Pharmacokinetic, pharmacodynamic, and pharmacogenetic targeted therapy of antiepileptic drugs

Therapeutic drug monitoring (TDM) is widely accepted as a method to improve the effectiveness and safety of the first generation antiepileptic drugs (AEDs) and to identify an individual's optimum concentration. Like the older AEDs, the new AEDs also have significant pharmacokinetic variability. A similar relationship between concentration and effect for the new and old AEDs in experimental seizure models suggests that it is reasonable to use TDM for the new AEDs. With the addition of generic formulations of the new AEDs, TDM can play an important role to validate bioequivalence in patients. There is a history of problems with generics of the older AEDs, primarily carbamazepine and phenytoin. The Biopharmaceutics Classification System, which correlates the solubility and permeability of a drug with oral drug absorption, predicts that there should be no significant problems with the majority of the new AEDs. Because of the controversy over the risk-benefit of generic substitution of AEDs, the use of TDM will provide a way to ensure patient safety while establishing that generics of AEDs proven to be bioequivalent in population studies are also bioequivalent in individuals. The goal of personalized medicine is to use genetic testing to target therapy and identify those individuals unlikely to respond to a drug or likely to respond adversely to the same drug. Of all the AEDs, only phenytoin undergoes significant metabolism by cytochrome P450 isozymes with significant genetic polymorphisms (CYP2C9, CYP2C19). Studies are still needed to identify genetic and biomarkers to identify patients at risk for serious idiosyncratic reactions. There have been significant advances in the understanding of the role of genetics in idiopathic as well as acquired epilepsies. Identification of experimental and clinical evidence linking functional changes associated with gene mutations to epilepsy syndromes will help provide new molecular targets for future AEDs.     

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.     

Zonisamide: a new antiepileptic drug

Although the significant progress in pharmacotherapy of epilepsy during last decade was achieved, about one third of patients are resistant to the current treatment. When the monotherapy is not efficient, the polytherapy should be applied. Zonisamide (ZNS) is a new antiepileptic drug (AED) efficient in treating refractory epilepsy. Its efficacy in different types of seizures was confirmed in various animal studies as well as in clinical conditions. ZNS inhibits voltage-dependent Na(+) channels and Ca(2+) channels of T-type. The drug influences also monoamine neurotransmission and exhibits free radical scavenging properties. ZNS has a linear and favorable pharmacokinetics with excellent oral bioavailability. Furthermore, ZNS treatment, compared to other anticonvulsants, is relatively safe and well tolerated. Since ZNS is often used in polytherapy, its interactions with other AEDs seem to be of particular importance. However, the experimental data are rather inconsistent and further studies are necessary to elucidate exact effects of coadministration of ZNS with other AEDs. Recently, the clinical and experimental studies have suggested some new indications for ZNS administration, as mania, neuropathic pain, Parkinson's disease or migraine prophylaxis. Nowadays, it is also well established that ZNS exerts neuroprotective properties.     

新型抗癫痫药加巴喷丁

加巴喷丁（gabapentin）是一种新型抗癫痫药，为γ-氨基丁酸（GABA）类似物，口服易吸收，与其他抗癫痫药物相互作用小，且耐受性好。临床研究表明，其作为添加用药治疗癫痫具有良好的临床疗效和安全性。现对其作用机制、药动学、药物相互作用、临床应用和药物不良反应等作一综述。     

Levetiracetam: a novel antiepileptic drug.

Levetiracetam is a new antiepileptic drug, structurally and mechanistically dissimilar to other marketed antiepileptic drugs. It is effective in reducing partial seizures in patients with epilepsy, both as adjunctive treatment and as monotherapy. Levetiracetam has many therapeutic advantages for patients with epilepsy. It has favorable pharmacokinetic characteristics (good bioavailability, linear pharmacokinetics, insignificant protein binding, lack of hepatic metabolism, and rapid achievement of steady-state concentrations) and a low potential for drug interactions. Recommended starting dosages are considered to be clinically effective; therefore, patients can have some protection from seizures soon after they begin levetiracetam. The most common adverse effects observed with levetiracetam are mild and include somnolence, asthenia, and dizziness. Clinical experience and data from meta-analyses indicate that levetiracetam is well tolerated, with efficacy comparable or slightly better than that observed with other new antiepileptic drugs. Levetiracetam may be particularly useful in patients who are unresponsive to other antiepileptic drugs, patients receiving drugs with increased potential for drug interactions, or those with hepatic impairment.     

Harnessing the clinical potential of antiepileptic drug therapy: dosage optimisation

For patients with epilepsy, effective seizure control is the most important determinant of good quality of life. To achieve this, antiepileptic drug (AED) dosages should be individualised to maximise therapeutic benefit and to avoid most--if not all--adverse effects. Several studies suggest that, in routine clinical practice, dosage individualisation is often suboptimal. This may lead to patients receiving unnecessarily large dosages. Conversely, it may lead to patients switching to an alternative therapy (when clinical response is deemed insufficient), without exploration of the full dosage range. Indeed, dosage optimisation--which should involve consideration of the treatment setting and individual patient characteristics--can be a complicated process requiring skill and patience. In general neurological practice, most AEDs should be started at a low dosage and gradually titrated upwards. Starting dosages are similar in most types of epilepsy; however, if a rapid onset of therapeutic action is required, phenytoin, phenobarbital (phenobarbitone), levetiracetam and gabapentin are probably the best tolerated AEDs for starting at full dosage. The initial target maintenance dosage of an AED should be based on the dose-response profile of the drug, and on specific patient characteristics. Usually, the lowest effective daily dose expected to provide seizure control should be used, although various factors (e.g. stage and severity of epilepsy, pharmacokinetic and pharmacodynamic considerations, attitude of the patient) will markedly influence dosage selection. If seizures are not controlled on the initial target dose, the dosage should be increased gradually until complete seizure control is achieved or intolerable adverse effects occur. In most patients who fail to respond to the initially prescribed drug, switching to another AED (monotherapy) is the best option. Combination therapy may be appropriate for patients unresponsive to 2 or more sequential monotherapies. Therapeutic drug monitoring (measurement of serum drug concentrations) is useful in various settings, such as when drug interactions are expected, toxicity is suspected, or when AEDs with nonlinear pharmacokinetics (e.g. phenytoin, carbamazepine) are used. No indications currently exist for routine therapeutic drug monitoring of the newer AEDs. In summary, dosage regimens of AEDs should be assessed regularly, and adjusted if necessary, so that patients can derive optimal therapeutic benefit. For patients considered 'difficult to treat' (i.e. those in whom seizures remain incompletely controlled after several attempts at treatment), referral to a specialist is recommended.     

Antipyretic analgesics in patients on antiepileptic drug therapy

Summary The effect of administration for three days of acetylsalicylic acid (1500 mg/day), phenylbutazone (300 mg/day), paracetamol (1500 mg/day) and tolfenamic acid (300 mg/day) on serum concentrations of phenytoin and carbamazepine were studied in a group of patients on continuous antiepileptic therapy. When measured 10 h after the last dose of the analgesics, the only significant effect was a decrease in total serum phenytoin after three days of phenylbutazone. When six patients on continuous phenytoin therapy took phenylbutazone for two weeks there was at two days an initial decrease, followed by a significant increase in total serum phenytoin and a concomitant increase in free phenytoin in serum. Even phenylbutazone was well tolerated by most of the patients. However, its use had to be discontinued in one patients due to obvious signs of phenytoin intoxication, with concomitant increases in the serum free and total phenytoin concentrations.     

Tumour and dendrimers: a review on drug delivery aspects

Tumour is a morbid state, characterized by spontaneous outgrowth of an abnormal mass of cells. The evolution of tumours is random, disorganized, a condition of numerous mutations. The properties are biased and incompletely comprehended. It is a malignant or benign condition that encompasses its own rules of morphogenesis, an immortal state that elucidates different physiology. It is a pathological crisis that still haunts the minds of scientists, physicians and patients, a complete cure of which is still a dream to be realized. The unpredictable microenvironment of cancerous cells in all of its existing forms i.e. leukaemic cells, solid tumours and sarcomas is well documented. This phenomenon expressed by cancerous sites in the body poses various obstacles towards drug efficacy. Thus, it has become necessary to address briefly the issues relating to tumour physiology, its vasculature and angiogenesis. The information could provide insight towards the development of tumour-targeted drug delivery. The salient features regarding these have been discussed.     

Clinical and economic outcomes of pharmacist-managed antiepileptic drug therapy

This study explores the associations between pharmacist-managed antiepileptic drug therapy in hospitalized Medicare patients and diagnoses indicating the need for these drugs. It also explores the following major heath care outcomes: death rate, hospital length of stay (LOS), Medicare charges, drug charges, laboratory charges, complications, and adverse drug reactions. Data were drawn from the 1998 MedPAR and 1998 National Clinical Pharmacy Services databases. Pharmacist-managed antiepileptic drug therapy was evaluated in a study population of 9380 Medicare patients with diagnosed epilepsy or seizure disorders treated in 794 United States hospitals. This population was derived from the 38,311 hospitalized Medicare patients with epilepsy or seizure disorders (MedPAR). In hospitals without pharmacist-managed antiepileptic drug therapy, death rates were 120.61% higher, with 374 excess deaths (chi(2)=5.983, df=1, p=0.014, odds ratio [OR]=1.553, 95% confidence interval [CI] 1.102-2.189). Hospital LOS was 14.68% higher, with 8069 patient-days (Mann-Whitney U test [U]=3833132, p=0.0009); total Medicare charges were 11.19% higher, with 14,372,550 dollars in excess total charges (U=3644199, p=0.0003); per-patient drug charges were $115 +/- $92 higher (p=NS); laboratory charges were 32.24% higher, with 5,664,970 dollars in excess charges; and aspiration pneumonia rate was 54.61% higher (chi(2)=5.848, df=1, p=0.015, OR=1.233, 95% CI 1.081-1.901). Although the frequencies of other complications and adverse effects were higher, these differences were not statistically significant compared with hospitals with pharmacist-managed antiepileptic drug therapy. Clinical and economic outcomes were improved among hospitalized Medicare patients whose antiepileptic drug therapy was managed by pharmacists.     

Strategies for optimizing antiepileptic drug therapy in elderly people

The elderly take more antiepileptic drugs (AEDs) than all other adults. This extensive use directly correlates with an increased prevalence of epilepsy in a growing population of older people, as well as other neuropsychiatric conditions such as neuropathic pain and behavioral disorders associated with dementia and for which AEDs are administered. The agents account for nearly 10% of all adverse drug reactions in the elderly and are the fourth leading cause of adverse drug reactions in nursing home residents. Numerous factors associated with advanced age contribute to the high frequency of untoward drug effects in this population; however, strategies are available to ensure optimal outcomes.     

Methotrexate: a detailed review on drug delivery and clinical aspects

Introduction: Uses of methotrexate (MTX) are well established for the treatment of various types of malignancy, psoriasis, rheumatological diseases and the medical termination of pregnancy. Formulation and targeting approaches for MTX with controlled release carriers, multiparticulate systems, prodrug and drug conjugates have been found to improve bioavailability, reduce adverse effects and maximize clinical efficacy, compared with conventional methods.

Areas covered: This exhaustive literature survey on different electronic databases covers drug delivery and clinical trials on MTX. This review deals with the challenges and achievements of controlled release, multiparticulate, prodrug and drug conjugate systems of MTX.

Expert opinion: Therapeutic drug monitoring of MTX is crucial to attain a good efficacy. In spite of the advantages of multiparticulate, prodrug and drug conjugates, clinical applications of such formulations of MTX are still under infancy. These drug delivery systems require the special attention of medical experts for its wider clinical usage, and pharmaceutical experts for its scale-up. The combination of MTX with other antineoplastic and immunosuppressants should also be subjected to clinical trials, such as the combination of misoprostol with MTX in abortion.     

Methotrexate: a detailed review on drug delivery and clinical aspects

INTRODUCTION: Uses of methotrexate (MTX) are well established for the treatment of various types of malignancy, psoriasis, rheumatological diseases and the medical termination of pregnancy. Formulation and targeting approaches for MTX with controlled release carriers, multiparticulate systems, prodrug and drug conjugates have been found to improve bioavailability, reduce adverse effects and maximize clinical efficacy, compared with conventional methods. AREAS COVERED: This exhaustive literature survey on different electronic databases covers drug delivery and clinical trials on MTX. This review deals with the challenges and achievements of controlled release, multiparticulate, prodrug and drug conjugate systems of MTX. EXPERT OPINION: Therapeutic drug monitoring of MTX is crucial to attain a good efficacy. In spite of the advantages of multiparticulate, prodrug and drug conjugates, clinical applications of such formulations of MTX are still under infancy. These drug delivery systems require the special attention of medical experts for its wider clinical usage, and pharmaceutical experts for its scale-up. The combination of MTX with other antineoplastic and immunosuppressants should also be subjected to clinical trials, such as the combination of misoprostol with MTX in abortion.     

抗癫痫药物过敏综合症:两个案例报道和文献综述(英文)

抗癫痫药物过敏综合反应(AED)的发生涉及严重的皮肤、血和肝损伤。在严重的情况下,爆发性肝衰竭可能需要肝移植,大多数病人因肝衰竭而死去。严重的皮肤不良反应主要有罕见但致命的:史蒂夫·约翰逊综合症(SJS),中毒性表皮坏死松解症(TEN)和超敏反应综合征等。上述不良反应的致死率高达5%–50%。早期的准确诊断和及时治疗可能降低死亡率。本文报道了两个癫痫患者对卡马西平(CBZ)或苯巴比妥(PB)的过敏综合反应案例,来阐明癫痫的治疗过程和早期表现有助于改善癫痫的治疗方案,同时防止了潜在严重的AED的皮肤不良反应。两个案例报告强调在卡马西平及苯巴比妥的治疗中引起的致命性过敏反应可能与患者肝脏中缺少环氧化物羟化酶及基因缺失有关。     

Levetiracetam: A new antiepileptic drug for the adjunctive therapy of chronic epilepsy

Levetiracetam has recently been licensed in Europe and the U.S.A. for use as an adjunctive agent in partial epilepsy with or without secondary generalization. The mode of action has yet to be elucidated, but may involve a new brain-specific binding site, the ligand for which is unknown. Levetiracetam has a favorable pharmacokinetic profile, with rapid and almost complete oral absorption, almost 100% bioavailability, linear, dose-dependent maximum plasma concentrations and minimal plasma protein binding. Excretion is mainly renal, with most of the drug being eliminated unchanged. Levetiracetam does not have an effect on the major drug-metabolizing hepatic enzymes, and thus is associated with a low incidence of interactions with other antiepileptic drugs (AEDs). These properties make it a well-tolerated drug, with the most common reported side effects being asthenia, somnolence, headache and dizziness. Antiepileptic properties of levetiracetam demonstrated in animal studies have been borne out by large double-blind, placebo-controlled clinical trials, with significantly improved responder rates (>/= 50% reduction in seizure frequency from baseline) and number of seizure- free patients versus placebo. In addition, efficacy appears to be maintained over the long term and no evidence for the development of tolerance to the effects of levetiracetam has been seen. (c) 2001 Prous Science. All rights reserved.     

Neuropharmacology of zonisamide,a new antiepileptic drug

• 1.1. Zonisamide readily crosses the blood-brain barrier and is readily absorbed after oral administration with a T_max of about 3 hr.
• 2.2. The half-life of ZNA in epileptic patients is about 28 hr.
• 3.3. Zonisamide has a broader therapeutic range than other antiepileptic drugs.
• 4.4. Neurotoxic, hemapoietic, renal, and liver effects have been minimal in patients participating in controlled clinical studies.
• 5.5. It is effective in several experimental models of epilepsy and in initial clinical trials has been shown to be effective in generalized tonic-clonic, simple, and complex partial seizures.