Papel de los bloqueadores de los canales de sodio dependientes de voltaje en el tratamiento del dolor crónico: usos potenciales en la práctica clínica según la evidencia disponible

Once patients have failed first line therapy, there is an apparent lack of knowledge on how to proceed with choosing subsequent therapy. To choose amongst alternative agents, an understanding of pharmacology, pharmacokinetics, and available evidence in targeting various pain conditions is necessary. This article focuses on the use of the carboxamide class of voltage-gated sodium channel blockers (carbamazepine, oxcarbazepine, eslicarbazepine acetate) for adjunct pain medication management; including research updates in pharmacology, pharmacokinetics, and evidence for pain along on this therapeutic group with promising future areas of research.Although evidence for voltage-gated sodium channel blockers in chronic pain management is limited, emerging research has identified this area as promising for additional clinical trials to better guide clinical practice.     

奥卡西平治疗创伤性癫痫的疗效观察和安全性分析

【目的】观察奥卡西平（oxcarbazepine,OXC）治疗创伤性癫痫（posttraumatic epilepsy,PTE）的临床疗效和安全性。【方法】连续性收集2007年3月-2008年9月期间在我院癫痫中心就诊符合入选条件的66例创伤性癫痫患者,10例未曾接受任何抗癫痫治疗和46例曾治疗不规范的患者调整为OXC单药治疗,10例曾服用德巴金的患者联合应用OXC,单药剂量维持量调整在600～1500mg,联合用药的维持量在600～1200mg。自身对比开放性观察12个月,评价OXC对创伤性癫痫的发作控制率、脑电图改善情况、不良反应和安全性。【结果】OXC对创伤性癫痫总有效率为85.94%,控制率为56.25%,治疗前后脑电图比较结果显示,治疗12个月后脑电图得到明显改善（P〈0.01）。常见的不良反应包括：头昏、嗜睡、无力、头痛、恶心、食欲下降、白细胞下降、手颤和皮疹。因不良反应而停药者2例,占3.03%。患者治疗前、治疗后不同时间血常规、肝肾功能和心电图对比均无明显变化（P〉0.05）。【结论】奥卡西平对66例创伤性癫痫患者的治疗效果较明显,不良反应轻,安全性高。     

多药转运蛋白对癫痫大鼠脑内奥卡西平浓度的影响

目的 观察多药转运蛋白家族的成员P-糖蛋白(P-glycoprotein,PGP)和多药耐药蛋白(multi-drug re-sistance associated protein,MRP)对匹罗卡品慢性癫痫大鼠模型海马内神经元细胞外液中奥卡西平浓度的影响,证明奥卡西平是否为PGP和MRP的底物,探讨PGP和MRP参与难治疗性癫痫耐药的机制.方法 建立匹罗卡品慢性癫痫动物模型,将32只大鼠分为对照组、模型组、维拉帕米干预组、丙磺舒干预组(每组8只),于腹腔注射奥卡西平(80 mg/kg)后30、60、90、120、150 min,通过微透析及高效液相色谱技术,检测大鼠海马神经元细胞外液中的药物浓度.结果 维拉帕米干预后,癫痫大鼠海马细胞外液中奥卡丙平的浓度于给药后90～120 min(1.26±0.09、0.93±0.10)明显高于模型组(0.87±0.06、0.66 4±0.04),两组比较有统计学差异(P<0.05);丙磺舒干预后60～150 min,大鼠海马内细胞外液中奥卡两平的浓度(1.07±0.11、1.32±0.13、1.02±0.10、0.87±0.08)显著高于模型组(0.81±0.08、0.87±0.06、0.66±0.04、0.58±0.06)(P<0.05).结论 奥卡西平是PGP和MRP的底物,PGP和MRP能够选择性的将奥卡西平泵出血脑屏障外,降低癫痫病灶内的药物浓度,上述机制可能参与了难治性癫痫患者对奥卡西平产生耐药.     

Oxcarbazepine, not its active metabolite, potentiates GABAA activation and aggravates absence seizures

Purpose:   Studies in genetic absence epileptic rats from Strasbourg (GAERS) indicate that enhancement of γ aminobutyric acid (GABA_A) receptor activity is a critical mechanism in the aggravation of seizures by carbamazepine (CBZ). We examined whether structural analogs of CBZ, oxcarbazepine (OXC), and its active metabolite, monohydroxy derivative (MHD), also potentiate GABA_A receptor current and aggravate seizures.
Methods:   In vitro studies in Xenopus oocytes compared the three drugs' effect on GABA_A receptor currents. In vivo studies compared seizure activity in GAERS after intraperitoneal drug administration.
Results:   OXC potentiated GABA_A receptor current and aggravated seizures in GAERS, similarly to the effect of CBZ. Conversely, MHD showed only a minor potentiation of GABA_A receptor current and did not aggravate seizures.
Discussion:   A hydroxyl group at the C-10 position on the CBZ tricyclic structure in MHD reduces GABA_A receptor potentiation and seizure aggravation. Reports of the aggravation of absence seizures in patients taking OXC may result from circulating unmetabolized OXC rather than MHD.     

Histologic and morphologic effects of valproic acid and oxcarbazepine on rat uterine and ovarian cells

Purpose:   To determine the histologic and morphologic effects of valproic acid (VPA) and oxcarbazepine (OXC) on rat uterine and ovarian cells.
Methods:   Fifty-six female prepubertal Wistar rats (21–24 days old and weighing between 47.5 and 58.1 g) were divided equally into four groups, which were given drinking water (controls), 300 mg/kg/day of VPA, 100 mg/kg/day of OXC or VPA + OXC via gavage, for 90 days. Ovaries and uteri of rats on proestrous and diestrous phases of estrous cycle were extirpated and placed in a fixation solution. The tissue specimens were assessed with apoptosis (TUNEL) staining protocols, eosinophil counting, and electron microscopic techniques.
Results:   In uteri, apoptosis in stroma, mitochondrial swelling, and cristolysis were observed in the VPA group, and OXC led to negative effects on epithelial cell and intracellular edema. In ovaries, both drugs increased apoptosis and intracytoplasmic edema. Organelle structure disruption was also observed in the OXC group. More conspicuous degenerative modifications were determined in the VPA + OXC group. In uteri, the number of TUNEL-positive luminal epithelial cells was 7.20 ± 1.32 in controls, and significantly increased to 29.60 ± 1.58, 34.20 ± 2.53, and 54.80 ± 2.04 in VPA, OXC, and VPA + OXC groups, respectively (p < 0.001). The highest number of TUNEL-positive glandular epithelium cells was observed in the VPA + OXC group; however, the number of TUNEL-positive stroma cells was highest in the VPA group. The highest number of eosinophils in stroma was in the VPA group.
Conclusion:   VPA and OXC trigger apoptotic and degenerative effects on rat uterine and ovarian cells. VPA also prevents implantation of embryo to the uterus and causes abortion via endometrial eosinophil infiltration.     

Oxcarbazepine is effective and safe in the treatment of neuropathic pain: pooled analysis of seven clinical studies

Abstract The results of 7 open-label clinical studies on oxcarbazepine (OXC) in different neuropathic pain conditions, sharing the same protocols, were pooled together in order to evaluate whether the results obtained in the individual trials were confirmed in the pooled analysis of this larger sample, providing more evidence for efficacy and tolerability of OXC in these conditions. Eligible patients (>18 years old) with a diagnosis of neuropathic pain were enrolled in seven open-label trials, consisting of a oneweek prospective Screening Phase followed by an eight-week Treatment Phase. Treatment with OXC was initiated at 150 mg/day, and the daily dose was increased by 150 mg/day on a 2–3 day basis to the maximum tolerated dose over four weeks, up to 1800 mg/day. The primary outcome measure was the change in the actual pain rating assessed on the visual analogue scale (VAS) between the end of the Screening Phase and the end of the Treatment Phase. One hundred and thirty-six patients were enrolled in the trials. The mean VAS score dropped from 77.13 at the end of the Screening Phase to 38.41 at the end of the trial for a mean reduction of 50.2%. The percentage of responders (mean VAS score reduction ≥50%) was 49.2%. OXC was well tolerated, with the most common adverse events consisting of vertigo, tremor, somnolence, hypotension and nausea. The results of this analysis suggest that OXC administered as monotherapy is an efficacious and safe option for the symptomatic treatment of pain associated with neuropathies.     

Hyponatremia Associated with Carbamazepine and Oxcarbazepine Therapy: A Review

Summary: Hyponatremia, an electrolyte disturbance usually without clinical significance, may sometimes lead to serious complications when overlooked or not treated appropriately. One cause of hyponatremia, the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, has been associated with some drugs, including carbamazepine (CBZ). Because of its antidiuretic effects, CBZ has been used successfully to treat diabetes insipidus centralis. Possible mechanisms for the antidiuretic effects of CBZ have been proposed. Altered sensitivity to serum osmolality by the hypothalamic osmoreceptors appears likely, but an increased sensitivity of the renal tubules to circulating ADH cannot be excluded. CBZ has led to hyponatremia in patients with epilepsy, neuralgia, mental retardation, and psychiatric disorders with a frequency varying from 4.8 to 40%. Oxcarbazepine (OCBZ), which is structurally related to CBZ, has shown similar hyponatremic effects, but whether hyponatremia occurs more often than with CBZ is not yet clear. Experience with OCBZ is still limited, and there is no definite explanation for a possible difference in antidiuretic potency. Most patients with CBZiOCBZ-induced hyponatremia are asymptomatic. In rare cases, water intoxication has been reported, necessitating treatment discontinuation.     

奥卡西平单药及添加治疗部分性癫(癎)的疗效和安全性前瞻研究

目的:评估奥卡西平单药与添加治疗部分性癫患者的疗效、耐受性和安全性。方法:前瞻性对在同济医院癫诊疗中心就诊的67名部分性癫患者应用奥卡西平后进行临床随访观察,分为单药治疗组和添加治疗组,用药的前3个月及后3个月进行对比观察。结果:2组患者治疗前后发作频率减少的平均百分率有显著性差异(P=0.002)。单药治疗组与添加治疗组相比,前者用药前3个月发作完全控制的百分率、用药后3个月发作频率减少50%的百分率和发作完全控制的百分率(P=0.02,0.017,0.019)均明显低于后者。单药治疗组或添加治疗组自身用药的3个月及后3个月发作减少50%的百分率、发作减少75%的百分率、发作完全控制百分率均无明显差异(P>0.05)。治疗引起的不良反应发生率为19.40%(13/67),主要出现于用药的前3月。结论:奥卡西平是治疗部分性癫的一线药物,可用于新诊断或其他药物无法耐受和疗效不佳患者的单药或添加治疗。     

Clobazam, Oxcarbazepine, Tiagabine, Topiramate, and Other New Antiepileptic Drugs

Summary: 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 carbam-azepine, 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.