我院神经内科重症监护室药源性肝酶升高病例分析

目的:为预防神经内科重症患者发生药源性肝损害提供参考。方法:采取回顾性分析的方法,对我院神经内科重症监护室2009-2013年上报的不良反应(ADR)中有关药源性肝酶升高的ADR报表进行归纳分析。结果:在28例应用药物后导致肝酶升高涉及的药品中,脑血管病药11例(39.29%),占首位;其次是抗感染药6例(21.43%)和中药5例(17.86%)。用药后首次出现肝酶升高的平均时间为(8±6.00)d,其中最快的为1 d(莫西沙星),肝酶升高达到峰值的平均时间为(10.54±6.72)d。28例患者中痊愈9例(32.14%),好转19例(67.86%);其中未停药3例(10.71%),停药25例(89.29%);停药后自行好转5例(17.86%),应用保肝药好转14例(50.00%)。结论:神经内科重症患者肝酶升高的发生率较高,尤其是老年患者以及合并感染的患者,但及时处理可好转。临床药师应注意监测患者肝功,发现肝酶异常及时治疗,更应在安全合理用药上当好医师的助手。     

Ticlopidine-Induced Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) occurs in association with a wide variety of disorders including infections, connective tissue diseases, and solid organ tumors. It also may coincide with administration of drugs such as mitomycin, metronidazole, oral contraceptives, cyclosporine, and many others. We report the occurrence of TTP in a patient shortly after the initiation of ticlopidine.     

基于医院信息系统的肝酶升高药品不良反应自动监测系统研究

目的:分析我院常用药品致急性肝功能损害情况。方法:建立医院信息系统(HIS)的肝酶升高药品不良反应(ADR)自动监测系统,对我院2010年12月974例发生肝功能损害的住院患者进行监测,并对其使用的药品进行统计、分析。结果:86例患者在药品使用过程中出现的肝酶升高可能与ADR有关,其中男性51例,女性35例;年龄1～95岁,平均(52.4±25.5)岁;涉及药品40种,抗菌药物占绝大多数,主要是头孢菌素类,其次为心血管系统药、非甾体抗炎药等。结论:该监测系统能及时、准确地发现ADR,监测结果与文献报道相符;特殊人群如老年人和婴幼儿易发生肝功能损伤的ADR;抗菌药物和心血管系统药等出现ADR大多与长期、联合用药有关。     

Elevated Pancreatic Enzymes after Extended Propofol Therapy

Propofol is a sedative hypnotic agent often administered for intensive care sedation. A 28-year-old man who suffered a severe head injury developed elevated pancreatic enzymes after receiving extended high-dosage propofol therapy. Amylase and lipase values gradually reduced toward normal after the drug was discontinued. Possible propofol-induced pancreatitis was reported with short-term but not with prolonged therapy. A definitive cause-and-effect relationship is unclear since head trauma also was reported to cause elevated pancreatic enzymes. Intensive care practitioners should be aware of this potential reaction.     

Liver Aminotransferases Are Elevated with Rhabdomyolysis in the Absence of Significant Liver Injury

Rhabdomyolysis is an uncommon finding in the emergency department. However, the clinical implications of rhabdomyolysis are important, with a significant minority of patients developing acute renal failure and multiorgan failure. When present, the cause of elevated aminotransferases in the setting of rhabdomyolysis is often unclear. We sought to determine the incidence of abnormal aminotransferases (defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >40 U/L) in the setting of rhabdomyolysis and how the aminotransferases decrease relative to the creatine phosphokinase (CPK) concentration as rhabdomyolysis resolves. A retrospective chart review of 215 cases of rhabdomyolysis with CPK of ≥1,000 U/L was performed. The incidence of an abnormal AST in the setting of rhabdomyolysis was 93.1% (95% confidence interval, 88.7% to 95.8%). An abnormal ALT was much less common and found in 75.0% (95% confidence interval, 68.7% to 80.2%) of patients with a CPK of ≥1,000 U/L (p?<?0.0001). In only one instance was the ALT?>?40 U/L while the AST was <40 U/L. Furthermore, AST concentrations (and not ALT) fall in parallel with CPK during the first 6 days of hospitalization for patients with rhabdomyolysis. Aminotransferase abnormalities, particularly AST, are common in the setting of rhabdomyolysis. AST concentrations decrease in parallel to CPK, suggesting skeletal muscle may be a significant source of AST elevation in these patients.     

Developmental Expression of Cytochrome P450 Enzymes in Human Liver

Abstract: Drug–metabolizing cytochrome P450 enzymes, the major phase I enzymes, are active in human liver already at very early stages of intrauterine development, although presumably at fairly low concentrations and in low numbers. During maturation, these enzymes go through various developmental programmes towards adulthood. The major increase both in abundance as well as in number of different enzymes takes place after birth, probably during the first year of life. Detailed information concerning these developmental changes is still limited. The major drug–metabolizing P450 enzymes appear to be primarily members of the CYP3A subfamily in all stages of development. The balance between different members of this subfamily, however, undergoes significant switches from the foetal predominant CYP3A7 to the major adult form CYP3A4. The ontogeny of the other cytochrome P450 enzymes is less well characterized, but the major switchon appears to occur mainly after birth. Developmental expression of P450 enzymes is one of the key factors determining the pharmacokinetic status of developing individuals both pre– and postnatally.     

羟氯喹在人肝微粒体CYP酶中的代谢研究

目的：探讨羟氯喹在人肝微粒体中的主要代谢酶及其代谢特点和参数。方法：建立高效液相色谱-荧光检测器（HPLC-FLD）测定孵育液中羟氯喹的方法,观察9种CYP酶特异性抑制剂对羟氯喹代谢的影响,计算羟氯喹的酶促动力学参数如米氏常数（Km）、最大反应速度（Vmax）和药物的内在清除率（CLint）。结果：9种酶抑制剂中孟鲁司特（CYP2CB抑制剂）、酮康唑（CYP3A4抑制剂）、噻氯匹定（CYP2B6抑制剂）能够显著抑制羟氯喹的代谢（P ＜ 0.05）。羟氯喹在人肝微粒体中Vmax为233.6 ng·mL-1·h-1·mgprotein-1,Km为14.5 ng·mL-1,CLint为16.2 h-1·mgprotein-1。结论：羟氯喹主要通过CYP2C8、CYP3A4和CYP2B6代谢,药物在体内清除速率慢,药物相互作用和蓄积是发生不良反应的重要因素。     

Cadmium Induced Changes in Gluconeogenic Enzymes in Rat Kidney and Liver

Male Sprague-Dawley rats were administered cadmium chloride 0, 50, 100, 150 and 200 ppm for 30 days. At the end of the treatments, the body weight gains, serum glucose, serum protein, serum glutamic oxalacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) were determined. Renal and hepatic key gluconeogenic enzymes; viz., pryuvate carboxylase, phosphoenol pyruvate carboxykinase, fructose-1, 6-diphosphatase and glucose-6-phosphatase were also determined. A significant decrease in body weight gain in rats treated with cadmium was observed. The serum glucose and protein levels were increased in rats receiving cadmium through feed. All four key gluconeogenic enzymes were increased in both kidney and liver tissues of rats treated with cadmium. The present results indicate that cadmium may induce gluconeogenesis from non-carbohydrate sources.     

The Role of Elevated Liver-Type Fatty Acid-Binding Proteins in Liver Diseases

Pharmaceutical Research - Liver-type fatty acid–binding protein (L-FABP) is mainly expressed in the liver as well as the proximal tubular epithelial cells in the kidney. In general, the...     

Effects of Aliphatic Chlorohydrocarbons on Drug-metabolizing Enzymes in Rat Liver in vivo

1. Various polychlorinated hydrocarbons were administered intragastrically to rats to examine their effects on the biotransformation capacity of the liver. Due to high toxicity, 1,1,2,2-tetrachloroethane and pentachloroethane were given at a dose level equivalent to one quarter of that of CCl₄ and the other chlorohydrocarbons (i.e. 2.6 mmol/kg).

2. Carbon tetrachloride at 10.3 mmol/kg was the most active in decreasing cytochrome P-450 content and the overall drug hydroxylation activities in rat liver. 1,1,2,2-Tetrachloroethane was the next most active in decreasing the hepatic drug oxidizing enzymic activities.

3. Epoxide hydratase activity in rat liver declined significantly after CCl₄, 1,1,2,2-tetrachloroethane and pentachloroethane administrations.

4. UDP-Glucuronosyltransferase was affected to a lesser extent than the microsomal mono-oxygenase or epoxide hydratase by chlorohydrocarbon treatment.     

Effects of Methapyrilene on Rat Hepatic Xenobiotic Metabolizing Enzymes and Liver Morphology

Effects of Methapyrilene on Rat Hepatic Xenobiotic MetabolizingEnzymes and Liver Morphology. GRAICHEN, M. E., NEPTUN, D. A.,DENT, J. G., POPP, J. A., AND LEONARD, T. B. (1985). Fundam.Appl. Toxicol. 5, 165–174. Short-term treatment of ratswith hepatocarcinogens elicits a consistent pattern of phenotypicchanges in hepatic drug metabolizing enzymes, the most strikingof which is a marked increase in microsomal epoxide hydrolase(EH) activity. The antihistaminic drug methapyrilene inducesa high incidence of hepatocellular carcinoma in F-344 rats.The studies reported here were designed to assess the effectsof methapyrilene on hepatic EH activity, cytochrome P-450-dependentmixed-function oxidase activities, liver morphology, and liver-derivedserum enzymes. Male F-344 rats were treated with three dailyoral doses of methapyrilene-HG, up to 300 mg/kg/day, and weresacrificed 48 hr after the last dose. Hepatic microsomal EHand cytosolic DT-diaphorase activities were increased in a dose-relatedfashion, to 420 and 230% of control, respectively. CytochromeP-450 content and benzphetamine-N-demethylase and ethoxycoumarin-O-deethylaseactivities were concomitantly decreased to 35–50% of control.Serum -glutamyl transpeptidase and alanine aminotransferaseactivities were elevated 22- to 27-fold, and serum bile acidsto 36-fold by treatment with methapyrilene. Periportal lesions,characterized by inflammation, nuclear and nucleolar enlargement,bile duct hyperplasia, and hepatocellular necrosis, were observedfollowing methapyrilene administration. The severity of theperiportal lesion correlated with elevations in the serum chemistryparameters. The increases noted in microsomal EH activity supportsthe suggestion that this enzyme may be a useful biochemicalmarker for exposure to hepatocarcinogens.     

益母草碱对小鼠肝药酶含量的影响

摘 要 目的：研究益母草碱对小鼠肝药酶含量的影响。 方法: 将40只ICR小鼠随机分为5组：空白对照组、益母草碱高（120 mg·kg-1）、中（90 mg·kg-1）、低剂量组（60 mg·kg-1）、阳性对照组（苯巴比妥钠,80 mg·kg-1）,每组8只。益母草碱组灌胃给药,1次/d,连续进行7 d;阳性对照组腹腔注射给药,1次/d,连续进行5 d;空白对照组给予同等体积的生理盐水。检测肝微粒体蛋白、细胞色素P450酶（CYP450）、细胞色素b5（CYPb5）、氨基比林N 脱甲基酶（ADM）、红霉素N 脱甲基酶（ERD）、谷胱甘肽S 转移酶（GST）含量。结果: 与空白对照组相比,益母草碱各剂量组肝微粒体蛋白含量变化不明显（P>0.05）,CYP450、CYPb5、ADM含量显著降低（P<0.01）,中、高剂量组的ERD和高剂量组的GST含量显著降低（P<0.01）。益母草碱各剂量组与阳性对照组相比,以上各指标差异均有统计学意义（P<0.01）。 结论: 益母草碱能明显降低小鼠肝微粒体肝药酶的含量,下调CYP3A和CYP2E1的表达,其作用效果与益母草碱给药剂量相关。     

不同生化分析仪肝酶检测结果的可比性评价

目的：通过对OLYMPUS AU640生化分析仪及日立-7600生化分析仪肝酶检测结果及方法比对和偏差评估,探讨不同分析仪间结果的可比性及结果被临床接受程度。方法：以日立-7600分析仪作比对仪器,OLYMPUS AU640生化分析仪作实验仪器,检测患者血浆中肝酶含量,计算试验方法与比对方法间的相对偏差,并用统计法分析二者的相关性,计算出医学决定水平处的系统误差,以美国CLIA′88允许误差范围的1/2为标准,判断不同检测仪器的临床可接受性。结果：α-L-岩藻糖苷酶（AFU）在中、高值处离群值较多。其他酶类检测结果偏差均可被临床接受。结论：生化同一检测项目存在两个以上的检测仪器时,应进行方法比对和偏倚评估,判断其临床可接受性,保证其检验结果的可比性,为临床提供准确一致的检验结果。     

辛伐他汀中效治疗致横纹肌溶解并肝酶增高1例

结合文献分析我院发生的辛伐他汀中效治疗致横纹肌溶解并肝酶增高病例1例。辛伐他汀中效治疗致横纹肌溶解并肝酶增高的具体发生机制仍不清楚,考虑与抑制CYP3A4酶活性的药物联合应用,会增加用药风险。辛伐他汀中效治疗致横纹肌溶解并肝酶增高是严重的、罕见的不良反应,应引起医疗机构的重视,做好不良反应监测,做到安全有效用药。     

Effects of Phenoxyacetic Acid Herbicides on Chicken Embryo Liver Drug Metabolizing Enzymes

Abstract: Chick embryos were treated on day 0 of incubation with two phenoxy herbicides, 2-methyl-4-chlorophenoxyacetic acid (MCPA) (0.4, 2 mg/egg) and 2,4-dichlorophenoxyacetic acid (2, 4-D) (1, 2, 4 mg/egg). Both herbicides seemed to exert toxic effects mainly on the liver of 19-day-old embryos. Specific histological analysis indicated biliary stasis. Ethoxycoumarin O-deethylase was depressed by MCPA but raised by 2, 4-D. Other hepatic monooxygenase activities were unaffected by the herbicides and no significant changes were found in cytochromes. The higher dose of MCPA increased NADPH-cytocrome P₄₅₀ reductase. 2,4-D treatment increased by activity of glutathione-S-transferases in the hepatic post-microsomal fraction while MCPA increased them at the lower dose and significantly reduced them at the higher. The phenoxyacetic herbicides appear thus to have some effects on hepatic drug metabolizing enzymes of the chick embryo which cannot be easily interpreted. Biliary retention, produced in particular by MCPA, could be partly responsible for these effects.     

Sex-related Differences in Rat Liver Microsomal Enzymes and Their Induction by Doxapram

Abstract— The effects of doxapram on the hepatic microsomal mono-oxygenase system of male and female rats were investigated. Male and female rats were administered doxapram (10–120 mg kg^?1 day^?1, i.p.) for 4 days. In female rats, administration of doxapram (20, 40, 60, 80, 100 and 120 mg kg^?1) elevated the parameters in a dose-dependent manner while doxapram (100 and 120 mg kg^?1) elevated the levels of cytochrome P450 and hexobarbitone hydroxylase in male rats. Doxapram (40 mg kg^?1) caused induction of hepatic drug metabolism typified by an increase of hepatic microsomal cytochrome P450 content and activities of hexobarbitone hydroxylase, benzphetamine N-demethylase and ethylmorphine N-demethylase in female rats, but no change in male rats. These findings were supported by the results of SDS/polyacrylamide-gel electrophoresis. However, 7-ethoxycoumarin O-de-ethylase and arylhydrocarbon hydroxylase activities were significantly increased in male rats. NADPH-cytochrome c reductase and NADH-cytochrome c reductase activities, and cytochrome b₅ content were unaffected in rats of both sexes. The sex-dependent cytochrome P450 species may be selectively sensitive to the action of doxapram.     

酒精代谢酶基因多态性与酒精性肝病关系

目的：研究酒精代谢酶基因多态性与酒精性肝病的关系。方法：检索PubMe暾据库及参考互联网文献．并进行分析综述。结果：酒精性肝病的形成和发展与酒精代谢关键酶（包括乙醇脱氢酶、乙醛脱氢酶和细胞色素4502E1）的基因多态性密切关联。结论：酒精性肝病与酒精代谢酶基因多态性有密切关系。     

Protective Effects of Zinc on Oxidative Stress Enzymes in Liver of Protein-Deficient Rats

Persons afflicted with protein malnutrition are generally deficient in a variety of essential micronutrients like zinc, copper, iron, and selenium, which in turn affects number of metabolic processes in the body. To evaluate the protective effects of zinc on the enzymes involved in oxidative stress induced in liver of protein-deficient rats, the current study was designed. Zinc sulfate at a dose level of 227mg/L zinc in drinking water was administered to female Sprague–Dawley normal control as well as protein-deficient rats for a total duration of 8 weeks. The effects of zinc treatment in conditions of protein deficiency were studied on rat liver antioxidant enzymes, which included catalase, glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), glutathione reduced (GSH), and glutathione-S-transferase (GST). Protein deficiency in normal rats resulted in a significant increase in hepatic activities of catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase and the levels of lipid peroxidation. A significant inhibition in the levels of reduced glutathione and the enzyme activity of superoxide dismutase has been observed after protein deficiency in normal rats. Interestingly, Zn treatment to protein-deficient animals lowered already raised activity catalase, glutathione peroxidase, and glutathione-S-transferase and levels of lipid peroxidation to significant levels when compared to protein-deficient animals. Also, Zn treatment to the protein-deficient animals resulted in a significant elevation in the levels of GSH and SOD activity as compared to their respective controls, thereby indicating its effectiveness in regulating their levels in adverse conditions. It has also been observed that concentrations of zinc, copper, iron, and selenium were found to be decreased significantly in protein-deficient animals. However, the levels of these elements came back to within normal limits when zinc was administrated to protein-deficient rats. This study concludes that zinc has thepotential to regulate the activities of oxidative stress enzymes as well as essential hepatic elements.     

Ethanol Induced Alteration of Microsomal Membrane Bound Enzymes of Rat Liver in Vitro

Abstract: Ethanol appeared to inhibit more readily the 0-demethylation of p-nitroanisole than the activity of arylhydrocarbon hydroxylase. Arylhydrocarbon hydroxylase was more sensitive to the inhibition by ethanol in control or phenobarbital pretreated rats than in rats administered 3,4-benzpyrene. Ethanol was shown to activate the glucuronidation of p-nitrophenol at 2.45 mol/l, which was followed by inhibition at higher ethanol concentrations. A similar activation could also be demonstrated in rats pretreated with phenobarbital or 3,4-benzpyrene. This activation was not seen in microsomes pretreated in vitro with detergents like digitonin and cetylpyridinium chloride. Glucose 6-phosphatase was not clearly inhibited until the ethanol concentration was as high as 4 mol/l. Digitonin and trypsin treatments of the microsomal membrane in vitro appeared to activate the measurable glucose 6-phosphatase activity.     

Inhibitory Effects of Trospium Chloride on Cytochrome P450 Enzymes in Human Liver Microsomes

Abstract Trospium chloride, an atropine derivative used for the treatment of urge incontinence, was tested for inhibitory effects on human cytochrome P-450 enzymes. Metabolic activities were determined in liver microsomes from two donors using the following selective substrates: dextromethorphan (CYP2D6), denitronifedipine (CYP3A4), caffeine (CYP1A2), chlorzoxazone (CYP2E1), S-(+)-mephenytoin (CYP2C19), S-(-)-warfarin (CYP2C9) and coumarin (CYP2A6). Incubations with each substrate were carried out without a possible inhibitor and in the presence of trospium chloride at varying concentrations (37–3000 μM) at 37° in 0.1 M KH₂PO₄ buffer containing up to 3% DMSO. Metabolite concentrations were determined by high-performance liquid chromatography (HPLC) in all cases except CYP2A6 where direct fluorescence spectroscopy was used. First, trospium chloride IC₅₀ values were determined for each substrate at respective K_M concentrations. Trospium chloride did not show relevant inhibitory effects on the metabolism of most substrates (IC₅₀ values considerably higher than 1 mM). The only clear inhibition was seen for the CYP2D6-dependent high-affinity O-demethylation of dextromethorphan, where IC₅₀ values of 27 μM and 44 μM were observed. Therefore, additional dextromethorphan concentrations (0.4–2000 μM) were tested. Trospium chloride was a competitive inhibitor of the reaction with K_i values of 20 and 51 μM, respectively. Thus, trospium chloride has negligible inhibitory effects on CYP3A4, CYP1A2, CYP2E1, CYP2C19, CYP2C9 and CYP2A6 activity but is a reasonably potent inhibitor of CYP2D6 in vitro. Compared to therapeutic trospium chloride peak plasma concentrations below 50 nM, the 1000-times higher competitive inhibition constant K_i however suggests that inhibition of CYP2D6 by trospium chloride is without any clinical relevance.