Synthetic HMG-CoA Reductase Inhibitor Research Articles

Pharmacokinetic and pharmacodynamic interaction of Rosuvastatin calcium with guggulipid extract in rats.

Background & objectivesRosuvastatin calcium (RC) is a potent and competitive synthetic inhibitor of HMG-CoA reductase used for the treatment of dyslipidemia. Guggulipid obtained from Commiphora mukul is used in the treatment of a wide variety of diseases such as atherosclerosis, hypercholesterolemia, rheumatism, and obesity. The present study evaluates the pharmacokinetic and pharmacodynamic interactions between RC and the standardized guggulipid extract in rats.Materials and methodsThe guggulipid extract was standardized for the presence of guggulsterones. The pharmacokinetic interaction was determined after a single dose administration of RC alone or in combination with the guggulipid extract or after multiple-dose administration of RC alone or RC along with the guggulipid extract for 14 days. To determine the pharmacodynamic interaction, RC and guggulipid extract were administered to hyperlipidemic rats for 14 days. The level of significance was determined using unpaired student’s t-test, one way ANOVA, the post-ANOVA Tukey test.ResultsStandardization of guggulipid extract showed it contains 7.5%w/w of guggulsterones. Guggulipid extract increased the bioavailability of RC in both single-dose and multiple-dose studies. Guggulipid extract reduced the rate of absorption (Ka) of RC but showed an increase in maximum serum concentration (Cmax). An in-vitro study using isolated rat intestine revealed that guggulipid extract decreased the rate of absorption of RC in the intestinal lumen. The hypolipidemic activity of RC was augmented by the guggulipid extract in hyperlipidemic rats.Interpretation & conclusionTherefore it is concluded that guggulipid extract increases the bioavailability of RC by delaying its Ka and augments its hypolipidemic action. However, it is recommended that a combination of RC with guggulipid extract should be used only after an adverse effect(s) of this combination are determined.

Beneficial effect of Combination with Korean Red Ginseng, Gastrodia Rhizoma and Polygoni Multiflori on Cholesterol and Erectile Dysfunction in Hyperlipidemia rats

ABSTRACT Objectives : This study was designed to investigate effects of the combinat ion with Korean Red Ginseng ( Panax ginseng C.A. Meyer), Gastrodia Rhizoma ( Gastrodia elata Blume) and Polygoni Multiflori Radix ( Polygonum multiflorum Thunberg) on metabolic disorders including cholesterol and erectile dysfunction in hyperlipidemia rats.Methods : Animals were divided into six groups; Control with normal diet, high fat/cholesterol-diet (HFCD), fluvastatin, Korean Red Ginseng treated (KRG), and the combination treated ( Korean Red Ginseng, Gastrodia Rhizoma and Polygoni Multiflori Radix; 1:1:1 for KGP1 and 2:1:1 for KGP2). The experimental groups initially received HFCD for 10 weeks and then treated orally with fluvastatin, KRG, KGP1 and KGP2 during the final 6 weeks. Erectile function was determined by the measurements of intraca vernosal pressure (ICP) and maximal arterial pressure (MAP) after electrical stimulation of the cavernosal nerve.Results : KGP2 decreased the level of total cholesterol and LDL cholesterol in the sera of HFCD rats without no changes of body weights. KRG, KGP1 and KGP2 decreased the level of C-reactive protein (CRP) levels except of fluvastatin, synthetic HMG-CoA reductase inhibitor. KRG, KGP 1 and KGP2 significantly increased the ICP, ICP/MAP ratio, area under the curve (AUC) compared with those o f normal rat. Morphometric analyses showed that KRG, KGP1 and KGP2 increased the volume of smooth muscle and the regular arrangement of collagen fibers in corpus cavernosum of HFCD rats. The penile expression of eNOS was increased by KRG, KGP1 and KGP2.Conclusions : Based on these results, we suggest that the combination with Korean Red Ginseng, Gastrodia Rhizoma and Polygoni Multiflori may improve hyperlipidemia through regulating the lipid profil es and erectile dysfunction in rats.Key words : Korean Red Ginseng, Gastrodia Rhizoma, Polygoni Multiflori, hyperlipidemia, erection

Pitavastatin: a different pharmacological profile

Pitavastatin, a synthetic HMG-CoA reductase inhibitor, is characterized by a cyclopropyl moiety that results in several pharmacological differences compared with other statins. These include inhibition of cholesterol synthesis and increased lipoprotein lipase expression at lower doses than other statins, and significant high-density and apolipoprotein A1-elevating activity that persists with time. Pitavastatin has a higher bioavailability (60%) than any other statin and the majority of the bioavailable fraction after oral dosing is excreted unchanged in the bile. The enterohepatic circulation of unchanged pitavastatin contributes to the prolonged duration of action, allowing once-daily, any-time dosing. Pitavastatin undergoes only minor metabolism by CYP2C9 but is not metabolized by CYP3A4. Neither pitavastatin nor its lactone form have inhibitory effects on cytochrome P450, and CYP3A4 inhibitors have no effect on pitavastatin plasma concentrations. Moreover, P-glycoprotein-mediated transport does not play a major role in the disposition of pitavastatin and pitavastatin does not inhibit P-glycoprotein activity. Pitavastatin is transported into the liver by several hepatic transporters, but organic anion-transporting polypeptide 1B1 inhibitors have relatively little effect on plasma pitavastatin concentrations compared with other statins. With the exception of multitransporter inhibitors, such as ciclosporin, interactions are generally of no clinical significance. As a result, pitavastatin has minimal drug–drug and drug–food interactions, making it a good treatment option in the large population of individuals with dyslipidemia who require multidrug therapy.

Development and Validation of a Reversed-Phase High-Performance Thin-Layer ChromatographyDensitometric Method for Determination of Atorvastatin Calcium in Bulk Drug and Tablets

Atorvastatin calcium is a synthetic HMG-CoA reductase inhibitor that is used as a cholesterol-lowering agent. A simple, sensitive, selective, and precise RP-HPTLC-densitometric determination of atorvastatin calcium both as bulk drug and from pharmaceutical formulation was developed and validated according to International Conference on Harmonization guidelines. The method used aluminum sheets precoated with silica gel 60 RP18F254S as the stationary phase, and the mobile phase consisted of methanol-water (3.5 + 1.5, v/v). The system gave a compact band for atorvastatin calcium with an Rf value of 0.62 +/- 0.02. Densitometric quantification was carried out at 246 nm. The linear regression analysis data for the calibration plots showed a good linear relationship with r = 0.9992 in the working concentration range of 100-800 ng/band. The method was validated for precision, accuracy, ruggedness, robustness, specificity, recovery, LOD, and LOQ. The LOD and LOQ were 6 and 18 ng, respectively. The drug underwent hydrolysis when subjected to acidic conditions and was found to be stable under alkali, oxidation, dry heat, and photodegradation conditions. Statistical analysis proved that the developed RP-HPTLC-densitometry method is reproducible and selective and that it can be applied for identification and quantitative determination of atorvastatin calcium in bulk drug and tablet formulation.

Transporter-mediated influx and efflux mechanisms of pitavastatin, a new inhibitor of HMG-CoA reductase

The purpose of this study was to gain a better understanding of the transport mechanism of pitavastatin, a novel synthetic HMG-CoA reductase inhibitor. Experiments were performed using oocytes of Xenopus laevis expressing several solute carrier (SLC) transporters and recombinant membrane vesicles expressing several human ABC transporters. The acid form of pitavastatin was shown to be a substrate for human OATP1, OATP2, OATP8, OAT3 and NTCP, and for rat Oatp1 and Oatp4 with relatively low K(m) values. In contrast, these SLC transporters were not involved in the uptake of the lactone form. A significant stimulatory effect was exhibited by pitavastatin lactone, while the acid form did not exhibit ATPase hydrolysis of P-glycoprotein. In the case of breast cancer resistant protein (BCRP), the acid form of pitavastatin is a substrate, whereas the lactone form is not. Taking these results into consideration, several SLC and ABC transporters were identified as critical to the distribution and excretion of pitavastatin in the body. This study showed, for the first time, that acid and lactone forms of pitavastatin differ in substrate activity towards uptake and efflux transporters. These results will potentially contribute to the differences in the pharmacokinetic profiles of pitavastatin.

Fluvastatin titrate-to-goal clinical practice study: Interim results

Fluvastatin, the newest addition to the class of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, is structurally different from the other agents. Fluvastatin is the first entirely synthetic HMG-CoA reductase inhibitor and, compared with the other drugs of its class, has a distinct pharmacologic profile, including short systemic exposure time (half-life of 1.2h), no active circulating metabolites, and a high degree of protein binding (98%). Fluvastatin is targeted to the liver, with a high rate of absorption (95%). The clinical development of fluvastatin has involved primarily adult patients whose cholesterol levels are in the 95th percentile of the adult population in the United States. This population represents fewer than 10% of all adults with hyper-cholesterolemia. Thus, the Fluvastatin Titrate-to-Goal Clinical Practice Study was undertaken to evaluate the efficacy and safety of fluvastatin in patients similar to those managed in clinical practices. The goal was to evaluate the efficacy and safety of fluvastatin 20 or 40 mg/day as monotherapy in patients with moderate hypercholesterolemia (type IIa or IIb), irrespective of age, race, gender, or presence of multiple other risk factors (i.e., hypertension and angina) for coronary heart disease (CHD) or established CHD. The study sample included 1,019 men and women, aged 18 to 75 years, who had a diagnosis of hypercholesterolemia: low-density lipoprotein cholesterol (LDL-C)≥160 mg/dl and triglyceride ≤350 mg/dl despite dietary intervention. These criteria, defined by the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, are assigned to the high-risk LDL-C classification. Interim study results indicate that significant reductions in levels of total cholesterol and LDL-C were achieved within 6 weeks of treatment with fluvastatin at a dosage of 20 mg/day. This effect was sustained at Week 12, with a mean reduction in total cholesterol levels of 15%, an LDL-C reduction of 21%, a triglyceride reduction of 11%, and an increase in high-density lipoprotein cholesterol levels of 4%. After 12 weeks of therapy with fluvastatin, the NCEP target goal (LDL-C < 160 mg/dl) was reached in 83% of all study patients as well as in 84% with hypertension, 85% of those with CHD, and 88% with angina. Headache, upper respiratory infection, a pepsia were the most frequently observed adverse effecting fluvastatin treatment. No significant changes in liv tion tests were seen in patients receiving fluvastati baseline to Week 12.

Introduction

Clinical CardiologyVolume 17, Issue S4 p. IV-1-IV-1 IntroductionFree Access Introduction Adrian Dobs M.D., Adrian Dobs M.D. Division of Endocrinology and Metabolism, The Johns Hopkins School of Medicine, Baltimore, Maryland, USASearch for more papers by this author Adrian Dobs M.D., Adrian Dobs M.D. Division of Endocrinology and Metabolism, The Johns Hopkins School of Medicine, Baltimore, Maryland, USASearch for more papers by this author First published: December 1994 https://doi.org/10.1002/clc.4960171602AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Levy RI, Troendle AJ, Fattu J., A quarter century of drug treatment of dyslipoproteinemia, with a focus on the new HMG-CoA reductase inhibitor fluvastatin. Circulation 87 (suppl 3), 45– 53 (1993) 2 The Expert Panel: Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med 148, 36– 69 (1988) 3 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II.) J Am Med Assoc 269, 3015– 3023 (1993) 4 Sempos CT, Cleeman JI, Carroll MD, Johnson CL, Bachorik PS, Gordon DJ, Burt VL, Briefel RR, Brown CD, Lippel K., Rifkind BM, Prevalence of high blood cholesterol among US adults: An update based on the guidelines from the second report of the National Cholesterol Education Program Adult Treatment Panel. J Am Med Assoc 269, 3009– 3014 (1993) 5 Kellick KA, Ellis AK, Focus on fluvastatin—the first totally synthetic HMG-CoA reductase inhibitor for the treatment of hypercholesterolemia. Hosp Formulary 29, 245– 250 (1994) 6 Lescol®, (fluvastatin sodium) package insert. Sandoz Pharmaceuticals Corp., East Hanover, N.J. (1993) 7 Jokubaitis LA, Updated clinical safety experience with fluvastatin. Am J Cardiol 73 (suppl), 18D– 24D (1994) Volume17, IssueS4December 1994Pages IV-1-IV-1 ReferencesRelatedInformation

Development of Electrochemical Methods for Determination of Atorvastatin and Analytical Application to Pharmaceutical Products and Spiked Human Plasma

Atorvastatin is a new synthetic inhibitor of HMG-CoA reductase that has been recently and intensively prescribed as an antihyperlipoproteinemic drug. The property was exploited in developing a highly sensitive stripping voltammetric procedure for the determination of the drug. The anodic current of adsorbed compound is measured by differential pulse and Osteryoung square wave adsorptive stripping voltammetry, preceded by a period of preconcentration. The effect of various parameters such as supporting electrolyte composition, pH, initial potential, scan rate, accumulation time, and ionic strength are discussed to characterize the interfacial and redox behavior. The methods were performed in Britton-Robinson buffer, and the corresponding calibration graphs were constructed and statistical parameters evaluated. Applying the differential pulse adsorptive stripping voltammetry and Osteryoung square wave adsorptive stripping voltammetric method at pH 2.0 linearity was achieved from 3.5 × 10−8 to 4.6 × 10−7 M for square wave adsorptive stripping voltammetry with limit detection and limit quantitation of 4.0 × 10−9 M, 2.0 × 10−9 M and 1.0 × 10−8 M, 2.0 × 10−8 M, respectively. Since the proposed methods enabled lower concentrations of atorvastatin to be determined, this method was tested for atorvastatin determination in pharmaceutical products and spiked human plasma.

New Therapy Update

Lescol XL® (fluvastatin sodium; Novartis Pharmaceuticals Corporation) is a newly released dosage and formulation of Lescol®. Lescol® was the first synthetic HMG-CoA reductase inhibitor used in the treatment of hypercholesterolemia. Lescol XL® is to be used in conjunction with diet to reduce total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and Apo-B, as well as to increase high-density lipoprotein (HDL) cholesterol. It is also indicated to slow the progression of coronary atherosclerosis. Lescol® blocks the production of cholesterol in the liver via competitive inhibition of HMG-CoA reductase. This stimulates the LDL receptors, thereby increasing uptake of the LDL particle. The drug is rapidly absorbed following oral ingestion. Peak concentrations of Lescol XL® are achieved in about 3 hours under fasting conditions, and are metabolized primarily through the 2c9 pathway. Administration of the drug following a high-fat meal delays its absorption. The drug is 98% bound to plasma proteins. It is metabolized in the liver via hydroxylation. Elimination is primarily via the feces as metabolites, with very little (<5%) excreted in the urine. Potential for drug accumulation exists in patients with hepatic insufficiency. Women tend to have slightly higher plasma concentrations than men. Liver function studies must be performed before therapy and at 12-week intervals after drug initiation or an increase in the dose. The drug must be discontinued if there is a three-fold increase above the upper limited normal in the liver function tests. The drug must be discontinued if myalgias develop or there is an increase in creatine phosphokinase enzymes. The most common adverse reactions, although rare, are diarrhea, dyspepsia, fatigue, nausea, and flatulence. Lescol XL® is contraindicated in patients with liver disease. It is contraindicated in patients who are pregnant or are trying to become pregnant. Prior to initiation of therapy, patients should be placed on a low-fat, low-cholesterol diet. In patients whose LDL cholesterol goal reduction is >25%, the recommended starting dose is 40 or 80 mg/day. The dosing range is 20–80 mg/day. The drug can be taken in the evening, without regard to meals. Periodic liver function checks should be performed, as noted above. Dosage changes can be made no more frequently than every 4 weeks. Lescol XL® (co-marketed with Reliant Pharmaceuticals) is a new dosage and preparation of the previously released synthetic HMG-CoA reductase inhibitor Lescol®. The higher dosage is encouraging in the management of elevated lipid levels and the progression of the coronary atheroclerotic process.

Clinical pharmacokinetics of fluvastatin.

Fluvastatin, the first fully synthetic HMG-CoA reductase inhibitor, has been shown to reduce cholesterol in patients with hyperlipidaemia, to prevent subsequent coronary events in patients with established coronary heart disease, and to alter endothelial function and plaque stability in animal models. Fluvastatin is relatively hydrophilic, compared with the semisynthetic HMG-CoA reductase inhibitors, and, therefore, it is extensively absorbed from the gastrointestinal tract. After absorption, it is nearly completely extracted and metabolised in the liver to 2 hydroxylated metabolites and an N-desisopropyl metabolite, which are excreted in the bile. Approximately 95% of a dose is recovered in the faeces, with 60% of a dose recovered as the 3 metabolites. The 6-hydroxy and N-desisopropyl fluvastatin metabolites are exclusively generated by cytochrome P450 (CYP) 2C9 and do not accumulate in the blood. CYP2C9, CYP3A4, CYP2C8 and CYP2D6 form the 5-hydroxy fluvastatin metabolite. Because of its hydrophilic nature and extensive plasma protein binding, fluvastatin has a small volume of distribution with minimal concentrations in extrahepatic tissues. The pharmacokinetics of fluvastatin are not influenced by renal function, due to its extensive metabolism and biliary excretion; limited data in patients with cirrhosis suggest a 30% reduction in oral clearance. Age and gender do not appear to affect the disposition of fluvastatin. CYP3A4 inhibitors (erythromycin, ketoconazole and itraconazole) have no effect on fluvastatin pharmacokinetics, in contrast to other HMG-CoA reductase inhibitors which are primarily metabolised by CYP3A and are subject to potential drug interactions with CYP3A inhibitors. Coadministration of fluvastatin with gastrointestinal agents such as cholestyramine, and gastric acid regulating agents (H2 receptor antagonists and proton pump inhibitors), significantly alters fluvastatin disposition by decreasing and increasing bioavailability, respectively. The nonspecific CYP inducer rifampicin (rifampin) significantly increases fluvastatin oral clearance. In addition to being a CYP2C9 substrate, fluvastatin demonstrates inhibitory effects on this isoenzyme in vitro and in vivo. In human liver microsomes, fluvastatin significantly inhibits the hydroxylation of 2 CYP2C9 substrates, tolbutamide and diclofenac. The oral clearances of the CYP2C9 substrates diclofenac, tolbutamide, glibenclamide (glyburide) and losartan are reduced by 15 to 25% when coadministered with fluvastatin. These alterations have not been shown to be clinically significant. There are inadequate data evaluating the potential interaction of fluvastatin with warfarin and phenytoin, 2 CYP2C9 substrates with a narrow therapeutic index, and caution is recommended when using fluvastatin with these agents. Fluvastatin does not appear to have a significant effect on other CYP isoenzymes or P-glycoprotein-mediated transport in vivo.

NK-104: a novel synthetic HMG-CoA reductase inhibitor

An elevated level of low-density lipoprotein (LDL)-cholesterol has been recognised as the most important risk factor for coronary artery disease (CAD). Development of the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) (‘statins’), a rate-limiting key enzyme of cholesterol synthesis pathway, has revolutionised the cholesterol-lowering therapy. In the last decade, effective primary and secondary preventive measures have been established in several statin trials to prevent future events of CAD by lowering LDL-cholesterol levels. These results supported the ‘lower is better’ hypothesis in the relationship between LDL-cholesterol levels and CAD. NK-104 (pitavastatin, previously named as itavastatin or nisvastatin, Kowa Company Ltd., Tokyo) has recently been developed as a new chemically synthesised and powerful statin. On the basis of reported data, the potency of NK-104 is dose-dependent and appears to be equivalent to that of atorvastatin. This new statin is safe and well-tolerated in the treatment of patients with hypercholesterolaemia. The cytochrome P450 system only slightly modifies NK-104, which suggests the clinical advantage of this agent, because the prevalence of clinically significant interactions with a number of other commonly used drugs can be considered to be extremely low. NK-104 can provide a new and potentially superior therapeutic agent when compared with currently available other statins. Randomised controlled clinical trials to assess the long-term effects of this new statin on CAD would be required.

Cerivastatin, an Inhibitor of HMG-CoA Reductase, Inhibits Urokinase/Urokinase-receptor Expression and MMP-9 Secretion by Peripheral Blood Monocytes

It is now recognised that acute myocardial infarction results from the rupture of atherosclerotic plaques. Lymphocytes and macrophages, which infiltrate rupture sites, contribute to plaque degradation by expressing urokinase (u-PA) bound to cell membrane by urokinase receptor (u-PAR) and by secreting metalloproteinase MMP-9. We have previously demonstrated that the uptake of oxidised LDL (ox-LDL) by monocytes induces an increase of u-PA and u-PAR expression. The present study shows that the expression of u-PA and u-PAR induced by ox-LDL on monocyte surface is suppressed by cerivastatin (a synthetic inhibitor of HMG-CoA reductase, Bayer) from 2 nM. This leads to reduced plasmin generation and monocyte adhesion to vitronectin. Furthermore, higher concentrations of cerivastatin (50-100 nM) reduce the expression of u-PA and u-PAR on unstimulated monocytes. It also inhibits MMP-9 secretion but has no effect on TIMP-1 secretion, suggesting that the decrease in MMP-9 has a real protective effect on plaque stabilisation. The inhibitory effect of cerivastatin on u-PA expression and MMP-9 secretion can be explained by the inhibition of NF-kappa B translocation into the nucleus, as shown by immunofluorescence. As farnesyl-pyrophosphate reverses the effect of cerivastatin, it is postulated that these effects could also be due to the inhibition of Ras prenylation. This was confirmed by confocal microscopy, which shows the Ras delocalisation from the monocyte membrane. The cerivastatin-induced effects on monocyte functions could explain, at least in part, the protective effect of this drug against atherothrombotic events.

Effect of NK-104, a new synthetic HMG-CoA reductase inhibitor, on triglyceride secretion and fatty acid oxidation in rat liver

For the investigation of the mechanism responsible for the hypotriglyceridemic effect of NK-104, a new synthetic inhibitor of HMG-CoA reductase, the rate-limiting enzyme for cholesterol synthesis, isolated rat liver was perfused with or without NK-104 in the presence of exogenous [1- 14C]oleic acid substrate. Addition of NK-104 tended to increase the ketone body production while it caused a significant decrease in the secretion rate of triglyceride by the perfused liver without affecting uptake of exogenous [1- 14C]oleic acid. The inhibitor also significantly decreased hepatic triglyceride concentration. The altered triglyceride secretion was accompanied by a concomitant decreased incorporation of exogenous [1- 14C]oleate into triglyceride. The conversion of exogenous [1- 14C]oleic acid substrate indicated an inverse relationship between the pathways of oxidation and esterification. No effect of NK-104 on hepatic secretion of cholesterol was observed. These results suggest that NK-104 exerts its hypotriglyceridemic action, primarily by diverting the exogenous free fatty acid to the pathways of oxidation at the expense of esterification.

Quantitation of the acid and lactone forms of atorvastatin and its biotransformation products in human serum by high-performance liquid chromatography with electrospray tandem mass spectrometry.

A method for simultaneous quantitation of both the acid and lactone forms of atorvastatin, a new synthetic inhibitor of HMG-CoA reductase that is being marketed for the treatment of high serum cholesterol, and both the acid and lactone forms of its two biotransformation products, 2-hydroxyatorvastatin and 4-hydroxyatorvastatin, in human serum (a total of six analytes) by high-performance liquid chromatography with electrospray tandem mass spectrometry was developed and validated. A deuterium labeled analog was used as internal standard for each of the six analytes. Each point of the calibration standard curve, which ranged from 0.5 to 200 ng/mL, contained the six analytes at equal concentrations. Three groups of quality control (QC) samples were used. In the first group, combination QC samples contained all six analytes at equal concentrations. In the second group, acid-only QC samples contained only the acid forms (i.e. three analytes) at equal concentrations. In the third group, lactone-only QC samples contained only the lactone forms (i.e. three analytes) at equal concentrations. After adding the internal standard to 0.5 mL of each standard and the QC sample kept at 4 degrees C, the samples were acidified with sodium acetate buffer (pH 5.0) and then extracted with methyl tert-butyl ether. Detection was by positive ion electrospray tandem mass spectrometry using eight selected reaction monitoring channels. The acid compounds were stable in human serum at room temperature but the lactone compounds were unstable as they hydrolyzed rapidly to their respective acid forms. The conversion of the lactone compounds in both QC and post-dose human serum samples was nearly complete after 24 h at room temperature. The lactone compounds in serum could be stabilized by lowering the working temperature to 4 degrees C or lowering the serum pH to 6.0. The acid-only and the lactone-only QC samples showed that, under the sample processing conditions used, the degree of the hydrolysis of the lactone compounds or the lactonization of the acid compounds during the assay procedure was minimal (< 5%). The intra-day C.V., inter-day C.V. and the deviations from the nominal concentrations for all six analytes were within 15%, demonstrating good precision and accuracy. The required lower limit of quantitation (LLQ) of 0.5 ng/mL was achieved for each analyte.

Cerivastatin, a new synthetic HMG CO-A reductase inhibitor in the treatment of patients with primary hyperlipidaemia

Cerivastatin, a new synthetic HMG CO-A reductase inhibitor in the treatment of patients with primary hyperlipidaemia

Efficacy and Safety of Atorvastatin in Patients with Hypercholesterolemia

Background:Previous studies indicated that a recently approved synthetic HMG-CoA reductase inhibitor, ato- rvastatin, reduces LDL cholesterol and triglyceride. To assess the efficacy on the level of serum LDL cholesterol and other lipoprotein fractions and its safety, we investigated 59 patients for lipid and side effect profile. Method:In patients with hypercholesterolemia, who showed 12-hours fasting serum LDL cholesterol >145 mg/dl and <250 mg/dl and triglyceride levels <400 mg/dl were enrolled to diet therapy for 4 weeks. After 4 weeks of diet therapy, serum lipid profile were reevaluated and patients with LDL cholesterol ≥130 mg/dl were as-signed to receive 10 mg dose of atorvastatin once daily for 4weeks. After 4 weeks of drug therapy, serum lipid profile were rechecked, if showed LDL cholesterol level≥130 mg/dl, assigned to receive 20 mg dose of atorva-statin once daily until 8 weeks. Result:Of the 59 patients were assigned to receive atorvastatin therapy, 52 pati-ents completed the study. Among lipid profiles, total cholesterol, triglyceride, LDL-cholesterol and apolipoprotein B levels showed significant reduction with mean reduction rate of 28%, 13%, 38%, 32% respectively after 4 weeks and 31%, 13%, 41% and 34% respectively after 8 weeks. HDL-Cholesterol and lipoprotein (a level did not show significant change after 8 weeks of therapy. Nine patients had mild adverse events, such as elevated ALT, epigastric pain, insomnia, thumb pain. postural hypotension, palpitation and constipation. Only three patie-nts of fifty-nine withdrew from the study due to adverse events related to drug treatment. Conclusion:The atorvastatin was highly effective and generally well tolerated with an acceptable safety profile in patients with primary hypercholestelemia. (Korean Circulation J 1999;29(2 :928-936

Cerivastatin.

Cerivastatin is a synthetic HMG-CoA reductase inhibitor with high liver selectivity, which lowers plasma cholesterol levels by inhibiting endogenous cholesterol synthesis. In vitro, the affinity of cerivastatin for HMG-CoA reductase was higher than that of lovastatin, simvastatin and pravastatin. This higher enzyme affinity was reflected in vivo, with a lower ED50 (dose causing 50% inhibition) for cerivastatin in rats and beagle dogs compared with lovastatin. Cerivastatin 0.2 mg/day significantly reduced low density lipoprotein (LDL)-cholesterol, total cholesterol and triglyceride levels, and increased high density lipoprotein (HDL)-cholesterol levels, in patients with type IIa hypercholesterolaemia. Available data indicate that cerivastatin has a tolerability profile similar to that of other HMG-CoA reductase inhibitors. No drug interactions were observed when cerivastatin was coadministered with digoxin, warfarin, cimetidine or the antacid magnesium/aluminium hydroxide.

Cerivastatin, a New Potent Synthetic HMG Co-A Reductase Inhibitor: Effect of 0.2 mg Daily in Subjects With Primary Hypercholesterolemia.

BACKGROUND: Reduction of serum cholesterol, most notably low-density lipoprotein cholesterol is associated with reductions in cardiovascular morbidity and mortality. Statins have been shown to effectively reduce low-density lipoprotein cholesterol via inhibition of the hydroxymethyl-coenzyme A (HMG-CoA) reductase. Cerivastatin is the most potent HMG-CoA reductase inhibitor currently under study in the United States. METHODS AND RESULTS: A parallel group, randomized, placebo-controlled, double-blind, multicenter study was conducted to compare the efficacy and safety of three different dosing regimens of 0.2 mg/day of cerivastatin, a new HMG-CoA reductase inhibitor, in patients with hypercholesterolemia. After a 10-week diet-placebo lead-in period, 319 patients with low-density lipoprotein cholesterol >160 mg/dL were randomized to 4 weeks of treatment with one of the following regimens: cervastatin 0.1 mg twice daily, cerivastatin 0.2 mg once daily with the evening meal, cerivastatin 0.2 mg once daily at bedtime or placebo. All three active treatment groups produced statistically significant (P <.05) changes compared to aseline and placebo in total cholesterol (0.1 mg twice daily \_18.9%; 0.2 mg once daily with the evening meal: \_21.9%; 0.2 mg once daily at bedtime: \_22.1%; placebo: 0.0%), low-density lipoprotein cholesterol (0.1 mg twice daily: \_25.7%; 0.2 mg once daily with the evening meal: \_29.4%; 0.2 mg once daily at bedtime: \_30.4%; placebo: 1.4%) and high-density lipoprotein cholesterol (0.1 mg twice daily: 5.3%; 0.2 mg once daily with the evening meal: baseline and placebo, were also reduced by all active treatments (0.1 mg twice daily: \_11.6% [P =.05]; 0.2 mg once daily with the evening meal: \_11.6% [P =.05]; and 0.2 mg at bedtime: \_10.9% [P =.07]). The percentage change in total cholesterol and low-density lipoprotein cholesterol after 4 weeks of therapy for the once-daily cerivastatin groups was statistically significantly greater (P <.05) than the cerivastatin twice daily regimen. A treatment responser was seen by 1 week of therapy and was maximal by 3 weeks. The drug was well tolerated in all three dosing regimens and resulted in no significant increase in biochemical or clinical side effects compared to placebo. CONCLUSION: Cerivastatin is a novel, highly potent, well-tolerated HMG-CoA reductase inhibitor that produces low-density lipoprotein cholesterol reductions of approximately 30% when administered at 0.2 mg once a day in the evenings.

Lipid-Lowering Effects of Fluvastatin in Renal Transplant Patients. A Clinical Observation

A Atherosclerosis-related cardiovascular disease remains an important cause of morbidity and mortality in renal transplant patients. We assessed the efficacy and safety of the newer synthetic HMG-CoA reductase inhibitor, fluvastatin, in 12 renal transplant patients who remained hypercholesterolemic, despite having been on the American Heart Association (AHA) Step I diet for 6 weeks. At 8 weeks, compared to the control phase, fluvastatin therapy, 20 mg/day, reduced the total cholesterol (TC) from 321 +/- 57 [+/-SD] to 301 +/- 123 mg/dl (p = 0.3); low-density lipoprotein cholesterol (LDL-C), from 209 +/- 56 to 176 +/- 81 mg/dl (p = 0.2); and the triglyceride (TG) levels from 343 +/- 119 to 277 +/- 117 mg/dl (p = 0.06); all these changes were statistically insignificant. However, the therapy significantly increased the high-density lipoprotein cholesterol (HDL-C) from 37 +/- 11 to 46 +/- 13 mg/dl (p = 0.006). During this short-term treatment period no adverse biochemical effects were noted with the therapy.

A Preliminary report of the safety and efficacy of fluvastatin for hypercholesterolemia in renal transplant patients receiving cyclosporine

<h2>Abstract</h2> Hypercholesterolemia is common following renaltransplantation and undoubtedly contributes to morbidity and mortality due to occlusive atherosclerosis in these patients. Although 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are more tolerable as low density lipoprotein cholesterol (LDL-C)-lowering agents than other classes of drugs, their use in transplant patients has been limited due to potentially serious interactions with cyclosporine. Fluvastatin is the first wholly synthetic HMG-CoA reductase inhibitor. Because it has a shorter half-life and greater protein-binding capacity than other drugs of this class and has no active circulating metabolites, fluvastatin may be safer than other HMG-CoA reductase inhibitors in this group of patients. To study this question, 19 renal transplant recipients (age, 21–70 years) with hypercholesterolemia (LDL-C > 180 mg/dL; triglycerides <400 mg/liter) were entered into a 14-week active-treatment period with fluvastatin at 20 mg/day following dietary stabilization and a 3-week placebo washout period. Changes in LDL-C levels were compared with those obtained in control hypercholesterolemic subjects treated in the same way. The lipid-lowering ability of fluvastatin was not impaired in these patients, indicating a lack of interaction with cyclosporine. Mean liver enzyme levels, creatinine phosphokinase (CPK), and creatine did not change significantly from baseline. Two subjects experienced myalgias without CPK elevations, and another subject experienced an asymptomatic increase in CPK to >10 times the upper limit of normal, related to exercise. In conclusion, fluvastatin safely and effectively lowers elevated LDL-C levels in renal transplant recipients.