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Sample records for adverse antiepileptic drug

  1. Idiosyncratic adverse reactions to antiepileptic drugs.

    PubMed

    Zaccara, Gaetano; Franciotta, Diego; Perucca, Emilio

    2007-07-01

    Idiosyncratic drug reactions may be defined as adverse effects that cannot be explained by the known mechanisms of action of the offending agent, do not occur at any dose in most patients, and develop mostly unpredictably in susceptible individuals only. These reactions are generally thought to account for up to 10% of all adverse drug reactions, but their frequency may be higher depending on the definition adopted. Idiosyncratic reactions are a major source of concern because they encompass most life-threatening effects of antiepileptic drugs (AEDs), as well as many other reactions requiring discontinuation of treatment. Based on the underlying mechanisms, idiosyncratic reactions can be differentiated into (1) immune-mediated hypersensitivity reactions, which may range from benign skin rashes to serious conditions such as drug-related rash with eosinophilia and systemic symptoms; (2) reactions involving unusual nonimmune-mediated individual susceptibility, often related to abnormal production or defective detoxification of reactive cytotoxic metabolites (as in valproate-induced liver toxicity); and (3) off-target pharmacology, whereby a drug interacts directly with a system other than that for which it is intended, an example being some types of AED-induced dyskinesias. Although no AED is free from the potential of inducing idiosyncratic reactions, the magnitude of risk and the most common manifestations vary from one drug to another, a consideration that impacts on treatment choices. Serious consequences of idiosyncratic reactions can be minimized by knowledge of risk factors, avoidance of specific AEDs in subpopulations at risk, cautious dose titration, and careful monitoring of clinical response.

  2. Cutaneous Adverse Drug Reactions in Dogs Treated with Antiepileptic Drugs

    PubMed Central

    Koch, Tina; Mueller, Ralf S.; Dobenecker, Britta; Fischer, Andrea

    2016-01-01

    Epilepsy is one of the most common neurologic disorders in dogs and life-long treatment with antiepileptic drugs (AED) is frequently required. Adverse events of AED targeting the skin are only rarely reported in veterinary medicine and the true incidence and spectrum of cutaneous reactions in epileptic dogs remains unknown. In this study, we hypothesized that cutaneous reactions commonly occur in epileptic dogs and are related to AED treatment. A retrospective case review of 185 dogs treated for epilepsy identified 20.0% with simultaneous appearance of dermatologic signs. In a subsequent prospective case investigation (n = 137), we identified newly appearing or distinct worsening of skin lesions following initiation of AED therapy in 10.9% of dogs treated for epilepsy (95% CI 6.8–17.7%). Cutaneous lesions were classified as probably drug-induced in 40.0% of these cases. Patch testing and intradermal testing were further investigated as potential diagnostic methods to confirm AED hypersensitivity. They were of high specificity but sensitivity and positive predictive value appeared inappropriate to recommend their routine use in clinical practice. PMID:27148543

  3. A prospective study of adverse drug reactions to antiepileptic drugs in children

    PubMed Central

    Anderson, Mark; Egunsola, Oluwaseun; Cherrill, Janine; Millward, Claire; Fakis, Apostolos; Choonara, Imti

    2015-01-01

    Objectives To prospectively determine the nature and rate of adverse drug reactions (ADRs) in children on antiepileptic drugs (AEDs) and to prospectively evaluate the effect of AEDs on behaviour. Setting A single centre prospective observational study. Participants Children (<18 years old) receiving one or more AEDs for epilepsy, at each clinically determined follow-up visit. Primary and secondary outcomes Primary outcome was adverse reactions of AEDs. Behavioural and cognitive functions were secondary outcomes. Results 180 children were recruited. Sodium valproate and carbamazepine were the most frequently used AEDs. A total of 114 ADRs were recorded in 56 of these children (31%). 135 children (75%) were on monotherapy. 27 of the 45 children (60%) on polytherapy had ADRs; while 29 (21%) of those on monotherapy had ADRs. The risk of ADRs was significantly lower in patients receiving monotherapy than polytherapy (RR: 0.61, 95% CI 0.47 to 0.79, p<0.0001). Behavioural problems and somnolence were the most common ADRs. 23 children had to discontinue their AED due to an ADR. Conclusions Behavioural problems and somnolence were the most common ADRs. Polytherapy significantly increases the likelihood of ADRs in children. Trail registration number EudraCT (2007-000565-37). PMID:26033949

  4. Adverse reactions to antiepileptic drugs: a follow-up study of 355 patients with chronic antiepileptic drug treatment. Collaborative Group for Epidemiology of Epilepsy.

    PubMed

    1988-01-01

    Three hundred fifty-five patients receiving chronic antiepileptic drug (AED) treatment were followed in 15 university and hospital centers for an average of 11 months to assess the effects of intensive monitoring of adverse drug reactions (ADRs) on the frequency of reports and on the overall management of epilepsy. One hundred forty-eight patients (41.6%) had one or more ADRs during the entire follow-up period. ADRs were reported by 31% of patients at admission and by 20% at last visit, with a downward trend in the number of reports. Concurrently, the number of patients who were seizure-free rose from 24.5 to 42.8%. During the observation period, the number of prescriptions fell from 640 to 568, mostly for phenobarbital (PB), phenytoin (PHT), and valproate (VPA). The outcome of the most common ADR was only partially related to drug changes. Even with the limitations of the unstandardized criteria used for ADR reporting, the present study shows that intensive monitoring of drug-related clinical events is not only a valuable tool to provide a comprehensive survey of drug toxicity in clinical practice, but is also an educational effort to improve the quality of care for patients with epilepsy. PMID:3191896

  5. Antiepileptic Drug-Related Adverse Reactions and Factors Influencing These Reactions

    PubMed Central

    KARIMZADEH, Parvaneh; BAKRANI, Vahid

    2013-01-01

    Objective According to the basic role of drug side effects in selection of an appropriate drug, patient compliance and the quality of life in epileptic patients, and forasmuch as new drugs with unknown side effect have been introduced, necessity of this research is explained. This study was conducted to evaluate the incidence and clinical characteristics of anti epileptic drug (AED) related adverse reactions in children. Material & Methods In this descriptive study, children less than 14 years old with AED side effects referred to the Children’s Medical Center and Mofid Childeren’s Hospital (Tehran, Iran) were evaluated during 2010-2012. The informations were: sex, age, incriminating drug, type of drug side effect, incubation period, history of drug usage, and patient and family allergy history. Exclusive criterions were age more than 14 years old and reactions due to reasons other than AEDs. Results A total of 70 patients with AED reaction were enrolled in this study. They included 26 (37%) females and 44 (63%) males. The maximum rate of incidence was seen at age less than 5 years old. All the patients had cutaneous eruptions that the most common cutaneous drug eruption was maculopapular rash. The most common culprit was phenobarbital (70%) and the least common was lamotrigine (1.4%). Conclusion In this study, we found higher rates of drug rash in patients treated with aromatic AEDs and lower rates with non-aromatic AEDs. Various endogenous and environmental factors may influence the propensity to develop these reactions. PMID:24665302

  6. Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs.

    PubMed

    Zaccara, Gaetano; Perucca, Emilio

    2014-12-01

    Interactions between antiepileptic drugs, or between antiepileptic drugs and other drugs, can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions involve changes in absorption, distribution or elimination, whereas pharmacodynamic interactions involve synergism and antagonism at the site of action. Most clinically important interactions of antiepileptic drugs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes (as well as P-glycoprotein) and can reduce the efficacy of co-administered medications such as oral anticoagulants, calcium antagonists, steroids, antimicrobial and antineoplastic drugs through this mechanism. Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses ≥ 200 mg/day) and perampanel (at doses ≥ 8 mg/day) have weaker inducing properties, and a lower propensity to cause interactions mediated by enzyme induction. Unlike enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, the serum concentration of which may increase leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include the increase in the serum concentration of phenobarbital and lamotrigine caused by valproic acid. There are also interactions whereby other drugs induce or inhibit the metabolism of antiepileptic drugs, examples being the increase in serum carbamazepine concentration by erythromycin, and the decrease in serum lamotrigine concentration by oestrogen-containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of

  7. [Endocrine effects of antiepileptic drugs].

    PubMed

    Leśkiewicz, Monika; Budziszewska, Bogusława; Lasoń, Władysław

    2008-01-01

    Both seizures and antiepileptic drugs may induce disturbances in hormonal system. Regarding endocrine effects of anticonvulsants, an interaction of these drugs with gonadal, thyroid, and adrenal axis deserves attention. Since majority of antiepileptic drugs block voltage dependent sodium and calcium channels, enhance GABAergic transmission and/or antagonize glutamate receptors, one may expect that similar neurochemical mechanisms are engaged in the interaction of these drugs with synthesis of hypothalamic neurohormones such as gonadotropin-releasing hormone (GnRH), thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH) and growth hormone releasing hormone (GHRH). Moreover some antiepileptic drugs may affect hormone metabolism via inhibiting or stimulating cytochrome P-450 iso-enzymes. An influence of antiepileptic drugs on hypothalamic-pituitary-gonadal axis appears to be sex-dependent. In males, valproate decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) but elevated dehydroepiandrosterone sulfate (DHEAS) concentrations. Carbamazepine decreased testosterone/sex-hormone binding globulin (SHBG) ratio, whereas its active metabolite--oxcarbazepine--had no effect on androgens. In females, valproate decreased FSH-stimulated estradiol release and enhanced testosterone level. On the other hand, carbamazepine decreased testosterone level but enhanced SHBG concentration. It has been reported that carbamazepine, oxcarbazepine or joined administration of carbamazepine and valproate decrease thyroxine (T4) level in patients with no effect on thyrotropin (TSH). While valproate itself has no effect on T4, phenytoin, phenobarbital and primidone, as metabolic enzyme inducers, can decrease the level of free and bound thyroxine. On the other hand, new antiepileptics such as levetiracetam, tiagabine, vigabatrine or lamotrigine had no effect on thyroid hormones. With respect to hormonal regulation of metabolic processes, valproate was

  8. Antiepileptic Drugs and Pregnancy Outcomes

    PubMed Central

    Wlodarczyk, Bogdan J.; Palacios, Ana M.; George, Timothy M.; Finnell, Richard H.

    2012-01-01

    The treatment of epilepsy in women of reproductive age remains a clinical challenge. While most women with epilepsy require anticonvulsant drugs for adequate control of their seizures, the teratogenicity associated with some antiepileptic drugs is a risk that needs to be carefully addressed. Antiepileptic medications are also used to treat an ever broadening range of medical conditions such as bipolar disorder, migraine prophylaxis, cancer and neuropathic pain. Despite the fact that the majority of pregnancies of women with epilepsy who are receiving pharmacological treatment are normal, studies have demonstrated that the risk of having a pregnancy complicated by a major congenital malformation is doubled when comparing the risk of untreated pregnancies. Furthermore, when antiepileptic drugs (AEDs) are used in polytherapy regimens, the risk is tripled, especially when valproic acid (VPA) is included. However, it should be noted that the risks are specific for each anticonvulsant drug. Some investigations have suggested that the risk of teratogenicity is increased in a dose-dependent manner. More recent studies have reported that in utero exposure to AEDs can have detrimental effects on the cognitive functions and language skills in later stages of life. In fact, the FDA just issued a safety announcement on the impact of VPA on cognition (Safety Announcement 6-30-2011). The purpose of this document is to review the most commonly used compounds in the treatment of women with epilepsy, and to provide information on the latest experimental and human epidemiological studies of the effects of antiepileptic drugs in the exposed embryos. PMID:22711424

  9. Antiepileptic drugs and memory.

    PubMed

    Thompson, P J

    1992-01-01

    Assessing the effects of medication on cognitive functions including memory is fraught with methodological problems. This article illustrates the range of approaches that have been employed. Medication effects have been more readily demonstrated in patients with intractable epilepsy, in whom drug dosages are higher and the risk of polytherapy is greater. Newly diagnosed cases and individuals treated with monotherapy show fewer effects. Evaluation of memory functions in most studies has been very limited, and where effects have been recorded these may well be secondary to changes in attentional level or mental processing speed.

  10. Teratogenic effects of antiepileptic drugs

    PubMed Central

    Hill, Denise S; Wlodarczyk, Bogdan J; Palacios, Ana M; Finnell, Richard H

    2010-01-01

    Many antiepileptic drugs (AEDs) have therapeutic applications that extend beyond epilepsy to include neuropathic pain, migraine headaches and psychiatric disorders. The risk of some AEDs has been clearly established, but for newer drugs, small sample sizes and polytherapy exposures preclude a conclusive determination of their teratogenic potential. Most women with epilepsy will require AED therapy throughout their entire pregnancy to control seizures; the vast majority of pregnancies in women with epilepsy have positive outcomes. A conservative estimate suggests that AED monotherapy doubles, and polytherapy triples, the risk for major congenital malformations. Furthermore, while evidence is still accruing, recent investigations suggest that exposure to select AEDs results in altered cognitive function later in development. There is no evidence to suggest that additional folic acid supplementation ameliorates the increased risk of congenital malformations conferred by in utero AED exposure. PMID:20518610

  11. Neurodevelopmental effects of antiepileptic drugs.

    PubMed

    Meador, Kimford J

    2002-07-01

    Although the vast majority of children born to women with epilepsy are normal, these children are at increased risk for both anatomic and cognitive impairments. Current evidence suggests that the defects are the result of in utero antiepileptic drug (AED) exposure combined with a genetic predispositon. However, the exact mechanisms underlying these effects remain to be delineated. AED polytherapy increases the risk, but it remains uncertain if specific AEDs pose an overall greater threat. Most women with epilepsy cannot avoid AEDs during pregnancy because of the greater risks posed by seizures to the mother and fetus. Therefore, current recommendations emphasize definitive diagnosis and the use of AED monotherapy at the lowest effective dose if treatment is indicated. Prenatal folate and multivitamins should also be given routinely to women of childbearing age who require AED therapy. PMID:12044257

  12. Efficacy of New Antiepileptic Drugs

    PubMed Central

    Schmidt, Dieter

    2011-01-01

    Regarding efficacy of new antiepileptic drugs (AEDs) for seizure control, there are three important clinical questions. How effective are new AEDs when corrected for the efficacy of placebo? And even more important: How do new AEDs fare in terms of seizure remission compared with established agents? And finally: Have patients seizure-free on new AEDs a better chance for lasting remission after withdrawal versus those withdrawing from older agents? The answers raise concerns. Although add-on therapy with marketed new AEDs is more effective than placebo, as expected, the treatment difference for becoming seizure-free is disappointingly small (6%; 95% CI: 4–8%; z = 6.47; p < 0.001). Although many, but not all, new AEDs have comparable efficacy to old standard drugs in well-controlled trials, none of the new AEDs is superior to old drugs in terms of seizure remission. So far, we have no antiepileptogenic treatments that prevent the development of epilepsy or modify its detrimental course. The sobering results suggest the need for novel experimental and clinical strategies for the development of more effective new AEDs that interrupt ictogenesis more effectively and prevent or abort epileptogenesis. Ideally, we need new drugs that block both ictogenesis and epileptogenesis, resulting in complete cure of epilepsy. PMID:21461260

  13. Antiepileptic Drug Withdrawal in Dogs with Epilepsy

    PubMed Central

    Gesell, Felix Kaspar; Hoppe, Sonja; Löscher, Wolfgang; Tipold, Andrea

    2015-01-01

    Epilepsy is one of the most common neurological disorders in dogs and is treated by chronic administration of antiepileptic drugs (AEDs). In human beings with epilepsy, it is common clinical practice to consider drug withdrawal after a patient has been in remission (seizure free) for three or more years, but withdrawal is associated with the risk of relapse. In the present study, the consequences of AED withdrawal were studied in dogs with epilepsy. Therefore, 200 owners of dogs with idiopathic or presumed idiopathic epilepsy were contacted by telephone interview, 138 cases could be enrolled. In 11 cases, the therapy had been stopped after the dogs had become seizure free for a median time of 1 year. Reasons for AED withdrawal were appearance or fear of adverse side effects, financial aspects, and the idea that the medication could be unnecessary. Following AED withdrawal, four of these dogs remained seizure free, seven dogs suffered from seizure recurrence, of which only three dogs could regain seizure freedom after resuming AED therapy. Due to the restricted case number, an exact percentage of dogs with seizure recurrence after AED withdrawal cannot be given. However, the present study gives a hint that similar numbers as in human patients are found, and the data can help owners of epileptic dogs and the responsible clinician to decide when and why to stop antiepileptic medication. PMID:26664952

  14. Antiepileptic Drug Withdrawal in Dogs with Epilepsy.

    PubMed

    Gesell, Felix Kaspar; Hoppe, Sonja; Löscher, Wolfgang; Tipold, Andrea

    2015-01-01

    Epilepsy is one of the most common neurological disorders in dogs and is treated by chronic administration of antiepileptic drugs (AEDs). In human beings with epilepsy, it is common clinical practice to consider drug withdrawal after a patient has been in remission (seizure free) for three or more years, but withdrawal is associated with the risk of relapse. In the present study, the consequences of AED withdrawal were studied in dogs with epilepsy. Therefore, 200 owners of dogs with idiopathic or presumed idiopathic epilepsy were contacted by telephone interview, 138 cases could be enrolled. In 11 cases, the therapy had been stopped after the dogs had become seizure free for a median time of 1 year. Reasons for AED withdrawal were appearance or fear of adverse side effects, financial aspects, and the idea that the medication could be unnecessary. Following AED withdrawal, four of these dogs remained seizure free, seven dogs suffered from seizure recurrence, of which only three dogs could regain seizure freedom after resuming AED therapy. Due to the restricted case number, an exact percentage of dogs with seizure recurrence after AED withdrawal cannot be given. However, the present study gives a hint that similar numbers as in human patients are found, and the data can help owners of epileptic dogs and the responsible clinician to decide when and why to stop antiepileptic medication.

  15. Advances in anti-epileptic drug testing.

    PubMed

    Krasowski, Matthew D; McMillin, Gwendolyn A

    2014-09-25

    In the past twenty-one years, 17 new antiepileptic drugs have been approved for use in the United States and/or Europe. These drugs are clobazam, ezogabine (retigabine), eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide. Therapeutic drug monitoring is often used in the clinical dosing of the newer anti-epileptic drugs. The drugs with the best justifications for drug monitoring are lamotrigine, levetiracetam, oxcarbazepine, stiripentol, and zonisamide. Perampanel, stiripentol and tiagabine are strongly bound to serum proteins and are candidates for monitoring of the free drug fractions. Alternative specimens for therapeutic drug monitoring are saliva and dried blood spots. Therapeutic drug monitoring of the new antiepileptic drugs is discussed here for managing patients with epilepsy. PMID:24925169

  16. The New Antiepileptic Drugs: Their Neuropharmacology and Clinical Indications

    PubMed Central

    HANAYA, Ryosuke; ARITA, Kazunori

    2016-01-01

    The administration of antiepileptic drugs (AEDs) is the first treatment of epilepsy, one of the most common neurological diseases. Therapeutic guidelines include newer AEDs as front-line drugs; monotherapy with new AEDs is delivered in Japan. While about 70% of patients obtain good seizure control by taking one to three AEDs, about 60% experience adverse effects and 33% have to change drugs. Compared to traditional AEDs, the prolonged administration of new AEDs elicits fewer adverse effects and fewer drug interactions and their teratogenicity may be lower. These characteristics increase drug compliance and allow combination therapy for drug-resistant epilepsy, although the antiepileptic effects of the new AEDs are not greater than of traditional AEDs. Comorbidities are not rare in epileptics; many adult patients present with stroke and brain tumors. In stroke patients requiring risk control and in chemotherapy-treated brain tumor patients, their fewer drug interactions render the new AEDs advantageous. Also, new AEDs offer favorable side benefits for concurrent diseases and conditions. Patients with stroke and traumatic brain injury often present with psychiatric/behavioral symptoms and cognitive impairment and some new AEDs alleviate such symptoms. This review presents an outline of the new AEDs used to treat adult patients based on the pharmacological activity of the drugs and discusses possible clinical indications from the perspective of underlying causative diseases and comorbidities. PMID:26935782

  17. The New Antiepileptic Drugs: Their Neuropharmacology and Clinical Indications.

    PubMed

    Hanaya, Ryosuke; Arita, Kazunori

    2016-05-15

    The administration of antiepileptic drugs (AEDs) is the first treatment of epilepsy, one of the most common neurological diseases. Therapeutic guidelines include newer AEDs as front-line drugs; monotherapy with new AEDs is delivered in Japan. While about 70% of patients obtain good seizure control by taking one to three AEDs, about 60% experience adverse effects and 33% have to change drugs. Compared to traditional AEDs, the prolonged administration of new AEDs elicits fewer adverse effects and fewer drug interactions and their teratogenicity may be lower. These characteristics increase drug compliance and allow combination therapy for drug-resistant epilepsy, although the antiepileptic effects of the new AEDs are not greater than of traditional AEDs. Comorbidities are not rare in epileptics; many adult patients present with stroke and brain tumors. In stroke patients requiring risk control and in chemotherapy-treated brain tumor patients, their fewer drug interactions render the new AEDs advantageous. Also, new AEDs offer favorable side benefits for concurrent diseases and conditions. Patients with stroke and traumatic brain injury often present with psychiatric/behavioral symptoms and cognitive impairment and some new AEDs alleviate such symptoms. This review presents an outline of the new AEDs used to treat adult patients based on the pharmacological activity of the drugs and discusses possible clinical indications from the perspective of underlying causative diseases and comorbidities.

  18. Effects of antiepileptic drugs in electrophysiological tests.

    PubMed

    Rump, S; Kowalczyk, M

    1987-01-01

    Methods of the study of antiepileptic drugs activity by means of analysis of their effects on bioelectrical ictal phenomena in the animal brain are described. The paper deals especially with EEG signal processing methods. Application of various nonparametric models (e.g. interval-amplitude scatter plots, power spectra analysis) as well as parametric models (e.g. autoregressive model, segmentation analysis) is discussed. A discriminative approach to some of these methods (especially to autoregressive model) is also presented. Special attention is stressed on the value of these methods for the study of anticonvulsant drugs activity.

  19. Emerging Antiepileptic Drugs for Severe Pediatric Epilepsies.

    PubMed

    Mudigoudar, Basanagoud; Weatherspoon, Sarah; Wheless, James W

    2016-05-01

    The medical management of the epilepsy syndromes of early childhood (eg, infantile spasms, Dravet syndrome, and Lennox-Gastaut syndrome) is challenging; and requires careful evaluation, classification, and treatment. Pharmacologic therapy continues to be the mainstay of management for these children, and as such it is important for the clinician to be familiar with the role of new antiepileptic drugs. This article reports the clinical trial data and personal experience in treating the severe epilepsies of childhood with the recently Food and Drug Administration-approved new antiepileptic drugs (vigabatrin, rufinamide, perampanel, and clobazam) and those in clinical trials (cannabidiol, stiripentol, and fenfluramine). Genetic research has also identified an increasing number of pediatric developmental and seizure disorders that are possibly treatable with targeted drug therapies, focused on correcting underlying neural dysfunction. We highlight recent genetic advances, and how they affect our treatment of some of the genetic epilepsies, and speculate on the use of targeted genetic treatment (precision medicine) in the future. PMID:27544474

  20. Epilepsy, sex hormones, and antiepileptic drugs.

    PubMed

    Mattson, R H; Cramer, J A

    1985-01-01

    Many factors associated with hormone function have an impact on the course of epilepsy. Patients with epilepsy may have disturbances in sexual function such as anovulatory cycles in women and decreased libido and potency in men. Data indicate seizures, especially those arising in the limbic system, may influence the hypothalamic pituitary axis. Antiepileptic drugs also influence sexual function through direct brain effects as well as through induced changes in pharmacokinetics of the sex steroid hormones. Pregnancy has been reported to be a time of increased seizures; however, this has often been associated with low drug levels, for reasons that include inadequate drug dose, possible changes in pharmacokinetics, and noncompliance. Some evidence suggests that hormones affect seizure frequency. Changes in seizures during the menstrual cycle (catamenial epilepsy) have been found in some women: seizures were fewer during the luteal phase but increased when progesterone levels declined. Some improvement in seizure frequency has been shown in pilot studies using medroxyprogesterone acetate, a synthetic progesterone. Current concepts of the interrelationship among epilepsy, sex hormones, and antiepileptic drugs are discussed.

  1. Interactions between antiepileptic drugs and hormones.

    PubMed

    Svalheim, Sigrid; Sveberg, Line; Mochol, Monika; Taubøll, Erik

    2015-05-01

    Antiepileptic drugs (AEDs) are known to have endocrine side effects in both men and women. These can affect fertility, sexuality, thyroid function, and bone health, all functions of major importance for well-being and quality of life. The liver enzyme inducing antiepileptic drugs (EIAEDs), like phenobarbital, phenytoin, and carbamazepine, and also valproate (VPA), a non-EIAED, are most likely to cause such side effects. AED treatment can alter the levels of different sex hormones. EIAEDs increase sex hormone binding globulin (SHBG) concentrations in both men and women. Over time, this elevation can lead to lower levels of bioactive testosterone and estradiol, which may cause menstrual disturbances, sexual problems, and eventually reduced fertility. VPA can cause weight gain in both men and women. In women, VPA can also lead to androgenization with increased serum testosterone concentrations, menstrual disturbances, and polycystic ovaries. Lamotrigine has not been shown to result in endocrine side effects. The newer AEDs have not yet been thoroughly studied, but case reports indicate that some of these drugs could also be suspected to cause such effects if endocrine changes commence after treatment initiation. It is important to be aware of possible endocrine side effects of AEDs as they can have a major impact on quality of life, and are, at least partly, reversible after AED discontinuation.

  2. Interactions between antiepileptic drugs and hormones.

    PubMed

    Svalheim, Sigrid; Sveberg, Line; Mochol, Monika; Taubøll, Erik

    2015-05-01

    Antiepileptic drugs (AEDs) are known to have endocrine side effects in both men and women. These can affect fertility, sexuality, thyroid function, and bone health, all functions of major importance for well-being and quality of life. The liver enzyme inducing antiepileptic drugs (EIAEDs), like phenobarbital, phenytoin, and carbamazepine, and also valproate (VPA), a non-EIAED, are most likely to cause such side effects. AED treatment can alter the levels of different sex hormones. EIAEDs increase sex hormone binding globulin (SHBG) concentrations in both men and women. Over time, this elevation can lead to lower levels of bioactive testosterone and estradiol, which may cause menstrual disturbances, sexual problems, and eventually reduced fertility. VPA can cause weight gain in both men and women. In women, VPA can also lead to androgenization with increased serum testosterone concentrations, menstrual disturbances, and polycystic ovaries. Lamotrigine has not been shown to result in endocrine side effects. The newer AEDs have not yet been thoroughly studied, but case reports indicate that some of these drugs could also be suspected to cause such effects if endocrine changes commence after treatment initiation. It is important to be aware of possible endocrine side effects of AEDs as they can have a major impact on quality of life, and are, at least partly, reversible after AED discontinuation. PMID:25797888

  3. [New antiepileptic drugs: characteristics and clinical applications].

    PubMed

    Ohtsuka, Yoko

    2014-05-01

    New antiepileptic drugs (AEDs) that have been used in many other countries for more than 10 years have only recently became available for use in Japan. Gabapentin, topiramate, lamotrigine and levetiracetam were licensed for use in Japan between 2006 and 2010. Stiripentol for Dravet syndrome and rufinamide for Lennox-Gastaut syndrome were also approved in 2012 and 2013 as orphan drugs. Clinical trials of other new AEDs such as oxcarbazepine, vigabatrin, lacosamide, and perampanel are in progress. In this review, the general characteristics of the new AEDs are discussed with regards to their effectiveness, tolerability, drug interaction, safety and mechanisms of action. The effectiveness, of the new AEDs compared with established AEDs is also discussed. Clinical applications of the new AEDs, focusing on gabapentin, topiramate, lamotrigine and levetiracetam are also discussed based on our domestic experience as well as overseas reports. PMID:24912297

  4. Old versus New: Why Do We Need New Antiepileptic Drugs?

    PubMed Central

    Lee, Sang Kun

    2014-01-01

    Achieving complete seizure remission without adverse events is the goal of epilepsy treatment. Recently, many new antiepileptic drugs (AEDs) have been developed. Even though the efficacy of new AEDs is not stronger than that of old AEDs, there are advantages in using new AEDs. They have unique or different mechanisms of action that enable the creation of possible synergistic combinations. They usually exhibit fewer or no pharmacokinetic drug interactions. Furthermore, the response to AEDs varies individually. A similar efficacy does not imply a similar response from all patients. Many new AEDs have fewer adverse events, including induction of congenital malformations. Other concerns about the long-term effects of established AEDs, such as bone health and development of atherosclerosis, may be alleviated by the use of new AEDs. New AEDs are needed to achieve better care of patients with epilepsy. PMID:25625087

  5. Chemical properties of antiepileptic drugs (AEDs).

    PubMed

    Bialer, Meir

    2012-07-01

    Between 1990 and 2011 the following fifteen new antiepileptic drugs (AEDs) were approved: eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, retigabine, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. These AEDs (except felbamate) offer appreciable advantages in terms of their favorable pharmacokinetics, improved tolerability and lower potential for drug interactions. All AEDs introduced after 1990 that are not second generation drugs (with the exception of vigabatrin and tiagabine) were developed empirically (sometimes serendipitously) utilizing mechanism-unbiased anticonvulsant animal models. The empirical nature of the discovery of new AEDs in the last three decades coupled with their multiple mechanisms of action explains their diverse chemical structures. The availability of old and new AEDs with various activity spectra and different tolerability profiles enables clinicians to better tailor drug choice to the characteristics of individual patients. With fifteen new AEDs having entered the market in the past 20years the antiepileptic market is crowded. Consequently, epilepsy alone is not attractive in 2011 to the pharmaceutical industry even though the clinical need of refractory epilepsy remains unmet. Due to this situation, future design of new AEDs must also have a potential in non-epileptic CNS disorders such as neuropathic pain, migraine prophylaxis and bipolar disorder or fibromyalgia as demonstrated by the sales revenues of pregabalin, topiramate and valproic acid. This review analyzes the effect that the emerging knowledge on the chemical properties of the old AEDs starting from phenobarbital (1912) has had on the design of subsequent AEDs and new therapeutics as well as the current approach to AED discovery. PMID:22210279

  6. Reflex sympathetic dystrophy associated with antiepileptic drugs.

    PubMed

    Falasca, G F; Toly, T M; Reginato, A J; Schraeder, P L; O'Connor, C R

    1994-01-01

    Reflex sympathetic dystrophy syndrome (RSDS) complicating antiepileptic drug (AED) therapy is not well acknowledged in the neurologic literature. We report 4 patients with reflex sympathetic dystrophy that occurred while they were receiving AEDs. All patients had shoulder and hand involvement, which in 2 was bilateral, and 1 had ipsilateral foot involvement. Two patients did not respond to a change in AEDs, but all improved with a course of prednisone. One patient with phenobarbital (PB)-associated RSDS relapsed on inadvertent rechallenge with secobarbital. A review of the literature showed that several other fibrosing disorders are associated with AED administration, including Dupuytren's contractures, frozen shoulder, plantar and hand nodules, and Peyronie's disease. RSD associated with AEDs is important to recognize because it may result in permanent disability if treatment is delayed.

  7. The Impact of Psychoactive Drugs on Seizures and Antiepileptic Drugs.

    PubMed

    Habibi, Mitra; Hart, Felecia; Bainbridge, Jacquelyn

    2016-08-01

    Psychiatric comorbidities are very common in patients with epilepsy, and in fact, a bidirectional relationship between epilepsy and some psychiatric disorders have been identified. However, despite their high prevalence, these comorbidities are not routinely recognized or adequately treated causing a significant burden for these patients. Atypical presentations of some of these psychiatric comorbidities in epilepsy, the concern that some psychotropic drugs may lower seizure threshold worsening frequency of seizures, possibility of many drug-drug interactions, and the negative impact of some antiepileptic drugs on psychiatric conditions are some of the challenges faced by clinicians. Although the main focus in epilepsy has remained on treatment of seizures, acknowledgment of these comorbidities and their timely diagnosis and appropriate treatment not only can impact patients' quality of life but also may improve their response to antiepileptic therapies. PMID:27315249

  8. Antiepileptic drugs, sex hormones, and PCOS.

    PubMed

    Verrotti, Alberto; D'Egidio, Claudia; Mohn, Angelika; Coppola, Giangennaro; Parisi, Pasquale; Chiarelli, Francesco

    2011-02-01

    Reproductive endocrine dysfunction in women with epilepsy is an important issue, and in recent years there is growing evidence to support the effect on sex hormones of both epilepsy per se and various antiepileptic drugs (AEDs). Focal epileptic discharges from the temporal lobe may have a direct influence on the function of the hypothalamic-pituitary axis, thereby altering the release of sex steroid hormones. The role of laterality and severity of epilepsy is still conflicting. The use of the liver enzyme-inducing AEDs--such as phenobarbital, phenytoin, and carbamazepine--can increase serum sex hormone-binding globulin concentrations, leading to diminished bioactivity of testosterone (T) and estradiol. Valproic acid, an enzyme inhibitor, has been associated with the occurrence of reproductive endocrine disorders characterized by high serum T, free androgen index, androstenedione, dehydroepiandrosterone sulfate concentrations, and with polycystic changes in ovaries and menstrual disorders. A better understanding of the effects of AEDs on sex hormones is key to selecting the appropriate AEDs and is crucial for reproductive health in female patients.

  9. Neurodevelopmental effects of fetal antiepileptic drug exposure.

    PubMed

    Velez-Ruiz, Naymee J; Meador, Kimford J

    2015-03-01

    Many studies investigating cognitive outcomes in children of women with epilepsy report an increased risk of mental impairment. Verbal scores on neuropsychometric measures may be selectively more involved. While a variety of factors contribute to the cognitive problems of children of women with epilepsy, antiepileptic drugs (AEDs) appear to play a major role. The mechanisms by which AEDs affect neurodevelopmental outcomes remain poorly defined. Animal models suggest that AED-induced apoptosis, altered neurotransmitter environment, and impaired synaptogenesis are some of the mechanisms responsible for cognitive and behavioral teratogenesis. AEDs that are known to induce apoptosis, such as valproate, appear to affect children's neurodevelopment in a more severe fashion. Fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains, and these appear to persist at least until the age of 6. Some studies have shown neurodevelopmental deficiencies associated with the use of phenobarbital and possibly phenytoin. So far, most of the investigations available suggest that fetal exposures to lamotrigine or levetiracetam are safer with regard to cognition when compared with other AEDs. Studies on carbamazepine show contradictory results, but most information available suggests that major poor cognitive outcomes should not be attributed to this medication. Overall, children exposed to polytherapy prenatally appear to have worse cognitive and behavioral outcomes compared with children exposed to monotherapy, and with the unexposed. There is an increase risk of neurodevelopmental deficits when polytherapy involves the use of valproate versus other agents. PMID:25693658

  10. Antiepileptic drug treatment strategies in neonatal epilepsy.

    PubMed

    Hernan, A E; Holmes, G L

    2016-01-01

    The highest risk of seizures across the lifespan is in the neonatal period. The enhanced excitability of the immature brain compared to the mature brain is related to the sequential development and expression of essential neurotransmitter signaling pathways. During the neonatal period there is an overabundance of excitatory receptors, and γ-amino-butyric acid (GABA) is potentially depolarizing, as opposed to hyperpolarizing in the older brain. While this enhanced excitability is required for regulation of activity-dependent synapse formation and refining of synaptic connections that are necessary for normal brain development, enhanced excitability predisposes the immature brain to seizures. In addition to being common, neonatal seizures are very difficult to treat; antiepileptic drugs used in older children and adults are less efficacious, and possibly detrimental to brain development. In an effort to target the unique features of neurotransmission in the neonate, bumetanide, an NKCC1 inhibitor which reduces intraneuronal Cl(-) and induces a significant shift of EGABA toward more hyperpolarized values in vitro, has been used to treat neonatal seizures. As the understanding of the pathophysiology of genetic forms of neonatal epilepsy has evolved there have been a few successful attempts to pharmacologically target the mutated protein. This approach, while promising, is challenging due to the findings that the genetic syndromes presenting in infancy demonstrate genetic heterogeneity in regard to both the mutated gene and its function. PMID:27323943

  11. Availability of antiepileptic drugs across Europe.

    PubMed

    Baftiu, Arton; Johannessen Landmark, Cecilie; Nikaj, Valent; Neslein, Inger-Lise; Johannessen, Svein I; Perucca, Emilio

    2015-12-01

    Europe consists of 53 countries with widely different economic conditions and different political, educational, and health care systems. This study was aimed at determining the availability of antiepileptic drugs (AEDs) across Europe. An electronic questionnaire was submitted to all 43 European chapters of the International League Against Epilepsy (ILAE). Outcome measures were availability of older, newer, and newest AEDs, generic products, indications, reimbursement rules, and reasons for lack of availability of AEDs. Countries were divided according to economic status as defined by the World Bank. Thirty-four chapters (79%) provided data. There were large differences in AED availability across countries, especially between high-income countries and the other countries. The newest AEDs were not available in any of the 12 non-high-income countries. Availability was higher in countries with public reimbursement systems. Reimbursement policies ranged from full reimbursement for all AEDs to complete lack of reimbursement. Main hurdles for poor access to AEDs included lack of regulatory approval, high prices and reimbursement restrictions. The availability of AEDs differs across European countries, with many hurdles hampering access to epilepsy medicines, particularly to new medications. These findings raise major concerns on the quality of epilepsy care in many countries. PMID:26477534

  12. Molecular Targets for Antiepileptic Drug Development

    PubMed Central

    Meldrum, Brian S.; Rogawski, Michael A.

    2007-01-01

    Summary This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the α subunits of voltage-gated Na+ channels and also T-type voltage-gated Ca2+ channels) or influence GABA-mediated inhibition. Recently, α2–δ voltage-gated Ca2+ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na+ channels and GABAA receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca2+ channel subunits and auxiliary proteins, A- or M-type voltage-gated K+ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABAB and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current Ih; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na+ channels underlying persistent Na+ currents or GABAA receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the

  13. Use of antiepileptic drugs in hepatic and renal disease.

    PubMed

    Asconapé, Jorge J

    2014-01-01

    The use of antiepileptic drugs in patients with renal or hepatic disease is common in clinical practice. Since the liver and kidney are the main organs involved in the elimination of most drugs, their dysfunction can have important effects on the disposition of antiepileptic drugs. Renal or hepatic disease can prolong the elimination of the parent drug or an active metabolite leading to accumulation and clinical toxicity. It can also affect the protein binding, distribution, and metabolism of a drug. The protein binding of anionic acidic drugs, such as phenytoin and valproate, can be reduced significantly by renal failure, causing difficulties in the interpretation of total serum concentrations commonly used in clinical practice. Dialysis can further modify the pharmacokinetic parameters or result in significant removal of the antiepileptic drugs. Antiepileptic drugs that are eliminated unchanged by the kidneys or undergo minimal metabolism include gabapentin, pregabalin, vigabatrin, and topiramate when used as monotherapy. Drugs eliminated predominantly by biotransformation include phenytoin, valproate, carbamazepine, tiagabine, and rufinamide. Drugs eliminated by a combination of renal excretion and biotransformation include levetiracetam, lacosamide, zonisamide, primidone, phenobarbital, ezogabine/retigabine, oxcarbazepine, eslicarbazepine, ethosuximide, and felbamate. Drugs in the latter group can be used cautiously in patients with either renal or liver failure. Antiepileptic drugs that are at high risk of being extracted by hemodialysis include ethosuximide, gabapentin, lacosamide, levetiracetam, pregabalin and topiramate. The use of antiepileptic drugs in the presence of hepatic or renal disease is complex and requires great familiarity with the pharmacokinetics of these agents. Closer follow-up of the patients and more frequent monitoring of serum concentrations are required to optimize clinical outcomes. PMID:24365310

  14. Hypoactive sexual desire disorder caused by antiepileptic drugs

    PubMed Central

    Singh, M.; Bathla, Manish; Martin, A.; Aneja, J.

    2015-01-01

    Female sexual dysfunction is common but poorly understood sexual problem in women. Sexual dysfunction in female is multi-factorial in origin and also observed with intake of drug acting on central nervous system. This case report describes a female epileptic patient who developed sexual dysfunction with intake of antiepileptic drugs. PMID:26157303

  15. Antiepileptic drugs in the treatment of anxiety disorders: role in therapy.

    PubMed

    Van Ameringen, Michael; Mancini, Catherine; Pipe, Beth; Bennett, Mark

    2004-01-01

    Pharmacotherapy for anxiety disorders is an active area of research. A variety of drug groups have been shown to be effective in treating many of the anxiety disorders, with selective serotonin reuptake inhibitors (SSRIs) being considered first-line agents for virtually all anxiety disorders. There is a clinical need for alternative drug treatments, as many patients do not achieve a complete response and experience significant adverse effects. The successful use of antiepileptic drugs in mood disorders has led clinicians and researchers to investigate their potential efficacy in other psychiatric disorders, particularly in anxiety disorders. There have been a number of investigations conducted in the form of case reports, case series and open-label trials, suggesting the potential usefulness of antiepileptic drug treatment in a variety of anxiety disorders. More reliable evidence for the use of antiepileptic drugs in anxiety disorders can be gleaned from recent placebo-controlled trials. Thus far, the strongest placebo-controlled evidence has demonstrated the efficacy of pregabalin in treating social phobia and generalised anxiety disorder, while smaller or less robust controlled trials have suggested the potential efficacy of gabapentin in social phobia, lamotrigine in post-traumatic stress disorder, and valproic acid in panic disorder. Antiepileptic drugs may have a place in the treatment of anxiety disorders; however, further investigation is warranted to determine in what circumstances they should be used as monotherapy or as augmenting agents in individuals who are partially or non-responsive to conventional therapy.

  16. Current approaches to the use of generic antiepileptic drugs.

    PubMed

    Krämer, G; Biraben, A; Carreno, M; Guekht, A; de Haan, G J; Jedrzejczak, J; Josephs, D; van Rijckevorsel, K; Zaccara, G

    2007-08-01

    Generic substitution is encouraged as a cost containment strategy for the management of health care resources. However, in epilepsy, the consequences of loss of symptom control are important, and antiepileptic drugs have narrow therapeutic indices. For this reason, generic substitution may be problematic, and certain health authorities have excluded antiepileptic drugs from overall policy recommendations on generic prescribing. The absence of bioequivalence data among generic forms and the relatively broad criteria for bioequivalence with the branded drug allow differences in drug exposure to arise that may be clinically relevant and necessitate monitoring of plasma levels when switching formulations to avoid loss of seizure control or emergence of side effects. Management of these issues carries a significant cost, which should be weighed carefully against the cost savings acquired when purchasing the drug. Both physicians and patients have a right to be informed and approve before pharmacists make a generic substitution or switch between generics.

  17. Epilepsy, Antiepileptic Drugs, and Aggression: An Evidence-Based Review

    PubMed Central

    Besag, Frank; Ettinger, Alan B.; Mula, Marco; Gobbi, Gabriella; Comai, Stefano; Aldenkamp, Albert P.; Steinhoff, Bernhard J.

    2016-01-01

    Antiepileptic drugs (AEDs) have many benefits but also many side effects, including aggression, agitation, and irritability, in some patients with epilepsy. This article offers a comprehensive summary of current understanding of aggressive behaviors in patients with epilepsy, including an evidence-based review of aggression during AED treatment. Aggression is seen in a minority of people with epilepsy. It is rarely seizure related but is interictal, sometimes occurring as part of complex psychiatric and behavioral comorbidities, and it is sometimes associated with AED treatment. We review the common neurotransmitter systems and brain regions implicated in both epilepsy and aggression, including the GABA, glutamate, serotonin, dopamine, and noradrenaline systems and the hippocampus, amygdala, prefrontal cortex, anterior cingulate cortex, and temporal lobes. Few controlled clinical studies have used behavioral measures to specifically examine aggression with AEDs, and most evidence comes from adverse event reporting from clinical and observational studies. A systematic approach was used to identify relevant publications, and we present a comprehensive, evidence-based summary of available data surrounding aggression-related behaviors with each of the currently available AEDs in both adults and in children/adolescents with epilepsy. A psychiatric history and history of a propensity toward aggression/anger should routinely be sought from patients, family members, and carers; its presence does not preclude the use of any specific AEDs, but those most likely to be implicated in these behaviors should be used with caution in such cases. PMID:27255267

  18. Epilepsy, Antiepileptic Drugs, and Aggression: An Evidence-Based Review.

    PubMed

    Brodie, Martin J; Besag, Frank; Ettinger, Alan B; Mula, Marco; Gobbi, Gabriella; Comai, Stefano; Aldenkamp, Albert P; Steinhoff, Bernhard J

    2016-07-01

    Antiepileptic drugs (AEDs) have many benefits but also many side effects, including aggression, agitation, and irritability, in some patients with epilepsy. This article offers a comprehensive summary of current understanding of aggressive behaviors in patients with epilepsy, including an evidence-based review of aggression during AED treatment. Aggression is seen in a minority of people with epilepsy. It is rarely seizure related but is interictal, sometimes occurring as part of complex psychiatric and behavioral comorbidities, and it is sometimes associated with AED treatment. We review the common neurotransmitter systems and brain regions implicated in both epilepsy and aggression, including the GABA, glutamate, serotonin, dopamine, and noradrenaline systems and the hippocampus, amygdala, prefrontal cortex, anterior cingulate cortex, and temporal lobes. Few controlled clinical studies have used behavioral measures to specifically examine aggression with AEDs, and most evidence comes from adverse event reporting from clinical and observational studies. A systematic approach was used to identify relevant publications, and we present a comprehensive, evidence-based summary of available data surrounding aggression-related behaviors with each of the currently available AEDs in both adults and in children/adolescents with epilepsy. A psychiatric history and history of a propensity toward aggression/anger should routinely be sought from patients, family members, and carers; its presence does not preclude the use of any specific AEDs, but those most likely to be implicated in these behaviors should be used with caution in such cases. PMID:27255267

  19. Breastfeeding in Children of Women Taking Antiepileptic Drugs

    PubMed Central

    Meador, Kimford J.; Baker, Gus A.; Browning, Nancy; Cohen, Morris J.; Bromley, Rebecca L.; Clayton-Smith, Jill; Kalayjian, Laura A.; Kanner, Andres; Liporace, Joyce D.; Pennell, Page B.; Privitera, Michael; Loring, David W.

    2014-01-01

    IMPORTANCE Breastfeeding is known to have beneficial effects, but concern exists that breastfeeding during maternal antiepileptic drug (AED) therapy may be harmful. We previously noted no adverse effects of breastfeeding associated with AED use on IQ at age 3 years, but IQ at age 6 years is more predictive of school performance and adult abilities. OBJECTIVES To examine the effects of AED exposure via breastfeeding on cognitive functions at age 6 years. DESIGN, SETTING, AND PARTICIPANTS Prospective observational multicenter study of long-term neurodevelopmental effects of AED use. Pregnant women with epilepsy receiving monotherapy (ie, carbamazepine, lamotrigine, phenytoin, or valproate) were enrolled from October 14, 1999, through April 14, 2004, in the United States and the United Kingdom. At age 6 years, 181 children were assessed for whom we had both breastfeeding and IQ data. All mothers in this analysis continued taking the drug after delivery. MAIN OUTCOMES AND MEASURES Differential Ability Scales IQ was the primary outcome. Secondary measures included measures of verbal, nonverbal, memory, and executive functions. For our primary analysis, we used a linear regression model with IQ at age 6 years as the dependent variable, comparing children who breastfed with those who did not. Similar secondary analyses were performed for the other cognitive measures. RESULTS In total, 42.9% of children were breastfed a mean of 7.2 months. Breastfeeding rates and duration did not differ across drug groups. The IQ at age 6 years was related to drug group (P italic> .001 [adjusted IQ worse by 7–13 IQ points for valproate compared to other drugs]), drug dosage (regression coefficient, −0.1; 95% CI, −0.2 to 0.0; P = .01 [higher dosage worse]), maternal IQ (regression coefficient, 0.2; 95% CI, 0.0 to 0.4; P = .01 [higher child IQ with higher maternal IQ]), periconception folate use (adjusted IQ 6 [95% CI, 2–10] points higher for folate, P = .005), and breastfeeding

  20. [Social aspects of epilepsy: marriage, pregnancy, driving, antiepileptic drug withdrawal and against social stigma].

    PubMed

    Tsuji, Sadatoshi

    2004-11-01

    Persons with epilepsy need adequate advice and effective counselling about issues such as marriage, pregnancy, risks of inheriting epilepsy, driving, employment and antiepileptic drug withdrawal, because these persons are not receiving important information and education about their condition and possible adverse effects of treatment. Furthermore, women with epilepsy have increased rates of pregnancy complications and poor fetal outcomes including congenital malformations and developmental delay related to both their epilepsy and antiepileptic drugs. However, approximately 90% of all women with epilepsy undergo normal pregnancy and give birth to children free of birth defects. Pregnancy is generally safe in women with epilepsy. The study of long-term prognosis of childhood-onset epilepsy in Japan shows that the majority of these patients have lower levels of educational background as well as employment and marital status compared with the general population (Wakamoto H. et al). Of patients with epilepsy, 60% to 70% achieve control with antiepileptic medication. However, several antiepileptic drug withdrawal studies show variable rates of success, with relapse rates ranging from 12% to 63% (Britton J.W.). Driving is listed as major problem in persons with epilepsy. However, the patients with seizure-free more than two years have been able to get the driver's license since June, 2002. Social attitudes towards epilepsy cause more distress to the patient than the disease itself. We should realize that persons with epilepsy are normal or near-normal. To ameliorate the social stigma against epilepsy, continuous and repetitive educational efforts would be needed.

  1. Antiepileptic drugs in the treatment of psychiatric disorders.

    PubMed

    Kaufman, Kenneth R

    2011-05-01

    The clinical interface between psychiatry and neurology is epilepsy; the pharmacological expression of this interface is antiepileptic drugs (AEDs), as they are used to treat both epilepsy and psychiatric disorders, especially bipolar disorders. The prevalence of psychiatric comorbidity and the risk of suicidal behavior/ideation/suicide are markedly increased in patients with epilepsy (PWE). Though AEDs receive initial indications for the treatment of epilepsy, currently the majority of AEDs are used to treat pain and psychiatric disorders. Thus in selecting the appropriate AEDs for treatment of PWE, consideration should be given to which AEDs best treat the epileptic disorder and the psychiatric comorbidity. This review is an overview of 21 AEDs in which negative psychotropic properties, approved indications in psychiatry, off-label studied uses in psychiatry, and principal uses in psychiatry are presented with literature review. A total of 40 psychiatric uses have been identified. Of the 21 AEDs reviewed, only 5 have U.S. Food and Drug Administration and/or European Medicines Agency psychiatric approval for limited uses; the majority of AEDs are used off-label. Many of these off-label uses are based on case reports, open-label studies, and poorly controlled or small-sample-size studies. In some instances, off-label use persists in the face of negative pivotal trials. Further placebo-controlled (augmentation and monotherapy) parallel-arm research with active comparators is required in the complex field of AED treatment of psychiatric disorders to minimize the treatment gap not only for PWE with psychiatric disorders, but also for psychiatric patients who would benefit from properly studied AEDs while minimizing adverse effects.

  2. Analysis of nocebo effects of antiepileptic drugs across different conditions.

    PubMed

    Zaccara, Gaetano; Giovannelli, Fabio; Giorgi, Filippo Sean; Franco, Valentina; Gasparini, Sara

    2016-07-01

    The aim of this study was to assess the nocebo effect in all randomised controlled trials (RCTs) exploring the effect of antiepileptic drugs (AEDs) in the clinical conditions in which these compounds have been studied with the exception of epilepsy. We searched for all double-blind, placebo-controlled trials performed in adult patients, testing AEDs in any clinical condition except epilepsy. The following data were extracted from the placebo arms: the number of randomized patients, the number of patients withdrawing because of adverse effects (AEs), and the number of patients with 11 predefined AEs (dizziness, ataxia/coordination abnormal, diplopia, somnolence, fatigue, headache, memory impairment, tremor, abnormal thinking, anxiety and depression). Outcome measures were the percentages of patients whithdrawing due to AEs and reporting the selected AEs. RCTs included in the analysis were grouped in six main categories of clinical conditions (pain, movement disorders, psychiatric disorders, substance abuse, obesity and binge eating disorders, and miscellanea). Proportions of patients with 95 % confidence intervals (CIs) have been calculated for all reported outcome measures. Thirteen AEDs were studied and the total number of selected RCTs was 157. Significant percentages of placebo-treated patients withdrawing due to AEs and with specific AEs were observed in several cases. Significant differences emerged across different conditions. Comparisons with results of a previous meta-analysis on all RCTs in patients with drug-resistant epilepsies showed that ataxia, diplopia and fatigue were significantly more frequent, and patients withdrawing were significantly less frequent, in placebo-treated epileptic patients. Significant differences have been identified in the AEDs-induced nocebo effect across different conditions. Placebo-treated epilepsy patients have significantly more frequent neurological AEs. PMID:26810717

  3. Therapeutic drug monitoring of antiepileptic drugs by use of saliva.

    PubMed

    Patsalos, Philip N; Berry, Dave J

    2013-02-01

    Blood (serum/plasma) antiepileptic drug (AED) therapeutic drug monitoring (TDM) has proven to be an invaluable surrogate marker for individualizing and optimizing the drug management of patients with epilepsy. Since 1989, there has been an exponential increase in AEDs with 23 currently licensed for clinical use, and recently, there has been renewed and extensive interest in the use of saliva as an alternative matrix for AED TDM. The advantages of saliva include the fact that for many AEDs it reflects the free (pharmacologically active) concentration in serum; it is readily sampled, can be sampled repetitively, and sampling is noninvasive; does not require the expertise of a phlebotomist; and is preferred by many patients, particularly children and the elderly. For each AED, this review summarizes the key pharmacokinetic characteristics relevant to the practice of TDM, discusses the use of other biological matrices with particular emphasis on saliva and the evidence that saliva concentration reflects those in serum. Also discussed are the indications for salivary AED TDM, the key factors to consider when saliva sampling is to be undertaken, and finally, a practical protocol is described so as to enable AED TDM to be applied optimally and effectively in the clinical setting. Overall, there is compelling evidence that salivary TDM can be usefully applied so as to optimize the treatment of epilepsy with carbamazepine, clobazam, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, primidone, topiramate, and zonisamide. Salivary TDM of valproic acid is probably not helpful, whereas for clonazepam, eslicarbazepine acetate, felbamate, pregabalin, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin, the data are sparse or nonexistent. PMID:23288091

  4. Role of antiepileptic drugs in the management of eating disorders.

    PubMed

    McElroy, Susan L; Guerdjikova, Anna I; Martens, Brian; Keck, Paul E; Pope, Harrison G; Hudson, James I

    2009-01-01

    Growing evidence suggests that antiepileptic drugs (AEDs) may be useful in managing some eating disorders. In the present paper, we provide a brief overview of eating disorders, the rationale for using AEDs in the treatment of these disorders and review the data supporting the effectiveness of specific AEDs in the treatment of patients with eating disorders. In addition, the potential mechanisms of action of AEDs in these conditions are discussed. Of the available AEDs, topiramate appears to have the broadest spectrum of action as an anti-binge eating, anti-purging and weight loss agent, as demonstrated in two placebo-controlled studies in bulimia nervosa and three placebo-controlled studies in binge-eating disorder (BED) with obesity. Topiramate may also have beneficial effects in night-eating syndrome and sleep-related eating disorder, but controlled trials in these conditions are needed. The results of one small controlled study suggest that zonisamide may have efficacy in BED with obesity. However, both topiramate and zonisamide are associated with adverse effect profiles that may limit their use in patients with eating disorders. Phenytoin may be effective in some patients with compulsive binge eating, particularly if co-morbid EEG abnormalities are present, but available data are too varied to allow definitive conclusions to be made. Carbamazepine and valproate may be effective in treating patients with bulimia nervosa or anorexia nervosa when they are used to treat an associated psychiatric (e.g. mood) or neurological (e.g. seizure) disorder; otherwise, both agents, particularly valproate, are associated with weight gain. In conclusion, AEDs have an emerging role in the management of some eating disorders.

  5. The long-term safety of antiepileptic drugs.

    PubMed

    Gaitatzis, Athanasios; Sander, Josemir W

    2013-06-01

    Antiepileptic drugs (AEDs) are used by millions of people worldwide for the treatment of epilepsy, as well as in many other neurological and psychiatric conditions. They are frequently associated with adverse effects (AEs), which have an impact on the tolerability and success of treatment. Half the people who develop intolerable AEs discontinue treatment early on after initiation, while the majority of people will continue to be exposed to their effects for long periods of time. The long-term safety of AEDs reflects their potential for chronic, cumulative dose effects; rare, but potentially serious late idiosyncratic effects; late, dose-related effects; and delayed, teratogenic or neurodevelopmental effects. These AEs can affect every body system and are usually insidious. With the exception of delayed effects, most other late or chronic AEs are reversible. To date, there is no clear evidence of a carcinogenic effect of AEDs in humans. While physicians are aware of the long-term AEs of old AEDs (the traditional liver enzyme-inducing AEDs and valproate), information about AEs of new AEDs (such as lamotrigine, levetiracetam, oxcarbazepine, topiramate or zonisamide), particularly of their teratogenic effects, has emerged over the years. Sporadic publications have raised issues about AEs of the newer AEDs eslicarbazepine, retigabine, rufinamide, lacosamide and perampanel but their long-term safety profiles may take years to be fully appreciated. Physicians should not only be aware of the late and chronic AEs of AEDs but should systematically enquire and screen for these according to the individual AED AE profile. Care should be taken for individuals with comorbid conditions that may render them more susceptible to specific AEs. Prevention and appropriate management of long-term AED AEs is expected to improve adherence to treatment, quality of life and control of epilepsy. PMID:23673774

  6. The rise and fall of borax as an antiepileptic drug.

    PubMed

    Jensen, John P A

    2006-04-01

    Five hundred eighty-six patients with epilepsy were treated with borax (hydrated sodium tetraborate) between 1912 and 1948 at the Kolonien Filadelfia Epilepsy Hospital, Dianalund, Denmark. A rough estimation shows that less than 5% experienced a more than 50% reduction in the total number of seizures. Charts were reviewed to find a connection between the concept of Bacillus epilepticus (1916) and the so-called renaissance of borax treatment described in 1923, and to find an explanation for the popularity of this seemingly ineffective antiepileptic drug.

  7. Teratogenic potential of antiepileptic drugs in the zebrafish model.

    PubMed

    Lee, Sung Hak; Kang, Jung Won; Lin, Tao; Lee, Jae Eun; Jin, Dong Il

    2013-01-01

    The zebrafish model is an attractive candidate for screening of developmental toxicity during early drug development. Antiepileptic drugs (AEDs) arouse concern for the risk of teratogenicity, but the data are limited. In this study, we evaluated the teratogenic potential of seven AEDs (carbamazepine (CBZ), ethosuximide (ETX), valproic acid (VPN), lamotrigine (LMT), lacosamide (LCM), levetiracetam (LVT), and topiramate (TPM)) in the zebrafish model. Zebrafish embryos were exposed to AEDs from initiation of gastrula (5.25 hours post-fertilization (hpf)) to termination of hatching (72 hpf) which mimic the mammalian teratogenic experimental design. The lethality and teratogenic index (TI) of AEDs were determined and the TI values of each drug were compared with the US FDA human pregnancy categories. Zebrafish model was useful screening model for teratogenic potential of antiepilepsy drugs and was in concordance with in vivo mammalian data and human clinical data.

  8. ISMP Adverse Drug Reactions

    PubMed Central

    2013-01-01

    The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration’s (FDA’s) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers. Write to Dr. Mancano at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-707-4936; e-mail: mmancano@temple.edu). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA’s MedWatch program and Temple University School of Pharmacy. ISMP is an FDA MedWatch partner. PMID:24421544

  9. Brain Graph Topology Changes Associated with Anti-Epileptic Drug Use.

    PubMed

    Haneef, Zulfi; Levin, Harvey S; Chiang, Sharon

    2015-06-01

    Neuroimaging studies of functional connectivity using graph theory have furthered our understanding of the network structure in temporal lobe epilepsy (TLE). Brain network effects of anti-epileptic drugs could influence such studies, but have not been systematically studied. Resting-state functional MRI was analyzed in 25 patients with TLE using graph theory analysis. Patients were divided into two groups based on anti-epileptic medication use: those taking carbamazepine/oxcarbazepine (CBZ/OXC) (n=9) and those not taking CBZ/OXC (n=16) as a part of their medication regimen. The following graph topology metrics were analyzed: global efficiency, betweenness centrality (BC), clustering coefficient, and small-world index. Multiple linear regression was used to examine the association of CBZ/OXC with graph topology. The two groups did not differ from each other based on epilepsy characteristics. Use of CBZ/OXC was associated with a lower BC. Longer epilepsy duration was also associated with a lower BC. These findings can inform graph theory-based studies in patients with TLE. The changes observed are discussed in relation to the anti-epileptic mechanism of action and adverse effects of CBZ/OXC.

  10. Neurological teratogenic effects of antiepileptic drugs during pregnancy

    PubMed Central

    Nie, Qingmei; Su, Baohua; Wei, Jianping

    2016-01-01

    Epilepsy is one of the few neurologic disorders that requires a constant treatment during pregnancy. Epilepsy affects 0.3–0.8% of pregnant women. Prescription of antiepileptic drugs (AEDs) to pregnant women with epilepsy requires monitoring and maintaining a balance between limiting seizures and decreasing fetal exposure to the potential teratogenic effects. AEDs are also commonly used for psychiatric disorders, pain disorders, and migraines. The types of malformations that can result in fetuses exposed to AEDs include minor anomalies, major congenital malformations, intrauterine growth retardation, cognitive dysfunction, low IQ, microcephaly, and infant mortality. In the present review, we analyzed and summarized the current understanding of neurological development in fetuses that are exposed to various AEDs administered to pregnant epileptic women. PMID:27698740

  11. Neurological teratogenic effects of antiepileptic drugs during pregnancy

    PubMed Central

    Nie, Qingmei; Su, Baohua; Wei, Jianping

    2016-01-01

    Epilepsy is one of the few neurologic disorders that requires a constant treatment during pregnancy. Epilepsy affects 0.3–0.8% of pregnant women. Prescription of antiepileptic drugs (AEDs) to pregnant women with epilepsy requires monitoring and maintaining a balance between limiting seizures and decreasing fetal exposure to the potential teratogenic effects. AEDs are also commonly used for psychiatric disorders, pain disorders, and migraines. The types of malformations that can result in fetuses exposed to AEDs include minor anomalies, major congenital malformations, intrauterine growth retardation, cognitive dysfunction, low IQ, microcephaly, and infant mortality. In the present review, we analyzed and summarized the current understanding of neurological development in fetuses that are exposed to various AEDs administered to pregnant epileptic women.

  12. Modifications of Antiepileptic Drugs for Improved Tolerability and Efficacy

    PubMed Central

    Landmark, Cecilie Johannessen; Johannessen, Svein I.

    2008-01-01

    Introduction A large number of antiepileptic drugs (AEDs) are available today, but they may not be satisfactory regarding clinical efficacy, tolerance, toxicity or pharmacokinetic properties. The purpose of this review is to focus upon the rationale behind the chemical modifications of several recently marketed AEDs or drugs in development and to categorize them according to the main purposes for the improvements: better efficacy or tolerability accompanied by improved pharmacokinetic properties. Material and Method AEDs that have been chemically modified to new derivatives during the last years are reviewed based on recent publications and PubMed-searches. Results and Discussion Improvement in pharmacokinetic parameters may affect both tolerability and efficacy. Modifications to improve tolerability include various valproate analogues, divided into aliphatic amides, cyclic derivatives or amino acid conjugates. Furthermore, there are the carbamazepine analogues oxcarbazepine and eslicarbazepine, the felbamate analogues fluorofelbamate and carisbamate (RWJ 33369), and the lamotrigine analogue JZP-4. The levetiracetam analogues brivaracetam and seletracetam and the derivatives of gabapentin, pregabalin and XP13512, have improved selectivity compared to their parent compounds. Other new drugs have new mechanisms of action related to GABA and glutamate receptors; the glutamate antagonists like topiramate (talampanel and NS-1209), and GABAA receptor agonists, benzodiazepine or progesterone analogues (ELB-139 and ganaxolone). Conclusion Further challenges for development of new AEDs include investigations of target molecules affected by pathophysiological processes and detailed structure-activity relationships with focus on stereoselectivity. These potential drugs may become of importance in future drug therapy in epilepsy and other CNS disorders. PMID:19787095

  13. Progress report on new antiepileptic drugs: a summary of the Seventh Eilat Conference (EILAT VII).

    PubMed

    Bialer, Meir; Johannessen, Svein I; Kupferberg, Harvey J; Levy, René H; Perucca, Emilio; Tomson, Torbjörn

    2004-01-01

    The Seventh Eilat Conference on New Antiepileptic Drugs (AEDs) (EILAT VII) took place in Villasimius, Sardinia, Italy from the 9th to 13th May 2004. Basic scientists, clinical pharmacologists and neurologists from 24 countries attended the conference,whose main themes included advances in pathophysiology of drug resistance, new AEDs in pediatric epilepsy syndromes, modes of AED action and spectrum of adverse effects and a re-appraisal of comparative responses to AED combinations. Consistent with previous formats of this conference, the central part of the conference was devoted to a review of AEDs in development, as well as updates on second-generation AEDs. This article summarizes the information presented on drugs in development, including atipamezole, BIA-2-093, fluorofelbamate, NPS 1776, pregabalin, retigabine, safinamide, SPM 927, stiripentol, talampanel,ucb 34714 and valrocemide (TV 1901). Updates on felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine,topiramate, vigabatrin, zonisamide, new oral and parenteral formulations of valproic acid and SPM 927 and the antiepileptic vagal stimulator device are also presented.

  14. Effects of the antiepileptic drug carbamazepine on human erythrocytes.

    PubMed

    Suwalsky, Mario; Mennickent, Sigrid; Norris, Beryl; Villena, Fernando; Sotomayor, Carlos P

    2006-12-01

    The structural effects of the antiepileptic drug carbamazepine (CBZ) on the human erythrocyte membrane and molecular models have been investigated in the present work. This report presents the following evidence that CBZ interacts with red cell membranes: (a) X-ray diffraction and fluorescence spectroscopy of phospholipid bilayers showed that CBZ perturbed a class of lipids found in the outer moiety of the erythrocyte membrane; (b) in isolated unsealed human erythrocytes (IUM) the drug induced a disordering effect on the polar head groups and acyl chains of the membrane lipid bilayer; (c) in scanning electron microscopy (SEM) studies on human erythrocytes the formation of echinocytes was observed, due to the preferential insertion of CBZ in the outer monolayer of the red cell membrane. The effects of the drug detected in the present work were observed at concentrations of the order of those currently appearing in serum when it is therapeutically administered. This is the first time that toxic effects of carbamazepine on the human erythrocyte membrane have been described. PMID:16844339

  15. Antiepileptic Drugs with Mood Stabilizing Properties and Their Relation with Psychotropic Drug Use in Institutionalized Epilepsy Patients with Intellectual Disability

    ERIC Educational Resources Information Center

    Leunissen, C. L. F.; de la Parra, N. M.; Tan, I. Y.; Rentmeester, Th. W.; Vader, C. I.; Veendrick-Meekes, M. J. B. M.; Aldenkamp, A. P.

    2011-01-01

    A large number of patients with epilepsy and intellectual disability take medication, amongst which antiepileptic and psychotropic drugs, often simultaneously. Certain antiepileptic drugs have mood-stabilizing properties, e.g. carbamazepine, valproic acid and lamotrigine. The aim of this study was to investigate whether the use of these…

  16. Fetal antiepileptic drug exposure: Adaptive and emotional/behavioral functioning at age 6 years

    PubMed Central

    Cohen, Morris J.; Meador, Kimford J.; Browning, Nancy; May, Ryan; Baker, Gus A.; Clayton-Smith, Jill; Kalayjian, Laura A.; Kanner, Andres; Liporace, Joyce D.; Pennell, Page B.; Privitera, Michael; Loring, David W.

    2014-01-01

    The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study is a prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study aimed to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, and valproate). In this report, we examine fetal AED exposure effects on adaptive and emotional/behavioral functioning at 6 years of age in 195 children (including three sets of twins) whose parent (in most cases, the mother) completed at least one of the rating scales. Adjusted mean scores for the four AED groups were in the low average to average range for parent ratings of adaptive functioning on the Adaptive Behavior Assessment System—Second Edition (ABAS-II) and for parent and teacher ratings of emotional/behavioral functioning on the Behavior Assessment System for Children (BASC). However, children whose mothers took valproate during pregnancy had significantly lower General Adaptive Composite scores than the lamotrigine and phenytoin groups. Further, a significant dose-related performance decline in parental ratings of adaptive functioning was seen for both valproate and phenytoin. Children whose mothers took valproate were also rated by their parents as exhibiting significantly more atypical behaviors and inattention than those in the lamotrigine and phenytoin groups. Based upon BASC parent and teacher ratings of attention span and hyperactivity, children of mothers who took valproate during their pregnancy were at a significantly greater risk for a diagnosis of ADHD. The increased likelihood of difficulty with adaptive functioning and ADHD with fetal valproate exposure should be communicated to women with epilepsy who require antiepileptic medication. Finally, additional research is needed to confirm these findings in larger prospective study samples, examine

  17. The antiepileptic drug carbamazepine affects sodium transport in toad epithelium.

    PubMed

    Suwalsky, Mario; Mennickent, Sigrid; Norris, Beryl; Cardenas, Hernán

    2006-09-01

    The present work investigates the effects of the antiepileptic drug carbamazepine (CBZ) on sodium transport in the isolated skin of the toad Pleurodema thaul. A submaximal concentration of the drug (0.2 mM) applied to the outer surface of the epithelium increased the electrical parameters short-circuit current (Isc) and potential difference (PD) by over 28%, whereas only a higher concentration (1 mM) induced over a 45% decrease in these parameters when applied to the inner surface. The amiloride test showed that the outer surface stimulatory effect was accompanied by an increase and the inner surface inhibitory effect by a decrease in the sodium electromotive force (ENa). Exploration of these effects of CBZ on the outer surface showed that 0.2 mM increased net Na+ (22Na) influx by 20% and 0.6 mM CBZ decreased Na+ mucosa-serosa flux by 19%, a result in agreement with the finding that higher concentrations of CBZ applied to the inner surface not only decreased ENa but also sodium conductance (GNa). PMID:16542818

  18. Adverse Reactions to Hallucinogenic Drugs.

    ERIC Educational Resources Information Center

    Meyer, Roger E. , Ed.

    This reports a conference of psychologists, psychiatrists, geneticists and others concerned with the biological and psychological effects of lysergic acid diethylamide and other hallucinogenic drugs. Clinical data are presented on adverse drug reactions. The difficulty of determining the causes of adverse reactions is discussed, as are different…

  19. Polycystic ovary syndrome in patients on antiepileptic drugs

    PubMed Central

    Viswanathan, Lakshminarayanapuram G.; Satishchandra, Parthasarathy; Bhimani, Bipin C.; Reddy, Janardhan YC; Rama Murthy, Batchu S.; Subbakrishna, Doddaballapura K.; Sinha, Sanjib

    2016-01-01

    Objective: This study aims to discuss the prevalence of polycystic ovary (PCO) and Polycystic ovary syndrome (PCOS) in women with epilepsy (WWE) on valproate (VPA), carbamazepine (CBZ), or phenobarbitone (PB), drug naive WWE and women with bipolar affective disorder (BPAD) on VPA. Materials and Methods: This prospective study included 190 women aged 18–45 years, who had epilepsy or BPAD (on VPA), and consented for study. Patients were grouped as Group 1 (n = 40): WWE on VPA, Group 2 (n = 50): WWE on CBZ, Group 3 (n = 50): WWE on PB, Group 4 (n = 30): drug naïve WWE, and Group 5 (n = 20): women with BPAD on VPA. All women were interviewed for medical, menstrual, drug and treatment history, nature of epilepsy, and seizure control. Chi-square test and Fisher's exact test were done to compare results between the groups. Results: Fifty-two women (52/190; 27.4%) had menstrual disturbances, in which oligomenorrhea was the most common (55.8%). There was a significant difference in the occurrence of PCOS in patients on VPA versus normal population (P = 0.05) and patients on other antiepileptic drugs (AEDs) (P = 0.02). There was, however, no significant difference in the occurrence of PCO between patients on VPA and the untreated epileptic women. VPA group (Epilepsy + BPAD) had a significantly higher occurrence of obesity than other treatment groups (P = 0.043, OR = 2.11). Conclusions: The study observed significantly higher occurrence of PCO in patients on VPA compared to other AEDs and the normal population. The importance of proper clinical evaluation before initiating VPA is highlighted. PMID:27570385

  20. Cognitive side-effects of antiepileptic drugs in children.

    PubMed

    Ijff, Dominique M; Aldenkamp, Albert P

    2013-01-01

    Although the causes of cognitive impairment in patients with epilepsy have not been completely elucidated, three factors are clearly involved: the underlying etiology of epilepsy, the effects of seizures or the epileptiform EEG discharges themselves, and the central nervous system effects of antiepileptic drugs (AEDs). All commonly used AEDs have some effect on cognitive function, and the effect may be substantial when crucial functions are involved, such as learning in children. With phenobarbital, there is a high risk for serious cognitive effects impacting attention and memory. Phenytoin may affect mental speed, mainly in higher dosing and polytherapy. Moderate monotherapy doses do not seem to induce much effect. Valproate does not seem to impair cognition if sufficiently controlled for hyperammonemia. For carbamazepine, there are conflicting reports, which may be due to selection bias or dosing. For oxcarbazepine, there is no evidence for any detrimental change compared to valproate but mild improvements on attentional tests. For topiramate, there is clear evidence for topiramate-induced cognitive impairment (attention, memory, and language function) in adults and children. Although data is sketchy, levetiracetam does not seem to have a negative impact on cognition. For lamotrigine, there is evidence of a cognitive-enhancing effect on attention. No evidence for cognitive side-effects has been found for vigabatrin. Ethosuximide is not associated with cognitive impairment although the evidence is sketchy. For gabapentin, tiagabine, zonisamide, and rufinamide no studies in children are available. PMID:23622218

  1. Epilepsy, sex hormones and antiepileptic drugs in female patients.

    PubMed

    Verrotti, Alberto; D'Egidio, Claudia; Coppola, Giangennaro; Parisi, Pasquale; Chiarelli, Francesco

    2009-12-01

    Women with epilepsy have a higher incidence of reproductive endocrine disorders than the general female population. These alterations include polycystic ovary syndrome, hyperandrogenemia, infertility, hypothalamic amenorrhea and hyperprolactinemia. Reproductive dysfunction is attributed both to epilepsy itself and to antiepileptic drugs (AEDs). Focal epileptic discharges from the temporal lobe may have a direct influence on the function of the hypothalamic-pituitary axis, thus altering the release of sex steroid hormones, including the production of luteinizing hormone, follicle-stimulating hormone, gonadotropin-releasing hormone and prolactin. AEDs may modulate hormone release from the hypothalamic-pituitary-gonadal axis and they may alter the metabolism of sex hormones and their binding proteins. Hepatic enzyme-inducing AEDs, such as carbamazepine and phenytoin, may be most clearly linked to altered metabolism of sex steroid hormones, but valproic acid, an enzyme inhibitor, has also been associated with a frequent occurrence of polycystic ovary syndrome and hyperandrogenism in women with epilepsy. Therefore, treatment of epilepsy and selection of AEDs are important for reproductive health in female patients. The aim of the present review is to critically evaluate the recently published data concerning the interactions between sex hormones, epilepsy and AEDs.

  2. The antiepileptic drug phenytoin affects sodium transport in toad epithelium.

    PubMed

    Suwalsky, Mario; Mennickent, Sigrid; Norris, Beryl; Cárdenas, Hernan

    2006-01-01

    The effects of phenytoin on isolated Pleurodema thaul toad skin were investigated. Low (micromolar) concentrations of the antiepileptic agent applied to the outside surface of the toad epithelium increased the electrical parameters (short-circuit current and potential difference) by over 40%, reflecting stimulation of Na(+) transport, whereas higher (millimolar concentrations, outside and inside surface) decreased both electric parameters, the effect being greater at the inside surface (40% and 80% decrease, respectively). The amiloride test showed that the stimulatory effect was accompanied by an increase and the inhibitory effect by a decrease in the sodium electromotive force (ENa). It is concluded that the drug interaction with membrane lipid bilayers might result in a distortion of the lipid-protein interface contributing to disturbance of Na(+) epithelial channel activity. After applying the Na(+)-K(+)-ATPase blocker ouabain and replacing the Na(+) ions in the outer Ringer's solution by choline, it was concluded that both active and passive transport are involved in sodium absorption, although active transport predominates. PMID:16314149

  3. Initial treatment of epilepsy with antiepileptic drugs: pediatric issues.

    PubMed

    Sankar, Raman

    2004-11-23

    The selection of an antiepileptic drug (AED) for initial treatment of epilepsy in infancy, childhood, and adolescence should ideally be made after a clear syndromic diagnosis of the patient's seizure disorder. A common cause of failure of the first AED is erroneous diagnosis. The availability of new-generation AEDs has expanded the choice of available agents with comparable efficacy for most syndromes. Efficacy data based on class I or II evidence are not available for many syndromes of childhood, and selection must therefore be based on the best data available. It is also important to assess the relative toxicity and tolerability of AEDs in making the selection. It is especially important to appreciate age-specific organ toxicities. Moreover, the use of AEDs in childhood requires an understanding of their neurobehavioral effects. Important neuropsychiatric co-morbidities in children with epilepsy include attention deficit/hyperactivity disorder, autistic spectrum disorders, depression and anxiety, and thought disorders. These problems can be exacerbated or ameliorated by specific AEDs. The effect of AEDs on body weight, insulin sensitivity, lipid profile, and bone health is becoming better appreciated. Newer AEDs may offer significant advantages in this regard. Co-morbid migraine in children with epilepsy may benefit from some AEDs. There remains a continuing need for the development of newer AEDs that are targeted for the developing brain to improve the efficacy and tolerability of treatment in childhood seizure disorders. PMID:15557549

  4. Modulating Behavior in C. elegans Using Electroshock and Antiepileptic Drugs

    PubMed Central

    Jia, Kailiang; Grill, Brock; Dawson-Scully, Ken

    2016-01-01

    The microscopic nematode Caenorhabditis elegans has emerged as a valuable model for understanding the molecular and cellular basis of neurological disorders. The worm offers important physiological similarities to mammalian models such as conserved neuron morphology, ion channels, and neurotransmitters. While a wide-array of behavioral assays are available in C. elegans, an assay for electroshock/electroconvulsion remains absent. Here, we have developed a quantitative behavioral method to assess the locomotor response following electric shock in C. elegans. Electric shock impairs normal locomotion, and induces paralysis and muscle twitching; after a brief recovery period, shocked animals resume normal locomotion. We tested electric shock responses in loss-of-function mutants for unc-25, which encodes the GABA biosynthetic enzyme GAD, and unc-49, which encodes the GABAA receptor. unc-25 and unc-49 mutants have decreased inhibitory GABAergic transmission to muscles, and take significantly more time to recover normal locomotion following electric shock compared to wild-type. Importantly, increased sensitivity of unc-25 and unc-49 mutants to electric shock is rescued by treatment with antiepileptic drugs, such as retigabine. Additionally, we show that pentylenetetrazol (PTZ), a GABAA receptor antagonist and proconvulsant in mammalian and C. elegans seizure models, increases susceptibility of worms to electric shock. PMID:27668426

  5. Adverse ocular reactions to drugs.

    PubMed Central

    Spiteri, M. A.; James, D. G.

    1983-01-01

    Drugs acting on various parts of the body may also affect the eye insidiously. Increased awareness of such drug toxicity by the prescribing doctor should encourage him to consider effects on the cornea, lens, retina, optic nerve and elsewhere when checking the patient's progress. The following review concerns adverse ocular effects of systemic drug administration. PMID:6356101

  6. Medical management of refractory epilepsy--practical treatment with novel antiepileptic drugs.

    PubMed

    Ben-Menachem, Elinor

    2014-01-01

    The ultimate treatment goal in epilepsy therapy is always freedom from seizures with as few treatment adverse effects as possible. If seizures persist with the first monotherapy, alternative monotherapy with another antiepileptic drug (AED) should be considered. Continuing seizures should lead to a reevaluation of differential diagnosis and adherence. Epilepsy surgery as an alternative therapy may be suitable in selected cases. If the diagnosis of epilepsy is established and epilepsy surgery is not appropriate, AED treatment should be optimized. Evidence for how to proceed is lacking. Concepts such as rational polytherapy have been advocated but remain speculative concerning better efficacy based on the use of AEDs with differing modes of action. A variety of new AEDs including rufinamide, lacosamide, vigabatrin, perampanel, and retigabine have been recently introduced in the United States. They are briefly characterized in this update review. PMID:24400690

  7. Current Status of the New Antiepileptic Drugs in Chronic Pain.

    PubMed

    Sidhu, Harpreet S; Sadhotra, Akshay

    2016-01-01

    Antiepileptic drugs (AEDs) are extensively used worldwide to treat a wide range of disorders other than epilepsy, such as neuropathic pain, migraine, and bipolar disorder. Due to this situation more than 20 new third-generation AEDs have been introduced in the market recently. The future design of new AEDs must also have potential to help in the non-epileptic disorders. The wide acceptance of second generation AEDs for the management of various non-epileptic disorders has caused the emergence of generics in the market. The wide use of approved AEDs outside epilepsy is based on both economic and scientific reasons. Bipolar disorders, migraine prophylaxis, fibromyalgia, and neuropathic pain represent the most attractive indication expansion opportunities for anticonvulsant developers, providing blockbuster revenues. Strong growth in non-epilepsy conditions will see Pfizer's Lyrica become the market leading brand by 2018. In this review, we mainly focus on the current status of new AEDs in the treatment of chronic pain and migraine prophylaxis. AEDs have a strong analgesic potential and this is demonstrated by the wide use of carbamazepine in trigeminal neuralgia and sodium valproate in migraine prophylaxis. At present, data on the new AEDs for non-epileptic conditions are inconclusive. Not all AEDs are effective in the management of neuropathic pain and migraine. Only those AEDs whose mechanisms of action are match with pathophysiology of the disease, have potential to show efficacy in non-epileptic disorder. For this better understanding of the pathophysiology of the disease and mechanisms of action of new AEDs are essential requirement before initiating pre-clinical and clinical trials. Many new AEDs show good results in the animal model and open-label studies but fail to provide strong evidence at randomized, placebo-controlled trials. The final decision regarding the clinical efficacy of the particular AEDs in a specific non-epileptic disorder should be

  8. Current Status of the New Antiepileptic Drugs in Chronic Pain

    PubMed Central

    Sidhu, Harpreet S.; Sadhotra, Akshay

    2016-01-01

    Antiepileptic drugs (AEDs) are extensively used worldwide to treat a wide range of disorders other than epilepsy, such as neuropathic pain, migraine, and bipolar disorder. Due to this situation more than 20 new third-generation AEDs have been introduced in the market recently. The future design of new AEDs must also have potential to help in the non-epileptic disorders. The wide acceptance of second generation AEDs for the management of various non-epileptic disorders has caused the emergence of generics in the market. The wide use of approved AEDs outside epilepsy is based on both economic and scientific reasons. Bipolar disorders, migraine prophylaxis, fibromyalgia, and neuropathic pain represent the most attractive indication expansion opportunities for anticonvulsant developers, providing blockbuster revenues. Strong growth in non-epilepsy conditions will see Pfizer’s Lyrica become the market leading brand by 2018. In this review, we mainly focus on the current status of new AEDs in the treatment of chronic pain and migraine prophylaxis. AEDs have a strong analgesic potential and this is demonstrated by the wide use of carbamazepine in trigeminal neuralgia and sodium valproate in migraine prophylaxis. At present, data on the new AEDs for non-epileptic conditions are inconclusive. Not all AEDs are effective in the management of neuropathic pain and migraine. Only those AEDs whose mechanisms of action are match with pathophysiology of the disease, have potential to show efficacy in non-epileptic disorder. For this better understanding of the pathophysiology of the disease and mechanisms of action of new AEDs are essential requirement before initiating pre-clinical and clinical trials. Many new AEDs show good results in the animal model and open-label studies but fail to provide strong evidence at randomized, placebo-controlled trials. The final decision regarding the clinical efficacy of the particular AEDs in a specific non-epileptic disorder should be

  9. Current Status of the New Antiepileptic Drugs in Chronic Pain

    PubMed Central

    Sidhu, Harpreet S.; Sadhotra, Akshay

    2016-01-01

    Antiepileptic drugs (AEDs) are extensively used worldwide to treat a wide range of disorders other than epilepsy, such as neuropathic pain, migraine, and bipolar disorder. Due to this situation more than 20 new third-generation AEDs have been introduced in the market recently. The future design of new AEDs must also have potential to help in the non-epileptic disorders. The wide acceptance of second generation AEDs for the management of various non-epileptic disorders has caused the emergence of generics in the market. The wide use of approved AEDs outside epilepsy is based on both economic and scientific reasons. Bipolar disorders, migraine prophylaxis, fibromyalgia, and neuropathic pain represent the most attractive indication expansion opportunities for anticonvulsant developers, providing blockbuster revenues. Strong growth in non-epilepsy conditions will see Pfizer’s Lyrica become the market leading brand by 2018. In this review, we mainly focus on the current status of new AEDs in the treatment of chronic pain and migraine prophylaxis. AEDs have a strong analgesic potential and this is demonstrated by the wide use of carbamazepine in trigeminal neuralgia and sodium valproate in migraine prophylaxis. At present, data on the new AEDs for non-epileptic conditions are inconclusive. Not all AEDs are effective in the management of neuropathic pain and migraine. Only those AEDs whose mechanisms of action are match with pathophysiology of the disease, have potential to show efficacy in non-epileptic disorder. For this better understanding of the pathophysiology of the disease and mechanisms of action of new AEDs are essential requirement before initiating pre-clinical and clinical trials. Many new AEDs show good results in the animal model and open-label studies but fail to provide strong evidence at randomized, placebo-controlled trials. The final decision regarding the clinical efficacy of the particular AEDs in a specific non-epileptic disorder should be

  10. Pharmacogenomics of adverse drug reactions

    PubMed Central

    2013-01-01

    Considerable progress has been made in identifying genetic risk factors for idiosyncratic adverse drug reactions in the past 30 years. These reactions can affect various tissues and organs, including liver, skin, muscle and heart, in a drug-dependent manner. Using both candidate gene and genome-wide association studies, various genes that make contributions of varying extents to each of these forms of reactions have been identified. Many of the associations identified for reactions affecting the liver and skin involve human leukocyte antigen (HLA) genes and for reactions relating to the drugs abacavir and carbamazepine, HLA genotyping is now in routine use prior to drug prescription. Other HLA associations are not sufficiently specific for translation but are still of interest in relation to underlying mechanisms for the reactions. Progress on non-HLA genes affecting adverse drug reactions has been less, but some important associations, such as those of SLCO1B1 and statin myopathy, KCNE1 and drug-induced QT prolongation and NAT2 and isoniazid-induced liver injury, are considered. Future prospects for identification of additional genetic risk factors for the various adverse drug reactions are discussed. PMID:23360680

  11. The effects of antiepileptic drugs on the growth of glioblastoma cell lines.

    PubMed

    Lee, Ching-Yi; Lai, Hung-Yi; Chiu, Angela; Chan, She-Hung; Hsiao, Ling-Ping; Lee, Shih-Tseng

    2016-05-01

    To determine the effects of antiepileptic drug compounds on glioblastoma cellular growth, we exposed glioblastoma cell lines to select antiepileptic drugs. The effects of selected antiepileptic drugs on glioblastoma cells were measured by MTT assay. For compounds showing significant inhibition, cell cycle analysis was performed. Statistical analysis was performed using SPSS. The antiepileptic compounds selected for screening included carbamazepine, ethosuximide, gabapentin, lamotrigine, levetiracetam, magnesium sulfate, oxcarbazepine, phenytoin, primidone, tiagabine, topiramate, valproic acid, and vigabatrin. Dexamethasone and temozolomide were used as a negative and positive control respectively. Our results showed temozolomide and oxcarbazepine significantly inhibited glioblastoma cell growth and reached IC50 at therapeutic concentrations. The other antiepileptic drugs screened were unable to reach IC50 at therapeutic concentrations. The metabolites of oxcarbazepine were also unable to reach IC50. Dexamethasone, ethosuximide, levetiracetam, and vigabatrin showed some growth enhancement though they did not reach statistical significance. The growth enhancement effects of ethosuximide, levetiracetam, and vigabatrin found in the study may indicate that these compounds should not be used for prophylaxis or short term treatment of epilepsy in glioblastoma. While valproic acid and oxcarbazepine were effective, the required dose of valproic acid was far above that used for the treatment of epilepsy and the metabolites of oxcarbazepine failed to reach significant growth inhibition ruling out the use of oral oxcarbazepine or valproic acid as monotherapy in glioblastoma. The possibility of using these compounds as local treatment is a future area of study. PMID:26758059

  12. Human placental perfusion method in the assessment of transplacental passage of antiepileptic drugs

    SciTech Connect

    Myllynen, Paeivi . E-mail: paivi.k.myllynen@oulu.fi; Pienimaeki, Paeivi; Vaehaekangas, Kirsi

    2005-09-01

    Epilepsy is one of the most common neurological diseases, affecting about 0.5 to 1% of pregnant women. It is commonly accepted that older antiepileptic drugs bear teratogenic potential. So far, no agreement has been reached about the safest antiepileptic drug during pregnancy. It is known that nearly all drugs cross the placenta at least to some extent. Nowadays, there is very little information available of the pharmacokinetics of drugs in the feto-placental unit. Detailed information about drug transport across the placenta would be valuable for the development of safe and effective treatments. For reasons of safety, human studies on placental transfer are restricted to a limited number of drugs. Interspecies differences limit the extrapolation of animal data to humans. Several in vitro methods for the study of placental transfer have been developed over the past decades. The placental perfusion method is the only experimental method that has been used to study human placental transfer of substances in organized placental tissue. The aim of this article is to review human placental perfusion data on antiepileptic drugs. According to perfusion data, it seems that most of the antiepileptic drugs are transferred across the placenta meaning significant fetal exposure.

  13. Psychotropic and Antiepileptic Drug Treatment in Early Childhood Special Education. Final Report.

    ERIC Educational Resources Information Center

    Gadow, Kenneth D.

    The effectiveness of psychotropic and antiepileptic drug treatment was investigated with approximately 2500 children receiving educational services in early childhood special education programs. The study consisted of three phases: phase 1 in which all teachers were surveyed to determine the prevalence of drug therapy and patterns of usage, phase…

  14. Adjusting to a seizure-free "new normal" life following discontinuation of antiepileptic drugs during adolescence.

    PubMed

    Chiu, Ya-Ping; Lee, Tzu-Ying; Lin, Kuang-Lin; Laadt, Virginia L

    2014-04-01

    This qualitative study sought to understand how children in adolescence adjust to their newly acquired normal life without epilepsy, following discontinuation of antiepileptic drugs during this dynamic period of growth and development. Three major themes with subthemes were identified: 1) setting the body and mind free; 2) engaging in self-regulation; and 3) protection by significant others. A sense of relief from constraints related to treatment schedules, special diets, and avoiding seizure-provoking activities was expressed by all participants. Freedom from side effects of the antiepileptic drugs improved life at home and school. Most of the participants said that they were not worried about seizure recurrence but would use caution against a possible relapse. Family members also must adjust to a new lifestyle. Medical staff needs to provide support and adequate care to adolescents during their period of identity adjustment following antiepileptic drug discontinuation. PMID:24632354

  15. ORAL ADVERSE DRUG REACTIONS TO CARDIOVASCULAR DRUGS.

    PubMed

    Torpet, Lis Andersen; Kragelund, Camilla; Reibel, Jesper; Nauntofte, Birgitte

    2004-01-01

    A great many cardiovascular drugs (CVDs) have the potential to induce adverse reactions in the mouth. The prevalence of such reactions is not known, however, since many are asymptomatic and therefore are believed to go unreported. As more drugs are marketed and the population includes an increasing number of elderly, the number of drug prescriptions is also expected to increase. Accordingly, it can be predicted that the occurrence of adverse drug reactions (ADRs), including the oral ones (ODRs), will continue to increase. ODRs affect the oral mucous membrane, saliva production, and taste. The pathogenesis of these reactions, especially the mucosal ones, is largely unknown and appears to involve complex interactions among the drug in question, other medications, the patient's underlying disease, genetics, and life-style factors. Along this line, there is a growing interest in the association between pharmacogenetic polymorphism and ADRs. Research focusing on polymorphism of the cytochrome P450 system (CYPs) has become increasingly important and has highlighted the intra- and inter-individual responses to drug exposure. This system has recently been suggested to be an underlying candidate regarding the pathogenesis of ADRs in the oral mucous membrane. This review focuses on those CVDs reported to induce ODRs. In addition, it will provide data on specific drugs or drug classes, and outline and discuss recent research on possible mechanisms linking ADRs to drug metabolism patterns. Abbreviations used will be as follows: ACEI, ACE inhibitor; ADR, adverse drug reaction; ANA, antinuclear antigen; ARB, angiotensin II receptor blocker; BAB, beta-adrenergic blocker; CCB, calcium-channel blocker; CDR, cutaneous drug reaction; CVD, cardiovascular drug; CYP, cytochrome P450 enzyme; EM, erythema multiforme; FDE, fixed drug eruption; I, inhibitor of CYP isoform activity; HMG-CoA, hydroxymethyl-glutaryl coenzyme A; NAT, N-acetyltransferase; ODR, oral drug reaction; RDM, reactive

  16. Changes in Antiepileptic Drug Prescribing Patterns in Large Institutions: Preliminary Results of a Five-Year Experience.

    ERIC Educational Resources Information Center

    Poindexter, Ann R.; And Others

    1993-01-01

    Antiepileptic drug prescriptions were analyzed for 337 institutionalized individuals with mental retardation, over 54 months. Results indicated decreasing numbers of individuals receiving (1) more than 2 antiepileptic drugs concurrently, and (2) barbiturates. Over 90% of a group undergoing barbiturate taper maintained the same or improved seizure…

  17. New generation antiepileptic drugs: what do they offer in terms of improved tolerability and safety?

    PubMed

    French, Jacqueline A; Gazzola, Deana M

    2011-08-01

    Over the last two decades a total of 11 antiepileptic drugs (AEDs) have been introduced to the US market. Randomized, placebo-controlled trials have yielded information about each drug's efficacy, tolerability, and safety profile; however, few studies have compared the newer generation AEDs directly with the older generation. Comparative studies are not always straightforward in their interpretation, as many characteristics of drugs, both favorable and unfavorable, may not be highlighted by such studies. In general, findings from the literature suggest that the newer generation AEDs (including vigabatrin, felbamate, gabapentin, lamotrigine, tiagabine, topiramate, levetiracetam, oxcarbazepine, zonisamide, pregabalin, rufinamide, and lacosamide) enjoy both improved tolerability and safety compared with older agents such as phenobarbital, phenytoin, carbamazepine, and valproate. This is partially supported by some of the findings of the QSS and the TTA Committee of the American Academy of Neurology (AAN), whose review of four AEDs (gabapentin, lamotrigine, topiramate, and tiagabine) is discussed. Briefly, when compared with carbamazepine, lamotrigine was better tolerated; topiramate adverse events (AEs) were fairly comparable to carbamazepine and valproate; and tiagabine compared with placebo was associated with a higher discontinuation rate due to AEs. The findings of the SANAD trial are also presented; when administered to patients with partial epilepsy, carbamazepine was most likely to fail due to AEs, and lamotrigine and gabapentin were least likely to fail due to AEs. When administered to patients with idiopathic generalized epilepsy, topiramate was most frequently associated with AE-related discontinuation, followed by valproate; and while valproate was the most efficacious drug in this arm of the study, lamotrigine was more tolerable. What makes the SANAD study valuable and somewhat unique is its head-to-head comparison of one drug with another. Such

  18. Antiepileptic drugs for the treatment of neuropathic pain: A systematic review

    PubMed Central

    Vargas-Espinosa, Maríam L.; Sanmartí-García, Gemma; Vázquez-Delgado, Eduardo

    2012-01-01

    Many therapies have been proposed for the management of neuropathic pain, and they include the use of different antiepileptic drugs. However, the lack of high quality studies indicates that results on the different neuropathic disorders under study do not recommend a particular drug treatment. This study makes a systematic review of the published literature on the use of several antiepileptic drugs to treat neuropathic pain, and has the objective of considering both its clinical characteristics and pharmacological use, which will depend on their level of scientific evidence and will follow the principles of evidence-based dentistry. The articles were stratified according to their scientific evidence using the SORT criteria (Strength of Recommendation Taxonomy), and it included those articles that only have level 1 or 2. Randomized clinical trials were stratified according to their level of quality using the JADAD scale, an instrument described by Jadad et al. (7). to assess the quality of clinical trials, while studies with a level below 3 were discarded. Recently, type A or B recommendations are given in favor or against the use of antiepileptic drugs to treat neuropathic pain on the basis of their scientific quality. Key words:Neuropathic pain, antiepileptic drugs (AEDs), trigeminal neuralgia, glossopharyngeal neuralgia, post- herpetic neuralgia, burning mouth syndrome, persistent idiopathic facial pain. PMID:22549682

  19. Cutaneous adverse drug reactions in Indian population: A systematic review

    PubMed Central

    Patel, Tejas K; Thakkar, Sejal H; Sharma, DC

    2014-01-01

    Background: Epidemiological data is limited for cutaneous adverse drug reactions (CADRs) in India. Most of the Indian studies have small sample size and are of limited duration. Aims: The aim of this study is to analyze CADRs with reference to the causative drugs and their clinical characteristics in Indian population. Materials and Methods: As per selection criteria, electronic databases were searched for publications describing CADRs from January-1995 to April-2013 by two independent investigators. Data of the causative drugs and clinical characteristics were extracted and summarized by absolute numbers, percentages, ranges, and means as presented by the authors. The subgroup analysis of causative drugs was performed for causality assessment, severe or nonsevere reactions and occurrence of common CADRs. Studies showing “definite” and “probable” categories of causality analysis were labeled as “definite and probable causality (DPC) studies”. The other included studies were labeled as “non-DPC studies”. Results: Of 8337 retrieved references, 18 prospective studies were selected for analysis. The pooled incidence was 9.22/1000 total among outpatient and inpatient cases. Commonly observed reactions were maculopapular rash (32.39%), fixed drug eruptions (FDEs) (20.13%), urticaria (17.49%) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) (6.84%). The major causative drug groups were antimicrobials (45.46%), nonsteroidal anti-inflammatory drugs (NSAIDs) (20.87%) and anti-epileptic drugs (14.57%). Commonly implicated drugs were sulfa (13.32%), β-lactams (8.96%) and carbamazepine (6.65%). High frequency of CADRs is observed with anti-epileptic drugs in DPC studies only. Carbamazepine, phenytoin and fluoroquinolones had higher severe to nonsevere cutaneous reaction ratio than other drugs. Antimicrobials were the main causative drugs for maculopapular rash, FDEs and SJS/TEN, and NSAIDs for the urticaria. The mortality for overall CADRs, SJS

  20. New generation antiepileptic drugs: what do they offer in terms of improved tolerability and safety?

    PubMed Central

    Gazzola, Deana M.

    2011-01-01

    Over the last two decades a total of 11 antiepileptic drugs (AEDs) have been introduced to the US market. Randomized, placebo-controlled trials have yielded information about each drug’s efficacy, tolerability, and safety profile; however, few studies have compared the newer generation AEDs directly with the older generation. Comparative studies are not always straightforward in their interpretation, as many characteristics of drugs, both favorable and unfavorable, may not be highlighted by such studies. In general, findings from the literature suggest that the newer generation AEDs (including vigabatrin, felbamate, gabapentin, lamotrigine, tiagabine, topiramate, levetiracetam, oxcarbazepine, zonisamide, pregabalin, rufinamide, and lacosamide) enjoy both improved tolerability and safety compared with older agents such as phenobarbital, phenytoin, carbamazepine, and valproate. This is partially supported by some of the findings of the QSS and the TTA Committee of the American Academy of Neurology (AAN), whose review of four AEDs (gabapentin, lamotrigine, topiramate, and tiagabine) is discussed. Briefly, when compared with carbamazepine, lamotrigine was better tolerated; topiramate adverse events (AEs) were fairly comparable to carbamazepine and valproate; and tiagabine compared with placebo was associated with a higher discontinuation rate due to AEs. The findings of the SANAD trial are also presented; when administered to patients with partial epilepsy, carbamazepine was most likely to fail due to AEs, and lamotrigine and gabapentin were least likely to fail due to AEs. When administered to patients with idiopathic generalized epilepsy, topiramate was most frequently associated with AE-related discontinuation, followed by valproate; and while valproate was the most efficacious drug in this arm of the study, lamotrigine was more tolerable. What makes the SANAD study valuable and somewhat unique is its head-to-head comparison of one drug with another. Such

  1. Use of antiepileptic drugs during pregnancy and risk of spontaneous abortion and stillbirth: population based cohort study

    PubMed Central

    Kjaersgaard, Maiken Ina Siegismund; Pedersen, Henrik Søndergaard; Howards, Penelope P; Sørensen, Merete Juul; Olsen, Jørn; Parner, Erik Thorlund; Pedersen, Lars Henning; Vestergaard, Mogens; Christensen, Jakob

    2014-01-01

    Objective To determine whether use of antiepileptic drugs during pregnancy may increase the risk of spontaneous abortion or stillbirth. Design Population based cohort study. Setting Register based study in Denmark, 1997-2008. Participants 983 305 pregnancies identified in the Danish medical birth register and the Danish national hospital discharge register from 1 February 1997 to 31 December 2008 were linked to the Danish Register of Medicinal Product Statistics to obtain information on use of antiepileptic drugs. Main outcome measures Risk ratio of spontaneous abortion and stillbirth after use of antiepileptic drugs during pregnancy, estimated by using binomial regression adjusting for potential confounders of maternal age, cohabitation, income, education, history of severe mental disorder, and history of drug misuse. Results Antiepileptic drugs were used in a total of 4700 (0.5%) pregnancies. 16 out of 100 pregnant women using antiepileptics and 13 out of 100 pregnant women not using antiepileptics experienced a spontaneous abortion. After adjusting for potential confounders pregnant women using antiepileptics had a 13% higher risk of spontaneous abortions than pregnant women not using antiepileptics (adjusted risk ratio 1.13, 95% confidence interval 1.04 to 1.24). However, the risk of spontaneous abortion was not increased in women with an epilepsy diagnosis (0.98, 0.87 to 1.09), only in women without a diagnosis of epilepsy (1.30, 1.14 to 1.49). In an analysis including women with at least two pregnancies with discordant antiepileptic drug use (for example, use in the first pregnancy but not in the second), the adjusted hazard ratio for spontaneous abortion was 0.83 (0.69 to 1.00) for exposed pregnancies compared with unexposed pregnancies. Stillbirth was identified in 18 women who used antiepileptic drugs (unadjusted risk ratio 1.29, 0.80 to 2.10). Conclusion Among women with epilepsy and when analysing the risk in antiepileptic drug discordant pregnancies

  2. Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth

    PubMed Central

    Dean, J; Hailey, H; Moore, S; Lloyd, D; Turnpenny, P; Little, J

    2002-01-01

    Objective: To investigate the frequency of neonatal and later childhood morbidity in children exposed to antiepileptic drugs in utero. Design: Retrospective population based study. Setting: Population of the Grampian region of Scotland. Participants: Mothers taking antiepileptic drugs in pregnancy between 1976 and 2000 were ascertained from hospital obstetric records and 149 (58% of those eligible) took part. They had 293 children whose health and neurodevelopment were assessed. Main outcome measures: Frequencies of neonatal withdrawal, congenital malformations, childhood onset medical problems, developmental delay, and behaviour disorders. Results: Neonatal withdrawal was seen in 20% of those exposed to antiepileptic drugs. Congenital malformations occurred in 14% of exposed pregnancies, compared with 5% of non-exposed sibs, and developmental delay in 24% of exposed children, compared with 11% of non-exposed sibs. After excluding cases with a family history of developmental delay, 19% of exposed children and 3% of non-exposed sibs had developmental delay, 31% of exposed children had either major malformations or developmental delay, 52% of exposed children had facial dysmorphism compared with 25% of those not exposed, 31% of exposed children had childhood medical problems (13% of non-exposed sibs), and 20% had behaviour disorders (5% of non-exposed). Conclusion: Prenatal antiepileptic drug exposure in the setting of maternal epilepsy is associated with developmental delay and later childhood morbidity in addition to congenital malformation. PMID:11950853

  3. Foetal Antiepileptic Drug Exposure and Verbal versus Non-Verbal Abilities at Three Years of Age

    ERIC Educational Resources Information Center

    Meador, Kimford J.; Baker, Gus A.; Browning, Nancy; Cohen, Morris J.; Clayton-Smith, Jill; Kalayjian, Laura A.; Kanner, Andres; Liporace, Joyce D.; Pennell, Page B.; Privitera, Michael; Loring, David W.

    2011-01-01

    We previously reported that foetal valproate exposure impairs intelligence quotient. In this follow-up investigation, we examined dose-related effects of foetal antiepileptic drug exposure on verbal and non-verbal cognitive measures. This investigation is an ongoing prospective observational multi-centre study in the USA and UK, which has enrolled…

  4. Recent and future antiepileptic drugs and their impact on cognition: what can we expect?

    PubMed

    Mula, Marco

    2012-06-01

    Cognitive problems are frequently observed in patients with epilepsy and the relative contribution of antiepileptic drugs (AEDs) in this respect is determinant. During the past few years, a number of new AEDs have been introduced, and new compounds will be probably available in the forthcoming years. The ideal AED would be the one characterized by good efficacy with no negative effects on cognitive functions, mood and behavior. This paper is aimed at discussing the potential impact on cognition of a number of new compounds, namely lacosamide, rufinamide, retigabine, eslicarbazepine acetate, brivaracetam, perampanel and ganaxolone. In almost all cases, specific data on cognitive functions are not yet available, and it is possible only to speculate on their potential impact considering the mechanism of action and the adverse event profile in placebo-controlled studies. Lacosamide, eslicarbazepine acetate and probably brivaracetam are promising and will probably exhibit very limited impact on cognition. Conversely, retigabine may be more problematic, needing low starting doses and slow titration rates to improve cognitive tolerability. Data on rufinamide are restricted to special populations such as Lennox-Gastaut syndrome. Perampanel and ganaxolone are still in Phase III development, but the mechanism of action of these compounds is in line with a more sedative than neutral profile. PMID:22650169

  5. Effect of second-generation antiepileptic drugs on diplopia: a meta-analysis of placebo-controlled studies.

    PubMed

    Han, Haiyan; Qu, Wensheng; Kang, Huicong; Hu, Xiaoqing; Zhen, Guohua; Zhu, Suiqiang; Xue, Zheng

    2012-08-01

    Different antiepileptic drugs (AEDs) may cause similar adverse effects, one of which is diplopia. However, the AEDs causing diplopia and the dose-response effect of each drug remains uncertain. In this study, we compared several second-generation AEDs to find out whether they would contribute to the risk of diplopia and their effect-causing dose. A meta-analysis was performed on 19 studies in agreement with our inclusion criteria. The results showed that eight commonly used second-generation AEDs (gabapentin, levetiracetam, oxcarbazepine, lamotrigine, pregabalin, topiramate, vigabatrin and zonisamide) could cause diplopia. The reported odds ratios (ORs) ranged from 1.406 to 7.996. Ranking risks from the highest to the lowest ORs of the eight AEDs of any dose resulted in the following order: use of oxcarbazepine (7.996), levetiracetam (7.472), lamotrigine (5.258), vigabatrin (3.562), pregabalin (3.048), topiramate (2.660), gabapentin (1.966), zonisamide (1.406). Taking into account the ORs above, we can conclude that second-generation AEDs of any dose may cause diplopia. However, the levetiracetam-caused diplopia needs to be further studied according to the data (OR, 7.472; 95% confidence interval, 0.375-148.772). These findings ask for better concerns about patients' quality of life when giving antiepileptic treatments.

  6. Effects of antiepileptic drugs on associative LTP-like plasticity in human motor cortex.

    PubMed

    Heidegger, Tonio; Krakow, Karsten; Ziemann, Ulf

    2010-10-01

    Antiepileptic drugs (AEDs) are used extensively in clinical practice but relatively little is known on their specific effects at the systems level of human cortex. Here we tested, using a double-blind randomized placebo-controlled crossover design in healthy subjects, the effects of a single therapeutic oral dose of seven AEDs with different modes of action (tiagabine, diazepam, gabapentin, lamotrigine, topiramate, levetiracetam and piracetam) on long-term potentiation (LTP)-like motor cortical plasticity induced by paired associative transcranial magnetic stimulation (PAS). PAS-induced LTP-like plasticity was assessed from the increase in motor evoked potential amplitude in a hand muscle contralateral to the stimulated motor cortex. Levetiracetam significantly reduced LTP-like plasticity when compared to the placebo condition. Tiagabine, diazepam, lamotrigine and piracetam resulted in nonsignificant trends towards reduction of LTP-like plasticity while gabapentin and topiramate had no effect. The particularly depressant effect of levetiracetam is probably explained by its unique mode of action through binding at the vesicle membrane protein SV2A. Enhancement of gamma-amino butyric acid-dependent cortical inhibition by tiagabine, diazepam and possibly levetiracetam, and blockage of voltage-gated sodium channels by lamotrigine, may also depress PAS-induced LTP-like plasticity but these mechanisms appear to be less relevant. Findings may inform about AED-related adverse effects on important LTP-dependent central nervous systems processes such as learning or memory formation. The particular depressant effect of levetiracetam on LTP-like plasticity may also relate to the unique properties of this drug to inhibit epileptogenesis, a potentially LTP-associated process.

  7. Adverse effects of antihypertensive drugs.

    PubMed

    Husserl, F E; Messerli, F H

    1981-09-01

    Early essential hypertension is asymptomatic and should remain so throughout treatment. In view of the increasing number of available antihypertensive agents, clinicians need to become familiar with the potential side effects of these drugs. By placing more emphasis on non-pharmacological treatment (sodium restriction, weight loss, exercise) and thoroughly evaluating each case in particular, the pharmacological regimen can be optimally tailored to the patient's needs. Potential side effects should be predicted and can often be avoided; if they become clinically significant they should be rapidly recognised and corrected. These side effects can be easily remembered in most instances, as they fall into 3 broad categories: (a) those caused by an exaggerated therapeutic effect; (b) those due to a non-therapeutic pharmacological effect; and (c) those caused by a non-therapeutic, non-pharmacological effect probably representing idiosyncratic reactions. This review focuses mainly on adverse effects of the second and third kind. Each group of drugs in general shares the common side effects of the first two categories, while each individual drug has its own idiosyncratic side effects.

  8. Mexiletine and its Interactions with Classical Antiepileptic Drugs: An Isobolographic Analysis.

    PubMed

    Borowicz-Reutt, Kinga K; Banach, Monika; Piskorska, Barbara

    2016-05-01

    Using the mouse maximal electroshock test, the reference model of tonic-clonic seizures, the aim of the present study was to determine the type of interaction between mexiletine (a class IB antiarrhythmic drug) and classical antiepileptics: valproate, carbamazepine, phenytoin, and phenobarbital. Isobolographic analysis of obtained data indicated antagonistic interactions between mexiletine and valproate (for fixed ratio combinations of 1:1 and 3:1). Additivity was observed between mexiletine and valproate applied in proportion of 1:3 as well as between mexiletine and remaining antiepileptics for the fixed ratios of 1:3, 1:1, and 3:1. Neither motor performance nor long-term memory were impaired by mexiletine or antiepileptic drugs regardless of whether they were administered singly or in combination. Mexiletine did not significantly affected brain concentrations of carbamazepine, phenobarbital or phenytoin. In contrast, the antiarrhythmic drug decreased by 23 % the brain level of valproate. This could be, at least partially, the reason of antagonistic interaction between the two drugs. In conclusion, the observed additivity suggests that mexiletine can be safely applied in epileptic patients treated with carbamazepine, phenytoin or phenobarbital. Because of undesirable pharmacodynamics and pharmacokinetic interactions with valproate, mexiletine should not be used in such combinations. PMID:26738990

  9. Antiepileptic drug use in a nursing home setting: a retrospective study in older adults

    PubMed Central

    Callegari, Camilla; Ielmini, Marta; Bianchi, Lucia; Lucano, Melissa; Bertù, Lorenza; Vender, Simone

    2016-01-01

    Summary The authors set out to examine qualitatively the use of antiepileptic drugs (AEDs) in a population of older adults in a nursing home setting, evaluating aspects such as specialist prescriptions and changes in dosage. This retrospective prevalence study was carried out in a state-funded nursing home that provides care and rehabilitation for elderly people. The first objective of the study was to determine the prevalence of AED use in this population. The second objective was to monitor AED dosage modifications during the fifteen-month study period, focusing on the safety and the tolerability of AEDs. In the period of time considered, 129 of 402 monitored patients received at least one anti-epileptic therapy. The prevalence of AED use was therefore 32%. Gabapentin was found to be the most commonly prescribed drug, with a frequency of 29%, and it was used mainly for anxiety disorders, psychosis, neuropathic pain and mood disorders. PMID:27358221

  10. New Developments in Antiepileptic Drug Resistance: An Integrative View

    PubMed Central

    Schmidt, Dieter; Löscher, Wolfgang

    2009-01-01

    Current theories on drug resistance in epilepsy include the drug transporter hypothesis, the drug target hypothesis, and a novel approach called the inherent severity model of epilepsy, which posits that the severity of the disease determines its relative response to medication. Valuable as each of these hypotheses is, none is currently a stand-alone theory that is able to convincingly explain drug resistance in human epilepsy. As a consequence, it may be of interest to update and integrate the various hypotheses of drug resistance and to explore possible links to the severity of epilepsy. The observation that a high frequency of seizures prior to onset of treatment is a prognostic signal of increased severity and future drug failure suggests that common neurobiological factors may underlie both disease severity and pharmacoresistance. Such a link has been proposed for depression; however, the evidence for a direct mechanistic link, genetic or otherwise, between drug response and disease severity of human epilepsy is still elusive. Although emerging data from experimental studies suggest that alterations in GABAA receptors may present one example of a mechanistic link, clearly more work is needed to explore whether common neurobiological factors may underlie both epilepsy severity and drug failure. PMID:19421380

  11. Fluorination of an antiepileptic drug: A self supporting transporter by oxygen enrichment mechanism.

    PubMed

    Natchimuthu, V; Amoros, J; Ravi, S

    2016-03-01

    Drug therapy of seizures involves producing high levels of antiepileptic drugs in the blood. Drug must enter the brain by crossing from the blood into the brain tissue, called a transvascular route (TVR). Even before the drug can reach the brain tissue, factors such as systemic toxicity, macrophage phagocytises and reduction in oxygen content limit the success of this TVR. Encapsulating the drug within a nano scale delivering system, synthesising drugs with low molecular weight are the best mechanisms to deliver the drug to the brain. But through this article, we have explored a possibility of attaching a molecule 4-(trifluoromethyl) benzoic acid (TFMBA), that possess more number of fluorine atom, to benzodiazepine (BDZ) resulting in an ionic salt (S)-(+)-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine5,11(10H,11aH)-dione with 4-(trifluoromethyl)benzoic acid. By this way, reducing the toxicity of BDZ than the conventional anti-epileptic drugs (AEDs), increasing the solubility, reducing the melting point, enriching the TVR with excess oxygen content with the support of fluorine. With all these important prerequisites fulfilled, the drug along with the attached molecule is expected to travel more comfortably through the TVR without any external support than any other conventional AEDs. FTIR, (1)H NMR, (13)C NMR, HRMS spectroscopy, HRTEM and In vitro cytotoxicity analysis supports this study. PMID:26708322

  12. Outcomes in Postoperative Pediatric Cardiac Surgical Patients Who Received an Antiepileptic Drug

    PubMed Central

    Dinh, Kimberly L.; McDade, Erin J.; Moffett, Brady S.; Wilfong, Angus A.; Cabrera, Antonio G.

    2016-01-01

    BACKGROUND: Advances in cardiac operations over the last few decades, including corrective operations in early life, have dramatically increased the survival of children with congenital heart disease. However, postoperative care has been associated with neurologic complications, with seizures being the most common manifestation. The primary objective of this study is to describe the outcomes in pediatric patients who received an antiepileptic drug (AED) post–cardiac surgery. METHOD: A retrospective cohort study was performed in all patients less than 18 years of age who received an AED in the cardiovascular intensive care unit at Texas Children's Hospital from June 2002 until June 2012. Cardiac surgical patients initiated on phenobarbital, phenytoin, and levetiracetam were queried. Patients were excluded if the AED was not initiated on the admission for surgery. Patients who received 1 AED were compared to patients who received 2 AED, and differences in outcomes examined between the 3 AEDs used were evaluated. RESULTS: A total of 37 patients met the study criteria. Patients were initiated on an AED a median of 4 days following surgery and became seizure free a median of 1 day after initiation, with 65% remaining seizure free after the first dose. Half of all patients required 2 AEDs for seizure control, with a higher proportion of adolescents requiring 2 AEDs (p = 0.04). No differences were found when comparing the collected outcomes between phenobarbital, fosphenytoin, or levetiracetam. CONCLUSION: No adverse events were reported with the AEDs reviewed. Further work is necessary to evaluate long-term neurodevelopmental outcomes in this population and whether outcomes are a result of the AED or of other clinical sequelae.

  13. Antiepileptic drug utilization in Bangladesh: experience from Dhaka Medical College Hospital

    PubMed Central

    2013-01-01

    Background Epilepsy is a common health problem which carries a huge medical social psychological and economic impact for a developing country. The aim of this hospital-based study was to get an insight into the effectiveness and tolerability of low cost antiepileptic drugs (AEDs) in Bangladeshi people with epilepsy. Methods This retrospective chart review was done from hospital records in weekly Epilepsy outdoor clinic of Department of Neurology, Dhaka Medical College Hospital (DMCH) from October 1998 to February 2013. A total of 854 epilepsy patients met the eligibility criteria (had a complete record of two years of follow up data) from hospital database. A checklist was used to take demographics (age and gender), epilepsy treatment and adverse event related data. At least two years of follow up data were considered for analysis. Results Out of 854 patients selected, majority of the patients attending outdoor clinic were >11-30 years age group (55.2%) with a mean age of 20.3 ± 9 years and with a male (53%) predominance. Focal epilepsy were more common (53%), among whom secondary generalized epilepsy was the most frequent diagnosis (67%) followed by complex partial seizure (21%). Among those with Idiopathic Generalized Epilepsy (46%), generalized tonic clonic seizure was encountered in 74% and absence seizure was observed in 13%. The number of patients on monotherapy and dual AED therapy were 67% and 24% respectively and polytherapy (i.e. >3 AEDs) was used only in 9%. CBZ (67%) was the most frequently prescribed AED, followed by VPA (43%), PHB (17%), and PHT (8%). CBZ was prescribed in 37% patients as monotherapy followed by VPA in 21% and PHB in 8% patients. Newer generation drugs eg lemotrigine and topiramate were used only as add on therapy in combination with CBZ and VPA in only 2% patients. The treatment retention rates over the follow up period for the AEDs in monotherapy varied between 86 and 91% and were highest for CBZ, followed by VPA. Most of the

  14. Comparing the effects of first-line antiepileptic drugs on the gait of dogs with idiopathic epilepsy.

    PubMed

    Suiter, E J; Packer, R M A; Volk, H A

    2016-06-25

    Idiopathic epilepsy (IE) is a common chronic neurological disease of the dog. Previous studies of anti-epileptic drug (AED) treatment have indicated that acceptable AED adverse effects are as important to owners as reductions in seizure frequency. AEDs in both dogs and human beings are frequently associated with the adverse-effect ataxia. The aim of this study was to compare ataxia levels in dogs with IE treated chronically with phenobarbitone or imepitoin, the two currently available first-line AED treatments. The gait of 6 imepitoin-treated dogs, 8 phenobarbitone-treated dogs and 10 age-matched healthy control dogs were compared. Fifty strides from a walking gait were analysed for each dog, quantifying ataxia via the variability in six established gait parameters. Three variables differed significantly between groups: lateral distance between (i) pelvic paw placements, (ii) thoracic paw placements and (iii) stance time, which were significantly more variable in the phenobarbitone-treated dogs than imepitoin-treated or control dogs. These results indicate that dogs treated with phenobarbitone experience ataxia compared with controls and imepitoin-treated dogs. Conversely, there was no difference between imepitoin-treated dogs and controls. These results along with further research are needed to quantify AEDs adverse effects, to help vets and owners make more informed drug-choices.

  15. Comparing the effects of first-line antiepileptic drugs on the gait of dogs with idiopathic epilepsy.

    PubMed

    Suiter, E J; Packer, R M A; Volk, H A

    2016-06-25

    Idiopathic epilepsy (IE) is a common chronic neurological disease of the dog. Previous studies of anti-epileptic drug (AED) treatment have indicated that acceptable AED adverse effects are as important to owners as reductions in seizure frequency. AEDs in both dogs and human beings are frequently associated with the adverse-effect ataxia. The aim of this study was to compare ataxia levels in dogs with IE treated chronically with phenobarbitone or imepitoin, the two currently available first-line AED treatments. The gait of 6 imepitoin-treated dogs, 8 phenobarbitone-treated dogs and 10 age-matched healthy control dogs were compared. Fifty strides from a walking gait were analysed for each dog, quantifying ataxia via the variability in six established gait parameters. Three variables differed significantly between groups: lateral distance between (i) pelvic paw placements, (ii) thoracic paw placements and (iii) stance time, which were significantly more variable in the phenobarbitone-treated dogs than imepitoin-treated or control dogs. These results indicate that dogs treated with phenobarbitone experience ataxia compared with controls and imepitoin-treated dogs. Conversely, there was no difference between imepitoin-treated dogs and controls. These results along with further research are needed to quantify AEDs adverse effects, to help vets and owners make more informed drug-choices. PMID:27302918

  16. Clinically significant pharmacokinetic drug interactions of antiepileptic drugs with new antidepressants and new antipsychotics.

    PubMed

    Spina, Edoardo; Pisani, Francesco; de Leon, Jose

    2016-04-01

    Antiepileptic drugs (AEDs) are frequently co-prescribed with new antidepressants (ADs) or new antipsychotics (APs). A PubMed search with no time limit was used to update the review of the clinically significant pharmacokinetic (PK) drug interactions DIs (DIs) between AEDs with new ADs and APs. Our best interpretation of what to expect regarding dosing changes in the average patient after combining AEDs with new ADs or new APs is summarized on updated tables that integrate the information on in vitro metabolism studies, therapeutic drug monitoring (TDM) studies, case report/series and prospective studies. There will be a need to periodically update these dose correction factors as new knowledge becomes available. These tables will provide some orientation to clinicians with no TDM access and may also encourage clinicians to further study TDM. The clinical relevance of the inductive properties of carbamazepine, phenytoin, phenobarbital and primidone on new ADs and new APs and the inhibitory properties of valproic acid and some new ADs, are relatively well understood. On the other hand, PK DI studies combining new AEDs with weak inductive properties (particularly oxcarbazepine doses≥1200mg/day), topiramate doses≥400mg/day, clobazam, eslicarbazepine, and rufinamide), with new ADs and new APs are needed. Valproic acid may be 1) an inhibitor and/or inducer of clozapine and olanzapine with potential for clinically relevant DIs, 2) an inhibitor of paliperidone, and 3) a weak inducer of aripiprazole. Fluoxetine and fluvoxamine are relevant inhibitors of phenytoin and valproic acid and possibly of clobazam, lacosamide, phenobarbital, or primidone. PMID:26896788

  17. Prenatal Exposure to Antiepileptic Drugs and Dental Agenesis

    PubMed Central

    Jacobsen, Pernille E.; Henriksen, Tine B.; Haubek, Dorte; Østergaard, John R.

    2014-01-01

    Objective The aim of the study was to investigate the association between prenatal exposure to AEDs and the risk of dental agenesis and to differentiate between the possible effects of the different drugs used. Methods Data on 214 exposed and 255 unexposed children, aged 12–18 years, were extracted from the Prescription Database of the Central Denmark Region and North Denmark Region and the Danish Medical Birth Registry. The children's dental charts were examined for the presence of dental agenesis. Results Overall, children exposed to AED in utero had an increased risk of developing dental agenesis, but as a group, the difference was not significant (OR = 1.7; [95% CI: 0.8–3.6]). The risk of developing dental agenesis was three-fold increased (OR = 3.1; [95% CI: 1.3–7.4]) in children exposed to valproate in mono- or in poly-therapy with other AEDs than carbamazepine or oxcarbazepine. The risk was further increased (OR = 11.2; [95% CI: 2.4–51.9]) in children exposed to valproate and carbamazepine or oxcarbazepine in combination. Conclusions The present study shows that dental agenesis is a potential congenital abnormality that is related to prenatal exposure to valproate, and dental agenesis may be considered a sensitive marker for the teratogenicity of valproate. PMID:24416231

  18. Drug interactions with the newer antiepileptic drugs (AEDs)--part 1: pharmacokinetic and pharmacodynamic interactions between AEDs.

    PubMed

    Patsalos, Philip N

    2013-11-01

    Since 1989 there has been an exponential introduction of new antiepileptic drugs (AEDs) into clinical practice and these include eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, retigabine (ezogabine), rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide; 16 in total. Because often the treatment of epilepsy is lifelong, and because patients are commonly prescribed polytherapy with other AEDs, AED interactions are an important consideration in the treatment of epilepsy and indeed can be a major therapeutic challenge. For new AEDs, their propensity to interact is particularly important because inevitably they can only be prescribed, at least in the first instance, as adjunctive polytherapy. The present review details the pharmacokinetic and pharmacodynamic interactions that have been reported to occur with the new AEDs. Interaction study details are described, as necessary, so as to allow the reader to take a view as to the possible clinical significance of particular interactions. The principal pharmacokinetic interaction relates to hepatic enzyme induction or inhibition whilst pharmacodynamic interactions principally entail adverse effect synergism, although examples of anticonvulsant synergism also exist. Overall, the new AEDs are less interacting primarily because many are renally excreted or not hepatically metabolised (e.g. gabapentin, lacosamide, levetiracetam, topiramate, vigabatrin) and most do not (or minimally) induce or inhibit hepatic metabolism. A total of 139 pharmacokinetic interactions between concurrent AEDs have been described. The least pharmacokinetic interactions (n ≤ 5) are associated with gabapentin, lacosamide, tiagabine, vigabatrin and zonisamide, whilst lamotrigine (n = 17), felbamate (n = 15), oxcarbazepine (n = 14) and rufinamide (n = 13) are associated with the most. To date, felbamate, gabapentin, oxcarbazepine, perampanel, pregabalin

  19. Foetal antiepileptic drug exposure and verbal versus non-verbal abilities at three years of age.

    PubMed

    Meador, Kimford J; Baker, Gus A; Browning, Nancy; Cohen, Morris J; Clayton-Smith, Jill; Kalayjian, Laura A; Kanner, Andres; Liporace, Joyce D; Pennell, Page B; Privitera, Michael; Loring, David W

    2011-02-01

    We previously reported that foetal valproate exposure impairs intelligence quotient. In this follow-up investigation, we examined dose-related effects of foetal antiepileptic drug exposure on verbal and non-verbal cognitive measures. This investigation is an ongoing prospective observational multi-centre study in the USA and UK, which has enrolled pregnant females with epilepsy on monotherapy from 1999 to 2004. The study seeks to determine if differential long-term neurodevelopmental effects exist across four commonly used drugs (carbamazepine, lamotrigine, phenytoin and valproate). This report compares verbal versus non-verbal cognitive outcomes in 216 children who completed testing at the age of three years. Verbal and non-verbal index scores were calculated from the Differential Ability Scales, Preschool Language Scale, Peabody Picture Vocabulary Test and Developmental Test of Visual-Motor Integration. Verbal abilities were lower than non-verbal in children exposed in utero to each drug. Preconceptional folate use was associated with higher verbal outcomes. Valproate was associated with poorer cognitive outcomes. Performance was negatively associated with valproate dose for both verbal and non-verbal domains and negatively associated with carbamazepine dose for verbal performance. No dose effects were seen for lamotrigine and phenytoin. Since foetal antiepileptic drug exposure is associated with lower verbal than non-verbal abilities, language may be particularly susceptible to foetal exposure. We hypothesize that foetal drug exposure may alter normal cerebral lateralization. Further, a dose-dependent relationship is present for both lower verbal and non-verbal abilities with valproate and for lower verbal abilities with carbamazepine. Preconceptional folate may improve cognitive outcomes. Additional research is needed to confirm these findings, extend the study to other drugs, define the risks associated with drug treatment for seizures in the neonates, and

  20. Foetal antiepileptic drug exposure and verbal versus non-verbal abilities at three years of age

    PubMed Central

    Meador, Kimford J.; Baker, Gus A.; Browning, Nancy; Cohen, Morris J.; Clayton-Smith, Jill; Kalayjian, Laura A.; Kanner, Andres; Liporace, Joyce D.; Pennell, Page B.; Privitera, Michael

    2011-01-01

    We previously reported that foetal valproate exposure impairs intelligence quotient. In this follow-up investigation, we examined dose-related effects of foetal antiepileptic drug exposure on verbal and non-verbal cognitive measures. This investigation is an ongoing prospective observational multi-centre study in the USA and UK, which has enrolled pregnant females with epilepsy on monotherapy from 1999 to 2004. The study seeks to determine if differential long-term neurodevelopmental effects exist across four commonly used drugs (carbamazepine, lamotrigine, phenytoin and valproate). This report compares verbal versus non-verbal cognitive outcomes in 216 children who completed testing at the age of three years. Verbal and non-verbal index scores were calculated from the Differential Ability Scales, Preschool Language Scale, Peabody Picture Vocabulary Test and Developmental Test of Visual-Motor Integration. Verbal abilities were lower than non-verbal in children exposed in utero to each drug. Preconceptional folate use was associated with higher verbal outcomes. Valproate was associated with poorer cognitive outcomes. Performance was negatively associated with valproate dose for both verbal and non-verbal domains and negatively associated with carbamazepine dose for verbal performance. No dose effects were seen for lamotrigine and phenytoin. Since foetal antiepileptic drug exposure is associated with lower verbal than non-verbal abilities, language may be particularly susceptible to foetal exposure. We hypothesize that foetal drug exposure may alter normal cerebral lateralization. Further, a dose-dependent relationship is present for both lower verbal and non-verbal abilities with valproate and for lower verbal abilities with carbamazepine. Preconceptional folate may improve cognitive outcomes. Additional research is needed to confirm these findings, extend the study to other drugs, define the risks associated with drug treatment for seizures in the neonates, and

  1. The effects of antiepileptic drugs on cognitive functional magnetic resonance imaging

    PubMed Central

    Beltramini, Guilherme Coco; Cendes, Fernando

    2015-01-01

    The cognitive dysfunction caused by antiepileptic drugs (AEDs) has been extensively described, although the mechanisms underlying such collateral effects are still poorly understood. The combination of functional magnetic resonance imaging (fMRI) studies with pharmacological intervention (pharmaco-MRI or ph-MRI) offers the opportunity to investigate the effect of drugs such as AEDs on brain activity, including cognitive tasks. Here we review the studies that investigated the effects of AEDs [topiramate (TPM), lamotrigine (LMT), carbamazepine (CBZ), pregabalin (PGB), valproate (VPA) and levetiracetam (LEV)] on cognitive fMRI tasks. Despite the scarcity of fMRI studies focusing on the impact of AEDs on cognitive task, the results of recent work have provided important information about specific drug-related changes of brain function. PMID:25853082

  2. Progress report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI).

    PubMed

    Bialer, Meir; Johannessen, Svein I; Levy, René H; Perucca, Emilio; Tomson, Torbjörn; White, H Steve

    2013-01-01

    The Eleventh Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT XI, took place in Eilat, Israel from the 6th to 10th of May 2012. About 100 basic scientists, clinical pharmacologists and neurologists from 20 countries attended the conference, whose main themes included "Indications overlapping with epilepsy" and "Securing the successful development of an investigational antiepileptic drug in the current environment". Consistent with previous formats of this conference, a large part of the program was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 1994. Like the EILAT X report, the current manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, 2-deoxy-glucose, ganaxolone, ICA-105665, imepitoin, NAX 801-2, perampanel and other AMPA receptor antagonists, tonabersat, valnoctamide and its homologue sec-propylbutylacetamide (SPD), VX-765 and YK3089. Since the previous Eilat conference, retigabine (ezogabine) has been marketed and four newer AEDs in development (NAX 810-2, SPD, tonabersat and VX-765) are included in this manuscript.

  3. Epileptiform activity and cognitive deficits in SNAP-25(+/-) mice are normalized by antiepileptic drugs.

    PubMed

    Corradini, Irene; Donzelli, Andrea; Antonucci, Flavia; Welzl, Hans; Loos, Maarten; Martucci, Roberta; De Astis, Silvia; Pattini, Linda; Inverardi, Francesca; Wolfer, David; Caleo, Matteo; Bozzi, Yuri; Verderio, Claudia; Frassoni, Carolina; Braida, Daniela; Clerici, Mario; Lipp, Hans-Peter; Sala, Mariaelvina; Matteoli, Michela

    2014-02-01

    Synaptosomal-associated protein of 25 kDa (SNAP-25) is a protein that participates in the regulation of synaptic vesicle exocytosis through the formation of the soluble NSF attachment protein receptor complex and modulates voltage-gated calcium channels activity. The Snap25 gene has been associated with schizophrenia, attention deficit hyperactivity disorder, and bipolar disorder, and lower levels of SNAP-25 have been described in patients with schizophrenia. We used SNAP-25 heterozygous (SNAP-25(+/-)) mice to investigate at which extent the reduction of the protein levels affects neuronal network function and mouse behavior. As interactions of genotype with the specific laboratory conditions may impact behavioral results, the study was performed through a multilaboratory study in which behavioral tests were replicated in at least 2 of 3 distinct European laboratories. Reductions of SNAP-25 levels were associated with a moderate hyperactivity, which disappeared in the adult animals, and with impaired associative learning and memory. Electroencephalographic recordings revealed the occurrence of frequent spikes, suggesting a diffuse network hyperexcitability. Consistently, SNAP-25(+/-) mice displayed higher susceptibility to kainate-induced seizures, paralleled by degeneration of hilar neurons. Notably, both EEG profile and cognitive defects were improved by antiepileptic drugs. These results indicate that reduction of SNAP-25 expression is associated to generation of epileptiform discharges and cognitive dysfunctions, which can be effectively treated by antiepileptic drugs.

  4. Antiepileptic drugs with histone deacetylase inhibition activity and prostate cancer risk: a population-based case-control study.

    PubMed

    Salminen, Jukka K; Tammela, Teuvo L J; Auvinen, Anssi; Murtola, Teemu J

    2016-05-01

    Previous studies suggest that antiepileptic drugs with histone deacetylase (HDAC) inhibitor properties may have prostate cancer preventive effects. We evaluated the association between antiepileptic drug use and prostate cancer risk in a population-based case-control study. The study included all new prostate cancer cases diagnosed in Finland in 1995-2002 and matched controls (24,657 case-control pairs) identified from the Finnish Cancer Registry and the Population Register Center, respectively. Information on antiepileptic drug purchases was obtained from the national prescription reimbursement database. Odds ratios and their 95 % confidence intervals were estimated using age-adjusted and multivariable-adjusted conditional logistic regression analysis. Compared to never-users of antiepileptic drugs, the overall prostate cancer risk was decreased among users of phenobarbital, carbamazepine, and valproic acid (multivariable-adjusted odds ratio (OR) 0.47, 95 % CI 0.24-0.92; OR 0.82, 95 % CI 0.71-0.94, and OR 0.62, 95 % CI 0.42-0.92, respectively), but not among users of other antiepileptic drugs. Overall prostate cancer risk decreased in a dose-dependent manner by cumulative amount, duration and yearly dosage (intensity) of HDAC inhibitors valproic acid and carbamazepine. The risk of advanced prostate cancer was decreased only among carbamazepine users (OR 0.65, 95 % CI 0.44-0.96). Our results support possible prostate cancer preventive effects of HDAC inhibitors. However, also phenobarbital use was associated with decreased prostate cancer risk, despite not having HDAC inhibiting activity. The mechanism of action for antiepileptic drugs in prostate cancer deserves further study. PMID:27038166

  5. Identifying Adverse Drug Events by Relational Learning.

    PubMed

    Page, David; Costa, Vítor Santos; Natarajan, Sriraam; Barnard, Aubrey; Peissig, Peggy; Caldwell, Michael

    2012-07-01

    The pharmaceutical industry, consumer protection groups, users of medications and government oversight agencies are all strongly interested in identifying adverse reactions to drugs. While a clinical trial of a drug may use only a thousand patients, once a drug is released on the market it may be taken by millions of patients. As a result, in many cases adverse drug events (ADEs) are observed in the broader population that were not identified during clinical trials. Therefore, there is a need for continued, post-marketing surveillance of drugs to identify previously-unanticipated ADEs. This paper casts this problem as a reverse machine learning task, related to relational subgroup discovery and provides an initial evaluation of this approach based on experiments with an actual EMR/EHR and known adverse drug events. PMID:24955289

  6. Adverse Drug Reactions in Children—A Systematic Review

    PubMed Central

    Smyth, Rebecca Mary Diane; Gargon, Elizabeth; Kirkham, Jamie; Cresswell, Lynne; Golder, Su; Smyth, Rosalind; Williamson, Paula

    2012-01-01

    Background Adverse drug reactions in children are an important public health problem. We have undertaken a systematic review of observational studies in children in three settings: causing admission to hospital, occurring during hospital stay and occurring in the community. We were particularly interested in understanding how ADRs might be better detected, assessed and avoided. Methods and Findings We searched nineteen electronic databases using a comprehensive search strategy. In total, 102 studies were included. The primary outcome was any clinical event described as an adverse drug reaction to one or more drugs. Additional information relating to the ADR was collected: associated drug classification; clinical presentation; associated risk factors; methods used for assessing causality, severity, and avoidability. Seventy one percent (72/102) of studies assessed causality, and thirty four percent (34/102) performed a severity assessment. Only nineteen studies (19%) assessed avoidability. Incidence rates for ADRs causing hospital admission ranged from 0.4% to 10.3% of all children (pooled estimate of 2.9% (2.6%, 3.1%)) and from 0.6% to 16.8% of all children exposed to a drug during hospital stay. Anti-infectives and anti-epileptics were the most frequently reported therapeutic class associated with ADRs in children admitted to hospital (17 studies; 12 studies respectively) and children in hospital (24 studies; 14 studies respectively), while anti-infectives and non-steroidal anti-inflammatory drugs (NSAIDs) were frequently reported as associated with ADRs in outpatient children (13 studies; 6 studies respectively). Fourteen studies reported rates ranging from 7%–98% of ADRs being either definitely/possibly avoidable. Conclusions There is extensive literature which investigates ADRs in children. Although these studies provide estimates of incidence in different settings and some indication of the therapeutic classes most frequently associated with ADRs, further

  7. Quantification of sewer exfiltration using the anti-epileptic drug carbamazepine as marker species for wastewater.

    PubMed

    Fenz, R; Blaschke, A P; Clara, M; Kroiss, H; Mascher, D; Zessner, M

    2005-01-01

    The anti-epileptic drug carbamazepine was used as marker species in wastewater to identify and quantify sewer exfiltration. In several studies carbamazepine turned out to be hardly removed in wastewater treatment and not or just slightly attenuated during bank infiltration. Concentrations in wastewater are generally 1000 times higher than the limit of quantification. In contrast to many other marker species a "young" drug as carbamazepine is discharged to the environment only by wastewater. The results from this study carried out in Linz, Austria indicate an average exfiltration rate, expressed as percentage of the dry weather flow that is lost on the city-wide scale, of 1%. This rate is lower than sewage losses reported in most other studies which attempted to quantify exfiltration on the basis of groundwater pollution. However, it was also possible to identify one area with significant higher sewage losses.

  8. Successful treatment of POLG-related mitochondrial epilepsy with antiepileptic drugs and low glycaemic index diet.

    PubMed

    Martikainen, Mika H; Päivärinta, Markku; Jääskeläinen, Satu; Majamaa, Kari

    2012-12-01

    Epilepsy is a common manifestation of mitochondrial disease associated with mutations of the mitochondrial polymerase γ (POLG). Prognosis of mitochondrial epilepsy is often poor and there are few reports of successful treatment of POLG-related epilepsy. We describe a 26-year-old woman who experienced severe headache during a three-day period, followed by symptoms of visual flashing, speech difficulty, and generalised seizures. EEG recording showed non-convulsive status epilepticus (left occipital area) and brain MRI revealed parieto-occipital T2-hyperintensities. Visual aura and aphasia persisted despite antiepileptic medication with phenytoin, oxcarbazepine, and levetiracetam. Mitochondrial disorder was clinically suspected and a homozygous c.2243G>C mutation (p.Trp748Ser) was discovered in the POLG1 gene. The patient was then set on a low glycaemic index treatment (LGIT) variant of the ketogenic diet, after which the headaches, aphasia, and visual aura progressively improved and disappeared. She returned home two weeks after onset of symptoms and has not had further seizures. She continues to receive levetiracetam monotherapy and LGIT. We conclude that, at least for this patient, the combination of three antiepileptic drugs and LGIT is effective and well tolerated as treatment for severe episodes of POLG-related mitochondrial epilepsy.

  9. Linezolid Induced Adverse Drug Reactions - An Update.

    PubMed

    Kishor, Kamal; Dhasmana, Neha; Kamble, Shashank Shivaji; Sahu, Roshan Kumar

    2015-01-01

    Treatment regimen recommended for resistant tuberculosis consists of various drugs and these drugs are prescribed for at least 12-15 months. Such a long duration therapy and high dose of antibiotics result in adverse drug reactions (ADRs). ADRs may lead to various complications in disease management like replacement of drugs, dose increment, therapy withdrawal, etc. Linezolid is one of those drugs, practiced as an anti-mycobacterial agent and it is an important member of drug regimen for MDR and XDR tuberculosis. Linezolid is a broad spectrum antibiotic known for its unique mechanism of inhibition of resistant pathogenic strains. However, it causes serious adverse effects like thrombocytopenia, optic neuropathy, peripheral neuropathy, lactic acidosis, etc. Literature suggests that Linezolid can cause severe ADRs which affect patient compliance and hinder in therapy to a larger extent. Recent studies confirm the possibility of ADRs to be predicted with genetic make-up of individuals. To effectively deliver the available treatment regimen and ensure patient compliance, it is important to manage ADRs more efficiently. The role of pharmacogenomics in reducing adverse drug effects has been recently explored. In the present review, we discussed about Linezolid induced adverse drug reactions, mechanisms and genetic associations. PMID:26424176

  10. Pharmacogenomics and adverse drug reactions in children

    PubMed Central

    Rieder, Michael J.; Carleton, Bruce

    2014-01-01

    Adverse drug reactions are a common and important complication of drug therapy in children. Over the past decade it has become increasingly apparent that genetically controlled variations in drug disposition and response are important determinants of adverse events for many important adverse events associated with drug therapy in children. While this research has been difficult to conduct over the past decade technical and ethical evolution has greatly facilitated the ability of investigators to conduct pharmacogenomic studies in children. Some of this research has already resulted in changes in public policy and clinical practice, for example in the case of codeine use by mothers and children. It is likely that the use of pharmacogenomics to enhance drug safety will first be realized among selected groups of children with high rates of drug use such as children with cancer, but it also likely that this research will be extended to other groups of children who have high rates of drug utilization and as well as providing insights into the mechanisms and pathophysiology of adverse drug reactions in children. PMID:24795743

  11. The Portland Neurotoxicity Scale: Validation of a Brief Self-Report Measure of Antiepileptic-Drug-Related Neurotoxicity

    ERIC Educational Resources Information Center

    Salinsky, Martin C.; Storzbach, Daniel

    2005-01-01

    The Portland Neurotoxicity Scale (PNS) is a brief patient-based survey of neurotoxicity complaints commonly encountered with the use of antiepileptic drugs (AEDs). The authors present data on the validity of this scale, particularly when used in longitudinal studies. Participants included 55 healthy controls, 23 epilepsy patient controls, and 86…

  12. ADVERSE DRUG REACTIONS IN THE ORAL CAVITY.

    PubMed

    Boras, Vanja Vučićević; Andabak-Rogulj, Ana; Brailo, Vlaho; Šimunković, Sonja Kraljević; Gabrić, Dragana; Vrdoljak, Danko Velimir

    2015-06-01

    Every medication may lead to adverse effects, even when used in standard doses and mode of application. In the oral cavity, adverse effects may affect every part of oral mucosa and are the result of medications taken either locally or systemically. Oral adverse reactions to drugs are not typical and therefore sometimes not easy to recognize. On diagnosing adverse side effects in the oral cavity, experienced clinician will usually diagnose the condition on the basis of detailed medical history and clinical finding. However, the only objective evidence for the offending drug is 're-challenge', i.e. exposure to the drug after its discontinuation. It carries a huge risk of anaphylactic reaction; therefore it has to be performed in a controlled hospital setting. Therapy is based on immediate exclusion of the offending drug and, if lesions are present in the oral cavity, topical or systemic corticosteroid therapy is prescribed. This article gives a review of patients with oral adverse drug reactions referred to the Department of Oral Medicine in Zagreb.

  13. Patients' preferences for treatment outcomes of add-on antiepileptic drugs: a conjoint analysis.

    PubMed

    Manjunath, Ranjani; Yang, Jui-Chen; Ettinger, Alan B

    2012-08-01

    To understand the relative importance of the outcomes of add-on antiepileptic drugs (AEDs) and the willingness of patients with epilepsy to accept therapeutic trade-offs between seizure control and tolerability, we administered a Web-enabled, choice-format conjoint survey to patients with a self-reported physician diagnosis of epilepsy and symptoms of partial seizures. Patients answered nine choice questions to evaluate treatment outcomes of two different hypothetical add-on AEDs. Patients were first asked to choose the better of the two medicines and then asked a follow-up question about whether or not they would add the selected AED to their current treatment regimen. Our study demonstrated that patients with epilepsy consider seizure reduction to be the top priority when ranking it against the reduction or elimination of side effects. This study aids in better understanding of patients' AED treatment preferences and may aid in management of epilepsy.

  14. The treatment of epilepsy in pregnancy: The neurodevelopmental risks associated with exposure to antiepileptic drugs.

    PubMed

    Bromley, R

    2016-09-01

    A number of antiepileptic drugs (AEDs) have been confirmed as teratogens due to their association with an increased malformation rate. The majority of research to date does not find an association between prenatal exposure to monotherapy carbamazepine, lamotrigine or phenytoin and neurodevelopmental outcome in comparison to control children and noted higher abilities in comparison to children exposed to valproate; but further work is needed before conclusions can be drawn. Data for levetiracetam was limited to one study, as was the evidence for topiramate. Sodium valproate exposure appeared to carry a dose dependent risk to the developing brain, with evidence of reduced levels of IQ, poorer verbal abilities and increased rate of autistic spectrum disorder both in comparison to control children and children exposed to other AEDs. The severity of the neurodevelopmental deficits associated with prenatal exposure to valproate highlight the critical need to consider neurodevelopmental outcomes as a central aspect of teratological research. PMID:27312074

  15. Postpartum depression in women with epilepsy: Influence of antiepileptic drugs in a prospective study

    PubMed Central

    Galanti, Melanie; Newport, D. Jeffrey; Pennell, Page B.; Titchner, Denicia; Newman, Melanee; Knight, Bettina T.; Stowe, Zachary N.

    2013-01-01

    Patients with epilepsy are at high risk for major depressive disorder (MDD) and, according to one report, postpartum depression (PPD) as well. The study described here sought to determine the prevalence and risk factors for PPD among women with epilepsy. Fifty-six women with epilepsy participating in a prospective study of perinatal antiepileptic drug (AED) pharmacokinetics were included. Participants completed the Beck Depression Inventory (BDI) during pregnancy and the postpartum period. Fourteen participants (25.0%) had a postnatal BDI score ≥12 indicative of PPD. Logistic regression indicated that significant risk factors for PPD among women with epilepsy included multiparity (odds ratio = 12.5) and AED polytherapy (odds ratio = 9.3). The rate of PPD was unaffected by the use of specific AEDs. In conclusion, PPD rates are higher among women with epilepsy than the general population, particularly those who are multiparous or receiving AED polytherapy, and there is no evidence that AED selection modifies this risk. PMID:19854113

  16. The Impact of Anti-Epileptic Drugs on Growth and Bone Metabolism

    PubMed Central

    Fan, Hueng-Chuen; Lee, Herng-Shen; Chang, Kai-Ping; Lee, Yi-Yen; Lai, Hsin-Chuan; Hung, Pi-Lien; Lee, Hsiu-Fen; Chi, Ching-Shiang

    2016-01-01

    Epilepsy is a common neurological disorder worldwide and anti-epileptic drugs (AEDs) are always the first choice for treatment. However, more than 50% of patients with epilepsy who take AEDs have reported bone abnormalities. Cytochrome P450 (CYP450) isoenzymes are induced by AEDs, especially the classical AEDs, such as benzodiazepines (BZDs), carbamazepine (CBZ), phenytoin (PT), phenobarbital (PB), and valproic acid (VPA). The induction of CYP450 isoenzymes may cause vitamin D deficiency, hypocalcemia, increased fracture risks, and altered bone turnover, leading to impaired bone mineral density (BMD). Newer AEDs, such as levetiracetam (LEV), oxcarbazepine (OXC), lamotrigine (LTG), topiramate (TPM), gabapentin (GP), and vigabatrin (VB) have broader spectra, and are safer and better tolerated than the classical AEDs. The effects of AEDs on bone health are controversial. This review focuses on the impact of AEDs on growth and bone metabolism and emphasizes the need for caution and timely withdrawal of these medications to avoid serious disabilities. PMID:27490534

  17. The Impact of Anti-Epileptic Drugs on Growth and Bone Metabolism.

    PubMed

    Fan, Hueng-Chuen; Lee, Herng-Shen; Chang, Kai-Ping; Lee, Yi-Yen; Lai, Hsin-Chuan; Hung, Pi-Lien; Lee, Hsiu-Fen; Chi, Ching-Shiang

    2016-01-01

    Epilepsy is a common neurological disorder worldwide and anti-epileptic drugs (AEDs) are always the first choice for treatment. However, more than 50% of patients with epilepsy who take AEDs have reported bone abnormalities. Cytochrome P450 (CYP450) isoenzymes are induced by AEDs, especially the classical AEDs, such as benzodiazepines (BZDs), carbamazepine (CBZ), phenytoin (PT), phenobarbital (PB), and valproic acid (VPA). The induction of CYP450 isoenzymes may cause vitamin D deficiency, hypocalcemia, increased fracture risks, and altered bone turnover, leading to impaired bone mineral density (BMD). Newer AEDs, such as levetiracetam (LEV), oxcarbazepine (OXC), lamotrigine (LTG), topiramate (TPM), gabapentin (GP), and vigabatrin (VB) have broader spectra, and are safer and better tolerated than the classical AEDs. The effects of AEDs on bone health are controversial. This review focuses on the impact of AEDs on growth and bone metabolism and emphasizes the need for caution and timely withdrawal of these medications to avoid serious disabilities. PMID:27490534

  18. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues.

    PubMed

    Crawford, P; Feely, M; Guberman, A; Kramer, G

    2006-04-01

    In response to increasing cost pressures, healthcare systems are encouraging the use of generic medicines. This review explores potential problems with generic substitution of antiepileptic drugs (AEDs). A broad search strategy identified approximately 70 relevant articles. Potential problems with generic substitution included: The limited evidence (mainly case reports with some pharmacokinetic studies) appears to support these concerns for older AEDs. As a result, restrictions on use of specific generic AEDs are in place in some countries and recommended by some lay epilepsy organisations. As more AEDs lose patent protection, it is important to examine the question of whether generic substitution may pose problems for patients with epilepsy, and whether there should be safeguards to ensure that both physician and patient are informed when generic substitution occurs.

  19. Failure of antiepileptic drugs in controlling seizures in epilepsy: What do we do next?

    PubMed

    Galindo-Mendez, Brahyan; Mayor, Luis C; Velandia-Hurtado, Fernando; Calderon-Ospina, Carlos

    2015-01-01

    Medically intractable epilepsy is a clinical condition of concern that arises when a patient with epilepsy suffers seizures, despite a trial of two or more antiepileptic drugs (AEDs) suitable for the type of epilepsy that are prescribed at maximum tolerated doses, does not achieve control of seizures. This diagnosis could be related to cortical dysplasias. We report the case of a 5-year-old girl with a previous normal neurological development and no family history of epilepsy who presented with focal-type seizures at age 4. She started treatment by taking different AEDs for seizure control. She continued having frequent seizures that sometimes progressed to generalized seizures and status epilepticus. After a focal cortical resection performed in the area where interictal spikes were detected, the pathology confirmed a type IIb cortical dysplasia as the cause of the epilepsy. This article discusses cortical dysplasias as a cause of pharmacoresistant epilepsy and its treatment. PMID:26101746

  20. Adverse Effects of Common Drugs: Dietary Supplements.

    PubMed

    Felix, Todd Matthew; Karpa, Kelly Dowhower; Lewis, Peter R

    2015-09-01

    Dietary supplement-induced adverse effects often resolve quickly after discontinuation of the offending product, especially in younger patients. The potential for unwanted outcomes can be amplified in elderly patients or those taking multiple prescription drugs, especially where interactions exist with drugs metabolized by cytochrome P450 enzymes. Attributing injury or illness to a specific supplement can be challenging, especially in light of multi-ingredient products, product variability, and variability in reporting, as well as the vast underreporting of adverse drug reactions. Clinicians prescribing a new drug or evaluating a patient with a new symptom complex should inquire about use of herbal and dietary supplements as part of a comprehensive evaluation. Clinicians should report suspected supplement-related adverse effects to the local or state health department, as well as the Food and Drug Administration's MedWatch program (available at https://www.safetyreporting.hhs.gov). Clinicians should consider discussing suspected adverse effects involving drugs, herbal products, or dietary supplements with their community- and hospital-based pharmacists, and explore patient management options with medical or clinical toxicology subspecialists.

  1. Solid Dispersion Approach Improving Dissolution Rate of Stiripentol: a Novel Antiepileptic Drug

    PubMed Central

    Afifi, Samar

    2015-01-01

    Some drugs have low bioavailability due to their poor aqueous solubility and/or slow dissolution rate in biological fluids. Stiripentol (STP) is a novel anticonvulsant drug that is structurally unrelated to the currently available antiepileptics. It has poor aqueous solubility and its solubility has to be enhanced accordingly. Polyethyleneglycol 6000 (PEG-6000) is commonly utilized as a hydrophilic carrier for poorly water soluble drugs in order to improve their bioavailability. STP and PEG-6000 binary system was obtained by physical mixture, solvent evaporation, co-evaporation and melting methods using different weight ratios. The properties of the prepared binary systems were evaluated using dissolution rate, phase solubility, Fourier-transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and scanning electron microscope (SEM) studies. The FTIR spectroscopic studies showed the stability of STP and absence of STP-PEG-6000 interaction. The DSC and SEM studies indicated the amorphous state of STP in its binary systems with PEG-6000. Dissolution profile of STP was significantly improved via complexation with PEG-6000 as compared with the pure drug. The binary system which was prepared using melting method showed the highest dissolution rate. The promising results of the prepared binary systems open the avenue for further oral formulation of STP. PMID:26664367

  2. Seizure control and pharmacokinetics of antiepileptic drugs in pregnant women with epilepsy.

    PubMed

    Brodtkorb, Eylert; Reimers, Arne

    2008-03-01

    The main concerns associated with epilepsy during pregnancy consist of maternal and fetal risks from uncontrolled seizures, and harmful effects of the treatment on the development of the offspring. Although seizure control is maintained in the majority, worsening occurs in a fraction of childbearing women with epilepsy. As multiple factors associated with pregnancy may have a negative impact on epilepsy, a careful analysis of the situation should be performed in those who deteriorate. Emotional and behavioural influence, including insufficient sleep and treatment non-compliance, as well as physical factors, such as emesis and pelvic distortion, should receive attention. The serum concentrations of almost all antiepileptic drugs decrease during pregnancy, particularly those which are metabolised by glucuronidation. The inter-individual variability is pronounced. In highly protein-bound drugs, such as phenytoin and valproate, unbound drug is less affected than total concentrations. Lamotrigine and levetiracetam concentrations may decrease by more than 50% in the course of pregnancy; monohydroxyoxcarbazepine by up to 30-40%. Appropriate clinical follow-up tailored to individual needs and supported by therapeutic drug monitoring should be performed in pregnant women with epilepsy. Education concerning reproductive issues is an essential part of the epilepsy service to fertile women.

  3. Local anesthetic and antiepileptic drug access and binding to a bacterial voltage-gated sodium channel.

    PubMed

    Boiteux, Céline; Vorobyov, Igor; French, Robert J; French, Christopher; Yarov-Yarovoy, Vladimir; Allen, Toby W

    2014-09-01

    Voltage-gated sodium (Nav) channels are important targets in the treatment of a range of pathologies. Bacterial channels, for which crystal structures have been solved, exhibit modulation by local anesthetic and anti-epileptic agents, allowing molecular-level investigations into sodium channel-drug interactions. These structures reveal no basis for the "hinged lid"-based fast inactivation, seen in eukaryotic Nav channels. Thus, they enable examination of potential mechanisms of use- or state-dependent drug action based on activation gating, or slower pore-based inactivation processes. Multimicrosecond simulations of NavAb reveal high-affinity binding of benzocaine to F203 that is a surrogate for FS6, conserved in helix S6 of Domain IV of mammalian sodium channels, as well as low-affinity sites suggested to stabilize different states of the channel. Phenytoin exhibits a different binding distribution owing to preferential interactions at the membrane and water-protein interfaces. Two drug-access pathways into the pore are observed: via lateral fenestrations connecting to the membrane lipid phase, as well as via an aqueous pathway through the intracellular activation gate, despite being closed. These observations provide insight into drug modulation that will guide further developments of Nav inhibitors. PMID:25136136

  4. Solid Dispersion Approach Improving Dissolution Rate of Stiripentol: a Novel Antiepileptic Drug.

    PubMed

    Afifi, Samar

    2015-01-01

    Some drugs have low bioavailability due to their poor aqueous solubility and/or slow dissolution rate in biological fluids. Stiripentol (STP) is a novel anticonvulsant drug that is structurally unrelated to the currently available antiepileptics. It has poor aqueous solubility and its solubility has to be enhanced accordingly. Polyethyleneglycol 6000 (PEG-6000) is commonly utilized as a hydrophilic carrier for poorly water soluble drugs in order to improve their bioavailability. STP and PEG-6000 binary system was obtained by physical mixture, solvent evaporation, co-evaporation and melting methods using different weight ratios. The properties of the prepared binary systems were evaluated using dissolution rate, phase solubility, Fourier-transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and scanning electron microscope (SEM) studies. The FTIR spectroscopic studies showed the stability of STP and absence of STP-PEG-6000 interaction. The DSC and SEM studies indicated the amorphous state of STP in its binary systems with PEG-6000. Dissolution profile of STP was significantly improved via complexation with PEG-6000 as compared with the pure drug. The binary system which was prepared using melting method showed the highest dissolution rate. The promising results of the prepared binary systems open the avenue for further oral formulation of STP.

  5. Interactions between non-vitamin K oral anticoagulants and antiepileptic drugs.

    PubMed

    Stöllberger, Claudia; Finsterer, Josef

    2016-10-01

    Atrial fibrillation (AF) is a frequent cause of stroke. Secondary prophylaxis by oral anticoagulants (OAC) is recommended after stroke in AF-patients. OAC can be achieved by vitamin-K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) like dabigatran, rivaroxaban, apixaban or edoxaban. Seizures are frequent after stroke, and antiepileptic drugs (AEDs) are indicated. The review, based on a literature research, aims to give an overview about pharmacokinetic knowledge and clinical data about drug-drug interactions (DDIs) between NOACs and AED. Carbamazepine, levetiracetam, phenobarbital, phenytoin and valproic acid might decrease the effect of NOACs by inducing P-glycoprotein (P-gp) activity. Carbamazepine, oxcarbazepine, phenytoin, phenobarbital and topiramate might decrease the effect of NOACs by inducing CYP3A4 activity. Controversial data - inhibition as well as induction of CYP3A4 - were found about valproic acid. The relevance of these DDIs is largely unknown since there are only sporadic case reports available. To increase the knowledge about DDIs between NOACs and AEDs we suggest subgroup analyses addressing effects and safety of VKAs versus NOACs in patients with AF on AEDs, in case they have been included in previously completed or still ongoing trials or registries. This could be easily feasible and would be desirable in view of the large data already accumulated. PMID:27450623

  6. Effect of antiepileptic drug therapy on thyroid hormones among adult epileptic patients: An analytical cross-sectional study

    PubMed Central

    Adhimoolam, Mangaiarkkarasi; Arulmozhi, Ranjitha

    2016-01-01

    Objective: The objective of the study was to evaluate and compare the effect of conventional and newer antiepileptic drugs (AEDs) on thyroid hormone levels in adult epileptic patients. Methods: A hospital-based, analytical cross-sectional study was conducted among the adult epileptic patients receiving conventional AEDs (Group 2) or newer AEDs (Group 3) for more than 6 months. Serum thyroid hormone levels including free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) were analyzed and the hormonal status was compared with healthy control subjects (Group 1). Findings: Sodium valproate and phenytoin were commonly used conventional AEDs; levetiracetam and topiramate were common among the newer drugs. There was a statistically significant decrease in serum fT4 and increase in serum TSH levels (P < 0.0001) in patients on long-term therapy with conventional antiepileptic agents than in the control group. No significant change in thyroid hormone levels (fT3, fT4, and TSH; P = 0.68, 0.37, and 0.90, respectively) was observed with newer antiepileptics-treated patients when compared to control group. One-way analysis of variance followed by post hoc Dunnett's test was performed using SPSS version 17.0 software package. Conclusion: The present study showed that conventional AEDs have significant alteration in the thyroid hormone levels than the newer antiepileptics in adult epileptic patients. PMID:27512707

  7. Immunomodulatory drugs: Oral and systemic adverse effects

    PubMed Central

    Mattila, Riikka; Gomez-Font, Rafael; Meurman, Jukka H.

    2014-01-01

    Objectives: The main objectives are to present the different adverses effects of the immunomodulatory drugs that can impair the quality of life of the immunosupressed patients and study the impact of immunomodualtion on oral diseases. Immunomodulatory drugs have changed the treatment protocols of many diseases where immune functions play a central role, such as rheumatic diseases. Their effect on oral health has not been systematically investigated, however. Study Design: We review current data on the new immunomodulatory drugs from the oral health perspective based on open literature search of the topic. Results: These target specific drugs appear to have less drug interactions than earlier immunomodulating medicines but have nevertheless potential side effects such as activating latent infections. There are some data showing that the new immunomodulatory drugs may also have a role in the treatment of certain oral diseases such as lichen planus or ameliorating symptoms in Sjögren´s syndrome, but the results have not been overly promising. Conclusions: In general, data are sparse of the effect of these new drugs vs. oral diseases and there are no properly powered randomized controlled trials published on this topic. Key words:Immunomodulatory drugs, oral diseases, adverse effects, therapeutic action. PMID:23986016

  8. P-glycoprotein alters blood–brain barrier penetration of antiepileptic drugs in rats with medically intractable epilepsy

    PubMed Central

    Ma, Aimei; Wang, Cuicui; Chen, Yinghui; Yuan, Weien

    2013-01-01

    P-glycoprotein is one of the earliest known multidrug transporters and plays an important role in resistance to chemotherapeutic drugs. In this study, we detected levels of P-glycoprotein and its mRNA expression in a rat brain model of medically intractable epilepsy established by amygdala kindling and drug selection. We investigated whether inhibition of P-glycoprotein affects the concentration of antiepileptic drugs in cortical extracellular fluid. We found that levels of P-glycoprotein and its mRNA expression were upregulated in epileptic cerebral tissue compared with cerebral tissue from normal rats. The concentrations of two antiepileptic drugs, carbamazepine and phenytoin, were very low in the cortical extracellular fluid of rats with medically intractable epilepsy, and were restored after blockade of P-glycoprotein by verapamil. These results show that increased P-glycoprotein levels alter the ability of carbamazepine and phenytoin to penetrate the blood–brain barrier and reduce the concentrations of these agents in extracellular cortical fluid. High P-glycoprotein levels may be involved in resistance to antiepileptic drugs in medically intractable epilepsy. PMID:24348021

  9. Selecting anti-epileptic drugs: a pediatric epileptologist’s view, a computer’s view

    PubMed Central

    Pestian, J; Matykiewicz, P; Holland-Bouley, K; Standridge, S; Spencer, M; Glauser, T

    2012-01-01

    Objective To identify which clinical characteristics are important to include in clinical decision support systems developed for Antiepileptic Drug (AEDs) selection. Methods Twenty-three epileptologists from the Childhood Absence Epilepsy network completed a survey related to AED selection. Using cluster analysis their responses where classified into subject matter groups and weighted for importance. Results Five distinct subject matter groups were identified and their relative weighting for importance were determined: disease characteristics (weight 4.8 ± 0.049), drug toxicities (3.82 ± 0.098), medical history (3.12 ± 0.102), systemic characteristics (2.57 ± 0.048) and genetic characteristics (1.08 ± 0.046). Conclusion Research about prescribing patterns exists but research on how such data can be used to train advanced technology is novel. As machine learning algorithms becomes more and more prevalent in clinical decisions support systems, developing methods for determining which data should be part of those algorithms is equally important. PMID:22998126

  10. Risk of recurrence after discontinuation of antiepileptic drug therapy in children with epilepsy

    PubMed Central

    Incecik, Faruk; Herguner, Ozlem M.; Altunbasak, Sakir; Mert, Gulen; Kiris, Nurcihan

    2014-01-01

    Objectives: The numerous antiepileptic drug (AED) withdrawal studies published in the last 40 years have relied mainly on heterogeneous study groups. There is still no general agreement on the criteria to predict safe discontinuation. The goal of this study was to assess the outcome of AED withdrawal in epileptic children. Materials and Methods: Three hundred and eight children with epilepsy were enrolled, and these patients followed at least 1 year after drug withdrawal. Time to seizure relapse and predictive factors were analyzed by survival methods. Results: Among the 308 patients, 179 (58.1%) were boys and 129 (41.9%) were girls and the mean age at the seizure onset was 60.41 ± 36.54 months (2-144 months). The recurrence occurred in 73 (23.7%) patients. Mental retardation, history of febrile seizure, etiological of epilepsy, abnormal first electroencephalogram (EEG), abnormal neuroimaging findings, and total number of AED before remission were significantly associated with relapse risk according to univariate analysis. In the multivariate analysis, abnormal first EEG and number of AED before remission (polytherapy) were the risk factors influencing seizure recurrence. Conclusions: In our study, recurrence rate was 23.7% in children and most occurred during the 1st year. The potential risk factors of recurrence are history of febrile seizure, mental retardation, etiological of epilepsy, abnormal first EEG, abnormal neuroimaging findings, and total number of AED before remission. However, we found abnormal first EEG and polytherapy as risk factors of recurrence in multivariate analysis. PMID:25250060

  11. Evaluation of neurotoxic and neuroprotective pathways affected by antiepileptic drugs in cultured hippocampal neurons.

    PubMed

    Morte, Maria I; Carreira, Bruno P; Falcão, Maria J; Ambrósio, António F; Soares-da-Silva, Patrício; Araújo, Inês M; Carvalho, Caetana M

    2013-12-01

    In this study we evaluated the neurotoxicity of eslicarbazepine acetate (ESL), and of its in vivo metabolites eslicarbazepine (S-Lic) and R-licarbazepine (R-Lic), as compared to the structurally-related compounds carbamazepine (CBZ) and oxcarbazepine (OXC), in an in vitro model of cultured rat hippocampal neurons. The non-related antiepileptic drugs (AEDs) lamotrigine (LTG) and sodium valproate (VPA) were also studied. We assessed whether AEDs modulate pro-survival/pro-apoptotic pathways, such as extracellular-regulated kinase (ERK1/2), Akt and stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK). We found that neither ESL nor its metabolites, CBZ or LTG, up to 0.3mM, for 24h of exposure, decreased cell viability. OXC was the most toxic drug decreasing cell viability in a concentration-dependent manner, leading to activation of caspase-3 and PARP cleavage. VPA caused the appearance of the apoptotic markers, but did not alter cell viability. ESL, S-Lic and OXC decreased the levels of phospho-ERK1/2 and of phospho-Akt, when compared to basal levels, whereas CBZ decreased phospho-SAPK/JNK and phospho-Akt levels. LTG and VPA increased the phosphorylation levels of SAPK/JNK. These results suggest that ESL and its main metabolite S-Lic, as well as CBZ, LTG and VPA, are less toxic to hippocampal neurons than OXC, which was the most toxic agent.

  12. The antiepileptic drug diphenylhydantoin affects the structure of the human erythrocyte membrane.

    PubMed

    Suwalsky, Mario; Mennickent, Sigrid; Norris, Beryl; Villena, Fernando; Cuevas, Francisco; Sotomayor, Carlos P

    2004-01-01

    Phenytoin (diphenylhydantoin) is an antiepileptic agent effective against all types of partial and tonic-clonic seizures. Phenytoin limits the repetitive firing of action potentials evoked by a sustained depolarization of mouse spinal cord neurons maintained in vitro. This effect is mediated by a slowing of the rate of recovery of voltage activated Na+ channels from inactivation. For this reasons it was thought of interest to study the binding affinities of phenytoin with cell membranes and their perturbing effects upon membrane structures. The effects of phenytoin on the human erythrocyte membrane and molecular models have been investigated in the present work. This report presents the following evidence that phenytoin interacts with cell membranes: a) X-ray diffraction and fluorescence spectroscopy of phospholipid bilayers showed that phenytoin perturbed a class of lipids found in the outer moiety of cell membranes; b) in isolated unsealed human erythrocyte membranes (IUM) the drug induced a disordering effect on the polar head groups and acyl chains of the erythrocyte membrane lipid bilayer; c) in scanning electron microscopy (SEM) studies on human erythrocytes the formation of echinocytes was observed, due to the insertion of phenytoin in the outer monolayer of the red cell membrane. This is the first time that an effect of phenytoin on the red cell shape is described. However, the effects of the drug were observed at concentrations higher than those currently found in plasma when phenytoin is therapeutically administered. PMID:18998414

  13. Relationship of Child IQ to Parental IQ and Education in Children with Fetal Antiepileptic Drug Exposure

    PubMed Central

    Meador, Kimford J.; Baker, Gus A.; Browning, Nancy; Clayton-Smith, Jill; Cohen, Morris J.; Kalayjian, Laura A.; Kanner, Andres; Liporace, Joyce D.; Pennell, Page B.; Privitera, Michael; Loring, David W.

    2011-01-01

    Clinical trial designs need to control for genetic and environmental influences when examining cognitive outcomes in children for whom clinical considerations preclude randomization. However, the contributions of maternal and paternal IQ and education to pediatric cognitive outcomes are uncertain in disease populations. The NEAD Study is an ongoing prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy to determine if differential long-term neurodevelopmental effects exist across four commonly used antiepileptic drugs (AEDs). Here, we examined the relationship of IQ and education in both parents to child IQ at age 3 years. IQ and education for both parents were statistically correlated to child IQ. However, paternal IQ and education were not significant after accounting for maternal IQ effects. Because maternal IQ and education are independently related to child cognitive outcome, both should be assessed in studies investigating the effects of fetal drug exposures or other environmental factors that could affect the child’s cognitive outcome. PMID:21546316

  14. Monitoring Adverse Drug Reactions: A Preliminary Study

    PubMed Central

    Reynolds, J. L.

    1981-01-01

    The feasibility of family physicians functioning as monitors of adverse drug reactions (ADR) was examined over one month in ten practices. This was done as a preliminary trial, before attempting to use the 200 family physicians of the National Reporting System of the College of Family Physicians of Canada to monitor ADRs on a national basis. Both of these trials were designed to examine the feasibility of family physicians acting as prospective monitors of ADRs in newly marketed drugs and to identify a drug group suitable for monitoring. This study examined the detection of ADRs, prescribing and practice profiles. No firm conclusion could be reached as to the value of family doctors monitoring ADRs. This study supports the evidence that older patients receive more drugs and are at even greater risk of an ADR. Antibiotics, cardiovascular, anti-inflammatory or antidepressant drugs are suggested as those most suitable for prospective monitoring in a family practice setting. PMID:21289786

  15. Dried blood spots for monitoring and individualization of antiepileptic drug treatment.

    PubMed

    Milosheska, Daniela; Grabnar, Iztok; Vovk, Tomaž

    2015-07-30

    Therapeutic drug monitoring (TDM) is a multi-disciplinary clinical specialty used for optimization and individualization of drug therapy in the general and special populations. Since most antiepileptic drugs (AEDs) are characterized by pronounced intra- and inter-individual variability, it can be especially valuable as an aid for dosing adjustments in patients with epilepsy. Dried blood spots (DBS) sampling technique is recognized as a suitable alternative for conventional sampling methods as TDM interventions should be applied in the most cost-effective, rational and clinically useful manner. In the present review we summarize the latest trends and applications of DBS in TDM of epilepsy. Quantification of AEDs in DBS was employed in various clinical settings and has been already reported for phenobarbital, phenytoin, valproic acid, clonazepam, clobazam, carbamazepine, topiramate, rufinamide, lamotrigine, 10-hydroxycarbazepine and levetiracetam. The major limitation of the published studies are restricted evaluation of critical parameters such as the impact of spotted blood volume, spot homogeneity and haematocrit effect, limited clinical validation and non-established correlations between the DBS and plasma concentrations of AEDs. Standardization of critical technical aspects for appropriate sampling, sample preparation and validation of the analytical procedures for quantification of the drugs, as well as appropriate interpretation of the results are the fields which should get more attention in upcoming studies. Limited data on clinical validation and the fact that this technique has been used in practice only for a few AEDs makes the routine implementation of TDM of AEDs using DBS method a big challenge that should be faced by the pharmaceutical scientists in the future. PMID:25896371

  16. Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age: an update.

    PubMed

    Italiano, Domenico; Perucca, Emilio

    2013-08-01

    Epilepsies occur across the entire age range, and their incidence peaks in the first years of life and in the elderly. Therefore, antiepileptic drugs (AEDs) are commonly used at the extremes of age. Rational prescribing in these age groups requires not only an understanding of the drugs' pharmacodynamic properties, but also careful consideration of potential age-related changes in their pharmacokinetic profile. The present article, which updates a review published in 2006 in this journal, focuses on recent findings on the pharmacokinetics of new-generation AEDs in neonates, infants, children, and the elderly. Significant new information on the pharmacokinetics of new AEDs in the perinatal period has been acquired, particularly for lamotrigine and levetiracetam. As a result of slow maturation of the enzymes involved in glucuronide conjugation, lamotrigine elimination occurs at a particularly slow rate in neonates, and becomes gradually more efficient during the first months of life. In the case of levetiracetam, elimination occurs primarily by renal excretion and is also slow at birth, but drug clearance increases rapidly thereafter and can even double within 1 week. In general, infants older than 2-3 months and children show higher drug clearance (normalized for body weight) than adults. This pattern was confirmed in recent studies that investigated the pediatric pharmacokinetics of several new AEDs, including levetiracetam, rufinamide, stiripentol, and eslicarbazepine acetate. At the other extreme of age, in the elderly, drug clearance is generally reduced compared with younger adults because of less efficient drug-metabolizing activity, decreased renal function, or both. This general pattern, described previously for several AEDs, was confirmed in recent studies on the effect of old age on the clearance of felbamate, levetiracetam, pregabalin, lacosamide, and retigabine. For those drugs which are predominantly eliminated by renal excretion, aging

  17. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study

    PubMed Central

    Meador, Kimford J; Baker, Gus A; Browning, Nancy; Cohen, Morris J; Bromley, Rebecca L; Clayton-Smith, Jill; Kalayjian, Laura A; Kanner, Andres; Liporace, Joyce D; Pennell, Page B; Privitera, Michael; Loring, David W

    2013-01-01

    Summary Background Many women of childbearing potential take antiepileptic drugs, but the cognitive effects of fetal exposure are uncertain. We aimed to assess effects of commonly used antiepileptic drugs on cognitive outcomes in children up to 6 years of age. Methods In this prospective, observational, assessor-masked, multicentre study, we enrolled pregnant women with epilepsy on antiepileptic drug monotherapy (carbamazepine, lamotrigine, phenytoin, or valproate) between October, 1999, and February, 2004, at 25 epilepsy centres in the UK and the USA. Our primary outcome was intelligence quotient (IQ) at 6 years of age (age-6 IQ) in all children, assessed with linear regression adjusted for maternal IQ, antiepileptic drug type, standardised dose, gestational birth age, and use of periconceptional folate. We also assessed multiple cognitive domains and compared findings with outcomes at younger ages. This study is registered with ClinicalTrials.gov, number NCT00021866. Findings We included 305 mothers and 311 children (six twin pairs) in the primary analysis. 224 children completed 6 years of follow-up (6-year-completer sample). Multivariate analysis of all children showed that age-6 IQ was lower after exposure to valproate (mean 97, 95% CI 94–101) than to carbamazepine (105, 102–108; p=0·0015), lamotrigine (108, 105–110; p=0·0003), or phenytoin (108, 104–112; p=0·0006). Children exposed to valproate did poorly on measures of verbal and memory abilities compared with those exposed to the other antiepileptic drugs and on non-verbal and executive functions compared with lamotrigine (but not carbamazepine or phenytoin). High doses of valproate were negatively associated with IQ (r=−0·56, p<0·0001), verbal ability (r=−0·40, p=0·0045), non-verbal ability (r=−0·42, p=0·0028), memory (r=−0·30, p=0·0434), and executive function (r=−0·42, p=0·0004), but other antiepileptic drugs were not. Age-6 IQ correlated with IQs at younger ages, and IQ

  18. Modern Methods for Analysis of Antiepileptic Drugs in the Biological Fluids for Pharmacokinetics, Bioequivalence and Therapeutic Drug Monitoring

    PubMed Central

    Park, Yoo-Sin; Kim, Shin-Hee; Kim, Sang-Hyun; Jun, Min-Young

    2011-01-01

    Epilepsy is a chronic disease occurring in approximately 1.0% of the world's population. About 30% of the epileptic patients treated with availably antiepileptic drugs (AEDs) continue to have seizures and are considered therapy-resistant or refractory patients. The ultimate goal for the use of AEDs is complete cessation of seizures without side effects. Because of a narrow therapeutic index of AEDs, a complete understanding of its clinical pharmacokinetics is essential for understanding of the pharmacodynamics of these drugs. These drug concentrations in biological fluids serve as surrogate markers and can be used to guide or target drug dosing. Because early studies demonstrated clinical and/or electroencephalographic correlations with serum concentrations of several AEDs, It has been almost 50 years since clinicians started using plasma concentrations of AEDs to optimize pharmacotherapy in patients with epilepsy. Therefore, validated analytical method for concentrations of AEDs in biological fluids is a necessity in order to explore pharmacokinetics, bioequivalence and TDM in various clinical situations. There are hundreds of published articles on the analysis of specific AEDs by a wide variety of analytical methods in biological samples have appears over the past decade. This review intends to provide an updated, concise overview on the modern method development for monitoring AEDs for pharmacokinetic studies, bioequivalence and therapeutic drug monitoring. PMID:21660146

  19. Adverse drug reactions: classification, susceptibility and reporting.

    PubMed

    Kaufman, Gerri

    2016-08-10

    Adverse drug reactions (ADRs) are increasingly common and are a significant cause of morbidity and mortality. Historically, ADRs have been classified as type A or type B. Type A reactions are predictable from the known pharmacology of a drug and are associated with high morbidity and low mortality. Type B reactions are idiosyncratic, bizarre or novel responses that cannot be predicted from the known pharmacology of a drug and are associated with low morbidity and high mortality. Not all ADRs fit into type A and type B categories; therefore, additional categories have been developed. These include type C (continuing), type D (delayed use), and type E (end of use) reactions. Susceptibility to ADRs is influenced by age, gender, disease states, pregnancy, ethnicity and polypharmacy. Drug safety is reliant on nurses and other healthcare professionals being alert to the possibility of ADRs, working with patients to optimise medicine use and exercising vigilance in the reporting of ADRs through the Yellow Card Scheme. PMID:27507394

  20. Ranking Adverse Drug Reactions With Crowdsourcing

    PubMed Central

    Gottlieb, Assaf; Hoehndorf, Robert; Dumontier, Michel

    2015-01-01

    Background There is no publicly available resource that provides the relative severity of adverse drug reactions (ADRs). Such a resource would be useful for several applications, including assessment of the risks and benefits of drugs and improvement of patient-centered care. It could also be used to triage predictions of drug adverse events. Objective The intent of the study was to rank ADRs according to severity. Methods We used Internet-based crowdsourcing to rank ADRs according to severity. We assigned 126,512 pairwise comparisons of ADRs to 2589 Amazon Mechanical Turk workers and used these comparisons to rank order 2929 ADRs. Results There is good correlation (rho=.53) between the mortality rates associated with ADRs and their rank. Our ranking highlights severe drug-ADR predictions, such as cardiovascular ADRs for raloxifene and celecoxib. It also triages genes associated with severe ADRs such as epidermal growth-factor receptor (EGFR), associated with glioblastoma multiforme, and SCN1A, associated with epilepsy. Conclusions ADR ranking lays a first stepping stone in personalized drug risk assessment. Ranking of ADRs using crowdsourcing may have useful clinical and financial implications, and should be further investigated in the context of health care decision making. PMID:25800813

  1. The safety and tolerability of newer antiepileptic drugs in children and adolescents.

    PubMed

    Kayani, Saima; Sirsi, Deepa

    2012-01-01

    Childhood epilepsy continues to be intractable in more than 25% of patients diagnosed with epilepsy. The introduction of new anti-epileptic drugs (AEDs) provides more options for treatment of children with epilepsy. We review the safety and tolerability of seven new AEDs (levetiracetam, lamotrigine, oxcarbazepine, rufinamide, topiramate, vigabatrin and zonisamide) focusing on their side effect profiles and safety in children and adolescents. Many considerations that are specific for children such as the impact of AEDs on the developing brain are not addressed during the development of new AEDs. They are usually approved as adjunctive therapies based upon clinical trials involving adult patients with partial epilepsy. However, 2 of the AEDs reviewed here (rufinamide and vigabatrin) have FDA approval in the U.S. for specific Pediatric epilepsy syndromes, which are discussed below. The Pediatrician or Neurologists decision on the use of a new AED is an evolutionary process largely dependent on the patient characteristics, personal/peer experiences and literature about efficacy and safety profiles of these medications. Evidence based guidelines are limited due to a lack of randomized controlled trials involving pediatric patients for many of these new AEDs. PMID:23650467

  2. A pilot randomized controlled clinical trial to improve antiepileptic drug adherence in young children with epilepsy.

    PubMed

    Modi, Avani C; Guilfoyle, Shanna M; Mann, Krista A; Rausch, Joseph R

    2016-03-01

    The primary aim was to examine the preliminary efficacy of a family tailored problem-solving intervention to improve antiepileptic drug (AED) adherence in families of children with new-onset epilepsy. Secondary aims were to assess changes in targeted mechanisms and treatment feasibility and acceptability. Fifty families (M(age) = 7.6 ± 3.0; 80% Caucasian; 42% idiopathic localization related) completed baseline questionnaires and were given an electronic monitor to observe daily AED adherence. If adherence was ≤ 95% in the first 7 months of the study, families were randomized (Supporting Treatment Adherence Regimens (STAR): n = 11; Treatment as Usual (TAU): n = 12). Twenty-one families were not randomized due to adherence being ≥95%. The STAR intervention included four face-to-face and two telephone problem-solving sessions over 8 weeks. Significant group differences in adherence were found during active intervention (weeks 4-6; TAU = -12.0 vs. STAR = 18.1, p < 0.01; and weeks session 6-8: TAU = -9.7 vs. STAR = 15.3, p < 0.05). Children who received the STAR intervention exhibited improved adherence compared to children in the TAU group during active treatment. Significant changes in epilepsy knowledge and management were noted for the STAR group. Families expressed benefitting from the STAR intervention. Future studies should include a larger sample size and booster intervention sessions to maintain treatment effects over time.

  3. Does in utero exposure of antiepileptic drugs lead to failure to reach full cognitive potential?

    PubMed

    McCorry, D; Bromley, R

    2015-05-01

    A clinical scenario of a young female on 800 mg of sodium valproate (VPA) who has recently failed lamotrigine (LTG) and levetiracetam (LEV) and who is currently planning a pregnancy is presented. Currently available data pertaining to the longer-term development of children exposed to antiepileptic drugs (AEDs) are reviewed along with considerations around the methodology and interpretation of such research. There is an accumulation of data highlighting significant risks associated with prenatal exposed to VPA, with the level of risk being mediated by dose. The majority of published evidence does not find a significant risk associated with carbamazepine (CBZ) exposure in utero for global cognitive abilities however the evidence for more specific cognitive skills are unclear. Limited data indicate that LTG may be a preferred treatment to VPA in terms of foetal outcome but further evidence is required. Too little data pertaining to LEV exposure is available and a lack of evidence regarding risk of this and other new AEDs should not be interpreted as evidence of safety. PMID:25819874

  4. Effects of pharmaceuticals on aquatic invertebrates. Part I. The antiepileptic drug carbamazepine.

    PubMed

    Oetken, M; Nentwig, G; Löffler, D; Ternes, T; Oehlmann, J

    2005-10-01

    The effects of the antiepileptic drug carbamazepine (CBZ) were studied in three freshwater invertebrate species representing different taxonomic groups, life histories, and habitats in aquatic ecosystems. The oligochaete Lumbriculus variegatus was exposed by way of CBZ-spiked sediments at nominal concentrations between 0.625 and 10 mg/kg dry weight (dw) for 28 days. At the end of the test, reproduction and biomass were monitored as end points. The non-biting midge Chironomus riparius was exposed to CBZ in a series of tests at nominal CBZ concentrations in sediment ranging from 0.16 to 100 mg/kg dw at 20 degrees C and 23 degrees C. Emergence and gender ratio were monitored at the end of the test. The freshwater snail Potamopyrgus antipodarum as the third test species was used in a chronic reproduction test for 28 days at aqueous CBZ concentrations from 0.4 to 250 mg/L. Whereas for the oligochaete and the snail no effects were observed, C. riparius exhibited a significant and concentration-dependent decrease of emergence in all test series. No observed effect concentrations and 10% effect concentrations were in the range of 33 to 140 and 70 to 210 microg/kg dw, respectively, based on measured CBZ concentrations in sediments. These low values indicate that CBZ may pose a potential threat for the survival of C. riparius and probably also for other aquatic insect populations in the field.

  5. Progress report on new antiepileptic drugs: A summary of the Twelfth Eilat Conference (EILAT XII).

    PubMed

    Bialer, Meir; Johannessen, Svein I; Levy, René H; Perucca, Emilio; Tomson, Torbjörn; White, H Steve

    2015-03-01

    The Twelfth Eilat Conference on New Antiepileptic Drugs (AEDs) - EILAT XII, took place in Madrid, Spain from August 31st to September 3rd 2014. About 130 basic scientists, clinical pharmacologists and neurologists from 22 countries attended the conference, whose main themes included "Conquering pharmacoresistant epilepsy", "Innovative emergency treatments", "Progress report on second-generation treatment" and "New methods and formulations". Consistent with previous formats of this conference, a large part of the program was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 2004. Like the EILAT X and EILAT XI reports, the current article focuses on the preclinical and clinical pharmacology of AEDs that are currently in development. These include adenosine-releasing silk, allopregnanolone (SAGE-547), AMP-X-0079, brivaracetam, bumetanide, cannabidiol, cannabidivarin, 2-deoxy-glucose, everolimus, ganaxolone, huperzine A, imepitoin, minocycline, NAX 801-2, pitolisant, PRX 0023, SAGE-217, valnoctamide and its homologue sec-butyl-propylacetamide (SPD), and VLB-01. Since the previous Eilat conference, perampanel has been introduced into the market and twelve novel potential epilepsy treatments are presented for the first time. PMID:25769377

  6. Medicine possession ratio as proxy for adherence to antiepileptic drugs: prevalence, associations, and cost implications

    PubMed Central

    Jacobs, Karen; Julyan, Marlene; Lubbe, Martie S; Burger, Johanita R; Cockeran, Marike

    2016-01-01

    Objective To determine the adherence status to antiepileptic drugs (AEDs) among epilepsy patients; to observe the association between adherence status and age, sex, active ingredient prescribed, treatment period, and number of comorbidities; and to determine the effect of nonadherence on direct medicine treatment cost of AEDs. Methods A retrospective study analyzing medicine claims data obtained from a South African pharmaceutical benefit management company was performed. Patients of all ages (N=19,168), who received more than one prescription for an AED, were observed from 2008 to 2013. The modified medicine possession ratio (MPRm) was used as proxy to determine the adherence status to AED treatment. The MPRm was considered acceptable (adherent) if the calculated value was ≥80%, but ≤110%, whereas an MPRm of <80% (unacceptably low) or >110% (unacceptably high) was considered nonadherent. Direct medicine treatment cost was calculated by summing the medical scheme contribution and patient co-payment associated with each AED prescription. Results Only 55% of AEDs prescribed to 19,168 patients during the study period had an acceptable MPRm. MPRm categories depended on the treatment period (P>0.0001; Cramer’s V=0.208) but were independent of sex (P<0.182; Cramer’s V=0.009). Age group (P<0.0001; Cramer’s V=0.067), active ingredient (P<0.0001; Cramer’s V=0.071), and number of comor-bidities (P<0.0001; Cramer’s V=0.050) were statistically but not practically significantly associated with MPRm categories. AEDs with an unacceptably high MPRm contributed to 3.74% (US$736,376.23) of the total direct cost of all AEDs included in the study, whereas those with an unacceptably low MPRm amounted to US$3,227,894.85 (16.38%). Conclusion Nonadherence to antiepileptic treatment is a major problem, encompassing ~20% of cost in our study. Adherence, however, is likely to improve with the treatment period. Further research is needed to determine the factors influencing

  7. Studies on the effects of acetylcholine and antiepileptic drugs on /sup 32/P incorporation into phospholipids of rat brain synaptosomes

    SciTech Connect

    Aly, M.I.; Abdel-Latif, A.A.

    1982-02-01

    Studies were conducted on the effects of antiepileptic drugs on the acetylcholine-stimulated /sup 32/P labeling of phospholipids in rat brain synaptosomes. Of the four antiepileptic drugs investigated in the present study, namely phenytoin, carbamazepine, phenobarbital, and valproate, only phenytoin blocked the acetylcholine-stimulated /sup 32/P labeling of phosphatidylinositol and phosphatidic acid, and the acetylcholine-stimulated breakdown of polyphosphoinositides. Phenytoin alone, like atropine alone, had no effect on the /sup 32/P labeling of phospholipids nor on the specific radioactivity of (/sup 32/P)ATP. Omission of Na/sup +/ drastically reduced both the /sup 32/P labeling of synaptosomal phospholipids and the specific radioactivity of (/sup 32/P)ATP and furthermore it significantly decreased the phosphoinositide effect. It was concluded that certain antiepileptic drugs, such as phenytoin, could exert their pharmacological actions through their antimuscarinic effects. In addition the finding that phenytoin, which acts to regulate NA/sup +/ and Ca/sup 2 +/ permeability of neuronal membranes, also inhibited the phosphoinositide effects in synaptosomes, support the conclusions that Ca2+ and Na+ are probably involved in the molecular mechanism underlying this phenomenon in excitable tissues.

  8. Role of P-glycoprotein in refractoriness of seizures to antiepileptic drugs in Lennox-Gastaut syndrome.

    PubMed

    Kumar, Achal; Tripathi, Deepak; Paliwal, Vimal Kumar; Neyaz, Zafar; Agarwal, Vikas

    2015-02-01

    Mechanism of seizure refractoriness to antiepileptic drugs in children with Lennox-Gastaut syndrome is not known. Efflux of antiepileptic drugs due to increased expression/function of P-glycoprotein, a multidrug efflux transporter protein on the cell surface is a proposed mechanism. The authors studied the expression/function of P-glycoprotein on peripheral blood mononuclear cells of 29 children with Lennox-Gastaut syndrome, 23 children with other epilepsies, and 19 healthy children. The authors found a higher P-glycoprotein expression/function in Lennox-Gastaut syndrome, a higher percent positive cells as compared to children with other epilepsy (P < 0.001) and to healthy controls (P = 0.012), higher P-glycoprotein expression as compared to healthy controls (P = 0.003), a higher total P-glycoprotein expression (relative florescence intensity × percent positive cells) as compared to children with other epilepsies (P < 0.001) and healthy controls (P < 0.001), and a higher P-glycoprotein function as compared to children with other epilepsies (P = 0.001) and healthy controls (P = 0.002). These findings may explain seizure refractoriness to anti-epileptic drugs in Lennox-Gastaut syndome.

  9. [Adverse drug reactions in pregnant women].

    PubMed

    Lacroix, Isabelle; Cabou, Cendrine; Montastruc, Jean-Louis; Damase-Michel, Christine

    2007-01-01

    A Prospective pharmacovigilance survey of adverse drug reactions (ADRs) in pregnant women was performed in collaboration with gynaecologists and obstetricians of Midi-Pyrenees area (south west of france). The aim of the study was to evaluate the incidence of adverse drug reactions in pregnant women. The incidence of ADRs in pregnant women was low: 0.3%. Moreover, a retrospective pharmacoepidemiological study was conducted to characterize ADRs in pregnant women. Reports of ADRs collected in the Midi-Pyrenees pharmacovigilance centre from 1982 to 2002 were used: type of ADRs, drugs involved and potential risk factors were compared for pregnant women and for age-matched non pregnant women. Forty seven and 94 reports of ADRs were collected in pregnant and non-pregnant women respectively. Anaphylactic reactions were only observed in pregnant women (3 cases, p = 0.04). We observed 1 ADR related stillbirth (due to anaphylactic reaction) in pregnant women. Drugs for gynaecological and cardiovascular systems were more frequently involved in ADRs in pregnant women than in controls. ADRs mainly occurred during the third trimester of pregnancy. The incidence of ADRs is very low in pregnant women. However, one must pay attention on the risk of anaphylactic reactions in pregnant women. PMID:18206108

  10. Cutaneous adverse drug reactions caused by antituberculosis drugs.

    PubMed

    Rezakovic, Saida; Pastar, Zrinjka; Kostovic, Kresimir

    2014-01-01

    Multidrug antituberculosis regimen is associated with diverse clinical patterns of cutaneous adverse drug reactions (CADR), ranging from mild and moderate such as pruritus, maculopapular exanthems, lichenoid eruptions, fixed drug eruptions and urticaria to severe and even life threatening ones like acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These adverse reactions to antituberculosis drugs are commonly observed adverse events. This is of particular importance for high HIV prevalence settings and developing countries where tuberculosis is common infection resulting in higher occurrence rate of these reactions. There is still significant heterogenity in definition and classification of CADR, as well as diversity in treatment modalities following adverse reactions and rechallenge management. The aim of this review is to discuss clinical presentation, occurrence of CADR caused by antituberculosis drugs, to identify risk factors for intolerance of the standard therapy as well as to draw attention to importance of multi-disciplinary approach, early detection, prompt diagnosis and in time management of antituberculosis drugs associated CADR. CADR can cause significant treatment interruption and alteration, resulting in increased risk of treatment failure, drug resistance, relapses and increased risk of complications including even lethal outcome. Finally, it can be concluded that it is of great importance to identify the best possible treatment and preventive regimens in order to enable continuity of the antituberculosis therapy to the full extent. PMID:25039910

  11. Comparative study of lacosamide and classical sodium channel blocking antiepileptic drugs on sodium channel slow inactivation.

    PubMed

    Niespodziany, Isabelle; Leclère, Nathalie; Vandenplas, Catherine; Foerch, Patrik; Wolff, Christian

    2013-03-01

    Many antiepileptic drugs (AEDs) exert their therapeutic activity by modifying the inactivation properties of voltage-gated sodium (Na(v) ) channels. Lacosamide is unique among AEDs in that it selectively enhances the slow inactivation component. Although numerous studies have investigated the effects of AEDs on Na(v) channel inactivation, a direct comparison of results cannot be made because of varying experimental conditions. In this study, the effects of different AEDs on Na(v) channel steady-state slow inactivation were investigated under identical experimental conditions using whole-cell patch-clamp in N1E-115 mouse neuroblastoma cells. All drugs were tested at 100 μM, and results were compared with those from time-matched control groups. Lacosamide significantly shifted the voltage dependence of Na(v) current (I(Na) ) slow inactivation toward more hyperpolarized potentials (by -33 ± 7 mV), whereas the maximal fraction of slow inactivated channels and the curve slope did not differ significantly. Neither SPM6953 (lacosamide inactive enantiomer), nor carbamazepine, nor zonisamide affected the voltage dependence of I(Na) slow inactivation, the maximal fraction of slow inactivated channels, or the curve slope. Phenytoin significantly increased the maximal fraction of slow inactivated channels (by 28% ± 9%) in a voltage-independent manner but did not affect the curve slope. Lamotrigine slightly increased the fraction of inactivated currents (by 15% ± 4%) and widened the range of the slow inactivation voltage dependence. Lamotrigine and rufinamide induced weak, but significant, shifts of I(Na) slow inactivation toward more depolarized potentials. The effects of lacosamide on Na(v) channel slow inactivation corroborate previous observations that lacosamide has a unique mode of action among AEDs that act on Na(v) channels. PMID:23239147

  12. Antiepileptic drug treatment of rolandic epilepsy and Panayiotopoulos syndrome: clinical practice survey and clinical trial feasibility

    PubMed Central

    Mellish, Louise C; Dunkley, Colin; Ferrie, Colin D; Pal, Deb K

    2015-01-01

    Background The evidence base for management of childhood epilepsy is poor, especially for the most common specific syndromes such as rolandic epilepsy (RE) and Panayiotopoulos syndrome (PS). Considerable international variation in management and controversy about non-treatment indicate the need for high quality randomised controlled trials (RCT). The aim of this study is, therefore, to describe current UK practice and explore the feasibility of different RCT designs for RE and PS. Methods We conducted an online survey of 590 UK paediatricians who treat epilepsy. Thirty-two questions covered annual caseload, investigation and management practice, factors influencing treatment, antiepileptic drug preferences and hypothetical trial design preferences. Results 132 responded (22%): 81% were paediatricians and 95% at consultant seniority. We estimated, annually, 751 new RE cases and 233 PS cases. Electroencephalography (EEG) is requested at least half the time in approximately 70% of cases; MRI brain at least half the time in 40%–65% cases and neuropsychological evaluation in 7%–8%. Clinicians reported non-treatment in 40%: main reasons were low frequency of seizures and parent/child preferences. Carbamazepine is the preferred older, and levetiracetam the preferred newer, RCT arm. Approximately one-half considered active and placebo designs acceptable, choosing seizures as primary and cognitive/behavioural measures as secondary outcomes. Conclusions Management among respondents is broadly in line with national guidance, although with possible overuse of brain imaging and underuse of EEG and neuropsychological assessments. A large proportion of patients in the UK remains untreated, and clinicians seem amenable to a range of RCT designs, with carbamazepine and levetiracetam the preferred active drugs. PMID:25202134

  13. Discontinuing antiepileptic drugs in patients who are seizure free on monotherapy

    PubMed Central

    Specchio, L; Tramacere, L; La Neve, A; Beghi, E

    2002-01-01

    Objectives: To assess the recurrence rate of epilepsy attributable to discontinuation of treatment in seizure free patients and to identify the risk factors for recurrence. Methods: 330 patients referred to an epilepsy centre who were seizure free for at least 2 years while on stable monotherapy were the study population. Discontinuation of antiepileptic drugs (AEDs) was proposed to all eligible patients or to their carers after discussion of the risks and benefits. Depending on whether they accepted or refused treatment withdrawal, the patients were stratified into two cohorts and followed up until seizure relapse or 31 March 1999, whichever came first. For each patient, records were taken of the main demographic and clinical variables. Results: The sample comprised 225 patients who entered the discontinuation programme and 105 who decided to continue treatment. Twenty nine patients (28%) continuing treatment had a relapse, compared with 113 (50%) of those entering the withdrawal programme. For patients continuing treatment, the probability of remission was 95% at 6 months, 91% at 12 months, 82% at 24 months, 80% at 36 months, and 68% at 60 months. The corresponding values for patients discontinuing treatment were 88%, 74%, 57%, 51%, and 48%. After adjusting for the principal prognostic factors, in patients discontinuing AEDs the risk of seizure relapse was 2.9 times that of patients continuing treatment. A relation was also found between relapse and duration of active disease, number of years of remission while on treatment, and abnormal psychiatric findings. Conclusions: Seizure free referral patients on stable monotherapy who elect to withdraw drug treatment are at higher risk of seizure relapse compared with patients continuing treatment. Severity of disease and seizure free period are significant prognostic factors. PMID:11784819

  14. Inverse Association between Sodium Channel-Blocking Antiepileptic Drug Use and Cancer: Data Mining of Spontaneous Reporting and Claims Databases

    PubMed Central

    Takada, Mitsutaka; Fujimoto, Mai; Motomura, Haruka; Hosomi, Kouichi

    2016-01-01

    Purpose: Voltage-gated sodium channels (VGSCs) are drug targets for the treatment of epilepsy. Recently, a decreased risk of cancer associated with sodium channel-blocking antiepileptic drugs (AEDs) has become a research focus of interest. The purpose of this study was to test the hypothesis that the use of sodium channel-blocking AEDs are inversely associated with cancer, using different methodologies, algorithms, and databases. Methods: A total of 65,146,507 drug-reaction pairs from the first quarter of 2004 through the end of 2013 were downloaded from the US Food and Drug Administration Adverse Event Reporting System. The reporting odds ratio (ROR) and information component (IC) were used to detect an inverse association between AEDs and cancer. Upper limits of the 95% confidence interval (CI) of < 1 and < 0 for the ROR and IC, respectively, signified inverse associations. Furthermore, using a claims database, which contains 3 million insured persons, an event sequence symmetry analysis (ESSA) was performed to identify an inverse association between AEDs and cancer over the period of January 2005 to May 2014. The upper limit of the 95% CI of adjusted sequence ratio (ASR) < 1 signified an inverse association. Results: In the FAERS database analyses, significant inverse associations were found between sodium channel-blocking AEDs and individual cancers. In the claims database analyses, sodium channel-blocking AED use was inversely associated with diagnoses of colorectal cancer, lung cancer, gastric cancer, and hematological malignancies, with ASRs of 0.72 (95% CI: 0.60 - 0.86), 0.65 (0.51 - 0.81), 0.80 (0.65 - 0.98), and 0.50 (0.37 - 0.66), respectively. Positive associations between sodium channel-blocking AEDs and cancer were not found in the study. Conclusion: Multi-methodological approaches using different methodologies, algorithms, and databases suggest that sodium channel-blocking AED use is inversely associated with colorectal cancer, lung cancer, gastric

  15. Anticoagulation-associated adverse drug events

    PubMed Central

    Piazza, Gregory; Nguyen, Thanh Nha; Cios, Deborah; Labreche, Matthew; Hohlfelder, Benjamin; Fanikos, John; Fiumara, Karen; Goldhaber, Samuel Z.

    2011-01-01

    Purpose Anticoagulant drugs are among the most common medications that cause adverse drug events (ADEs) in hospitalized patients. We performed a five-year retrospective study at Brigham and Women’s Hospital to determine clinical characteristics, types, root causes, and outcomes of anticoagulant-associated adverse drug events (ADEs). Methods We reviewed all inpatient anticoagulant-associated ADEs, including adverse drug reactions (ADRs) and medication errors, reported at Brigham and Women’s Hospital through the Safety Reporting System from May 2004 to May 2009. We also collected data regarding the cost associated with hospitalizations in which ADRs occurred. Results Of 463 anticoagulant-associated ADEs, 226 were MEs (48.8%), 141 were ADRs (30.5%), and 96 (20.7%) involved both a medication error and ADR. Seventy percent of anticoagulant-associated ADEs were potentially preventable. Transcription errors (48%) were the most frequent root cause of anticoagulant-associated medication errors, while medication errors (40%) were a common root cause of anticoagulant-associated ADRs. Death within 30 days of anticoagulant-associated ADEs occurred in 11% of patients. After an anticoagulant-associated ADR, most hospitalization expenditures were attributable to nursing costs (mean $33,189 per ADR) followed by pharmacy costs (mean $7,451 per ADR). Conclusion Most anticoagulant-associated ADEs among inpatients result from medication errors and are therefore potentially preventable. We observed an elevated 30-day mortality rate among patients who suffered an anticoagulant-associated ADE and high hospitalization costs following ADRs. Further Quality Improvement efforts to reduce anticoagulant-associated medication errors are warranted to improve patient safety and decrease health care expenditures. PMID:22114827

  16. Idiosyncratic Adverse Drug Reactions: Current Concepts

    PubMed Central

    Naisbitt, Dean J.

    2013-01-01

    Idiosyncratic drug reactions are a significant cause of morbidity and mortality for patients; they also markedly increase the uncertainty of drug development. The major targets are skin, liver, and bone marrow. Clinical characteristics suggest that IDRs are immune mediated, and there is substantive evidence that most, but not all, IDRs are caused by chemically reactive species. However, rigorous mechanistic studies are very difficult to perform, especially in the absence of valid animal models. Models to explain how drugs or reactive metabolites interact with the MHC/T-cell receptor complex include the hapten and P-I models, and most recently it was found that abacavir can interact reversibly with MHC to alter the endogenous peptides that are presented to T cells. The discovery of HLA molecules as important risk factors for some IDRs has also significantly contributed to our understanding of these adverse reactions, but it is not yet clear what fraction of IDRs have a strong HLA dependence. In addition, with the exception of abacavir, most patients who have the HLA that confers a higher IDR risk with a specific drug will not have an IDR when treated with that drug. Interindividual differences in T-cell receptors and other factors also presumably play a role in determining which patients will have an IDR. The immune response represents a delicate balance, and immune tolerance may be the dominant response to a drug that can cause IDRs. PMID:23476052

  17. Idiosyncratic adverse drug reactions: current concepts.

    PubMed

    Uetrecht, Jack; Naisbitt, Dean J

    2013-04-01

    Idiosyncratic drug reactions are a significant cause of morbidity and mortality for patients; they also markedly increase the uncertainty of drug development. The major targets are skin, liver, and bone marrow. Clinical characteristics suggest that IDRs are immune mediated, and there is substantive evidence that most, but not all, IDRs are caused by chemically reactive species. However, rigorous mechanistic studies are very difficult to perform, especially in the absence of valid animal models. Models to explain how drugs or reactive metabolites interact with the MHC/T-cell receptor complex include the hapten and P-I models, and most recently it was found that abacavir can interact reversibly with MHC to alter the endogenous peptides that are presented to T cells. The discovery of HLA molecules as important risk factors for some IDRs has also significantly contributed to our understanding of these adverse reactions, but it is not yet clear what fraction of IDRs have a strong HLA dependence. In addition, with the exception of abacavir, most patients who have the HLA that confers a higher IDR risk with a specific drug will not have an IDR when treated with that drug. Interindividual differences in T-cell receptors and other factors also presumably play a role in determining which patients will have an IDR. The immune response represents a delicate balance, and immune tolerance may be the dominant response to a drug that can cause IDRs. PMID:23476052

  18. Use of antiepileptic drugs during pregnancy and lactation: Type of information provided by searching Google.

    PubMed

    Lavi-Blau, Tal; Ekstein, Dana; Neufeld, Miri Y; Eyal, Sara

    2016-02-01

    Surveys among women with epilepsy (WWE) show that they receive their essential pregnancy-related information from many sources, including the internet. Our aim was to assess the types of websites provided by searching Google for the use of four antiepileptic drugs (AEDs) during pregnancy and lactation. The search was performed on 40 computers used by health-care professionals, on 40 computers used by nonhealth-care professionals, and on 5 computers used by WWE in Israel and on 8 computers used by nonhealth-care professionals in the U.S. On each computer, a Google search was conducted for term combinations that included one AED name ("carbamazepine","valproic acid", "lamotrigine", "levetiracetam", or "Keppra") and "Pregnancy", "Lactation", or "Breastfeeding". The top three and top ten websites retrieved in every search were mapped (a total of 45 and 150 websites, respectively, from each computer). Across all searches in English, on both U.S. and Israeli computers, the majority of websites listed among the first three and first ten results were those of independent health portals. The representation of the Epilepsy Foundation website was 10% or less, and only a few results were obtained from the NIH's general public-oriented MedlinePlus. In Hebrew, results included almost exclusively Israeli or Hebrew-translated websites. As in English, results from public-oriented, professionally-written websites in Hebrew accounted for less than 50% of entries. Overall, the availability of readable and high-quality information on AEDs used by pregnant and breastfeeding women is limited. Guiding patients towards accurate web resources can help them navigate among the huge amount of available online information. PMID:26773680

  19. Association of Interictal Epileptiform Discharges with Sleep and Anti-Epileptic Drugs

    PubMed Central

    Mohan, Latika; Singh, Jayvardhan; Singh, Yogesh; Kathrotia, Rajesh; Goel, Arun

    2016-01-01

    Background The presence of interictal epileptiform discharges (IEDs) in electroencephalogram (EEG) is diagnostic of epilepsy. Latent IEDs are activated during sleep. Anti-epileptic drugs (AEDs) improve sleep. AEDs, sleep, and IEDs may interact and affect epilepsy management. Purpose To explore the occurrence of IEDs and its association with sleep and AED status in suspected patients of epilepsy. Methods EEG records were collected of suspected patients of epilepsy who reported to the electrophysiology laboratory of a tertiary care hospital during 1 year. The anthropometric details, clinical presentations, and AED status of the patients were recorded from the EEG records. Patients were divided into 2 categories based on whether AEDs had been started prior to the EEG evaluation (category-I) or not (category-II). The occurrences of IEDs in EEG recordings in both categories were analyzed. Results In 1 year, 138 patients were referred for diagnostic EEG evaluation. One-hundred-two patients fulfilled the inclusion criteria, of which 57 patients (53%) belonged to category-I and 45 patients (47%) belonged to category-II. Incidence of IEDs, suggestive of definite diagnosis of epilepsy in category-I was 88% and in category-II was 69%, and this difference was statistically significant (p = 0.02). Conclusion The increased proportion of IEDs in category-I patients may be due to high clinical suspicion or compounding interaction of AEDs and sleep. More extensive studies are required to delineate the complex interaction of AEDs, sleep, and IEDs so that judicious yet prompt management of epilepsy can be carried out. PMID:27780990

  20. Evidence-based guideline: Antiepileptic drug selection for people with HIV/AIDS

    PubMed Central

    Birbeck, G.L.; French, J.A.; Perucca, E.; Simpson, D.M.; Fraimow, H.; George, J.M.; Okulicz, J.F.; Clifford, D.B.; Hachad, H.; Levy, R.H.

    2012-01-01

    Objective: To develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. Methods: The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED-ARV interactions. Results and Recommendations: AED-ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of ∼50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of ∼50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme-inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors, as pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C). PMID:22218281

  1. Low potency and limited efficacy of antiepileptic drugs in the mouse 6 Hz corneal kindling model.

    PubMed

    Leclercq, K; Matagne, A; Kaminski, R M

    2014-05-01

    Corneal kindling is a useful alternative to electrically induced amygdala or hippocampal kindling, which requires advanced surgical and EEG techniques that may not be easily available in many laboratories. Therefore the first aim of this study was to evaluate whether repeated 6 Hz corneal stimulation in mice would lead to an increased and persistent seizure response as described for higher frequency (50/60 Hz) corneal kindling. Male NMRI mice stimulated twice daily (except weekends) for 3 s with 6 Hz electrical current at 44 mA displayed robust kindling development, i.e., a progressive increase in seizure severity. The majority of the animals (about 90%) developed a fully kindled state, defined as at least 10 consecutive stage 3-5 seizures within 5 weeks of corneal stimulation. Afterwards, the fully kindled state was maintained for at least 8 weeks with only two days of stimulations per week. Next, the protective efficacy of four mechanistically different antiepileptic drugs (AEDs; clonazepam, valproate, carbamazepine and levetiracetam) was assessed and compared between 6 Hz and 50 Hz fully kindled mice. All tested AEDs showed a relatively lower potency in the 6 Hz kindling model and a limited efficacy against partial seizures was observed with carbamazepine and levetiracetam. We can conclude that 6 Hz kindling may be more advantageous than the previously described 50/60 Hz corneal kindling models due to its robustness and persistence of the fully kindled state. Furthermore, the observed low potency and limited efficacy of AEDs in 6 Hz fully kindled mice suggest that this model could be a useful tool in the discovery of novel AEDs targeting treatment resistant epilepsy.

  2. Comparative persistence of antiepileptic drugs in patients with epilepsy: A STROBE-compliant retrospective cohort study.

    PubMed

    Lai, Edward Chia-Cheng; Hsieh, Cheng-Yang; Su, Chien-Chou; Yang, Yea-Huei Kao; Huang, Chin-Wei; Lin, Swu-Jane; Setoguchi, Soko

    2016-08-01

    We compared persistence of antiepileptic drugs (AEDs) including carbamazepine, oxcarbazepine, gabapentin, lamotrigine, topiramate, valproic acid, and phenytoin in an Asian population with epilepsy.A retrospective cohort study was conducted by analyzing Taiwan's National Health Insurance Research Database (NHIRD). Adult epilepsy patients newly prescribed with AEDs between 2005 and 2009 were included. The primary outcome was persistence, defined as the treatment duration from the date of AED initiation to the date of AED discontinuation, switching, hospitalization due to seizure or disenrollment from databases, whichever came first. Cox proportional hazard models were used to estimate the risk of non-persistence with AEDs.Among the 13,061 new users of AED monotherapy (mean age: 58 years; 60% men), the persistence ranged from 218.8 (gabapentin) to 275.9 (oxcarbazepine) days in the first treatment year. The risks of non-persistence in patients receiving oxcarbazepine (adjusted hazard ratio [HR], 0.78; 95% CI, 0.74-0.83), valproic acid (0.88; 0.85-0.92), lamotrigine (0.72; 0.65-0.81), and topiramate (0.90; 0.82-0.98) were significantly lower than in the carbamazepine group. Compared with carbamazepine users, the non-persistence risk was higher in phenytoin users (1.10; 1.06-1.13), while gabapentin users (1.03; 0.98-1.09) had similar risk. For risk of hospitalization due to seizure and in comparison with carbamazepine users, oxcarbazepine (0.66; 0.58-0.74) and lamotrigine (0.46; 0.35-0.62) users had lower risk, while phenytoin (1.35; 1.26-1.44) users had higher risk. The results remained consistent throughout series of sensitivity and stratification analyses.The persistence varied among AEDs and was better for oxcarbazepine, valproic acid, lamotrigine, and topiramate, but worse for phenytoin when compared with carbamazepine. PMID:27583857

  3. Use of antiepileptic drugs during pregnancy and lactation: Type of information provided by searching Google.

    PubMed

    Lavi-Blau, Tal; Ekstein, Dana; Neufeld, Miri Y; Eyal, Sara

    2016-02-01

    Surveys among women with epilepsy (WWE) show that they receive their essential pregnancy-related information from many sources, including the internet. Our aim was to assess the types of websites provided by searching Google for the use of four antiepileptic drugs (AEDs) during pregnancy and lactation. The search was performed on 40 computers used by health-care professionals, on 40 computers used by nonhealth-care professionals, and on 5 computers used by WWE in Israel and on 8 computers used by nonhealth-care professionals in the U.S. On each computer, a Google search was conducted for term combinations that included one AED name ("carbamazepine","valproic acid", "lamotrigine", "levetiracetam", or "Keppra") and "Pregnancy", "Lactation", or "Breastfeeding". The top three and top ten websites retrieved in every search were mapped (a total of 45 and 150 websites, respectively, from each computer). Across all searches in English, on both U.S. and Israeli computers, the majority of websites listed among the first three and first ten results were those of independent health portals. The representation of the Epilepsy Foundation website was 10% or less, and only a few results were obtained from the NIH's general public-oriented MedlinePlus. In Hebrew, results included almost exclusively Israeli or Hebrew-translated websites. As in English, results from public-oriented, professionally-written websites in Hebrew accounted for less than 50% of entries. Overall, the availability of readable and high-quality information on AEDs used by pregnant and breastfeeding women is limited. Guiding patients towards accurate web resources can help them navigate among the huge amount of available online information.

  4. Comparison of body composition in persons with epilepsy on conventional & new antiepileptic drugs

    PubMed Central

    Sarangi, Sudhir Chandra; Tripathi, Manjari; Kakkar, Ashish Kumar; Gupta, Yogendra Kumar

    2016-01-01

    Background & objectives: Certain antiepileptic drugs (AEDs) such as valproic acid (VPA) are known to affect body weight, and lipid profile. However, evidences regarding effects of AEDs on the body composition are deficient. This cross-sectional study compared the body composition and lipid profile among patients with epilepsy on newer and conventional AEDs. Methods: The patients with epilepsy (n=109) on treatment with conventional and newer AEDs (levetiracetam, lamotrigine and clobazam) for > 6 months were enrolled. Of these, 70 were on monotherapy: levetiracetam (n=12), VPA (n=16), carbamazepine (n=20) and phenytoin (n=22) and the remaining on polytherapy. Their body composition [body fat mass, lean dry mass (LDM), total body water (TBW), intracellular water (ICW), extracellular water (ECW) and basal metabolic rate (BMR) was estimated and biochemical parameters were assessed. Results: Levetiracetam group had no significant difference with VPA, carbamazepine, phenytoin and control groups, except low LDM (17.8±2.4) than VPA groups (20.2±2.7, P<0.05). In comparison with control, AEDs monotherapy groups had no significant difference, except higher LDM and ECW in VPA group. Among groups based on conventional and newer AEDs, there was no significant difference in body composition parameters except for higher LDM (as % of BW) in conventional AEDs only treated group than control (P<0.01). Interpretation & conclusions: The alterations observed in body composition with valproic acid in contrast to other AEDs like levetiracetam, carbamazepine and phenytoin could affect treatment response in epilepsy especially in subjects with already altered body composition status like obese and thin frail patients, which needs to be established by prospective studies (CTRI/2013/05/003701). PMID:27241646

  5. Adverse skeletal effects of drugs - beyond Glucocorticoids.

    PubMed

    O'Sullivan, Susannah; Grey, Andrew

    2015-01-01

    Osteoporotic fractures are an important public health problem with significant individual and societal costs. In addition to the major risk factors for osteoporotic fracture, low bone mineral density (BMD), age, low body weight and history of fracture or falls, some drugs are now considered to be important secondary risk factor for bone loss and fracture, particularly amongst predisposed individuals. Currently available data are often generated from small observational clinical studies, making risk assessment and development of management guidelines difficult. In many cases, the exposed population has a low baseline risk for fracture and additional assessment and treatment may not be necessary. In this review, we focus on drugs other than glucocorticoids identified as potentially causing adverse skeletal effects, summarizing the existing evidence from preclinical and clinical studies, and suggest recommendations for patient management. PMID:25039381

  6. Adverse immunologic effects of antithyroid drugs.

    PubMed Central

    Wing, S S; Fantus, I G

    1987-01-01

    Propylthiouracil and methimazole are frequently used in the management of hyperthyroidism. Two patients in whom adverse immunologic effects other than isolated agranulocytosis developed during treatment with propylthiouracil are described. A review of the literature revealed 53 similar cases over a 35-year period. Rash, fever, arthralgias and granulocytopenia were the most common manifestations. Vasculitis, particularly with cutaneous manifestations, occurs and may be fatal. The clinical evidence suggests that an immunologic mechanism is involved. A number of different autoantibodies were reported, but antinuclear antibodies were infrequent, and none of the cases met the criteria for a diagnosis of systemic lupus erythematosus. Thus, the reactions do not represent a true drug-induced lupus syndrome. Current hypotheses and experimental data regarding the cause of the reactions are reviewed. No specific clinical subgroup at high risk can be identified, and manifestations may occur at any dosage and at any time during therapy. Cross-reactivity between the two antithyroid drugs can be expected. Except for minor symptoms (e.g., mild arthralgias or transient rash), such reactions are an indication for withdrawal of the drug and the use of alternative methods to control the hyperthyroidism. In rare cases of severe vasculitis a short course of high-dose glucocorticoid therapy may be helpful. PMID:3539299

  7. Heterogeneous effects of antiepileptic drugs in an in vitro epilepsy model--a functional multineuron calcium imaging study.

    PubMed

    Hongo, Yoshie; Takasu, Keiko; Ikegaya, Yuji; Hasegawa, Minoru; Sakaguchi, Gaku; Ogawa, Koichi

    2015-07-01

    Epilepsy is a chronic brain disease characterised by recurrent seizures. Many studies of this disease have focused on local neuronal activity, such as local field potentials in the brain. In addition, several recent studies have elucidated the collective behavior of individual neurons in a neuronal network that emits epileptic activity. However, little is known about the effects of antiepileptic drugs on neuronal networks during seizure-like events (SLEs) at single-cell resolution. Using functional multineuron Ca(2+) imaging (fMCI), we monitored the activities of multiple neurons in the rat hippocampal CA1 region on treatment with the proconvulsant bicuculline under Mg(2+) -free conditions. Bicuculline induced recurrent synchronous Ca(2+) influx, and the events were correlated with SLEs. Other proconvulsants, such as 4-aminopyridine, pentetrazol, and pilocarpine, also induced synchronous Ca(2+) influx. We found that the antiepileptic drugs phenytoin, flupirtine, and ethosuximide, which have different mechanisms of action, exerted heterogeneous effects on bicuculline-induced synchronous Ca(2+) influx. Phenytoin and flupirtine significantly decreased the peak, the amount of Ca(2+) influx and the duration of synchronous events in parallel with the duration of SLEs, whereas they did not abolish the synchronous events themselves. Ethosuximide increased the duration of synchronous Ca(2+) influx and SLEs. Furthermore, the magnitude of the inhibitory effect of phenytoin on the peak synchronous Ca(2+) influx level differed according to the peak amplitude of the synchronous event in each individual cell. Evaluation of the collective behavior of individual neurons by fMCI seems to be a powerful tool for elucidating the profiles of antiepileptic drugs.

  8. Comparative persistence of antiepileptic drugs in patients with epilepsy: A STROBE-compliant retrospective cohort study

    PubMed Central

    Lai, Edward Chia-Cheng; Hsieh, Cheng-Yang; Su, Chien-Chou; Yang, Yea-Huei Kao; Huang, Chin-Wei; Lin, Swu-Jane; Setoguchi, Soko

    2016-01-01

    Abstract We compared persistence of antiepileptic drugs (AEDs) including carbamazepine, oxcarbazepine, gabapentin, lamotrigine, topiramate, valproic acid, and phenytoin in an Asian population with epilepsy. A retrospective cohort study was conducted by analyzing Taiwan's National Health Insurance Research Database (NHIRD). Adult epilepsy patients newly prescribed with AEDs between 2005 and 2009 were included. The primary outcome was persistence, defined as the treatment duration from the date of AED initiation to the date of AED discontinuation, switching, hospitalization due to seizure or disenrollment from databases, whichever came first. Cox proportional hazard models were used to estimate the risk of non-persistence with AEDs. Among the 13,061 new users of AED monotherapy (mean age: 58 years; 60% men), the persistence ranged from 218.8 (gabapentin) to 275.9 (oxcarbazepine) days in the first treatment year. The risks of non-persistence in patients receiving oxcarbazepine (adjusted hazard ratio [HR], 0.78; 95% CI, 0.74–0.83), valproic acid (0.88; 0.85–0.92), lamotrigine (0.72; 0.65–0.81), and topiramate (0.90; 0.82–0.98) were significantly lower than in the carbamazepine group. Compared with carbamazepine users, the non-persistence risk was higher in phenytoin users (1.10; 1.06–1.13), while gabapentin users (1.03; 0.98–1.09) had similar risk. For risk of hospitalization due to seizure and in comparison with carbamazepine users, oxcarbazepine (0.66; 0.58–0.74) and lamotrigine (0.46; 0.35–0.62) users had lower risk, while phenytoin (1.35; 1.26–1.44) users had higher risk. The results remained consistent throughout series of sensitivity and stratification analyses. The persistence varied among AEDs and was better for oxcarbazepine, valproic acid, lamotrigine, and topiramate, but worse for phenytoin when compared with carbamazepine. PMID:27583857

  9. Effects of antiepileptic drugs on the serum folate and vitamin B12 in various epileptic patients

    PubMed Central

    Huang, Hong-Li; Zhou, Hao; Wang, Nuan; Yu, Chun-Yu

    2016-01-01

    Epilepsy is a common neurodegenerative disease with an increasing morbidity. Clinical treatment of epilepsy includes symptomatic treatment, etiological treatment, surgery and prevention. The aim of the present study was to determine the effects of antiepileptic drugs (AEDs) on serum folate and vitamin B12 in various epileptic patients, and to examine the correlation between these effects and secondary cerebrovascular events. A total of 68 epileptic patients, diagnosed between May 2012 and May 2014, were included in the present study. The study included 8 cases of autonomic seizures, 10 cases of absence seizures, 13 cases of complex partial seizures, 28 cases of generalized tonic-clonic seizures, and 9 cases of simple partial seizures. The patients received appropriate AED treatment according to the characteristics of epileptic seizure and the treatment guidance. The differences in the serum levels of folate and vitamin B12 in these patients, and the differences in the secondary cerebrovascular events in these patients after 1 year follow-up were analyzed. The difference in the AEDs used by various epileptic patients was statistically significant (P<0.05). The proportion of AED monotherapy in the autonomic seizure group and petit mal group was highest, and the proportion of two AED in combination with the psychomotor seizure, grand mal and simple partial seizure groups was highest. The serum levels of folate and vitamin B12 in these patients following treatment were significantly lower than those prior to treatment (P<0.05). The differences in the serum levels of folate and vitamin B12 in these groups following treatment were not statistically significant (P>0.05). The difference in the incidence of cerebrovascular events in these groups at follow up was not statistically significant (P>0.05). The multifactorial logistic regression analysis revealed that the serum levels of folate and vitamin B12 were the independent risk factors for epilepsy with secondary

  10. Effects of antiepileptic drugs on the serum folate and vitamin B12 in various epileptic patients

    PubMed Central

    Huang, Hong-Li; Zhou, Hao; Wang, Nuan; Yu, Chun-Yu

    2016-01-01

    Epilepsy is a common neurodegenerative disease with an increasing morbidity. Clinical treatment of epilepsy includes symptomatic treatment, etiological treatment, surgery and prevention. The aim of the present study was to determine the effects of antiepileptic drugs (AEDs) on serum folate and vitamin B12 in various epileptic patients, and to examine the correlation between these effects and secondary cerebrovascular events. A total of 68 epileptic patients, diagnosed between May 2012 and May 2014, were included in the present study. The study included 8 cases of autonomic seizures, 10 cases of absence seizures, 13 cases of complex partial seizures, 28 cases of generalized tonic-clonic seizures, and 9 cases of simple partial seizures. The patients received appropriate AED treatment according to the characteristics of epileptic seizure and the treatment guidance. The differences in the serum levels of folate and vitamin B12 in these patients, and the differences in the secondary cerebrovascular events in these patients after 1 year follow-up were analyzed. The difference in the AEDs used by various epileptic patients was statistically significant (P<0.05). The proportion of AED monotherapy in the autonomic seizure group and petit mal group was highest, and the proportion of two AED in combination with the psychomotor seizure, grand mal and simple partial seizure groups was highest. The serum levels of folate and vitamin B12 in these patients following treatment were significantly lower than those prior to treatment (P<0.05). The differences in the serum levels of folate and vitamin B12 in these groups following treatment were not statistically significant (P>0.05). The difference in the incidence of cerebrovascular events in these groups at follow up was not statistically significant (P>0.05). The multifactorial logistic regression analysis revealed that the serum levels of folate and vitamin B12 were the independent risk factors for epilepsy with secondary

  11. Large-Scale Phenotype-Based Antiepileptic Drug Screening in a Zebrafish Model of Dravet Syndrome1,2,3

    PubMed Central

    Dinday, Matthew T.

    2015-01-01

    Abstract Mutations in a voltage-gated sodium channel (SCN1A) result in Dravet Syndrome (DS), a catastrophic childhood epilepsy. Zebrafish with a mutation in scn1Lab recapitulate salient phenotypes associated with DS, including seizures, early fatality, and resistance to antiepileptic drugs. To discover new drug candidates for the treatment of DS, we screened a chemical library of ∼1000 compounds and identified 4 compounds that rescued the behavioral seizure component, including 1 compound (dimethadione) that suppressed associated electrographic seizure activity. Fenfluramine, but not huperzine A, also showed antiepileptic activity in our zebrafish assays. The effectiveness of compounds that block neuronal calcium current (dimethadione) or enhance serotonin signaling (fenfluramine) in our zebrafish model suggests that these may be important therapeutic targets in patients with DS. Over 150 compounds resulting in fatality were also identified. We conclude that the combination of behavioral and electrophysiological assays provide a convenient, sensitive, and rapid basis for phenotype-based drug screening in zebrafish mimicking a genetic form of epilepsy. PMID:26465006

  12. Assessment of oral side effects of Antiepileptic drugs and traumatic oro-facial injuries encountered in Epileptic children

    PubMed Central

    Ghafoor, P A Fazal; Rafeeq, Mohammed; Dubey, Alok

    2014-01-01

    Background: Epilepsy is a chronic disorder with unpredictably recurring seizure. Uncontrolled attacks can put patients at risk of suffering oro-facial trauma. Antiepileptic drugs (AED) provide satisfactory control of seizures in most of the patients with epilepsy. However use of AED has been found to cause many side effects inclusive of side effects in the oral cavity also. Materials & Methods: This study was conducted on 150 epileptic children, who were on anti epileptic medication for one year. Results: Gingival over growth was seen as common side effect of the AED drugs. Lip and cheek biting were the most common soft tissue injury, while tooth fracture was the most common hard tissue dental injury. Conclusion: General physicians, physicians & dentists should be well aware of the potential side effects of AED. A Dentist should be well versed and trained to manage oro-facial injuries in the emergency department. How to cite the article: Ghafoor PA, Rafeeq M, Dubey A. Assessment of oral side effects of Antiepileptic drugs and traumaticoro-facial injuries encountered in Epileptic children. J Int Oral Health 2014;6(2):126-8. PMID:24876713

  13. Learning Lessons from Adverse Drug Reactions in Children

    PubMed Central

    Sammons, Helen M.; Choonara, Imti

    2016-01-01

    Drug toxicity is, unfortunately, a significant problem in children both in the hospital and in the community. Drug toxicity in children is different to that seen in adults. At least one in 500 children will experience an adverse drug reaction each year. For children in hospital, the risk is far greater (one in ten). Additionally, different and sometimes unique adverse drug reactions are seen in the paediatric age groups. Some of the major cases of drug toxicity historically have occurred in neonates. It is important that we understand the mechanism of action of adverse drug reactions. Greater understanding alongside rational prescribing should hopefully reduce drug toxicity in children in the future. PMID:27417239

  14. Intrapatient variation in antiepileptic drug plasma concentration after generic substitution vs stable brand-name drug regimens.

    PubMed

    Contin, Manuela; Alberghini, Lucia; Candela, Carmina; Benini, Giulia; Riva, Roberto

    2016-05-01

    Generic substitution of antiepileptic drugs (AEDs) is still a matter of controversy and concern among clinicians and patients. We aimed to assess intrasubject variation in plasma concentrations of lamotrigine (LTG), levetiracetam (LEV) and topiramate (TPM) after generic substitution compared with a stable brand-name drug regimen in a population of patients with epilepsy. A retrospective analysis was performed on prospectively collected and stored data from our therapeutic drug monitoring (TDM) database for the years 2009-2014. The main outcome variable was the proportion of patients who, after switching from branded to generic formulations, showed a greater than ±20% change in AED plasma concentrations compared to the proportion of control patients showing a change in AED plasma concentrations of the same extent while receiving stable branded formulations over repeated TDM tests. Fifty patients on LTG, 27 on LEV and 16 on TPM showing at least one TDM test while receiving generic products fulfilled the inclusion/exclusion criteria for the analysis and were compared with 200 control patients for LTG, 120 for LEV and 80 for TPM. The proportion of patients showing an intrasubject change greater than ±20% in AED plasma concentrations was similar in the brand name vs generic group compared with the control one for LTG (22% vs 33%) and LEV (44% vs 38%), while it was higher in the control group for TPM (41% vs 6%, p<0.01). These are the first data in the literature about the within-patient variation in steady-state plasma concentrations of a series of stable treatments with brand-name AEDs in a real clinical setting. In conclusion, a significant interday variability in intrapatient LTG, LEV and TPM plasma concentrations can be observed even in patients stabilized with the same brand name product over time. This suggests that any change in plasma AED concentration and possible related clinical effects after generic substitution may be not necessarily related to the switch

  15. 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.

  16. Drug interactions with the newer antiepileptic drugs (AEDs)--Part 2: pharmacokinetic and pharmacodynamic interactions between AEDs and drugs used to treat non-epilepsy disorders.

    PubMed

    Patsalos, Philip N

    2013-12-01

    Since antiepileptic drugs (AEDs) are prescribed to treat various non-epilepsy-related disorders in addition to the fact that patients with epilepsy may develop concurrent disorders that will need treatment, the propensity for AEDs to interact with non-AEDs is considerable and indeed can present a difficult clinical problem. The present review details the pharmacokinetic and pharmacodynamic interactions that have been reported to occur with the new AEDs (eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, retigabine (ezogabine), rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide) and drugs used to treat non-epilepsy disorders. Interaction study details are described, as necessary, so as to allow the reader to take a view as to the possible clinical significance of particular interactions. Pharmacokinetic interactions relate to hepatic enzyme induction or inhibition and involved a variety of drugs including psychoactive drugs, cardioactive drugs, oral contraceptives, antituberculous agents, analgesics and antineoplastic drugs. A total of 68 pharmacokinetic interactions have been described, with lamotrigine (n = 22), topiramate (n = 18) and oxcarbazepine (n = 7) being associated with most, whilst lacosamide, pregabalin, stiripentol and vigabatrin are associated with none. Overall, only three pharmacodynamic interactions have been described and occur with oxcarbazepine, perampanel and pregabalin. PMID:23794036

  17. Ziconotide: new drug. Limited analgesic efficacy, too many adverse effects.

    PubMed

    2008-10-01

    (1) When oral morphine does not relieve severe pain and when there is no specific treatment for the underlying cause, the first option is to try subcutaneous or intravenous administration. If this standard treatment fails or is poorly tolerated, intrathecal injection is usually preferred as the direct route to the central nervous system. However, one-quarter to one-half of patients still do not achieve adequate pain relief, and adverse effects are relatively frequent; (2) Ziconotide is not an opiate and is not related to the usual classes of drugs that interfere with nervous transmission in the posterior horn of the spinal cord. Marketing authorization has been granted for "severe, chronic pain in patients who require intrathecal analgesia". The Summary of Product Characteristics (SPC) recommends continuous infusion via an intrathecal catheter connected to a pump; (3) Clinical evaluation of ziconotide does not include any trials versus morphine in patients with nociceptive pain, or any trials versus tricyclic or antiepileptic drugs in patients with neurogenic pain; (4) In a trial in 220 patients in whom systemic morphine had failed, the mean pain score on a 100-mm visual analogue scale was 69.8 mm after three weeks on ziconotide, compared to 75.8 mm with placebo. This difference, although statistically significant, is clinically irrelevant. The proportion of "responders" (reduction of at least 30% in the initial pain score) was respectively 16.1% and 12.0% (no statistically significant difference); (5) The two other placebo-controlled trials included 112 patients with pain linked to cancer or HIV infection, and 257 patients with non-cancer pain. After a titration phase lasting 5 to 6 days, a combined analysis of the two trials showed that the mean pain score was 48.8 mm with ziconotide and 68.4 mm with placebo (statistically significant difference). However, many patients did not complete the titration phase. Efficacy also appeared to differ according to the type

  18. The effect of epilepsy and antiepileptic drugs on sexual, reproductive and gonadal health of adults with epilepsy.

    PubMed

    Hamed, Sherifa A

    2016-06-01

    Epilepsy is a common chronic medical illness. Hyposexuality is the most frequent abnormality in men and women with epilepsy. In men with epilepsy, hypoandrogenimia, hypogonadism and sperm abnormalities are common. Testicular atrophy was also infrequently reported. In women with epilepsy, hyperandrogenism, polycystic ovaries (PCOs) and PCO syndrome are frequent. Decreased serum free testosterone, dehydroepiandrosterone levels, free androgen index and free testosterone/leutinizing hormone (LH) ratio and increased sex hormone binding globulin, estradiol, prolactin, LH, follicle stimulating hormone (FSH) levels and LH/FSH ratio are common with epilepsy. Disturbance of central and/or peripheral control of hypothalamic-pituitary-gonadal axis and alteration of central neurotrasmitters (GABA, glutamate and serotonin) by epileptic discharges or antiepileptic drugs (AEDs), direct gonadal toxicity by AEDs and pcyshicatric/psychosocial factors are all incriminated in sexual, reproductive and gonadal abnormalities associated with epilepsy. Patients may benefit from multidisplinary evaluation, tight seizure control, change the AED, androgen therapy, genital vasodilators, L-carnitine supplementation and psychotherapy.

  19. Predictive value of isolated epileptiform discharges for a favorable therapeutic response to antiepileptic drugs in nonepileptic psychiatric patients.

    PubMed

    Boutros, Nash N; Kirollos, Sandra B; Pogarell, Oliver; Gallinat, Jürgen

    2014-02-01

    The efficacy of antiepileptic drugs (AEDs) in treating behavioral symptoms in nonepileptic psychiatric patients with abnormal EEGs is currently unknown. Although isolated epileptiform discharges have been reported in many psychiatric conditions, they are most commonly observed in patients with aggression, panic, or autistic spectrum disorders. The literature search was guided by 3 criteria: (1) studies had patients who did not experience seizures, (2) patients had EEGs, and (3) an AED was administered. Most important finding is that the number of "controlled" studies was extremely small. Overall, most reports suggest that the use of an AED can be associated with clinical and, at times, improved EEG abnormalities. Additionally, six controlled studies were found for other psychiatric disorders, such as learning disabilities with similar results. Overall, the use of anticonvulsants to treat nonepileptic psychiatric patients needs further controlled studies to better define indications, adequate EEG work-up, best AED to be used, and optimal durations of treatment attempts.

  20. Modulation of Antioxidant Enzymatic Activities by Certain Antiepileptic Drugs (Valproic Acid, Oxcarbazepine, and Topiramate): Evidence in Humans and Experimental Models

    PubMed Central

    Cárdenas-Rodríguez, Noemí; Coballase-Urrutia, Elvia; Rivera-Espinosa, Liliana; Romero-Toledo, Arantxa; Sampieri, Aristides III; Ortega-Cuellar, Daniel; Montesinos-Correa, Hortencia; Floriano-Sánchez, Esaú; Carmona-Aparicio, Liliana

    2013-01-01

    It is estimated that at least 100 million people worldwide will suffer from epilepsy at some point in their lives. This neurological disorder induces brain death due to the excessive liberation of glutamate, which activates the postsynaptic N-methyl-D-aspartic acid (NMDA) receptors, which in turn cause the reuptake of intracellular calcium (excitotoxicity). This excitotoxicity elicits a series of events leading to nitric oxide synthase (NOS) activation and the generation of reactive oxygen species (ROS). Several studies in experimental models and in humans have demonstrated that certain antiepileptic drugs (AEDs) exhibit antioxidant effects by modulating the activity of various enzymes associated with this type of stress. Considering the above-mentioned data, we aimed to compile evidence elucidating how AEDs such as valproic acid (VPA), oxcarbazepine (OXC), and topiramate (TPM) modulate oxidative stress. PMID:24454986

  1. Modulation of antioxidant enzymatic activities by certain antiepileptic drugs (valproic acid, oxcarbazepine, and topiramate): evidence in humans and experimental models.

    PubMed

    Cárdenas-Rodríguez, Noemí; Coballase-Urrutia, Elvia; Rivera-Espinosa, Liliana; Romero-Toledo, Arantxa; Sampieri, Aristides; Ortega-Cuellar, Daniel; Montesinos-Correa, Hortencia; Floriano-Sánchez, Esaú; Carmona-Aparicio, Liliana

    2013-01-01

    It is estimated that at least 100 million people worldwide will suffer from epilepsy at some point in their lives. This neurological disorder induces brain death due to the excessive liberation of glutamate, which activates the postsynaptic N-methyl-D-aspartic acid (NMDA) receptors, which in turn cause the reuptake of intracellular calcium (excitotoxicity). This excitotoxicity elicits a series of events leading to nitric oxide synthase (NOS) activation and the generation of reactive oxygen species (ROS). Several studies in experimental models and in humans have demonstrated that certain antiepileptic drugs (AEDs) exhibit antioxidant effects by modulating the activity of various enzymes associated with this type of stress. Considering the above-mentioned data, we aimed to compile evidence elucidating how AEDs such as valproic acid (VPA), oxcarbazepine (OXC), and topiramate (TPM) modulate oxidative stress.

  2. A Review for the Analysis of Antidepressant, Antiepileptic and Quinolone Type Drugs in Pharmaceuticals and Environmental Samples.

    PubMed

    Rani, Susheela; Malik, Ashok Kumar; Kaur, Ramandeep; Kaur, Ripneel

    2016-09-01

    The analysis of drugs in various biological fluids is an important criterion for the determination of the physiological performance of a drug. After sampling of the biological fluid, the next step in the analytical process is sample preparation. Sample preparation is essential for isolation of desired components from complex biological matrices and greatly influences their reliable and accurate determination. The complexity of biological fluids adds to the challenge of direct determination of the drug by chromatographic analysis, therefore demanding a sample preparation step that is often time consuming, tedious and frequently overlooked. However, direct online injection methods offer the advantage of reducing sample preparation steps and enabling effective pre-concentration and clean-up of biological fluids. These procedures can be automated and therefore reduce the requirements for handling potentially infectious biomaterial, improve reproducibility, and minimize sample manipulations and potential contamination. This review is focused on the discovery and development of high-performance liquid chromatography (HPLC) and gas chromatography (GC) with different detectors. The drugs covered in this review are antiepileptics, antidepressant (AD), and quinolones. The application of these methods for determination of these drugs in biological, environmental and pharmaceutical samples has also been discussed.

  3. Common Variants of KCNJ10 Are Associated with Susceptibility and Anti-Epileptic Drug Resistance in Chinese Genetic Generalized Epilepsies

    PubMed Central

    Guo, Yong; Yan, Kui Po; Qu, Qiang; Qu, Jian; Chen, Zi Gui; Song, Tao; Luo, Xiang-Ying; Sun, Zhong-Yi; Bi, Chang-Long; Liu, Jin-Fang

    2015-01-01

    To explore genetic mechanism of genetic generalized epilepsies (GGEs) is challenging because of their complex heritance pattern and genetic heterogeneity. KCNJ10 gene encodes Kir4.1 channels and plays a major role in modulating resting membrane potentials in excitable cells. It may cause GGEs if mutated. The purpose of this study was to investigate the possible association between KCNJ10 common variants and the susceptibility and drug resistance of GGEs in Chinese population. The allele-specific MALDI–TOF mass spectrometry method was used to assess 8 single nucleotide polymorphisms (SNPs) of KCNJ10 in 284 healthy controls and 483 Chinese GGEs patients including 279 anti-epileptic drug responsive patients and 204 drug resistant patients. We found the rs6690889 TC+TT genotypes were lower frequency in the GGEs group than that in the healthy controls (6.7% vs 9.5%, p = 0.01, OR = 0.50[0.29–0.86]). The frequency of rs1053074 G allele was lower in the childhood absence epilepsy (CAE) group than that in the healthy controls (28.4% vs 36.2%, p = 0.01, OR = 0.70[0.53–0.93]). The frequency of rs12729701 G allele and AG+GG genotypes was lower in the CAE group than that in the healthy controls (21.2% vs 28.4%, p = 0.01, OR = 0.74[0.59–0.94] and 36.3% vs 48.1%, p = 0.01, OR = 0.83[0.72–0.96], respectively). The frequency of rs12402969 C allele and the CC+CT genotypes were higher in the GGEs drug responsive patients than that in the drug resistant patients (9.3% vs 5.6%, OR = 1.73[1.06–2.85], p = 0.026 and 36.3% vs 48.1%, p = 0.01, OR = 0.83[0.72–0.96], respectively). This study identifies potential SNPs of KCNJ10 gene that may contribute to seizure susceptibility and anti-epileptic drug resistance. PMID:25874548

  4. Using Literature-Based Discovery to Explain Adverse Drug Effects.

    PubMed

    Hristovski, Dimitar; Kastrin, Andrej; Dinevski, Dejan; Burgun, Anita; Žiberna, Lovro; Rindflesch, Thomas C

    2016-08-01

    We report on our research in using literature-based discovery (LBD) to provide pharmacological and/or pharmacogenomic explanations for reported adverse drug effects. The goal of LBD is to generate novel and potentially useful hypotheses by analyzing the scientific literature and optionally some additional resources. Our assumption is that drugs have effects on some genes or proteins and that these genes or proteins are associated with the observed adverse effects. Therefore, by using LBD we try to find genes or proteins that link the drugs with the reported adverse effects. These genes or proteins can be used to provide insight into the processes causing the adverse effects. Initial results show that our method has the potential to assist in explaining reported adverse drug effects. PMID:27318993

  5. Promoting adverse drug reaction reporting: comparison of different approaches

    PubMed Central

    Ribeiro-Vaz, Inês; Santos, Cristina Costa; Cruz-Correia, Ricardo

    2016-01-01

    ABSTRACT OBJECTIVE To describe different approaches to promote adverse drug reaction reporting among health care professionals, determining their cost-effectiveness. METHODS We analyzed and compared several approaches taken by the Northern Pharmacovigilance Centre (Portugal) to promote adverse drug reaction reporting. Approaches were compared regarding the number and relevance of adverse drug reaction reports obtained and costs involved. Costs by report were estimated by adding the initial costs and the running costs of each intervention. These costs were divided by the number of reports obtained with each intervention, to assess its cost-effectiveness. RESULTS All the approaches seem to have increased the number of adverse drug reaction reports. We noted the biggest increase with protocols (321 reports, costing 1.96 € each), followed by first educational approach (265 reports, 20.31 €/report) and by the hyperlink approach (136 reports, 15.59 €/report). Regarding the severity of adverse drug reactions, protocols were the most efficient approach, costing 2.29 €/report, followed by hyperlinks (30.28 €/report, having no running costs). Concerning unexpected adverse drug reactions, the best result was obtained with protocols (5.12 €/report), followed by first educational approach (38.79 €/report). CONCLUSIONS We recommend implementing protocols in other pharmacovigilance centers. They seem to be the most efficient intervention, allowing receiving adverse drug reactions reports at lower costs. The increase applied not only to the total number of reports, but also to the severity, unexpectedness and high degree of causality attributed to the adverse drug reactions. Still, hyperlinks have the advantage of not involving running costs, showing the second best performance in cost per adverse drug reactions report. PMID:27143614

  6. Adverse drug reactions in veterinary patients associated with drug transporters.

    PubMed

    Mealey, Katrina L

    2013-09-01

    For many drugs used in veterinary practice, plasma and tissue concentrations are highly dependent on the activity of drug transporters. This article describes how functional changes in drug transporters, whether mediated by genetic variability or drug-drug interactions, affect drug disposition and, ultimately, drug safety and efficacy in veterinary patients. A greater understanding of species, breed, and individual (genetic) differences in drug transporter function, as well as drug-drug interactions involving drug transporters, will result in improved strategies for drug design and will enable veterinarians to incorporate individualized medicine in their practices.

  7. Adverse drug reactions in veterinary patients associated with drug transporters.

    PubMed

    Mealey, Katrina L

    2013-09-01

    For many drugs used in veterinary practice, plasma and tissue concentrations are highly dependent on the activity of drug transporters. This article describes how functional changes in drug transporters, whether mediated by genetic variability or drug-drug interactions, affect drug disposition and, ultimately, drug safety and efficacy in veterinary patients. A greater understanding of species, breed, and individual (genetic) differences in drug transporter function, as well as drug-drug interactions involving drug transporters, will result in improved strategies for drug design and will enable veterinarians to incorporate individualized medicine in their practices. PMID:23890239

  8. [Adverse drug reactions in the elderly: What dermatologists should know].

    PubMed

    Kratzsch, D; Simon, J-C; Treudler, R

    2016-02-01

    Pharmacotherapy in the elderly represents a challenge for dermatologists in regard to comorbidities, drug interactions, and compliance. Age-associated multimorbidity often results in polypharmacy and elevates the risk of adverse drug reactions. Crucial age-related alterations in pharmacokinetics must be considered when selecting drugs, particularly decreased total body water, altered proportion between muscle mass and adipose tissue, as well as decreased renal function. The purpose of this review is to help the reader identify relevant adverse drug reactions of often prescribed systemic dermatological pharmacons in geriatric patients and makes recommendations for their adequate application. PMID:26643292

  9. [Adverse drug reaction - Definitions, risk factors and pharmacovigilance].

    PubMed

    Krähenbühl, Stephan

    2015-12-01

    Adverse drug reactions (ADR} are the downside of active pharmacotherapies and can only partially be avoided. Risk factors have been identified for certain ADR which should be taken into account for the choice and dosing of critical drugs. Medical staff have a legal obligation to report severe ADR and ADR caused by newly licensed drugs. Such reports are important for monitoring the safety of drugs that are on the market. PMID:26654809

  10. Adverse Drug Reactions Causing Admission to a Paediatric Hospital

    PubMed Central

    Gallagher, Ruairi M.; Mason, Jennifer R.; Bird, Kim A.; Kirkham, Jamie J.; Peak, Matthew; Williamson, Paula R.; Nunn, Anthony J.; Turner, Mark A.; Pirmohamed, Munir; Smyth, Rosalind L.

    2012-01-01

    Objective(s) To obtain reliable information about the incidence of adverse drug reactions, and identify potential areas where intervention may reduce the burden of ill-health. Design Prospective observational study. Setting A large tertiary children’s hospital providing general and specialty care in the UK. Participants All acute paediatric admissions over a one year period. Main Exposure Any medication taken in the two weeks prior to admission. Outcome Measures Occurrence of adverse drug reaction. Results 240/8345 admissions in 178/6821 patients admitted acutely to a paediatric hospital were thought to be related to an adverse drug reaction, giving an estimated incidence of 2.9% (95% CI 2.5, 3.3), with the reaction directly causing, or contributing to the cause, of admission in 97.1% of cases. No deaths were attributable to an adverse drug reaction. 22.1% (95% CI 17%, 28%) of the reactions were either definitely or possibly avoidable. Prescriptions originating in the community accounted for 44/249 (17.7%) of adverse drug reactions, the remainder originating from hospital. 120/249 (48.2%) reactions resulted from treatment for malignancies. The drugs most commonly implicated in causing admissions were cytotoxic agents, corticosteroids, non-steroidal anti-inflammatory drugs, vaccines and immunosuppressants. The most common reactions were neutropenia, immunosuppression and thrombocytopenia. Conclusions Adverse drug reactions in children are an important public health problem. Most of those serious enough to require hospital admission are due to hospital-based prescribing, of which just over a fifth may be avoidable. Strategies to reduce the burden of ill-health from adverse drug reactions causing admission are needed. PMID:23226510

  11. Effects of antiepileptic drugs on learning as assessed by a repeated acquisition of response sequences task in rats.

    PubMed

    Shannon, Harlan E; Love, Patrick L

    2007-02-01

    Patients with epilepsy can have impaired cognitive abilities. Antiepileptic drugs (AEDs) may contribute to the cognitive deficits observed in patients with epilepsy, and have been shown to induce cognitive impairments in healthy individuals. However, there are few systematic data on the effects of AEDs on specific cognitive domains. We have previously demonstrated that a number of AEDs can impair working memory and attention. The purpose of the present study was to evaluate the effects of AEDs on learning as measured by a repeated acquisition of response sequences task in nonepileptic rats. The GABA-related AEDs phenobarbital and chlordiazepoxide significantly disrupted performance by shifting the learning curve to the right and increasing errors, whereas tiagabine and valproate did not. The sodium channel blockers carbamazepine and phenytoin suppressed responding at higher doses, whereas lamotrigine shifted the learning curve to the right and increased errors, and topiramate was without significant effect. Levetiracetam also shifted the learning curve to the right and increased errors. The disruptions produced by triazolam, chlordiazepoxide, lamotrigine, and levetiracetam were qualitatively similar to the effects of the muscarinic cholinergic receptor antagonist scopolamine. The present results indicate that AEDs can impair learning, but there are differences among AEDs in the magnitude of the disruption in nonepileptic rats, with drugs that enhance GABA receptor function and some that block sodium channels producing the most consistent impairment of learning. PMID:17174158

  12. Prescribing pattern of anti-epileptic drugs in an Italian setting of elderly outpatients: a population-based study during 2004–07

    PubMed Central

    Oteri, Alessandro; Trifirò, Gianluca; Gagliostro, Maria Silvia; Tari, Daniele Ugo; Moretti, Salvatore; Bramanti, Placido; Spina, Edoardo; Caputi, Achille Patrizio; Arcoraci, Vincenzo

    2010-01-01

    AIMS The aims of the study were to assess the trend of older and newer anti-epileptic drugs (AEDs) in the elderly population and to analyze the effects of a health-policy intervention with regard to AED use in general practice in a setting in Southern Italy. METHODS Data were extracted from the ‘Caserta-1’ Local-Health-Unit Arianna database in the years 2004–07. Patients aged over 65 years, receiving at least one AED prescription and registered in the lists of 88 general practitioners, were selected. The use of older and newer AEDs was calculated as 1 year prevalence and incidence of use and defined daily dose (DDD) per 1000 inhabitants day−1. Sub-analyses by gender, age and indication of use were performed. RESULTS Most of AED users were treated because of neuropathic pain (64.8%). However, the main indication of use for older AEDs (57.8%) was epilepsy, whereas newer AEDs (79.5%) were used for neuropathic pain. Prevalence and incidence of newer AED use increased until 2006, followed by a reduction in 2007. Newer AEDs, particularly gabapentin and pregabalin, were used in the treatment of more patients than older AEDs. However phenobarbital, accounting for more than 50% of total AED volume, was the most prescribed medication during the entire study period. CONCLUSIONS An increasing use of AEDs has been observed during 2004–07, mostly due to the prescription of newer compounds for neuropathic pain. The fall in the use of newer AEDs during 2007 coincides with revised re-imbursement criteria for gabapentin and pregabalin. The large use of phenobarbital in the elderly should be considered in the light of a risk of adverse drug reactions. PMID:20840443

  13. A Survey of Adverse Drug Reactions in Family Practice

    PubMed Central

    Reynolds, J. L.

    1984-01-01

    In this study, 232 Canadian family physicians recorded suspected adverse drug reactions (SADRs) in their practices for five months. Patients' age and sex, the drug(s) implicated, type of reaction and any disability were recorded on a card and sent to a central coordinating office each week. The number of SADRs in clinical practice seems to be small. An estimated 300,000 patients were involved in the study, and a total of 314 suspected adverse drug reactions in 314 patients were reported. A proposal is made for a surveillance system for new drugs. Family physicians would monitor all patients taking a drug or group of drugs and matched controls. The status of patients and controls would be recorded regularly and any SADRs reported to a central coordinating centre. PMID:21283495

  14. [Endocrinologic adverse effects of psychotropic drugs].

    PubMed

    Elenitza, Irene María

    2005-01-01

    Psychotropic drugs affect the regulatory mechanisms of different neuroendocrine axis. This chapter reviews the interactions between psychotropic drugs and prolactin, the hypothalamic-pituitary-thyroid axis and the hypothalamic-pituitary-gonadal axis. Hyperprolactinemia can cause galactorrhea, amenorrhea, sexual disfunction, impaired spermatogenesis and increased risk for osteoporosis and fractures. Atypical antipsychotics cause less hyperprolactinemia than conventional antipsychotics. Lithium has important effects on thyroid function. During lithium treatment, affectively ill patients show, in varying degrees and combinations, reduced levels of thyroid hormones and clinical evidence of subclinical hypothyroidism, overt hypothyroidism and goiter. Recent literature reports suggest that valproic acid, may be associated with polycistic ovarian syndrome. Until additional data is available, women starting valproate therapy should be warned about the possibility of endocrinology side effects.

  15. 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. PMID:26830290

  16. Prevalence of Different Combinations of Antiepileptic Drugs and CNS Drugs in Elderly Home Care Service and Nursing Home Patients in Norway

    PubMed Central

    Johannessen Landmark, Cecilie; Granas, Anne Gerd

    2016-01-01

    Introduction. Antiepileptic drugs (AEDs) are used to treat different conditions in elderly patients and are among the drug classes most susceptible to be involved in drug-drug interactions (DDI). The aim of the study was to describe and compare use of AEDs between home care service and nursing home patients, as these patients are not included in nationwide databases of drug utilization. In the combined population, we investigate DDI of AEDs with other central nervous system- (CNS-) active drugs and DDIs involving AEDs in general. Materials and Methods. Point-prevalence study of Norwegian patients in home care services and nursing homes in 2009. At the patient level, we screened for different DDIs involving AEDs. Results. In total, 882 patients (7.8%) of 11,254 patients used AEDs and number of users did not differ between home care services and nursing homes (8.2% versus 7.7%). In the combined population, we identified 436 potential DDIs in 45% of the patients. Conclusions. In a large population of elderly, home care service and nursing home patients do not differ with respect to exposure of AEDs but use more AEDs as compared to the general population of similar age. The risk of DDIs with AEDs and other CNS-active drugs should be taken into consideration and individual clinical evaluations are assessed in this population. PMID:27525114

  17. Prevalence of Different Combinations of Antiepileptic Drugs and CNS Drugs in Elderly Home Care Service and Nursing Home Patients in Norway.

    PubMed

    Halvorsen, Kjell H; Johannessen Landmark, Cecilie; Granas, Anne Gerd

    2016-01-01

    Introduction. Antiepileptic drugs (AEDs) are used to treat different conditions in elderly patients and are among the drug classes most susceptible to be involved in drug-drug interactions (DDI). The aim of the study was to describe and compare use of AEDs between home care service and nursing home patients, as these patients are not included in nationwide databases of drug utilization. In the combined population, we investigate DDI of AEDs with other central nervous system- (CNS-) active drugs and DDIs involving AEDs in general. Materials and Methods. Point-prevalence study of Norwegian patients in home care services and nursing homes in 2009. At the patient level, we screened for different DDIs involving AEDs. Results. In total, 882 patients (7.8%) of 11,254 patients used AEDs and number of users did not differ between home care services and nursing homes (8.2% versus 7.7%). In the combined population, we identified 436 potential DDIs in 45% of the patients. Conclusions. In a large population of elderly, home care service and nursing home patients do not differ with respect to exposure of AEDs but use more AEDs as compared to the general population of similar age. The risk of DDIs with AEDs and other CNS-active drugs should be taken into consideration and individual clinical evaluations are assessed in this population. PMID:27525114

  18. Anti-epileptic drugs and bone loss: Phenytoin reduces pro-collagen I and alters the electrophoretic mobility of osteonectin in cultured bone cells.

    PubMed

    Wilson, Emma L; Garton, Mark; Fuller, Heidi R

    2016-05-01

    Phenytoin is an antiepileptic drug used in the management of partial and tonic-clonic seizures. In previous studies we have shown that valproate, another antiepileptic drug, reduced the amount of two key bone proteins, pro-collagen I and osteonectin (SPARC, BM-40), in both skin fibroblasts and cultured osteoblast-like cells. Here we show that phenytoin also reduces pro-collagen I production in osteoblast-like cells, but does not appear to cause a decrease in osteonectin message or protein production. Instead, a 24h exposure to a clinically relevant concentration of phenytoin resulted in a dose-dependent change in electrophoretic mobility of osteonectin, which was suggestive of a change in post-translational modification status. The perturbation of these important bone proteins could be one of the mechanisms to explain the bone loss that has been reported following long-term treatment with phenytoin.

  19. Systematic Analysis of Adverse Event Reports for Sex Differences in Adverse Drug Events.

    PubMed

    Yu, Yue; Chen, Jun; Li, Dingcheng; Wang, Liwei; Wang, Wei; Liu, Hongfang

    2016-04-22

    Increasing evidence has shown that sex differences exist in Adverse Drug Events (ADEs). Identifying those sex differences in ADEs could reduce the experience of ADEs for patients and could be conducive to the development of personalized medicine. In this study, we analyzed a normalized US Food and Drug Administration Adverse Event Reporting System (FAERS). Chi-squared test was conducted to discover which treatment regimens or drugs had sex differences in adverse events. Moreover, reporting odds ratio (ROR) and P value were calculated to quantify the signals of sex differences for specific drug-event combinations. Logistic regression was applied to remove the confounding effect from the baseline sex difference of the events. We detected among 668 drugs of the most frequent 20 treatment regimens in the United States, 307 drugs have sex differences in ADEs. In addition, we identified 736 unique drug-event combinations with significant sex differences. After removing the confounding effect from the baseline sex difference of the events, there are 266 combinations remained. Drug labels or previous studies verified some of them while others warrant further investigation.

  20. Systematic Analysis of Adverse Event Reports for Sex Differences in Adverse Drug Events

    PubMed Central

    Yu, Yue; Chen, Jun; Li, Dingcheng; Wang, Liwei; Wang, Wei; Liu, Hongfang

    2016-01-01

    Increasing evidence has shown that sex differences exist in Adverse Drug Events (ADEs). Identifying those sex differences in ADEs could reduce the experience of ADEs for patients and could be conducive to the development of personalized medicine. In this study, we analyzed a normalized US Food and Drug Administration Adverse Event Reporting System (FAERS). Chi-squared test was conducted to discover which treatment regimens or drugs had sex differences in adverse events. Moreover, reporting odds ratio (ROR) and P value were calculated to quantify the signals of sex differences for specific drug-event combinations. Logistic regression was applied to remove the confounding effect from the baseline sex difference of the events. We detected among 668 drugs of the most frequent 20 treatment regimens in the United States, 307 drugs have sex differences in ADEs. In addition, we identified 736 unique drug-event combinations with significant sex differences. After removing the confounding effect from the baseline sex difference of the events, there are 266 combinations remained. Drug labels or previous studies verified some of them while others warrant further investigation. PMID:27102014

  1. Predicting Adverse Drug Events from Personal Health Messages

    PubMed Central

    Chee, Brant W.; Berlin, Richard; Schatz, Bruce

    2011-01-01

    Adverse drug events (ADEs) remain a large problem in the United States, being the fourth leading cause of death, despite post market drug surveillance. Much post consumer drug surveillance relies on self-reported “spontaneous” patient data. Previous work has performed datamining over the FDA’s Adverse Event Reporting System (AERS) and other spontaneous reporting systems to identify drug interactions and drugs correlated with high rates of serious adverse events. However, safety problems have resulted from the lack of post marketing surveillance information about drugs, with underreporting rates of up to 98% within such systems1,2. We explore the use of online health forums as a source of data to identify drugs for further FDA scrutiny. In this work we aggregate individuals’ opinions and review of drugs similar to crowd intelligence3. We use natural language processing to group drugs discussed in similar ways and are able to successfully identify drugs withdrawn from the market based on messages discussing them before their removal. PMID:22195073

  2. Intrinsic excitability measures track antiepileptic drug action and uncover increasing/decreasing excitability over the wake/sleep cycle.

    PubMed

    Meisel, Christian; Schulze-Bonhage, Andreas; Freestone, Dean; Cook, Mark James; Achermann, Peter; Plenz, Dietmar

    2015-11-24

    Pathological changes in excitability of cortical tissue commonly underlie the initiation and spread of seizure activity in patients suffering from epilepsy. Accordingly, monitoring excitability and controlling its degree using antiepileptic drugs (AEDs) is of prime importance for clinical care and treatment. To date, adequate measures of excitability and action of AEDs have been difficult to identify. Recent insights into ongoing cortical activity have identified global levels of phase synchronization as measures that characterize normal levels of excitability and quantify any deviation therefrom. Here, we explore the usefulness of these intrinsic measures to quantify cortical excitability in humans. First, we observe a correlation of such markers with stimulation-evoked responses suggesting them to be viable excitability measures based on ongoing activity. Second, we report a significant covariation with the level of AED load and a wake-dependent modulation. Our results indicate that excitability in epileptic networks is effectively reduced by AEDs and suggest the proposed markers as useful candidates to quantify excitability in routine clinical conditions overcoming the limitations of electrical or magnetic stimulation. The wake-dependent time course of these metrics suggests a homeostatic role of sleep, to rebalance cortical excitability.

  3. Efficacy of Anti-Epileptic Drugs in the Treatment of Tumor and Its Associated Epilepsy: An in vitro Perspective.

    PubMed

    Kaur, Taranjeet; Manchanda, Shaffi; Saini, Vedangana; Lakhman, Sukhwinder S; Kaur, Gurcharan

    2016-03-01

    The change in the therapeutic targets from neuron to glia has proved beneficial in the treatment of many psychiatric disorders. The anti-epileptic drugs (AEDs) have been widely prescribed for the treatment of partial and complete seizures, bipolar disorder among others. The current study was carried out to explore the efficacy of some conventional and novel AEDs for the treatment of tumor-associated epilepsy which develops in 29-49% of the patients diagnosed with brain tumors. We used C6 glioma cell line as model system to study the effect of selected AEDs, viz., gabapentin (GBP), valproic acid (VPA) and topiramate (TPM). Morphometry, cell cycle analysis, apoptosis, expression of different protein markers, viz., GFAP, HSP70 and nuclear factor-κB (NFκB) were studied in AED-treated cultures. The study was further extended to rat hypothalamic primary explant cultures, and cell migration and expression of plasticity markers - neural cell adhesion molecule (NCAM) and polysialylation of NCAM (PSA-NCAM) - were studied in the explants. TPM was observed to show more pronounced increase in apoptosis of glioblastoma cells accompanied by significant downregulation in the expression of HSP70 and NFκB. TPM-treated explants also showed highest process ramification and cellular migration accompanied by intense expression of the plasticity markers as compared to those treated with GBP and VPA. Among the 3 AEDs tested, TPM was observed to show more promising effects on cytoprotection and plasticity of C6 glioma cells.

  4. Efficacy of Anti-Epileptic Drugs in the Treatment of Tumor and Its Associated Epilepsy: An in vitro Perspective.

    PubMed

    Kaur, Taranjeet; Manchanda, Shaffi; Saini, Vedangana; Lakhman, Sukhwinder S; Kaur, Gurcharan

    2016-03-01

    The change in the therapeutic targets from neuron to glia has proved beneficial in the treatment of many psychiatric disorders. The anti-epileptic drugs (AEDs) have been widely prescribed for the treatment of partial and complete seizures, bipolar disorder among others. The current study was carried out to explore the efficacy of some conventional and novel AEDs for the treatment of tumor-associated epilepsy which develops in 29-49% of the patients diagnosed with brain tumors. We used C6 glioma cell line as model system to study the effect of selected AEDs, viz., gabapentin (GBP), valproic acid (VPA) and topiramate (TPM). Morphometry, cell cycle analysis, apoptosis, expression of different protein markers, viz., GFAP, HSP70 and nuclear factor-κB (NFκB) were studied in AED-treated cultures. The study was further extended to rat hypothalamic primary explant cultures, and cell migration and expression of plasticity markers - neural cell adhesion molecule (NCAM) and polysialylation of NCAM (PSA-NCAM) - were studied in the explants. TPM was observed to show more pronounced increase in apoptosis of glioblastoma cells accompanied by significant downregulation in the expression of HSP70 and NFκB. TPM-treated explants also showed highest process ramification and cellular migration accompanied by intense expression of the plasticity markers as compared to those treated with GBP and VPA. Among the 3 AEDs tested, TPM was observed to show more promising effects on cytoprotection and plasticity of C6 glioma cells. PMID:27536020

  5. Preclinical evaluation of 2,2,3,3-tetramethylcyclopropanecarbonyl-urea, a novel, second generation to valproic acid, antiepileptic drug.

    PubMed

    Sobol, Eyal; Yagen, Boris; Steve White, H; Wilcox, Karen S; Lamb, John G; Pappo, Orit; Wlodarczyk, Bogdan J; Finnell, Richard H; Bialer, Meir

    2006-09-01

    2,2,3,3-Tetramethylcyclopropanecarbonylurea (TMCU) is an amide derivative of a tetramethylcyclopropyl analogue of valproic acid (VPA), one of the leading antiepileptic drugs. Structural considerations used in the design of TMCU aimed to enhance the anticonvulsant potency of VPA and to prevent its two life-threatening side effects; i.e., teratogenicity and hepatotoxicity. The anticonvulsant activity of TMCU was evaluated in the MES, scMet, 6-Hz, scBic and scPic tests, and also in the hippocampal kindling model of partial seizures and lamotrigine-resistant amygdala kindling model of therapy-resistant seizures. Minimal motor impairment was determined using the rotorod test in mice and the positional sense test, muscle tone test, and gait and stance test in rats. The antinociceptive effect of TMCU was evaluated in the mouse formalin model of acute-tonic pain. The molecular mechanisms of action of TMCU were investigated in electrophysiological studies using the whole-cell patch-clamp technique. Teratogenicity studies were performed in a SWV/Fnn-mouse model of VPA-induced teratogenicity. TMCU hepatotoxicity was evaluated following 1-week intraperitoneal and oral administration of 50, 250 and 500 mg/kg doses to rats. In the hepatotoxicity study the blood levels of TMCU were evaluated at day 1 and day 7 of the treatment. TMCU mutagenicity was evaluated in the Ames test.

  6. Efficacy of Anti-Epileptic Drugs in the Treatment of Tumor and Its Associated Epilepsy: An in vitro Perspective

    PubMed Central

    Kaur, Taranjeet; Manchanda, Shaffi; Saini, Vedangana; Lakhman, Sukhwinder S.; Kaur, Gurcharan

    2016-01-01

    The change in the therapeutic targets from neuron to glia has proved beneficial in the treatment of many psychiatric disorders. The anti-epileptic drugs (AEDs) have been widely prescribed for the treatment of partial and complete seizures, bipolar disorder among others. The current study was carried out to explore the efficacy of some conventional and novel AEDs for the treatment of tumor-associated epilepsy which develops in 29-49% of the patients diagnosed with brain tumors. We used C6 glioma cell line as model system to study the effect of selected AEDs, viz., gabapentin (GBP), valproic acid (VPA) and topiramate (TPM). Morphometry, cell cycle analysis, apoptosis, expression of different protein markers, viz., GFAP, HSP70 and nuclear factor-κB (NFκB) were studied in AED-treated cultures. The study was further extended to rat hypothalamic primary explant cultures, and cell migration and expression of plasticity markers - neural cell adhesion molecule (NCAM) and polysialylation of NCAM (PSA-NCAM) - were studied in the explants. TPM was observed to show more pronounced increase in apoptosis of glioblastoma cells accompanied by significant downregulation in the expression of HSP70 and NFκB. TPM-treated explants also showed highest process ramification and cellular migration accompanied by intense expression of the plasticity markers as compared to those treated with GBP and VPA. Among the 3 AEDs tested, TPM was observed to show more promising effects on cytoprotection and plasticity of C6 glioma cells. PMID:27536020

  7. Adverse outcome pathways and drug-induced liver injury testing

    PubMed Central

    Vinken, Mathieu

    2015-01-01

    Drug-induced liver injury is a prominent reason for premarketing and postmarketing drug withdrawal and can be manifested in a number of ways, such as cholestasis, steatosis and fibrosis. The mechanisms driving these toxicological processes have been well characterized and have been emdedded in adverse outcome pathway frameworks in recent years. This paper reviews these constructs and simultaneously illustrates their use in the preclinical testing of drug-induced liver injury. PMID:26119269

  8. Vitamin D in epilepsy: vitamin D levels in epilepsy patients, patients on antiepileptic drug polytherapy and drug-resistant epilepsy sufferers.

    PubMed

    Nagarjunakonda, S; Amalakanti, S; Uppala, V; Rajanala, L; Athina, S

    2016-01-01

    The objective of this study was to assess vitamin D levels in epileptic patients and to compare its serum levels in patients on antiepileptic monotherapy and polytherapy. We analyzed the serum 25-hydroxy (25-OH) vitamin D levels in 98 consecutive subjects (43 epileptic patients and 55 non-epileptics). Factors influencing its serum levels such as degree of sun exposure, physical activity and dietary intake were taken into consideration. Overall, 41% had deficient, 49% had insufficient and 9% had sufficient levels of serum vitamin D. Elderly individuals (>60 years) and people employed in offices and schools had lower blood vitamin D levels. Across both the sexes, epileptic patients and non-epileptics, epileptic patients on monotherapy and polytherapy and patients with drug-responsive and -resistant seizures, there were no significant differences in serum 25-OH vitamin D levels. Our study shows that people with epilepsy suffer with vitamin D deficiency along with their normal peers.

  9. Low plasma antioxidant status in patients with epilepsy and the role of antiepileptic drugs on oxidative stress

    PubMed Central

    Menon, Bindu; Ramalingam, Krishnan; Kumar, Rajendiran Vinoth

    2014-01-01

    Background: Oxidative stress has been implicated in various disorders including epilepsy. We studied the antioxidant status in patients with epilepsy and aimed at determining whether there was any difference in the antioxidant levels between patients and controls, patients who are not on antiepileptic drugs (AEDs), and on treatment, between individual AEDs and patients on monotherapy and polytherapy. Materials and Methods: Antioxidant levels like catalase, glutathione peroxidase (GPx), vitamin E, glutathione (GSH), thiol group (SH), uric acid, and total antioxidant capacity (TAC) were compared between 100 patients with epilepsy and equal number of controls. Twenty-five patients who were not on AEDs were compared with patients on AEDs and the control group. Patients were divided into monotherapy and polytherapy group and antioxidant status was compared between the two groups and between individual drugs. Results: Catalase, SH, vitamin E, and TAC were significantly low in patients with epilepsy than those in the control group (P < 0.001). GSH and uric acid did not show any difference; GPx in patients was significantly higher than those in the control group There were no differences in the antioxidant levels between the treated and the untreated groups; however, it was lower in untreated patients than controls (P < 0.001), suggesting that AEDs do not modify the oxidative stress. Patients on Valproate (VPA) showed higher catalase and GPx levels. Catalase was higher in the monotherapy than polytherapy group (P < 0.04). Conclusion: Our study found significantly low levels of antioxidant in patients as compared to controls. AED did not influence the antioxidant status suggesting that seizures induce oxidative stress. PMID:25506160

  10. ARWAR: A network approach for predicting Adverse Drug Reactions.

    PubMed

    Rahmani, Hossein; Weiss, Gerhard; Méndez-Lucio, Oscar; Bender, Andreas

    2016-01-01

    Predicting novel drug side-effects, or Adverse Drug Reactions (ADRs), plays an important role in the drug discovery process. Existing methods consider mainly the chemical and biological characteristics of each drug individually, thereby neglecting information hidden in the relationships among drugs. Complementary to the existing individual methods, in this paper, we propose a novel network approach for ADR prediction that is called Augmented Random-WAlk with Restarts (ARWAR). ARWAR, first, applies an existing method to build a network of highly related drugs. Then, it augments the original drug network by adding new nodes and new edges to the network and finally, it applies Random Walks with Restarts to predict novel ADRs. Empirical results show that the ARWAR method presented here outperforms the existing network approach by 20% with respect to average Fmeasure. Furthermore, ARWAR is capable of generating novel hypotheses about drugs with respect to novel and biologically meaningful ADR.

  11. Obtaining pediatric indications for new anti-epileptic drugs: how and when.

    PubMed

    Garofalo, Elizabeth

    2006-01-01

    Drug development in children poses a number of challenges that must be overcome to obtain adequate information in product labeling. Trials in children must be supported by appropriate toxicology and formulation work, which tends to delay completion of work in children until after the drug is available for adults. The Pediatric Research Equity Act (PREA) contains a decision tree to help companies devise an appropriate pediatric program for drugs in development. The medical community does not currently endorse the assumption that the progression of epilepsy and response to treatment is the same in adults and children. Therefore, a complete drug development program in children is necessary and includes efficacy and safety trials along with pharmacokinetic studies. These studies are needed to justify the risk/benefit in children. Formulations appropriate for children are needed. Seizure diaries must be maintained by caretakers and in the case of infants, seizures may need to be counted by EEG. Early planning and discussion of a pediatric program with regulatory agencies will facilitate this work.

  12. [Direct reporting by patients of adverse drug reactions in Spain].

    PubMed

    Esther Salgueiro, M; Jimeno, Francisco J; Aguirre, Carmelo; García, Montserrat; Ordóñez, Lucía; Manso, Gloria

    2013-01-01

    The Spanish Pharmacovigilance System for Medicinal Products for Human Use, integrated by regional centers of pharmacovigilance coordinated by the Spanish Agency for Medicines and Health Products, is responsible for developing the Program of Spontaneous Reporting of Suspected Adverse Drug Reactions in our country. Although, until now, reports were only requesting to health professionals, the current understanding of the role of patients in the clinical setting and the experience gained in other countries of our environment, have demonstrated the convenience of developing active participation systems to patients in the reporting of suspected adverse drug reactions. In addition, this is taking into account in the new European legislation on pharmacovigilance. PMID:23461502

  13. [Direct reporting by patients of adverse drug reactions in Spain].

    PubMed

    Esther Salgueiro, M; Jimeno, Francisco J; Aguirre, Carmelo; García, Montserrat; Ordóñez, Lucía; Manso, Gloria

    2013-01-01

    The Spanish Pharmacovigilance System for Medicinal Products for Human Use, integrated by regional centers of pharmacovigilance coordinated by the Spanish Agency for Medicines and Health Products, is responsible for developing the Program of Spontaneous Reporting of Suspected Adverse Drug Reactions in our country. Although, until now, reports were only requesting to health professionals, the current understanding of the role of patients in the clinical setting and the experience gained in other countries of our environment, have demonstrated the convenience of developing active participation systems to patients in the reporting of suspected adverse drug reactions. In addition, this is taking into account in the new European legislation on pharmacovigilance.

  14. Preventing adverse drug reactions in the general population.

    PubMed

    Pezalla, Edmund

    2005-10-01

    In 2000, the number of patient deaths attributable to adverse drug reactions (ADRs) was estimated to be 218,000 annually. More than 51% of approved drugs in the market today may have serious side effects not detected before marketing approval. The causes of ADRs are many, ranging from drug-drug interactions to simple patient noncompliance. Until the use of electronic medical records becomes ubiquitous, other partnerships must be undertaken to lower the incidence of ADRs. Health plans and pharmacy benefit managers must work together to take effective steps to increase ADR monitoring and reporting and to proactively avoid ADRs through pharmacy management tools. PMID:16265935

  15. Adverse reactions to sulfa drugs: implications for malaria chemotherapy.

    PubMed

    Björkman, A; Phillips-Howard, P A

    1991-01-01

    National adverse drug reaction registers in Sweden and the United Kingdom provided data on the type, severity and frequency of reported adverse reactions attributed to sulfa drugs. Reactions to the ten principal drugs were examined in terms of their half-lives and usual indications for use. Of 8339 reactions reported between 1968 and 1988, 1272 (15%) were blood dyscrasias, 3737 (45%) were skin disorders, and 578 (7%) involved the liver. These side-effects occurred with all types of sulfa drugs investigated, although at different relative rates, and 3525 (42%) of them were classified as serious. The overall case fatality rate (CFR) was 1:15 serious reactions, and was highest in patients with white blood cell dyscrasias (1:7). Drugs with longer elimination half-lives had higher CFRs, particularly for fatalities after skin reactions. In Sweden, the estimated incidences of serious reactions were between 9 and 33 per 100,000 short-term users of sulfa drugs (two weeks), between 53 and 111 among those on malaria prophylaxis, and between 1744 and 2031 in patients on continuous therapy. For dapsone, the incidence appeared to increase with higher doses. Our results indicate that sulfa drugs with short elimination half-lives deserve to be considered for use in combination with proguanil or chlorproguanil for malaria chemotherapy and possibly prophylaxis. The smaller risk of adverse reactions associated with lower-dose dapsone suggests that it should also be evaluated as a potentially safe alternative.

  16. Status epilepticus induction has prolonged effects on the efficacy of antiepileptic drugs in the 6-Hz seizure model.

    PubMed

    Leclercq, Karine; Kaminski, Rafal M

    2015-08-01

    Several factors may influence the efficacy of antiepileptic drugs (AEDs) in patients with epilepsy, and treatment resistance could be related to genetics, neuronal network alterations, and modification of drug transporters or targets. Consequently, preclinical models used for the identification of potential new, more efficacious AEDs should reflect at least a few of these factors. Previous studies indicate that induction of status epilepticus (SE) may alter drug efficacy and that this effect could be long-lasting. In this context, we wanted to assess the protective effects of mechanistically diverse AEDs in mice subjected to pilocarpine-induced SE in another seizure model. We first determined seizure thresholds in mice subjected to pilocarpine-induced SE in the 6-Hz model, 2 weeks and 8 weeks following SE. We then evaluated the protective effects of mechanistically diverse AEDs in post-SE and control animals. No major differences in 6-Hz seizure susceptibility were observed between control groups, while the seizure threshold of pilocarpine mice at 8 weeks after SE was higher than at 2 weeks and higher than in control groups. Treatment with AEDs revealed major differences in drug response depending on their mechanism of action. Diazepam produced a dose-dependent protection against 6-Hz seizures in control and pilocarpine mice, both at 2 weeks and 8 weeks after SE, but with a more pronounced increase in potency in post-SE animals at 2 weeks. Levetiracetam induced a potent and dose-dependent protection in pilocarpine mice, 2 weeks after SE, while its protective effects were observed only at much higher doses in control mice. Its potency decreased in post-SE mice at 8 weeks and was very limited (30% protection at the highest tested dose) in the control group. Carbamazepine induced a dose-dependent protection at 2 weeks in control mice but only limited effect (50% at the highest tested dose) in pilocarpine mice. Its efficacy deeply decreased in post-SE mice at 8 weeks

  17. A Clinical Evaluation of Gingival Overgrowth in Children on Antiepileptic Drug Therapy

    PubMed Central

    Chopra, Saroj; Thomas, Abi M; Pandian, Jeyraj

    2016-01-01

    Introduction Gingival overgrowth, a well-known side effect of chronic phenytoin therapy has also been known to be caused by other anti epileptic drugs (AED’s). Various factors like plaque, gingival inflammation, and periodontal health have been postulated to effect gingival overgrowth. Aim To identify the AED having an effect on gingival overgrowth and to study the factors affecting it. Materials and Methods Three groups of 30 children each on monotherapy of phenytoin, sodium valproate, and carbamazepine were longitudinally followed for six months. Their oral and epileptic health status was assessed and were monitored for change in plaque levels, gingival inflammation, probing depth and the status of gingival overgrowth at baseline, at the end of 3 months and finally at the end of 6 months. The data was recorded and statistically analysed. Results Phenytoin caused gingival overgrowth in a significant number of children (53.6%) within 3 months. Sodium valproate also led to gingival overgrowth, but not upto statistically significant levels. Patients on carbamazepine did not show any signs of gingival overgrowth. Gingival overgrowth is seen more on buccal side, in the anterior segment and in the lower arch. No correlation could be found between, either plaque level, or gingival inflammation with gingival overgrowth. Probing depth could be positively correlated with gingival overgrowth. Conclusion Phenytoin is the drug, which can be chiefly implicated for causing gingival overgrowth. Sodium valproate carries the potential for gingival overgrowth, although only up to clinically insignificant levels in 6 months. Carbamazepine can be considered a safe drug in children in relation to gingival overgrowth. PMID:26894172

  18. Prediction of adverse drug reactions using decision tree modeling.

    PubMed

    Hammann, F; Gutmann, H; Vogt, N; Helma, C; Drewe, J

    2010-07-01

    Drug safety is of great importance to public health. The detrimental effects of drugs not only limit their application but also cause suffering in individual patients and evoke distrust of pharmacotherapy. For the purpose of identifying drugs that could be suspected of causing adverse reactions, we present a structure-activity relationship analysis of adverse drug reactions (ADRs) in the central nervous system (CNS), liver, and kidney, and also of allergic reactions, for a broad variety of drugs (n = 507) from the Swiss drug registry. Using decision tree induction, a machine learning method, we determined the chemical, physical, and structural properties of compounds that predispose them to causing ADRs. The models had high predictive accuracies (78.9-90.2%) for allergic, renal, CNS, and hepatic ADRs. We show the feasibility of predicting complex end-organ effects using simple models that involve no expensive computations and that can be used (i) in the selection of the compound during the drug discovery stage, (ii) to understand how drugs interact with the target organ systems, and (iii) for generating alerts in postmarketing drug surveillance and pharmacovigilance.

  19. Signal Detection of Adverse Drug Reaction of Amoxicillin Using the Korea Adverse Event Reporting System Database

    PubMed Central

    2016-01-01

    We conducted pharmacovigilance data mining for a β-lactam antibiotics, amoxicillin, and compare the adverse events (AEs) with the drug labels of 9 countries including Korea, USA, UK, Japan, Germany, Swiss, Italy, France, and Laos. We used the Korea Adverse Event Reporting System (KAERS) database, a nationwide database of AE reports, between December 1988 and June 2014. Frequentist and Bayesian methods were used to calculate disproportionality distribution of drug-AE pairs. The AE which was detected by all the three indices of proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC) was defined as a signal. The KAERS database contained a total of 807,582 AE reports, among which 1,722 reports were attributed to amoxicillin. Among the 192,510 antibiotics-AE pairs, the number of amoxicillin-AE pairs was 2,913. Among 241 AEs, 52 adverse events were detected as amoxicillin signals. Comparing the drug labels of 9 countries, 12 adverse events including ineffective medicine, bronchitis, rhinitis, sinusitis, dry mouth, gastroesophageal reflux, hypercholesterolemia, gastric carcinoma, abnormal crying, induration, pulmonary carcinoma, and influenza-like symptoms were not listed on any of the labels of nine countries. In conclusion, we detected 12 new signals of amoxicillin which were not listed on the labels of 9 countries. Therefore, it should be followed by signal evaluation including causal association, clinical significance, and preventability. PMID:27510377

  20. The effect of imepitoin, a recently developed antiepileptic drug, on thyroid parameters and fat metabolism in healthy Beagle dogs.

    PubMed

    Bossens, K; Daminet, S; Duchateau, L; Rick, M; Van Ham, L; Bhatti, S

    2016-07-01

    Since early 2013, imepitoin has been used in most European countries for the management of recurrent single generalised epileptic seizures in dogs with idiopathic epilepsy. It has been reported that imepitoin is as effective as phenobarbital (PB) in controlling seizures in dogs with newly diagnosed idiopathic epilepsy and it has a clinically superior safety profile. As the use of imepitoin gains popularity, its effect on serum thyroid parameters warrants further investigation since long-term PB administration influences thyroid parameters in dogs, which could lead to misinterpretation of laboratory results and incorrect diagnosis of thyroidal illness. A prospective study was conducted to compare the effect of orally administered PB and imepitoin on serum concentrations of total thyroxine (TT4), triiodothyronine, free thyroxine, thyroglobulin autoantibodies, thyroid-stimulating hormone, cholesterol and triglycerides in healthy Beagle dogs. These parameters were determined prior to and at 6, 12 and 18 weeks after antiepileptic drug administration. The starting dose of PB (5 mg/kg PO twice daily; range, 4.4-6.0 mg/kg) was monitored and adjusted to obtain optimal therapeutic serum concentrations (30-35 g/mL). Imepitoin was administered at 30 mg/kg PO twice daily (range, 29.2-35.7 mg/kg). Imepitoin administration did not affect any of the thyroid parameters over an 18-week period. In contrast, serum TT4 concentrations decreased significantly over time in dogs receiving PB (P <0.05). Serum cholesterol concentrations increased significantly over time in dogs in the imepitoin group, but not to the same extent as commonly seen in dogs with primary hypothyroidism.

  1. The effect of imepitoin, a recently developed antiepileptic drug, on thyroid parameters and fat metabolism in healthy Beagle dogs.

    PubMed

    Bossens, K; Daminet, S; Duchateau, L; Rick, M; Van Ham, L; Bhatti, S

    2016-07-01

    Since early 2013, imepitoin has been used in most European countries for the management of recurrent single generalised epileptic seizures in dogs with idiopathic epilepsy. It has been reported that imepitoin is as effective as phenobarbital (PB) in controlling seizures in dogs with newly diagnosed idiopathic epilepsy and it has a clinically superior safety profile. As the use of imepitoin gains popularity, its effect on serum thyroid parameters warrants further investigation since long-term PB administration influences thyroid parameters in dogs, which could lead to misinterpretation of laboratory results and incorrect diagnosis of thyroidal illness. A prospective study was conducted to compare the effect of orally administered PB and imepitoin on serum concentrations of total thyroxine (TT4), triiodothyronine, free thyroxine, thyroglobulin autoantibodies, thyroid-stimulating hormone, cholesterol and triglycerides in healthy Beagle dogs. These parameters were determined prior to and at 6, 12 and 18 weeks after antiepileptic drug administration. The starting dose of PB (5 mg/kg PO twice daily; range, 4.4-6.0 mg/kg) was monitored and adjusted to obtain optimal therapeutic serum concentrations (30-35 g/mL). Imepitoin was administered at 30 mg/kg PO twice daily (range, 29.2-35.7 mg/kg). Imepitoin administration did not affect any of the thyroid parameters over an 18-week period. In contrast, serum TT4 concentrations decreased significantly over time in dogs receiving PB (P <0.05). Serum cholesterol concentrations increased significantly over time in dogs in the imepitoin group, but not to the same extent as commonly seen in dogs with primary hypothyroidism. PMID:27240915

  2. [Adverse drug reactions reporting is helping "non substituable" prescription!].

    PubMed

    Jacquot, Julien; Bagheri, Haleh; Montastruc, Jean-Louis

    2014-01-01

    In August 2012, general practitioners of Haute- Garonne received a letter from Health insurance system, informing that prescriptions could be endorsed by "not substituable" after reporting an adverse drug reactions (ADR). Compared to an equivalent period before this letter, we observed an increase of ADRs reports for generics, mainly concerning gastrointestinal ADR and lack of efficacy. PMID:24927508

  3. A time-indexed reference standard of adverse drug reactions.

    PubMed

    Harpaz, Rave; Odgers, David; Gaskin, Greg; DuMouchel, William; Winnenburg, Rainer; Bodenreider, Olivier; Ripple, Anna; Szarfman, Ana; Sorbello, Alfred; Horvitz, Eric; White, Ryen W; Shah, Nigam H

    2014-11-11

    Undetected adverse drug reactions (ADRs) pose a major burden on the health system. Data mining methodologies designed to identify signals of novel ADRs are of deep importance for drug safety surveillance. The development and evaluation of these methodologies requires proper reference benchmarks. While progress has recently been made in developing such benchmarks, our understanding of the performance characteristics of the data mining methodologies is limited because existing benchmarks do not support prospective performance evaluations. We address this shortcoming by providing a reference standard to support prospective performance evaluations. The reference standard was systematically curated from drug labeling revisions, such as new warnings, which were issued and communicated by the US Food and Drug Administration in 2013. The reference standard includes 62 positive test cases and 75 negative controls, and covers 44 drugs and 38 events. We provide usage guidance and empirical support for the reference standard by applying it to analyze two data sources commonly mined for drug safety surveillance.

  4. A time-indexed reference standard of adverse drug reactions

    PubMed Central

    Harpaz, Rave; Odgers, David; Gaskin, Greg; DuMouchel, William; Winnenburg, Rainer; Bodenreider, Olivier; Ripple, Anna; Szarfman, Ana; Sorbello, Alfred; Horvitz, Eric; White, Ryen W.; Shah, Nigam H.

    2014-01-01

    Undetected adverse drug reactions (ADRs) pose a major burden on the health system. Data mining methodologies designed to identify signals of novel ADRs are of deep importance for drug safety surveillance. The development and evaluation of these methodologies requires proper reference benchmarks. While progress has recently been made in developing such benchmarks, our understanding of the performance characteristics of the data mining methodologies is limited because existing benchmarks do not support prospective performance evaluations. We address this shortcoming by providing a reference standard to support prospective performance evaluations. The reference standard was systematically curated from drug labeling revisions, such as new warnings, which were issued and communicated by the US Food and Drug Administration in 2013. The reference standard includes 62 positive test cases and 75 negative controls, and covers 44 drugs and 38 events. We provide usage guidance and empirical support for the reference standard by applying it to analyze two data sources commonly mined for drug safety surveillance. PMID:25632348

  5. Mining for adverse drug events with formal concept analysis.

    PubMed

    Estacio-Moreno, Alexander; Toussaint, Yannick; Bousquet, Cédric

    2008-01-01

    The pharmacovigilance databases consist of several case reports involving drugs and adverse events (AEs). Some methods are applied consistently to highlight all signals, i.e. all statistically significant associations between a drug and an AE. These methods are appropriate for verification of more complex relationships involving one or several drug(s) and AE(s) (e.g; syndromes or interactions) but do not address the identification of them. We propose a method for the extraction of these relationships based on Formal Concept Analysis (FCA) associated with disproportionality measures. This method identifies all sets of drugs and AEs which are potential signals, syndromes or interactions. Compared to a previous experience of disproportionality analysis without FCA, the addition of FCA was more efficient for identifying false positives related to concomitant drugs. PMID:18487830

  6. Clinical risk factors associated with anti-epileptic drug responsiveness in canine epilepsy.

    PubMed

    Packer, Rowena M A; Shihab, Nadia K; Torres, Bruno B J; Volk, Holger A

    2014-01-01

    The nature and occurrence of remission, and conversely, pharmacoresistance following epilepsy treatment is still not fully understood in human or veterinary medicine. As such, predicting which patients will have good or poor treatment outcomes is imprecise, impeding patient management. In the present study, we use a naturally occurring animal model of pharmacoresistant epilepsy to investigate clinical risk factors associated with treatment outcome. Dogs with idiopathic epilepsy, for which no underlying cause was identified, were treated at a canine epilepsy clinic and monitored following discharge from a small animal referral hospital. Clinical data was gained via standardised owner questionnaires and longitudinal follow up data was gained via telephone interview with the dogs' owners. At follow up, 14% of treated dogs were in seizure-free remission. Dogs that did not achieve remission were more likely to be male, and to have previously experienced cluster seizures. Seizure frequency or the total number of seizures prior to treatment were not significant predictors of pharmacoresistance, demonstrating that seizure density, that is, the temporal pattern of seizure activity, is a more influential predictor of pharmacoresistance. These results are in line with clinical studies of human epilepsy, and experimental rodent models of epilepsy, that patients experiencing episodes of high seizure density (cluster seizures), not just a high seizure frequency pre-treatment, are at an increased risk of drug-refractoriness. These data provide further evidence that the dog could be a useful naturally occurring epilepsy model in the study of pharmacoresistant epilepsy.

  7. Improvement of physicochemical properties of an antiepileptic drug by salt engineering.

    PubMed

    Rahman, Ziyaur; Zidan, Ahmed S; Samy, Raghu; Sayeed, Vilayat A; Khan, Mansoor A

    2012-09-01

    The focus of the present investigation was to evaluate the feasibility of using cyclamic salt of lamotrigine in order to improve its solubility and intrinsic dissolution rate (IDR). The salt was prepared by solution crystallization method and characterized chemically by fourier transform infrared spectroscopy (FTIR), proton ((1)H) and carbon ((13)C) nuclear magnetic resonance (liquid and solid, NMR) spectroscopy, physically by powder X-ray diffraction (PXRD), thermally by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), physicochemically for solubility, IDR, solution and solid-state stability, and polymorphism by solution recrystallization and slurry conversion studies. The FTIR, NMR, PXRD, DSC, and TGA spectra and thermograms indicated the salt formation. The salt formation increased lamotrigine solubility by 19-fold and IDR by 4.9-fold in water. The solution and solid-state stability were similar to parent molecule and were resistant to polymorphic transformation. In conclusion, cyclamic salt of lamotrigine provides another potential avenue for the pharmaceutical development of lamotrigine with improved physicochemical properties especially for pediatric population. It is also possible that appropriate dosage forms can be formulated with much lower drug amount and better safety profile than existing products. PMID:22588676

  8. Antiepileptic drugs (AEDs) polypharmacy could lead to buried pharmacokinetic interactions due to CYP450.

    PubMed

    Tolou-Ghamari, Z

    2012-09-01

    CYP450 enzymes are basics for the metabolism of several medications such as numerous AEDs. As AEDs polypharmacy could lead to hidden pharmacokinetic interactions due to CYP450, there fore, the aim of this study was to determine a proper guide line for AEDs prescription in Iranian epileptic population. A cross-sectional study of fifty-four patients' (n=23 females; n= 31 males with a mean age of 27 years) located in the Epilepsy Ward of Kashani Hospital of Isfahan University of Medical Sciences was carried out during the year 2011. Variables including sex, age, age of seizureonset, type and number of AEDs were recorded in d-Base. Results showed that the number of prescriptions based on AEDs polypharmacy was 77.8%. The most important drugs in prescriptions were carbamazepine (n=41) that is a potent inducer of CYP450 and valproic acid (n=31) that is a potent inhibitor of CYP450 simultaneously. Administration of AEDs was based on: three (n=17), four (n=7), five (n=4) or six (n=3) AEDs simultaneously. To avoid side effects, in prescribing AEDs that act as CYP450 inhibitors or inducers concomitantly, their spectrum of interactions should be predicted.

  9. Adverse Drug Event Prevention: 2014 Action Plan Conference.

    PubMed

    Ducoffe, Aaron R; Baehr, Avi; Peña, Juliet C; Rider, Briana B; Yang, Sandra; Hu, Dale J

    2016-09-01

    Adverse drug events (ADEs) have been highlighted as a national patient safety and public health challenge by the National Action Plan for Adverse Drug Event Prevention (ADE Action Plan), which was released by the Office of Disease Prevention and Health Promotion in August 2014. The following October, the ADE Prevention: 2014 Action Plan Conference provided an opportunity for federal agencies, national experts, and stakeholders to coordinate and collaborate in the initiative to reduce preventable ADEs. The single-day conference included morning plenary sessions focused on the surveillance, evidence-based prevention, incentives and oversights, and additional research needs of the drug classes highlighted in the ADE Action Plan: anticoagulants, diabetes agents, and opioids. Afternoon breakout sessions allowed for facilitated discussions on measures for tracking national progress in ADE prevention and the identification of opportunities to ensure safe and high-quality health care and medication use.

  10. Adverse drug reactions in an elderly outpatient population.

    PubMed

    Schneider, J K; Mion, L C; Frengley, J D

    1992-01-01

    The prevalence of adverse drug reactions (ADRs) in elderly outpatients was investigated, along with factors that might be associated with their occurrence. The medical records of elderly patients attending an interdisciplinary geriatric clinic and a general medical clinic during 1988 were audited to collect a variety of demographic and treatment data and to detect documentation of first-time ADRs. Subjects were classified as having had an ADR if a physician documented this or if a relevant symptom was noted in the record and a score of 1 or above was obtained on the Adverse Drug Reaction Probability Scale. The presence of potential drug interactions was also assessed. The sample size was 463 patients, of whom 332 attended the medical clinic and 131 attended the geriatric clinic. Potential drug interactions were identified in the records of 143 subjects (31%). There were 107 documented ADRs in 97 patients (21%). Of these patients, 86 were noted by the physicians as having had an ADR. Twelve patients were hospitalized as a direct result of an ADR. Significant risk factors for ADRs were attendance in the geriatric clinic, the use of potentially harmful drug combinations, and the use of drugs that require therapeutic monitoring. Patient age and the number of drugs had no association with ADRs. In the elderly population studied, patients with frailty arising from multiple pathologies were more likely to have ADRs than the more robust elderly, even when their therapeutic regimens were simplified. PMID:1570873

  11. Identification of phototransformation products of the antiepileptic drug gabapentin: Biodegradability and initial assessment of toxicity.

    PubMed

    Herrmann, Manuel; Menz, Jakob; Olsson, Oliver; Kümmerer, Klaus

    2015-11-15

    The anticonvulsant drug Gabapentin (GAB) is used for the treatment of various diseases (e.g. epilepsy, bipolar disorder, neuropathic pain) and is being consumed in high amounts. As GAB is not metabolized and shows a weak elimination in sewage treatment plants (STPs), it has been detected in surface water and even in raw potable water. Moreover, the confirmed teratogenic effects of GAB indicate the need for further investigations regarding options for the elimination of GAB in the water cycle. Little is known about the behavior of GAB during treatment with UV light, which is normally used for the disinfection of potable water and discussed for advanced wastewater treatment. In this study, GAB was exposed to polychromatic UV irradiation at different initial concentrations in aqueous solution. Afterwards the structures of the resulting phototransformation products (PTPs) were identified and elucidated by means of high-resolution mass spectrometry. GAB and photolytic mixtures were submitted to the Closed Bottle Test (CBT; OECD 301 D) to assess biodegradability. Furthermore, the toxicity of GAB and its photolytic mixtures was initially addressed on screening level using a modified luminescent bacteria test (LBT) and the umu-test (ISO/FDIS 13829). Environmentally realistic concentrations of GAB were disclosed by predicting STP influent concentrations (24.3 and 23.2 μg L(-1)). GAB with initial concentration of 100 mg L(-1) was eliminated by 80% after 128 min of direct UV irradiation, but just 9% of non-purgeable organic carbon (NPOC) was removed indicating the formation of dead-end transformation products (TPs). Structures of different PTPs were elucidated and several identical PTPs could also be identified at lower initial treatment concentrations (20 mg L(-1), 5 mg L(-1), 1 mg L(-1) and 0.1 mg L(-1)). GAB was classified as not readily biodegradable. Moreover, photo treatment did not result in better biodegradable PTPs. With increasing UV treatment duration, photolytic

  12. The Brain Activity in Brodmann Area 17: A Potential Bio-Marker to Predict Patient Responses to Antiepileptic Drugs

    PubMed Central

    Xu, Xin; Fang, Weidong; Zeng, Kebin; Yang, Mingming; Li, Chenyu; Wang, Shasha; Li, Minghui; Wang, Xuefeng

    2015-01-01

    In this study, we aimed to predict newly diagnosed patient responses to antiepileptic drugs (AEDs) using resting-state functional magnetic resonance imaging tools to explore changes in spontaneous brain activity. We recruited 21 newly diagnosed epileptic patients, 8 drug-resistant (DR) patients, 11 well-healed (WH) patients, and 13 healthy controls. After a 12-month follow-up, 11 newly diagnosed epileptic patients who showed a poor response to AEDs were placed into the seizures uncontrolled (SUC) group, while 10 patients were enrolled in the seizure-controlled (SC) group. By calculating the amplitude of fractional low-frequency fluctuations (fALFF) of blood oxygen level-dependent signals to measure brain activity during rest, we found that the SUC patients showed increased activity in the bilateral occipital lobe, particularly in the cuneus and lingual gyrus compared with the SC group and healthy controls. Interestingly, DR patients also showed increased activity in the identical cuneus and lingual gyrus regions, which comprise Brodmann’s area 17 (BA17), compared with the SUC patients; however, these abnormalities were not observed in SC and WH patients. The receiver operating characteristic (ROC) curves indicated that the fALFF value of BA17 could differentiate SUC patients from SC patients and healthy controls with sufficient sensitivity and specificity prior to the administration of medication. Functional connectivity analysis was subsequently performed to evaluate the difference in connectivity between BA17 and other brain regions in the SUC, SC and control groups. Regions nearby the cuneus and lingual gyrus were found positive connectivity increased changes or positive connectivity changes with BA17 in the SUC patients, while remarkably negative connectivity increased changes or positive connectivity decreased changes were found in the SC patients. Additionally, default mode network (DMN) regions showed negative connectivity increased changes or negative

  13. ACEA (a highly selective cannabinoid CB1 receptor agonist) stimulates hippocampal neurogenesis in mice treated with antiepileptic drugs.

    PubMed

    Andres-Mach, Marta; Haratym-Maj, Agnieszka; Zagaja, Miroslaw; Rola, Radoslaw; Maj, Maciej; Chrościńska-Krawczyk, Magdalena; Luszczki, Jarogniew J

    2015-10-22

    Hippocampal neurogenesis plays a very important role in learning and memory functions. In a search for best neurological drugs that protect neuronal cells and stimulate neurogenesis with no side effects, cannabinoids proved to be a strong group of substances having many beneficial properties. The aim of this study was to evaluate the impact of ACEA (arachidonyl-2'-chloroethylamide--a highly selective cannabinoid CB1 receptor agonist) combined with a classical antiepileptic drug sodium valproate (VPA) on neural precursor cells' proliferation and differentiation in the mouse brain. All experiments were performed on adolescent CB57/BL male mice injected i.p. with VPA (10mg/kg), ACEA (10mg/kg) and PMSF (30 mg/kg) (phenylmethylsulfonyl fluoride--a substance protecting ACEA against degradation by the fatty-acid amidohydrolase) for 10 days. Next an acute response of proliferating neural precursor cells to ACEA and VPA administration was evaluated with Ki-67 staining (Time point 1). Next, in order to determine whether acute changes translated into long-term alterations in neurogenesis, proliferating cells were labeled with 5-bromo-2deoxyuridine (BrdU) followed by confocal microscopy used to determine the percentage of BrdU-labeled cells that showed mature cell phenotypes (Time point 2). Results indicate that ACEA with PMSF significantly increase the total number of Ki-67-positive cells when compared to the control group. Moreover, ACEA in combination with VPA increased the number of Ki-67-positive cells, whereas VPA administered alone had no impact on proliferating cells' population. Accordingly, neurogenesis study results indicate that the combination of ACEA+PMSF administered alone and in combination with VPA considerably increases the total number of BrdU-positive cells in comparison to the control group while ACEA+PMSF alone and in combination with VPA increased total numbers of BrdU-positive cells, newly born neurons and astrocytes as compared to VPA group but not to

  14. Adverse Effects of Common Drugs: Children and Adolescents.

    PubMed

    Karpa, Kelly Dowhower; Felix, Todd Matthew; Lewis, Peter R

    2015-09-01

    Drug use and harms are increasingly common among newborns, infants, children, and adolescents during ambulatory practice, emergency department, and in-hospital treatment, including treatment in pediatric intensive care units. The pharmacokinetic and pharmacodynamic parameters of drugs often are different for children compared with adults and must be considered before prescribing. Drug exposure and the potential for harms also should be considered for fetuses and breastfeeding infants. As with adult patients, a thorough drug and allergy history (including nonprescription drugs and herbal and dietary supplements) should be obtained and reviewed at each medical visit. Children and adolescents are increasingly at risk of drug harm/overdose through accidental or intentional ingestion of nonprescription and prescription drugs (eg, cough and cold preparations, candy-appearing vitamins, stimulants, narcotics). Parents and caregivers should receive training in the proper use, storage, and administration of all drugs. Prescribing clinicians should be vigilant in withholding unnecessary drugs, such as antibiotics for viral infections. When prescribing, clinicians should be aware of common drugs frequently associated with adverse reactions, including stimulants, antipsychotics, analgesics, asthma therapies, acne therapies, and tumor necrosis factor inhibitors. Scientifically based prescribing practices should be used and consultation with evidence-based resources and pharmacists sought as needed. PMID:26375994

  15. Clarifying adverse drug events: a clinician's guide to terminology, documentation, and reporting.

    PubMed

    Nebeker, Jonathan R; Barach, Paul; Samore, Matthew H

    2004-05-18

    Adverse drug events cause substantial morbidity and mortality, yet they remain underappreciated and misunderstood. The terminology to describe errors and patient harm associated with medications causes much confusion. This article uses the case study of a patient with multiple adverse drug events to clarify key terms, such as adverse event, adverse drug reaction, adverse drug event, medication error, and side effect. The case discussion illustrates clinical approaches to analyzing the causal connection between a suspect drug and an adverse event. Examples and rationale for meaningful documentation of adverse drug events are provided, along with an outline of the types of events that should be reported to regulatory agencies.

  16. Antiepileptic drugs and the risk of ischaemic stroke and myocardial infarction: a population-based cohort study

    PubMed Central

    Renoux, Christel; Dell'Aniello, Sophie; Saarela, Olli; Filion, Kristian B; Boivin, Jean-François

    2015-01-01

    Objectives Hepatic enzyme-inducing antiepileptic drugs (AEDs) increase serum lipid levels and other atherogenic markers via the induction of cytochrome P450 and may therefore increase the risk of vascular events. We sought to assess the risk of ischaemic stroke and myocardial infarction (MI) according to AED enzymatic properties. Design Population-based cohort study with nested case–control analysis. Setting 650 general practices in the UK contributing to the Clinical Practice Research Datalink. Participants A cohort of 252 407 incident AED users aged 18 or older between January 1990 and April 2013. For each case of ischaemic stroke or MI, up to 10 controls were randomly selected among the cohort members in the risk sets defined by the case and matched on age, sex, indication for AED, calendar time and duration of follow-up. Interventions Current use of enzyme-inducing and enzyme-inhibiting AEDs compared with non-inducing AEDs. Primary outcome measures Incidence rate ratios (RRs) of ischaemic stroke and MI. Results 5069 strokes and 3636 MIs were identified during follow-up. Inducing AEDs use was associated with a small increased risk of ischaemic stroke (RR=1.16, 95% CI 1.02 to 1.33) relative to non-inducing AEDs, most likely due to residual confounding. However, current use of inducing AEDs for ≥24 months was associated with a 46% increased risk of MI (RR=1.46, 95% CI 1.15 to 1.85) compared with the same duration of non-inducing AED, corresponding to a risk difference of 1.39/1000 (95% CI 0.33 to 2.45) persons per year. Current use of inhibiting AED was associated with a decreased risk of MI (RR=0.81, 95% CI 0.66 to 1.00). Conclusions The use of enzyme-inducing AEDs was not associated with an increased risk of ischaemic stroke; a small increase of MI with prolonged use was observed. In contrast, use of inhibiting AEDs was associated with a decreased risk of MI. PMID:26270948

  17. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes.

    PubMed

    Glauser, Tracy; Ben-Menachem, Elinor; Bourgeois, Blaise; Cnaan, Avital; Guerreiro, Carlos; Kälviäinen, Reetta; Mattson, Richard; French, Jacqueline A; Perucca, Emilio; Tomson, Torbjorn

    2013-03-01

    The purpose of this report was to update the 2006 International League Against Epilepsy (ILAE) report and identify the level of evidence for long-term efficacy or effectiveness for antiepileptic drugs (AEDs) as initial monotherapy for patients with newly diagnosed or untreated epilepsy. All applicable articles from July 2005 until March 2012 were identified, evaluated, and combined with the previous analysis (Glauser et al., 2006) to provide a comprehensive update. The prior analysis methodology was utilized with three modifications: (1) the detectable noninferiority boundary approach was dropped and both failed superiority studies and prespecified noninferiority studies were analyzed using a noninferiority approach, (2) the definition of an adequate comparator was clarified and now includes an absolute minimum point estimate for efficacy/effectiveness, and (3) the relationship table between clinical trial ratings, level of evidence, and conclusions no longer includes a recommendation column to reinforce that this review of efficacy/evidence for specific seizure types does not imply treatment recommendations. This evidence review contains one clarification: The commission has determined that class I superiority studies can be designed to detect up to a 20% absolute (rather than relative) difference in the point estimate of efficacy/effectiveness between study treatment and comparator using an intent-to-treat analysis. Since July, 2005, three class I randomized controlled trials (RCT) and 11 class III RCTs have been published. The combined analysis (1940-2012) now includes a total of 64 RCTs (7 with class I evidence, 2 with class II evidence) and 11 meta-analyses. New efficacy/effectiveness findings include the following: levetiracetam and zonisamide have level A evidence in adults with partial onset seizures and both ethosuximide and valproic acid have level A evidence in children with childhood absence epilepsy. There are no major changes in the level of evidence

  18. Adverse Drug Event Ontology: Gap Analysis for Clinical Surveillance Application.

    PubMed

    Adam, Terrence J; Wang, Jin

    2015-01-01

    Adverse drug event identification and management are an important patient safety problem given the potential for event prevention. Previous efforts to provide structured data methods for population level identification of adverse drug events have been established, but important gaps in coverage remain. ADE identification gaps contribute to suboptimal and inefficient event identification. To address the ADE identification problem, a gap assessment was completed with the creation of a proposed comprehensive ontology using a Minimal Clinical Data Set framework incorporating existing identification approaches, clinical literature and a large set of inpatient clinical data. The new ontology was developed and tested using the National Inpatient Sample database with the validation results demonstrating expanded ADE identification capacity. In addition, the newly proposed ontology elements are noted to have significant inpatient mortality, above median inpatient costs and a longer length of stay when compared to existing ADE ontology elements and patients without ADE exposure.

  19. Adverse Drug Event Ontology: Gap Analysis for Clinical Surveillance Application

    PubMed Central

    Adam, Terrence J.; Wang, Jin

    2015-01-01

    Adverse drug event identification and management are an important patient safety problem given the potential for event prevention. Previous efforts to provide structured data methods for population level identification of adverse drug events have been established, but important gaps in coverage remain. ADE identification gaps contribute to suboptimal and inefficient event identification. To address the ADE identification problem, a gap assessment was completed with the creation of a proposed comprehensive ontology using a Minimal Clinical Data Set framework incorporating existing identification approaches, clinical literature and a large set of inpatient clinical data. The new ontology was developed and tested using the National Inpatient Sample database with the validation results demonstrating expanded ADE identification capacity. In addition, the newly proposed ontology elements are noted to have significant inpatient mortality, above median inpatient costs and a longer length of stay when compared to existing ADE ontology elements and patients without ADE exposure. PMID:26306223

  20. (R)-[11C]PK11195 brain uptake as a biomarker of inflammation and antiepileptic drug resistance: evaluation in a rat epilepsy model.

    PubMed

    Bogdanović, Renée Marie; Syvänen, Stina; Michler, Christina; Russmann, Vera; Eriksson, Jonas; Windhorst, Albert D; Lammertsma, Adriaan A; de Lange, Elisabeth C; Voskuyl, Rob A; Potschka, Heidrun

    2014-10-01

    Neuroinflammation has been suggested as a key determinant of the intrinsic severity of epilepsy. Glial cell activation and associated inflammatory signaling can influence seizure thresholds as well as the pharmacodynamics and pharmacokinetics of antiepileptic drugs. Based on these data, we hypothesized that molecular imaging of microglia activation might serve as a tool to predict drug refractoriness of epilepsy. Brain uptake of (R)-[11C]PK11195, a ligand of the translocator protein 18 kDa and molecular marker of microglia activation, was studied in a chronic model of temporal lobe epilepsy in rats with selection of phenobarbital responders and non-responders. In rats with drug-sensitive epilepsy, (R)-[11C]PK11195 brain uptake values were comparable to those in non-epileptic controls. Analysis in non-responders revealed enhanced brain uptake of up to 39% in different brain regions. The difference might be related to the fact that non-responders exhibited higher baseline seizure frequencies than responders indicating a more pronounced intrinsic disease severity. In hippocampal sections, ED1 immunostaining argued against a general difference in microglia activation between both groups. Our data suggest that TSPO PET imaging might serve as a biomarker for drug resistance in temporal lobe epilepsy. However, it needs to be considered that our findings indicate that the TSPO PET data might merely reflect seizure frequency. Future experimental and clinical studies should further evaluate the validity of TSPO PET data to predict the response to phenobarbital and other antiepileptic drugs in longitudinal studies with scanning before drug exposure and with a focus on the early phase following an epileptogenic brain insult.

  1. [Interactions and adverse drug reactions: how to obtain information].

    PubMed

    Fattinger, K E

    1999-04-15

    Adverse drug reactions (ADR) are common. They may mimick many other diseases. It is therefore important to consider always ADR as possible causes for new complaints. Interactions are less common but they may also be the source of serious problems. First informations on both topics are commonly found in the Swiss Drug Compendium ("Arzneimittel-Kompendium der Schweiz") and in the accompanying "Grundlagen der Pharmakotherapie". Further information is found in several standard text books, on new substances eventually also via the internet. Rare side-effects require a Medline-search or eventually consultation of the WHO-database on ADR. Several institutions in Switzerland provide information on ADR (an index is found in an annex of the "Arzneimittel-Kompendium der Schweiz"). It is essential for drug safety monitoring that every physician communicates observation of ADR. PMID:10355337

  2. Factors affecting the development of adverse drug reactions (Review article)

    PubMed Central

    Alomar, Muaed Jamal

    2013-01-01

    Objectives To discuss the effect of certain factors on the occurrence of Adverse Drug Reactions (ADRs). Data Sources A systematic review of the literature in the period between 1991 and 2012 was made based on PubMed, the Cochrane database of systematic reviews, EMBASE and IDIS. Key words used were: medication error, adverse drug reaction, iatrogenic disease factors, ambulatory care, primary health care, side effects and treatment hazards. Summary Many factors play a crucial role in the occurrence of ADRs, some of these are patient related, drug related or socially related factors. Age for instance has a very critical impact on the occurrence of ADRs, both very young and very old patients are more vulnerable to these reactions than other age groups. Alcohol intake also has a crucial impact on ADRs. Other factors are gender, race, pregnancy, breast feeding, kidney problems, liver function, drug dose and frequency and many other factors. The effect of these factors on ADRs is well documented in the medical literature. Taking these factors into consideration during medical evaluation enables medical practitioners to choose the best drug regimen. Conclusion Many factors affect the occurrence of ADRs. Some of these factors can be changed like smoking or alcohol intake others cannot be changed like age, presence of other diseases or genetic factors. Understanding the different effects of these factors on ADRs enables healthcare professionals to choose the most appropriate medication for that particular patient. It also helps the healthcare professionals to give the best advice to patients. Pharmacogenomics is the most recent science which emphasizes the genetic predisposition of ADRs. This innovative science provides a new perspective in dealing with the decision making process of drug selection. PMID:24648818

  3. Methods and systems to detect adverse drug reactions in hospitals.

    PubMed

    Thürmann, P A

    2001-01-01

    Detection of adverse drug reactions (ADRs) in hospitals offers the chance to detect serious ADRs resulting in hospitalisation and ADRs occurring in hospitalised patients, i.e. patients with high comorbidity and receiving drugs that are administered only in hospitals. The most commonly applied methods involve stimulated spontaneous reporting of doctors and nurses, comprehensive collection by trained specialists and, more recently, computer-assisted approaches using routine data from hospital information systems. The different methods of ADR detection used result in different rates and types of ADRs and, consequently, in different drug classes being responsible for these ADRs. Another factor influencing the results of surveys is the interpretation of the term ADR, where some authors adhere to the strict definition of the World Health Organization and many others include intended and unintended poisoning as well as errors in prescribing and dispensing, thus referring to adverse drug events. Depending on the method used for screening of patients, a high number of possible ADRs and only few definite ADRs are found, or vice versa. These variations have to be taken into account when comparing the results of further analyses performed with these data. ADR rates and incidences in relation to the number of drugs prescribed or patients exposed have been calculated in only a few surveys and projects, and this interesting pharmacoepidemiological approach deserves further study. In addition, the pharmacoeconomic impact of ADRs, either resulting in hospitalisation or prolonging hospital stay, has been estimated using different approaches. However, a common standardised procedure for such calculations has not yet been defined. Although detection of ADRs in hospitals offers the opportunity to detect severe ADRs of newly approved drugs, these ADRs are still discovered by spontaneous reporting systems. The prospects offered by electronic hospital information systems as well as

  4. Patient stratification and identification of adverse event correlations in the space of 1190 drug related adverse events

    PubMed Central

    Roitmann, Eva; Eriksson, Robert; Brunak, Søren

    2014-01-01

    Purpose: New pharmacovigilance methods are needed as a consequence of the morbidity caused by drugs. We exploit fine-grained drug related adverse event information extracted by text mining from electronic medical records (EMRs) to stratify patients based on their adverse events and to determine adverse event co-occurrences. Methods: We analyzed the similarity of adverse event profiles of 2347 patients extracted from EMRs from a mental health center in Denmark. The patients were clustered based on their adverse event profiles and the similarities were presented as a network. The set of adverse events in each main patient cluster was evaluated. Co-occurrences of adverse events in patients (p-value < 0.01) were identified and presented as well. Results: We found that each cluster of patients typically had a most distinguishing adverse event. Examination of the co-occurrences of adverse events in patients led to the identification of potentially interesting adverse event correlations that may be further investigated as well as provide further patient stratification opportunities. Conclusions: We have demonstrated the feasibility of a novel approach in pharmacovigilance to stratify patients based on fine-grained adverse event profiles, which also makes it possible to identify adverse event correlations. Used on larger data sets, this data-driven method has the potential to reveal unknown patterns concerning adverse event occurrences. PMID:25249979

  5. Adverse drug reactions and drug-drug interactions with over-the-counter NSAIDs.

    PubMed

    Moore, Nicholas; Pollack, Charles; Butkerait, Paul

    2015-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen have a long history of safe and effective use as both prescription and over-the-counter (OTC) analgesics/antipyretics. The mechanism of action of all NSAIDs is through reversible inhibition of cyclooxygenase enzymes. Adverse drug reactions (ADRs) including gastrointestinal bleeding as well as cardiovascular and renal effects have been reported with NSAID use. In many cases, ADRs may occur because of drug-drug interactions (DDIs) between the NSAID and a concomitant medication. For example, DDIs have been reported when NSAIDs are coadministered with aspirin, alcohol, some antihypertensives, antidepressants, and other commonly used medications. Because of the pharmacologic nature of these interactions, there is a continuum of risk in that the potential for an ADR is dependent on total drug exposure. Therefore, consideration of dose and duration of NSAID use, as well as the type or class of comedication administered, is important when assessing potential risk for ADRs. Safety findings from clinical studies evaluating prescription-strength NSAIDs may not be directly applicable to OTC dosing. Health care providers can be instrumental in educating patients that using OTC NSAIDs at the lowest effective dose for the shortest required duration is vital to balancing efficacy and safety. This review discusses some of the most clinically relevant DDIs reported with NSAIDs based on major sites of ADRs and classes of medication, with a focus on OTC ibuprofen, for which the most data are available. PMID:26203254

  6. A prospective study of adverse drug reactions in hospitalized children

    PubMed Central

    Martínez-Mir, Inocencia; García-López, Mercedes; Palop, Vicente; Ferrer, José M; Rubio, Elena; Morales-Olivas, Francisco J

    1999-01-01

    Aims There are few publications of adverse drug reactions (ADRs) among paediatric patients, though ADR incidence is usually stated to be higher during the first year of life and in male patients. We have carried out a prospective study to assess the extent, pattern and profile risk for ADRs in hospitalized patients between 1 and 24 months of age. Methods An intensive events monitoring scheme was used. A total of 512 successive admissions to two medical paediatric wards (47 beds) were analysed. The hospital records were screened daily during two periods (summer, 105 days and winter, 99 days), and adverse clinical events observed were recorded. Results A total of 282 events were detected; of these, 112 were considered to be manifestations of ADRs. The cumulative incidence was 16.6%, no differences being observed between periods. Although there were no differences between patients under and over 12 months of age, risk was found to be significantly higher among girls compared with boys (RR = 1.66, 95% CI 1.03–2.52). The gastro-intestinal system was most frequently affected. The therapeutic group most commonly implicated was anti-infective drugs and vaccines (41.5%). The ADRs were mild or moderate in over 90% of cases. A consistent relationship was noted between the number of drugs administered and the incidence of ADRs. Conclusions Hospitalized patients exhibited an ADR risk profile that included female sex and the number of drugs administered. No particular age predisposition was observed. The most commonly prescribed drugs are those most often implicated in ADRs in paediatric patients. PMID:10383547

  7. Adverse drug reactions: a hospital pharmacy-based reporting scheme.

    PubMed

    Winstanley, P A; Irvin, L E; Smith, J C; Orme, M L; Breckenridge, A M

    1989-07-01

    A pharmacy-based adverse drug reaction (ADR) reporting scheme, using pharmacists, nurses and medical practitioners as initiators of reports, was set up at the end of 1984 in the Royal Liverpool Hospital in order to encourage reporting. New reports were inspected at weekly intervals by a staff pharmacist, and a clinical pharmacologist. Reports were forwarded to the Committee on Safety of Medicines if the reaction was considered to be serious by the clinicians, or the ADR team or involved 'black triangle' drugs. The total number of ADR reports was increased eightfold by the introduction of the scheme (from 14 in 1984 to 76, 102 and 94 in 1985, 1986 and 1987 respectively), and this rate of reporting has been sustained. PMID:2775609

  8. Exposure to rufinamide and risks of CNS adverse events in drug-resistant epilepsy: a meta-analysis of randomized, placebo-controlled trials

    PubMed Central

    Alsaad, Abdulaziz M S; Koren, Gideon

    2014-01-01

    Aim Epilepsy is a complex disease necessitating continuous development of new therapeutic strategies to encounter drug-resistant cases. Among new adjuvant antiepileptic drugs, rufinamide is structurally distinct from other antiepileptic drugs. It is used to treat partial-onset seizures and seizures associated with Lennox-Gastaut syndrome (LGS) in adult and children. To date, there has been no attempt to evaluate systematically the risks of adverse events with rufinamide. Methods We performed a quantitative risk analysis of central nervous system (CNS) adverse events of rufinamide from all randomized, double-blind, add-on, placebo-controlled trials. The meta-analysis was undertaken with fixed effects models. Results Of the 886 publications reviewed, 99 papers were retrieved and five articles met the inclusion criteria. One thousand two hundred and fifty-two patients were included. Our study showed that exposure to rufinamide was associated with a significant increase in risk of somnolence [relative ratio (RR) 1.87; 95% confidence interval (CI) 1.33, 2.62; P = 0.0003], dizziness (RR 2.66; 95% CI 2.00, 3.55; P = 0.00001), fatigue (RR 2.14; 95% CI 1.57, 2.91; P = 0.01) and headache (RR 1.28; 95% CI 1.02, 1.59, P = 0.03). In addition, exposure to rufinamide was associated with higher treatment discontinuation rates as compared with placebo (RR 2.65; 95% CI 1.74, 4.03; P = 0.00001). Conclusions The risk of CNS adverse events appears to be increased in patients exposed to rufinamide as well as the treatment discontinuation rates. However, although statistical associations were significant, additional long term safety studies are required to confirm the clinical significance of these findings, as most reports described only mild and moderate adverse events. PMID:25132372

  9. The multinational drug companies in Zaire: their adverse effect on cost and availability of essential drugs.

    PubMed

    Glucksberg, H; Singer, J

    1982-01-01

    An analysis of the types and costs of drugs imported by seven multinational pharmaceutical companies in Zaire, an underdeveloped country in Africa, reveals that three-fourths of the drugs consisted of expensive and nonessential items. The prices of essential drugs (24 percent of their total imports) were much higher than those of available generic sources (average difference of 300 percent). The importation of nonessential drugs and high prices paid for essential drugs exacerbate the scarcity of needed items because of Zaire's limited supply of hard currency. In addition, two drug firms imported and promoted the sale of aminopyrone-dipyrone analgesic-antipyretics, drugs now rarely used in Western industrialized countries because of potentially fatal complications. Thus, in Zaire, the multinational pharmaceutical industry has an adverse effect on the availability and cost of drugs, as well as on the pattern of drug usage.

  10. Antimicrobial resistance: consideration as an adverse drug event.

    PubMed

    Martin, Steven J; Micek, Scott T; Wood, G Christopher

    2010-06-01

    Antimicrobial resistance has increased dramatically in the past 15 to 20 yrs and presents a patient safety concern unlike any other in the intensive care unit. Antimicrobial resistance in critically ill patients increases morbidity, mortality, length of hospital stay, and healthcare costs. Some organisms may have intrinsically high levels of resistance or may be spread between patients by poor infection control practices. However, a major driver of antimicrobial resistance is antibiotic use. As such, the development of antimicrobial resistance can often be thought of as an adverse drug event. This article explores the link between drug use, drug dosing, other selective pressures and resistance, and describes concepts to minimize the negative impact of antimicrobial therapy. Two broad themes of these concepts are minimizing the use of antibiotics whenever possible and optimizing antibiotic usage when they are needed. Strategies for minimizing the use of antimicrobials include using optimal diagnostic procedures to ensure the need for antimicrobials, streamlining or discontinuing therapy when possible based on culture results, and using the shortest duration of therapy needed for documented infections. Strategies for optimizing antimicrobial use include using optimal dosing based on the manufacturer's instructions and current pharmacodynamic data, guiding better prescribing based on local susceptibility patterns and formulary restriction, and avoiding drugs with more propensity to foster resistance.

  11. Predicting risk of adverse drug reactions in older adults

    PubMed Central

    Lavan, Amanda Hanora; Gallagher, Paul

    2016-01-01

    Adverse drug reactions (ADRs) are common in older adults, with falls, orthostatic hypotension, delirium, renal failure, gastrointestinal and intracranial bleeding being amongst the most common clinical manifestations. ADR risk increases with age-related changes in pharmacokinetics and pharmacodynamics, increasing burden of comorbidity, polypharmacy, inappropriate prescribing and suboptimal monitoring of drugs. ADRs are a preventable cause of harm to patients and an unnecessary waste of healthcare resources. Several ADR risk tools exist but none has sufficient predictive value for clinical practice. Good clinical practice for detecting and predicting ADRs in vulnerable patients includes detailed documentation and regular review of prescribed and over-the-counter medications through standardized medication reconciliation. New medications should be prescribed cautiously with clear therapeutic goals and recognition of the impact a drug can have on multiple organ systems. Prescribers should regularly review medication efficacy and be vigilant for ADRs and their contributory risk factors. Deprescribing should occur at an individual level when drugs are no longer efficacious or beneficial or when safer alternatives exist. Inappropriate prescribing and unnecessary polypharmacy should be minimized. Comprehensive geriatric assessment and the use of explicit prescribing criteria can be useful in this regard. PMID:26834959

  12. Treatment of cardiac arrhythmias in a mouse model of Rett syndrome with Na+-channel-blocking antiepileptic drugs.

    PubMed

    Herrera, José A; Ward, Christopher S; Pitcher, Meagan R; Percy, Alan K; Skinner, Steven; Kaufmann, Walter E; Glaze, Daniel G; Wehrens, Xander H T; Neul, Jeffrey L

    2015-04-01

    One quarter of deaths associated with Rett syndrome (RTT), an X-linked neurodevelopmental disorder, are sudden and unexpected. RTT is associated with prolonged QTc interval (LQT), and LQT-associated cardiac arrhythmias are a potential cause of unexpected death. The standard of care for LQT in RTT is treatment with β-adrenergic antagonists; however, recent work indicates that acute treatment of mice with RTT with a β-antagonist, propranolol, does not prevent lethal arrhythmias. In contrast, acute treatment with the Na(+) channel blocker phenytoin prevented arrhythmias. Chronic dosing of propranolol may be required for efficacy; therefore, we tested the efficacy of chronic treatment with either propranolol or phenytoin on RTT mice. Phenytoin completely abolished arrhythmias, whereas propranolol showed no benefit. Surprisingly, phenytoin also normalized weight and activity, but worsened breathing patterns. To explore the role of Na(+) channel blockers on QT in people with RTT, we performed a retrospective analysis of QT status before and after Na(+) channel blocker antiepileptic therapies. Individuals with RTT and LQT significantly improved their QT interval status after being started on Na(+) channel blocker antiepileptic therapies. Thus, Na(+) channel blockers should be considered for the clinical management of LQT in individuals with RTT.

  13. N-alkylprotoporphyrin formation and hepatic porphyria in dogs after administration of a new antiepileptic drug candidate: mechanism and species specificity.

    PubMed

    Nicolas, Jean-Marie; Chanteux, Hugues; Mancel, Valérie; Dubin, Guy-Marie; Gerin, Brigitte; Staelens, Ludovicus; Depelchin, Olympe; Kervyn, Sophie

    2014-10-01

    A new antiepileptic synaptic vesicle 2a (SV2a) ligand drug candidate was tested in 4-week oral toxicity studies in rat and dog. Brown pigment inclusions were found in the liver of high-dose dogs. The morphology of the deposits and the accompanying liver changes (increased plasma liver enzymes, increased total hepatic porphyrin level, decreased liver ferrochelatase activity, combined induction, and inactivation of cytochrome P-450 CYP2B11) suggested disruption of the heme biosynthetic cascade. None of these changes was seen in rat although this species was exposed to higher parent drug levels. Toxicokinetic analysis and in vitro metabolism assays in hepatocytes showed that dog is more prone to oxidize the drug candidate than rat. Mass spectrometry analysis of liver samples from treated dogs revealed an N-alkylprotoporphyrin adduct. The elucidation of its chemical structure suggested that the drug transforms into a reactive metabolite which is structurally related to a known reference porphyrogenic agent allylisopropylacetamide. That particular metabolite, primarily produced in dog but neither in rat nor in human, has the potential to alkylate the prosthetic heme of CYP. Overall, the data suggested that the drug candidate should not be porphyrogenic in human. This case study further exemplifies the species variability in the susceptibility to drug-induced porphyria.

  14. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase

    PubMed Central

    Ferrajolo, Carmen; Capuano, Annalisa; Verhamme, Katia M C; Schuemie, Martijn; Rossi, Francesco; Stricker, Bruno H; Sturkenboom, Miriam C J M

    2010-01-01

    AIM To identify which drugs are associated with reports of suspected hepatic injury in children and adolescents. METHODS Using a worldwide pharmacovigilance database, VigiBase, we conducted a case/non-case study on suspected adverse drug reactions (ADRs) occurring in the population <18 years old. Cases were all the records with hepatic ADRs and non-cases were all the other ADR records. Records regarding topically administered drugs were excluded from both groups. The association between drug and suspected hepatic ADRs was calculated using the reporting odds ratio (ROR) as a measure of disproportionality while adjusting for gender, country, reporter and calendar year. Sub-analyses were performed within therapeutic class and by excluding vaccination-related reports to reduce confounding. RESULTS Overall, 6595 (1%) out of 624 673 ADR records in children and adolescents concerned hepatic injury. Most of the reported hepatic injuries concerned children 12–17 years of age. Drugs that were most frequently reported as suspected cause and were associated with hepatic injury comprised paracetamol, valproic acid, carbamazepine, methotrexate, minocycline, zidovudine, pemoline, ceftriaxone, bosentan, ciclosporin, atomoxetine, olanzapine, basiliximab, erythromycin and voriconazole. The association between hepatotoxicity and all these drugs, except for basiliximab, is already known. CONCLUSIONS Drug-induced hepatic injury is infrequently reported (only 1% of total) as a suspected ADR in children and adolescents. The drugs associated with reported hepatotoxicity (paracetamol, antiepileptic and anti-tuberculosis agents) are known to be hepatotoxic in adults as well, but age related changes in associations were observed. VigiBase is useful as a start to plan further drug safety studies in children. PMID:21039766

  15. Adverse Drug Events caused by Serious Medication Administration Errors

    PubMed Central

    Sawarkar, Abhivyakti; Keohane, Carol A.; Maviglia, Saverio; Gandhi, Tejal K; Poon, Eric G

    2013-01-01

    OBJECTIVE To determine how often serious or life-threatening medication administration errors with the potential to cause patient harm (or potential adverse drug events) result in actual patient harm (or adverse drug events (ADEs)) in the hospital setting. DESIGN Retrospective chart review of clinical events that transpired following observed medication administration errors. BACKGROUND Medication errors are common at the medication administration stage for hospitalized patients. While many of these errors are considered capable of causing patient harm, it is not clear how often patients are actually harmed by these errors. METHODS In a previous study where 14,041 medication administrations in an acute-care hospital were directly observed, investigators discovered 1271 medication administration errors, of which 133 had the potential to cause serious or life-threatening harm to patients and were considered serious or life-threatening potential ADEs. In the current study, clinical reviewers conducted detailed chart reviews of cases where a serious or life-threatening potential ADE occurred to determine if an actual ADE developed following the potential ADE. Reviewers further assessed the severity of the ADE and attribution to the administration error. RESULTS Ten (7.5% [95% C.I. 6.98, 8.01]) actual adverse drug events or ADEs resulted from the 133 serious and life-threatening potential ADEs, of which 6 resulted in significant, three in serious, and one life threatening injury. Therefore 4 (3% [95% C.I. 2.12, 3.6]) serious and life threatening potential ADEs led to serious or life threatening ADEs. Half of the ten actual ADEs were caused by dosage or monitoring errors for anti-hypertensives. The life threatening ADE was caused by an error that was both a transcription and a timing error. CONCLUSION Potential ADEs at the medication administration stage can cause serious patient harm. Given previous estimates of serious or life-threatening potential ADE of 1.33 per 100

  16. An overview on adverse drug reactions to traditional Chinese medicines.

    PubMed

    Chan, Kelvin; Zhang, Hongwei; Lin, Zhi-Xiu

    2015-10-01

    The safe use of Chinese materia medica (CMM) and products in traditional Chinese medicine (TCM) practice conventionally relies on correct pharmacognostic identification, good agricultural and manufacturing practices based on pharmacopoeia standards and rational/correct CMM combinations with TCM-guided clinical prescribing. These experience-based principles may not absolutely ensure safety without careful toxicological investigations when compared with development of new pharmaceutical drugs. Clinically observed toxicity reports remain as guidance for gathering toxicological evidence, though essential as pharmacovigilance, but are considered as late events for ensuring safety. The overview focuses on the following factors: global development of TCM that has affected conventional healthcare; examples of key toxic substances in CMM; reported adverse drug reactions (ADRs) consequential to taking CMM and TCM products; and proposals on rational approaches to integrate the knowledge of biomedical science and the principles of TCM practice for detecting early ADRs if both TCM products and orthodox drugs are involved. It is envisaged that good control of the quality and standards of CMM and proprietary Chinese medicines can certainly reduce the incidence of ADRs in TCM practice when these medications are used.

  17. An overview on adverse drug reactions to traditional Chinese medicines

    PubMed Central

    Chan, Kelvin; Zhang, Hongwei; Lin, Zhi-Xiu

    2015-01-01

    The safe use of Chinese materia medica (CMM) and products in traditional Chinese medicine (TCM) practice conventionally relies on correct pharmacognostic identification, good agricultural and manufacturing practices based on pharmacopoeia standards and rational/correct CMM combinations with TCM-guided clinical prescribing. These experience-based principles may not absolutely ensure safety without careful toxicological investigations when compared with development of new pharmaceutical drugs. Clinically observed toxicity reports remain as guidance for gathering toxicological evidence, though essential as pharmacovigilance, but are considered as late events for ensuring safety. The overview focuses on the following factors: global development of TCM that has affected conventional healthcare; examples of key toxic substances in CMM; reported adverse drug reactions (ADRs) consequential to taking CMM and TCM products; and proposals on rational approaches to integrate the knowledge of biomedical science and the principles of TCM practice for detecting early ADRs if both TCM products and orthodox drugs are involved. It is envisaged that good control of the quality and standards of CMM and proprietary Chinese medicines can certainly reduce the incidence of ADRs in TCM practice when these medications are used. PMID:25619530

  18. Adverse drug reactions to herbal and synthetic expectorants.

    PubMed

    Ernst, E; Sieder, C; März, R

    1995-01-01

    Our knowledge relating to adverse drug reactions (ADRs) of phytomedicines is highly fragmentary. The aim of this study was to define the prevalence of ADRs following medication with herbal or synthetic expectorants. In a multicentre, comparative post-marketing surveillance study of more than 3000 patients with acute bronchitis, about half were treated with a herbal remedy (SinupretR) and the other half with various other expectorants. In ascending order of incidence, ADRs were noted during mono-medication of SinupretR (0.8%), Ambroxol (1.0%) and acetylcysteine (4.3%). When concomitant drugs were used, this rank order was unchanged but incidence rates were markedly increased (3.4, 6.5 and 8.2%, respectively). The most frequent ADRs were gastrointestinal symptoms. It is concluded that expectorants are associated with ADRs in roughly 1-5% of cases undergoing single drug treatment and in 3-10% when more than one medication is being used. Amongst the expectorants used in this study, the herbal preparation SinupretR is associated with the lowest incidence of ADRs.

  19. Adverse drug reactions in older people: detection and prevention.

    PubMed

    Petrovic, Mirko; van der Cammen, Tischa; Onder, Graziano

    2012-06-01

    Adverse drug reactions (ADRs) in older adults are an important healthcare problem since they are frequently a cause of hospitalization, occur commonly during admission, and are an important cause of morbidity and mortality. Older adults are particularly susceptible to ADRs because they are usually on multiple drug regimens and because age is associated with changes in pharmacokinetics and pharmacodynamics. The presentation of an ADR in older adults is often atypical, which further complicates its recognition. One potential strategy for improving recognition of ADRs is to identify those patients who are at risk of an ADR. The recently developed GerontoNet ADR Risk Score is a practical tool for identification of older patients who are at increased risk for an ADR and who may represent a target for interventions aimed at reducing ADRs. Provision of adequate education in the domain of clinical geriatric pharmacology can improve recognition of ADRs. Besides formal surveillance systems, built-in computer programs with electronic prescribing databases and clinical pharmacist involvement in patient care within multidisciplinary geriatric teams might help to minimize the occurrence of ADRs. In addition, a number of actions can be taken in hospitals to stimulate appropriate prescribing and to assure adequate communication between primary and hospital care. In older adults with complex medical problems and needs, a global evaluation obtained through a comprehensive geriatric assessment may be helpful in simplifying drug prescription and prioritizing pharmacological and healthcare needs, resulting in an improvement in quality of prescribing. PMID:22642780

  20. An overview on adverse drug reactions to traditional Chinese medicines.

    PubMed

    Chan, Kelvin; Zhang, Hongwei; Lin, Zhi-Xiu

    2015-10-01

    The safe use of Chinese materia medica (CMM) and products in traditional Chinese medicine (TCM) practice conventionally relies on correct pharmacognostic identification, good agricultural and manufacturing practices based on pharmacopoeia standards and rational/correct CMM combinations with TCM-guided clinical prescribing. These experience-based principles may not absolutely ensure safety without careful toxicological investigations when compared with development of new pharmaceutical drugs. Clinically observed toxicity reports remain as guidance for gathering toxicological evidence, though essential as pharmacovigilance, but are considered as late events for ensuring safety. The overview focuses on the following factors: global development of TCM that has affected conventional healthcare; examples of key toxic substances in CMM; reported adverse drug reactions (ADRs) consequential to taking CMM and TCM products; and proposals on rational approaches to integrate the knowledge of biomedical science and the principles of TCM practice for detecting early ADRs if both TCM products and orthodox drugs are involved. It is envisaged that good control of the quality and standards of CMM and proprietary Chinese medicines can certainly reduce the incidence of ADRs in TCM practice when these medications are used. PMID:25619530

  1. Targeting γ-aminobutyric acid (GABA) carriers to the brain: potential relevance as antiepileptic pro-drugs.

    PubMed

    Semreen, Mohammad H; El-Shorbagi, Abdel-Nasser; Al-Tel, Taleb H; Alsalahat, Izzeddin M M

    2010-05-01

    The search for antiepileptic compounds with more selective activity continues to be an area of intensive investigation in medicinal chemistry. 3,5-Disubstituted tetrahydro-2H-1,3,5-thiadiazine-2-thione (THTT) derivatives, 3a-g, potential prodrugs incorporating the neurotransmitter GABA were synthesized and studied for crossing the blood-brain barrier (BBB). Compounds were prepared from primary amines and carbon disulfide to give dithiocarbamates 2a-g which upon reaction in situ with formaldehyde provided the intermediates Ia-g. Addition of Ia-g onto GABA furnished the title compounds 3a-g. The structures were verified by spectral data and the amounts of the compounds in the brain were investigated by using HPLC. The concentration profiles of the tested compounds in mice brain were determined and the in vivo anticonvulsant activity was measured. PMID:20632978

  2. N-valproyl-L-phenylalanine as new potential antiepileptic drug: synthesis, characterization and in vitro studies on stability, toxicity and anticonvulsant efficacy.

    PubMed

    De Caro, Viviana; Scaturro, Anna Lisa; Sutera, Flavia Maria; Avellone, Giuseppe; Schiera, Gabriella; Ferrantelli, Evelina; Carafa, Maria; Rizzo, Valerio; Carletti, Fabio; Sardo, Pierangelo; Giannola, Libero Italo

    2014-01-01

    Valproic acid (VPA) is considered first-line drug in treatment of generalized idiopathic seizures such as absence, generalized tonic-clonic and myoclonic seizures. Among major antiepileptic drugs, VPA is also considered effective in childhood epilepsies and infantile spasms. Due to its broad activity, VPA acts as a mood stabilizer in bipolar disorder and it is useful in migraine prophylaxis. Despite its long-standing usage, severe reactions to VPA, such as liver toxicity and teratogenicity, are reported. To circumvent side effects due to structural characteristics of VPA, we synthesized in good yield a new VPA-aminoacid conjugate, the N-valproyl-L-Phenylalanine, and characterized by FT-IR, MS, (13)C and (1)H- NMR analyses. The Log D(pH7.4) value (0.19) indicated that new molecule was potentially able to cross biological membranes. The resistance to chemical and enzymatic hydrolysis of N-valproyl-L-phenylalanine was also assessed. All trials suggested that the compound, at the pH conditions of the entire gastro-intestinal tract, remained unmodified. Furthermore, the new compound did not undergo enzymatic cleavage both in plasma and in cerebral medium up to 24 h. The toxicity assay on primary cultures of astrocytes indicated that the synthetized conjugate was less toxic than both free VPA and L-Phenylalanine. In this paper, the anticonvulsant activity of the new compound against epileptic burst discharges evoked in vitro in rat hippocampal slices was also evaluated. These preliminary results underline that N-valproyl-L-phenylalanine as new potential antiepileptic agent could represent a good candidate to further investigations.

  3. Knowledge and attitudes to reporting adverse drug reactions.

    PubMed

    Pulford, Andrew; Malcolm, William

    The reporting of adverse drug reactions (ADRs) by health professionals forms an important component of ongoing surveillance of post-marketing drug safety. The extension of responsibility for all health professionals to report ADRs has coincided with national immunization programmes, such as the national childhood immunization, human papillomavirus (HPV), and seasonal and H1N1 influenza programmes. The study objective was to evaluate knowledge of, and attitudes to, reporting ADRs among the professional groups most likely to see suspected reactions to vaccines. This included nursing professionals, whose views have not been included in previous studies. A survey of 91 practice nurses, health visitors, school nurses and GPs working in Ayrshire and Arran during June, July and August 2007 was undertaken. The respondents' knowledge of ADR reporting varied considerably. Although the majority of respondents recognized that it is the responsibility of health professionals to report suspected ADRs, there were lower levels of knowledge about the purpose of the Yellow Card system specifically; less than 50% of the respondents reported good knowledge about the system. The study suggests implications for practice with regard to the implementation of large-scale immunization programmes and potential solutions to under-reporting among these professional groups.

  4. Pharmacovigilance on twitter? Mining tweets for adverse drug reactions.

    PubMed

    O'Connor, Karen; Pimpalkhute, Pranoti; Nikfarjam, Azadeh; Ginn, Rachel; Smith, Karen L; Gonzalez, Graciela

    2014-01-01

    Recent research has shown that Twitter data analytics can have broad implications on public health research. However, its value for pharmacovigilance has been scantly studied - with health related forums and community support groups preferred for the task. We present a systematic study of tweets collected for 74 drugs to assess their value as sources of potential signals for adverse drug reactions (ADRs). We created an annotated corpus of 10,822 tweets. Each tweet was annotated for the presence or absence of ADR mentions, with the span and Unified Medical Language System (UMLS) concept ID noted for each ADR present. Using Cohen's kappa1, we calculated the inter-annotator agreement (IAA) for the binary annotations to be 0.69. To demonstrate the utility of the corpus, we attempted a lexicon-based approach for concept extraction, with promising success (54.1% precision, 62.1% recall, and 57.8% F-measure). A subset of the corpus is freely available at: http://diego.asu.edu/downloads.

  5. Pharmacovigilance on twitter? Mining tweets for adverse drug reactions.

    PubMed

    O'Connor, Karen; Pimpalkhute, Pranoti; Nikfarjam, Azadeh; Ginn, Rachel; Smith, Karen L; Gonzalez, Graciela

    2014-01-01

    Recent research has shown that Twitter data analytics can have broad implications on public health research. However, its value for pharmacovigilance has been scantly studied - with health related forums and community support groups preferred for the task. We present a systematic study of tweets collected for 74 drugs to assess their value as sources of potential signals for adverse drug reactions (ADRs). We created an annotated corpus of 10,822 tweets. Each tweet was annotated for the presence or absence of ADR mentions, with the span and Unified Medical Language System (UMLS) concept ID noted for each ADR present. Using Cohen's kappa1, we calculated the inter-annotator agreement (IAA) for the binary annotations to be 0.69. To demonstrate the utility of the corpus, we attempted a lexicon-based approach for concept extraction, with promising success (54.1% precision, 62.1% recall, and 57.8% F-measure). A subset of the corpus is freely available at: http://diego.asu.edu/downloads. PMID:25954400

  6. Successful Drug Development Despite Adverse Preclinical Findings Part 2: Examples

    PubMed Central

    Kuroda, Junji; Plassmann, Stephanie; Hayashi, Makoto; Prentice, David E.

    2010-01-01

    To illustrate the process of addressing adverse preclinical findings (APFs) as outlined in the first part of this review, a number of cases with unexpected APF in toxicity studies with drug candidates is discussed in this second part. The emphasis is on risk characterization, especially regarding the mode of action (MoA), and risk evaluation regarding relevance for man. While severe APFs such as retinal toxicity may turn out to be of little human relevance, minor findings particularly in early toxicity studies, such as vasculitis, may later pose a real problem. Rodents are imperfect models for endocrine APFs, non-rodents for human cardiac effects. Liver and kidney toxicities are frequent, but they can often be monitored in man and do not necessarily result in early termination of drug candidates. Novel findings such as the unusual lesions in the gastrointestinal tract and the bones presented in this review can be difficult to explain. It will be shown that well known issues such as phospholipidosis and carcinogenicity by agonists of peroxisome proliferator-activated receptors (PPAR) need to be evaluated on a case-by-case basis. The latter is of particular interest because the new PPAR α and dual α/γ agonists resulted in a change of the safety paradigm established with the older PPAR α agonists. General toxicologists and pathologists need some understanding of the principles of genotoxicity and reproductive toxicity testing. Both types of preclinical toxicities are major APF and clinical monitoring is difficult, generally leading to permanent use restrictions. PMID:22272032

  7. Evaluation of outpatient adverse drug reactions leading to hospitalization.

    PubMed

    Wu, Wenchen Kenneth; Pantaleo, Nicholas

    2003-02-01

    Outpatient adverse drug reaction (ADR)related hospitalization through the emergency department of a nonprofit hospital and the contributing factors are reviewed. Patients who were hospitalized because of suspected ADRs were selected from daily admissions reports and patient medication profiles from 1997 and 1998 by the pharmacy department of a nonprofit community teaching hospital. Hospital charges for individual patients were obtained from the institution's accounting system. Suspected drugs, their therapeutic class, and the organ systems involved in the ADRs were identified. A total of 191 patients who had a complete medical history and cost information were included in the study. Of those patients, 56% were female, and 45% of the patients were 75 years of older. The average hospital charge per ADR patient was $9491. Room and board accounted for more than 50% of total charges. The average length of stay for study patients was 8.0 +/- 10.3 days. Major therapeutic classes implicated in ADRs included antidiabetic agents (27.8%), anticoagulants (15.2%), anticonvulsants (10.0%), beta-blockers (7.9%), and angiotensin-converting-enzyme inhibitors (7.9%). Organ systems most commonly involved in ADR admissions were the endocrine (30.9%) and cardiovascular (24.1%) systems. The implicationed therapeutic groups and organ systems exhibited a different pattern from those of earlier ADR studies. The elderly and the poor are most affected by ADRs. The availability of new drugs and the shift in disease treatment necessitate the continuous monitoring of new ADRs. Patients and family members should be integral components of a multidisciplinary strategy for minimizing the personal and social impact of ADRs.

  8. Adverse Drug Reactions Causing Admission to Medical Wards

    PubMed Central

    Mouton, Johannes P.; Njuguna, Christine; Kramer, Nicole; Stewart, Annemie; Mehta, Ushma; Blockman, Marc; Fortuin-De Smidt, Melony; De Waal, Reneé; Parrish, Andy G.; Wilson, Douglas P.K.; Igumbor, Ehimario U.; Aynalem, Getahun; Dheda, Mukesh; Maartens, Gary; Cohen, Karen

    2016-01-01

    Abstract Limited data exist on the burden of serious adverse drug reactions (ADRs) in sub-Saharan Africa, which has high HIV and tuberculosis prevalence. We determined the proportion of adult admissions attributable to ADRs at 4 hospitals in South Africa. We characterized drugs implicated in, risk factors for, and the preventability of ADR-related admissions. We prospectively followed patients admitted to 4 hospitals’ medical wards over sequential 30-day periods in 2013 and identified suspected ADRs with the aid of a trigger tool. A multidisciplinary team performed causality, preventability, and severity assessment using published criteria. We categorized an admission as ADR-related if the ADR was the primary reason for admission. There were 1951 admissions involving 1904 patients: median age was 50 years (interquartile range 34–65), 1057 of 1904 (56%) were female, 559 of 1904 (29%) were HIV-infected, and 183 of 1904 (10%) were on antituberculosis therapy (ATT). There were 164 of 1951 (8.4%) ADR-related admissions. After adjustment for age and ATT, ADR-related admission was independently associated (P ≤ 0.02) with female sex (adjusted odds ratio [aOR] 1.51, 95% confidence interval [95% CI] 1.06–2.14), increasing drug count (aOR 1.14 per additional drug, 95% CI 1.09–1.20), increasing comorbidity score (aOR 1.23 per additional point, 95% CI 1.07–1.41), and use of antiretroviral therapy (ART) if HIV-infected (aOR 1.92 compared with HIV-negative/unknown, 95% CI 1.17–3.14). The most common ADRs were renal impairment, hypoglycemia, liver injury, and hemorrhage. Tenofovir disoproxil fumarate, insulin, rifampicin, and warfarin were most commonly implicated, respectively, in these 4 ADRs. ART, ATT, and/or co-trimoxazole were implicated in 56 of 164 (34%) ADR-related admissions. Seventy-three of 164 (45%) ADRs were assessed as preventable. In our survey, approximately 1 in 12 admissions was because of an ADR. The range of ADRs and implicated drugs reflect

  9. A curated and standardized adverse drug event resource to accelerate drug safety research

    PubMed Central

    Banda, Juan M.; Evans, Lee; Vanguri, Rami S.; Tatonetti, Nicholas P.; Ryan, Patrick B.; Shah, Nigam H.

    2016-01-01

    Identification of adverse drug reactions (ADRs) during the post-marketing phase is one of the most important goals of drug safety surveillance. Spontaneous reporting systems (SRS) data, which are the mainstay of traditional drug safety surveillance, are used for hypothesis generation and to validate the newer approaches. The publicly available US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data requires substantial curation before they can be used appropriately, and applying different strategies for data cleaning and normalization can have material impact on analysis results. We provide a curated and standardized version of FAERS removing duplicate case records, applying standardized vocabularies with drug names mapped to RxNorm concepts and outcomes mapped to SNOMED-CT concepts, and pre-computed summary statistics about drug-outcome relationships for general consumption. This publicly available resource, along with the source code, will accelerate drug safety research by reducing the amount of time spent performing data management on the source FAERS reports, improving the quality of the underlying data, and enabling standardized analyses using common vocabularies. PMID:27193236

  10. A curated and standardized adverse drug event resource to accelerate drug safety research.

    PubMed

    Banda, Juan M; Evans, Lee; Vanguri, Rami S; Tatonetti, Nicholas P; Ryan, Patrick B; Shah, Nigam H

    2016-01-01

    Identification of adverse drug reactions (ADRs) during the post-marketing phase is one of the most important goals of drug safety surveillance. Spontaneous reporting systems (SRS) data, which are the mainstay of traditional drug safety surveillance, are used for hypothesis generation and to validate the newer approaches. The publicly available US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data requires substantial curation before they can be used appropriately, and applying different strategies for data cleaning and normalization can have material impact on analysis results. We provide a curated and standardized version of FAERS removing duplicate case records, applying standardized vocabularies with drug names mapped to RxNorm concepts and outcomes mapped to SNOMED-CT concepts, and pre-computed summary statistics about drug-outcome relationships for general consumption. This publicly available resource, along with the source code, will accelerate drug safety research by reducing the amount of time spent performing data management on the source FAERS reports, improving the quality of the underlying data, and enabling standardized analyses using common vocabularies. PMID:27193236

  11. Teratogenicity of Antiepileptic Medications

    PubMed Central

    Kluger, Benzi M.; Meador, Kimford J.

    2009-01-01

    Antiepileptic drugs (AEDs) are frequently used to treat several conditions that are common in women of childbearing age, including epilepsy, headaches, and mood disorders. Moreover, as in the case of epilepsy and severe psychiatric disease, clinicians frequently do not have the option of stopping these medications or switching to another class of drugs. Overall, AEDs have been associated with an increased risk of major congenital malformations, minor anomalies, specific congenital syndromes, and developmental disorders seen in childhood. However, the differential effects of individual AEDs remain uncertain. Data are accumulating which strongly suggest that these risks are highest in patients receiving polypharmacy and valproate. There is also modest evidence to suggest an increased risk for phenobarbital. While other older AEDs appear to carry some teratogenic risk, there is not adequate evidence to further stratify their risk. Clinical and basic science research regarding newer AEDs suggests equivalent, if not safer, profiles compared with older AEDs, but these data are inconclusive. Management of women with epilepsy should include a discussion of these risks, prophylactic treatment with folic acid, and the minimal use of polypharmacy and valproate needed to maintain optimum seizure control. PMID:18777479

  12. Adverse drug reactions to unlicensed and off-label drugs on paediatric wards: a prospective study.

    PubMed

    Turner, S; Nunn, A J; Fielding, K; Choonara, I

    1999-09-01

    To determine the incidence of adverse drug reactions (ADRs) to unlicensed and off-label drugs used in paediatric inpatients, we carried out prospective surveillance on five different paediatric wards in a regional children's hospital for 13 wk. Comparison of the use of each drug with its summary of product characteristics was made to determine whether the drug was used in an unlicensed or off-label manner. The presence of an ADR was determined using previously defined criteria. In total, 4455 courses of drugs were administered to 936 patients in 1046 admissions. In 507 (48%) of the 1046 admissions, patients received one or more unlicensed or off-label drugs. ADRs occurred in 116 (11%) of the 1046 patient admissions. ADRs were associated with 112 (3.9%) of the 2881 licensed drug prescriptions and 95 (6%) of the 1574 unlicensed or off-label drug prescriptions. Use of drugs in an off-label or unlicensed manner to treat children is widespread. ADRs are a significant problem following unlicensed or off-label drug prescriptions. PMID:10519338

  13. Core Concepts Involving Adverse Psychotropic Drug Effects: Assessment, Implications, and Management.

    PubMed

    Goldberg, Joseph F; Ernst, Carrie L

    2016-09-01

    Adverse effects from psychiatric drugs can profoundly influence treatment adherence and outcomes. Good care involves addressing adverse effects no differently than any other component of treatment. Knowledge about adverse effect assessment and management fosters a proper context that helps clinicians not sacrifice a drug's potential therapeutic benefits because of greater concerns about its tolerability. This article provides an overview of basic concepts related to the assessment and management of suspected adverse effects from psychotropic drugs. Key points are discussed regarding clinical, pharmacogenetic, pharmacokinetic, and pharmacodynamic risk factors for treatment-emergent adverse effects, alongside recommendations for their systematic assessment. PMID:27514295

  14. [Application analysis of adverse drug reaction terminology WHOART and MedDRA].

    PubMed

    Liu, Jing; Xie, Yan-ming; Gai, Guo-zhong; Liao, Xing

    2015-12-01

    Drug safety has always been a global focus. Discovery and accurate information acquisition of adverse drug reaction have been the most crucial concern. Terminology of adverse drug reaction makes adverse reaction medical report meaningful, standardized and accurate. This paper discussed the domestic use of the terminology WHOART and MedDRA in terms of content, structure, and application situation. It also analysed the differences between the two terminologies and discusses the future trend of application in our country PMID:27245013

  15. Perception of Nigerian medical students on adverse drug reaction reporting.

    PubMed

    Abubakar, Abdullahi Rabiu; Chedi, Bashir A Z; Mohammed, Khalid Garba; Haque, Mainul

    2015-01-01

    Spontaneous reporting (SPR) and intensive monitoring are the conventional systems used for detecting, recording, and reporting adverse drug reactions (ADRs). Using spontaneous reporting a lot of successes has been made as existing ADRs were identified and new ones prevented through this methods. The aim of this appraisal was to evaluate the knowledge, attitude, and the practice of medical students with regards to ADRs reporting and to see if differences exist between the level of study and genders. The questionnaire was adopted, modified, and validated from previous studies. It comprised of 25 questions. It was administered year-IV and V medical students of Bayero University Kano, Nigeria. The data collected were coded and analyzed using the Statistical Package for the Social Sciences (SPSS) version 20, currently known as IBM SPSS Statistics. The response rate was 74%. Among the 108 participants, 80% got the definition of ADRs correct; 63% of them knew the precise functions of pharmacovigilance (PV). In addition, 82% strongly agreed that ADR reporting is health care workers responsibility; 82% also said PV should be taught in detail. Meanwhile, 99% have noticed patient experiencing ADRs; 67% said even mild ADRs should be reported. The outcome of this study showed good knowledge and attitude with respect to ADRs and PV among the medical students surveyed. Unfortunately, the practice of medical students was found to be unsatisfactory. There is a need to upgrade the students teaching the curriculum with respect to ADRs monitoring. PMID:26605155

  16. Nevirapine: Most Common Cause of Cutaneous Adverse Drug Reactions in an Outpatient Department of a Tertiary Care Hospital

    PubMed Central

    Pawar, Mayur Popat; Pore, Shraddha Milind; Pradhan, Shekhar Nana; Bhoi, Umesh Yedu; Ramanand, Sunita Jaiprakash

    2015-01-01

    Introduction Skin is the most commonly involved organ in adverse drug reactions. Most of the cutaneous adverse drug reactions (CADRs) being of mild to moderate severity are likely to be diagnosed and treated in an outpatient setting. Consequently, knowledge regarding morphological pattern, severity and drugs implicated in causation of these CADRs has important implications for healthcare personnel. Aim To determine the current clinical pattern of CADRs and to assess their causality and severity with the help of standard scales. Study design and setting A prospective, observational study was conducted in the outpatient department of skin and venereal disease in a tertiary care hospital. Materials and Methods Patients with suspected CADR after consumption of systemic drug(s) were enrolled in the study. Data regarding demographics, clinical manifestations of CADR, drug history preceding the reaction, concomitant illness, relevant laboratory investigations etc was obtained. This data was then analysed for morphological pattern, causality and severity. CADRs with causality assessment possible and above on the basis of World Health Organization-Uppsala Monitoring Centre causality assessment system were considered for analysis. Statistics Descriptive statistics were used to express results of pattern, severity and causality of CADRs. Results Ninety patients were enrolled in the study. Male to female ratio for CADRs was 1:2.33. Maculopapular rash was most commonly encountered CADR in 76.67% cases followed by urticaria (8.89%), Stevens-Johnson syndrome (4.4%) and fixed dose eruptions (3.33%). Antiretrovirals were implicated in 75.56% (68/90) of CADRs. Nevirapine was suspected in 52 out of 90 (57.77%) cases of CADRs which included 39 cases of maculopapular rash, five cases of urticaria, four cases of Stevens-Johnson syndrome, and two cases each of pustular rash and angioedema respectively. Antimicrobials, antiepileptics and Non-steroidal Anti-inflammatory Drugs (NSAIDs) were

  17. Simultaneous analysis of 22 antiepileptic drugs in postmortem blood, serum and plasma using LC-MS-MS with a focus on their role in forensic cases.

    PubMed

    Deeb, Shaza; McKeown, Denise A; Torrance, Hazel J; Wylie, Fiona M; Logan, Barry K; Scott, Karen S

    2014-10-01

    In recent years, there has been a growth in reports of antiepileptic drugs (AEDs) being misused on their own or in combination with other drugs of abuse in a variety of toxicological case types such as drug abuse, suicide, overdose and drug facilitated crime. To our knowledge, there are no simultaneous quantification methods for the analysis of the most commonly encountered AEDs in postmortem whole blood and clinical plasma/serum samples at the same time. A simple, accurate and cost-effective liquid chromatography-tandem mass spectrometric (LC-MS-MS) method has been developed and validated for the simultaneous quantification of carbamazepine (CBZ) and its metabolite CBZ-10,11-epoxide, eslicarbazepine acetate, oxcarbazepine and S-licarbazepine as a metabolite, gabapentin, lacosamide, lamotrigine, levetiracetam, pregabalin, phenobarbital, phenytoin and its metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin, retigabine (ezogabine) and its metabolite N-acetyl retigabine, rufinamide, stiripentol, topiramate, tiagabine, valproic acid, vigabatrin and zonisamide in postmortem whole blood, serum and plasma which would be suitable for routine forensic toxicological analysis and therapeutic drug monitoring. All AEDs were detected and quantified within 17 min without endogenous interferences. The correlation coefficient (R(2)) was >0.995 for all AEDs with accuracy ranging from 90 to 113% and precision <13% for all analytes. The recovery ranged from 70 to 98%. No carryover was observed in a blank control injected after the highest standard and the matrix effect was acceptable and ranged from 90 to 120%. The method has been successfully verified using authentic case samples that had previously been quantified using different methods. PMID:25217536

  18. Psychotropic drugs in Bulgaria-frequency and risk of adverse drug reactions.

    PubMed

    Dimitrova, Z; Doma, A; Petkova, V; Getov, I; Verkkunen, E

    2002-01-01

    The aim of the study is to determine the frequency and risk of appearance of adverse drug reactions/ADRs/during the treatment with psychotropic drugs. The first part of the study is an analysis of the use of the psychotropic drugs for one-year period of time in our country, performed by DDD methodology. An attempt is made to equalize the Bulgarian list of the psychotropic drugs with the ATC classification and to estimate the DDD/1000/day. The data for Bulgaria is compared with that of the other countries. The collected data for the psychotropic drug use is divided into 2 groups: Psycholeptics and Psychoanaleptics. It is made an attempt to explain the main differences between them. The number of the standard therapeutic courses/NT/is used for assessment of the frequency and risk of ADRs. The results from the study show that the determined frequency of appearance of ADR for the different drugs is within "rare" and "very rare' for 100,000 inhabitants, according to the WHO terminology. Only for the drug Tardyl (EGIS Pharmaceuticals, Hungary) with INN Aminobarbitalum + Glutethimidum + Promethazini hydrochloridum the frequency is above 1%. That fact makes us to recommend a limitation of the prescription and usage of this drug to the Bulgarian Ministry of Health and to the National Drug Agency. PMID:12064062

  19. Modulation of Cytokine Production by Drugs with Antiepileptic or Mood Stabilizer Properties in Anti-CD3- and Anti-CD40-Stimulated Blood In Vitro

    PubMed Central

    Hamer, Hajo; Schönherr, Jeremias; Petersein, Charlotte; Munzer, Alexander; Kirkby, Kenneth Clifford; Bauer, Katrin; Sack, Ulrich

    2014-01-01

    Increased cytokine production possibly due to oxidative stress has repeatedly been shown to play a pivotal role in the pathophysiology of epilepsy and bipolar disorder. Recent in vitro and animal studies of valproic acid (VPA) report antioxidative and anti-inflammatory properties, and suppression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α. We tested the effect of drugs with antiepileptic or mood stabilizer properties, namely, primidone (PRM), carbamazepine (CBZ), levetiracetam (LEV), lamotrigine (LTG), VPA, oxcarbazepine (OXC), topiramate (TPM), phenobarbital (PB), and lithium on the production of the following cytokines in vitro: interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-17, IL-22, and TNF-α. We performed a whole blood assay with stimulated blood of 14 healthy female subjects. Anti-human CD3 monoclonal antibody OKT3, combined with 5C3 antibody against CD40, was used as stimulant. We found a significant reduction of IL-1 and IL-2 levels with all tested drugs other than lithium in the CD3/5C3-stimulated blood; VPA led to a decrease in IL-1β, IL-2, IL-4, IL-6, IL-17, and TNF-α production, which substantiates and adds knowledge to current hypotheses on VPA's anti-inflammatory properties. PMID:24757498

  20. Knockout of P-glycoprotein does not alter antiepileptic drug efficacy in the intrahippocampal kainate model of mesial temporal lobe epilepsy in mice.

    PubMed

    Bankstahl, Marion; Klein, Sabine; Römermann, Kerstin; Löscher, Wolfgang

    2016-10-01

    Pharmacoresistance to antiepileptic drugs (AEDs) is a major challenge in epilepsy therapy, affecting at least 30% of patients. Thus, there is considerable interest in the mechanisms responsible for such pharmacoresistance, with particular attention on the specific cellular and molecular factors that lead to reduced drug sensitivity. Current hypotheses of refractory epilepsy include the multidrug transporter hypothesis, which posits that increased expression or function of drug efflux transporters, such as P-glycoprotein (Pgp), in brain capillaries reduces the local concentration of AEDs in epileptic brain regions to subtherapeutic levels. In the present study, this hypothesis was addressed by evaluating the efficacy of six AEDs in wildtype and Pgp deficient Mdr1a/b(-/-) mice in the intrahippocampal kainate model of mesial temporal lobe epilepsy. In this model, frequent focal electrographic seizures develop after an initial kainate-induced status epilepticus. These seizures are resistant to major AEDs, but the mechanisms of this resistance are unknown. In the present experiments, the focal nonconvulsive seizures were resistant to carbamazepine and phenytoin, whereas high doses of valproate and levetiracetam exerted moderate and phenobarbital and diazepam marked anti-seizure effects. All AEDs suppressed generalized convulsive seizures. No significant differences between wildtype and Pgp-deficient mice were observed in anti-seizure drug efficacies. Also, the individual responder and nonresponder rates in each experiment did not differ between mouse genotypes. This does not argue against the multidrug transporter hypothesis in general, but indicates that Pgp is not involved in the mechanisms explaining that focal electrographic seizures are resistant to some AEDs in the intrahippocampal mouse model of partial epilepsy. This was substantiated by the finding that epileptic wildtype mice do not exhibit increased Pgp expression in this model.

  1. Knockout of P-glycoprotein does not alter antiepileptic drug efficacy in the intrahippocampal kainate model of mesial temporal lobe epilepsy in mice.

    PubMed

    Bankstahl, Marion; Klein, Sabine; Römermann, Kerstin; Löscher, Wolfgang

    2016-10-01

    Pharmacoresistance to antiepileptic drugs (AEDs) is a major challenge in epilepsy therapy, affecting at least 30% of patients. Thus, there is considerable interest in the mechanisms responsible for such pharmacoresistance, with particular attention on the specific cellular and molecular factors that lead to reduced drug sensitivity. Current hypotheses of refractory epilepsy include the multidrug transporter hypothesis, which posits that increased expression or function of drug efflux transporters, such as P-glycoprotein (Pgp), in brain capillaries reduces the local concentration of AEDs in epileptic brain regions to subtherapeutic levels. In the present study, this hypothesis was addressed by evaluating the efficacy of six AEDs in wildtype and Pgp deficient Mdr1a/b(-/-) mice in the intrahippocampal kainate model of mesial temporal lobe epilepsy. In this model, frequent focal electrographic seizures develop after an initial kainate-induced status epilepticus. These seizures are resistant to major AEDs, but the mechanisms of this resistance are unknown. In the present experiments, the focal nonconvulsive seizures were resistant to carbamazepine and phenytoin, whereas high doses of valproate and levetiracetam exerted moderate and phenobarbital and diazepam marked anti-seizure effects. All AEDs suppressed generalized convulsive seizures. No significant differences between wildtype and Pgp-deficient mice were observed in anti-seizure drug efficacies. Also, the individual responder and nonresponder rates in each experiment did not differ between mouse genotypes. This does not argue against the multidrug transporter hypothesis in general, but indicates that Pgp is not involved in the mechanisms explaining that focal electrographic seizures are resistant to some AEDs in the intrahippocampal mouse model of partial epilepsy. This was substantiated by the finding that epileptic wildtype mice do not exhibit increased Pgp expression in this model. PMID:27288003

  2. Adverse drug reactions associated with antiretroviral therapy in South Africa.

    PubMed

    Birbal, Sumeshni; Dheda, Mukesh; Ojewole, Elizabeth; Oosthuizen, Frasia

    2016-09-01

    South Africa has one of the highest prevalences of HIV and AIDS in the world. HIV/AIDS patients face countless challenges, one of which is the risk of adverse drug reactions (ADRs). This study aimed to describe the ADRs reported in South Africa with reference to the type of ADRs, antiretrovirals (ARVs) implicated, seriousness of the ADRs and patient demographics associated with specific ADRs. A retrospective quantitative study was carried out using ADR reports submitted to the National Department of Health (NDoH) from 1 January 2010 to 31 December 2014. A descriptive and inferential analysis was carried out to determine the strength of the relationships between different variables. A total of 2 489 reports were analysed. This study found evidence of ADRs among patients on regimens based on stavudine (n = 1 256, 50.46%), efavirenz (n = 572, 22.98%), zidovudine (n = 209, 8.40%), tenofovir (n = 203, 8.16%) and nevirapine (n = 153, 6.15%). The 10 most common ADRs reported with the use of ARVs were peripheral neuropathy (n = 472, 19%), lipodystrophy (n = 471, 18.9%), serious skin reactions (n = 266, 10.7%), gynaecomastia (n = 219, 8.8%), renal failure (n = 140, 5.6%), dizziness (n = 133, 5.3%), hyperlactatemia (n = 118, 4.7%), psychosis/hallucinations (n = 47, 1.9%), sleep disturbances (n = 44, 1.8%) and vomiting (n = 44, 1.8%). Female patients were more likely to experience peripheral neuropathy, lipodystrophy, skin rash, anaemia and hyperlactatemia, while male patients were more prone to experience gynaecomastia and peripheral neuropathy. In addition, patients aged 30-44 years reported the most ADRs. Most reactions resulted from the use of stavudine, efavirenz, zidovudine, nevirapine and tenofovir in the population groups identified in this study. PMID:27681148

  3. Epidemiology of adverse drug reactions in the elderly by drug class.

    PubMed

    Beyth, R J; Shorr, R I

    1999-03-01

    As the growth of the elderly population continues, the burden on the health care system and society will also increase. Since chronic diseases such as hypertension, coronary artery disease, arthritis, stroke, cancer and diabetes mellitus are more prevalent with age, the number of people with multiple chronic diseases will also increase. These patients are likely to be treated for some or all of their conditions with drug therapies. When used appropriately, drugs may be the single most important intervention in the care of an older patient, but when used inappropriately they no longer provide therapeutic benefit, and they may even endanger the health of an older patient by causing an adverse drug reaction (ADR). Factors believed to be responsible for increased adverse reactions in elderly patients are polypharmacy (including prescription and over-the-counter medications), increased drug-drug interaction, pharmacokinetic changes, pharmacodynamic changes, the pathology of aging and compliance. The exact role that age plays in ADRs is not clear. This is in part because few older patients are included in the large randomised trials, and so much of the information used to ascertain the age-associated risks of drugs comes from observational studies. Although the interactions of aging, concurrent comorbidities and polypharmacy are known, older patients do appear to be at increased risk. Improvements in the management of drug therapies of older patients can lead to improvements in their overall health, functioning and safety, as well as providing potential benefits to society by ameliorating some of the burden of their health care. PMID:10220106

  4. Illicit Drug Use and Adverse Birth Outcomes: Is It Drugs or Context?

    PubMed Central

    Strobino, Donna M.

    2008-01-01

    Prenatal drug use is commonly associated with adverse birth outcomes, yet no studies have controlled for a comprehensive set of associated social, psychosocial, behavioral, and biomedical risk factors. We examined the degree to which adverse birth outcomes associated with drug use are due to the drugs versus surrounding factors. Data are from a clinical sample of low-income women who delivered at Johns Hopkins Hospital between 1995 and 1996 (n = 808). Use of marijuana, cocaine, and opiates was determined by self-report, medical record, and urine toxicology screens at delivery. Information on various social, psychosocial, behavioral, and biomedical risk factors was gathered from a postpartum interview or the medical record. Multivariable regression models of birth outcomes (continuous birth weight and low birth weight ([LBW] <2,500 g)) were used to assess the effect of drug use independent of associated factors. In unadjusted results, all types of drug use were related to birth weight decrements and increased odds of LBW. However, only the effect of cocaine on continuous birth weight remained significant after adjusting for all associated factors (−142 g, p = 0.05). No drug was significantly related to LBW in fully adjusted models. About 70% of the unadjusted effect of cocaine use on continuous birth weight was explained by surrounding psychosocial and behavioral factors, particularly smoking and stress. Most of the unadjusted effects of opiate use were explained by smoking and lack of early prenatal care. Thus, prevention efforts that aim to improve newborn health must also address the surrounding context in which drug use frequently occurs. PMID:18791865

  5. The risk of adverse drug reactions in older patients: beyond drug metabolism.

    PubMed

    Onder, Graziano; Lattanzio, Fabrizia; Battaglia, Miriam; Cerullo, Francesco; Sportiello, Roberta; Bernabei, Roberto; Landi, Francesco

    2011-09-01

    Changes in pharmacokinetics and pharmacodynamics, associated with increasing age, are often considered the only culprits of increasing Adverse Drug Reactions (ADR) rate observed in older adults, but other factors may be responsible for a reduction in drug efficacy and increase the risk of iatrogenic illness in this population. The aging process is characterized by a high level of complexity, which makes the care of older adults and the use of medications a challenging task. In particular, comorbidity, geriatric syndromes, cognitive and functional deficits, limited life expectancy are typical conditions observed in older adults which may reduce the efficacy of prescribed drugs and increase the risk of iatrogenic illness. As a consequence, a comprehensive assessment and management of the health care problems, with the goal of recognizing and preventing potential drug-related problems and improve quality of prescribing is necessary to reduce the risk of ADR. Several studies have assessed the effect of a comprehensive geriatric assessment and management on drug prescribing and drug related illness, showing a substantial improvement in quality of prescription and a reduction in rate of ADR. In addition, clinical guidelines providing recommendations regarding the use of drugs in chronic disease rarely assess the level of complexity observed in older adults and therefore they should be applied with caution in this population. PMID:21495971

  6. Suppression of inter-ictal spikes by CM40907. A double-blind placebo-controlled investigation and review of spike counting as a methodology for assessing the antiepileptic effect of drugs.

    PubMed

    Yepez-Lasso, R; Duncan, J S; Shorvon, S D

    1990-04-01

    To assess the efficacy of CM40907--a new antiepileptic drug--in suppressing inter-ictal spikes, 6 patients with severe intractable epilepsy and frequent spikes in their inter-ictal EEGs were entered in a double-blind placebo-controlled trial. The results show that CM40907 is efficacious in reducing spike counts in the first hour after oral administration. The results of the study are presented and inter-ictal spike counting as a method is discussed.

  7. Quality check of spontaneous adverse drug reaction reporting forms of different countries.

    PubMed

    Bandekar, M S; Anwikar, S R; Kshirsagar, N A

    2010-11-01

    Adverse drug reactions (ADRs) are considered as one of the leading causes of death among hospitalized patients. Thus reporting of adverse drug reactions become an important phenomenon. Spontaneous adverse drug reaction reporting form is an essential component and a major tool of the pharmacovigilance system of any country. This form is a tool to collect information of ADRs which helps in establishing the causal relationship between the suspected drug and the reaction. As different countries have different forms, our aim was to study, analyze the suspected adverse drug reaction reporting form of different countries, and assess if these forms can capture all the data regarding the adverse drug reaction. For this analysis we identified 18 points which are essential to make a good adverse drug reaction report, enabling proper causality assessment of adverse reaction to generate a safety signal. Adverse drug reaction reporting forms of 10 different countries were collected from the internet and compared for 18 points like patient information, information about dechallenge-rechallenge, adequacy of space and columns to capture necessary information required for its causality assessment, etc. Of the ADR forms that we analyzed, Malaysia was the highest scorer with 16 out of 18 points. This study reveals that there is a need to harmonize the ADR reporting forms of all the countries because there is a lot of discrepancy in data captured by the existing ADR reporting forms as the design of these forms is different for different countries. These incomplete data obtained result in inappropriate causality assessment.

  8. Effects of derivatization reagents consisting of n-alkyl chloroformate/n-alcohol combinations in LC-ESI-MS/MS analysis of zwitterionic antiepileptic drugs.

    PubMed

    Kostić, Nađa; Dotsikas, Yannis; Malenović, Anđelija; Medenica, Mirjana

    2013-11-15

    In the current study, three antiepileptic drugs with zwitterionic properties, namely vigabatrin, pregabalin and gabapentin, were chosen as model analytes to undergo derivatization by applying various n-alkyl chloroformate/n-alcohol combinations, followed by LC-ESI-MS/MS analysis. The employment of 16 combinations per drug using methyl, ethyl, propyl or butyl chloroformate coupled with methanol, ethanol, propanol or butanol, greatly affected a series of parameters of the derivatives, such as retention time on C8 column, signal expressed via areas, limit of detection values, as well as the yields of the main and side reactions. Practically, even slight modification of n-alkyl group of either chloroformate or alcohol resulted in significant changes in the chromatographic and mass spectrometric behavior of the novel derivative. It was clearly demonstrated that all the estimated parameters were highly correlated with the length of n-alkyl groups of the involved chloroformate and alcohol. The most significant influence was monitored in peak area values, indicating that the length of the n-alkyl chain plays an important role in electrospray ionization efficiency. For this parameter, increasing the n-alkyl chain from methyl to butyl led to increment up to 2089%, 508.7% and 1075% for area values of derivatized vigabatrin, pregabalin and gabapentin, respectively. These changes affected also the corresponding values of limits of detection, with the estimated improvements up to 1553%, 397.7% and 875.0% for the aforementioned derivatized drugs, respectively. Besides the obvious utilization of these conclusions in the development of bioanalytical methods for these analytes with the current protocol, this study offers valuable data which can be useful in more general approaches, giving insights into the effects of this derivatization reaction and its performances.

  9. FT-Raman, FT-IR and UV-visible spectral investigations and ab initio computations of anti-epileptic drug: Vigabatrin

    NASA Astrophysics Data System (ADS)

    Edwin, Bismi; Joe, I. Hubert

    2013-10-01

    Vibrational analysis of anti-epileptic drug vigabatrin, a structural GABA analog was carried out using NIR FT-Raman and FTIR spectroscopic techniques. The equilibrium geometry, various bonding features and harmonic vibrational wavenumbers were studied using density functional theory method. The detailed interpretation of the vibrational spectra has been carried out with the aid of VEDA.4 program. Vibrational spectra, natural bond orbital analysis and optimized molecular structure show clear evidence for the effect of electron charge transfer on the activity of the molecule. Predicted electronic absorption spectrum from TD-DFT calculation has been compared with the UV-vis spectrum. The Mulliken population analysis on atomic charges and the HOMO-LUMO energy were also calculated. Good consistency is found between the calculated results and experimental data for the electronic absorption as well as IR and Raman spectra. The blue-shifting of the Csbnd C stretching wavenumber reveals that the vinyl group is actively involved in the conjugation path. The NBO analysis confirms the occurrence of intramolecular hyperconjugative interactions resulting in ICT causing stabilization of the system.

  10. Comparative safety of anti-epileptic drugs among infants and children exposed in utero or during breastfeeding: protocol for a systematic review and network meta-analysis

    PubMed Central

    2014-01-01

    Background Epilepsy affects about 1% of the general population. Anti-epileptic drugs (AEDs) prevent or terminate seizures in individuals with epilepsy. Pregnant women with epilepsy may continue taking AEDs. Many of these agents cross the placenta and increase the risk of major congenital malformations, early cognitive and developmental delays, and infant mortality. We aim to evaluate the comparative safety of AEDs approved for chronic use in Canada when administered to pregnant and breastfeeding women and the effects on their infants and children through a systematic review and network meta-analysis. Methods Studies examining the effects of AEDs administered to pregnant and breastfeeding women regardless of indication (e.g., epilepsy, migraine, pain, psychiatric disorders) on their infants and children will be included. We will include randomized clinical trials (RCTs), quasi-RCTs, non-RCTs, controlled before-after, interrupted time series, cohort, registry, and case-control studies. The main literature search will be executed in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. We will seek unpublished literature through searches of trial protocol registries and conference abstracts. The literature search results screening, data abstraction, and risk of bias appraisal will be performed by two individuals, independently. Conflicts will be resolved through discussion. The risk of bias of experimental and quasi-experimental studies will be appraised using the Cochrane Effective Practice and Organization of Care Risk-of-Bias tool, methodological quality of observational studies will be appraised using the Newcastle-Ottawa Scale, and quality of reporting of safety outcomes will be conducted using the McMaster Quality Assessment Scale of Harms (McHarm) tool. If feasible and appropriate, we will conduct random effects meta-analysis. Network meta-analysis will be considered for outcomes that fulfill network meta-analysis assumptions. The primary

  11. Reporting of adverse events for marketed drugs: Need for strengthening safety database.

    PubMed

    Apte, Aditi Anand

    2016-01-01

    Pharmacovigilance is an evolving discipline in the Indian context. However, there is limited regulatory guidance for adverse event reporting outside the purview of clinical trials. There are number of deficiencies in the framework for adverse event reporting from the perspective of pharma industry, health-care professional and general public due to which adverse events for marketed drugs are highly underreported. This article discusses the need to strengthen national safety database by promoting and mandating reporting of adverse events by all the stakeholders.

  12. Could chiropractors screen for adverse drug events in the community? Survey of US chiropractors

    PubMed Central

    2010-01-01

    Background The "Put Prevention into Practice" campaign of the US Public Health Service (USPHS) was launched with the dissemination of the Clinician's Handbook of Preventive Services that recommended standards of clinical care for various prevention activities, including preventive clinical strategies to reduce the risk of adverse drug events. We explored whether nonprescribing clinicians such as chiropractors may contribute to advancing drug safety initiatives by identifying potential adverse drug events in their chiropractic patients, and by bringing suspected adverse drug events to the attention of the prescribing clinicians. Methods Mail survey of US chiropractors about their detection of potential adverse drug events in their chiropractic patients. Results Over half of responding chiropractors (62%) reported having identified a suspected adverse drug event occurring in one of their chiropractic patients. The severity of suspected drug-related events detected ranged from mild to severe. Conclusions Chiropractors or other nonprescribing clinicians may be in a position to detect potential adverse drug events in the community. These detection and reporting mechanisms should be standardized and policies related to clinical case management of suspected adverse drug events occurring in their patients should be developed. PMID:21083911

  13. Simultaneous determination of ten antiepileptic drugs in human plasma by liquid chromatography and tandem mass spectrometry with positive/negative ion-switching electrospray ionization and its application in therapeutic drug monitoring.

    PubMed

    Yin, Lei; Wang, Tingting; Shi, Meiyun; Zhang, Ying; Zhao, Xiaojun; Yang, Yan; Gu, Jingkai

    2016-03-01

    A simple, rapid, and high-throughput liquid chromatography with tandem mass spectrometry method for the simultaneous quantitation of ten antiepileptic drugs in human plasma has been developed and validated. The method required only 10 μL of plasma. After simple protein precipitation using acetonitrile, the analytes and internal standard diphenhydramine were separated on a Zorbax SB-C18 column (50 × 4.6 mm, 2.7 μm) using acetonitrile/water as the mobile phase at a flow rate of 0.9 mL/min. The total run time was 6 min for each sample. The validation results of specificity, matrix effects, recovery, linearity, precision, and accuracy were satisfactory. The lower limit of quantification was 0.04 μg/mL for carbamazepine, 0.02 μg/mL for lamotrigine, 0.01 μg/mL for oxcarbazepine, 0.4 μg/mL for 10-hydroxycarbazepine, 0.1 μg/mL for carbamazepine-10,11-epoxide, 0.15 μg/mL for levetiracetam, 0.06 μg/mL for phenytoin, 0.3 μg/mL for valproic acid, 0.03 μg/mL for topiramate, and 0.15 μg/mL for phenobarbital. The intraday precision and interday precision were less than 7.6%, with the accuracy ranging between -8.1 and 7.9%. The method was successfully applied to therapeutic drug monitoring of 1237 patients with epilepsy after administration of standard antiepileptic drugs. The method has been proved to meet the high-throughput requirements in therapeutic drug monitoring. PMID:26711223

  14. The Antiepileptic Drug Levetiracetam Suppresses Non-Convulsive Seizure Activity and Reduces Ischemic Brain Damage in Rats Subjected to Permanent Middle Cerebral Artery Occlusion

    PubMed Central

    Cuomo, Ornella; Rispoli, Vincenzo; Leo, Antonio; Politi, Giovanni Bosco; Vinciguerra, Antonio; di Renzo, Gianfranco; Cataldi, Mauro

    2013-01-01

    The antiepileptic drug Levetiracetam (Lev) has neuroprotective properties in experimental stroke, cerebral hemorrhage and neurotrauma. In these conditions, non-convulsive seizures (NCSs) propagate from the core of the focal lesion into perilesional tissue, enlarging the damaged area and promoting epileptogenesis. Here, we explore whether Lev neuroprotective effect is accompanied by changes in NCS generation or propagation. In particular, we performed continuous EEG recordings before and after the permanent occlusion of the middle cerebral artery (pMCAO) in rats that received Lev (100 mg/kg) or its vehicle immediately before surgery. Both in Lev-treated and in control rats, EEG activity was suppressed after pMCAO. In control but not in Lev-treated rats, EEG activity reappeared approximately 30-45 min after pMCAO. It initially consisted in single spikes and, then, evolved into spike-and-wave and polyspike-and-wave discharges. In Lev-treated rats, only rare spike events were observed and the EEG power was significantly smaller than in controls. Approximately 24 hours after pMCAO, EEG activity increased in Lev-treated rats because of the appearance of polyspike events whose power was, however, significantly smaller than in controls. In rats sacrificed 24 hours after pMCAO, the ischemic lesion was approximately 50% smaller in Lev-treated than in control rats. A similar neuroprotection was observed in rats sacrificed 72 hours after pMCAO. In conclusion, in rats subjected to pMCAO, a single Lev injection suppresses NCS occurrence for at least 24 hours. This electrophysiological effect could explain the long lasting reduction of ischemic brain damage caused by this drug. PMID:24236205

  15. Fosinopril and zofenopril, two angiotensin-converting enzyme (ACE) inhibitors, potentiate the anticonvulsant activity of antiepileptic drugs against audiogenic seizures in DBA/2 mice.

    PubMed

    Sarro, Giovambattista De; Paola, Eugenio Donato Di; Gratteri, Santo; Gareri, Pietro; Rispoli, Vincenzo; Siniscalchi, Antonio; Tripepi, Giovanni; Gallelli, Luca; Citraro, Rita; Russo, Emilio

    2012-03-01

    The renin-angiotensin system (RAS) exists in the brain and it may be involved in pathogenesis of neurological and psychiatric disorders including seizures. The aim of the present research was to evaluate the effects of some angiotensin-converting enzyme inhibitors (ACEi; captopril, enalapril, fosinopril and zofenopril), commonly used as antihypertensive agents, in the DBA/2 mice animal model of generalized tonic-clonic seizures. Furthermore, the co-administration of these compounds with some antiepileptic drugs (AEDs; carbamazepine, diazepam, felbamate, gabapentin, lamotrigine, phenobarbital, phenytoin, topiramate and valproate) was studied in order to identify possible positive interactions in the same model. All ACEi were able to decrease the severity of audiogenic seizures with the exception of enalapril up to the dose of 100mg/kg, the rank order of activity was as follows: fosinopril>zofenopril>captopril. The co-administration of ineffective doses of all ACE inhibitors with AEDs, generally increased the potency of the latter. Fosinopril was the most active in potentiating the activity of AEDs and the combination of ACEi with lamotrigine and valproate was the most favorable, whereas, the co-administrations with diazepam and phenobarbital seemed to be neutral. The increase in potency was generally associated with an enhancement of motor impairment, however, the therapeutic index of combined treatment of AEDs with ACEi was predominantly more favorable than control. ACEi administration did not influence plasma and brain concentrations of the AEDs studied excluding pharmacokinetic interactions and concluding that it is of pharmacodynamic nature. In conclusion, fosinopril, zofenopril, enalapril and captopril showed an additive anticonvulsant effect when co-administered with some AEDs, most notably carbamazepine, felbamate, lamotrigine, topiramate and valproate, implicating a possible therapeutic relevance of such drug combinations.

  16. Postmarket Drug Surveillance Without Trial Costs: Discovery of Adverse Drug Reactions Through Large-Scale Analysis of Web Search Queries

    PubMed Central

    Gabrilovich, Evgeniy

    2013-01-01

    Background Postmarket drug safety surveillance largely depends on spontaneous reports by patients and health care providers; hence, less common adverse drug reactions—especially those caused by long-term exposure, multidrug treatments, or those specific to special populations—often elude discovery. Objective Here we propose a low cost, fully automated method for continuous monitoring of adverse drug reactions in single drugs and in combinations thereof, and demonstrate the discovery of heretofore-unknown ones. Methods We used aggregated search data of large populations of Internet users to extract information related to drugs and adverse reactions to them, and correlated these data over time. We further extended our method to identify adverse reactions to combinations of drugs. Results We validated our method by showing high correlations of our findings with known adverse drug reactions (ADRs). However, although acute early-onset drug reactions are more likely to be reported to regulatory agencies, we show that less acute later-onset ones are better captured in Web search queries. Conclusions Our method is advantageous in identifying previously unknown adverse drug reactions. These ADRs should be considered as candidates for further scrutiny by medical regulatory authorities, for example, through phase 4 trials. PMID:23778053

  17. [Objectives and practical aspects of antiepileptic medication].

    PubMed

    Auvin, Stéphane

    2015-01-01

    Antiepileptics are a group of drugs with various pharmacological properties and mechanisms of action. They are grouped together due to the fact that they are used to treat epilepsy. There are around twenty molecules in this group. Particular care needs to be taken when prescribing them for children as they carry risks.

  18. Genetic polymorphisms affect efficacy and adverse drug reactions of DMARDs in rheumatoid arthritis.

    PubMed

    Zhang, Ling Ling; Yang, Sen; Wei, Wei; Zhang, Xue Jun

    2014-11-01

    Disease-modifying antirheumatic drugs (DMARDs) and biological agents are critical in preventing the severe complications of rheumatoid arthritis (RA). However, the outcome of treatment with these drugs in RA patients is quite variable and unpredictable. Drug-metabolizing enzymes (dihydrofolate reductase, cytochrome P450 enzymes, N-acetyltransferases, etc.), drug transporters (ATP-binding cassette transporters), and drug targets (tumor necrosis factor-α receptors) are coded for by variant alleles. These gene polymorphisms may influence the pharmacokinetics, pharmacodynamics, and side effects of medicines. The cause for differences in efficacy and adverse drug reactions may be genetic variation in drug metabolism among individuals. Polymorphisms in drug transporter genes may change the distribution and excretion of medicines, and the sensitivity of the targets to drugs is strongly influenced by genetic variations. In this article, we review the genetic polymorphisms that affect the efficacy of DMARDs or the occurrence of adverse drug reactions associated with DMARDs in RA.

  19. A continuous GRASP to determine the relationship between drugs and adverse reactions

    SciTech Connect

    Hirsch, Michael J.; Meneses, Claudio N.; Pardalos, Panos M.; Ragle, Michelle; Resende, Mauricio G. C.

    2007-11-05

    Adverse drag reactions (ADRs) are estimated to be one of the leading causes of death. Many national and international agencies have set up databases of ADR reports for the express purpose of determining the relationship between drugs and adverse reactions that they cause. We formulate the drug-reaction relationship problem as a continuous optimization problem and utilize C-GRASP, a new continuous global optimization heuristic, to approximately determine the relationship between drugs and adverse reactions. Our approach is compared against others in the literature and is shown to find better solutions.

  20. Antiepileptic carbamazepine drug treatment induces alteration of membrane in red blood cells: possible positive effects on metabolism and oxidative stress.

    PubMed

    Ficarra, Silvana; Misiti, Francesco; Russo, Annamaria; Carelli-Alinovi, Cristiana; Bellocco, Ersilia; Barreca, Davide; Laganà, Giuseppina; Leuzzi, Ugo; Toscano, Giovanni; Giardina, Bruno; Galtieri, Antonio; Tellone, Ester

    2013-04-01

    Carbamazepine (CBZ) is an iminostilbene derivative commonly used for treatment of neuralgic pain and bipolar affective disorders. CBZ blood levels of treated patients are within the range of micromolar concentrations and therefore, significant interactions of this drug with erythrocytes are very likely. Moreover, the lipid domains of the cell membrane are believed to be one of the sites where iminostilbene derivatives exert their effects. The present study aimed to deeply characterize CBZ effects on erythrocytes, in order to identify extra and/or cytosolic cell targets. Our results indicate that erythrocyte morphological changes promoted by the drug, may be triggered by an alteration in band 3 functionality i.e. at the level of anionic flux. In addition, from a metabolic point of view this perturbation could be considered, at least in part, as a beneficial event because it could favour the CO2 elimination. Since lipid peroxidation, superoxide and free radical scavenging activities, caspase 3 activity and hemoglobin (Hb) functionality were not modified within the CBZ treated red blood cell (RBC), band 3 protein (B3) may well be a specific membrane target for CBZ and responsible for CBZ-induced toxic effects in erythrocytes. However some beneficial effects of this drug have been evidenced; among them an increased release of ATP and nitric oxide (NO) derived metabolites from erythrocytes to lumen, leading to an increased NO pool in the vasculature. In conclusion, these results indicate that CBZ, though considered responsible for toxic effects on erythrocytes, can also exhibit effects that at least in some conditions may be seen as beneficial.

  1. Adverse drug reactions and drug–drug interactions with over-the-counter NSAIDs

    PubMed Central

    Moore, Nicholas; Pollack, Charles; Butkerait, Paul

    2015-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen have a long history of safe and effective use as both prescription and over-the-counter (OTC) analgesics/antipyretics. The mechanism of action of all NSAIDs is through reversible inhibition of cyclooxygenase enzymes. Adverse drug reactions (ADRs) including gastrointestinal bleeding as well as cardiovascular and renal effects have been reported with NSAID use. In many cases, ADRs may occur because of drug–drug interactions (DDIs) between the NSAID and a concomitant medication. For example, DDIs have been reported when NSAIDs are coadministered with aspirin, alcohol, some antihypertensives, antidepressants, and other commonly used medications. Because of the pharmacologic nature of these interactions, there is a continuum of risk in that the potential for an ADR is dependent on total drug exposure. Therefore, consideration of dose and duration of NSAID use, as well as the type or class of comedication administered, is important when assessing potential risk for ADRs. Safety findings from clinical studies evaluating prescription-strength NSAIDs may not be directly applicable to OTC dosing. Health care providers can be instrumental in educating patients that using OTC NSAIDs at the lowest effective dose for the shortest required duration is vital to balancing efficacy and safety. This review discusses some of the most clinically relevant DDIs reported with NSAIDs based on major sites of ADRs and classes of medication, with a focus on OTC ibuprofen, for which the most data are available. PMID:26203254

  2. Evaluation of the relationship between C677T variants of methylenetetrahydrofolate reductase gene and hyperhomocysteinemia in children receiving antiepileptic drug therapy.

    PubMed

    Vurucu, Sebahattin; Demirkaya, Erkan; Kul, Mustafa; Unay, Bulent; Gul, Davut; Akin, Ridvan; Gokçay, Erdal

    2008-04-01

    Homocysteine (Hcy) is a sulfur-containing amino acid involved in methionine metabolism. Elevated plasma Hcy concentration is a possible risk factor for vascular disease. Folate and vitamin B-12 are vitamins that are necessary for remethylization of Hcy to methionine. The methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in remethylation of Hcy to methionine and supplies the required 5-methyltetrahydrofolate as the methyl donor for this reaction. It is well known that some antiepileptic drugs (AED) can lead to hyperhomocysteinemia by affecting the levels of folate and vitamin B-12. The C677T variant of MTHFR gene can also lead to hyperhomocysteinemia particularly when serum folate level is decreased. In this study, we investigated the levels of serum folate, vitamin B-12 and Hcy in epileptic patients receiving carbamazepine (CBZ) or valproic acid (VPA) as monotherapy, and we also evaluated the probable contribution of the C677T variant of MTHFR gene in hyperhomocysteinemia. A total of 93 patients with idiopathic epilepsy receiving CBZ or VPA as monotherapy were included in this study. CBZ and VPA groups consisted of 29 and 64 patients, respectively. The control group comprised 62 healthy children. We measured serum folate, vitamin B-12 and Hcy levels in each group. We found that mean serum folate level was statistically lower and mean Hcy level was higher in epileptic patients receiving CBZ or VPA when compared with those of controls'. We also determined the C677T variants of MTHFR gene (as normal, heterozygote or homozygote) in epileptic patients. We compared the variant groups for serum folate, vitamin B-12 and Hcy levels and found no significant differences among them. In conclusion, C677T variants of MTHFR gene have no contribution in hyperhomocysteinemia in epileptic patients receiving CBZ or VPA. PMID:18234410

  3. Evaluation of cytochrome P450 inductions by anti-epileptic drug oxcarbazepine, 10-hydroxyoxcarbazepine, and carbamazepine using human hepatocytes and HepaRG cells.

    PubMed

    Sugiyama, Ikuo; Murayama, Norie; Kuroki, Ayaka; Kota, Jagannath; Iwano, Shunsuke; Yamazaki, Hiroshi; Hirota, Takashi

    2016-09-01

    Anti-epileptic drug oxcarbazepine is structurally related to carbamazepine, but has reportedly different metabolic pathway. Auto-induction potentials of oxcarbazepine, its pharmacologically active metabolite 10-hydroxyoxcarbazepine and carbamazepine were evaluated by cytochrome P450 (CYP) 1A2, CYP2B6 and CYP3A4 mRNA levels and primary metabolic rates using human hepatocytes and HepaRG cells. For the CYP1A2 the induction potential determined as the fold change in mRNA levels was 7.2 (range: 2.3-11.5) and 10.0 (6.2-13.7) for oxcarbazepine and carbamazepine, respectively, while 10-hydroxyoxcarbazepine did not induce. The fold change in mRNA levels for CYP2B6 was 11.5 (3.2-19.3), 7.0 (2.5-10.8) and 14.8 (3.1-29.1) for oxcarbazepine, 10-hydroxyoxcarbazepine and carbamazepine, respectively. The fold change for CYP3A4 induction level by oxcarbazepine, 10-hydroxyoxcarbazepine and carbamazepine was 3.5 (1.2-7.4), 2.7 (0.8-5.7) and 8.3 (3.5-14.5), respectively. The data suggest lower induction potential of oxcarbazepine and 10-hydroxyoxcarbazepine relative to carbamazepine. The results in HepaRG cells showed similar trend as the human hepatocytes. After incubation for 72 h in hepatocytes and HepaRG cells, auto-induction was evident for only carbamazepine metabolism. The 10-keto group instead of double bond at C10 position is evidently a determinant factor for limited auto-induction of P450 enzymes by oxcarbazepine. PMID:26711482

  4. The antiepileptic drug mephobarbital is not transported by P-glycoprotein or multidrug resistance protein 1 at the blood-brain barrier: a positron emission tomography study

    PubMed Central

    Mairinger, Severin; Bankstahl, Jens P.; Kuntner, Claudia; Römermann, Kerstin; Bankstahl, Marion; Wanek, Thomas; Stanek, Johann; Löscher, Wolfgang; Müller, Markus; Erker, Thomas; Langer, Oliver

    2013-01-01

    Summary Aim of this study was to determine whether the carbon-11-labelled antiepileptic drug [11C]mephobarbital is a substrate of P-glycoprotein (Pgp) and can be used to assess Pgp function at the blood-brain barrier (BBB) with positron emission tomography (PET). We performed paired PET scans in rats, wild-type (FVB) and Mdr1a/b(−/−) mice, before and after intravenous administration of the Pgp inhibitor tariquidar (15 mg/kg). Brain-to-blood AUC0-60 ratios in rats and brain AUC0-60 values of [11C]mephobarbital in wild-type and Mdr1a/b(−/−) mice were similar in scan 1 and scan 2, respectively, suggesting that in vivo brain distribution of [11C]mephobarbital is not influenced by Pgp efflux. Absence of Pgp transport was confirmed in vitro by performing concentration equilibrium transport assay in cell lines transfected with MDR1 or Mdr1a. PET experiments in wild-type mice, with and without pretreatment with the multidrug resistance protein (MRP) inhibitor MK571 (20 mg/kg), and in Mrp1(−/−) mice suggested that [11C]mephobarbital is also not transported by MRPs at the murine BBB, which was also supported by in vitro transport experiments using human MRP1-transfected cells. Our results are surprising as phenobarbital, the N-desmethyl derivative of mephobarbital, has been shown to be a substrate of Pgp, which suggests that N-methylation abolishes Pgp affinity of barbiturates. PMID:22342565

  5. Optimising the retrieval of information on adverse drug effects.

    PubMed

    Golder, Su

    2013-12-01

    Pharmaceutical interventions have brought about many benefits to health, improving the population's well-being and life expectancy. However, these interventions are not without potential harmful side-effects and yet searching for the evidence on adverse effects is challenging. This article summarises a PhD whose main aim was to develop a better understanding of the implications of using different sources and approaches to identifying relevant data on adverse effects. The author is Su Golder, who has recently completed her PhD at the University of York and who has already published several articles on specific aspects of her research, including this journal. This article is the first in the Dissertations into Practice series to report on a PhD study, and it summarises her research in a way which emphasises the implications for practice.

  6. Subchronic treatment with antiepileptic drugs modifies pentylenetetrazol-induced seizures in mice: Its correlation with benzodiazepine receptor binding

    PubMed Central

    Rocha, Luisa

    2008-01-01

    Experiments using male CD1 mice were carried out to investigate the effects of subchronic (daily administration for 8 days) pretreatments with drugs enhancing GABAergic transmission (diazepam, 10 mg/kg, ip; gabapentin, 100 mg/kg, po; or vigabatrin, 500 mg/kg, po) on pentylenetetrazol (PTZ)-induced seizures, 24 h after the last injection. Subchronic administration of diazepam reduced latencies to clonus, tonic extension and death induced by PTZ. Subchronic vigabatrin produced enhanced latency to the first clonus but faster occurrence of tonic extension and death induced by PTZ. Subchronic gabapentin did not modify PTZ-induced seizures. Autoradiography experiments revealed reduced benzodiazepine receptor binding in several brain areas after subchronic treatment with diazepam or gabapentin, whereas subchronic vigabatrin did not induce significant receptor changes. The present results indicate differential effects induced by the subchronic administration of diazepam, vigabatrin, and gabapentin on the susceptibility to PTZ-induced seizures, benzodiazepine receptor binding, or both. PMID:18830436

  7. Quantification of new antiepileptic drugs by liquid chromatography/electrospray ionization tandem mass spectrometry and its application to cellular uptake experiment using human placental choriocarcinoma BeWo cells.

    PubMed

    Furugen, Ayako; Kobayashi, Masaki; Nishimura, Ayako; Takamura, Shigeo; Narumi, Katsuya; Yamada, Takehiro; Iseki, Ken

    2015-10-01

    A method for quantification of new antiepileptic drugs, including lamotrigine (LTG), levetiracetam (LEV), gabapentin (GBP), and topiramate (TPM), in cellular samples, using liquid chromatography/electrospray ionization tandem mass spectrometry was developed to better understand the membrane transport mechanisms of these drugs. Cell lysate was deproteinized by methanol containing LEV-d3 as an internal standard (IS). Chromatographic separation was performed on a C18 column using gradient elution with methanol-water-formic acid (10:90:0.1, v/v/v) and methanol-formic acid (100:0.1, v/v). Analytes were detected in positive ion electrospray mode with selected reaction monitoring (SRM). This method was applicable for a linear range of 5 to 500pmol for LTG; 5 to 1000pmol for LEV; 10 to 10,000pmol for GBP; and 5 to 5000pmol for TPM. The intra-day precision, inter-day precision, and accuracy data were assessed and found to be acceptable. This developed and validated method was then successfully applied to the investigation of uptake of the new antiepileptic drugs in placental choriocarcinoma BeWo cells. The intracellular concentration of these drugs in BeWo cells, accumulating over 30min at 37°C was in the order of GBP>LTG>LEV≈TPM. Furthermore, the uptake of GBP at 4°C was much lower than that at 37°C. The uptake of GBP was saturated at high concentrations. The kinetic parameters calculated for GBP uptake in BeWo cells were determined as Km of 105.4±6.4μM and Vmax at 8153±348pmol/mg protein/min. The novel method described here should enable investigators to elucidate the transport mechanisms of these antiepileptic drugs in BeWo cells.

  8. Determination of a selection of anti-epileptic drugs and two active metabolites in whole blood by reversed phase UPLC-MS/MS and some examples of application of the method in forensic toxicology cases.

    PubMed

    Karinen, Ritva; Vindenes, Vigdis; Hasvold, Inger; Olsen, Kirsten Midtbøen; Christophersen, Asbjørg S; Øiestad, Elisabeth

    2015-07-01

    Quantitative determination of anti-epileptic drug concentrations is of great importance in forensic toxicology cases. Although the drugs are not usually abused, they are important post-mortem cases where the question of both lack of compliance and accidental or deliberate poisoning might be raised. In addition these drugs can be relevant for driving under the influence cases. A reversed phase ultra-performance liquid chromatography-tandem mass spectrometry method has been developed for the quantitative analysis of the anti-epileptic compounds carbamazepine, carbamazepine-10,11-epoxide, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, 10-OH-carbazepine, phenobarbital, phenytoin, pregabalin, and topiramate in whole blood, using 0.1 mL sample volume with methaqualone as internal standard. Sample preparation was a simple protein precipitation with acetonitrile and methanol. The diluted supernatant was directly injected into the chromatographic system. Separation was performed on an Acquity UPLC® BEH Phenyl column with gradient elution and a mildly alkaline mobile phase. The mass spectrometric detection was performed in positive ion mode, except for phenobarbital, and multiple reaction monitoring was used for drug quantification. The limits of quantification for the different anti-epileptic drugs varied from 0.064 to 1.26 mg/L in blood, within-day and day-to-day relative standard deviations from 2.2 to 14.7% except for phenobarbital. Between-day variation for phenobarbital was 20.4% at the concentration level of 3.5 mg/L. The biases for all compounds were within ±17.5%. The recoveries ranged between 85 and 120%. The corrected matrix effects were 88-106% and 84-110% in ante-mortem and post-mortem whole blood samples, respectively.

  9. Adverse reactions to antituberculosis drugs in Manguinhos, Rio de Janeiro, Brazil

    PubMed Central

    Damasceno, Glauciene Santana; Guaraldo, Lusiele; Engstrom, Elyne Montenegro; Filha, Mariza Miranda Theme; Santos, Reinaldo Souza-; Vasconcelos, Ana Gloria Godoi; Rozenfeld, Suely

    2013-01-01

    OBJECTIVES: This study aimed to characterize and estimate the frequency of adverse reactions to antituberculosis drugs in the population treated at the Centro de Saúde Escola Germano Sinval Faria, a primary health care clinic in Manguinhos, Rio de Janeiro City, and to explore the relationship between adverse drug reactions and some of the patients' demographic and health characteristics. METHODS: This descriptive study was conducted via patient record review of incident cases between 2004 and 2008. RESULTS: Of the 176 patients studied, 41.5% developed one or more adverse reactions to antituberculosis drugs, totaling 126 occurrences. The rate of adverse reactions to antituberculosis drugs was higher among women, patients aged 50 years or older, those with four or more comorbidities, and those who used five or more drugs. Of the total reactions, 71.4% were mild. The organ systems most affected were as follows: the gastrointestinal tract (29.4%), the skin and appendages (21.4%), and the central and peripheral nervous systems (14.3%). Of the patients who experienced adverse reactions to antituberculosis drugs, 65.8% received no drug treatment for their adverse reactions, and 4.1% had one of the antituberculosis drugs suspended because of adverse reactions. “Probable reactions” (75%) predominated over “possible reactions” (24%). In the study sample, 64.3% of the reactions occurred during the first two months of treatment, and most (92.6%) of the reactions were ascribed to the combination of rifampicin + isoniazid + pyrazinamide (Regimen I). A high dropout rate from tuberculosis treatment (24.4%) was also observed. CONCLUSION: This study suggests a high rate of adverse reactions to antituberculosis drugs. PMID:23644852

  10. Assessment of Adverse Drug Reactions Based on Spontaneous Signals at Secondary Care Public Hospital.

    PubMed

    Ponnusankar, S; Tejaswini, M; Chaitanya, M

    2015-01-01

    Adverse drug reactions are considered to be among the leading causes of morbidity and mortality. Approximately 5-25% of hospital admissions are due to adverse drug reactions and 6-15% of hospitalized patients experience serious adverse drug reactions, causing significant prolongation of hospital stay. Thus this study was aimed at determining adverse drug reactions by conducting spontaneous reporting in secondary care Govt. District Head Quarters Hospital at Ooty. A prospective Spontaneous Adverse Drug Reaction reporting study was conducted over a period of 12 months from July 2012 to June 2013. The assessment, categorization, causality, severity and preventability were assessed using standard criteria. A total of 47 suspected adverse drug reactions were reported during the study period. Over all incidences was 1.29% among the study population. Antibiotics (31.91%) were the class of drug most commonly involved, while ciprofloxacin (14.89%) was the most frequently reported. Type H (Hypersensitivity) reactions (51.06%) accounted for majority of the reports and a greater share of the adverse drug reactions are probable (89.36%) based on causality assessment. Mild reactions accounted 82.97% based on modified Hartwig and Siegel severity scale. In 76.59% of the reports, the reaction was considered to be preventable based on Schumock and Thornton preventability scale. The implementation of monitoring based on spontaneous reporting will be useful for the detection and evaluation is associated with increase in morbidity and duration of hospitalization. This study also has established the vital role of clinical pharmacist in the adverse drug reaction monitoring program. PMID:26664067

  11. Adverse drug reactions and organ damage: The liver.

    PubMed

    Licata, Anna

    2016-03-01

    Drug-induced liver injury (DILI) is among the most challenging acute or chronic liver conditions to be handled by physicians. Despite its low incidence in the general population, DILI is a frequent cause of acute liver failure. As such, the possibility of DILI should be considered in all patients who present with acute liver damage, independent of any known pre-existing liver disease. DILI can be classified as intrinsic/dose-dependent (e.g., acetaminophen toxicity) or idiosyncratic/dose-independent, with the latter form being relatively uncommon. Amoxicillin-clavulanate is the antimicrobial that is most frequently associated with idiosyncratic DILI. Large, ongoing, prospective studies in western countries have reported other drugs associated with DILI, including nonsteroidal anti-inflammatory drugs, statins, and herbal and dietary supplements. An important safety issue, DILI is one of the most frequently cited reasons for cessation of drug development during or after preclinical studies and for withdrawal of a drug from the market. This review summarizes the epidemiology, risk factors, commonly implicated drugs, clinical features, and diagnosis of DILI, with the aim of aiding physicians in the management of this debated problem. Old and new biomarkers for DILI and pharmacogenetic studies are also described. PMID:26827101

  12. 21 CFR 314.80 - Postmarketing reporting of adverse drug experiences.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... scientific and medical journals either as case reports or as the result of a formal clinical trial. (2) As... adverse drug experiences that occurred in clinical trials if they were previously submitted as part of...

  13. Quantitative evaluation of initial symptoms as predictors to detect adverse drug reactions using Bayes' theory: expansion and evaluation of drug-adverse drug reaction-initial symptom combinations using adverse event reporting system database.

    PubMed

    Kobayashi, Daisuke; Hosaka, Shigeru; Inoue, Emiko; Ohshima, Kimie; Kutsuma, Nobuaki; Oshima, Shinji; Okuno, Yasushi

    2013-01-01

    In prescription dispensing in Japan, to avoid adverse drug reactions (ADR) pharmacists provide patients with information concerning the initial symptoms (IS) of any ADR that might be caused by the drugs they have been prescribed. However, the usefulness of such information for preventing ADR has not been quantitatively evaluated. We previously performed a trial calculation of the usefulness of rash as a predictor of drug-induced liver disorders by applying Bayes' theorem and showed that the predictive utility of IS can be quantitatively evaluated using likelihood ratios. However, for other drug-ADR-IS combinations it was difficult to obtain the information required for the calculations from Japanese data alone. In this study, using the Adverse Event Reporting System (AERS) database of the U.S. Food and Drug Administration (FDA), we evaluated 132 drug-ADR-IS combinations that were considered to be potentially clinical significant. Regarding bezafibrate-associated rhabdomyolysis and cibenzoline-associated hypoglycemia, these ADR were not detected in cases involving monotherapy. For 58 combinations, no events that were considered to be IS of the target ADR developed. Fever, nausea, and decreased appetite were the IS of many ADR, making them very useful predictors. In contrast, pruritus and rash were not very useful. Fever might be a predictor of thiamazole-induced agranulocytosis or levofloxacin- or terbinafine-induced liver disorder, tremors might be useful for predicting paroxetine-induced serotonin syndrome, and decreased appetite might be a useful indicator of terbinafine-induced liver dysfunction. PMID:24292049

  14. Adverse drug reaction profile of microtubule-damaging antineoplastic drugs: A focused pharmacovigilance study in India

    PubMed Central

    Manohar, Hasitha Diana; Adiga, Shalini; Thomas, Joseph; Sharma, Ajitha

    2016-01-01

    Objectives: The aim of the study was to analyze the adverse drug reaction (ADR) profile of microtubule-damaging antineoplastic drugs (taxanes and vinca alkaloids) and to look for unexpected ADRs among the local population. Focused study on these drugs, rampantly used in oncology department for a wide variety of tumors including early and advanced malignancies, would enable better treatment care by physicians. Materials and Methods: Data on ADRs were collected from the cancer patients belonging to both gender and of all ages, on taxanes- or vinca-based cancer chemotherapy and reported in the Indian Pharmacopoeia Commission form. Causality was assessed using the WHO criteria and Naranjo's Algorithm. Preventability and severity of ADRs were also assessed. Results: A total of 97 ADRs were reported among 488 patients on microtubule-damaging anticancer drugs admitted over a period of 1 year. The incidence rate was 19.87%. Gastrointestinal system (40.2%) was the most affected followed by bone marrow (33%) and skin (8.2%). The highest incidence of ADRs was reported among paclitaxel (54.6%), and vincristine (39.2%). Most of the reported ADRs were of milder nature and preventable. The WHO causality assessment scale indicated 71.1% possible reactions. Conclusions: This study showed that most ADRs are preventable with effective ADR monitoring. There is a great need to create awareness among healthcare professionals regarding the importance of the pharmacovigilance system. Judicious use of the preventive measures will lead to a reduction in the incidence of ADRs due to the drug armamentarium, thereby enabling additional economic benefit to the patient and society. PMID:27721535

  15. Role of plasma homocysteine levels and MTHFR polymorphisms on IQ scores in children and young adults with epilepsy treated with antiepileptic drugs.

    PubMed

    Di Rosa, Gabriella; Lenzo, Patrizia; Parisi, Eleonora; Neri, Milena; Guerrera, Silvia; Nicotera, Antonio; Alibrandi, Angela; Germanò, Eva; Caccamo, Daniela; Spanò, Maria; Tortorella, Gaetano

    2013-12-01

    Homocysteine (Hcy) is a sulfur-containing amino acid involved in methionine metabolism. High plasma total Hcy (tHcy) has been quite frequently reported in patients with epilepsy treated with antiepileptic drugs (AEDs) mainly related to plasma folate reduction induced by AEDs themselves. The role of C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene (MTHFR) on the increase of plasma tHcy in patients with epilepsy taking AEDs is still controversial. Cognitive impairment may be associated with epilepsy either as the result of the epileptic syndrome per se or as a side effect induced by the AEDs. High plasma tHcy levels were associated with lower cognitive performances in patients affected by Alzheimer's disease and mild cognitive impairment and in healthy elderly. We searched for a correlation between plasma tHcy levels with the intelligence quotient (IQ) scores in a population of children and young adults with epilepsy treated with old and/or newer AEDs. The study group encompassed 179 patients (92 M, 51.5%) followed at our Unit of Child Neuropsychiatry and aged between 4 and 25years (mean+SD: 14.03±4.25). The inclusion criteria included the following: 1) diagnosis of epilepsy of "unknown cause" (cryptogenic) according to the ILAE classification, 2) age older than 3years, 3) stabilized antiepileptic treatment for at least 6months, and 4) clinical records of cognitive tests, plasma tHcy value, and results of MTHFR polymorphisms. Patients' mean tHcy value was 9.71±3.13μM/L (tHcy<9μM/L as our laboratory cutoff in nonepileptic controls). The mean TIQ score was 85.22 (SD±24.12); the mean VIQ score was 86.32 (SD±20.86); and the mean PIQ score was 86.94 (SD±21.51). C677T and A1298C MTHFR polymorphisms were detected in 74/92 (80%) examined patients and distributed into the following: CT (22.3%), TT (14.9%), CC (10.3%) for C677T, AC (16%), CC (1.1%), and AA (30.3%) for A1298C. Plasma tHcy levels were not significantly related to the IQ scores

  16. Adverse drug reactions: 'six rights' to ensure best practice for children.

    PubMed

    Kanneh, Agnes

    2011-06-01

    In the second of a two-part article on adverse drug reactions Agnes Kanneh describes the six 'rights' of the recipient of a drug. These are: that the right person should receive the right drug, in the right dose, at the right time within the right intervals, via the right route, followed by the right (correct) documentation. The author argues that the observance of these 'rights' by children's nurses ensures the best pharmacotherapeutic practice, thus a robust practical safeguard in adverse drug reactions and threats to the good reputation of the nursing profession.

  17. Comparative Long-Term Effectiveness of a Monotherapy with Five Antiepileptic Drugs for Focal Epilepsy in Adult Patients: A Prospective Cohort Study

    PubMed Central

    Zhu, Pan; He, Ru-Qian; Bao, Yi-Xin; Zheng, Rong-Yuan; Xu, Hui-Qin

    2015-01-01

    Objective To evaluate and compare long-term effectiveness of five antiepileptic drugs (AEDs) for monotherapy of adult patients with focal epilepsy in routine clinical practice. Methods Adult patients with focal epilepsy, who were prescribed with carbamazepine (CBZ), valproate (VPA), lamotrigine (LTG), topiramate (TPM), or oxcarbazepine (OXC) as monotherapy, during the period from January 2004 to June 2012 registered in Wenzhou Epilepsy Follow Up Registry Database (WEFURD), were included in the study. Prospective long-term follow-up was conducted until June 2013. The endpoints were time to treatment failure, time to seizure remission, and time to first seizure. Results This study included 654 patients: CBZ (n=125), VPA (n=151), LTG (n=135), TPM (n=76), and OXC (n=167). The retention rates of CBZ, VPA, LTG, TPM, and OXC at the third year were 36.1%, 32.4%, 57.6%, 37.9%, and 41.8%, respectively. For time to treatment failure, LTG was significantly better than CBZ and VPA (LTG vs. CBZ, hazard ratio, [HR] 0.80 [95% confidence interval: 0.67-0.96], LTG vs. VPA, 0.53 [0.37-0.74]); TPM was worse than LTG (TPM vs. LTG, 1.77 [1.15-2.74]), and OXC was better than VPA (0.86 [0.78-0.96]). After initial target doses, the seizure remission rates of CBZ, VPA, LTG, TPM, and OXC were 63.0%, 77.0%, 83.6%, 67.9%, and 75.3%, respectively. LTG was significantly better than CBZ (1.44 [1.15-1.82]) and OXC (LTG vs. OXC, 0.76 [0.63-0.93]); OXC was less effective than LTG in preventing the first seizure (1.20 [1.02-1.40]). Conclusion LTG was the best, OXC was better than VPA only, while VPA was the worst. The others were equivalent for comparisons between five AEDs regarding the long-term treatment outcomes of monotherapy for adult patients with focal epilepsy in a clinical practice. For selecting AEDs for these patients among the first-line drugs, LTG is an appropriate first choice; others are reservation in the first-line but VPA is not. PMID:26147937

  18. Reporting of adverse events for marketed drugs: Need for strengthening safety database

    PubMed Central

    Apte, Aditi Anand

    2016-01-01

    Pharmacovigilance is an evolving discipline in the Indian context. However, there is limited regulatory guidance for adverse event reporting outside the purview of clinical trials. There are number of deficiencies in the framework for adverse event reporting from the perspective of pharma industry, health-care professional and general public due to which adverse events for marketed drugs are highly underreported. This article discusses the need to strengthen national safety database by promoting and mandating reporting of adverse events by all the stakeholders. PMID:27453826

  19. The radiology of adverse drug reactions and toxic hazards

    SciTech Connect

    Ansell, G.

    1985-01-01

    Dr. Ansell has produced a scholarly review of the radiology of drug reactions and toxic hazards in his latest book, which is based on over 1,200 articles in the world literature. About 800 of these articles are taken from outside the radiology literature, which indicates the need for this subject to be brought to the attention of the radiologist, particularly as concern about drug reactions and toxic hazards is always increasing. The book includes sections covering the chest, gastrointestinal tract, renal tract, skeletal system and soft tissues, and skull and central nervous system. Each section treats specific substances, such as steroids and heavy metals; specific radiologic signs, such as ureteric dilation; specific symptoms, such as dysphagia; industrial toxins; radiographic abnormalities are discussed; and numerous high-quality radiographs.

  20. Can Drosophila melanogaster represent a model system for the detection of reproductive adverse drug reactions?

    PubMed

    Avanesian, Agnesa; Semnani, Sahar; Jafari, Mahtab

    2009-08-01

    Once a molecule is identified as a potential drug, the detection of adverse drug reactions is one of the key components of its development and the FDA approval process. We propose using Drosophila melanogaster to screen for reproductive adverse drug reactions in the early stages of drug development. Compared with other non-mammalian models, D. melanogaster has many similarities to the mammalian reproductive system, including putative sex hormones and conserved proteins involved in genitourinary development. Furthermore, the D. melanogaster model would present significant advantages in time efficiency and cost-effectiveness compared with mammalian models. We present data on methotrexate (MTX) reproductive adverse events in multiple animal models, including fruit flies, as proof-of-concept for the use of the D. melanogaster model. PMID:19482095

  1. Drug-drug interactions and adverse drug reactions in polypharmacy among older adults: an integrative review 1

    PubMed Central

    Rodrigues, Maria Cristina Soares; de Oliveira, Cesar

    2016-01-01

    ABSTRACT Objective: to identify and summarize studies examining both drug-drug interactions (DDI) and adverse drug reactions (ADR) in older adults polymedicated. Methods: an integrative review of studies published from January 2008 to December 2013, according to inclusion and exclusion criteria, in MEDLINE and EMBASE electronic databases were performed. Results: forty-seven full-text studies including 14,624,492 older adults (≥ 60 years) were analyzed: 24 (51.1%) concerning ADR, 14 (29.8%) DDI, and 9 studies (19.1%) investigating both DDI and ADR. We found a variety of methodological designs. The reviewed studies reinforced that polypharmacy is a multifactorial process, and predictors and inappropriate prescribing are associated with negative health outcomes, as increasing the frequency and types of ADRs and DDIs involving different drug classes, moreover, some studies show the most successful interventions to optimize prescribing. Conclusions: DDI and ADR among older adults continue to be a significant issue in the worldwide. The findings from the studies included in this integrative review, added to the previous reviews, can contribute to the improvement of advanced practices in geriatric nursing, to promote the safety of older patients in polypharmacy. However, more research is needed to elucidate gaps. PMID:27598380

  2. 3D Pharmacophoric Similarity improves Multi Adverse Drug Event Identification in Pharmacovigilance

    PubMed Central

    Vilar, Santiago; Tatonetti, Nicholas P.; Hripcsak, George

    2015-01-01

    Adverse drugs events (ADEs) detection constitutes a considerable concern in patient safety and public health care. For this reason, it is important to develop methods that improve ADE signal detection in pharmacovigilance databases. Our objective is to apply 3D pharmacophoric similarity models to enhance ADE recognition in Offsides, a pharmacovigilance resource with drug-ADE associations extracted from the FDA Adverse Event Reporting System (FAERS). We developed a multi-ADE predictor implementing 3D drug similarity based on a pharmacophoric approach, with an ADE reference standard extracted from the SIDER database. The results showed that the application of our 3D multi-type ADE predictor to the pharmacovigilance data in Offsides improved ADE identification and generated enriched sets of drug-ADE signals. The global ROC curve for the Offsides ADE candidates ranked with the 3D similarity score showed an area of 0.7. The 3D predictor also allows the identification of the most similar drug that causes the ADE under study, which could provide hypotheses about mechanisms of action and ADE etiology. Our method is useful in drug development, screening potential adverse effects in experimental drugs, and in drug safety, applicable to the evaluation of ADE signals selected through pharmacovigilance data mining. PMID:25744369

  3. 3D Pharmacophoric Similarity improves Multi Adverse Drug Event Identification in Pharmacovigilance

    NASA Astrophysics Data System (ADS)

    Vilar, Santiago; Tatonetti, Nicholas P.; Hripcsak, George

    2015-03-01

    Adverse drugs events (ADEs) detection constitutes a considerable concern in patient safety and public health care. For this reason, it is important to develop methods that improve ADE signal detection in pharmacovigilance databases. Our objective is to apply 3D pharmacophoric similarity models to enhance ADE recognition in Offsides, a pharmacovigilance resource with drug-ADE associations extracted from the FDA Adverse Event Reporting System (FAERS). We developed a multi-ADE predictor implementing 3D drug similarity based on a pharmacophoric approach, with an ADE reference standard extracted from the SIDER database. The results showed that the application of our 3D multi-type ADE predictor to the pharmacovigilance data in Offsides improved ADE identification and generated enriched sets of drug-ADE signals. The global ROC curve for the Offsides ADE candidates ranked with the 3D similarity score showed an area of 0.7. The 3D predictor also allows the identification of the most similar drug that causes the ADE under study, which could provide hypotheses about mechanisms of action and ADE etiology. Our method is useful in drug development, screening potential adverse effects in experimental drugs, and in drug safety, applicable to the evaluation of ADE signals selected through pharmacovigilance data mining.

  4. Alert systems for post-marketing surveillance of adverse drug reactions.

    PubMed

    Praus, M; Schindel, F; Fescharek, R; Schwarz, S

    1993-12-30

    When monitoring spontaneous reports of adverse reactions to registered drugs, it is important to detect any change in the number of reported adverse reactions in the course of time. Sales adjusted adverse drug reaction rates are usually compared in order to be able to take drug exposure into account. Here we review the so-called arithmetic and some statistical procedures which could form the basis for an alert system. The advantages and disadvantages of each of these methods are discussed. The importance of data requirements and the problems which arise when using an alert system are pointed out and then clarified with the help of the example of diphtheria/tetanus vaccine. PMID:8134741

  5. Biometrical issues in the analysis of adverse events within the benefit assessment of drugs.

    PubMed

    Bender, Ralf; Beckmann, Lars; Lange, Stefan

    2016-07-01

    The analysis of adverse events plays an important role in the benefit assessment of drugs. Consequently, results on adverse events are an integral part of reimbursement dossiers submitted by pharmaceutical companies to health policy decision-makers. Methods applied in the analysis of adverse events commonly include simple standard methods for contingency tables. However, the results produced may be misleading if observations are censored at the time of discontinuation due to treatment switching or noncompliance, resulting in unequal follow-up periods. In this paper, we present examples to show that the application of inadequate methods for the analysis of adverse events in the reimbursement dossier can lead to a downgrading of the evidence on a drug's benefit in the subsequent assessment, as greater harm from the drug cannot be excluded with sufficient certainty. Legal regulations on the benefit assessment of drugs in Germany are presented, in particular, with regard to the analysis of adverse events. Differences in safety considerations between the drug approval process and the benefit assessment are discussed. We show that the naive application of simple proportions in reimbursement dossiers frequently leads to uninterpretable results if observations are censored and the average follow-up periods differ between treatment groups. Likewise, the application of incidence rates may be misleading in the case of recurrent events and unequal follow-up periods. To allow for an appropriate benefit assessment of drugs, adequate survival time methods accounting for time dependencies and duration of follow-up are required, not only for time-to-event efficacy endpoints but also for adverse events. © 2016 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.

  6. Worldwide withdrawal of medicinal products because of adverse drug reactions: a systematic review and analysis.

    PubMed

    Onakpoya, Igho J; Heneghan, Carl J; Aronson, Jeffrey K

    2016-07-01

    We have systematically identified medicinal products withdrawn worldwide because of adverse drug reactions, assessed the level of evidence used for making the withdrawal decisions, and explored the patterns of withdrawals over time. We searched PubMed, the WHO database of withdrawn products, and selected texts. We included products that were withdrawn after launch from 1950 onwards, excluding non-human and over-the-counter medicines. We assessed the levels of evidence on which withdrawals were based using the Oxford Center for Evidence Based Medicine Levels of Evidence. Of 353 medicinal products withdrawn from any country, only 40 were withdrawn worldwide. Anecdotal reports were cited as evidence for withdrawal in 30 (75%) and deaths occurred in 27 (68%). Hepatic, cardiac, and nervous system toxicity accounted for over 60% of withdrawals. In 28 cases, the first withdrawal was initiated by the manufacturer. The median interval between the first report of an adverse drug reaction that led to withdrawal and the first withdrawal was 1 year (range 0-43 years). Worldwide withdrawals occurred within 1 year after the first withdrawal in any country. In conclusion, the time it takes for drugs to be withdrawn worldwide after reports of adverse drug reactions has shortened over time. However, there are inconsistencies in current withdrawal procedures when adverse drug reactions are suspected. A uniform method for establishing worldwide withdrawal of approved medicinal products when adverse drug reactions are suspected should be developed, to facilitate global withdrawals. Rapid synthesis of the evidence on harms should be a priority when serious adverse reactions are suspected. PMID:26941185

  7. Systematic Review of Adverse Effects from Herbal Drugs Reported in Randomized Controlled Trials.

    PubMed

    Lee, Ji Young; Jun, Seung Ah; Hong, Sung Shin; Ahn, Yo Chan; Lee, Dong Soo; Son, Chang Gue

    2016-09-01

    Herbal drugs have become a popular form of healthcare, raising concerns about their safety. This study aimed to characterize the adverse effects of herbal drugs through a systematic review of results reported in randomized controlled trials (RCTs). Using eight electronic databases including PubMed, the Cochrane library and six Korean medical databases, the frequency of reported toxicity was recorded based on drug composition and indication. Among 4957 potentially relevant articles, 242 papers comprised of 244 studies met our inclusion criteria; these included 111 studies of a single herb and 133 of multiple herbs. These studies accounted for a total 15 441 participants (male = 5590; female = 9851; 7383 for single and 8058 for multiple herb studies). There were 480 cases (3.1%) of adverse events (344 for single, 136 for multiple herb studies; p < 0.01). A total of 259 cases reported blood test abnormalities, including five cases of abnormality in hepatic functional enzymes. The most frequently reported adverse event was digestive symptoms (44.3%), followed by nervous system symptoms (17.3%) and behaviors such as loss of appetite (16.3%). This is the first systematic review of adverse effects of herbal drugs among clinical studies, and the results indicate that herbal drugs are relatively safe. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27196988

  8. Adverse drug reactions to self-medication: a study in a pharmacovigilance database.

    PubMed

    Berreni, Aurélia; Montastruc, François; Bondon-Guitton, Emmanuelle; Rousseau, Vanessa; Abadie, Delphine; Durrieu, Geneviève; Chebane, Leila; Giroud, Jean-Paul; Bagheri, Haleh; Montastruc, Jean-Louis

    2015-10-01

    Although self-medication is widely developed, there are few detailed data about its adverse drug reactions (ADRs). This study investigated the main characteristics of ADRs with self-medication recorded in the Midi-Pyrénées PharmacoVigilance between 2008 and 2014. Self-medication included first OTC drugs and second formerly prescribed drugs later used without medical advice (reuse of previously prescribed drugs). Among the 12 365 notifications recorded, 160 (1.3%) were related to SM with 186 drugs. Around three-forth of the ADRs were 'serious'. Mean age was 48.8 years with 56.3% females. The most frequent ADRs were gastrointestinal and neuropsychiatric and main drug classes involved NSAIDs, analgesics, and benzodiazepines. Phytotherapy-homeopathy accounted for 9.1% of drugs.

  9. Use of internet search logs to evaluate potential drug adverse events.

    PubMed

    Sarntivijai, S; Abernethy, D R

    2014-08-01

    Internet search logs provide an abundant source of data that can be explored for purposes such as identifying drug exposure-adverse event relationships. The methodology to rigorously conduct such evaluations is not well characterized, and the utility of such analyses is not well defined. In this issue, White and colleagues propose an approach using Internet search logs for this purpose and compare it to parallel analyses conducted using the US Food and Drug Administration's spontaneous reporting database.

  10. Adverse Drug Reaction Reporting Program of the Ontario Medical Association: the first 3 years.

    PubMed Central

    Gowdey, C W; Brennan, M

    1985-01-01

    This paper describes the Adverse Drug Reaction Reporting Program developed and operated by the Committee on Drugs and Pharmaco-therapy of the Ontario Medical Association. Analyses were done to demonstrate some of the trends derived from the reports. Some of the clinical observations based on the reports, which are published quarterly and circulated to physicians and to pharmacy, nursing and hospital organizations, are also reviewed. PMID:3871167

  11. Identifying adverse drug event information in clinical notes with distributional semantic representations of context.

    PubMed

    Henriksson, Aron; Kvist, Maria; Dalianis, Hercules; Duneld, Martin

    2015-10-01

    For the purpose of post-marketing drug safety surveillance, which has traditionally relied on the voluntary reporting of individual cases of adverse drug events (ADEs), other sources of information are now being explored, including electronic health records (EHRs), which give us access to enormous amounts of longitudinal observations of the treatment of patients and their drug use. Adverse drug events, which can be encoded in EHRs with certain diagnosis codes, are, however, heavily underreported. It is therefore important to develop capabilities to process, by means of computational methods, the more unstructured EHR data in the form of clinical notes, where clinicians may describe and reason around suspected ADEs. In this study, we report on the creation of an annotated corpus of Swedish health records for the purpose of learning to identify information pertaining to ADEs present in clinical notes. To this end, three key tasks are tackled: recognizing relevant named entities (disorders, symptoms, drugs), labeling attributes of the recognized entities (negation, speculation, temporality), and relationships between them (indication, adverse drug event). For each of the three tasks, leveraging models of distributional semantics - i.e., unsupervised methods that exploit co-occurrence information to model, typically in vector space, the meaning of words - and, in particular, combinations of such models, is shown to improve the predictive performance. The ability to make use of such unsupervised methods is critical when faced with large amounts of sparse and high-dimensional data, especially in domains where annotated resources are scarce.

  12. Identifying adverse drug event information in clinical notes with distributional semantic representations of context.

    PubMed

    Henriksson, Aron; Kvist, Maria; Dalianis, Hercules; Duneld, Martin

    2015-10-01

    For the purpose of post-marketing drug safety surveillance, which has traditionally relied on the voluntary reporting of individual cases of adverse drug events (ADEs), other sources of information are now being explored, including electronic health records (EHRs), which give us access to enormous amounts of longitudinal observations of the treatment of patients and their drug use. Adverse drug events, which can be encoded in EHRs with certain diagnosis codes, are, however, heavily underreported. It is therefore important to develop capabilities to process, by means of computational methods, the more unstructured EHR data in the form of clinical notes, where clinicians may describe and reason around suspected ADEs. In this study, we report on the creation of an annotated corpus of Swedish health records for the purpose of learning to identify information pertaining to ADEs present in clinical notes. To this end, three key tasks are tackled: recognizing relevant named entities (disorders, symptoms, drugs), labeling attributes of the recognized entities (negation, speculation, temporality), and relationships between them (indication, adverse drug event). For each of the three tasks, leveraging models of distributional semantics - i.e., unsupervised methods that exploit co-occurrence information to model, typically in vector space, the meaning of words - and, in particular, combinations of such models, is shown to improve the predictive performance. The ability to make use of such unsupervised methods is critical when faced with large amounts of sparse and high-dimensional data, especially in domains where annotated resources are scarce. PMID:26291578

  13. Facilitating adverse drug event detection in pharmacovigilance databases using molecular structure similarity: application to rhabdomyolysis

    PubMed Central

    Vilar, Santiago; Harpaz, Rave; Chase, Herbert S; Costanzi, Stefano; Rabadan, Raul

    2011-01-01

    Background Adverse drug events (ADE) cause considerable harm to patients, and consequently their detection is critical for patient safety. The US Food and Drug Administration maintains an adverse event reporting system (AERS) to facilitate the detection of ADE in drugs. Various data mining approaches have been developed that use AERS to detect signals identifying associations between drugs and ADE. The signals must then be monitored further by domain experts, which is a time-consuming task. Objective To develop a new methodology that combines existing data mining algorithms with chemical information by analysis of molecular fingerprints to enhance initial ADE signals generated from AERS, and to provide a decision support mechanism to facilitate the identification of novel adverse events. Results The method achieved a significant improvement in precision in identifying known ADE, and a more than twofold signal enhancement when applied to the ADE rhabdomyolysis. The simplicity of the method assists in highlighting the etiology of the ADE by identifying structurally similar drugs. A set of drugs with strong evidence from both AERS and molecular fingerprint-based modeling is constructed for further analysis. Conclusion The results demonstrate that the proposed methodology could be used as a pharmacovigilance decision support tool to facilitate ADE detection. PMID:21946238

  14. Drug target prediction using adverse event report systems: a pharmacogenomic approach

    PubMed Central

    Takarabe, Masataka; Kotera, Masaaki; Nishimura, Yosuke; Goto, Susumu; Yamanishi, Yoshihiro

    2012-01-01

    Motivation: Unexpected drug activities derived from off-targets are usually undesired and harmful; however, they can occasionally be beneficial for different therapeutic indications. There are many uncharacterized drugs whose target proteins (including the primary target and off-targets) remain unknown. The identification of all potential drug targets has become an important issue in drug repositioning to reuse known drugs for new therapeutic indications. Results: We defined pharmacological similarity for all possible drugs using the US Food and Drug Administration's (FDA's) adverse event reporting system (AERS) and developed a new method to predict unknown drug–target interactions on a large scale from the integration of pharmacological similarity of drugs and genomic sequence similarity of target proteins in the framework of a pharmacogenomic approach. The proposed method was applicable to a large number of drugs and it was useful especially for predicting unknown drug–target interactions that could not be expected from drug chemical structures. We made a comprehensive prediction for potential off-targets of 1874 drugs with known targets and potential target profiles of 2519 drugs without known targets, which suggests many potential drug–target interactions that were not predicted by previous chemogenomic or pharmacogenomic approaches. Availability: Softwares are available upon request. Contact: yamanishi@bioreg.kyushu-u.ac.jp Supplementary Information: Datasets and all results are available at http://cbio.ensmp.fr/~yyamanishi/aers/. PMID:22962489

  15. [The Beers List as an aid to prevent adverse drug reactions in elderly patients].

    PubMed

    Vingerhoets, R W; van Marum, R J; Jansen, P A F

    2005-09-17

    Elderly patients are highly susceptible for developing adverse drug reactions (ADR) that can lead to hospitalisation or death. Most of these ADR can be prevented if doctors adjust their prescriptions. Beers et al. have developed a list of drugs that should not be prescribed to elderly patients since they are known for their association with serious ADR. In The Netherlands, 20% of elderly patients receive drugs that are in the so-called Beers list. Although the Beers list has not been adjusted to the Dutch situation, avoidance of these drugs may reduce drug-related hospital admittance. Development of an improved list of drugs that should not be prescribed to elderly patients is needed that is applicable to The Netherlands. PMID:16201599

  16. Adverse drug reactions as the cause of emergency department admission: focus on the elderly.

    PubMed

    Ventura, Maria Teresa; Laddaga, Rocco; Cavallera, Pierfranco; Pugliese, Piervito; Tummolo, Roberto A; Buquicchio, Rosalba; Pierucci, Paola; Passalacqua, Gianni

    2010-09-01

    The use of medications could be responsible of both side effects and adverse drug reaction (ADR). Identifying risk factors could improve the possibility of avoiding severe reactions in old people. We investigated the prevalence of unpredictable drug adverse reactions among patients admitted to the emergency departments (EDs) of three large Italian hospitals in the period 2005-2008. Clinical characteristics and demographics were carefully recorded in a dedicated database. The assessment of the drug reactions was carried out by an allergist after the first emergency evaluation. Over the considered period, 56,031 patients were admitted at the ED, 2644 (21.2%) of which for ADR. Out of those patients, 55 (2.1%) were identified as unpredictable ADRs. In 96% of the cases the clinical presentation was cutaneous and antibiotics were the most frequently responsible drugs. Patients over 65 years accounted for 37% of the reactions. In those patients the multiple drug regimens were significantly more frequent, as well as the presence of comorbidities. Smoking habit, alcohol abuse and personal and familiar history of atopy did not differ between the younger and the elderly. In the older group, antibiotics were more frequently involved, whereas in the <65 years, nonsteroidal antinflammatory drugs accounted for most reactions. Our date outline that in the elderly the comorbidities and correlated multiple regime therapy cause an increased incidence of ADRs, thus suggesting a careful management of therapeutics regimens by means of educational campaigns for patients and guidelines for doctors finalized to avoid excessive drug prescription. PMID:20095805

  17. Identifying plausible adverse drug reactions using knowledge extracted from the literature

    PubMed Central

    Shang, Ning; Xu, Hua; Rindflesch, Thomas C.; Cohen, Trevor

    2014-01-01

    Pharmacovigilance involves continually monitoring drug safety after drugs are put to market. To aid this process; algorithms for the identification of strongly correlated drug/adverse drug reaction (ADR) pairs from data sources such as adverse event reporting systems or Electronic Health Records have been developed. These methods are generally statistical in nature, and do not draw upon the large volumes of knowledge embedded in the biomedical literature. In this paper, we investigate the ability of scalable Literature Based Discovery (LBD) methods to identify side effects of pharmaceutical agents. The advantage of LBD methods is that they can provide evidence from the literature to support the plausibility of a drug/ ADR association, thereby assisting human review to validate the signal, which is an essential component of pharmacovigilance. To do so, we draw upon vast repositories of knowledge that has been extracted from the biomedical literature by two Natural Language Processing tools, MetaMap and SemRep. We evaluate two LBD methods that scale comfortably to the volume of knowledge available in these repositories. Specifically, we evaluate Reflective Random Indexing (RRI), a model based on concept-level co-occurrence, and Predication-based Semantic Indexing (PSI), a model that encodes the nature of the relationship between concepts to support reasoning analogically about drug-effect relationships. An evaluation set was constructed from the Side Effect Resource 2 (SIDER2), which contains known drug/ADR relations, and models were evaluated for their ability to “rediscover” these relations. In this paper, we demonstrate that both RRI and PSI can recover known drug-adverse event associations. However, PSI performed better overall, and has the additional advantage of being able to recover the literature underlying the reasoning pathways it used to make its predictions. PMID:25046831

  18. Monitoring adverse reactions to food additives in the U.S. Food and Drug Administration.

    PubMed

    Tollefson, L

    1988-12-01

    Technological advances in food science have resulted in the development of numerous food additives, most of which require premarket approval by the Food and Drug Administration (FDA). Concomitant with the benefits of these additives, such as extending the shelf life of certain food commodities, is the potential for various risks. These potential risks include the possibility of the consumer experiencing an adverse reaction to the additive. In order to ascertain the character and the gravity of alleged adverse reactions to food products which it regulates, the FDA's Center for Food Safety and Applied Nutrition has developed the Adverse Reaction Monitoring System (ARMS). This postmarketing surveillance system for food additives is designed to analyze consumer reports of adverse reactions in order to alert FDA officials about any potential public health hazard associated with an approved food additive, and to delineate specific syndromes which may lead to focused clinical investigations. To date, among the products routinely monitored in the ARMS, sulfiting agents and the artificial sweetener aspartame have generated the largest volume of consumer reports describing adverse reactions. An overview of the analyses of the sulfite and aspartame adverse reaction reports is presented, along with a description of the mechanics of the postmarketing surveillance system, and a detailed discussion of its limitations.

  19. Integrating Multiple Evidence Sources to Predict Adverse Drug Reactions Based on a Systems Pharmacology Model

    PubMed Central

    Cao, D-S; Xiao, N; Li, Y-J; Zeng, W-B; Liang, Y-Z; Lu, A-P; Xu, Q-S; Chen, AF

    2015-01-01

    Identifying potential adverse drug reactions (ADRs) is critically important for drug discovery and public health. Here we developed a multiple evidence fusion (MEF) method for the large-scale prediction of drug ADRs that can handle both approved drugs and novel molecules. MEF is based on the similarity reference by collaborative filtering, and integrates multiple similarity measures from various data types, taking advantage of the complementarity in the data. We used MEF to integrate drug-related and ADR-related data from multiple levels, including the network structural data formed by known drug–ADR relationships for predicting likely unknown ADRs. On cross-validation, it obtains high sensitivity and specificity, substantially outperforming existing methods that utilize single or a few data types. We validated our prediction by their overlap with drug–ADR associations that are known in databases. The proposed computational method could be used for complementary hypothesis generation and rapid analysis of potential drug–ADR interactions. PMID:26451329

  20. [Analysis of 103 cases with adverse drug reactions induced by sanqizongzaogan injection].

    PubMed

    Chen, Yamei; Li, Yaowang; Zhu, Guanghui

    2010-01-01

    To analyze the characteristics and relative factors of adverse drug reactions (ADR) induced by sanqizongzaogan injection, in order to provide reference for the clinical use of sanqizongzaogan injection properly. The 103 reported cases of ADR induced by sanqizongzaogan injection in China over 15 years were retrospectively analyzed. The 103 ADR cases, 41.7% occurred in patients aged above 60. The most common presentation of ADR was drug eruption, followed by allergic reactions (20.4%) and allergic shock (9.7%). The occurrence of ADR is affected by many factors. We should control the drug indication strictly, check patients drug allergy history carefully before prescription, monitor ADR afterwards, promote clinical rational drug-usage. PMID:20394303

  1. Identifying Adverse Effects of HIV Drug Treatment and Associated Sentiments Using Twitter

    PubMed Central

    Adrover, Cosme; Bodnar, Todd; Huang, Zhuojie

    2015-01-01

    Background Social media platforms are increasingly seen as a source of data on a wide range of health issues. Twitter is of particular interest for public health surveillance because of its public nature. However, the very public nature of social media platforms such as Twitter may act as a barrier to public health surveillance, as people may be reluctant to publicly disclose information about their health. This is of particular concern in the context of diseases that are associated with a certain degree of stigma, such as HIV/AIDS. Objective The objective of the study is to assess whether adverse effects of HIV drug treatment and associated sentiments can be determined using publicly available data from social media. Methods We describe a combined approach of machine learning and crowdsourced human assessment to identify adverse effects of HIV drug treatment solely on individual reports posted publicly on Twitter. Starting from a large dataset of 40 million tweets collected over three years, we identify a very small subset (1642; 0.004%) of individual reports describing personal experiences with HIV drug treatment. Results Despite the small size of the extracted final dataset, the summary representation of adverse effects attributed to specific drugs, or drug combinations, accurately captures well-recognized toxicities. In addition, the data allowed us to discriminate across specific drug compounds, to identify preferred drugs over time, and to capture novel events such as the availability of preexposure prophylaxis. Conclusions The effect of limited data sharing due to the public nature of the data can be partially offset by the large number of people sharing data in the first place, an observation that may play a key role in digital epidemiology in general. PMID:27227141

  2. Pharmacogenomics of severe cutaneous adverse reactions and drug-induced liver injury.

    PubMed

    Kaniwa, Nahoko; Saito, Yoshiro

    2013-06-01

    Rare but severe adverse drug reactions (ADRs) are an important issue in drug development and in the proper usage of drugs during the post-approval phase. The ability to predict patient susceptibility to severe ADRs would prevent drug administration to high-risk patients. This would save lives and ensure the quality of life for these patients, but occurrence of idiosyncratic severe ADRs had been very difficult to predict for a long time. However, in this decade, genetic markers have been found for several ADRs, especially for severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI). In this review, we summarize recent progress in identifying genetic markers for SCARS and DILI, and discuss issues that remain unresolved. As for SCARs, associations of HLA-B*15:02 or HLA-A*31:01 and HLA-B*58:01 have been revealed for carbamazepine- and allopurinol-related Stevens-Johnson syndrome and toxic epidermal neclolysis, respectively. HLA-B*57:01 is strongly associated with abacavir-induced hypersensitivity syndrome. Several HLA alleles also demonstrate drug-specific associations with DILI, such as HLA-A*33:03 for ticlopidine, HLA-B*57:01 for flucloxacillin and HLA-DQA1*02:01 for lapatinib. Efforts should be continued to find other genetic markers to achieve high predictability for ADRs, with the goal being development of genetic tests for use in clinical settings.

  3. Difficulties in Treatment and Management of Epilepsy and Challenges in New Drug Development

    PubMed Central

    Wahab, Abdul

    2010-01-01

    Epilepsy is a serious neurological disorder that affects around 50 million people worldwide. Almost 30% of epileptic patients suffer from pharmacoresistance, which is associated with social isolation, dependent behaviour, low marriage rates, unemployment, psychological issues and reduced quality of life. Currently available antiepileptic drugs have a limited efficacy, and their negative properties limit their use and cause difficulties in patient management. Antiepileptic drugs can provide only symptomatic relief as these drugs suppress seizures but do not have ability to cure epileptogenesis. The long term use of antiepileptic drugs is limited due to their adverse effects, withdrawal symptoms, deleterious interactions with other drugs and economic burden, especially in developing countries. Furthermore, some of the available antiepileptic drugs may even potentiate certain type of seizures. Several in vivo and in vitro animal models have been proposed and many new antiepileptic drugs have been marketed recently, but large numbers of patients are still pharmacoresistant. This review will highlight the difficulties in treatment and management of epilepsy and the limitations of available antiepileptic drugs and animal seizure models.

  4. Difficulties in Treatment and Management of Epilepsy and Challenges in New Drug Development

    PubMed Central

    Wahab, Abdul

    2010-01-01

    Epilepsy is a serious neurological disorder that affects around 50 million people worldwide. Almost 30% of epileptic patients suffer from pharmacoresistance, which is associated with social isolation, dependent behaviour, low marriage rates, unemployment, psychological issues and reduced quality of life. Currently available antiepileptic drugs have a limited efficacy, and their negative properties limit their use and cause difficulties in patient management. Antiepileptic drugs can provide only symptomatic relief as these drugs suppress seizures but do not have ability to cure epileptogenesis. The long term use of antiepileptic drugs is limited due to their adverse effects, withdrawal symptoms, deleterious interactions with other drugs and economic burden, especially in developing countries. Furthermore, some of the available antiepileptic drugs may even potentiate certain type of seizures. Several in vivo and in vitro animal models have been proposed and many new antiepileptic drugs have been marketed recently, but large numbers of patients are still pharmacoresistant. This review will highlight the difficulties in treatment and management of epilepsy and the limitations of available antiepileptic drugs and animal seizure models. PMID:27713344

  5. Adverse drug reaction and concepts of drug safety in Ayurveda: An overview

    PubMed Central

    Ajanal, Manjunath; Nayak, Shradda; Prasad, Buduru Sreenivasa; Kadam, Avinash

    2013-01-01

    Drug safety is a very basic and fundamental concept in medical practice. ADRs play an important role in assessing patient safety in any system of medicine. Pharmacovigilance study is thus significant to understand treatment outcomes. Current raised issue with respect to complementary and alternative system medicine (CAM) like Ayurveda is increased in number of safety reports along with report misinterpretation; this generates the negative impact on system. Although, Ayurveda which is holistic system of medicine from India has elaborated the causes and methods of drug-induced consequences along with preventive measures the available data in classical texts is scattered. The compilation and analysis along with modern concept drug safety is need of the hour. Present literature review was conducted from various compendium of Ayurveda and electronic data base with search terms of ‘Vyapad’, ‘Viruddha’, ‘Ahita’, ‘herb–herb interaction’, ‘idiosyncrasy’, ‘Prakritiviruddha’ etc. The reported information was analysed for the possible correlation on concept of ADR and Pharmacovigilance of current science. Overall review demonstrated that drug interaction, iatrogenic, over dose, administration of unsuitable drugs, reprehensive drug administration with respect to disease, complication from five procedural therapies (Panchakarma) and reprehensible preparation of mineral drug are nearer to the modern causes of ADR. Thus, concept of drug safety and ADR is not new to the Ayurveda. The concept “Drug which is not appropriate to be used as medicine”(Abheshaja) of Ayurveda sounds similar as that of modern pharmacovigilance. PMID:24563588

  6. Recent Literature on Medication Errors and Adverse Drug Events in Older Adults

    PubMed Central

    Naples, Jennifer G.; Hanlon, Joseph T.; Schmader, Kenneth E.; Semla, Todd P.

    2015-01-01

    Medication errors and adverse drug events are common in older adults, but locating literature addressing these issues is often challenging. The objective of this article was to summarize recent studies addressing medication errors and adverse drug events in a single location to improve accessibility for individuals working with older adults. The authors conducted a comprehensive literature search for studies published in 2014 and identified 51 potential articles. After critical review, 17 studies were selected for inclusion based on innovation, rigorous observational or experimental study designs, and use of reliable, valid measures. Four articles characterizing potentially inappropriate prescribing and interventions to optimize medication regimens were annotated and critiqued in detail. We hope that health policy makers and clinicians find this information helpful in improving the quality of care for older adults. PMID:26804210

  7. Adverse Outcome Pathways as Tools to Assess Drug-Induced Toxicity.

    PubMed

    Vinken, Mathieu

    2016-01-01

    Adverse outcome pathways (AOPs) are novel tools in toxicology and human risk assessment with broad potential. AOPs are designed to provide a clear-cut mechanistic representation of toxicological effects that span over different layers of biological organization. AOPs share a common structure consisting of a molecular initiating event, a series of key events connected by key event relationships, and an adverse outcome. Development and evaluation of AOPs ideally complies with guidelines issued by the Organization for Economic Cooperation and Development. AOP frameworks have yet been proposed for major types of drug-induced injury, especially in the liver, including steatosis, fibrosis, and cholestasis. These newly postulated AOPs can serve a number of purposes pertinent to safety assessment of drugs, in particular the establishment of quantitative structure-activity relationships, the development of novel in vitro toxicity screening tests, and the elaboration of prioritization strategies. PMID:27311472

  8. [Underreporting adverse drug reactions--limitations of the Dutch Hospital Data database].

    PubMed

    Dijkers, Fred W

    2013-01-01

    Data of adverse drug reaction (ADR)-related hospitalizations derived from the Dutch Hospital Data database with reasons for hospitalization have a limited value since they are incomplete. This is attributed to underreporting and misclassification. It seems that caregivers are not careful in registering ADRs. Since 2005, many instruments (rules and agreements) have been devised to promote the safety of medical therapy. It is uncertain whether these instruments will diminish the number of ADR-related hospitalizations. Having a lot of rules is no guarantee that the process will improve. In the vast majority of the rules and agreements, patients have only a modest position. Yet they can play an important role in pharmacovigilance as is shown in a study of web-based intensive monitoring of adverse drug reactions.

  9. The Impact of Herbal Drug Use on Adverse Drug Reaction Profiles of Patients on Antiretroviral Therapy in Zimbabwe

    PubMed Central

    Mudzviti, Tinashe; Maponga, Charles C.; Khoza, Star; Ma, Qing; Morse, Gene D.

    2012-01-01

    Background. The main objective was to determine the impact of herbal drug use on adverse drug reactions in patients on antiretroviral therapy (ART). Methodology. Patients receiving first-line ART from the national roll-out program participated in this cross-sectional study. Participants were interviewed and a data collection sheet was used to collect information from the corresponding medical record. Results. The majority (98.2%) of participants were using at least one herbal drug together with ART. The most common herbal remedies used were Allium Sativum (72.7%), Bidens pilosa (66.0%), Eucalyptus globulus (52.3%), Moringa oleifera (44.1%), Lippia javanica (36.3%), and Peltoforum africanum (34.3%). Two indigenous herbs, Musakavakadzi (OR = 0.25; 95% CI 0.076–0.828) and Peltoforum africanum (OR = 0.495; 95% CI 0.292–0.839) reduced the occurrence of adverse drug events. Conclusions. The use of herbal drugs is high in the HIV-infected population and there is need for pharmacovigilance programs to recognize the role they play in altering ADR profiles. PMID:22506106

  10. [Analysis of the cardiac side effects of antipsychotics: Japanese Adverse Drug Event Report Database (JADER)].

    PubMed

    Ikeno, Takashi; Okumara, Yasuyuki; Kugiyama, Kiyotaka; Ito, Hiroto

    2013-08-01

    We analyzed the cases of side effects due to antipsychotics reported to Japan's Pharmaceuticals and Medical Devices Agency (PMDA) from Jan. 2004 to Dec. 2012. We used the Japanese Adverse Drug Event Report Database (JADER) and analyzed 136 of 216,945 cases using the defined terms. We also checked the cardiac adverse effects listed in the package inserts of the antipsychotics involved. We found cases of Ikr blockade resulting in sudden death (49 cases), electrocardiogram QT prolonged (29 cases), torsade de pointes (TdP, 19 cases), ventricular fibrillation (VF, 10 cases). M2 receptor blockade was observed in tachycardia (8 cases) and sinus tachycardia (3 cases). Calmodulin blockade was involved in reported cardiomyopathy (3 cases) and myocarditis (1 case). Multiple adverse events were reported simultaneously in 14 cases. Our search of package inserts revealed warnings regarding electrocardiogram QT prolongation (24 drugs), tachycardia (23), sudden death (18), TdP (14), VF (3), myocarditis (1) and cardiomyopathy (1). We suggest that when an antipsychotic is prescribed, the patient should be monitored regularly with ECG, blood tests, and/or biochemical tests to avoid adverse cardiac effects. PMID:25069255

  11. Digging Up the Human Genome: Current Progress in Deciphering Adverse Drug Reactions

    PubMed Central

    Chung, Wen-Hung

    2014-01-01

    Adverse drug reactions (ADRs) are a major clinical problem. In addition to their clinical impact on human health, there is an enormous cost associated with ADRs in health care and pharmaceutical industry. Increasing studies revealed that genetic variants can determine the susceptibility of individuals to ADRs. The development of modern genomic technologies has led to a tremendous advancement of improving the drug safety and efficacy and minimizing the ADRs. This review will discuss the pharmacogenomic techniques used to unveil the determinants of ADRs and summarize the current progresses concerning the identification of biomarkers for ADRs, with a focus on genetic variants for genes encoding drug-metabolizing enzymes, drug-transporter proteins, and human leukocyte antigen (HLA). The knowledge gained from these cutting-edge findings will form the basis for better prediction and management for ADRs, ultimately making the medicine personalized. PMID:24734245

  12. Novel Data Mining Methodologies for Adverse Drug Event Discovery and Analysis

    PubMed Central

    Harpaz, Rave; DuMouchel, William; Shah, Nigam H.; Madigan, David; Ryan, Patrick; Friedman, Carol

    2013-01-01

    Introduction Discovery of new adverse drug events (ADEs) in the post-approval period is an important goal of the health system. Data mining methods that can transform data into meaningful knowledge to inform patient safety have proven to be essential. New opportunities have emerged to harness data sources that have not been used within the traditional framework. This article provides an overview of recent methodological innovations and data sources used in support of ADE discovery and analysis. PMID:22549283

  13. Establishing causality in pediatric adverse drug reactions: use of the Naranjo probability scale.

    PubMed

    Avner, Marina; Finkelstein, Yaron; Hackam, Dan; Koren, Gideon

    2007-01-01

    Carbamazepine hypersensitivity syndrome is a rare, life-threatening condition. Its diagnosis is critical to avoid future exposure to aromatic anticonvulsants. Pediatricians rarely use a systematic approach to establish the cause of drug reactions in the clinical setting. We describe the use of the Naranjo adverse drug reaction probability scale to establish causality in three cases of suspected anticonvulsant hypersensitivity syndrome with the aim of introducing clinicians to this effective tool. Our analysis reveals that this method is useful, but also highlights potential areas for its improvement.

  14. [Non-steroid anti-inflammatory drugs and adverse gastrointestinal effects. An unresolved problem].

    PubMed

    López, A

    1999-01-01

    Non-steroid anti-inflammatory drugs are a class of medicine widely used throughout the world. This is a pharmacological group in continuous growth, to which some new molecules have been added in recent years. The great drawback of non-steroid anti-inflammatory drugs are their adverse effects, outstanding of which due to their frequency and importance being those that occur in the gastrointestinal tract. By means of a search in Medline and other databases, this work reviews the latest data published on the incidence of dyspepsia, gastroduodenal lesions, gastrointestinal complications and mortality associated with consumption of non-steroid anti-inflammatory drugs. Similarly, a brief description is made of the mechanism of lesions to the stomach of the non-steroid anti-inflammatory drugs and the different risk factors that condition the appearance of adverse effects at the gastrointestinal level. Finally, an analysis is made of the preventive strategy and the different medicines that can be used to this end and a contrast is made of the evidence extracted from the different published studies and the reality of the use of the different "gastroprotectors". This review concludes with a series of questions that still remain unresolved concerning treatment with non-steroid anti-inflammatory drugs and their lesions to the stomach.

  15. Predicting and detecting adverse drug reactions in old age: challenges and opportunities.

    PubMed

    Mangoni, Arduino A

    2012-05-01

    Increased, often inappropriate, drug exposure, pharmacokinetic and pharmacodynamic changes, reduced homeostatic reserve and frailty increase the risk of adverse drug reactions (ADRs) in the older population, thereby imposing a significant public health burden. Predicting and diagnosing ADRs in old age presents significant challenges for the clinician, even when specific risk scoring systems are available. The picture is further compounded by the potential adverse impact of several drugs on more 'global' health indicators, for example, physical function and independence, and the fragmentation of care (e.g., increased number of treating doctors and care transitions) experienced by older patients during their clinical journey. The current knowledge of drug safety in old age is also curtailed by the lack of efficacy and safety data from pre-marketing studies. Moreover, little consideration is given to individual patients' experiences and reporting of specific ADRs, particularly in the presence of cognitive impairment. Pending additional data on these issues, the close review and monitoring of individual patients' drug prescribing, clinical status and biochemical parameters remain essential to predict and detect ADRs in old age. Recently developed strategies, for example, medication reconciliation and trigger tool methodology, have the potential for ADRs risk mitigation in this population. However, more information is required on their efficacy and applicability in different healthcare settings. PMID:22512705

  16. Avoiding adverse drug reactions in the elderly patient: issues and strategies.

    PubMed

    French, D G

    1996-09-01

    Primary care providers are faced with numerous challenges when prescribing drugs for elderly patients. Multiple drug use, coexisting illness, and normal physiologic changes associated with aging place older persons at increased risk for adverse drug reactions (ADRs). Sample selection bias in drug clinical trials and inappropriate prescribing of contraindicated drugs contribute to the risk profile. Because multiple drug use and ADRs are relatively common in the elderly, special caution should be used when prescribing for this population. The primary care provider should have a good understanding of the factors that put the elderly at increased risk for ADR, the classes of drugs inappropriate for elderly patients, the physiologic changes of aging that may produce an altered pharmacologic response, and the issues associated with adherence to drug therapy. This article identifies factors that contribute to ADRs in the elderly and proposes strategies to reduce or avoid risk. Identifying and preventing ADRs in older Americans is a Healthy People 2000 health protection goal, perhaps more important given projected demographics over the next 20 to 30 years. PMID:8884797

  17. Clinically significant drug interactions.

    PubMed

    Ament, P W; Bertolino, J G; Liszewski, J L

    2000-03-15

    A large number of drugs are introduced every year, and new interactions between medications are increasingly reported. Consequently, it is no longer practical for physicians to rely on memory alone to avoid potential drug interactions. Multiple drug regimens carry the risk of adverse interactions. Precipitant drugs modify the object drug's absorption, distribution, metabolism, excretion or actual clinical effect. Nonsteroidal anti-inflammatory drugs, antibiotics and, in particular, rifampin are common precipitant drugs prescribed in primary care practice. Drugs with a narrow therapeutic range or low therapeutic index are more likely to be the objects for serious drug interactions. Object drugs in common use include warfarin, fluoroquinolones, antiepileptic drugs, oral contraceptives, cisapride and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Many other drugs, act as precipitants or objects, and a number of drugs act as both. Regularly updated manuals of drug interactions and CD-ROM-formatted programs are useful office references. PMID:10750880

  18. Orlistat-associated adverse effects and drug interactions: a critical review.

    PubMed

    Filippatos, Theodosios D; Derdemezis, Christos S; Gazi, Irene F; Nakou, Eleni S; Mikhailidis, Dimitri P; Elisaf, Moses S

    2008-01-01

    Orlistat, an anti-obesity drug, is a potent and specific inhibitor of intestinal lipases. In light of the recent US FDA approval of the over-the-counter sale of orlistat (60 mg three times daily), clinicians need to be aware that its use may be associated with less well known, but sometimes clinically relevant, adverse effects. More specifically, the use of orlistat has been associated with several mild-to-moderate gastrointestinal adverse effects, such as oily stools, diarrhoea, abdominal pain and faecal spotting. A few cases of serious hepatic adverse effects (cholelithiasis, cholostatic hepatitis and subacute liver failure) have been reported. However, the effects of orlistat on non-alcoholic fatty liver disease are beneficial. Orlistat-induced weight loss seems to have beneficial effects on blood pressure. No effect has been observed on calcium, phosphorus, magnesium, iron, copper or zinc balance or on bone biomarkers. Interestingly, the use of orlistat has been associated with rare cases of acute kidney injury, possibly due to the increased fat malabsorption resulting from the inhibition of pancreatic and gastric lipase by orlistat, leading to the formation of soaps with calcium and resulting in increased free oxalate absorption and enteric hyperoxaluria. Orlistat has a beneficial effect on carbohydrate metabolism. No significant effect on cancer risk has been reported with orlistat.Orlistat interferes with the absorption of many drugs (such as warfarin, amiodarone, ciclosporin and thyroxine as well as fat-soluble vitamins), affecting their bioavailability and effectiveness. This review considers orlistat-related adverse effects and drug interactions. The clinical relevance and pathogenesis of these effects is also discussed.

  19. [Pharmacogenetic research in the association between human leukocyte antigen and adverse drug reactions].

    PubMed

    Xiong, Yan; Zhang, Wei; Chen, Xiaoping

    2014-07-01

    With the rapid development of pharmacogenetics, more and more studies have shown evidence in the association between polymorphisms at the human leukocyte antigen (HLA) loci and severe adverse drug reactions (SADRs). Several HLA-B alleles proved to be associated with SADRs for drugs such as carbamazepine, allopurinol, lamotrigine, and flucloxacillin. The USA Food and Drug Administration (FDA) has even recommended routine screening for HLA-B allele before the use of abacavir and carbamazepine. With the completion of human genome project and the Hapmap project, several new pharmacogenetics approaches such as genome-wide association study (GWAS) have emerged. These newly developed methods will undoubtedly accelerate the identification and clinical utilization of the pharmacogenetic biomakers. In addition, the immunogenetic mechanisms by which the HLA alleles cause SADRs are explored at the cellular and molecular level. This review focuses on the recent progresses in HLA alleles and ADRs regarding both the clinical translation and modern pharmacogenetic methods. PMID:25080918

  20. Automated Summarization of Publications Associated with Adverse Drug Reactions from PubMed

    PubMed Central

    Finkelstein, Joseph; Chen, Qinlang; Adams, Hayden; Friedman, Carol

    2016-01-01

    Academic literature provides rich and up-to-date information concerning adverse drug reactions (ADR), but it is time consuming and labor intensive for physicians to obtain information of ADRs from academic literature because they would have to generate queries, review retrieved articles and summarize the results. In this study, a method is developed to automatically detect and summarize ADRs from journal articles, rank them and present them to physicians in a user-friendly interface. The method studied ADRs for 6 drugs and returned on average 4.8 ADRs that were correct. The results demonstrated this method was feasible and effective. This method can be applied in clinical practice for assisting physicians to efficiently obtain information about ADRs associated with specific drugs. Automated summarization of ADR information from recent publications may facilitate translation of academic research into actionable information at point of care. PMID:27570654

  1. Wheeze as an Adverse Event in Pediatric Vaccine and Drug Randomized Controlled Trials: A Systematic Review

    PubMed Central

    Marangu, Diana; Kovacs, Stephanie; Walson, Judd; Bonhoeffer, Jan; Ortiz, Justin R.; John-Stewart, Grace; Horne, David J.

    2016-01-01

    Introduction Wheeze is an important sign indicating a potentially severe adverse event in vaccine and drug trials, particularly in children. However, there are currently no consensus definitions of wheeze or associated respiratory compromise in randomized controlled trials (RCTs). Objective To identify definitions and severity grading scales of wheeze as an adverse event in vaccine and drug RCTs enrolling children <5 years and to determine their diagnostic performance based on sensitivity, specificity and inter-observer agreement. Methods We performed a systematic review of electronic databases and reference lists with restrictions for trial settings, English language and publication date ≥ 1970. Wheeze definitions and severity grading were abstracted and ranked by a diagnostic certainty score based on sensitivity, specificity and inter-observer agreement. Results Of 1,205 articles identified using our broad search terms, we identified 58 eligible trials conducted in 38 countries, mainly in high-income settings. Vaccines made up the majority (90%) of interventions, particularly influenza vaccines (65%). Only 15 trials provided explicit definitions of wheeze. Of 24 studies that described severity, 11 described wheeze severity in the context of an explicit wheeze definition. The remaining 13 studies described wheeze severity where wheeze was defined as part of a respiratory illness or a wheeze equivalent. Wheeze descriptions were elicited from caregiver reports (14%), physical examination by a health worker (45%) or a combination (41%). There were 21/58 studies in which wheeze definitions included combined caregiver report and healthcare worker assessment. The use of these two methods appeared to have the highest combined sensitivity and specificity. Conclusion Standardized wheeze definitions and severity grading scales for use in pediatric vaccine or drug trials are lacking. Standardized definitions of wheeze are needed for assessment of possible adverse events as

  2. Quality of Reporting of Serious Adverse Drug Events to an Institutional Review Board

    PubMed Central

    Dorr, David A.; Burdon, Rachel; West, Dennis P.; Lagman, Jennifer; Georgopoulos, Christina; Belknap, Steven M.; McKoy, June M.; Djulbegovic, Benjamin; Edwards, Beatrice J.; Weitzman, Sigmund A.; Boyle, Simone; Tallman, Martin S.; Talpaz, Moshe; Sartor, Oliver; Bennett, Charles L.

    2009-01-01

    Purpose Serious adverse drug event (sADE) reporting to Institutional Review Boards (IRB) is essential to ensure pharmaceutical safety. However, the quality of these reports has not been studied. Safety reports are especially important for cancer drugs that receive accelerated Food and Drug Administration approval, like imatinib, as preapproval experience with these drugs is limited. We evaluated the quality, accuracy, and completeness of sADE reports submitted to an IRB. Experimental Design sADE reports submitted to an IRB from 14 clinical trials with imatinib were reviewed. Structured case report forms, containing detailed clinical data fields and a validated causality assessment instrument, were developed. Two forms were generated for each ADE, the first populated with data abstracted from the IRB reports, and the second populated with data from the corresponding clinical record. Completeness and causality assessments were evaluated for each of the two sources, and then compared. Accuracy (concordance between sources) was also assessed. Results Of 115 sADEs reported for 177 cancer patients to the IRB, overall completeness of adverse event descriptions was 2.4-fold greater for structured case report forms populated with information from the clinical record versus the corresponding forms from IRB reports (95.0% versus 40.3%, P < 0.05). Information supporting causality assessments was recorded 3.5-fold more often in primary data sources versus IRB adverse event descriptions (93% versus 26%, P < 0.05). Some key clinical information was discrepant between the two sources. Conclusions The use of structured syndrome-specific case report forms could enhance the quality of reporting to IRBs, thereby improving the safety of pharmaceuticals administered to cancer patients. PMID:19458059

  3. Recognizing Severe Adverse Drug Reactions: Two Case Reports After Switching Therapies to the Same Generic Company.

    PubMed

    Gallelli, Luca; Gallelli, Giuseppe; Codamo, Giuseppe; Argentieri, Angela; Michniewicz, Andzelika; Siniscalchi, Antonio; Stefanelli, Roberta; Cione, Erika; Caroleo, Maria C; Longo, Paola; De Sarro, Giovambattista

    2016-01-01

    Generic formulations represent a way to reduce the costs of brand compounds when their patent is expired. While, the bio-equivalence in generic drugs is guaranteed, some excipients as well as dyes could be different and this could reduce the drug safety. Herein, we report the development of Adverse Drug Reactions (ADRs) in two patients after the switch from brand to generic formulations. We have tested cytochrome P450 enzymes expression as well as drug serum levels. None of these markers were altered. Checking deeply into both patient's medical history, they harbored poly-sensitivity or allergy to pollen and graminacea and used different active ingredients for different health problems coming from the same generic company Almus(®). This company used different dyes and excipients compared to the branded drugs made by distinguished companies. In conclusion, we strongly suggest to both pharmacists and physicians to be careful in giving the advice to change the drug, thinking to reduce health sanitary costs without considering the personal clinical history of each one. Paradoxically this behavior is causing other health issues, bringing to an increase of the overall costs for patients as well as for National Health System.

  4. Suspected adverse drug reactions in elderly patients reported to the Committee on Safety of Medicines.

    PubMed

    Castleden, C M; Pickles, H

    1988-10-01

    1. Spontaneous reports of suspected adverse drug reactions (ADRs) reported to the Committee on Safety of Medicines (CSM) have been studied in relation to patient age. 2. The proportion of reports received for the elderly increased between 1965 and 1983. 3. There was a correlation between the use of drugs and the number of ADR reports. Thus age-related prescription figures for two non-steroidal anti-inflammatory drugs (NSAI) and co-trimoxazole matched ADR reports for each drug in each age group. 4. The reported ADR was more likely to be serious or fatal in the elderly. 5. The commonest ADRs reported for the elderly affected the gastrointestinal (GIT) and haemopoietic systems, where more reports were received than would be expected from prescription figures. 6. The drug suspected of causing a GIT reaction was a NSAI in 75% of the reports. 7. Ninety-one per cent of fatal reports of GIT bleeds and perforations associated with NSAI drugs were in patients over 60 years of age. PMID:3263875

  5. Knowledge discovery of drug data on the example of adverse reaction prediction

    PubMed Central

    2014-01-01

    Background Antibiotics are the widely prescribed drugs for children and most likely to be related with adverse reactions. Record on adverse reactions and allergies from antibiotics considerably affect the prescription choices. We consider this a biomedical decision-making problem and explore hidden knowledge in survey results on data extracted from a big data pool of health records of children, from the Health Center of Osijek, Eastern Croatia. Results We applied and evaluated a k-means algorithm to the dataset to generate some clusters which have similar features. Our results highlight that some type of antibiotics form different clusters, which insight is most helpful for the clinician to support better decision-making. Conclusions Medical professionals can investigate the clusters which our study revealed, thus gaining useful knowledge and insight into this data for their clinical studies. PMID:25079450

  6. Infantile Spasms and Cytomegalovirus Infection: Antiviral and Antiepileptic Treatment

    ERIC Educational Resources Information Center

    Dunin-Wasowicz, Dorota; Kasprzyk-Obara, Jolanta; Jurkiewicz, Elzbieta; Kapusta, Monika; Milewska-Bobula, Bogumila

    2007-01-01

    From 1 January 1995 to 31 December 2004, 22 patients (13 males, nine females; age range 2-12mo) with infantile spasms and cytomegalovirus (CMV) infection were treated with intravenous ganciclovir (GCV) and antiepileptic drugs. GCV was given for 3 to 12 weeks with a 1-month interval (one, two, or three courses). Epileptic spasms occurred before…

  7. Adverse Health Consequences of Performance-Enhancing Drugs: An Endocrine Society Scientific Statement

    PubMed Central

    Pope, Harrison G.; Wood, Ruth I.; Rogol, Alan; Nyberg, Fred; Bowers, Larry

    2014-01-01

    Despite the high prevalence of performance-enhancing drug (PED) use, media attention has focused almost entirely on PED use by elite athletes to illicitly gain a competitive advantage in sports, and not on the health risks of PEDs. There is a widespread misperception that PED use is safe or that adverse effects are manageable. In reality, the vast majority of PED users are not athletes but rather nonathlete weightlifters, and the adverse health effects of PED use are greatly underappreciated. This scientific statement synthesizes available information on the medical consequences of PED use, identifies gaps in knowledge, and aims to focus the attention of the medical community and policymakers on PED use as an important public health problem. PED users frequently consume highly supraphysiologic doses of PEDs, combine them with other PEDs and/or other classical drugs of abuse, and display additional associated risk factors. PED use has been linked to an increased risk of death and a wide variety of cardiovascular, psychiatric, metabolic, endocrine, neurologic, infectious, hepatic, renal, and musculoskeletal disorders. Because randomized trials cannot ethically duplicate the large doses of PEDs and the many factors associated with PED use, we need observational studies to collect valid outcome data on the health risks associated with PEDs. In addition, we need studies regarding the prevalence of PED use, the mechanisms by which PEDs exert their adverse health effects, and the interactive effects of PEDs with sports injuries and other high-risk behaviors. We also need randomized trials to assess therapeutic interventions for treating the adverse effects of PEDs, such as the anabolic-androgen steroid withdrawal syndrome. Finally, we need to raise public awareness of the serious health consequences of PEDs. PMID:24423981

  8. Combing signals from spontaneous reports and electronic health records for detection of adverse drug reactions

    PubMed Central

    Harpaz, Rave; Vilar, Santiago; DuMouchel, William; Salmasian, Hojjat; Haerian, Krystl; Shah, Nigam H; Chase, Herbert S; Friedman, Carol

    2013-01-01

    Objective Data-mining algorithms that can produce accurate signals of potentially novel adverse drug reactions (ADRs) are a central component of pharmacovigilance. We propose a signal-detection strategy that combines the adverse event reporting system (AERS) of the Food and Drug Administration and electronic health records (EHRs) by requiring signaling in both sources. We claim that this approach leads to improved accuracy of signal detection when the goal is to produce a highly selective ranked set of candidate ADRs. Materials and methods Our investigation was based on over 4 million AERS reports and information extracted from 1.2 million EHR narratives. Well-established methodologies were used to generate signals from each source. The study focused on ADRs related to three high-profile serious adverse reactions. A reference standard of over 600 established and plausible ADRs was created and used to evaluate the proposed approach against a comparator. Results The combined signaling system achieved a statistically significant large improvement over AERS (baseline) in the precision of top ranked signals. The average improvement ranged from 31% to almost threefold for different evaluation categories. Using this system, we identified a new association between the agent, rasburicase, and the adverse event, acute pancreatitis, which was supported by clinical review. Conclusions The results provide promising initial evidence that combining AERS with EHRs via the framework of replicated signaling can improve the accuracy of signal detection for certain operating scenarios. The use of additional EHR data is required to further evaluate the capacity and limits of this system and to extend the generalizability of these results. PMID:23118093

  9. A prospective study of adverse drug reactions as a cause of admission to a paediatric hospital

    PubMed Central

    MARTÍNEZ-MIR, I.; GARCÍA-LÓPEZ, M.; PALOP, V.; FERRER, J. M.; ESTAÑ, L.; RUBIO, E.; MORALES-OLIVAS, F. J.

    1996-01-01

    1A total of 512 consecutive paediatric hospital admissions of children 2 years old or less were evaluated to assess the extent and pattern of admission caused by suspected adverse drug reactions (ADRs). The proportion of suspected ADRs related to hospital admissions was 4.3%. 2The organ-systems most commonly implicated were the central nervous system (40.5%), digestive system (16.7%), and skin and appendages (14.3%). Together, they accounted for 71.5% of admissions attributed to ADRs. The most common clinical manifestations inducing admission were convulsions (4 cases), dizziness (4), vomiting (3), and tremor, fever, itching and apnoea (2 cases each). 3The four classes of drugs most frequently suspected in admissions due to ADRs were respiratory drugs (35%), anti-infective agents (25%), drugs active on the central nervous system (15%) and drugs used in dermatology (10%). The most common drugs related to ADRs were a combination of chlorpheniramine, diphenhydramine, phenylephrine, guaiphenesin and salicylic acid (4 cases), followed by fenoterol, adrenaline, paracetamol, DTP vaccine and antipolio vaccine (2 cases each). 4There were no significant differences between children older and younger than 1 year (odds ratio 0.89; 95% CI 0.37–2.17) or between the sexes as regards hospital admittance due to suspected ADRs (odds ratio 1.94; 95% CI 0.72–5.42). 5The results of this kind of study may be influenced by patterns of drug utilization. Nevertheless, the lack of specific studies of drug effects in young children makes it desirable to carry out pharmacoepidemiological studies in this age group. PMID:8877022

  10. Drugs and adverse reactions: an economic view of a medical problem.

    PubMed

    Pedroni, G

    1984-01-01

    This monograph attempts to show how patient, physician and drug producer should assess the value and risks of a drug from the economic point of view. The value of a drug lies in its efficacy against disease and pain; the risks are the various side effects. A hypothetical example illustrates the evaluation from the point of view of an individual patient. A distinction must be made here between diseases which may prove fatal and those of a less serious nature. This means that a distinction must also be made in evaluating the risks attached to a drug and the individual attitude to side effects. For the physician, the task of recognizing an adverse drug reaction (ADR) is an extremely complex one. A 11-step flow chart for decision making is presented as a benchmark procedure. Several empirical studies on the incidence of ADRs in ambulatory and hospitalized patients are shown to use shortcuts, which are entirely justified in daily medical practice, but questionable in a scientific analysis. For various reasons the drug manufacturer too is anxious to recognize ADRs at an early stage and to avoid them whenever possible. Prolonged clinical trials, however, produce a steep rise in costs and delay the launching of the product, while the additional information obtained is not always comprehensive and exhaustive. Moreover, the mere fact of recognizing an ADR does not mean that it can be prevented. The producer is therefore forced to consider the risks and costs involved in speeding up or delaying the introduction of a product. The fact that the drug has been approved for sale does not automatically release introduction of a product. The fact that the drug has been approved for sale does not automatically release him from the obligation to carry out further intensive monitoring for the entire period that it is on the market.

  11. Patterns of Adverse Drug Reactions in Different Age Groups: Analysis of Spontaneous Reports by Community Pharmacists

    PubMed Central

    Yu, Yun Mi; Shin, Wan Gyoon; Lee, Ju-Yeun; Choi, Soo An; Jo, Yun Hee; Youn, So Jung; Lee, Mo Se; Choi, Kwang Hoon

    2015-01-01

    Purpose To evaluate the clinical manifestations and causative drugs associated with adverse drug reactions (ADRs) spontaneously reported by community pharmacists and to compare the ADRs by age. Methods ADRs reported to the Regional Pharmacovigilance Center of the Korean Pharmaceutical Association by community pharmacists from January 2013 to June 2014 were included. Causality was assessed using the WHO-Uppsala Monitoring Centre system. The patient population was classified into three age groups. We analyzed 31,398 (74.9%) ADRs from 9,705 patients, identified as having a causal relationship, from a total pool of 41,930 ADRs from 9,873 patients. Median patient age was 58.0 years; 66.9% were female. Results Gastrointestinal system (34.4%), nervous system (14.4%), and psychiatric (12.1%) disorders were the most frequent symptoms. Prevalent causative drugs were those for acid-related disorders (11.4%), anti-inflammatory products (10.5%), analgesics (7.2%), and antibacterials (7.1%). Comparisons by age revealed diarrhea and antibacterials to be most commonly associated with ADRs in children (p < 0.001), whereas dizziness was prevalent in the elderly (p < 0.001). Anaphylactic reaction was the most frequent serious event (19.7%), mainly associated with cephalosporins and non-steroidal anti-inflammatory drugs. Among 612 ADRs caused by nonprescription drugs, the leading symptoms and causative drugs were skin disorders (29.6%) and non-steroidal anti-inflammatory drugs (16.2%), respectively. Conclusions According to the community pharmacist reports, the leading clinical manifestations and causative drugs associated with ADRs in outpatients differed among age groups. PMID:26172050

  12. Beyond the prescription: medication monitoring and adverse drug events in older adults

    PubMed Central

    Steinman, Michael A.; Handler, Steven M.; Gurwitz, Jerry H.; Schiff, Gordon D.; Covinsky, Kenneth E.

    2014-01-01

    Whether a given patient will suffer harm from a medication or how severe that harm will be is difficult to precisely predict. As a result, many adverse drug events (ADEs) occur in patients in whom it was reasonable to believe that the drug's benefits exceeded its risks. Improving safety and reducing the burden of ADEs in older adults requires addressing this uncertainty by focusing not only on the appropriateness of the initial prescribing decision but also on detecting and mitigating adverse events once they have started to occur. Such enhanced monitoring of signs, symptoms, and laboratory parameters can determine whether an adverse event has only mild and short-term impacts or major long-term effects on morbidity and mortality. While current medication monitoring practices are often suboptimal, several strategies can be leveraged to improve the quality and outcomes of monitoring. These strategies include using health information technology to link pharmacy and laboratory data, prospective delineation of risk, and patient outreach and activation, all within a framework of team-based approaches to patient management. While many of these strategies are theoretically possible now, they are poorly utilized and will be difficult to implement without a significant restructuring of medical practice. An enhanced focus on medication monitoring will also require a new conceptual framework to re-engineer the prescribing process. In this approach, prescribing quality hinges not on static attributes of the initial prescribing decision, but entails a dynamic process in which the benefits and harms of drugs are actively monitored, managed, and reassessed over time. PMID:21797831

  13. Development and Validation of a Risk Model for Predicting Adverse Drug Reactions in Older People during Hospital Stay: Brighton Adverse Drug Reactions Risk (BADRI) Model

    PubMed Central

    Tangiisuran, Balamurugan; Scutt, Greg; Stevenson, Jennifer; Wright, Juliet; Onder, G.; Petrovic, M.; van der Cammen, T. J.; Rajkumar, Chakravarthi; Davies, Graham

    2014-01-01

    Background Older patients are at an increased risk of developing adverse drug reactions (ADR). Of particular concern are the oldest old, which constitute an increasingly growing population. Having a validated clinical tool to identify those older patients at risk of developing an ADR during hospital stay would enable healthcare staff to put measures in place to reduce the risk of such an event developing. The current study aimed to (1) develop and (2) validate an ADR risk prediction model. Methods We used a combination of univariate analysis and multivariate binary logistic regression to identify clinical risk factors for developing an ADR in a population of older people from a UK teaching hospital. The final ADR risk model was then validated in a European population (European dataset). Results Six-hundred-ninety patients (median age 85 years) were enrolled in the development stage of the study. Ninety-five reports of ADR were confirmed by independent review in these patients. Five clinical variables were identified through multivariate analysis and included in our final model; each variable was attributed a score of 1. Internal validation produced an AUROC of 0.74, a sensitivity of 80%, and specificity of 55%. During the external validation stage the AUROC was 0.73, with sensitivity and specificity values of 84% and 43% respectively. Conclusions We have developed and successfully validated a simple model to use ADR risk score in a population of patients with a median age of 85, i.e. the oldest old. The model is based on 5 clinical variables (≥8 drugs, hyperlipidaemia, raised white cell count, use of anti-diabetic agents, length of stay ≥12 days), some of which have not been previously reported. PMID:25356898

  14. High Yield Research Opportunities in Geriatric Emergency Medicine: Prehospital Care, Delirium, Adverse Drug Events, and Falls

    PubMed Central

    Carpenter, Christopher R.; Shah, Manish N.; Hustey, Fredric M.; Heard, Kennon; Gerson, Lowell W.

    2011-01-01

    Emergency services constitute crucial and frequently used safety nets for older persons, an emergency visit by a senior very often indicates high vulnerability for functional decline and death, and interventions via the emergency system have significant opportunities to change the clinical course of older patients who require its services. However, the evidence base for widespread employment of emergency system-based interventions is lacking. In this article, we review the evidence and offer crucial research questions to capitalize on the opportunity to optimize health trajectories of older persons seeking emergency care in four areas: prehospital care, delirium, adverse drug events, and falls. PMID:21498881

  15. [Nalmefene and Opioid Withdrawal Syndrome: Analysis of the Global Pharmacovigilance Database for Adverse Drug Reactions].

    PubMed

    Dahmke, Hendrike; Kupferschmidt, Hugo; Kullak-Ublick, Gerd A; Weiler, Stefan

    2015-10-14

    Nalmefene (Selincro®) is a selective opioid receptor antagonist, licensed in April 2014 in Switzerland for the reduction of alcohol consumption in adults with a high drinking risk level. 200 reports of adverse drug reactions of nalmefene have been documented worldwide in the WHO global pharmacovigilance database between 7th March 1997 to 1st March 2015. In 21 cases (10,5%) nalmefene and an opioid were administered concomitantly, causing withdrawal symptoms. Until now, the regional pharmacovigilance center in Zurich received four cases of nalmefene combined with opioids. This combination should be avoided.

  16. Tramadol hydrochloride: pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems.

    PubMed

    Vazzana, M; Andreani, T; Fangueiro, J; Faggio, C; Silva, C; Santini, A; Garcia, M L; Silva, A M; Souto, E B

    2015-03-01

    Tramadol hydrochloride (TrHC) is a synthetic analgesic drug exhibiting opioid and non-opioid properties, acting mainly on the central nervous system. It has been mostly used to treat pain, although its use to treat anxiety and depression has also been documented. These properties arise from the fact that they inhibit serotonin (5-HT) reuptake augmenting 5-HT concentration on the synaptic cleft. Despite this, TrHC has also been described to have several side effects which are mainly due to its fast metabolization and excretion which in turn requires multiple doses per day. To surpass this limitation, new pharmaceutical formulations are being developed intending the protection, target and sustained delivery as well as a reduction on daily dose aiming a reduction on the side effects. In the present work we have revised the efficacy, safety, biological and adverse effects of TrHC, and the added value of developing a novel drug delivery system for topical administration.

  17. Study of Natural Health Product Adverse Reactions (SONAR): Active Surveillance of Adverse Events Following Concurrent Natural Health Product and Prescription Drug Use in Community Pharmacies

    PubMed Central

    Vohra, Sunita; Cvijovic, Kosta; Boon, Heather; Foster, Brian C.; Jaeger, Walter; LeGatt, Don; Cembrowski, George; Murty, Mano; Tsuyuki, Ross T.; Barnes, Joanne; Charrois, Theresa L.; Arnason, John T.; Necyk, Candace; Ware, Mark; Rosychuk, Rhonda J.

    2012-01-01

    Background Many consumers use natural health products (NHPs) concurrently with prescription medications. As NHP-related harms are under-reported through passive surveillance, the safety of concurrent NHP-drug use remains unknown. To conduct active surveillance in participating community pharmacies to identify adverse events related to concurrent NHP-prescription drug use. Methodology/Principal Findings Participating pharmacists asked individuals collecting prescription medications about (i) concurrent NHP/drug use in the previous three months and (ii) experiences of adverse events. If an adverse event was identified and if the patient provided written consent, a research pharmacist conducted a guided telephone interview to gather additional information after obtaining additional verbal consent and documenting so within the interview form. Over a total of 112 pharmacy weeks, 2615 patients were screened, of which 1037 (39.7%; 95% CI: 37.8% to 41.5%) reported concurrent NHP and prescription medication use. A total of 77 patients reported a possible AE (2.94%; 95% CI: 2.4% to 3.7%), which represents 7.4% of those using NHPs and prescription medications concurrently (95%CI: 6.0% to 9.2%). Of 15 patients available for an interview, 4 (26.7%: 95% CI: 4.3% to 49.0%) reported an AE that was determined to be “probably” due to NHP use. Conclusions/Significance Active surveillance markedly improves identification and reporting of adverse events associated with concurrent NHP-drug use. Although not without challenges, active surveillance is feasible and can generate adverse event data of sufficient quality to allow for meaningful adjudication to assess potential harms. PMID:23028841

  18. Does Illicit Drug Use Influence Inpatient Adverse Events, Death, Length of Stay, and Discharge After Orthopaedic Trauma?

    PubMed

    Babatunde, Victor D; Menendez, Mariano E; Ring, David

    2016-01-01

    Illicit drug use among adults is increasing, but its associated risk following orthopaedic trauma remains largely unexplored. This study assessed the relationship of illicit drug use with inpatient adverse events, in-hospital mortality, prolonged length of stay, and nonroutine discharge. With the use of the Nationwide Inpatient Sample database, 7,118,720 orthopaedic trauma inpatients from 2002 to 2011 were identified and separated into illicit drug users (1.5%) and non-illicit drug users (98.5%). Multivariable regression modeling was used to determine the association between illicit drug use and each outcome variable. Illicit drug use was associated with higher odds of inpatient adverse events, but not greater likelihood of inpatient death. Illicit drug users were also more likely to experience prolonged hospital stay and nonroutine discharge. Prompt recognition and effective treatment interventions for orthopaedic trauma patients with a history of illicit drug use may improve inpatient outcomes. PMID:27082887

  19. The expert explorer: a tool for hospital data visualization and adverse drug event rules validation.

    PubMed

    Băceanu, Adrian; Atasiei, Ionuţ; Chazard, Emmanuel; Leroy, Nicolas

    2009-01-01

    An important part of adverse drug events (ADEs) detection is the validation of the clinical cases and the assessment of the decision rules to detect ADEs. For that purpose, a software called "Expert Explorer" has been designed by Ideea Advertising. Anonymized datasets have been extracted from hospitals into a common repository. The tool has 3 main features. (1) It can display hospital stays in a visual and comprehensive way (diagnoses, drugs, lab results, etc.) using tables and pretty charts. (2) It allows designing and executing dashboards in order to generate knowledge about ADEs. (3) It finally allows uploading decision rules obtained from data mining. Experts can then review the rules, the hospital stays that match the rules, and finally give their advice thanks to specialized forms. Then the rules can be validated, invalidated, or improved (knowledge elicitation phase).

  20. Ontology-based knowledge management for personalized adverse drug events detection.

    PubMed

    Cao, Feng; Sun, Xingzhi; Wang, Xiaoyuan; Li, Bo; Li, Jing; Pan, Yue

    2011-01-01

    Since Adverse Drug Event (ADE) has become a leading cause of death around the world, there arises high demand for helping clinicians or patients to identify possible hazards from drug effects. Motivated by this, we present a personalized ADE detection system, with the focus on applying ontology-based knowledge management techniques to enhance ADE detection services. The development of electronic health records makes it possible to automate the personalized ADE detection, i.e., to take patient clinical conditions into account during ADE detection. Specifically, we define the ADE ontology to uniformly manage the ADE knowledge from multiple sources. We take advantage of the rich semantics from the terminology SNOMED-CT and apply it to ADE detection via the semantic query and reasoning. PMID:21893837

  1. ADEpedia: a scalable and standardized knowledge base of Adverse Drug Events using semantic web technology.

    PubMed

    Jiang, Guoqian; Solbrig, Harold R; Chute, Christopher G

    2011-01-01

    A source of semantically coded Adverse Drug Event (ADE) data can be useful for identifying common phenotypes related to ADEs. We proposed a comprehensive framework for building a standardized ADE knowledge base (called ADEpedia) through combining ontology-based approach with semantic web technology. The framework comprises four primary modules: 1) an XML2RDF transformation module; 2) a data normalization module based on NCBO Open Biomedical Annotator; 3) a RDF store based persistence module; and 4) a front-end module based on a Semantic Wiki for the review and curation. A prototype is successfully implemented to demonstrate the capability of the system to integrate multiple drug data and ontology resources and open web services for the ADE data standardization. A preliminary evaluation is performed to demonstrate the usefulness of the system, including the performance of the NCBO annotator. In conclusion, the semantic web technology provides a highly scalable framework for ADE data source integration and standard query service.

  2. Adverse drug events in a sentinel hospital in the State of Goiás, Brazil.

    PubMed

    Silva, Ana Elisa Bauer de Camargo; Reis, Adriano Max Moreira; Miasso, Adriana Inocenti; Santos, Jânia Oliveira; Cassiani, Silvia Helena De Bortoli

    2011-01-01

    This was a retrospective, descriptive and documental study with the aim of identifying adverse drug events which occurred in the medication administration process and to classify these medication errors. This study was developed in the internal medicine unit of a general hospital of Goiás, Brazil. Report books used by nursing staff from the period 2002 to 2007, were analyzed. A total of 230 medication errors were identified, most of which occurred in the preparation and administration of the medications (64.3%). Medication errors were of omission (50.9%), of dose (16.5%), of schedule (13.5%) and of administration technique (12.2%) and were more frequent with antineoplastic and immunomodulating agents (24.3%) and anti-infective agents (20.9%). It was found that 37.4% of drugs were high alert medications. Considering the medication errors detected it is important to promote a culture of safety in the hospital. PMID:21584386

  3. Hospitalizations Due to Adverse Drug Events in the Elderly—A Retrospective Register Study

    PubMed Central

    Laatikainen, Outi; Sneck, Sami; Bloigu, Risto; Lahtinen, Minna; Lauri, Timo; Turpeinen, Miia

    2016-01-01

    Adverse drug events (ADEs) are more likely to affect geriatric patients due to physiological changes occurring with aging. Even though this is an internationally recognized problem, similar research data in Finland is still lacking. The aim of this study was to determine the number of geriatric medication-related hospitalizations in the Finnish patient population and to discover the potential means of recognizing patients particularly at risk of ADEs. The study was conducted retrospectively from the 2014 emergency department patient records in Oulu University Hospital. A total number of 290 admissions were screened for ADEs, adverse drug reactions (ADRs) and drug-drug interactions (DDIs) by a multi-disciplinary research team. Customized Naranjo scale was used as a control method. All admissions were categorized into “probable,” “possible,” or “doubtful” by both assessment methods. In total, 23.1% of admissions were categorized as “probably” or “possibly” medication-related. Vertigo, falling, and fractures formed the largest group of ADEs. The most common ADEs were related to medicines from N class of the ATC-code system. Age, sex, residence, or specialty did not increase the risk for medication-related admission significantly (min p = 0.077). Polypharmacy was, however, found to increase the risk (OR 3.3; 95% CI, 1.5–6.9; p = 0.01). In conclusion, screening patients for specific demographics or symptoms would not significantly improve the recognition of ADEs. In addition, as ADE detection today is largely based on voluntary reporting systems and retrospective manual tracking of errors, it is evident that more effective methods for ADE detection are needed in the future. PMID:27761112

  4. Retrospective Analysis of Pattern of Cutaneous Adverse Drug Reactions in Tertiary Hospital of Pauri Garhwal

    PubMed Central

    Dimri, Deepak; Thapliyal, Swati; Thawani, Vijay

    2016-01-01

    Introduction Cutaneous Adverse Drug Reactions (CADR) are the common drug induced adverse reactions which usually have wide range of manifestations and severity. Aim To describe the prevalence and clinical spectrum of CADR’s in a tertiary hospital of the Garhwal region in Uttarakhand, India. Materials and Methods All patients suspected of having CADRs reported in the various out-patient departments, and in-patients of HNB Base & Teaching Hospital, from 1st January 2012 to 31st December 2014 were retrospectively analysed. Drug history was recorded in a format specified in Indian National Pharmacovigilance Programme. Results Total 111 cases of CADRs were reported from Jan 2012 to Dec 2014. Mean age of patients was 33.34±18.7 years and maximum ADRs were reported in the age group of 20-39 years (36.9%). Female were affected more than male (W:M :: 66:45). Most of the ADRs were exanthematous eruptions (EE) type (33.3%). Medicine department reported maximum cases of CADRs (47.7%), followed by Dermatology. Most of the CADRs were reported with antimicrobial agents (69.4%). Significant associations of different types of various cutaneous reactions were observed in relation to the duration (in days) of ADRs (p = 0.038), types of outcome (p= 0.006), different departments (p= 0.014) and between different groups of medicines (p = 0.008). Conclusion CADRs have proved a significant problem in healthcare for decades. Major bulk of CADR result from physician prescribed drugs. Hence, awareness on part of the physician can help in timely detection of cutaneous reactions, thereby restricting damage from them. PMID:27437240

  5. Nursing implications for prevention of adverse drug events in the intensive care unit.

    PubMed

    George, Elisabeth L; Henneman, Elizabeth A; Tasota, Frederick J

    2010-06-01

    Adverse drug events are common in the intensive care unit setting. Despite the existence of many long-standing safety principles (such as the "five rights") and new mechanisms to promote medication safety, there is still a gap between practice and the goal of patient safety. This is the result of the many human and system factors that impact care delivery. Research supports the role of the nurse as having a positive impact on patient outcomes. Future research requires the evaluation of new strategies and technologies to support safe medication administration. For example, patient simulation is being used to teach student and novice nurses principles of medication administration in a "safe" setting that more closely resembles the clinical environment. The Institute of Nursing repeatedly has stressed the need to address the organizational, technical, and human issues that impact patient safety, with an emphasis on the need to transform the nurse work environment to keep patients safe. This transformation will require a new level of interdisciplinary research and nursing involvement to address better care for our patients and, in particular, reduce adverse drug events.

  6. Investigating clandestine drug laboratories: adverse medical effects in law enforcement personnel.

    PubMed

    Burgess, J L; Barnhart, S; Checkoway, H

    1996-10-01

    A retrospective cohort study was conducted among an international group of 46 law enforcement chemists and 13 Washington State clandestine drug laboratory investigation team members with more than 2,800 combined investigations. Each participant completed a questionnaire concerning previous drug laboratory investigations and adverse health effects during response activities. Methamphetamine laboratories accounted for 81-97% of all responses. Total illness incident rates varied between 0.75-3.4% of responses. Most exposures were through inhalation, and many occurred in the years prior to use of personal protective equipment. Symptoms were primarily those of headache and respiratory, mucous membrane, and skin irritation. Most illness episodes occurred during the processing phase of laboratory responses, and none occurred during the entry phase. A majority of illness episodes occurred in laboratories with leak/spills, fire/explosion, or uncontrolled reactions. Responding to an active laboratory was associated with a 7 to 15-fold risk of becoming ill as compared with setup, in-transit, or former (equipment removed) laboratory responses. No other laboratories characteristics were consistently associated with a significantly elevated relative risk of adverse health effects. PMID:8892555

  7. Drug therapy and adverse drug reactions to terbutaline in obstetric patients: a prospective cohort study in hospitalized women.

    PubMed

    Hernández-Hernández, Dulce; Vargas-Rivera, María; Nava-Ocampo, Alejandro A; Palma-Aguirre, José; Sumano-López, Héctor

    2002-04-01

    BACKGROUND: Adverse drug reactions (ADR's) could be expected more frequently in pregnant women. This study was performed in order to identify ADR's to tocolytic drugs in hospitalised pregnant women. METHODS: A prospective cohort study was performed in two General Hospitals of the Instituto Mexicano del Seguro Social (IMSS) in Mexico City. Two hundred and seven women undergoing labor, premature labor, threatened abortion or suffering any obstetric related disease were included. Drug prescription and signs and symptoms of any potential ADR were registered daily during the hospital stay. Any potential ADR to tocolytic drugs was evaluated and classified by three of the authors using the Kramer's algorithm. RESULTS: Of the 207 patients, an ADR was positively classified in 25 cases (12.1%, CI95% 8.1 to 17.5%). All ADR's were classified as minor reactions. Grouping patients with diagnosis of threatened abortion, premature labor or under labor (n= 114), 24 ADR's were related to terbutaline, accounting for a rate of 21.1 ADR's per 100 obstetric patients. Obstetric patients suffering an ADR were older than obstetric patients without any ADR. However, the former received less drugs/day x patient-1 and had a shorter hospital stay (p < 0.05) whereas the dose of terbutaline was similar between the two groups. Terbutaline inhibited uterine motility in women with and without any ADR at a similar rate, 70 and 76% respectively (x2 = 0.07; p = 0.8). CONCLUSION: Terbutaline, used as a tocolytic drug, was related to a high frequency of minor ADRs and to a high rate of effcicacy. PMID:11934352

  8. Factors Affecting the Timing of Signal Detection of Adverse Drug Reactions.

    PubMed

    Hashiguchi, Masayuki; Imai, Shungo; Uehara, Keiko; Maruyama, Junya; Shimizu, Mikiko; Mochizuki, Mayumi

    2015-01-01

    We investigated factors affecting the timing of signal detection by comparing variations in reporting time of known and unknown ADRs after initial drug release in the USA. Data on adverse event reactions (AERs) submitted to U.S. FDA was used. Six ADRs associated with 6 drugs (rosuvastatin, aripiprazole, teriparatide, telithromycin, exenatide, varenicline) were investigated: Changes in the proportional reporting ratio, reporting odds ratio, and information component as indexes of signal detection were followed every 3 months after each drugs release, and the time for detection of signals was investigated. The time for the detection of signal to be detected after drug release in the USA was 2-10 months for known ADRs and 19-44 months for unknown ones. The median lag time for known and unknown ADRs was 99.0-122.5 days and 185.5-306.0 days, respectively. When the FDA released advisory information on rare but potentially serious health risks of an unknown ADR, the time lag to report from the onset of ADRs to the FDA was shorter. This study suggested that one factor affecting signal detection time is whether an ADR was known or unknown at release. PMID:26641634

  9. High-Performance Signal Detection for Adverse Drug Events using MapReduce Paradigm.

    PubMed

    Fan, Kai; Sun, Xingzhi; Tao, Ying; Xu, Linhao; Wang, Chen; Mao, Xianling; Peng, Bo; Pan, Yue

    2010-01-01

    Post-marketing pharmacovigilance is important for public health, as many Adverse Drug Events (ADEs) are unknown when those drugs were approved for marketing. However, due to the large number of reported drugs and drug combinations, detecting ADE signals by mining these reports is becoming a challenging task in terms of computational complexity. Recently, a parallel programming model, MapReduce has been introduced by Google to support large-scale data intensive applications. In this study, we proposed a MapReduce-based algorithm, for common ADE detection approach, Proportional Reporting Ratio (PRR), and tested it in mining spontaneous ADE reports from FDA. The purpose is to investigate the possibility of using MapReduce principle to speed up biomedical data mining tasks using this pharmacovigilance case as one specific example. The results demonstrated that MapReduce programming model could improve the performance of common signal detection algorithm for pharmacovigilance in a distributed computation environment at approximately liner speedup rates. PMID:21347109

  10. Adverse and Advantageous Selection in the Medicare Supplemental Market: A Bayesian Analysis of Prescription drug Expenditure.

    PubMed

    Li, Qian; Trivedi, Pravin K

    2016-02-01

    This paper develops an extended specification of the two-part model, which controls for unobservable self-selection and heterogeneity of health insurance, and analyzes the impact of Medicare supplemental plans on the prescription drug expenditure of the elderly, using a linked data set based on the Medicare Current Beneficiary Survey data for 2003-2004. The econometric analysis is conducted using a Bayesian econometric framework. We estimate the treatment effects for different counterfactuals and find significant evidence of endogeneity in plan choice and the presence of both adverse and advantageous selections in the supplemental insurance market. The average incentive effect is estimated to be $757 (2004 value) or 41% increase per person per year for the elderly enrolled in supplemental plans with drug coverage against the Medicare fee-for-service counterfactual and is $350 or 21% against the supplemental plans without drug coverage counterfactual. The incentive effect varies by different sources of drug coverage: highest for employer-sponsored insurance plans, followed by Medigap and managed medicare plans. PMID:25504934

  11. Adverse and Advantageous Selection in the Medicare Supplemental Market: A Bayesian Analysis of Prescription drug Expenditure.

    PubMed

    Li, Qian; Trivedi, Pravin K

    2016-02-01

    This paper develops an extended specification of the two-part model, which controls for unobservable self-selection and heterogeneity of health insurance, and analyzes the impact of Medicare supplemental plans on the prescription drug expenditure of the elderly, using a linked data set based on the Medicare Current Beneficiary Survey data for 2003-2004. The econometric analysis is conducted using a Bayesian econometric framework. We estimate the treatment effects for different counterfactuals and find significant evidence of endogeneity in plan choice and the presence of both adverse and advantageous selections in the supplemental insurance market. The average incentive effect is estimated to be $757 (2004 value) or 41% increase per person per year for the elderly enrolled in supplemental plans with drug coverage against the Medicare fee-for-service counterfactual and is $350 or 21% against the supplemental plans without drug coverage counterfactual. The incentive effect varies by different sources of drug coverage: highest for employer-sponsored insurance plans, followed by Medigap and managed medicare plans.

  12. Sulfites--a food and drug administration review of recalls and reported adverse events.

    PubMed

    Timbo, Babgaleh; Koehler, Kathleen M; Wolyniak, Cecilia; Klontz, Karl C

    2004-08-01

    Sulfite-sensitive individuals can experience adverse reactions after consuming foods containing sulfiting agents (sulfites), and some of these reactions may be severe. In the 1980s and 1990s, the U.S. Food and Drug Administration (FDA) acted to reduce the likelihood that sulfite-sensitive individuals would unknowingly consume foods containing sulfites. The FDA prohibited the use of sulfites on fruits and vegetables (except potatoes) to be served or presented fresh to the public and required that the presence of detectable levels of sulfites be declared on food labels, even when these sulfites are used as a processing aid or are a component of another ingredient in the food. In the present study, data from FDA recall records and adverse event reports were used to examine the current status of problems of sensitivity to sulfites in foods. From 1996 through 1999, the FDA processed a total of 59 recalls of foods containing undeclared sulfites; these 59 recalls involved 93 different food products. Fifty (55%) of the recalled products were classified as class I, a designation indicating that a consumer reasonably could have ingested > or = 10 mg of undeclared sulfites on a single occasion, a level that could potentially cause a serious adverse reaction in a susceptible person. From 1996 through mid-1999, the FDA received a total of 34 reports of adverse reactions allegedly due to eating foods containing undeclared sulfites. The average of 10 reports per year, although derived from a passive surveillance system, was lower than the average of 111 reports per year that the FDA received from 1980 to 1987, a decrease that may have resulted in part from FDA regulatory action.

  13. Adverse drug reactions associated with the use of disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis.

    PubMed

    Machado-Alba, Jorge Enrique; Ruiz, Andrés Felipe; Machado-Duque, Manuel Enrique

    2014-12-01

    This study describes the adverse drug reactions (ADRs) and their incidence in patients with rheumatoid arthritis who were treated in the Colombian health system. A retrospective cohort study was conducted using information from all patients who were diagnosed with rheumatoid arthritis and attended specialized health care centers in the cities of Bogotá, Cali, Manizales, Medellin, and Pereira between 1 December 2009 and 30 August 2013. The ADRs were obtained from medical records and the pharmacovigilance system registry and sorted by frequency and affected tissue according to World Health Organization Adverse Reaction Terminology (WHO-ART). A total of 949 reports of ADRs were obtained from 419 patients (32.8 ADRs per 100 patient-years); these patients were from a cohort of 1,364 patients being treated for rheumatoid arthritis and followed up for an average of 23.8 months (± 12.9). The cohort was mostly female (366, 87.4%) and had a mean age of 52.7 years (± 13.1). The highest numbers of ADRs were reported following the use of tocilizumab, rituximab, and infliximab (28.8, 23.1, and 13.3 reports per 100 patient-years respectively). The most frequently reported ADRs were elevated transaminase levels and dyspepsia. Overall, 87.7% of ADRs were classified as type A, 36.6% as mild, 40.7% as moderate, and 22.7% as severe. As a result, 73.2% of patients who experienced an ADR stopped taking their drugs. The occurrence of ADRs in patients treated for rheumatoid arthritis is common, especially in those associated with the use of biotechnologically produced anti-rheumatic drugs. This outcome should be studied in future research and monitoring is needed to reduce the risks in these patients.

  14. Adverse drug reactions associated with the use of disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis.

    PubMed

    Machado-Alba, Jorge Enrique; Ruiz, Andrés Felipe; Machado-Duque, Manuel Enrique

    2014-12-01

    This study describes the adverse drug reactions (ADRs) and their incidence in patients with rheumatoid arthritis who were treated in the Colombian health system. A retrospective cohort study was conducted using information from all patients who were diagnosed with rheumatoid arthritis and attended specialized health care centers in the cities of Bogotá, Cali, Manizales, Medellin, and Pereira between 1 December 2009 and 30 August 2013. The ADRs were obtained from medical records and the pharmacovigilance system registry and sorted by frequency and affected tissue according to World Health Organization Adverse Reaction Terminology (WHO-ART). A total of 949 reports of ADRs were obtained from 419 patients (32.8 ADRs per 100 patient-years); these patients were from a cohort of 1,364 patients being treated for rheumatoid arthritis and followed up for an average of 23.8 months (± 12.9). The cohort was mostly female (366, 87.4%) and had a mean age of 52.7 years (± 13.1). The highest numbers of ADRs were reported following the use of tocilizumab, rituximab, and infliximab (28.8, 23.1, and 13.3 reports per 100 patient-years respectively). The most frequently reported ADRs were elevated transaminase levels and dyspepsia. Overall, 87.7% of ADRs were classified as type A, 36.6% as mild, 40.7% as moderate, and 22.7% as severe. As a result, 73.2% of patients who experienced an ADR stopped taking their drugs. The occurrence of ADRs in patients treated for rheumatoid arthritis is common, especially in those associated with the use of biotechnologically produced anti-rheumatic drugs. This outcome should be studied in future research and monitoring is needed to reduce the risks in these patients. PMID:25711751

  15. Phase I trial with biomarker studies of vatalanib (PTK787) in patients with newly diagnosed glioblastoma treated with enzyme inducing anti-epileptic drugs and standard radiation and temozolomide.

    PubMed

    Gerstner, Elizabeth R; Eichler, April F; Plotkin, Scott R; Drappatz, Jan; Doyle, Colin L; Xu, Lei; Duda, Dan G; Wen, Patrick Y; Jain, Rakesh K; Batchelor, Tracy T

    2011-06-01

    Targeting angiogenesis in glioblastoma (GBM) may improve patient outcome by normalizing tumor vasculature and improving delivery of chemotherapeutics and oxygen. Consequently, concomitant administration of small molecule inhibitors of the VEGF pathway will likely have a positive impact on chemoradiation treatment outcome. We conducted a Phase I study of vatalanib, a small molecule inhibitor of VEGFR, PDGFR, and c-kit in patients with newly diagnosed GBM receiving radiation, temozolomide, and an enzyme-inducing anti-epileptic drug in order to determine the MTD of vatalanib in this patient population. We incorporated circulating biomarker and SNP analyses and pharmacokinetic studies. Nineteen patients were enrolled and the MTD was not reached at the time of study termination. Vatalanib was well tolerated with only 2 DLTs (thrombocytopenia and elevated transaminases). Other grade 3/4 toxicities included leukopenia, lymphopenia, neutropenia, and hand-foot syndrome. There were no wound-healing complications. Of the 13 patients evaluable for a radiographic response, 2 had a partial response and 9 had stable disease. Vatalanib significantly increased PlGF and sVEGFR1 in plasma circulation and decreased sVEGFR2 and sTie2. Plasma collagen IV increased significantly by day 50 of treatment. Vatalanib was well tolerated and this study demonstrates the safety of oral small molecule inhibitors in newly diagnosed GBM patients. Blood biomarkers may be useful as pharmacodynamic markers of response to anti-angiogenic therapies. PMID:20821342

  16. [The history of adverse drug reactions, relief for these health damage and safety measures in Japan].

    PubMed

    Takahashi, Haruo

    2009-01-01

    The first remarkable adverse drug reaction (ADR) reported in Japan was anaphylactic shock caused by penicillin. Although intradermal testing for antibiotics had been exercised as prediction method of anaphylactic shock for a long time, it was discontinued in 2004 because of no evidence for prediction. The malformation of limbs, etc. caused by thalidomide was a global problem, and thalidomide was withdrawn from the market. Teratogenicity testing during new drug development has been implemented since 1963. Chinoform (clioquinol)-iron chelate was detected from green tongue and green urine in patients with subacute myelo-optic neuropathy (SMON) and identified as a causal material of SMON in 1970. Chinoform was withdrawn from the market, and a fund for relief the health damage caused by ADR was established in 1979. The co-administration of sorivudine and fluorouracil anticancer agents induced fatal agranulocytosis, and sorivudine was withdrawn from the market after being on sale for one month in 1993. The guidelines for package inserts were corrected with this opportunity, and early phase pharmacovigilance of new drugs was introduced later. Since acquired immune deficiency syndrome, and hepatitis B and C were driven by virus-infected blood products, the Ministry of Health, Labor and Welfare tightened regulations regarding biological products in 2003, and a fund for relief of health damage caused by infections driven from biological products was established in 2004. The other remarkable ADRs were quadriceps contracture induced by the repeated administration of muscular injection products and Creutzfeldt-Jakob disease caused by the transplantation of human dry cranial dura matter, etc. The significance of safety measures for drugs based on experiences related to ADRs is worthy of notice. New drugs are approved based on a benefit-risk assessment, if the expected therapeutic benefits outweigh the possible risks associated with treatment. Since unexpected, rare and serious

  17. 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

  18. EMPADE Study: Evaluation of Medical Prescriptions and Adverse Drug Events in COPD Patients Admitted to Intensive Care Unit

    PubMed Central

    Khan, M. Amer; Khan, M. Nematullah; Sultan, Ihtisham; Khan, M. Aamer; Ali, S. Amir; Farooqui, Afroze

    2015-01-01

    Introduction Inappropriate drug usage may preclude ideal benefit due to increased medical cost, antimicrobial resistance, adverse effects and mortality. Therefore drug utilization studies have become a plausible means in evaluating the healthcare systems. COPD management usually involves more than one drug which may escalate the risk of ADEs (adverse drug events). Aim The present study was aimed at assessing the current drug practice and ADEs in COPD management in ICU. Materials and Methods A total of 1,044 patients admitted for the treatment of COPD were included in the study. Their prescriptions were recorded for evaluation of drug utilization and patients were counseled for assessing ADEs. Results were evaluated by Chi-square test and percentages. Result All-embracing 15,360 drugs were prescribed at an average of 14.71 drugs per patient, wherein β2-agonists were extensively prescribed agents followed by inhaled-corticosteroids and anti-cholinergics. 372 ADEs were reported in 252 patients, wherein restlessness was the most frequent ADE and theophylline was found to be associated with highest cases of ADEs. Conclusion Practitioners should prescribe least number of drugs to mitigate the likelihood of adverse outcomes in patients due to numerous drugs usage, which may be achieved by following GOLD guidelines. The present work may help in improving the current management of COPD by rectifying the flaws delineated in this article. PMID:26675667

  19. Constructing Clinical Decision Support Systems for Adverse Drug Event Prevention: A Knowledge-based Approach.

    PubMed

    Koutkias, Vassilis; Kilintzis, Vassilis; Stalidis, George; Lazou, Katerina; Collyda, Chrysa; Chazard, Emmanuel; McNair, Peter; Beuscart, Regis; Maglaveras, Nicos

    2010-11-13

    A knowledge-based approach is proposed that is employed for the construction of a framework suitable for the management and effective use of knowledge on Adverse Drug Event (ADE) prevention. The framework has as its core part a Knowledge Base (KB) comprised of rule-based knowledge sources, that is accompanied by the necessary inference and query mechanisms to provide healthcare professionals and patients with decision support services in clinical practice, in terms of alerts and recommendations on preventable ADEs. The relevant Knowledge Based System (KBS) is developed in the context of the EU-funded research project PSIP (Patient Safety through Intelligent Procedures in Medication). In the current paper, we present the foundations of the framework, its knowledge model and KB structure, as well as recent progress as regards the population of the KB, the implementation of the KBS, and results on the KBS verification in decision support operation.

  20. Text Mining for Adverse Drug Events: the Promise, Challenges, and State of the Art

    PubMed Central

    Harpaz, Rave; Callahan, Alison; Tamang, Suzanne; Low, Yen; Odgers, David; Finlayson, Sam; Jung, Kenneth; LePendu, Paea; Shah, Nigam H.

    2014-01-01

    Text mining is the computational process of extracting meaningful information from large amounts of unstructured text. Text mining is emerging as a tool to leverage underutilized data sources that can improve pharmacovigilance, including the objective of adverse drug event detection and assessment. This article provides an overview of recent advances in pharmacovigilance driven by the application of text mining, and discusses several data sources—such as biomedical literature, clinical narratives, product labeling, social media, and Web search logs—that are amenable to text-mining for pharmacovigilance. Given the state of the art, it appears text mining can be applied to extract useful ADE-related information from multiple textual sources. Nonetheless, further research is required to address remaining technical challenges associated with the text mining methodologies, and to conclusively determine the relative contribution of each textual source to improving pharmacovigilance. PMID:25151493

  1. Ci4SeR--curation interface for semantic resources--evaluation with adverse drug reactions.

    PubMed

    Souvignet, Julien; Asfari, Hadyl; Declerck, Gunnar; Lardon, Jérémy; Trombert-Paviot, Béatrice; Jaulent, Marie-Christine; Bousquet, Cédric

    2014-01-01

    Evaluation and validation have become a crucial problem for the development of semantic resources. We developed Ci4SeR, a Graphical User Interface to optimize the curation work (not taking into account structural aspects), suitable for any type of resource with lightweight description logic. We tested it on OntoADR, an ontology of adverse drug reactions. A single curator has reviewed 326 terms (1020 axioms) in an estimated time of 120 hours (2.71 concepts and 8.5 axioms reviewed per hour) and added 1874 new axioms (15.6 axioms per hour). Compared with previous manual endeavours, the interface allows increasing the speed-rate of reviewed concepts by 68% and axiom addition by 486%. A wider use of Ci4SeR would help semantic resources curation and improve completeness of knowledge modelling.

  2. A Critical Approach to Evaluating Clinical Efficacy, Adverse Events and Drug Interactions of Herbal Remedies.

    PubMed

    Izzo, Angelo A; Hoon-Kim, Sung; Radhakrishnan, Rajan; Williamson, Elizabeth M

    2016-05-01

    Systematic reviews and meta-analyses represent the uppermost ladders in the hierarchy of evidence. Systematic reviews/meta-analyses suggest preliminary or satisfactory clinical evidence for agnus castus (Vitex agnus castus) for premenstrual complaints, flaxseed (Linum usitatissimum) for hypertension, feverfew (Tanacetum partenium) for migraine prevention, ginger (Zingiber officinalis) for pregnancy-induced nausea, ginseng (Panax ginseng) for improving fasting glucose levels as well as phytoestrogens and St John's wort (Hypericum perforatum) for the relief of some symptoms in menopause. However, firm conclusions of efficacy cannot be generally drawn. On the other hand, inconclusive evidence of efficacy or contradictory results have been reported for Aloe vera in the treatment of psoriasis, cranberry (Vaccinium macrocarpon) in cystitis prevention, ginkgo (Ginkgo biloba) for tinnitus and intermittent claudication, echinacea (Echinacea spp.) for the prevention of common cold and pomegranate (Punica granatum) for the prevention/treatment of cardiovascular diseases. A critical evaluation of the clinical data regarding the adverse effects has shown that herbal remedies are generally better tolerated than synthetic medications. Nevertheless, potentially serious adverse events, including herb-drug interactions, have been described. This suggests the need to be vigilant when using herbal remedies, particularly in specific conditions, such as during pregnancy and in the paediatric population. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26887532

  3. Polypharmacy and adverse drug reactions in Japanese elderly taking antihypertensives: a retrospective database study

    PubMed Central

    Sato, Izumi; Akazawa, Manabu

    2013-01-01

    Background The concomitant use of multiple medications by elderly patients with hypertension is a relatively common and growing phenomenon in Japan. This has been attributed to several factors, including treatment guidelines recommending prescription of multiple medications and a continuing increase in the elderly population with multiple comorbidities. Objective This study was aimed at investigating the association between polypharmacy, defined as the concomitant use of five or more medications, and risk of adverse drug reaction (ADR) in elderly Japanese hypertensive patients to examine the hypothesis that risk of ADR increases with the administration of an increasing number of co-medications. Methods Using a retrospective cohort design, the data regarding all hypertensive patients aged 65 years or older were extracted from the Risk/Benefit Assessment of Drugs – Analysis and Response Council antihypertensive medication database. The data were reviewed for classification of patients into one of three groups according to drug use at the initiation of therapy – a monotherapy group composed of patients who had taken the investigated drug only, a co-medication group composed of patients who had taken the investigated drug and a maximum of three other medications, and a polypharmacy group composed of patients who had taken the investigated drug and four or more other medications – and determination of the number of ADR events experienced. Estimated rate ratios (RRs) and 95% confidence intervals (CIs) were calculated using a Poisson regression model adjusted for drug category and patient age and sex. Various sensitivity analyses were performed to confirm the robustness of the study findings. Results Of 61,661 elderly Japanese patients (men, 41.8%; 75 years or older, 35.1%) registered in the database, 2491 patients (4.0%) experienced a total of 3144 ADR events during the study period. The rate of ADR per 10,000 person-days was 2.0 for the monotherapy group, 5.1 for

  4. Evaluating the risk of patient re-identification from adverse drug event reports

    PubMed Central

    2013-01-01

    Background Our objective was to develop a model for measuring re-identification risk that more closely mimics the behaviour of an adversary by accounting for repeated attempts at matching and verification of matches, and apply it to evaluate the risk of re-identification for Canada’s post-marketing adverse drug event database (ADE).Re-identification is only demonstrably plausible for deaths in ADE. A matching experiment between ADE records and virtual obituaries constructed from Statistics Canada vital statistics was simulated. A new re-identification risk is considered, it assumes that after gathering all the potential matches for a patient record (all records in the obituaries that are potential matches for an ADE record), an adversary tries to verify these potential matches. Two adversary scenarios were considered: (a) a mildly motivated adversary who will stop after one verification attempt, and (b) a highly motivated adversary who will attempt to verify all the potential matches and is only limited by practical or financial considerations. Methods The mean percentage of records in ADE that had a high probability of being re-identified was computed. Results Under scenario (a), the risk of re-identification from disclosing the province, age at death, gender, and exact date of the report is quite high, but the removal of province brings down the risk significantly. By only generalizing the date of reporting to month and year and including all other variables, the risk is always low. All ADE records have a high risk of re-identification under scenario (b), but the plausibility of that scenario is limited because of the financial and practical deterrent even for highly motivated adversaries. Conclusions It is possible to disclose Canada’s adverse drug event database while ensuring that plausible re-identification risks are acceptably low. Our new re-identification risk model is suitable for such risk assessments. PMID:24094134

  5. Harmonising adverse drug reaction terminology: the role of the Council for International Organizations of Medical Sciences.

    PubMed

    Venulet, J; Bankowski, Z

    1998-09-01

    Health professionals from different countries are known to differ considerably in their use of medical terminology, including the terminology used for adverse drug reactions (ADRs) and in the exact meanings attributed to terms. To remedy this situation, the Council for International Organizations of Medical Sciences (CIOMS) has attempted to provide definitions and basic requirements for proper use of ADR terms. The work has concentrated on terms liable to be misinterpreted and those used for serious and frequently reported ADRs. For every selected term a short monograph has been prepared. It consists of a preamble, definition, basic requirements for use of the term and additional comments, if any. In cooperation with medical experts, drug regulators and the pharmaceutical industry, 13 papers have been published so far. Approximately 160 terms have been defined and work on another 50 terms continues. The full collection of monographs will eventually appear in the form of a book and CD-ROM intended to help doctors fill in case reports, and regulatory agencies and the pharmaceutical industry assess reports. Pharmaceutical companies receive numerous reports of suspected ADRs from medical practitioners and other prescribing professionals. Each company is required to transmit these reports to the drug regulatory agency of the country, or countries, in which the drug is used. Therefore, in addition to receiving the correct name of the ADR, collecting and evaluating centres, regardless of whether they are part of a regulatory agency or a pharmaceutical company, need to be provided with sufficient supporting data to be convinced that what is reported was what was actually observed, and that the ADR term used represents the observed event.

  6. Clinical Risk Factors for In-Hospital Adverse Cardiovascular Events After Acute Drug Overdose

    PubMed Central

    Manini, Alex F.; Hoffman, Robert S.; Stimmel, Barry; Vlahov, David

    2015-01-01

    Objectives It was recently demonstrated that adverse cardiovascular events (ACVE) complicate a high proportion of hospitalizations for patients with acute drug overdoses. The aim of this study was to derive independent clinical risk factors for ACVE in patients with acute drug overdoses. Methods This prospective cohort study was conducted over 3 years at two urban university hospitals. Patients were adults with acute drug overdoses enrolled from the ED. In-hospital ACVE was defined as any of myocardial injury, shock, ventricular dysrhythmia, or cardiac arrest. Results There were 1,562 patients meeting inclusion/exclusion criteria (mean age, 41.8 years; female, 46%; suicidal, 38%). ACVE occurred in 82 (5.7%) patients (myocardial injury, 61; shock, 37; dysrhythmia, 23; cardiac arrests, 22) and there were 18 (1.2%) deaths. On univariate analysis, ACVE risk increased with age, lower serum bicarbonate, prolonged QTc interval, prior cardiac disease, and altered mental status. In a multivariable model adjusting for these factors as well as patient sex and hospital site, independent predictors were: QTc > 500 msec (3.8% prevalence, odds ratio [OR] 27.6), bicarbonate < 20 mEql/L (5.4% prevalence, OR 4.4), and prior cardiac disease (7.1% prevalence, OR 9.5). The derived prediction rule had 51.6% sensitivity, 93.7% specificity, and 97.1% negative predictive value; while presence of two or more risk factors had 90.9% positive predictive value. Conclusions The authors derived independent clinical risk factors for ACVE in patients with acute drug overdose, which should be validated in future studies as a prediction rule in distinct patient populations and clinical settings. PMID:25903997

  7. Adverse Drug Reactions in a Tertiary Care Emergency Medicine Ward - Prevalence, Preventability and Reporting

    PubMed Central

    Rydberg, Diana M.; Holm, Lennart; Engqvist, Ida; Fryckstedt, Jessica; Lindh, Jonatan D.; Stiller, Carl-Olav; Asker-Hagelberg, Charlotte

    2016-01-01

    Purpose To identify the prevalence and preventability of adverse drug reactions (ADRs) in an emergency ward setting in a tertiary hospital in Sweden and to what extent the detected ADRs were reported to the Medical Product Agency (MPA). Methods In this prospective cross sectional observational study, 706 patients admitted to one of the Emergency Wards, at the Karolinska University Hospital in Solna, Stockholm during September 2008 –September 2009, were included. The electronic patient records were reviewed for patients’ demographic parameters, prevalence of possible ADRs and assessment of their preventability. In addition, the extent of formal and required ADR reporting to national registers was studied. Results Approximately 40 percent of the patient population had at least one possible ADR (n = 284). In the multivariable regression model, age and number of drugs were significantly associated with risk of presenting with an ADR (p<0.01 and p<0.001, respectively). Sex was not identified as a significant predictor of ADRs (p = 0.27). The most common ADRs were cardiovascular, followed by electrolyte disturbances, and hemorrhage. In 18 percent of the patient population ADRs were the reason for admission or had contributed to admission and 24% of these ADRs were assessed as preventable. The under-reporting of ADRs to the MPA was 99%. Conclusions ADRs are common in Emergency Medicine in tertiary care in Sweden, but under-reporting of ADRs is substantial. The most frequent ADRs are caused by cardiovascular drugs, and significantly associated with age and number of drugs. However, only a minority of the detected serious ADRs contributing to admission could have been avoided by increased risk awareness. PMID:27622270

  8. Adverse event management in mass drug administration for neglected tropical diseases.

    PubMed

    Caplan, Arthur; Zink, Amanda

    2014-03-01

    The ethical challenges of reporting and managing adverse events (AEs) and serious AEs (SAEs) in the context of mass drug administration (MDA) for the treatment of neglected tropical diseases (NTDs) require reassessment of domestic and international policies on a global scale. Although the World Health Organization has set forth AE/SAE guidelines specifically for NTD MDA that incorporate suspected causality, and recommends that only SAEs get reported in this setting, most regulatory agencies continue to require the reporting of all SAEs exhibiting even a merely temporal relationship to activities associated with an MDA program. This greatly increases the potential for excess "noise" and undue risk aversion and is not only impractical but arguably unethical where huge proportions of populations are being treated for devastating diseases, and no good baseline exists against which to compare possible AE/SAE reports. Other population-specific variables that might change the way drug safety ought to be assessed include differing efficacy rates of a drug, background morbidity/mortality rates of the target disease in question, the growth rate of the incidence of disease, the availability of rescue or salvage therapies, and the willingness of local populations to take risks that other populations might not. The fact that NTDs are controllable and potentially eradicable with well-tolerated, effective, existing drugs might further alter our assessment of MDA safety and AE/SAE tolerability. At the same time, diffuseness of population, communication barriers, lack of resources, and other difficult surveillance challenges may present in NTD-affected settings. These limitations could impair the ability to monitor an MDA program's success, as well as hinder efforts to obtain informed consent or provide rescue therapy. Denying beneficial research interventions and MDA programs intended to benefit millions requires sound ethical justification based on more than the identification of

  9. ADESSA: A Real-Time Decision Support Service for Delivery of Semantically Coded Adverse Drug Event Data.

    PubMed

    Duke, Jon D; Friedlin, Jeff

    2010-11-13

    Evaluating medications for potential adverse events is a time-consuming process, typically involving manual lookup of information by physicians. This process can be expedited by CDS systems that support dynamic retrieval and filtering of adverse drug events (ADE's), but such systems require a source of semantically-coded ADE data. We created a two-component system that addresses this need. First we created a natural language processing application which extracts adverse events from Structured Product Labels and generates a standardized ADE knowledge base. We then built a decision support service that consumes a Continuity of Care Document and returns a list of patient-specific ADE's. Our database currently contains 534,125 ADE's from 5602 product labels. An NLP evaluation of 9529 ADE's showed recall of 93% and precision of 95%. On a trial set of 30 CCD's, the system provided adverse event data for 88% of drugs and returned these results in an average of 620ms.

  10. Extent of poly-pharmacy, occurrence and associated factors of drug-drug interaction and potential adverse drug reactions in Gondar Teaching Referral Hospital, North West Ethiopia.

    PubMed

    Admassie, Endalkachew; Melese, Tesfahun; Mequanent, Woldeselassie; Hailu, Wubshet; Srikanth, B Akshaya

    2013-10-01

    The aim of this study was to assess the extent of poly-pharmacy, occurrence, and associated factors for the occurrence of drug-drug interaction (DDI) and potential adverse drug reaction (ADR) in Gondar University Teaching Referral Hospital. Institutional-based retrospective cross-sectional study. This study was conducted on prescriptions of both in and out-patients for a period of 3 months at Gondar University Hospital. Both bivariate analysis and multivariate logistic regression were used to identify risk factors for the occurrence of DDI and possible ADRs. All the statistical calculations were performed using SPSS(®) software. A total of 12,334 prescriptions were dispensed during the study period of which, 2,180 prescriptions were containing two or more drugs per prescription. A total of 21,210 drugs were prescribed and the average number of drugs per prescription was 1.72. Occurrences of DDI of all categories (Major, Moderate, and Minor) were analyzed and DDI were detected in 711 (32.6%) prescriptions. Sex was not found to be a risk factor for the occurrence of DDI and ADR, while age and number of medications per prescription were found to be significant risk factors for the occurrence of DDI and ADR. The mean number of drugs per prescription was 1.72 and hence with regard to the WHO limit of drugs per prescription, Gondar hospital was able to maintain the limit and prescriptions containing multiple drugs supposed to be taken systemically. Numbers of drugs per prescription as well as older age were found to be predisposing factors for the occurrence of DDI and potential ADRs while sex was not a risk factor. PMID:24350048

  11. Ocular Adverse Events Associated with Antibody-Drug Conjugates in Human Clinical Trials.

    PubMed

    Eaton, Joshua Seth; Miller, Paul E; Mannis, Mark J; Murphy, Christopher J

    2015-12-01

    This article reviews ocular adverse events (AEs) reported in association with administration of antibody-drug conjugates (ADCs) in human clinical trials. References reporting ocular toxicity or AEs associated with ADCs were collected using online publication searches. Articles, abstracts, or citations were included if they cited ocular toxicities or vision-impairing AEs with a confirmed or suspected association with ADC administration. Twenty-two references were found citing ocular or vision-impairing AEs in association with ADC administration. All references reported use of ADCs in human clinical trials for treatment of various malignancies. The molecular target and cytotoxic agent varied depending on the ADC used. Ocular AEs affected a diversity of ocular tissues. The most commonly reported AEs involved the ocular surface and included blurred vision, dry eye, and corneal abnormalities (including microcystic corneal disease). Most ocular AEs were not severe (≤ grade 2) or dose limiting. Clinical outcomes were not consistently reported, but when specified, most AEs improved or resolved with cessation of treatment or with ameliorative therapy. A diverse range of ocular AEs are reported in association with administration of ADCs for the treatment of cancer. The toxicologic mechanism(s) and pathogenesis of such events are not well understood, but most are mild in severity and reversible. Drug development and medical professionals should be aware of the clinical features of these events to facilitate early recognition and intervention in the assessment of preclinical development programs and in human clinical trials.

  12. Using technology to prevent adverse drug events in the intensive care unit.

    PubMed

    Hassan, Erkan; Badawi, Omar; Weber, Robert J; Cohen, Henry

    2010-06-01

    Critically ill patients are particularly susceptible to adverse drug events (ADEs) due to their rapidly changing and unstable physiology, complex therapeutic regimens, and large percentage of medications administered intravenously. There are a wide variety of technologies that can help prevent the points of failure commonly associated with ADEs (i.e., the five "Rights": right patient; right drug; right route; right dose; right frequency). These technologies are often categorized by their degree of complexity to design and engineer and the type of error they are designed to prevent. Focusing solely on the software and hardware design of technology may over- or underestimate the degree of difficulty to avoid ADEs at the bedside. Alternatively, we propose categorizing technological solutions by identifying the factors essential for success. The two major critical success factors are: 1) the degree of clinical assessment required by the clinician to appropriately evaluate and disposition the issue identified by a technology; and 2) the complexity associated with effective implementation. This classification provides a way of determining how ADE-preventing technologies in the intensive care unit can be successfully integrated into clinical practice. Although there are limited data on the effectiveness of many technologies in reducing ADEs, we will review the technologies currently available in the intensive care unit environment. We will also discuss critical success factors for implementation, common errors made during implementation, and the potential errors using these systems.

  13. Using technology to prevent adverse drug events in the intensive care unit.

    PubMed

    Hassan, Erkan; Badawi, Omar; Weber, Robert J; Cohen, Henry

    2010-06-01

    Critically ill patients are particularly susceptible to adverse drug events (ADEs) due to their rapidly changing and unstable physiology, complex therapeutic regimens, and large percentage of medications administered intravenously. There are a wide variety of technologies that can help prevent the points of failure commonly associated with ADEs (i.e., the five "Rights": right patient; right drug; right route; right dose; right frequency). These technologies are often categorized by their degree of complexity to design and engineer and the type of error they are designed to prevent. Focusing solely on the software and hardware design of technology may over- or underestimate the degree of difficulty to avoid ADEs at the bedside. Alternatively, we propose categorizing technological solutions by identifying the factors essential for success. The two major critical success factors are: 1) the degree of clinical assessment required by the clinician to appropriately evaluate and disposition the issue identified by a technology; and 2) the complexity associated with effective implementation. This classification provides a way of determining how ADE-preventing technologies in the intensive care unit can be successfully integrated into clinical practice. Although there are limited data on the effectiveness of many technologies in reducing ADEs, we will review the technologies currently available in the intensive care unit environment. We will also discuss critical success factors for implementation, common errors made during implementation, and the potential errors using these systems. PMID:20502181

  14. A research framework for pharmacovigilance in health social media: Identification and evaluation of patient adverse drug event reports.

    PubMed

    Liu, Xiao; Chen, Hsinchun

    2015-12-01

    Social media offer insights of patients' medical problems such as drug side effects and treatment failures. Patient reports of adverse drug events from social media have great potential to improve current practice of pharmacovigilance. However, extracting patient adverse drug event reports from social media continues to be an important challenge for health informatics research. In this study, we develop a research framework with advanced natural language processing techniques for integrated and high-performance patient reported adverse drug event extraction. The framework consists of medical entity extraction for recognizing patient discussions of drug and events, adverse drug event extraction with shortest dependency path kernel based statistical learning method and semantic filtering with information from medical knowledge bases, and report source classification to tease out noise. To evaluate the proposed framework, a series of experiments were conducted on a test bed encompassing about postings from major diabetes and heart disease forums in the United States. The results reveal that each component of the framework significantly contributes to its overall effectiveness. Our framework significantly outperforms prior work.

  15. A research framework for pharmacovigilance in health social media: Identification and evaluation of patient adverse drug event reports.

    PubMed

    Liu, Xiao; Chen, Hsinchun

    2015-12-01

    Social media offer insights of patients' medical problems such as drug side effects and treatment failures. Patient reports of adverse drug events from social media have great potential to improve current practice of pharmacovigilance. However, extracting patient adverse drug event reports from social media continues to be an important challenge for health informatics research. In this study, we develop a research framework with advanced natural language processing techniques for integrated and high-performance patient reported adverse drug event extraction. The framework consists of medical entity extraction for recognizing patient discussions of drug and events, adverse drug event extraction with shortest dependency path kernel based statistical learning method and semantic filtering with information from medical knowledge bases, and report source classification to tease out noise. To evaluate the proposed framework, a series of experiments were conducted on a test bed encompassing about postings from major diabetes and heart disease forums in the United States. The results reveal that each component of the framework significantly contributes to its overall effectiveness. Our framework significantly outperforms prior work. PMID:26518315

  16. In Silico Models for Repeated-Dose Toxicity (RDT): Prediction of the No Observed Adverse Effect Level (NOAEL) and Lowest Observed Adverse Effect Level (LOAEL) for Drugs.

    PubMed

    Pizzo, Fabiola; Benfenati, Emilio

    2016-01-01

    The preclinical stage in drug development requires the determination of repeated-dose toxicity (RDT) in animal models. The main outcome of RDT studies is the determination of the no observed adverse effect level (NOAEL) and the lowest observed adverse effect level (LOAEL). NOAEL is important since it serves to calculate the maximum recommended starting dose (MRSD) which is the safe starting dose for clinical studies in human beings. Since in vivo RDT studies are expensive and time-consuming, in silico approaches could offer a valuable alternative. However, NOAEL and LOAEL modeling suffer some limitations since they do not refer to a single end point but to several different effects and the doses used in experimental studies strongly influence the final results. Few attempts to model NOAEL and LOAEL have been reported. The available database and models for the prediction of NOAEL and LOAEL are reviewed here. PMID:27311467

  17. Systematic drug safety evaluation based on public genomic expression (Connectivity Map) data: myocardial and infectious adverse reactions as application cases.

    PubMed

    Wang, Kejian; Weng, Zuquan; Sun, Liya; Sun, Jiazhi; Zhou, Shu-Feng; He, Lin

    2015-02-13

    Adverse drug reaction (ADR) is of great importance to both regulatory agencies and the pharmaceutical industry. Various techniques, such as quantitative structure-activity relationship (QSAR) and animal toxicology, are widely used to identify potential risks during the preclinical stage of drug development. Despite these efforts, drugs with safety liabilities can still pass through safety checkpoints and enter the market. This situation raises the concern that conventional chemical structure analysis and phenotypic screening are not sufficient to avoid all clinical adverse events. Genomic expression data following in vitro drug treatments characterize drug actions and thus have become widely used in drug repositioning. In the present study, we explored prediction of ADRs based on the drug-induced gene-expression profiles from cultured human cells in the Connectivity Map (CMap) database. The results showed that drugs inducing comparable ADRs generally lead to similar CMap expression profiles. Based on such ADR-gene expression association, we established prediction models for various ADRs, including severe myocardial and infectious events. Drugs with FDA boxed warnings of safety liability were effectively identified. We therefore suggest that drug-induced gene expression change, in combination with effective computational methods, may provide a new dimension of information to facilitate systematic drug safety evaluation.

  18. Systematic drug safety evaluation based on public genomic expression (Connectivity Map) data: myocardial and infectious adverse reactions as application cases.

    PubMed

    Wang, Kejian; Weng, Zuquan; Sun, Liya; Sun, Jiazhi; Zhou, Shu-Feng; He, Lin

    2015-02-13

    Adverse drug reaction (ADR) is of great importance to both regulatory agencies and the pharmaceutical industry. Various techniques, such as quantitative structure-activity relationship (QSAR) and animal toxicology, are widely used to identify potential risks during the preclinical stage of drug development. Despite these efforts, drugs with safety liabilities can still pass through safety checkpoints and enter the market. This situation raises the concern that conventional chemical structure analysis and phenotypic screening are not sufficient to avoid all clinical adverse events. Genomic expression data following in vitro drug treatments characterize drug actions and thus have become widely used in drug repositioning. In the present study, we explored prediction of ADRs based on the drug-induced gene-expression profiles from cultured human cells in the Connectivity Map (CMap) database. The results showed that drugs inducing comparable ADRs generally lead to similar CMap expression profiles. Based on such ADR-gene expression association, we established prediction models for various ADRs, including severe myocardial and infectious events. Drugs with FDA boxed warnings of safety liability were effectively identified. We therefore suggest that drug-induced gene expression change, in combination with effective computational methods, may provide a new dimension of information to facilitate systematic drug safety evaluation. PMID:25576362

  19. Medication safety program reduces adverse drug events in a community hospital

    PubMed Central

    Cohen, M; Kimmel, N; Benage, M; Cox, M; Sanders, N; Spence, D; Chen, J

    2005-01-01

    Background: There is widespread interest in improving medication safety, particularly in the hospital setting. Numerous suggestions have been made as to how this should be done, but there is a paucity of data demonstrating the effectiveness of any of the interventions that have been proposed. Objectives: To assess the impact of a wide ranging, community hospital based patient safety program on patient harm as measured by the rate of adverse drug events. Design: An audit of discharged hospital patients was conducted from January 2001 to December 2003. Baseline data were collected for the first 6 months and multiple drug protocols and other interventions were instituted on the nursing units and in the pharmacy department over the subsequent 9 months (transition period). These interventions were largely based on information about medication risks acquired from internal medication event reporting. Each month of the study adverse drug events (ADE) were sought from a random sample of inpatient charts. A trigger tool was used to detect clues to ADEs, the presence of which was confirmed or excluded by detailed manual chart review. The severity of these events was categorized using the classification system of the National Coordinating Council for Medication Error and Reporting and Prevention. Main outcome measures and results: Median ADEs per 1000 doses of medication dispensed declined significantly from 2.04 to 0.65 (p<0.001). Median ADEs per 100 patient days declined significantly from 5.07 to 1.30 (p<0.001). The proportion of inpatients with one or more ADE in the baseline period was 31% and declined threefold (p<0.001). The severity of reported medication events also declined. The number of ADEs associated conclusively with patient harm was 1.67 per total doses delivered in the baseline period and declined eightfold (p<0.001). Conclusion: The implementation of a carefully planned series of low cost interventions focused on high risk medications, driven by information

  20. Profile of rheumatology patients willing to report adverse drug reactions: bias from selective reporting

    PubMed Central

    Protić, Dragana; Vujasinović-Stupar, Nada; Bukumirić, Zoran; Pavlov-Dolijanović, Slavica; Baltić, Snežana; Mutavdžin, Slavica; Marković-Denić, Ljiljana; Zdravković, Marija; Todorović, Zoran

    2016-01-01

    Background Adverse drug reactions (ADRs) have a significant impact on human health and health care costs. The aims of our study were to determine the profile of rheumatology patients willing to report ADRs and to identify bias in such a reporting system. Methods Semi-intensive ADRs reporting system was used in our study. Patients willing to participate (N=261) completed the questionnaire designed for the purpose of the study at the hospital admission. They were subsequently classified into two groups according to their ability to identify whether they had experienced ADRs during the previous month. Group 1 included 214 out of 261 patients who were able to identify ADRs, and group 2 consisted of 43 out of 261 patients who were not able to identify ADRs in their recent medical history. Results Group 1 patients were more significantly aware of their diagnosis than the patients from group 2. Marginal significance was found between rheumatology patients with and without neurological comorbidities regarding their awareness of ADRs. The majority of patients reported ADRs of cytotoxic drugs. The most reported ADRs were moderate gastrointestinal discomforts. Conclusion We may draw a profile of rheumatological patients willing to report ADRs: 1) The majority of them suffer from systemic inflammatory diseases and are slightly more prone to neurological comorbidities. 2) They are predominantly aware of their diagnosis but less able to identify the drugs that may cause their ADRs. 3) They tend to report mainly moderate gastrointestinal ADRs; that is, other cohorts of patients and other types of ADRs remain mainly undetected in such a reporting, which could represent a bias. Counseling and education of patients as well as developing a network for online communication might improve patients’ reporting of potential ADRs. PMID:26893547

  1. Systematic drug safety evaluation based on public genomic expression (Connectivity Map) data: Myocardial and infectious adverse reactions as application cases

    SciTech Connect

    Wang, Kejian; Weng, Zuquan; Sun, Liya; Sun, Jiazhi; Zhou, Shu-Feng; He, Lin

    2015-02-13

    Adverse drug reaction (ADR) is of great importance to both regulatory agencies and the pharmaceutical industry. Various techniques, such as quantitative structure–activity relationship (QSAR) and animal toxicology, are widely used to identify potential risks during the preclinical stage of drug development. Despite these efforts, drugs with safety liabilities can still pass through safety checkpoints and enter the market. This situation raises the concern that conventional chemical structure analysis and phenotypic screening are not sufficient to avoid all clinical adverse events. Genomic expression data following in vitro drug treatments characterize drug actions and thus have become widely used in drug repositioning. In the present study, we explored prediction of ADRs based on the drug-induced gene-expression profiles from cultured human cells in the Connectivity Map (CMap) database. The results showed that drugs inducing comparable ADRs generally lead to similar CMap expression profiles. Based on such ADR-gene expression association, we established prediction models for various ADRs, including severe myocardial and infectious events. Drugs with FDA boxed warnings of safety liability were effectively identified. We therefore suggest that drug-induced gene expression change, in combination with effective computational methods, may provide a new dimension of information to facilitate systematic drug safety evaluation. - Highlights: • Drugs causing common toxicity lead to similar in vitro gene expression changes. • We built a model to predict drug toxicity with drug-specific expression profiles. • Drugs with FDA black box warnings were effectively identified by our model. • In vitro assay can detect severe toxicity in the early stage of drug development.

  2. Torsadogenic Risk of Antipsychotics: Combining Adverse Event Reports with Drug Utilization Data across Europe

    PubMed Central

    Raschi, Emanuel; Poluzzi, Elisabetta; Godman, Brian; Koci, Ariola; Moretti, Ugo; Kalaba, Marija; Bennie, Marion; Barbui, Corrado; Wettermark, Bjorn; Sturkenboom, Miriam; De Ponti, Fabrizio

    2013-01-01

    Background Antipsychotics (APs) have been associated with risk of torsade de Pointes (TdP). This has important public health implications. Therefore, (a) we exploited the public FDA Adverse Event Reporting System (FAERS) to characterize their torsadogenic profile; (b) we collected drug utilization data from 12 European Countries to assess the population exposure over the 2005-2010 period. Methods FAERS data (2004-2010) were analyzed based on the following criteria: (1) ≥4 cases of TdP/QT abnormalities; (2) Significant Reporting Odds Ratio, ROR [Lower Limit of the 95% confidence interval>1], for TdP/QT abnormalities, adjusted and stratified (Arizona CERT drugs as effect modifiers); (3) ≥4 cases of ventricular arrhythmia/sudden cardiac death (VA/SCD); (4) Significant ROR for VA/SCD; (5) Significant ROR, combined by aggregating TdP/QT abnormalities with VA and SCD. Torsadogenic signals were characterized in terms of signal strength: from Group A (very strong torsadogenic signal: all criteria fulfilled) to group E (unclear/uncertain signal: only 2/5 criteria). Consumption data were retrieved from 12 European Countries and expressed as defined daily doses per 1,000 inhabitants per day (DID). Results Thirty-five antipsychotics met at least one criterium: 9 agents were classified in Group A (amisulpride, chlorpromazine, clozapine, cyamemazine, haloperidol, olanzapine, quetiapine, risperidone, ziprasidone). In 2010, the overall exposure to antipsychotics varied from 5.94 DID (Estonia) to 13.99 (France, 2009). Considerable increment of Group A agents was found in several Countries (+3.47 in France): the exposure to olanzapine increased across all Countries (+1.84 in France) and peaked 2.96 in Norway; cyamemazine was typically used only in France (2.81 in 2009). Among Group B drugs, levomepromazine peaked 3.78 (Serbia); fluphenazine 1.61 (Slovenia). Conclusions This parallel approach through spontaneous reporting and drug utilization analyses highlighted drug- and

  3. Indications of newer and older anti-epileptic drug use: findings from a southern Italian general practice setting from 2005–2011

    PubMed Central

    Italiano, Domenico; Capuano, Annalisa; Alibrandi, Angela; Ferrara, Rosarita; Cannata, Angelo; Trifirò, Gianluca; Sultana, Janet; Ferrajolo, Carmen; Tari, Michele; Tari, Daniele Ugo; Perrotta, Margherita; Pagliaro, Claudia; Rafaniello, Concita; Spina, Edoardo; Arcoraci, Vincenzo

    2015-01-01

    Aims The aim of the study was to analyze the prescribing pattern of both newer and older AEDs. Methods A population of almost 150 000 individuals registered with 123 general practitioners was included in this study. Patients who received at least one AED prescription over 2005–2011 were identified. The 1 year prevalence and cumulative incidence of AED use, by drug class and individual drug, were calculated over the study period. Potential predictors of starting therapy with newer AEDs were also investigated. Results The prevalence of use per 1000 inhabitants of older AEDs increased from 10.7 (95% CI10.1, 11.2) in 2005 to 13.0 (95% CI12.4, 13.6) in 2011, while the incidence remained stable. Newer AED incidence decreased from 9.4 (95% CI 8.9, 9.9) in 2005 to 7.0 (95% CI 6.6, 7.5) in 2011, with a peak of 15.5 (95% CI 14.8, 16.1) in 2006. Phenobarbital and valproic acid were the most commonly prescribed AEDs as starting therapy for epilepsy. Gabapentin and pregabalin accounted for most new pain-related prescriptions, while valproic acid and lamotrigine were increasingly used for mood disorders. Female gender (OR 1.36, 95% CI 1.20, 1.53), age ranging between 45–54 years (OR 1.39, 95% CI 1.16, 1.66) and pain as an indication (OR 16.7, 95% CI, 13.1, 21.2) were associated with newer AEDs starting therapy. Conclusions Older AEDs were mainly used for epileptic and mood disorders, while newer drugs were preferred for neuropathic pain. Gender, age, indication of use and year of starting therapy influenced the choice of AED type. The decrease of newer AED use during 2007 is probably related to the restricted reimbursement criteria for gabapentin and pregabalin. PMID:25556909

  4. Predicting adverse drug reactions in older adults; a systematic review of the risk prediction models

    PubMed Central

    Stevenson, Jennifer M; Williams, Josceline L; Burnham, Thomas G; Prevost, A Toby; Schiff, Rebekah; Erskine, S David; Davies, J Graham

    2014-01-01

    Adverse drug reaction (ADR) risk-prediction models for use in older adults have been developed, but it is not clear if they are suitable for use in clinical practice. This systematic review aimed to identify and investigate the quality of validated ADR risk-prediction models for use in older adults. Standard computerized databases, the gray literature, bibliographies, and citations were searched (2012) to identify relevant peer-reviewed studies. Studies that developed and validated an ADR prediction model for use in patients over 65 years old, using a multivariable approach in the design and analysis, were included. Data were extracted and their quality assessed by independent reviewers using a standard approach. Of the 13,423 titles identified, only 549 were associated with adverse outcomes of medicines use. Four met the inclusion criteria. All were conducted in inpatient cohorts in Western Europe. None of the models satisfied the four key stages in the creation of a quality risk prediction model; development and validation were completed, but impact and implementation were not assessed. Model performance was modest; area under the receiver operator curve ranged from 0.623 to 0.73. Study quality was difficult to assess due to poor reporting, but inappropriate methods were apparent. Further work needs to be conducted concerning the existing models to enable the development of a robust ADR risk-prediction model that is externally validated, with practical design and good performance. Only then can implementation and impact be assessed with the aim of generating a model of high enough quality to be considered for use in clinical care to prioritize older people at high risk of suffering an ADR. PMID:25278750

  5. Predicting adverse drug reactions in older adults; a systematic review of the risk prediction models.

    PubMed

    Stevenson, Jennifer M; Williams, Josceline L; Burnham, Thomas G; Prevost, A Toby; Schiff, Rebekah; Erskine, S David; Davies, J Graham

    2014-01-01

    Adverse drug reaction (ADR) risk-prediction models for use in older adults have been developed, but it is not clear if they are suitable for use in clinical practice. This systematic review aimed to identify and investigate the quality of validated ADR risk-prediction models for use in older adults. Standard computerized databases, the gray literature, bibliographies, and citations were searched (2012) to identify relevant peer-reviewed studies. Studies that developed and validated an ADR prediction model for use in patients over 65 years old, using a multivariable approach in the design and analysis, were included. Data were extracted and their quality assessed by independent reviewers using a standard approach. Of the 13,423 titles identified, only 549 were associated with adverse outcomes of medicines use. Four met the inclusion criteria. All were conducted in inpatient cohorts in Western Europe. None of the models satisfied the four key stages in the creation of a quality risk prediction model; development and validation were completed, but impact and implementation were not assessed. Model performance was modest; area under the receiver operator curve ranged from 0.623 to 0.73. Study quality was difficult to assess due to poor reporting, but inappropriate methods were apparent. Further work needs to be conducted concerning the existing models to enable the development of a robust ADR risk-prediction model that is externally validated, with practical design and good performance. Only then can implementation and impact be assessed with the aim of generating a model of high enough quality to be considered for use in clinical care to prioritize older people at high risk of suffering an ADR.

  6. Predicting adverse drug reactions in older adults; a systematic review of the risk prediction models.

    PubMed

    Stevenson, Jennifer M; Williams, Josceline L; Burnham, Thomas G; Prevost, A Toby; Schiff, Rebekah; Erskine, S David; Davies, J Graham

    2014-01-01

    Adverse drug reaction (ADR) risk-prediction models for use in older adults have been developed, but it is not clear if they are suitable for use in clinical practice. This systematic review aimed to identify and investigate the quality of validated ADR risk-prediction models for use in older adults. Standard computerized databases, the gray literature, bibliographies, and citations were searched (2012) to identify relevant peer-reviewed studies. Studies that developed and validated an ADR prediction model for use in patients over 65 years old, using a multivariable approach in the design and analysis, were included. Data were extracted and their quality assessed by independent reviewers using a standard approach. Of the 13,423 titles identified, only 549 were associated with adverse outcomes of medicines use. Four met the inclusion criteria. All were conducted in inpatient cohorts in Western Europe. None of the models satisfied the four key stages in the creation of a quality risk prediction model; development and validation were completed, but impact and implementation were not assessed. Model performance was modest; area under the receiver operator curve ranged from 0.623 to 0.73. Study quality was difficult to assess due to poor reporting, but inappropriate methods were apparent. Further work needs to be conducted concerning the existing models to enable the development of a robust ADR risk-prediction model that is externally validated, with practical design and good performance. Only then can implementation and impact be assessed with the aim of generating a model of high enough quality to be considered for use in clinical care to prioritize older people at high risk of suffering an ADR. PMID:25278750

  7. Disentangling incentives effects of insurance coverage from adverse selection in the case of drug expenditure: a finite mixture approach.

    PubMed

    Munkin, Murat K; Trivedi, Pravin K

    2010-09-01

    This paper takes a finite mixture approach to model heterogeneity in incentive and selection effects of drug coverage on total drug expenditure among the Medicare elderly US population. Evidence is found that the positive drug expenditures of the elderly population can be decomposed into two groups different in the identified selection effects and interpreted as relatively healthy with lower average expenditures and relatively unhealthy with higher average expenditures, accounting for approximately 25 and 75% of the population, respectively. Adverse selection into drug insurance appears to be strong for the higher expenditure component and weak for the lower expenditure group.

  8. Trends in the use of antiepileptic drugs (AEDs) among pregnant women in the U.S., 2001-2007: a Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP) study

    PubMed Central

    Bobo, William V.; Davis, Robert L.; Toh, Sengwee D.; Li, De-Kun; Andrade, Susan E.; Cheetham, T. Craig; Pawloski, Pamala; Dublin, Sascha; Pinheiro, Simone; Hammad, Tarek; Scott, Pamela E.; Epstein, Richard A.; Arbogast, Patrick G.; Morrow, James A.; Dudley, Judith A.; Lawrence, Jean M.; Avalos, Lyndsay A.; Cooper, William O.

    2012-01-01

    Background Little is known about the extent of antiepileptic drug (AED) use in pregnancy, particularly for newer agents. Our objective was to assess whether AED use has increased among pregnant women in the U.S., 2001-2007. Methods We analyzed data from the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP) database, 1 January 2001 to 31 December 2007. We identified live-born deliveries among women, aged 15-45 years on delivery date, who were members of MEPREP health plans (N = 585,615 deliveries). Pregnancy exposure to AEDs, determined through outpatient pharmacy dispensing files. Older AEDs were available for clinical use before 1993; other agents were considered newer AEDs. Information on sociodemographic and medical/reproductive factors was obtained from linked birth certificate files. Maternal diagnoses were identified based on ICD-9 codes. Results Prevalence of AED use during pregnancy increased between 2001 (15.7 per 1,000 deliveries) and 2007 (21.9 per 1,000 deliveries), driven primarily by a five-fold increase in the use of newer AEDs. Thirteen percent of AED-exposed deliveries involved a combination of two or more AEDs. Psychiatric disorders were the most prevalent diagnoses, followed by epileptic and pain disorders, among AED users regardless of AED type, year of conception or gestational period. Conclusions AED use during pregnancy increased between 2001 and 2007, driven by a five-fold increase in the use of newer AEDs. Nearly one in eight AED-exposed deliveries involved the concomitant use of more than one AED. Additional investigations of the reproductive safety of newer AEDs may be needed. PMID:23061694

  9. Evaluating the efficacy of memantine on improving cognitive functions in epileptic patients receiving anti-epileptic drugs: A double-blind placebo-controlled clinical trial (Phase IIIb pilot study)

    PubMed Central

    Marimuthu, Priya; Varadarajan, Sathyanarayanan; Krishnan, Muthuraj; Shanmugam, Sundar; Kunjuraman, Gireesh; Ravinder, Jamuna Rani; Arumugam, Balasubramanian; Alex, Divya; Swaminathan, Porchelvan

    2016-01-01

    Objectives: People with epilepsy have greater cognitive and behavioral dysfunction than the general population. There is no specific treatment available for cognitive impairment of these patients. We aimed to evaluate the effects of memantine, an N-methyl-D-aspartate-type glutamate receptor noncompetitive antagonist, on improving cognition and memory functions in epileptic patients with cognitive and memory impairment, who received anti-epileptic drugs (AEDs). Methods: We did a randomized, double-blind, placebo-controlled parallel group trial, in SRM Medical College Hospital and Research Centre, Kattankulathur, Kancheepuram, Tamil Nadu, India between April 2013 and September 2013. Fifty-nine epileptic patients taking AEDs with subjective memory complaints were recruited and randomized to either Group 1 to receive 16 weeks of once-daily memantine, (5 mg for first 8 weeks, followed by memantine 10 mg for next 8 weeks) or Group 2 to receive once daily placebo. This trial is registered with Clinical Trial Registry of India CTRI/2013/04/003573. Results: Of 59 randomized patients, 55 patients completed the study (26 memantine and 29 placebo). Memantine group showed statistically significant improvement in total mini mental state examination score from baseline (P = 0.765) to 16th week (P < 0.001) in comparison with the placebo. The Weshler's Memory Scale total score in memantine group improved significantly after 8 weeks (P = 0.002) compared with baseline (P = 0.873) and highly significant at the end of 16th week (P < 0.001). The self-rated quality of life and memory in memantine group also significantly improved at the study end. Conclusion: We conclude that once-daily memantine (10 mg) treatment significantly improved cognition, memory and quality of life in epileptic patients with mild to moderate cognitive impairment and was found to have a favorable safety profile. PMID:27570386

  10. Mechanistic and conformational studies on the interaction of a platinum(II) complex containing an antiepileptic drug, levetiracetam, with bovine serum albumin by optical spectroscopic techniques in aqueous solution.

    PubMed

    Shahabadi, Nahid; Hadidi, Saba

    2015-02-01

    Fluorescence spectroscopy in combination with circular dichroism (CD) and ultraviolet-visible (UV-vis) absorption spectroscopy were employed to investigate the binding of a new platinum(II) complex containing an antiepileptic drug "Levetiracetam" to bovine serum albumin (BSA) under the physiological conditions. In the mechanism discussion, it was proved that the fluorescence quenching of BSA by Pt(II) complex is a result of the formation of Pt(II) complex-BSA complex. The thermodynamic parameters ΔG, ΔH, and ΔS at different temperatures (283, 298, and 310 K) were calculated, and the negative value for ΔH and ΔS indicate that the hydrogen bonds and van der Waals interactions play major roles in Pt(II) complex-BSA association. Binding studies concerning the number of binding sites (n~1) and apparent binding constant K b were performed by fluorescence quenching method. The site marker competitive experiments indicated that the binding of Pt(II) complex to BSA primarily took place in site II. Based on the Förster's theory, the average binding distance between Pt(II) complex and BSA was obtained (r = 5.29 nm). Furthermore, UV-vis, CD, and synchronous fluorescence spectrum were used to investigate the structural change of BSA molecules with addition of Pt(II) complex. These results indicate that the binding of Pt(II) complex to BSA causes apparent change in the secondary structure of BSA and do affect the microenvironment around the tryptophan residue.

  11. Mechanistic and conformational studies on the interaction of a platinum(II) complex containing an antiepileptic drug, levetiracetam, with bovine serum albumin by optical spectroscopic techniques in aqueous solution.

    PubMed

    Shahabadi, Nahid; Hadidi, Saba

    2015-02-01

    Fluorescence spectroscopy in combination with circular dichroism (CD) and ultraviolet-visible (UV-vis) absorption spectroscopy were employed to investigate the binding of a new platinum(II) complex containing an antiepileptic drug "Levetiracetam" to bovine serum albumin (BSA) under the physiological conditions. In the mechanism discussion, it was proved that the fluorescence quenching of BSA by Pt(II) complex is a result of the formation of Pt(II) complex-BSA complex. The thermodynamic parameters ΔG, ΔH, and ΔS at different temperatures (283, 298, and 310 K) were calculated, and the negative value for ΔH and ΔS indicate that the hydrogen bonds and van der Waals interactions play major roles in Pt(II) complex-BSA association. Binding studies concerning the number of binding sites (n~1) and apparent binding constant K b were performed by fluorescence quenching method. The site marker competitive experiments indicated that the binding of Pt(II) complex to BSA primarily took place in site II. Based on the Förster's theory, the average binding distance between Pt(II) complex and BSA was obtained (r = 5.29 nm). Furthermore, UV-vis, CD, and synchronous fluorescence spectrum were used to investigate the structural change of BSA molecules with addition of Pt(II) complex. These results indicate that the binding of Pt(II) complex to BSA causes apparent change in the secondary structure of BSA and do affect the microenvironment around the tryptophan residue. PMID:25427597

  12. A Retrospective Analysis of Spontaneous Adverse Drug Reactions Reports Relating to Paediatric Patients

    PubMed Central

    Rosli, Rosliana; Abd Aziz, Noorizan; Manan, Mohamed Mansor

    2016-01-01

    Background Spontaneous reporting on adverse drug reactions (ADR) has been established in Malaysia since 1987, and although these reports are monitored by the Malaysia drug monitoring authority, the National Pharmaceutical Control Bureau, information about ADRs in the paediatric patient population still remains unexplored. The aims of this study, therefore, were to characterize the ADRs reported in respect to the Malaysian paediatric population and to relate the data to specific paediatric age groups. Methods Data on all ADRs reported to the National Pharmaceutical Control Bureau between 2000 and 2013 for individuals aged from birth to 17 years old were analysed with respect to age and gender, type of reporter, suspected medicines (using the Anatomical Therapeutic Chemical classification), category of ADR (according to system organ class) as well as the severity of the ADR. Results In total, 11,523 ADR reports corresponding to 22,237 ADRs were analysed, with half of these reporting one ADR per report. Vaccines comprised 55.7% of the 11,523 ADR reports with the remaining being drug related ADRs. Overall, 63.9% of ADRs were reported for paediatric patients between 12 and 17 years of age, with the majority of ADRs reported in females (70.7%). The most common ADRs reported were from the following system organ classes: application site disorders (32.2%), skin and appendages disorders (20.6%), body as a whole general disorders (12.8%) and central and peripheral nervous system disorders (11.2%). Meanwhile, ADRs in respect to anti-infectives for systemic use (2194/5106; 43.0%) were the most frequently reported across all age groups, followed by drugs from the nervous system (1095/5106; 21.4%). Only 0.28% of the ADR cases were reported as fatal. A large proportion of the reports were received from healthcare providers in government health facilities. Discussion ADR reports concerning vaccines and anti-infectives were the most commonly reported in children, and are mainly

  13. Antiepileptic Activity of Preferential Inhibitors of Persistent Sodium Current

    PubMed Central

    Anderson, Lyndsey L.; Thompson, Christopher H.; Hawkins, Nicole A.; Nath, Ravi D.; Petersohn, Adam A.; Rajamani, Sridharan; Bush, William S.; Frankel, Wayne N.; Vanoye, Carlos G.; Kearney, Jennifer A.; George, Alfred L.

    2014-01-01

    Objective Evidence from basic neurophysiology and molecular genetics has implicated persistent sodium current conducted by voltage-gated sodium (NaV) channels as a contributor to the pathogenesis of epilepsy. Many antiepileptic drugs target NaV channels and modulate neuronal excitability mainly by a use-dependent block of transient sodium current, although suppression of persistent current may also contribute to the efficacy of these drugs. We hypothesized that a drug or compound capable of preferential inhibition of persistent sodium current would have antiepileptic activity. Methods We examined the antiepileptic activity of two selective persistent sodium current blockers ranolazine, an FDA-approved drug for treatment of angina pectoris, and GS967, a novel compound with more potent effects on persistent current, in the epileptic Scn2aQ54 mouse model. We also examined the effect of GS967 in the maximal electroshock model and evaluated effects of the compound on neuronal excitability, propensity for hilar neuron loss, development of mossy fiber sprouting and survival of Scn2aQ54 mice. Results We found that ranolazine was capable of reducing seizure frequency by ~50% in Scn2aQ54 mice. The more potent persistent current blocker GS967 reduced seizure frequency by greater than 90% in Scn2aQ54 mice and protected against induced seizures in the maximal electroshock model. GS967 greatly attenuated abnormal spontaneous action potential firing in pyramidal neurons acutely isolated from Scn2aQ54 mice. In addition to seizure suppression in vivo, GS967 treatment greatly improved the survival of Scn2aQ54 mice, prevented hilar neuron loss, and suppressed the development of hippocampal mossy fiber sprouting. Significance Our findings indicate that the selective persistent sodium current blocker GS967 has potent antiepileptic activity and this compound could inform development of new agents. PMID:24862204

  14. Development of an Adverse Drug Reaction Risk Assessment Score among Hospitalized Patients with Chronic Kidney Disease

    PubMed Central

    Saheb Sharif-Askari, Fatemeh; Syed Sulaiman, Syed Azhar; Saheb Sharif-Askari, Narjes; Al Sayed Hussain, Ali

    2014-01-01

    Background Adverse drug reactions (ADRs) represent a major burden on the healthcare system. Chronic kidney disease (CKD) patients are particularly vulnerable to ADRs because they are usually on multiple drug regimens, have multiple comorbidities, and because of alteration in their pharmacokinetics and pharmacodynamic parameters. Therefore, one step towards reducing this burden is to identify patients who are at increased risk of an ADR. Objective To develop a method of identifying CKD patients who are at increased risk for experiencing ADRs during hospitalisation. Materials and Methods Factors associated with ADRs were identified by using demographic, clinical and laboratory variables of patients with CKD stages 3 to 5 (estimated glomerular filtration rate, 10–59 ml/min/1.73 m2) who were admitted between January 1, 2012, and December 31, 2012, to the renal unit of Dubai Hospital. An ADR risk score was developed by constructing a series of logistic regression models. The overall model performance for sequential models was evaluated using Akaike Information Criterion for goodness of fit. Odd ratios of the variables retained in the best model were used to compute the risk scores. Results Of 512 patients (mean [SD] age, 60 [16] years), 62 (12.1%) experienced an ADR during their hospitalisation. An ADR risk score included age 65 years or more, female sex, conservatively managed end-stage renal disease, vascular disease, serum level of C-reactive protein more than 10 mg/L, serum level of albumin less than 3.5 g/dL, and the use of 8 medications or more during hospitalization. The C statistic, which assesses the ability of the risk score to predict ADRs, was 0.838; 95% CI, 0.784–0.892). Conclusion A score using routinely available patient data can be used to identify CKD patients who are at increased risk of ADRs. PMID:24755778

  15. Melanoma Associated with TNFα Inhibitors: a Research on Adverse Drug events And Reports (RADAR) Project

    PubMed Central

    Nardone, B.; Hammel, J.A.; Raisch, D.W.; Weaver, L.L.; Schneider, D.; West, D.P.

    2014-01-01

    Background Tumor necrosis factor-alpha inhibitors (TNFαIs) are used for treatment of inflammatory disorders. There is evidence linking these agents with occurrence of malignancies. For four out of five TNFαIs the Food and Drug Administration (FDA) label states, “melanoma has been reported in patients treated with these agents.” Objectives Determine whether a statistically-significant association exists between administration of TNFαIs and development of malignant melanoma. Methods We searched the FDA Adverse Events Reporting System (FAERS) database for terms related to melanoma and TNFαIs for detection of safety signals. We also searched a large urban academic electronic medical record (EMR) database for which we calculated the relative risk (RR) of melanoma in subjects exposed to TNFαIs vs. non-exposed subjects. Results There were 972 reports of melanoma associated with a TNFαIs identified in the FAERS database, with 69 reports among individuals using more than one TNFαI. A safety signal was detected for infliximab (I) golimumab (G), etanercept (E), and adalimumab (A). Cetrolizumab pegol (CP) had no detectible safety signal. For TNFαIs as a class of drugs, a safety signal was detectable in the FAERS database, and RR was significant in the EMR database. For the EMR cohort, 6,045 patients were exposed to TNFαIs and 35 cases of melanoma were detected. Significance for RR was detected for A (RR = 1.8, p = 0.02) and E (RR 2.35, p = 0.0004). Conclusions We identified a significant association between exposure to TNFαIs and malignant melanoma in two different analyses. Our findings add to existing evidence linking these agents with the occurrence of malignant melanoma. Additional investigations are required to further explore this association and the risk of melanoma with TNFαI therapy. PMID:24328939

  16. A systematic review of observational studies evaluating costs of adverse drug reactions

    PubMed Central

    Batel Marques, Francisco; Penedones, Ana; Mendes, Diogo; Alves, Carlos

    2016-01-01

    Introduction The growing evidence of the increased frequency and severity of adverse drug events (ADEs), besides the negative impact on patient’s health status, indicates that costs due to ADEs may be steadily rising. Observational studies are an important tool in pharmacovigilance. Despite these studies being more susceptible to bias than experimental designs, they are more competent in assessing ADEs and their associated costs. Objective To identify and characterize the best available evidence on ADE-associated costs. Methods MEDLINE, Cochrane Library, and Embase were searched from 1995 to 2015. Observational studies were included. The methodological quality of selected studies was assessed by Cochrane Collaboration tool for experimental and observational studies. Studies were classified according to the setting analyzed in “ambulatory”, “hospital”, or both. Costs were classified as “direct” and “indirect”. Data were analyzed using descriptive statistics. The total incremental cost per patient with ADE was estimated. Results Twenty-nine (94%) longitudinal observational studies and two (7%) cross-sectional studies were included. Twenty-three (74%) studies were assessed with the highest methodological quality score. The studies were mainly conducted in the US (61%). Twenty (65%) studies evaluated any therapeutic group. Twenty (65%) studies estimated costs of ADEs leading to or prolonging hospitalization. The “direct costs” were evaluated in all studies, whereas only two (7%) also estimated the “indirect costs”. The “direct costs” in ambulatory ranged from €702.21 to €40,273.08, and the in hospital from €943.40 to €7,192.36. Discussion Methodological heterogeneities were identified among the included studies, such as design, type of ADEs, suspected drugs, and type and structure of costs. Despite such discrepancies, the financial burden associated with ADE costs was found to be high. In the light of the present findings

  17. A systematic review of observational studies evaluating costs of adverse drug reactions

    PubMed Central

    Batel Marques, Francisco; Penedones, Ana; Mendes, Diogo; Alves, Carlos

    2016-01-01

    Introduction The growing evidence of the increased frequency and severity of adverse drug events (ADEs), besides the negative impact on patient’s health status, indicates that costs due to ADEs may be steadily rising. Observational studies are an important tool in pharmacovigilance. Despite these studies being more susceptible to bias than experimental designs, they are more competent in assessing ADEs and their associated costs. Objective To identify and characterize the best available evidence on ADE-associated costs. Methods MEDLINE, Cochrane Library, and Embase were searched from 1995 to 2015. Observational studies were included. The methodological quality of selected studies was assessed by Cochrane Collaboration tool for experimental and observational studies. Studies were classified according to the setting analyzed in “ambulatory”, “hospital”, or both. Costs were classified as “direct” and “indirect”. Data were analyzed using descriptive statistics. The total incremental cost per patient with ADE was estimated. Results Twenty-nine (94%) longitudinal observational studies and two (7%) cross-sectional studies were included. Twenty-three (74%) studies were assessed with the highest methodological quality score. The studies were mainly conducted in the US (61%). Twenty (65%) studies evaluated any therapeutic group. Twenty (65%) studies estimated costs of ADEs leading to or prolonging hospitalization. The “direct costs” were evaluated in all studies, whereas only two (7%) also estimated the “indirect costs”. The “direct costs” in ambulatory ranged from €702.21 to €40,273.08, and the in hospital from €943.40 to €7,192.36. Discussion Methodological heterogeneities were identified among the included studies, such as design, type of ADEs, suspected drugs, and type and structure of costs. Despite such discrepancies, the financial burden associated with ADE costs was found to be high. In the light of the present findings

  18. Risk-Taking Behavior among Adolescents with Prenatal Drug Exposure and Extrauterine Environmental Adversity

    PubMed Central

    Lambert, Brittany L.; Bann, Carla M.; Bauer, Charles R.; Shankaran, Seetha; Bada, Henrietta S.; Lester, Barry M.; Whitaker, Toni M.; LaGasse, Linda L.; Hammond, Jane; Higgins, Rosemary D.

    2014-01-01

    Objective High-risk environments characterized by familial substance use, poverty, inadequate parental monitoring, and violence exposure are associated with an increased propensity for adolescents to engage in risk-taking behaviors (e.g., substance use, sexual behavior, and delinquency). However, additional factors such as drug exposure in utero and deficits in inhibitory control among drug-exposed youth may further influence the likelihood that adolescents in high-risk environments will engage in risk-taking behavior. This study examined the influence of prenatal substance exposure, inhibitory control, and sociodemographic/environmental risk factors on risk-taking behaviors in a large cohort of adolescents with and without prenatal cocaine exposure (PCE). Method Risk-taking behavior (delinquency, substance use, and sexual activity) was assessed in 963 adolescents (433 cocaine-exposed, 530 nonexposed) at 15 years of age. Results PCE predicted later arrests and early onset of sexual behavior in controlled analyses. Associations were partially mediated, however, by adolescent inhibitory control problems. PCE was not associated with substance use at this age. In addition, male gender, low parental involvement, and violence exposure were associated with greater odds of engaging in risk-taking behavior across the observed domains. Conclusions Study findings substantiate concern regarding the association between prenatal substance exposure and related risk factors and the long-term outcomes of exposed youth. Access to the appropriate social, educational, and medical services are essential in preventing and intervening with risk-taking behaviors and the potential consequences (e.g., adverse health outcomes, incarceration), especially among high-risk adolescent youth and their families. PMID:24220515

  19. New mixed ligand zinc(II) complexes based on the antiepileptic drug sodium valproate and bioactive nitrogen-donor ligands. Synthesis, structure and biological properties.

    PubMed

    Darawsheh, Mohanad; Abu Ali, Hijazi; Abuhijleh, A Latif; Rappocciolo, Emilia; Akkawi, Mutaz; Jaber, Suhair; Maloul, Salam; Hussein, Yasmeen

    2014-07-23

    Starting from the precursor [Zinc Valproate complex] (1), new mixed ligand zinc(II) complexes of valproic acid and nitrogen-based ligands, formulating as, [Zn(valp)22,9-dmphen] (2), [Zn2(valp)4(quin)2] (3), [Zn(valp)2(2-ampy)2] (4), and [Zn(valp)2(2-ampic)2] (5) (valp = valproate, 2,9-dmphen = 2,9-dimethyl-1,10-phenanthroline, quin = quinoline, 2-ampy = 2-aminopyridine, 2-ampic = 2-amino-6-picoline) were synthesized and characterized using IR, (1)H NMR, (13)C{(1)H} NMR and UV-Vis spectrometry. The crystal structures of complexes 2, 3 and 4 were determined using single-crystal X-ray diffraction. The complexes were also evaluated for their anti-bacterial activity using in-vitro agar diffusion method against three Gram-positive (Micrococcus luteus, Staphylococcus aureus, and Bacillus subtilis) and three Gram-negative (Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis) species. Complex 2 showed considerable activity against all tested microorganisms and the effect of complexation on the anti-bacterial activity of the parent ligand of 2 was also investigated. The anti-bacterial activity of 2,9-dmphen against Gram-negative bacteria was enhanced upon complexation with zinc valproate. On the other hand, complexes 1 and 3 showed weak inhibition activity against the tested species and complexes 4 and 5 didn't show any activity at all. Two methods were used for testing the inhibition of ferriprotoporphyrinIX bio-mineralization: a semi-quantitative micro-assay and a previously self-developed quantitative in-vitro method. Both were used to study the efficiency of these complexes in inhibiting the formation of the Malaria pigment which considered being the target of many known anti-malarial drugs such as Chloroquine and Amodiaquine. Results showed that the efficiency of complex 2 in preventing the formation of β-Hematin was 80%. The efficiency of Amodiaquine as a standard drug was reported to give 91%.

  20. Drug Interaction and Pharmacist

    PubMed Central

    Ansari, JA

    2010-01-01

    The topic of drug–drug interactions has received a great deal of recent attention from the regulatory, scientific, and health care communities worldwide. Nonsteroidal anti-inflammatory drugs, antibiotics and, in particular, rifampin are common precipitant drugs prescribed in primary care practice. Drugs with a narrow therapeutic range or low therapeutic index are more likely to be the objects for serious drug interactions. Object drugs in common use include warfarin, fluoroquinolones, antiepileptic drugs, oral contraceptives, cisapride, and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. The pharmacist, along with the prescriber has a duty to ensure that patients are aware of the risk of side effects and a suitable course of action should they occur. With their detailed knowledge of medicine, pharmacists have the ability to relate unexpected symptoms experienced by patients to possible adverse effects of their drug therapy. PMID:21042495

  1. Systems biology approaches for identifying adverse drug reactions and elucidating their underlying biological mechanisms.

    PubMed

    Boland, Mary Regina; Jacunski, Alexandra; Lorberbaum, Tal; Romano, Joseph D; Moskovitch, Robert; Tatonetti, Nicholas P

    2016-01-01

    Small molecules are indispensable to modern medical therapy. However, their use may lead to unintended, negative medical outcomes commonly referred to as adverse drug reactions (ADRs). These effects vary widely in mechanism, severity, and populations affected, making ADR prediction and identification important public health concerns. Current methods rely on clinical trials and postmarket surveillance programs to find novel ADRs; however, clinical trials are limited by small sample size, whereas postmarket surveillance methods may be biased and inherently leave patients at risk until sufficient clinical evidence has been gathered. Systems pharmacology, an emerging interdisciplinary field combining network and chemical biology, provides important tools to uncover and understand ADRs and may mitigate the drawbacks of traditional methods. In particular, network analysis allows researchers to integrate heterogeneous data sources and quantify the interactions between biological and chemical entities. Recent work in this area has combined chemical, biological, and large-scale observational health data to predict ADRs in both individual patients and global populations. In this review, we explore the rapid expansion of systems pharmacology in the study of ADRs. We enumerate the existing methods and strategies and illustrate progress in the field with a model framework that incorporates crucial data elements, such as diet and comorbidities, known to modulate ADR risk. Using this framework, we highlight avenues of research that may currently be underexplored, representing opportunities for future work.

  2. Designing a national combined reporting form for adverse drug reactions and medication errors.

    PubMed

    Tanti, A; Serracino-Inglott, A; Borg, J J

    2015-06-09

    The Maltese Medicines Authority was tasked with developing a reporting form that captures high-quality case information on adverse drug reactions (ADRs) and medication errors in order to fulfil its public-health obligations set by the European Union (EU) legislation on pharmacovigilance. This paper describes the process of introducing the first combined ADR/medication error reporting form in the EU for health-care professionals, the analysis of reports generated by it and the promotion of the system. A review of existing ADR forms was carried out and recommendations from the European Medicines Agency and World Health Organization audits integrated. A new, combined ADR/medication error reporting form was developed and pilot tested based on case studies. The Authority's quality system (ISO 9001 certified) was redesigned and a promotion strategy was deployed. The process used in Malta can be useful for countries that need to develop systems relative to ADR/medication error reporting and to improve the quality of data capture within their systems.

  3. Patient reporting of suspected adverse drug reactions: a review of published literature and international experience

    PubMed Central

    Blenkinsopp, A; Wilkie, P; Wang, M; Routledge, P A

    2007-01-01

    Aims To synthesize data from published studies and international experience to identify evidence of potential benefits and drawbacks of direct patient reporting of suspected adverse drug reactions (ADRs) by patients. Methods Structured search of MEDLINE, CINAHL and PsycINFO supplemented by internet searches and requests for information to key contacts. Results Seven studies (eight papers) were included in the review. None of the studies concerned spontaneous reporting by patients. Information on patient reporting systems was obtained for six countries, with summary data reported by four. Patient reports identified possible new ADRs that had not previously been reported by health professionals. The quality of patient reports appears to be similar to that of health professional reports. There is some evidence that patients report an ADR when they consider their health professional has not paid attention to their concerns. Patient reports may, at least initially, be more time consuming to process. Conclusions Overall, the evidence indicates that patient reporting of suspected ADRs has more potential benefits than drawbacks. Evaluation of patient reporting systems is needed to provide further evidence. PMID:17274788

  4. Raising the Minimum Effective Dose of Serotonin Reuptake Inhibitor Antidepressants: Adverse Drug Events.

    PubMed

    Safer, Daniel J

    2016-10-01

    This review focuses on the dose-response of serotonin reuptake inhibitor (SRI) antidepressants for efficacy and for adverse drug events (ADEs). Dose-response is identified by placebo-controlled, double-blind, fixed-dose clinical trials comparing various doses for efficacy and for ADEs. Reports from the great majority of clinical trials have consistently found that the minimum SRI effective dose is usually optimal for efficacy in the treatment of depression disorders, even though most American medical practitioners raise the dose when early antidepressant treatment results are negative or partial. To better understand this issue, the medical literature was comprehensively reviewed to ascertain the degree to which SRI medications resulted in a flat dose response for efficacy and then to identify specific ADEs that are dose-dependent. Strong evidence from fixed-dose trial data for the efficacy of nonascendant, minimum effective doses of SRIs was found for the treatment of both major depression and anxiety disorders. Particularly important was the finding that most SRI ADEs have an ascending dose-response curve. These ADEs include sexual dysfunction, hypertension, cardiac conduction risks, hyperglycemia, decreased bone density, sweating, withdrawal symptoms, and agitation. Thus, routinely raising the SRI dose above the minimum effective dose for efficacy can be counter-productive. PMID:27518478

  5. Developing and integrating an adverse drug reaction reporting system with the hospital information system.

    PubMed

    Kataoka, Satoshi; Ohe, Kazuhiko; Mochizuki, Mayumi; Ueda, Shiro

    2002-01-01

    We have developed an adverse drug reaction (ADR) reporting system integrating it with Hospital Information System (HIS) of the University of Tokyo Hospital. Since this system is designed with JAVA, it is portable without re-compiling to any operating systems on which JAVA virtual machines work. In this system, we implemented an automatic data filling function using XML-based (extended Markup Language) files generated by HIS. This new specification would decrease the time needed for physicians and pharmacists to fill the spontaneous ADR reports. By clicking a button, the report is sent to the text database through Simple Mail Transfer Protocol (SMTP) electronic mails. The destination of the report mail can be changed arbitrarily by administrators, which adds this system more flexibility for practical operation. Although we tried our best to use the SGML-based (Standard Generalized Markup Language) ICH M2 guideline to follow the global standard of the case report, we eventually adopted XML as the output report format. This is because we found some problems in handling two bytes characters with ICH guideline and XML has a lot of useful features. According to our pilot survey conducted at the University of Tokyo Hospital, many physicians answered that our idea, integrating ADR reporting system to HIS, would increase the ADR reporting numbers.

  6. Adverse Drug Reactions in a Complementary Medicine Hospital: A Prospective, Intensified Surveillance Study

    PubMed Central

    Süsskind, M.; Thürmann, P. A.; Lüke, C.; Jeschke, E.; Tabali, M.; Matthes, H.; Ostermann, T.

    2012-01-01

    Background. Anthroposophic medicine is one of the widely used approaches of complementary and alternative medicine. However, few prospective studies have generated safety data on its use. Objectives. We aimed to assess adverse drug reactions (ADRs) caused by anthroposophical medicines (AMEDs) in the anthroposophical Community Hospital Havelhoehe, GERMANY. Study Design and Methods. Between May and November 2007, patients of six medical wards were prospectively assessed for ADRs. Suspected ADRs occurring during hospitalization were documented and classified in terms of organ manifestation (WHO SOC-code), causality (according to the Uppsala Monitoring Centre WHO criteria), and severity. Only those ADRs with a severity of grade 2 and higher according to the CTCAE classification system are described here. Results. Of the 3,813 patients hospitalized, 174 patients (4.6%) experienced 211 ADRs (CTCAE grade 2/3 n = 191, 90.5%, CTCAE grade 4/5 n = 20, 9.5%) of which 57 ADRs (27.0%) were serious. The median age of patients with ADRs (62.1% females) was 72.0 (IQR: 61.0; 80.0). Six patients (0.2%) experienced six ADRs (2.8% of ADRs) caused by eight suspected AMEDs, all of which were mild reactions (grade 2). Conclusion. Our data show that ADRs caused by AMEDs occur rarely and are limited to mild symptoms. PMID:22315630

  7. Formalizing MedDRA to support semantic reasoning on adverse drug reaction terms.

    PubMed

    Bousquet, Cédric; Sadou, Éric; Souvignet, Julien; Jaulent, Marie-Christine; Declerck, Gunnar

    2014-06-01

    Although MedDRA has obvious advantages over previous terminologies for coding adverse drug reactions and discovering potential signals using data mining techniques, its terminological organization constrains users to search terms according to predefined categories. Adding formal definitions to MedDRA would allow retrieval of terms according to a case definition that may correspond to novel categories that are not currently available in the terminology. To achieve semantic reasoning with MedDRA, we have associated formal definitions to MedDRA terms in an OWL file named OntoADR that is the result of our first step for providing an "ontologized" version of MedDRA. MedDRA five-levels original hierarchy was converted into a subsumption tree and formal definitions of MedDRA terms were designed using several methods: mappings to SNOMED-CT, semi-automatic definition algorithms or a fully manual way. This article presents the main steps of OntoADR conception process, its structure and content, and discusses problems and limits raised by this attempt to "ontologize" MedDRA.

  8. A team agent approach to postmarketing surveillance of adverse drug reactions.

    PubMed

    Ji, Yanqing; Ying, Hao; Barth-Jones, Daniel; Yen, John; Zhu, Shizhou; Miller, Richard; Michael Massanari, R

    2005-01-01

    Current postmarketing surveillance methods largely rely on spontaneous reports which suffer from serious underreporting, latency, and inconsistent reporting. Thus they are not ideal for rapidly identifying rare adverse drug reactions (ADRs). We propose an active, multi-agent computer software system, where each agent is empowered with teamwork capabilities such as anticipating information needs, identifying relevant ADR information, and continuously monitoring and proactively sharing such information in a collaborative fashion with other agents. The main purpose of this system is to help regulatory authorities (e.g., FDA in the U.S.) find previously unrecognized ADRs as early as possible. Another objective is to promote increased filing of on-line ADR reports thereby, addressing the severe underreporting problem with the current system. The proposed system has the potential to significantly accelerate the process of ADR discovery and response by utilizing electronic patient data distributed across many different sources and locations more effectively. Our preliminary system design is presented and some issues related to it are discussed. PMID:17281878

  9. Adverse Drug Reactions in HIV/AIDS Patients at a Tertiary Care Hospital in Penang, Malaysia.

    PubMed

    Khan, Kashifullah; Khan, Amer Hayat; Sulaiman, Syed Azhar; Soo, Chow Ting; Akhtar, Ali

    2016-01-01

    In the current study we explored the occurrence of adverse drug reactions (ADRs) to antiretroviral therapy among human immune-deficiency virus (HIV)/AIDS patients. We concluded an observational retrospective study in all patients who were diagnosed with HIV infection and were receiving highly active antiviral therapy from Jan. 2007 to Dec. 2012 at Hospital Pulau Pinang, Malaysia. Patient socio-demographic details along with clinical features and susceptible ADRs were observed during the study period. Out of 743 patients, 571 (76.9%) were men, and 172 (23.1%) were women. Overall 314 (42.2%) patients experienced ADRs. A total of 425 ADRs were reported, with 311 (73.1%) occurring in men and 114 (26.8%) in women, with a significant statistical relationship (P value (P) = 0.02, OR = 1.21). Overall 239 (56.2%) ADRs were recorded among Chinese, 94 (22.1%) in Malay, and 71 (16.7%) in Indian patients, which had a statistically significant association with ADRs (P = 0.05, OR = 1.50). Out of a total 425 among ADRs, lipodystrophy was recorded in 151 (35.5%) followed by skin rashes in 80 (18.8%), anemia in 74 (17.4%), and peripheral neuropathy in 27 (6.3%) patients. These findings suggest a need of intensive monitoring of ADRs in HIV treatment centres across Malaysia.

  10. 78 FR 54469 - Solicitation of Written Comments on Draft National Action Plan for Adverse Drug Event Prevention

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-04

    ... HUMAN SERVICES Solicitation of Written Comments on Draft National Action Plan for Adverse Drug Event... sending comments electronically. Written responses should be addressed to the Department of Health and... submissions will not be considered. Written materials submitted for consideration should not exceed 10...

  11. AOP: An R Package For Sufficient Causal Analysis in Pathway-based Screening of Drugs and Chemicals for Adversity

    EPA Science Inventory

    Summary: How can I quickly find the key events in a pathway that I need to monitor to predict that a/an beneficial/adverse event/outcome will occur? This is a key question when using signaling pathways for drug/chemical screening in pharma-cology, toxicology and risk assessment. ...

  12. The no-observed-adverse-effect-level in drug safety evaluations: use, issues, and definition(s).

    PubMed

    Dorato, Michael A; Engelhardt, Jeffery A

    2005-08-01

    The no-observed-adverse-effect-level (NOAEL) is an important part of the non-clinical risk assessment. It is a professional opinion based on the design of the study, indication of the drug, expected pharmacology, and spectrum of off-target effects. There is no consistent standard definition of NOAEL. This is based, in part, on the varied definitions of what constitutes an adverse effect. Toxicologists, either investigating or reviewing, have not been consistent in defining an effect as either adverse or acceptable. The common definition of NOAEL, "the highest experimental point that is without adverse effect," serves us well in general discussions. It does not, however, address the interpretation of risk based on toxicologically relevant effects, nor does it consider the progression of effect with respect to duration and/or dose. This paper will discuss the issues and application of a functional definition of the NOAEL in toxicology evaluations.

  13. Adverse Drug Reaction Identification and Extraction in Social Media: A Scoping Review

    PubMed Central

    Bellet, Florelle; Asfari, Hadyl; Souvignet, Julien; Texier, Nathalie; Jaulent, Marie-Christine; Beyens, Marie-Noëlle; Burgun, Anita; Bousquet, Cédric

    2015-01-01

    Background The underreporting of adverse drug reactions (ADRs) through traditional reporting channels is a limitation in the efficiency of the current pharmacovigilance system. Patients’ experiences with drugs that they report on social media represent a new source of data that may have some value in postmarketing safety surveillance. Objective A scoping review was undertaken to explore the breadth of evidence about the use of social media as a new source of knowledge for pharmacovigilance. Methods Daubt et al’s recommendations for scoping reviews were followed. The research questions were as follows: How can social media be used as a data source for postmarketing drug surveillance? What are the available methods for extracting data? What are the different ways to use these data? We queried PubMed, Embase, and Google Scholar to extract relevant articles that were published before June 2014 and with no lower date limit. Two pairs of reviewers independently screened the selected studies and proposed two themes of review: manual ADR identification (theme 1) and automated ADR extraction from social media (theme 2). Descriptive characteristics were collected from the publications to create a database for themes 1 and 2. Results Of the 1032 citations from PubMed and Embase, 11 were relevant to the research question. An additional 13 citations were added after further research on the Internet and in reference lists. Themes 1 and 2 explored 11 and 13 articles, respectively. Ways of approaching the use of social media as a pharmacovigilance data source were identified. Conclusions This scoping review noted multiple methods for identifying target data, extracting them, and evaluating the quality of medical information from social media. It also showed some remaining gaps in the field. Studies related to the identification theme usually failed to accurately assess the completeness, quality, and reliability of the data that were analyzed from social media. Regarding

  14. Adverse events of sacral neuromodulation for fecal incontinence reported to the federal drug administration

    PubMed Central

    Bielefeldt, Klaus

    2016-01-01

    AIM: To investigate the nature and severity of AE related to sacral neurostimulation (SNS). METHODS: Based on Pubmed and Embase searches, we identified published trials and case series of SNS for fecal incontinence (FI) and extracted data on adverse events, requiring an active intervention. Those problems were operationally defined as infection, device removal explant or need for lead and/or generator replacement. In addition, we analyzed the Manufacturer and User Device Experience registry of the Federal Drug Administration for the months of August - October of 2015. Events were included if the report specifically mentioned gastrointestinal (GI), bowel and FI as indication and if the narrative did not focus on bladder symptoms. The classification, reporter, the date of the recorded complaint, time between initial implant and report, the type of AE, steps taken and outcome were extracted from the report. In cases of device removal or replacement, we looked for confirmatory comments by healthcare providers or the manufacturer. RESULTS: Published studies reported adverse events and reoperation rates for 1954 patients, followed for 27 (1-117) mo. Reoperation rates were 18.6% (14.2-23.9) with device explants accounting for 10.0% (7.8-12.7) of secondary surgeries; rates of device replacement or explant or pocket site and electrode revisions increased with longer follow up. During the period examined, the FDA received 1684 reports of AE related to SNS with FI or GI listed as indication. A total of 652 reports met the inclusion criteria, with 52.7% specifically listing FI. Lack or loss of benefit (48.9%), pain or dysesthesia (27.8%) and complication at the generator implantation site (8.7%) were most commonly listed. Complaints led to secondary surgeries in 29.7% of the AE. Reoperations were performed to explant (38.2%) or replace (46.5%) the device or a lead, or revise the generator pocket (14.6%). Conservative management changes mostly involved changes in stimulation

  15. Monitoring adverse drug reactions in children using community pharmacies: a pilot study

    PubMed Central

    Stewart, Derek; Helms, Peter; McCaig, Dorothy; Bond, Christine; McLay, James

    2005-01-01

    Aims To determine the feasibility of a community pharmacy-based parental adverse drug reaction (ADR) reporting system for children. Design Prospective study of parent-reported ADRs using a questionnaire issued to the parent or guardians of children 0–11 years of age collecting prescribed medicine for amoxicillin, and/or salbutamol, and collecting prescribed medicine for, or purchasing, paracetamol or ibuprofen suspension. Setting Seven community pharmacies in Grampian, Scotland. Results During a 4-week period 360 prescriptions or purchases for the study medications occurred. Two hundred and sixty-seven parents (85.5%) agreed to participate in the study. One hundred and six participants (40%) returned a total of 122 questionnaires. The demographics of responders and nonresponders including medication, age of child, and social status as assessed by the Depcat score were similar. There was no evidence of under-representation of any socio-economic group. Possible adverse events were detected using a symptom tick list and perceived ADRs using free text entry. Using the symptom tick list approach the most commonly reported symptoms were diarrhoea (28.9%) and tiredness (31.6%) for amoxicillin. The levels of diarrhoea and tiredness reported for ibuprofen, paracetamol and salbutamol were 15% and 20%, 7.4% and 18.5%, and 20% and 0%, respectively. Using the freehand section of the questionnaire 15 specific ADRs were reported by parents (12.3%). Eight children (21.2%) reported ADRs attributed to amoxicilin [diarrhoea (n = 4), fever (n = 1), anorexia (n = 1), hyperactivity (n = 1) and nonspecific (n = 1)], five to paracetamol [diarrhoea (n = 3), anorexia, irritability, crying and very angry (n = 1) and not stated (n = 1)], two to ibuprofen [diarrhoea (n = 1), not stated (n =)]. Only one off-label prescription was identified and this was for salbutamol syrup prescribed to a child under 2 years of age. Conclusions The prospective monitoring of paediatric ADRs, using a

  16. [Active surveillance of adverse drug reaction in the era of big data: challenge and opportunity for control selection].

    PubMed

    Wang, S F; Zhan, S Y

    2016-07-01

    Electronic healthcare databases have become an important source for active surveillance of drug safety in the era of big data. The traditional epidemiology research designs are needed to confirm the association between drug use and adverse events based on these datasets, and the selection of the comparative control is essential to each design. This article aims to explain the principle and application of each type of control selection, introduce the methods and parameters for method comparison, and describe the latest achievements in the batch processing of control selection, which would provide important methodological reference for the use of electronic healthcare databases to conduct post-marketing drug safety surveillance in China. PMID:27453095

  17. [Active surveillance of adverse drug reaction in the era of big data: challenge and opportunity for control selection].

    PubMed

    Wang, S F; Zhan, S Y

    2016-07-01

    Electronic healthcare databases have become an important source for active surveillance of drug safety in the era of big data. The traditional epidemiology research designs are needed to confirm the association between drug use and adverse events based on these datasets, and the selection of the comparative control is essential to each design. This article aims to explain the principle and application of each type of control selection, introduce the methods and parameters for method comparison, and describe the latest achievements in the batch processing of control selection, which would provide important methodological reference for the use of electronic healthcare databases to conduct post-marketing drug safety surveillance in China.

  18. Adverse Drug Reaction Profile in Patients on Anti-tubercular Treatment Alone and in Combination with Highly Active Antiretroviral Therapy

    PubMed Central

    Sadiq, Shamiya; Khajuria, Vijay; Mahajan, Annil; Singh, Jang B.

    2015-01-01

    Background and Objectives Adverse drug reactions are very common among patients on anti-tubercular treatment alone or in combination with highly active antiretroviral therapy but comparatively studied very less. Hence, the current study was done to evalaute the adverse drug reaction (ADR) profile in patients receiving anti-tubercular treatment (ATT) and ATT with highly active antiretroviral therapy (HAART). Materials and Methods A one year prospective, cross-sectional observational study was undertaken using suspected adverse drug data collection form available under Pharmacovigilance Programme of India. Results Seventy four patients receiving ATT & 32 patients on both ATT & HAART presented with 74 and 45 adverse drug events (ADE) respectively. Males were more affected than females in both the groups. DOTS category- 1 regimen was mostly responsible for ADE in both the groups. Epigastric pain was the most common ADE in TB patients, while anaemia was the most common presentation in TB with HIV group. On comparison, ADE rate of TB with HIV co-morbid patients was more (55.8%) than TB patients (0.36%) (p < 0.001). Urban population presented more with ADR in TB/HIV group unlike rural population in TB group (p<0.0001). Whereas, illiterate were more involved in TB group unlike literate in TB/HIV group (p<0.05). Type A reactions were more common in TB group (p < 0.001). Addition of drugs for the management of ADR events was more in TB/HIV group (p < 0.001) as compared to TB group. Rest all the parameters were comparable. Conclusion The study underscores that concomitant HAART and ATT, result in more ADRs in comparison to ATT alone demanding collaboration & integration of National AIDS Control programme and PvPI to enhance drug safety in this field. PMID:26557538

  19. ADReCS: an ontology database for aiding standardization and hierarchical classification of adverse drug reaction terms.

    PubMed

    Cai, Mei-Chun; Xu, Quan; Pan, Yan-Jing; Pan, Wen; Ji, Nan; Li, Yin-Bo; Jin, Hai-Jing; Liu, Ke; Ji, Zhi-Liang

    2015-01-01

    Adverse drug reactions (ADRs) are noxious and unexpected effects during normal drug therapy. They have caused significant clinical burden and been responsible for a large portion of new drug development failure. Molecular understanding and in silico evaluation of drug (or candidate) safety in laboratory is thus so desired, and unfortunately has been largely hindered by misuse of ADR terms. The growing impact of bioinformatics and systems biology in toxicological research also requires a specialized ADR term system that works beyond a simple glossary. Adverse Drug Reaction Classification System (ADReCS; http://bioinf.xmu.edu.cn/ADReCS) is a comprehensive ADR ontology database that provides not only ADR standardization but also hierarchical classification of ADR terms. The ADR terms were pre-assigned with unique digital IDs and at the same time were well organized into a four-level ADR hierarchy tree for building an ADR-ADR relation. Currently, the database covers 6544 standard ADR terms and 34,796 synonyms. It also incorporates information of 1355 single active ingredient drugs and 134,022 drug-ADR pairs. In summary, ADReCS offers an opportunity for direct computation on ADR terms and also provides clues to mining common features underlying ADRs.

  20. Prevalence, nature and potential preventability of adverse drug events – a population-based medical record study of 4970 adults

    PubMed Central

    Hakkarainen, Katja M; Gyllensten, Hanna; Jönsson, Anna K; Andersson Sundell, Karolina; Petzold, Max; Hägg, Staffan

    2014-01-01

    Aims To estimate the 3 month prevalence of adverse drug events (ADEs), categories of ADEs and preventable ADEs, and the preventability of ADEs among adults in Sweden. Further, to identify drug classes and organ systems associated with ADEs and estimate their seriousness. Methods A random sample of 5025 adults in a Swedish county council in 2008 was drawn from the Total Population Register. All their medical records in 29 inpatient care departments in three hospitals, 110 specialized outpatient clinics and 51 primary care units were reviewed retrospectively in a stepwise manner, and complemented with register data on dispensed drugs. ADEs, including adverse drug reactions (ADRs), sub-therapeutic effects of drug therapy (STEs), drug dependence and abuse, drug intoxications from overdose, and morbidities due to drug-related untreated indication, were detected during a 3 month study period, and assessed for preventability. Results Among 4970 included individuals, the prevalence of ADEs was 12.0% (95% confidence interval (CI) 11.1, 12.9%), and preventable ADEs 5.6% (95% CI 5.0, 6.2%). ADRs (6.9%; 95% CI 6.2, 7.6%) and STEs (6.4%; 95% CI 5.8, 7.1%) were more prevalent than the other ADEs. Of the ADEs, 38.8% (95% CI 35.8–41.9%) was preventable, varying by ADE category and seriousness. ADEs were frequently associated with nervous system and cardiovascular drugs, but the associated drugs and affected organs varied by ADE category. Conclusions The considerable burden of ADEs and preventable ADEs from commonly used drugs across care settings warrants large-scale efforts to redesign safer, higher quality healthcare systems. The heterogeneous nature of the ADE categories should be considered in research and clinical practice for preventing, detecting and mitigating ADEs. PMID:24372506