Emerging drugs for epilepsy

Epilepsy affects ≤ 1% of the world's population. Antiepileptic drugs (AEDs) are the mainstay of treatment, although more than a third of patients are not rendered seizure free with existing medications. Uncontrolled epilepsy is associated with increased mortality and physical injuries, and a range of psychosocial morbidities, posing a substantial economic burden on individuals and society. Limitations of the present AEDs include suboptimal efficacy and their association with a host of adverse reactions. Continued efforts are being made in drug development to overcome these shortcomings employing a range of strategies, including modification of the structure of existing drugs, targeting novel molecular substrates and non-mechanism-based drug screening of compounds in traditional and newer animal models. This article reviews the need for new treatments and discusses some of the emerging compounds that have entered clinical development. The ultimate goal is to develop novel agents that can prevent the occurrence of seizures and the progression of epilepsy in at risk individuals.     

New anti-epileptic drugs

Epilepsy represents the most common serious neurological disorder, with a prevalence of 0.4 - 1%. Approximately 30% of patients are resistant to currently available drugs. New anti-epileptic drugs are needed to treat refractory epilepsy, improve upon current therapies, improve the prognosis of epilepsy and to prevent the epileptogenic process. Designing compounds with specific physiological targets would seem the most rational method of anti-epileptic drug development, but results from this approach have been disappointing; the widespread screening of compounds in animal models has been much more fruitful. Older methods of animal screening have used acute seizure models, which bear scant relationship to the human condition. More modern methods have included the development of animal models of chronic epilepsy; although more expensive, it is likely that these models will be more sensitive and more specific in determining anti-epileptic efficacy. In this review, we consider the possible physiological targets for anti-epileptic drugs, the animal models of epilepsy, problems with clinical trials and ten promising anti-epileptic drugs in development (AWD 131-138, DP16 (DP-VPA), ganaxolone, levetiracetam, losigamone, pregabalin, remacemide, retigabine, rufinamide and soretolide). Perhaps the most important advances will come about from the realisation that epilepsy is a symptom, not a disease. Preclinical testing should be used to determine the spectrum of epilepsies that a drug can treat, and to direct later clinical trials, which need to select patients based on carefully defined epilepsy syndromes and aetiologies. Not only will such an approach improve the sensitivity of clinical trials, but also will lead to a more rational basis on which to treat.     

Basic mechanisms of antiepileptic drugs and their pharmacokinetic/pharmacodynamic interactions: an update

This article aims to summarize the current views of AED action and the promising new targets for the pharmacotherapy of epilepsy. In the first section of this paper, a neurobiological basis of epilepsy treatment and brief pharmacological characteristics of classical and new AEDs will be presented. In the second part, the results of experimental studies that have combined AEDs with similar or different mechanisms of action will be discussed.     

An assessment of rufinamide as an anti-epileptic in comparison with other drugs in clinical development

This article evaluates rufinamide, a new anti-epileptic drug (AED) in Phase III development. This review is done against the background of therapeutic challenges of epilepsy, old established AEDs, newly introduced AEDs and AEDs in clinical development. Pharmacological properties of 12 AEDs in clinical trials (Phases I - III) are compared: ADCI, AWD 131-138, DP-VPA, ganaxolone, levetiracetam, losigamone, pregabalin, remacemide hydrochloride, retigabine, rufinamide, soretolide and TV1901. One of these, levetiracetam has been approved in the USA and is waiting approval in other countries. The protective index of rufinamide, as shown in rodent models of epilepsy, is much higher than that of most common AEDs. Features which make it a desirable AED are: (i) a broad spectrum of anti-epileptic actions including both partial and symptomatic generalised epilepsy; (ii) a statistically significant reduction in seizure frequency in clinical trials; (iii) efficacy and safety shown in a broad range of age groups including children and the elderly; (iv) rapid oral absorption enabling quick titration to effective dose and (v) a benign adverse event profile. Most of the events did not lead to discontinuation in clinical trials. These features offer considerable advantages over the existing anti-epileptic drugs. It is one of the two drugs in development which have reached Phase III and is expected to be approved by the year 2001 - 2002.     

Pharmacotherapy of the third-generation AEDs: lacosamide,retigabine and eslicarbazepine acetate

Introduction: The search for new, more effective antiepileptic drugs (AEDs) continues. The three most recently approved drugs, the so-called third-generation AEDs, include lacosamide, retigabine and eslicarbazepine acetate and are licensed as adjunctive treatment of partial epilepsy in adults.

Areas covered: For the above three AEDs, their mechanisms of action, pharmacokinetic characteristics, drug–drug interactions, pharmacotherapeutics, dose and administration and therapeutic drug monitoring are reviewed in this paper.

Expert opinion: Lacosamide and retigabine act through novel mechanisms, while eslicarbazepine acetate, a pro-drug for eslicarbazepine, acts in a similar manner to several other AEDs. All three AEDs are associated with linear pharmacokinetic and rapid absorption and undergo metabolism. Their drug–drug interaction profile is low (lacosamide and retigabine) to modest (eslicarbazepine) in propensity. At the highest approved doses for the three AEDs, responder rates were similar. The most commonly observed adverse effects compared with placebo were dizziness, headache, diplopia and nausea for lacosamide; dizziness, somnolence and fatigue for retigabine and dizziness and somnolence for eslicarbazepine acetate. The precise role that these new AEDs will have in the treatment of epilepsy and whether they will make a significant impact on the prognosis of intractable epilepsy is not yet known and will have to await further clinical experience.     

Influence of agmatine on the protective action of numerous antiepileptic drugs against pentetrazole-induced seizures in miceA

The aim of this study was to assess the influence of agmatine (an endogenous neuromodulator/neurotransmitter in the brain) on the protective action of numerous classical and second-generation antiepileptic drugs (clonazepam, ethosuximide, gabapentin, phenobarbital, tiagabine, vigabatrin, and valproate) in the mouse pentetrazole-induced clonic seizure model.The results indicate that agmatine (up to 100 mg/kg, ip, 45 min before the test) did not alter the threshold for pentetrazole-induced clonic seizures in mice. However, agmatine (100 mg/kg, ip) significantly attenuated the anticonvulsant effects of vigabatrin against pentetrazole-induced clonic seizures by elevating the ED₅₀ value of vigabatrin from 517.5 to 790.3 mg/kg (p < 0.01). In contrast, agmatine at a dose of 50 mg/kg did not significantly affect the anticonvulsant action of vigabatrin, although a reduction in the ED₅₀ value of the antiepileptic drug from 517.5 to 629.1 mg/kg was documented. Moreover, agmatine at doses of 50 and 100 mg/kg (ip) had no significant impact on the anticonvulsant action of clonazepam, ethosuximide, gabapentin, phenobarbital, tiagabine, or valproate in pentetrazole-induced seizures in mice.In conclusion, the combination of agmatine with vigabatrin seems to be unfavorable due to the reduction of the anticonvulsant effect of vigabatrin after concomitant administration of agmatine in the pentetrazole-induced seizure model. Therefore, the utmost caution is advised when combining agmatine with vigabatrin in further clinical settings.     

Assessment of drug–drug interactions between moxonidine and antiepileptic drugs in the maximal electroshock seizure test in mice

Hypertension is a common comorbid condition with epilepsy, and drug interactions between antihypertensive and antiepileptic drugs (AEDs) are likely in patients. Experimental studies showed that centrally active imidazoline compounds belonging to antihypertensive drugs can affect seizure susceptibility. The purpose of this study was to assess the effect of moxonidine, an I₁-imidazoline receptor agonist, on the anticonvulsant efficacy of numerous AEDs (carbamazepine, phenobarbital, valproate, phenytoin, oxcarbazepine, topiramate and lamotrigine) in the mouse model of maximal electroshock. Besides, the combinations of moxonidine and AEDs were investigated for adverse effects in the passive avoidance task and the chimney test. Drugs were administered intraperitoneally (ip). Moxonidine at doses of 1 and 2 mg/kg ip did not affect the convulsive threshold. Among tested AEDs, moxonidine (2 mg/kg) potentiated the protective effect of valproate against maximal electroshock. This interaction could be pharmacodynamic because the brain concentration of valproate was not significantly changed by moxonidine. The antihypertensive drug did not cause adverse effects when combined with AEDs. This study shows that moxonidine may have a neutral or positive effect on the anticonvulsant activity of AEDs in patients with epilepsy. The enhancement of the anticonvulsant action of valproate by moxonidine needs further investigations to elucidate potential mechanisms involved.     

格列奈类药物的药动学及与其他药物的相互作用

格列奈类药物吸收迅速,t_(1/2)短,单一疗法耐受性良好,不良反应发生率低于磺脲类药物,但与其他药物联用时,可能发生与CYP3A4、CYP2C8及CYP2C9同工酶和有机阴离子转运多肽1B1(OATP1B1)转运体相关的药动学相互作用,从而降低药物疗效或增加低血糖等不良事件的风险。本文就格列奈类药物的药动学性质及与其他药物的药动学相互作用作一综述。     

新型抗癫痫药之间及其与传统抗癫痫药的相互作用和机制*

分别综述了几种新型抗癫痫药（托吡酯、非氨酯、奥卡西平、拉莫三嗪、唑尼沙胺、左乙拉西坦、噻加宾、加巴喷丁及氨己烯酸）与传统抗癫痫药联合应用时以及这些新型抗癫痫药之间的相互作用及其发生机制，阐明细胞色素P450酶和葡萄糖苷酸转移酶在新型抗癫痫药的相互作用中的意义及重要性。为临床合理联合应用提供理论依据，提高抗癫痫治疗的可靠性、安全性和有效性。     

Influence of cholestyramine on the pharmacokinetics of rosiglitazone and its metabolite,desmethylrosiglitazone, after oral and intravenous dosing of rosiglitazone: Impact on oral bioavailability,absorption, and metabolic disposition in rats

The possible influence of the bile acid-sequestering agent cholestyramine (CSA), which is a basic co-medication in hypercholesterolemic patients, on the pharmacokinetics of rosiglitazone (RGL) and its circulating metabolite desmethylrosiglitazone (DMRGL) was investigated following a single oral and intravenous dose of RGL to Wistar rats. The pharmacokinetic parameters of RGL and DMRGL were evaluated following oral or intravenous administration of RGL to rats at 10?mg?kg^?1 with and without pre-treatment (0.5?h before RGL administration) of CSA at 0.057, 0.115, 0.23 and 0.34?g?kg^?1 doses. With an increase in CSA dose there was dose-dependent decrease in area under the curve (AUC)_(0?∞) and C_max with no change in T_max, K_el and t_1/2 values for both RGL and DMRGL following oral administration of RGL. The oral bioavailability of RGL was reduced by 19.9, 35.6, 53.8 and 72.0% in rats following pre-treatment with CSA at 0.057, 0.115, 0.230 and 0.340?g?kg^?1, respectively. There was no change in the above-mentioned pharmacokinetic parameters for RGL and DMRGL in rats when RGL was given intravenously following pre-treatment with the above-mentioned oral doses of CSA. Another objective of the study was to determine the effect of staggered oral CSA dosing at 1, 2 and 4?h after oral RGL administration at 10?mg?kg^?1. AUC_(0?∞) of RGL and DMRGL was reduced following CSA staggered administration at 1?h, whereas 2- and 4-h staggered dose administration of CSA had no effect on the AUC_(0?∞) of RGL and DMRGL. Irrespective of CSA staggered dose administration there was no change in other pharmacokinetic parameters, namely C_max, T_max, K_el and t_1/2. The apparent formation rate constant (K_f) of DMRGL was also calculated to show that only the absorption of RGL was affected, not the apparent formation rate of DMRGL. The authors also studied the in vitro adsorption of RGL (100, 250, 500?µg?ml^?1) at various pH conditions (pH 2, 4 and 7) and different concentrations of CSA (15, 30, 60 and 120?mg?ml^?1). The percentage binding of CSA was in the range 50–72% (at pH 2), 74–89% (at pH 4) and 97–100% (at pH 7). In conclusion, we carried out a systematic investigation demonstrating mechanistically the interaction potential of RGL when co-administered with CSA. The applicability of the metabolite data after intravenous and oral dosing and pH-based binding experiments further adds credence to the key findings.     

Influence of β-adrenoceptor antagonists on the pharmacokinetics of rizatriptan, a 5-HT1B/1D agonist: differential effects of propranolol, nadolol and metoprolol

AIMS: Patients with migraine may receive the 5-HT1B/1D agonist, rizatriptan (5 or 10 mg), to control acute attacks. Patients with frequent attacks may also receive propranolol or other beta-adrenoceptor antagonists for migraine prophylaxis. The present studies investigated the potential for pharmacokinetic or pharmacodynamic interaction between beta-adrenoceptor blockers and rizatriptan. METHODS: Four double-blind, placebo-controlled, randomized crossover investigations were performed in a total of 51 healthy subjects. A single 10 mg dose of rizatriptan was administered after 7 days' administration of propranolol (60 and 120 mg twice daily), nadolol (80 mg twice daily), metoprolol (100 mg twice daily) or placebo. Rizatriptan pharmacokinetics were assessed. In vitro incubations of rizatriptan and sumatriptan with various beta-adrenoceptor blockers were performed in human S9 fraction. Production of the indole-acetic acid-MAO-A metabolite of each triptan was measured. RESULTS: Administration of rizatriptan during propranolol treatment (120 mg twice daily for 7.5 days) increased the AUC(0, infinity) for rizatriptan by approximately 67% and the Cmax by approximately 75%. A reduction in the dose of propranolol (60 mg twice daily) and/or the incorporation of a delay (1 or 2 h) between propranolol and rizatriptan administration did not produce a statistically significant change in the effect of propranolol on rizatriptan pharmacokinetics. Administration of rizatriptan together with nadolol (80 mg twice daily) or metoprolol (100 mg twice daily) for 7 days did not significantly alter the pharmacokinetics of rizatriptan. No untoward adverse experiences attributable to the pharmacokinetic interaction between propranolol and rizatriptan were observed, and no subjects developed serious clinical, laboratory, or other significant adverse experiences during coadministration of rizatriptan with any of the beta-adrenoceptor blockers. In vitro incubations showed that propranolol, but not other beta-adrenoceptor blockers significantly inhibited the production of the indole-acetic acid metabolite of rizatriptan and sumatriptan. CONCLUSIONS: These results suggest that propranolol increases plasma concentrations of rizatriptan by inhibiting monoamine oxidase-A. When prescribing rizatriptan to migraine patients receiving propranolol for prophylaxis, the 5 mg dose of rizatriptan is recommended. Administration with other beta-adrenoceptor blockers does not require consideration of a dose adjustment.     

Acyl glucuronides: the good,the bad and the ugly

Acyl glucuronidation is the major metabolic conjugation reaction of most carboxylic acid drugs in mammals. The physiological consequences of this biotransformation have been investigated incompletely but include effects on drug metabolism, protein binding, distribution and clearance that impact upon pharmacological and toxicological outcomes. In marked contrast, the exceptional but widely disparate chemical reactivity of acyl glucuronides has attracted far greater attention. Specifically, the complex transacylation and glycation reactions with proteins have provoked much inconclusive debate over the safety of drugs metabolised to acyl glucuronides. It has been hypothesised that these covalent modifications could initiate idiosyncratic adverse drug reactions. However, despite a large body of in vitro data on the reactions of acyl glucuronides with protein, evidence for adduct formation from acyl glucuronides in vivo is limited and potentially ambiguous. The causal connection of protein adduction to adverse drug reactions remains uncertain. This review has assessed the intrinsic reactivity, metabolic stability and pharmacokinetic properties of acyl glucuronides in the context of physiological, pharmacological and toxicological perspectives. Although numerous experiments have characterised the reactions of acyl glucuronides with proteins, these might be attenuated substantially in vivo by rapid clearance of the conjugates. Consequently, to delineate a relationship between acyl glucuronide formation and toxicological phenomena, detailed pharmacokinetic analysis of systemic exposure to the acyl glucuronide should be undertaken adjacent to determining protein adduct concentrations in vivo. Further investigation is required to ascertain whether acyl glucuronide clearance is sufficient to prevent covalent modification of endogenous proteins and consequentially a potential immunological response. Copyright © 2010 John Wiley & Sons, Ltd.     

Influence of green and black tea on folic acid pharmacokinetics in healthy volunteers: potential risk of diminished folic acid bioavailability

Previous in vitro studies using Caco-2 cell monolayers suggested a possible interaction between green and black tea and folic acid at the level of intestinal absorption. The main purpose of the present study was to investigate a possible pharmacokinetic interaction between tea and folic acid in healthy volunteers. In an open-labeled randomized cross-over study, the pharmacokinetic interaction between tea and folic acid (0.4 mg and 5 mg) was investigated in healthy volunteers. Water was used as the reference drink. Subjects ingested 0.4 mg folic acid tablets with water, green or black tea (0.3 g extract/250 ml) or 5 mg folic acid tablets with water or green tea (0.3 g extract/250 ml). Blood samples were collected over a period of 8 h. Serum folate analysis was carried out by a competitive immunoassay which uses direct chemiluminescent technology. At the 0.4 mg folic acid dose, green and black tea reduced the mean C(max) of serum folate by 39.2% and 38.6%, and the mean AUC(0 --> infinity) by 26.6% and 17.9%, respectively. At the 5 mg folic acid dose, the mean C(max) of serum folate was reduced by 27.4% and the mean AUC(0 --> infinity) was decreased significantly by 39.9% by the co-application of green tea. The present results suggest an in vivo interaction between tea and folic acid with even low concentrations of green and black tea extracts yielding decreased bioavailabilities of folic acid. Copyright (c) 2008 John Wiley & Sons, Ltd.     

Multidrug resistance (MDR) in cancer: Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs

In recent years, there has been an increased understanding of P-glycoprotein (P-GP)-mediated pharmacokinetic interactions. In addition, its role in modifying the bioavailability of orally administered drugs via induction or inhibition has been also been demonstrated in various studies. This overview presents a background on some of the commonly documented mechanisms of multidrug resistance (MDR), reversal using modulators of MDR, followed by a discussion on the functional aspects of P-GP in the context of the pharmacokinetic interactions when multiple agents are coadministered. While adverse pharmacokinetic interactions have been documented with first and second generation MDR modulators, certain newer agents of the third generation class of compounds have been less susceptible in eliciting pharmacokinetic interactions. Although the review focuses on P-GP and the pharmacology of MDR reversal using MDR modulators, relevance of these drug transport proteins in the context of pharmacokinetic implications (drug absorption, distribution, clearance, and interactions) will also be discussed.     

In vitro evaluation of the effects of anti‐fungals,benzodiazepines and non‐steroidal anti‐inflammatory drugs on the glucuronidation of 19‐norandrosterone: implications on doping control analysis

We have studied whether the phase II metabolism of 19‐norandrosterone, the most representative metabolite of 19‐nortestosterone (nandrolone), can be altered in the presence of other drugs that are not presently included on the Prohibited List of the World Anti‐Doping Agency. In detail, we have evaluated the effect of non‐prohibited drugs belonging to the classes of anti‐fungals, benzodiazepines, and non‐steroidal anti‐inflammatory drugs on the glucuronidation of 19‐norandrosterone. In vitro assays based on the use of either pooled human liver microsomes or specific recombinant isoforms of uridine diphosphoglucuronosyl‐transferase were designed and performed to monitor the formation of 19‐norandrosterone glucuronide from 19‐norandrosterone. Determination of 19‐norandrosterone (free and conjugated fraction) was performed by gas chromatography – mass spectrometry after sample pretreatment consisting of an enzymatic hydrolysis (performed only for the conjugated fraction), liquid/liquid extraction with tert‐butylmethyl ether, and derivatization to form the trimethylsilyl derivative. In parallel, a method based on reversed‐phase liquid chromatography coupled to tandem mass spectrometry in positive electrospray ionization with acquisition in selected reaction monitoring mode was also developed to identify the non‐prohibited drugs considered in this study. Incubation experiments have preliminarily shown that the glucuronidation of 19‐norandrosterone is principally carried out by UGT2B7 (39%) and UGT2B17 (31%). Inhibition studies have shown that the yield of the glucuronidation reaction is reduced in the presence of the anti‐fungals itraconazole, ketoconazole, and miconazole, of the benzodiazepine triazolam and of the non‐steroidal anti‐inflammatory drugs diclofenac and ibuprofen, while no alteration was recorded in the presence of all other compounds considered in this study. Copyright © 2015 John Wiley & Sons, Ltd.     

Physiologically based pharmacokinetic modeling to predict complex drug–drug interactions: a case study of AZD2327 and its metabolite,competitive and time‐dependent CYP3A inhibitors

4‐{(R)‐(3‐Aminophenyl)[4‐(4‐fluorobenzyl)‐piperazin‐1‐yl]methyl}‐N,N‐diethylbenzamide (AZD2327) is a highly potent and selective agonist of the δ ‐opioid receptor. AZD2327 and N‐deethylated AZD2327 (M1) are substrates of cytochrome P450 3A (CYP3A4) and comprise a complex multiple inhibitory system that causes competitive and time‐dependent inhibition of CYP3A4. The aim of the current work was to develop a physiologically based pharmacokinetic (PBPK) model to predict quantitatively the magnitude of CYP3A4 mediated drug–drug interaction with midazolam as the substrate. Integrating in silico, in vitro and in vivo PK data, a PBPK model was successfully developed to simulate the clinical accumulation of AZD2327 and its primary metabolite. The inhibition of CYP3A4 by AZD2327, using midazolam as a probe drug, was reasonably predicted. The predicted maximum concentration (C_max) and area under the concentration–time curve (AUC) for midazolam were increased by 1.75 and 2.45‐fold, respectively, after multiple dosing of AZD2327, indicating no or low risk for clinically relevant drug–drug interactions (DDI). These results are in agreement with those obtained in a clinical trial with a 1.4 and 1.5‐fold increase in C_max and AUC of midazolam, respectively. In conclusion, this model simulated DDI with less than a two‐fold error, indicating that complex clinical DDI associated with multiple mechanisms, pathways and inhibitors (parent and metabolite) can be predicted using a well‐developed PBPK model. Copyright © 2015 John Wiley & Sons, Ltd.     

5-HT receptors as targets for the development of novel anxiolytic drugs: models,mechanisms and future directions

The introduction of buspirone for the treatment of anxiety, together with the eventual suggestion of a mode of action involving the serotonin (5-HT)_1A receptor subtype, has generated considerable research activity and renewed interest in the potential role of 5-HT in anxiety. The further identification of multiple 5-HT₁ receptors, coupled with the possibility that these subtypes potentially are involved in discrete biobehavioral regulation and pathophysiological conditions, has greatly expanded the search for tools capable of probing these receptors and has raised hopes for a new generation of more specific compounds to treat other disorders associated with the 5-HT system such as depression, aggression, and sleep and eating disturbances. The involvement of 5-HT in anxiety has prompted a careful reevaluation of several traditional areas of research. This has included those methods used in the in vivo evaluation of drugs in preclinical animal test procedures used to assess potential anxiolytic activity, as well as the mechanisms associated with adaptive changes occurring during long-term drug administration. The proliferation of various procedures for studying the anxiolytic effects of 5-HT drugs has not always been accompanied by systematic behavioral and pharmacological validation. At the present time, this area of research is characterized by numerous inconsistent findings. Procedures that are objective and impartial to the behavioral effects of drugs provide distinct advantages for addressing some of these issues, as will the results from carefully controlled clinical studies. The main objective of this article is to provide an overview of the recent developments in research involving the 5-HT system and anxiety. The emphasis will be on the 5-HT₁ receptor system and a review of the results in the predominant animal models used to evaluate these drugs, as well as an overview of the mechanisms currently believed to be responsible for the therapeutic activity of this class of compounds. Studies with the pigeon are reviewed, since this species appears distinctly sensitive to the anxiolytic-like effects of 5-HT_1A drugs in conflict procedures. Although chronic administration of 5-HT_1A drugs appears necessary for clinical anxiolytic and antidepressant activity, the most noteworthy neuropharmacological effects in animals seem to occur in 5-HT₂ and, perhaps, 5-HT₃ receptors which are downregulated. Studies summarizing the activity of drugs interacting with 5-HT_1C/2 and 5-HT₃ receptor sites are also discussed as they too may be involved in anxiety or the actions of anxiolytic drugs. The growing evidence suggesting an interaction between 5-HT receptor types, particularly between 5-HT_1A and 5-HT_1C/2 receptors, is reviewed, since drugs with these combined properties appear to be particularly efficacious in animal models of anxiety and warrant further detailed analyses. The development of drugs targeted specifically at multiple receptors may provide distinct therapeutic advantages for disorders such as anxiety and depression that appear to involve multiple neurotransmitter systems.