New antiepileptic drugs: review on drug interactions.

During the Past decade, nine new antiepileptic drugs (AEDs) namely, Felbamate, Gabapentin, Levetiracetam, Lamotrigine, Oxcarbazepine, Tiagabine, Topiramate, Vigabatrin and Zonisamide have been marketed worldwide. The introduction of these drugs increased appreciably the number of therapeutic combinations used in the treatment of epilepsy and with it, the risk of drug interactions. In general, these newer antiepileptic drugs exhibit a lower potential for drug interactions than the classic AEDs, like phenytoin, carbamazepine and valproic acid, mostly because of their pharmacokinetic characteristics. For example, vigabatrin, levetiracetam and gabapentin, exhibit few or no interactions with other AEDs. Felbamate, tiagabine, topiramate and zonisamide are sensitive to induction by known anticonvulsants with inducing effects but are less vulnerable to inhibition by common drug inhibitors. Felbamate, topiramate and oxcarbazepine are mild inducers and may affect the disposition of oral contraceptives with a risk of failure of contraception. These drugs also inhibit CYP2C19 and may affect the disposition of phenytoin. Lamotrigine is eliminated mostly by glucuronidation and is susceptible to inhibition by valproic acid and induction by classic AEDs such as phenytoin, carbamazepine, phenobarbital and primidone.     

The adverse effects of antiepileptic drugs in children

Efficacy of antiepileptic drugs (AEDs) are often equivalent, hence selection of an AED is often determined by the adverse effects (AEs). The development of neurocognitive AEs is almost inevitable with use of AEDs, especially in high-risk groups. Teratogenesis with major or minor malformations is of great concern during the first trimester of pregnancy, but an increasing body of information suggests that potential neurocognitive developmental delay may also occur with use of AEDs in the latter part of pregnancy. Decreased bone mineral density has been found in adults and children receiving both enzyme-inducing AEDs and valproate, an enzyme-inhibiting drug. AEDs may influence the lipid profile, body weight, reproductive, hormonal and other endocrine functions, and sleep architecture. There are age-specific AEs related to pharmacokinetic differences that have been highlighted in this review with emphasis on the pediatric population. A classification of AEs using different parameters is also included.     

The adverse effects of antiepileptic drugs in children

Efficacy of antiepileptic drugs (AEDs) are often equivalent, hence selection of an AED is often determined by the adverse effects (AEs). The development of neurocognitive AEs is almost inevitable with use of AEDs, especially in high-risk groups. Teratogenesis with major or minor malformations is of great concern during the first trimester of pregnancy, but an increasing body of information suggests that potential neurocognitive developmental delay may also occur with use of AEDs in the latter part of pregnancy. Decreased bone mineral density has been found in adults and children receiving both enzyme-inducing AEDs and valproate, an enzyme-inhibiting drug. AEDs may influence the lipid profile, body weight, reproductive, hormonal and other endocrine functions, and sleep architecture. There are age-specific AEs related to pharmacokinetic differences that have been highlighted in this review with emphasis on the pediatric population. A classification of AEs using different parameters is also included.     

Behavioral adverse effects of antiepileptic drugs in epilepsy

Patient tolerability is a significant limiting factor in the treatment of epilepsy and adverse effect profiles often determine drug retention rates. A full appreciation of the behavioral effects of a wide range of antiepileptic drugs (AEDs) is therefore essential to make informed treatment decisions. In this timely review, we highlight key alterations in mood, emotional experience, and other behavioral/psychiatric features, which can exert a crucial impact on patients' quality of life and well-being. With a view to prescribing both in general and in relation to more specific clinical characteristics, the evidence reviewed indicates that the incidence and characteristics of behavioral effects may be related to age, epilepsy type, the presence of learning disability, and previous psychiatric history. Medication parameters including dosage, titration rate, efficacy in controlling seizures, and concurrent AEDs can also contribute to the occurrence of behavioral effects. However, there are a number of limitations in drawing conclusions from the available literature. These include variation in study design, treatment group, and assessment tools that lead to difficulties comparing findings across studies, and problems with the consistency of available information relating to the study methodology. Future longitudinal studies assessing the impact of tolerance or developmental change on behavioral effects and specific studies comparing the effects of commonly prescribed agents across subgroups of patients with epilepsy will make an informative contribution to the available literature. A valuable outcome of further research may be the development of specific instruments that are sensitive to the behavioral effects associated with particular AEDs.     

Long-term neurocognitive adverse effects of prenatal antiepileptic drug exposure

Most women with epilepsy use antiepileptic medication during pregnancy because of seizure-related risks to mother and fetus. Most of the children exposed prenatally to antiepileptic medication are born healthy; however, there is increased risk for major congenital malformations and also unfavorable neurocognitive long-term development of the offspring. The increased risk has been correlated mainly with prenatal exposure to polytherapy and certain antiepileptic medications. Many confounding risk factors make it difficult to correlate the prenatal exposure and neurodevelopmental problems, and data of newer antiepileptic medications are lacking. In the future, larger prospective, controlled studies with extended follow-up are required to evaluate the long-term neurocognitive effects of prenatal antiepileptic medication exposure.     

Long-term neurocognitive adverse effects of prenatal antiepileptic drug exposure

Most women with epilepsy use antiepileptic medication during pregnancy because of seizure-related risks to mother and fetus. Most of the children exposed prenatally to antiepileptic medication are born healthy; however, there is increased risk for major congenital malformations and also unfavorable neurocognitive long-term development of the offspring. The increased risk has been correlated mainly with prenatal exposure to polytherapy and certain antiepileptic medications. Many confounding risk factors make it difficult to correlate the prenatal exposure and neurodevelopmental problems, and data of newer antiepileptic medications are lacking. In the future, larger prospective, controlled studies with extended follow-up are required to evaluate the long-term neurocognitive effects of prenatal antiepileptic medication exposure.     

Newer anticonvulsants: comparative review of drug interactions and adverse effects

The tolerability and drug interaction profiles of 6 new anticonvulsants: oxcarbazepine, vigabatrin, lamotrigine, gabapentin, tiagabine and topiramate, are reviewed. In general, these new anticonvulsants are well tolerated and drug interaction problems are minor with the exception of the risk of failure of oral contraceptives during treatment with oxcarbazepine or topiramate. In this review, the clinical implications of the tolerability of these drugs are discussed for different patient groups. The choice of which new anticonvulsant for which patient depends upon individual factors, in particular, seizure type, tolerability and practical administration factors. Treating elderly patients may be complicated by an increased sensitivity to adverse effects as these patients very often receive polytherapy for accompanying diseases. Drugs with very simple pharmacokinetic properties may be preferred in this group. Women of childbearing age face specific problems related to the epilepsy and to treatment with anticonvulsants. These include impaired fertility, failure of oral contraceptives and the risk of birth defects. Some new anticonvulsants may be suggested in preference to classical drugs to avoid these problems, but the human experience with newer anticonvulsants is still limited and, therefore, so is knowledge of the risk of congenital malformations in the offspring of mothers taking anticonvulsants. Psychiatric and behavioural changes frequently complicate treatment of patients with mental retardation. Some of the new anticonvulsants, in particular those affecting the gamma-aminobutyric acid (GABA) system such as vigabatrin, seem to exacerbate this problem and should be used with caution in these patients.     

Neither dosage nor serum levels of antiepileptic drugs are predictive for efficacy and adverse effects

In order to assess whether doses or serum levels are predictive for the efficacy and adverse effects of antiepileptic drugs (AEDs), measures for exposure to drug combinations have to be used. For doses, the ratio of the observed prescribed daily dose (PDD) and the average defined daily dose (DDD) considered effective for the main indication of the drug was used. In analogy for serum levels, the OSL/ATL ratio,i.e. the ratio of the observed serum level and the average therapeutic level was used. In polypharmacy these ratios can be summed as they are normalized measures of strength. The correlations of these ratios with outcome measures were studied in 200 patients attending out-patient clinics of special centres for epilepsy; half of these patients were treated with monopharmacy and half with polypharmacy. As outcome measures the following indices were used: the index of seizures, which quantifies seizure type and frequency, the seizure activity index, the neurotoxicity score, the systemic toxicity score, and the composite index of impairments, which is the sum of the seizure activity index and the neurotoxicity score and the systemic toxicity score. When all data were pooled, the correlation coefficient between the PDD/DDD ratio and the OSL/ATL ratio was 0.77. However, when the data were examined separately for the monopharmacy and polypharmacy groups, the correlation was 0.31 for the monopharmacy group and 0.50 for the polypharmacy group. Neither the PDD/DDD ratio nor the OSL/ATL ratio correlated with the composite index of impairments or with any of the individual indices. Factors such as the difficulty of titrating the endpoint of seizure suppression and the development of tolerance to adverse drug effects may perhaps be responsible for these findings. This observational study signals the problem.     

Orlistat-associated adverse effects and drug interactions: a critical review.

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.     

Neuroprotective effects of antiepileptic drugs

Experimental and clinical data indicate that epilepsy and seizures lead to neuronal cell loss and irreversible brain damage. This neurodegeneration results not only in the central nervous system dysfunction but may also be responsible for the decreased efficacy of some antiepileptic drugs (AEDs). The aim of this review was to assemble current literature data on neuroprotective properties of AEDs. The list of hypothetical neuroprotectants is long and consists of substances which act via different mechanisms. We focus on AEDs since this heterogeneous group of pharmaceuticals, as far as mechanisms of their action and mechanisms of neuronal death are concerned, should provide protection in addition to antiseizure effect itself. Most studies on neuroprotection are based on animal experimental models of neuronal degeneration. Electrically and pharmacologically evoked seizures as well as different models of ischemia are frequently used. Although our knowledge about properties of AEDs is still not complete and discrepancies occasionally occur, the group seems to be promising in terms of neuroprotection. Some of the drugs, though, turn out to be neutral or even have adverse effects on the central nervous system, especially on immature brain tissue (barbiturates and benzodiazepines). Unfortunatelly, we cannot fully extrapolate animal data to humans, therefore further well designed clinical trials are necessary to determine neuroprotective properties of AEDs in humans. However, there is a hope that AEDs will have a potential to serve as neuroprotectants not only in seizures, but perhaps, in other neurodegenerative conditions in humans as well. The novel AEDs (especially lamotrigine, tiagabine, and topiramate) seem particularly promising.     

Therapeutic drug monitoring of the newer antiepileptic drugs

The aim of the present review is to discuss the potential value of therapeutic drug monitoring (TDM) of the newer antiepileptic drugs (AEDs) felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, and zonisamide. Studies of the relationship between serum concentrations and clinical efficacy of these drugs are reviewed, and the potential value of TDM of the drugs is discussed based on their pharmacokinetic properties and mode of action. Analytical methods for the determination of the serum concentrations of these drugs are also briefly described. There are only some prospective data on the serum concentration-effect relationships, and few studies have been designed primarily to study these relationships. As TDM is not widely practiced for the newer AEDs, there are no generally accepted target ranges for any of these drugs, and for most a wide range in serum concentration is associated with clinical efficacy. Furthermore, a considerable overlap in drug concentrations related to toxicity and nonresponse is reported. Nevertheless, the current tentative target ranges for felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine (10-hydroxy-carbazepine metabolite), tiagabine, topiramate, vigabatrin, and zonisamide are 125 to 250 micromol/L, 70 to 120 micromol/L, 10 to 60 micromol/L, 35 to 120 micromol/L, 50 to 140 micomol/L, 50 to 250 nmol/L, 15 to 60 micromol/L, 6 to 278 micromol/L, and 45 to 180 micromol/L, respectively. Further systematic studies designed specifically to evaluate concentration-effect relationships of the new AEDs are urgently needed. Although routine monitoring in general cannot be recommended at present, measurements of some of the drugs is undoubtedly of help with individualization of treatment in selected cases in a particular clinical setting.     

老年高血压患者服药后血压控制情况及其不良反应

目的:探讨门诊就诊的老年高血压患者服用降压药物后血压控制情况及其常见的不良反应。方法:采用问卷调查和体格检查相结合的方法,对在我院门诊就诊的955例高血压患者的服药情况及出现的不良反应进行统计分析。结果:被调查者使用较多的降压药物是硝苯地平控释片(伲福达)、硝苯地平片剂(心痛定)和美托洛尔(倍他乐克),分别占所有被调查患者的69.8%、30.8%和27.5%。其次是吲达帕胺(寿比山)、依那普利(怡那林)、特拉唑嗪(高特灵)、贝那普利(洛汀新)和卡托普利。日常血压收缩压控制理想者(<140mmHg)约占患者的50%,舒张压控制理想者多于收缩压控制理想者。服药后不良反应中,钙离子拮抗剂以踝部水肿、利尿剂以低血钾多见,ACEI类药物主要表现为干咳,β受体阻滞剂以心动过缓为主要不良反应,α受体阻滞剂特拉唑嗪的不良反应主要为直立性低血压。治疗依从性的调查还表明约半数高血压患者在服药过程中存在不正确现象。结论:门诊老年高血压患者治疗过程中不良反应较多,且总体血压控制良好率不高。     

Panax ginseng: a systematic review of adverse effects and drug interactions.

Panax ginseng C. A. Meyer is a perennial herb native to Korea and China and has been used as an herbal remedy in eastern Asia for thousands of years. Modern therapeutic claims refer to vitality, immune function, cancer, cardiovascular diseases, improvement of cognitive and physical performance and sexual function. A recent systematic review of randomised controlled trials found that the efficacy of ginseng root extract could not be established beyond doubt for any of these indications. In order to obtain a balanced assessment of the therapeutic value of P. ginseng it is also necessary to consider the safety profile. In view of the extremely widespread use of P. ginseng it seems important to ask whether this herbal medicine involves health risks for the consumer. This review was conducted as a systematic attempt to document and evaluate all the available safety data on P. ginseng root extracts. Systematic searches were performed in five electronic databases and the reference lists of all papers located were checked for further relevant publications. All articles containing original data on adverse events and drug interactions with P. ginseng were included. Information was also requested from 12 manufacturers of ginseng preparations, the spontaneous reporting schemes of the WHO and national drug safety bodies. No language restrictions were imposed. Data from clinical trials suggest that the incidence of adverse events with ginseng monopreparations is similar to that with placebo. The most commonly experienced adverse events are headache, sleep and gastrointestinal disorders. The possibility of more serious adverse events is indicated in isolated case reports and data from spontaneous reporting schemes; however, causality is often difficult to determine from the evidence provided. Combination products containing ginseng as one of several constituents have been associated with serious adverse events and even fatalities. Interpretation of these cases is difficult as ingredients other than P. ginseng may have caused the problems. Possible drug interactions have been reported between P. ginseng and warfarin, phenelzine and alcohol. Collectively, these data suggest that P. ginseng monopreparations are rarely associated with adverse events or drug interactions. The ones that are documented are usually mild and transient. Combined preparations are more often associated with such events but causal attribution is usually not possible.     

抗癫痫药物与华法林相互作用的研究进展

口服抗凝药华法林的抗凝作用受很多因素的影响,如患者的年龄、体重、合并症等。与其他药物的相互作用也是影响华法林抗凝作用的重要因素之一,其中一些抗癫痫药物对华法林的影响较大且机制复杂,作用持续时间也较长,对于联用华法林的癫痫患者,抗癫痫药物的选择与监测更为重要。本文通过整合国内外相关研究,探讨和总结华法林与抗癫痫药物间的相互作用机制和应对策略,比较不同抗癫痫药物的药代动力学特性及与华法林相互作用的差异,从而为抗癫痫药物的选择和相应剂量的调整提供参考,以降低用药风险。