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PubMed2004

Diabetic neuropathy: an intensive review.

PURPOSE: The epidemiology, classification, pathology, and treatment of diabetic neuropathy are reviewed. SUMMARY: Diabetic peripheral neuropathy is a common complication of diabetes that can cause significant morbidity and mortality. Some 30% of hospitalized and 20% of community-dwelling diabetes patients have peripheral neuropathy; the annual incidence rate is approximately 2%. The primary risk factor is hyperglycemia. Sensorimotor neuropathy is marked by pain, paresthesia, and sensory loss. Cardiac autonomic neuropathy (CAN) may contribute to myocardial infarction, malignant arrhythmia, and sudden death. Gastroparesis is the most debilitating complication of gastrointestinal autonomic neuropathy. Genitourinary autonomic neuropathy can cause sexual dysfunction and neurogenic bladder. The pathology of diabetic neuropathy involves oxidative stress, advanced glycation end products, polyol pathway flux, and protein kinase C activation; all contribute to microvascular disease and nerve dysfunction. For symptom management current evidence from clinical trials supports the use of desipramine, amitriptyline, capsaicin, tramadol, gabapentin, bupropion, and venlafaxine as preferred medications. Citalopram, nonsteroidal antiinflammatory drugs, and opioid analgesics may be used as adjuvant agents. Lamotrigine, oxcarbazepine, paroxetine, levodopa, and alpha-lipoic acid are alternative considerations. Evidence supporting the use of zonisamide, fluoxetine, mexiletine, dextromethorphan, and phenytoin is considered equivocal. Complementary therapies have also shown efficacy. The symptoms of CAN may be ameliorated with fludrocortisone, clonidine, midodrine, dihydroergotamine or caffeine, octreotide, and beta-blockers. Gastroparesis may be treated with metoclopramide or erythromycin. The most promising disease-modifying therapy is ruboxistaurin, which is in Phase III trials. Glycemic control remains the foundation of prevention and the prerequisite of adequate treatment. CONCLUSION: Diabetic neuropathy is a many-faceted complication of diabetes that can be managed symptomatically with an array of drugs.

Analgesics, Opioid↗
PubMedDate not supplied

Medical treatment of patients with infantile spasms.

Infantile spasms are the main feature in West syndrome, an age-related epilepsy syndrome that affects 1 in every 2,000-4,000 infants. The authors provide a comprehensive review of the literature about infantile spasms and their therapy. In the United States, the drug of choice for infantile spasms, at least the cryptogenic cases, has been adrenocorticotropic hormone (ACTH). It is generally considered to be more effective than corticosteroids. Adrenocorticotropic hormone appears to alter long-term prognosis of cryptogenic infantile spasms, and helps in some cases of symptomatic infantile spasm. Vigabatrin has been considered the drug of choice for infantile spasms secondary to tuberous sclerosis, and possibly, according to many neurologists, for all cases of infantile spasm. Recent concerns regarding retinopathy associated with vigabatrin therapy are, however, limiting the use of this drug. Valproic acid benefits 40%-70% of patients who failed a trial of ACTH. Nitrazepam is as effective as ACTH in acutely controlling infantile spasms; however, its long-term effects on prognosis have not been studied. Pyridoxine, lamotrigine, topiramate, zonisamide, ketogenic diet, immunoglobulin therapy, felbamate, and thyrotropin-releasing hormone have all been used for the treatment of infantile spasms, but are usually reserved for cases refractory to vigabatrin and/or ACTH.

Adrenocorticotropic Hormone↗
PubMed2001

Contribution of sodium valproate to the syndrome of inappropriate secretion of antidiuretic hormone.

We report the case of a 62-year-old man who was administered sodium valproate (VPA) and who subsequently developed the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). He had been taking VPA for treatment of idiopathic generalized tonic-clonic convulsions since he was 56 years old. After substituting VPA with zonisamide, the serum sodium level returned to normal. We consider this episode of SIADH to be the result of a combination of factors including a weakness of the central nervous system and the long-term administration of VPA.

Diagnosis, Differential↗
PubMed2002

Marketed new antiepileptic drugs: are they better than old-generation agents?

Until a decade ago, the pharmacologic armamentarium for the management of epilepsy was restricted to a little more than a handful of drugs that had been introduced 20 to 70 years earlier. This situation has changed dramatically, with as many as nine new-generation drugs (oxcarbazepine, gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, zonisamide, vigabatrin, and felbamate, in addition to the water-soluble phenytoin prodrug fosphenytoin) having been introduced in Europe, the United States, or other parts of the world. These drugs represent a welcome addition because they produce an appreciable reduction in seizure frequency in up to 40% to 50% of patients who had been refractory to older-generation drugs. However, only a few patients with truly refractory disease can be made seizure-free by these new drugs, and the search for more effective anticonvulsants should continue. Although in patients with newly diagnosed epilepsy the efficacy of new-generation drugs is not superior to that of older agents, some of the newer drugs offer advantages in terms of improved tolerability, ease of use, and reduced interaction potential. However, the increased availability of treatment options implies that drug choice in patients with epilepsy is more complicated than in the past, and there is a concern that inadequate knowledge of indications, contraindications, and mode of use of the newer drugs could result in some patients receiving suboptimal treatment or being exposed to undue risks from side effects and drug interactions. Although measurement of plasma drug concentrations is often used to adjust the dosage of classic antiepileptic drugs, therapeutic drug monitoring has been claimed to be of little or no value with newer-generation drugs. This view has been challenged in light of the evidence that pharmacokinetic variability contributes to an important extent to differences in dosage requirements for most of these drugs.

Anticonvulsants↗
PubMed1994

Developments in antiepileptic drug therapy.

Development of new antiepileptic drugs has continued to progress, with both the evolution of new drugs, as well as new formulations of old drugs. It is hoped that, with advances in the understanding of the molecular basis of epilepsy, novel antiepileptic drugs will come about through design rather than serendipity. This article concentrates on a selection of the more promising antiepileptic drugs and reviews their recent progress. Felbamate, lamotrigine, vigabatrin, zonisamide, and gabapentin are already in clinical use in certain countries. Stiripentol and other potential antiepileptic drugs are also reviewed. In addition, there have been strategies to improve the pharmacokinetics of currently used antiepileptic drugs and we have concentrated on controlled-release carbamazepine and oxcarbazepine, both available in certain countries. It is, however, increasingly apparent that good comparative studies are needed before definitive advice can be given in the drug treatment of epilepsy.

Anticonvulsants↗
PubMed2002

New antiepileptic drugs.

BACKGROUND: Eight novel anticonvulsant drugs have been introduced in the United States in the past 10 years, as well as two new intravenous preparations of anticonvulsant drugs. The role of each in the treatment of patients with epilepsy is being refined as experience and research data accumulate. REVIEW SUMMARY: Gabapentin, tiagabine, and oxcarbazepine are effective for partial seizures, whereas felbamate, lamotrigine, topiramate, levetiracetam, and zonisamide treat both partial and generalized seizure types. In general, these newer agents differ from older agents by relative lack of drug-drug interactions, and many show improved tolerability compared with phenytoin and carbamazepine. Each has distinguishing features that can prove useful in specific clinical situations. Despite limited Food and Drug Administration indications, all are useful in monotherapy under certain circumstances. Fosphenytoin avoids the adverse effects of intravenous phenytoin vehicle, and intravenous valproate represents a much needed option in patients who require rapid loading of this medication. CONCLUSIONS: The greater number of antiseizure drugs available today makes it possible to tailor treatment to individual patient needs, allowing more patients to be free of debilitating adverse effects. Additionally, some patients can achieve complete seizure freedom even after failing one or more other antiepileptic drugs.

Journal Article↗
PubMedDate not supplied

Obesity: new perspectives and pharmacotherapies.

There is a widespread epidemic of obesity in the United States, which has been associated with an increased risk of diabetes mellitus, cancer, and cardiovascular diseases. Although lifestyle modifications and long-term dietary vigilance remain cornerstones of weight reduction treatment, the continued availability of U.S. Food and Drug Administration-approved pharmacotherapies has expanded the options available for the management of obesity. These agents include anorexiants, thermogenic drugs, and lipid-partitioning drugs. As knowledge regarding the possible causes of obesity increases, there are new drugs under investigation, which include beta3-adrenergic receptor agonists, modifiers of leptin, and cannabinoid receptor-1 antagonists (rimonabant). Also under investigation are antidiabetic agents (metformin, exenatide), anticonvulsant drugs (topiramate, zonisamide), antidepressants (bupropion, fluoxetine), and growth hormones. New targets for pharmacotherapy include uncoupling proteins, fatty acid synthase, neuropeptide Y, melanocortin, ghrelin, various regulatory gut peptides, and ciliary neurotropic factor. Pharmacologic agents are in clinical development that target these substances.

Anti-Obesity Agents↗
PubMed2005

Gender aspects of pharmacokinetics of new and old AEDs: pregnancy and breast-feeding.

Alterations in drug disposition in pregnancy and drug transfer into breast milk during lactation are the most important gender-related aspects of the pharmacokinetics of antiepileptic drugs(AEDs). The effect of pregnancy on drug disposition has been fairly well characterized for the old AEDs. Total and unbound plasma concentrations of phenobarbital decline up to 50%. Total phenytoin levels may drop to approximately 40% of prepregnancy concentrations,but unbound concentrations considerably less. Unbound valproate levels remain unchanged despite a fairly marked decrease in total concentrations, and changes in unbound and total plasma concentrations of carbamazepine are minor. In contrast, pregnancy has a pronounced effect on lamotrigine, with a 300% increase in apparent clearance in the third trimester. Much less is known about the kinetics of other new AEDs during pregnancy. Umbilical cord/maternal plasma concentration ratios close to unity suggest free transplacental passage of most AEDs,whereas higher ratios indicate fetal accumulation of valproate and gabapentin. Milk/maternal plasma concentration ratios close to 1 demonstrate extensive transfer to breast milk of many AEDs including ethosuximide, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and zonisamide. Plasma levels are, however, in general low in the nursed infant, although pharmacological concentrations have been reported occasionally for carbamazepine, ethosuximide, lamotrigine, and phenobarbital. For most of the new-generation AEDs, there is an urgent need for further kinetic data from pregnancy and breast-feeding.

Anticonvulsants↗
PubMed2005

Pharmacokinetic variability of new antiepileptic drugs at different ages.

Newer generation antiepileptic drugs (AEDs) are increasingly used to treat epilepsies in infants, children, and the elderly. For rational prescribing in these populations, it is essential to understand the pharmacokinetic changes that occur during development and aging. Data obtained in recent years indicate that the apparent oral clearance (CL/F) of lamotrigine, topiramate, levetiracetam, oxcarbazepine, gabapentin, tiagabine, zonisamide, vigabatrin, and felbamate is considerably higher in children than in adults,the magnitude of the difference being on average in the order of 20%to 120%, depending on the drug and the age distribution of the assessed population. Information on the pharmacokinetics of these drugs in newborns is completely lacking or very sparse. Studies in the elderly have demonstrated that significant pharmacokinetic changes also occur at the other extreme of age. On average, CL/F values of newer generation AEDs have been found to be reduced by 10% to 50% compared with those found in young or middle-aged adults. These pharmacokinetic changes are clinically important and con-tribute to age-related differences in dosage requirements.

Aging↗
PubMed2005

The pharmacokinetics and interactions of new antiepileptic drugs: an overview.

In the past decade 10 new antiepileptic drugs (AEDs)have been introduced: felbamate, gabapentin, lamotrigine, levetiracetem, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin,and zonisamide. The pharmacokinetics (PK) of these new AEDs as well as their potential for drug interactions are reviewed in this article. In general, new AEDs have better PK profiles and are less involved in drug interactions than the 4 established AEDs: phenobarbital,phenytoin, carbamazepine, and valproic acid. However, in spite of the large therapeutic arsenal of old and new AEDs, about 30% of epileptic patients are still not seizure-free, and thus, there is a substantial need to develop new AEDs.

Algorithms↗
PubMed2003

Ziprasidone metabolism, aldehyde oxidase, and clinical implications.

Ziprasidone (Geodon, Zeldox), a recently approved atypical antipsychotic agent for the treatment of schizophrenia, undergoes extensive metabolism in humans with very little (<5%) of the dose excreted as unchanged drug. Two enzyme systems have been implicated in ziprasidone metabolism: the cytosolic enzyme, aldehyde oxidase, catalyzes the predominant reductive pathway, and cytochrome P4503A4 (CYP3A4) is responsible for two alternative oxidation pathways. The involvement of two competing pathways in ziprasidone metabolism greatly reduces the potential for pharmacokinetic interactions between ziprasidone and other drugs. Because CYP3A4 only mediates one third of ziprasidone metabolism, the likelihood of interactions between ziprasidone and CYP3A4 inhibitors/ substrates is low. Furthermore, aldehyde oxidase activity does not appear to be altered when drugs or xenobiotics are coadministered. Aldehyde oxidase, a molybdenum-containing enzyme, catalyzes the oxidation of N-heterocyclic drugs such as famciclovir and zaleplon, in addition to reducing some agents such as zonisamide. Both reactions can occur simultaneously. Although in vitro inhibitors of aldehyde oxidase have been identified, there are no reported clinical interactions with aldehyde oxidase inhibitors or inducers. There is no evidence of genetic polymorphism in aldehyde oxidase, and thus it not surprising that ziprasidone exposure demonstrates unimodality in humans. Aldehyde oxidase is unrelated to the similarly named enzyme aldehyde dehydrogenase, which is predominantly responsible for the oxidation of acetaldehyde during ethanol metabolism. Consequently, it is unlikely that there would be any pharmacokinetic interaction between ethanol and ziprasidone.

Aldehyde Oxidase↗
PubMed2006

Modern antiepileptic drugs: guidelines and beyond.

PURPOSE OF REVIEW: Ten antiepileptic drugs have been licensed since 1990. Their usage will be briefly reviewed focusing on new data and inclusion in guidelines. The hypotheses exploring the underlying basis of pharmacoresistance will be presented. RECENT FINDINGS: Lamotrigine, gabapentin, topiramate, and oxcarbazepine are available for use as monotherapy in many countries following comparative studies with older antiepileptic drugs. Zonisamide and pregabalin have recently obtained licences as adjuvant therapy in the US and Europe for partial epilepsy with or without secondary generalization. The UK National Institute for Clinical Excellence guideline has advised, largely based on cost, against the routine use of modern antiepileptic drugs, except when older drugs have failed or are contraindicated. This contrasts with the US guidelines which are less conservative. Surgically resected specimens from patients with refractory epilepsy have led to the development of two hypotheses to explain pharmacoresistant epilepsy. SUMMARY: The introduction of 10 new antiepileptic drugs has provided greater choice for patients and doctors, although evidence in support of their superiority over the older drugs is sparse. This has led to conflicting advice in guidelines. Recent developments in the understanding of pharmacoresistance may explain the relatively high incidence of refractory epilepsy.

Anticonvulsants↗
PubMed2004

Statistics on deliveries of mothers with epilepsy at Yokohama City University Hospital.

PURPOSE: To survey and summarize the treatment of pregnant women with epilepsy and to obtain data for the improvement of daily treatment regimens. METHODS: We reviewed medical records of 36 deliveries of 25 mothers with epilepsy at Yokohama City University Hospital from September 1991 to December 2000 and statistically compared the differences in drug-taking profiles, complications during pregnancy, types of delivery, and complications at delivery between the epilepsy group and a control group (656 total deliveries after 22 weeks except for epilepsy cases in 1991 and 1992 at Yokohama City University Hospital). RESULTS: Of the 25 mothers with epilepsy, three with idiopathic generalized epilepsy, 12 were symptomatic for partial epilepsy. Their mean age at delivery was 29.0 years. The mean age at onset of epilepsy was 13.9 years. Of the 36 pregnancies, 30 (83.3%) cases continued antiepileptic drug (AED) taking throughout the pregnancies; 23 (63.9%) cases received monotherapy. Phenobarbital was the most frequently used drug in monotherapies. Seven (19.4%) cases received polytherapy. Seven (19.4%) patients experienced epileptic seizures during pregnancy. One case showed a low serum AED level. No statistically significant difference was found in complications during pregnancy, types of delivery, or complications at delivery, excluding abnormal rotation in the birth canal. Congenital malformation (cleft lip with palate) was observed in one (2.9%) case. The mother was 39 years old at delivery and had myoma uteri. Onset of epilepsy was at 14 years. She had been taking three kinds of AEDs: 1,400 mg/day of sodium valproate (VPA), 1.5 mg/day of clonazepam (CZP), and 200 mg/day of zonisamide (ZNS). Serum concentrations at pregnancy week 10 were 85.3 microg/ml VPA, 18.1 microg/L CZP, and 10.5 microg/ml ZNS. She also had been taking folic acid, 5 mg/day, but the serum concentration was not measured. CONCLUSIONS: The method of treatment and the management of pregnancy were left to the discretion of each doctor. However, in most cases, monotherapy was selected; and the frequency of complications was not significantly different from that of the control group, excluding the frequency of abnormal rotation in the birth canal. However, we could have been more proactive in calculating the risks of pregnancy for women with epilepsy and adjusted treatment in anticipation of a planned pregnancy, before the patient actually became pregnant. Additionally, a closer working relationship between the obstetrician and the physician who treats the epilepsy would seem to be a further requirement for the patient's well-being, as well as her child's, during pregnancy.

Abnormalities, Drug-Induced↗
PubMed1995

Clobazam, oxcarbazepine, tiagabine, topiramate, and other new antiepileptic drugs.

Clinical investigators recently have studied at least 21 new antiepileptic drugs (AEDs) in people with epilepsy. This review briefly examines 15 of these new AEDs: clobazam (CLB), dezinamide, flunarizine (FNR), loreclezole, milacemide (MLM), MK-801, nafimidone, ORG-6370, oxcarbazepine (OCBZ), progabide (PGB), ralitoline, stiripentol, tiagabine (TGB), topiramate (TPM), and zonisamide (ZNS). CLB, PGB, and TGB represent agents that act on the GABA system, and MLM acts on the glycine system. MK-801 and ZNS (in part) are excitatory amino acid antagonists, and FNR is a calcium-channel antagonist. OCBZ is a keto analogue of carbamazepine, which is not metabolized to the epoxide and may have fewer side effects. The remaining agents are novel compounds with a variety of suspected mechanisms. TPM appears especially effective for intractable partial seizures but has a high incidence of cognitive side effects. None of these new AEDs is useful for all patients with inadequate seizure control or ongoing toxicity. The role of each will require further clinical study and experience.

Animals↗
PubMed1997

An overview of the efficacy and tolerability of new antiepileptic drugs.

To evaluate the efficacy and tolerability of recently developed antiepileptic drugs (AEDs), a systematic review of placebo-controlled, randomized controlled trials (RCTs) of the AEDs as add-on therapy in refractory partial epilepsy was conducted. Two or more RCTs meeting our inclusion criteria were found for gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), and zonisamide (ZNS). The outcome selected for estimation of efficacy was the proportion of patients experiencing a > or = 50% reduction in seizure frequency from baseline. Tolerability was estimated on the basis of rates of patient withdrawal from study for any reason. Efficacy and tolerability odds ratios (ORs) and 95% confidence intervals (95% CIs) for each measure were generated for each trial included in the analysis, and overall efficacy and tolerability ORs were calculated for each AED across all trials and drug dosages evaluated. Because 95% CIs for both efficacy and tolerability overlapped for the six drugs, conclusive evidence of between-drug differences in effectiveness or safety were not obtained from the analysis. However, the data suggest that the drug with the highest OR for efficacy (TPM) may be approximately twice as effective as the AED with the lowest OR for efficacy (GBP), and that the treatment that appears to most frequently cause withdrawal (ZNS) may be about four times more likely to do so that the AED with the lowest withdrawal rate (LTG). RCTs comparing newer AEDs with the older standard drugs and with each other are needed to further evaluate their relative utility.

Anticonvulsants↗
PubMed2000

Conduct of trials in private clinical practice.

PURPOSE: Trials of antiepileptic medications are usually based in tertiary referral centers with teaching hospital resources. Epilepsy Research & Services (ERS) is part of a private outpatient neurological clinic that is involved in research as part of multicenter clinical trials, adhering to Good Clinical Research Practice. ERS is subject to external monitoring and auditing, but does so outside of the teaching hospital environment. METHODS: The clinic is operated by a neurologist supported by a research assistant, administrative and nursing staff and has no formal university attachment. Patients are recruited for trials from routine referrals for clinical care. The center has formal ties with the ethics committee of the local teaching hospital, but none of the team is formally attached to that hospital. RESULTS: The center conducted trials of zonisamide, oxcarbazepine, gabapentin, remacemide, tiagabine, vigabatrin, felbamate, and lamotrigine both as add-on trials in refractory seizure disorders and as monotherapy trials in de novo epilepsy. More than 200 patients have been recruited for trials at ERS (with some patients being involved in more than one trial). External review endorsed ERS as a superior environment for such research and as a model for other centers. CONCLUSIONS: Private practice is a viable alternative for the conduct of clincial trials and should be considered when establishing such protocols. Simplicity of administration and clinical practice, which more closely mirrors standard patient care, may enhance recruitment and management.

Ambulatory Care Facilities↗
PubMed2005

Practical management issues for idiopathic generalized epilepsies.

The idiopathic generalized epilepsies (IGE) are a group of epilepsies that are genetically determined, have no structural or anatomic cause, and usually begin early in life. Neurologic examination, intelligence, and imaging studies are normal, and EEG shows only epileptiform abnormalities (i.e., no abnormal slow activity or evidence for diffuse encephalopathy). In some IGE, the genetic substrate has been identified, whereas in most, it remains unknown. Depending on the age at onset and predominant seizure type, individual subtypes of IGE (syndromes) are defined. However, overall, there are more similarities than there are differences among the various subtypes, and the IGE are best viewed as a spectrum or continuum of conditions. In general, IGE respond to treatment, with 80-90% becoming fully controlled. However, not all antiepileptic drugs (AED) are equally effective in IGE. Some AED are ill advised because they either do not work or exacerbate seizure types other than generalized tonic-clonic (GTC) seizures, that is, absence and myoclonic seizures. These include carbamazepine, oxcarbazepine, phenytoin, gabapentin, and tiagabine. Their use is the main cause of "pseudo-intractability," and at least in the United States where PHT and CBZ are the most commonly used AEDs, patients with IGE are often on inadequate medications. For patients with clear IGE, the drug of choice is generally valproic acid because it effectively controls absence myoclonic seizures and GTC seizures. Second-line drugs (when first-line drugs fail or are not tolerated) may include benzodiazepines, but the use of second-line drugs is evolving rapidly. Some of the newer AEDs are considered broad spectrum, meaning that they work in IGE and focal epilepsies, although the evidence is largely preliminary at this point. These newer AEDs include lamotrigine, topiramate, levetiracetam, and zonisamide.

Age Factors↗
PubMed2005

Evidence-based treatment of idiopathic generalized epilepsies with new antiepileptic drugs.

With the introduction of over ten new antiepileptic drugs (AEDs) since 1993, the hope has been that at least some of these agents would be useful for not just partial seizures, but also for the primary generalized seizures of the idiopathic generalized epilepsies (IGE). The development of evidence-based treatment guidelines in the IGE, however, faces a number of challenges, particularly after an antiepileptic drug (AED) receives approval for one indication. The majority of patients with IGE are controlled with first-line therapy if appropriately selected. Case reports or series typically appear with use in refractory patients, but these studies lack the rigor to allow formulation of guidelines. Still we are beginning to see some good class I and II data to support use of selected second-generation AEDs. It is postulated that lamotrigine (LTG), levetiracetam (LEV), topiramate (TPM), and zonisamide (ZSM) may have efficacy for a broad spectrum of seizure types including those of IGE. At the present time good class I and II evidence exists to support the use of LTG for typical absence, LEV for idiopathic myoclonic seizures, and TPM for primary generalized tonic-clonic seizures, even though only TPM has FDA approval for primary generalized seizures. This article examines the available rigorous evidence that can support these uses and also discusses some selected other reports that suggest a spectrum of efficacy for these new agents.

Anticonvulsants↗