降脂药益多酯的临床观察

益多酯治疗32例高脂血症患者,口服250mg bid,疗程为3mo(月),治疗后降血清总胆固醇总有效率67％,平均下降20％(p<0.001);降血清甘油三酯总有效率84％,平均下降率49％(p<0.001)高密度脂蛋白-胆固醇的总有效率73％,平均升高率46％(p<0.01)。在服药过程中,未见不良反应。作者认为本药是一可取的降脂药物,值得推广应用。     

安络宁治疗高脂血症的疗效观察

本文应用安络宁片治疗32例高脂血症患者,口服3片tid,疗程为3 mo(月),32例高胆固醇血症者治疗后总有效率为84％,平均下降率29％(p<0.001)。13例高甘油三酯血症者,总有效率85％,平均下降32％(p<0.001);28例高密度脂蛋白胆固醇偏低者,总有效率100％,平均升高率62％(p<0.001)。除1例在治疗过程中,出现肝功能絮浊试验轻度增高外,余无不良反应。作者认为本药除有较好的降脂作用外,尚有明显提高HDL-C的效果,值得推广应用。     

HPLC法测定苍耳丸中连翘酯苷A和绿原酸

目的 建立同时测定苍耳丸中连翘酯苷A和绿原酸的HPLC法.方法 采用HPLC法测定.色谱柱:Shim-pack VP-ODS(150 mm×4.6 mm,5μm);流动相:乙腈-0.2％磷酸溶液,梯度洗脱;体积流量:1.0 mL/min;检测波长:330 nm;进样量:10 μL;柱温:40℃.结果 连翘酯苷A在0.232～1.856 μg与峰面积积分值呈现良好的线性关系(r=0.999 6),平均回收率为97.82％,RSD值为1.55％;绿原酸在0.25～2.00 μg与峰面积积分值呈良好的线性关系(r=0.999 8),平均回收率为101.1％,RSD值为1.18％.结论 该方法简便,结果准确,重现性好,可作为苍耳丸的质量控制方法.     

贝诺酯片剂的研制及生物利用度研究

通过减小药物粒径,提高贝诺酯片剂的生物利用度。在市售片以A(500mg)基础上研制了新处方片剂B(400mg)。建立贝诺酯片剂体外溶出度试验方法,即以表面活性剂溶液作溶出介质,以浆法进行溶出度测定。用HPLC法测定贝诺酯在体内的水解产物水杨酸和扑热息痛的血药浓度。结果表明药物研磨粉碎前后体外溶出速度常数分别为0.0152min-1及0.0337min^-1(P<0.001)。A及B体外平均溶出时间分别为42.25min及15.77min(P<0.001)。体内研究表明A及B水杨酸的C_max,T_p,AUC之间均无显著性差异(P>0.1)(A,B的服用量分别为4.5g及3.6g),B的相对生物利用度为125.59%。     

吗替麦考酚酯联合激素治疗膜性肾病的疗效及安全性观察

目的 评价吗替麦考酚酯(MMF)联合激素治疗特发性膜性肾病(IMN)的疗效及安全性.方法 46例激素抵抗型IMN患者完全随机分为观察组(23例,MMF+泼尼松口服)和对照组(23例,环磷酰胺静脉滴注+泼尼松口服),疗程12个月.观察患者治疗前、治疗6及12个月尿蛋白、血白蛋白、Cr、TG及TC水平变化,评价治疗疗效及不良反应.结果 观察组治疗6及12个月后尿蛋白[(4.6±2.2)、(3.3±1.5)g/d]、TG[(2.4±1.7)、(2.2±1.3) mmol/L]及TC[(6.5±2.2)、(6.2 ±2.1) mmol/L]较治疗前[(6.8±1.5)g/d、(2.9±1.6) mmol/L、(9.1 ±2.5) mmol/L]明显降低,差异有统计学意义(P＜O.05或P＜O.01);血白蛋白[(35±5)、(39±4)g/L]较治疗前[(23±5) g/L]明显升高(均P＜0.05);治疗前后Cr无明显变化[(102±46)、(97±43)、(92±41) μmol/L,P＞O.05].观察组治疗6、12个月各指标与对照组[尿蛋白:(4.8±3.1)、(3.6±2.1)g/d;血白蛋白:(32±5)、(38±5)/L;Cr:(99±41)、(94±38)μmol/L;TG(2.5±1.4)、(2.3±1.6) mmol/L;TC:(6.7±2.7)、(6.3±2.9) mmol/L]比较,差异无统计学意义(均P＞0.05).观察组与对照组患者治疗6及12个月时的总有效率差异无统计学意义[65.2％(15/23)比60.9％( 14/23)、73.9％( 17/23)比69.6％( 16/23),均P＞O.05],但12个月内不良反应发生率[8.7％(2/23)]明显低于对照组[34.8％ (8/23)],差异有统计学意义(P＜0.01).结论 MMF联合激素治疗激素抵抗型IMN在达到相似临床疗效的基础上,副作用小,患者耐受性好,值得进一步深入研究.     

老年人腹形肥胖与非酒精性脂肪肝的关系探讨

目的探讨老年人腹形肥胖与非酒精性脂肪肝的关系。方法选择老年腹形肥胖患者共57例,对照组57例,检查两组的血浆甘油三脂及腹部B超。结果老年腹形肥胖组与对照组血浆甘油三脂TG分别为(2.067±0.596)mmol/l和(0.959±0.333)mol/l,B超检出脂肪肝例数分别为26例和7例,统计学分析表明,老年腹形肥胖组甘油三脂(TG)明显高于非腹形肥胖组(p<0.001),B超脂肪肝检出率老年腹形肥胖组明显高于非腹形肥胖组(p<0.005)。结论老年人腹形肥胖与非酒精性脂肪肝关系密切。     

反相高效液相色谱法测定阿德福韦酯的含量及有关物质

目的建立反相高效液相色谱法测定阿德福韦酯的含量及有关物质。方法ODS-C18色谱柱(200mm×4.6mm,5μm),以0.02m o l/L磷酸二氢钾(pH 6.0)∶乙腈(60∶40)为流动相,流速1.0m l/m in,检测波长254nm。结果含量测定在0.05~0.4μg/m l的浓度范围内呈良好线性关系(r=0.9997),平均回收率为100.27%,日间RSD=0.44%(n=6)。结论该方法简便、快速、结果准确、重现性好,可供本品质量控制用。     

非诺贝特治疗245例高脂血症的疗效观察

245例高脂血症口服非诺贝特的近期疗效观察,发现其具有明显的降血清胆固醇和甘油三酯的作用,有效率分别为81.4％及94.5％;平均下降率为22.6％及56.5％(p<0.001),在服药一个月时,即有明显下降。对高密度脂蛋白-胆固醇的提高亦有较好效果(78.7％),平均升高率29.2％(p<0.001)。副反应轻微,偶见血清谷丙转氨酶或尿素氮暂时性增高,停药后即恢复正常。本品远期疗效有待进一步观察。     

三蕊胶囊中维胺酯含量测定方法的改进

目的改进维胺酯的紫外分光光度检测方法,建立维胺酯的高效液相色谱含量测定方法。方法色谱柱为HypersilC18,流动相为甲醇-水(90∶10),检测波长为370 nm。结果用紫外检测维胺酯含量在1.0~25.0μg/m l范围内线性关系良好,平均加样回收率为107.2%(RSD为1.1%,n=9)。而用高效液相检测维胺酯含量在1.6~32.0μg/m l范围内线性关系良好,平均加样回收率为99.6%(RSD为2.0%,n=9)。结论采用高效液相测定维胺酯含量方法专属,可排除有关物质和辅料的影响,比用紫外分光光度法测定更准确可靠。     

国产头孢哌酮药代动力学和药效学研究

文报告14例病人国产头孢哌酮的药代动力学与药效学研究结果。国产和进口头孢哌酮2g恒速静滴1h,血浓峰值分别为211μg/ml和252μg/ml。国产品V_n值为0.24L/kg,进口品为0.17L/kg(p<0.05),其余各项动力学参数无显著差异,药时曲线方程国产品为y=165.40e~(-2.3258t)+155.53e~(-0.2127t),进口品为y=145.93e~(-3.1223t)+230.99e~(-0.3199t)。国产品以双室模型模拟相关性为r=0.9669,败血症病人显效血浓为287±68μg/ml,呼吸道感染病人显放血浓为223±51μg/ml。产生毒副反应组与未产生毒副反应组血浓分别为295和178μg/ml(p<0.01)。     

Treatment of hyperlipoproteinaemia type II a with a new anion exchange resin Secholex®

Summary Eleven patients with hyperlipoproteinaemia type II A, who were relatively resistant to hypolipidaemic drugs, were treated for four to six months with an anion exchange resin, Secholex^® (PDX chloride), 15 g per day. The mean monthly plasma cholesterol level decreased by 10–18% (p<0.01 andp<0.001 respectively) from its pre-treatment value of 431±50 mg/100 ml (mean ±95% confidence limits). The reduction of plasma cholesterol was due mainly to a decrease in low density lipoproteins (LDL) of 50 mg/100 ml (p<0.01). Very low density lipoproteins (VLDL) were moderately (p<0.05) reduced and high density lipoproteins (HDL) remained unchanged. The mean pretreatment plasma triglyceride level (110±30 mg/100 ml) did not alter significantly. Nine of the patients had previously received clofibrate and in them Secholex reduced plasma cholesterol by 17% and clofibrate by 6%. Excluding one patient on clofibrate who had an unexpected increase in plasma cholesterol, there was little difference between the efficacy of clofibrate and Secholex. After four months two patients withdrew from the trial because of constipation. There was slight transient increase in mean serum alkaline phosphatase and a decrease in serum uric acid during treatment with Secholex.     

The effects of clofibrate on plasma glucose,lipoproteins, fibrinogen,and other biochemical and haematological variables in patients with mature onset diabetes mellitus

Summary We have studied the effects of clofibrate treatment on glucose tolerance and plasma insulin, plasma triglyceride, cholesterol and non-esterified fatty acid (NEFA) levels, and on various haematological variables (including plasma fibrinogen level, red cell flexibility, whole blood viscosity, and plasma -thromboglobulin level) in patients with mature-onset diabetes. Twenty-two patients (11 men and 11 women) were randomly allotted to treatment with clofibrate, 1 g twice daily, or a corn-oil placebo for 12 weeks, and then changed to the alternate medication for another 12 weeks. Half the patients took clofibrate in the first 12 weeks of the study, and half took the placebo. The patients stayed on their usual diet, and 13 also took tolbutamide before and during the trial. The trial was double-blind. At the beginning, middle and end of the trial fasting measurements were made, and plasma glucose, insulin, triglyceride, and NEFA concentrations were then measured repeatedly during the next 8 h (from 8.00 a. m. to 4 p. m.), to allow calculation of the mean 8-h concentration of these substances. In general, plasma concentrations of glucose, triglyceride, cholesterol, NEFA and fibrinogen were lower when the patients were taking clofibrate then when they were taking the corn-oil placebo, but higher when taking the placebo than at entry to the trial. We favour the explanation that clofibrate has lowered these concentrations, when compared with the placebo. The alternative interpretation, that 2 g per day of the placebo increases plasma concentrations of glucose, triglyceride, cholesterol, NEFA and fibrinogen, and that clofibrate has little effect, seems unlikely. The first interpretation, that clofibrate has a positive effect when compared with an inert placebo, has been adopted when interpreting the results. Clofibrate treatment led to a 15% lower fasting blood glucose level, and 11% lower mean 8-h glucose concentration than did placebo (p<0.01) but it did not significantly change plasma insulin concentration. The fasting and mean 8-hour concentrations of plasma triglyceride and fasting plasma cholesterol concentrations were reduced by clofibrate (by 44%, 33% and 10% respectively, p<0.05). Clofibrate decreased the fasting plasma NEFA level by 27% (p<0.01), and the mean 8-h plasma NEFA concentration by 23% (p<0.05). A weak relationship between the mean 8-h levels of plasma NEFA and plasma glucose (r=0.49, p<0.05) was consistent with the suggestion that the change in plasma glucose could, in part, be due to a change in NEFA concentration. The mean plasma fibrinogen concentration was decreased 23% by clofibrate (p<0.01). There was a positive correlation between the observed decrease during treatment and the baseline fibrinogen concentration (r=0.80, p<0.001), i. e. the greatest decrease occurred in those subjects with the highest plasma fibrinogen concentrations. Whole blood viscosity fell slightly, but erythrocyte flexibility was not significantly changed by clofibrate. The mean haemoglobin concentration and leucocyte count fell slightly during clofibrate treatment and the platelet count rose. -thromboglobulin was not affected. Clofibrate treatment was associated with rises in plasma albumin, urea, creatine kinase and aspartate aminotransferase, and falls in plasma bilirubin, -glutamyl-transpeptidase and alkaline phosphatase. Most of these changes occurred within the reference range.     

Bioavailability of p-chlorophenoxyisobutyric acid (clofibrinic acid) after repeated doses of its calcium salt to humans

Summary Plasma concentrations and bioavailability of clofibrinic acid have been estimated under conditions approaching the steady-state during a ten-day period of administration as clofibrate or as a calcium clofibrinate-carbonate combination (1:1 w/w) at a dosage interval of 12 h. Formulation — related differences in bioavailability were not significant, and the 95% confidence limits of these differences were within –2% to +8% of the mean for the reference formulation of clofibrate. The mean steadystate plasma concentrations of clofibrinic acid measured on the tenth day of dosing were 116 µg/ml±22 S.D. and 119 µg/ml±23 S.D. after administration of 885 mg as clofibrate and the calcium clofibrinate-carbonate combination respectively. The peaks of mean plasma concentrations were 70 µg/ml±15 S.D., 119 µg/ml±32 S.D. and 131 µg/ml±26 S.D. on the first, fifth and tenth day of dosing with clofibrate, and 62 µg/ml±13 S.D., 127 µg/ml±S.D. and 143 µg/ml±25 S.D. on the corresponding days of dosing with the calcium clofibrinate-carbonate combination. After the last dose on the tenth day of dosing, the mean apparent half-lives of elimination of clofibrinic acid from plasma were 24.2 h±4.4 S.D. and 25.5 h±3.2 S.D. after administration of clofibrate and the calcium clofibrinate-carbonate combination respectively.     

Interaction of clofibrate with warfarin. I. Effect of clofibrate on the disposition of the optical enantiomorphs of warfarin

Four volunteers each received single oral doses of the R and S enantiomorphs of warfarin on separate occasions, both before and during clofibrate coadministration. Three of the subjects showed evidence for a drug interaction as manifested by an increase in the hypoprothrombinemic response to the S enantiomorph during clofibrate coadministration (0.10>p>0.05). No changes were observed in the response to the R enantiomorph. The volume of distribution of the R enantiomorph was increased (0.01>p> 0.005), as was the plasma clearance (0.10>p> 0.05), in all four subjects during clofibrate coadministration. No significant changes were found in the volume of distribution or clearance of the S enantiomorph. This study indicates that differential changes in the clearance of the enantiomorphs of warfarin are not the mechanism responsible for the interaction of clofibrate with warfarin. Although the results indicate that plasma protein displacement of warfarin occurs in vivo,it can be concluded that the mechanism underlying the long-term enhanced hypoprothrombinemic effect of warfarin in the presence of clofibrate is of a pharmacodynamic nature.This investigation was supported in part by NIH Grants GM22209 and 1-PO1-HL-15833. T. D. B. is a recipient of a Merck, Sharp & Dohme International Fellowship in Clinical Pharmacology. T. F. B. is a recipient of a Pharmaceutical Manufacturers Association Foundation Faculty Development Award.     

氯苯丁酯引起大鼠肝肿大与肝细胞生长因子产生的可能关系

目的研究氯苯丁酯引起的大鼠肝脏肿大与血浆中ＨＧＦ水平变化的关系。方法氯苯丁酯（５００，４００，３００，１００ｍｇ·ｋｇ－１·ｄ－１）加入饲料中喂养大鼠，在不同时间处死大鼠，取出肝脏称重和制备血清，以原代培养大鼠肝细胞ＤＮＡ合成检测ＨＧＦ的生物学活性。结果氯苯丁酯处理后的大鼠血清能显著增加原代培养大鼠肝细胞３Ｈ－ＴｄＲ的参入，ｃｐｍ值随着血清被稀释而逐渐降低，但仍高于对照组。大鼠血清中ＨＧＦ的释放在给药后４ｄ达到最高水平，为正常对照组的６倍以上，给药２ｗｋ后仍维持在正常水平的２倍以上。而氯苯丁酯引起肝脏肿大发生在给药２ｗｋ后，并维持在正常水平的１．８倍以上。结论氯苯丁酯引起的肝脏肿大可能部分与ＨＧＦ促肝细胞的增殖作用有关     

Drug treatment of lipoproteinaemia type II. Effect on plasma lipids of a new phenoxyacetic acid derivative,clofibrate, and nicotinic acid

Summary The plasma lipid-reducing effect of a new phenoxyacetic acid derivative (GP 45.699) has been studied in nine patients with lipoproteinaemia Type II A or Type II B. GP 45, 699, 0.75 g per day produced a marked (average 26%) fall in the plasma cholesterol. Doubling the dose led to further reduction of cholesterol, but plasma triglycerides rose. This was associated with an increase in plasma triglyceride turnover as measured by an intravenous fat-loading test (Intralipid), an elevation in serum simplastin A, and with a rise in the SGOT and SGPT levels. — It is suggested that GP 45.699 which is related chemically to clofibrate, has a marked effect on cholesterol catabolism and on the rate of turnover of plasma triglycerides. It also affects liver cells causing increased synthesis of plasma triglycerides or pre-beta-lipoprotein, and, in some cases receiving high doses (1.5 g daily), there may also be liver damage. Despite its promising capacity to reduce the plasmacholesterol level, there may not be sufficient justification for its routine use in cases of lipoproteinaemias.     

Effect of polyenyl phosphatidyl choline on clofibrate-induced increase in LDL cholesterol

Summary In a double-blind, randomised, cross-over trial clofibrate and a combination of polyenyl phosphatidyl choline (PPC) plus clofibrate were tested in 67 patients with hyperlipoproteinemia. Each treatment lasted for 4 weeks and was separated by a 4 week placebo period. The daily doses were clofibrate 1.2 g and PPC 1.8 g + clofibrate 1.2 g, respectively. The results revealed that polypenyl phosphatidyl choline prevented the elevation of LDL-cholesterol induced by clofibrate treatment, and that the lipid-lowering potency of the combination did not differ significantly from that of clofibrate. Since elevation of LDL-cholesterol is considered to increase the risk of coronary heart disease, the combination appears to offer a therapeutic advantage. Despite the significance of this clinical observation, a final decision may only be obtained from a prospective, long term investigation in patients with coronary heart disease and hyperlipoproteinemia.This work was presented in part at the IVth International Symposium on Atherosclerosis, Tokyo, Japan, August 24–28, 1976.     

SEPARATION OF TWO CONJUGATES OF CLOFJBRIC ACID (CPIB) FOUND IN THE URINE OF SUBJECTS TAKING CLOFIBRATE

1. Two main conjugates of CPIB (2-[chlorophenoxy]-2-methylpropionic acid) are present in the urine of subjects taking clofibrate. The metabolites can be separated by thin-layer chromatography (TLC). 2. Both conjugates are hydrolysed by dilute alkali, but only one is hydrolysed by the enzyme beta-glucuronidase. In eighty-five urine specimens this conjugate accounted for an average of 54.5% (range 25-70%) of the total CPIB, while 2.6-12.45% (mean 5.1%) was present as free CPIB.     

Anticholesterolemic effect of 3,4-di(OH)-phenylpropionic amides in high-cholesterol fed rats

Two amide synthetic derivatives of 3,4-di(OH)-hydrocinnamate (HC), 3,4-dihydroxyphenylpropionic (l-serine methyl ester) amide (E030) and 3,4-dihydroxyphenylpropionic (l-aspartic acid) amide (E076), were investigated to compare their lipid-lowering efficacy with HC. Male rats were fed a 1 g/100 g high-cholesterol diet for 6 weeks with supplements of either clofibrate (0.02%, w/w), HC (0.025%, w/w), E030 (0.039%, w/w) or E076 (0.041%, w/w). The clofibrate supplement was used as a positive control for the lipid-lowering efficacy. The food intakes and body weight gains were not significantly different among the groups. The plasma and hepatic cholesterol and triglyceride levels were lower in clofibrate, HC, E030, and E076-supplemented groups compared to the control group. The supplementation of HC and its amide derivatives was as effective as clofibrate in increasing the ratio of HDL-cholesterol to total plasma cholesterol and reducing the atherogenic index (AI). The hepatic cholesterol level in the HC and E076 groups was significantly lower than that in the clofibrate group. The hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA reductase) and acyl-CoA:cholesterol acyltransferase (ACAT) activities were significantly lower in the all test groups than in the control group. The excretion of neutral sterol was significantly higher in the HC, E030, and E076-supplemented groups compared to the control group. The plasma AST and ALT activities, indirect indexes of hepatic toxicity, were significantly lower in the HC, E030, and E076-supplemented groups than in the control group. Accordingly, the current results suggest that E030 and E076, two amide synthetic derivatives of HC, are effective in lowering lipid activity.