Comparison of lifibrol to other lipid-regulating agents in experimental animals

In vitro data suggests that lifibrol lowers plasma cholesterol by inhibiting cholesterol synthesis. We report that lifibrol is far less potent in vitro and in vivo than lovastatin for inhibiting ¹⁴C-acetate incorporation into sterols. Moreover, several major differences between lifobrol and lovastatin were noted in various animal models. In contrast, lifibrol exhibited several activities in common with gemfibrozil, another phenoxy-acid-type drug. Specifically, in normal rats lifibrol, like gemfibrozil, lowered plasma non- HDL-cholesterol and triglycerides, and increased liver weight and hepatic peroxisomal marker enzyme activities. Lovastatin only lowered plasma triglycerides. In cholesterol-fed rats lifibrol and gemfibrozil lowered non-HDL-cholesterol and elevated HDL-cholesterol while lovastatin was inactive. Finally, lovastatin but not lifibrol exhibited hypocholesterolemic activity in normal guinea pigs and resin-primed dogs. Our interpretation is that these data do not support the notion that lifibrol lowers plasma cholesterol in vivo by inhibiting cholesterol synthesis.     

Preventive effect of MK-733 (simvastatin), an inhibitor of HMG-CoA reductase, on hypercholesterolemia and atherosclerosis induced by cholesterol feeding in rabbits

MK-733 was found to prevent an increase of serum cholesterol levels in cholesterol-fed rabbits, and lovastatin also markedly inhibited their increase. MK-733 and lovastatin inhibited the increase of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) cholesterol, and it slightly affected the high density lipoprotein (HDL) cholesterol levels. MK-733 and lovastatin suppressed the increase of serum phospholipid levels and slightly affected the triglyceride levels. MK-733 suppressed the development of atherosclerosis in coronary arteries and aorta, and lovastatin also diminished their development.     

Long-term administration of the HMG-CoA reductase inhibitor lovastatin in two patients with cholesteryl ester storage disease

OBJECTIVE: In order to suppress de novo cholesterol and VLDL biosynthesis, a long-term therapy trial with lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, was initiated in two patients with cholesteryl ester storage disease (CESD), and concentrations of plasma lipids were monitored over a period of 9 years. METHODS: We studied two male patients with enzymatically confirmed CESD in whom long-term lovastatin therapy (8 and 9 years) was begun at the age of 7 and 19 years. The diagnosis of CESD was confirmed by the measurement of human lysosomal acid lipase (hLAL) activity in cultured skin fibroblasts and leukocytes. Restriction fragment length polymorphism (RFLP) analysis revealed that both subjects are homozygotes for the common CESD splice site mutation. Levels of serum lipids and lipoproteins were measured yearly. RESULTS: During the first year, total serum cholesterol decreased from 317 to 201 mg/dl in Patient A and from 228 to 120 mg/dl in Patient B, due mainly to the reduction of low-density lipoprotein (LDL) cholesterol from 262 to 151 mg/dt in Patient A and from 166 to 66 mg/dl in Patient B. Accordingly, the LDL cholesterol : high density lipoprotein (HDL) cholesterol ratio was markedly reduced in both patients after one year of therapy. The treatment was continued and, after 9 years of further medication, low total cholesterol and LDL cholesterol levels were still maintained. CONCLUSIONS: The study demonstrates that HMG-CoA reductase inhibitors are well tolerated drugs during long-term treatment of CESD patients and may help to prevent the development of premature atherosclerosis.     

Effects of gemfibrozil and other fibric acid derivatives on blood lipids and lipoproteins

Fibric acid derivatives (FADs) are a class of drugs that have been shown to reduce the production of very low-density lipoprotein (VLDL) while enhancing VLDL clearance due to the stimulation of lipoprotein lipase activity. The drugs can reduce plasma triglyceride levels while raising high-density lipoprotein (HDL) cholesterol levels. Their effects on low-density lipoprotein (LDL) cholesterol levels are less marked and more variable. There is evidence that oral gemfibrozil (Lopid, Parke-Davis, Morris Plains, NJ) can reduce the risk of serious coronary events, specifically in those patients who had elevations of both LDL cholesterol levels and total plasma triglyceride levels with lower HDL cholesterol levels. Newer FADs (bezafibrate, ciprofibrate, fenofibrate) have been shown to have greater efficacy in reducing LDL cholesterol than gemfibrozil but, in general, these drugs are not as effective as the other primary drugs used to lower LDL levels. The FADs are also used to treat adult patients with very high levels of triglycerides who have pancreatitis and whose disease cannot be managed with dietary therapy. The FADs are well tolerated, with dyspepsia and abdominal pain the most common adverse effects. A small risk of cholelithiasis exists with these drugs, and caution should be used when combining these drugs with HMG-CoA reductase inhibitors because the combination increases the incidence of hyperlipidemic myositis and rhabdomyolysis.     

Short- and long-term effects of lovastatin and pravastatin alone and in combination with cholestyramine on serum lipids,lipoproteins and apolipoproteins in primary hypercholesterolaemia

Summary The effects of the HMG CoA reductase inhibitors lovastatin and pravastatin on serum lipids, lipoproteins and apolipoproteins have been studied in 35 patients with primary hypercholesterolaemia.LDL cholesterol was lowered to the same extent by both agents compared on a mg basis of each drug per day. HDL cholesterol was increased by lovastatin but not by pravastatin. The reduction in serum triglycerides, VLDL triglycerides and VLDL cholesterol was more pronounced after lovastatin than pravastatin. After 1 year the effect of combined treatment with 40 mg pravastatin and 8 g cholestyramine on the reduction in LDL cholesterol (–39%) in 13 patients was comparable to that of 80 mg lovastatin plus 8 g cholestyramine (–40%) in 12 patients with identical baseline values.Differences were also found in the effects of the combination therapy with the two drugs on HDL cholesterol, serum triglycerides, VLDL triglycerides, VLDL cholesterol, and apolipoproteins.     

A bright future of researching AMPA receptor agonists for depression treatment

Management of dyslipoproteinaemia is one of the key strategies in the prevention of cardiovascular disease. The major target of hypolipidaemic drugs is the reduction of low density lipoprotein (LDL) cholesterol. Lifibrol, a novel lipid-lowering agent, is highly potent in reducing total cholesterol, LDL cholesterol, and apolipoprotein B. Its efficacy in lowering serum triglycerides, lipoprotein(a) and fibrinogen implies additional benefit in the prophylaxis and treatment of coronary heart disease. Thus, lifibrol appears to be a multivalent anti-atherosclerotic agent. The hypolipidaemic properties of lifibrol have been examined in several clinical trials and in various animal models. The mode of action of lifibrol involves at least three mechanisms: lifibrol enhances LDL catabolism by sterol-independent stimulation of LDL receptor activity, reduces cholesterol absorption from the intestine, and slightly decreases hepatic cholesterol biosynthesis. Lifibrol’s lipid-lowering profile and putative mode of action clearly distinguish it from other classes of hypolipidaemic drugs, such as HMG-CoA reductase inhibitors or fibric acid derivatives. Thus, lifibrol may represent a new class of agents affecting lipid metabolism.     

Lifibrol: first member of a new class of lipid-lowering drugs?

Management of dyslipoproteinaemia is one of the key strategies in the prevention of cardiovascular disease. The major target of hypolipidaemic drugs is the reduction of low density lipoprotein (LDL) cholesterol. Lifibrol, a novel lipid-lowering agent, is highly potent in reducing total cholesterol, LDL cholesterol, and apolipoprotein B. Its efficacy in lowering serum triglycerides, lipoprotein(a) and fibrinogen implies additional benefit in the prophylaxis and treatment of coronary heart disease. Thus, lifibrol appears to be a multivalent anti-atherosclerotic agent. The hypolipidaemic properties of lifibrol have been examined in several clinical trials and in various animal models. The mode of action of lifibrol involves at least three mechanisms: lifibrol enhances LDL catabolism by sterol-independent stimulation of LDL receptor activity, reduces cholesterol absorption from the intestine, and slightly decreases hepatic cholesterol biosynthesis. Lifibrol's lipid-lowering profile and putative mode of action clearly distinguish it from other classes of hypolipidaemic drugs, such as HMG-CoA reductase inhibitors or fibric acid derivatives. Thus, lifibrol may represent a new class of agents affecting lipid metabolism.     

Mode of action and adverse effects of lipid lowering drugs

Serum lipids, cholesterol and triglycerides are incorporated into hydrophilic lipoproteins, which include chylomicrons, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low density lipoproteins (LDL) and high density lipoproteins (HDL). An elevated level of these lipoproteins, except for HDL, is the basis of all hyperlipidemias. However, only some of the lipoprotein fractions, particularly LDL and remnant particles, are potential risk factors for atherogenesis and subsequent cardiovascular disease. Several classes of pharmacological agents are currently available to increase the breakdown and reduce the synthesis of LDL and remnant factors. These include nicotinic acid and its analogs, fibric acid derivatives (e.g., clofibrate, gemfibrozil, bezafibrate), bile acid resins (e.g., cholestyramine), HMG-CoA reductase inhibitors (e.g., lovastatin, simvastatin, pravastatin) and probucol. Lipid lowering drugs of different classes have a synergistic effect on lipid metabolism and combination therapy is often used. Lipid lowering drugs are prescribed as long-term preventive therapy in apparently asymptomatic people. Several studies indicate that secondary prevention with lipid lowering drugs is cost-effective, particularly in patients with symptomatic coronary artery disease.     

Influence of sodium monoketocholate on the hypolipidemic activity of lovastatin in healthy and diabetic rats

Recent findings regarding the physiological transport mechanisms and metabolism of bile acids have led to an increased interest in their synthetic derivatives, especially as transmucous transporters. The aim of this study was to examine the influence of the synthetic sodium salt of monoketocholic acid (Na-MKHA) on the hypolipidemic activity of lovastatin. The effects of a 7 days administration of lovastatin (20 mg/kg b.w.) (experimental group 1, n=5) and a combination of lovastatin (20 mg/kg b.w.) and Na-MKHA (2 mg/kg b.w.) (experimental group 2, n=5) in group of healthy and diabetic male Wistar rats were investigated. The animals in the control group of healthy (n=5) and diabetic (n=5) rats were treated with physiological saline (10 ml/kg b.w.) per os twice a day. In the healthy rats, lovastatin increased the low density lipoprotein (LDL) (32.14%) and non-high density lipoprotein (HDL) (15.38%) cholesterol and decreased HDL cholesterol levels (9.89%), and also increased the investigated atherogenic ratios. Na-MKHA significantly potentiated lovastatin activity, and its effects on the LDL (p<0.05; 102.70%), HDL (p<0.01; 32.93%) and non-HDL (p<0.05; 65%) cholesterol levels, as well as the LDL/HDL (p<0.02; 231.11%), total cholesterol/HDL (p<0.02; 70.52%) and non-HDU/HDL cholesterol ratios (p<0.02; 167.12%). In diabetic animals, the potentiating effect of Na-MKHA was not significant. The stimulatory effect of Na-MKHA is probably a consequence of the intensified transmembrane transport of lovastatin due to the direct action of bile acids on the cell membranes, as well as a result of their enhanced transport via specific bile acid transport systems.     

Understanding and Treating Dyslipidemia Associated With Noninsulin-Dependent Diabetes Mellitus and Hypertension

Hypertension and diabetes appear to increase coronary heart disease risk in part by causing an abnormality in lipid metabolism. Most affected are patients with familial dyslipidemic hypertension (FDH) and noninsulin-dependent diabetes mellitus (NIDDM). The lipid disorders most often encountered in these patients are increased levels of triglycerides, very low-density lipoprotein (VLDL) cholesterol, and small, dense low-density lipoprotein (LDL) cholesterol, and low levels of high-density lipoprotein (HDL) cholesterol. These abnormalities appear to result from increased hepatic secretion of VLDL particles due to increased concentrations of free fatty acids and glucose, reduced VLDL clearance due to reduced activity of lipoprotein lipase, and reduced LDL clearance due to glycosylation of ligand proteins. Treatment of the dyslipidemia associated with FDH should follow the guidelines from the National Cholesterol Education Program. Treatment in men and women with NIDDM should be considered when LDL cholesterol levels are 130 mg/dl or above, triglyceride levels are 200 mg/dl or above, or non-HDL cholesterol levels are 160 mg/dl or greater. Aggressive lifestyle changes should be initiated first, including weight loss in obese patients, control of glucose levels in those with NIDDM, avoidance of antihypertensive drugs that may worsen lipid levels in patients with FDH, and eating a diet restricting saturated fat and cholesterol. Addition of lipid-altering drugs should be considered if such changes do not achieve effective lipid control. The agent should be tailored to the patient's lipid profile, in general by using bile acid resins, niacin, or reductase inhibitors to lower LDL cholesterol and gemfibrozil or niacin to lower triglycerides. Niacin should be avoided in patients with NIDDM.     

Lovastatin: a new cholesterol-lowering agent

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, dosage and administration, and adverse effects of lovastatin are reviewed. Lovastatin is the first agent marketed in a new class of pharmacologic compounds called the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors. By competitively inhibiting HMG CoA reductase, the drug disrupts the biosynthesis of cholesterol in hepatic and peripheral cells. This increases the synthesis of low-density-lipoprotein (LDL) receptors and thereby increases the uptake of LDL cholesterol from the plasma. In doses of 20 to 80 mg daily, lovastatin decreases total and LDL cholesterol concentrations 25 to 45%. It also substantially reduces concentrations of triglycerides, very-low-density-lipoprotein (VLDL) cholesterol, and apolipoprotein B and slightly increases high-density-lipoprotein (HDL) cholesterol concentrations. Lovastatin is effective in patients with heterozygous familial and nonfamilial (polygenic) hypercholesterolemia but is ineffective in patients with homozygous familial hypercholesterolemia. It is also effective in combination with bile acid sequestrants, nicotinic acid, and gemfibrozil. Administration of lovastatin once daily in the evening (to enhance compliance) or twice daily is recommended to maximize the drug's cholesterol-lowering effects. Headache and gastrointestinal complaints are the most common adverse effects. Treatment has been withdrawn from 1.9% of patients receiving the drug because of elevated aminotransferase concentrations. The relationship of lovastatin to the development of lens opacities requires further evaluation. Lovastatin is highly effective in the treatment of primary hypercholesterolemia and represents an important therapeutic advance. Safety with long-term use and effect on coronary heart disease remain to be established.     

Hypolipidemic Activity of 3-Amino-1-(2,3,4-mononitro-, mono-, or dihalophenyl)propan-1-ones in Rodents

A series of 3-amino-1-(2,3,4-mononitro-, mono-, or dihalophenyl)propan-1-ones were synthesized and shown to be effective in lowering both serum cholesterol and triglyceride levels significantly in CF₁ mice and Sprague-Dawley rats. All analogs showed better activity than the standard drugs, lovastatin and clofibrate, in reducing the serum cholesterol and triglyceride levels in mice at 8 mg/kg/day intraperitoneally. The best active analogs, 3-morpholino-1-(3-nitrophenyl)propan-1-one ( 4 ) and 3-piperidino-1-(3-nitrophenyl)propan-1-one ( 5 ), exhibited 58% and 67% reduction of serum cholesterol levels, respectively, and 42% and 46% reduction of serum triglyceride levels, respectively, after 16 days of administration at 8 mg/kg/day intraperitoneally in CF₁ mice. In Sprague-Dawley rats at 8 mg/kg/day oral administration, both compounds ( 4 and 5 ) significantly decreased the serum cholesterol and triglyceride levels. Rat tissue lipid levels were reduced significantly by compound 4, while less effects resulted from compound 5. The cholesterol and triglyceride levels in chylomicrons, VLDL, and LDL fractions were reduced by both analogs while the HDL cholesterol levels were significantly increased. Compound 5 was also effective in lowering serum cholesterol and triglyceride levels in hyperlipidemic mice, at 8 mg/kg/day intraperitoneally, but not effective in hyperlipidemic rats at 8 mg/kg/day intraperitoneally, but not effective in hyperlipidemic rats at 8 mg/kg/day orally. Cholesterol and triglyceride lowering effects of the agents were correlated with inhibition of the activities of liver acetyl CoA synthetase, HMG CoA reductase, phosphatidylate phosphohydrolase, and lipoprotein lipase, and with elevation of the activity of cholesterol ester hydrolase.     

Combination Therapy with Low-Dose Lovastatin and Niacin Is as Effective as Higher-Dose Lovastatin

Study Objectives . To determine if low-dose lovastatin in combination with niacin causes a greater percentage reduction in low-density lipoprotein (LDL) cholesterol than lovastatin alone, and to determine if the combination increases the risk of serious adverse effects. Design . Prospective, randomized, open-label, clinical trial. Setting . Family medicine clinic of a university-affiliated hospital. Patients . Patients with fasting LDL cholesterol concentrations of at least 150 mg/dl after 4 weeks of dietary stabilization and washout of any cholesterol-lowering drugs. Interventions . Twenty-eight patients received lovastatin 20 mg/day for 4 weeks after dietary stabilization and washout. If LDL cholesterol remained above 130 mg/dl (100 mg/dl in patients with coronary artery disease), they were randomized to receive either lovastatin 40 mg/day or a combination of lovastatin 20 mg/day and niacin 500 mg 3 times/day. Measurements and Main Results . There was no difference in actual or percentage reductions of LDL cholesterol, total cholesterol, and triglycerides between the groups. A greater increase in high-density lipoprotein (HDL) cholesterol occurred with combination therapy (p=0.024). There was no difference in liver function tests, glucose, or uric acid between the therapies. Based on drug-acquisition cost, combination therapy is approximately 40% less expensive than monotherapy. Conclusion . Low-dose niacin plus low-dose lovastatin was as effective as higher-dose lovastatin in lowering total cholesterol, LDL cholesterol, and triglyceride levels. The combination may offer benefit in raising HDL cholesterol levels.     

Lipid-lowering effects of TAK-475, a squalene synthase inhibitor,in animal models of familial hypercholesterolemia

The lipid-lowering effects of 1-[2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-1,2,3,5-tetrahydro-2-oxo-5-(2,3-dimethoxyphenyl)-4,1-benzoxazepine-3-yl] acetyl] piperidin-4-acetic acid (TAK-475), a novel squalene synthase inhibitor, were examined in two models of familial hypercholesterolemia, low-density lipoprotein (LDL) receptor knockout mice and Watanabe heritable hyperlipidemic (WHHL) rabbits. Two weeks of treatment with TAK-475 in a diet admixture (0.02% and 0.07%; approximately 30 and 110 mg/kg/day, respectively) significantly lowered plasma non-high-density lipoprotein (HDL) cholesterol levels by 19% and 41%, respectively, in homozygous LDL receptor knockout mice. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, simvastatin and atorvastatin (in 0.02% and 0.07% admixtures), also reduced plasma levels of non-HDL cholesterol. In homozygous WHHL rabbits, 4 weeks of treatment with TAK-475 (0.27%; approximately 100 mg/kg/day) lowered plasma total cholesterol, triglyceride and phospholipid levels by 17%, 52% and 26%, respectively. In Triton WR-1339-treated rabbits, TAK-475 inhibited to the same extent the rate of secretion from the liver of the cholesterol, triglyceride and phospholipid components of very-low-density lipoprotein (VLDL). These results suggest that the lipid-lowering effects of TAK-475 in WHHL rabbits are based partially on the inhibition of secretion of VLDL from the liver. TAK-475 had no effect on plasma aspartate aminotransferase and alanine aminotransferase activities. Thus, the squalene synthase inhibitor TAK-475 revealed lipid-lowering effects in both LDL receptor knockout mice and WHHL rabbits.     

Inhibition of cholesterol synthesis causes both hypercholesterolemia and hypocholesterolemia in hamsters

Effects of FR194738 ((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[2-methyl-2-(3-thienylmethoxy)propyloxy]benzylamine hydrochloride), a squalene epoxidase inhibitor, on lipid metabolism were compared with those of pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, in hamsters. Drugs were given for 10 d either as a diet mixture or as a bolus oral gavage, and similar results were obtained with each type of administration. FR194738 (0.01-0.32% as a diet mixture; 10-100 mg/kg as an oral gavage) dose-dependently decreased serum total cholesterol, non high density lipoprotein (HDL) cholesterol, HDL cholesterol and triglyceride levels, and the changes in serum parameters were similar. Pravastatin (0.01-0.32% as a diet mixture; 1-100 mg/kg as an oral gavage) increased serum cholesterol levels, and dose-dependently decreased serum triglyceride levels. Although oral gavage of FR194738 at 32 mg/kg and pravastatin at 3.2 and 10 mg/kg increased hepatic HMG-CoA reductase activity, the degree of the changes was far greater with the latter than the former drug. FR194738 slightly increased hepatic cholesterol content at 32 mg/kg, whereas pravastatin dose-dependently increased hepatic cholesterol content until it leveled off at 32 and 100 mg/kg. It is concluded that inhibition of squalene epoxidase and HMG-CoA reductase triggers both hypercholesterolemic (hepatic cholesterol synthesis) and hypocholesterolemic (hepatic cholesterol uptake) mechanisms. FR194738 appears to induce a greater enhancement of the latter rather than the former, whereas pravastatin has a greater effect on the former.     

Comparison of gemfibrozil and fenofibrate in patients with dyslipidemic coronary heart disease

STUDY OBJECTIVE: To compare the lipid-lowering effects of gemfibrozil and fenofibrate in patients with dyslipidemic coronary heart disease. DESIGN: Open label, fixed-dosage, retrospective-prospective, one-way crossover from gemfibrozil to fenofibrate. SETTING: University-affiliated outpatient clinics. PATIENTS: Eighty patients with coronary heart disease with a baseline low-density lipoprotein cholesterol (LDL) level above 130 mg/dl or a triglyceride level of 200 mg/dl or higher who had been receiving gemfibrozil 600 mg twice/day. Thirty-nine (49%) patients had received concomitant therapy with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) for a minimum of 9 months. INTERVENTION: All patients received gemfibrozil 600 mg twice/day for at least 3 months before being switched to fenofibrate 201 mg/day. Patients receiving concomitant statin therapy before crossover continued the statin at the same dosage after crossover. Before crossover, a fasting lipid profile was determined and patients were queried about the side effects of lipid-lowering therapy. A repeat fasting lipid profile was obtained 12 weeks after the crossover. MEASUREMENTS AND MAIN RESULTS: Patients were stratified into those receiving versus those not receiving concomitant statin therapy. In both of these groups, fenofibrate was associated with significantly greater reductions in total cholesterol, LDL, and triglycerides than gemfibrozil (all p < 0.001). In addition, fenofibrate was associated with a significantly greater increase in high-density lipoprotein cholesterol (HDL) than gemfibrozil (p < 0.001). No patients reported new-onset adverse effects after the crossover. CONCLUSIONS: Compared with gemfibrozil, fenofibrate produced significantly greater reductions in total cholesterol, LDL, and triglycerides and significantly greater increases in HDL. These changes were evident in patients receiving and not receiving concomitant statin therapy.     

Synthesis and Pharmacological Studies of 3-Amino-2-methyl-1-phenylpropanones as Hypolipidemic Agents in Rodents

A series of 3-amino-2-methyl-1-phenylpropanones were synthesized and proven to have potent hypolipidemic activity in rodents by lowering both serum cholesterol and triglyceride levels at 8 mg/kg/day, i.p. and orally. Many of these analogs showed significantly higher activity than standard drugs, lovastatin and clofibrate at their therapeutic doses. 2-Methyl-3-(perhydroazepin-1-yl)-1-phenylpropanone (@!4), 3-(4-methylpiperazin-1-yl)-1-phenylpropanone ( 5 ), and 2-methyl-3-(4-pyrrolidinocarbonyl-methylpiperazin-1-yl)-1-(4-fluorophenyl) propanone ( 17 ) showed the best overall activities in lowering both serum cholesterol and triglyceride levels in CF₁ mice at 8 mg/kg/day after 16 days of treatment. Compounds 4, 5 , and 17 lowered serum cholesterol levels 63%, 58%, and 42%, respectively, after 16 days at 8 mg/kg/day i.p. These agents reduced the serum triglyceride levels by 33%, 37%, and 54%, respectively. In Sprague-Dawley rats these compounds also demonstrated significant serum lipid lowering effects by decreasing both serum cholesterol and triglyceride levels after 14 days of oral drug administration at 8 mg/kg/day. Compound 17 reduced the rat aorta cholesterol levels by 37%, triglyceride levels by 50%, and neutral lipid levels by 34% after 14 days of oral administration. These compounds lowered the chylomicron, VLDL, and LDL cholesterol and triglyceride levels while elevating the HDL cholesterol levels significantly. In hyperlipidemic rodents, these analogs also demonstrated significant serum lipid lowering effects but were less active than in normalipidemic rodents. The activities of some enzymes, such as mouse hepatic acetyl CoA synthetase, HMG CoA reductase, phosphatidylate phosphohydrolase, and hepatic lipoprotein lipase, were significantly reduced by these compounds.     

Atorvastatin: an updated review of its pharmacological properties and use in dyslipidaemia.

Atorvastatin is a synthetic hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. In dosages of 10 to 80 mg/day, atorvastatin reduces levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride and very low-density lipoprotein (VLDL)-cholesterol and increases high-density lipoprotein (HDL)-cholesterol in patients with a wide variety of dyslipidaemias. In large long-term trials in patients with primary hypercholesterolaemia. atorvastatin produced greater reductions in total cholesterol. LDL-cholesterol and triglyceride levels than other HMG-CoA reductase inhibitors. In patients with coronary heart disease (CHD), atorvastatin was more efficacious than lovastatin, pravastatin. fluvastatin and simvastatin in achieving target LDL-cholesterol levels and, in high doses, produced very low LDL-cholesterol levels. Aggressive reduction of serum LDL-cholesterol to 1.9 mmol/L with atorvastatin 80 mg/day for 16 weeks in patients with acute coronary syndromes significantly reduced the incidence of the combined primary end-point events and the secondary end-point of recurrent ischaemic events requiring rehospitalisation in the large. well-designed MIRACL trial. In the AVERT trial, aggressive lipid-lowering therapy with atorvastatin 80 mg/ day for 18 months was at least as effective as coronary angioplasty and usual care in reducing the incidence of ischaemic events in low-risk patients with stable CHD. Long-term studies are currently investigating the effects of atorvastatin on serious cardiac events and mortality in patients with CHD. Pharmacoeconomic studies have shown lipid-lowering with atorvastatin to be cost effective in patients with CHD, men with at least one risk factor for CHD and women with multiple risk factors for CHD. In available studies atorvastatin was more cost effective than most other HMG-CoA reductase inhibitors in achieving target LDL-cholesterol levels. Atorvastatin is well tolerated and adverse events are usually mild and transient. The tolerability profile of atorvastatin is similar to that of other available HMG-CoA reductase inhibitors and to placebo. Elevations of liver transaminases and creatine phosphokinase are infrequent. There have been rare case reports of rhabdomyolysis occurring with concomitant use of atorvastatin and other drugs. CONCLUSION: Atorvastatin is an appropriate first-line lipid-lowering therapy in numerous groups of patients at low to high risk of CHD. Additionally it has a definite role in treating patients requiring greater decreases in LDL-cholesterol levels. Long-term studies are under way to determine whether achieving very low LDL-cholesterol levels with atorvastatin is likely to show additional benefits on morbidity and mortality in patients with CHD.     

Hypolipidemic Activity of o-(N-Phthalimido)acetophenone in Sprague Dawley Rats

o-(N-Phthalimido)acetophenone has proven to be an effective hypolipidemic agent in rats at 20 mg/kg/ day orally. The agent suppressed the activity of the rate-limiting enzyme of the liver involved in de novo synthesis of triglycerides. The synthetic rate-limiting enzyme for cholesterol esters was also inhibited by the drug in vivo. o-(N-Phthalimido)acetophenone lowered cholesterol in the liver and the aorta wall and generally caused an increase in phospholipids in body tissues. Serum lipoproteins were modulated by the drug with a decrease in cholesterol and triglycerides in the chylomicron, very low-density lipoproteins (VLDL), and low-density lipoproteins (LDL) and an increase in high-density lipoprotein (HDL) cholesterol. The phospholipid content was increased in the chylomicron, VLDL, and LDL fractions. In hyperlipidemic rats, o-(N-phthalimido)acetophenone lowered elevated blood lipid levels at 20 mg/kg/day orally after 3 weeks of administration. The hypolipidemic rat after drug treatment had a lower LDL cholesterol and a higher HDL cholesterol content, which is therapeutically desirable to protect against cardiovascular disease.     

Pharmacological comparison of the statins

The statins (3-hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors) represent drugs of first choice for treatment of hypercholesterolemia. The safety and efficacy of atorvastatin (CAS 134523-00-5), simvastatin (CAS 79902-63-9), lovastatin (CAS 75330-75-7), pravastatin (CAS 81093-37-0) and fluvastatin (CAS 93957-54-1) has been well documented. Statins decrease dose-dependently low-density lipoprotein (LDL) cholesterol as well as coronary events and total mortality. Clinical outcome data indicate that for simvastatin the lowest number of treated patients is needed to prevent one major coronary event (NNT 15). Based on an approximately 30% reduction of LDL (valid surrogate parameter) atorvastatin (5 mg/day) and simvastatin (10 mg/day) are the most potent agents whereas 40 mg of lovastatin or pravastatin and 60 mg of fluvastatin are needed to reach this "therapeutic target". While all statins share the same mode of action their pharmacokinetic properties and their susceptibility to drug interactions differ slightly. Agents inhibiting CYP3A4 (e.g. grapefruit juice, itraconazole, cyclosporine) should be discouraged if a patient is on atorvastatin, lovastatin or simvastatin. Likewise, fluconazole interferes with the CYP2C9-mediated hepatic elimination of fluvastatin. Moreover, coadministration of gemfibrozil should be avoided because it seems to increase the very low risk for statin-induced rhabdomyolysis. Several statins are available and their equieffective doses have been defined. Selection of a particular drug should be primarily based on clinical outcome data. However, costs and in certain situations the pharmacokinetic profile including the interaction potential of the statins should be taken into account.