他汀类药物肌肉毒性研究进展

探讨他汀类抗动脉粥样硬化药物肌肉毒性研究进展。他汀类药物临床广泛用于抗动脉粥样硬化和预防心血管疾病;但它们可导致横纹肌溶解症为代表的肌肉毒性,甚至死亡;与贝特类药物联用时,肌肉毒性表现为协同作用。目前认为该肌肉毒性发生的原因有CoQ代谢障碍、扰动胞浆内钙稳态、药动学相互作用、抑制肌肉细胞分化等。他汀类药物肌肉毒性机制研究目前较为分散,尚无统一的观点和认知;抑制肌肉细胞分化可能是他汀类药物肌肉毒性、及其与贝特类药物联合用药时肌肉毒性协同作用机制研究的有效切入点。     

贝特类调脂药物研究进展

贝特类药物又称苯氧芳酸类药物,是指包括吉非贝齐、氯贝特、非诺贝特、苯扎贝特和环丙贝特等在内的一类调脂药物。这类药物口服吸收快而完全,服药后1~2 h内即可检测到血浆中药物浓度,与血浆蛋白结合率高。贝特类药物     

他汀类和贝特类降脂药物联合使用增加横纹肌溶解的危险

美国研究者称，他汀类(statin)药物和贝特类(fibrate)(纤维酸衍生物)降脂药物联合使用比单独使用他汀类药物增加因横纹肌溶解的住院危险。阿托伐他汀(atorvastatin)(Ⅰ)、普伐他汀(pravastatin)(Ⅱ)、辛伐他汀(simvastatin)(Ⅲ)单药治疗发生横纹肌溶解的住院危险相似，     

非诺贝特引起横纹肌溶解症

1名48岁女性慢性肾功能不全透析患者,因血脂增高给予非诺贝特200mg口服,1次/晚。服药前查Hb97g/L,PLT202×109/L,血Cr907μmol/L,BUN30.62mmol/L,TG2.56mmol/L,TC5.4mmol/L,ALT16U/L,AST37U/L,CK52U/L,LDH182U/L,血电解质正常。服药11d后,患者出现乏力、周身肌肉酸痛,尿色加深,尿量自1800ml/d减少至250ml/d。查:Hb79g/L,PLT102×109/L,Cr1112μmol/L,BUN37.1mmol/L,K 8.7mmol/L,CK1979U/L,ALT619U/L,AST1880U/L,LDH3470U/L。尿常规:蛋白( )、潜血(┼┼┼)。血气分析:pH7.503,PCO236.1mmHg,PO255mmHg,SO20.863。确诊为横纹肌溶解症,合并肝、肾功能损害。立即停用非诺贝特,予血液透析滤过治疗。6d后肌肉疼痛、乏力好转,尿量恢复至650ml;8d后Hb、PLT、血CK恢复正常;12d后肝功能恢复正常。     

非诺贝特致横纹肌溶解症1例

1　病例介绍患者 ,男 ,52岁。 2 0 0 2年 5月 9日入院 ,磁共振成像 (MRI)显示垂体囊肿引发腺垂体功能减退。给予氢化可的松 2 0mg·d 1,po。患者伴有冠心病、动脉粥样硬化及高脂血症 ,给予口服阿司匹林肠溶片、乳果糖 (杜秘克 )及相应常规治疗 ,低脂饮食。 2 0 0 2年 5月 15日因血为乳糜样 ,加用非诺贝特 (商品名 :力平脂 ,法国利博福尼制药公司生产 ,批号 :69884) 2 0 0mg,bid。用药第 6天 ,患者主诉左腓肠肌处突发针刺样疼痛 ,伴四肢肌肉酸痛 ,无力。急查肌酸磷酸激酶 (CK)为 73 2 9U·L 1,远超正常值 (18～ 198U·L 1) 10倍以上。诊…     

苯扎贝特致横纹肌溶解症一例报告

目的通过对1例苯扎贝特致横纹肌溶解症患者的研究观察,进一步了解横纹肌溶解症（RML）。方法以1例苯扎贝特致横纹肌溶解症（RML）的患者为研究观察对象,分析苯扎贝特致横纹肌溶解症的临床特征。结果苯扎贝特致横纹肌溶解症的临床特征主要为：全身肌肉痛明显,以四肢为重,以活动（起、坐）时为主;无发热、胸闷、憋气及心前区疼痛;无腹痛和腹泻;无血尿及少尿等特征。结论贝特类药物引起横纹肌溶解症,常见于老年及肾功能不全患者,可引起肾衰竭而导致死亡。因此要掌握苯扎贝特致横纹肌溶解症的临床特征,做到早发现,早治疗。     

阿托伐他汀钙联用苯扎贝特相关横纹肌溶解症

1例46岁女性患者,因高脂血症及原发性高血压口服阿司匹林0.1 g,1次/d;阿托伐他汀钙10 mg,1次/d;苯扎贝特0.2 g,2次/d;硝苯地平30 mg,2次/d,共10 d。治疗第8天,患者出现双下肢肌肉疼痛;第9天疼痛蔓延至双侧肩背部、双上肢及全身。随后全身肌肉疼痛加剧,双下肢肌肉僵硬,尿液呈棕红色。血生化检查:肌酸激酶21 507 U/L,肌酸激酶同工酶5460 U/L,乳酸脱氢酶1517 U/L,丙氨酸转氨酶194 U/L,天冬氨酸转氨酶895 U/L,肌酐268μmol/L。给予血液净化、碱化尿液、保护肝肾功能等治疗,患者好转。     

非诺贝特胶囊致横纹肌溶解症及肝功能损害1例

非诺贝特为烟酸类衍生物,可有效降低血三酰甘油、极低密度脂蛋白,升高高密度脂蛋白,在临床广泛应用于高脂血症。说明书中不良反应项下提及胃肠道反应,皮肤过敏反应,肝、肾功能损害以及对肌肉的损害,罕见横纹肌溶解。现将口服非诺贝特胶囊引起横纹肌溶解及肝损伤患者1例报道如下。     

辛伐他汀与非诺贝特合用致横纹肌溶解症1例

1例76岁女性糖尿病患者,因高血脂联合使用辛伐他汀(40mg/晚)和非诺贝特(200mg/早),出现双侧腓肠肌压痛,CK值为10268 IU/L。停用两种降脂药后,给予补液和改善微循环等对症治疗,症状逐渐好转。     

苯扎贝特抗动脉粥样硬化疗效观察

目的 研究苯扎贝特降血脂治疗外的抗动脉粥样硬化作用.方法 将56例高甘油三脂(TG)血症患者随机分为苯扎贝特组和安慰剂组.苯扎贝特200 mg Tid 治疗8周与安慰剂组比较空腹血甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)和颈动脉内-中膜厚度(IMT)的变化....     

In Vitro-In Vivo Myotoxicity of Intramuscular Liposomal Formulations

Purpose. The first objective was to study the in vitro myotoxicity of empty liposomes and to examine whether liposome size, charge and fluidity affect liposome myotoxicity. The second objective was to investigate the effect of liposomal encapsulation on the in vitro and in vivo myotoxicity of loxapine compared to the loxapine commercial preparation (Loxitane^®). Methods. The in vitro myotoxicity of empty liposomes and loxapine liposomes was evaluated by the cumulative efflux of the cytosolic enzyme creatine kinase (CK) from the isolated rat extensor digitorum longus (EDL) muscle over a 2 hour period. In the in vivo studies, the area under plasma CK curve over 12 hours was used to evaluate muscle damage. Results. The in vitro myotoxicity for all empty liposomal formulations was not statistically different from negative controls (untreated control muscles and normal saline injected muscles). However, these empty liposomal formulations were significantly less myotoxic than the positive controls (muscles injected with phenytoin and muscle sliced in half). In vitro-in vivo studies showed that the liposomal encapsulation of loxapine resulted in significant (P < 0.05) reduction in myotoxicity (80% in vitro and 60% in vivo) compared to the commercially available formulation which contains propylene glycol (70% V/V) and polysor-bate 80 (5% W/V) prepared at equal concentration. Conclusions. Results indicate that empty liposomes do not induce myotoxicity. Furthermore, liposomal size, charge and fluidity do not affect myotoxicity. In addition, in vitro and in vivo studies have demonstrated that liposomal encapsulation of loxapine can reduce myotoxicity compared to a formulation containing organic cosolvents.     

Comparative Effects of Fibrates on Drug Metabolizing Enzymes in Human Hepatocytes

No HeadingPurpose. The induction potential of different fibric acid derivatives on human drug metabolizing enzymes was evaluated to help assess the role of enzyme induction on pharmacokinetic drug interactions.Methods. Effects of gemfibrozil, fenofibric acid, and clofibric acid on expression levels of cytochromes P450 (CYPs) 3A4 and 2C8 and UDP-glucuronyltransferase (UGT) 1A1 were evaluated in primary human hepatocyte cultures. The potential for these fibrates to activate human pregnane X receptor (PXR) also was studied in a cell-based PXR reporter gene assay.Results. All three fibrates caused increases in mRNA levels of CYP3A4 (2- to 5-fold), CYP2C8 (2- to 6-fold), and UGT1A1 (2- to 3-fold). On average, the effects on CYP3A4 were less than (30% of rifampin), while those on CYP2C8 and UGT1A1 were comparable to or slightly higher than (up to 200% of rifampin) the corresponding effects observed with rifampin (10 M). Consistent with the mRNA results, all fibrates caused moderate (<2- to 3-fold) increases in CYP3A4 activity (measured by testosterone 6 hydroxylase), as compared to about a 10-fold increase by rifampin. Significant increases (3- to 6-fold) in amodiaquine N-deethylase (a functional probe for CYP2C8 activity) also were observed with clofibric acid, fenofibric acid, and rifampin, in agreement with the mRNA finding. However, in contrast to the mRNA induction, marked decreases (>60%) in CYP2C8 activity were obtained with gemfibrozil treatment. Consistent with this finding, co-incubation of amodiaquine with gemfibrozil, but not with fenofibric acid, clofibric acid, or rifampin, in human liver microsomes or hepatocytes resulted in significantly decreased amodiaquine N-deethylase activity (IC₅₀ = 80 M for gemfibrozil, >500 M for fenofibric or clofibric acid, and >50 M for rifampin). Similar to rifampin, all three fibrates caused a modest change in the glucuronidation of chrysin, a nonspecific substrate of UGTs. No significant activation on human pregnane X receptor (PXR) was observed with the three fibrates in a PXR reporter gene assay.Conclusions. In human hepatocytes, both fenofibric acid and clofibric acid are inducers of CYP3A4 and CYP2C8. Gemfibrozil is also an inducer of CYP3A4, but acts as both an inducer and an inhibitor of CYP2C8. In this system, all fibrates are weak inducers of UGT1A1. The enzyme inducing effects of fibrates appear to be mediated via a mechanism(s) other than PXR activation. These results suggest that fibrates may have potential to cause various pharmacokinetic drug interactions via their differential effects on enzyme induction and/or inhibition.     

In Vitro Myotoxicity of Selected Cationic Macromolecules Used in Non-Viral Gene Delivery

Purpose. Cationic lipid/DNA complexes have been proposed as a method of in vivo gene delivery via intravenous or intramuscular injection. A concern with using these polycationic molecules is whether they are associated with tissue toxicity at the injection site. Therefore, the objective of these studies was to investigate the myotoxic potential of selected non-viral gene delivery macromolecules (e.g., cationic lipids and polymers) with and without plasmid DNA (pDNA) in vitro. Methods. Myotoxicity was assessed by the cumulative release of creatine kinase (CK) over 90 minutes from the isolated rodent extensor digitorum longus muscle into a carbogenated balanced salt solution (BBS, pH 7.4, 37°C) following a 15 L injection of the test formulation. Phenytoin (Dilantin^®) and normal saline served as positive and negative controls, respectively. Results. The myotoxicity of plasmid DNA (pDNA, ~5000bp, 1 mg/ ml) was not statistically different from normal saline. However, the myotoxicity of Dilantin^® was 16-times higher than either normal saline or pDNA (p < 0.05). Cationic liposomes were found to be less myotoxic than polylysine and PAMAM dendrimers. Polylysine's myotoxicity was found to be dependent upon concentration and molecular weight. The myotoxicity of formulations of cationic liposomes(s), lower molecular weight polylysine (25,000) and higher concentration of PAMAM dendrimers with pDNA were found to be statistically less significant than those formulations without pDNA. Conclusions. The cationic liposomes were less myotoxic compared to the dendrimers and polylysine. Myotoxicity was dependent upon the type of cationic lipid macromolecule, concentration, molecular weight and the presence of pDNA. A possible explanation for this reduced tissue damage in cationic lipids complexed with pDNA is that the formation of complex reduces the overall positive charge of the injectable system resulting in less damage.     

冠心病住院患者调脂药物应用情况调查

目的 调查冠心病住院患者中调脂药物的应用情况。方法 对347例确诊的冠心病患者在住院期间应用他汀类及贝特类调脂药物的使用情况进行调查，并对不同水平的LDL—C中他汀类药物的应用进行调查。结果 在347例患者中有221例的LDL—C＞2.6mmol/L，占63．69％，但仅有160例使用他汀类药物，使用率为46．1％；而使用贝特类药物的患者只有22例，使用率为6．3％。结论 在冠心病住院患者中存在着他汀类药物量使用不足的现象。     

Effect of Indian Polyvalent Antivenom in the Prevention and Reversal of Local Myotoxicity Induced by Common Cobra (Naja naja) Venom from Sri Lanka In Vitro

Bites by many Asiatic and African cobras (Genus: Naja) cause severe local dermonecrosis and myonecrosis, resulting in permanent disabilities. We studied the time scale in which two Indian polyvalent antivenoms, VINS and Bharat, remain capable of preventing or reversing in vitro myotoxicity induced by common cobra (Naja naja) venom from Sri Lanka using the chick biventer cervicis nerve-muscle preparation. VINS fully prevented while Bharat partially prevented (both in manufacturer recommended concentrations) the myotoxicity induced by Naja naja venom (10 µg/mL) when added to the organ baths before the venom. However, both antivenoms were unable to reverse the myotoxicity when added to organ baths 5 and 20 min post-venom. In contrast, physical removal of the venom from the organ baths by washing the preparation 5 and 20 min after the venom resulted in full and partial prevention of the myotoxicity, respectively, indicating the lag period for irreversible cellular injury. This suggests that, although the antivenoms contain antibodies against cytotoxins of the Sri Lankan Naja naja venom, they are either unable to reach the target sites as efficiently as the cytotoxins, unable to bind efficiently with the toxins at the target sites, or the binding with the toxins simply fails to prevent the toxin-target interactions.     

Rhabdomyolysis Caused by a Potential Sitagliptin-Lovastatin Interaction

A 75-year-old woman with diabetes mellitus, hypertension, and hyperlipidemia came to the emergency department with generalized and upper-extremity weakness; she had experienced a fall 2 months earlier. On admission, her drug therapy included lovastatin 40 mg/day, controlled-release diltiazem 240 mg/day, and glimepiride 1 mg/day. Nineteen days earlier, sitagliptin 100 mg/day had been started; it was discontinued 2 weeks later, and glimepiride was begun. A cardiology consultation performed on the day of admission determined that a markedly elevated creatine kinase-myocardial band isoenzyme level and borderline-high troponin I level were diagnostic of rhabdomyolysis secondary to statin use. Because the patient had been taking lovastatin for the past 12 years, the possibility that the rhabdomyolysis may have been caused by a drug interaction between lovastatin and a concomitant drug was evaluated. As it had been 10 months since her last dosage adjustment of diltiazem, it was unlikely that the statin-induced rhabdomyolysis was precipitated by diltiazem. Use of the Drug Interaction Probability Scale to determine the strength of a lovastatin-sitagliptin interaction indicated a possible association (score of 4). Multiple drug interactions have been reported with lovastatin. To our knowledge, however, this is the first case report of a possible sitagliptin-lovastatin interaction that may have caused rhabdomyolysis. Studies must be performed to further evaluate the in vivo effect of sitagliptin on the cytochrome P450 3A4 enzyme system and to elucidate other mechanisms that may potentiate such a drug-drug interaction. In the meantime, however, clinicians should be aware of this possible drug interaction.     

In Vitro Neutralization of the Myotoxicity of Australian Mulga Snake (Pseudechis australis) and Sri Lankan Russell’s Viper (Daboia russelii) Venoms by Australian and Indian Polyvalent Antivenoms

We studied the neutralisation of Sri Lankan Russell’s viper (Daboia russelii) and Australian mulga snake (Pseudechis australis) venom-induced myotoxicity by Indian (Vins and Bharat) and Australian (Seqirus) polyvalent antivenoms, using the in vitro chick biventer skeletal muscle preparation. Prior addition of Bharat or Vins antivenoms abolished D. russelii venom (30 µg/mL)-mediated inhibition of direct twitches, while Australian polyvalent antivenom was not protective. Bharat antivenom prevented, while Vins and Australian polyvalent antivenoms partially prevented, the inhibition of responses to exogenous KCl. Myotoxicity of Mulga venom (10 µg/mL) was fully neutralised by the prior addition of Australian polyvalent antivenom, partially neutralised by Vins antivenom but not by Bharat antivenom. Although the myotoxicity of both venoms was partially prevented by homologous antivenoms when added 5 min after the venom, with an increasing time delay between venom and antivenom, the reversal of myotoxicity gradually decreased. However, antivenoms partially prevented myotoxicity even 60 min after venom. The effect of antivenoms on already initiated myotoxicity was comparable to physical removal of the toxins by washing the bath at similar time points, indicating that the action of the antivenoms on myotoxicity is likely to be due to trapping the toxins or steric hindrance within the circulation, not allowing the toxins to reach target sites in muscles.     

Comparative studies on the influence of different fibrates on serum lipoproteins in endogenous hyperlipoproteinaemia

Summary Two trials have been performed in the same patients with hyperlipoproteinaemia Types IIb (12 cases), III (6 cases) and IV (11 cases). In the first study the lipid-lowering properties of bezafibrate, fenofibrate, gemfibrozil, etofibrate and etofylline clofibrate were compared and in a separate trial the influence of combined treatment with gemfibrozil plus colestipol and bezafibrate plus probucol on lipoproteins were investigated. The mean percentage lipid-lowering effect of each fibrate on serum and VLDL fraction was significant in the Types IIb, III and IV patients, but there were significant differences between the fibrates. In general, gemfibrozil and bezafibrate decreased plasma lipid levels more than etofibrate and etofylline clofibrate in Type IIb patients. In Type IV cases gemfibrozil and bezafibrate were significantly potent in reducing the triglyceride level than fenofibrate, etofibrate or etofylline clofibrate. All the fibrates produced an increase in HDL cholesterol, but there were significant differences between them were in the Type IV patients. The influence of fibrates on the LDL fraction was much more variable. In hyperlipoproteinaemia Type IIb, a decrease in both LDL cholesterol and LDL apolipoprotein B was observed. In Type III and IV patients, however, an increase in LDL concentration occurred. The addition of colestipol to gemfibrozil therapy led to a further decrease in total cholesterol, LDL cholesterol and LDL apolipoprotein B in Type IIb patients. In patients with hyperlipoproteinaemia Types III and IV colestipol prevented the increase in LDL concentration after treatment with gemfibrozil alone. The effect of probucol on LDL cholesterol was comparable to that of colestipol. Combined treatment with gemfibrozil and colestipol caused an increase in HDL cholesterol concentration in contrast to combined treatment with bezafibrate and probucol. It is concluded that combined therapy with fibrates plus bile acid sequestrant would be of practical value in patients with hyperlipoproteinaemia Types IIb, III and IV.     

长期使用质子泵抑制剂致骨质疏松的研究进展

质子泵抑制剂(proton pump inhibitors,PPIs)是一类治疗酸相关疾病的常用药物,由于其安全性高、副作用小而广泛应用.近年来,随着使用PPIs的人逐年增加,长期使用PPIs产生的副作用也随之受到关注.质子泵抑制剂的长期使用造成骨质疏松症大多根据流行病学统计分析而佐证,其机制尚不明确.但研究普遍认为,使用PPIs会使钙吸收降低,干扰骨代谢,进而增加骨质疏松风险.随着骨代谢研究的深入,也出现了多种治疗骨质疏松的靶向药物.本文就长期服用质子泵抑制剂引发骨质疏松的流行病学、相关机制以及药源性骨质疏松治疗的研究进展作一综述.