Current issues in the treatment of acute posterior circulation stroke

This article presents a narrative review of the non-medical, medical and endovascular aspects of the management of acute ischaemic stroke in the posterior circulation, a potentially devastating condition with high mortality and substantial disability in many of those who survive. Optimal management requires a combination of supportive measures and specific interventions and is best delivered within a high-dependency or intensive care environment. Non-medical measures include management of physiological parameters, respiratory support where necessary and prompt treatment of complications such as the development of hydrocephalus. Deterioration in conscious state and progression of symptoms may occur some time after initial presentation and after admission to hospital; when such progression is detected, very rapid therapeutic reperfusion may be feasible. Reperfusion strategies include intravenous and intra-arterial thrombolysis (IAT) and mechanical methods to aid reperfusion, including the use of mechanical clot disruption, clot retrieval or stenting devices. The optimal reperfusion strategy, including considerations of whether to use intravenous or intra-arterial thrombolytic approaches, the use of bridging intravenous treatment prior to intra-arterial treatment, and the use of pharmacological or mechanical adjuncts to IAT is not known. However, it seems likely that the important determinant of therapeutic efficacy is the speed and safety with which reperfusion can be achieved. It may also be that the time available to achieve reperfusion is longer than in the anterior circulation.     

Current issues in the management of hypertension

Major trials evaluating antihypertensive therapy are reviewed, and the current issues surrounding the choice of therapy in mild and isolated systolic hypertension are discussed. Several major trials have shown that patients with mild hypertension benefit from therapy. These results have prompted widespread use of antihypertensive agents; however, there are still no clear guidelines on when drug therapy should be initiated. Only the Hypertension Detection and Follow-up Program has shown significant decreases in coronary heart disease (CHD) related deaths. Thiazide diuretics are recommended as agents of first choice in the stepped-care approach to the management of uncomplicated mild to moderate hypertension. The Multiple Risk Factor Intervention Trial evaluated the effects of modifying several cardiovascular risk factors in more than 12,000 high-risk men. It failed to document significant differences in CHD-related mortality in patients who received special care as compared with those who received usual care. Concerns have been raised about the contribution of antihypertensive therapy, particularly diuretics, to the lack of differences in therapeutic outcomes. There is renewed interest in lipid alterations secondary to antihypertensive agents and the effect of diuretic-induced hypokalemia. Antihypertensive therapy should be instituted with an individualized assessment of the potential benefits of therapy relative to the short- and long-term risks of treatment.     

Current and emerging drug therapies for the treatment of depression in adults with epilepsy

Introduction: Depression is the most frequent psychiatric comorbidity among people with epilepsy. It can impact on quality of life and increases the risk of morbidity and premature mortality.

Areas covered: The authors review the available data on current and emerging drug treatments for depression in epilepsy. Sources have been identified through Medline/PubMed searches while ongoing clinical trials have been identified through a ClinicalTrials.gov search.

Expert opinion: SSRIs are the drug class with the largest amount of data. Though promising, the level of evidence provided by these studies is still low as the majority have relevant methodological limitations. Antiepileptic drugs under development have the unique opportunity to be of multi-use in the treatment of epilepsy and depression. The serotoninergic system has already been identified as a potential area of interest, but new targets are still needed in epilepsy and depression. For this reason, it is important that basic scientists working on these two conditions develop collaborative projects and integrate findings.     

Current benzodiazepine issues

This article deals with some of the recent evidence bearing on the issues of the liability of benzodiazepines to lead to abuse, dependence, and adverse behavioral effects. Reviews of epidemiological, clinical and experimental literature indicated that the previous conclusion about abuse of these drugs still holds: the vast majority of the use of benzodiazepines is appropriate. Problems of nonmedical use arise nearly exclusively among people who abuse other drugs. Nevertheless, there are reasons for concern about patients who take benzodiazepines regularly for long periods of time. These drugs can produce physiological dependence when taken chronicaly, and although this does not appear to result in dose escalation or other evidence of psychological dependence, physiological dependence can result in patient discomfort if drug use is abruptly discontiniued. Also, physicians are currently prescribing shorter-acting benzodiazepines in preference to longer-acting benzodiazepines. The shorter-acting drugs can produce a more intense withdrawal syndrome following chronic administration. Furthermore, rates of use of benzodiazepines increase with age, and elderly patients are more likely than younger ones to take the drug chronically. The clearest adverse effect of benzodiazepines is impairment of memory. This, too, may be particular concern in older patients whose recall in the absence of drug is typically impaired relative to younger individuals, and who are more compromised following drug administration.This article was supported by USPHS Grant DA-00254 and by funding from Hoffmann-La Roche, Inc.     

Current issues in German healthcare

Germany has developed a model of social health insurance for financing healthcare. The basic characteristics of this model are compulsory membership, income-dependent contributions paid by employers and employees, a comprehensive package of healthcare entitlements, stringent government regulation and implementation by not-for-profit health insurers--the sickness funds--which operate under public law. Since the mid-1970s, when health care cost containment gradually evolved as a new issue in German healthcare policy-making, a long series of reform programmes have been initiated. Two recent development can be noted: the introduction of market competition in health insurance and the introduction of fixed budgets. Market competition in health insurance is now an explicit policy tool in Germany. This article analyses the German healthcare system, the history of healthcare reforms and the current healthcare acts. Special emphasis is given to the German drug market and its regulation. The paper describes the present cost-containment policy for pharmaceutical products, especially the global budget concept which was introduced for medicines and patients' copayments.     

Methodological issues associated with clinical trials in epilepsy

Introduction: despite methodological advances in epilepsy clinical trials, the proportion of patients reaching seizure-freedom has not substantially changed over the years. We review the main methodological limitations of current trials, the possible strategies to overcome these limits, and the issues that need to be addressed in next future.

Area covered: references were identified by PubMed search until March 2017 and unpublished literature was searched on ClinicalTrials.gov. Add-on trials mainly involve refractory epilepsy subjects, reducing overall response to the investigational drug. The inclusion of subjects with earlier disease from less developed countries has partially allowed overcoming this limitation, but has introduced more random variability of results. Monotherapy trials rise methodological, economical, and ethical concerns with different regulatory requirements in European Union and in the United States of America. Newer trial designs, such as futility trials or ‘time-to-event’ design, have been implemented. Moreover, both add-on and monotherapy trials results might be affected by patient’s ability to recognize and record seizures, and by randomness of seizures occurrence over time. Possible strategies to achieve more reliable outcomes are detailed.

Expert commentary: clinical trial methodology needs to be optimized to better address regulatory agencies requirements and to encounter both patients’ and clinicians’ needs.     

Pharmacogenomics in the treatment of epilepsy

Genetic variability has recently been implicated in the development of familial epilepsy syndromes and in heterogeneous responses of epilepsy patients to drug treatment. Mutations in distinct proteins have been shown to underlie the development of epilepsy, increase propensity for drug resistance, and alter drug metabolism. Improved understanding of how individual genetic variability may alter the efficacy of pharmacological therapeutic interventions is an important and timely goal. The investigation of relationships between genotype and patient responses to drug treatment is termed pharmacogenomics.     

Zonisamide in the treatment of epilepsy

Introduction: Epilepsy affects approximately 3 million people in the USA and up to 2% of the worldwide population. The yearly direct medical cost of epilepsy in the USA alone is estimated to be $9.5 billion. Epilepsy affects both children and adults and can significantly impair quality of life. Zonisamide is a second-generation antiepileptic drug (AED) that has broad-spectrum efficacy, a favorable side-effect profile and simpler dosing than earlier drugs.

Areas covered: The history of the development of zonisamide is reviewed in this paper. The data available demonstrating zonisamide's mechanism of action as a voltage-gated sodium channel inhibitor, a T-type calcium channel inhibitor, an enhancer of GABA release and an inhibitor of glutamate release are also reviewed. Four key Phase III clinical trials are reviewed in detail, as are subsequent postmarketing trials that have expanded the therapeutic indication for zonisamide.

Expert opinion: From the available clinical data, zonisamide is a viable first-line and adjunctive therapeutic for partial-onset epilepsy and should be considered as an adjunctive therapeutic for a wide-range of generalized epilepsies.     

Zonisamide in the treatment of epilepsy

INTRODUCTION: Epilepsy affects approximately 3 million people in the USA and up to 2% of the worldwide population. The yearly direct medical cost of epilepsy in the USA alone is estimated to be $9.5 billion. Epilepsy affects both children and adults and can significantly impair quality of life. Zonisamide is a second-generation antiepileptic drug (AED) that has broad-spectrum efficacy, a favorable side-effect profile and simpler dosing than earlier drugs. AREAS COVERED: The history of the development of zonisamide is reviewed in this paper. The data available demonstrating zonisamide's mechanism of action as a voltage-gated sodium channel inhibitor, a T-type calcium channel inhibitor, an enhancer of GABA release and an inhibitor of glutamate release are also reviewed. Four key Phase III clinical trials are reviewed in detail, as are subsequent postmarketing trials that have expanded the therapeutic indication for zonisamide. EXPERT OPINION: From the available clinical data, zonisamide is a viable first-line and adjunctive therapeutic for partial-onset epilepsy and should be considered as an adjunctive therapeutic for a wide-range of generalized epilepsies.     

Valproic acid in epilepsy : pregnancy-related issues.

Valproic acid (sodium valproate) is widely used as a first-line antiepileptic agent. As with many antiepileptic drugs, there are a number of consequences associated with the use of valproic acid in women of child-bearing potential. Most pregnancies have a favourable outcome in women with epilepsy, and these women should not be discouraged from becoming pregnant. Unlike many other antiepileptic drugs, valproic acid has no significant pharmacokinetic interactions with the steroid hormones used in oral contraceptives. During pregnancy, the major risks to mother and child result from loss of seizure control on the one hand, and an elevated risk of major congenital malformations due to antiepileptic drug treatment on the other. In particular, an elevated risk of major congenital malformations associated with valproic acid use has been a consistent finding in studies of patient registries and several large case series. In addition, developmental delay, characterised by low verbal IQ, has also been reported in children exposed to valproic acid in utero, although the relative risk is not precisely known. For these reasons, pregnancies in women being treated with valproic acid need to be planned, and the benefit-risk ratios associated with continuing valproic acid or changing treatment need to be discussed with the patient. When treatment with valproic acid is the most appropriate treatment to achieve optimal seizure control, a number of measures can be implemented to minimise risk to the fetus. These include the use of the lowest possible effective dose of valproic acid in monotherapy (ideally <1000 mg/day), appropriate folic acid supplementation and close antenatal monitoring. Regular counselling is a prerequisite for informed planning of pregnancies and optimisation of the probability of a healthy outcome. Future research on valproic acid and pregnancy should involve risk assessment in large, population-based prospective studies.     

Zonisamide in the treatment of epilepsy

Importance of the field: More than 1 million epilepsy patients suffer from insufficiently controlled epilepsy, both in the USA and in Europe. Zonisamide is an antiepileptic drug with multiple mechanisms of action, corresponding to efficacy in diverse epilepsy syndromes.

Areas covered in this review: Here, an update on pharmacodynamics, pharmacokinetics, clinical efficacy and safety in childhood and adult epilepsies is given based on an analysis of controlled and uncontrolled studies, European, US and East Asian, and on clinical experience with zonisamide (ZNS) published up to 2009.

What the reader will gain: Evidence is presented that ZNS is effective not only in adult focal epilepsies, for which it has been approved in the USA and in Europe, but also may offer treatment options for compassionate use in a spectrum of difficult-to-treat epilepsy syndromes. Its favorable pharmacokinetic profile allows for easy combination with most available antiepileptic drugs.

Take home message: Provided that additional studies on ZNS are performed to extend approval and to generate comparative data, ZNS has a potential to gain importance in the treatmnt of a wide spectrum of epilepsy patients.     

Current issues in biowaivers and biosimilars

International Conference on Biowaivers and Biosimilars

San Antonio, TX, USA, 10–12 September 2012

An International Conference on Biowaivers and Biosimilars was held in San Antonio (TX, USA) on September 10–12, 2012. The conference was organized by OMICS Group Inc. The topics covered wide-ranging issues that are especially relevant to the current considerations of biosimilarity. Speakers came from North America and Europe, as well as from Argentina, Brazil, India and Israel.     

Ketogenic diets in the treatment of epilepsy

Epilepsy (a proneness to recurrent seizures) is the most common serious neurological disorder, with an incidence of around 40-70 cases per 100,000 population in developed countries, and a lifetime risk of 1-3%.(1-3) Seizures have been reported to cease on absolute fasting, and early studies suggested that a diet high in fat and low in carbohydrate would produce similar conditions to fasting; the anticonvulsant effect was attributed to the production of ketones.(2) The ketogenic diet was introduced as a treatment for epilepsy in the 1920s, but its use waned with the introduction of phenytoin and other antiepileptic drugs.(2-4) However, around 30% of patients continue to have seizures while taking one or more antiepileptic drugs, and some patients have significant unwanted effects with such medication.(1,2) During the past two decades, there has been a renaissance of interest in dietary therapy.(2) Here, we focus on the use of ketogenic diets in the treatment of epilepsy.     

Oxcarbazepine in the treatment of epilepsy.

Oxcarbazepine is a new antiepileptic drug (AED) that has been registered in more than 50 countries worldwide since 1990 and recently received approval in the United States and the European Union. Oxcarbazepine is a keto analog of carbamazepine and has a more favorable pharmacokinetic profile. It is rapidly absorbed after oral administration and undergoes rapid and almost complete reductive metabolism to form the pharmacologically active 10-monohydroxy derivative. Oxcarbazepine exhibits linear pharmacokinetics, no autoinduction, and minimal interaction with other AEDs. Ten controlled trials demonstrated that oxcarbazepine is safe and efficacious in the treatment of partial seizures across a wide range of ages (children to adults), situations (recent onset to treatment-resistant epilepsy), and uses (monotherapy and adjunctive therapy). The most common treatment-emergent adverse events are related to the central nervous system. Treatment-emergent hyponatremia (defined as serum sodium level < 125 mEq/L) occurred in 3% of patients treated with oxcarbazepine in clinical trials. According to the efficacy and safety profile established in the controlled trials, oxcarbazepine represents an important new treatment option indicated for monotherapy and adjunctive therapy in adults with partial seizures and as adjunctive therapy in children aged 4 years or older with partial seizures. Although structurally similar to carbamazepine, significant differences exist in the pharmacokinetics, drug interaction potential, adverse-effect profile, and dosage and titration between these two agents, and they should be considered distinct therapeutic agents.     

Current issues in pediatric medication adherence

With the recent emphasis on investigating the efficacy of medication in children, it is also important to assess what determines whether pediatric patients do or do not take their medication. In general, children are no better at adhering to drug therapy than older individuals. Dealing with medication nonadherence is essential given its association with a failure to achieve the desired treatment goal. In addition to the many factors that influence adherence in adults, there are some unique challenges faced in the pediatric age group including the role of family (and its dysfunction), the changes of adolescence, and the lack of appropriate drug formulations. Intervention strategies to improve adherence include behavioral and educational strategies. Although there is no consensus as to what is the best approach to promote adherence with therapy, attention should be given to determining what barriers exist and trying to overcome them by involving children and their parents in the treatment planning process. If possible, the medication regimen, taking into account the frequency and timing of administration, should be tailored to the child and family's lifestyle and daily routine. Consideration should be given to the palatability and formulations of medications prescribed for young children. The use of simplified regimens of better tasting medications and age-appropriate delivery mechanisms may enhance the ability of pediatric patients to adhere to their drug therapy.