丙戊酸药物肝毒性的研究进展

药物肝毒性是临床医师和患者十分关注的问题。英国药物安全委员会对1964～2000年间英国儿童致死性药物副作用统计发现,最常见的死因为肝功衰竭,占15．11％(50／331)。引起肝功衰竭的主要药物是丙戊酸盐类药物(Valproic acid,VPA),占9．37％(31／331)。VPA引起的致死性肝坏死更容易发生在婴儿。因此,深入研究VPA肝毒性的发生机理和防治措施,对防治该药毒副作用,促进该药在临床的安全应用,均有重要意义。     

丙戊酸钠及其代谢产物的体外肝毒性研究

目的 研究丙戊酸钠及3个代谢产物（2-丙基-4-五烯酸、3-羟基丙戊酸、5-羟基丙戊酸）对体外人正常肝细胞L02增殖活性及对肝细胞损伤相关指标的影响。方法 实验分为对照组和实验组,对照组细胞常规培养,实验组加入丙戊酸钠及3个代谢产物,采用CCK-8法检测细胞增殖活性,PCR法检测CYP1A1、CYP1A2、PCNA、Bax及Bcl-2的mRNA相对含量,Western Blotting法检测蛋白表达,同时检测细胞上清液中谷草转氨酶（AST）、谷丙转氨酶（ALT）、乳酸脱氢酶（LDH）的含量。结果 与对照组相比,随着丙戊酸钠及3个代谢产物浓度和时间的增加,对 L02细胞增殖活性的抑制逐渐增强,CYP1A1、CYP1A2及Bax的mRNA相对含量和蛋白表达量升高,PCNA及Bcl-2的 mRNA相对含量和蛋白表达量均有下降,AST、ALT、LDH含量升高。结论 丙戊酸钠及3个代谢产物与肝毒性有关。     

丙戊酸钠与双丙戊酸钠的毒性比较

目的 比较丙戊酸钠与双丙戊酸钠2种供试品毒性的大小.方法 采用大鼠和小鼠2种动物,分别灌胃给予不同剂量的丙戊酸钠和双丙戊酸钠,观察大鼠和小鼠的毒性反应症状、死亡情况、病理变化,并计算出供试品对2种动物的LD50值.结果 2种供试品对大鼠和小鼠的毒性反应症状及病理变化基本一致,但是在剂量相当的情况下丙戊酸钠的毒性反应症状比双丙戊酸钠的严重,死亡的动物数更多,LD50值更小.结论 丙戊酸钠的毒性比双丙戊酸钠的毒性大.     

丙戊酸钠致丙戊酸钠脑病1例

1临床资料 患者,女,45岁,病历号234731.既往体健,主因头痛伴视物不清20余天,突发肢体抽搐7d收入院.入院查体:神清语利,神经系统查体无阳性体征.MRI示:右枕叶占位.于2004年9月16日,上午8点,在全麻下行右顶枕开颅,肿物切除术,肿物大小4cm×3cm×2cm.术后处理:注意神态、瞳孔及生命体征变化.给予脱水、抗感染治疗.给予注射用丙戊酸钠(VPA,商品名:德巴金)、苯巴比妥钠注射液预防术后癫痫.用量:丙戊酸钠800mg,24h微量泵入,qd;10%苯巴比妥钠2mL,肌注,1次/8h.     

不同丙戊酸盐和丙戊酸剂型对丙戊酸血药浓度的影响

目的：研究不同丙戊酸盐和丙戊酸剂型对丙戊酸血药浓度的影响。方法：回顾性分析某院270例丙戊酸血药浓度监测报告,记录患者姓名、年龄、体质量、丙戊酸的用法与用量、联合用药情况（合用药品及其用法与用量）和血药浓度监测结果。分析不同丙戊酸盐和丙戊酸剂型对丙戊酸标准血药浓度的影响。结果：二元Logistic回归分析结果表明丙戊酸盐类型和剂型对标准血药浓度有显著影响（P<0.05）;丙戊酸镁的标准血药浓度[（9.18±3.54）μg·kg·mL^-1·mg^-1]大于丙戊酸钠盐的标准血药浓度[（6.76±2.54）μg·kg·mL^-1·mg^-1];丙戊酸缓释片的标准血药浓度[（8.38±3.49）μg·kg·mL^-1·mg^-1]大于丙戊酸普通片的标准血药浓度[（6.88±2.54）μg·kg·mL^-1·mg^-1],差异均具有显著性（P<0.05）。结论：不同丙戊酸盐和丙戊酸剂型对丙戊酸血药浓度存在明显影响,如何选择丙戊酸盐和丙戊酸剂型对丙戊酸的合理运用具有重要意义。     

丙戊酸肝毒性的早期预警及预防研究状况

丙戊酸是临床上主要的一线抗癫痫药,还广泛用于其他神经疾病的治疗,治疗范围广,但肝毒性是丙戊酸较严重的不良反应,2岁以下且联合用药的癫痫患者肝毒性风险显著增大,严重时甚至发生致死性、急性肝坏死。因此,临床上选择合适的生物标志物预警丙戊酸肝毒性的发生以及早期实施药物干预进行预防显得尤为重要。本文就近几年丙戊酸肝毒性的预警和预防方面的研究进展做一综述。     

丙戊酸钠的肝脏毒性及防治

本文介绍了丙戊酸钠肝毒性的临床表现为肝酶增加、血氨升高、抑制凝血、低血糖和酸中毒、微囊状脂肪变性及抑制β氧化;并对其提出了预防和治疗措施.     

丙戊酸钠对幼鼠代谢的影响及肝毒性的试验探讨

目的：通过观察丙戊酸钠（VPA）作用后的Wistar幼鼠的肝功能、瘦素、胰岛素的变化分析对其影响因素。方法：选用SPF级3周龄雄性Wistar大鼠36只,平均体重48g。并随机分为两组（每组23只）,空白对照组：经口灌胃等量蒸馏水：VPA组：经口灌胃VPA300mg／（kg·d）,每周2次;3个月后检测体重变化、瘦素、胰岛素、血清A1月、血清AST、血清GST、肝MDA、肝GSH以及肝GST。结果：与空白对照组比较,VPA组AST、肝GST、瘦素、胰岛素显著升高（P〈0．01）,体重显著增加（P〈0．05）,肝GSH含量显著降低（P〈0．01）,而血清ASL、血清GST、肝MDA则均无统计学意义（P〉0．05）。结论：长期应用VPA会造成肝毒性及心血管系统潜在危险。     

丙戊酸联合碳酸锂治疗帕金森病模型小鼠的实验研究

目的探讨丙戊酸联合碳酸锂(MPTP)对帕金森病(PD)小鼠模型的治疗作用。方法60只小鼠腹腔注射MPTP制作PD小鼠模型后均分为五组,分别予以丙戊酸联合碳酸锂(A组)、碳酸锂(B组)、丙戊酸(C组)和生理盐水(D组)处理。采用免疫组织化学及Western blot方法检测PD相关标志物酪氨酸羟化酶(TH),高效液相色谱-电化学检测仪(HPLC-ECD)检测纹状体单胺类递质变化。结果与空白对照组(E组,12只)比较,D组TH阳性细胞数明显减少,多巴胺(DA)及其代谢产物二羟苯乙酸(DOPAC)明显下降。A、B、C组纹状体TH表达较D、E组明显增多,尤其A组明显;A组DOPAC含量较D组明显升高(P<0.05)。结论丙戊酸联合碳酸锂对MPTP诱导的PD小鼠有明显的治疗作用。     

组蛋白去乙酰化酶抑制剂丙戊酸肝细胞毒性相关作用机制研究

目的研究丙戊酸肝细胞毒性相关机制。方法使用人肝癌细胞系HepG2,VPA、TSA处理,检测细胞活性、凋亡情况、线粒体膜电位、PI3K/AKT/mTOR通路活性、Bcl-2、Bax凋亡通路和自噬激活情况。结果5 mmol/L、10 mmol/L VPA处理24 h,细胞活性明显降低;5μmol/L TSA处理24 h,细胞活性明显降低。因此选用10 mmol/L VPA、5μmol/L TSA。10 mmol/L VPA处理24 h或5μmol/L TSA处理24 h,细胞凋亡率显著升高,细胞线粒体膜电位降低,细胞PI3K/AKT/mTOR通路活性降低,细胞Bcl-2活性降低,Bax活性升高,cleaved-caspase-3比例升高,细胞LC3Ⅱ表达增加,p62表达降低,VPA的作用强于TSA。结论 PI3K/Akt/mTOR通路抑制以及线粒体异常引起的凋亡在VPA相关肝毒性中发挥重要作用,而且VPA的肝毒性也与其HDAC抑制剂活性具有一定关联。     

The relationship between glucuronide conjugate levels and hepatotoxicity after oral administration of valproic acid

The aim of this study was to investigate the relationship between hepatotoxicity, levels of glucuronide conjugates of valproic acid (VPA), and the toxic metabolites of VPA (4-ene VPA and 2,4-diene VPA). We also examined whether hepatotoxicity could be predicted by the urinary excretion levels of VPA and its toxic metabolites. VPA was administrated orally in rats in amounts ranging from 20 mg/kg to 500 mg/kg. Free and total (free plus glucuronide conjugated) VPA, 4-ene VPA, and 2,4-diene VPA were quantified in urine and liver using gas chromatography-mass spectrometry. Serum levels of aspartate aminotransferase, alanine aminotransferase, and α-glutathione S-transferase (α-GST) were also determined to measure the level of hepatotoxicity. The serum α-GST level increased slightly at the 20 mg/kg dose, and substantially increased at the 100 and 500 mg/kg dose; aspartate aminotransferase and alanine aminotransferase levels did not change with the administration of increasing doses of VPA. The liver concentration of free 4-ene VPA and the urinary excretion of total 4-ene VPA were the only measures that correlated with the increase in the serum α-GST level (p < 0.094 and p < 0.023 respectively). From these results, we conclude that hepatotoxicity of VPA correlates with liver concentration of 4-ene VPA and can be predicted by the urinary excretion of total 4-ene VPA.     

Effect of valproic acid on zinc metabolism in the rat

Previous studies have suggested that the mechanism of valproic acid (VPA) hepatotoxicity may involve a drug-induced Zn deficiency. To test this hypothesis, the uptake of 65Zn or tissue Zn concentration was determined in plasma, liver, bone, kidney, and brain of adult male rats, administered parenteral VPA according to one of 3 schedules: 750 mg/kg; 500 mg/kg; and 100 mg/kg/day X 7 days. Histopathological changes in liver and weight loss were observed in rats 5 days after administration of VPA (750 mg/kg). The plasma Zn level in VPA toxic rats was significantly depressed compared to saline-injected controls, although the Zn content of liver and bone was unaffected. Furthermore, tissue uptake of 65Zn was not altered in rats 6 h after receiving VPA 500 mg/kg or after chronic administration at 100 mg/kg/day. On the basis of the present study, there is no evidence that Zn deficiency is induced by hepatotoxic doses of VPA in rats.     

丙戊酸钠及其代谢产物与肝损伤的相关性分析

目的研究丙戊酸钠及3个代谢产物(2-丙基-4-五烯酸、3-羟基丙戊酸、5-羟基丙戊酸)对肝损伤参考指标的相关性分析。方法共收集328例癫痫患者血样,其中,123例肝功能异常癫痫患者血样为试验组,205例肝功能正常癫痫患者血样为对照组,采用LC-MS/MS方法测定两组血样(丙戊酸钠及代谢产物)的血药浓度,通过ROC曲线分析丙戊酸及其代谢产物浓度对肝功能异常的诊断价值。结果肝功能异常组患者丙戊酸钠及其3个代谢产物平均血药浓度均高于对照组,差异有统计学意义(P<0.05)。丙戊酸钠及其代谢产物的血药浓度均可作为诊断肝损伤的参考指标,5-羟基丙戊酸比丙戊酸钠有更好的诊断价值。结论丙戊酸钠代谢产物与肝毒性有关,能够作为肝损伤的诊断指标,可将其应用于临床,为丙戊酸钠有效给药提供参考。     

Disposition of valproic acid in patients with liver disease

Summary The disposition of valproic acid (di-n-propylacetate; VA) has been studied after a single oral dose of a solution of 450 mg in 7 patients with alcoholic cirrhosis and in 4 patients recovering from acute hepatitis. The diagnosis was based on biochemical function tests and histological findings. The pharmacokinetic parameters were compared with those reported for healthy volunteers. VA in therapeutic concentration (80 µg/ml) in plasma was less bound to plasma proteins in patients with alcoholic cirrhosis (70.7±11.3%) and in patients recovering from acute hepatitis (78.1±14.1%) than in controls (88.7±5.2%). The reduced binding affected the blood/plasma concentration ratio and the apparent distribution volume Vd₍₎; the latter was increased from the normal value of 0.14±0.05 l/kg to 0.22±0.09 (p<0.05) in alcoholic cirrhotics, and to 0.20±0.07 (p=0.056) in patients recovering from acute hepatitis. The half-life of elimination T_{1/2 ()} (controls=12.2±3.7 h) was significantly (p<0.05) prolonged in cirrhotics (18.9±5.1 h) and in patients recovering from acute hepatitis (17.0±3.7 h). The plasma of total drug was not impaired, which can best be explained by the lower plasma protein binding, which might have increased the of this drug which shows restricted clearance. In addition, the plasma of free drug was significantly (p<0.02) reduced in alcoholic cirrhotics. During a two day urine collection no measurable amount of unchanged VA was recovered. There was considerable excretion of VA-conjugates, which could be hydrolyzed either by HCl or by -glucuronidase/arylsulphatase (4–23% of the dose). These percentages were in the same range as in normals (26.7±16.1%). The study indicates that elimination of VA is slightly impaired in patients with dysfunction of the liver.Supported by the Robert Bosch Foundation, Stuttgart, Federal Republic of Germany     

高胆固醇与心血管危险因素相关性研究

目的探讨高胆固醇血症患者与血压、ALT、AST、血糖、血尿酸、尿素氮、肌酐水平,体重及体重指数、脂肪肝发生率的关系。方法收集海南医学院附属医院高胆固醇血症患者430例以及胆固醇正常者100例,抽血检测其血脂代谢水平（TG、TC、LDL、HDL）以及ALT、AST、血糖、血尿酸、尿素氮、肌酐水平和B超检出脂肪肝的水平,同时测量体重及体重指数,并测量血压。结果与胆固醇正常的体检者相比,高胆固醇血症患者的AST、血尿酸、肌酐水平及脂肪肝患病率、体重及体重指数、血压明显高于正常者,在统计学上有显著性差异。结论高胆固醇与体重指数、血压、脂肪肝、ALT、血尿酸、血尿素氮呈正相关。     

Combined effects of a high-fat diet and chronic valproic acid treatment on hepatic steatosis and hepatotoxicity in rats

Aim： To investigate the potential interactive effects of a high-fat diet （HFD） and valproic acid （VPA） on hepatic steatosis and hepatotoxicity in rats. Methods： Male SD rats were orally administered VPA （100 or 500 mg.kgl.d1） combined with HFD or a standard diet for 8 weeks. Blood and liver samples were analyzed to determine lipid levels and hepatic function biomarkers using commercial kit assays. Low- molecular-weight compounds in serum, urine and bile samples were analyzed using a metabonomic approach based on GC/TOF-MS. Results： HFD alone induced extensive hepatocyte steatosis and edema in rats, while VPA alone did not cause significant liver lesions. VPA significantly aggravated HFD-induced accumulation of liver lipids, and caused additional spotty or piecemeal necrosis, accompanied by moderate infiltration of inflammatory cells in the liver. Metabonomic analysis of serum, urine and bile samples revealed that HFD significantly increased the levells of amino acids, free fatty acids （FFAs） and 3-hydroxy-butanoic acid, whereas VPA markedly decreased the levels of amino acids, FFAs and the intermediate products of the tricarboxylic acid cycle （TCA） compared with the control group. HFD aggravated VPA-induced inhibition on lipid and amino acid metabolism. Conclusion： HFD magnifies VPA-induced impairment of mitochondria113-oxidation of FFAs and TCA, thereby increases hepatic steatosis and hepatotoxicity. The results suggest the patients receiving VPA treatment should be advised to avoid eating HFD.     

Evidence for a potential protective effect of carnitine-pantothenic acid co-treatment on valproic acid-induced hepatotoxicity

Valproic acid is approved for treatment of seizures and manic episodes of bipolar disorder, and continues to be one of the most commonly prescribed antiepileptic drugs in the world. Hepatotoxicity is a rare but serious side effect resulting from its use, particularly in young patients. This adverse effect does not display normal dose–response curves and can be lethal in children. A review of the purported mechanisms of action suggest hepatotoxicity results from increased oxidative stress, caused by a reduction in beta-oxidation and an increase in activation of certain metabolizing enzymes. There is also evidence that both carnitine and pantothenic acid are involved in the regulation of valproic acid-induced hepatotoxic processes, and clinical evidence has shown that treatment with either compound shows protective effects against hepatotoxicity. These results suggest a potential increase in protective effects with cotreatment of carnitine and pantothenic acid.     

A new approach on methamphetamine-induced hepatotoxicity: involvement of mitochondrial dysfunction

Abstract

1.?Methamphetamine (METH) is a highly addictive stimulant that is among the most widely abused illicit drugs. Clinical evidence has shown that the liver is a target of METH toxicity. The exact cellular and molecular mechanisms involved in METH-induced hepatotoxicity have not yet been completely understood.

2.?In this study, the cellular pathways involved in METH liver toxicity were investigated in freshly isolated rat hepatocytes. METH cytotoxicity was associated with reactive oxygen species (ROS) formation, lipid peroxidation and rapid glutathione (GSH) depletion which is a third marker of cellular oxidative stress. Our results showed that the hepatocyte mitochondrial membrane potential (ΔΨm) was rapidly decreased by METH, which was prevented by antioxidants and ROS scavenger, suggesting that mitochondrial membrane damage was a consequence of ROS formation. Incubation of hepatocytes with METH also caused release of cytochrome c from mitochondria into the cytosol before cell lysis ensued.

3.?Our findings showed that cytotoxic action of METH is mediated by oxidative stress and subsequent changes in mitochondrial membrane conformation and cytochrome c release into the cytosol which causes mitochondrial collapse of ΔΨm.     

小剂量红霉素治疗早产儿胃肠道功能紊乱

目的:评价小剂量红霉素治疗早产儿胃肠道功能紊乱的疗效。方法:将诊断明确的129例患儿随机分为治疗组65例,对照组64例,对照组予常规对症支持治疗,治疗组在常规处理基础上加用小剂量红霉素3~5mg/(kg·d)缓慢静脉滴注,1次/d,连用4~10d。结果:治疗组呕吐症状、胃潴留缓解以及奶量增加和体重增长有效率分别是83.1%、81.5%、73.8%、78.5%,均明显高于对照组(P<0.05),且无明显副作用。结论:小剂量红霉素治疗早产儿胃肠道功能紊乱安全有效,具有一定的临床价值。