抗惊厥新药氟桂利嗪,磷苯妥英,咪太唑仑和司替戊醇

重点介绍进入临床研究阶段的４个新抗癫痫药。氟桂利嗪为选择性钙通道拮抗剂，是一种长效抗惊厥药，对复杂性部分性癫痫发作的效果与苯妥英和卡马产类似、磷苯妥英在体内迅速转变为苯妥英，注射剂型较苯妥英的水溶性好，且无静注剂激症状；咪达唑仑为水溶性苯二氮类药物，其镇静、肌松、对脑电描记测量的影响均强于地西泮（安定），对顽固性癫痫持续状态有效；司替戊醇有抗惊厥和抑制细胞色素Ｐ４５０的作用，故明显其它抗惊厥药物的     

抗惊厥新药氟桂利嗪、磷苯妥英、咪达唑仑和司替戊醇

重点介绍进入临床研究阶段的4个新抗癫痫药。氟桂利嗪为选择性钙通道拮抗剂，是一种长效抗惊厥药，对复杂性部分性癫痫发作的效果与苯妥美和卡马西平类似；磷苯妥美在体内迅速转变为苯妥英，注射剂型轻苯妥英的水溶性好，且无静注刺激症状；咪达唑仑为水溶性苯二氮类药物，其镇静、肌松、对脑电描记测量的影响均强于地西泮（安定），对顽固性癫痫持续状态有效；司替戊醇有抗惊厥和抑制细胞色素P450的作用，故明显影响其它机惊厥药物的代谢。该药已在患局部性癫痫、顽固性癫痫和顽固性无惊厥的癫痫病人上显示一些疗效。     

瑞替加滨的合成

对硝基苯胺经酰化、硝基还原、氨基保护、硝化、氨基脱保护,与对氟苯甲醛缩合得到N-[2-硝基-4-(4-氟苯亚甲胺基)苯基]氨基甲酸乙酯,再用Pd/C催化氢化同时还原硝基和亚胺得到抗癫痫药瑞替加滨,总收率约44％.     

卡马西平、拉莫三嗪和司替戊醇对丙戊酸及其代谢物血浆浓度的影响

目的 研究卡马西平、拉莫三嗪和司替戊醇对丙戊酸及其代谢物血浆浓度的影响.方法 24只SD雄性大鼠随机分成4组,每组6只.第1组灌胃给予200 mg·kg-1丙戊酸,第2组灌胃给予200 mg·kg-1丙戊酸+50 mg·kg-1卡马西平,第3组灌胃给予200 mg·kg-1丙戊酸+10 mg·kg-1拉莫三嗪,第4组灌...     

伊布替尼的合成

4-硝基嘧啶(2)与N-氯代丁二酰亚胺反应得4-氯-6-硝基嘧啶(3);3与水合肼(4)经亲核取代得4-肼基-6-硝基嘧啶盐酸盐(5).4-苯氧基苯甲醛(6)在N,N-二甲基甲酰胺中与亚硫酸氢钠硫化加成,与5回流反应得4-硝基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶(7);7经硝基还原得4-氨基-3-(...     

质子泵抑制剂与细胞色素P450的关系

质子泵抑制剂(PPI)被公认为是治疗酸相关性疾病(如消化性溃疡,胃食管反流性疾病(GERD),Zolling-Ellison综合征等)的最有效药物.自从1988年第1个PPI-奥美拉唑问世以来,相继出现了兰索拉唑、泮托拉唑、雷贝拉唑、埃索美拉唑[1].PPI特异性作用于H ,K -ATP酶,在胃酸分泌的最终环节抑制质子泵的功能,达到高效抑酸的目的.但不同的PPI的药动学不尽相同.PPI在肝脏被充分的生物转化并不同程度地被各种细胞色素P-450(CYP450)同工酶代谢.参与PPIs代谢的细胞色素P450同工酶主要包括CYP2C19和CYP3A4[2,3].在不同个体和种族间存在CYP2C19基因多态性.CYP2C19基因多态性是影响PPI代谢和临床效果的一个关键因素.     

司帕沙星对戊巴比妥钠催眠作用的影响

以戊巴比妥钠 (PBS)催眠时间作为细胞色素 P4 5 0 (CYP)体内活性指标 ,观察司帕沙星 (SPX)对小鼠 CYP的影响。结果 SPX单次给药 (5 0 ,10 0 mg·kg-1,ig) 1h后 ,使 PBS催眠时间显著延长 ,但延长程度小于西米替丁组。SPX连续给药 5 d (5 0 ,10 0 mg· kg-1·d-1,ig) ,在末次给药 36 h后 ,则见 PBS催眠时间缩短 ,但缩短程度小于苯巴比妥组。提示 SPX单次给药后可能抑制 CYP,但连续给药对 CYP有诱导作用。     

司替戊醇及其自纳米乳在大鼠血浆和脑组织中的药物浓度比较

目的:建立测定大鼠血浆和脑组织中司替戊醇(STP)质量浓度的方法,并比较STP及其自纳米乳在血浆、脑组织中的药物浓度.方法:以占吨酮为内标,采用高效液相色谱-荧光检测法(HPLC-FLR)测定.色谱柱为Diamonsil C18,流动相为乙腈-25 mmol/L KH2PO4水溶液[44:56(V/V),pH 2.6]...     

他克莫司给药后个体代谢差异与CYP3A基因型的相关性研究进展

他克莫司是近年来兴起的临床常用抗生素类免疫抑制剂,对于接受器官移植的患者具有明显的免疫抑制改善作用。他克莫司体内代谢个体差异较大,治疗窗和安全范围小,有研究表明可能由于编码细胞色素P450酶系基因的相关作用导致他克莫司药物代谢动力学个体间变异。本文通过总结最新研究内容,对影响他克莫司代谢的相关基因进行概述。     

Stiripentol

Stiripentol (STP) is a new antiepileptic compound produced by Biocodex. It is not structurally related to any of the other currently marketed antiepileptic products as it belongs to the group of aromatic allylic alcohols. It has recently been proved to increase GABAergic transmission in experimental models. It has been studied and used in France and Canada for > 10 years, but its clinical development was delayed due to the inhibitory effect of STP on hepatic cytochrome P450 (CYP). Clinical studies were based on the fact that STP also acts as an inhibitor of CYP3A4, CYP1A2 and CYP2C19 in vivo in epileptic patients. Although the studies in adult patients were disappointing, the trials conducted in paediatric populations demonstrated a specific efficacy of STP in a severe form of early childhood epilepsy, Dravet syndrome (severe myoclonic epilepsy in infancy), when combined with valproate and clobazam. Based on these results, STP was granted orphan drug status in the European Union for the treatment of Dravet syndrome. The French experience in compassionate use suggests that STP might also be of benefit when combined with carbamazepine in paediatric patients with pharmacoresistant partial epilepsy. Nevertheless, two controlled adjunctive-therapy trials were recently completed in paediatric populations with epilepsy. The interactions of STP with a large number of drugs need to be carefully taken into account by adjusting the doses of the combined antiepileptic drugs in order to improve the tolerability of the therapeutic association.     

Protective effect of stiripentol on acetaminophen-induced hepatotoxicity in rat

Acetaminophen (APAP) is mainly eliminated at a therapeutic dose through glucuronidation and sulfatation and a small fraction is oxidized by cytochromes P450 (CYP) 2E1, 3A4, and 1A2 to N-acetyl-p-benzoquinone-imine (NAPQI), a highly reactive metabolite further conjugated with glutathione into APAP-GSH, and then metabolized to APAP-cystein and APAP-mercapturate excreted in urine. After APAP overdose, the glucuronidation and sulfatation pathways are saturated and the production of NAPQI increases, causing hepatic injury. Stiripentol (STP); (200 mg/kg), an anticonvulsant drug inhibitor of CYP1A2 and CYP3A4 in vivo in humans was tested against APAP-induced toxicity in rat in comparison with N-acetylcysteine (NAC; 100 mg/kg). The mortality rates 24 h after APAP overdose (2 x 500 mg/kg) were 63% (control), 38% (NAC), 0% (STP), and 4% (STP + NAC). The mean plasma transaminase concentrations 5 and 24 h after overdose were significantly higher in control than in STP and NAC groups. The percentage of rats without microscopic liver necrosis 5 h after APAP overdose was significantly higher in rats receiving STP (100%), NAC (83%), or STP + NAC (83%) than controls (42%). In another experiment, four similar groups were administered 50 mg/kg APAP. Plasma AUC(0-5 h) for APAP-GSH, APAP-cystein, and APAP-mercapturate as well as urine APAP-mercapturate mean amounts were significantly lower in STP animals than in the other groups. STP (200 mg/kg) inhibited NAPQI synthesis through CYP inhibition, thus preventing both liver necrosis and mortality in rats.     

Stiripentol for the treatment of seizures in Dravet syndrome

Introduction: Dravet syndrome is an early childhood-onset epilepsy syndrome characterized by drug-resistant seizures, frequent episodes of status epilepticus, and the development of neurocognitive impairment. Seizure freedom in this condition is rare and there is a higher rate of sudden unexplained death in epilepsy patients (SUDEP) than other epilepsy syndromes. Stiripentol is a recently approved medication with an indication specifically for the treatment of seizures in children with Dravet syndrome.

Areas covered: Review of relevant literature including the current and emerging treatment of seizures in children with Dravet syndrome, with a focus on stiripentol. This includes a review of the literature regarding the mechanism of action, clinical efficacy, and safety/tolerability of stiripentol.

Expert opinion: Stiripentol has been available through expanded access programs resulting in a reduction of seizures and episodes of status epilepticus. With the Federal Drug Administration (FDA) approval, this treatment option will be more readily available to the Dravet syndrome population in the United States. The approval comes at a time of other treatment options also receiving approval (cannabidiol) and several products in ongoing studies (fenfluramine, TAK-935) providing additional treatment options and hope on the horizon for those impacted by this severe epilepsy syndrome.     

The xenobiotic inhibitor profile of cytochrome P4502C8

AIMS: To investigate inhibition of recombinant CYP2C8 by: (i) prototypic CYP isoform selective inhibitors (ii) imidazole/triazole antifungal agents (known inhibitors of CYP), and (iii) certain CYP3A substrates (given the apparent overlapping substrate specificity of CYP2C8 and CYP3A). METHODS: CYP2C8 and NADPH-cytochrome P450 oxidoreductase were coexpressed in Spodoptera frugiperda (Sf21) cells using the baculovirus expression system. CYP isoform selective inhibitors, imidazole/triazole antifungal agents and CYP3A substrates were screened for their inhibitory effects on CYP2C8-catalysed torsemide tolylmethylhydroxylation and, where appropriate, the kinetics of inhibition were characterized. The conversion of torsemide to its tolylmethylhydroxy metabolite was measured using an h.p.l.c. procedure. RESULTS: At concentrations of the CYP inhibitor 'probes' employed for isoform selectivity, only diethyldithiocarbamate and ketoconazole inhibited CYP2C8 by > 10%. Ketoconazole, at an added concentration of 10 microM, inhibited CYP2C8 by 89%. Another imidazole, clotrimazole, also potently inhibited CYP2C8. Ketoconazole and clotrimazole were both noncompetitive inhibitors of CYP2C8 with apparent Ki values of 2.5 microM. The CYP3A substrates amitriptyline, quinine, terfenadine and triazolam caused near complete inhibition (82-91% of control activity) of CYP2C8 at concentrations five-fold higher than the known CYP3A Km. Kinetic studies with selected CYP3A substrates demonstrated that most inhibited CYP2C8 noncompetitively. Apparent Ki values for midazolam, quinine, terfenadine and triazolam ranged from 5 to 25 microM. CONCLUSIONS: Inhibition of CYP2C8 occurred at concentrations of ketoconazole and diethyldithiocarbamate normally employed for selective inhibition of CYP3A and CYP2E1, respectively. Some CYP3A substrates have the capacity to inhibit CYP2C8 activity and this may have implications for inhibitory drug interactions in vivo.     

介导候选药代谢的肝细胞色素P450酶表型鉴定的定性和定量方法

新药研发需要对候选药物的代谢途径、每个代谢途径对总清除率的贡献以及参与代谢的酶进行详细研究。候选药物经过肝细胞色素P450(CYP)酶代谢的比例(f_m)可以用放射性同位素标记的方法在人体水平测定,而肝中某酶亚型的代谢占总的CYP参与代谢的比例(f_CYPi)可以用体外酶表型鉴定的方法来测定,这两个参数的乘积f_m×f_CYPi即为某个CYP酶亚型代谢参与某候选药物体内清除的百分比,对研究体内药物-药物相互作用具有重要意义。本文从定性和定量两方面综述体外酶表型鉴定的研究方法。     

2-(2,4-二氟苯基)-3-(N-甲基-N-取代基酰胺基)-1-(1H 1,2,4-三唑-1-基)-2-丙醇类化合物的合成及抗真菌活性的研究

目的:寻找新的高效、低毒、广谱的抗真菌药物。方法:设计合成了21 个三唑类化合物作为真菌细胞色素P450 14α-去甲基化酶的抑制剂,并通过体外抗真菌实验测定其抗真菌活性。结果:21 个化合物均为新化合物。体外抗真菌试验表明所有目标化合物对试验真菌均有不同程度的抑制作用,特别是对白色念珠菌和近平滑念珠菌具有很好的活性。结论:所有化合物都不同程度地对真菌细胞色素P450 14α-去甲基化酶有抑制作用,化合物15 对8 种不同真菌均显示了较高的活性,有进一步研究价值。     

细胞色素P450酶基因多态性的研究进展及临床意义

细胞色素P450（cytochrome P450,CYP）是重要的药物代谢酶,参与催化多种内源和外源化合物,特别是多种临床药物的生物转化。CYP存在广泛的基因多态性和表型多态性,体现在个体对于各种化合物的代谢存在明显差异。本文综述了CYP的基因多态性、与药物代谢相关的CYP各亚型的特点和临床意义,主要目的是合理解释和预测临床上药物间相互作用和药物不良反应等,为实现临床个体化给药提供科学依据。     

Cytochrome P450 3A and P-glycoprotein drug–drug interactions with voclosporin

Aims

Voclosporin is a novel calcineurin inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. Pharmacokinetic drug interactions between voclosporin and a CYP3A inhibitor, inducer and substrate and a P-glycoprotein inhibitor and substrate were evaluated.

Methods

Voclosporin 0.4 mg kg⁻¹ was administered to 24 subjects in each of five studies, as follows: every 12 h (Q12H) alone and concomitantly with ketoconazole 400 mg once daily (QD); single dose before and single dose after rifampin 600 mg QD; Q12H where midazolam 7.5 mg was administered as a single dose alone before voclosporin and with last the dose of voclosporin; Q12H alone and concomitantly with verapamil 80 mg every 8 h; and Q12H with digoxin 0.25 mg QD. The noncompartmental pharmacokinetic parameters maximal concentration (C_max) and area under the concentration–time curve (AUC) were obtained, and geometric least squares mean ratios and 90% confidence intervals were evaluated.

Results

Ketoconazole increased voclosporin C_max (6.4-fold) and AUC (18-fold); rifampin reduced voclosporin AUC (0.9-fold); voclosporin did not change exposure of midazolam or α-hydroxy-midazolam; verapamil increased voclosporin C_max (2.1-fold) and AUC (2.7-fold); and voclosporin increased digoxin C_max (0.5-fold), AUC (0.25-fold) and urinary excretion (0.2-fold).

Conclusions

Administration of voclosporin concomitantly with strong inhibitors and inducers of CYP3A resulted in increased and decreased exposures, respectively, and should be considered contraindicated. Drug–drug interactions involving voclosporin and CYP3A substrates are not expected. Administration of voclosporin concomitantly with inhibitors and substrates of P-glycoprotein resulted in increased voclosporin and substrate exposures, respectively. Appropriate concentration and safety monitoring is recommended with co-administration of voclosporin and P-glycoprotein substrates and inhibitors.