辅酶Q10对他汀类药物引起肌病的影响

羟甲基戊二酸单酰辅酶A(HMG-CoA)还原酶抑制剂即他汀类药物,目前临床广泛用于高血脂症的治疗.他汀类药物引起的不良反应肌病越来越受到关注.辅酶Q10(CoQ10)的缺乏则是引起肌病的重要原因,而他汀药物可能通过抑制CoQ10的合成及转运,减少血液循环中的CoQ10,对肌肉组织和线粒体中CoQ10的水平也有一定影响.试验证明,CoQ10和他汀类药物联合使用可以缓解他汀类药物引起的肌痛症状.文中综述了他汀类药物对血液循环和肌肉组织中CoQ10影响、他汀类药物对线粒体损伤及联用CoQ10后缓解他汀类药物引起的肌痛的研究进展.     

Effect of coenzyme Q10 on cutaneous healing in skin-incised mice

Coenzyme Q10 (CoQ10) is a biosynthesized quinone with 10 isoprene side chains in humans. To investigate the anti-inflammatory and wound healing effect of CoQ10, we performed in vivo and in vitro experiments. In vivo studies, there were 3 groups; Naive (without skin incision), Control (with skin incision) and CoQ10 (100 mg/kg treatment with skin incision). Collagen-like polymer (CLP) level of CoQ10 group was increased significantly compared to the control group (p<0.05). Also, CoQ10 group showed significant inhibition on myeloperoxidase (MPO) and PLA₂ level compared to the control group (p<0.05). These data show that CoQ10 may have an anti-inflammatory and a wound healing effect. CoQ10 showed significant antioxidant activity in vivo on malondialdehyde (MDA) and superoxide dismutase (SOD) levels compared to the control group (p<0.05). Although CoQ10 did not show antioxidant activity in cell free system of DPPH radical scavenge, it had a potent antioxidant activity in cell culture system of both silica- and zymosan-induced reactive oxygen species generation using Raw 264.7 cells. This result may be associated with the conversion of CoQ10 to the reduced form (CoQ10H₂) in the presence of some kinds of intracellular reducing agents. In conclusion, it is considered that CoQ10 appears to have a cutaneous healing effect in vivo, which may be related to the secondary action of CoQ10.     

Hepatoprotective effect of coenzyme Q10 in rats with acetaminophen toxicity

The potential protective effect of coenzyme Q10 against acute liver injury induced by a single dose of acetaminophen (700 mg/kg, p.o.) was investigated in rats. Coenzyme Q10 treatment was given as two i.p. injections, 10 mg/kg each, at 1 and 12 h following acetaminophen administration. Coenzyme Q10 significantly reduced the levels of serum aminotransferases, suppressed lipid peroxidation, prevented the decreases of reduced glutathione and catalase activity, decreased the elevations of tumor necrosis factor-α and nitric oxide as well as attenuating the reductions of selenium and zinc ions in liver tissue resulting from acetaminophen administration. Histopathological liver tissue damage mediated by acetaminophen was ameliorated by coenzyme Q10. Immunohistochemical analysis revealed that coenzyme Q10 significantly decreased the acetaminophen-induced overexpression of inducible nitric oxide synthase, nuclear factor-κB, caspase-3 and p53 in liver tissue. It was concluded that coenzyme Q10 protects rat liver against acute acetaminophen hepatotoxicity, most probably through its antioxidant, anti-inflammatory and antiapoptotic effects.     

Therapeutic use of coenzyme Q10 and coenzyme Q10-related compounds and formulations

Importance of the field: Coenzyme Q₁₀ (CoQ₁₀) is found in blood and in all organs. CoQ₁₀ deficiencies are due to autosomal recessive mutations, ageing-related oxidative stress and carcinogenesis processes, and also statin treatment. Many neurodegenerative disorders, diabetes, cancer and muscular and cardiovascular diseases have been associated with low CoQ₁₀ levels, as well as different ataxias and encephalomyopathies.

Areas covered in this review: We review the efficacy of a variety of commercial formulations which have been developed to solubilise CoQ₁₀ and promote its better absorption in vivo, and its use in the therapy of pathologies associated with low CoQ₁₀ levels, with emphasis in the results of the clinical trials. Also, we review the use of its analogues idebenone and MitoQ^®.

What the reader will gain: This review covers the most relevant aspects related with the therapeutic use of CoQ₁₀, including existing formulations and their effects on its bioavailability.

Take home message: CoQ₁₀ does not cause serious adverse effects in humans and new formulations have been developed that increase CoQ₁₀ absorption. Oral CoQ₁₀ is a viable antioxidant strategy in many diseases, providing a significant to mild symptomatic benefit. Idebenone and MitoQ are promising substitutive CoQ₁₀-related drugs which are well tolerated and safe.     

Effect of carnitine and coenzyme Q10 on the calcium uptake in heart sarcoplasmic reticulum of rats treated with anthracyclines.

The effect of the association of carnitine and coenzyme Q10 on doxorubicin cardiotoxicity has been investigated. The two drugs administered to rats for two weeks have lower protective activity when they are administered separately rather than given in association (carnitine 200 mg/kg/day, coenzyme Q10 10 mg/kg/day) for the acute toxic effect of doxorubicin on perfused functioning isolated hearts. The sarcoplasmic reticulum damage measured by calcium-uptake is lower in rat hearts treated with the combined drugs. Deferoxamine and phosphocreatine, two compounds which protect from peroxidative damage due to iron and copper ions, show very strong protection from acute doxorubicin toxicity in isolated perfused hearts. Carnitine and coenzyme Q10 do not protect sarcoplasmic reticulum from iron ions damage, suggesting that their mechanism of protection is not directly related to peroxidation due to metal ion-dependent cardiotoxicity of doxorubicin.     

辅酶 Q10对脓毒血症休克大鼠血管平滑肌细胞功能的影响

目的探讨辅酶 Q10对脓毒血症休克大鼠血管平滑肌细胞功能的影响及其作用机制研究。方法采用 SD大鼠尾静脉注射脂多糖( LPS)的方法建立脓毒症休克动物模型,分离取出主动脉, 0.2%胶原酶消化分离平滑肌细胞( SMCs),自然纯化及差速贴壁纯化血管平滑肌细胞,将分离后的 SMC分别接种到 96孔板中,分为 4组,分别为正常对照组、正常对照组 +辅酶 Q10、LPS组、 LPS+辅酶 Q10组,分别检测 4组的增殖和氧化应激产物产生情况,在 6、12、24、48 h后分别检测正常对照组、正常对照组 +辅酶 Q10、LPS组、 LPS+辅酶 Q10组 SMCs丙二醛水平,在 48 h后检测 α-肌动蛋白( α-actin)、骨桥蛋白( OPN)的相对表达量。结果随时间推移, LPS组中 SMC细胞凋亡和氧化应激产物均较正常对照组增多,在 48 h时达到峰值,分别增多 11.4倍和 5.6倍; LPS+辅酶 Q10组中氧化应激产物较 LPS组减少近 50%;在 48 h时辅酶 Q10在正常培养环境下对 SMC的 α-actin、OPN蛋白的相对表达量差异无统计学意义( P>0.05),而对脓毒症休克 SD大鼠分离的 SMC可以明显减低氧化应激产物的生成及上调 α-actin蛋白的相对表达量近 1.57倍,下调 OPN蛋白的相对表达量 1.17倍。结论由 LPS所致的脓毒症休克的发病机制与血管中膜平滑肌细胞表型改变密切相关,辅酶 Q10可明显减低氧化应激产物的生成及上调 α-actin蛋白的相对表达量,缓解了因 LPS所致脓毒血症休克的血管病理化转变。收缩型平滑肌细胞是正常情况下血管壁的重要组成部分,而疾病病理血管则表现为合成型,为脓毒血症休克的病理性血管形成提供理论基础。     

Effect of coenzyme Q10 on hemodynamic response to ocular timolol

Coenzyme Q10 (CoQ10) is an essential component of the mitochondrial membrane and plays an important role in the maintenance of normal cardiac function. To evaluate the effects of ocular timolol on the cardiovascular system and determine the protective effect of CoQ10, 16 patients with glaucoma were studied using impedance cardiography. Following instillation of 1 mg timolol maleate in each eye, heart rate (HR) and stroke index (SI) decreased, and total peripheral resistance index (TPRI) increased significantly. Reexamination was performed after 6 weeks of 90 mg oral CoQ10. Despite decreases in HR, percent changes in HR were significantly less after CoQ10 at 120 min. Stroke index showed an initial increase which was not observed without CoQ10. These data suggest that CoQ10 delayed the appearance of inotropic blockade of timolol and hastened the disappearance of chronotropic blockade. Additional study of six normal volunteers with 6 weeks of oral CoQ10 showed a similar decrease of intraocular pressure after timolol instillation as compared to those without CoQ10. Thus, administration of oral CoQ10 in patients receiving ocular timolol may be useful in mitigating cardiovascular side effects without affecting intraocular pressure in the treatment of glaucoma.     

Therapeutic effect of coenzyme Q10 against experimentally-induced hepatocellular carcinoma in rats

The therapeutic potential of coenzyme Q10 was investigated in rats with hepatocellular carcinoma induced by trichloroacetic acid (0.5 g/kg/day, p.o., for five days). Coenzyme Q10 treatment (0.4 mg/kg/day, i.p.) was applied for four weeks following trichloroacetic acid administration. Coenzyme Q10 significantly suppressed lipid peroxidation, prevented the depletion of reduced glutathione and superoxide dismutase activity, and decreased the elevations of tumor necrosis factor-α and nitric oxide in liver tissue of rats with hepatocellular carcinoma. Also, the histopathological dysplastic changes induced by trichloroacetic acid in liver tissue were ameliorated by coenzyme Q10. Immunohistochemical analysis revealed that coenzyme Q10 significantly decreased the expression of hepPar-1, alpha-fetoprotein, inducible nitric oxide synthase, cyclooxygenase-2 and nuclear factor-κB in liver tissue of rats with hepatocellular carcinoma. It was concluded that coenzyme Q10 may represent a potential therapeutic option for liver carcinogenesis.     

Thirteen-week repeated dose oral toxicity study of coenzyme Q10 in rats

As part of a safety evaluation of Coenzyme Q10, a subchronic toxicology study was conducted. Coenzyme Q10 was repeatedly administered orally to male and female Crl:CD(SD) rats at daily dose levels of 300, 600 and 1200 mg/kg for 13 weeks. Neither death nor any toxicological signs were observed in any group during the administration period. No change related to the test substance administered was observed in any group with regard to body weight, food consumption, ophthalmoscopy, hematology, blood biochemistry, necropsy, organ weights or histopathology. Based on these results, the non-observed-adverse-effect level (NOAEL) of Coenzyme Q10 was considered to be 1200 mg/kg/day for male and female rats under these study conditions.     

Control of arterial tone after long-term coenzyme Q10 supplementation in senescent rats

1. Age-associated deterioration of arterial function may result from long-lasting oxidative stress. Since coenzyme Q (Q₁₀) has been suggested to protect the vascular endothelium from free radical-induced damage, we investigated the effects of long-term dietary Q₁₀ supplementation on arterial function in senescent Wistar rats.
2. At 16 months of age, 18 rats were divided into two groups. The control group was kept on a standard diet while the other group was supplemented with Q₁₀ (10 mg kg⁻¹ day⁻¹). In addition, nine rats (age 2 months) also ingesting a standard diet were used as the young control group. After 8 study weeks the responses of the mesenteric arterial rings in vitro were examined.
3. Endothelium-independent arterial relaxations to isoprenaline and nitroprusside (SNP) were attenuated in aged rats. Increased dietary Q₁₀ clearly enhanced the relaxation to isoprenaline, but did not affect the response to SNP. In addition, vasodilation of noradrenaline-precontracted rings to acetylcholine (ACh), which was also impaired in aged vessels, was improved after Q₁₀ supplementation. Cyclooxygenase inhibition with diclofenac enhanced the relaxation to ACh only in young rats, while it abolished the difference between the old controls and Q₁₀ supplemented rats, suggesting that the improved endothelium-dependent vasodilation observed in Q₁₀ supplemented rats was largely mediated by prostacyclin (PGI₂).
4. In conclusion, long-term Q₁₀ supplementation improved endothelium-dependent vasodilation and enhanced β-adrenoceptor-mediated arterial relaxation in senescent Wistar rats. The mechanisms underlying the improvement of endothelial function may have included augmented endothelial production of PGI₂, increased sensitivity of smooth muscle to PGI₂, or both.

     

Effect of treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on serum coenzyme Q10 in diabetic patients.

Serum coenzyme Q10 (CoQ10: 2-(3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34 ,38 -tetracontadecaenyl)-5,6-dimethoxy-3-methyl-1,4-benzoquinone, CAS 303-98-0) and cholesterol levels were measured to assess the effect of cholesterol-lowering therapy in patients with non-insulin-dependent diabetes mellitus (NIDDM). Twenty healthy volunteers, 97 NIDDM patients and 2 patients with familial hypercholesterolemia were studied. None had overt heart failure or any other heart disease. Mean serum CoQ10 concentrations were significantly (p < 0.01) lower in diabetic patients with normal serum cholesterol concentrations, either with or without administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA RIs) including simvastatin (normal: 0.91 +/- 0.26 (mean +/- SD) mumol 1(-1); diabetic with HMG-CoA RI: 0.63 +/- 0.19; diabetic without HMG-CoA RI: 0.66 +/- 0.21). CoQ10 concentrations were higher (1.37 +/- 0.48, p < 0.001) in diabetic patients with hypercholesterolemia. Simvastatin or low density lipoprotein apheresis decreased serum CoQ10 concentrations along with decreasing serum cholesterol. Oral CoQ10 supplementation in diabetic patients receiving HMG-CoA RI significantly (p < 0.001) increased serum CoQ10 from 0.81 +/- 0.24 to 1.47 +/- 0.44 mumol 1(-1), without affecting cholesterol levels. It significantly (p < 0.03) decreased cardiothoracic ratios from 51.4 +/- 5.1 to 49.2 +/- 4.7%. In conclusion, serum CoQ10 levels in NIDDM patients are decreased and may be associated with subclinical diabetic cardiomyopathy reversible by CoQ10 supplementation.     

Effect of coenzyme Q10 on warfarin hydroxylation in rat and human liver microsomes

Our previous animal study has suggested that the accelerated metabolism of warfarin enantiomers with concurrent coenzyme Q(10) (CoQ(10)) treatment accounts for the reduced anticoagulant effect of warfarin in rats. The present study was to assess the effect of CoQ(310) on individual hydroxylation pathways of the in vitro microsomal metabolism of warfarin enantiomers and to extrapolate in vitro data to in vivo situation. The effect of the antioxidant CoQ(10) on the hydroxylation of warfarin enantiomers was examined using rat and human liver microsomes. Based on the in vitro kinetic data, together with the information retrieved from the literature, the magnitude of warfarin-CoQ(10) interaction in man was quantitatively predicted. In rat liver microsomes, CoQ(10) exhibited a selective activation effect on the 4'-hydroxylation of S-warfarin, with a K(A) value (i.e. dissociation constant of the enzyme-activator complex) being one third and one fifth of those for the 6- and 7-hydroxylation, respectively. The activation effect of CoQ(10) was selective towards the 6- and 7-hydroxylation of R-warfarin at low substrate concentrations, but towards the 4'-hydoxylation of the R-enantiomer at high substrate concentrations. In human liver microsomes, CoQ(10) was a selective activator of the 7-hydroxylation of both R- and S-enantiomers of warfarin, with K(A) values being half to one twelfth of those for the other pathways. A relatively accurate prediction was made for the increase in the total and hepatic clearance of both S- and R-warfarin in rats with concurrent CoQ(10) treatment based on their respective overall hydroxylation, when the active transport of CoQ(10)into the hepatocytes was taken into consideration. In man, one would expect about 32% and 17% increase in the total clearance of S- and R-warfarin, respectively, with coadministration of 100 mg CoQ(10). In both species, CoQ(10) had enzyme activation effect, which appeared to be regioselective but not stereoselective, on the formation of the phenolic metabolites of warfarin enantiomers. A moderate increase in the total clearance of warfarin enantiomers could occur with coadministration of CoQ(10)in humans.     

辅酶Q_(10)微生物发酵生产的研究进展

利用微生物发酵生产的辅酶Q10(CoQ10)产物活性好,并可通过诱变育种和优化工艺大幅度提高生产能力。文章综述菌种的突变育种、发酵工艺的优化。     

The effect of coenzyme Q10 on the action of phospholipase

Using dimyristoyl L-alpha-phosphatidylcholine as a substrate, the effect of coenzyme Q10 on phospholipid digestion by phospholipase A2 and phospholipase C was investigated. Free myristic acids released by phospholipase A2, and myristic acids of dimyristoyl glyceride released by phospholipase C were methylated and determined quantitatively by gas-chromatography. Phospholipase A2 or phospholipase C released myristic acids dose-dependently from the substrate. Coenzyme Q10 prevented dose-dependently the hydrolysis of the substrate caused by phospholipase. These results suggest that pharmacological action of coenzyme Q10 could be attributed to its protection of membrane phospholipids against the attack of phospholipases.     

国产辅酶Q10有关物质的评价研究

目的综合考察国产辅酶Q10有关物质的含量情况。方法参考美国药典和欧洲药典,采用HPLC法测定了31批辅酶Q10原料及其各种类型制剂中辅酶Q9和(2Z)-异构体的含量。结果辅酶Q10原料及其各种类型制剂中均检出辅酶Q9和(2Z)-异构体。结论该研究可为国产辅酶Q10质量评价提供实验数据。     

Research on coenzyme Q10 in clinical medicine and in immunomodulation

Coenzyme Q10 (CoQ10) is a redox component in the respiratory chain. CoQ10 is necessary for human life to exist; and a deficiency can be contributory to ill health and disease. A deficiency of CoQ10 in myocardial disease has been found and controlled therapeutic trials have established CoQ10 as a major advance in the therapy of resistant myocardial failure. The cardiotoxicity of adriamycin, used in treatment modalities of cancer, is significantly reduced by CoQ10, apparently because the side-effects of adriamycin include inhibition of mitochondrial CoQ10 enzymes. Models of the immune system including phagocytic rate, circulating antibody level, neoplasia, viral and parasitic infections were used to demonstrate that CoQ10 is an immunomodulating agent. It was concluded that CoQ10, at the mitochondrial level, is essential for the optimal function of the immune system.     

辅酶Q10中枢神经系统的安全性评价

目的 考察大剂量ig辅酶Q10对小鼠中枢神经系统的影响,为临床安全性评价提供实验依据。方法 将小鼠随机分为溶媒对照组、紫苏油对照组、阳性对照组（氯丙嗪或地西泮）和辅酶Q10低、中、高剂量组（1.5、3.0和6.0 g/kg,相当于临床等效剂量的75、150和300倍）,每组12只,雌雄各半,40 mL/kg单次ig给药。直接观察小鼠一般行为活动;转棒法观察小鼠运动协调能力;Anymaze动物行为学视频分析系统观察小鼠自发活动和与阈下剂量戊巴比妥钠的协同作用。结果 与溶媒对照组、紫苏油对照组比较,辅酶Q10 3个剂量组对小鼠一般行为活动、自发活动、运动协调能力和与阈下剂量戊巴比妥钠的协同作用均无显著差异。结论 大剂量ig辅酶Q10对小鼠中枢神经系统未见明显毒性作用。     

HPLC测定辅酶Q_(10)软胶囊中的主药并检查有关物质

目的建立测定软胶囊中辅酶Q10的含量及有关物质检查的方法。方法采用硅胶吸附HPLC法,色谱柱为TianheKromasil Silica(250 mm×4.6 mm,5μm),流动相为正己烷-正丁醇(99.2:0.8),柱温为35℃。结果辅酶Q10进样量1.320~6.032μg与峰面积的线性关系良好(r=0.9993),分析方法精密度的RSD=0.42%;辅酶Q10的最低检出限为0.57 ng(S/N=3)。结论所建方法简便、灵敏、准确,可用于辅酶Q10的含量测定及有关物质的检查。     

The effect of coenzyme Q10 on the pharmacokinetic parameters of theophylline

Interaction of a drug with other drugs and dietary supplements is becoming an emerging issue for patients and health insurance authorities due to awareness of adverse drug event. In this study, we examined the effects of coenzyme Q10 (CoQ10), one of the most popular dietary supplements, on the pharmacokinetic parameters of theophylline in rats. The pharmacokinetic parameters of theophylline changed significantly when the drug was administered after five consecutive days of pretreatment with CoQ10. Time to reach maximum plasma concentration of theophylline delayed when the drug was administered after the pretreatment with CoQ10. Maximum plasma concentration and area under the curve of theophylline were about two-fold increased and other pharmacokinetic parameters such as half-life and volume of distribution were also changed significantly. Therefore, although CoQ10 is generally considered a safe dietary supplement, it appears that patients on theophylline therapy should use caution when they take CoQ10.