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PubMed2005

Diet, lifestyle, and nonstatin trials: review of time to benefit.

How rapidly benefits accrue from nonstatin, lipid-lowering therapies is a 21st-century question posed to data collected in the 20th century. The 3 early dietary trials conducted in institutional settings where diet was strictly controlled demonstrate that, compared with a control diet, cholesterol-lowering diets reduce coronary event rates over several years. These data do not reveal whether a more homogeneous high-risk population would demonstrate an earlier time to benefit. Dietary counseling trials of men with coronary disease conducted in the 1950s and 1960s failed to demonstrate a consistent benefit from dietary therapy, in part because of confounding factors from methodologic flaws in trial design. By the 1980s and 1990s, improvements in trial design, such as larger numbers of subjects, control of confounding risk factors, and limiting trial end points to those directly attributable to atherosclerotic events, were in place. Subsequently, 5 randomized clinical trials showed a consistent benefit of dietary therapy, with significant reductions by 1 to 2 years in fatal events, nonfatal events, and total mortality; 2 of these studies, each including omega-3 fatty acids as part of the dietary intervention, reported a rapid and significant time to benefit (within 3 to 6 months). Additional lifestyle benefits of cardiac rehabilitation (a surrogate for physical activity) and smoking cessation clearly show long-term benefit at 1 and 5 years, respectively. Nonstatin drug and surgical therapies either have shown no significant benefit (estrogen, dextrothyroxine) or benefit after 1 to 5 years of therapy (intestinal bypass surgery, cholestyramine, clofibrate, niacin, and a combination of niacin and clofibrate). In conclusion, rapid time to benefit has been observed in older lifestyle and nonstatin trials that have included omega-3 fatty acids as a component of dietary therapy. Lifestyle changes in diet, physical activity, weight loss, and smoking cessation remain important and effective therapies with which significant long-term benefits can be expected.

Diet, Fat-Restricted↗

PubMed2006

ACAT inhibitor pactimibe sulfate (CS-505) reduces and stabilizes atherosclerotic lesions by cholesterol-lowering and direct effects in apolipoprotein E-deficient mice.

The objective of the present study was to determine whether a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, pactimibe sulfate (CS-505), could reduce atherosclerotic lesions beyond and independent of the reduction achieved by cholesterol lowering alone from two different types of lesions. (1) Early lesion model. Twelve-week-old apolipoprotein E (apoE)(-/-) mice were treated with 0.03 or 0.1% (w/w) CS-505, 0.1 or 0.3% avasimibe (CI-1011), or 3% cholestyramine for 12 weeks. Each treatment significantly reduced plasma cholesterol by a similar degree (43-48%). The antiatherosclerotic activity of 0.1% CS-505, however, was more efficacious than the effects of the other treatments (90% versus 40-50%). (2) Advanced lesion model. Twenty-four-week-old apoE(-/-) mice were treated with 0.03 or 0.1% CS-505 or 0.1% CI-1011 for 12 weeks. CS-505 at 0.1% revealed enhanced lesion reduction compared with 0.1% CI-1011 (77% versus 54%), whereas the plasma cholesterol-lowering effect of 0.1% CS-505 was almost the same as that of 0.1% CI-1011. Furthermore, immunohistochemical analysis demonstrated that CS-505 significantly reduced the number of macrophages and expression of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-13. These data indicate that CS-505 can reduce and stabilize atherosclerotic lesions. This antiatherosclerotic activity is exerted via both cholesterol lowering and direct ACAT inhibition in plaque macrophages.

Animals↗

PubMed2006

Thyrotoxicosis and thyroid storm.

Thyroid storm represents the extreme manifestation of thyrotoxicosis as a true endocrine emergency. Although Grave's disease is the most common underlying disorder in thyroid storm, there is usually a precipitating event or condition that transform the patient into life-threatening thyrotoxicosis. Treatment of thyroid storm involves decreasing new hormone synthesis, inhibiting the release of thyroid hormone, and blocking the peripheral effects of thyroid hormone. This multidrug, therapeutic approach uses thionamides, iodine, beta-adrenergic receptor antagonists, corticosteroids in certain circumstances, and supportive therapy. Certain conditions may warrant the use of alternative therapy with cholestyramine, lithium carbonate, or potassium perchlorate. After the critical illness of thyroid storm subsides, definitive treatment of the underlying thyrotoxicosis can be planned.

Adrenergic beta-Antagonists↗

PubMed2006

Lipoprotein effects of combined ezetimibe and colesevelam hydrochloride versus ezetimibe alone in hypercholesterolemic subjects: a pilot study.

Two drug classes act in the intestine to lower cholesterol. Ezetimibe inhibits cholesterol absorption, whereas bile acid-binding resins enhance cholesterol excretion via enhanced conversion to bile acids. Combining these 2 classes may be beneficial, but cholestyramine binds ezetimibe, and the combined effect of colesevelam hydrochloride and ezetimibe was little studied. The aim of the study was to determine if adding colesevelam HCl to ezetimibe provides additional lowering of low-density lipoprotein- and apolipoprotein B-containing lipoproteins or alters ezetimibe levels. Twenty subjects with low-density lipoprotein cholesterol (LDL-C) levels of 130 mg/dL or higher were enrolled and taught a National Cholesterol Education Program Step I diet. At a second baseline visit, lipoproteins were measured and subjects were randomly allocated to (1) ezetimibe 10 mg daily with placebo colesevelam HCl twice daily (E) or (2) ezetimibe 10 mg daily with 1.875 g colesevelam HCl twice daily (E + C). Lipoproteins were measured 6 and 12 weeks after initiating treatment. Baseline characteristics (mean +/- SD) were statistically indistinguishable in E vs E + C: LDL-C (mg/dL), 167 +/- 26 and 158 +/- 27; triglyceride, 134 +/- 75 and 140 +/- 67; and BMI, 29.4 +/- 4.9 and 27.8 +/- 6.6 kg/m(2), respectively. Percent changes after 12 weeks in E vs E + C were as follows: LDL-C, -24 +/- 12 vs -30 +/- 11 (P = .102); triglyceride, -19 +/- 34 vs 36 +/- 85 (P = .054; at 6 weeks, P = .009); total cholesterol, -19 +/- 9 vs -15 +/- 8 (P = .50); non-high-density lipoprotein cholesterol, -25 +/- 10 vs -21 +/- 11 (P = .70); apolipoprotein B, -31 +/- 14 vs -22 +/- 14 (P = .41). Plasma ezetimibe levels at 12 weeks were 21% lower in E + C vs E, a nonsignificant difference (P = .54). In conclusion, in the short term, colesevelam HCl may not consistently add cholesterol-lowering benefit to ezetimibe. This observation requires confirmation.

Adult↗

PubMed2000

Defining patient risks from expanded preventive therapies.

In clinical trials, all lipid-lowering agents have been associated with mild, asymptomatic elevations of alanine aminotransferase (ALT) and asparate aminotransferase enzymes. This, along with the fact that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are hepatotoxic in some animals, led the US Food and Drug Administration (FDA) to recommend monitoring of liver enzymes for all lipid-lowering agents, except the bile acid sequestrants. Because the drugs act by different mechanisms, ALT elevations may be a pharmacodynamic effect related to lipid lowering, rather than a direct effect of the drug. Animal studies support this assumption. ALT elevations of 3 times the upper limit of normal occur in <3% of patients in clinical trials of lipid-lowering drugs. The elevations are transient and often dose-related, and they usually revert to normal while continuing therapy and have never been associated with hepatotoxicity. Confounding factors include alcohol, acetaminophen, and pre-existing liver disease, such as chronic hepatitis C and type II diabetes with fatty liver, which are both associated with mild, intermittent elevations of ALT. The more important issue is whether or not lipid-lowering agents are hepatotoxic. There are case reports of hepatotoxicity (cholestasis, jaundice, hepatitis, chronic active hepatitis, fatty liver, cirrhosis and acute liver failure) with all of the drugs, except cholestyramine. To date there are just 5 cases of documented liver failure linked to lovastatin. There is no evidence that monitoring reduces the rate of hepatotoxicity. Mild elevations of ALT that occur with many drugs, including HMG-CoA reductase inhibitors, do not predict hepatotoxicity. Liver enzyme elevations appear to be a class characteristic of lipid-lowering agents. Hepatotoxicity is a rare idiosyncratic reaction, occurring only with sustained released nicotinic acid.

Alanine Transaminase↗

PubMed1999

Efficacy and safety of simvastatin for high-risk hypercholesterolemia.

Ten years' experience of treatment with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin in 45 hypercholesterolemic high-risk patients is reported. All patients started with 20 mg simvastatin/day. The simvastatin dose was increased to 40 mg in 22 patients. Fourteen patients needed further addition of cholestyramine. Simvastatin reduced plasma cholesterol by 33% after 1 month and was further reduced after adjustment of the lipid-lowering treatment. The mean reduction in plasma cholesterol varied between 30% and 35% in 2 to 10 years. Low-density lipoprotein cholesterol demonstrated mean reductions of 34% to 42%. Mean plasma triglycerides were reduced by 26% after 1 month and by 1% to 19% the following years. High-density lipoprotein (HDL) cholesterol increased initially by 8% and remained elevated at 7% to 11% during the first 6 years, but then dropped slightly below baseline. HDL2 cholesterol increased by 9% to 25% the first 6 years and then decreased. HDL3 cholesterol showed a persistent elevation during simvastatin treatment. About half of the subjects had minor transient but clinical insignificant increases in creatine kinase. No cases of myopathy were seen. Mean serum aspartate aminotransferase and alanine aminotransferase increased significantly but within the normal ranges during the 10 years. The tolerability and compliance of simvastatin treatment was excellent as judged from patients' reports and from analyses of low-density lipoprotein cholesterol. This 10-year study demonstrates that simvastatin is an effective and safe drug with excellent tolerability with only few minor side effects, and causes a pronounced and persistent cholesterol-lowering effect during long-term treatment of hypercholesterolemic patients at risk.

Alanine Transaminase↗

PubMed1995

Efficacy and safety of pravastatin in the treatment of patients with type I or type II diabetes mellitus and hypercholesterolemia.

PURPOSE: Patients with type I and type II diabetes mellitus have an increased risk of coronary heart disease. In many diabetics, hypercholesterolemia is present and further exacerbates this risk. We investigated the efficacy and safety of pravastatin in the treatment of patients with type I or type II diabetes mellitus and hypercholesterolemia. PATIENTS AND METHODS: In this 24-week, multi-center, double-blind, placebo-controlled study, 94 patients (45 men, 49 women), 18 to 70 years of age, with type I or type II diabetes mellitus and hypercholesterolemia (fasting plasma low-density lipoprotein cholesterol [LDL-C] levels > 150 mg/dL and above the 75th percentile for the US population by age and gender) were randomized to receive pravastatin 20 mg hs or matching placebo. Two patients were randomized to treatment with drug for every 1 randomized to placebo. The dose could be doubled after 10 weeks, and cholestyramine or colestipol could be added after 18 weeks, as needed, to attempt to lower the LDL-C levels to below the 50th percentile for the US population. RESULTS: Significant reductions in LDL-C (-27.6%), total cholesterol (-22.1%), very-low-density lipoprotein cholesterol (-22.6%), and triglycerides (-12.8%) (P < or = 0.001 versus placebo for all reductions), and significant increases in high-density lipoprotein cholesterol (4.4%) (P < or = 0.05 versus placebo) were noted in the pravastatin treatment group (average dose 29.5 mg) at 16 weeks. The beneficial lipid-lowering effects of pravastatin were maintained throughout the 24 weeks of the study. Pravastatin was well tolerated, and the frequency of side effects was similar in the pravastatin and placebo groups. No clinically significant changes in the control of diabetes, as assessed by fasting blood glucose levels and glycosylated hemoglobin measurements, were seen during this study. CONCLUSION: The results of this study demonstrate that pravastatin is well tolerated and effective in lowering total cholesterol and LDL-C in patients with type I or type II diabetes mellitus and hypercholesterolemia.

Adult↗

PubMed1988

Predictors of total and low-density lipoprotein cholesterol change after partial ileal bypass.

POSCH is a prospective, randomized secondary intervention trial examining the effect of maximal lipoprotein modification achieved by partial ileal bypass on overall mortality and the course of coronary heart disease. In the initial 189 surgical patients, total cholesterol levels decreased from 256.7 +/- 2.6 mg/dl to 166.6 +/- 2 mg/dl, and low-density lipoprotein cholesterol levels decreased from 181.5 +/- 2.7 mg/dl to 94.1 +/- 1.7 mg/dl 3 months after operation. These significant decreases were sustained through 5 years of follow-up (p less than 0.001). The total cholesterol level was 29.2 +/- 0.9 percent lower and the low-density lipoprotein cholesterol level was 43.2 +/- 1 percent lower at 5 years compared with the baseline level. Decreases of similar magnitude were seen in each of the common WHO lipoprotein phenotypes. The baseline total cholesterol level was the only significant independent preoperative predictor of the 5 year total cholesterol level (correlation coefficient 0.547; p less than 0.001), and the baseline low-density lipoprotein cholesterol level was the only significant independent preoperative determinant of the 5 year low-density lipoprotein cholesterol level (correlation coefficient 0.599; p less than 0.001). These relationships are expressed by the following equations: 5 year total cholesterol = 0.54 X baseline total cholesterol + 42.3, and 5 year low-density lipoprotein cholesterol = 0.455 X baseline low-density lipoprotein cholesterol + 19.2. The decrease in total and low-density lipoprotein cholesterol levels after partial ileal bypass are greater than reported by any trial of drug or diet intervention, including the Lipid Research Clinics Coronary Primary Prevention Trial which examined cholestyramine. Estimation of the change in total and low-density lipoprotein cholesterol levels after partial ileal bypass can be made based on preoperative lipid analysis and is essential in comparing different therapeutic modalities and assessing the role of partial ileal bypass among strategies aimed at lowering coronary heart disease risk.

Adult↗

PubMed2002

LXR alpha is the dominant regulator of CYP7A1 transcription.

Cholesterol 7 alpha-hydroxylase (CYP7A1) catalyzes the rate-limiting step in the classic pathway of bile acid biosynthesis. Dietary cholesterol stimulates CYP7A1 transcription via activation of oxysterol receptor, LXR alpha, whereas bile acids repress transcription through FXR-mediated induction of SHP protein. The aim of this study was to determine the quantitative role that LXR- and FXR-regulated pathways play in regulating CYP7A1 and SHP in both rat and hamster models. In rats fed a 2% cholesterol diet, both SHP and CYP7A1 mRNA levels were elevated. The inability to induce CYP7A1 mRNA levels by cholesterol feeding in hamsters led to a decline in SHP mRNA levels. Elimination of hepatic bile acid flux by cholestyramine or bile fistula resulted in a marked repression of rat SHP mRNA levels. These results suggest that under conditions of both SHP and LXR alpha activation, stimulatory effect of LXR alpha overrides the inhibitory effect of FXR and results in an induction of rat CYP7A1 mRNA levels.

Animals↗

PubMed2002

Effects of streptozotocin-induced diabetes on acetoacetyl-CoA synthetase activity in rats.

In order to investigate the physiological role of acetoacetyl-CoA synthetase (acetoacetate-CoA ligase, EC 6.2.1.16), a cytosolic acetoacetate-activating enzyme, effects of streptozotocin (STZ)-induced diabetes on the enzyme activity was investigated in rats. At 72 hr of the STZ administration (80 mg/kg body weight, injected intravenously), hepatic enzyme specific activity decreased to 23% of its initial activity. However, the enzyme activities in non-hepatic tissues were not significantly affected by the STZ treatment. Feeding of rats with both 4% cholestyramine and 0.4% pravastatin for 3 days remarkably increased the hepatic acetoacetyl-CoA synthetase activity and decreased the plasma ketone bodies level in the diabetic rats. These results suggest that acetoacetyl-CoA synthetase has important roles in the regulation of ketone body utilization in rat liver and that these hypocholesterolemic agents have the ability to remedy the impaired utilization of ketone bodies under the diabetic condition.

Animals↗

PubMed1998

Reduced hepatic expression of CYP7A1 and CYP2C13 in rats with spontaneous hyperlipidaemia.

A strain of hyperlipidaemic Sprague-Dawley (HSD) rat was compared with normal Sprague-Dawley (SD) rats for expression of cholesterol 7alpha-hydroxylase activity (CYP7A1) and other cytochrome P450 (P450) enzymes in liver. Hepatic microsomal CYP7A1 activity in male HSD rats was 2-3-fold lower than in male SD rats with CYP7A1 apoprotein levels being similarly reduced. CYP7A1 expression was subject to diurnal variation in HSD rats as found in SD rats. Treatment of HSD rats with cholestyramine caused an increase in hepatic microsomal cholesterol 7alpha-hydroxylase activity of 3.3-fold compared with a 3.5-fold increase in SD rats with similar changes in apoprotein levels. These results indicate that the lower activity in HSD rats is not due to a defect in the catalytic activity of the enzyme, regulation affecting diurnal variation or regulation through bile acid feedback inhibition. No difference between hepatic microsomal methoxyresorufin-O-demethylase, benzoxyresorufin-O-debenzylase or chlorzoxazone 6-hydroxylase activities in SD and HSD rats was found, nor was there any difference in the levels of CYP1A2, CYP2D1, CYP2E1, CYP3A1, CYP3A2 or NADPH cytochrome P450 reductase determined by immunoblotting using specific anti-peptide antibodies. However, unlike in male SD rats, CYP2C13 was absent in male HSD rats and this was associated with a two-fold reduction in testosterone 6beta-hydroxylase activity. In conclusion, while HSD rats do not have a general reduction in P450 levels, they do lack CYP2C13 and have lowered cholesterol 7alpha-hydroxylase activity, as a result of a reduced level of expression of the enzyme.

Animals↗

PubMed1998

Improved assay of hepatic microsomal cholesterol 7 alpha-hydroxylase activity by the use of hydroxypropyl-beta-cyclodextrin and an NADPH-regenerating system.

Cholesterol 7 alpha-hydroxylase, the key enzyme in bile acid synthesis, has been implicated in atherosclerosis and gallstone disease. The aim of this study was to check if the use of hydroxypropyl-beta-cyclodextrin (HPBCD), a vehicle for solubilizing cholesterol, augmented the rate of 7 alpha-hydroxycholesterol formation in hamster liver microsomes compared to classical assays in which labeled cholesterol was delivered in Tween 80. We observed that [14C]cholesterol carried by HPBCD enhanced the sensitivity of the assay tenfold. However, linearity of 7 alpha-hydroxycholesterol formation with time was short because of the rapid transformation of 7 alpha-hydroxycholesterol into 7 alpha-hydroxy-cholesten-3-one and 7 alpha,12 alpha-dihydroxy-cholesten-3-one when NADPH alone was present in the incubation medium. In order to avoid the transformation of 7 alpha-hydroxycholesterol into 7 alpha-hydroxy-cholesten-3-one, which is essentially NAD(+)-dependent, but is also NADP(+)-dependent, NADPH (1 mmol/l) plus an NADPH-regenerating system must be present in the medium. In this improved assay, the optimal pH was 7.4 and the apparent Km for control and cholestyramine-fed hamsters had a similar value of 315 mumol/l; linearity in the formation of 7 alpha-hydroxycholesterol was also apparent after a relatively short time period (10 min), but with a markedly greater slope of the curve. With a short incubation time (6 min), microsomes from livers of hamsters (five and nine weeks old) that were fed with a commercial ground diet yielded rates of 7 alpha-hydroxycholesterol formation of 115 +/- 10 and 150 +/- 16 pmol/min.mg protein, respectively, whereas microsomes from hamsters fed with a lithogenic sucrose-rich diet (five weeks old) yielded rates of 7 alpha-hydroxycholesterol formation of 77 +/- 7 pmol/min.mg protein, which were significantly lower (-33%) than those of corresponding control hamsters. This improved cholesterol 7 alpha-hydroxylase assay is very sensitive, simple and rapid, and does not necessitate sophisticated equipment. It can be particularly useful for determining cholesterol 7 alpha-hydroxylase activity in liver biopsies from dyslipidemic or lithiasic patients.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed2000

Cardiovascular risk changes after lipid lowering medications: are they predictable?

Changes in cardiovascular risk after lipid lowering medications are generally expressed as relative risk reduction (RRR). Comparison of the eight major studies published in this last decade indicates that the RRRs ranged from a minimum (19%) for the LRC Study with cholestyramine, to maximal values of 34-37% for studies such as the HHS, 4S and AFCAPS/TexCAPS. These RRRs were barely related to the drugs' effects on major lipid parameters, e.g. LDL cholesterol. Instead, by using the absolute risk reduction (ARRs), easily calculated by subtracting the percentage end points for the drug treated from these values of the placebo group in all studies, a wide range of values was found, also adding to the series a non pharmacological study such as the Program on the Surgical Control of the Hyperlipidemias (POSCH) trial. Calculated ARRs were directly correlated to the baseline cardiovascular (CV) risk in all studies, thus allowing an easy prediction of a drug's effect in the selected population. Drugs with different mechanisms (statins, fibrates and resins) all fitted into this correlation nomogram. These findings clearly indicate that the CV effects of lipid changes, such as LDL cholesterol and triglyceride reduction or HDL rises, are in the same direction, and can be well predicted. The similar, almost identical behavior of drugs affecting LDL cholesterolemia to a different degree or not at all, indicates that novel approaches should be sought to improve risk reduction and that individual therapy should be ideally pursued, rather than a 'one drug' approach.

Anticholesteremic Agents↗

PubMed1997

Cerivastatin: pharmacology of a novel synthetic and highly active HMG-CoA reductase inhibitor.

The pyridine derivative cerivastatin is a new entirely synthetic and enantiomerically pure inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. As a sodium salt cerivastatin is present in the active, open ring form. Cerivastatin inhibited the membrane-bound (non-solubilized) HMG-CoA reductase of the native microsomal fraction isolated from rat liver with a Ki value of 1.3 x 10(-9) M. The reference compound lovastatin was 100-fold less potent and exhibited a Ki value of 150 x 10(-9) M. Cerivastatin inhibited the cholesterol synthesis in the human hepatoma cell line HepG2 cells with a similar IC50 value of 1.0 x 10(-9) M. In vivo studies reflected its high in vitro activity. In both rats and dogs, cerivastatin inhibited the hepatic [14C]cholesterol synthesis from [14C]acetate with an oral ED50 value of 0.002 mg/kg body weight, while lovastatin exhibited an oral ED50 value of 0.3 mg/kg in rats, showing again the ratio of 100 or more between cerivastatin and lovastatin. In the small intestine and testes, cerivastatin was at least 50-fold less active with oral ED50 values higher than 0.1 mg/kg, which is indicative for a high liver selectivity of cerivastatin. In cholestyramine-primed dogs cerivastatin dose-dependently lowered the serum cholesterol concentrations by up to 59% with 0.1 mg/kg after 20 days. Interestingly, the serum triglycerides were markedly reduced by 53 and 76% with 0.03 and 0.1 mg/kg, respectively. In normal chow fed dogs the low density lipoprotein (LDL) concentrations were reduced by up to 75% after 0.1 mg cerivastatin/kg. The ratio of HDL/LDL increased by 81% compared with a change of only 14% in the placebo treated control group. The antiatherogenic effect of cerivastatin was shown in rabbits fed a diet enriched with 0.2% cholesterol. After 9 weeks on diet 0.1 mg cerivastatin/kg decreased the accumulation of cholesterol ester in the arterial tissue by 73%. In summary, these data as compared to published data on other HMG-CoA reductase inhibitors demonstrate cerivastatin to be the most active compound in this class. Vastatins used in therapy are effective in mg doses, while cerivastatin offers a new low dose therapy in the microg range.

Administration, Oral↗

PubMed1998

Preclinical review of cerivastatin sodium--a step forward in HMG-CoA reductase inhibition.

Epidemiological studies have established that elevated concentrations of plasma cholesterol, particularly the low density lipoprotein (LDL) cholesterol, is one of the major risk factors for the development of arteriosclerosis and ischemic heart disease. Treatment with HMG-CoA reductase inhibitors (vastatins) has become the most successful drug treatment in lowering total plasma and LDL cholesterol concentrations in the last years. The vastatins already available for treatment are therapeutically used in a dose-range between 10 and 80 mg/day. The new enantiomerically pure pyridine derivative cerivastatin sodium has demonstrated its efficacy in significantly lower doses in the microgram-range, not only in preclinical but also in clinical studies with daily doses of only 0.1-0.3 mg. The differences in the therapeutic doses are reflected by the Ki- and IC50-values from enzyme inhibition tests in comparison with various HMG-CoA reductase inhibitors. Cerivastatin sodium exhibits much higher enzyme affinity with factors between 70 and almost 200. The Ki-value for cerivastatin sodium was 1.3 x 10(-9) M in comparison to 150 x 10(-9) M for lovastatin. The extremely high enzyme affinity of cerivastatin sodium was also reflected in its high activity in vivo. In acute in vivo studies cerivastatin sodium inhibited the hepatic [14C]cholesterol synthesis from [14C]acetate in both rats and dogs by 50% after oral administration at doses of 0.002 mg/kg body weight (ED50-values). This dose was comparable to 0.3 mg/kg of lovastatin. In subchronic dog studies a dose of 0.03 mg/kg lowered the serum LDL cholesterol concentration by 35% which is comparable with doses of 8-10 mg lovastatin/kg. Interesting results were observed in cholestyramine-primed dogs when 0.1 mg cerivastatin sodium/kg p.o. markedly decreased the serum triglycerides up to 70%. Cerivastatin shows a favourable pharmacokinetic profile with high liver selectivity. Rat studies have shown almost complete absorption and rapid hepatic clearance. Cerivastatin was highly bound to plasma proteins of rats, dogs and humans (>98%). Cerivastatin metabolites were excreted mainly via feces. The metabolism of cerivastatin sodium in man follows two metabolic pathways, demethylation to metabolite M1 and stereospecific hydroxylation to M23. The three major metabolites M1, M23 and the hydroxylated and demethylated metabolite M24 are highly active inhibitors not only in vitro but also in vivo. The human specific metabolites M23 and M24 inhibited the HMG-CoA reductase isolated from rat liver with the same potency as the parent compound cerivastatin sodium (IC50: 1.0-1.2 x 10(-9) M). M1 was slightly less active. Corresponding pharmacological activity was observed in vivo. M23 and M24 inhibited [14C]cholesterol synthesis from [14C]acetate in rat liver with ED50)-values between 0.001 and 0.002 mg/kg body weight which is similar to cerivastatin sodium and M1 exhibited an ED50-value of <0.006 mg/kg The strong inhibitory activity of these metabolites, in addition to cerivastatin's high enzyme affinity may explain the extraordinary pharmacological activity of cerivastatin and its ultra-low dose in man and demonstrates cerivastatin to be the most active HMG-CoA reductase inhibitor amongst all vastatins.

Animals↗

PubMed1999

The effect of aggressive and moderate lowering of LDL-cholesterol and low dose anticoagulation on plasma lipids, apolipoproteins and lipoprotein families in post coronary artery bypass graft trial.

The reported results (The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. New Engl J Med 1997;336:153-162) of the Post Coronary Artery Bypass Graft (Post CABG) trial have shown that aggressive lowering was more effective than moderate lowering of low density lipoprotein (LDL) cholesterol in reducing the progression of atherosclerosis in saphenous-vein grafts (27 vs. 39%; P < 0.001); low dose warfarin had no effect on the progression of atherosclerosis. The present report describes the effect of long-term (an average of 4.3 years) aggressive treatment with high (40-80 mg/day) and moderate treatment with low (2.5-5 mg/day) doses of lovastatin on lipids, apolipoproteins (apo) and apoA- and apoB-containing lipoprotein families. To achieve the target LDL-cholesterol levels (60-85 mg/dl for aggressive group and 134-140 mg/dl for moderate group), cholestyramine (8 g/day) was given to 25% of subjects on aggressive and 5% of subjects on moderate treatment. Although with both treatment strategies there were significant decreases (P<0.001) in the levels of total cholesterol, LDL-cholesterol, apoB, LDL-apoB and cholesterol-rich Lp-B family, percent changes in the levels of these variables were greater in the aggressive- than in the moderate-treatment groups. These treatments had only marginal effects in increasing the levels of high density lipoprotein cholesterol, apoA-I and Lp-A-I and Lp-A-I:A-II families. The long-term aggressive treatment exerted no effect on the concentrations of triglycerides, apoC-IlI, apoC-III in VLDL + LDL and triglyceride-rich Lp-Bc families. Neither treatment affected the levels of Lp(a). The potentially modifying influence of warfarin and apoE phenotypes on lovastatin-induced changes in lipoprotein variables was found to be of little significance. It is likely that the beneficial effect of lovastatin in reducing the progression of atherosclerosis in grafts is mediated through its specific lowering effect on cholesterol-rich Lp-B particles.

Anticholesteremic Agents↗

PubMed1978

Pseudomembranous colitis associated with antibiotic therapy in a child: report of a case and review of the literature.

A case of pseudomembranous colitis is presented in a child with multiple medical problems who received intraoperative antibiotics. Despite aggressive medical management and operative intervention, the patient died. All patients who develop diarrhea after receiving antibiotics should be suspected of having pseudomembranous colitis. Sigmoidoscopy and hyaque enema should be performed to confirm the diagnosis and all antibiotics should be discontinued. Aggressive medical management consisting of intravenous fluids, albumin, lactinex granules, fecal enemas, and cholestyramine should be instituted. Surgery should be considered only in the face of perforation, toxic megacolon, peritonitis, and failure of medical management with disease limited to the colon.

Anti-Bacterial Agents↗

PubMed1987

Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases.

We have observed two types of paucity of interlobular bile ducts (PILBD) in children with chronic cholestasis: the syndromic type, which is more frequent (80 cases), and the nonsyndromic type (31 cases). Study of patients with syndromic PILBD has enabled us to recognize five major features: peculiar facies (95%), chronic cholestasis (91%), posterior embryotoxon (88%), butterfly-like vertebral arch defects (87%), and peripheral pulmonary artery hypoplasia or stenosis, either isolated or associated with complex cardiovascular abnormalities (85%). By observing these major features, it is possible to differentiate the "complete" syndrome, in which all five features are present (26 cases), from the "partial" syndrome, in which only four (42 cases) or three (12 cases) major features are present. Other less frequent features were observed in patients with complete or partial syndrome: growth retardation (50%), mental retardation (16%), renal disturbances, other vascular malformations, bone abnormalities, high-pitched voice, and delayed puberty. Death occurred in 21 (26%) patients with syndromic PILBD. Therapy consisted of supplementation of medium-chain triglycerides and fat-soluble vitamins and administration of cholestyramine or phenobarbital. An autosomal dominant mode of transmission, with variable penetrance, seems likely.

Bile Ducts, Intrahepatic↗