (lower frequencies), than that of healthy controls in fronto-centro-temporal, but not in parieto-occipital regions. Post-treatment, this higher complexity decreased to healthy control subject levels selectively in fronto-central regions, while the increased complexity in temporal sites remained higher. Comparative power analysis identified spectral slowing in frontal regions in pre-treatment schizophrenia subjects, consistent with previous findings, whereas no antipsychotic treatment effect was observed. In summary, multiscale entropy measures identified abnormal dynamical EEG signal complexity in anterior brain areas in schizophrenia that normalized selectively in fronto-central areas with antipsychotic treatment. These findings show that entropy-based analytic methods may serve as a novel approach for characterizing and understanding abnormal cortical dynamics in schizophrenia, and elucidating the therapeutic mechanisms of antipsychotics. PMID:20149880

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

    PubMed Central

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

    2016-01-01

    The liver is the center for drug and xenobiotic metabolism, which is influenced most with medication/xenobiotic-mediated toxic activity. Drug-induced hepatotoxicity is common and its actual frequency is hard to determine due to underreporting, difficulties in detection or diagnosis, and incomplete observation of exposure. The death rate is high, up to about 10% for drug-induced liver damage. Endorsed medications represented >50% of instances of intense liver failure in a study from the Acute Liver Failure Study Group 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 natural products in the treatment of various disorders led the investigators to look into their potential in countering drug-induced liver toxicity. Several natural products have been reported to date to mitigate the drug-induced toxicity. The dietary nature and less adverse reactions of the natural products provide them an extra edge over other candidates of supplementary medication. In this paper, we have discussed the mechanism involved in drug-induced liver toxicity and the potential of herbal antioxidants as supplementary medication. PMID:26858648

  9. 21 CFR 864.7415 - Abnormal hemoglobin assay.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Abnormal hemoglobin assay. 864.7415 Section 864... hemoglobin assay. (a) Identification. An abnormal hemoglobin assay is a device consisting of the reagents... hemoglobin types. (b) Classification. Class II (performance standards). [45 FR 60618, Sept. 12, 1980] ...

  10. 21 CFR 864.7415 - Abnormal hemoglobin assay.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Abnormal hemoglobin assay. 864.7415 Section 864... hemoglobin assay. (a) Identification. An abnormal hemoglobin assay is a device consisting of the reagents... hemoglobin types. (b) Classification. Class II (performance standards). [45 FR 60618, Sept. 12, 1980] ...

  11. Cytomorphological effects of mitomycin C on urothelial cells: eosinophils may be clue to the drug-induced changes.

    PubMed

    Guler Simsek, Gulcin; Vargol, Erdem; Simsek, Hulya

    2014-01-01

    Cytomorphological changes of mitomycin C on urothelial cells may be misinterpreted as a neoplastic process. A 60-year old male patient who was given an eight-week course of intravesical mitomycin C due to non-invasive low grade transitional cell carcinoma. During his follow-up care, the findings of a urine cytology exam were as follows: nuclear enlargement of cells, wrinkled nuclear membranes, little hyperchromasia, pleomorphism, abnormal nuclear morphology and disordered orientation of the urothelium. Furthermore, there were eosinophils nearby the atypical cells. This report aimed at reminding the cytomorphologic changes of mitomycin C may be misinterpreted as carcinoma, so the presence of eosinophils is required to predict the drug-induced changes.

  12. [Drug-induced acute pancreatitis: about 10 cases].

    PubMed

    Maghrebi, Houcine; Rhaeim, Rami; Haddad, Anis; Makni, Amin; Mohamed, Jouini; Montasser, Kacem; Zoubeir, Ben Safta

    2017-01-01

    Drug-induced acute pancreatitis (AP) accounts for approximately 2% of acute pancreatitis. Its incidence is increasing, with more than 260 incriminated drugs. However, very few cases have been described in the literature due to accountability problem. We report our experience with 10 cases whose data were collected over a period of 7 years. Clinical presentation of AP was often equivocal. Ranson's score ranged from 0 to 5. We recorded 5 cases of edematous pancreatitis and 5 cases of necro-bleeding pancreatitis. These pancreatitis were often successfully treated without recurrence after discontinuation of the incriminated drug.

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

    PubMed

    Iryna, Klyarytskaya; Helen, Maksymova; Elena, Stilidi

    2015-01-01

    The study presented here was accomplished to assess the course of drug-induced liver diseases in patient's rheumatoid arthritis receiving long-term methotrexate therapy. Diabetes mellitus was revealed as the most significant risk factor. The combination of diabetes mellitus with other risk factors (female sex) resulted in increased hepatic fibrosis, degree of hepatic encephalopathy and reduction of hepatic functions. The effectiveness and safety of ursodeoxycholic acid and cytolytic type-with S-Adenosyl methionine was also evaluated. 13C-MBT: 13C-methacetin breath test; ALT: alanine aminotransferase; AP: alkaline phosphatase; AST: aspartic transaminase; DILD: drug-induced liver disease; DM: diabetes mellitus; HE: hepatic encephalopathy; HFM: hepatic functional mass; SAMe: S-Adenosyl methionine; UDCA: ursodeoxycholic acid. Iryna K, Helen M, Elena S. Drug-induced Liver Disease in Patients with Diabetes Mellitus. Euroasian J Hepato-Gastroenterol 2015;5(2):83-86.

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

    PubMed

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

    2014-03-01

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

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Chatterjee, Sagnik, E-mail: Sagnik.Chatterjee@pharm.kuleuven.be; Richert, Lysiane, E-mail: l.richert@kaly-cell.com; Augustijns, Patrick, E-mail: Patrick.Augustijns@pharm.kuleuven.be

    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 bymore » 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

  16. An Abnormal Psychology Community Based Interview Assignment

    ERIC Educational Resources Information Center

    White, Geoffry D.

    1977-01-01

    A course option in abnormal psychology involves students in interviewing and observing the activities of individuals in the off-campus community who are concerned with some aspect of abnormal psychology. The technique generates student interest in the field when they interview people about topics such as drug abuse, transsexualism, and abuse of…

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

    PubMed

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

    2011-06-01

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

  18. Effects of Trans-Resveratrol on hyperglycemia-induced abnormal spermatogenesis, DNA damage and alterations in poly (ADP-ribose) polymerase signaling in rat testis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Abdelali, Ala

    Diabetes induces oxidative stress, DNA damage and alters several intracellular signaling pathways in organ systems. This study investigated modulatory effects of Trans-Resveratrol on type 1 diabetes mellitus (T1DM)-induced abnormal spermatogenesis, DNA damage and alterations in poly (ADP-ribose) polymerase (PARP) signaling in rat testis. Trans-Resveratrol administration (5mg/kg/day, ip) to Streptozotocin-induced T1DM adult male Wistar rats from day 22–42 resulted in recovery of induced oxidative stress, abnormal spermatogenesis and inhibited DNA synthesis, and led to mitigation of 8-hydroxy-2'-deoxyguanosine formation in the testis and spermatozoa, and DNA double-strand breaks in the testis. Trans-Resveratrol aggravated T1DM-induced up-regulation of aminoacyl tRNA synthetase complex-interacting multifunctional proteinmore » 2 expression; however, it did not modify the up-regulated total PARP and down-regulated PARP1 expressions, but recovered the decreased SirT1 (Sirtuin 1) levels in T1DM rat testis. Trans-Resveratrol, when given alone, reduced the poly (ADP-ribosyl)ation (pADPr) process in the testis due to an increase in PAR glycohydrolase activity, but when given to T1DM rats it did not affect the pADPr levels. T1DM with or without Trans-Resveratrol did not induce nuclear translocation of apoptosis-inducing factor and the formation of 50 kb DNA breaks, suggesting to the lack of caspase-3-independent cell death called parthanatos. T1DM with or without Trans-Resveratrol did not increase necrotic cell death in the testis. Primary spermatocytes, Sertoli cells, Leydig cells and intra-testicular vessels showed the expression of PARP pathway related proteins. In conclusion, Trans-Resveratrol mitigates T1DM-induced sperm abnormality and DNA damage, but does not significantly modulate PARP signaling pathway, except the SirT1 expression, in the rat testis. - Highlights: • Resveratrol inhibits diabetes-induced abnormal sperm morphogenesis • Resveratrol recovers

  19. Nightmare and Abnormal Dreams: Rare Side Effects of Metformin?

    PubMed Central

    Yanto, Theo Audi; Kosasih, Felicia Nathania

    2018-01-01

    Background Metformin is widely known as an antidiabetic agent which has significant gastrointestinal side effects, but nightmares and abnormal dreams as its adverse reactions are not well reported. Case Presentation Herein we present a case of 56-year-old male patient with no known history of recurrent nightmares and sleep disorder, experiencing nightmare and abnormal dreams directly after consumption of 750 mg extended release metformin. He reported his dream as an unpleasant experience which awakened him at night with negative feelings. The nightmare only lasted for a night, but his dreams every night thereafter seemed abnormal. The dreams were vivid and indescribable. The disappearance and occurrence of abnormal dreams ensued soon after the drug was discontinued and rechallenged. The case was assessed using Naranjo Adverse Drug Reaction (ADR) probability scale and resulted as probable causality. Conclusion Metformin might be the underlying cause of nightmare and abnormal dreams in this patient. More studies are needed to confirm the association and causality of this findings. PMID:29581904

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Shirakawa, Maho; Sekine, Shuichi; Tanaka, Ayaka

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

  1. Retinal abnormalities in β-thalassemia major.

    PubMed

    Bhoiwala, Devang L; Dunaief, Joshua L

    2016-01-01

    Patients with beta (β)-thalassemia (β-TM: β-thalassemia major, β-TI: β-thalassemia intermedia) have a variety of complications that may affect all organs, including the eye. Ocular abnormalities include retinal pigment epithelial degeneration, angioid streaks, venous tortuosity, night blindness, visual field defects, decreased visual acuity, color vision abnormalities, and acute visual loss. Patients with β-thalassemia major are transfusion dependent and require iron chelation therapy to survive. Retinal degeneration may result from either retinal iron accumulation from transfusion-induced iron overload or retinal toxicity induced by iron chelation therapy. Some who were never treated with iron chelation therapy exhibited retinopathy, and others receiving iron chelation therapy had chelator-induced retinopathy. We will focus on retinal abnormalities present in individuals with β-thalassemia major viewed in light of new findings on the mechanisms and manifestations of retinal iron toxicity. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. SU-E-J-122: Detecting Treatment-Induced Metabolic Abnormalities in Craniopharyngioma Patients Undergoing Surgery and Proton Therapy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hua, C; Shulkin, B; Li, Y

    Purpose: To identify treatment-induced defects in the brain of children with craniopharyngioma receiving surgery and proton therapy using fluorodeoxyglucose positron emission tomography (FDG PET). Methods: Forty seven patients were enrolled on a clinical trial for craniopharyngioma with serial imaging and functional evaluations. Proton therapy was delivered using the double-scattered beams with a prescribed dose of 54 Cobalt Gray Equivalent. FDG tracer uptake in each of 63 anatomical regions was computed after warping PET images to a 3D reference template in Talairach coordinates. Regional uptake was deemed significantly low or high if exceeding two standard deviations of normal population from themore » mean. For establishing the normal ranges, 132 children aged 1–20 years with noncentral nervous system related diseases and normal-appearing cerebral PET scans were analyzed. Age- and gender-dependent regional uptake models were developed by linear regression and confidence intervals were calculated. Results: Most common PET abnormality before proton therapy was significantly low uptake in the frontal lobe, the occipital lobe (particularly in cuneus), the medial and ventral temporal lobe, cingulate gyrus, caudate nuclei, and thalamus. They were related to injury from surgical corridors, tumor mass effect, insertion of a ventricular catheter, and the placement of an Ommaya reservoir. Surprisingly a significantly high uptake was observed in temporal gyri and the parietal lobe. In 13 patients who already completed 18-month PET scans, metabolic abnormalities improved in 11 patients from baseline. One patient had persistent abnormalities. Only one revealed new uptake abnormalities in thalamus, brainstem, cerebellum, and insula. Conclusion: Postoperative FDG PET of craniopharyngioma patients revealed metabolic abnormalities in specific regions of the brain. Proton therapy did not appear to exacerbate these surgery- and tumor-induced defects. In patients with

  3. Pulmonary and generalized lysosomal storage induced by amphiphilic drugs.

    PubMed Central

    Hruban, Z

    1984-01-01

    Administration of amphiphilic drugs to experimental animals causes formation of myelinoid bodies in many cell types, accumulation of foamy macrophages in pulmonary alveoli and pulmonary alveolar proteinosis. These changes are the result of an interaction between the drugs and phospholipids which leads to an alteration in physicochemical properties of the phospholipids. Impairment of the digestion of altered pulmonary secretions in phagosomes of macrophages results in accumulation of foam cells in pulmonary alveoli. Impairment of the metabolism of altered phospholipids removed by autophagy induces an accumulation of myelinoid bodies. The administration of amphiphilic compounds thus causes pulmonary intra-alveolar histiocytosis which is a part of a drug-induced lysosomal storage or generalized lipidosis. The accumulation of drug-lipid complexes in myelinoid bodies and in pulmonary foam cells may lead to alteration of cellular functioning and to clinical disease. Currently over 50 amphiphilic drugs are known. Unique pharmacological properties necessitate clinical use of some of these drugs. The occurrence and severity of potential clinical side effects depend on the nature of each drug, dosage and duration of treatment, simultaneous administration of other drugs and foods, individual metabolic pattern of the patient and other factors. Further studies on factors preventing and potentiating adverse effects of amphiphilic drugs are indicated. Images FIGURE 1. FIGURE 2. FIGURE 3. FIGURE 4. FIGURE 5. FIGURE 6. FIGURE 7. FIGURE 8. FIGURE 9. FIGURE 10. PMID:6376111

  4. Acute organic brain syndrome due to drug-induced eosinophilia.

    PubMed

    Ng, S C; Lee, M K; Teh, A

    1989-11-01

    A 72 year old man developed acute organic brain syndrome associated with marked eosinophilia following self medication with a variety of drugs. Investigations revealed no other known causes of eosinophilia. Withdrawal of drugs resulted in dramatic drop in eosinophil count paralleled by clinical resolution of neurological problems. To our knowledge drug-induced eosinophilia has not previously been associated with acute organic brain syndrome.

  5. Drugp-Induced Rhabdomyolysis Atlas (DIRA) for idiosyncratic adverse drug reaction management.

    PubMed

    Wen, Zhining; Liang, Yu; Hao, Yingyi; Delavan, Brian; Huang, Ruili; Mikailov, Mike; Tong, Weida; Li, Menglong; Liu, Zhichao

    2018-06-11

    Drug-induced rhabdomyolysis (DIR) is an idiosyncratic and fatal adverse drug reaction (ADR) characterized in severe muscle injuries accompanied by multiple-organ failure. Limited knowledge regarding the pathophysiology of rhabdomyolysis is the main obstacle to developing early biomarkers and prevention strategies. Given the lack of a centralized data resource to curate, organize, and standardize widespread DIR information, here we present a Drug-Induced Rhabdomyolysis Atlas (DIRA) that provides DIR-related information, including: a classification scheme for DIR based on drug labeling information; postmarketing surveillance data of DIR; and DIR drug property information. To elucidate the utility of DIRA, we used precision dosing, concomitant use of DIR drugs, and predictive modeling development to exemplify strategies for idiosyncratic ADR (IADR) management. Published by Elsevier Ltd.

  6. Exercise-induced Hypoalgesia in People With Knee Osteoarthritis With Normal and Abnormal Conditioned Pain Modulation.

    PubMed

    Fingleton, Caitríona; Smart, Keith M; Doody, Catherine M

    2017-05-01

    Normal efficiency of exercise-induced hypoalgesia (EIH) has been demonstrated in people with knee osteoarthritis (OA), while recent evidence suggests that EIH may be associated with features of pain sensitization such as abnormal conditioned pain modulation (CPM). The aim of this study was to investigate whether people with knee OA with abnormal CPM have dysfunctional EIH compared with those with normal CPM and pain-free controls. Forty peoples with knee OA were subdivided into groups with abnormal and normal CPM, as determined by a decrease/increase in pressure pain thresholds (PPTs) following the cold pressor test. Abnormal CPM (n=19), normal CPM (n=21), and control participants (n=20) underwent PPT testing before, during, and after aerobic and isometric exercise protocols. Between-group differences were analyzed using repeated-measures analysis of variance and within-group differences were analyzed using Wilcoxon signed-rank tests. Significant differences were demonstrated between groups for changes in PPTs postaerobic (F2,55=4.860; P=0.011) and isometric (F2,57=4.727; P=0.013) exercise, with significant decreases in PPTs demonstrated during and postexercise in the abnormal CPM group (P<0.05), and significant increases in PPTs shown during and postexercise in the normal CPM and control groups (P<0.05). Results are suggestive of dysfunctional EIH in response to aerobic and isometric exercise in knee OA patients with abnormal CPM, and normal function of EIH in knee OA patients with an efficient CPM response. Identification of people with knee OA with inefficient endogenous pain modulation may allow for a more individualized and graded approach to exercises in these individuals.

  7. [Machine Learning-based Prediction of Seizure-inducing Action as an Adverse Drug Effect].

    PubMed

    Gao, Mengxuan; Sato, Motoshige; Ikegaya, Yuji

    2018-01-01

     During the preclinical research period of drug development, animal testing is widely used to help screen out a drug's dangerous side effects. However, it remains difficult to predict side effects within the central nervous system. Here, we introduce a machine learning-based in vitro system designed to detect seizure-inducing side effects before clinical trial. We recorded local field potentials from the CA1 alveus in acute mouse neocortico-hippocampal slices that were bath-perfused with each of 14 different drugs, and at 5 different concentrations of each drug. For each of these experimental conditions, we collected seizure-like neuronal activity and merged their waveforms as one graphic image, which was further converted into a feature vector using Caffe, an open framework for deep learning. In the space of the first two principal components, the support vector machine completely separated the vectors (i.e., doses of individual drugs) that induced seizure-like events, and identified diphenhydramine, enoxacin, strychnine and theophylline as "seizure-inducing" drugs, which have indeed been reported to induce seizures in clinical situations. Thus, this artificial intelligence-based classification may provide a new platform to pre-clinically detect seizure-inducing side effects of drugs.

  8. Cue-Induced Craving to Paraphernalia and Drug Images in Opioid Dependence

    PubMed Central

    McHugh, R. Kathryn; Fulciniti, Francesca; Mashhoon, Yasmin; Weiss, Roger D.

    2016-01-01

    Background and Objectives Stimuli that are repeatedly paired with substance use, such as drug paraphernalia, can themselves elicit drug craving. The aim of this study was to examine whether particular cue types elicit greater craving responses than others among individuals with opioid dependence. Methods Participants seeking inpatient treatment for opioid dependence were recruited for a study of cue-induced craving. This sample (N=50), included 25 primary heroin users, 20 primary prescription opioid users, and 5 users of heroin and prescription opioids equally. Participants completed a cue reactivity task, in which images of drug-related stimuli were presented on a computer screen, each followed by a question assessing state drug craving. Results Overall, participants reported higher craving following paraphernalia stimuli relative to drug stimuli. However, this was moderated by opioid type; there was significantly higher craving in response to images of paraphernalia cues in the heroin group, and higher craving in response to drug cues in the prescription opioid group. Discussion and Conclusions These findings highlight potential differences in cue reactivity to opioid paraphernalia and drug cues, which appears to be moderated by drug type. Scientific Significance Cue-induced craving is an important factor in relapse. This study adds further to the literature on cue-induced craving in opioid dependence, suggesting that craving may vary based on both cue type and opioid type. Future studies designed to discriminate the impact of substance of abuse, route of administration, and cue type will help to further understand cue-induced craving in this population. PMID:26848719

  9. Acute organic brain syndrome due to drug-induced eosinophilia.

    PubMed Central

    Ng, S. C.; Lee, M. K.; Teh, A.

    1989-01-01

    A 72 year old man developed acute organic brain syndrome associated with marked eosinophilia following self medication with a variety of drugs. Investigations revealed no other known causes of eosinophilia. Withdrawal of drugs resulted in dramatic drop in eosinophil count paralleled by clinical resolution of neurological problems. To our knowledge drug-induced eosinophilia has not previously been associated with acute organic brain syndrome. PMID:2616421

  10. Endocide-Induced Abnormal Growth Forms of Invasive Giant Salvinia (Salvinia molesta).

    PubMed

    Li, Shiyou; Wang, Ping; Su, Zushang; Lozano, Emily; LaMaster, Olivia; Grogan, Jason B; Weng, Yuhui; Decker, Thomas; Findeisen, John; McGarrity, Monica

    2018-05-22

    Giant salvinia (Salvinia molesta) is one of the most noxious invasive species in the world. The fern is known to have primary, secondary, and tertiary growth forms, which are also commonly hypothesized as growth stages. The identification of these forms is primarily based on the size and folding status of the floating leaves. However, we identified 12 forms in the greenhouse and the field. Our experiments showed that the folding of floating leaves is a reversible trait dependent on water access. The floating leaves quickly fold in response to water shortage, reducing water loss and needs, decreasing growth, and avoiding trichome damage. The leaves re-open to allow trichomes repel water and enhance growth when having adequate water supply. Larger secondary or tertiary forms do not produce small-leaf primary forms without high intensity stress. These results do not support the hypothesis that three growth forms represent sequential growth stages. The abnormal small-leaf forms are the result of endocide-induced autotoxicity and some of them never grow into other forms. The development of abnormal forms and reversible leaf folding strategy in response to high stress along with rapid asexual reproduction are major adaptive traits contributing to the invasiveness of S. molesta.

  11. Toxin-Induced Autoimmune Hepatitis Caused by Raw Cashew Nuts.

    PubMed

    Crismale, James F; Stueck, Ashley; Bansal, Meena

    2016-08-01

    A 64-year-old man with no past medical history presented with abnormally elevated liver enzymes 1 year after developing a diffuse rash thought to be related to eating large quantities of raw cashew nuts. Liver biopsy was performed, which revealed features concerning for drug- or toxin-induced autoimmune hepatitis. The patient began treatment with azathioprine and prednisone, and liver enzymes normalized. We describe a unique case of a toxin-induced autoimmune hepatitis precipitated not by a drug or dietary supplement but by a food product.

  12. Effects of resocialization on post-weaning social isolation-induced abnormal aggression and social deficits in rats.

    PubMed

    Tulogdi, Aron; Tóth, Máté; Barsvári, Beáta; Biró, László; Mikics, Eva; Haller, József

    2014-01-01

    As previously shown, rats isolated from weaning develop abnormal social and aggressive behavior characterized by biting attacks targeting vulnerable body parts of opponents, reduced attack signaling, and increased defensive behavior despite increased attack counts. Here we studied whether this form of violent aggression could be reversed by resocialization in adulthood. During the first weak of resocialization, isolation-reared rats showed multiple social deficits including increased defensiveness and decreased huddling during sleep. Deficits were markedly attenuated in the second and third weeks. Despite improved social functioning in groups, isolated rats readily showed abnormal features of aggression in a resident-intruder test performed after the 3-week-long resocialization. Thus, post-weaning social isolation-induced deficits in prosocial behavior were eliminated by resocialization during adulthood, but abnormal aggression was resilient to this treatment. Findings are compared to those obtained in humans who suffered early social maltreatment, and who also show social deficits and dysfunctional aggression in adulthood. © 2013 Wiley Periodicals, Inc.

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

    PubMed

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

    2015-12-01

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

  14. AgHalo: A Facile Fluorogenic Sensor to Detect Drug-Induced Proteome Stress.

    PubMed

    Liu, Yu; Fares, Matthew; Dunham, Noah P; Gao, Zi; Miao, Kun; Jiang, Xueyuan; Bollinger, Samuel S; Boal, Amie K; Zhang, Xin

    2017-07-17

    Drug-induced proteome stress that involves protein aggregation may cause adverse effects and undermine the safety profile of a drug. Safety of drugs is regularly evaluated using cytotoxicity assays that measure cell death. However, these assays provide limited insights into the presence of proteome stress in live cells. A fluorogenic protein sensor is reported to detect drug-induced proteome stress prior to cell death. An aggregation prone Halo-tag mutant (AgHalo) was evolved to sense proteome stress through its aggregation. Detection of such conformational changes was enabled by a fluorogenic ligand that fluoresces upon AgHalo forming soluble aggregates. Using 5 common anticancer drugs, we exemplified detection of differential proteome stress before any cell death was observed. Thus, this sensor can be used to evaluate drug safety in a regime that the current cytotoxicity assays cannot cover and be generally applied to detect proteome stress induced by other toxins. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Transient abnormal Q waves during exercise electrocardiography

    PubMed Central

    Alameddine, F F; Zafari, A M

    2004-01-01

    Myocardial ischaemia during exercise electrocardiography is usually manifested by ST segment depression or elevation. Transient abnormal Q waves are rare, as Q waves indicate an old myocardial infarction. The case of a patient with exercise induced transient abnormal Q waves is reported. The potential mechanisms involved in the development of such an abnormality and its clinical implications are discussed. PMID:14676264

  16. Epigenetic regulation of dorsal raphe GABA(B1a) associated with isolation-induced abnormal responses to social stimulation in mice.

    PubMed

    Araki, Ryota; Hiraki, Yosuke; Nishida, Shoji; Kuramoto, Nobuyuki; Matsumoto, Kinzo; Yabe, Takeshi

    2016-02-01

    In isolation-reared mice, social encounter stimulation induces locomotor hyperactivity and activation of the dorsal raphe nucleus (DRN), suggesting that dysregulation of dorsal raphe function may be involved in abnormal behaviors. In this study, we examined the involvement of dorsal raphe GABAergic dysregulation in the abnormal behaviors of isolation-reared mice. We also studied an epigenetic mechanism underlying abnormalities of the dorsal raphe GABAergic system. Both mRNA and protein levels of GABA(B1a), a GABA(B) receptor subunit, were increased in the DRN of isolation-reared mice, compared with these levels in group-reared mice. In contrast, mRNA levels for other GABAergic system-related genes (GABA(A) receptor α1, β2 and γ2 subunits, GABA(B) receptor 1b and 2 subunits, and glutamate decarboxylase 67 and 65) were unchanged. Intra-DRN microinjection of 0.06 nmol baclofen (a GABA(B) receptor agonist) exacerbated encounter-induced hyperactivity and aggressive behavior, while microinjection of 0.3 nmol phaclofen (a GABA(B) receptor antagonist) attenuated encounter-induced hyperactivity and aggressive behavior in isolation-reared mice. Furthermore, microinjection of 0.06 nmol baclofen elicited encounter-induced hyperactivity in group-reared mice. Neither baclofen nor phaclofen affected immobility time in the forced swim test and hyperactivity in a novel environment of isolation reared mice. Bisulfite sequence analyses revealed that the DNA methylation level of the CpG island around the transcription start site (TSS) of GABA(B1a) was decreased in the DRN of isolation-reared mice. Chromatin immunoprecipitation analysis showed that histone H3 was hyperacetylated around the TSS of GABA(B1a) in the DRN of isolation-reared mice. These findings indicate that an increase in dorsal raphe GABA(B1a) expression via epigenetic regulation is associated with abnormal responses to social stimulation such as encounter-induced hyperactivity and aggressive behavior in isolation

  17. Gamma-tubulin-containing abnormal centrioles are induced by insufficient Plk4 in human HCT116 colorectal cancer cells.

    PubMed

    Kuriyama, Ryoko; Bettencourt-Dias, Monica; Hoffmann, Ingrid; Arnold, Marc; Sandvig, Lisa

    2009-06-15

    Cancer cells frequently induce aberrant centrosomes, which have been implicated in cancer initiation and progression. Human colorectal cancer cells, HCT116, contain aberrant centrioles composed of disorganized cylindrical microtubules and displaced appendages. These cells also express unique centrosome-related structures associated with a subset of centrosomal components, including gamma-tubulin, centrin and PCM1. During hydroxyurea treatment, these abnormal structures become more abundant and undergo a change in shape from small dots to elongated fibers. Although gamma-tubulin seems to exist as a ring complex, the abnormal structures do not support microtubule nucleation. Several lines of evidence suggest that the fibers correspond to a disorganized form of centriolar microtubules. Plk4, a mammalian homolog of ZYG-1 essential for initiation of centriole biogenesis, is not associated with the gamma-tubulin-specific abnormal centrosomes. The amount of Plk4 at each centrosome was less in cells with abnormal centrosomes than cells without gamma-tubulin-specific abnormal centrosomes. In addition, the formation of abnormal structures was abolished by expression of exogenous Plk4, but not SAS6 and Cep135/Bld10p, which are downstream regulators required for the organization of nine-triplet microtubules. These results suggest that HCT116 cells fail to organize the ninefold symmetry of centrioles due to insufficient Plk4.

  18. Effects and mechanisms of caffeine to improve immunological and metabolic abnormalities in diet-induced obese rats.

    PubMed

    Liu, Chih-Wei; Tsai, Hung-Cheng; Huang, Chia-Chang; Tsai, Chang-Youh; Su, Yen-Bo; Lin, Ming-Wei; Lee, Kuei-Chuan; Hsieh, Yun-Cheng; Li, Tzu-Hao; Huang, Shiang-Fen; Yang, Ying-Ying; Hou, Ming-Chih; Lin, Han-Chieh; Lee, Fa-Yauh; Lee, Shou-Dong

    2018-05-01

    In obesity, there are no effective therapies for parallel immune and metabolic abnormalities, including systemic/tissue insulin-resistance/inflammation, adiposity and hepatic steatosis. Caffeine has anti-inflammation, antihepatic steatosis, and anti-insulin resistance effects. In this study, we evaluated the effects and molecular mechanisms of 6 wk of caffeine treatment (HFD-caf) on immunological and metabolic abnormalities of high-fat diet (HFD)-induced obese rats. Compared with HFD vehicle (HFD-V) rats, in HFD-caf rats the suppressed circulating immune cell inflammatory [TNFα, MCP-1, IL-6, intercellular adhesion molecule 1 (ICAM-1), and nitrite] profiles were accompanied by decreased liver, white adipose tissue (WAT), and muscle macrophages and their intracellular cytokine levels. Metabolically, the increase in metabolic rates reduced lipid accumulation in various tissues, resulting in reduced adiposity, lower fat mass, decreased body weight, amelioration of hepatic steatosis, and improved systemic/muscle insulin resistance. Further mechanistic approaches revealed an upregulation of tissue lipogenic [(SREBP1c, fatty acid synthase, acetyl-CoA carboxylase)/insulin-sensitizing (GLUT4 and p-IRS1)] markers in HFD-caf rats. Significantly, ex vivo experiments revealed that the cytokine release by the cocultured peripheral blood mononuclear cell (monocyte) and WAT (adipocyte), which are known to stimulate macrophage migration and hepatocyte lipogenesis, were lower in HFD-V groups than HFD-caf groups. Caffeine treatment simultaneously ameliorates immune and metabolic pathogenic signals present in tissue to normalize immunolgical and metabolic abnormalities found in HFD-induced obese rats.

  19. Alterations in myocardial free fatty acid clearance precede mechanical abnormalities in canine tachycardia-induced heart failure.

    PubMed

    Freeman, G L; Colston, J T; Miller, D D

    1994-01-01

    The purpose of this study was to evaluate whether abnormalities of free fatty acid metabolism are present before the onset of overt mechanical dysfunction in dogs with tachycardia-induced heart failure. We studied six dogs chronically instrumented to allow assessment of left ventricular function in the pressure-volume plane. Free fatty acid clearance was assessed according to the washout rate of a free fatty acid analog, iodophenylpentadecanoic acid ([123I]PPA or IPPA). IPPA clearance was measured within 1 hour of the hemodynamic assessment. The animals were studied under baseline conditions and 11.7 +/- 3.6 days after ventricular pacing at a rate of 240 beats/min. Hemodynamic studies after pacing showed a nonsignificant increase in left ventricular end-diastolic pressure (11.7 +/- 4.7 to 17.4 +/- 6.5 mm Hg) and a nonsignificant decrease in the maximum derivative of pressure with respect to time (1836 +/- 164 vs 1688 +/- 422 mm Hg/sec). There was also no change in the time constant of left ventricular relaxation, which was 34.8 +/- 7.67 msec before and 35.3 +/- 7.3 msec after pacing. However, a significant prolongation in the clearance half-time of [123I]PPA, from 86.1 +/- 23.9 to 146.5 +/- 22.6 minutes (p < 0.01) was found. Thus abnormal lipid clearance appears before the onset of significant mechanical dysfunction in tachycardia-induced heart failure. This suggests that abnormal substrate metabolism may play an important role in the pathogenesis of this condition.

  20. The intersection of stress, drug abuse and development.

    PubMed

    Thadani, Pushpa V

    2002-01-01

    Use or abuse of licit and illicit substances is often associated with environmental stress. Current clinical evidence clearly demonstrates neurobehavioral, somatic growth and developmental deficits in children born to drug-using mothers. However, the effects of environmental stress and its interaction with prenatal drug exposure on a child's development is unknown. Studies in pregnant animals under controlled conditions show drug-induced long-term alterations in brain structures and functions of the offspring. These cytoarchitecture alterations in the brain are often associated with perturbations in neurotransmitter systems that are intimately involved in the regulation of the stress responses. Similar abnormalities have been observed in the brains of animals exposed to other adverse exogenous (e.g., environmental stress) and/or endogenous (e.g., glucocorticoids) experiences during early life. The goal of this article is to: (1) provide evidence and a perspective that common neural systems are influenced during development both by perinatal drug exposure and early stress exposure; and (2) identify gaps and encourage new research examining the effects of early stress and perinatal drug exposure, in animal models, that would elucidate how stress- and drug-induced perturbations in neural systems influence later vulnerability to abused drugs in adult offspring.

  1. Drug-induced acne and rose pearl: similarities*

    PubMed Central

    Pontello Junior, Rubens; Kondo, Rogerio Nabor

    2013-01-01

    Drug-induced acne is a common skin condition whose classic symptoms can be similar to a rose pearl, as in the case of a male patient presenting with this condition after excessive use of a cream containing corticosteroids. PMID:24474128

  2. [Antiepileptic drug-induced osteopathy. Subtypes, pathogenesis, prevention, early diagnosis and treatment].

    PubMed

    Bartl, R

    2007-07-29

    Published reports of studies on the long-term effects of anti-epileptic drugs (AED) on bone--its density, thickness, vitamin D metabolism and risk of fracture--have shown considerable methodological inadequacies (34). Despite these problems it has been clearly shown that patients with epilepsy who are on anti-epileptic drugs have a greater than normal risk of bone loss, abnormal mineralization and fractures. A patient on long-term treatment with AED has a two- to three-fold risk of sustaining a fracture. On average 50% of patients (ranging from 4-70% in different studies [18]) have an osteopathy (34). Type, dosage and duration of AED treatment determine the exact picture of the osteopathy--regardless of whether or not they are enzyme-inducing. Among the enzyme-inducing drugs, especially phenytoin, primidone, phenobarbital and carbamezapine have been investigated for their influence on vitamin D metabolism. Bone loss has also been noted even without evidence of vitamin D deficiency. Mixed forms of osteoporosis and osteomalacia occur particularly often and must be taken into account in any differentiated form of treatment. But the question remains unanswered whether current AEDs, such as lamotrigine, gabapentin or levetiracetam will cause little or no osteopathy. Comparable to the situation during long-term systemic administration of glucocorticoids, initial diagnosis, including the inexpensive dual-energy X-ray absorptiometry (DXA) and the serum concentration of 25-hydroxyvitamin D, must be obtained to determine whether initially there are any bone changes. In addition to a differentiated and clearly defined treatment of osteopathy in a patient with epilepsy, the aim must be to minimize the tendency towards seizures and their severity. The annual cost of adequate vitamin D substitution is about EUR 50, while biphosphonate treatment costs about EUR 500; the costs of vertebral or forearm fractures are about EUR 1000 and those of hip fracture about EUR 15,000. These

  3. Radiation induced abnormalities in early in vitro mouse embryos

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kirkpatrick, J.F.

    1973-08-01

    Female mice were superovulated and mated, and the two-cell embryos were collected and cultured in vitro. The embryos were exposed to x-irradiation (0 to 491 rads) during the two-cell stage before the appearance of the next cleavage plate, placed in new unirradiated culture medium and observed during subsequent development. Morphological abnormalities, which occurred as a result of irradiation, included fragmentation, disintegration, granlation, incomplete cleavage, cleavage cessation, nuclear degeneration and pycnosis and cytoplasmic vacuolization. There was no damage to the zona pellucida. The types of abnormalities indicate an agreement with the results of previous in vivo studies. A distinct correlation existedmore » between morphological abnormalities and embryo death. The greatest number of abnormalities resulted within five hours following irradiation, but increased through 20 hours post-exposure. At doses above 300 rads, the magnitude of damage was greater in the in vitro embryos than that shown in previous in vivo studies. (auth)« less

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2012-04-01

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

  7. [Talc-induced pulmonary granulomas in drug addicts].

    PubMed

    Latartseva, L N; Kryvenko, O N

    2013-01-01

    Among the diseases accompanied by granuloma formation in the lung, there is so-called granulomatosis developing in injection drug users who have been long injecting suspensions of oral medications containing talc and other water insoluble fillers. 102 deaths of chronic intravenous drug users were examined; 12 of whom showed pulmonary talc-induced granulomatosis. Their morphology was studied using polarized light microscopy. The main mechanisms of thanatogenesis in lethal cases within the first hours after intravenous injection of talc-containing oral medication suspensions are explained.

  8. Cerebrospinal fluid flow abnormalities in patients with neoplastic meningitis. An evaluation using /sup 111/In-DTPA ventriculography

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Grossman, S.A.; Trump, D.L.; Chen, D.C.

    1982-11-01

    Cerebrospinal fluid flow dynamics were evaluated by /sup 111/In-diethylenetriamine pentaacetic acid (/sup 111/In-DTPA) ventriculography in 27 patients with neoplastic meningitis. Nineteen patients (70 percent) had evidence of cerebrospinal fluid flow disturbances. These occurred as ventricular outlet obstructions, abnormalities of flow in the spinal canal, or flow distrubances over the cortical convexities. Tumor histology, physical examination, cerebrospinal fluid analysis, myelograms, and computerized axial tomographic scans were not sufficient to predict cerebrospinal fluid flow patterns. These data indicate that cerebrospinal fluid flow abnormalities are common in patients with neoplastic meningitis and that /sup 111/In-DTPA cerebrospinal fluid flow imaging is useful in characterizingmore » these abnormalities. This technique provides insight into the distribution of intraventricularly administered chemotherapy and may provide explanations for treatment failure and drug-induced neurotoxicity in patients with neoplastic meningitis.« less

  9. Abnormal bone formation induced by implantation of osteosarcoma-derived bone-inducing substance in the X-linked hypophosphatemic mouse

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yoshikawa, H.; Masuhara, K.; Takaoka, K.

    1985-01-01

    The X-linked hypophosphatemic mouse (Hyp) has been proposed as a model for the human familial hypophosphatemia (the most common form of vitamin D-resistant rickets). An osteosarcoma-derived bone-inducing substance was subcutaneously implanted into the Hyp mouse. The implant was consistently replaced by cartilage tissue at 2 weeks after implantation. The cartilage matrix seemed to be normal, according to the histological examination, and 35sulphur (TVS) uptake was also normal. Up to 4 weeks after implantation the cartilage matrix was completely replaced by unmineralized bone matrix and hematopoietic bone marrow. Osteoid tissue arising from the implantation of bone inducing substance in the Hypmore » mouse showed no radiologic or histologic sign of calcification. These findings suggest that the abnormalities of endochondral ossification in the Hyp mouse might be characterized by the failure of mineralization in cartilage and bone matrix. Analysis of the effects of bone-inducing substance on the Hyp mouse may help to give greater insight into the mechanism and treatment of human familial hypophosphatemia.« less

  10. Antithyroid drug-induced agranulocytosis.

    PubMed

    Sun, Ming-Tsung; Tsai, Chen-Hao; Shih, Kuang-Chung

    2009-08-01

    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/microL. 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.

  11. Acute Opioid-Induced Myoclonic Reaction after Use of Fentanyl as an Anesthetic Drug for an Emergency Cesarean Section.

    PubMed

    Almedallah, Dana Khaled; Alshamlan, Dana Yousef; Shariff, Erum Mubbashir

    2018-01-01

    Myoclonus is an abnormal involuntary movement that has been previously reported with administration of high doses of opioids for prolonged periods of time. In this case, however, we report an acute myoclonic reaction and review the literature on the possible causative pathophysiology. We report the case of a 24-year-old woman who was admitted for postdated cesarean section. She started to have abnormal involuntary movements after administration of an epidural anesthesia containing 700 μg of fentanyl with 115 mL (0.5) bupivacaine and 40 mL (2%) lidocaine. Upon examination, the patient was conscious, alert, and oriented. Her vital signs were stable. Her movements can be described as generalized, sudden, involuntary, jerking movements, involving the upper limbs, head, torso as well as the lower limbs. The frequency of these jerks was about every 1-2 min lasting for 10 s. There was no change in level of consciousness during these abnormal movements. The rest of the neurological examination was normal. Laboratory values showed normoglycemia and normal serum biochemistry. A routine electroencephalogram showed no epileptiform activity. Brain imaging was normal. Based on history, examination, and laboratory findings, we made the diagnosis of drug-induced myoclonus, which in this clinical scenario was secondary to fentanyl. We discontinued fentanyl and, gradually, the intensity and frequency of the abnormal movements decreased and disappeared after a few hours. A clear definitive explanation of the acute effect of opioids is still to be reached. It involves an interaction of complex neuroanatomical pathways and neurophysiological receptors. Nonetheless, a unanimous effort is needed to raise awareness about the role of opioids in the development of abnormal movements and their clinical management, to insure that they do not go unnoticed in the clinical scenarios, and to further add more scientific content that could help in reaching an explanatory theory.

  12. Hepatitis B virus X protein (HBx)-induced abnormalities of nucleic acid metabolism revealed by (1)H-NMR-based metabonomics.

    PubMed

    Dan Yue; Zhang, Yuwei; Cheng, Liuliu; Ma, Jinhu; Xi, Yufeng; Yang, Liping; Su, Chao; Shao, Bin; Huang, Anliang; Xiang, Rong; Cheng, Ping

    2016-04-14

    Hepatitis B virus X protein (HBx) plays an important role in HBV-related hepatocarcinogenesis; however, mechanisms underlying HBx-mediated carcinogenesis remain unclear. In this study, an NMR-based metabolomics approach was applied to systematically investigate the effects of HBx on cell metabolism. EdU incorporation assay was conducted to examine the effects of HBx on DNA synthesis, an important feature of nucleic acid metabolism. The results revealed that HBx disrupted metabolism of glucose, lipids, and amino acids, especially nucleic acids. To understand the potential mechanism of HBx-induced abnormalities of nucleic acid metabolism, gene expression profiles of HepG2 cells expressing HBx were investigated. The results showed that 29 genes involved in DNA damage and DNA repair were differentially expressed in HBx-expressing HepG2 cells. HBx-induced DNA damage was further demonstrated by karyotyping, comet assay, Western blotting, immunofluorescence and immunohistochemistry analyses. Many studies have previously reported that DNA damage can induce abnormalities of nucleic acid metabolism. Thus, our results implied that HBx initially induces DNA damage, and then disrupts nucleic acid metabolism, which in turn blocks DNA repair and induces the occurrence of hepatocellular carcinoma (HCC). These findings further contribute to our understanding of the occurrence of HCC.

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

    PubMed

    Gao, Mengxuan; Igata, Hideyoshi; Takeuchi, Aoi; Sato, Kaoru; Ikegaya, Yuji

    2017-02-01

    Various biological factors have been implicated in convulsive seizures, involving side effects of drugs. For the preclinical safety assessment of drug development, it is difficult to predict seizure-inducing side effects. Here, we introduced a machine learning-based in vitro system designed to detect seizure-inducing side effects. We recorded local field potentials from the CA1 alveus in acute mouse neocortico-hippocampal slices, while 14 drugs were bath-perfused at 5 different concentrations each. For each experimental condition, we collected seizure-like neuronal activity and merged their waveforms as one graphic image, which was further converted into a feature vector using Caffe, an open framework for deep learning. In the space of the first two principal components, the support vector machine completely separated the vectors (i.e., doses of individual drugs) that induced seizure-like events and identified diphenhydramine, enoxacin, strychnine and theophylline as "seizure-inducing" drugs, which indeed were reported to induce seizures in clinical situations. Thus, this artificial intelligence-based classification may provide a new platform to detect the seizure-inducing side effects of preclinical drugs. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  14. [A case of loxoprofen-induced pulmonary eosinophilia].

    PubMed

    Ii, T; Doutsu, Y; Ashitani, J; Taniguchi, H; Mizuta, M; Toshimori, H; Matsukura, S

    1992-05-01

    A 65-year-old female suffering from lumbago, headache, and hypertension had been treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and antihypertensive drugs. On June 13, 1990, 2 weeks after the commencement of loxoprofen administration, she developed cough and low grade fever. She was treated with antibiotics and NSAIDs without improvement. Laboratory data showed marked eosinophilia (2200/mm3), elevation of IgE (3090 IU/ml), and liver dysfunction. Her chest X-ray revealed no active lesion, but the percentage of eosinophils in BALF was elevated (38%). Because drug-induced eosinophilic pneumonia was suspected, all drugs were discontinued. Her symptoms improved and the abnormalities of laboratory data normalized. The lymphocyte stimulation test was weakly positive with three NSAIDs (loxoprofen, pranoprofen, and alminoprofen). The challenge test by loxoprofen reproduced eosinophilia and liver dysfunction, suggesting that she had loxoprofen-induced eosinophilic pneumonia. To our knowledge, this is the first reported case of loxoprofen-induced lung injury.

  15. Screening drug-induced arrhythmia [corrected] using human induced pluripotent stem cell-derived cardiomyocytes and low-impedance microelectrode arrays.

    PubMed

    Navarrete, Enrique G; Liang, Ping; Lan, Feng; Sanchez-Freire, Verónica; Simmons, Chelsey; Gong, Tingyu; Sharma, Arun; Burridge, Paul W; Patlolla, Bhagat; Lee, Andrew S; Wu, Haodi; Beygui, Ramin E; Wu, Sean M; Robbins, Robert C; Bers, Donald M; Wu, Joseph C

    2013-09-10

    Drug-induced arrhythmia is one of the most common causes of drug development failure and withdrawal from market. This study tested whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with a low-impedance microelectrode array (MEA) system could improve on industry-standard preclinical cardiotoxicity screening methods, identify the effects of well-characterized drugs, and elucidate underlying risk factors for drug-induced arrhythmia. hiPSC-CMs may be advantageous over immortalized cell lines because they possess similar functional characteristics as primary human cardiomyocytes and can be generated in unlimited quantities. Pharmacological responses of beating embryoid bodies exposed to a comprehensive panel of drugs at 65 to 95 days postinduction were determined. Responses of hiPSC-CMs to drugs were qualitatively and quantitatively consistent with the reported drug effects in literature. Torsadogenic hERG blockers, such as sotalol and quinidine, produced statistically and physiologically significant effects, consistent with patch-clamp studies, on human embryonic stem cell-derived cardiomyocytes hESC-CMs. False-negative and false-positive hERG blockers were identified accurately. Consistent with published studies using animal models, early afterdepolarizations and ectopic beats were observed in 33% and 40% of embryoid bodies treated with sotalol and quinidine, respectively, compared with negligible early afterdepolarizations and ectopic beats in untreated controls. We found that drug-induced arrhythmias can be recapitulated in hiPSC-CMs and documented with low impedance MEA. Our data indicate that the MEA/hiPSC-CM assay is a sensitive, robust, and efficient platform for testing drug effectiveness and for arrhythmia screening. This system may hold great potential for reducing drug development costs and may provide significant advantages over current industry standard assays that use immortalized cell lines or animal models.

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

    PubMed Central

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

    2015-01-01

    Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens. PMID:26515599

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori

    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 hepatotoxicmore » 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 m

  18. [The clinicopathological analysis of 88 patients with abnormal liver function test of unknown etiology].

    PubMed

    Pang, Shu-zhen; Ou, Xiao-juan; Shi, Xiao-yan; Wang, Tai-ling; Duan, Wei-jia; Jia, Ji-dong

    2011-01-01

    To evaluate the clinical and histological features of patients with abnormal liver tests of unknown etiology, and then to investigate the diagnosis and differential diagnosis. Patients with abnormal liver function test hospitalized and had liver biopsies during 2008 - 2009 constituted this retrospective study cohort. After excluding those patients diagnosed with hepatotropic viral hepatitis, space occupying lesions of the liver, alcoholic liver disease and obstruction of bile duct caused by stone or malignancy and AMA/AMA-M(2) positive of primary biliary cirrhosis (PBC), the clinical and histological characteristics were evaluated. Out of the 180 patients who underwent liver biopsy, 88 patients were included in the present analysis. The final diagnosis involved 15 categories of diseases, with drug-induced liver injury (DILI) [34.09% (30/88)], autoimmune liver diseases [22.73% (20/88)], and nonalcoholic fatty liver disease (NAFLD) [12.50% (11/88)] being the most common causes, following by genetic and other rare diseases. DILI, autoimmune liver disease and NAFLD were the most common causes of abnormal liver tests in these non-viral liver diseases. Some rare diseases such as hereditary metabolic liver disease also represent a considerable proportion in patients with abnormal liver function test.

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

    PubMed

    Devarbhavi, Harshad; Andrade, Raúl J

    2014-05-01

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

  20. Case ascertainment and estimated incidence of drug-induced long-QT syndrome: study in Southwest France

    PubMed Central

    Molokhia, Mariam; Pathak, Atul; Lapeyre-Mestre, Maryse; Caturla, Laetitia; Montastruc, Jean Louis; McKeigue, Paul

    2008-01-01

    AIMS The aim of this study was to investigate the incidence and reporting rate of drug-induced long-QT syndrome (LQTS) in France [defined by evidence of torsades de pointes (TdP), QT prolongation and exposure to a relevant drug] and to assess feasibility of case collection for drug-induced LQTS. METHODS A retrospective population-based study was carried out in Southwest France in five institutions: three main hospitals, one private clinic and one cardiac emergency unit, searched from 1 January 1999 to 1 January 2005 (population coverage of 614 000). The study population consisted of 861 cases with International Classification of Diseases-10 diagnostic codes for ventricular tachycardia (I147.2), ventricular fibrillation (I149.0) and sudden cardiac death (I146.1) from hospital discharge summaries, supplemented by cases reported to national or regional pharmacovigilance systems, and voluntary reporting by physicians, validated according to internationally defined criteria for drug-induced LQTS. RESULTS Of 861 patients coded with arrhythmias or sudden cardiac death, there were 40 confirmed surviving acquired cases of drug-induced LQTS. We estimated that the incidence of those who survive to reach hospital drug-induced LQTS is approximately 10.9 per million annually in France (95% confidence interval 7.8, 14.8). CONCLUSIONS Many cases of drug-induced LQTS may not survive before they reach hospital, as the reporting rate for drug-induced LQTS identified through the cardiology records and also reported to pharmacovigilance systems for the Midi-Pyrenees area is 3/40 (7.5%). Using the methods outlined it is possible to assemble cases to study genetic susceptibility to drug-induced LQTS and adapt these methods more widely. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Drug-induced long-QT syndrome (LQTS) is a potentially fatal condition that has led to a number of postmarketing withdrawals in recent years. However, many cases may not survive long enough to reach hospital, and

  1. [Morinda Officinalis How improves cellphone radiation-induced abnormality of LH and LHR in male rats].

    PubMed

    Li, Rong; Yang, Wei-qun; Chen, Hui-qin; Zhang, Yong-hong

    2015-09-01

    To investigate the effects of Morina Officinalis How (MOH) on the abnormal levels of serum luteotrophic hormone (LH) and LH receptor (LHR) in the testis tissue induced by cellphone radiation (CPR) in rats. Fifty adult male SD rats were randomly divided into five groups of equal number: sham CPR, untreated CPR, negative double distilled water (DDW) control, aqueous MOH extract, and alcohol MOH extract. All the animals were exposed to mobile phone radiation except those of the sham CPR group. Then, the rats of the latter two groups were treated intragastrically with MOH at 20 g per kg of the body weight per day in water and alcohol, respectively. After 2. weeks of treatment, all the rats were sacrificed for measurement of the levels of serum LH and LHR in the testis tissue. The levels of serum LH and LHR were 30.15 ± 8.71 and 33.28 ± 6.61 in the aqueous MOH group and 0.96 ± 0.06 and 0.94 ± 0.08 in the alcohol MOH group, both significantly decreased as compared with the negative DDW controls (P < 0.05), but with no remarkable difference between the two MOH groups (P > 0.05). MOH can improve CPR-induced abnormality of LH and LHR in adult male rats.

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

    PubMed

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

    2014-08-01

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

  3. Drug-, toxin-, and radiation therapy-induced eosinophilic pneumonia.

    PubMed

    Solomon, Joshua; Schwarz, Marvin

    2006-04-01

    A significant number of drugs and toxins have been associated with eosinophilic pneumonia. Antibiotics and NSAID, are the most commonly reported drugs. Toxins suspected to cause eosinophilic pneumonia include cigarette smoke and illicit drugs. Drug- or toxin-induced eosinophilic pneumonia is indistinguishable from idiopathic acute or chronic eosinophilic pneumonia by clinical, radiographic, and histopathologic criteria. The diagnosis is supported by a temporal relationship to a drug or toxin. The condition usually resolves with removal from the agent and recurs with rechallenge. Treatment involves discontinuation of the offending drug or toxin and treatment with corticosteroids in severe respiratory failure. There are also mass outbreaks of eosinophilic pneumonia reported, such as the toxic-oil syndrome in 1981 and the eosinophilia-myalgia syndrome related to the ingestion of L-tryptophan in 1989. A recent report has described an outbreak of acute eosinophilic pneumonia found in soldiers in Iraq. Radiation therapy has also been associated with the development of eosinophilic pneumonia in patients receiving this treatment for breast cancer.

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

    PubMed

    Borroni, Riccardo G

    2015-01-01

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

  5. Cytidine deamination induced HIV-1 drug resistance

    PubMed Central

    Mulder, Lubbertus C. F.; Harari, Ariana; Simon, Viviana

    2008-01-01

    The HIV-1 Vif protein is essential for overcoming the antiviral activity of DNA-editing apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3 (APOBEC3) cytidine deaminases. We show that naturally occurring HIV-1 Vif point mutants with suboptimal anti-APOBEC3G activity induce the appearance of proviruses with lamivudine (3TC) drug resistance-associated mutations before any drug exposure. These mutations, ensuing from cytidine deamination events, were detected in >40% of proviruses with partially defective Vif mutants. Transfer of drug resistance from hypermutated proviruses via recombination allowed for 3TC escape under culture conditions prohibitive for any WT viral growth. These results demonstrate that defective hypermutated genomes can shape the phenotype of the circulating viral population. Partially active Vif alleles resulting in incomplete neutralization of cytoplasmic APOBEC3 molecules are directly responsible for the generation of a highly diverse, yet G-to-A biased, proviral reservoir, which can be exploited by HIV-1 to generate viable and drug-resistant progenies. PMID:18391217

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

    PubMed

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

    2013-01-01

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

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

    PubMed Central

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

    2017-01-01

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

  8. Bcr-Abl induces abnormal cytoskeleton remodeling, beta1 integrin clustering and increased cell adhesion to fibronectin through the Abl interactor 1 pathway.

    PubMed

    Li, Yingzhu; Clough, Nancy; Sun, Xiaolin; Yu, Weidong; Abbott, Brian L; Hogan, Christopher J; Dai, Zonghan

    2007-04-15

    Hematopoietic cells isolated from patients with Bcr-Abl-positive leukemia exhibit multiple abnormalities of cytoskeletal and integrin function. These abnormalities are thought to play a role in the pathogenesis of leukemia; however, the molecular events leading to these abnormalities are not fully understood. We show here that the Abi1 pathway is required for Bcr-Abl to stimulate actin cytoskeleton remodeling, integrin clustering and cell adhesion. Expression of Bcr-Abl induces tyrosine phosphorylation of Abi1. This is accompanied by a subcellular translocation of Abi1/WAVE2 to a site adjacent to membrane, where an F-actin-enriched structure containing the adhesion molecules such as beta1-integrin, paxillin and vinculin is assembled. Bcr-Abl-induced membrane translocation of Abi1/WAVE2 requires direct interaction between Abi1 and Bcr-Abl, but is independent of the phosphoinositide 3-kinase pathway. Formation of the F-actin-rich complex correlates with an increased cell adhesion to fibronectin. More importantly, disruption of the interaction between Bcr-Abl and Abi1 by mutations either in Bcr-Abl or Abi1 not only abolished tyrosine phosphorylation of Abi1 and membrane translocation of Abi1/WAVE2, but also inhibited Bcr-Abl-stimulated actin cytoskeleton remodeling, integrin clustering and cell adhesion to fibronectin. Together, these data define Abi1/WAVE2 as a downstream pathway that contributes to Bcr-Abl-induced abnormalities of cytoskeletal and integrin function.

  9. Alleviation by garlic of antitumor drug-induced damage to the intestine.

    PubMed

    Horie, T; Awazu, S; Itakura, Y; Fuwa, T

    2001-03-01

    Antitumour drugs such as methotrexate (MTX) and 5-fluorouracil (5-FU) induce intestinal damage. This is a serious side effect of cancer chemotherapy. The present studies examined whether or not aged garlic extract (AGE) protects against damage from these antitumor drugs. Both drugs were administered orally for 4 or 5 d to rats fed a standard laboratory diet with and without 2% AGE. The small intestinal absorption of the poorly absorbable compound, fluorescein isothiocyanate--labeled dextran (FD-4; average molecular weight, 4400) was used to evaluate the damage to the intestine using the in vitro everted intestine technique and the in situ intestinal loop technique. FD-4 absorption increased in the antitumour drug-treated rats fed the diet without garlic. Interestingly, FD-4 absorption was depressed in rats fed the diet containing AGE. These results suggest that AGE may protect the small intestine of rats from antitumour drug-induced damage.

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

    PubMed

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

    2015-09-09

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

  11. [Assessment on the criminal responsibility of drug-induced mental disorders: a questionnaire survey].

    PubMed

    Zhang, Sheng-yu; Zhao, Hai; Tang, Tao; Guan, Wei

    2014-12-01

    To understand the assessment on the criminal responsibility of drug-induced mental disorders and judicial experts' opinions. The judicial experts from institutes of forensic psychiatry in Shanghai were selected. They were asked to finish a self-made questionnaire of assessment on the criminal responsibility of drug-induced mental disorders by letters and visits. Most of experts knew the special regulation, "not suitable for evaluation" towards the criminal responsibility of drug-induced mental disorders of the guideline promulgated by Ministry of Justice. Before and after the guideline was issued, no expert made a no-responsibility opinion in such cases. After the guideline was issued, some experts made a full-responsibility or limited-responsibility opinion in such cases. There was a little disagreement among the experts in the case that the crime was unrelated with mental symptoms or the criminals used drugs even though he knew it could induced insanity. But there were still many obvious disagreements among experts in the case that crime was related to such symptoms and person was no ability to debate. Most experts agreed to settle the disagreements with improved legislative perfection. Most experts are not strictly complying with the assessment guidelines during their practice, and there is still an obvious disagreement towards the criminal responsibility of drug-induced mental disorders.

  12. Use of abnormal and health psychology as topics in a classroom format to reduce alcohol and other drug abuse among college students at risk.

    PubMed

    Miley, W M

    2001-12-01

    This study was done to assess whether classes containing topics derived from two college courses, Abnormal Psychology and Health Psychology, could be used in a class room format to reduce alcohol and other drug abuse among at-risk college students. Topics covered included stress and stress management, alcohol and other drug use and abuse, chronic illnesses and psychological disorders that develop from an unhealthy lifestyle, and factors that play a role in good health and well-being. Students were enrolled in a semester-long course for college credit as an alternative to punitive sanctions for on-campus alcohol violations and other drug violations. The Midwest Institute on Drug Use Survey and the CORE Alcohol and Drug Survey were administered on the first and last days of class. Analysis indicated a significant self-reported reduction in drug use and associated negative symptoms and behavioral effects. Women were more likely to report reductions in drug use than men.

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

    PubMed

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

    2015-09-15

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

  14. Protease-mediated drug delivery

    NASA Astrophysics Data System (ADS)

    Dickson, Eva F.; Goyan, Rebecca L.; Kennedy, James C.; Mackay, M.; Mendes, M. A. K.; Pottier, Roy H.

    2003-12-01

    Drugs used in disease treatment can cause damage to both malignant and normal tissue. This toxicity limits the maximum therapeutic dose. Drug targeting is of high interest to increase the therapeutic efficacy of the drug without increasing systemic toxicity. Certain tissue abnormalities, disease processes, cancers, and infections are characterized by high levels of activity of specific extracellular and/or intracellular proteases. Abnormally high activity levels of specific proteases are present at sites of physical or chemical trauma, blood clots, malignant tumors, rheumatoid arthritis, inflammatory bowel disease, gingival disease, glomerulonerphritis, and acute pancreatitis. Abnormal protease activity is suspected in development of liver thrombosis, pulmonary emphysema, atherosclerosis, and muscular dystrophy. Inactiviating disease-associated proteases by the administration of appropriate protease inhibitors has had limited success. Instead, one could use such proteases to target drugs to treat the condition. Protease mediated drug delivery offers such a possibility. Solubilizing groups are attached to insoluble drugs via a polypeptide chain which is specifically cleavable by certian proteases. When the solubilized drug enounters the protease, the solubilizing moieties are cleaved, and the drug precipitates at the disease location. Thus, a smaller systemic dosage could result in a therapeutic drug concentration at the treatment site with less systemic toxicity.

  15. Drug-induced liver injury: present and future

    PubMed Central

    Suk, Ki Tae

    2012-01-01

    Liver injury due to prescription and nonprescription medications is a growing medical, scientific, and public health problem. Worldwide, the estimated annual incidence rate of drug-induced liver injury (DILI) is 13.9-24.0 per 100,000 inhabitants. DILI is one of the leading causes of acute liver failure in the US. In Korea, the annual extrapolated incidence of cases hospitalized at university hospital is 12/100,000 persons/year. Most cases of DILI are the result of idiosyncratic metabolic responses or unexpected reactions to medication. There is marked geographic variation in relevant agents; antibiotics, anticonvulsants, and psychotropic drugs are the most common offending agents in the West, whereas in Asia, 'herbs' and 'health foods or dietary supplements' are more common. Different medical circumstances also cause discrepancy in definition and classification of DILI between West and Asia. In the concern of causality assessment, the application of the Roussel Uclaf Causality Assessment Method (RUCAM) scale frequently undercounts the cases caused by 'herbs' due to a lack of previous information and incompatible time criteria. Therefore, a more objective and reproducible tool that could be used for the diagnosis of DILI caused by 'herbs' is needed in Asia. In addition, a reporting system similar to the Drug-Induced Liver Injury Network (DILIN) in the US should be established as soon as possible in Asia. PMID:23091804

  16. Trivalent dimethylarsenic compound induces histone H3 phosphorylation and abnormal localization of Aurora B kinase in HepG2 cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Suzuki, Toshihide, E-mail: toshi-su@pharm.teikyo-u.ac.j; Miyazaki, Koichi; Kita, Kayoko

    2009-12-15

    Trivalent dimethylarsinous acid [DMA(III)] has been shown to induce mitotic abnormalities, such as centrosome abnormality, multipolar spindles, multipolar division, and aneuploidy, in several cell lines. In order to elucidate the mechanisms underlying these mitotic abnormalities, we investigated DMA(III)-mediated changes in histone H3 phosphorylation and localization of Aurora B kinase, which is a key molecule in cell mitosis. DMA(III) caused the phosphorylation of histone H3 (ser10) and was distributed predominantly in mitotic cells, especially in prometaphase cells. By contrast, most of the phospho-histone H3 was found to be localized in interphase cells after treatment with inorganic arsenite [iAs(III)], suggesting the involvementmore » of a different pathway in phosphorylation. DMA(III) activated Aurora B kinase and slightly activated ERK MAP kinase. Phosphorylation of histone H3 by DMA(III) was effectively reduced by ZM447439 (Aurora kinase inhibitor) and slightly reduced by U0126 (MEK inhibitor). By contrast, iAs(III)-dependent histone H3 phosphorylation was markedly reduced by U0126. Aurora B kinase is generally localized in the midbody during telophase and plays an important role in cytokinesis. However, in some cells treated with DMA(III), Aurora B was not localized in the midbody of telophase cells. These findings suggested that DMA(III) induced a spindle abnormality, thereby activating the spindle assembly checkpoint (SAC) through the Aurora B kinase pathway. In addition, cytokinesis was not completed because of the abnormal localization of Aurora B kinase by DMA(III), thereby resulting in the generation of multinucleated cells. These results provide insight into the mechanism of arsenic tumorigenesis.« less

  17. In-vivo genotoxicity of the alkaloid drug pilocarpine nitrate in bone marrow cells and male germ cells of mice.

    PubMed

    Hegde, M J; Sujatha, T V

    1995-10-01

    Pilocarpine nitrate, an alkaloid drug of plant origin induces spindle disfunction in bone marrow cells of mice. Further studies were carried out to investigate its mutagenic effects in somatic and germ cells of mice by assessing chromosome aberrations at mitotic metaphase and as micronuclei in bone marrow cells and sperm-shape abnormality in cauda epididymides. The dose and time yield effects of the drug were investigated. The statistically significant results that were obtained for both chromosomal aberrations and micronucleus test but not for the sperm-shape abnormality test, indicated the genotoxicity of this compound in somatic cells but not in germ cells.

  18. Phytotherapy of nephrotoxicity-induced by cancer drugs: an updated review

    PubMed Central

    Heidari-Soreshjani, Saeid; Asadi-Samani, Majid; Yang, Qian; Saeedi-Boroujeni, Ali

    2017-01-01

    Context: Kidney is one of the vital organs maintaining homeostasis of body and thus dysfunction of kidney affects quality of life and health severely. Anticancer drugs, particularly chemotherapeutic agents, cause high toxicity leading kidney dysfunction and irreparable kidney injury. Therefore, attention has recently been paid to seeking out alternatives such as nature-based drugs that are effective but less toxic. In this regard, this systematic review article is to report and introduce the most important medicinal plants and their derivatives that are used to reduce anticancer drug-induced nephrotoxicity. Evidence Acquisitions: The word nephrotoxicity alongside the words cancer or chemotherapy in combination with some herbal terms such as medicinal plant, plants, herbs, and extracts were administered to search for relevant publications indexed in PubMed. Results: According to this study, 16 medicinal plants, 12 plant-based derivatives, and three traditional plant-based formulations were found to help control and modulate anticancer drug-induced nephrotoxicity indices. Conclusions: Anticancer drugs cause nephrotoxicity through activating pathways of oxidative stress, damage-associated molecular patterns (DAMPs) production, inflammatory processes, and cell apoptosis, while medicinal plants and their derivatives can cause reduction in nephrotoxicity and anticancer drugs side effects via their antioxidant and anti-inflammatory properties. PMID:28975109

  19. Lactobacillus fermentum NS9 restores the antibiotic induced physiological and psychological abnormalities in rats.

    PubMed

    Wang, T; Hu, X; Liang, S; Li, W; Wu, X; Wang, L; Jin, F

    2015-01-01

    Gut microbiota play a vital role in maintaining the health of the host. Many factors affect gut microbiota; application of broad range antibiotics disturb microbiota, while probiotic application protects the microbiota. To investigate how probiotics alter the physiological and psychological changes induced by antibiotics, we tested the performance of ampicillin-treated rats in the presence or absence of Lactobacillus fermentum strain NS9, in elevated plus maze and Morris water maze. The results showed that NS9 normalised the composition of gut microbiota and alleviated the ampicillin-induced inflammation in the colon. The levels of the mineralocorticoid and N-methyl-D-aspartate receptors were also elevated in the hippocampus of the ampillicin+NS9 treated group. NS9 administration also reduced the anxiety-like behaviour and alleviated the ampicillin-induced impairment in memory retention. These findings suggest that NS9 is beneficial to the host, because it restores the physiological and psychological abnormalities induced by ampicillin. Our results highlight how gut contents regulate the brain, and shed light on the clinical applications of probiotics to treat the side effect of antibiotics and mental disorders.

  20. Cyclosporine A: Novel concepts in its role in drug-induced gingival overgrowth

    PubMed Central

    Ponnaiyan, Deepa; Jegadeesan, Visakan

    2015-01-01

    Cyclosporine is a selective immunosuppressant that has a variety of applications in medical practice. Like phenytoin and the calcium channel blockers, the drug is associated with gingival overgrowth. This review considers the pharmacokinetics, pharmacodynamics, and unwanted effects of cyclosporine, in particular the action of the drug on the gingival tissues. In addition, elucidates the current concepts in mechanisms of cyclosporine-induced gingival overgrowth. Clinical and cell culture studies suggest that the mechanism of gingival overgrowth is a result of the interaction between the drug and its metabolites with susceptible gingival fibroblasts. Plaque-induced gingival inflammation appears to enhance this interaction. However, understanding of the pathogenesis of gingival overgrowth is incomplete at best. Hence, it would be pertinent to identify and explore possible risk factors relating to both prevalence and severity of drug-induced gingival overgrowth. Newer molecular approaches are needed to clearly establish the pathogenesis of gingival overgrowth and to provide novel information for the design of future preventive and therapeutic modalities. PMID:26759584

  1. Cyclosporine A: Novel concepts in its role in drug-induced gingival overgrowth.

    PubMed

    Ponnaiyan, Deepa; Jegadeesan, Visakan

    2015-01-01

    Cyclosporine is a selective immunosuppressant that has a variety of applications in medical practice. Like phenytoin and the calcium channel blockers, the drug is associated with gingival overgrowth. This review considers the pharmacokinetics, pharmacodynamics, and unwanted effects of cyclosporine, in particular the action of the drug on the gingival tissues. In addition, elucidates the current concepts in mechanisms of cyclosporine-induced gingival overgrowth. Clinical and cell culture studies suggest that the mechanism of gingival overgrowth is a result of the interaction between the drug and its metabolites with susceptible gingival fibroblasts. Plaque-induced gingival inflammation appears to enhance this interaction. However, understanding of the pathogenesis of gingival overgrowth is incomplete at best. Hence, it would be pertinent to identify and explore possible risk factors relating to both prevalence and severity of drug-induced gingival overgrowth. Newer molecular approaches are needed to clearly establish the pathogenesis of gingival overgrowth and to provide novel information for the design of future preventive and therapeutic modalities.

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tolosa, Laia

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

  3. Longxuetongluo Capsule Improves Erythrocyte Function against Lipid Peroxidation and Abnormal Hemorheological Parameters in High Fat Diet-Induced ApoE−/− Mice

    PubMed Central

    Zheng, Jiao; Liu, Binglin; Lun, Qixing; Yao, Weijuan; Zhao, Yunfang; Xiao, Wei; Huang, Wenzhe; Wang, Yonghua; Li, Jun; Tu, Pengfei

    2016-01-01

    Chinese dragon's blood, the red resin of Dracaena cochinchinensis, one of the renowned traditional medicines, has been used to facilitate blood circulation and disperse blood stasis for thousands of years. Phenolic compounds are considered to be responsible for its main biological activities. In this study, total phenolic compounds of Chinese dragon's blood were made into capsule (Longxuetongluo Capsule, LTC) and their effects on the abnormal hemorheological properties were examined by high fat diet (HFD) induced ApoE−/− mice. Compared to the model group, LTC recovered the abnormal hemorheological parameters in HFD-induced ApoE−/− mice by reducing whole blood viscosity (WBV) at high rate and improving erythrocyte function. In conclusion, LTC could ameliorate erythrocyte deformability and osmotic fragility through the reduction of lipid peroxidation on plasma and erythrocyte membranes in HFD-induced ApoE−/− mice, which supported the traditional uses of Chinese dragon's blood as an effective agent for improving blood microcirculation in hypercholesterolemia. PMID:26649134

  4. Abnormal stress echocardiography findings in cardiac amyloidosis.

    PubMed

    Ong, Kevin C; Askew, J Wells; Dispenzieri, Angela; Maleszewski, Joseph J; Klarich, Kyle W; Anavekar, Nandan S; Mulvagh, Sharon L; Grogan, Martha

    2016-06-01

    Cardiac involvement in immunoglobulin light chain (amyloid light chain, AL) amyloidosis is characterized by myocardial interstitial deposition but can also cause obstructive deposits in the coronary microvasculature. We retrospectively identified 20 patients who underwent stress echocardiography within 1 year prior to the histologic diagnosis of AL amyloidosis. Only patients with cardiac amyloidosis and no known obstructive coronary disease were included. Stress echocardiograms (13 exercise; 7 dobutamine) were performed for evaluation of dyspnea and/or chest pain. Stress-induced wall motion abnormalities (WMAs) occurred in 11 patients (55%), 4 of whom had normal left ventricular wall thickness. Coronary angiogram was performed in 9 of 11 patients and demonstrated no or mild epicardial coronary artery disease. Seven (54%) patients had an abnormal exercise blood pressure which occurred with similar likelihood between those with and without stress-induced WMAs. Stress-induced WMAs and abnormal exercise blood pressure may occur in patients with cardiac AL amyloidosis despite the absence of significant epicardial coronary artery disease. This finding should raise the possibility of cardiac amyloidosis even in the absence of significant myocardial thickening.

  5. Mechanism of drug-induced gingival overgrowth revisited: a unifying hypothesis

    PubMed Central

    Brown, RS; Arany, PR

    2015-01-01

    Drug-induced gingival overgrowth (DIGO) is a disfiguring side effect of anti-convulsants, calcineurin inhibitors, and calcium channel blocking agents. A unifying hypothesis has been constructed which begins with cation flux inhibition induced by all three of these drug categories. Decreased cation influx of folic acid active transport within gingival fibroblasts leads to decreased cellular folate uptake, which in turn leads to changes in matrix metalloproteinases metabolism and the failure to activate collagenase. Decreased availability of activated collagenase results in decreased degradation of accumulated connective tissue which presents as DIGO. Studies supporting this hypothesis are discussed. PMID:24893951

  6. Resveratrol Treatment after Status Epilepticus Restrains Neurodegeneration and Abnormal Neurogenesis with Suppression of Oxidative Stress and Inflammation.

    PubMed

    Mishra, Vikas; Shuai, Bing; Kodali, Maheedhar; Shetty, Geetha A; Hattiangady, Bharathi; Rao, Xiaolan; Shetty, Ashok K

    2015-12-07

    Antiepileptic drug therapy, though beneficial for restraining seizures, cannot thwart status epilepticus (SE) induced neurodegeneration or down-stream detrimental changes. We investigated the efficacy of resveratrol (RESV) for preventing SE-induced neurodegeneration, abnormal neurogenesis, oxidative stress and inflammation in the hippocampus. We induced SE in young rats and treated with either vehicle or RESV, commencing an hour after SE induction and continuing every hour for three-hours on SE day and twice daily thereafter for 3 days. Seizures were terminated in both groups two-hours after SE with a diazepam injection. In contrast to the vehicle-treated group, the hippocampus of animals receiving RESV during and after SE presented no loss of glutamatergic neurons in hippocampal cell layers, diminished loss of inhibitory interneurons expressing parvalbumin, somatostatin and neuropeptide Y in the dentate gyrus, reduced aberrant neurogenesis with preservation of reelin + interneurons, lowered concentration of oxidative stress byproduct malondialdehyde and pro-inflammatory cytokine tumor necrosis factor-alpha, normalized expression of oxidative stress responsive genes and diminished numbers of activated microglia. Thus, 4 days of RESV treatment after SE is efficacious for thwarting glutamatergic neuron degeneration, alleviating interneuron loss and abnormal neurogenesis, and suppressing oxidative stress and inflammation. These results have implications for restraining SE-induced chronic temporal lobe epilepsy.

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

    PubMed

    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.

  8. Amygdala abnormalities in first-degree relatives of individuals with schizophrenia unmasked by benzodiazepine challenge

    PubMed Central

    Wolf, Daniel H.; Satterthwaite, Theodore D.; Loughead, James; Pinkham, Amy; Overton, Eve; Elliott, Mark A.; Dent, Gersham W.; Smith, Mark A.; Gur, Ruben C.; Gur, Raquel E.

    2014-01-01

    Rationale Impaired emotion processing in schizophrenia predicts broader social dysfunction and has been related to negative symptom severity and amygdala dysfunction. Pharmacological modulation of emotion-processing deficits and related neural abnormalities may provide useful phenotypes for pathophysiological investigation. Objectives We used an acute benzodiazepine challenge to identify and modulate potential emotion-processing abnormalities in 20 unaffected first-degree relatives of individuals with schizophrenia, compared to 25 control subjects without a family history of psychosis. Methods An oral 1mg dose of the short-acting anxiolytic benzodiazepine alprazolam was administered in a balanced crossover placebo-controlled double-blind design, preceding identical 3T fMRI sessions approximately 1 week apart. Primary outcomes included fMRI activity in amygdala and related regions during two facial emotion-processing tasks: emotion identification and emotion memory. Results Family members exhibited abnormally strong alprazolam-induced reduction in amygdala and hippocampus activation during emotion identification, compared to equal reduction in both groups for the emotion memory task. Conclusions GABAergic modulation with alprazolam produced differential responses in family members vs. controls, perhaps by unmasking underlying amygdalar and/or GABAergic abnormalities. Such pharmacological fMRI paradigms could prove useful for developing drugs targeting specific neural circuits to treat or prevent schizophrenia. PMID:21603892

  9. Cardiovascular safety of prokinetic agents: A focus on drug-induced arrhythmias.

    PubMed

    Giudicessi, J R; Ackerman, M J; Camilleri, M

    2018-02-14

    Gastrointestinal sensorimotor dysfunction underlies a wide range of esophageal, gastric, and intestinal motility and functional disorders that collectively constitute nearly half of all referrals to gastroenterologists. As a result, substantial effort has been dedicated toward the development of prokinetic agents intended to augment or restore normal gastrointestinal motility. However, the use of several clinically efficacious gastroprokinetic agents, such as cisapride, domperidone, erythromycin, and tegaserod, is associated with unfavorable cardiovascular safety profiles, leading to restrictions in their use. The purpose of this review is to detail the cellular and molecular mechanisms that lead commonly to drug-induced cardiac arrhythmias, specifically drug-induced long QT syndrome, torsades de pointes, and ventricular fibrillation, to examine the cardiovascular safety profiles of several classes of prokinetic agents currently in clinical use, and to explore potential strategies by which the risk of drug-induced cardiac arrhythmia associated with prokinetic agents and other QT interval prolonging medications can be mitigated successfully. © 2018 John Wiley & Sons Ltd.

  10. Risk factors for abnormal liver function tests in patients with ileal pouch-anal anastomosis for underlying inflammatory bowel disease.

    PubMed

    Navaneethan, Udayakumar; Remzi, Feza H; Nutter, Benjamin; Fazio, Victor W; Shen, Bo

    2009-10-01

    Liver involvement is common in patients with inflammatory bowel disease (IBD). However, the frequency and the significance of liver function test (LFT) abnormalities in patients with ileal pouch-anal anastomosis (IPAA) for underlying IBD have not been studied. The aim of this study was to evaluate the prevalence and to identify risk factors for abnormal LFTs in patients with IPAA and underlying IBD. All patients were identified from our prospectively maintained Pouchitis Database between 2002 and 2008. Abnormal LFTs were classified as the following: (i) any abnormal elevation of transaminases, and/or alkaline phosphatase (ALP), and/or bilirubin; (ii) hepatitis, if there was more than twice the elevation of transaminases; and (iii) cholestatic, if there was more than 1.5 times elevation of ALP. Clinical, endoscopic, and histological variables were assessed using Cox proportional hazard models for evaluating risk for abnormal LFTs. A total of 545 IPAA patients with underlying IBD were identified from the database, of which 373 patients who had LFTs done after their pouch surgery were included. This included 346 patients with ulcerative colitis, 25 with indeterminate colitis, and 2 with Crohn's colitis before surgery. Their mean age was 45.9+/-13.8 years. A total of 65 patients (17.4%) (40 men, 25 women, median age: 47 years) had abnormal LFTs. Of the patients, 52 (13.9%) had abnormal transaminases, whereas 15 (4%) were classified as having hepatitis. Thirty-five (9.4%) patients had an abnormal ALP level, with 18 (4.8%) classified as cholestatic. The most common cause of an abnormal LFT was transient elevation in 32 (49.2%) patients, followed by fatty liver (fatty change on imaging with body mass index (BMI) > or =25 kg/m(2) in the absence of other causes, including alcohol abuse and drug-induced hepatitis) in 10 (15.4%), drug-induced abnormal LFTs in 7 (10.7%), and chronic hepatitis B or C in 6 (9.2%). Primary sclerosing cholangitis (PSC) was responsible for abnormal

  11. Drug-Induced Anaphylaxis in Latin American Countries.

    PubMed

    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 < .01). Severe DIA was less frequent with underlying asthma (N = 22 vs 35 [38.6% vs 61.4%], P < .05) or atopy (N = 62 vs 71 [43% vs 59% ], P < .01). Nonsteroidal anti-inflammatory drugs (NSAIDs) (N = 178 [57.8%]), beta-lactam antibiotics (N = 44 [14.3%]), and other antibiotics (N = 16 [5.2%]) were the most frequently implicated drug classes. Anaphylaxis was rated as severe in N = 133 (50.4%) and anaphylactic shock (AS) was present in N = 90 (34.1%). Epinephrine was only used in N = 73 (27.6%) overall, but in N = 70 (77.8%) of patients with AS. In 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

  12. Chronic Treatment with Mood-Stabilizers Attenuates Abnormal Hyperlocomotion of GluA1-Subunit Deficient Mice

    PubMed Central

    Maksimovic, Milica; Vekovischeva, Olga Y.; Aitta-aho, Teemu; Korpi, Esa R.

    2014-01-01

    Abnormal excitatory glutamate neurotransmission and plasticity have been implicated in schizophrenia and affective disorders. Gria1−/− mice lacking GluA1 subunit (encoded by Gria1 gene) of AMPA-type glutamate receptor show robust novelty-induced hyperactivity, social deficits and heightened approach features, suggesting that they could be used to test for anti-manic activity of drugs. Here, we tested the efficacy of chronic treatment with established anti-manic drugs on behavioural properties of the Gria1−/− mice. The mice received standard mood stabilizers (lithium and valproate) and novel ones (topiramate and lamotrigine, used more as anticonvulsants) as supplements in rodent chow for at least 4 weeks. All drugs attenuated novelty-induced locomotor hyperactivity of the Gria1−/− mice, especially by promoting the habituation, while none of them attenuated 2-mg/kg amphetamine-induced hyperactivity as compared to control diet. Treatment with lithium and valproate reversed the elevated exploratory activity of Gria1−/− mice. Valproate treatment also reduced struggling behaviour in tail suspension test and restored reciprocally-initiated social contacts of Gria1−/− mice to the level shown by the wild-type Gria1+/+ mice. Gria1−/− mice consumed slightly more sucrose during intermittent sucrose exposure than the wild-types, but ran similar distances on running wheels. These behaviours were not consistently affected by lithium and valproate in the Gria1−/− mice. The efficacy of various anti-manic drug treatments on novelty-induced hyperactivity suggests that the Gria1−/− mouse line can be utilized in screening for new therapeutics. PMID:24932798

  13. Photo-inducible Crosslinked Nanoassemblies for pH-Controlled Drug Release

    PubMed Central

    Dickerson, Matthew; Winquist, Nickolas; Bae, Younsoo

    2014-01-01

    Purpose To control drug release from block copolymer nanoassemblies by variation in the degree of photo-crosslinking and inclusion of acid sensitive linkers. Methods Poly(ethylene glycol)-poly(aspartate-hydrazide-cinnamate) (PEG-CNM) block copolymers were prepared and conjugated with a model drug, doxorubicin (DOX), through acid sensitive hydrazone linkers. The block copolymers formed photo-inducible, self-assembled nanoassemblies (piSNAs), which were used to produce photo-inducible crosslinked nanoassemblies (piCNAs) through UV crosslinking. The nanoassemblies were characterized to determine particle size, surface charge, pH- and crosslinking-dependent DOX release, in vitro cytotoxicity, and intracellular uptake as a function of photo-crosslinking degree. Results Nanoassemblies with varying photo-crosslinking degrees were successfully prepared while retaining particle size and surface charge. Photo-crosslinking caused no noticeable change in DOX release from the nanoassemblies at pH 7.4, but the DOX-loaded nanoassemblies modulated drug release as a function of crosslinking at pH 6.0. The nanoassemblies showed similar cytotoxicity regardless of crosslinking degrees, presumably due to the low cellular uptake and cell nucleus drug accumulation. Conclusion Photo-crosslinking is useful to control drug release from pH-sensitive block copolymer nanoassemblies as a function of crosslinking without altering the particle properties, and thus providing unique tools to investigate the pharmaceutical effects of drug release on cellular response. PMID:24254196

  14. Targeting Histone Abnormality in Triple Negative Breast Cancer

    DTIC Science & Technology

    2015-08-01

    Casero RA, Davidson NE. Molecular mechanisms of polyamine analogues in cancer cells. Anti - Cancer Drugs, 16(3): 229-241, 2005. PMID: 15711175 18 3...1 AWARD NUMBER: W81XWH-14-1-0237 TITLE: Targeting Histone Abnormality in Triple-Negative Breast Cancer PRINCIPAL INVESTIGATOR: Yi...TITLE AND SUBTITLE 5a. CONTRACT NUMBER Targeting Histone Abnormality in Triple-Negative Breast Cancer 5b. GRANT NUMBER W81XWH-14-1-0237 5c

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

    PubMed

    Jing, Jing; Teschke, Rolf

    2018-03-28

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

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

    PubMed Central

    Jing, Jing; Teschke, Rolf

    2017-01-01

    Abstract Cases of suspected herb-induced liver injury (HILI) caused by herbal Traditional Chinese Medicines (TCMs) and of drug-induced liver injury (DILI) are commonly published in the scientific literature worldwide. As opposed to the multiplicity of botanical chemicals in herbal TCM products, which are often mixtures of several herbs, conventional Western drugs contain only a single synthetic chemical. It is therefore of interest to study how HILI by TCM and DILI compare with each other, and to what extent results from each liver injury type can be transferred to the other. China is among the few countries with a large population using synthetic Western drugs as well as herbal TCM. Therefore, China is well suited to studies of liver injury comparing drugs with TCM herbs. Despite some concordance, recent analyses of liver injury cases with verified causality, using the Roussel Uclaf Causality Assessment Method, revealed major differences in HILI caused by TCMs as compared to DILI with respect to the following features: HILI cases are less frequently observed as compared to DILI, have a smaller proportion of females and less unintentional rechallenge events, and present a higher rate of hepatocellular injury features. Since many results were obtained among Chinese residents who had access to and had used Western drugs and TCM herbs, such ethnic homogeneity supports the contention that the observed differences of HILI and DILI in the assessed population are well founded. PMID:29577033

  17. Confinement-Induced Drug-Tolerance in Mycobacteria Mediated by an Efflux Mechanism

    PubMed Central

    Luthuli, Brilliant B.; Purdy, Georgiana E.; Balagaddé, Frederick K.

    2015-01-01

    Tuberculosis (TB) is the world’s deadliest curable disease, responsible for an estimated 1.5 million deaths annually. A considerable challenge in controlling this disease is the prolonged multidrug chemotherapy (6 to 9 months) required to overcome drug-tolerant mycobacteria that persist in human tissues, although the same drugs can sterilize genetically identical mycobacteria growing in axenic culture within days. An essential component of TB infection involves intracellular Mycobacterium tuberculosis bacteria that multiply within macrophages and are significantly more tolerant to antibiotics compared to extracellular mycobacteria. To investigate this aspect of human TB, we created a physical cell culture system that mimics confinement of replicating mycobacteria, such as in a macrophage during infection. Using this system, we uncovered an epigenetic drug-tolerance phenotype that appears when mycobacteria are cultured in space-confined bioreactors and disappears in larger volume growth contexts. Efflux mechanisms that are induced in space-confined growth environments contribute to this drug-tolerance phenotype. Therefore, macrophage-induced drug tolerance by mycobacteria may be an effect of confined growth among other macrophage-specific mechanisms. PMID:26295942

  18. Evolution of the Food and Drug Administration approach to liver safety assessment for new drugs: current status and challenges.

    PubMed

    Senior, John R

    2014-11-01

    Prompted by approval in 1997 of troglitazone and bromfenac, two drugs that promptly began to show serious and sometimes fatal liver toxicity, we began at the Food and Drug Administration (FDA) a series of annual conferences in 1999 to consider issues of drug-induced liver injury (DILI). First inviting reviewers of new drug applications we opened the audiences in 2001 to pharmaceutical industry and academic consultants to industry and FDA, and slides shown at the meetings were posted on the internet to be available at the website of the American Association for the Study of Liver Diseases (AASLD)-go to ( http://www.aasld.org/dili/Pages/default.aspx ). Observations by Dr. Hyman J. Zimmerman that "drug-induced hepatocellular jaundice is a serious lesion" with possible mortality formed a basis for developing a computer program to plot peak serum values for alanine aminotransferase (ALT) and total bilirubin (TBL) in an x-y log-log graph for all subjects enrolled in clinical trials. This program had the capability to show the time course of all liver tests for individuals who had both hepatocellular injury and reduced whole liver function, plus clinical narratives to diagnose the severity and most likely cause of the abnormalities. We called the program eDISH (for evaluation of Drug-Induced Serious Hepatotoxicity), and began in 2004 to use it to assess DILI in clinical trial subjects. From 2008, comments made by the presenters at the conferences about their slides and ensuing discussions have been added to the website. All this has raised awareness of the problem, and since 1997, the FDA has not had to withdraw a single drug because of post-marketing hepatotoxicity. Many issues still remain to be resolved; among the most controversial is the best method to estimate likelihood that a given liver injury was actually caused by the drug in question. On November 9, 2012, a workshop was convened to discuss the best practices for the assessment of drug-induced liver injury

  19. Minimal T-wave representation and its use in the assessment of drug arrhythmogenicity.

    PubMed

    Shakibfar, Saeed; Graff, Claus; Kanters, Jørgen K; Nielsen, Jimmi; Schmidt, Samuel; Struijk, Johannes J

    2017-05-01

    Recently, numerous models and techniques have been developed for analyzing and extracting features from the T wave which could be used as biomarkers for drug-induced abnormalities. The majority of these techniques and algorithms use features that determine readily apparent characteristics of the T wave, such as duration, area, amplitude, and slopes. In the present work the T wave was down-sampled to a minimal rate, such that a good reconstruction was still possible. The entire T wave was then used as a feature vector to assess drug-induced repolarization effects. The ability of the samples or combinations of samples obtained from the minimal T-wave representation to correctly classify a group of subjects before and after receiving d,l-sotalol 160 mg and 320 mg was evaluated using a linear discriminant analysis (LDA). The results showed that a combination of eight samples from the minimal T-wave representation can be used to identify normal from abnormal repolarization significantly better compared to the heart rate-corrected QT interval (QTc). It was further indicated that the interval from the peak of the T wave to the end of the T wave (Tpe) becomes relatively shorter after I K r inhibition by d,l-sotalol and that the most pronounced repolarization changes were present in the ascending segment of the minimal T-wave representation. The minimal T-wave representation can potentially be used as a new tool to identify normal from abnormal repolarization in drug safety studies. © 2016 Wiley Periodicals, Inc.

  20. Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy.

    PubMed

    Montero, Joan; Sarosiek, Kristopher A; DeAngelo, Joseph D; Maertens, Ophélia; Ryan, Jeremy; Ercan, Dalia; Piao, Huiying; Horowitz, Neil S; Berkowitz, Ross S; Matulonis, Ursula; Jänne, Pasi A; Amrein, Philip C; Cichowski, Karen; Drapkin, Ronny; Letai, Anthony

    2015-02-26

    There is a lack of effective predictive biomarkers to precisely assign optimal therapy to cancer patients. While most efforts are directed at inferring drug response phenotype based on genotype, there is very focused and useful phenotypic information to be gained from directly perturbing the patient's living cancer cell with the drug(s) in question. To satisfy this unmet need, we developed the Dynamic BH3 Profiling technique to measure early changes in net pro-apoptotic signaling at the mitochondrion ("priming") induced by chemotherapeutic agents in cancer cells, not requiring prolonged ex vivo culture. We find in cell line and clinical experiments that early drug-induced death signaling measured by Dynamic BH3 Profiling predicts chemotherapy response across many cancer types and many agents, including combinations of chemotherapies. We propose that Dynamic BH3 Profiling can be used as a broadly applicable predictive biomarker to predict cytotoxic response of cancers to chemotherapeutics in vivo. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Radiation-induced myocardial perfusion abnormalities in breast cancer patients following external beam radiation therapy.

    PubMed

    Eftekhari, Mohammad; Anbiaei, Robabeh; Zamani, Hanie; Fallahi, Babak; Beiki, Davood; Ameri, Ahmad; Emami-Ardekani, Alireza; Fard-Esfahani, Armaghan; Gholamrezanezhad, Ali; Seid Ratki, Kazem Razavi; Roknabadi, Alireza Momen

    2015-01-01

    Radiation therapy for breast cancer can induce myocardial capillary injury and increase cardiovascular morbidity and mortality. A prospective cohort was conducted to study the prevalence of myocardial perfusion abnormalities following radiation therapy of left-sided breast cancer patients as compared to those with right-sided cancer. To minimize potential confounding factors, only those patients with low 10-year risk of coronary artery disease (based on Framingham risk scoring) were included. All patients were initially treated by modified radical mastectomy and then were managed by postoperative 3D Conformal Radiation Therapy (CRT) to the surgical bed with an additional 1-cm margin, delivered by 46-50 Gy (in 2 Gy daily fractions) over a 5-week course. The same dose-adjusted chemotherapy regimen (including anthracyclines, cyclophosphamide and taxol) was given to all patients. Six months after radiation therapy, all patients underwent cardiac SPECT for the evaluation of myocardial perfusion. A total of 71 patients with a mean age of 45.3±7.2 years [35 patients with leftsided breast cancer (exposed) and 36 patients with right-sided cancer (controls)] were enrolled. Dose-volume histogram (DVH) [showing the percentage of the heart exposed to >50% of radiation] was significantly higher in patients with left-sided breast cancer. Visual interpretation detected perfusion abnormalities in 42.9% of cases and 16.7% of controls (P=0.02, Odds ratio=1.46). In semiquantitative segmental analysis, only apical (28.6% versus 8.3%, P=0.03) and anterolateral (17.1% versus 2.8%, P=0.049) walls showed significantly reduced myocardial perfusion in the exposed group. Summed Stress Score (SSS) of>3 was observed in twelve cases (34.3%), while in five of the controls (13.9%),(Odds ratio=1.3). There was no significant difference between the groups regarding left ventricular ejection fraction. The risk of radiation induced myocardial perfusion abnormality in patients treated with CRT on the

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

    PubMed

    Haasum, Ylva; Fastbom, Johan; Johnell, Kristina

    2016-01-01

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

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

    PubMed Central

    Haasum, Ylva; Fastbom, Johan; Johnell, Kristina

    2016-01-01

    Objectives Many drugs increase the risk of falls in old age. Although persons with Parkinson’s disease (PD) are at increased risk of experiencing falls and fractures, the use of fall-risk inducing drugs (FRIDs) in this population has not previously been investigated. The objective of this study was to investigate the burden of use of FRIDs in older persons treated with anti-Parkinson drugs (APD; used as a proxy for PD), compared to persons without APD. Methods We analyzed individual data on age, sex, type of housing and drug use in 1 346 709 persons aged ≥ 65 years in the Swedish Prescribed Drug Register on the date of 30 September 2008. Main outcome measure was the use of FRIDs. Results FRIDs were used by 79% of persons with APD and 75% of persons without APD. Persons with APD were more likely to use ≥ 1 FRIDs compared to persons without APD (adjusted OR: 1.09; 95% CI: 1.06-1-12). The association was stronger for concomitant use of ≥ 5 FRIDS (adjusted OR: 1.49; 95% CI: 1.44–1.55). Conclusions The high use of FRIDs among persons with APD indicates that these patients may be at increased risk of drug-induced falls. Further studies are needed to investigate how these drugs affect the risk of falling in persons with PD. PMID:27537366

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

    PubMed

    Lee, Jeonghwan; Kim, Sejoong

    2018-03-08

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

    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.

  7. MicroRNAs and Drug-induced Kidney Injury

    PubMed Central

    Pavkovic, Mira; Vaidya, Vishal S.

    2016-01-01

    Drug-induced kidney injury (DIKI) is a severe complication in hospitalized patients associated with higher probabilities of developing progressive chronic kidney disease or end-stage renal diseases. Furthermore, DIKI is a problem during preclinical and clinical phases of drug development leading to high rates of project terminations. Understanding the molecular perturbations caused by DIKI would pave the way for a new class of therapeutics to mitigate the damage. Yet, another approach to ameliorate DIKI is identifying sensitive and specific translational biomarkers that outperform the current diagnostic analytes like serum creatinine and facilitate early diagnosis. MicroRNAs (miRNAs), a class of non-coding RNAs, are increasingly being recognized to have a two-pronged approach towards DIKI management: 1) miRNAs have a regulatory role in gene expression and signaling pathways thereby making them novel interventional targets and 2) miRNAs enable diagnosis and prognosis of DIKI because of their stable presence in biofluids. In this review, apart from summarizing the literature on miRNAs in DIKI, we report small RNA sequencing results showing miRNA expression profiles at baseline in normal kidney samples from mice and humans. Additionally, we also compared the miRNA expression in biopsies of normal human kidneys to patients with acute tubular necrosis, and found 76 miRNAs significantly downregulated and 47 miRNAs upregulated (FDR adjusted p<0.05, +/−2-fold change). In summary, we highlight the transformative potential of miRNAs in therapeutics and translational medicine with a focus on drug-induced kidney damage. PMID:27126472

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

    PubMed Central

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

    2014-01-01

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

  9. Modeling Drug- and Chemical-Induced Hepatotoxicity with Systems Biology Approaches

    PubMed Central

    Bhattacharya, Sudin; Shoda, Lisl K.M.; Zhang, Qiang; Woods, Courtney G.; Howell, Brett A.; Siler, Scott Q.; Woodhead, Jeffrey L.; Yang, Yuching; McMullen, Patrick; Watkins, Paul B.; Andersen, Melvin E.

    2012-01-01

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

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

    PubMed

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

    2017-09-01

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

  11. Preventing Drug-Induced Liver Injury: How Useful Are Animal Models?

    PubMed

    Ballet, François

    2015-01-01

    Drug-induced liver injury (DILI) is the most common organ toxicity encountered in regulatory animal toxicology studies required prior to the clinical development of new drug candidates. Very few reports have evaluated the value of these studies for predicting DILI in humans. Indeed, compounds inducing liver toxicity in regulatory toxicology studies are not always correlated with a risk of DILI in humans. Conversely, compounds associated with the occurrence of DILI in phase 3 studies or after market release are often tested negative in regulatory toxicology studies. Idiosyncratic DILI is a rare event that is precipitated in an individual by the simultaneous occurrence of several critical factors. These factors may relate to the host (e.g. human leukocyte antigen polymorphism, inflammation), the drug (e.g. reactive metabolites) or the environment (e.g. diet/microbiota). This type of toxicity therefore cannot be detected in conventional animal toxicology studies. Several animal models have recently been proposed for the identification of drugs with the potential to cause idiosyncratic DILI: rats treated with lipopolysaccharide, Sod2(+/-) mice, panels of inbred mouse strains or chimeric mice with humanized livers. These models are not suitable for use in the prospective screening of new drug candidates. Humans therefore constitute the best model for predicting and assessing idiopathic DILI. © 2015 S. Karger AG, Basel.

  12. Fluorescent nanodiamond tracking reveals intraneuronal transport abnormalities induced by brain-disease-related genetic risk factors

    NASA Astrophysics Data System (ADS)

    Haziza, Simon; Mohan, Nitin; Loe-Mie, Yann; Lepagnol-Bestel, Aude-Marie; Massou, Sophie; Adam, Marie-Pierre; Le, Xuan Loc; Viard, Julia; Plancon, Christine; Daudin, Rachel; Koebel, Pascale; Dorard, Emilie; Rose, Christiane; Hsieh, Feng-Jen; Wu, Chih-Che; Potier, Brigitte; Herault, Yann; Sala, Carlo; Corvin, Aiden; Allinquant, Bernadette; Chang, Huan-Cheng; Treussart, François; Simonneau, Michel

    2017-05-01

    Brain diseases such as autism and Alzheimer's disease (each inflicting >1% of the world population) involve a large network of genes displaying subtle changes in their expression. Abnormalities in intraneuronal transport have been linked to genetic risk factors found in patients, suggesting the relevance of measuring this key biological process. However, current techniques are not sensitive enough to detect minor abnormalities. Here we report a sensitive method to measure the changes in intraneuronal transport induced by brain-disease-related genetic risk factors using fluorescent nanodiamonds (FNDs). We show that the high brightness, photostability and absence of cytotoxicity allow FNDs to be tracked inside the branches of dissociated neurons with a spatial resolution of 12 nm and a temporal resolution of 50 ms. As proof of principle, we applied the FND tracking assay on two transgenic mouse lines that mimic the slight changes in protein concentration (∼30%) found in the brains of patients. In both cases, we show that the FND assay is sufficiently sensitive to detect these changes.

  13. Abnormal dopaminergic modulation of striato-cortical networks underlies levodopa-induced dyskinesias in humans

    PubMed Central

    Haagensen, Brian N.; Christensen, Mark S.; Madsen, Kristoffer H.; Rowe, James B.; Løkkegaard, Annemette; Siebner, Hartwig R.

    2015-01-01

    Dopaminergic signalling in the striatum contributes to reinforcement of actions and motivational enhancement of motor vigour. Parkinson's disease leads to progressive dopaminergic denervation of the striatum, impairing the function of cortico-basal ganglia networks. While levodopa therapy alleviates basal ganglia dysfunction in Parkinson's disease, it often elicits involuntary movements, referred to as levodopa-induced peak-of-dose dyskinesias. Here, we used a novel pharmacodynamic neuroimaging approach to identify the changes in cortico-basal ganglia connectivity that herald the emergence of levodopa-induced dyskinesias. Twenty-six patients with Parkinson's disease (age range: 51–84 years; 11 females) received a single dose of levodopa and then performed a task in which they had to produce or suppress a movement in response to visual cues. Task-related activity was continuously mapped with functional magnetic resonance imaging. Dynamic causal modelling was applied to assess levodopa-induced modulation of effective connectivity between the pre-supplementary motor area, primary motor cortex and putamen when patients suppressed a motor response. Bayesian model selection revealed that patients who later developed levodopa-induced dyskinesias, but not patients without dyskinesias, showed a linear increase in connectivity between the putamen and primary motor cortex after levodopa intake during movement suppression. Individual dyskinesia severity was predicted by levodopa-induced modulation of striato-cortical feedback connections from putamen to the pre-supplementary motor area (Pcorrected = 0.020) and primary motor cortex (Pcorrected = 0.044), but not feed-forward connections from the cortex to the putamen. Our results identify for the first time, aberrant dopaminergic modulation of striatal-cortical connectivity as a neural signature of levodopa-induced dyskinesias in humans. We argue that excessive striato-cortical connectivity in response to levodopa produces an

  14. Drug-induced systemic lupus erythematosus in a child after 3 years of treatment with carbamazepine.

    PubMed

    Molina-Ruiz, Ana María; Lasanta, Begoña; Barcia, Ana; Pérez-Vega, Elisa; Requena, Luis

    2017-02-01

    Drug-induced lupus erythematosus (DILE) is a less severe variant of systemic lupus erythematosus (SLE) that generally resolves within weeks or months after the withdrawal of the implicated drug. DILE is unusual during childhood, with the most frequent age of presentation being at 50-70 years of age. Among different drugs, most commonly procainamide and hydralazine have been implicated as a cause of DILE. However carbamazepine (CBZ) is considered a low-risk drug and very few cases have been reported in children. We describe the case of CBZ-induced SLE in a 9-year-old girl following 3 years of CBZ therapy. This case report shows that drug-induced SLE is an important side-effect to be considered, even after long-term treatment with CBZ, and also during childhood. © 2015 The Australasian College of Dermatologists.

  15. Analysis of the adverse reactions induced by natural product-derived drugs

    PubMed Central

    Zeng, Zhi-Ping; Jiang, Jian-Guo

    2010-01-01

    Compared with the therapeutic effects of established medicinal drugs, it is often considered that natural product-derived drugs are of a more benign nature in side-effects, which has made natural medicines become a popular form of therapy. Traditional Chinese medicine (TCM) is generally considered as being natural and harmless. TCM has been paid much more attention than before and widely used for the treatment nowadays. However, with the increasing cases of adverse drug reactions (ADRs), the ADRs induced by TCM are becoming more widely recognized. Some ADRs are sometimes even life-threatening. This article reviews literatures on ADRs induced by TCM which was published in the past 10 years. A total of 3122 cases including complete data are selected for the present analysis. From the data of the 3122 cases, statistics is carried out to the distribution of administration routes and time of the occurrence of ADRs, the prognosis of ADRs, sex and age factors, types and clinical symptoms of ADRs, and drugs involved in ADRs. In addition, occurrence and influencing factors of TCM-induced diseases are also analysed, which includes spices confusion, processing drugs improperly, toxic components, long-term medication, improper concerted application, interaction of TCM and Western medicine. It is concluded that the efficacy and toxicity of TCM, often using the compound prescription involving various plants and animals, resulted from a variety of chemical constituents, which lead to a comprehensive response in the human body. The ‘toxicity’ of TCM should be correctly recognized and reasonably utilized. PMID:20233209

  16. Abnormal development of tapetum and microspores induced by chemical hybridization agent SQ-1 in wheat.

    PubMed

    Wang, Shuping; Zhang, Gaisheng; Song, Qilu; Zhang, Yingxin; Li, Zheng; Guo, Jialin; Niu, Na; Ma, Shoucai; Wang, Junwei

    2015-01-01

    Chemical hybridization agent (CHA)-induced male sterility is an important tool in crop heterosis. To demonstrate that CHA-SQ-1-induced male sterility is associated with abnormal tapetal and microspore development, the cytology of CHA-SQ-1-treated plant anthers at various developmental stages was studied by light microscopy, scanning and transmission electron microscopy, in situ terminal deoxynucleotidyl transferasemediated dUTP nick end-labelling (TUNEL) assay and DAPI staining. The results indicated that the SQ-1-treated plants underwent premature tapetal programmed cell death (PCD), which was initiated at the early-uninucleate stage of microspore development and continued until the tapetal cells were completely degraded; the process of microspore development was then blocked. Microspores with low-viability (fluorescein diacetate staining) were aborted. The study suggests that premature tapetal PCD is the main cause of pollen abortion. Furthermore, it determines the starting period and a key factor in CHA-SQ-1-induced male sterility at the cell level, and provides cytological evidence to further study the mechanism between PCD and male sterility.

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

    PubMed

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

    2017-03-01

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

  18. Arsenite promotes centrosome abnormalities under a p53 compromised status induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Liao, W.-T.; Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    2010-02-15

    Epidemiological evidence indicated that residents, especially cigarette smokers, in arseniasis areas had significantly higher lung cancer risk than those living in non-arseniasis areas. Thus an interaction between arsenite and cigarette smoking in lung carcinogenesis was suspected. In the present study, we investigated the interactions of a tobacco-specific carcinogen 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone (nicotine-derived nitrosamine ketone, NNK) and arsenite on lung cell transformation. BEAS-2B, an immortalized human lung epithelial cell line, was selected to test the centrosomal abnormalities and colony formation by NNK and arsenite. We found that NNK, alone, could enhance BEAS-2B cell growth at 1-5 muM. Under NNK exposure, arsenite wasmore » able to increase centrosomal abnormality as compared with NNK or arsenite treatment alone. NNK treatment could also reduce arsenite-induced G2/M cell cycle arrest and apoptosis, these cellular effects were found to be correlated with p53 dysfunction. Increased anchorage-independent growth (colony formation) of BEAS-2B cells cotreated with NNK and arsenite was also observed in soft agar. Our present investigation demonstrated that NNK could provide a p53 compromised status. Arsenite would act specifically on this p53 compromised status to induce centrosomal abnormality and colony formation. These findings provided strong evidence on the carcinogenic promotional role of arsenite under tobacco-specific carcinogen co-exposure.« less

  19. Haematopoietic growth factor in antithyroid-drug-induced agranulocytosis.

    PubMed

    Andrès, E; Kurtz, J E; Perrin, A E; Dufour, P; Schlienger, J L; Maloisel, F

    2001-08-01

    Drug-induced agranulocytosis (DIA) is often caused by antithyroid drugs. We retrospectively studied the use of granulocyte colony-stimulating factor (G-CSF) therapy in antithyroid-DIA. Data for 20 patients (10 treated with G-CSF) with antithyroid-DIA (neutrophil count <0.5x10(9)/l) were extracted from a cohort study of DIA patients (n=110). G-CSF (300 microg/day subcutaneously) was used where the neutrophil count was <0.1x10(9)/l, or the patient was aged >70 years, or there were severe features of infection or underlying disease. Mean patient age was 62 years (range 34-87); sex ratio (M/F) was 0.05. Carbimazole (n=19) and benzylthiouracile (n=1) were the causative drugs, at mean doses of 30 mg/day (range 20-60) and 100 mg/day (range 50-150), respectively, for a mean of 37 days (range 31-90). Antithyroid drugs were prescribed for Graves' disease (n=8), thyrotoxicosis related to amiodarone intake (n=6) and multinodular goitre (n=6). Clinical features included isolated fever (n=7), pneumonia (n=5), septicaemia or septic shock (n=5) and acute tonsillitis (n=3). Mean neutrophil count was 0.07+/-0.1x10(9)/l. No patient died. Mean durations of haematological recovery, antibiotic therapy and hospitalization were significantly reduced with G-CSF: 6.8+/-4 days vs. 11.6+/-5; 7.5+/-3.8 days vs. 12+/-4.5; and 7.3+/-4.8 days vs. 13+/-6.1, respectively (all p<0.05). G-CSF induced flu-like symptoms in 30% of patients, but reduced overall costs.

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

    PubMed

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

    2012-01-01

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

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Liu, Cong; Sekine, Shuichi, E-mail: ssekine@facult

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

  2. Alleviation of metabolic abnormalities induced by excessive fructose administration in Wistar rats by Spirulina maxima.

    PubMed

    Jarouliya, Urmila; Zacharia, J Anish; Kumar, Pravin; Bisen, P S; Prasad, G B K S

    2012-03-01

    Diabetes mellitus is a metabolic disorder characterized by hyperglycaemia. Several natural products have been isolated and identified to restore the complications of diabetes. Spirulina maxima is naturally occurring fresh water cyanobacterium, enriched with proteins and essential nutrients. The aim of the study was to determine whether S. maxima could serve as a therapeutic agent to correct metabolic abnormalities induced by excessive fructose administration in Wistar rats. Oral administration of 10 per cent fructose solution to Wistar rats (n = 5 in each group) for 30 days resulted in hyperglycaemia and hyperlipidaemia. Aqueous suspension of S. maxima (5 or 10%) was also administered orally once daily for 30 days. The therapeutic potential of the preparation with reference to metformin (500 mg/kg) was assessed by monitoring various biochemical parameters at 10 day intervals during the course of therapy and at the end of 30 days S. maxima administration. Significant (P<0.001) reductions in blood glucose, lipid profile (triglycerides, cholesterol and LDL, VLDL) and liver function markers (SGPT and SGOT) were recorded along with elevated level of HDL-C at the end of 30 days therapy of 5 or 10 per cent S. maxima aquous extract. Co-administration of S. maxima extract (5 or 10% aqueous) with 10 per cent fructose solution offered a significant protection against fructose induced metabolic abnormalities in Wistar rats. The present findings showed that S. maxima exhibited anti-hyperglycaemic, anti-hyperlipidaemic and hepatoprotective activity in rats fed with fructose. Further studies are needed to understand the mechanisms.

  3. Alleviation of metabolic abnormalities induced by excessive fructose administration in Wistar rats by Spirulina maxima

    PubMed Central

    Jarouliya, Urmila; Anish, Zacharia J.; Kumar, Pravin; Bisen, P.S.; Prasad, G.B.K.S.

    2012-01-01

    Background & objectives: Diabetes mellitus is a metabolic disorder characterized by hyperglycaemia. Several natural products have been isolated and identified to restore the complications of diabetes. Spirulina maxima is naturally occurring fresh water cyanobacterium, enriched with proteins and essential nutrients. The aim of the study was to determine whether S. maxima could serve as a therapeutic agent to correct metabolic abnormalities induced by excessive fructose administration in Wistar rats. Methods: Oral administration of 10 per cent fructose solution to Wistar rats (n=5 in each group) for 30 days resulted in hyperglycaemia and hyperlipidaemia. Aqueous suspension of S. maxima (5 or 10%) was also administered orally once daily for 30 days. The therapeutic potential of the preparation with reference to metformin (500 mg/kg) was assessed by monitoring various biochemical parameters at 10 day intervals during the course of therapy and at the end of 30 days S. maxima administration. Results: Significant (P<0.001) reductions in blood glucose, lipid profile (triglycerides, cholesterol and LDL, VLDL) and liver function markers (SGPT and SGOT) were recorded along with elevated level of HDL-C at the end of 30 days therapy of 5 or 10 per cent S. maxima aquous extract. Co-administration of S. maxima extract (5 or 10% aqueous) with 10 per cent fructose solution offered a significant protection against fructose induced metabolic abnormalities in Wistar rats. Interpretation & Conclusions: The present findings showed that S. maxima exhibited anti-hyperglycaemic, anti-hyperlipidaemic and hepatoprotective activity in rats fed with fructose. Further studies are needed to understand the mechanisms. PMID:22561632

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

    PubMed

    Tutton, P J; Barkla, D H

    1978-08-25

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

  5. Streptozotocin induced oxidative stress, innate immune system responses and behavioral abnormalities in male mice.

    PubMed

    Amiri, Shayan; Haj-Mirzaian, Arya; Momeny, Majid; Amini-Khoei, Hossein; Rahimi-Balaei, Maryam; Poursaman, Simin; Rastegar, Mojgan; Nikoui, Vahid; Mokhtari, Tahmineh; Ghazi-Khansari, Mahmoud; Hosseini, Mir-Jamal

    2017-01-06

    Recent evidence indicates the involvement of inflammatory factors and mitochondrial dysfunction in the etiology of psychiatric disorders such as anxiety and depression. To investigate the possible role of mitochondrial-induced sterile inflammation in the co-occurrence of anxiety and depression, in this study, we treated adult male mice with the intracerebroventricular (i.c.v.) infusion of a single low dose of streptozotocin (STZ, 0.2mg/mouse). Using valid and qualified behavioral tests for the assessment of depressive and anxiety-like behaviors, we showed that STZ-treated mice exhibited behaviors relevant to anxiety and depression 24h following STZ treatment. We observed that the co-occurrence of anxiety and depressive-like behaviors in animals were associated with abnormal mitochondrial function, nitric oxide overproduction and, the increased activity of cytosolic phospholipase A 2 (cPLA 2 ) in the hippocampus. Further, STZ-treated mice had a significant upregulation of genes associated with the innate immune system such as toll-like receptors 2 and 4. Pathological evaluations showed no sign of neurodegeneration in the hippocampus of STZ-treated mice. Results of this study revealed that behavioral abnormalities provoked by STZ, as a cytotoxic agent that targets mitochondria and energy metabolism, are associated with abnormal mitochondrial activity and, consequently the initiation of innate-inflammatory responses in the hippocampus. Our findings highlight the role of mitochondria and innate immunity in the formation of sterile inflammation and behaviors relevant to anxiety and depression. Also, we have shown that STZ injection (i.c.v.) might be an animal model for depression and anxiety disorders based on sterile inflammation. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  6. In vitro cytokine expression by peripheral mononuclear cells in herbal drug-induced skin eruption.

    PubMed

    Norisugi, Osamu; Yoshihisa, Yoko; Shimizu, Kyoko; Shimizu, Tadamichi

    2014-01-01

    Herbal medicine is widely used worldwide and is associated with side-effects such as skin eruptions. Herbal drugs are often produced by combining multiple crude drugs, mostly of plant origin. Determining which medi-cinal plants are associated with the herbal drugs that induce skin eruptions can therefore be difficult. This study investigated mRNA expression of several cytokines in peripheral mononuclear cells (PBMCs) from two patients with herbal drug-induced skin eruptions; one reacted to keishi-bukuryo-gan (KBG), composed of 5 medicinal plants, and the other patient reacted to senna. PBMCs (1×106) from the 2 patients were cultured for 24 h with the supernatant from the medicinal plants from KBG or senna in various concentrations, and a reverse transcription-polymerase chain reaction (RT-PCR) analysis was performed. A high mRNA level of interleukin (IL)-4 and IL-5 was detected in PBMCs stimulated by KBG and two of its components. Senna stimulated a high level of IL-4 and IL-5 mRNA levels in PBMCs from patient with senna-induced drug reaction.

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Dalmas, Deidre A., E-mail: Deidre.A.Dalmas@gsk.com; Scicchitano, Marshall S., E-mail: Marshall.S.Scicchitano@gsk.com; Mullins, David, E-mail: David.R.Mullins@gsk.com

    2011-12-15

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

  8. The Possible Potential Therapeutic Targets for Drug Induced Gingival Overgrowth

    PubMed Central

    Alitheen, Noorjahan Banu

    2013-01-01

    Gingival overgrowth is a side effect of certain medications. The most fibrotic drug-induced lesions develop in response to therapy with phenytoin, the least fibrotic lesions are caused by cyclosporin A, and the intermediate fibrosis occurs in nifedipine-induced gingival overgrowth. Fibrosis is one of the largest groups of diseases for which there is no therapy but is believed to occur because of a persistent tissue repair program. During connective tissue repair, activated gingival fibroblasts synthesize and remodel newly created extracellular matrix. Proteins such as transforming growth factor (TGF), endothelin-1 (ET-1), angiotensin II (Ang II), connective tissue growth factor (CCN2/CTGF), insulin-like growth factor (IGF), and platelet-derived growth factor (PDGF) appear to act in a network that contributes to the development of gingival fibrosis. Since inflammation is the prerequisite for gingival overgrowth, mast cells and its protease enzymes also play a vital role in the pathogenesis of gingival fibrosis. Drugs targeting these proteins are currently under consideration as antifibrotic treatments. This review summarizes recent observations concerning the contribution of TGF-β, CTGF, IGF, PDGF, ET-1, Ang II, and mast cell chymase and tryptase enzymes to fibroblast activation in gingival fibrosis and the potential utility of agents blocking these proteins in affecting the outcome of drug-induced gingival overgrowth. PMID:23690667

  9. Taurine protects methamphetamine-induced developmental angiogenesis defect through antioxidant mechanism

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Shao, Xue; Hu, Zhengtao; Hu, Chunyan

    Investigations have characterized addictive drug-induced developmental cardiovascular malformation in human, non-human primate and rodent. However, the underlying mechanism of malformation caused by drugs during pregnancy is still largely unknown, and preventive and therapeutic measures have been lacking. Using {sup 1}H NMR spectroscopy, we profiled the metabolites from human embryo endothelial cells exposed to methamphetamine (METH) and quantified a total of 226 peaks. We identified 11 metabolites modified robustly and found that taurine markedly increased. We then validated the hypothesis that this dramatic increase in taurine could attribute to its effect in inhibiting METH-induced developmental angiogenesis defect. Taurine supplement showed amore » more significant potential than other metabolites in protecting against METH-induced injury in endothelial cells. Taurine strongly attenuated METH-induced inhibition of proliferation and migration in endothelial cells. Furthermore, death rate and vessel abnormality of zebrafish embryos treated with METH were greatly reversed by taurine. In addition, taurine supplement caused a rapid decrease in reactive oxygen species generation and strongly attenuated the excitable arise of antioxidase activities in the beginning of METH exposure prophase. Dysregulations of NF-κB, p-ERK as well as Bax, which reflect apoptosis, cell cycle arrest and oxidative stress in vascular endothelium, were blocked by taurine. Our results provide the first evidence that taurine prevents METH-caused developmental angiogenesis defect through antioxidant mechanism. Taurine could serve as a potential therapeutic or preventive intervention of developmental vascular malformation for the pregnant women with drug use. Highlights: ► Metabonomics findings. ► Abnormal development. ► Dysregulations of key proteins.« less

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

    PubMed

    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.

  11. Functional changes in cerebral 5-hydroxytryptamine metabolism in the mouse induced by anticonvulsant drugs.

    PubMed Central

    Chadwick, D; Gorrod, J W; Jenner, P; Marsden, C D; Reynolds, E H

    1978-01-01

    1 Acute administration of clonazepam, diazepam, and diphenylhydantoin to mice elevated cerebral 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA); chronic administration had less effect. 2 Acute administration of clonazepam and diazepam but not diphenylhydantoin raised cerebral trytophan levels; chronic administration of clonazepam caused a smaller elevation of cerebral tryptophan but chronic administration of diazepam still caused a large rise in cerebral tryptophan. 3 Neither clonazepam nor diazepam caused induction of drug metabolizing enzymes on chronic administration but diphenylhydantoin had a marked effect. 4 These data suggest that the altered 5-HT metabolism caused by these compounds is unrelated to a common action on tryptophan levels, and that the reduced effect of clonazepam and diazepam on chronic administration cannot be attributed to increased metabolism of these compounds. 5 Clonazepam induced abnormal head movements in mice in a dose-dependent manner. Pretreatment of animals with tranylcypromine increased the intensity of movement, although pargyline was without effect. Similar effects were observed with diazepam and diphenylhydantoin, suggesting that the increase in cerebral 5-HT caused by these compounds is of functional significance in stimulating 5-HT receptors. PMID:620092

  12. Sulthiame-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.

    PubMed

    Fong, Choong Yi; Hashim, Nurmaira; Gan, Chin Seng; Chow, Tak Kuan; Tay, Chee Geap

    2016-11-01

    Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and potentially life-threatening acute drug-induced hypersensitivity reaction. Antiepileptic drugs (AEDs) predominantly aromatic AEDs are commonly reported in DRESS. To date there are no reports of sulthiame AED causing DRESS syndrome. We report a 10-year-old girl of Indian descent with AED resistant epilepsy on maintenance sodium valproate and clonazepam. Sulthiame AED was initiated to try to improve her seizure control. Five weeks after commencing sulthiame, she developed fever with a diffuse erythematous morbilliform maculopapular rash, elevated transaminases and atypical lymphocytes. At day 3 of illness, she deteriorated with worsening elevation of liver transaminases, thrombocytopenia, progression of rash, hepatosplenomegaly, pneumonitis and markedly elevated inflammatory markers. Immunomodulatory treatment of pulse methylprednisolone was given from day 7 which was associated with improvement inflammatory markers and complete resolution of rash from day 30 of illness. The diagnosis of sulthiame-induced DRESS syndrome was made based on clinical, laboratory and skin histology findings. She was HLA-B heterozygous for HLA-B ∗ 15:123 and 15:240 and HLA-A homozygous for HLA-A ∗ 11:01:09. Both these HLA-A and HLA-B typing has not been reported before in cutaneous drug reactions. This is the first reported case of sulthiame-induced DRESS syndrome. Our case expands the list of possible susceptible HLA alleles associated with cutaneous drug reactions. It also raises the awareness of possible DRESS syndrome among patients commenced on sulthiame who will require immediate discontinuation of sulthiame and consideration of prompt treatment of corticosteroids. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  13. Drug-induced parkinsonism following chronic methamphetamine use by a patient on haloperidol decanoate.

    PubMed

    Matthew, Binoj J; Gedzior, Joanna S

    2015-01-01

    This report attempts to highlight that use of an antipsychotic and concurrent chronic use of methamphetamine can cause drug-induced parkinsonism. Methamphetamine is usually not encountered in the list of agents that induce drug-induced parkinsonism and so its consideration particularly during chronic use by a patient who is also on an antipsychotic is worthwhile because of its popularity as an illegal narcotic. This case report describes just such a case of drug-induced parkinsonism which is a subacute syndrome that mimics Parkinson's disease. Although less alarming than dystonia, it is more common, more difficult to treat and can be the cause of significant disability during maintenance treatment especially in the elderly. In most cases, symptoms are reversible in days or weeks, but occasionally, especially in the elderly, or if long-acting injectable antipsychotics are used-as in this case-symptoms may last for weeks or months. The report also illustrates the neuronal workings due to chronic methamphetamine-use and the additive effects of dopamine blockade by antipsychotics such as haloperidol. © The Author(s) 2015.

  14. Gap Junction Inhibition Prevents Drug-induced Liver Toxicity and Fulminant Hepatic Failure

    PubMed Central

    Patel, Suraj J; Milwid, Jack M; King, Kevin R; Bohr, Stefan; Iracheta, Arvin; Li, Matthew; Vitalo, Antonia; Parekkadan, Biju; Jindal, Rohit; Yarmush, Martin L

    2013-01-01

    Drug-induced liver injury (DILI) limits the development and utilization of numerous therapeutic compounds, and consequently presents major challenges to the pharmaceutical industry and clinical medicine1, 2. Acetaminophen (APAP) containing compounds are among the most frequently prescribed drugs, and also the most common cause of DILI3. Here we describe a pharmacological strategy that targets gap junction communication to prevent amplification of fulminant hepatic failure and APAP-induced hepatotoxicity. We report that connexin 32 (Cx32), a key hepatic gap junction protein, is an essential mediator of DILI by showing that mice deficient in Cx32 are protected against liver damage, acute inflammation, and death. We identified a small molecule inhibitor of Cx32 as a novel hepatoprotectant that achieves the same result in wildtype mice when coadministered with known hepatotoxic drugs. These findings demonstrate that gap junction inhibition is an effective therapy for limiting DILI, and suggest a novel pharmaceutical strategy to improve drug safety. PMID:22252509

  15. Induced Abnormality In Mir- and Earth-Grown Super Dwarf Wheat

    NASA Technical Reports Server (NTRS)

    Bubenheim, David L.; Stieber, Joseph; Campbell, William F.; Salisbury, Frank B.; Levinski, Margarita; Sytchev, Vladimir; Podolsky, Igor; Chernova, Lola; Ivanova, Irene; Kliss, Mark (Technical Monitor)

    1998-01-01

    Super-dwarf wheat grown on the Mir space station using the Svet "Greenhouse" exhibited morphological, metabolic and reproductive abnormalities compared with normal wheat. Of prominent importance were the abnormalities associated with reproductive ontogeny and the total absence of seed formation on Mir. Changes in the apical meristem associated with transition from the vegetative phase to floral initiation and development of the reproductive spike were all typical of 'Super Dwarf' wheat up to the point of anthesis. Observation of ruptured anthers from the Mir-grown plants revealed what appeared to be normally developed pollen. These pollen grains however, contain only one nucleus, while normal viable pollen is trinucleate. A potentially important difference in the flight experiment, compared with ground reference studies, was identified - a high level of atmospheric ethylene (1200 ppb). Ground studies conducted exposing "Super-dwarf" wheat to ethylene at just prior to anthesis resulted in manifestation of the same abnormalities observed in the space flight samples.

  16. Drug-induced liver injury: Do we know everything?

    PubMed Central

    Alempijevic, Tamara; Zec, Simon; Milosavljevic, Tomica

    2017-01-01

    Interest in drug-induced liver injury (DILI) has dramatically increased over the past decade, and it has become a hot topic for clinicians, academics, pharmaceutical companies and regulatory bodies. By investigating the current state of the art, the latest scientific findings, controversies, and guidelines, this review will attempt to answer the question: Do we know everything? Since the first descriptions of hepatotoxicity over 70 years ago, more than 1000 drugs have been identified to date, however, much of our knowledge of diagnostic and pathophysiologic principles remains unchanged. Clinically ranging from asymptomatic transaminitis and acute or chronic hepatitis, to acute liver failure, DILI remains a leading causes of emergent liver transplant. The consumption of unregulated herbal and dietary supplements has introduced new challenges in epidemiological assessment and clinician management. As such, numerous registries have been created, including the United States Drug-Induced Liver Injury Network, to further our understanding of all aspects of DILI. The launch of LiverTox and other online hepatotoxicity resources has increased our awareness of DILI. In 2013, the first guidelines for the diagnosis and management of DILI, were offered by the Practice Parameters Committee of the American College of Gastroenterology, and along with the identification of risk factors and predictors of injury, novel mechanisms of injury, refined causality assessment tools, and targeted treatment options have come to define the current state of the art, however, gaps in our knowledge still undoubtedly remain. PMID:28443154

  17. A Comparative Analysis of Drug-Induced Hepatotoxicity in Clinically Relevant Situations

    PubMed Central

    Thiel, Christoph; Cordes, Henrik; Fabbri, Lorenzo; Aschmann, Hélène Eloise; Baier, Vanessa; Atkinson, Francis; Blank, Lars Mathias; Kuepfer, Lars

    2017-01-01

    Drug-induced toxicity is a significant problem in clinical care. A key problem here is a general understanding of the molecular mechanisms accompanying the transition from desired drug effects to adverse events following administration of either therapeutic or toxic doses, in particular within a patient context. Here, a comparative toxicity analysis was performed for fifteen hepatotoxic drugs by evaluating toxic changes reflecting the transition from therapeutic drug responses to toxic reactions at the cellular level. By use of physiologically-based pharmacokinetic modeling, in vitro toxicity data were first contextualized to quantitatively describe time-resolved drug responses within a patient context. Comparatively studying toxic changes across the considered hepatotoxicants allowed the identification of subsets of drugs sharing similar perturbations on key cellular processes, functional classes of genes, and individual genes. The identified subsets of drugs were next analyzed with regard to drug-related characteristics and their physicochemical properties. Toxic changes were finally evaluated to predict both molecular biomarkers and potential drug-drug interactions. The results may facilitate the early diagnosis of adverse drug events in clinical application. PMID:28151932

  18. Abnormal Current–Voltage Hysteresis Induced by Reverse Bias in Organic–Inorganic Hybrid Perovskite Photovoltaics

    DOE PAGES

    Rajagopal, Adharsh; Williams, Spencer T.; Chueh, Chu-Chen; ...

    2016-02-29

    In this study, reverse bias (RB)-induced abnormal hysteresis is investigated in perovskite solar cells (PVSCs) with nickel oxide (NiOx)/methylammonium lead iodide (CH 3NH 3PbI 3) interfaces. Through comprehensive current-voltage (I-V) characterization and bias-dependent external quantum efficiency (EQE) measurements, we demonstrate that this phenomenon is caused by the interfacial ion accumulation intrinsic to CH 3NH 3PbI 3. Subsequently, via systematic analysis we discover that the abnormal I-V behavior is remarkably similar to tunnel diode I-V characteristics and is due to the formation of a transient tunnel junction at NiO x/CH 3NH 3PbI 3 interfaces under RB. The detailed analysis navigating themore » complexities of I-V behavior in CH 3NH 3PbI 3-based solar cells provided here ultimately illuminates possibilities in modulating ion motion and hysteresis via interfacial engineering in PVSCs. Moreover, this work shows that RB can alter how CH 3NH 3PbI 3 contributes to the functional nature of devices and provides the first steps toward approaching functional perovskite interfaces in new ways for metrology and analysis of complex transient processes.« less

  19. Structural, Metabolic, and Functional Brain Abnormalities as a Result of Prenatal Exposure to Drugs of Abuse: Evidence from Neuroimaging

    PubMed Central

    Roussotte, Florence; Soderberg, Lindsay

    2010-01-01

    Prenatal exposure to alcohol and stimulants negatively affects the developing trajectory of the central nervous system in many ways. Recent advances in neuroimaging methods have allowed researchers to study the structural, metabolic, and functional abnormalities resulting from prenatal exposure to drugs of abuse in living human subjects. Here we review the neuroimaging literature of prenatal exposure to alcohol, cocaine, and methamphetamine. Neuroimaging studies of prenatal alcohol exposure have reported differences in the structure and metabolism of many brain systems, including in frontal, parietal, and temporal regions, in the cerebellum and basal ganglia, as well as in the white matter tracts that connect these brain regions. Functional imaging studies have identified significant differences in brain activation related to various cognitive domains as a result of prenatal alcohol exposure. The published literature of prenatal exposure to cocaine and methamphetamine is much smaller, but evidence is beginning to emerge suggesting that exposure to stimulant drugs in utero may be particularly toxic to dopamine-rich basal ganglia regions. Although the interpretation of such findings is somewhat limited by the problem of polysubstance abuse and by the difficulty of obtaining precise exposure histories in retrospective studies, such investigations provide important insights into the effects of drugs of abuse on the structure, function, and metabolism of the developing human brain. These insights may ultimately help clinicians develop better diagnostic tools and devise appropriate therapeutic interventions to improve the condition of children with prenatal exposure to drugs of abuse. PMID:20978945

  20. Clinical features and treatment of drug fever caused by anti-tuberculosis drugs.

    PubMed

    Fang, Yong; Xiao, Heping; Tang, Shenjie; Liang, Li; Sha, Wei; Fang, Yuanyuan

    2016-07-01

    Tuberculosis is a major global health problem. However, anti-tuberculosis drug treatment has many adverse effects, such as drug-caused fever. The aim of this study was to investigate the clinical features and treatments of anti-tuberculosis drugs-induced fever. A total of 78 inpatients and outpatients with pulmonary tuberculosis accompanied by drug fever during the anti-tuberculosis treatment were analysed retrospectively from April 2006 to March 2013. Among the anti-tuberculosis drugs that caused the drug fever, rifampicin was the most common one, followed by para-aminosalicylic and pyrazinamide. The symptoms occurred within 2 months after treatment, mainly in the 1-3 weeks, and the main symptom was high fever with body temperature above 39°C. The accompanying symptoms include rash, chills, headache, stuffy nose, runny nose, nausea, vomiting and joint pain. Routine blood examination found that eosinophilia increased in 15 cases and decreased in another 15. Among 63 patients who underwent liver function tests, there were 10 cases of abnormal function and 4 cases of liver damage. When the drug fever was suspected, the measure of withdrawal was taken first. All the suspected drugs were withdrawn in 59 cases, while gradual withdrawal was conducted in 19 cases. Patients with complications were first treated in accordance with the principles of complications treatment and then were gradually given some drugs after recovery. The patients without complications were gradually given some drugs after the body temperature was back to normal. Drug fever is an allergic reaction, the resolution of which depends on whether it was accompanied by liver damage and/or rash or not. © 2014 John Wiley & Sons Ltd.

  1. Albendazole Induced Recurrent Acute Toxic Hepatitis: A Case Report.

    PubMed

    Bilgic, Yilmaz; Yilmaz, Cengiz; Cagin, Yasir Furkan; Atayan, Yahya; Karadag, Nese; Harputluoglu, Murat Muhsin Muhip

    2017-01-01

    Drug induced acute toxic hepatitis can be idiosyncratic. Albendazole, a widely used broad spectrum antiparasitic drug is generally accepted as a safe drug. It may cause asymptomatic transient liver enzyme abnormalities but acute toxic hepatitis is very rare. Case Report : Herein, we present the case of 47 year old woman with recurrent acute toxic hepatitis after a single intake of albendazole in 2010 and 2014. The patient was presented with symptoms and findings of anorexia, vomiting and jaundice. For diagnosis, other acute hepatitis etiologies were excluded. Roussel Uclaf Causality Assessment Method (RUCAM) score was calculated and found to be 10, which meant highly probable drug hepatotoxicity. Within 2 months, all pathological findings came to normal. There are a few reported cases of albendazole induced toxic hepatitis, but at adults, there is no known recurrent acute toxic hepatitis due to albendazole at this certainty according to RUCAM score. Physicians should be aware of this rare and potentially fatal adverse effect of albendazole. © Acta Gastro-Enterologica Belgica.

  2. Electrocardiographic abnormalities and relative bradycardia in patients with hantavirus-induced nephropathia epidemica.

    PubMed

    Kitterer, Daniel; Greulich, Simon; Grün, Stefan; Segerer, Stephan; Mustonen, Jukka; Alscher, M Dominik; Braun, Niko; Latus, Joerg

    2016-09-01

    Nephropathia epidemica (NE), caused by Puumala virus (PUUV), is characterized by acute kidney injury (AKI) and thrombocytopenia. Cardiac involvement with electrocardiographic (ECG) abnormalities has been previously reported in NE; however, its prognostic value is unknown. Relative bradycardia is an important clinical sign in various infectious diseases, and previous smaller studies have described pulse-temperature deficit in patients with PUUV infection. We performed a cross-sectional survey of 471 adult patients with serologically confirmed NE. Data were collected retrospectively from medical records and prospectively at follow-up visits. Patients for whom ECGs were recorded during the acute phase of disease were enrolled retrospectively (n=263). Three patients were excluded because of documented pre-existing ECG abnormalities prior to NE. All patients with ECG abnormalities during the acute phase underwent follow-up. A total of 46 patients had ECG abnormalities at the time of admission to hospital (18%). T-wave inversion was the most frequent ECG abnormality (n=31 patients), followed by ST segment changes (nine patients with elevation and six with depression). No major adverse cardiac events occurred during follow-up (median 37months; range 34-63months). Of note, ECG abnormalities reverted to normal in the majority of the patients during follow-up. During the acute phase of NE, 149 of 186 patients had relative bradycardia, without implications for disease course. Transient ECG abnormalities were detected in 18% of patients during acute NE but were not associated with negative cardiovascular outcome. Relative bradycardia was identified in 80% of the patients with acute NE. Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  3. Electromagnetic induction and radiation-induced abnormality of wave propagation in excitable media

    NASA Astrophysics Data System (ADS)

    Ma, Jun; Wu, Fuqiang; Hayat, Tasawar; Zhou, Ping; Tang, Jun

    2017-11-01

    Continuous wave emitting from sinus node of the heart plays an important role in wave propagating among cardiac tissue, while the heart beating can be terminated when the target wave is broken into turbulent states by electromagnetic radiation. In this investigation, local periodical forcing is applied on the media to induce continuous target wave in the improved cardiac model, which the effect of electromagnetic induction is considered by using magnetic flux, then external electromagnetic radiation is imposed on the media. It is found that target wave propagation can be blocked to stand in a local area and the excitability of media is suppressed to approach quiescent but homogeneous state when electromagnetic radiation is imposed on the media. The sampled time series for membrane potentials decrease to quiescent state due to the electromagnetic radiation. It could accounts for the mechanism of abnormality in heart failure exposed to continuous electromagnetic field.

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

    PubMed

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

    2003-05-01

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

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

    PubMed

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

    2015-02-01

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

  6. Alterations and Abnormal Mitosis of Wheat Chromosomes Induced by Wheat-Rye Monosomic Addition Lines

    PubMed Central

    Fu, Shulan; Yang, Manyu; Fei, Yunyan; Tan, Feiquan; Ren, Zhenglong; Yan, Benju; Zhang, Huaiyu; Tang, Zongxiang

    2013-01-01

    Background Wheat-rye addition lines are an old topic. However, the alterations and abnormal mitotic behaviours of wheat chromosomes caused by wheat-rye monosomic addition lines are seldom reported. Methodology/Principal Findings Octoploid triticale was derived from common wheat T. aestivum L. ‘Mianyang11’×rye S. cereale L. ‘Kustro’ and some progeny were obtained by the controlled backcrossing of triticale with ‘Mianyang11’ followed by self-fertilization. Genomic in situ hybridization (GISH) using rye genomic DNA and fluorescence in situ hybridization (FISH) using repetitive sequences pAs1 and pSc119.2 as probes were used to analyze the mitotic chromosomes of these progeny. Strong pSc119.2 FISH signals could be observed at the telomeric regions of 3DS arms in ‘Mianyang11’. However, the pSc119.2 FISH signals were disappeared from the selfed progeny of 4R monosomic addition line and the changed 3D chromosomes could be transmitted to next generation stably. In one of the selfed progeny of 7R monosomic addition line, one 2D chromosome was broken and three 4A chromosomes were observed. In the selfed progeny of 6R monosomic addition line, structural variation and abnormal mitotic behaviour of 3D chromosome were detected. Additionally, 1A and 4B chromosomes were eliminated from some of the progeny of 6R monosomic addition line. Conclusions/Significance These results indicated that single rye chromosome added to wheat might cause alterations and abnormal mitotic behaviours of wheat chromosomes and it is possible that the stress caused by single alien chromosome might be one of the factors that induced karyotype alteration of wheat. PMID:23936213

  7. Non-chemotherapy drug-induced neutropenia - an update.

    PubMed

    Andrès, Emmanuel; Mourot-Cottet, Rachel

    2017-11-01

    To date, non-chemotherapy drug-induced severe neutropenia (neutrophil count of ≤0.5 x 10 9 /L) also called idiosyncratic drug-induced agranulocytosis is little discussed in the literature. In the present paper, we report and discuss the clinical data and management of this rare disorder. Areas covered: To do this, we carried out a review of the literature using PubMed database of the US National Library of Medicine. We also used data from the American Society of Hematology educational books, textbooks of Hematology and Internal medicine, and information gleaned from international meetings. Expert opinion: Idiosyncratic agranulocytosis remains a potentially serious adverse event due to the frequency of severe sepsis with severe deep tissue infections (e.g., pneumonia), septicemia, and septic shock in approximately two-thirds of all hospitalized patients. In this context, several prognostic factors have been identified that may be helpful when identifying 'susceptible' patients. Old age (>65 years), septicemia or shock, renal failure, and a neutrophil count ≤0.1 × 10 9 /L have been consensually accepted as poor prognostic factors. In our experience, modern management with pre-established procedures, intravenous broad-spectrum antibiotics and hematopoietic growth factors (particularly G-CSF) is likely to improve the prognosis. Thus with appropriate management, the mortality rate is currently between 5 to 10%.

  8. Drug-induced sedation endoscopy in pediatric obstructive sleep apnea syndrome.

    PubMed

    Boudewyns, A; Verhulst, S; Maris, M; Saldien, V; Van de Heyning, P

    2014-12-01

    To describe the pattern of upper airway (UA) obstruction during drug-induced sedation endoscopy (DISE) and to evaluate the outcome of DISE-directed treatment. Prospective study of DISE in surgically naive obstructive sleep apnea syndrome (OSAS) children without syndromic comorbidity or craniofacial abnormalities. Treatment was individually tailored according to UA findings during DISE and polysomnographic data. Reported values are median (lower-upper quartile). Thirty-seven children aged 4.1 years (2.1-6.0), with body mass index z-score 0.3 (-0.9 to 0.9), and obstructive apnea-hypopnea index (oAHI) 9.0/h (6.1-19.3) were included. Adenotonsillar obstruction was found in 33 cases (89%) as an isolated entity or as part of a multi-level obstruction. These children were treated with adenotonsillectomy (n = 28), adenoidectomy (n = 3), or tonsillectomy (n = 2). The remaining four patients received non-surgical treatment. Pre-postoperative polysomnographic data in 22 patients showed a significant improvement in oAHI from 8.6/h (6.7-20.7) to 1.0/h (0.6-2.0) (P = 0.001). Only two of these 22 children had residual OSAS (oAHI ≥ 5/h), indicating a success rate of 91%. Based on UA findings during DISE, a non-surgical treatment was proposed for 11% of children. A 91% success rate was obtained in those treated with (adeno)tonsillectomy. These data suggest that DISE may be helpful to identify patients most likely to benefit from UA surgery. Copyright © 2014 Elsevier B.V. All rights reserved.

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

    PubMed Central

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

    2018-01-01

    More than 20% of clinically used drugs are glucuronidated by a microsomal enzyme UDP-glucuronosyltransferase (UGT). Inhibition or induction of UGT can result in an increase or decrease in blood drug concentration. To avoid drug-drug interactions and adverse drug reactions in individuals, therefore, it is important to understand whether UGTs are involved in metabolism of drugs and drug candidates. While most of glucuronides are inactive metabolites, acyl-glucuronides that are formed from compounds with a carboxylic acid group can be highly toxic. Animals such as mice and rats are widely used to predict drug metabolism and drug-induced toxicity in humans. However, there are marked species differences in the expression and function of drug-metabolizing enzymes including UGTs. To overcome the species differences, mice in which certain drug-metabolizing enzymes are humanized have been recently developed. Humanized UGT1 (hUGT1) mice were created in 2010 by crossing Ugt1-null mice with human UGT1 transgenic mice in a C57BL/6 background. hUGT1 mice can be promising tools to predict human drug glucuronidation and acyl-glucuronide-associated toxicity. In this review article, studies of drug metabolism and toxicity in the hUGT1 mice are summarized. We further discuss research and strategic directions to advance the understanding of drug glucuronidation in humans. PMID:29079228

  10. Induced abnormality in Mir- and Earth grown Super Dwarf wheat.

    PubMed

    Bubenheim, D L; Stieber, J; Campbell, W F; Salisbury, F B; Levinski, M; Sytchev, V; Podolsky, I; Chernova, L; Pdolsky, I

    2003-01-01

    Super-dwarf wheat grown on the Mir space station using the Svet "Greenhouse" exhibited morphological, metabolic and reproductive abnormalities compared with Earth-grown wheat. Of prominent importance were the abnormalities associated with reproductive ontogeny and the total absence of seed formation on Mir. Changes in the apical meristem associated with transition from the vegetative phase to floral initiation and development of the reproductive spike were all typical of 'Super-Dwarf' wheat up to the point of anthesis. Observation of ruptured anthers from the Mir-grown plants revealed what appeared to be normally developed pollen. These pollen gains, however, contained only one nuclei, while normal viable pollen is tri-nucleate. A potentially important difference in the flight experiment, compared with ground reference studies, was the presence of a high level of atmospheric ethylene (1,200 ppb). Ground studies conducted by exposing 'Super-Dwarf' wheat to ethylene just prior to anthesis resulted in manifestation of the same abnormalities observed in the space flight samples. c2002 Published by Elsevier Science Ltd on behalf of COSPAR.

  11. Induced abnormality in Mir- and Earth grown Super Dwarf wheat

    NASA Technical Reports Server (NTRS)

    Bubenheim, D. L.; Stieber, J.; Campbell, W. F.; Salisbury, F. B.; Levinski, M.; Sytchev, V.; Podolsky, I.; Chernova, L.; Pdolsky, I.

    2003-01-01

    Super-dwarf wheat grown on the Mir space station using the Svet "Greenhouse" exhibited morphological, metabolic and reproductive abnormalities compared with Earth-grown wheat. Of prominent importance were the abnormalities associated with reproductive ontogeny and the total absence of seed formation on Mir. Changes in the apical meristem associated with transition from the vegetative phase to floral initiation and development of the reproductive spike were all typical of 'Super-Dwarf' wheat up to the point of anthesis. Observation of ruptured anthers from the Mir-grown plants revealed what appeared to be normally developed pollen. These pollen gains, however, contained only one nuclei, while normal viable pollen is tri-nucleate. A potentially important difference in the flight experiment, compared with ground reference studies, was the presence of a high level of atmospheric ethylene (1,200 ppb). Ground studies conducted by exposing 'Super-Dwarf' wheat to ethylene just prior to anthesis resulted in manifestation of the same abnormalities observed in the space flight samples. c2002 Published by Elsevier Science Ltd on behalf of COSPAR.

  12. Tualang Honey Protects against BPA-Induced Morphological Abnormalities and Disruption of ERα, ERβ, and C3 mRNA and Protein Expressions in the Uterus of Rats

    PubMed Central

    Mohamad Zaid, Siti Sarah; Kassim, Normadiah M.; Othman, Shatrah

    2015-01-01

    Bisphenol A (BPA) is an endocrine disrupting chemical (EDC) that can disrupt the normal functions of the reproductive system. The objective of the study is to investigate the potential protective effects of Tualang honey against BPA-induced uterine toxicity in pubertal rats. The rats were administered with BPA by oral gavage over a period of six weeks. Uterine toxicity in BPA-exposed rats was determined by the degree of the morphological abnormalities, increased lipid peroxidation, and dysregulated expression and distribution of ERα, ERβ, and C3 as compared to the control rats. Concurrent treatment of rats with BPA and Tualang honey significantly improved the uterine morphological abnormalities, reduced lipid peroxidation, and normalized ERα, ERβ, and C3 expressions and distribution. There were no abnormal changes observed in rats treated with Tualang honey alone, comparable with the control rats. In conclusion, Tualang honey has potential roles in protecting the uterus from BPA-induced toxicity, possibly accounted for by its phytochemical properties. PMID:26788107

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

    PubMed Central

    ARAI, KEISUKE; KURAMITSU, KAORI; FUKUMOTO, TAKUMI; KIDO, MASAHIRO; TAKEBE, ATSUSHI; TANAKA, MOTOFUMI; KINOSHITA, HISOKA; AJIKI, TETSUO; TOYAMA, HIROCHIKA; ASARI, SADAKI; GOTO, TADAHIRO; KU, YONSON

    2016-01-01

    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. PMID:27492209

  14. Nicotine Reduces Antipsychotic-Induced Orofacial Dyskinesia in Rats

    PubMed Central

    Bordia, Tanuja; McIntosh, J. Michael

    2012-01-01

    Antipsychotics are an important class of drugs for the management of schizophrenia and other psychotic disorders. They act by blocking dopamine receptors; however, because these receptors are present throughout the brain, prolonged antipsychotic use also leads to serious side effects. These include tardive dyskinesia, repetitive abnormal involuntary movements of the face and limbs for which there is little treatment. In this study, we investigated whether nicotine administration could reduce tardive dyskinesia because nicotine attenuates other drug-induced abnormal movements. We used a well established model of tardive dyskinesia in which rats injected with the commonly used antipsychotic haloperidol develop vacuous chewing movements (VCMs) that resemble human orofacial dyskinesias. Rats were first administered nicotine (minipump; 2 mg/kg per day). Two weeks later, they were given haloperidol (1 mg/kg s.c.) once daily. Nicotine treatment reduced haloperidol-induced VCMs by ∼20% after 5 weeks, with a significant ∼60% decline after 13 weeks. There was no worsening of haloperidol-induced catalepsy. To understand the molecular basis for this improvement, we measured the striatal dopamine transporter and nicotinic acetylcholine receptors (nAChRs). Both haloperidol and nicotine treatment decreased the transporter and α6β2* nAChRs (the asterisk indicates the possible presence of other nicotinic subunits in the receptor complex) when given alone, with no further decline with combined drug treatment. By contrast, nicotine alone increased, while haloperidol reduced α4β2* nAChRs in both vehicle and haloperidol-treated rats. These data suggest that molecular mechanisms other than those directly linked to the transporter and nAChRs underlie the nicotine-mediated improvement in haloperidol-induced VCMs in rats. The present results are the first to suggest that nicotine may be useful for improving the tardive dyskinesia associated with antipsychotic use. PMID:22144565

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Henninger, Christian; Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf; Huelsenbeck, Johannes

    2012-05-15

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

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

    PubMed

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

    2011-12-01

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

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

    PubMed

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

    2017-06-22

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

  18. Novel Analysis Software for Detecting and Classifying Ca2+ Transient Abnormalities in Stem Cell-Derived Cardiomyocytes

    PubMed Central

    Penttinen, Kirsi; Siirtola, Harri; Àvalos-Salguero, Jorge; Vainio, Tiina; Juhola, Martti; Aalto-Setälä, Katriina

    2015-01-01

    Comprehensive functioning of Ca2+ cycling is crucial for excitation–contraction coupling of cardiomyocytes (CMs). Abnormal Ca2+ cycling is linked to arrhythmogenesis, which is associated with cardiac disorders and heart failure. Accordingly, we have generated spontaneously beating CMs from induced pluripotent stem cells (iPSC) derived from patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), which is an inherited and severe cardiac disease. Ca2+ cycling studies have revealed substantial abnormalities in these CMs. Ca2+ transient analysis performed manually lacks accepted analysis criteria, and has both low throughput and high variability. To overcome these issues, we have developed a software tool, AnomalyExplorer based on interactive visualization, to assist in the classification of Ca2+ transient patterns detected in CMs. Here, we demonstrate the usability and capability of the software, and we also compare the analysis efficiency to manual analysis. We show that AnomalyExplorer is suitable for detecting normal and abnormal Ca2+ transients; furthermore, this method provides more defined and consistent information regarding the Ca2+ abnormality patterns and cell line specific differences when compared to manual analysis. This tool will facilitate and speed up the analysis of CM Ca2+ transients, making it both more accurate and user-independent. AnomalyExplorer can be exploited in Ca2+ cycling analysis to study basic disease pathology and the effects of different drugs. PMID:26308621

  19. Novel Analysis Software for Detecting and Classifying Ca2+ Transient Abnormalities in Stem Cell-Derived Cardiomyocytes.

    PubMed

    Penttinen, Kirsi; Siirtola, Harri; Àvalos-Salguero, Jorge; Vainio, Tiina; Juhola, Martti; Aalto-Setälä, Katriina

    2015-01-01

    Comprehensive functioning of Ca2+ cycling is crucial for excitation-contraction coupling of cardiomyocytes (CMs). Abnormal Ca2+ cycling is linked to arrhythmogenesis, which is associated with cardiac disorders and heart failure. Accordingly, we have generated spontaneously beating CMs from induced pluripotent stem cells (iPSC) derived from patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), which is an inherited and severe cardiac disease. Ca2+ cycling studies have revealed substantial abnormalities in these CMs. Ca2+ transient analysis performed manually lacks accepted analysis criteria, and has both low throughput and high variability. To overcome these issues, we have developed a software tool, AnomalyExplorer based on interactive visualization, to assist in the classification of Ca2+ transient patterns detected in CMs. Here, we demonstrate the usability and capability of the software, and we also compare the analysis efficiency to manual analysis. We show that AnomalyExplorer is suitable for detecting normal and abnormal Ca2+ transients; furthermore, this method provides more defined and consistent information regarding the Ca2+ abnormality patterns and cell line specific differences when compared to manual analysis. This tool will facilitate and speed up the analysis of CM Ca2+ transients, making it both more accurate and user-independent. AnomalyExplorer can be exploited in Ca2+ cycling analysis to study basic disease pathology and the effects of different drugs.

  20. Quasi-resonance enhancement of laser-induced-fluorescence diagnosis of endometriosis

    NASA Astrophysics Data System (ADS)

    Hill, Ralph H., Jr.; Vancaillie, Thierry G.

    1990-05-01

    Endometriosis, a common disease in women in the reproductive age group, is defined pathologically by the presence of endometrial tissue (inner lining of the uterus) outside the uterus. The displaced tissue is histologically identical to endometrium. In addition to being a highly prevalent disease, this disease is associated with many distressing and debilitating symptoms. Motivated by the need to improve diagnosis by endoscopic imaging instrumentation, we have previously used several drugs to cause selective laser-induced fluorescence of active surgically induced endometriosis in the rabbit model in vivo using ultraviolet-wavelength (351.1 and 363.8 nm) excitation from an argon-ion laser. In the present study we have investigated methods of enhancing differentiation between normal and abnormal tissue by using other excitation wavelengths. In addition to an enhanced capability for detecting abnormal tissue, there are several other advantages associated with using visible-wavelength excitation, such as deeper penetration into the tissue, as well as increased equipment performance, reliability, versatility, and availability. The disadvantage is that because only wavelengths longer than the excitation wavelength can be used for detection, some of the spectral information is lost. Because human endomeiriosis samples were somewhat limited in quantity, as well as specimen size, we used normal ovarian tissue for the laser-induced-fluorescence differentiation-enhancement studies. Positive enhancement of the laser-induced- fluorescence differentiation was found in human ovarian tissue in vitro utilizing 514.5-nm excitation from an argonion laser. Additionally, preliminary verification of this concept was accomplished in active surgically induced endometriosis in the rabbit model in vivo with visible argon-ion laser excitation of two tetracycline-based drugs. Future experiments with other drug treatments and excitation/detection parameters are planned.

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

    PubMed Central

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

    2016-01-01

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

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kostadinova, Radina; Boess, Franziska; Applegate, Dawn

    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 vitromore » 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

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

    PubMed

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

    2016-01-01

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

  4. Synaptic plasticity and levodopa-induced dyskinesia: electrophysiological and structural abnormalities.

    PubMed

    Picconi, Barbara; De Leonibus, Elvira; Calabresi, Paolo

    2018-02-28

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic neurons located in the midbrain. The gold-standard therapy for PD is the restoration of dopamine (DA) levels through the chronic administration of the DA precursor levodopa (L-DOPA). Although levodopa therapy is the main therapeutic approach for PD, its use is limited by the development of very disabling dyskinetic movements, mainly due to the fluctuation of DA cerebral content. Experimental animal models of PD identified in DA D1/ERK-signaling pathway aberrant activation, occurring in striatal projection neurons, coupled with structural spines abnormalities, the molecular and neuronal basis of L-DOPA-induced dyskinesia (LIDs) occurrence. Different electrophysiological approaches allowed the identification of  the alteration of homeostatic structural and synaptic changes, the neuronal bases of LIDs either in vivo in parkinsonian patients or in vitro in experimental animals. Here, we report the most recent studies showing electrophysiological and morphological evidence of aberrant synaptic plasticity in parkinsonian patients during LIDs in different basal ganglia nuclei and also in cortical transmission, accounting for the complexity of the synaptic changes during dyskinesias. All together, these studies suggest that LIDs are associated with a loss of homeostatic synaptic mechanisms.

  5. Velopharyngeal Incoordination Caused by Phenytoin-Induced Toxicity.

    PubMed

    Hwang, Chang Ho

    2017-02-01

    Phenytoin induces lymphoid proliferation, resulting in complications that can range from tissue hyperplasia to lymphoma. Some of the complications resolve spontaneously after drug discontinuation. This report describes for the first time a case of dysphagia with lack of velopharyngeal coordination and nasopharyngeal reflux combined with massive palatine tonsillar hypertrophy. The condition did not develop before phenytoin administration, was induced by phenytoin, and spontaneously resolved upon drug discontinuation. The patient was referred for a video-fluoroscopic swallowing study owing to a recurring nasal reflux of foods that had developed since phenytoin administration. The video-fluoroscopic swallowing study revealed incidentally that the large bilateral elongated masses extended downward into the larynx and disturbed velar elevation. This finding was confirmed by computed tomography of the neck, which showed that palatine tonsillar hypertrophy disturbed the laryngopharynx on both sides. The symptoms (sleep apnea and nasal reflux) and the abnormal imaging findings disappeared without surgery approximately 1 month after drug discontinuation. This case suggests that dysphagia related to phenytoin-induced lymphoid hypertrophy may be treated by phenytoin discontinuation followed by a sufficient amount of time to allow symptom resolution rather than by prompt surgery.

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

    PubMed

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

    2018-02-01

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

  7. Laser-induced disruption of systemically administered liposomes for targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Mackanos, Mark A.; Larabi, Malika; Shinde, Rajesh; Simanovskii, Dmitrii M.; Guccione, Samira; Contag, Christopher H.

    2009-07-01

    Liposomal formulations of drugs have been shown to enhance drug efficacy by prolonging circulation time, increasing local concentration and reducing off-target effects. Controlled release from these formulations would increase their utility, and hyperthermia has been explored as a stimulus for targeted delivery of encapsulated drugs. Use of lasers as a thermal source could provide improved control over the release of the drug from the liposomes with minimal collateral tissue damage. Appropriate methods for assessing local release after systemic delivery would aid in testing and development of better formulations. We use in vivo bioluminescence imaging to investigate the spatiotemporal distribution of luciferin, used as a model small molecule, and demonstrate laser-induced release from liposomes in animal models after systemic delivery. These liposomes were tested for luciferin release between 37 and 45 °C in PBS and serum using bioluminescence measurements. In vivo studies were performed on transgenic reporter mice that express luciferase constitutively throughout the body, thus providing a noninvasive readout for controlled release following systemic delivery. An Nd:YLF laser was used (527 nm) to heat tissues and induce rupture of the intravenously delivered liposomes in target tissues. These data demonstrate laser-mediated control of small molecule delivery using thermally sensitive liposomal formulations.

  8. Maternal urinary tract infection and related drug treatments during pregnancy and risk of congenital abnormalities in the offspring.

    PubMed

    Bánhidy, F; Acs, N; Puhó, E H; Czeizel, A E

    2006-12-01

    The association between urinary tract infection (UTI) of pregnant women and preterm birth/low birthweight is known, but the possible association between UTI and congenital abnormalities (CAs) was evaluated rarely. Only one study showed an association with atrial septal defect, thus we decided to check this possible association. The population-based large data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA); most maternal UTIs were based on medically recorded data. SETTING The HCCSCA, 1980-1996, contained 22 843 newborns or fetuses with CAs and 38 151 matched controls, i.e. newborn infants without any HCAs. Hungarian informative offspring: live births, stillbirths and prenatally diagnosed malformed fetuses. Case-control pair analysis. Twenty-five CA groups. A total of 1542 (6.75%) mothers in the case group had UTI during entire pregnancy compared with 2188 (5.74%) mothers in the control group (adjusted prevalence odds ratios [POR] with 95% CI: 1.15, 1.06-1.24). We did not find a higher prevalence of UTI during the second and/or third months of pregnancy in total case group (adjusted POR with 95% CI: 1.1, 0.9-1.2) and in any group of CAs including atrial septal defect type II. No evidence for the teratogenic effect of maternal UTI and related drug treatments during early pregnancy.

  9. Genetic variants associated with antithyroid drug-induced agranulocytosis: a genome-wide association study in a European population.

    PubMed

    Hallberg, Pär; Eriksson, Niclas; Ibañez, Luisa; Bondon-Guitton, Emmanuelle; Kreutz, Reinhold; Carvajal, Alfonso; Lucena, M Isabel; Ponce, Esther Sancho; Molokhia, Mariam; Martin, Javier; Axelsson, Tomas; Yue, Qun-Ying; Magnusson, Patrik K E; Wadelius, Mia

    2016-06-01

    Drug-induced agranulocytosis is a potentially life-threatening adverse reaction. Genome-wide association studies (GWASs) in ethnic Chinese people in Taiwan and Hong Kong have shown an association between agranulocytosis induced by antithyroid drugs and the HLA alleles HLA-B*38:02 and HLA-DRB1*08:03. We aimed to identify genetic variants associated with antithyroid drug-induced agranulocytosis in a white European population. We did a GWAS in 234 European adults with any non-chemotherapy drug-induced agranulocytosis (absolute neutrophil count ≤0·5 × 10(9)/L [≤500/μL]) and 5170 population controls. 39 of the 234 patients had agranulocytosis that was induced by antithyroid drugs (thiamazole [methimazole], carbimazole, or propylthiouracil). After imputation and HLA allele prediction, 9 380 034 single nucleotide polymorphisms (SNPs) and 180 HLA alleles were tested for association. The genome-wide significance threshold was p<5 × 10(-8). Agranulocytosis induced by non-chemotherapy drugs in general was significantly associated with the HLA region on chromosome 6, with odds ratios (ORs) of 3·24 (95% CI 2·31-4·55, p=1·20 × 10(-11)) for HLA-B*27:05 and 3·57 (2·61-4·90, p=2·32 × 10(-15)) for the top SNP (rs114291795). Drug-specific analysis showed that the association with HLA-B*27:05 was largely driven by cases induced by antithyroid drugs. In a multiple logistic regression model, the OR for HLA-B*27:05 was 7·30 (3·81-13·96) when antithyroid drug-induced agranulocytosis was compared with population controls (p=1·91 × 10(-9)) and 16·91 (3·44-83·17) when compared with a small group of hyperthyroid controls (p=5·04 × 10(-4)). Three SNPs were strongly associated with antithyroid drug-induced agranulocytosis: rs652888 (OR 4·73, 95% CI 3·00-7·44, p=1·92 × 10(-11)) and rs199564443 (17·42, 7·38-41·12, p=7·04 × 10(-11)), which were independent of HLA-B*27:05, and rs1071816 (5·27, 3·06-9·10, p=2·35 × 10

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

    PubMed

    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

  11. Neural Progenitor Cells Rptor Ablation Impairs Development but Benefits to Seizure-Induced Behavioral Abnormalities.

    PubMed

    Chen, Ling-Lin; Wu, Mei-Ling; Zhu, Feng; Kai, Jie-Jing; Dong, Jing-Yin; Wu, Xi-Mei; Zeng, Ling-Hui

    2016-12-01

    Previous study suggests that mTOR signaling pathway may play an important role in epileptogenesis. The present work was designed to explore the contribution of raptor protein to the development of epilepsy and comorbidities. Mice with conditional knockout of raptor protein were generated by cross-bred Rptor flox/flox mice with nestin-CRE mice. The expression of raptor protein was analyzed by Western blotting in brain tissue samples. Neuronal death and mossy fiber sprouting were detected by FJB staining and Timm staining, respectively. Spontaneous seizures were recorded by EEG-video system. Morris water maze, open field test, and excitability test were used to study the behaviors of Rptor CKO mice. As the consequence of deleting Rptor, downstream proteins of raptor in mTORC1 signaling were partly blocked. Rptor CKO mice exhibited decrease in body and brain weight under 7 weeks old and accordingly, cortical layer thickness. After kainic acid (KA)-induced status epilepticus, overactivation of mTORC1 signaling was markedly reversed in Rptor CKO mice. Although low frequency of spontaneous seizure and seldom neuronal cell death were observed in both Rptor CKO and control littermates, KA seizure-induced mossy fiber spouting were attenuated in Rptor CKO mice. Additionally, cognitive-deficit and anxiety-like behavior after KA-induced seizures were partly reversed in Rptor CKO mice. Loss of the Rptor gene in mice neural progenitor cells affects normal development in young age and may contribute to alleviate KA seizure-induced behavioral abnormalities, suggesting that raptor protein plays an important role in seizure comorbidities. © 2016 John Wiley & Sons Ltd.

  12. Antidiabetic drugs restore abnormal transport of amyloid-β across the blood-brain barrier and memory impairment in db/db mice.

    PubMed

    Chen, Fang; Dong, Rong Rong; Zhong, Kai Long; Ghosh, Arijit; Tang, Su Su; Long, Yan; Hu, Mei; Miao, Ming Xing; Liao, Jian Min; Sun, Hong Bing; Kong, Ling Yi; Hong, Hao

    2016-02-01

    Previous studies have shown significant changes in amyloid-β (Aβ) transport across the blood-brain barrier (BBB) under diabetic conditions with hypoinsulinemia, which is involved in diabetes-associated cognitive impairment. Present study employed db/db mice with hyperinsulinemia to investigate changes in Aβ transport across the BBB, hippocampal synaptic plasticity, and restorative effects of antidiabetic drugs. Our results showed that db/db mice exhibited similar changes in Aβ transport across the BBB to that of insulin-deficient mice. Chronic treatment of db/db mice with antidiabetic drugs such as metformin, glibenclamide and insulin glargine significantly decreased Aβ influx across the BBB determined by intra-arterial infusion of (125)I-Aβ(1-40), and expression of the receptor for advanced glycation end products (RAGE) participating in Aβ influx. Insulin glargine, but not, metformin or glibenclamide increased Aβ efflux across the BBB determined by stereotaxic intra-cerebral infusion of (125)I-Aβ(1-40), and expression of the low-density lipoprotein receptor related protein 1 (LRP1) participating in Aβ efflux. Moreover, treatment with these drugs significantly decreased hippocampal Aβ(1-40) or Aβ(1-42) and inhibited neuronal apoptosis. The drugs also ameliorated memory impairment confirmed by improved performance on behavioral tasks. However, insulin glargine or glibenclamide, but not metformin, restored hippocampal synaptic plasticity characterized by enhancing in vivo long-term potentiation (LTP). Further study found that these three drugs significantly restrained NF-κB, but only insulin glargine enhanced peroxisome proliferator-activated receptor γ (PPARγ) activity at the BBB in db/db mice. Our data indicate that the antidiabetic drugs can partially restore abnormal Aβ transport across the BBB and memory impairment under diabetic context. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Noradrenergic mechanisms in cocaine-induced reinstatement of drug seeking in squirrel monkeys.

    PubMed

    Platt, Donna M; Rowlett, James K; Spealman, Roger D

    2007-08-01

    Norepinephrine (NE) uptake and NE receptor mechanisms play important modulating roles in the discriminative stimulus and stimulant effects of cocaine. The present study investigated the role of NE mechanisms in cocaine priming-induced reinstatement of extinguished drug seeking. Squirrel monkeys (Saimiri sciureus) were trained to stability under a second-order fixed interval, fixed ratio schedule of drug self-administration in which operant responding was maintained jointly by i.v. cocaine injections and presentations of a cocaine-paired stimulus. Drug seeking was then extinguished by replacing cocaine with vehicle and eliminating the cocaine-paired stimulus. In test sessions during which the cocaine-paired stimulus was reintroduced but only vehicle was available for self-administration, priming with cocaine, the dopamine transport inhibitor 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909), and the NE transport inhibitors nisoxetine and talsupram induced dose-dependent reinstatement of drug seeking. The maximum effect of the NE transport inhibitors was less than half that of cocaine. Both nisoxetine and talsupram augmented the priming effects of a low but not a high dose of cocaine. The priming effects of nisoxetine were blocked by the alpha1-adrenoceptor antagonist prazosin, the alpha2-adrenoceptor agonist clonidine, and the beta-adrenoceptor antagonist propranolol, but not by the dopamine receptor antagonist flupenthixol. The priming effects of cocaine were antagonized by clonidine and flupenthixol. Neither nisoxetine nor cocaine increased physiological (salivary cortisol) or behavioral (self-directed behaviors) markers of stress. These findings suggest that NE transporter inhibition and alpha2-adrenoceptor mechanisms play a significant role in cocaine-induced reinstatement of drug seeking that is not secondary to activation of brain stress pathways.

  14. Possible association between different congenital abnormalities and use of different sulfonamides during pregnancy.

    PubMed

    Czeizel, Andrew E; Puhó, Erzsébet; Sørensen, Henrik T; Olsen, Jørn

    2004-06-01

    The objective of the study presented here was to check the debated human teratogenic potential of sulfonamide drugs. Five different sulfonamides such as sulfamethazine, sulfathiourea, sulfamethoxypyridazine, sulfamethoxydiazine and the combination of sulfamethazine-sulfathiourea-sulfamethoxypyridazine were differentiated. Cases with congenital abnormalities were compared with their matched controls without congenital abnormalities in the population-based large data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980 and 1996. Of 38,151 newborn infants without any congenital abnormalities (control group), 163 (0.4%) had mothers who were treated with the sulfonamides studied during pregnancy, while of 22,843 cases with congenital abnormalities, 140 (0.6%) had mothers who were treated with the sulfonamides studied during pregnancy. The analysis of cases and matched controls indicated a higher rate of cardiovascular malformation (adjusted prevalence odds ratios [POR] with 95% CI: 3.5, 1.9-6.4) and clubfoot (adjusted POR with 95% CI: 2.6, 1.1-6.2) in infants born to mothers with sulfonamide treatment in the second and third months of pregnancy. The detailed analysis of different sulfonamides showed a possible association between cardiovascular malformations (adjusted POR with 95%; CI: 6.5, 2.6-15.9), particularly ventricular septal defect (17.1, 1.3-141.1) and sulfamethoxydiazine during the second and third months of pregnancy. In addition, a possible association was found between clubfoot and sulfathiourea, both during the entire pregnancy (adjusted POR with 95% CI: 2.3, 1.2-4.3) and in the second and third months of gestation (3.9, 1.1-13.8). Thus, maternal treatment of sulfamethoxydiazine may cause ventricular septal defect, while sulfathiourea may induce clubfoot; however, further studies are needed to verify or reject these associations.

  15. Reinstatement of cocaine seeking induced by drugs, cues, and stress in adolescent and adult rats

    PubMed Central

    Carroll, Marilyn E.

    2010-01-01

    Rationale In human and animal studies, adolescence marks a period of increased vulnerability to the initiation and subsequent abuse of drugs. Adolescents may be especially vulnerable to relapse, and a critical aspect of drug abuse is that it is a chronically relapsing disorder. However, little is known of how vulnerability factors such as adolescence are related to conditions that induce relapse, triggered by the drug itself, drug-associated cues, or stress. Objective The purpose of this study was to compare adolescent and adult rats on drug-, cue-, and stress-induced reinstatement of cocaine-seeking behavior. Methods On postnatal days 23 (adolescents) and 90 (adults), rats were implanted with intravenous catheters and trained to lever press for i.v. infusions of cocaine (0.4 mg/kg) during two daily 2-h sessions. The rats then self-administered i.v. cocaine for ten additional sessions. Subsequently, visual and auditory stimuli that signaled drug delivery were unplugged, and rats were allowed to extinguish lever pressing for 20 sessions. Rats were then tested on cocaine-, cue-, and yohimbine (stress)-induced cocaine seeking using a within-subject multicomponent reinstatement procedure. Results Results indicated that adolescents had heightened cocaine seeking during maintenance and extinction compared to adults. During reinstatement, adolescents (vs adults) responded more following cocaine- and yohimbine injections, while adults (vs adolescents) showed greater responding following presentations of drug-associated cues. Conclusion These results demonstrated that adolescents and adults differed across several measures of drug-seeking behavior, and adolescents may be especially vulnerable to relapse precipitated by drugs and stress. PMID:19953228

  16. Drug-induced glucose-6-phosphate dehydrogenase deficiency-related hemolysis risk assessment.

    PubMed

    Yang, Yang; Li, Zuofeng; Nan, Peng; Zhang, Xiaoyan

    2011-06-01

    Glucose-6-phosphate dehydrogenase (G6PD) is an essential enzyme that protects human red blood cells from premature destruction caused by oxidative damage. People suffering from G6PD deficiency would be vulnerable to various oxidative substances, such as fava beans and oxidant drugs. Until now, many institutes, organizations or domain experts have compiled low-risk or high-risk drugs collection for patients with G6PD deficiency, mainly from the case report or clinical trails. Recently, we have explored a classification system to predict drug-induced hemolytic potential. In this paper, we screen the normally used over-the-counter (OTC) drugs for "high-risk" and "low-risk" ones to G6PD deficient patients by this system. Copyright © 2011 Elsevier Ltd. All rights reserved.

  17. Emotional withdrawal, CT abnormalities and drug response in late life depression.

    PubMed

    Altamura, A Carlo; Bassetti, Roberta; Santini, Annalisa; Frisoni, G B; Mundo, Emanuela

    2004-03-01

    In this study, the authors investigated if CNS degenerative abnormalities could correlate with depressive symptoms in elderly patients, if the presence of mild/moderate cognitive impairment could be related to the response to treatment and the role of peculiar clinical features in influencing the response to treatment. Fifty-three patients (60-75 years) diagnosed as affected by late onset (after 60 years) Major Depressive Episodes according to DSM-IV criteria were studied. Brain vascular and degenerative markers were assessed by computed tomography (CT) through measurements of a lateralized version of the bifrontal index and a rating scale addressing subcortical disease. The presence of mild/moderate cognitive impairment [(24-28 total score at the Mini-Mental State Examination (MMSE)], and of specific symptoms were assessed at baseline and evaluated with respect to the antidepressant response. Patients with CT abnormalities showed higher baseline scores on Hamilton Rating Scale for Depression (HAM-D) items "late insomnia" (t=-2.674, P=.002), "somatic symptoms" (t=-3.355 P=.002), and Brief Psychiatric Rating Scale (BPRS) item "emotional withdrawal" (t=-3.355, P=.002). No significant correlation was found between the vascular index and baseline clinical symptoms, while the HAM-D "depressed mood" item was negatively correlated to the right frontal index (R=-0.692, P=.006). Patients with CT abnormalities showed a lower reduction of HAM-D total scores than patients with normal CT (time effect: F=29.277, P<.0001; group effect: F=5.154, P<.03), while a significant reduction of symptoms in time (time effect: F=33.33, P<.0001) but no differences between groups were found on Hamilton Rating Scale for Anxiety (HAM-A). Both patients with and without mild cognitive impairment improved on the HAM-D (time effect: F=19.668, P<.0001), BPRS (time effect: F=18.345, P<.0001), and HAM-A (time effect: F=17.959, P<.0001) total scores. Patients with emotional withdrawal showed lower

  18. The sigma-1 antagonist BMY-14802 inhibits L-DOPA-induced abnormal involuntary movements by a WAY-100635-sensitive mechanism

    PubMed Central

    Paquette, Melanie A.; Foley, Katherine; Brudney, Elizabeth G.; Meshul, Charles K.; Johnson, Steven W.; Berger, S. Paul

    2010-01-01

    Rationale Levodopa (L-DOPA), the gold standard treatment for Parkinson's disease (PD), eventually causes L-DOPA-induced dyskinesia (LID) in up to 80% of patients. In the 6-hydroxydopamine (6-OHDA) rat model of PD, L-DOPA induces a similar phenomenon, which has been termed abnormal involuntary movement (AIM). We previously demonstrated that BMY-14802 suppresses AIM expression in this model. Objectives Although BMY-14802 is widely used as a sigma-1 antagonist, it is also an agonist at serotonin (5-HT) 1A and adrenergic α-1 receptors. The current study was conducted to determine which of these mechanisms underlies BMY-14802's AIM-suppressing effect. This characterization included testing the 5-HT1A agonist buspirone and multiple sigma agents. When these studies implicated a 5-HT1A mechanism, we subsequently undertook a pharmacological reversal study, evaluating whether the 5-HT1A antagonist WAY-100635 counteracted BMY-14802's AIM-suppressing effects. Results Buspirone dose-dependently suppressed AIM, supporting past findings. However, no AIM-suppressing effects were produced by drugs with effects at sigma receptors, including BD-1047, finasteride, SM-21, DTG, trans-dehydroandrosterone (DHEA), carbetapentane, and opipramol. Finally, we show for the first time that the AIM-suppressing effect of BMY-14802 was dose-dependently prevented by WAY-100635 but not by the α-1 antagonist prazosin. Conclusions BMY-14802 exerts its AIM-suppressing effects via a 5-HT1A agonist mechanism, similar to buspirone. Other 5-HT1A agonists have failed clinical trials, possibly due to submicromolar affinity at other receptors, including D2, which may exacerbate PD symptoms. BMY-14802 is a promising candidate for clinical trials due to its extremely low affinity for the D2 receptor and lack of extrapyramidal effects during prior clinical trials for schizophrenia. PMID:19283364

  19. Neurophysiological model of the normal and abnormal human pupil

    NASA Technical Reports Server (NTRS)

    Krenz, W.; Robin, M.; Barez, S.; Stark, L.

    1985-01-01

    Anatomical, experimental, and computer simulation studies were used to determine the structure of the neurophysiological model of the pupil size control system. The computer simulation of this model demonstrates the role played by each of the elements in the neurological pathways influencing the size of the pupil. Simulations of the effect of drugs and common abnormalities in the system help to illustrate the workings of the pathways and processes involved. The simulation program allows the user to select pupil condition (normal or an abnormality), specific site along the neurological pathway (retina, hypothalamus, etc.) drug class input (barbiturate, narcotic, etc.), stimulus/response mode, display mode, stimulus type and input waveform, stimulus or background intensity and frequency, the input and output conditions, and the response at the neuroanatomical site. The model can be used as a teaching aid or as a tool for testing hypotheses regarding the system.

  20. Risk of specific congenital abnormalities in offspring of women with diabetes.

    PubMed

    Nielsen, G L; Nørgard, B; Puho, E; Rothman, K J; Sørensen, H T; Czeizel, A E

    2005-06-01

    To assess the extent to which the increased risk of congenital abnormalities seen in women with pre-gestational insulin-treated diabetes mellitus is unspecific or related to the embryology of specific organs. Cases with congenital abnormalities were identified in the population-based Hungarian Congenital Abnormality Registry from 1980 to 1996 with two newborn children without congenital abnormality selected from the National Birth Registry as controls. We adjusted for parity, maternal age, and use of antipsychotic drugs. Among cases we found 63/22,843 babies with maternal diabetes compared with 50/38,151 in the control group [adjusted prevalence odds ratio (POR) 2.1; 95% CI 1.5-3.1]. The association was strongest for the following congenital abnormalities: renal agenesis (POR: 14.8; 95% CI, 3.5-62.1), obstructive congenital abnormalities of the urinary tract (POR: 4.3; 95% CI, 1.3-13.9), cardiovascular congenital abnormalities (POR: 3.4; 95% CI, 2.0-5.7), and multiple congenital abnormalities (POR: 5.0; 95% CI, 2.4-10.2). These data indicate that pre-gestational maternal diabetes is associated with strong teratogenic effects on the kidney, urinary tract, and heart, and strongly associated with multiple congenital abnormalities. We found no material association between diabetes and spinal congenital abnormalities and limb deficiencies.

  1. Investigation of Drug-Induced Hepatotoxicity and Its Remediation Pathway with Reaction-Based Fluorescent Probes.

    PubMed

    Cheng, Dan; Xu, Wang; Yuan, Lin; Zhang, Xiaobing

    2017-07-18

    Drug-induced liver injury (DILI) is considered a serious problem related to public health, due to its unpredictability and acute response. The level of peroxynitrite (ONOO - ) generated in liver has long been regarded as a biomarker for the prediction and measurement of DILI. Herein we present two reaction-based fluorescent probes (Naph-ONOO - and Rhod-ONOO - ) for ONOO - through a novel and universally applicable mechanism: ONOO - -mediated deprotection of α-keto caged fluorophores. Among them, Rhod-ONOO - can selectively accumulate and react in mitochondria, one of the main sources of ONOO - , with a substantial lower nanomolar sensitivity of 43 nM. The superior selectivity and sensitivity of two probes enable real-time imaging of peroxynitrite generation in lipopolysaccharide-stimulated live cells, with a remarkable difference from cells doped with other interfering reactive oxygen species, in either one- or two-photon imaging modes. More importantly, we elucidated the drug-induced hepatotoxicity pathway with Rhod-ONOO - and revealed that CYP450/CYP2E1-mediated enzymatic metabolism of acetaminophen leads to ONOO - generation in liver cells. This is the first time to showcase the drug-induced hepatotoxicity pathways by use of a small-molecule fluorescent probe. We hence conclude that fluorescent probes can engender a deeper understanding of reactive species and their pathological revelations. The reaction-based fluorescent probes will be a potentially useful chemical tool to assay drug-induced hepatotoxicity.

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

    PubMed

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

    2014-01-01

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

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

    PubMed

    Kuroda, Yukihiro; Saito, Madoka

    2010-03-01

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

  4. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin.

    PubMed

    Wang, Yupeng; Gao, Wenqing; Shi, Xuyan; Ding, Jingjin; Liu, Wang; He, Huabin; Wang, Kun; Shao, Feng

    2017-07-06

    Pyroptosis is a form of cell death that is critical for immunity. It can be induced by the canonical caspase-1 inflammasomes or by activation of caspase-4, -5 and -11 by cytosolic lipopolysaccharide. The caspases cleave gasdermin D (GSDMD) in its middle linker to release autoinhibition on its gasdermin-N domain, which executes pyroptosis via its pore-forming activity. GSDMD belongs to a gasdermin family that shares the pore-forming domain. The functions and mechanisms of activation of other gasdermins are unknown. Here we show that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5), can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis. GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis. After chemotherapy, cleavage of GSDME by caspase-3 induced pyroptosis in certain GSDME-expressing cancer cells. GSDME was silenced in most cancer cells but expressed in many normal tissues. Human primary cells exhibited GSDME-dependent pyroptosis upon activation of caspase-3 by chemotherapy drugs. Gsdme -/- (also known as Dfna5 -/- ) mice were protected from chemotherapy-induced tissue damage and weight loss. These findings suggest that caspase-3 activation can trigger necrosis by cleaving GSDME and offer new insights into cancer chemotherapy.

  5. A novel mixed phospholipid functionalized monolithic column for early screening of drug induced phospholipidosis risk.

    PubMed

    Zhao, XiangLong; Chen, WeiJia; Liu, ZhengHua; Guo, JiaLiang; Zhou, ZhengYin; Crommen, Jacques; Moaddel, Ruin; Jiang, ZhengJin

    2014-11-07

    Drug-induced phospholipidosis (PLD) is characterized by the excessive accumulation of phospholipids, resulting in multilamellar vesicle structure within lysosomes. In the present study, a novel mixed phospholipid functionalized monolithic column was developed for the first time through a facile one-step co-polymerization approach. The phospholipid composition of the monolith can be adjusted quantitatively and accurately to mimic the mixed phospholipid environment of different biomembranes on a solid matrix. The mixed phospholipid functionalized monolith as a promising immobilized artificial membrane technique was used to study drug-phospholipid interaction. Scanning electron microscopy, elemental analysis, FT-IR spectra, ζ-potential analysis and micro-HPLC were carried out to characterize the physicochemical properties and separation performance of the monolith. Mechanism studies revealed that both hydrophobic and electrostatic interactions play an important role in the retention of analytes. The ratio of their contributions to retention can be easily manipulated by adjusting the composition of the mixed phospholipids, in order to better mimic the interaction between drugs and cell membrane. The obtained mixed phospholipid functionalized monolithic columns were applied to the screening of drug-induced PLD potency. Data from 79 drugs on the market demonstrated that the chromatographic hydrophobicity index referring to the mixed phospholipid functionalized monolith at pH 7.4 (CHI IAM7.4) for the selected drugs were highly correlated with the drug-induced PLD potency data obtained from other in vivo or in vitro assays. Moreover, the effect of the acidic phospholipid phosphatidylserine proportion on prediction accuracy was also investigated. The monolith containing 20% phosphatidylserine and 80% phosphatidylcholine exhibited the best prediction ability for the drug-induced PLD potency of the tested compounds. This research has led to the successful development of a

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

    PubMed

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

    2018-08-01

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

  7. Abnormal pupillary light reflex with chromatic pupillometry in Gaucher disease.

    PubMed

    Narita, Aya; Shirai, Kentarou; Kubota, Norika; Takayama, Rumiko; Takahashi, Yukitoshi; Onuki, Takanori; Numakura, Chikahiko; Kato, Mitsuhiro; Hamada, Yusuke; Sakai, Norio; Ohno, Atsuko; Asami, Maya; Matsushita, Shoko; Hayashi, Anri; Kumada, Tomohiro; Fujii, Tatsuya; Horino, Asako; Inoue, Takeshi; Kuki, Ichiro; Asakawa, Ken; Ishikawa, Hitoshi; Ohno, Koyo; Nishimura, Yoko; Tamasaki, Akiko; Maegaki, Yoshihiro; Ohno, Kousaku

    2014-02-01

    The hallmark of neuronopathic Gaucher disease (GD) is oculomotor abnormalities, but ophthalmological assessment is difficult in uncooperative patients. Chromatic pupillometry is a quantitative method to assess the pupillary light reflex (PLR) with minimal patient cooperation. Thus, we investigated whether chromatic pupillometry could be useful for neurological evaluations in GD. In our neuronopathic GD patients, red light-induced PLR was markedly impaired, whereas blue light-induced PLR was relatively spared. In addition, patients with non-neuronopathic GD showed no abnormalities. These novel findings show that chromatic pupillometry is a convenient method to detect neurological signs and monitor the course of disease in neuronopathic GD.

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

    PubMed

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

    1999-06-01

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

  9. Nonsteroid anti-inflammatory drug-induced gastroduodenal injury.

    PubMed

    Lai, Larry H; Chan, Francis K L

    2009-11-01

    This article reviews selected publications related to nonsteroid anti-inflammatory drug (NSAID)-induced gastroduodenal toxicity in recent years. This article provides a comprehensive review of the latest evidence on the epidemiology of NSAID-induced gastroduodenal injury, recommendations on optimal gastroprotective regimens among patients in need of NSAID, risk stratification approach by considering gastrointestinal and cardiovascular risks, and negative interaction between proton pump inhibitors (PPIs) and clopidogrel. Current evidence indicates that a PPI and a cyclooxygenase (COX)-2-selective NSAID provides the best gastric protection. In light of potential cardiovascular hazard of NSAIDs, physicians should select an NSAID according to individual patients' cardiovascular risk (i.e., naproxen vs. a nonnaproxen NSAID). The choice of gastroprotective therapy depends on the number and nature of gastrointestinal risk factors. PPI co-therapy is recommended in patients with high gastrointestinal risk on aspirin. Whether there is any clinically important interaction between PPIs and clopidogrel remains uncertain.

  10. Mucosal protective agents prevent exacerbation of NSAID-induced small intestinal lesions caused by antisecretory drugs in rats.

    PubMed

    Satoh, Hiroshi; Amagase, Kikuko; Takeuchi, Koji

    2014-02-01

    Antisecretory drugs such as histamine H₂-receptor antagonists and proton pump inhibitors are commonly used for the treatment of upper gastrointestinal mucosal lesions induced by nonsteroidal anti-inflammatory drugs (NSAIDs). However, it has recently been reported that these drugs exacerbate NSAID-induced small intestinal lesions in rats. Unfortunately, there are few effective agents for the treatment of this complication. We examined the effects of mucosal protective agents (MPAs) (misoprostol, irsogladine, and rebamipide) and mucin of porcine stomach on diclofenac-induced intestinal lesions and the exacerbation of the lesions by ranitidine or omeprazole. The effects of the drugs on intestinal motility and mucus distribution/content were also examined. Male Wistar rats (180-220 g) were used. Each drug was administered orally under fed conditions. Diclofenac (1-10 mg/kg) produced multiple lesions in the small intestine dose-dependently. Both ranitidine (30 mg/kg) and omeprazole (100 mg/kg) significantly increased the intestinal lesions induced by low doses (3 and 6 mg/kg) of diclofenac. Misoprostol (0.03-0.3 mg/kg), irsogladine (3-30 mg/kg), and rebamipide (30-300 mg/kg), as well as mucin (30-300 mg/kg) inhibited the formation of intestinal lesions caused by a high dose (10 mg/kg) of diclofenac alone and prevented the exacerbation of diclofenac-induced lesions by antisecretory drugs. Diclofenac (10 mg/kg) markedly increased the intestinal motility and decreased the mucosal mucus, and the decrease of mucus was significantly inhibited by the MPAs. These results indicate the usefulness of the MPAs for the treatment of intestinal lesions induced by NSAIDs alone or by coadministration with antisecretory drugs, and suggest that mucus plays an important role in the protection of intestinal mucosa by the MPAs.

  11. [Drug-induced gynecomastia].

    PubMed

    Hugues, F C; Gourlot, C; Le Jeunne, C

    2000-02-01

    Drugs are a very common cause of gynecomastia and should always be entertained as the possible causal agent of such a condition. This drug side-effect is due to an impaired balance in the serum estrogen/serum androgen ratio, whatever the mechanism, or a rise in prolactin level. Sex hormones, antiandrogens, are frequently involved as well as spironolactone, cimetidine, verapamil and cancer chemotherapy (especially alkylating agents). Diazepam, tricyclic antidepressants, neuroleptics, calcium channel blockers, captopril, digitalis glycosides, omeprazole, some antibiotics and growth hormone are all possibly, but less often, the responsible agent. Criteria of the French method for determining drug causality are discussed.

  12. The Pea Seedling as a Model of Normal and Abnormal Morphogenesis

    ERIC Educational Resources Information Center

    Kurkdjian, Armen; And Others

    1974-01-01

    Describes several simple and inexpensive experiments designed to facilitate the study of normal and abnormal morphogenesis in the biology laboratory. Seedlings of the common garden pea are used in the experiments, and abnormal morphogenesis (tumors) are induced by a virulent strain of the crown-gall organism, Agrobacterium tumefaciens. (JR)

  13. The impact of commonly prescribed drugs on male fertility.

    PubMed

    Hayashi, Tetsuo; Miyata, Akiomi; Yamada, Takumi

    2008-09-01

    To analyze the impact of commonly used drugs on male fertility, we assessed the clinical characteristics of patients with impaired semen quality while they were taking medication for chronic diseases and after switching therapies. Of 1768 infertile males, 201 patients were taking medications and had impaired semen quality without any seminal tract obstruction, spermatogenic abnormalities or hypogonadotropic hypogonadism. Of these 201 men, a total of 165 had no history of testicular diseases nor abnormalities in any examinations. Amongst them, H1 receptor antagonists were the most common medication taken, followed by antiepileptics and antibiotics. They were divided into two groups: an intervention group (73 patients), who could stop or switch their medications, and a control group (92 patients), who could not. In the intervention group, semen quality improvement rate and conception rate (93% and 85%, respectively) were much higher than those of the control group (12% and 10%, respectively). After switching therapies, the time interval before conception was 7.3 months, which was significantly shorter in asthenozoospermia than oligozoospermia. Our results confirm the potential fertility hazards of commonly used drugs and their reversibility. Moreover, after switching medication, drug-induced asthenozoospermia was cured more rapidly than oligozoospermia, suggesting that further delineation of such differences may help to elucidate mechanisms of spermatogenesis and might facilitate the development of non-hormonal male contraceptive agents.

  14. Effect of Time-Dependent Pinning Pressure on Abnormal Grain Growth: Phase Field Simulation

    NASA Astrophysics Data System (ADS)

    Kim, Jeong Min; Min, Guensik; Shim, Jae-Hyeok; Lee, Kyung Jong

    2018-05-01

    The effect of the time-dependent pinning pressure of precipitates on abnormal grain growth has been investigated by multiphase field simulation with a simple precipitation model. The application of constant pinning pressure is problematic because it always induces abnormal grain growth or no grain growth, which is not reasonable considering the real situation. To produce time-dependent pinning pressure, both precipitation kinetics and precipitate coarsening kinetics have been considered with two rates: slow and fast. The results show that abnormal grain growth is suppressed at the slow precipitation rate. At the slow precipitation rate, the overall grain growth caused by the low pinning pressure in the early stage indeed plays a role in preventing abnormal grain growth by reducing the mobility advantage of abnormal grains. In addition, the fast precipitate coarsening rate tends to more quickly transform abnormal grain growth into normal grain growth by inducing the active growth of grains adjacent to the abnormal grains in the early stage. Therefore, the present study demonstrates that the time dependence of the pinning pressure of precipitates is a critical factor that determines the grain growth mode.

  15. Effect of Time-Dependent Pinning Pressure on Abnormal Grain Growth: Phase Field Simulation

    NASA Astrophysics Data System (ADS)

    Kim, Jeong Min; Min, Guensik; Shim, Jae-Hyeok; Lee, Kyung Jong

    2018-03-01

    The effect of the time-dependent pinning pressure of precipitates on abnormal grain growth has been investigated by multiphase field simulation with a simple precipitation model. The application of constant pinning pressure is problematic because it always induces abnormal grain growth or no grain growth, which is not reasonable considering the real situation. To produce time-dependent pinning pressure, both precipitation kinetics and precipitate coarsening kinetics have been considered with two rates: slow and fast. The results show that abnormal grain growth is suppressed at the slow precipitation rate. At the slow precipitation rate, the overall grain growth caused by the low pinning pressure in the early stage indeed plays a role in preventing abnormal grain growth by reducing the mobility advantage of abnormal grains. In addition, the fast precipitate coarsening rate tends to more quickly transform abnormal grain growth into normal grain growth by inducing the active growth of grains adjacent to the abnormal grains in the early stage. Therefore, the present study demonstrates that the time dependence of the pinning pressure of precipitates is a critical factor that determines the grain growth mode.

  16. Drug-induced pulmonary disease

    MedlinePlus

    ... are known to cause lung disease in some people. These include: Antibiotics, such as nitrofurantoin and sulfa drugs Heart medicines, such as amiodarone Chemotherapy drugs such as bleomycin, cyclophosphamide, and methotrexate Street drugs

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

    PubMed Central

    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

  18. Redox/methylation mediated abnormal DNA methylation as regulators of ambient fine particulate matter-induced neurodevelopment related impairment in human neuronal cells

    NASA Astrophysics Data System (ADS)

    Wei, Hongying; Liang, Fan; Meng, Ge; Nie, Zhiqing; Zhou, Ren; Cheng, Wei; Wu, Xiaomeng; Feng, Yan; Wang, Yan

    2016-09-01

    Fine particulate matter (PM2.5) has been implicated as a risk factor for neurodevelopmental disorders including autism in children. However, the underlying biological mechanism remains unclear. DNA methylation is suggested to be a fundamental mechanism for the neuronal responses to environmental cues. We prepared whole particle of PM2.5 (PM2.5), water-soluble extracts (Pw), organic extracts (Po) and carbon core component (Pc) and characterized their chemical constitutes. We found that PM2.5 induced significant redox imbalance, decreased the levels of intercellular methyl donor S-adenosylmethionine and caused global DNA hypomethylation. Furthermore, PM2.5 exposure triggered gene-specific promoter DNA hypo- or hypermethylation and abnormal mRNA expression of autism candidate genes. PM2.5-induced DNA hypermethylation in promoter regions of synapse related genes were associated with the decreases in their mRNA and protein expression. The inhibiting effects of antioxidative reagents, a methylation-supporting agent and a DNA methyltransferase inhibitor demonstrated the involvement of redox/methylation mechanism in PM2.5-induced abnormal DNA methylation patterns and synaptic protein expression. The biological effects above generally followed a sequence of PM2.5 ≥ Pwo > Po > Pw > Pc. Our results implicated a novel epigenetic mechanism for the neurodevelopmental toxicity of particulate air pollution, and that eliminating the chemical components could mitigate the neurotoxicity of PM2.5.

  19. Redox/methylation mediated abnormal DNA methylation as regulators of ambient fine particulate matter-induced neurodevelopment related impairment in human neuronal cells.

    PubMed

    Wei, Hongying; Liang, Fan; Meng, Ge; Nie, Zhiqing; Zhou, Ren; Cheng, Wei; Wu, Xiaomeng; Feng, Yan; Wang, Yan

    2016-09-14

    Fine particulate matter (PM2.5) has been implicated as a risk factor for neurodevelopmental disorders including autism in children. However, the underlying biological mechanism remains unclear. DNA methylation is suggested to be a fundamental mechanism for the neuronal responses to environmental cues. We prepared whole particle of PM2.5 (PM2.5), water-soluble extracts (Pw), organic extracts (Po) and carbon core component (Pc) and characterized their chemical constitutes. We found that PM2.5 induced significant redox imbalance, decreased the levels of intercellular methyl donor S-adenosylmethionine and caused global DNA hypomethylation. Furthermore, PM2.5 exposure triggered gene-specific promoter DNA hypo- or hypermethylation and abnormal mRNA expression of autism candidate genes. PM2.5-induced DNA hypermethylation in promoter regions of synapse related genes were associated with the decreases in their mRNA and protein expression. The inhibiting effects of antioxidative reagents, a methylation-supporting agent and a DNA methyltransferase inhibitor demonstrated the involvement of redox/methylation mechanism in PM2.5-induced abnormal DNA methylation patterns and synaptic protein expression. The biological effects above generally followed a sequence of PM2.5 ≥ Pwo > Po > Pw > Pc. Our results implicated a novel epigenetic mechanism for the neurodevelopmental toxicity of particulate air pollution, and that eliminating the chemical components could mitigate the neurotoxicity of PM2.5.

  20. Redox/methylation mediated abnormal DNA methylation as regulators of ambient fine particulate matter-induced neurodevelopment related impairment in human neuronal cells

    PubMed Central

    Wei, Hongying; Liang, Fan; Meng, Ge; Nie, Zhiqing; Zhou, Ren; Cheng, Wei; Wu, Xiaomeng; Feng, Yan; Wang, Yan

    2016-01-01

    Fine particulate matter (PM2.5) has been implicated as a risk factor for neurodevelopmental disorders including autism in children. However, the underlying biological mechanism remains unclear. DNA methylation is suggested to be a fundamental mechanism for the neuronal responses to environmental cues. We prepared whole particle of PM2.5 (PM2.5), water-soluble extracts (Pw), organic extracts (Po) and carbon core component (Pc) and characterized their chemical constitutes. We found that PM2.5 induced significant redox imbalance, decreased the levels of intercellular methyl donor S-adenosylmethionine and caused global DNA hypomethylation. Furthermore, PM2.5 exposure triggered gene-specific promoter DNA hypo- or hypermethylation and abnormal mRNA expression of autism candidate genes. PM2.5-induced DNA hypermethylation in promoter regions of synapse related genes were associated with the decreases in their mRNA and protein expression. The inhibiting effects of antioxidative reagents, a methylation-supporting agent and a DNA methyltransferase inhibitor demonstrated the involvement of redox/methylation mechanism in PM2.5-induced abnormal DNA methylation patterns and synaptic protein expression. The biological effects above generally followed a sequence of PM2.5 ≥ Pwo > Po > Pw > Pc. Our results implicated a novel epigenetic mechanism for the neurodevelopmental toxicity of particulate air pollution, and that eliminating the chemical components could mitigate the neurotoxicity of PM2.5. PMID:27624276

  1. Drug induced hepatotoxicity: data from the Serbian pharmacovigilance database.

    PubMed

    Petronijevic, Marija; Ilic, Katarina; Suzuki, Ayako

    2011-04-01

    The main aim of this study was to determine the most frequently reported drugs to the Serbian Pharmacovigilance Database (SPD) with suspected induced hepatotoxicity. Additionally, reasons for the low reporting rate of adverse drug reactions (ADRs) in Serbia were identified. Retrospective observational study of spontaneously reported ADRs recorded in the SPD from January 1995 to December 2008 was performed. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify cases of hepatobiliary disorders (HD). Drugs were classified using the Anatomical Therapeutic Chemical (ATC) classification. Medline and WHO-UMC databases were used to address specific queries suggested by our results. The questionnaire was used to investigate the health care professionals' knowledge and practice related to spontaneous reporting. Among the 1804 reports of ADRs recorded in the SPD between 1995 and 2008, 70 (3.9%) cases of HD were identified. Drugs most frequently associated with hepatotoxicity were anti-infectives for systemic use, drugs affecting the nervous system, herbal products, hypolipemics, and anticoagulant drugs (26.83, 24.39, 12.20, 9.76, and 8.54% cases, respectively). Four cases (5.71%) of liver injury resulted in death, which accounted for 10.26% of all ADR fatalities reported to the SPD. The main reasons for not reporting ADRs were lack of reporting knowledge (30.26%), well-known ADRs (29.89%), and insecurity about causality relationship (15.50%). Anti-infectives, nervous system drugs, and herbal products were the most common drug classes reported for hepatotoxicity in Serbia. There is a need for additional education about ADRs, and enhanced reporting by health care professionals. Copyright © 2011 John Wiley & Sons, Ltd.

  2. Gastric emptying abnormal in duodenal ulcer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Holt, S.; Heading, R.C.; Taylor, T.V.

    1986-07-01

    To investigate the possibility that an abnormality of gastric emptying exists in duodenal ulcer and to determine if such an abnormality persists after ulcer healing, scintigraphic gastric emptying measurements were undertaken in 16 duodenal ulcer patients before, during, and after therapy with cimetidine; in 12 patients with pernicious anemia, and in 12 control subjects. No difference was detected in the rate or pattern of gastric emptying in duodenal ulcer patients before and after ulcer healing with cimetidine compared with controls, but emptying of the solid component of the test meal was more rapid during treatment with the drug. Comparison ofmore » emptying patterns obtained in duodenal ulcer subjects during and after cimetidine treatment with those obtained in pernicious anemia patients and controls revealed a similar relationship that was characterized by a tendency for reduction in the normal differentiation between the emptying of solid and liquid from the stomach. The similarity in emptying patterns in these groups of subjects suggests that gastric emptying of solids may be influenced by changes in the volume of gastric secretion. The failure to detect an abnormality of gastric emptying in duodenal ulcer subjects before and after ulcer healing calls into question the widespread belief that abnormally rapid gastric emptying is a feature with pathogenetic significance in duodenal ulcer disease.« less

  3. Neuronal plasticity and neurotrophic factors in drug responses

    PubMed Central

    Castrén, Eero; Antila, Hanna

    2017-01-01

    Neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF) and other members of the neurotrophin family, are central mediators of the activity-dependent plasticity through which environmental experiences, such as sensory information are translated into the structure and function of neuronal networks. Synthesis, release and action of BDNF is regulated by neuronal activity and BDNF in turn leads to trophic effects such as formation, stabilization and potentiation of synapses through its high-affinity TrkB receptors. Several clinically available drugs directly activate neurotrophins and neuronal plasticity. In particular, antidepressant drugs rapidly activate TrkB signaling and gradually increase BDNF expression, and the behavioral effects of antidepressants are mediated by and dependent on BDNF signaling through TrkB at least in rodents. These findings indicate that antidepressants, widely used drugs, effectively act as TrkB activators. They further imply that neuronal plasticity is a central mechanism in the action of antidepressant drugs. Indeed, it was recently discovered that antidepressants reactivate a state of plasticity in the adult cerebral cortex that closely resembles the enhanced plasticity normally observed during postnatal critical periods. This state of induced plasticity, known as iPlasticity, allows environmental stimuli to beneficially reorganize networks abnormally wired during early life. iPlasticity has been observed in cortical as well as subcortical networks and is induced by several pharmacological and non-pharmacological treatments. iPlasticity is a new pharmacological principle where drug treatment and rehabilitation cooperate: the drug acts permissively to enhance plasticity and rehabilitation provides activity to guide the appropriate wiring of the plastic network. Optimization of iPlastic drug treatment with novel means of rehabilitation may help improve the efficacy of available drug treatments and expand the use of

  4. Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling.

    PubMed

    Kuijper, Isoude A; Yang, Huan; Van De Water, Bob; Beltman, Joost B

    2017-01-01

    Drug-induced liver injury (DILI) is a significant threat to human health and a major problem in drug development. It is hard to predict due to its idiosyncratic nature and which does not show up in animal trials. Hepatic adaptive stress response pathway activation is generally observed in drug-induced liver injury. Dynamical pathway modeling has the potential to foresee adverse effects of drugs before they go in trial. Ordinary differential equation modeling can offer mechanistic insight, and allows us to study the dynamical behavior of stress pathways involved in DILI. Areas covered: This review provides an overview on the progress of the dynamical modeling of stress and death pathways pertinent to DILI, i.e. pathways relevant for oxidative stress, inflammatory stress, DNA damage, unfolded proteins, heat shock and apoptosis. We also discuss the required steps for applying such modeling to the liver. Expert opinion: Despite the strong progress made since the turn of the century, models of stress pathways have only rarely been specifically applied to describe pathway dynamics for DILI. We argue that with minor changes, in some cases only to parameter values, many of these models can be repurposed for application in DILI research. Combining both dynamical models with in vitro testing might offer novel screening methods for the harmful side-effects of drugs.

  5. Protection of cisplatin-induced spermatotoxicity, DNA damage and chromatin abnormality by selenium nano-particles

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Rezvanfar, Mohammad Amin; Rezvanfar, Mohammad Ali; Shahverdi, Ahmad Reza

    Cisplatin (CIS), an anticancer alkylating agent, induces DNA adducts and effectively cross links the DNA strands and so affects spermatozoa as a male reproductive toxicant. The present study investigated the cellular/biochemical mechanisms underlying possible protective effect of selenium nano-particles (Nano-Se) as an established strong antioxidant with more bioavailability and less toxicity, on reproductive toxicity of CIS by assessment of sperm characteristics, sperm DNA integrity, chromatin quality and spermatogenic disorders. To determine the role of oxidative stress (OS) in the pathogenesis of CIS gonadotoxicity, the level of lipid peroxidation (LPO), antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidasemore » (GSH-Px) and peroxynitrite (ONOO) as a marker of nitrosative stress (NS) and testosterone (T) concentration as a biomarker of testicular function were measured in the blood and testes. Thirty-two male Wistar rats were equally divided into four groups. A single IP dose of CIS (7 mg/kg) and protective dose of Nano-Se (2 mg/kg/day) were administered alone or in combination. The CIS-exposed rats showed a significant increase in testicular and serum LPO and ONOO level, along with a significant decrease in enzymatic antioxidants levels, diminished serum T concentration and abnormal histologic findings with impaired sperm quality associated with increased DNA damage and decreased chromatin quality. Coadministration of Nano-Se significantly improved the serum T, sperm quality, and spermatogenesis and reduced CIS-induced free radical toxic stress and spermatic DNA damage. In conclusion, the current study demonstrated that Nano-Se may be useful to prevent CIS-induced gonadotoxicity through its antioxidant potential. Highlights: ► Cisplatin (CIS) affects spermatozoa as a male reproductive toxicant. ► Effect of Nano-Se on CIS-induced spermatotoxicity was investigated. ► CIS-exposure induces oxidative sperm DNA

  6. Foot abnormalities of wild birds

    USGS Publications Warehouse

    Herman, C.M.; Locke, L.N.; Clark, G.M.

    1962-01-01

    The various foot abnormalities that occur in birds, including pox, scaly-leg, bumble-foot, ergotism and freezing are reviewed. In addition, our findings at the Patuxent Wildlife Research Center include pox from dove, mockingbird, cowbird, grackle and several species of sparrows. Scaly-leg has been particularly prevalent on icterids. Bumble foot has been observed in a whistling swan and in a group of captive woodcock. Ergotism is reported from a series of captive Canada geese from North Dakota. Several drug treatments recommended by others are presented.

  7. Prenatal ethanol exposure-induced adrenal developmental abnormality of male offspring rats and its possible intrauterine programming mechanisms.

    PubMed

    Huang, Hegui; He, Zheng; Zhu, Chunyan; Liu, Lian; Kou, Hao; Shen, Lang; Wang, Hui

    2015-10-01

    Fetal adrenal developmental status is the major determinant of fetal tissue maturation and offspring growth. We have previously proposed that prenatal ethanol exposure (PEE) suppresses fetal adrenal corticosterone (CORT) synthesis. Here, we focused on PEE-induced adrenal developmental abnormalities of male offspring rats before and after birth, and aimed to explore its intrauterine programming mechanisms. A rat model of intrauterine growth retardation (IUGR) was established by PEE (4g/kg·d). In PEE fetus, increased serum CORT concentration and decreased insulin-like growth factor 1 (IGF1) concentration, with lower bodyweight and structural abnormalities as well as a decreased Ki67 expression (proliferative marker), were observed in the male fetal adrenal cortex. Adrenal glucocorticoid (GC)-metabolic activation system was enhanced while gene expression of IGF1 signaling pathway with steroidogenic acute regulatory protein (StAR), 3β-hydroxysteroid dehydrogenase (3β-HSD) was decreased. Furthermore, in the male adult offspring of PEE, serum CORT level was decreased but IGF1 was increased with partial catch-up growth, and Ki67 expression demonstrated no obvious change. Adrenal GC-metabolic activation system was inhibited, while IGF1 signaling pathway and 3β-HSD was enhanced with the steroidogenic factor 1 (SF1), and StAR was down-regulated in the adult adrenal. Based on these findings, we propose a "two-programming" mechanism for PEE-induced adrenal developmental toxicity: "the first programming" is a lower functional programming of adrenal steroidogenesis, and "the second programming" is GC-metabolic activation system-related GC-IGF1 axis programming. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Management of Psychotropic Drug-Induced DRESS Syndrome: A Systematic Review.

    PubMed

    Bommersbach, Tanner J; Lapid, Maria I; Leung, Jonathan G; Cunningham, Julie L; Rummans, Teresa A; Kung, Simon

    2016-06-01

    Drug rash with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous eruption that has been linked to several common drugs and drug categories, including antiepileptics, allopurinol, sulfonamides, and various antibiotics; however, because of a number of recent case reports linking psychotropic medications to this condition, DRESS is increasingly recognized among psychiatrists. We systematically reviewed all psychotropic drugs linked to DRESS syndrome, and this article summarizes the clinical management relevant to psychiatric professionals. A comprehensive search was performed using Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Database of Systematic Reviews, Web of Science, Scopus, and Litt's Drug Eruption and Reaction Database for articles published in English during the past 20 years (1996-2015) using the search terms (1) psychotropic drugs OR serotonin uptake inhibitors AND DRESS or (2) psychotropic drugs AND drug reaction (or rash) eosinophilia systemic syndrome, and all article abstracts were screened for inclusion and exclusion criteria by 3 reviewers. Two independent reviewers examined the full text of 163 articles, of which 96 (25 original articles, 12 review articles, 55 case reports, and 4 letters to the editor) were included in the systematic review. We identified 1072 cases of psychotropic drug-induced DRESS, with carbamazepine, lamotrigine, phenytoin, valproate, and phenobarbital being the most implicated drugs. Based on our review of the literature, we outline management principles that include prompt withdrawal of the causative drug, hospitalization, corticosteroid therapy, and novel treatments, including intravenous immunoglobulin, cyclophosphamide, and cyclosporine, for corticosteroid-resistant DRESS. Finally, we outline strategies for treating comorbid psychiatric illness after a DRESS reaction to the psychotropic medication. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  9. Treatment of non-steroidal anti-inflammatory drug induced enteropathy.

    PubMed Central

    Bjarnason, I; Hopkinson, N; Zanelli, G; Prouse, P; Smethurst, P; Gumpel, J M; Levi, A J

    1990-01-01

    Non-steroidal anti-inflammatory drug induced small intestinal inflammation may have an adverse effect on the joints of patients with rheumatoid arthritis. We therefore assessed small intestinal and joint inflammation in patients with rheumatoid arthritis before and after three to nine months' treatment with sulphasalazine (n = 40) and other second line drugs (n = 20), while keeping the dosage of non-steroidal anti-inflammatory drug at the same level. Sulphasalazine significantly decreased the mean (SD) faecal excretion of 111indium labelled leucocytes from 2.39 (2.22)% to 1.33 (1.13)% (normal less than 1%, p less than 0.01) and improved the joint inflammation as assessed by a variety of parameters. There was no significant correlation between the effects of sulphasalazine treatment on the intestine and the joints. Treatment with other second line drugs had no significant effect on the faecal excretion of 111indium (1.58 (1.04)% and 1.86 (1.51)%, respectively) but improved joint inflammation significantly. The lack of correlation between the intestinal and joint inflammation and their response to treatment suggests that the two are not causally related. PMID:1973396

  10. Exposure of spermatozoa to dibutyl phthalate induces abnormal embryonic development in a marine invertebrate Galeolaria caespitosa (Polychaeta: Serpulidae).

    PubMed

    Lu, Yonggang; Lin, Minjie; Aitken, Robert John

    2017-10-01

    In this study, we have investigated the impact of dibutyl phthalate (DBP) on early embryogenesis in a sessile marine invertebrate, Galeolaria caespitosa. DBP was found to induce sperm dysfunction as well as impaired and defective embryogenesis characterised by a particular pattern of abnormality. Thus, after the first cleavage, one blastomere in these abnormal embryos was able to carry out further mitoses, while the other arrested. Analysis of microtubules, chromosomes and actin filaments demonstrated that the mitotic spindles in the abnormal embryos were irregularly bent, shortened and unable to anchor to the cortex, resulting in the defective segregation of chromosomes. Within the non-dividing blastomeres, karyokinesis was found to continue at a slow pace as indicated by the presence of multiple sets of abnormal mitotic spindles. However, cytokinesis had been disrupted in these arrested cells due to a failure to assemble the contractile actin ring, as a result of which one pole of the embryos remained as one large, undivided cell. DBP was found to suppress the activity of superoxide dismutase in spermatozoa and, in association with this change, DBP-treated cells experienced oxidative stress as indicated by the presence of lipid aldehydes, such as 4-hydroxynonenal (4-HNE) in the sperm acrosome and neck. Adduction of lipid aldehydes at the level of the acrosome would be expected to impede the acrosome reaction and account for the significant decrease in fertilisation rates. 4-HNE generated as a consequence of lipid peroxidation in the sperm neck resulted in alkylation of the sperm centrioles. Such paternally damaged centrioles were inherited by the embryos and disrupted cytoskeletal protein organisation during early cleavage, generating the observed abnormalities in embryonic development. This research emphasises the vulnerability of spermatozoa to oxidative damage and highlights novel potential mechanisms for reproductive toxicity involving the alkylation of

  11. Substance-P antagonists: effect on spontaneous and drug-induced locomotor activity in the rat.

    PubMed

    Elliott, P J; Iversen, S D

    1987-05-01

    The substance P (SP) antagonists (D-Pro4, D-Trp7,9, Leu11) SP(4-11), (D-Pro4, D-Trp7,9, Phe11)SP(4-11) and (D-Pro4, D-Trp7,9,10, Leu11) SP (4-11) were infused into the lateral ventricles (i.c.v.) and their effects on spontaneous and drug-induced locomotor activity were investigated. The drug DiMeC7, the stable substance P agonist, was used to stimulate locomotor activity because of its prolonged action. Only (D-Pro4, D-Trp7,9,10) SP (4-11) was found to attenuate the drug-induced increases in motor activity, indicating that it is a substance P antagonist with activity in the CNS.

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

    PubMed Central

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

    2014-01-01

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

  13. Interplay between Antibiotic Efficacy and Drug-Induced Lysis Underlies Enhanced Biofilm Formation at Subinhibitory Drug Concentrations

    PubMed Central

    Yu, Wen; Hallinen, Kelsey M.

    2017-01-01

    ABSTRACT Subinhibitory concentrations of antibiotics have been shown to enhance biofilm formation in multiple bacterial species. While antibiotic exposure has been associated with modulated expression of many biofilm-related genes, the mechanisms of drug-induced biofilm formation remain a focus of ongoing research efforts and may vary significantly across species. In this work, we investigate antibiotic-induced biofilm formation in Enterococcus faecalis, a leading cause of nosocomial infections. We show that biofilm formation is enhanced by subinhibitory concentrations of cell wall synthesis inhibitors but not by inhibitors of protein, DNA, folic acid, or RNA synthesis. Furthermore, enhanced biofilm is associated with increased cell lysis, increases in extracellular DNA (eDNA) levels, and increases in the density of living cells in the biofilm. In addition, we observe similar enhancement of biofilm formation when cells are treated with nonantibiotic surfactants that induce cell lysis. These findings suggest that antibiotic-induced biofilm formation is governed by a trade-off between drug toxicity and the beneficial effects of cell lysis. To understand this trade-off, we developed a simple mathematical model that predicts changes in antibiotic-induced biofilm formation due to external perturbations, and we verified these predictions experimentally. Specifically, we demonstrate that perturbations that reduce eDNA (DNase treatment) or decrease the number of living cells in the planktonic phase (a second antibiotic) decrease biofilm induction, while chemical inhibitors of cell lysis increase relative biofilm induction and shift the peak to higher antibiotic concentrations. Overall, our results offer experimental evidence linking cell wall synthesis inhibitors, cell lysis, increased eDNA levels, and biofilm formation in E. faecalis while also providing a predictive quantitative model that sheds light on the interplay between cell lysis and antibiotic efficacy in

  14. Abnormal maximal finger tapping in abstinent cannabis users.

    PubMed

    Flavel, Stanley C; White, Jason M; Todd, Gabrielle

    2013-11-01

    To investigate movement speed and rhythmicity in abstinent cannabis users, we hypothesized that abstinent cannabis users exhibit decreased maximal finger tapping frequency and increased variability of tapping compared with non-drug users. The study involved 10 healthy adult cannabis users and 10 age-matched and gender-matched controls with no history of illicit drug use. Subjects underwent a series of screening tests prior to participation. Subjects were then asked to tap a strain gauge as fast as possible with the index finger of their dominant hand (duration 5 s). The average intertap interval did not significantly differ between groups, but the coefficient of variation of the intertap interval was significantly greater in the cannabis group than in controls (p=0.011). The cannabis group also exhibited a slow tapping frequency at the beginning of the task. Rhythmicity of finger tapping is abnormal in individuals with a history of cannabis use. The abnormality appears to be long lasting and adds to the list of functional changes present in abstinent cannabis users. Copyright © 2013 John Wiley & Sons, Ltd.

  15. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Induced Dyspepsia.

    PubMed

    Yap, Paul Ray-Yee; Goh, Khean-Lee

    2015-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed group of drugs in the world. They are used primarily for pain relief in chronic inflammatory joint disease and act by inhibiting enzymes COX1 and COX2 and ultimately preventing the production of active prostanoids which are required for the innate inflammatory pathway. The use of NSAIDs have been associated with the development of gastrointestinal (GI) symptoms ranging from simple dyspepsia to life threatening GI bleeds and perforations. The definition of dyspepsia has evolved over the years and this has hampered accurate studies on the prevalence of dyspepsia as different studies used varying criteria to define dyspepsia. It is now known that NSAIDs significantly increase the risk of dyspepsia.The risk of developing peptic ulcer disease vary with specific NSAIDs and dosages but there is no correlation between the symptoms of dyspepsia and underlying peptic ulcers. The pathogenesis of dyspepsia with NSAIDs is not completely understood. Peptic ulceration alone is not able to account for the majority of dyspepsia symptoms encountered by NSAIDs users. Erosive oesophagitis secondary to NSAIDs may be contributing factor to the prevalence of dyspepsia in NSAIDs users. Altered gut permeability and changes in gastric mechanosensory function due to NSAIDs may also be a contributory factor. Management of NSAID induced dyspepsia is involves a multipronged approach. Drug avoidance if possible would be ideal. Other options include using the lowest effective dose, changing to an NSAIDs with a safer GI risk profile, avoiding concurrent use with other NSAIDs or if the patient has a previous history of peptic ulcer disease, and co-prescribing with anti-secretory medications such as proton pump inhibitors. Eradication of Helicobacter pylori has a protective role against developing peptic ulcers and may also improve symptoms of NSAIDs induced dyspepsia.

  16. [Antipsychotic-induced weight gain--pharmacogenetic studies].

    PubMed

    Olajossy-Hilkesberger, Luiza; Godlewska, Beata; Marmurowska-Michałowskal, Halina; Olajossy, Marcin; Landowski, Jerzy

    2006-01-01

    Drug-naive patients with schizophrenia often present metabolic abnormalities and obesity. Weight gain may be the side effect of treatment with many antipsychotic drugs. Genetic effects, besides many other factors, are known to influence obesity in patients with schizophrenia treated with antipsychotics. Numerous studies of several genes' polymorphisms have been performed. -759C/T polymorphism of 5HT2C gene attracted most attention. In 5 independent studies of this polymorphism the association between T allele with the lower AP-induced weight gain was detected. No associations could be detected between weight gain and other polymorphisms of serotonergic system genes as well as histaminergic system genes. Studies of adrenergic and dopaminergic system have neither produced any unambiguous results. Analysis of the newest candidate genes (SAP-25, leptin gene) confirmed the role of genetic factors in AP-induced weight gain. It is worth emphasising, that the studies have been conducted in relatively small and heterogenic groups and that various treatment strategies were used.

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

    PubMed

    Miglani, Sonam; Patyar, Rakesh Raman; Patyar, Sazal; Reshi, Mohammad Rafi

    2016-10-01

    Aim of the present study was to assess the hepatoprotective activity of goat milk on antitubercular drug-induced hepatotoxicity in rats. Hepatotoxicity was induced in rats using a combination of isoniazid, rifampicin, and pyrazinamide given orally as a suspension for 30 days. Treatment groups received goat milk along with antitubercular drugs. Liver damage was assessed using biochemical and histological parameters. Administration of goat milk (20 mL/kg) along with antitubercular drugs (Group III) reversed the levels of serum alanine aminotransferase (82 ± 25.1 vs. 128.8 ± 8.9 units/L) and aspartate aminotransferase (174.7 ± 31.5 vs. 296.4 ± 56.4 units/L, p<0.01) compared with antitubercular drug treatment Group II. There was a significant decrease in serum alanine aminotransferase (41.8 ± 4.1 vs. 128.8 ± 8.9 ​ units/L, p<0.01) and aspartate aminotransferase (128.8 ± 8.54 vs. 296.4 ± 56.4 units/L, p<0.001) levels in Group IV (goat milk 40 mL/kg) compared with antitubercular drug treatment Group II. Goat milk (20 mL/kg and 40 mL/kg) was effective in reversing the rise in malondialdehyde level compared with the antitubercular drug suspension groups (58.5 ± 2 vs. 89.88 ± 2.42 μmol/mL of tissue homogenate, p<0.001 and 69.7 ± 0.78 vs. 89.88 ± 2.42 μmol/mL of tissue homogenate, p<0.001, respectively). Similarly, both doses of milk significantly prevented a fall in superoxide dismutase level (6.23 ± 0.29 vs. 3.1 ± 0.288 units/mL, p<0.001 and 7.8 ± 0.392 vs. 3.1 ± 0.288 units/mL, p<0.001) compared with the group receiving antitubercular drugs alone. Histological examination indicated that goat milk reduced inflammation and necrotic changes in hepatocytes in the treatment groups. The results indicated that goat milk prevented the antitubercular drug-induced hepatotoxicity and is an effective hepatoprotective agent. Copyright © 2016. Published by Elsevier B.V.

  18. Preliminary Evaluation of Three-Dimensional Primary Human Hepatocyte Culture System for Assay of Drug-Metabolizing Enzyme-Inducing Potential.

    PubMed

    Arakawa, Hiroshi; Kamioka, Hiroki; Jomura, Tomoko; Koyama, Satoshi; Idota, Yoko; Yano, Kentaro; Kojima, Hajime; Ogihara, Takuo

    2017-01-01

    Drug-induced liver injury (DILI) is a common reason for withdrawal of candidate drugs from clinical trials, or of approved drugs from the market. DILI may be induced not only by intact parental drugs, but also by metabolites or intermediates, and therefore should be evaluated in the enzyme-induced state. Here, we present a protocol for assay of drug-metabolizing enzyme-inducing potential using three-dimensional (3D) primary cultures of human hepatocytes (hepatocyte spheroids). Hepatocyte spheroids could be used up to 21 d after seeding (pre-culture for 7 d and exposure to inducer for up to 14 d), based on preliminary evaluation of basal activities of CYP subtypes and mRNA expression of the corresponding transcription factor and xenobiotic receptors (aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR) and pregnane X receptor (PXR)). After 2 d exposure of hepatocyte spheroids to omeprazole, phenobarbital and rifampicin (typical inducers of CYP1A2, 2B6 and 3A4, respectively), CYP1A2, 2B6 and 3A4 mRNA expression levels were significantly increased. The mRNA induction of CYP2B6 remained reasonably stable between days 2 and 14 of exposure to inducers, while induction of both CYP1A2 and 3A4 continued to increase up to day 14. These enzyme activities were all significantly increased compared with the control until day 14. Our findings indicate that our 3D hepatocyte spheroids system would be especially suitable for long-term testing of enzyme activity induction by drugs, either to predict or to verify clinical events.

  19. Is exposure to cocaine or cigarette smoke during pregnancy associated with infant visual abnormalities?

    PubMed

    Hajnal, Beatrice Latal; Ferriero, Donna M; Partridge, J Colin; Dempsey, Delia A; Good, William V

    2004-08-01

    The aim of this study was to assess the association between cocaine or cigarette smoke exposure in utero and visual outcome. A total of 153 healthy infants (89 males, 64 females; gestational age range 34 to 42 weeks) were prospectively enrolled in a masked, race-matched study. Quantitative analyses of urine and meconium were used to document exposure to cigarette smoke and cocaine. Infants with exposure to other illicit drugs, excepting marijuana, were excluded. At 6 weeks of age, grating acuity and visual system abnormalities (VSA; eyelid oedema, gaze abnormalities, and visual inattention) of 96 infants from the original study sample were assessed with the Teller acuity card procedure and a detailed neurological examination. Neither cocaine nor cigarette smoke exposure was associated with acuity or VSA. However, VSAs were associated with abnormal neurological examination, independent of drug exposure and other risk factors (odds ratio 7.9; 95% confidence interval 2.0 to 31.5;p=0.004). This unexpected finding could prove a helpful clinical marker for the infant at risk for neurological abnormalities.

  20. Effects of chronic prenatal MK-801 treatment on object recognition, cognitive flexibility, and drug-induced locomotor activity in juvenile and adult rat offspring.

    PubMed

    Gallant, S; Welch, L; Martone, P; Shalev, U

    2017-06-15

    Patients with schizophrenia display impaired cognitive functioning and increased sensitivity to psychomimetic drugs. The neurodevelopmental hypothesis of schizophrenia posits that disruption of the developing brain predisposes neural networks to lasting structural and functional abnormalities resulting in the emergence of such symptoms in adulthood. Given the critical role of the glutamatergic system in early brain development, we investigated whether chronic prenatal exposure to the glutamate NMDA receptor antagonist, MK-801, induces schizophrenia-like behavioural and neurochemical changes in juvenile and adult rats. Pregnant Long-Evans rats were administered saline or MK-801 (0.1mg/kg; s.c.) at gestation day 7-19. Object recognition memory and cognitive flexibility were assessed in the male offspring using a novel object preference task and a maze-based set-shifting procedure, respectively. Locomotor-activating effects of acute amphetamine and MK-801 were also assessed. Adult, but not juvenile, prenatally MK-801-treated rats failed to show novel object preference after a 90min delay, suggesting that object recognition memory may have been impaired. In addition, the set-shifting task revealed impaired acquisition of a new rule in adult prenatally MK-801-treated rats compared to controls. This deficit appeared to be driven by regression to the previously learned behaviour. There were no significant differences in drug-induced locomotor activity in juvenile offspring or in adult offspring following acute amphetamine challenges. Unexpectedly, MK-801-induced locomotor activity in adult prenatally MK-801-treated rats was lower compared to controls. Glutamate transmission dysfunction during early development may modify behavioural parameters in adulthood, though these parameters do not appear to model deficits observed in schizophrenia. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. [Case of loxoprofen sodium-induced eosinophilic pneumonia that occurred ipsilaterally after VATS lobectomy for lung cancer].

    PubMed

    Izumo, Takehiro; Kondo, Mitsuko; Mae, Masahiro; Onizawa, Shigemitsu; Nagara, Naoki; Nozu, Tomoko; Tamaoki, Jun; Ohnuki, Takamasa; Nagai, Atsushi

    2007-10-01

    A 76-year-old man was admitted because of dry cough and dyspnea two weeks after VATS lobectomy for lung cancer. Chest radiographs and computed tomography showed interstitial shadows in the only operative lung side. Although antibiotic drugs were given because we believed it to be postoperative pneumonia, abnormal shadows on chest radiographs increased. A bronchoalveolar lavage fluid (BALF) study performed on the 21" day after operation showed that the proportions of eosinophils, basophils and mast cells had increased, and the CD4/CD8 ratio was 4.42. The drug lymphocyte stimulation test for loxoprofen sodium was positive. Based on the clinical course, laboratory data and BALF study, we arrived at a diagnosis of drug-induced pneumonia caused by loxoprofen sodium. Treatment with corticosteroid resulted in marked improvement of the chest radiographs and clinical findings. Drug-induced pneumonia usually occurs bilaterally, but it occurred only on the operative side in this case. Although rare, it is important to recognize that unilateral drug-induced pneumonia is one of the differential diagnose of postoperative pneumonia.

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Nassirpour, Rounak, E-mail: Rounak.nassirpour@pfiz

    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 asmore » their interspecies translatability. Increasing concordance of miRNA findings by standardizing methodology most suitable for their detection and quantitation, as well as characterization of their expression pattern in a cell type specific manner, will accelerate progress toward validation of these miRNAs as biomarkers in pre-clinical, and clinical settings. This review aims to highlight the current pre-clinical findings surrounding miRNAs as biomarkers in two important segments of the nephron, the glomerulus and tubules. - Highlights: • miRNAs are promising biomarkers of drug-induced kidney injury. • Summarized pre-clinical miRNA biomarkers of drug-induced nephrotoxicity. • Described the strengths and challenges associated with miRNAs as biomarkers.« less

  3. Axonal abnormalities in vanishing white matter.

    PubMed

    Klok, Melanie D; Bugiani, Marianna; de Vries, Sharon I; Gerritsen, Wouter; Breur, Marjolein; van der Sluis, Sophie; Heine, Vivi M; Kole, Maarten H P; Baron, Wia; van der Knaap, Marjo S

    2018-04-01

    We aimed to study the occurrence and development of axonal pathology and the influence of astrocytes in vanishing white matter. Axons and myelin were analyzed using electron microscopy and immunohistochemistry on Eif2b4 and Eif2b5 single- and double-mutant mice and patient brain tissue. In addition, astrocyte-forebrain co-culture studies were performed. In the corpus callosum of Eif2b5- mutant mice, myelin sheath thickness, axonal diameter, and G-ratio developed normally up to 4 months. At 7 months, however, axons had become thinner, while in control mice axonal diameters had increased further. Myelin sheath thickness remained close to normal, resulting in an abnormally low G-ratio in Eif2b5- mutant mice. In more severely affected Eif2b4-Eif2b5 double-mutants, similar abnormalities were already present at 4 months, while in milder affected Eif2b4 mutants, few abnormalities were observed at 7 months. Additionally, from 2 months onward an increased percentage of thin, unmyelinated axons and increased axonal density were present in Eif2b5 -mutant mice. Co-cultures showed that Eif2b5 mutant astrocytes induced increased axonal density, also in control forebrain tissue, and that control astrocytes induced normal axonal density, also in mutant forebrain tissue. In vanishing white matter patient brains, axons and myelin sheaths were thinner than normal in moderately and severely affected white matter. In mutant mice and patients, signs of axonal transport defects and cytoskeletal abnormalities were minimal. In vanishing white matter, axons are initially normal and atrophy later. Astrocytes are central in this process. If therapy becomes available, axonal pathology may be prevented with early intervention.

  4. Abnormal pupillary light reflex with chromatic pupillometry in Gaucher disease

    PubMed Central

    Narita, Aya; Shirai, Kentarou; Kubota, Norika; Takayama, Rumiko; Takahashi, Yukitoshi; Onuki, Takanori; Numakura, Chikahiko; Kato, Mitsuhiro; Hamada, Yusuke; Sakai, Norio; Ohno, Atsuko; Asami, Maya; Matsushita, Shoko; Hayashi, Anri; Kumada, Tomohiro; Fujii, Tatsuya; Horino, Asako; Inoue, Takeshi; Kuki, Ichiro; Asakawa, Ken; Ishikawa, Hitoshi; Ohno, Koyo; Nishimura, Yoko; Tamasaki, Akiko; Maegaki, Yoshihiro; Ohno, Kousaku

    2014-01-01

    The hallmark of neuronopathic Gaucher disease (GD) is oculomotor abnormalities, but ophthalmological assessment is difficult in uncooperative patients. Chromatic pupillometry is a quantitative method to assess the pupillary light reflex (PLR) with minimal patient cooperation. Thus, we investigated whether chromatic pupillometry could be useful for neurological evaluations in GD. In our neuronopathic GD patients, red light-induced PLR was markedly impaired, whereas blue light-induced PLR was relatively spared. In addition, patients with non-neuronopathic GD showed no abnormalities. These novel findings show that chromatic pupillometry is a convenient method to detect neurological signs and monitor the course of disease in neuronopathic GD. PMID:25356393

  5. How to Diagnose and Exclude Drug-Induced Liver Injury.

    PubMed

    Watkins, Paul B

    2015-01-01

    The diagnosis of drug-induced liver injury (DILI) is largely a diagnosis of exclusion because, with the possible exception of protein:drug adducts in paracetamol overdose, there are no laboratory, biopsy or imaging tests that alone are capable of establishing an unequivocal diagnosis of DILI. However, it is increasingly appreciated that drugs that cause DILI typically have characteristic clinical presentations or 'signatures' that can be very useful in the diagnosis of DILI. Indeed, knowing a drug's DILI signature (or sometimes signatures) and the incidence rate of DILI during treatment with that drug are perhaps the most useful pieces of historical information in arriving at the diagnosis of DILI. Components of the signature include the typical latency from the onset of treatment, whether there are extrahepatic manifestations, whether the injury is hepatocellular, cholestatic or mixed, and sometimes characteristic features on biopsy or serological testing (e.g. liver autoantibodies). A major advance has been the establishment of the LiverTox website (http://livertox.nih.gov/) which provides open access to standardized entries for over 600 different drugs, including the characteristic clinical presentations of DILI when known. LiverTox will also calculate the causality score for individual cases using the RUCAM instrument and case-specific data entered by the site user. However, the problem with standard diagnostic instruments such as the RUCAM is that DILI signatures are not incorporated into the scoring system. The person entering data must therefore subjectively weigh the RUCAM score with the characteristic DILI signature(s) of the drug to arrive at a diagnosis. In the future, it should be possible to construct improved diagnostic instruments that objectively incorporate DILI signatures, data-based estimates of the incidence rates of DILI from each implicated drug, and perhaps genetic variants associated with the risk of DILI. © 2015 S. Karger AG, Basel.

  6. Early physiological abnormalities after simian immunodeficiency virus infection.

    PubMed

    Horn, T F; Huitron-Resendiz, S; Weed, M R; Henriksen, S J; Fox, H S

    1998-12-08

    Central nervous system (CNS) damage and dysfunction are devastating consequences of HIV infection. Although the CNS is one of the initial targets for HIV infection, little is known about early viral-induced abnormalities that can affect CNS function. Here we report the detection of early physiological abnormalities in simian immunodeficiency virus-infected monkeys. The acute infection caused a disruption of the circadian rhythm manifested by rises in body temperature, observed in all five individuals between 1 and 2 weeks postinoculation (p.i.), accompanied by a reduction in daily motor activity to 50% of control levels. Animals remained hyperthermic at 1 and 2 months p.i. and returned to preinoculation temperatures at 3 months after viral inoculation. Although motor activity recovered to baseline values at 1 month p.i., activity levels then decreased to approximately 50% of preinoculation values over the next 2 months. Analysis of sensory-evoked responses 1 month p.i. revealed distinct infection-induced changes in auditory-evoked potential peak latencies that persisted at 3 months after viral inoculation. These early physiological abnormalities may precede the development of observable cognitive or motor deficiencies and can provide an assay to evaluate agents to prevent or alleviate neuronal dysfunction.

  7. Rescue of ATP7B function in hepatocyte-like cells from Wilson's disease induced pluripotent stem cells using gene therapy or the chaperone drug curcumin.

    PubMed

    Zhang, Shiqiang; Chen, Shen; Li, Wen; Guo, Xiangpeng; Zhao, Ping; Xu, Jianyong; Chen, Yan; Pan, Qiong; Liu, Xiaorong; Zychlinski, Daniela; Lu, Hai; Tortorella, Micky D; Schambach, Axel; Wang, Yan; Pei, Duanqing; Esteban, Miguel A

    2011-08-15

    Directed hepatocyte differentiation from human induced pluripotent stem cells (iPSCs) potentially provides a unique platform for modeling liver genetic diseases and performing drug-toxicity screening in vitro. Wilson's disease is a genetic disease caused by mutations in the ATP7B gene, whose product is a liver transporter protein responsible for coordinated copper export into bile and blood. Interestingly, the spectrum of ATP7B mutations is vast and can influence clinical presentation (a variable spectrum of hepatic and neural manifestations), though the reason is not well understood. We describe the generation of iPSCs from a Chinese patient with Wilson's disease that bears the R778L Chinese hotspot mutation in the ATP7B gene. These iPSCs were pluripotent and could be readily differentiated into hepatocyte-like cells that displayed abnormal cytoplasmic localization of mutated ATP7B and defective copper transport. Moreover, gene correction using a self-inactivating lentiviral vector that expresses codon optimized-ATP7B or treatment with the chaperone drug curcumin could reverse the functional defect in vitro. Hence, our work describes an attractive model for studying the pathogenesis of Wilson's disease that is valuable for screening compounds or gene therapy approaches aimed to correct the abnormality. In the future, once relevant safety concerns (including the stability of the mature liver-like phenotype) and technical issues for the transplantation procedure are solved, hepatocyte-like cells from similarly genetically corrected iPSCs could be an option for autologous transplantation in Wilson's disease.

  8. Methamphetamine-induced dopaminergic toxicity prevented owing to the neuroprotective effects of salicylic acid.

    PubMed

    Thrash-Williams, Bessy; Karuppagounder, Senthilkumar S; Bhattacharya, Dwipayan; Ahuja, Manuj; Suppiramaniam, Vishnu; Dhanasekaran, Muralikrishnan

    2016-06-01

    Methamphetamine (Schedule-II drug, U.S. Drug Enforcement Administration) is one of the most abused illicit drug following cocaine, marijuana, and heroin in the USA. There are numerous health impairments and substantial economic burden caused by methamphetamine abuse. Salicylic acid, potent anti-inflammatory drug and a known neuroprotectant has shown to protect against toxicity-induced by other dopaminergic neurotoxins. Hence, in this study we investigated the neuroprotective effects of salicylic acid against methamphetamine-induced toxicity in mice. The current study investigated the effects of sodium salicylate and/or methamphetamine on oxidative stress, monoamine oxidase, mitochondrial complex I & IV activities using spectrophotometric and fluorimetric methods. Behavioral analysis evaluated the effect on movement disorders-induced by methamphetamine. Monoaminergic neurotransmitter levels were evaluated using high pressure liquid chromatography-electrochemical detection. Methamphetamine caused significant generation of reactive oxygen species and decreased complex-I activity leading to dopamine depletion. Striatal dopamine depletion led to significant behavioral changes associated with movement disorders. Sodium salicylate (50 & 100mg/kg) significantly scavenged reactive oxygen species, blocked mitochondrial dysfunction and exhibited neuroprotection against methamphetamine-induced neurotoxicity. In addition, sodium salicylate significantly blocked methamphetamine-induced behavioral changes related to movement abnormalities. One of the leading causative theories in nigral degeneration associated with movement disorders such as Parkinson's disease is exposure to stimulants, drugs of abuse, insecticide and pesticides. These neurotoxic substances can induce dopaminergic neuronal insult by oxidative stress, apoptosis, mitochondrial dysfunction and inflammation. Salicylic acid due to its antioxidant and anti-inflammatory effects could provide neuroprotection against the

  9. Cadmium-induced immune abnormality is a key pathogenic event in human and rat models of preeclampsia.

    PubMed

    Zhang, Qiong; Huang, Yinping; Zhang, Keke; Huang, Yanjun; Yan, Yan; Wang, Fan; Wu, Jie; Wang, Xiao; Xu, Zhangye; Chen, Yongtao; Cheng, Xue; Li, Yong; Jiao, Jinyu; Ye, Duyun

    2016-11-01

    With increased industrial development, cadmium is an increasingly important environmental pollutant. Studies have identified various adverse effects of cadmium on human beings. However, the relationships between cadmium pollution and the pathogenesis of preeclampsia remain elusive. The objective of this study is to explore the effects of cadmium on immune system among preeclamptic patients and rats. The results showed that the cadmium levels in the peripheral blood of preeclamptic patients were significantly higher than those observed in normal pregnancy. Based on it, a novel rat model of preeclampsia was established by the intraperitoneal administration of cadmium chloride (CdCl2) (0.125 mg of Cd/kg body weight) on gestational days 9-14. Key features of preeclampsia, including hypertension, proteinuria, placental abnormalities and small foetal size, appeared in pregnant rats after the administration of low-dose of CdCl2. Cadmium increased immunoglobulin production, mainly angiotensin II type 1-receptor-agonistic autoantibodies (AT1-AA), by increasing the expression of activation-induced cytosine deaminase (AID) in B cells. AID is critical for the maturation of antibody and autoantibody responses. In addition, angiotensin II type 1-receptor-agonistic autoantibody, which emerged recently as a potential pathogenic contributor to PE, was responsible for the deposition of complement component 5 (C5) in kidneys of pregnant rats via angiotensin II type 1 receptor (AT1R) activation. C5a is a fragment of C5 that is released during C5 activation. Selectively interfering with C5a signalling by a complement C5a receptor-specific antagonist significantly attenuated hypertension and proteinuria in Cd-injected pregnant rats. Our results suggest that cadmium induces immune abnormalities that may be a key pathogenic contributor to preeclampsia and provide new insights into treatment strategies of preeclampsia. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. From the Cover: Potentiation of Drug-Induced Phospholipidosis In Vitro through PEGlyated Graphene Oxide as the Nanocarrier.

    PubMed

    Yang, Liecheng; Zhong, Xiaoyan; Li, Qian; Zhang, Xihui; Wang, Yangyun; Yang, Kai; Zhang, Leshuai W

    2017-03-01

    Cationic amphiphilic drugs (CADs) are small molecules that can induce phospholipidosis (PLD), causing the intracellular accumulation of phospholipid in the lamellar bodies. Nanotechnology based drug delivery systems have been used widely, while it is unknown if drug-induced PLD (DIP) can be potentiated through drug retention by indigestible nanocarriers. Due to the high drug loading capacity of graphene, we investigated if PEGylated graphene oxide (PEG-GO) loaded with CAD could potentiate DIP. Tamoxifen induced the accumulation of NBD-PE, a fluorescence labeled phospholipid in human hepatoma HepG2 cells, while PEG-GO loaded with tamoxifen (PEG-GO/tamoxifen) further potentiated PLD. PEG-GO/tamoxifen induced more gene expression of PLD marker than tamoxifen alone. PEG-GO enhanced DIP was also observed for other CAD, indicating that nanocarrier potentiated DIP could be universal. More lamellar bodies were observed in PEG-GO/tamoxifen treated cells than tamoxifen alone by transmission electron microscopy. When compared with tamoxifen alone, PEG-GO/tamoxifen showed a delayed but potent PLD. In addition, the retarded PLD recovery by PEG-GO/tamoxifen indicated that the reversibility of DIP was interfered. Confocal microscopy revealed the increased number of lysosomes, greater expression of lysosomal associated membrane protein 2 (LAMP2) (a PLD marker), and an increase in the co-localization between lysosome/LAMP2 and NBD-PE by PEG-GO/tamoxifen rather than tamoxifen alone. Finally, we found that PEG-GO or/and tamoxifen-induced PLD seemed to have no correlation with autophagy. This research suggests pharmaceutical companies and regulatory agencies that if nanoparticles are used as the vectors for drug delivery, the adverse drug effects may be further potentiated probably through the long-term accumulation of nanocarriers. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e

  11. Short-term treatment with VEGF receptor inhibitors induces retinopathy of prematurity-like abnormal vascular growth in neonatal rats.

    PubMed

    Nakano, Ayuki; Nakahara, Tsutomu; Mori, Asami; Ushikubo, Hiroko; Sakamoto, Kenji; Ishii, Kunio

    2016-02-01

    Retinal arterial tortuosity and venous dilation are hallmarks of plus disease, which is a severe form of retinopathy of prematurity (ROP). In this study, we examined whether short-term interruption of vascular endothelial growth factor (VEGF) signals leads to the formation of severe ROP-like abnormal retinal blood vessels. Neonatal rats were treated subcutaneously with the VEGF receptor (VEGFR) tyrosine kinase inhibitors, KRN633 (1, 5, or 10 mg/kg) or axitinib (10 mg/kg), on postnatal day (P) 7 and P8. The retinal vasculatures were examined on P9, P14, or P21 in retinal whole-mounts stained with an endothelial cell marker. Prevention of vascular growth and regression of some preformed capillaries were observed on P9 in retinas of rats treated with KRN633. However, on P14 and P21, density of capillaries, tortuosity index of arterioles, and diameter of veins significantly increased in KRN633-treated rats, compared to vehicle (0.5% methylcellulose)-treated animals. Similar observations were made with axitinib-treated rats. Expressions of VEGF and VEGFR-2 were enhanced on P14 in KRN633-treated rat retinas. The second round of KRN633 treatment on P11 and P12 completely blocked abnormal retinal vascular growth on P14, but thereafter induced ROP-like abnormal retinal blood vessels by P21. These results suggest that an interruption of normal retinal vascular development in neonatal rats as a result of short-term VEGFR inhibition causes severe ROP-like abnormal retinal vascular growth in a VEGF-dependent manner. Rats treated postnatally with VEGFR inhibitors could serve as an animal model for studying the mechanisms underlying the development of plus disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Incubation of extinction responding and cue-induced reinstatement, but not context- or drug priming-induced reinstatement, after withdrawal from methamphetamine

    PubMed Central

    Adhikary, Sweta; Caprioli, Daniele; Venniro, Marco; Kallenberger, Paige; Shaham, Yavin; Bossert, Jennifer M.

    2016-01-01

    In rats trained to self-administer methamphetamine, extinction responding in the presence of drug-associated contextual and discrete cues progressively increases after withdrawal (incubation of methamphetamine craving). The conditioning factors underlying this incubation are unknown. Here, we studied incubation of methamphetamine craving under different experimental conditions to identify factors contributing to this incubation. We also determined whether the rats’ response to methamphetamine priming incubates after withdrawal. We trained rats to self-administer methamphetamine in a distinct context (context A) for 14 days (6-h/day). Lever presses were paired with a discrete light cue. We then tested groups of rats in context A or a different non-drug context (context B) after 1 day, 1 week, or 1 month for extinction responding with or without the discrete cue. Subsequently, we tested the rats for reinstatement of drug seeking induced by exposure to contextual, discrete cue, or drug priming (0, 0.25, and 0.5 mg/kg). Operant responding in the extinction sessions in contexts A or B was higher after 1 week and 1 month of withdrawal than after 1 day; this effect was context-independent. Independent of the withdrawal period, operant responding in the extinction sessions was higher when responding led to contingent delivery of the discrete cue. After extinction, discrete cue-induced reinstatement, but not context- or drug priming-induced reinstatement, progressively increased after withdrawal. Together, incubation of methamphetamine craving, as assessed in extinction tests, is primarily mediated by time-dependent increases in non-reinforced operant responding, and this effect is potentiated by exposure to discrete, but not contextual, cues. PMID:26989042

  13. FXR: Big fish or small fry for drug-induced liver injury?

    PubMed

    Ballet, François

    2016-02-01

    By integrating network analysis and molecular modeling, a "system pharmacology" approach identified FXR as a potential off-target protein mediating non-steroidal anti-inflammatory drugs (NSAID)-induced liver injury. In vitro assays showed that NSAID are potent FXR antagonists that inhibit FXR transcriptional activity. Given the role of FXR in bile acid homeostasis, liver inflammation and cell proliferation, the data suggest that FXR antagonism could mediate, at least in part, NSAID-induced liver injury. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  14. Enigma of drug-induced altered states of consciousness among the !Kung Bushmen of the Kalahari Desert.

    PubMed

    Dobkin De Rios, M

    1986-03-01

    This article examines data presented in Katz' book, Boiling Energy: Community Healing among the Kalahari Kung, particularly with regard to plant drugs present in the community during the 1968 visit. The author argues that the similarity of the Bushman trance state, kia and that of drug-induced altered states of consciousness has been paid too little attention in the research, and that an enigma currently exists with regard to the degree to which plant drugs may have influenced the !Kung trance phenomenon and healing beliefs. The author discusses the existing evidence for plant drug use based on Katz' research and the specimens currently on hand at the Harvard Botanical Museum herbarium, and presents a Table which contrasts drug-induced behaviors and ideologies of societies known or suspected to have used mind-altering drugs with similar behavior/beliefs of the !Kung. It is suggested that the influence of a number of psychoactive drugs may have played a much more pivotal role in Bushman behavior and belief than is generally acknowledged.

  15. Rescue strategies against non-steroidal anti-inflammatory drug-induced gastroduodenal damage.

    PubMed

    Lim, Yun Jeong; Lee, Jeong Sang; Ku, Yang Suh; Hahm, Ki-Baik

    2009-07-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed drugs worldwide, which attests to their efficacy as analgesic, antipyretic and anti-inflammatory agents as well as anticancer drugs. However, NSAID use also carries a risk of major gastroduodenal events, including symptomatic ulcers and their serious complications that can lead to fatal outcomes. The development of "coxibs" (selective cyclooxygenase-2 [COX-2] inhibitors) offered similar efficacy with reduced toxicity, but this promise of gastroduodenal safety has only partially been fulfilled, and is now dented with associated risks of cardiovascular or intestinal complications. Recent advances in basic science and biotechnology have given insights into molecular mechanisms of NSAID-induced gastroduodenal damage beyond COX-2 inhibition. The emergence of newer kinds of NSAIDs should alleviate gastroduodenal toxicity without compromising innate drug efficacy. In this review, novel strategies for avoiding NSAID-associated gastroduodenal damage will be described.

  16. A case of pulmonary hemorrhage due to drug-induced pneumonitis secondary to ticagrelor therapy.

    PubMed

    Whitmore, Timothy J; O'Shea, John P; Starac, Diana; Edwards, Mark G; Waterer, Grant W

    2014-03-01

    We report a case of significant pulmonary hemorrhage developing shortly after commencing ticagrelor and aspirin therapy and requiring coronary artery bypass grafting to safely cease the antiplatelet therapy. Lung biopsy findings were consistent with drug-induced lung injury. Clinicians should be aware of this significant adverse event with this drug class.

  17. Drug induced exocytosis of glycogen in Pompe disease.

    PubMed

    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.

  18. Stem cell-derived models to improve mechanistic understanding and prediction of human drug-induced liver injury.

    PubMed

    Goldring, Christopher; Antoine, Daniel J; Bonner, Frank; Crozier, Jonathan; Denning, Chris; Fontana, Robert J; Hanley, Neil A; Hay, David C; Ingelman-Sundberg, Magnus; Juhila, Satu; Kitteringham, Neil; Silva-Lima, Beatriz; Norris, Alan; Pridgeon, Chris; Ross, James A; Young, Rowena Sison; Tagle, Danilo; Tornesi, Belen; van de Water, Bob; Weaver, Richard J; Zhang, Fang; Park, B Kevin

    2017-02-01

    Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug-induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalized toxicology to determine interindividual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury means that no current single-cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human drug-induced liver injury. Nevertheless, a single-cell model of a human hepatocyte which emulates key features of a hepatocyte is likely to be valuable in assessing potential chemical risk; furthermore, understanding how to generate a relevant hepatocyte will also be critical to efforts to build complex multicellular models of the liver. Currently, hepatocyte-like cells differentiated from stem cells still fall short of recapitulating the full mature hepatocellular phenotype. Therefore, we convened a number of experts from the areas of preclinical and clinical hepatotoxicity and safety assessment, from industry, academia, and regulatory bodies, to specifically explore the application of stem cells in hepatotoxicity safety assessment and to make recommendations for the way forward. In this short review, we particularly discuss the importance of benchmarking stem cell-derived hepatocyte-like cells to their terminally differentiated human counterparts using defined phenotyping, to make sure the cells are relevant and comparable between labs, and outline why this process is essential before the cells are introduced into chemical safety assessment. (Hepatology 2017;65:710-721). © 2016 by the American Association for the Study of Liver Diseases.

  19. Abnormal uterine bleeding in perimenopause.

    PubMed

    Goldstein, S R; Lumsden, M A

    2017-10-01

    Abnormal uterine bleeding is one of the commonest presenting complaints encountered in a gynecologist's office or primary-care setting. The wider availability of diagnostic tools has allowed prompt diagnosis and treatment of an increasing number of menstrual disorders in an office setting. This White Paper reviews the advantages and disadvantages of transvaginal ultrasound, blind endometrial sampling and diagnostic hysteroscopy. Once a proper diagnosis has been established, appropriate therapy may be embarked upon. Fortunately, only a minority of such patients will have premalignant or malignant disease. When bleeding is sufficient to cause severe anemia or even hypovolemia, prompt intervention is called for. In most of the cases, however, the abnormal uterine bleeding will be disquieting to the patient and significantly affect her 'quality of life'. Sometimes, reassurance and expectant management will be sufficient in such patients. Overall, however, in cases of benign disease, some intervention will be required. The use of oral contraceptive pills especially those with a short hormone-free interval, the insertion of the levonorgestrel intrauterine system, the incorporation of newer medical therapies including antifibrinolytic drugs and selective progesterone receptor modulators and minimally invasive treatments have made outpatient therapy increasingly effective. For others, operative hysteroscopy and endometrial ablation are proven therapeutic tools to provide both long- and short-term relief of abnormal uterine bleeding, thus avoiding, or deferring, hysterectomy.

  20. Protection of a Ceramide Synthase 2 Null Mouse from Drug-induced Liver Injury

    PubMed Central

    Park, Woo-Jae; Park, Joo-Won; Erez-Roman, Racheli; Kogot-Levin, Aviram; Bame, Jessica R.; Tirosh, Boaz; Saada, Ann; Merrill, Alfred H.; Pewzner-Jung, Yael; Futerman, Anthony H.

    2013-01-01

    Very long chain (C22-C24) ceramides are synthesized by ceramide synthase 2 (CerS2). A CerS2 null mouse displays hepatopathy because of depletion of C22-C24 ceramides, elevation of C16-ceramide, and/or elevation of sphinganine. Unexpectedly, CerS2 null mice were resistant to acetaminophen-induced hepatotoxicity. Although there were a number of biochemical changes in the liver, such as increased levels of glutathione and multiple drug-resistant protein 4, these effects are unlikely to account for the lack of acetaminophen toxicity. A number of other hepatotoxic agents, such as d-galactosamine, CCl4, and thioacetamide, were also ineffective in inducing liver damage. All of these drugs and chemicals require connexin (Cx) 32, a key gap junction protein, to induce hepatotoxicity. Cx32 was mislocalized to an intracellular location in hepatocytes from CerS2 null mice, which resulted in accelerated rates of its lysosomal degradation. This mislocalization resulted from the altered membrane properties of the CerS2 null mice, which was exemplified by the disruption of detergent-resistant membranes. The lack of acetaminophen toxicity and Cx32 mislocalization were reversed upon infection with recombinant adeno-associated virus expressing CerS2. We establish that Gap junction function is compromised upon altering the sphingolipid acyl chain length composition, which is of relevance for understanding the regulation of drug-induced liver injury. PMID:24019516

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

    PubMed

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

    2017-12-01

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

  2. Cardiovascular Autonomic Dysfunction in Patients with Drug-Induced Parkinsonism

    PubMed Central

    Ryu, Dong-Woo; Oh, Ju-Hee; Lee, Yang-Hyun; Park, Sung-Jin; Jeon, Kipyung; Lee, Jong-Yun; Ho, Seong Hee; So, Jungmin; Im, Jin Hee; Lee, Kwang-Soo

    2017-01-01

    Background and Purpose Recent studies have shown that several nonmotor symptoms differ between Parkinson's disease (PD) and drug-induced parkinsonism (DIP). However, there have been no reports on cardiovascular autonomic function in DIP, and so this study investigated whether cardiovascular autonomic function differs between PD and DIP patients. Methods This study consecutively enrolled 20 DIP patients, 99 drug-naïve PD patients, and 25 age-matched healthy controls who underwent head-up tilt-table testing and 24-h ambulatory blood pressure monitoring. Results Orthostatic hypotension was more frequent in patients with PD or DIP than in healthy controls. In DIP, orthostatic hypotension was associated with the underlying psychiatric diseases and neuroleptics use, whereas prokinetics were not related to orthostatic hypotension. The supine blood pressure, nighttime blood pressure, and nocturnal blood pressure dipping did not differ significantly between the DIP and control groups. Supine hypertension and nocturnal hypertension were more frequent in PD patients than in controls. Conclusions The included DIP patients frequently exhibited orthostatic hypotension that was associated with the underlying diseases as well as the nature of and exposure time to the offending drugs. Clinicians should individualize the manifestations of DIP according to underlying diseases as well as the action mechanism of and exposure time to each offending drug. PMID:27730767

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

    PubMed

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

    2017-01-01

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

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhou, Xiaobing; Graduate School of Peking Union Medical College, Dongcheng District, Beijing, 100730; Ma, Ben

    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 resultsmore » 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.« less

  5. Abnormal epithelial structure and chronic lung inflammation after repair of chlorine-induced airway injury

    PubMed Central

    Mo, Yiqun; Chen, Jing; Humphrey, David M.; Fodah, Ramy A.; Warawa, Jonathan M.

    2014-01-01

    Chlorine is a toxic gas used in a variety of industrial processes and is considered a chemical threat agent. High-level chlorine exposure causes acute lung injury, but the long-term effects of acute chlorine exposure are unclear. Here we characterized chronic pulmonary changes following acute chlorine exposure in mice. A/J mice were exposed to 240 parts per million-hour chlorine or sham-exposed to air. Chlorine inhalation caused sloughing of bronchial epithelium 1 day after chlorine exposure, which was repaired with restoration of a pseudostratified epithelium by day 7. The repaired epithelium contained an abnormal distribution of epithelial cells containing clusters of club or ciliated cells rather than the uniformly interspersed pattern of these cells in unexposed mice. Although the damaged epithelium in A/J mice was repaired rapidly, and minimal airway fibrosis was observed, chlorine-exposed mice developed pneumonitis characterized by infiltration of alveoli with neutrophils and prominent, large, foamy macrophages. Levels of CXCL1/KC, CXCL5/LPS-induced CXC chemokine, granulocyte colony-stimulating factor, and VEGF in bronchoalveolar (BAL) fluid from chlorine-exposed mice showed steadily increasing trends over time. BAL protein levels were increased on day 4 and remained elevated out to day 28. The number of bacteria cultured from lungs of chlorine-exposed mice 4 wk after exposure was not increased compared with sham-exposed mice, indicating that the observed pneumonitis was not driven by bacterial infection of the lung. The results indicate that acute chlorine exposure may cause chronic abnormalities in the lungs despite rapid repair of injured epithelium. PMID:25398987

  6. Attenuation of abnormalities in the lipid metabolism during experimental myocardial infarction induced by isoproterenol in rats: beneficial effect of ferulic acid and ascorbic acid.

    PubMed

    Yogeeta, Surinder Kumar; Hanumantra, Rao Balaji Raghavendran; Gnanapragasam, Arunachalam; Senthilkumar, Subramanian; Subhashini, Rajakannu; Devaki, Thiruvengadam

    2006-05-01

    The present study aims at evaluating the effect of the combination of ferulic acid and ascorbic acid on isoproterenol-induced abnormalities in lipid metabolism. The rats were divided into eight groups: Control, isoproterenol, ferulic acid alone, ascorbic acid alone, ferulic acid+ascorbic acid, ferulic acid+isoproterenol, ascorbic acid+isoproterenol and ferulic acid+ascorbic acid+isoproterenol. Ferulic acid (20 mg/kg b.w.t.) and ascorbic acid (80 mg/kg b.w.t.) both alone and in combination was administered orally for 6 days and on the fifth and the sixth day, isoproterenol (150 mg/kg b.w.t.) was injected intraperitoneally to induce myocardial injury to rats. Induction of rats with isoproterenol resulted in a significant increase in the levels of triglycerides, total cholesterol, free fatty acids, free and ester cholesterol in both serum and cardiac tissue. A rise in the levels of phospholipids, lipid peroxides, low density lipoprotein and very low density lipoprotein-cholesterol was also observed in the serum of isoproterenol-intoxicated rats. Further, a decrease in the level of high density lipoprotein in serum and in the phospholipid levels, in the heart of isoproterenol-intoxicated rats was observed, which was paralleled by abnormal activities of lipid metabolizing enzymes: total lipase, cholesterol ester synthase, lipoprotein lipase and lecithin: cholesterol acyl transferase. Pre-cotreatment with the combination of ferulic acid and ascorbic acid significantly attenuated these alterations and restored the levels to near normal when compared to individual treatment groups. Histopathological observations were also in correlation with the biochemical parameters. These findings indicate the synergistic protective effect of ferulic acid and ascorbic acid on isoproterenol-induced abnormalities in lipid metabolism.

  7. Drug Tolerance in Replicating Mycobacteria Mediated by a Macrophage-Induced Efflux Mechanism

    PubMed Central

    Adams, Kristin N.; Takaki, Kevin; Connolly, Lynn E.; Wiedenhoft, Heather; Winglee, Kathryn; Humbert, Olivier; Edelstein, Paul H.; Cosma, Christine L.; Ramakrishnan, Lalita

    2011-01-01

    SUMMARY Treatment of tuberculosis, a complex granulomatous disease, requires long-term multidrug therapy to overcome tolerance, an epigenetic drug resistance that is widely attributed to nonreplicating bacterial subpopulations. Here, we deploy Mycobacterium marinum-infected zebrafish larvae for in vivo characterization of antitubercular drug activity and tolerance. We describe the existence of multi-drug tolerant organisms that arise within days of infection, are enriched in the replicating intracellular population, and are amplified and disseminated by the tuberculous granuloma. Bacterial efflux pumps that are required for intracellular growth mediate this macrophage-induced tolerance. This newly discovered tolerant population also develops when Mycobacterium tuberculosis infects cultured macrophages, suggesting that it contributes to the burden of drug tolerance in human tuberculosis. Efflux pump inhibitors like verapamil reduce this tolerance. Thus, the addition of this currently approved drug, or more specific inhibitors, to standard antitubercular therapy may shorten the duration of curative treatment. PMID:21376383

  8. Abnormal Uterine Bleeding.

    PubMed

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

    2017-07-01

    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 evidence on the treatment of women with abnormal uterine bleeding, both acute and chronic. Didactically, the treatment options were based on the current International Federation of Gynecology and Obstetrics (FIGO) classification system (PALM-COEIN). The etiologies of PALM-COEIN are: uterine Polyp (P), Adenomyosis (A), Leiomyoma (L), precursor and Malignant lesions of the uterine body (M), Coagulopathies (C), Ovulatory dysfunction (O), Endometrial dysfunction (E), Iatrogenic (I), and Not yet classified (N). The articles were selected according to the recommendation grades of the PubMed, Cochrane and Embase databases, and those in which the main objective was the reduction of uterine menstrual bleeding were included. Only studies written in English were included. All editorial or complete papers that were not consistent with abnormal uterine bleeding, or studies in animal models, were excluded. The main objective of the treatment is the reduction of menstrual flow and morbidity and the improvement of quality of life. It is important to emphasize that the treatment in the acute phase aims to hemodynamically stabilize the patient and stop excessive bleeding, while the treatment in the chronic phase is based on correcting menstrual dysfunction according to its etiology and clinical manifestations. The treatment may be surgical or pharmacological, and the latter is based mainly on hormonal therapy, anti-inflammatory drugs and antifibrinolytics. Thieme Revinter Publicações Ltda Rio de Janeiro

  9. Dietary high-fat lard intake induces thyroid dysfunction and abnormal morphology in rats.

    PubMed

    Shao, Shan-shan; Zhao, Yuan-fei; Song, Yong-feng; Xu, Chao; Yang, Jian-mei; Xuan, Shi-meng; Yan, Hui-li; Yu, Chun-xiao; Zhao, Meng; Xu, Jin; Zhao, Jia-jun

    2014-11-01

    Excess dietary fat intake can induce lipotoxicity in non-adipose tissues. The aim of this study was to observe the effects of dietary high-fat lard intake on thyroid in rats. Male Sprague-Dawley rats were fed a high-fat lard diet for 24 weeks, and then the rats were fed a normal control diet (acute dietary modification) or the high-fat lard diet for another 6 weeks. The serum lipid profile, total thyroxine (TT4), free thyroxine (FT4) and thyrotropin (TSH) levels were determined at the 12, 18, 24 and 30 weeks. High-frequency ultrasound scanning of the thyroid glands was performed at the 24 or 30 weeks. After the rats were sacrificed, the thyroid glands were collected for histological and immunohistochemical analyses. The high-fat lard diet significantly increased triglyceride levels in both the serum and thyroid, and decreased serum TT4 and FT4 levels in parallel with elevated serum TSH levels. Ultrasonic imaging revealed enlarged thyroid glands with lowered echotexture and relatively heterogeneous features in the high-fat lard fed rats. The thyroid glands from the high-fat lard fed rats exhibited enlarged follicle cavities and flattened follicular epithelial cells under light microscopy, and dilated endoplasmic reticulum cisternae, twisted nuclei, fewer microvilli and secretory vesicles under transmission electron microscopy. Furthermore, the thyroid glands from the high-fat lard fed rats showed markedly low levels of thyroid hormone synthesis-related proteins TTF-1 and NIS. Acute dietary modification by withdrawal of the high-fat lard diet for 6 weeks failed to ameliorate the high-fat lard diet-induced thyroid changes. Dietary high-fat lard intake induces significant thyroid dysfunction and abnormal morphology in rats, which can not be corrected by short-term dietary modification.

  10. Effect of dopaminergic drugs on the reserpine-induced lowering of hippocampal theta wave frequency in rats.

    PubMed

    Nakagawa, T; Ukai, K; Ohyama, T; Gomita, Y; Okamura, H

    2000-05-01

    The effects of dopaminergic drugs on the lowering of hippocampal theta wave frequency induced by reserpine 1 mg/kg s.c. were examined. Sibutramine (monoamine reuptake inhibitor) 10 mg/kg p.o., methamphetamine (monoamine releaser) 1 mg/kg, quinpirole (dopamine D2 receptor agonist) 10 mg/kg i.p., and SKF 38393 (dopamine D1 receptor agonist) 10 mg/kg i.p. each antagonized the reserpine-induced lowering of hippocampal theta wave frequency in rats. Moreover, the combined administration of SKF 38393 1 mg/kg i.p. and quinpirole 1 mg/kg i.p. synergistically antagonized a reserpine-induced lowering of this frequency. Dosulepin, amitriptyline, and desipramine, which are weak inhibitors of dopamine reuptake, each had little effect on the reserpine-induced lowering of theta wave frequency at a dose of 40 mg/kg p.o. Furthermore, atropine (muscarinic anticholinergic drug) 20 mg/kg p.o. decreased theta wave power in the low-frequency range following a shift to the lower range by reserpine. A positive correlation was observed for each of the above drugs between a reversal of reserpine-induced lowering of theta wave frequency and a reversal of impairment of reserpine-induced conditioned avoidance responses (ACAR) in rats. These results suggest that the reserpine-induced lowering of hippocampal theta wave frequency plays a role in the impairment of reserpine-induced ACAR, and that dopamine D1 and D2 receptors play important roles in antagonizing this lowering of frequency.

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

    PubMed

    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 ( r 2 =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

  12. Drug-induced exanthems: correlation of allergy testing with histologic diagnosis.

    PubMed

    Seitz, Cornelia S; Rose, Christian; Kerstan, Andreas; Trautmann, Axel

    2013-11-01

    Skin biopsies are commonly performed to confirm drug-induced exanthem (DIE). However, the relevance of histologic examination in discriminating between DIE and non-DIE (NDIE) is controversial. A retrospective analysis was performed to evaluate the reliability of histologic diagnosis of DIE. In all, 91 patients with a skin biopsy specimen of an acute exanthem temporally related to a single identifiable drug underwent complete allergy testing. Their biopsy specimens were retrospectively re-evaluated by 2 dermatopathologists blinded to the original reports to test for discrimination between DIE versus NDIE. In 35 patients, non-IgE-mediated drug allergy was confirmed by allergy testing, whereas in 56 patients drug hypersensitivity could be excluded. Sensitivity of pathology reports for diagnosis of DIE reached 62.9% with a positive predictive value of 40.7%. Specificity was 41.1% with a negative predictive value of 69.7%. No significant difference in tissue eosinophilia was detected between DIE and NDIE. This was a retrospective study. Dermatopathologic evaluation of skin biopsy specimens is of limited use in differentiating between DIE and NDIE. All efforts should be made to subject these patients to thorough allergy testing for definitely confirming or ruling out drug hypersensitivity. Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

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

    PubMed

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

    2017-07-01

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

  14. [Possible malignant hyperthermia as reaction to an overdose of myotonolytic, antidepressive and sedative drugs (author's transl)].

    PubMed

    Hackl, J M; Engl, J; Hofstädter, F; Bonelli, S; Rumpl, E; Dworzak, E; Puschendorf, B

    1981-08-07

    A 51-year-old male patient with no history of musculo-skeletal or myopathic abnormalities, but suffering from manic-depressive psychosis, attempted suicide with an overdose of dolpersin hydrochloride (Mydocalm), dipenzepine hydrochloride (Noveril), meprobamate (Mepronox) and nitrazepam (Mogadon). He developed high fever, muscle rigidity, tachycardia, arrhythmias, hypotension and mottled cyanosis, symptoms well-known in persons with malignant hyperthermia, an autosomally inherited disease of skeletal muscle. There is also discussed the manifestation and the symptoms of an acute rhabdomyolysis. The diagnosis was confirmed by chemical pathological laboratory findings, including respiratory and metabolic acidosis, myoglobinaemia accompanied by myoglobin diuresis, and elevated creatine phosphokinase (CPK values up to 2790 U/l). Electron microscopic examination of muscle tissue revealed signs of myolysis and mitochondrial reactions with pleoconic hyperplasia. No inhalation anaesthetics or skeletal muscle relaxants, such as succinyl choline, were used in this case. Therefore, malignant hyperthermia might have been induced by a combination of drugs which were not known to induce this abnormal muscular reaction. However, the muscle relaxant effect of dolpersin hydrochloride may have acted as a possible inducer of the attack.

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

    PubMed

    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.

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

    PubMed Central

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

    2018-01-01

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

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

    PubMed

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

    2008-09-01

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

  18. Incubation of extinction responding and cue-induced reinstatement, but not context- or drug priming-induced reinstatement, after withdrawal from methamphetamine.

    PubMed

    Adhikary, Sweta; Caprioli, Daniele; Venniro, Marco; Kallenberger, Paige; Shaham, Yavin; Bossert, Jennifer M

    2017-07-01

    In rats trained to self-administer methamphetamine, extinction responding in the presence of drug-associated contextual and discrete cues progressively increases after withdrawal (incubation of methamphetamine craving). The conditioning factors underlying this incubation are unknown. Here, we studied incubation of methamphetamine craving under different experimental conditions to identify factors contributing to this incubation. We also determined whether the rats' response to methamphetamine priming incubates after withdrawal. We trained rats to self-administer methamphetamine in a distinct context (context A) for 14 days (6 hours/day). Lever presses were paired with a discrete light cue. We then tested groups of rats in context A or a different non-drug context (context B) after 1 day, 1 week or 1 month for extinction responding with or without the discrete cue. Subsequently, we tested the rats for reinstatement of drug seeking induced by exposure to contextual, discrete cue, or drug priming (0, 0.25 and 0.5 mg/kg). Operant responding in the extinction sessions in contexts A or B was higher after 1 week and 1 month of withdrawal than after 1 day; this effect was context-independent. Independent of the withdrawal period, operant responding in the extinction sessions was higher when responding led to contingent delivery of the discrete cue. After extinction, discrete cue-induced reinstatement, but not context- or drug priming-induced reinstatement, progressively increased after withdrawal. Together, incubation of methamphetamine craving, as assessed in extinction tests, is primarily mediated by time-dependent increases in non-reinforced operant responding, and this effect is potentiated by exposure to discrete, but not contextual, cues. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

  19. Recent Insights Into Molecular Mechanisms of Propofol-Induced Developmental Neurotoxicity: Implications for the Protective Strategies.

    PubMed

    Bosnjak, Zeljko J; Logan, Sarah; Liu, Yanan; Bai, Xiaowen

    2016-11-01

    Mounting evidence has demonstrated that general anesthetics could induce developmental neurotoxicity, including acute widespread neuronal cell death, followed by long-term memory and learning abnormalities. Propofol is a commonly used intravenous anesthetic agent for the induction and maintenance of anesthesia and procedural and critical care sedation in children. Compared with other anesthetic drugs, little information is available on its potential contributions to neurotoxicity. Growing evidence from multiple experimental models showed a similar neurotoxic effect of propofol as observed in other anesthetic drugs, raising serious concerns regarding pediatric propofol anesthesia. The aim of this review is to summarize the current findings of propofol-induced developmental neurotoxicity. We first present the evidence of neurotoxicity from animal models, animal cell culture, and human stem cell-derived neuron culture studies. We then discuss the mechanism of propofol-induced developmental neurotoxicity, such as increased cell death in neurons and oligodendrocytes, dysregulation of neurogenesis, abnormal dendritic development, and decreases in neurotrophic factor expression. Recent findings of complex mechanisms of propofol action, including alterations in microRNAs and mitochondrial fission, are discussed as well. An understanding of the toxic effect of propofol and the underlying mechanisms may help to develop effective novel protective or therapeutic strategies for avoiding the neurotoxicity in the developing human brain.

  20. Light induced cytosolic drug delivery from liposomes with gold nanoparticles.

    PubMed

    Lajunen, Tatu; Viitala, Lauri; Kontturi, Leena-Stiina; Laaksonen, Timo; Liang, Huamin; Vuorimaa-Laukkanen, Elina; Viitala, Tapani; Le Guével, Xavier; Yliperttula, Marjo; Murtomäki, Lasse; Urtti, Arto

    2015-04-10

    Externally triggered drug release at defined targets allows site- and time-controlled drug treatment regimens. We have developed liposomal drug carriers with encapsulated gold nanoparticles for triggered drug release. Light energy is converted to heat in the gold nanoparticles and released to the lipid bilayers. Localized temperature increase renders liposomal bilayers to be leaky and triggers drug release. The aim of this study was to develop a drug releasing system capable of releasing its cargo to cell cytosol upon triggering with visible and near infrared light signals. The liposomes were formulated using either heat-sensitive or heat- and pH-sensitive lipid compositions with star or rod shaped gold nanoparticles. Encapsulated fluorescent probe, calcein, was released from the liposomes after exposure to the light. In addition, the pH-sensitive formulations showed a faster drug release in acidic conditions than in neutral conditions. The liposomes were internalized into human retinal pigment epithelial cells (ARPE-19) and human umbilical vein endothelial cells (HUVECs) and did not show any cellular toxicity. The light induced cytosolic delivery of calcein from the gold nanoparticle containing liposomes was shown, whereas no cytosolic release was seen without light induction or without gold nanoparticles in the liposomes. The light activated liposome formulations showed a controlled content release to the cellular cytosol at a specific location and time. Triggering with visual and near infrared light allows good tissue penetration and safety, and the pH-sensitive liposomes may enable selective drug release in the intracellular acidic compartments (endosomes, lysosomes). Thus, light activated liposomes with gold nanoparticles are an attractive option for time- and site-specific drug delivery into the target cells. Copyright © 2015 Elsevier B.V. All rights reserved.

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

    NASA Astrophysics Data System (ADS)

    Biswas, Souvik

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

  2. Sodium valproate induced gingival enlargement with pre-existing chronic periodontitis.

    PubMed

    Joshipura, Vaibhavi

    2012-04-01

    Gingival enlargement is a common clinical feature of gingival and periodontal diseases. Currently, more than 20 prescription medications are associated with gingival enlargement. Although the mechanisms of action may be different, the clinical and microscopic appearance of drug-induced gingival enlargement is similar with any drug. Gingival enlargement produces esthetic changes, and clinical symptoms including pain, tenderness, bleeding, speech disturbances, abnormal tooth movement, dental occlusion problems, enhancement of caries development and periodontal disorders. Sodium valproate is considered to produce gingival enlargement, but very rarely. This case report features sodium valproate induced gingival enlargement in a patient with pre-existing chronic periodontitis, who came to the Dental Department, Chinmaya Mission Hospital, Bangalore. The case is special as the patient did not develop the enlargement in spite of taking phenytoin for 1 year and developed enlargement with sodium valproate within 6 months.

  3. Morphological abnormalities in the cladoceran Ilyocryptus spinifer (Apipucos Reservoir, Pernambuco State, Brazil).

    PubMed

    Elmoor-Loureiro, L M

    2004-02-01

    In a sample taken from Apipucos Reservoir (Recife, PE, Brazil) for taxonomic study, a high percentage (40%) was found of cladoceran Ilyocryptus spinifer individuals with morphological abnormalities on their postabdomen. There was not a fixed pattern of the malformations, which varied in gravity, and could affect the postanal spines or terminal claws. The postabdominal abnormalities are described and compared to the ones described in the literature. The hypothesis of the morphological abnormalities being induced by an occasional environmental toxicant is discussed.

  4. Early physiological abnormalities after simian immunodeficiency virus infection

    PubMed Central

    Horn, Thomas F. W.; Huitron-Resendiz, Salvador; Weed, Michael R.; Henriksen, Steven J.; Fox, Howard S.

    1998-01-01

    Central nervous system (CNS) damage and dysfunction are devastating consequences of HIV infection. Although the CNS is one of the initial targets for HIV infection, little is known about early viral-induced abnormalities that can affect CNS function. Here we report the detection of early physiological abnormalities in simian immunodeficiency virus-infected monkeys. The acute infection caused a disruption of the circadian rhythm manifested by rises in body temperature, observed in all five individuals between 1 and 2 weeks postinoculation (p.i.), accompanied by a reduction in daily motor activity to 50% of control levels. Animals remained hyperthermic at 1 and 2 months p.i. and returned to preinoculation temperatures at 3 months after viral inoculation. Although motor activity recovered to baseline values at 1 month p.i., activity levels then decreased to approximately 50% of preinoculation values over the next 2 months. Analysis of sensory-evoked responses 1 month p.i. revealed distinct infection-induced changes in auditory-evoked potential peak latencies that persisted at 3 months after viral inoculation. These early physiological abnormalities may precede the development of observable cognitive or motor deficiencies and can provide an assay to evaluate agents to prevent or alleviate neuronal dysfunction. PMID:9844017

  5. Drug-induced gynecomastia.

    PubMed

    Thompson, D F; Carter, J R

    1993-01-01

    Gynecomastia is a relatively common physical finding in men. A wide variety of drugs have been implicated in its cause. Sufficient evidence in the literature suggests that calcium-channel blockers, cancer chemotherapeutic agents, and histamine2-receptor blockers may play a role in the disorder. Evidence for digitalis glycosides and neuroleptic agents is insufficient. Ketoconazole and spironolactone can also produce gynecomastia, and data for marijuana are contradictory. Large numbers of drugs have only case reports of temporal association with the disorder.

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

    DTIC Science & Technology

    2017-06-08

    currently on the market and for which drug-protein interaction information is available . These predictions are publicly accessible at http://avoid...associated with these ADRs via DDIs. We made the predictions publicly available via internet access. Keywords: Drug-drug interactions, Adverse drug reactions...ˆDeceased Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research

  7. Arsenite-induced mitotic death involves stress response and is independent of tubulin polymerization

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Taylor, B. Frazier; McNeely, Samuel C.; Miller, Heather L.

    2008-07-15

    Arsenite, a known mitotic disruptor, causes cell cycle arrest and cell death at anaphase. The mechanism causing mitotic arrest is highly disputed. We compared arsenite to the spindle poisons nocodazole and paclitaxel. Immunofluorescence analysis of {alpha}-tubulin in interphase cells demonstrated that, while nocodazole and paclitaxel disrupt microtubule polymerization through destabilization and hyperpolymerization, respectively, microtubules in arsenite-treated cells remain comparable to untreated cells even at supra-therapeutic concentrations. Immunofluorescence analysis of {alpha}-tubulin in mitotic cells showed spindle formation in arsenite- and paclitaxel-treated cells but not in nocodazole-treated cells. Spindle formation in arsenite-treated cells appeared irregular and multi-polar. {gamma}-tubulin staining showed that cellsmore » treated with nocodazole and therapeutic concentrations of paclitaxel contained two centrosomes. In contrast, most arsenite-treated mitotic cells contained more than two centrosomes, similar to centrosome abnormalities induced by heat shock. Of the three drugs tested, only arsenite treatment increased expression of the inducible isoform of heat shock protein 70 (HSP70i). HSP70 and HSP90 proteins are intimately involved in centrosome regulation and mitotic spindle formation. HSP90 inhibitor 17-DMAG sensitized cells to arsenite treatment and increased arsenite-induced centrosome abnormalities. Combined treatment of 17-DMAG and arsenite resulted in a supra-additive effect on viability, mitotic arrest, and centrosome abnormalities. Thus, arsenite-induced abnormal centrosome amplification and subsequent mitotic arrest is independent of effects on tubulin polymerization and may be due to specific stresses that are protected against by HSP90 and HSP70.« less

  8. Piracetam and aniracetam antagonism of centrally active drug-induced antinociception.

    PubMed

    Galeotti, N; Ghelardini, C; Bartolini, A

    1996-04-01

    The effects of the nootropic drugs piracetam and aniracetam on antinociception induced by baclofen, bicuculline, and picrotoxin and on baclofen-induced muscle relaxation were studied in mice. Antinociception was investigated using both the hot plate (thermal stimulus) and abdominal constriction (chemical stimulus) tests. Both behaviour inhibition and muscle relaxation were observed by using the rota-rod test. Piracetam (30 mg/kg, IP) and aniracetam (10 mg/kg, PO) reduced baclofen, bicuculline, and picrotoxin antinociception without modifying analgesia induced by non-GABAergic drugs such as morphine, physostigmine, clomipramine, and diphenhydramine. In this concentration range, piracetam, and aniracetam were also able to reduce the inhibition of rota-rod performance. At higher doses piracetam (100 mg/kg, IP) and aniracetam (100 mg/kg, PO) were able to completely prevent baclofen antinociception. However, when prevention of GABAergic antinociception was complete, piracetam and aniracetam were able to block non-GABAergic antinociception also. comparing the effects of piracetam and aniracetam with those exerted by the GABAB antagonist CGP 35348, a reduction of non-GABAergic analgesia was also observed using higher doses of CGP 35348 (2.5 micrograms per mouse ICV). The present results indicate that piracetam and aniracetam, by preventing both of the investigated effects of baclofen, have some selectivity against GABAB-mediated inhibition. The well-known activity of piracetam and aniracetam on learning and memory might, therefore, depend, at least in part, on the removal of inhibitory GABAB mechanisms that impair attention and cognitive functions.

  9. Drugs of abuse in pregnancy, poor neonatal development, and future neurodegeneration. Is oxidative stress the culprit?

    PubMed

    Neri, Margherita; Bello, Stefania; Turillazzi, Emanuela; Riezzo, Irene

    2015-01-01

    The abuse of licit and illicit drugs is a worldwide issue that is a cause for concern in pregnant women. It may lead to complications in pregnancy that may affect the mother, fetus, and /or neonate. The effects of any substance on the developing embryo and fetus are dependent upon dosing, timing, duration of drug exposure, and the extent of drug distribution. Teratogenic effects have been described when exposure takes place during the embryonic stage; however drugs have subtle effects, including abnormal growth and/or maturation, alterations in neurotransmitters and their receptors, and brain organization. The mechanisms by which intrauterine exposure to many substances may result in neuronal injury have not been completely elucidated. Oxidative stress and epigenetic changes have been recently implicated in the pathogenesis of long - term adverse health sequelae, and neuro-developmental impairment in the offspring of addicted mothers. Transgenerational epigenetics may also explain the alarming datum that developmental abnormalities, impairment in learning and memory, and attention deficit can occur even in the absence of direct fetal exposure, when drugs are consumed prior to conception. There is a growing body of evidence demonstrating a link between redox state unbalance, epigenetic markers, developmental anomalies, and neurodegeneration. The reviewed literature data uphold redox homeostasis disruption as an important factor in the pathogenesis of drug of abuse- induced neurodegeneration, and highlight the potential for new therapies that could prevent neurodegeneration through antioxidant and epigenetic modulatory mechanisms. This therefore reveals important targets for novel neuroprotective strategies.

  10. Abnormal Canine Bone Development Associated with Hypergravity Exposure

    NASA Technical Reports Server (NTRS)

    Morgan, J. P.; Fisher, G. L.; McNeill, K. L.; Oyama, J.

    1979-01-01

    Chronic centrifugation of 85- to 92-day-old Beagles at 2.0 x g and 2.6 x g for 26 weeks during the time of active skeletal growth caused skeletal abnormalities in the radius and the ulna of ten of 11 dogs. The pattern of change mimicked that found in naturally occurring and experimentally induced premature distal ulnar physeal closure or delayed growth at this physis. Minimal changes in bone density were detected by sensitive photon absorptiometric techniques. Skeletal abnormalities also were found in five of the six cage-control dogs, although the run-control dogs were radiographically normal.

  11. Analytical modeling of drug dynamics induced by eluting stents in the coronary multi-layered curved domain.

    PubMed

    d'Errico, Michele; Sammarco, Paolo; Vairo, Giuseppe

    2015-09-01

    Pharmacokinetics induced by drug eluting stents (DES) in coronary walls is modeled by means of a one-dimensional multi-layered model, accounting for vessel curvature and non-homogeneous properties of the arterial tissues. The model includes diffusion mechanisms, advection effects related to plasma filtration through the walls, and bio-chemical drug reactions. A non-classical Sturm-Liouville problem with discontinuous coefficients is derived, whose closed-form analytical solution is obtained via an eigenfunction expansion. Soundness and consistency of the proposed approach are shown by numerical computations based on possible clinical treatments involving both hydrophilic and hydrophobic drugs. The influence of the main model parameters on drug delivery mechanisms is analyzed, highlighting the effects induced by vessel curvature and yielding comparative indications and useful insights into the concurring mechanisms governing the pharmacokinetics. Copyright © 2015. Published by Elsevier Inc.

  12. Therapeutic efficacy of DL-alpha-lipoic acid on cyclosporine A induced renal alterations.

    PubMed

    Amudha, Ganapathy; Josephine, Anthony; Mythili, Yenjerla; Sundarapandiyan, Rajaguru; Varalakshmi, Palaninathan

    2007-10-01

    The present study was designed to evaluate the possible beneficial effect of lipoic acid in preventing the renal damage induced by cyclosporine A in rats. Male albino rats of Wistar strain were divided into four groups and treated as follows. Two groups received cyclosporine A by oral gavage (25 mg/kg/body weight) for 21 days to induce nephrotoxicity, one of which simultaneously received lipoic acid treatment (20 mg/kg body weight) for 21 days. A vehicle (olive oil) and a lipoic acid drug control were also included. Cyclosporine A induced renal damage was evident from the decreased activities of tissue marker enzymes (alkaline phosphatase, acid phosphatase, lactate dehydrogenase, aspartate transaminase and alanine transaminase) and decreased activities of ATPases (Na+, K+-ATPase, Ca2+-ATPase and Mg2+ ATPase). An apparent increase in the levels of serum constituents (urea, uric acid and creatinine) and urinary marker enzymes (N-acetyl-beta-D-glucosaminidase, beta-glucosidase, beta-galactosidase, cathepsin-D and gamma-glutamyl transpeptidase) along with significant decline in creatinine clearance were seen in the cyclosporine treated rats, which was reversed upon treatment with lipoic acid. Ultrastructural observations were also in agreement with the above abnormal changes. Lipoic acid effectively reverted these abnormal biochemical changes and minimized the morphological lesions in renal tissue. Hence, this study clearly exemplifies that lipoic acid might be an ideal choice against cyclosporine A induced cellular abnormalities.

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

    PubMed

    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.

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

    PubMed

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

    2014-01-01

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

  15. Protection of cisplatin-induced spermatotoxicity, DNA damage and chromatin abnormality by selenium nano-particles.

    PubMed

    Rezvanfar, Mohammad Amin; Rezvanfar, Mohammad Ali; Shahverdi, Ahmad Reza; Ahmadi, Abbas; Baeeri, Maryam; Mohammadirad, Azadeh; Abdollahi, Mohammad

    2013-02-01

    Cisplatin (CIS), an anticancer alkylating agent, induces DNA adducts and effectively cross links the DNA strands and so affects spermatozoa as a male reproductive toxicant. The present study investigated the cellular/biochemical mechanisms underlying possible protective effect of selenium nano-particles (Nano-Se) as an established strong antioxidant with more bioavailability and less toxicity, on reproductive toxicity of CIS by assessment of sperm characteristics, sperm DNA integrity, chromatin quality and spermatogenic disorders. To determine the role of oxidative stress (OS) in the pathogenesis of CIS gonadotoxicity, the level of lipid peroxidation (LPO), antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) and peroxynitrite (ONOO) as a marker of nitrosative stress (NS) and testosterone (T) concentration as a biomarker of testicular function were measured in the blood and testes. Thirty-two male Wistar rats were equally divided into four groups. A single IP dose of CIS (7 mg/kg) and protective dose of Nano-Se (2 mg/kg/day) were administered alone or in combination. The CIS-exposed rats showed a significant increase in testicular and serum LPO and ONOO level, along with a significant decrease in enzymatic antioxidants levels, diminished serum T concentration and abnormal histologic findings with impaired sperm quality associated with increased DNA damage and decreased chromatin quality. Coadministration of Nano-Se significantly improved the serum T, sperm quality, and spermatogenesis and reduced CIS-induced free radical toxic stress and spermatic DNA damage. In conclusion, the current study demonstrated that Nano-Se may be useful to prevent CIS-induced gonadotoxicity through its antioxidant potential. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Measurement of caspase-2 activation during different anti-tumor drugs induced apoptosis by FRET technique

    NASA Astrophysics Data System (ADS)

    Lin, Juqiang; Zeng, Shaoqun; Luo, Qingming; Rong, Chen; Zhang, Zhihong

    2007-11-01

    Caspase-2 is important for the engagement of the mitochondrial apoptotic pathway, in the presence of DNA-damaging agents, such as cisplatin; however, the mechanism by which caspase-2 executes apoptosis remains obscure. In this study, we carried out the measurements of the dynamics of caspase-2 activation in a single living cell by a FRET (fluorescence resonance energy transfer) probe. A FRET probe was constructed that encoded a CRS (caspase-2 recognition site) fused with a cyan fluorescent protein (CFP) and a red fluorescent protein (DsRed) (CFP-CRS-DsRed). Using this probe, we found that during TRAIL-induced apoptosis, caspase-2 was not activated, and caspase-2 activation occurred in etoposide and cisplatin treated cells. However, during cisplatin-induced apoptosis caspase-2 activation was initiated much earlier than that of etoposide. Cisplatin and etoposide is one of the most broadly used drugs in the Clinical applications of cancer chemotherapy, and TRAIL, which belongs to the TNF family proteins, can selectively induce apoptosis in many transformed cells but not in normal cells. Most of anticancer drugs can induce apoptosis mediated by the activation of caspase pathway. Thus, the perfect synergistic effect group of multi-drug can be selected by using our FRET probe.

  17. Compulsive methamphetamine taking under punishment is associated with greater cue-induced drug seeking in rats.

    PubMed

    Torres, Oscar V; Jayanthi, Subramanian; Ladenheim, Bruce; McCoy, Michael T; Krasnova, Irina N; Cadet, Jean Lud

    2017-05-30

    Methamphetamine (METH) addicts lose control over drug consumption despite suffering multiple adverse medicolegal consequences. To mimic the negative events associated with drug addiction in humans, we recently introduced a rat model of self-administration (SA) with response-contingent punishment on METH intake. These procedures allowed us to distinguish between two addiction-like phenotypes in rats, those that sustained METH taking despite negative consequences (shock-resistant, SR) and rats that significantly reduced their METH intake (shock-sensitive, SS). Here, we further developed our adverse consequence model and examined incubation of METH craving by measuring cue-induced drug seeking in SR and SS rats. Male Sprague-Dawley rats were trained to self-administer METH (0.1mg/kg/injection) or saline intravenously (i.v.) during twenty-two 9-h sessions that consisted of 3 separate 3-h sessions separated by 30min. Subsequently, rats were subjected to incremental footshocks during thirteen additional 9-h METH SA sessions performed in a fashion identical to the training phase. Cue-induced drug craving was then assessed at 2 and 21days after the footshock phase. All rats escalated their intake of METH, with both phenotypes showing similar drug taking patterns during SA training. In addition, rats that continued their METH intake despite negative consequences showed even greater cue-induced drug craving following withdrawal than the rats that reduced METH intake following negative consequences. Taken together, our adverse consequence-based model highlights the possibility of identifying rats by addiction-like phenotypes and subsequent vulnerability to relapse-like behaviors. The use of similar SA models should help in the development of better therapeutic approaches to treat different stages of METH addiction. Published by Elsevier B.V.

  18. Abnormal epithelial structure and chronic lung inflammation after repair of chlorine-induced airway injury.

    PubMed

    Mo, Yiqun; Chen, Jing; Humphrey, David M; Fodah, Ramy A; Warawa, Jonathan M; Hoyle, Gary W

    2015-01-15

    Chlorine is a toxic gas used in a variety of industrial processes and is considered a chemical threat agent. High-level chlorine exposure causes acute lung injury, but the long-term effects of acute chlorine exposure are unclear. Here we characterized chronic pulmonary changes following acute chlorine exposure in mice. A/J mice were exposed to 240 parts per million-hour chlorine or sham-exposed to air. Chlorine inhalation caused sloughing of bronchial epithelium 1 day after chlorine exposure, which was repaired with restoration of a pseudostratified epithelium by day 7. The repaired epithelium contained an abnormal distribution of epithelial cells containing clusters of club or ciliated cells rather than the uniformly interspersed pattern of these cells in unexposed mice. Although the damaged epithelium in A/J mice was repaired rapidly, and minimal airway fibrosis was observed, chlorine-exposed mice developed pneumonitis characterized by infiltration of alveoli with neutrophils and prominent, large, foamy macrophages. Levels of CXCL1/KC, CXCL5/LPS-induced CXC chemokine, granulocyte colony-stimulating factor, and VEGF in bronchoalveolar (BAL) fluid from chlorine-exposed mice showed steadily increasing trends over time. BAL protein levels were increased on day 4 and remained elevated out to day 28. The number of bacteria cultured from lungs of chlorine-exposed mice 4 wk after exposure was not increased compared with sham-exposed mice, indicating that the observed pneumonitis was not driven by bacterial infection of the lung. The results indicate that acute chlorine exposure may cause chronic abnormalities in the lungs despite rapid repair of injured epithelium. Copyright © 2015 the American Physiological Society.

  19. Methamphetamine-induced striatal apoptosis in the mouse brain: Comparison of a binge to an acute bolus drug administration

    PubMed Central

    Zhu, Judy P.Q.; Xu, Wenjing; Angulo, Nieves; Angulo, Jesus A.

    2010-01-01

    Methamphetamine (METH) is a psychostimulant that induces neural damage in experimental animals and humans. A binge (usually in the 5–10 mg/kg dose range 4× at 2 h intervals) and the acute bolus drug administration (20–40 mg/kg) of METH have been employed frequently to study neurotoxicity in the brain. In this study we have compared these drug delivery schedules to determine their efficacy to induce striatal apoptosis. Exposure of male mice to a binge of METH at 10 mg/kg 4× at 2 h intervals (cumulative dose of 40 mg/kg) was approximately four times less effective in inducing apoptotic cell death (TUNEL staining) 24 h after METH treatment in the striatum than a single bolus administration of 30 mg/kg of METH. The residual TUNEL staining observed three days after METH treatment is proportionately equivalent between a binge and the acute bolus drug administration. Interestingly, a binge of METH induces a hyperthermic response of longer duration. This study demonstrates that an acute bolus drug administration of METH is more effective inducing striatal apoptosis in mice, and therefore, is more suitable for studies assessing the impact of METH on sites post-synaptic to the striatonigral dopamine terminals. PMID:16165214

  20. Impact of long-term potassium supplementation on thiazide diuretic-induced abnormalities of glucose and uric acid metabolisms.

    PubMed

    Zhang, Jian-Liang; Yu, Hui; Hou, Ying-Wei; Wang, Ke; Bi, Wen-Shan; Zhang, Liang; Wang, Qian; Li, Pan; Yu, Man-Li; Zhao, Xian-Xian

    2018-04-01

    Treatment of hypertension with thiazide diuretics may trigger hypokalemia, hyperglycemia, and hyperuricemia. Some studies suggest simultaneous potassium supplementation in hypertensive patients using thiazide diuretics. However, few clinical studies have reported the impact of long-term potassium supplementation on thiazide diuretic-induced abnormalities in blood glucose and uric acid (UA) metabolisms. One hundred hypertensive patients meeting the inclusion criteria were equally randomized to two groups: IND group receiving indapamide (1.25-2.5 mg daily) alone, and IND/KCI group receiving IND (1.25-2.5 mg daily) plus potassium chloride (40 mmol daily), both for 24 weeks. At the end of 24-week follow-up, serum K + level in IND group decreased from 4.27 ± 0.28 to 3.98 ± 0.46 mmol/L (P < 0.001), and fasting plasma glucose (FPG) and UA increased from 5.11 ± 0.52 to 5.31 ± 0.57 mmol/L (P < 0.05), and from 0.404 ± 0.078 to 0.433 ± 0.072 mmol/L (P < 0.05), respectively. Serum K + level in IND/KCl group decreased from 4.27 ± 0.36 to 3.89 ± 0.28 mmol/L (P < 0.001), and FPB and UA increased from 5.10 ± 0.41 to 5.35 ± 0.55 mmol/L (P < 0.01), and from 0.391 ± 0.073 to 0.457 ± 0.128 mmol/L (P < 0.001), respectively. The difference value between the serum K + level and FPG before and after treatment was not statistically significant between the two groups. However, the difference value in UA in IND/KCl group was significantly higher than that in IND group (0.066 (95% confidence interval (CI): 0.041-0.090)  mmol/L vs. 0.029 (95% CI: 0.006-0.058) mmol/L, P < 0.05). The results showed that long-term routine potassium supplementation could not prevent or attenuate thiazide diuretic-induced abnormalities of glucose metabolism in hypertensive patients; rather, it may aggravate the UA metabolic abnormality.

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

    PubMed

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

    2018-01-01

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

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Cros, C., E-mail: caroline.cros@hotmail.co.uk; Skinner, M., E-mail: Matthew.Skinner@astrazeneca.com; Moors, J.

    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 ofmore » 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

  3. The abdominal skin of female Sprague-Dawley rats is more sensitive than the back skin to drug-induced phototoxicity.

    PubMed

    Kuga, Kazuhiro; Yasuno, Hironobu; Sakai, Yumi; Harada, Yumiko; Shimizu, Fumi; Miyamoto, Yumiko; Takamatsu, Yuki; Miyamoto, Makoto; Sato, Keiichiro

    2017-11-01

    In vivo phototoxicity studies are important to predict drug-induced phototoxicity in humans; however, a standard methodology has not established. To determine differences in sensitivity to drug-induced phototoxicity among various skin sites, we evaluated phototoxic reactions in the back and abdominal skin of female Sprague-Dawley rats orally dosed with phototoxic drugs (pirfenidone, 8-methoxysoraren, doxycycline, and lomefloxacin) or a non-phototoxic drug (gatifloxacin) followed by solar-simulated light irradiation comprising 18J/cm 2 ultraviolet A. Tissue reactions were evaluated by macroscopic and microscopic examination and immunohistochemistry for γ-H2AX, and tissue concentrations of pirfenidone, doxycycline, and lomefloxacin were measured by tandem mass spectrometry. In addition, the thicknesses of the skin layers at both sites were measured in drug-naïve rats. The abdominal skin showed more severe reactions to all phototoxic drugs than the back skin, whereas the minimal erythema dose in drug-naïve rats and skin concentrations of each drug were comparable between the sites. Furthermore, histopathological lesions and γ-H2AX-positive cells in the abdominal skin were detected in deeper layers than in the back skin. The stratum corneum and dermis in the abdominal skin were significantly thinner than in the back skin, indicating a difference in the depth of light penetration and potentially contributing to the site differences observed in sensitivity to phototoxicity. Gatifloxacin did not induce any phototoxic reactions at either site. In conclusion, the abdominal skin is more sensitive to drug-induced phototoxicity than the back skin and may represent a preferable site for irradiation in this rat phototoxicity model. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Drug-induced immune hemolytic anemia

    MedlinePlus

    Immune hemolytic anemia secondary to drugs; Anemia - immune hemolytic - secondary to drugs ... In some cases, a drug can cause the immune system to mistake your own red blood cells for foreign substances. The body responds by making ...

  5. Opiate-induced Changes in Brain Adenosine Levels and Narcotic Drug Responses

    PubMed Central

    Wu, Manhong; Sahbaie, Peyman; Zheng, Ming; Lobato, Robert; Boison, Detlev; Clark, J. David; Peltz, Gary

    2012-01-01

    We have very little information about the metabolomic changes that mediate neurobehavioral responses, including addiction. It was possible that opioid-induced metabolomic changes in brain could mediate some of the pharmacodynamic effects of opioids. To investigate this, opiate-induced brain metabolomic responses were profiled using a semi-targeted method in C57BL/6 and 129Sv1 mice, which exhibit extreme differences in their tendency to become opiate dependent. Escalating morphine doses (10–40 mg/kg) administered over a 4-day period selectively induced a two-fold decrease (p<0.00005) in adenosine abundance in the brainstem of C57BL/6 mice, which exhibited symptoms of narcotic drug dependence; but did not decrease adenosine abundance in 129Sv1 mice, which do not exhibit symptoms of dependence. Based on this finding, the effect of adenosine on dependence was investigated in genetically engineered mice with alterations in adenosine tone in the brain and in pharmacologic experiments. Morphine withdrawal behaviors were significantly diminished (P<0.0004) in genetically engineered mice with reduced adenosine tone in the brainstem, and by treatment with an adenosine receptor1 (A1) agonist (2-chloro-N6-cyclopentyladenosine, 0.5 mg/kg) or an A2a receptor (A2a) antagonist (SCH 58261 1 mg/kg). These results indicate that adenosine homeostasis plays a crucial role in narcotic drug responses. Opiate-induced changes in brain adenosine levels may explain many important neurobehavioral features associated with opiate addiction and withdrawal. PMID:23098802

  6. Prescription Drugs: HCFA’s Proposed Drug Utilization Review System Ignores Quality of Care Issues

    DTIC Science & Technology

    1989-07-13

    Parkinsonism , 32,000 with hip fractures attributable to dOfg-induced falls, 163,000 with drug-induced memory loss or impaired thinking, and 243,000...year there are approximately 61,000 older adults with drug-induced Parkinsonism , 32,000 with hip fractures attributable to drug-induced falls, 163,000...particu- larly phenytoin and warfarin). A drug in one category may interact with a drug in another category to raise the concentration of the drugs in the

  7. Abnormally banded chromosomal regions in doxorubicin-resistant B16-BL6 murine melanoma cells.

    PubMed

    Slovak, M L; Hoeltge, G A; Ganapathi, R

    1986-08-01

    B16-BL6 murine melanoma cells were selected for cytogenetic evaluation during the stepwise development of increasing resistance in vitro to the antitumor antibiotic, doxorubicin (DOX). Karyotypic studies demonstrated extensive heteroploidy with both numerical and structural abnormalities which were not present in the parental DOX-sensitive B16-BL6 cells. Trypsin-Giemsa banding revealed the presence of several marker chromosomes containing abnormally banding regions (ABRs) in the 44-fold B16-BL6 DOX-resistant subline. These ABRs appeared to be more homogeneously staining at the higher DOX concentrations. Length measurements (ABR index) in seven banded metaphases indicated a direct correlation with increasing DOX concentration. When the DOX-resistant cells were grown in drug-free medium for 1 yr, the drug-resistant phenotype gradually declined in parallel with the level of resistance and the ABR index. DOX-induced cytogenetic damage examined by sister chromatid exchange methodology in parental B16-BL6 cells indicated a linear sister chromatid exchange:DOX dose-response relationship. However, after continuous treatment of parental B16-BL6 cells with DOX (0.01 microgram/ml) for 30 days, sister chromatid exchange scores were found to return to base-line values. The B16-BL6 resistant cells demonstrated a cross-resistant phenotype with N-trifluoroacetyladriamycin-14-valerate, actinomycin D, and the Vinca alkaloids but not with 1-beta-D-arabinofuranosylcytosine. The results suggest that ABR-containing chromosomes in DOX-resistant sublines may represent cytogenetic alterations of specific amplified genes involved in the expression of DOX resistance. Further studies are required to identify and define the possible gene products and to correlate their relationship to the cytotoxic action of doxorubicin.

  8. Circulating Plasma and Exosomal microRNAs as Indicators of Drug-Induced Organ Injury in Rodent Models

    PubMed Central

    Cho, Young-Eun; Kim, Sang-Hyun; Lee, Byung-Heon; Baek, Moon-Chang

    2017-01-01

    This study was performed to evaluate whether microRNAs (miRNAs) in circulating exosomes may serve as biomarkers of drug-induced liver, kidney, or muscle-injury. Quantitative PCR analyses were performed to measure the amounts of liver-specific miRNAs (miR-122, miR-192, and miR-155), kidney-specific miR-146a, or muscle-specific miR-206 in plasma and exosomes from mice treated with liver, kidney or muscle toxicants. The levels of liver-specific miRNAs in circulating plasma and exosomes were elevated in acetaminophen-induced liver injury and returned to basal levels by treatment with antioxidant N-acetyl-cysteine. Circulating miR-146a and miR-206 were increased in cisplatin-induced nephrotoxicity and bupivacaine-induced myotoxicity, respectively. Taken together, these results indicate that circulating plasma and exosomal miRNAs can be used as potential biomarkers specific for drug-induced liver, kidney or muscle injury. PMID:28208010

  9. Drug exposure in pregnant women.

    PubMed

    Czeizel, A E

    2004-01-01

    The objectives of this paper are to describe the Hungarian case-control surveillance system of congenital abnormalities (HCCSCA), to summarize the principles of this activity and our main experiences. Among the main principles, the importance of the time factor (the first trimester concept is outdated), the differentiation of isolated and multiple manifestations of the seemingly same congenital abnormalities, noxa specificity, the separation of drugs and pregnancy supplements within medicinal products (or medicines) are stressed. After some methodological problems (recall bias, chance effect), the main experiences regarding the risk and benefit of medicines are summarized. The conclusion is that the results of our studies based on the data set of the HCCSCA showed that at present the exaggerated teratogenic risk of drugs is much more harmful for the fetus than the real teratogenic effect of some drugs themselves. Medical doctors and other experts therefore need more education to know the principles and findings of modern human teratology because it may help us to have a better balance between the risk and benefit of drug use during pregnancy.

  10. Age-Related Inducibility of Carboxylesterases by the Antiepileptic Agent Phenobarbital and Implications in Drug Metabolism and Lipid Accumulation 1, 2

    PubMed Central

    Xiao, Da; Chen, Yi-Tzai; Yang, Dongfang; Yan, Bingfang

    2014-01-01

    Carboxylesterases (CES) constitute a class of hydrolytic enzymes that play critical roles in drug metabolism and lipid mobilization. Previous studies with a large number of human liver samples have suggested that the inducibility of carboxylesterases is inversely related with age. To directly test this possibility, neonatal (10 days of age) and adult mice were treated with the antiepileptic agent phenobarbital. The expression and hydrolytic activity were determined on six major carboxylesterases including ces1d, the ortholog of human CES1. Without exception, all carboxylesterases tested were induced to a greater extent in neonatal than adult mice. The induction was detected at mRNA, protein and catalytic levels. Ces1d was greatly induced and found to rapidly hydrolyze the antiplatelet agent clopidogrel and support the accumulation of neutral lipids. Phenobarbital represents a large number of therapeutic agents that induce drug metabolizing enzymes and transporters in a species-conserved manner. The higher inducibility of carboxylesterases in the developmental age likely represents a general phenomenon cross species including human. Consequently, individuals in the developmental age may experience greater drug-drug interactions. The greater induction of ces1d also provides a molecular explanation to the clinical observation that children on antiepileptic drugs increase plasma lipids. PMID:22513142

  11. [Drug-induced extrapyramidal disorders].

    PubMed

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

    1995-01-01

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

  12. Current concepts of metabolic abnormalities in HIV patients: focus on lipodystrophy.

    PubMed

    Kolter, Donald P

    2003-12-01

    HIV infection is associated with a number of metabolic abnormalities, including lipodystrophy, a difficult-to-define disorder whose characteristics include hyperlipidemia, insulin resistance, and fat redistribution. Current data suggest that lipodystrophy is caused by multiple factors. Dual-nucleoside reverse transcriptase inhibitor therapy combined with protease inhibitor therapy has been shown to increase the risk of metabolic abnormalities, but susceptibility independent of drug effects has also been shown. While many of the treatments for the broad range of signs and symptoms of lipodystrophy bring about improvements in patient status, none have been demonstrated to bring about a return to baseline levels.

  13. CRISPR correction of the PRKAG2 gene mutation in the patient's induced pluripotent stem cell-derived cardiomyocytes eliminates electrophysiological and structural abnormalities.

    PubMed

    Ben Jehuda, Ronen; Eisen, Binyamin; Shemer, Yuval; Mekies, Lucy N; Szantai, Agnes; Reiter, Irina; Cui, Huanhuan; Guan, Kaomei; Haron-Khun, Shiraz; Freimark, Dov; Sperling, Silke R; Gherghiceanu, Mihaela; Arad, Michael; Binah, Ofer

    2018-02-01

    Mutations in the PRKAG2 gene encoding the γ-subunit of adenosine monophosphate kinase (AMPK) cause hypertrophic cardiomyopathy (HCM) and familial Wolff-Parkinson-White (WPW) syndrome. Patients carrying the R302Q mutation in PRKAG2 present with sinus bradycardia, escape rhythms, ventricular preexcitation, supraventricular tachycardia, and atrioventricular block. This mutation affects AMPK activity and increases glycogen storage in cardiomyocytes. The link between glycogen storage, WPW syndrome, HCM, and arrhythmias remains unknown. The purpose of this study was to investigate the pathological changes caused by the PRKAG2 mutation. We tested the hypothesis that patient's induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) display clinical aspects of the disease. Using clustered regularly interspaced short palindromic repeats (CRISPR) technology, we corrected the mutation and then generated isogenic iPSC-CMs. Action potentials were recorded from spontaneously firing and paced cardiomyocytes using the patch clamp technique. Using a microelectrode array setup, we recorded electrograms from iPSC-CMs clusters. Transmission electron microscopy was used to detect ultrastructural abnormalities in the mutated iPSC-CMs. PRKAG2-mutated iPSC-CMs exhibited abnormal firing patterns, delayed afterdepolarizations, triggered arrhythmias, and augmented beat rate variability. Importantly, CRISPR correction eliminated the electrophysiological abnormalities, the augmented glycogen, storage, and cardiomyocyte hypertrophy. PRKAG2-mutated iPSC-CMs displayed functional and structural abnormalities, which were abolished by correcting the mutation in the patient's iPSCs using CRISPR technology. Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

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

    PubMed

    Ong, Edmund; Cahill, Catherine

    2015-07-03

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

  15. A non-human primate model for investigating drug-induced risk of orthostatic hypotension and sympathetic dysfunction: Preclinical correlate to a clinical test.

    PubMed

    Bhatt, Siddhartha; Foote, Stephen; Smith, Andrew; Butler, Paul; Steidl-Nichols, Jill

    2015-01-01

    Drug induced orthostatic hypotension (OH) is an important clinical concern and can be an unexpected hurdle during drug development. OH is defined as an abnormal decrease in blood pressure (BP) triggered by a rapid postural change. The sympathetic nervous system is critical for controlling normal cardiovascular function and compensatory responses to changes in posture. Thus, OH can also serve as a surrogate indicator of sympathetic dysfunction. However, preclinical conscious models for investigating risk of OH and/or sympathetic dysfunction are lacking. Herein, we describe a conscious nonhuman primate (NHP) model which mimics the widely used clinical tilt table test for OH. Male, Cynomolgus NHPs (n = 7-8) implanted with radio-telemetry transmitters were placed in modified tilt chairs in a supine position. Subsequently, a 90° head up tilt was performed for 3 min followed by return to the supine position. BP and heart rate were continuously monitored. Test compounds were administered either intravenously or via oral gavage in a crossover design, with blood samples collected at the end of the each tilt to assess total drug concentrations. Tilt responses were assessed following treatment with positive control compounds that cause sympathetic dysfunction; hexamethonium (ganglionic blocker) and prazosin (alpha-1 adrenergic receptor antagonist). Both compounds induced marked OH as evidenced by robust and sustained BP reduction in response to a head up tilt (decrease of 25-35 mmHg for hexamethonium, decrease of 21-44 mmHg for prazosin). OH incidence rates increased in a dose-dependent manner. OH incidences following treatment with minoxidil (vasodilator) were markedly lower to those observed with hexamethonium and prazosin indicating the role of sympathetic dysfunction in causing OH. These data demonstrate that the NHP tilt test is a valuable model for investigating OH risk. This model fills an important preclinical gap for assessing such a safety concern and can be

  16. Nail toxicity induced by cancer chemotherapy.

    PubMed

    Gilbar, Peter; Hain, Alice; Peereboom, Veta-Marie

    2009-09-01

    To provide a comprehensive literature review of chemotherapy-induced nail toxicity, including clinical presentation, implicated drugs and approaches for prevention and management. A search of MEDLINE and EMBASE (1966-2008) databases was conducted using the terms (and variations of the terms) antineoplastic agents, nails, nail toxicity, onycholysis, and paronychia. Bibliographies from selected articles were reviewed for appropriate references. The retrieved literature was reviewed to include all articles relevant to the clinical presentation, diagnosis, incidence, prevention, and treatment of chemotherapy-induced nail toxicity. Nail toxicity is a relatively uncommon adverse effect linked to a number of chemotherapeutic agents. Clinical presentation varies, depending on which nail structure is affected and the severity of the insult. Nail changes may involve all or some nails. Toxicity may be asymptomatic and limited to cosmetic concerns, however, more severe effects, involving pain and discomfort can occur. Taxanes and anthracyclines are the antineoplastic drug groups most commonly implicated. It is suggested that the administration schedule may influence the incidence of nail abnormalities, for example reported cases linked to the weekly administration of paclitaxel.Before instituting chemotherapy, patients should be educated regarding potential nail toxicities and strategies for prevention implemented. Management includes appropriate nail cutting, avoiding potential irritants, topical, or oral antimicrobials, and possibly cessation or dose reduction of the offending agent. Cryotherapy, through the application of frozen gloves or socks, has been beneficial in reducing docetaxel-induced nail toxicity and may be effective for other drugs.

  17. Drug Screening Using a Library of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Reveals Disease Specific Patterns of Cardiotoxicity

    PubMed Central

    Liang, Ping; Lan, Feng; Lee, Andrew S.; Gong, Tingyu; Sanchez-Freire, Veronica; Wang, Yongming; Diecke, Sebastian; Sallam, Karim; Knowles, Joshua W.; Wang, Paul J.; Nguyen, Patricia K.; Bers, Donald M.; Robbins, Robert C.; Wu, Joseph C.

    2013-01-01

    Background Cardiotoxicity is a leading cause for drug attrition during pharmaceutical development and has resulted in numerous preventable patient deaths. Incidents of adverse cardiac drug reactions are more common in patients with pre-existing heart disease than the general population. Here we generated a library of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with various hereditary cardiac disorders to model differences in cardiac drug toxicity susceptibility for patients of different genetic backgrounds. Methods and Results Action potential duration (APD) and drug-induced arrhythmia were measured at the single cell level in hiPSC-CMs derived from healthy subjects and patients with hereditary long QT syndrome (LQT), familial hypertrophic cardiomyopathy (HCM), and familial dilated cardiomyopathy (DCM). Disease phenotypes were verified in LQT, HCM, and DCM iPSC-CMs by immunostaining and single cell patch clamp. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and the human ether-a-go-go-related gene (hERG) expressing human embryonic kidney (HEK293) cells were used as controls. Single cell PCR confirmed expression of all cardiac ion channels in patient-specific hiPSC-CMs as well as hESC-CMs, but not in HEK293 cells. Disease-specific hiPSC-CMs demonstrated increased susceptibility to known cardiotoxic drugs as measured by APD and quantification of drug-induced arrhythmias such as early after depolarizations (EADs) and delayed after depolarizations (DADs). Conclusions We have recapitulated drug-induced cardiotoxicity profiles for healthy subjects, LQT, HCM, and DCM patients at the single cell level for the first time. Our data indicate that healthy and diseased individuals exhibit different susceptibilities to cardiotoxic drugs and that use of disease-specific hiPSC-CMs may predict adverse drug responses more accurately than standard hERG test or healthy control hiPSC-CM/hESC-CM screening assays. PMID:23519760

  18. Involvement of the Lateral Orbitofrontal Cortex in Drug Context-induced Reinstatement of Cocaine-seeking Behavior in Rats

    PubMed Central

    Lasseter, Heather C.; Ramirez, Donna R.; Xie, Xiaohu; Fuchs, Rita A.

    2009-01-01

    Orbitofrontal cortex (OFC) damage produces impaired decision-making, impulsivity, and perseveration and potentially contributes to compulsive drug seeking in cocaine users. To further explore this phenomenon, we assessed the role of the lateral OFC (lOFC) in drug context-induced cocaine-seeking behavior in the reinstatement model of drug relapse. Rats were trained to lever press for intravenous cocaine infusions in a distinct environmental context (cocaine-paired context) followed by extinction training in a different context (extinction-paired context). Reinstatement of cocaine seeking (non-reinforced lever presses) was assessed in the cocaine context in the absence of response-contingent stimuli. In experiment 1, we evaluated whether acute inhibition of lOFC output alters context-induced cocaine-seeking behavior by infusing the GABAB+A agonists, baclofen+muscimol, or vehicle into the lOFC immediately before exposure to the cocaine-paired context. In experiments 2–3, we assessed how prolonged loss of lOFC output affects drug context-induced cocaine seeking by administering bilateral NMDA or sham lesions of the lOFC either before or after self-administration and extinction training. Remarkably, OFC functional inactivation attenuated, post-training lesions failed to alter, and pre-training lesions potentiated drug context-induced cocaine seeking without altering responding in the extinction context. These results suggest that neural activity in the lOFC promotes context-induced cocaine-seeking behavior. However, prolonged loss of lOFC output enhances the motivational salience of cocaine-paired contextual stimuli likely by eliciting compensatory neuroadaptations, with the effects of post-training lOFC lesions reflecting an intermediate state of compensatory neuroplasticity. Overall, these findings support the idea that OFC dysfunction may promote cue reactivity and enhance relapse propensity in cocaine users. PMID:19769591

  19. Amyloid β-Derived Diffusible Ligands (ADDLs) Induce Abnormal Autophagy Associated with Aβ Aggregation Degree.

    PubMed

    Wen, Jie; Fang, Fang; Guo, Shu-Han; Zhang, Ying; Peng, Xiang-Lei; Sun, Wei-Min; Wei, Xiao-Ran; He, Jin-Sheng; Hung, Tao

    2018-02-01

    Autophagy is disturbed in Alzheimer's disease (AD) and maintaining normal autophagy homeostasis is a new therapeutic strategy for AD treatment. Amyloid β-derived diffusible ligands (ADDLs), the most toxic species of which are oligomeric forms of amyloid β peptide (Aβ) that originate from amyloid β precursor protein (APP) via autophagy; however, whether ADDLs are involved in autophagy-related AD pathogenesis remains unclear. In this study, we primarily defined the specific subsets of ADDLs, A-0, A-12, A-24, and A-48, which were generated from ADDL aggregation mixtures at different time courses of assembly. The secondary structures of ADDL subsets were detected by circular dichroism (CD). Neuronal or non-neuronal cells were exposed to the subsets of ADDLs in vitro, and then, autophagic markers were detected. Our results first showed that exogenous or endogenous LC3 puncta (autophagosomes) were induced in the cytoplasm of cells exposed to ADDLs and that the LC3 puncta were the strongest with A-24 exposure. Then, the CD spectroscopy data also indicated that the proportion of α-helices decreased, whereas the proportion of β-strands and β-turns increased during ADDL assembly from 0 to 24 h. In addition, the quantitative Western blot data demonstrated that the ratio of LC3B-II/I was significantly increased, and SQSTM1/p62 decreased over time. Finally, our results indicated that the level of phosphorylated p70 S6 kinase (p-p70 S6 kinase), which is a substrate protein in the MTOR pathway, and the ratio of p-p70 S6 kinase/p70 S6 kinase significantly decreased following A-24 exposure. Taken together, our data suggest that ADDL-induced abnormal autophagy is correlated with Aβ aggregation degree and the MTOR pathway, which might contribute to ADDL-induced AD pathogenesis.

  20. The red tide toxin, brevetoxin, induces embryo toxicity and developmental abnormalities.

    PubMed Central

    Kimm-Brinson, K L; Ramsdell, J S

    2001-01-01

    Brevetoxins are lipophilic polyether toxins produced by the red tide dinoflagellate Gymnodinium breve, and their neurotoxic effects on adult animals have been documented. In this study, we characterized adverse developmental effects of brevetoxin-1 (PbTx-1) using an exposure paradigm that parallels the maternal oocyte transfer of toxin. Medaka fish (Oryzias latipes) embryos were exposed to PbTx-1 via microinjection of toxin reconstituted in a triolein oil droplet. Embryos microinjected with doses of 0.1-8.0 ng/egg (ppm) of brevetoxin-1 exhibited pronounced muscular activity (hyperkinesis) after embryonic day 4. Upon hatching, morphologic abnormalities were commonly found in embryos at the following lowest adverse effect levels: 1.0-3.0 ppm, lateral curvature of the spinal column; 3.1-3.4 ppm, herniation of brain meninges through defects in the skull; and 3.4-4.0 ppm, malpositioned eye. Hatching abnormalities were also commonly observed at brevetoxin doses of 2.0 ppm and higher with head-first, as opposed to the normal tail-first, hatching, and doses > 4.1 ng/egg produced embryos that developed but failed to hatch. Given the similarity of developmental processes found between higher and lower vertebrates, teratogenic effects of brevetoxins have the potential to occur among different phylogenetic classes. The observation of developmental abnormalities after PbTx-1 exposure identifies a new spectrum of adverse effects that may be expected to occur following exposure to G. breve red tide events. PMID:11335186

  1. Evaluation of naranjo adverse drug reactions probability scale in causality assessment of drug-induced liver injury.

    PubMed

    García-Cortés, M; Lucena, M I; Pachkoria, K; Borraz, Y; Hidalgo, R; Andrade, R J

    2008-05-01

    Causality assessment in hepatotoxicity is challenging. The current standard liver-specific Council for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method scale is complex and difficult to implement in daily practice. The Naranjo Adverse Drug Reactions Probability Scale is a simple and widely used nonspecific scale, which has not been specifically evaluated in drug-induced liver injury. To compare the Naranjo method with the standard liver-specific Council for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method scale in evaluating the accuracy and reproducibility of Naranjo Adverse Drug Reactions Probability Scale in the diagnosis of hepatotoxicity. Two hundred and twenty-five cases of suspected hepatotoxicity submitted to a national registry were evaluated by two independent observers and assessed for between-observer and between-scale differences using percentages of agreement and the weighted kappa (kappa(w)) test. A total of 249 ratings were generated. Between-observer agreement was 45% with a kappa(w) value of 0.17 for the Naranjo Adverse Drug Reactions Probability Scale, while there was a higher agreement when using the Council for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method scale (72%, kappa(w): 0.71). Concordance between the two scales was 24% (kappa(w): 0.15). The Naranjo Adverse Drug Reactions Probability Scale had low sensitivity (54%) and poor negative predictive value (29%) and showed a limited capability to distinguish between adjacent categories of probability. The Naranjo scale lacks validity and reproducibility in the attribution of causality in hepatotoxicity.

  2. Host-guest interaction induced supramolecular amphiphilic star architecture and uniform nanovesicle formation for anticancer drug delivery

    NASA Astrophysics Data System (ADS)

    Zhu, Jing-Ling; Liu, Kerh Li; Wen, Yuting; Song, Xia; Li, Jun

    2016-01-01

    A star polymer of poly[(R,S)-3-hydroxybutyrate] (PHB) with adamantyl end-terminals extended from an α-cyclodextrin (α-CD) core is designed. It subsequently self-assembles to form controllable and uniform nanovesicles induced by host-guest interactions between heptakis(2,6-di-O-methyl)-β-CD and the adamantyl ends. The nanovesicles are suitable for loading and intracellular delivery of the anticancer drug doxorubicin.A star polymer of poly[(R,S)-3-hydroxybutyrate] (PHB) with adamantyl end-terminals extended from an α-cyclodextrin (α-CD) core is designed. It subsequently self-assembles to form controllable and uniform nanovesicles induced by host-guest interactions between heptakis(2,6-di-O-methyl)-β-CD and the adamantyl ends. The nanovesicles are suitable for loading and intracellular delivery of the anticancer drug doxorubicin. Electronic supplementary information (ESI) available: Polymer synthesis, characterization, preparation of drug-loaded nanovesicles, intracellular drug release and cytotoxicity assays, TEM and DLS measurements. See DOI: 10.1039/c5nr06744h

  3. Diabetes synergistically exacerbates poststroke dementia and tau abnormality in brain.

    PubMed

    Zhang, Ting; Pan, Bai-Shen; Sun, Guang-Chun; Sun, Xiao; Sun, Feng-Yan

    2010-07-01

    This study investigated whether exacerbation of poststroke dementia by diabetes associated abnormal tau phosphorylation and its mechanism. Streptozotocin (STZ) injection and/or a high fat diet (HFD) were used to treat rats to induce type 1 and 2 diabetes. Animals were randomly divided into STZ, HFD, STZ-HFD, and normal diet (NPD) groups. Focal ischemic stroke was induced by middle cerebral artery occlusion (MCAO). Cognitive function was tested by the Morris water maze. STZ or STZ-HFD treatment exacerbated ischemia-induced cognitive deficits, brain infarction and reduction of synaptophysin expression. Moreover, we found that diabetes further increased AT8, a marker of hyperphosphorylated tau, protein and immunopositive stained cells in the hippocampus of rats following MCAO while reduced the level of phosphorylated glycogen synthase kinase 3-beta at serine-9 residues (p-ser9-GSK-3beta), indicating activation of GSK-3beta. We conclude that diabetes further deteriorates ischemia-induced brain damage and cognitive deficits which may be associated with abnormal phosphorylation of tau as well as activation of GSK-3beta. These findings may be helpful for developing new strategies to prevent/delay formation of poststroke dementia in patients with diabetes. 2010 Elsevier Ltd. All rights reserved.

  4. Gamma abnormalities during perception of illusory figures in autism.

    PubMed

    Brown, Caroline; Gruber, Thomas; Boucher, Jill; Rippon, Gina; Brock, Jon

    2005-06-01

    This experiment was designed to test the hypothesis that perceptual abnormalities in autism might be associated with alteration of induced gamma activity patterns overlying visual cortical regions. EEG was recorded from six adolescents with autism and eight controls matched on chronological age, and verbal and nonverbal mental age, whilst identifying the presence or absence of an illusory Kanizsa shape. Although there were no reaction time or accuracy differences between the groups there were significant task-related differences in cortical activity. Control participants showed typical gamma-band activity over parietal regions at around 350 msec post onset of shape trials, similar to gamma patterns found in previous studies with non-impaired adults. In contrast, autistic participants showed overall increased activity, including an early 100 msec gamma peak and a late induced peak, 50 to 70 msec earlier than that shown by the control group. We interpret the abnormal gamma activity to reflect decreased "signal to noise" due to decreased inhibitory processing. In this experiment we did not establish a link between altered perception and abnormal gamma, as the autistic participants' behaviour did not differ from the controls. Future work should be designed to replicate this phenomenon and establish the perceptual consequences of altered gamma activity.

  5. Cellular and molecular etiology of hepatocyte injury in a murine model of environmentally induced liver abnormality

    PubMed Central

    Al-Griw, M.A.; Alghazeer, R.O.; Al-Azreg, S.A.; Bennour, E.M.

    2016-01-01

    Exposures to a wide variety of environmental substances are negatively associated with many biological cell systems both in humans and rodents. Trichloroethane (TCE), a ubiquitous environmental toxicant, is used in large quantities as a dissolvent, metal degreaser, chemical intermediate, and component of consumer products. This increases the likelihood of human exposure to these compounds through dermal, inhalation and oral routes. The present in vivo study was aimed to investigate the possible cellular and molecular etiology of liver abnormality induced by early exposure to TCE using a murine model. The results showed a significant increase in liver weight. Histopathological examination revealed a TCE-induced hepatotoxicity which appeared as heavily congested central vein and blood sinusoids as well as leukocytic infiltration. Mitotic figures and apoptotic changes such as chromatin condensation and nuclear fragments were also identified. Cell death analysis demonstrates hepatocellular apoptosis was evident in the treated mice compared to control. TCE was also found to induce oxidative stress as indicated by an increase in the levels of lipid peroxidation, an oxidative stress marker. There was also a significant decrease in the DNA content of the hepatocytes of the treated groups compared to control. Agarose gel electrophoresis also provided further biochemical evidence of apoptosis by showing internucleosomal DNA fragmentation in the liver cells, indicating oxidative stress as the cause of DNA damage. These results suggest the need for a complete risk assessment of any new chemical prior to its arrival into the consumer market. PMID:27800299

  6. Drug induced liver injury with analysis of alternative causes as confounding variables.

    PubMed

    Teschke, Rolf; Danan, Gaby

    2018-04-01

    Drug-induced liver injury (DILI) is rare compared to the worldwide frequent acute or chronic liver diseases. Therefore, patients included in series of suspected DILI are at high risk of not having DILI, whereby alternative causes may confound the DILI diagnosis. The aim of this review is to evaluate published case series of DILI for alternative causes. Relevant studies were identified using a computerized search of the Medline database for publications from 1993 through 30 October 2017. We used the following terms: drug hepatotoxicity, drug induced liver injury, hepatotoxic drugs combined with diagnosis, causality assessment and alternative causes. Alternative causes as variables confounding the DILI diagnosis emerged in 22 published DILI case series, ranging from 4 to 47%. Among 13 335 cases of suspected DILI, alternative causes were found to be more likely in 4555 patients (34.2%), suggesting that the suspected DILI was probably not DILI. Biliary diseases such as biliary obstruction, cholangitis, choledocholithiasis, primary biliary cholangitis and primary sclerosing cholangitis were among the most missed diagnoses. Alternative causes included hepatitis B, C and E, cytomegalovirus, Epstein-Barr virus, ischemic hepatitis, cardiac hepatopathy, autoimmune hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and alcoholic liver disease. In more than one-third of published global DILI case series, alternative causes as published in these reports confounded the DILI diagnosis. In the future, published DILI case series should include only patients with secured DILI diagnosis, preferentially established by prospective use of scored items provided by robust diagnostic algorithms such as the updated Roussel Uclaf causality assessment method. © 2018 The British Pharmacological Society.

  7. Targeting Histone Abnormality in Triple Negative Breast Cancer

    DTIC Science & Technology

    2016-08-01

    mechanisms of polyamine analogues in cancer cells. Anti - Cancer Drugs, 16(3): 229-241, 2005. PMID: 15711175 3. Huang Y, Nayak S, Jankowitz R, Davidson NE...immunoprecipitated with anti -LSD1 antibody followed by IB with anti -HDAC5 and LSD1 antibodies in indicated breast cancer cell lines. IgG was used as...AWARD NUMBER: W81XWH-14-1-0237 TITLE: Targeting Histone Abnormality in Triple-Negative Breast Cancer PRINCIPAL INVESTIGATOR: Yi Huang

  8. [Antipsychotic-drug-induced hyperprolactinemia: physiopathology, clinical features and guidance].

    PubMed

    Besnard, I; Auclair, V; Callery, G; Gabriel-Bordenave, C; Roberge, C

    2014-02-01

    Hyperprolactinemia is a frequent but neglected adverse effect observed in patients treated with antipsychotic-drugs. In this review, we summarize its physiopathogenetic mechanism, its clinical manifestations in men and women, and the way to manage it. Prolactin is a hormone secreted by lactotroph cells in the anterior pituitary. Its synthesis and release are under the control of peptides, steroids and neurotransmitters. The main inhibitory regulation is made by dopamine, which binds dopamine receptors D2 on the membrane of lactotroph cells. Antipsychotic-drugs block these receptors and thus remove the inhibitory effect of dopamine on prolactin secretion. All antipsychotic-drugs block D2 receptors and all can induce hyperprolactinemia. Nonetheless, it seems that the faster the antipsychotic-drug dissociates from D2 receptors, the lesser the increase of prolactin in the plasma. Another way to explain hyperprolactinemia is the ability of antipsychotic-drugs to cross the blood-brain barrier. The role of their metabolites should also be considered. For these reasons, one can distinguish prolactin-raising (conventional neuroleptics, amisulpride, risperidone) and prolactin-sparing (clozapine, aripiprazole, olanzapine) antipsychotics. An English study showed that 18% of men and 47% of women treated with antipsychotics for severe mental illness had a prolactin level above the normal range. Hyperprolactinemia is in fact more frequent in women than in men. Sometimes it is asymptomatic, but the higher the prolactin level is, the more patients have clinical manifestations. Some symptoms are due to the hypogonadism caused by prolactin, which disturbs hypothalamic-pituitary axis function, and others are due to direct effects on target tissues. Consequently, patients can suffer from sexual dysfunction, infertility, amenorrhea, gynecomastia or galactorrhoea. Data suggest that these symptoms are common, but patients don't mention them spontaneously and clinicians underestimate their

  9. The physiological determinants of drug-induced lysosomal stress resistance

    PubMed Central

    Woldemichael, Tehetina; Rosania, Gus R.

    2017-01-01

    Many weakly basic, lipophilic drugs accumulate in lysosomes and exert complex, pleiotropic effects on organelle structure and function. Thus, modeling how perturbations of lysosomal physiology affect the maintenance of lysosomal ion homeostasis is necessary to elucidate the key factors which determine the toxicological effects of lysosomotropic agents, in a cell-type dependent manner. Accordingly, a physiologically-based mathematical modeling and simulation approach was used to explore the dynamic, multi-parameter phenomenon of lysosomal stress. With this approach, parameters that are either directly involved in lysosomal ion transportation or lysosomal morphology were transiently altered to investigate their downstream effects on lysosomal physiology reflected by the changes they induce in lysosomal pH, chloride, and membrane potential. In addition, combinations of parameters were simultaneously altered to assess which parameter was most critical for recovery of normal lysosomal physiology. Lastly, to explore the relationship between organelle morphology and induced stress, we investigated the effects of parameters controlling organelle geometry on the restoration of normal lysosomal physiology following a transient perturbation. Collectively, our results indicate a key, interdependent role of V-ATPase number and membrane proton permeability in lysosomal stress tolerance. This suggests that the cell-type dependent regulation of V-ATPase subunit expression and turnover, together with the proton permeability properties of the lysosomal membrane, is critical to understand the differential sensitivity or resistance of different cell types to the toxic effects of lysosomotropic drugs. PMID:29117253

  10. Abnormal neural activity as a potential biomarker for drug-naive first-episode adolescent-onset schizophrenia with coherence regional homogeneity and support vector machine analyses.

    PubMed

    Liu, Yi; Zhang, Yan; Lv, Luxian; Wu, Renrong; Zhao, Jingping; Guo, Wenbin

    2018-02-01

    Patients with adolescent-onset schizophrenia (AOS) hold the same but severe form of symptoms with adult-onset schizophrenia, and with worse outcome and poor treatment response to antipsychotics. Several dominant brain regions of schizophrenia patients show significantly abnormal structural and functional connectivity during resting-state scans. However, coherence regional homogeneity (Cohe-ReHo) in drug-naive first-episode patients with AOS remains unclear. A total of 48 drug-naive first-episode AOS outpatients and 31 healthy controls underwent resting-state functional magnetic resonance scans. Cohe-ReHo and support vector machine analyses were used to analyze the data. Compared with the healthy controls, the AOS group showed significantly decreased Cohe-ReHo values distributed over brain regions, including the left postcentral gyrus, left superior temporal gyrus, left paracentral lobule, right precentral gyrus, right inferior parietal lobule (IPL), right middle frontal gyrus, and bilateral precuneus. No region with increased Cohe-ReHo values was observed in the AOS group compared with healthy controls. In addition, the right IPL was correlated with fluency (r=-0.324, p=0.030). However, the correlation was not significant after the Bonferroni correction at p<0.0083 (0.05/6). A combination of the Cohe-ReHo values in the bilateral precuneus and right IPL discriminated the patients from controls with the sensitivity, specificity, and accuracy of 91.67%, 87.10%, and 89.87%, respectively. Our findings suggested that the AOS patients exhibited diminished Cohe-ReHo values in some regions within the DMN network and sensorimotor network. The abnormalities in particular brain regions (bilateral precuneus and right IPL) may serve as potential biomarkers for AOS. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Reliability of the Roussel Uclaf Causality Assessment Method for Assessing Causality in Drug-Induced Liver Injury*

    PubMed Central

    Rochon, James; Protiva, Petr; Seeff, Leonard B.; Fontana, Robert J.; Liangpunsakul, Suthat; Watkins, Paul B.; Davern, Timothy; McHutchison, John G.

    2013-01-01

    The Roussel Uclaf Causality Assessment Method (RUCAM) was developed to quantify the strength of association between a liver injury and the medication implicated as causing the injury. However, its reliability in a research setting has never been fully explored. The aim of this study was to determine test-retest and interrater reliabilities of RUCAM in retrospectively-identified cases of drug induced liver injury. The Drug-Induced Liver Injury Network is enrolling well-defined cases of hepatotoxicity caused by isoniazid, phenytoin, clavulanate/amoxicillin, or valproate occurring since 1994. Each case was adjudicated by three reviewers working independently; after an interval of at least 5 months, cases were readjudicated by the same reviewers. A total of 40 drug-induced liver injury cases were enrolled including individuals treated with isoniazid (nine), phenytoin (five), clavulanate/amoxicillin (15), and valproate (11). Mean ± standard deviation age at protocol-defined onset was 44.8 ± 19.5 years; patients were 68% female and 78% Caucasian. Cases were classified as hepatocellular (44%), mixed (28%), or cholestatic (28%). Test-retest differences ranged from −7 to +8 with complete agreement in only 26% of cases. On average, the maximum absolute difference among the three reviewers was 3.1 on the first adjudication and 2.7 on the second, although much of this variability could be attributed to differences between the enrolling investigator and the external reviewers. The test-retest reliability by the same assessors was 0.54 (upper 95% confidence limit = 0.77); the interrater reliability was 0.45 (upper 95% confidence limit = 0.58). Categorizing the RUCAM to a five-category scale improved these reliabilities but only marginally. Conclusion The mediocre reliability of the RUCAM is problematic for future studies of drug-induced liver injury. Alternative methods, including modifying the RUCAM, developing drug-specific instruments, or causality assessment based on

  12. Eye movement abnormalities in essential tremor

    PubMed Central

    Plinta, Klaudia; Krzak-Kubica, Agnieszka; Zajdel, Katarzyna; Falkiewicz, Marcel; Dylak, Jacek; Ober, Jan; Szczudlik, Andrzej; Rudzińska, Monika

    2016-01-01

    Abstract Essential tremor (ET) is the most prevalent movement disorder, characterized mainly by an action tremor of the arms. Only a few studies published as yet have assessed oculomotor abnormalities in ET and their results are unequivocal. The aim of this study was to assess the oculomotor abnormalities in ET patients compared with the control group and to find the relationship between oculomotor abnormalities and clinical features of ET patients. We studied 50 ET patients and 42 matched by age and gender healthy controls. Saccadometer Advanced (Ober Consulting, Poland) was used to investigate reflexive, pace-induced and cued saccades and conventional electrooculography for evaluation of smooth pursuit and fixation. The severity of the tremor was assessed by the Clinical Rating Scale for Tremor. Significant differences between ET patients and controls were found for the incidence of reflexive saccades dysmetria and deficit of smooth pursuit. Reflexive saccades dysmetria was more frequent in patients in the second and third phase of ET compared to the first phase. The reflexive saccades latency increase was correlated with severity of the tremor. In conclusion, oculomotor abnormalities were significantly more common in ET patients than in healthy subjects. The most common oculomotor disturbances in ET were reflexive saccades dysmetria and slowing of smooth pursuit. The frequency of reflexive saccades dysmetria increased with progression of ET. The reflexive saccades latency increase was related to the severity of tremor. PMID:28149393

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

    PubMed

    Suemaru, K; Kawasaki, H; Gomita, Y

    1997-06-01

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

  14. Tremorolytic effects of safinamide in animal models of drug-induced parkinsonian tremor.

    PubMed

    Podurgiel, Samantha; Collins-Praino, Lyndsey E; Yohn, Samantha; Randall, Patrick A; Roach, Arthur; Lobianco, Christophe; Salamone, John D

    2013-04-01

    Safinamide is an α-aminoamide derivative that is currently in Phase III clinical trial development as an add-on therapy to levodopa or dopamine agonists for patients with Parkinson's disease. Safinamide is a monoamine oxidase B inhibitor with additional non-dopaminergic actions. The present experiments were performed to evaluate the ability of safinamide to attenuate parkinsonian motor impairments using the tremulous jaw movement model, an animal model of parkinsonian tremor. In rats, tremulous jaw movements can be induced with dopamine (DA) antagonists, DA depletion, and cholinomimetics, and can be reversed by various antiparkinsonian drugs, including L-DOPA, DA agonists, anticholinergics and adenosine A2A antagonists. In these present experiments, tremulous jaw movements were induced with the anticholinesterase galantamine (3.0mg/kg IP), the muscarinic agonist pilocarpine (0.5mg/kg IP), and the dopamine D2 antagonist pimozide (1.0mg/kg IP). Safinamide significantly reduced the number of tremulous jaw movements induced by galantamine, pilocarpine, and pimozide, with consistent effects across all three drugs at a dose range of 5.0-10.0mg/kg. The results of this study support the use of safinamide as a treatment for parkinsonian tremor. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Neurofeedback Effects on Evoked and Induced EEG Gamma Band Reactivity to Drug-related Cues in Cocaine Addiction

    PubMed Central

    Horrell, Timothy; El-Baz, Ayman; Baruth, Joshua; Tasman, Allan; Sokhadze, Guela; Stewart, Christopher; Sokhadze, Estate

    2010-01-01

    Introduction Preoccupation with drug and drug-related items is a typical characteristic of cocaine addicted individuals. It has been shown in multiple accounts that prolonged drug use has a profound effect on the EEG recordings of drug addicts when compared to controls during cue reactivity tests. Cue reactivity refers to a phenomenon in which individuals with a history of drug abuse exhibit excessive psychophysiological responses to cues associated with their drug of choice. One of the aims of this pilot study was to determine the presence of an attentional bias to preferentially process drug-related cues using evoked and induced gamma reactivity measures in cocaine addicts before and after biobehavioral treatment based on neurofeedback. Another aim was to show that central SMR amplitude increase and frontal theta control is possible in an experimental outpatient drug users group over 12 neurofeedback sessions. Method Ten current cocaine abusers participated in this pilot research study using neurofeedback combined with Motivational Interviewing sessions. Eight of them completed all planned pre- and post –neurofeedback cue reactivity tests with event-related EEG recording and clinical evaluations. Cue reactivity test represented a visual oddball task with images from the International Affective Picture System and drug-related pictures. Evoked and induced gamma responses to target and non-target drug cues were analyzed using wavelet analysis. Results Outpatient subjects with cocaine addiction completed the biobehavioral intervention and successfully increased SMR while keeping theta practically unchanged in 12 sessions of neurofeedback training. The addition of Motivational Interviewing helped retain patients in the study. Clinical evaluations immediately after completion of the treatment showed decreased self-reports on depression and stress scores, and urine tests collaborated reports of decreased use of cocaine and marijuana. Effects of neurofeedback resulted

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

    NASA Astrophysics Data System (ADS)

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

    2008-10-01

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

  17. Drug-Induced Liver Injury: Pattern Recognition and Future Directions

    PubMed Central

    Haque, Tanvir; Sasatomi, Eizaburo; Hayashi, Paul H.

    2016-01-01

    Drug-induced liver injury (DILI) remains a significant clinical challenge and is the leading cause of acute liver failure in most countries. An aging population that uses more medications, a constant influx of newly developed drugs and a growing risk from unfamiliar herbal and dietary supplements will make DILI an increasing part of clinical practice. Currently, the most effective strategy for disease management is rapid identification, withholding the inciting agents, supportive care and having a firm understanding of the expected natural history. There are resources available to aid the clinician, including a new online “textbook” as well as causality assessment tools, but a heightened awareness of risk and the disease’s varying phenotypes and good history-taking remain cornerstones to diagnosis. Looking ahead, growing registries of cases, pharmacoepidemiology studies and translational research into the mechanisms of injury may produce better diagnostic tools, markers for risk and disease, and prevention and therapeutics. PMID:26696029

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

    PubMed Central

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

    2013-01-01

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

  19. In vitro screening of 50 highly prescribed drugs for thiol adduct formation--comparison of potential for drug-induced toxicity and extent of adduct formation.

    PubMed

    Gan, Jinping; Ruan, Qian; He, Bing; Zhu, Mingshe; Shyu, Wen C; Humphreys, W Griffith

    2009-04-01

    Reactive metabolite formation has been associated with drug-induced liver, skin, and hematopoietic toxicity of many drugs that has resulted in serious clinical toxicity, leading to clinical development failure, black box warnings, or, in some cases, withdrawal from the market. In vitro and in vivo screening for reactive metabolite formation has been proposed and widely adopted in the pharmaceutical industry with the aim of minimizing the property and thus the risk of drug-induced toxicity (DIT). One of the most common screening methods is in vitro thiol trapping of reactive metabolites. Although it is well-documented that many hepatotoxins form thiol adducts, there is no literature describing the adduct formation potential of safer drugs that are widely used. The objective of this study was to quantitatively assess the thiol adduct formation potential of 50 drugs (10 associated with DIT and 40 not associated) and document apparent differences in adduct formation between toxic and safer drugs. Dansyl glutathione was used as a trapping agent to aid the quantitation of adducts following in vitro incubation of drugs with human liver microsomes in the presence and absence of NADPH. Metabolic turnover of these drugs was also monitored by LC/UV. Overall, 15 out of the 50 drugs screened formed detectable levels of thiol adducts. There were general trends toward more positive findings in the DIT group vs the non-DIT group. These trends became more marked when the relative amount of thiol adducts was taken into account and improved further when dose and total daily reactive metabolite burdens were considered. In conclusion, there appears to be a general trend between the extent of thiol adduct formation and the potential for DIT, which would support the preclinical measurement and minimization of the property through screening of thiol adduct formation as part of an overall discovery optimization paradigm.

  20. Paliperidone for the treatment of ketamine-induced psychosis: a case report.

    PubMed

    Zuccoli, M L; Muscella, A; Fucile, C; Carrozzino, R; Mattioli, F; Martelli, A; Orengo, S

    2014-01-01

    Ketamine is an anaesthetic and analgesic drug synthesized in the 1960s from phencyclidine. The recreational use of ketamine increased among the dance culture of techno and house music, in particular in clubs, discotheques, and rave parties. The psychotropic effects of ketamine are now well known and they range from dissociation to positive, negative, and cognitive schizophrenia-like symptoms. We report a case of a chronic oral consumption of ketamine which induced agitation, behavioral abnormalities, and loss of contact with reality in a poly-drug abuser; these symptoms persisted more than two weeks after the drug consumption had stopped. Antipsychotic treatment with paliperidone led to a successful management of the psychosis, getting a complete resolution of the clinical picture. Paliperidone has proven to be very effective in the treatment of ketamine-induced disorders. Moreover, the pharmacological action and metabolism of paliperidone are poorly dependent from the activity of liver enzymes, so that it seems to be one of the best second generation antipsychotics for the treatment of smokers and alcohol abusers.

  1. Pregnancy following induced abortion: maternal morbidity, congenital abnormalities and neonatal death. Royal College of General Practitioners/Royal College of Obstetricians and Gynaecologists Joint Study.

    PubMed

    Frank, P I; Kay, C R; Scott, L M; Hannaford, P C; Haran, D

    1987-09-01

    In a prospective cohort study of the long-term sequelae of induced abortion, a comparison is made between a group of 6418 women who had an induced abortion (cases) and a control group of 8059 women recruited with an unplanned pregnancy which was not terminated with an induced abortion (controls). The present paper reports on 729 cases and 1754 controls who had a post-recruitment pregnancy. In general, prior induced abortion had no material effect on the rate of pregnancy-related morbidity, nor on the rate of congenital abnormalities and neonatal death in the offspring. There was, however, a significant difference in two specific conditions. In the post-index pregnancy in the cases there was an increased relative risk (RR 2.26) of the occurrence of urinary tract infection and a decreased risk (RR 0.25) of pregnancy-related anaemia.

  2. Drug-induced lung injury associated with sorafenib: analysis of all-patient post-marketing surveillance in Japan.

    PubMed

    Horiuchi-Yamamoto, Yuka; Gemma, Akihiko; Taniguchi, Hiroyuki; Inoue, Yoshikazu; Sakai, Fumikazu; Johkoh, Takeshi; Fujimoto, Kiminori; Kudoh, Shoji

    2013-08-01

    Sorafenib is a multi-kinase inhibitor currently approved in Japan for unresectable and/or metastatic renal cell carcinoma and unresectable hepatocellular carcinoma. Although drug-induced lung injury has recently been the focus of interest in Japanese patients treated with molecular targeting agents, the clinical features of patients receiving sorafenib remain to be completely investigated. All-patient post-marketing surveillance data was obtained within the frame of Special Drug Use Investigation; between April 2008 and March 2011, we summarized the clinical information of 62 cases with drug-induced lung injury among approximately 13,600 sorafenib-treated patients in Japan. In addition, we summarized the results of evaluation by a safety board of Japanese experts in 34 patients in whom pulmonary images were available. For the calculation of reporting frequency, interim results of Special Drug Use Investigation were used. In the sets of completed reports (2,407 in renal cell carcinoma and 647 in hepatocellular carcinoma), the reporting frequency was 0.33 % (8 patients; fatal, 4/8) and 0.62 % (4 patients; fatal, 2/4), respectively. Major clinical symptoms included dyspnea, cough, and fever. Evaluation of the images showed that 18 cases out of 34 patients had a pattern of diffuse alveolar damage. The patients with hepatocellular carcinoma showed a greater incidence and earlier onset of lung injury than those with renal cell carcinoma. Although the overall reporting frequency of sorafenib-induced lung injury is not considered high, the radiological diffuse alveolar damage pattern led to a fatal outcome. Therefore, early recognition of sorafenib-induced lung injury is crucial for physicians and patients.

  3. Sperm shape abnormality and urine mutagenicity in mice treated with niclosamide.

    PubMed

    Vega, S G; Guzmán, P; García, L; Espinosa, J; Cortinas de Nava, C

    1988-02-01

    Niclosamide, a widely used anthelmintic drug in underdeveloped countries, is known to be mutagenic in the Salmonella typhimurium microsomal test system. The urine obtained from mice treated with niclosamide is mutagenic in the TA98 and TA1538 strains. Its effects on mouse-sperm morphology were evaluated in CD1 and (BALB/cJ x DBA/2J) F1 mice after 5 daily oral niclosamide doses of either 60, 80, 100 or 120 mg/kg. A statistically significant increase in abnormal sperm morphology was detected in both CD1 and (BALB/cJ x DBA/2J) F1 mice. No drug-related effects on testis weight nor on sperm count were observed in either genotype. Urine samples obtained from niclosamide-treated F1 mice were assayed with the Salmonella typhimurium strain TA1538 both in the absence and presence of beta-glucuronidase. In the absence of glucuronidase, urine mutagenicity increased with increasing dose and the highest doses were toxic. In the presence of glucuronidase, urine mutagenicity and toxicity also increased. Only at the highest dose (120 mg/kg), however, was there a positive correlation between the urine mutagenic activity and an increase in the number of abnormal sperm. The results of this study suggest that the increase in abnormal sperm depends on the systemic presence of non-conjugated niclosamide metabolites.

  4. Study of Abnormal Liver Function Test during Pregnancy in a Tertiary Care Hospital in Chhattisgarh.

    PubMed

    Mishra, Nalini; Mishra, V N; Thakur, Parineeta

    2016-10-01

    Abnormal liver function tests (LFTs) in pregnancy require proper interpretation in order to avoid pitfalls in the diagnosis. The underlying disorder can have a significant effect on the outcome of both mother and foetus. The present study was done with the objective to study the clinical profile, incidence and possible causes of derangements of liver function tests. Eighty pregnant women with abnormal liver dysfunction were studied prospectively. Women with chronic liver disease and drug-induced abnormal liver function test were excluded. All available LFTs including LDH were studied along with some more definitive tests to aid identification of underlying cause. Foetomaternal outcome was noted in all. The incidence of abnormal LFT was 0.9 %. 13/80 (16.75 %) women had liver disorder not specific to pregnancy, whereas 67/80 (83.25 %) women had pregnancy-specific liver dysfunction. Of these, 65(81.25 %) women with liver dysfunction had pre-eclampsia including 11 (13.75 %) with HELLP and six women with eclampsia. 48/65 (60 %) women had pre-eclampsia in the absence of HELLP syndrome or eclampsia. The mean value for bilirubin (mg %) in hypertensive disorders of pregnancy ranged from 1.64 to 3.8, between 5 and 10 for ICP and AFLP and >10 in infective hepatitis. Transaminases were highest in infective hepatitis, whereas alkaline phosphate was highest in ICP. Total 27 (33.75 %) women suffered from adverse outcome with four (5 %) maternal deaths and 23 (28.75 %) major maternal morbidities. 33/80 (41.25 %) women had intrauterine death. 26.25 % babies were small for date. Pregnancy-specific disorders are the leading cause of abnormal liver function test during pregnant state particularly in the third trimester. Pre-eclampsia-related disorder is the commonest. Gestational age of pregnancy and relative values of various liver function tests in different pregnancy-specific and pregnancy nonspecific disorders appear to be the best guide to clinch the diagnosis.

  5. Drug-Induced Thrombophilic or Prothrombotic States: An Underestimated Clinical Problem That Involves Both Legal and Illegal Compounds.

    PubMed

    Girolami, A; Cosi, E; Tasinato, V; Santarossa, C; Ferrari, S; Girolami, B

    2017-10-01

    Vascular thrombosis, both arterial and venous, is a condition associated with significant morbidity and mortality. There are multiple risk factors for thrombosis, both congenital and acquired, and in the majority of cases, these risk factors are not modifiable. Over the past 2 decades, multiple drugs (both illegal and legal) have been associated with increased risk of thrombosis. However, due to limited scientific literature regarding the prothrombotic tendencies of these drugs, there is a concomitant limited understanding of the pathophysiology of drug-induced thrombosis. As drugs are one of the few modifiable risk factors for thrombosis, further study and dissemination of knowledge regarding drug-associated and drug-induced thrombosis are essential and have the potential to lead to decreased future incidence of thrombosis. The mechanisms at the basis of the thrombophilic activity of these drugs are variable and sometimes still ill recognized. Increased levels of clotting factors, reduction in coagulation natural inhibitors, decreased fibrinolysis, activated clotting factors, increased blood viscosity, endothelial damage, and increased platelet number and activation are the most frequent causes. Arterial steal or coronary arteries no flow has also been implicated. In some cases due to the intake of several drugs, more than one mechanism is present in a given patient. The purpose of the present review is to analyze all the drugs demonstrated to be potentially thrombotic. It is hoped that a prudent use or nonuse of these drugs might result in a reduction of thrombosis-associated diseases.

  6. Drug-induced liver injury caused by iodine-131

    PubMed Central

    Kim, Chei Won; Park, Ji Sun; Oh, Se Hwan; Park, Jae-Hyung; Shim, Hyun-Ik; Yoon, Jae Woong; Park, Jin Seok; Hong, Seong Bin; Kim, Jun Mi; Le, Trong Binh; Lee, Jin Woo

    2016-01-01

    Iodine-131 is a radioisotope that is routinely used for the treatment of differentiated thyroid cancer after total or near-total thyroidectomy. However, there is some evidence that iodine-131 can induce liver injury . Here we report a rare case of drug-induced liver injury (DILI) caused by iodine-131 in a patient with regional lymph node metastasis after total thyroidectomy. A 47-year-old woman was admitted with elevated liver enzymes and symptoms of general weakness and nausea. Ten weeks earlier she had undergone a total thyroidectomy for papillary thyroid carcinoma and had subsequently been prescribed levothyroxine to reduce the level of thyroid-stimulating hormone. Eight weeks after surgery she underwent iodine-131 ablative therapy at a dose of 100 millicuries, and subsequently presented with acute hepatitis after 10 days. To rule out all possible causative factors, abdominal ultrasonography, endoscopic ultrasonography (on the biliary tree and gall bladder), and a liver biopsy were performed. DILI caused by iodine-131 was suspected. Oral prednisolone was started at 30 mg/day, to which the patient responded well. PMID:27209646

  7. Drug-induced liver injury caused by iodine-131.

    PubMed

    Kim, Chei Won; Park, Ji Sun; Oh, Se Hwan; Park, Jae-Hyung; Shim, Hyun-Ik; Yoon, Jae Woong; Park, Jin Seok; Hong, Seong Bin; Kim, Jun Mi; Le, Trong Binh; Lee, Jin Woo

    2016-06-01

    Iodine-131 is a radioisotope that is routinely used for the treatment of differentiated thyroid cancer after total or near-total thyroidectomy. However, there is some evidence that iodine-131 can induce liver injury . Here we report a rare case of drug-induced liver injury (DILI) caused by iodine-131 in a patient with regional lymph node metastasis after total thyroidectomy. A 47-year-old woman was admitted with elevated liver enzymes and symptoms of general weakness and nausea. Ten weeks earlier she had undergone a total thyroidectomy for papillary thyroid carcinoma and had subsequently been prescribed levothyroxine to reduce the level of thyroid-stimulating hormone. Eight weeks after surgery she underwent iodine-131 ablative therapy at a dose of 100 millicuries, and subsequently presented with acute hepatitis after 10 days. To rule out all possible causative factors, abdominal ultrasonography, endoscopic ultrasonography (on the biliary tree and gall bladder), and a liver biopsy were performed. DILI caused by iodine-131 was suspected. Oral prednisolone was started at 30 mg/day, to which the patient responded well.

  8. Effect of drug-induced hyperuricaemia on renal function in Nigerians with pulmonary tuberculosis.

    PubMed

    Adebisi, S A; Oluboyo, P O; Okesina, A B

    2000-01-01

    Some anti-tuberculosis chemotherapeutic agents have been established as causing hyperuricaemia. Hyperuricaemia in turn causes renal damage. This study therefore aims at establishing the effect of anti-tuberculosis drugs-induced hyperuricaemia on renal function of the patients. Fifty patients with newly diagnosed pulmonary tuberculosis with mean age of 36.8 years (SD 13.69) consisting of 14 females and 17 males were longitudinally studied each for 6 months to determine the effect of drug-induced hyperuricaemia on their renal function. The Biochemical indices determined included serum urate level, serum creatinine level, and creatinine clearance of newly diagnosed patient with tuberculosis, before and during treatment with anti-tuberculosis therapy. Serum urate level revealed that 16 (51.6%) and 15 (48.4%) of the patients were hyperuricaemic at the end of the first and second months of anti-tuberculosis therapy. There was no significant difference in the mean serum creatinine level of the control group 96 micromol/L when compared with both the pre-treat value 89 micromol/L (P > 0.25) as well as the value at the end of the sixth month of treatment 91 micromol/L (P > 0.40). However, there was a statistically significant difference in the mean creatinine clearance of the control group 102 ml/min/1.73 m2 when compared with the patient's mean pre-treatment value (89 ml/min/1.73 m2) P < 0.05. Also the mean creatinine clearance increased to (103 ml/min/1.73 m2) by the end of the 6th month of treatment, a value that is statistically significant when compared with the pretreatment value of (89 ml/min/1.73 m2) P < 0.05. We submit as follows: that pulmonary tuberculosis as a disease with significant impairment of renal function; despite the associated drug-induced hyperuricaemia recorded during the treatment, renal function steadily improved with the treatment of pulmonary tuberculosis to the extent that comparable values with control was obtained at the end of treatment. We

  9. MicroRNA-122 Influences the Development of Sperm Abnormalities from Human Induced Pluripotent Stem Cells by Regulating TNP2 Expression

    PubMed Central

    Huang, Yongyi; Liu, Jianjun; Zhao, Yanhui; Jiang, Lizhen; Huang, Qin

    2013-01-01

    Sperm abnormalities are one of the main factors responsible for male infertility; however, their pathogenesis remains unclear. The role of microRNAs in the development of sperm abnormalities in infertile men has not yet been investigated. Here, we used human induced pluripotent stem cells to investigate the influence of miR-122 expression on the differentiation of these cells into spermatozoa-like cells in vitro. After induction, mutant miR-122-transfected cells formed spermatozoa-like cells. Flow cytometry of DNA content revealed a significant increase in the haploid cell population in spermatozoa-like cells derived from mutant miR-122-transfected cells as compared to those derived from miR-122-transfected cells. During induction, TNP2 and protamine mRNA and protein levels were significantly higher in mutant miR-122-transfected cells than in miR-122-transfected cells. High-throughput isobaric tags for relative and absolute quantification were used to identify and quantify the different protein expression levels in miR-122- and mutant miR-122-transfected cells. Among all the proteins analyzed, the expression of lipoproteins, for example, APOB and APOA1, showed the most significant difference between the two groups. This study illustrates that miR-122 expression is associated with abnormal sperm development. MiR-122 may influence spermatozoa-like cells by suppressing TNP2 expression and inhibiting the expression of proteins associated with sperm development. PMID:23327642

  10. Designing of Protein Kinase C β-II Inhibitors against Diabetic complications: Structure Based Drug Design, Induced Fit docking and analysis of active site conformational changes

    PubMed Central

    Vijayakumar, Balakrishnan; Velmurugan, Devadasan

    2012-01-01

    Protein Kinase C β-II (PKC β-II) is an important enzyme in the development of diabetic complications like cardiomyopathy, retinopathy, neuropathy, nephropathy and angiopathy. PKC β-II is activated in vascular tissues during diabetic vascular abnormalities. Thus, PKC β-II is considered as a potent drug target and the crystal structure of the kinase domain of PKC β-II (PDB id: 2I0E) was used to design inhibitors using Structure-Based Drug Design (SBDD) approach. Sixty inhibitors structurally similar to Staurosporine were retrieved from PubChem Compound database and High Throughput Virtual screening (HTVs) was carried out with PKC β-II. Based on the HTVs results and the nature of active site residues of PKC β-II, Staurosporine inhibitors were designed using SBDD. Induced Fit Docking (IFD) studies were carried out between kinase domain of PKC β-II and the designed inhibitors. These IFD complexes showed favorable docking score, glide energy, glide emodel and hydrogen bond and hydrophobic interactions with the active site of PKC β-II. Binding free energy was calculated for IFD complexes using Prime MM-GBSA method. The conformational changes induced by the inhibitor at the active site of PKC β-II were observed for the back bone Cα atoms and side-chain chi angles. PASS prediction tool was used to analyze the biological activities for the designed inhibitors. The various physicochemical properties were calculated for the compounds. One of the designed inhibitors successively satisfied all the in silico parameters among the others and seems to be a potent inhibitor against PKC β-II. PMID:22829732

  11. Fialuridine induces acute liver failure in chimeric TK-NOG mice: a model for detecting hepatic drug toxicity prior to human testing.

    PubMed

    Xu, Dan; Nishimura, Toshi; Nishimura, Sachiko; Zhang, Haili; Zheng, Ming; Guo, Ying-Ying; Masek, Marylin; Michie, Sara A; Glenn, Jeffrey; Peltz, Gary

    2014-04-01

    Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers. Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po) for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers. FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology studies could improve

  12. Methamphetamine-induced increases in putamen gray matter associate with inhibitory control.

    PubMed

    Groman, Stephanie M; Morales, Angelica M; Lee, Buyean; London, Edythe D; Jentsch, James David

    2013-10-01

    Problematic drug use is associated with difficulty in exerting self-control over behaviors, and this difficulty may be a consequence of atypical morphometric characteristics that are exhibited by drug-experienced individuals. The extent to which these structural abnormalities result from drug use or reflect neurobiological risk factors that predate drug use, however, is unknown. The purpose of this study is to determine how methamphetamine affects corticostriatal structure and how drug-induced changes relate to alterations in inhibitory control. Structural magnetic resonance images and positron emission tomography (PET) scans, assessing dopamine D₂-like receptor and transporter availability, were acquired in monkeys trained to acquire, retain, and reverse three-choice visual discrimination problems before and after exposure to an escalating dose regimen of methamphetamine (or saline, as a control). Voxel-based morphometry was used to compare changes in corticostriatal gray matter between methamphetamine- and saline-exposed monkeys. The change in gray matter before and after the dosing regimen was compared to the change in the behavioral performance and in dopaminergic markers measured with PET. Methamphetamine exposure, compared to saline, increased gray matter within the right putamen. These changes were positively correlated with changes in performance of methamphetamine-exposed monkeys in the reversal phase, and were negatively correlated with alterations in D₂-like receptor and DAT availability. The results provide the first evidence that exposure to a methamphetamine dosing regimen that resembles human use alters the structural integrity of the striatum and that gray-matter abnormalities detected in human methamphetamine users are due, at least in part, to the pharmacological effects of drug experience.

  13. Evaluation of drug-induced tissue injury by measuring alanine aminotransferase (ALT) activity in silkworm hemolymph

    PubMed Central

    2012-01-01

    Background Our previous studies suggest silkworms can be used as model animals instead of mammals in pharmacologic studies to develop novel therapeutic medicines. We examined the usefulness of the silkworm larvae Bombyx mori as an animal model for evaluating tissue injury induced by various cytotoxic drugs. Drugs that induce hepatotoxic effects in mammals were injected into the silkworm hemocoel, and alanine aminotransferase (ALT) activity was measured in the hemolymph 1 day later. Results Injection of CCl4 into the hemocoel led to an increase in ALT activity. The increase in ALT activity was attenuated by pretreatment with N-acetyl-L-cysteine. Injection of benzoic acid derivatives, ferric sulfate, sodium valproate, tetracycline, amiodarone hydrochloride, methyldopa, ketoconazole, pemoline (Betanamin), N-nitroso-fenfluramine, and D-galactosamine also increased ALT activity. Conclusions These findings indicate that silkworms are useful for evaluating the effects of chemicals that induce tissue injury in mammals. PMID:23137391

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

    PubMed Central

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

    2016-01-01

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

  15. Feeling Abnormal: Simulation of Deviancy in Abnormal and Exceptionality Courses.

    ERIC Educational Resources Information Center

    Fernald, Charles D.

    1980-01-01

    Describes activity in which student in abnormal psychology and psychology of exceptional children classes personally experience being judged abnormal. The experience allows the students to remember relevant research, become sensitized to the feelings of individuals classified as deviant, and use caution in classifying individuals as abnormal.…

  16. Zebrafish as model organisms for studying drug-induced liver injury

    PubMed Central

    Vliegenthart, A D Bastiaan; Tucker, Carl S; Del Pozo, Jorge; Dear, James W

    2014-01-01

    Drug-induced liver injury (DILI) is a major challenge in clinical medicine and drug development. New models are needed for predicting which potential therapeutic compounds will cause DILI in humans, and new markers and mediators of DILI still need to be identified. This review highlights the strengths and weaknesses of using zebrafish as a high-throughput in vivo model for studying DILI. Although the zebrafish liver architecture is different from that of the mammalian liver, the main physiological processes remain similar. Zebrafish metabolize drugs using similar pathways to those in humans; they possess a wide range of cytochrome P450 enzymes that enable metabolic reactions including hydroxylation, conjugation, oxidation, demethylation and de-ethylation. Following exposure to a range of hepatotoxic drugs, the zebrafish liver develops histological patterns of injury comparable to those of mammalian liver, and biomarkers for liver injury can be quantified in the zebrafish circulation. The zebrafish immune system is similar to that of mammals, but the zebrafish inflammatory response to DILI is not yet defined. In order to quantify DILI in zebrafish, a wide variety of methods can be used, including visual assessment, quantification of serum enzymes and experimental serum biomarkers and scoring of histopathology. With further development, the zebrafish may be a model that complements rodents and may have value for the discovery of new disease pathways and translational biomarkers. PMID:24773296

  17. Drug-induced tremor

    MedlinePlus

    ... Drugs that can cause tremor include the following: Cancer medicines such as thalidomide and cytarabine Seizure medicines such as valproic acid (Depakote) and sodium valproate (Depakene) Asthma medicines such as theophylline and ...

  18. A transcriptomics data-driven gene space accurately predicts liver cytopathology and drug-induced liver injury

    PubMed Central

    Kohonen, Pekka; Parkkinen, Juuso A.; Willighagen, Egon L.; Ceder, Rebecca; Wennerberg, Krister; Kaski, Samuel; Grafström, Roland C.

    2017-01-01

    Predicting unanticipated harmful effects of chemicals and drug molecules is a difficult and costly task. Here we utilize a ‘big data compacting and data fusion’—concept to capture diverse adverse outcomes on cellular and organismal levels. The approach generates from transcriptomics data set a ‘predictive toxicogenomics space’ (PTGS) tool composed of 1,331 genes distributed over 14 overlapping cytotoxicity-related gene space components. Involving ∼2.5 × 108 data points and 1,300 compounds to construct and validate the PTGS, the tool serves to: explain dose-dependent cytotoxicity effects, provide a virtual cytotoxicity probability estimate intrinsic to omics data, predict chemically-induced pathological states in liver resulting from repeated dosing of rats, and furthermore, predict human drug-induced liver injury (DILI) from hepatocyte experiments. Analysing 68 DILI-annotated drugs, the PTGS tool outperforms and complements existing tests, leading to a hereto-unseen level of DILI prediction accuracy. PMID:28671182

  19. Abnormal Uterine Bleeding

    MedlinePlus

    ... abnormal uterine bleeding? Abnormal uterine bleeding is any heavy or unusual bleeding from the uterus (through your ... one symptom of abnormal uterine bleeding. Having extremely heavy bleeding during your period can also be considered ...

  20. Antituberculosis Drug-Induced Fixed Drug Eruption: A Case Report.

    PubMed

    Vaghela, Jitendra H; Nimbark, Vivek; Barvaliya, Manish; Mehta, Hita; Chavada, Bhavesh

    2018-05-21

    Fixed drug eruption (FDE) was caused by fixed-dose combination (FDC) of antituberculosis drugs in the form of tablet Forecox ® (rifampicin [rifampin] 225 mg + isoniazid 150 mg + pyrazinamide 750 mg + ethambutol 400 mg) in a 40-year-old male patient with a history of drug allergy. The patient developed FDE after taking the third dose of tablet Forecox ® for pulmonary tuberculosis. Tablet Forecox ® was withdrawn and the patient recovered from the reaction after 15 days of treatment for FDE. As per World Health Organization-Uppsala Monitoring Centre (WHO-UMC) and Naranjo causality assessment criteria, the association between the reaction and tablet Forecox ® was possible and probable, respectively. The reaction was moderately (Level 4b) severe according to the Modified Hartwig and Siegel scale. As there is an increased risk of allergic reaction in patients with a history of drug allergy, FDCs should not be used in order to avoid complexity in identifying the culprit drug.

  1. Varenicline and Abnormal Sleep Related Events

    PubMed Central

    Savage, Ruth L.; Zekarias, Alem; Caduff-Janosa, Pia

    2015-01-01

    Study Objectives: To assess adverse drug reaction reports of “abnormal sleep related events” associated with varenicline, a partial agonist to the α4β2 subtype of nicotinic acetylcholine receptors on neurones, indicated for smoking cessation. Design: Twenty-seven reports of “abnormal sleep related events” often associated with abnormal dreams, nightmares, or somnambulism, which are known to be associated with varenicline use, were identified in the World Health Organisation (WHO) Global Individual Case Safety Reports Database. Original anonymous reports were obtained from the four national pharmacovigilance centers that submitted these reports and assessed for reaction description and causality. Measurements and Results: These 27 reports include 10 of aggressive activity occurring during sleep and seven of other sleep related harmful or potentially harmful activities, such as apparently deliberate self-harm, moving a child or a car, or lighting a stove or a cigarette. Assessment of these 17 reports of aggression or other actual or potential harm showed that nine patients recovered or were recovering on varenicline withdrawal and there were no consistent alternative explanations. Thirteen patients experienced single events, and two had multiple events. Frequency was not stated for the remaining two patients. Conclusions: The descriptions of the reports of aggression during sleep with violent dreaming are similar to those of rapid eye movement sleep behavior disorder and also nonrapid eye movement (NREM) sleep parasomnias in some adults. Patients who experience somnambulism or dreams of a violent nature while taking varenicline should be advised to consult their health providers. Consideration should be given to clarifying the term sleep disorders in varenicline product information and including sleep related harmful and potentially harmful events. Citation: Savage RL, Zekarias A, Caduff-Janosa P. Varenicline and abnormal sleep related events. SLEEP 2015

  2. [Irrational use of drugs as a source of drug - induced diseases].

    PubMed

    Woroń, Jarosław; Porebski, Grzegorz; Kostka-Trabka, Elzbieta; Goszcz, Aleksandra

    2007-01-01

    The irrational use of medication, by which we understand the administration of drugs for indications where their effectiveness has not been confirmed, the disregard of restrictions and warnings against their use, and the use of drug combinations which do not increase the therapeutic effect but to the contrary increase the risk of adverse drug reactions, is a serious problem encountered in paediatric pharmacotherapy. Each year the centres for monitoring of adverse drug reactions receive many reports, the analysis of which show that the reasons of occurrence of adverse drug reactions after drug administration, are specifically due to irrational use of medications. In order to prevent in an active way the occurrence, of adverse drug reactions following drug administration it is worthwhile to bring to attention the reasons for their occurrence which not infrequently bring about pathological effects. Our work which is based on reports received by the Regional Centre for Adverse Drug Reactions Monitoring in Krakow concerning the occurrence of adverse drug reactions in an attempt to bring to attention in our view important problems in current pharmacotherapy.

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

    PubMed Central

    Danan, Gaby; Teschke, Rolf

    2015-01-01

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

  4. [Protective effect of Liuweidihuang Pills against cellphone electromagnetic radiation-induced histomorphological abnormality, oxidative injury, and cell apoptosis in rat testes].

    PubMed

    Ma, Hui-rong; Cao, Xiao-hui; Ma, Xue-lian; Chen, Jin-jin; Chen, Jing-wei; Yang, Hui; Liu, Yun-xiao

    2015-08-01

    To observe the effect of Liuweidihuang Pills in relieving cellphone electromagnetic radiation-induced histomorphological abnormality, oxidative injury, and cell apoptosis in the rat testis. Thirty adult male SD rats were equally randomized into a normal, a radiated, and a Liuweidihuang group, the animals in the latter two groups exposed to electromagnetic radiation of 900 MHz cellphone frequency 4 hours a day for 18 days. Meanwhile, the rats in the Liuweidihuang group were treated with the suspension of Liuweidihuang Pills at 1 ml/100 g body weight and the other rats intragastrically with the equal volume of purified water. Then all the rats were killed for observation of testicular histomorphology by routine HE staining, measurement of testicular malondialdehyde (MDA) and glutathione (GSH) levels by colorimetry, and determination of the expressions of bax and bcl-2 proteins in the testis tissue by immunohistochemistry. Compared with the normal controls, the radiated rats showed obviously loose structure, reduced layers of spermatocytes, and cavitation in the seminiferous tubules. Significant increases were observed in the MDA level (P < 0.01) and bax expression (P < 0.01) but decreases in the GSH level (P < 0.01) and bcl-2 expression (P < 0.01) in the testis issue of the radiated rats. In comparison with the radiated rats, those of the Liuweidihuang group exhibited nearly normal testicular structure, significantly lower MDA level (P < 0.05), bax expression (P < 0.01), and bcl-2 expression (P < 0.01). Liuweidihuang Pills can improve cellphone electromagnetic radiation-induced histomorphological abnormality of the testis tissue and reduce its oxidative damage and cell apoptosis.

  5. The lysosomotropic drug LeuLeu-OMe induces lysosome disruption and autophagy-independent cell death in Trypanosoma brucei

    PubMed Central

    Koh, Hazel X.; Aye, Htay M.; Tan, Kevin S. W.; He, Cynthia Y.

    2015-01-01

    Background: Trypanosoma brucei is a blood-borne, protozoan parasite that causes African sleeping sickness in humans and nagana in animals. The current chemotherapy relies on only a handful of drugs that display undesirable toxicity, poor efficacy and drug-resistance. In this study, we explored the use of lysosomotropic drugs to induce bloodstream form T. brucei cell death via lysosome destabilization. Methods: We measured drug concentrations that inhibit cell proliferation by 50% (IC50) for several compounds, chosen based on their lysosomotropic effects previously reported in Plasmodium falciparum. The lysosomal effects and cell death induced by L-leucyl-L-leucyl methyl ester (LeuLeu-OMe) were further analyzed by flow cytometry and immunofluorescence analyses of different lysosomal markers. The effect of autophagy in LeuLeu-OMe-induced lysosome destabilization and cytotoxicity was also investigated in control and autophagy-deficient cells. Results: LeuLeu-OMe was selected for detailed analyses due to its strong inhibitory profile against T. brucei with minimal toxicity to human cell lines in vitro. Time-dependent immunofluorescence studies confirmed an effect of LeuLeu-OMe on the lysosome. LeuLeu-OMe-induced cytotoxicity was also found to be dependent on the acidic pH of the lysosome. Although an increase in autophagosomes was observed upon LeuLeu-OMe treatment, autophagy was not required for the cell death induced by LeuLeu-OMe. Necrosis appeared to be the main cause of cell death upon LeuLeu-OMe treatment. Conclusions: LeuLeu-OMe is a lysosomotropic agent capable of destabilizing lysosomes and causing necrotic cell death in bloodstream form of T. brucei. PMID:28357304

  6. Prevention and management of non-steroidal anti-inflammatory drugs-induced small intestinal injury

    PubMed Central

    Park, Sung Chul; Chun, Hoon Jai; Kang, Chang Don; Sul, Donggeun

    2011-01-01

    Non-steroidal anti-inflammatory drug (NSAID)-induced small bowel injury is a topic that deserves attention since the advent of capsule endoscopy and balloon enteroscopy. NSAID enteropathy is common and is mostly asymptomatic. However, massive bleeding, stricture, or perforation may occur. The pathogenesis of small intestine injury by NSAIDs is complex and different from that of the upper gastrointestinal tract. No drug has yet been developed that can completely prevent or treat NSAID enteropathy. Therefore, a long-term randomized study in chronic NSAID users is needed. PMID:22180706

  7. Curcumin-induced mitotic arrest is characterized by spindle abnormalities, defects in chromosomal congression and DNA damage

    PubMed Central

    Manson, Margaret M.

    2013-01-01

    The chemopreventive agent curcumin has anti-proliferative effects in many tumour types, but characterization of cell cycle arrest, particularly with physiologically relevant concentrations, is still incomplete. Following oral ingestion, the highest concentrations of curcumin are achievable in the gut. Although it has been established that curcumin induces arrest at the G2/M stage of the cell cycle in colorectal cancer lines, it is not clear whether arrest occurs at the G2/M transition or in mitosis. To elucidate the precise stage of arrest, we performed a direct comparison of the levels of curcumin-induced G2/M boundary and mitotic arrest in eight colorectal cancer lines (Caco-2, DLD-1, HCA-7, HCT116p53+/+, HCT116p53–/–, HCT116p21–/–, HT-29 and SW480). Flow cytometry confirmed that these lines underwent G2/M arrest following treatment for 12h with clinically relevant concentrations of curcumin (5–10 μM). In all eight lines, the majority of this arrest occurred at the G2/M transition, with a proportion of cells arresting in mitosis. Examination of the mitotic index using fluorescence microscopy showed that the HCT116 and Caco-2 lines exhibited the highest levels of curcumin-induced mitotic arrest. Image analysis revealed impaired mitotic progression in all lines, exemplified by mitotic spindle abnormalities and defects in chromosomal congression. Pre-treatment with inhibitors of the DNA damage signalling pathway abrogated curcumin-induced mitotic arrest, but had little effect at the G2/M boundary. Moreover, pH2A.X staining seen in mitotic, but not interphase, cells suggests that this aberrant mitosis results in DNA damage. PMID:23125222

  8. Drug induced rhabdomyolysis

    PubMed Central

    Hohenegger, Martin

    2012-01-01

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

  9. Natural Dietary Pigments: Potential Mediators against Hepatic Damage Induced by Over-The-Counter Non-Steroidal Anti-Inflammatory and Analgesic Drugs

    PubMed Central

    Jaramillo-Juárez, Fernando

    2018-01-01

    Over-the-counter (OTC) analgesics are among the most widely prescribed and purchased drugs around the world. Most analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, are metabolized in the liver. The hepatocytes are responsible for drug metabolism and detoxification. Cytochrome P450 enzymes are phase I enzymes expressed mainly in hepatocytes and they account for ≈75% of the metabolism of clinically used drugs and other xenobiotics. These metabolic reactions eliminate potentially toxic compounds but, paradoxically, also result in the generation of toxic or carcinogenic metabolites. Cumulative or overdoses of OTC analgesic drugs can induce acute liver failure (ALF) either directly or indirectly after their biotransformation. ALF is the result of massive death of hepatocytes induced by oxidative stress. There is an increased interest in the use of natural dietary products as nutritional supplements and/or medications to prevent or cure many diseases. The therapeutic activity of natural products may be associated with their antioxidant capacity, although additional mechanisms may also play a role (e.g., anti-inflammatory actions). Dietary antioxidants such as flavonoids, betalains and carotenoids play a preventive role against OTC analgesics-induced ALF. In this review, we will summarize the pathobiology of OTC analgesic-induced ALF and the use of natural pigments in its prevention and therapy. PMID:29364842

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Pan, Jian-Bo; Ji, Nan; Pan, Wen

    2014-01-01

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

  11. Drug-induced diarrhea

    MedlinePlus

    ... treat cancer. Drugs used to treat heartburn and stomach ulcers, such as omeprazole (Prilosec), esomeprazole (Nexium), lansoprazole (Prevacid), ... any medical emergency or for the diagnosis or treatment of any medical condition. A licensed physician should ...

  12. Psychotic and Bipolar Disorders: Antipsychotic Drugs.

    PubMed

    Holder, Sarah D; Edmunds, Alaina L; Morgan, Sherri

    2017-04-01

    Antipsychotic drugs block dopamine receptors and are used to manage psychosis as well as other mental illnesses that may or may not have psychotic features, such as bipolar disorders and major depressive disorder. First-generation antipsychotic drugs are more likely to cause adverse effects such as extrapyramidal symptoms and tardive dyskinesia. Adverse effects of second-generation antipsychotic drugs typically are related to metabolic abnormalities such as weight gain, abnormal blood glucose levels, and elevated lipid levels. Neuroleptic malignant syndrome is a rare but serious adverse effect of antipsychotic drugs that causes mental status changes, hyperthermia, and generalized rigidity. Timely diagnosis is essential due to a high risk of related morbidities if the syndrome remains untreated. Some adverse effects of antipsychotics can be identified and managed so that patients can continue beneficial therapy while minimizing the physiologic consequences. Patients taking antipsychotic drugs should be monitored regularly for adverse effects. Antipsychotics are also associated with potential drug interactions, the most lethal being prolongation of the QT interval, which can lead to fatal arrhythmias. Antipsychotic drugs can be used in special populations, such as pregnant women, children, and elderly patients, per recommendation from a mental health subspecialist. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

  13. Contribution of a mesocorticolimbic subcircuit to drug context-induced reinstatement of cocaine-seeking behavior in rats.

    PubMed

    Lasseter, Heather C; Xie, Xiaohu; Arguello, Amy A; Wells, Audrey M; Hodges, Matthew A; Fuchs, Rita A

    2014-02-01

    Cocaine-seeking behavior triggered by drug-paired environmental context exposure is dependent on orbitofrontal cortex (OFC)-basolateral amygdala (BLA) interactions. Here, we present evidence supporting the hypothesis that dopaminergic input from the ventral tegmental area (VTA) to the OFC critically regulates these interactions. In experiment 1, we employed site-specific pharmacological manipulations to show that dopamine D1-like receptor stimulation in the OFC is required for drug context-induced reinstatement of cocaine-seeking behavior following extinction training in an alternate context. Intra-OFC pretreatment with the dopamine D1-like receptor antagonist, SCH23390, dose-dependently attenuated cocaine-seeking behavior in an anatomically selective manner, without altering motor performance. Furthermore, the effects of SCH23390 could be surmounted by co-administration of a sub-threshold dose of the D1-like receptor agonist, SKF81297. In experiment 2, we examined effects of D1-like receptor antagonism in the OFC on OFC-BLA interactions using a functional disconnection manipulation. Unilateral SCH23390 administration into the OFC plus GABA agonist-induced neural inactivation of the contralateral or ipsilateral BLA disrupted drug context-induced cocaine-seeking behavior relative to vehicle, while independent unilateral manipulations of these brain regions were without effect. Finally, in experiment 3, we used fluorescent retrograde tracers to demonstrate that the VTA, but not the substantia nigra, sends dense intra- and interhemispheric projections to the OFC, which in turn has reciprocal bi-hemispheric connections with the BLA. These findings support that dopaminergic input from the VTA, via dopamine D1-like receptor stimulation in the OFC, is required for OFC-BLA functional interactions. Thus, a VTA-OFC-BLA neural circuit promotes drug context-induced motivated behavior.

  14. Prenatal drug use and the production of infant health.

    PubMed

    Noonan, Kelly; Reichman, Nancy E; Corman, Hope; Dave, Dhaval

    2007-04-01

    We estimate the effect of illicit drug use during pregnancy on two measures of poor infant health: low birth weight and abnormal infant health conditions. We use data from a national longitudinal study of urban parents that includes postpartum interviews with mothers, hospital medical record data on the mothers and their newborns, and information about the neighborhood in which the mother resides. We address the potential endogeneity of prenatal drug use. Depending on how prenatal drug use is measured, we find that it increases low birth weight by 4-6 percentage points and that it increases the likelihood of an abnormal infant health condition by 7-12 percentage points. Copyright (c) 2006 John Wiley & Sons, Ltd.

  15. Oseltamivir use and severe abnormal behavior in Japanese children and adolescents with influenza: Is a self-controlled case series study applicable?

    PubMed

    Fukushima, Wakaba; Ozasa, Kotaro; Okumura, Akihisa; Mori, Masaaki; Hosoya, Mitsuaki; Nakano, Takashi; Tanabe, Takuya; Yamaguchi, Naoto; Suzuki, Hiroshi; Mori, Mitsuru; Hatayama, Hideaki; Ochiai, Hirotaka; Kondo, Kyoko; Ito, Kazuya; Ohfuji, Satoko; Nakamura, Yosikazu; Hirota, Yoshio

    2017-08-24

    Since the 1990s, self-controlled designs including self-controlled case series (SCCS) studies have been occasionally used in post-marketing evaluation of drug or vaccine safety. An SCCS study was tentatively applied to evaluate the relationship between oseltamivir use and abnormal behavior Type A (serious abnormal behavior potentially leading to an accident or harm to another person) in influenza patients. From the original prospective cohort study with approximately 10,000 Japanese children and adolescents with influenza (aged <18years), 28 subjects (mean age: 7.3years) who developed abnormal behavior Type A after the first visit to the collaborating hospitals/clinics were analyzed. We hypothesized four combination patterns of the effect period (i.e., the period that effect of oseltamivir on occurrence of abnormal behavior Type A is likely) and the control period. Mantel-Haenszel rate ratio (M-H RR) and its 95% confidence interval (CI) were calculated as the relative risk estimate. Among 28 subjects in the SCCS study, 24 subjects (86%) were administered oseltamivir and 4 subjects (14%) were not. Abnormal behavior Type A was more likely to occur in the effect period than the control period in every pattern (M-H RR: 1.90-29.1). We observed the highest estimate when the effect period was set between the initial intake of oseltamivir and T max (M-H RR: 29.1, 95% CI: 4.21-201). Abnormal behavior Type A was more likely to develop up to approximately 30 times during the period between the initial intake of oseltamivir and T max . However, this period overlapped with the early period of influenza where high fever was observed. Since useful approaches to control the influence of the natural disease course of influenza were not available in this study, we could not deny the possibility that abnormal behavior was induced by influenza itself. The SCCS study was not an optimal method to evaluate the relationship between oseltamivir use and abnormal behavior. Copyright © 2017

  16. Drug-Sensing by the Ribosome Induces Translational Arrest via Active Site Perturbation

    PubMed Central

    Arenz, Stefan; Meydan, Sezen; Starosta, Agata L.; Berninghausen, Otto; Beckmann, Roland; Vázquez-Laslop, Nora; Wilson, Daniel N.

    2014-01-01

    SUMMARY During protein synthesis, nascent polypeptide chains within the ribosomal tunnel can act in cis to induce ribosome stalling and regulate expression of downstream genes. The Staphylococcus aureus ErmCL leader peptide induces stalling in the presence of clinically important macrolide antibiotics, such as erythromycin, leading to the induction of the downstream macrolide resistance methyltransferase ErmC. Here, we present a cryo-electron microscopy (EM) structure of the erythromycin-dependent ErmCL-stalled ribosome at 3.9 Å resolution. The structure reveals how the ErmCL nascent chain directly senses the presence of the tunnel-bound drug and thereby induces allosteric conformational rearrangements at the peptidyltransferase center (PTC) of the ribosome. ErmCL-induced perturbations of the PTC prevent stable binding and accommodation of the aminoacyl-tRNA at the A-site leading to inhibition of peptide bond formation and translation arrest. PMID:25306253

  17. Drug-seeking behavior in an invertebrate system: evidence of morphine-induced reward, extinction and reinstatement in crayfish

    PubMed Central

    Nathaniel, Thomas I.; Panksepp, Jules; Huber, Robert

    2009-01-01

    Several lines of evidence suggest that exploring the neurochemical basis of reward in invertebrate species may provide clues for the fundamental behavioral and neurobiology underpinnings of drug addiction. How the presence of drug-sensitive reward relates to a decrease in drug-seeking behavior and reinstatement of drug seeking behavior in invertebrate systems is not known. The present study of a conditioned place preference (CPP) paradigm in crayfish (Orconectes rusticus) explores morphine-induced reward, extinction and reinstatement. Repeated intra-circulatory infusions of 2.5μg/g, 5.0μg/g and 10.0μg/g doses of morphine over 5 days serve as a reward when paired with a distinct visual or tactile environment. Morphine-induced CPP was extinguished after repeated saline injections for 5 days in the previously morphine-paired compartment. After the previously established CPP had been eliminated during the extinction phase, morphine-experienced crayfish were challenged with 2.5 μg/g, 5.0 μg/g and 10.0 μg/g respectively. The priming injections of morphine reinstated CPP in all training doses, suggesting that morphine-induced CPP is unrelenting, and that with time, it can be reinstated by morphine following extinction in an invertebrate model just like in mammals. Together with other recent studies, this work demonstrates the advantage of using crayfish as an invertebrate animal model to investigate the basic biological processes that underline exposure to mammalian drugs of abuse. PMID:18822319

  18. Pharmacogenetics of drugs withdrawn from the market.

    PubMed

    Zhang, Wei; Roederer, Mary W; Chen, Wang-Qing; Fan, Lan; Zhou, Hong-Hao

    2012-01-01

    The safety and efficacy of candidate compounds are critical factors during the development of drugs, and most drugs have been withdrawn from the market owing to severe adverse reactions. Individuals/populations with different genetic backgrounds may show significant differences in drug metabolism and efficacy, which can sometimes manifest as severe adverse drug reactions. With an emphasis on the mechanisms underlying abnormal drug effects caused by genetic mutations, pharmacogenetic studies may enhance the safety and effectiveness of drug use, provide more comprehensive delineations of the scope of usage, and change the fates of drugs withdrawn from the market.

  19. Levetiracetam reduces abnormal network activations in temporal lobe epilepsy.

    PubMed

    Wandschneider, Britta; Stretton, Jason; Sidhu, Meneka; Centeno, Maria; Kozák, Lajos R; Symms, Mark; Thompson, Pamela J; Duncan, John S; Koepp, Matthias J

    2014-10-21

    We used functional MRI (fMRI) and a left-lateralizing verbal and a right-lateralizing visual-spatial working memory (WM) paradigm to investigate the effects of levetiracetam (LEV) on cognitive network activations in patients with drug-resistant temporal lobe epilepsy (TLE). In a retrospective study, we compared task-related fMRI activations and deactivations in 53 patients with left and 54 patients with right TLE treated with (59) or without (48) LEV. In patients on LEV, activation patterns were correlated with the daily LEV dose. We isolated task- and syndrome-specific effects. Patients on LEV showed normalization of functional network deactivations in the right temporal lobe in right TLE during the right-lateralizing visual-spatial task and in the left temporal lobe in left TLE during the verbal task. In a post hoc analysis, a significant dose-dependent effect was demonstrated in right TLE during the visual-spatial WM task: the lower the LEV dose, the greater the abnormal right hippocampal activation. At a less stringent threshold (p < 0.05, uncorrected for multiple comparisons), a similar dose effect was observed in left TLE during the verbal task: both hippocampi were more abnormally activated in patients with lower doses, but more prominently on the left. Our findings suggest that LEV is associated with restoration of normal activation patterns. Longitudinal studies are necessary to establish whether the neural patterns translate to drug response. This study provides Class III evidence that in patients with drug-resistant TLE, levetiracetam has a dose-dependent facilitation of deactivation of mesial temporal structures. © 2014 American Academy of Neurology.

  20. [Cost comparative analysis of drug therapy for non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcer in Japan].

    PubMed

    Hashiguchi, Masayuki; Yamauchi, Nobuaki; Uchikura, Takeshi; Mochizuki, Mayumi

    2008-04-01

    Drug selection for the treatment of non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcer was analyzed pharmacoeconomically. Two patterns consisting of continuation of an NSAID plus administration of the prostaglandin (PG) preparation misoprostol (PG model) for 8 weeks and continuation of an NSAID plus administration of the proton-pump inhibitors omeprazole and lansoprazole (PPI model) for 8 weeks were examined. Decision analysis models were created on the basis of reports of clinical studies and epidemiologic studies relating to the drugs and gastric ulcer, and cost-comparative analyses were conducted based on the number of persons who had ulcer healing as health outcomes. Costs were estimated with respect to health expenditures from the third-party payer (public) perspective. In the case of continuation of an NSAID plus administration of the proton-pump inhibitor omeprazole for 8 weeks, the health outcomes improved and costs were reduced in comparison with continuation of an NSAID plus administration of misoprostol, thus making the administration of omeprazole the dominant choice. With continuation of an NSAID plus administration of lansoprazole for 8 weeks, the cost-savings of lansoprazole were inferior to those of misoprostol. The generic omeprazole product was the most cost-saving among the four drugs (misoprostol, original omeprazole product, generic omeprazole product, and lansoprazole) examined.

  1. [Recommendation for the prevention and treatment of non-steroidal anti-inflammatory drug-induced gastrointestinal ulcers and its complications].

    PubMed

    2017-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are a broad class of non glucocorticoid drugs which are extensively used in anti-inflammatory, analgesic, and antipyretic therapies. However, NSAIDs may cause many side effects, most commonly in gastrointestinal(GI) tract. Cardiovascular system, kidney, liver, central nervous system and hematopoietic system are also involved. NSAID-induced GI side effects not only endanger the patients' health, increase mortality, but also greatly increase the cost of medical care. Therefore, how to reduce GI side effects is of particular concern to clinicians. The Chinese Rheumatism Data Center(CRDC) and Chinese Systemic Lupus Erythematosus Treatment and Research Group(CSTAR) compose a "Recommendation for the prevention and treatment of non-steroidal anti-inflammatory drug-induced gastrointestinal ulcers and its complications" , as following: (1) GI lesions are the most common side effects of NSAIDs. (2) NSAID-induced GI side effects include gastritis, esophagitis, gastric and duodenal ulcers, bleeding, perforation and obstruction. (3) With the application of capsule endoscopy and small intestinal endoscopy, growing attention is being paid to the NASID-induced small intestine mucosa damage, which is mainly erosion and ulcer. (4) Risk factors related to NSAID-induced GI ulcers include: Helicobacter pylori (Hp) infection, age> 65 years, past history of GI ulcers, high doses of NSAIDs, multiple-drug combination therapy, and comorbidities, such as cardiovascular disease and nephropathy.(5) GI and cardiovascular function should be evaluated before using NSAIDs and gastric mucosal protective agents. (6) The risk of GI ulcers and complications caused by selective cyclooxygenase-2 (COX-2) inhibitors is less than that of non-selective COX-2 inhibitors. (7)Hp eradication therapy helps to cure GI ulcers and prevent recurrence when Hp infection is positive in NSAID-induced ulcers. (8) Proton pump inhibitor (PPI) is the first choice for the

  2. Medical management of oral motor disorders: dystonia, dyskinesia and drug-induced dystonic extrapyramidal reactions.

    PubMed

    Clark, Glenn T

    2006-08-01

    This article reviews three of the involuntary hyperkinetic motor disorders that affect the orofacial region, namely orofacial dystonia, oromandibular dyskinesia, as well as medication-induced extrapyramidal syndrome-dystonic reactions. Specifically, it discusses and contrasts the clinical features and management strategies for spontaneous primary and drug-induced motor disorders in the orofacial region. The article provides a list of medications reported to cause drug-related extrapyramidal motor activity above and beyond the more commonly known antipsychotics medications. It provides a needed update because the number and use of medications causing involuntary jaw muscle activity are increasing. For example, selective serotonin reuptake inhibitors (SSRI), stimulant medications and illegal drugs have all been reported to induce an orofacial motor activation as adverse reactions. This article also discusses briefly the genetic and traumatic events associated with spontaneous dystonia. Finally, this article presents an approach for management of the orofacial motor disorders that involves the following three steps: (1) collect a full clinical history and examination, including magnetic resonance imaging of the brain; (2) after ruling out CNS disease, adverse medications reactions and local pathology, try one or more of the motor-suppressive medications that may be helpful in these cases (e.g., cholinergic receptor antagonizers or blockers, and GABA-ergic including benzodiazepines); and (3) if the disorder is severe enough and focal enough to consider, and motor-suppressive medications are not adequate, then consider botulinum toxin injections. The contraindications, side effects, and usual approach for these medications and injections are discussed.

  3. Comedications alter drug-induced liver injury reporting frequency: Data mining in the WHO VigiBase™

    PubMed Central

    Suzuki, Ayako; Yuen, Nancy A.; Ilic, Katarina; Miller, Richard T.; Reese, Melinda J.; Brown, H. Roger; Ambroso, Jeffrey I.; Falls, J. Gregory; Hunt, Christine M.

    2015-01-01

    Polypharmacy is common, and may modify mechanisms of drug-induced liver injury. We examined the effect of these drug–drug interactions on liver safety reports of four drugs highly associated with hepatotoxicity. In the WHO VigiBase™, liver event reports were examined for acetaminophen, isoniazid, valproic acid, and amoxicillin/clavulanic acid. Then, we evaluated the liver event reporting frequency of these 4 drugs in the presence of co-reported medications. Each of the 4 primary drugs was reported as having more than 2000 liver events, and co-reported with more than 600 different medications. Overall, the effect of 2275 co-reported drugs (316 drug classes) on the reporting frequency was analyzed. Decreased liver event reporting frequency was associated with 245 drugs/122 drug classes, including anti-TNFα, opioids, and folic acid. Increased liver event reporting frequency was associated with 170 drugs/82 drug classes; in particular, halogenated hydrocarbons, carboxamides, and bile acid sequestrants. After adjusting for age, gender, and other co-reported drug classes, multiple co-reported drug classes were significantly associated with decreased/increased liver event reporting frequency in a drug-specific/unspecific manner. In conclusion, co-reported medications were associated with changes in the liver event reporting frequency of drugs commonly associated with hepatotoxicity, suggesting that comedications may modify drug hepatic safety. PMID:25988394

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

    PubMed

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

    2018-05-18

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

  5. Effect of the Anti-depressant Sertraline, the Novel Anti-seizure Drug Vinpocetine and Several Conventional Antiepileptic Drugs on the Epileptiform EEG Activity Induced by 4-Aminopyridine.

    PubMed

    Sitges, Maria; Aldana, Blanca Irene; Reed, Ronald Charles

    2016-06-01

    Seizures are accompanied by an exacerbated activation of cerebral ion channels. 4-aminopyridine (4-AP) is a pro-convulsive agent which mechanism of action involves activation of Na(+) and Ca(2+) channels, and several antiepileptic drugs control seizures by reducing these channels permeability. The antidepressant, sertraline, and the anti-seizure drug vinpocetine are effective inhibitors of cerebral presynaptic Na(+) channels. Here the effectiveness of these compounds to prevent the epileptiform EEG activity induced by 4-AP was compared with the effectiveness of seven conventional antiepileptic drugs. For this purpose, EEG recordings before and at three intervals within the next 30 min following 4-AP (2.5 mg/kg, i.p.) were taken in anesthetized animals; and the EEG-highest peak amplitude values (HPAV) calculated. In control animals, the marked increase in the EEG-HPAV observed near 20 min following 4-AP reached its maximum at 30 min. Results show that this epileptiform EEG activity induced by 4-AP is prevented by sertraline and vinpocetine at a dose of 2.5 mg/kg, and by carbamazepine, phenytoin, lamotrigine and oxcarbazepine at a higher dose (25 mg/kg). In contrast, topiramate (25 mg/kg), valproate (100 mg/kg) and levetiracetam (100 mg/kg) failed to prevent the epileptiform EEG activity induced by 4-AP. It is concluded that 4-AP is a useful tool to elicit the mechanism of action of anti-seizure drugs at clinical meaningful doses. The particular efficacy of sertraline and vinpocetine to prevent seizures induced by 4-AP is explained by their high effectiveness to reduce brain presynaptic Na(+) and Ca(2+) channels permeability.

  6. [Mechanism of action of antiepileptic drugs].

    PubMed

    Saidón, Patricia

    2003-01-01

    Antiepileptic drugs (DAEs) act through different mechanisms of action: increase in central inhibition, inhibition of excitatorios mechanisms and modification of the excitability through their action on the ionic channels. Epilepsy is characterized by an abnormal and hypersynchronic unloading of a neuronal population. The activity of numerous drugs is associated to increase in gabaergic activity. Another group of drugs decreases excitatory mechanisms, through the inhibition of ionic channels, or through a decrease in the activity of the excitatory neurotransmitters. There are some of antiepileptic drugs, especially within the group of drugs of recent appearance, for wich the mechanism of action remains unknown.

  7. Methotrimeprazine-induced Corneal Deposits and Cataract Revealed by Urine Drug Profiling Test

    PubMed Central

    Kim, Seong Taeck; Kim, Joon Mo; Kim, Won Young; Choi, Gwang Ju

    2010-01-01

    Two schizophrenic patients who had been taking medication for a long period presented with visual disturbance of 6-month duration. Slit-lamp examination revealed fine, discrete, and brownish deposits on the posterior cornea. In addition, bilateral star-shaped anterior subcapsular lens opacities, which were dense, dust-like granular deposits, were noted. Although we strongly suspected that the patient might have taken one of the drugs of the phenothiazine family, we were unable to obtain a history of medications other than haloperidol and risperidone, which were taken for 3 yr. We performed a drug profiling test using urine samples and detected methotrimeprazine. The patient underwent surgery for anterior subcapsular lens opacities. Visual acuity improved in both eyes, but the corneal deposits remained. We report an unusual case of methotrimeprazine-induced corneal deposits and cataract in a patient with psychosis, identified by using the urine drug profiling test. PMID:21060765

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

    NASA Astrophysics Data System (ADS)

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

    2013-12-01

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

  9. Neuroimaging markers of glutamatergic and GABAergic systems in drug addiction: relationships to resting-state functional connectivity

    PubMed Central

    Moeller, Scott J.; London, Edythe D.; Northoff, Georg

    2015-01-01

    Drug addiction is characterized by widespread abnormalities in brain function and neurochemistry, including drug-associated effects on concentrations of the excitatory and inhibitory neurotransmitters glutamate and gamma-aminobutyric acid (GABA), respectively. In healthy individuals, these neurotransmitters drive the resting state, a default condition of brain function also disrupted in addiction. Here, our primary goal was to review in vivo magnetic resonance spectroscopy and positron emission tomography studies that examined markers of glutamate and GABA abnormalities in human drug addiction. Addicted individuals tended to show decreases in these markers compared with healthy controls, but findings also varied by individual characteristics (e.g., abstinence length). Interestingly, select corticolimbic brain regions showing glutamatergic and/or GABAergic abnormalities have been similarly implicated in resting-state functional connectivity deficits in drug addiction. Thus, our secondary goals were to provide a brief review of this resting-state literature, and an initial rationale for the hypothesis that abnormalities in glutamatergic and/or GABAergic neurotransmission may underlie resting-state functional deficits in drug addiction. In doing so, we suggest future research directions and possible treatment implications. PMID:26657968

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

    PubMed

    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.

  11. Stress-Induced Mutagenesis: Implications in Cancer and Drug Resistance.

    PubMed

    Fitzgerald, Devon M; Hastings, P J; Rosenberg, Susan M

    2017-03-01

    Genomic instability underlies many cancers and generates genetic variation that drives cancer initiation, progression, and therapy resistance. In contrast with classical assumptions that mutations occur purely stochastically at constant, gradual rates, microbes, plants, flies, and human cancer cells possess mechanisms of mutagenesis that are upregulated by stress responses. These generate transient, genetic-diversity bursts that can propel evolution, specifically when cells are poorly adapted to their environments-that is, when stressed. We review molecular mechanisms of stress-response-dependent (stress-induced) mutagenesis that occur from bacteria to cancer, and are activated by starvation, drugs, hypoxia, and other stressors. We discuss mutagenic DNA break repair in Escherichia coli as a model for mechanisms in cancers. The temporal regulation of mutagenesis by stress responses and spatial restriction in genomes are common themes across the tree of life. Both can accelerate evolution, including the evolution of cancers. We discuss possible anti-evolvability drugs, aimed at targeting mutagenesis and other variation generators, that could be used to delay the evolution of cancer progression and therapy resistance.

  12. Stress-Induced Mutagenesis: Implications in Cancer and Drug Resistance

    PubMed Central

    Fitzgerald, Devon M.; Hastings, P.J.; Rosenberg, Susan M.

    2017-01-01

    Genomic instability underlies many cancers and generates genetic variation that drives cancer initiation, progression, and therapy resistance. In contrast with classical assumptions that mutations occur purely stochastically at constant, gradual rates, microbes, plants, flies, and human cancer cells possess mechanisms of mutagenesis that are upregulated by stress responses. These generate transient, genetic-diversity bursts that can propel evolution, specifically when cells are poorly adapted to their environments—that is, when stressed. We review molecular mechanisms of stress-response-dependent (stress-induced) mutagenesis that occur from bacteria to cancer, and are activated by starvation, drugs, hypoxia, and other stressors. We discuss mutagenic DNA break repair in Escherichia coli as a model for mechanisms in cancers. The temporal regulation of mutagenesis by stress responses and spatial restriction in genomes are common themes across the tree of life. Both can accelerate evolution, including the evolution of cancers. We discuss possible anti-evolvability drugs, aimed at targeting mutagenesis and other variation generators, that could be used to delay the evolution of cancer progression and therapy resistance. PMID:29399660

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

    PubMed

    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.

  14. Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I.

    PubMed

    Harting, Inga; Neumaier-Probst, Eva; Seitz, Angelika; Maier, Esther M; Assmann, Birgit; Baric, Ivo; Troncoso, Monica; Mühlhausen, Chris; Zschocke, Johannes; Boy, Nikolas P S; Hoffmann, Georg F; Garbade, Sven F; Kölker, Stefan

    2009-07-01

    In glutaric aciduria type I, an autosomal recessive disease of mitochondrial lysine, hydroxylysine and tryptophan catabolism, striatal lesions are characteristically induced by acute encephalopathic crises during a finite period of brain development (age 3-36 months). The frequency of striatal injury is significantly less in patients diagnosed as asymptomatic newborns by newborn screening. Most previous studies have focused on the onset and mechanism of striatal injury, whereas little is known about neuroradiological abnormalities in pre-symptomatically diagnosed patients and about dynamic changes of extrastriatal abnormalities. Thus, the major aim of the present retrospective study was to improve our understanding of striatal and extrastriatal abnormalities in affected individuals including those diagnosed by newborn screening. To this end, we systematically analysed magnetic resonance imagings (MRIs) in 38 patients with glutaric aciduria type I diagnosed before or after the manifestation of neurological symptoms. To identify brain regions that are susceptible to cerebral injury during acute encephalopathic crises, we compared the frequency of magnetic resonance abnormalities in patients with and without such crises. Major specific changes after encephalopathic crises were found in the putamen (P < 0.001), nucleus caudatus (P < 0.001), globus pallidus (P = 0.012) and ventricles (P = 0.001). Analysis of empirical cumulative distribution frequencies, however, demonstrated that isolated pallidal abnormalities did not significantly differ over time in both groups (P = 0.544) suggesting that isolated pallidal abnormalities are not induced by acute crises--in contrast to striatal abnormalities. The manifestation of motor disability was associated with signal abnormalities in putamen, caudate, pallidum and ventricles. In addition, we found a large number of extrastriatal abnormalities in patients with and without preceding encephalophatic crises. These abnormalities

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

    PubMed

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

    2013-01-01

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

  16. Drug-Induced Liver Injury: Advances in Mechanistic Understanding that will Inform Risk Management

    PubMed Central

    Mosedale, Merrie; Watkins, Paul B.

    2016-01-01

    Drug-induced liver injury (DILI) is a major public health problem. Intrinsic (dose-dependent) DILI associated with acetaminophen overdose is the number one cause of acute liver failure in the US. However the most problematic type of DILI impacting drug development is idiosyncratic, occurring only very rarely among treated patients and often only after several weeks or months of treatment with the offending drug. Recent advances in our understanding of the pathogenesis of DILI suggest that three mechanisms may underlie most hepatocyte effects in response to both intrinsic and idiosyncratic DILI drugs: mitochondrial dysfunction, oxidative stress, and alterations in bile acid homeostasis. However, in some cases, hepatocyte stress promotes an immune response that results in clinically important idiosyncratic DILI. This review discusses recent advances in our understanding of the pathogenesis of both intrinsic and idiosyncratic DILI as well as emerging tools and techniques that will likely improve DILI risk identification and management. PMID:27861792

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2017-01-01

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

  19. Reversal of Phenotypic Abnormalities by CRISPR/Cas9-Mediated Gene Correction in Huntington Disease Patient-Derived Induced Pluripotent Stem Cells.

    PubMed

    Xu, Xiaohong; Tay, Yilin; Sim, Bernice; Yoon, Su-In; Huang, Yihui; Ooi, Jolene; Utami, Kagistia Hana; Ziaei, Amin; Ng, Bryan; Radulescu, Carola; Low, Donovan; Ng, Alvin Yu Jin; Loh, Marie; Venkatesh, Byrappa; Ginhoux, Florent; Augustine, George J; Pouladi, Mahmoud A

    2017-03-14

    Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in HTT. Here we report correction of HD human induced pluripotent stem cells (hiPSCs) using a CRISPR-Cas9 and piggyBac transposon-based approach. We show that both HD and corrected isogenic hiPSCs can be differentiated into excitable, synaptically active forebrain neurons. We further demonstrate that phenotypic abnormalities in HD hiPSC-derived neural cells, including impaired neural rosette formation, increased susceptibility to growth factor withdrawal, and deficits in mitochondrial respiration, are rescued in isogenic controls. Importantly, using genome-wide expression analysis, we show that a number of apparent gene expression differences detected between HD and non-related healthy control lines are absent between HD and corrected lines, suggesting that these differences are likely related to genetic background rather than HD-specific effects. Our study demonstrates correction of HD hiPSCs and associated phenotypic abnormalities, and the importance of isogenic controls for disease modeling using hiPSCs. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  20. Establishment of a novel experimental protocol for drug-induced seizure liability screening based on a locomotor activity assay in zebrafish.

    PubMed

    Koseki, Naoteru; Deguchi, Jiro; Yamashita, Akihito; Miyawaki, Izuru; Funabashi, Hitoshi

    2014-08-01

    As drug-induced seizures have severe impact on drug development, evaluating seizure induction potential of candidate drugs at the early stages of drug discovery is important. A novel assay system using zebrafish has attracted interest as a high throughput toxicological in vivo assay system, and we tried to establish an experimental method for drug-induced seizure liability on the basis of locomotor activity in zebrafish. We monitored locomotor activity at high-speed movement (> 20 mm/sec) for 60 min immediately after exposure, and assessed seizure liability potential in some drugs using locomotor activity. However this experimental procedure was not sufficient for predicting seizures because the potential of several drugs with demonstrated seizure potential in mammals was not detected. We, therefore, added other parameters for locomotor activity such as extending exposure time or conducting flashlight stimulation (10 Hz) which is a known seizure induction stimulus, and these additional parameters improved seizure potential detection in some drugs. The validation study using the improved methodology was used to assess 52 commercially available drugs, and the prediction rate was approximately 70%. The experimental protocol established in this present study is considered useful for seizure potential screening during early stages of drug discovery.