HMG-CoA还原酶抑制剂抗肾间质纤维化的作用机制

HMG-CoA还原酶是胆固醇合成过程中的关键性限速酶,他汀类药物作为HMG-CoA还原酶抑制剂是治疗血脂异常的经典药物,其作用不仅局限于此,多效性还表现在可以改善内皮功能,延缓动脉粥样硬化,抗血栓形成等。导致肾间质纤维的作用机制多种多样,往往表现为炎症细胞、因子等的浸润,肾小管上皮细胞的增殖及凋亡,细胞外基质的沉积,肾小管上皮间充质转分化等。而他汀类药物通过减轻炎症细胞、因子的浸润,抗凋亡、抗氧化应激,减轻细胞外基质沉积等作用延缓肾间质纤维化的进程。现将HMG-CoA还原酶抑制剂抗肾间质纤维化的作用机制作一综述。     

The influence of statin characteristics on their safety and tolerability

The efficacy of the statins for both primary and secondary prevention has now been clearly established in patients across the spectrum of cardiovascular risk. In addition to their primary effect in reducing plasma cholesterol, the statins possess various 'pleiotropic' effects that may contribute to their clinical effectiveness in reducing cardiovascular events, e.g. improvement of endothelial function, reduction of low-density lipoprotein-cholesterol oxidation and stabilisation of atheromatous plaques. Although statins share similar chemical characteristics, they differ significantly in terms of their molecular synthesis, solubility and pharmacokinetic behaviour and metabolism. Side-effects secondary to longterm statin therapy are rare, but rhabdomyolysis may occur when statins are administered together with other drugs that have a direct toxic effect on muscle or which inhibit statin metabolism. Among the various statins, it would appear that fluvastatin has the lowest propensity to interact with other drugs and the least potential to induce myotoxicity.     

Effect of HMG-CoA reductase inhibitors on plasma polyunsaturated fatty acid concentrations in patients with hyperlipidemia

We investigated the effect of 12 months’ HMG-CoA reductase inhibitor treatment on plasma polyunsaturated fatty acid concentrations in 19 patients with hyperlipidemia. Arachidonic acid concentrations were significantly increased following treatment (from 110.1±20.4 mg/l to 129.2±31.6 mg/l,P<0.05). The ratio of eicosapentaenoic acid to arachidonic acid was significantly decreased at the end of 12 months’ treatment (from 0.702±0.370 to 0.541±0.204,P<0.05). These results suggest that HMG-CoA reductase inhibitors may increase the synthesis of metabolites from arachidonic acid in patients with hyperlipidemia, and that the addition of fish oil is more effective for the prevention of coronary heart disease than HMG-CoA reductase inhibitors alone.     

Acute effects of HMG-CoA reductase inhibitors on biliary lipids in patients with interrupted enterohepatic circulation

HMG-CoA reductase inhibitors decrease serum cholesterol by inhibiting hepatic cholesterol synthesis, but their influence on biliary lipids is not well characterized. In the present study Pravastatin (80 mg) was administered as a single oral dose to 10 patients with external bile fistula, after 1 week of interruption of the enterohepatic circulation, in order to assess the effect of inhibition of hepatic cholesterol synthesis on biliary lipids in conditions of stimulated bile acid synthesis. Bile was collected every hour for 12 h. On the day before, the same procedure was applied with a placebo, and collected bile used as control. Pravastatin decreased both bile acid and phospholipid concentration to about 60% of basal values; this change was still significant after 10 h. Cholesterol concentration was also decreased to about 70% of basal values, but this change was significant only from the 5th to the 7th h. The per cent of cholic and chenodeoxycholic acid was not affected by the drug, but the ratio of glyco- to tauroconjugated bile acids was decreased to about half the initial values. Bilirubin concentration exhibited a late increase, suggesting a reduction in the bile flow. These results suggest that, in patients with interrupted enterohepatic circulation, biliary excretion of bile acids can be largely dependent on hepatic cholesterol synthesis.     

Rosuvastatin: a new inhibitor of HMG-CoA reductase for the treatment of dyslipidemia

Rosuvastatin (Crestor^®, AstraZeneca) is a synthetic statin that represents an advance on the pharmacologic and clinical properties of other agents in this class. Relative to other statins, rosuvastatin possesses a greater number of binding interactions with HMG-CoA reductase and has a high affinity for the active site of the enzyme. Rosuvastatin is relatively hydrophilic and is selectively taken up by, and active in, hepatic cells. Rosuvastatin has the longest terminal half-life of the statins and is only minimally metabolized by the cytochrome P450 (CYP 450) enzyme system with no significant involvement of the 3A4 enzyme. Consistent with this finding is the absence of clinically significant drug interactions between rosuvastatin and other drugs known to inhibit CYP 450 enzymes. In patients with hypercholesterolemia, rosuvastatin 10–40 mg has been shown to reduce low-density lipoprotein cholesterol (LDL-C) levels by 52–63%, as well as increase high-density lipoprotein cholesterol (HDL-C) levels by up to 14% and reduce triglycerides (TG) by up to 28%. Studies have shown that rosuvastatin is superior to atorvastatin, simvastatin and pravastatin in reducing LDL-C and favorably modifying other components of the atherogenic lipid profile. The significant decreases in LDL-C with rosuvastatin treatment should help to improve attainment of lipid goals and reduce the requirement for dose titration. In addition, the effects of rosuvastatin on HDL-C and TG levels will be of benefit in treating patients with abnormalities such as mixed dyslipidemia and the metabolic syndrome. Rosuvastatin is well tolerated, with a safety profile comparable with that of other currently available statins.     

HMG CoA reductase inhibition and left ventricular mass in hypertrophic cardiomyopathy: a randomized placebo-controlled pilot study

BACKGROUND: Statins reduce cardiomyocyte hypertrophy in animal models of hypertrophic cardiomyopathy, aortic banding and heart failure after myocardial infarction. We investigated the effect of the hydroxymethylglutaryl coenzyme A reductase inhibitor atorvastatin on left ventricular (LV) mass in patients with hypertrophic cardiomyopathy in a randomized placebo-controlled double-blind pilot study. MATERIALS AND METHODS: Patients with hypertrophic cardiomyopathy were randomized to be treated once daily by atorvastatin 80 mg or placebo for nine months. LV mass was assessed by serial cardiac magnetic resonance imaging. LV systolic and diastolic function was determined by echocardiography. Markers of collagen metabolism and inflammation were also assessed. RESULTS: Out of 78 screened patients with hypertrophic cardiomyopathy 28 (2 x 14) patients were eligible for randomization. Eleven patients in each group completed the study with cardiac magnetic resonance imaging assessments meeting the evaluation standards at baseline and at follow-up. Low-density lipoprotein cholesterol levels in the atorvastatin group decreased from 3.24 +/- 1.14 mmol L(-1) (125 +/- 44 mg dL(-1)) at baseline to 1.37 +/- 0.49 mmol L(-1) (53 +/- 19 mg dL(-1)) at follow-up (P < 0.001), but were unchanged in the placebo group. Baseline LV mass was 228 +/- 51 g in the placebo and 232 +/- 67 g in the atorvastatin group. The primary endpoint of change in LV mass from baseline to follow-up was 2 +/- 10% in the atorvastatin group versus 0 +/- 13% in the placebo group (P = NS). Parameters of LV volumes and diameters, systolic and diastolic function, and markers of collagen metabolism were also unchanged in both groups. CONCLUSION: In patients with hypertrophic cardiomyopathy, this randomized placebo-controlled double-blind pilot study did not demonstrate an effect of 9-month treatment with atorvastatin 80 mg on LV mass reduction.     

Cataracts by lipid lowering drugs? Three different HMG-CoA reductase inhibitors studied in hypercholesterolemic rabbits

We evaluated the effects of a lipid-lowering drug therapy with simvastatin, lovastatin, and pravastatin on the crystalline lens of the hypercholesterolemic rabbit. A threefold therapeutic dose was administered. Ocular examinations in mydriasis prior to treatment and after 14 and 30 weeks, respectively, were performed, including photographic documentation. Some degree of congenital lens opacities prior to treatment was frequently observed. No development of new cataracts could be proved during the study period.     

Joint effects of HMG-CoA reductase inhibitors and eicosapentaenoic acids on serum lipid profile and plasma fatty acid concentrations in patients with hyperlipidemia

HMG-CoA reductase inhibitors reduce serum total cholesterol concentrations and the risk of coronary heart disease in patients with hypercholesterolemia. Recently, it has been reported that patients with combined hyperlipidemia are also at risk of coronary heart disease. However, HMG-CoA reductase inhibitor therapy alone does not sufficiently reduce serum triglyceride concentrations. Epidemiological and clinical evidence has shown that fish oil can lower plasma lipid levels, especially triglycerides. Consequently, we investigated the effects of the combination of HMG-CoA reductase inhibitors and eicosapentaenoic acid, a major component of fish oil, on hyperlipidemia. We administered 900-1,800 mg/day of the ethyl ester of eicosapentaenoic acid to patients with hyperlipidemia who had been treated with HMG-CoA reductase inhibitors for 30 +/- 6 months (means +/- SE). Serum total cholesterol and triglyceride concentrations were significantly decreased 3 months after the administration of eicosapentaenoic acid (from 5.63 +/- 0.23 mmol/l to 5.02 +/- 0.20 mmol/l, P < 0.05; from 2.07 +/- 0.41 mmol/l to 1.08 +/- 0.17 mmol/l, P < 0.01, respectively). Serum high-density lipoprotein-cholesterol concentrations were significantly increased after the treatment (from 1.23 +/- 0.12 mmol/l to 1.34 +/- 0.13 mmol/l, P < 0.05). Plasma eicosapentaenoic acid concentrations and the ratio to arachidonic acid in plasma were also significantly increased 3 months after the treatment (from 101.9 +/- 8.1 mg/l to 181.8 +/- 23.9 mg/l, P < 0.001; from 0.640 +/- 0.075 to 1.211 +/- 0.170, P < 0.001, respectively). These results suggested that the combination therapy of HMG-CoA reductase inhibitors and eicosapentaenoic acid was effective for patients with hyperlipidemia.     

The use of statins in optimising reduction of cardiovascular risk: focus on fluvastatin

Patients with widely differing degrees of cardiovascular risk can derive benefit from effective lipid-lowering therapy with statins, including patients with normal or low cholesterol levels. Clinical trials with fluvastatin have shown that it is effective in patients across a broad spectrum of cardiovascular risk. The lipid-lowering effects of fluvastatin are smaller than some statins, but major clinical outcome studies have consistently demonstrated morbidity and mortality benefits with reductions of low-density lipoprotein cholesterol of <30%. As treatment with statins is generally life-long and patients often receive multiple concomitant medications, optimal statin therapy should be well tolerated and serious consideration should be given to the avoidance of drug interactions. Although serious side-effects of statins are very rare, it is important that fluvastatin is less susceptible to drug interactions than other statins, because serious side-effects of statin therapy are generally associated with concomitant medications affecting statin metabolism. In addition, an extended-release formulation of fluvastatin has been developed to provide liver selectivity with a sustained exposure to the drug, thus improving its efficacy, and safety and tolerability profiles.     

Pitavastatin

The growing number of trials that have highlighted the benefit of intensive lowering of total- and low density lipoprotein (LDL)-cholesterol levels especially with statins has created a need for more efficacious agents. Pitavastatin is a new synthetic 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitor, which was developed, and has been available in Japan since July 2003. Metabolism of pitavastatin by the cytochrome P450 (CYP) system is minimal, principally through CYP 2C9, with little involvement of the CYP 3A4 isoenzyme, potentially reducing the risk of drug-drug interactions between pitavastatin and other drugs known to inhibit CYP enzymes. To date, human and animal studies have shown pitavastatin to be potentially as effective in lowering LDL-cholesterol levels as rosuvastatin; although, head-to-head studies are yet to be conducted.     

Use of principal component analysis in the evaluation of adherence to statin treatment: a method to determine a potential target population for public health intervention

The prevalence of statin use is high but adherence low. For public health intervention to be rational, subpopulations of nonadherent subjects must be defined. To categorise statin users with respect to patterns of reimbursement, this study was performed using the main French health reimbursement database for the Aquitaine region of south-western France. The cohort included subjects who submitted a reimbursement for at least one delivery of a statin (index) during the inclusion period (1st of September 2004-31st of December 2004). Indicators of adherence from reimbursement data were considered for principal component analysis. The 119,570 subjects included and analysed had a sex ratio of 1.1, mean (SD) age of 65.9 (11.9), and 13% were considered incident statin users. Principal component analysis found three dimensions that explained 67% of the variance. Using a K-means classification combined with a hierarchical ascendant classification, six groups were characterised. One group was considered nonadherent (10% of study population) and one group least adherent (1%). This novel application of principal component analysis identified groups that may be potential targets for intervention. The least adherent group appears to be one of the most appropriate because of both its relatively small size for case review with prescribing physicians and its very poor adherence.     

Tissue selectivity of hydroxymethylglutaryl coenzyme a (HMG CoA) reductase inhibitors

Hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors are a class of lipid-lowering medications, with a major activity on plasma cholesterol levels, now enjoying a vast popularity among physicians and patients. These drugs, affecting a very early and key step of sterol biosynthesis, differ to a large extent in their physicochemical properties, tissue distribution and side effects in animals, possibly in humans. Some of these agents (namely lovastatin and simvastatin) are strikingly lipophilic and require enzymatic conversion from the lactone to the open-ring forms, whereas pravastatin, active per se, is hydrophilic. Liver uptake of pravastatin is regulated by a carrier-mediated mechanism. Other HMG CoA reductase inhibitors have been designed, with the objective of obtaining high levels of hepato-selectivity. Evaluation of available date in terms of potential advantages in tissue, namely liver selectivity, of HMG CoA reductase inhibitors, suggests, that, indeed, altered sterol biosynthesis in a number of tissues may potentially result in the appearance of significant side effects. While there is no clear-cut relationship between tissue selectivity and lipophilicity, the presence of this latter feature seems, in general, to dictate a lesser absortion to peripheral tissues vs the liver. At present, the toxicological profile of major HMG CoA reductase inhibitors appears safe; it is, however, possible that in selected patient groups liver selectivity may offer a considerable therapeutic advantage.     

Apolipoprotein(a) polymorphism predicts the increase of Lp(a) by pravastatin in patients with familial hypercholesterolaemia treated with bile acid sequestration

Abstract. HMG-CoA reductase inhibitors effectively reduce the concentration of low density lipoproteins (LDL) in plasma. Lipoprotein(a) [Lp(a)] may be as atherogenic as LDL. A few studies, only one of which was placebo controlled, suggest that the HMG CoA reductase inhibitors either do not affect Lp(a) or they increase Lp(a). The response of Lp(a) to HMG-CoA reductase inhibition has not been related to apolipo-protein(a) phenotypes in previous studies. We conducted a double-blind, placebo controlled study of pravastatin in 51 patients with familial hypercholester-olemia (FH) ( n = 43) or probable FH ( n = 8). All patients had LDL-cholesterol concentrations above 4.1 mmol 1^-1 despite treatment with diet and bile acid sequestration. In patients assigned to pravastatin ( n = 34), the mean concentrations of total cholesterol and LDL cholesterol fell significantly ( P< 0.01) when compared to placebo. Lp(a) increased ( P< 0.01) from a mean (±SD) of 33.6 ± 40.8 mgdl^-1 to 411 ± 46.1 mg dl^-1 on pravastatin but was unchanged during placebo treatment. The percentage increase in Lp(a) was the same in patients with different apo(a) phenotypes, and hence the absolute increase in Lp(a) was greatest in patients with the low molecular weight apo(a) phenotypes.     

Aldehyde reductase activity in the antennae of Helicoverpa armigera

In the present study, we identified two aldehyde reductase activities in the antennae of Helicoverpa species, NADH and NADPH‐dependent activity. We expressed one of these proteins of H. armigera, aldo‐keto reductase (AKR), which bears 56% identity to bovine aldose reductase, displays a NADPH‐dependent activity and is mainly expressed in the antennae of adults. Whole‐mount immunostaining showed that the enzyme is concentrated in the cells at the base of chemosensilla and in the nerves. The enzyme activity of H. armigera AKR is markedly different from those of mammalian enzymes. The best substrates are linear aliphatic aldehydes of 8–10 carbon atoms, but not hydroxyaldehydes. Both pheromone components of H. armigera, which are unsaturated aldehydes of 16 carbons, are very poor substrates. Unlike mammalian AKRs, the H. armigera enzyme is weakly affected by common inhibitors and exhibits a different behaviour from the action of thiols. A model of the enzyme suggests that the four cysteines are in their reduced form, as are the seven cysteines of mammalian enzymes. The occurrence of orthologous proteins in other insect species, that do not use aldehydes as pheromones, excludes the possibility of classifying this enzyme among the pheromone‐degrading enzymes, as has been previously described in other insect species.     

Hepatic HMGCoA reductase in human cholelithiasis: effects of chenodeoxycholic and ursodeoxycholic acids*

Abstract. To study further the role of hepatic cholesterol synthesis in patients with gallstones, the activity of the rate-limiting step in cholesterbgenesis, hydroxy-methyl glutaryl co-enzyme A reductase (HMGCoAR), was measured in operative wedge liver biopsies from ten patients with untreated cholesterol gallstones, six with pigment stones and ten controls. Hepatic HMGCoAR was also measured in six patients with cholesterol-rich gallstones treated for 1–24 months with 14-6-18-6 mg chenodeoxycholic acid (CDCA) kg^-1 day^-1, in two patients with radiolucent pigment stones treated with 17-3 and 17-7 mg CDCA kg^-1 day^-1 and in ten other patients with cholesterol-rich stones given 4–5-7-2 mg ursodeoxycholic acid kg^-1 day^-1 for 1–6 months. HMGCoAR activity was also related to the free and esterified cholesterol content of both hepatic homogenates and the microsomal fractions. Compared with the controls (HMGCoAR activity 14-6±1 6 (SEM) pmole mg microsomal protein^-1 min^-1), the mean activity in untreated cholesterol cholelithiasis was 32 2 ±2-0 (P < 0–001), but was near normal in patients with pigment stones (16-2 + 1 5). In cholesterol gallstone patients, chenodeoxycholic acid treatment reduced the mean enzyme activity by 51% compared with the untreated gallstone group (P < 0001) and in smaller doses, ursodeoxycholic acid therapy lowered it by 40% (P < 0001) but in the two patients with pigment stones, CDCA did not seem to affect HMGCoAR activity. Despite this four-fold variation in enzyme activity, there were no significant differences in mean free or esterified cholesterol concentrations in whole liver homogenates or in the microsomal fraction from any of the patient groups. Presented in part at the European Society for Clinical Investigation, Rotterdam, April 1978 (Maton P.N. & Dowling R.H (1978) Eur J Clin Invest 8, 329 (abstract)) and at the V International Bile Acid Meeting, Freiburg, June 1978 (Maton P.N. & Dowling R.H. (1978) in: Biological Effects of Bile Acids (ed. by G. Paumgartner, A. Stiehl and W. Gerok), pp. 91–98. MTP Press, Lancaster).     

Antihypercholesterolemic effects of atorvastatin in patients previously receiving other 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors: an open-label study

Background: Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, was introduced in Japan in May 2000 with purportedly potent cholesterol-lowering effects. However, only a handful of studies have assessed its efficacy and tolerability in Japanese patients.Objective: This study was conducted to assess the efficacy and tolerability of atorvastatin in Japanese patients with hypercholesterolemia.Methods: Outpatients at the Hiramitsu Clinic who were receiving HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia were enrolled in this open-label study. Previous HMG-CoA reductase inhibitor therapy was discontinued, and patients were uniformly switched to atorvastatin 10 mg/d with no intervening washout period. Clinical laboratory values and serumlipid levels were used as safety indices, and achievement rates of target total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were used to assess efficacy. Target TC/HDL-C levels in patients with Japan Atherosclerosis Society category B hypercholesterolemia (patients with risk factors) and category C hypercholesterolemia (patients with coronary heart disease) were <200/<120 mg/dL and <180/<100 mg/dL, respectively.Results: Seventy-nine patients (23 men, 56 women; mean [±SD] age, 63.9 ± 11.2 years) completed the study. The mean duration of atorvastatin therapy was 62.7 ± 9.0 days. The switch to atorvastatin produced significant reductions in mean levels of TC (from 212.8 ± 29.0 mg/dL to 165.7 ± 24.8 mg/dL; P < 0.001) and LDL-C (from 135.2 ± 24.3 mg/dL to 92.2 ± 20.7 mg/dL; P < 0.001). Achievement rates of target TC and LDL-C levels dramatically improved in patients with Japan Atherosclerosis Society category B or C hypercholesterolemia. In patients with category B hypercholesterolemia, the achievement rate improved from 30.8% (20/65) at baseline to 87.7% (57/65) with regard to target TC levels and from 26.2% (17/65) to 92.3% (60/65) with regard to target LDL-C levels. In category C, the corresponding results were 30.0% (3/10) to 80.0% (8/10) and 10.0% (1/10) to 70.0% (7/10). No side effects sufficiently serious to warrant discontinuation of atorvastatin therapy were observed.Conclusion: In this study, atorvastatin was effective and well tolerated for the treatment of hypercholesterolemia in Japanese patients.     

Chemical space of Escherichia coli dihydrofolate reductase inhibitors: New approaches for discovering novel drugs for old bugs

Escherichia coli Dihydrofolate reductase is an important enzyme that is essential for the survival of the Gram-negative microorganism. Inhibitors designed against this enzyme have demonstrated application as antibiotics. However, either because of poor bioavailability of the small-molecules resulting from their inability to cross the double membrane in Gram-negative bacteria or because the microorganism develops resistance to the antibiotics by mutating the DHFR target, discovery of new antibiotics against the enzyme is mandatory to overcome drug-resistance. This review summarizes the field of DHFR inhibition with special focus on recent efforts to effectively interface computational and experimental efforts to discover novel classes of inhibitors that target allosteric and active-sites in drug-resistant variants of EcDHFR.