Amelioration of erectile dysfunction following a switch from carbamazepine to oxcarbazepine: recent clinical experience

Oxcarbazepine is an antiepileptic drug (AED) indicated for use as monotherapy and add-on therapy in adults and children 4 years of age and older. Despite being structurally related to carbamazepine, oxcarbazepine differs substantially in its pharmacokinetic and safety profile; oxcarbazepine has a much lower risk of pharmacokinetic drug-drug interactions than carbamazepine. Carbamazepine has also been shown to induce the hepatic synthesis of sex hormone-binding globulin, thus reducing free serum testosterone levels and possibly causing erectile dysfunction (ED) in some men; these effects have not been observed with oxcarbazepine. This paper provides a discussion of recent clinical experience with men who presented in private clinical practice with complaints of ED while being treated with carbamazepine for seizure disorders. The four illustrative case studies presented in this report suggest that switching AED treatment from carbamazepine to oxcarbazepine in men with epilepsy can reduce the ED side effects observed with carbamazepine.     

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.     

Eslicarbazepine acetate for the treatment of partial epilepsy

Introduction: Eslicarbazepine acetate (ESL) is a third generation AED structurally related to carbamazepine and oxcarbazepine, but without several of the drawbacks associated with these compounds. ESL is completely metabolized to its eslicarbazpine, which selectively binds inactivated voltage-gated sodium channels and thus selectively reduces the activity of rapidly firing (epileptic) neurons. In addition, ESL has pharmacokinetic properties allowing once daily dosing.

Areas covered: This review summarizes data from the initial phase I to III studies, which demonstrated efficacy of ESL as add-on treatment in partial onset epilepsy, and more recent studies that demonstrate efficacy of ESL as monotherapy. Real-life observational studies are also reviewed, and seem to confirm the notion of ESL as a well-tolerated AED. As a new AED, ESL needs to be subject to close monitoring regarding long-term adverse events. Future independent studies will most likely clarify the role of ESL in the management of partial onset seizures.

Expert opinion: The role of ESL in management of partial onset seizures is discussed, as is the need for close monitoring and evaluation for broad-spectrum pharmacodynamics properties. The characteristics of the molecule and efficacy and safety profiles seem, however, very promising.     

Oxcarbapezine: anticonvulsant profile and safety

Oxcarbazepine is a molecule chemically related to carbamazepine that shares most of the pharmacological and therapeutic effects of carbamazepine while displaying a more favorable profile regarding tolerability and drug-drug interactions. In contrast to carbamazepine, oxcarbazepine is metabolized through cytochrome P450-independent reductases, and is thus devoid of inductive effects on hepatic oxidative metabolism. Oxcarbazepine has been shown to be useful both as monotherapy and adjunctive therapy in patients with partial seizures with or without secondary generalization. The drug has been documented as safe and effective in adults as well as children aged 4-16 years. Additional data suggests that oxcarbazepine might improve cognition and psychomotor performance and might increase alertness, in contrast to the cognition/psychomotor impairment observed with some other antiepileptic drugs. Both the pharmacokinetic advantages over other anticonvulsant drugs and the lack of pharmacological interactions with oxcarbazepine may point to this drug as a first-line treatment for the management of partial and tonic-clonic epilepsy.(c) 2001 Prous Science. All rights reserved.     

Oxcarbazepine. A review of its pharmacology and therapeutic potential in epilepsy, trigeminal neuralgia and affective disorders.

Oxcarbazepine is the 10-keto analogue of carbamazepine but has a distinct pharmacokinetic profile. In contrast to the oxidative metabolism of carbamazepine, oxcarbazepine is rapidly reduced to its active metabolite, 10,11-dihydro-10-hydroxy-carbamazepine. With the possible exception of the P450IIIA isozyme of the cytochrome P450 family, neither oxcarbazepine nor its monohydroxy derivative induce hepatic oxidative metabolism. Direct comparison of oxcarbazepine and carbamazepine has shown no difference in efficacy between these 2 agents in terms of reducing seizure frequency in patients with partial epilepsy with or without secondary generalisation, or with tonic-clonic seizures. Substitution of oxcarbazepine for carbamazepine in multiple antiepileptic drug regimens improved seizure control in some patients with refractory epilepsy; however, the rise in serum concentrations of concurrent antiepileptic agents secondary to elimination of carbamazepine-associated hepatic enzyme induction may have also played a role. Substitution of oxcarbazepine for carbamazepine was associated with improved cognition and alertness in some patients with epilepsy. Limited data indicate that oxcarbazepine may be a useful alternative to carbamazepine in the management of trigeminal neuralgia. Experience in patients with acute mania is promising, but the value of oxcarbazepine in managing affective disorders, particularly as a prophylactic agent, is not established. Oxcarbazepine may be better tolerated than carbamazepine; however, the current published database is small and the potential for oxcarbazepine to induce the type of serious idiosyncratic reactions occasionally associated with carbamazepine is unknown. Hyponatraemia has been reported in patients treated with oxcarbazepine. Although apparently asymptomatic, fluid restriction may be deemed necessary in some patients to reduce the risk of precipitating seizures secondary to low serum sodium. Thus, oxcarbazepine appears to be an effective substitute for carbamazepine in those patients intolerant of this agent, or experiencing significant drug interactions. Wider clinical experience should help clarify the long term efficacy and tolerability of oxcarbazepine. Pharmacokinetic advantages over current antiepileptic drugs, carbamazepine in particular, may then favour oxcarbazepine for consideration as a first-line agent in the management of partial and tonic-clonic epilepsy.     

Induction of microsomal enzymes in rat liver by oxcarbazepine, 10,11-dihydro-10-hydroxy-carbamazepine and carbamazepine

1. The effects of the new anti-epileptic drug, oxcarbazepine, its major metabolite in man, 10,11-dihydro-10-hydroxy-carbamazepine, and carbamazepine, on hepatic microsomal enzyme activities have been studied in rats after repeated administration of equimolar doses.

2. All three compounds caused a qualitatively similar induction of the mono-oxygenase system, the greatest increase being observed in the activity of 4-nitroanisole O-demethylase. Oxcarbazepine is as potent as carbamazepine, while 10,11-dihydro-10-hydroxy-carbamazepine is a weak inducer.

3. The observation that oxcarbazepine is a potent inducer in rats but not in man is explained by the species differences in its metabolism.     

A viewpoint on rational and irrational fixed-drug combinations

Introduction: Considering that there are around 30% of patients with epilepsy resistant to monotherapy, the use of synergistic combinations of antiepileptic drugs is of particular importance. This review shows most beneficial as well as irrational combined treatments both from an experimental and clinical point of view.

Areas covered: Preferably, experimental data derived from studies evaluating synergy, additivity, or antagonism by relevant methods, in terms of anticonvulsant or neurotoxic effects and pharmacokinetic data have been considered. Although there have been no randomized clinical trials on this issue, the clinical data have been analyzed from studies on considerable numbers of patients. Case-report studies have been not considered.

Expert commentary: The experimental data provide a strong support that co-administration of lamotrigine with carbamazepine is negative, considering the anticonvulsant and neurotoxic effects. Clinical reports do not entirely support this conclusion. Other experimentally documented negative combinations comprise lamotrigine+ oxcarbazepine and oxcarbazepine+ phenytoin. From the experimental and clinical point of view, a combination of lamotrigine+ valproate may deserve recommendation. Other most positive experimental and clinical combinations include carbamazepine+valproate, phenytoin+phenobarbital, carbamazepine+gabapentin, carbamazepine+topiramate, levetiracetam+valproate, levetiracetam+carbamazepine. Certainly, experimental data have some limitations (non-epileptic animals, acute administration of antiepileptic drugs) so all experimental recommendations need a careful clinical evaluation.     

Topiramate therapeutic monitoring in patients with epilepsy: effect of concomitant antiepileptic drugs

The authors assessed the effect of concomitant antiepileptic therapy on steady-state plasma concentrations of the new antiepileptic drug (AED) topiramate and the potential relation between topiramate plasma levels and side effects in a cohort of 116 patients with epilepsy. On the basis of concomitant AEDs, patients were divided into two subgroups, otherwise comparable for age and weight-adjusted daily dose of topiramate. Group A (n = 73) received topiramate plus AED inducers of cytochrome P450 (CYP) metabolism, such as carbamazepine, phenobarbital, and phenytoin. Group B (n = 43) received topiramate plus AEDs without inducing properties of CYP metabolism (namely valproic acid and lamotrigine). Weight-normalized topiramate clearance values, calculated as dosing rate/steady-state plasma drug concentration, were about 1.5-fold in patients receiving AED inducers compared with patients receiving AED noninducers. Topiramate plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 25 to 800 mg/d, although, at a given daily dose, a large interpatient variability was observed in matched plasma drug concentrations within each group of patients. Thirty-nine patients (34%) reported side effects associated with topiramate, mostly central nervous system effects. No consistent relation was observed between topiramate plasma concentrations and adverse effects, either in the cohort of patients as a whole or within each subgroup. From a clinical point of view, patients receiving concurrent treatment with enzyme-inducing AEDs can show twofold lower topiramate plasma concentrations compared with patients receiving valproic acid or lamotrigine, and appropriate topiramate dosage adjustments may be required when concomitant AED inducers are either added or withdrawn. Due to the observed variability in topiramate metabolic variables and the complex spectrum of possible pharmacokinetic and pharmacodynamic interactions with the most commonly coprescribed AEDs, monitoring of plasma topiramate concentrations may help the physician in the pharmacokinetic optimization of the drug dosage schedule in individual patients.     

奥卡西平和卡马西平治疗脑卒中后继发性癫痫疗效与安全性的Meta分析

目的 系统评价奥卡西平与卡马西平治疗脑卒中后继发性癫痫的疗效和安全性。方法 计算机检索PubMed、Cochrane Library、EMbase、万方、中国知网、维普、中国生物医学文献数据库（CBM）等收录的奥卡西平和卡马西平治疗脑卒中后继发性癫痫的相关文献,检索时限为建库以来到2017年8月,使用RevMan5.3软件进行Meta分析。结果 共纳入6项研究,包含517例患者。Meta分析结果显示：奥卡西平组控制癫痫的总体有效率高于卡马西平组,差异有统计学意义（RR=1.44,95%CI：1.29~1.60,P<0.000 01）;奥卡西平组总不良反应发生率低于卡马西平组,差异有统计学意义（RR=0.39,95%CI：0.26~0.57,P<0.000 01）;皮疹、头晕、嗜睡、恶心、呕吐发生率的比较差异均无统计学意义。结论 奥卡西平治疗脑卒中后继发性癫痫的疗效优于卡马西平,安全性较卡马西平好。由于本研究纳入的文献数量和样本量较少,因此还需更多大样本、多中心的高质量临床随机对照试验（randomized controlled trials,RCT）进一步研究验证。     

Sexual dysfunction related to antiepileptic drugs in patients with epilepsy

Introduction: Epilepsy is a common disease that is mostly treated with antiepileptic drugs (AEDs). However, the sexual dysfunction (SD) side effects related to the use of AEDs have not received sufficient attention.

Areas covered: The purpose of this review is to examine the current evidence on SD-related side effects of AEDs. The incidence, clinical features and major types of SD are summarized. Furthermore, various AEDs that may cause SDs are addressed in detail. Finally, we briefly summarize the treatments for SD related to AEDs.

Expert opinion: SD related to AEDs is common. Symptoms include erectile dysfunction (ED), hyposexuality, hypersexuality and ejaculatory dysfunction. Traditional AEDs such as valproate and enzyme-inducing AEDs (EIAEDs) may produce high incidences of decreased libido. Recently, sexual function changes related to new AEDs have been reported. Topiramate, pregabalin and gabapentin may cause SD, whereas oxcarbazepine, lamotrigine and levetiracetam may improve sexual function. Although the treatment for SD related to AEDs remains unclear, switching to another AED may be an option. Further studies are necessary to better understand and treat SD related to AEDs.     

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

1. 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.

2. 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.

3. 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.

     

Induction of microsomal enzymes in rat liver by oxcarbazepine, 10,11-dihydro-10-hydroxy-carbamazepine and carbamazepine

1. The effects of the new anti-epileptic drug, oxcarbazepine, its major metabolite in man, 10,11-dihydro-10-hydroxy-carbamazepine, and carbamazepine, on hepatic microsomal enzyme activities have been studied in rats after repeated administration of equimolar doses. 2. All three compounds caused a qualitatively similar induction of the mono-oxygenase system, the greatest increase being observed in the activity of 4-nitroanisole O-demethylase. Oxcarbazepine is as potent as carbamazepine, while 10,11-dihydro-10-hydroxy-carbamazepine is a weak inducer. 3. The observation that oxcarbazepine is a potent inducer in rats but not in man is explained by the species differences in its metabolism.     

Single centre 20 year survey of antiepileptic drug-induced hypersensitivity reactions

BackgroundEpilepsy is a chronic neurological disease which affects about 1% of the human population. There are 50 million patients in the world suffering from this disease and 2 million new cases per year are observed. The necessary treatment with antiepileptic drugs (AEDs) increases the risk of adverse reactions. In case of 15% of people receiving AEDs, cutaneous reactions, like maculopapular or erythematous pruritic rash, may appear within four weeks of initiating therapy with AEDs.MethodsThis study involved 300 epileptic patients in the period between September 1989 and September 2009. A cutaneous adverse reaction was defined as a diffuse rash, which had no other obvious reason than a drug effect, and resulted in contacting a physician.ResultsAmong 300 epileptic patients of Neurological Practice in Kielce (132 males and 168 females), a skin reaction to at least one AED was found in 30 patients. As much as 95% of the reactions occurred during therapies with carbamazepine, phenytoin, lamotrigine or oxcarbazepine. One of the patients developed Stevens-Johnson syndrome.ConclusionSome hypersensitivity problems of epileptic patients were obviously related to antiepileptic treatment. Among AEDs, gabapentin, topiramate, levetiracetam, vigabatrin, and phenobarbital were not associated with skin lesions, although the number o patients in the case of the latter was small.     

治疗癫痫新药醋酸艾司利卡西平研究进展

查阅国内外关于醋酸艾司利卡西平治疗癫痫的最新文献。文献结果表明,醋酸艾司利平口服吸收快、半衰期长、药物动力学呈线性,无明显的药物相互关系。与卡马西平、奥卡西平相比较,醋酸艾司利平治疗效果更加显著。     

应用群体药动学模型制订患儿抗癫痫给药方案的药学会诊实践

目的 为优化癫痫患儿卡马西平和丙戊酸给药方案提供参考。方法 药师参与1例脑外伤术后癫痫患儿的药学会诊,总结分析其使用卡马西平和丙戊酸血药浓度异常的原因,应用群体药动学模型为患儿调整给药剂量,并评价笔者团队所建模型的预测能力。结果 患儿病情得到了有效控制。结论 药师应用群体药动学模型优化抗癫痫药物治疗方案,为临床合理用药提供参考。     

Effectiveness and Tolerability of Carbamazepine vs. Oxcarbazepine as Mood Stabilizers

Abstract

Background.?Patients with bipolar illness or maniac-type schizoaffective disorder often present a variety of symptoms and mixed responses to treatment. Several anticonvulsants have been found effective in the treatment of mood disorders. In the early 70's, the clinical efficacy of carbamazepine in the treatment of acute mania was reported. Oxcarbazepine has been available in the United States since 2000. Both drugs display a different spectrum of properties and side effect profiles. Objective.?To compare the effectiveness and tolerability of carbamazepine and oxcarbazepine in a naturalistic setting. Methods.?A retrospective and concurrent chart review of all patients treated with carbamazepine or oxcarbazepine (n = 33) as mood stabilizers between 01 and 12 2002. The effectiveness was evaluated using the Positive And Negative Syndrome Scale (PANSS). Tolerability was assessed according to side effects recorded on charts. Patients with charts that were not complete were excluded from this study. Results.?There were no significant differences in efficacy between groups on positive (F = 3.575, P = 0.075), negative (F = 2.641, P = 0.121), or the general subscales (F = 1.111, P = 0.306) of the PANSS. Patients in both groups developed gastrointestinal upset and headache, but no significant differences in tolerability between the two therapies were found (χ² = 0.466, df = 1, P = 0.659) and (χ² = 0.195, df = 1, P = 0.367 respectively). Conclusion.?In summary, the patient charts reviewed demonstrated that carbamazepine, as well as, oxcarbazepine are equally effective and tolerable as mood stabilizers.     

New AMPA antagonists in epilepsy

Introduction: Epilepsy is a common neurological disorder; however, its therapy is not satisfactory because a large number of patients suffer from refractory seizures and/or has a low quality of life due to antiepileptic drug (AED) side effects. Glutamate is the major excitatory neurotransmitter in the brain, AMPA receptors (AMPARs) represent a validated target for AEDs' development. Evidences support their role during seizures and neurodegeneration. Development of AMPAR ligands has led to two different branches of research, with the identification of competitive and noncompetitive antagonists.

Areas covered: We herein describe the architecture of AMPAR and the main structure–activity relationships of antagonists. Finally, we report the effects of AMPAR antagonists in preclinical models and clinical trials in epileptic patients. We reviewed the most relevant research in the field, focusing on research advances for the oldest AMPA antagonists and the new most promising molecules identified.

Expert opinion: Overall, the development of AMPAR antagonists confirms their great clinical potential; their arrival to clinical practice has been slowed down by their unfavorable pharmacokinetic profile and tolerability; however, their clinical use might be justified by their efficacy and the new drugs developed such as perampanel have been greatly ameliorated from both points of view.     

Oxcarbazepine induced toxic epidermal necrolysis - a rare case report

Carbamazepine, is well known to cause Stevens–Johnson syndrome and toxic epidermal necrolysis(TEN). Oxcarbazepine, a 10-keto analog of carbamazepine, is an anticholinergic, anticonvulsant and mood stabilizing drug, used primarily in the treatment of epilepsy. Its efficacy is similar to carbamazepine but allergic reactions and enzyme induction is low. We describe a case of oxcarbazepine induced TEN, who presented with erythematous ulcerative maculopapular rash.KEY WORDS: Carbamazepine, oxcarbazepine, Stevens–Johnson syndrome, toxic epidermal necrolysis     

A state of art review on vardenafil in men with erectile dysfunction and associated underlying diseases

Introduction: Erectile dysfunction (ED) is a common male sexual disorder among men. Many governing bodies advocate the use of oral PDE5 inhibitors as a first-line therapy for ED. The clinical efficacy of these PDE5 inhibitors has been demonstrated in a number of placebo-controlled trials and reported by many systematic reviews on the effectiveness of PDE5 inhibitors in restoring the erectile function and improved frequency of successful sexual intercourse attempts across different spectra of underlying diseases.

Areas covered: This review article examines the drug profile of vardenafil and its role in restoring erectile function; highlights a number of clinical trials on vardenafil in men with underlying cardiovascular and metabolic conditions as well as in post-radical prostatectomy cases; and addresses the efficacy of vardenafil in comparison with other PDE5 inhibitors.

Expert opinion: Given the multi-factorial nature of ED, a holistic approach should be taken when dealing with ED patients. There is a need for long-term surveillance and management of underlying medical conditions, and despite the strict adherence to all the necessary steps to maximize its efficacy, PDE5 inhibitors could still fail due to the potential drug intolerance, progression of underlying disease or development of medical conditions.     

Avanafil for the treatment of erectile dysfunction

Introduction: Erectile dysfunction (ED) affects millions of men worldwide, and the incidence of ED will continue to increase as the aging population grows. The first generation of phosphodiesterase-5 (PDE5) inhibitors, the mainstay of oral ED therapy, has revolutionized the treatment of this condition, but not without some drawbacks. Avanafil, the only United States and European Union-approved second-generation PDE5 inhibitor, is a safe and efficacious alternative to its predecessors.

Areas covered: We reviewed the current and most up-to-date literature regarding Avanafil, as well as the pivotal trials that measured efficacy and tolerability. As Avanafil is still a relatively new drug, there is still a relative paucity of literature which inherently limited the search parameters. We searched the PUBMED database for articles detailing the clinical trials, chemistry, pharmacokinetics and dynamics, safety, and efficacy of the drug.

Expert commentary: Avanafil’s unique pharmacologic profile both narrows and minimizes side effects while reducing the time of onset of action to half of its closest competitor, providing men who suffer with ED a return to a more spontaneous sex life.