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PubMed1995

Preliminary report: genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis.

Stromelysin is a member of the family of metalloproteinases that degrade extracellular matrix. In situ hybridisation and histopathological studies suggest that stromelysin activity may be important in the connective tissue remodelling processes associated with atherogenesis and plaque rupture. Single strand conformation polymorphism analysis identified a common polymorphism in the stromelysin gene promoter located 1171 bp upstream from the start of transcription in which one allele has a run of six adenosines (6A) and another has five adenosines (5A). 72 men with coronary heart disease, were genotyped. They were participants in the St Thomas' Atherosclerosis Regression Study who were randomised to receive usual care (UC), dietary intervention (D), or diet plus cholestyramine (DC), with angiography at baseline and at 39 months. In these patients the frequency of the 5A allele was 0.49 (95% CI from 0.41 to 0.57) and was not significantly different from that in a sample of 354 healthy UK men. In the UC group, patients who were homozygous for the 6A allele showed greater progression of angiographic disease than those with other genotypes: the minimum absolute width of coronary segments decreased by 0.04 (SEM 0.10) mm for 5A5A, 0.20 (0.07) mm for 5A6A, and 0.67 (0.19) mm for 6A6A (P < 0.01). The findings were similar but slightly less significant for the change in mean absolute width of coronary segments (P < 0.05). No significant associations were seen in patients in the D or DC groups. In data pooled from the three treatment groups, the 6A6A genotype was significantly associated with greater progression of coronary atherosclerosis than other genotypes in patients with baseline percentage diameter stenosis less than 20% (P < 0.05), but not in those with baseline percentage diameter stenosis greater than or equal to 20%. These results provide the first evidence of a link between genetic variation in stromelysin and progression of coronary atherosclerosis and support the hypothesis that connective tissue remodeling mediated by metalloproteinases contribute to the pathogenesis of atherosclerosis.

Base Sequence↗
PubMed1994

Phytosterolaemia in three unrelated South African families.

Phytosterolaemia (beta-sitosterolaemia), a rare, autosomal recessive disorder, has not hitherto been reported in Southern Africa. We report four new homozygous patients, from three unrelated families with significant beta-sitosterolaemia (6.6-11.3%), campesterolaemia (2.2-4.6%) and clearly detectable, though unquantified, levels of cholestanol. Three of the four patients had characteristic cutaneous and tendinous xanthomas within the first decade of life. The fourth patient, a 5 year old, was free of xanthomas despite persistently elevated concentrations of plant sterols in her plasma. All our patients were female bringing the male:female ratio in reported cases to 8:23. All were at or below the 50th percentile for height and weight, and presented at some stage with borderline, hypochromic anaemia associated with red cell abnormalities and thrombocytopaenia. The oldest patient showed suggestive clinical evidence of atherosclerosis affecting her aorta, ileofemoral bifurcation and possibly coronary arteries. All homozygotes responded to a diet restricted in phytosterols and the administration of cholestyramine with falls in plasma sterols of up to 68%. The recent discovery of a possible inherited defect in the synthesis of HMG CoA reductase in patients with phytosterolaemia makes this disorder a model system for studying the biological role of this enzyme in regulating the absorption and clearance of sterols other than cholesterol, and the factors governing the sterol composition of cell membranes.

Adolescent↗
PubMed1990

Cholesterol-mediated regulation of HMG-CoA reductase in microsomes from human skin fibroblasts and rat liver.

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity was determined in microsomes from human skin fibroblasts and rat liver that had been variously manipulated in vivo or in tissue culture to up- and down-regulate the enzyme. The cholesterol content of these microsomal preparations was then altered by depletion to or enrichment from either cholesterol-free or cholesterol-rich lipid vesicles. Microsomes from human skin fibroblasts responded to cholesterol depletion by increasing HMG-CoA reductase activity and by decreasing it in response to cholesterol enrichment. This was independent of the initial enzyme activity or the tissue culture conditions. Alterations in cholesterol content of rat liver microsomes in vitro failed to demonstrate any significant changes in HMG-CoA reductase activity whether the microsomes started with low enzyme activity (cholesterol-fed rats) or with high enzyme activity (cholestyramine-treated rats). The results are discussed in relation to previously published data and in respect to differences in the control of the human skin fibroblast and rat liver enzymes.

Animals↗
PubMed1984

Effects of bile and bile salt infusions on renal function in dogs.

A previous study in dogs indicated that 4 h of acute biliary obstruction was associated with an increment in the glomerular filtration rate (GFR), renal perfusion, and urinary sodium excretion. These effects could also be transmitted to a "recipient" dog following 2 h of cross circulation. In this study we examined the possible role of bile and bile products in reproducing these effects. The i.v. infusion of 15 mL of undiluted gallbladder bile produced a marked diuresis and natriuresis, while arterial pressure and GFR declined. Bile diluted as much as 1/100 in isotonic saline could produce an effect when infused intravenously. When bile diluted to 1/250 was infused into th left renal artery at 0.5 mL/min, a diuretic and natriuretic response was obtained. GFR and renal blood flow declined with more concentrated solutions, though blood pressure remained normal. Dialysis of bile, or prior incubation with cholestyramine or plasma, failed to uncover a renal vasodilator effect. Following the first two procedures, the diuretic properties of infused bile were lost. The infusion of small amounts of synthetic bile salts (taurocholate or glycocholate) into the left renal artery caused marked increments in urinary sodium excretion without any change in renal hemodynamics. The infusion of bilirubin was without effect on renal function. Taurine and glycine, the amino acids present in the conjugated bile acids, were injected i.v. Both caused marked diuresis and natriuresis, but only glycine increased GFR and renal perfusion. The plasma levels of these substances, however, were unchanged following 4 h of acute biliary obstruction. We conclude that while bile salts probably cause the diuresis of biliary obstruction, the mechanism for the increase in GFR has not yet been identified.

Animals↗
PubMed1995

Bile salt-dependent inhibition of gallbladder emptying.

Little is known about the inhibitory controls of gallbladder emptying. Since cholestyramine, a binding agent that reduces luminal concentration of bile salt, has been reported to accelerate gallbladder emptying, suggesting that bile salt is inhibitory, we hypothesized that fat-stimulated gallbladder emptying is inhibited by a bile salt-dependent mechanism. To test this idea, we compared gallbladder emptying in 10 dogs equipped with duodenal and jejunal fistulas that allowed for complete diversion of the native bile while varying concentrations of bile salt were perfused into the small intestine. In six dogs, 30 mM oleate and 5, 10, or 20 mM sodium taurocholate was perfused into the whole intestine. Since bile salt availability alters fat absorption, in a separate experiment in seven dogs we also compared gallbladder emptying while 30 mM oleate and 5 mM taurocholate were perfused between fistula and 0, 5, 10, or 20 mM taurocholate were perfused beyond jejunal fistula to separate fat from varying concentrations of bile salt. We found that intestinal taurocholate inhibited fat-stimulated gallbladder emptying in a dose-dependent fashion (P < 0.01; analysis of variance, significant linear dose effect) and that the inhibitory effect of bile salt persisted when 5-20 mM taurocholate was perfused beyond the jejunal fistula (0 vs. average of 5-20 mM taurocholate, P < 0.05, paired t-test). We conclude that fat-stimulated gallbladder emptying is inhibited by a bile salt-dependent inhibitory mechanism.

Anastomosis, Surgical↗
PubMed2001

Endogenous neurotensin facilitates enterohepatic bile acid circulation by enhancing intestinal uptake in rats.

Initial studies on the digestive hormone neurotensin (NT) showing that intestinal NT mRNA expression and blood levels were altered in rats fed chow containing bile acid (BA) and the BA chelator cholestyramine led us to investigate the role of NT in the enterohepatic circulation of BA. In fasted, anesthetized rats with common bile ducts cannulated for bile collection, intravenous NT infusion (10 pmol. kg(-1). min(-1)) enhanced BA output relative to control over 3 h in animals administered donor bile into the duodenum (30 microl/min). This suggested that the effect of NT was on the return of BA from the intestine to the liver, which is rate determining in the normal process. In rats prepared as described above and administered [(3)H]taurocholate ([(3)H]TC; 5 mM, 1 ml) duodenally, NT infusion (3-10 pmol x kg(-1) x min(-1)) increased the [(3)H]TC recovery rate in bile approximately twofold, whereas sulfated CCK-8 (12-50 pmol x kg(-1) x min(-1)) had no effect. To investigate the roles of endogenous NT and CCK, we administered [(3)H]TC into the rat duodenum or lower jejunum and tested the effect of the NT antagonist SR-48692 (2 nmol x kg(-1) x min(-1)) or CCK-A antagonist lorglumide (100 nmol x kg(-1) x min(-1)). SR-48692 reduced the [(3)H]TC recovery rate by congruent with 50% and congruent with 24% in the duodenum and jejunum, respectively, whereas lorglumide had no effect. These results suggest that NT or a similar peptide is an endogenous regulator of enterohepatic BA cycling, which acts by enhancing BA uptake in the intestine.

Anastomosis, Surgical↗
PubMed1985

Restriction of gut-derived endotoxin impairs DNA synthesis for liver regeneration.

The influence of restricting gut-derived endotoxin availability on liver regeneration after partial hepatectomy was evaluated. Partial hepatectomy was performed by 67% liver resection of ether-anesthetized rats. Liver regeneration was quantified after partial hepatectomy by [3H]thymidine incorporation into hepatic DNA; endotoxemia due to absorption of endogenous endotoxin from the gut into the portal circulation was determined by qualitative lysate assay of perchloric acid-extracted plasma samples, and plasma levels of the hepatotrophic factors insulin and glucagon were measured by radioimmunoassay. Treatments to restrict gut-derived endotoxin included chronic gavage with neomycin and cefazolin for gut sterilization, chronic gavage with cholestyramine to bind endotoxin within the gut, subcutaneous administration of polymyxin B to neutralize the lipid A portion of circulating endotoxin, intraperitoneal induction of endotoxin tolerance by progressively higher doses of endotoxin, and experimentation with isolator-reared defined flora Fisher rats that were Gram-negative bacteria deficient and therefore endotoxin deficient. All treatments to restrict endogenous endotoxin impaired DNA synthesis in regenerating livers particularly 21 h posthepatectomy when replication was increasing most rapidly in normal rats. We hypothesize that impairment of DNA synthesis after partial hepatectomy in endotoxin-restricted animals was due to the observed lack of normal systemic endotoxemic as well as hyperinsulinemic and hyperglucagonemic responses to 67% liver resection.

Animals↗
PubMed2000

APO E gene and gene-environment effects on plasma lipoprotein-lipid levels.

Apolipoprotein E (apo E) is important in plasma lipid metabolism and is a component of several plasma lipoprotein-lipid particles. Three major apo E isoforms are encoded by three common alleles at the APO E locus. The E2 allele is associated with lower and the E4 allele with higher total plasma cholesterol and LDL cholesterol levels compared with the E3 allele. Available data generally indicate that APO E2, and possibly E3, genotype individuals reduce plasma total and low-density lipoprotein (LDL) cholesterol levels more than APO E4 individuals with statin therapy. Some evidence also indicates that APO E2 individuals are more likely to respond favorably to gemfibrozil and cholestyramine. On the other hand, it appears that with probucol, APO E4 genotype individuals may improve plasma lipoprotein-lipid profiles more than APO E3 individuals. APO E2 and E3 genotype perimenopausal women appear to improve plasma lipoprotein-lipid profiles more with hormone replacement therapy than APO E4 women. On the other hand, low-fat diet interventions tend to reduce plasma LDL cholesterol and, perhaps, plasma total cholesterol levels more in APO E4 than in APO E2 or E3 individuals. Both cross-sectional and longitudinal studies generally indicate that APO E2 and E3 individuals improve plasma lipoprotein-lipid profiles more with exercise training than APO E4 individuals. Although these data are hardly definitive, they lend strong support for the possibility that in the near future individuals will be directed to what might be their optimal therapy for improving plasma lipoprotein-lipid profiles and cardiovascular disease risk based partially on APO E genotype.

Apolipoproteins E↗
PubMed2000

Update on primary biliary cirrhosis.

The diagnosis of primary biliary cirrhosis (PBC) is most often made in the asymptomatic phase, sometimes before the development of abnormal liver biochemistry. The antimitochondrial antibody remains the predominant hallmark, although not all patients test positive, even when the most sensitive techniques are used. The etiology of PBC remains elusive; studies suggest that the interlobular bile duct destruction is immune based, and associated autoimmune diseases are common. There are no surrogate markers that predict outcome in asymptomatic patients, whose chance of survival is less than that of age- and sex-matched populations but much better than the median survival of eight years in patients with symptomatic PBC. Symptoms common in this disease are fatigue, pruritus and xanthelasma, as well as complications of portal hypertension and osteoporosis. Treatment includes symptomatic and preventive measures, as well as specific therapeutic measures. Immunosuppressive therapy has yielded disappointing results in the long term management of PBC, and the only therapy shown to improve survival is the hydrophobic dihydroxy bile acid ursodeoxycholic acid. Treatment at a dose of 13 to 15 mg/kg/day is optimal, given in separate doses or as a single dose at least 4 h from giving the oral anion exchange resin cholestyramine, which may be used to control pruritus. However, liver transplantation remains the only cure for this disease, and the best postoperative survival is seen in patients whose serum bilirubin does not exceed 180 micromol/L at the time of liver transplantation. Recurrence takes place but is rarely symptomatic and does not deter from the benefits of transplantation.

Biomarkers↗
PubMed2003

Lymphocytic and collagenous colitis: the emerging entity of microscopic colitis. An update on pathophysiology, diagnosis and management.

Microscopic colitis (MC) encompasses the two morphologically distinct entities of collagenous colitis (CC) and lymphocytic colitis (LC). MC was first described less than 30 years ago but is presently recognized as a relatively common cause of chronic diarrhea in the adult population. Remarkably, up to 10% of adults who have a colonoscopy for the investigation of chronic diarrhea, and have endoscopically normal appearing mucosa, may have MC. Patients with MC generally present with chronic diarrhea, which can be associated with cramping and bloating. Endoscopic and radiological examinations are usually normal. Histological assessment reveals inflammation consisting predominantly of lymphocytic infiltration, and a thickened subepithelial collagen band is diagnostic of CC. Both LC and CC can be associated with autoimmune diseases such as celiac disease, diabetes, arthritis and thyroiditis, yet the mechanisms involved in the pathogenesis remain unclear. Emerging studies suggest that a stepwise approach be taken in the medical management of MC. This approach includes antidiarrheal agents and stopping of any offending agents; budesonide or bismuth subsalicylate; and cholestyramine or 5-acetylsalicylic acid agents. In resistant cases, oral corticosteroids and other immune modulatory therapy have been used.

Algorithms↗
PubMed2005

Clostridium difficile-associated diarrhea in 200 Canadian children.

OBJECTIVE: Clostridium difficile-associated diarrhea is a major problem in adults. The present study was conducted to assess risk factors and outcomes in children with C difficile-associated diarrhea. METHODS: Laboratory records at a university-affiliated pediatric hospital were reviewed for all C difficile toxin-positive stools (cell culture cytotoxin assay) between 2000 and 2003. Charts on identified patients were reviewed. RESULTS: Two hundred patients with a diagnosis of C difficile-associated diarrhea were identified between February 2000 and November 2003. There were 107 males and 93 females (mean age 5.4 years; median age 2.6 years). Underlying factors were identified in 19% (12 patients underwent chemotherapy; seven patients had Crohn's disease; six were transplantation recipients; seven an immunodeficiency; four with Hirschsprung disease; two diagnoses of 'other'). Of the 200 identified patients, 149 (74.5%) had documentation of antibiotics in the previous two months (32 penicillins; 38 cephalosporins; three clindamycin, nine other single-agent, 59 multiple; eight not specified), and 111 (55.5%) had been hospitalized in the previous month. The symptoms of C difficile-associated diarrhea included bloody stools in 12.5% and frequent watery stools in 79%. Hospitalization was required in 27 of 116 outpatients; stay was prolonged in seven of the 84 patients already hospitalized. Fifty-five per cent received metronidazole, 34% were not treated, and treatment data were not available for the remainder. Recurrence occurred in 31% of those treated and retreatment consisted of vancomycin (15%), probiotics (15%) and cholestyramine (6%). No colectomies were required but two deaths occurred. CONCLUSIONS: The majority of pediatric patients developing symptomatic C difficile-associated diarrhea had antibiotic exposure or hospitalization within the previous one to two months. This is higher than previously reported. One-third had spontaneous symptom resolution. For those treated, recurrence rates were high. Mortality was significantly lower than described in adults, in agreement with prior literature.

Child↗
PubMed2006

[Crigler-Najjar syndrome: diagnosis and treatment].

INTRODUCTION: Crigler-Najjar syndrome (CNS) is a very rare disease characterized by severe indirect hyperbilirubinemia from birth with normal liver function. It may cause kernicterus at any age. This disease is due to a total or partial deficiency of the UDP-glucuronosyltransferase enzyme caused by a mutation of the five exons of the ULT1A1 gene. PATIENTS AND METHODS: We reviewed the clinical outcomes of 7 children diagnosed with CNS between 1987 and 2004. RESULTS: There were three boys and four girls (two of which were homozygote twins). Two children had familial consanguinity. Three out of the six families had another healthy child. The mean follow-up was 8.3 years (14 months-17 years). In all patients, jaundice was detected in the first 3 days of life. The children were admitted to hospital between the fourth and the sixtieth day of life with jaundice and indirect bilirubin levels of between 12.5 and 32 mg/dl. In all patients, hemolysis was ruled out and hepatic function was normal. The diagnosis was based on genetic study in 4 patients, on inactive UGT enzyme in liver in 1 patient, and on clinical features exclusively in 2 patients. Treatment consisted of phenobarbital and phototherapy from 8 to 16 hours a day in all patients except three. Associated calcium salts were found in 5 patients and cholestyramine was found in two. Two patients developed kernicterus. Two underwent liver transplantation and bilirubin levels became normal. The remaining patients maintained indirect bilirubin from 15 to 25 mg/dl with no associated neurological alterations. CONCLUSIONS: Patients with CNS are at greater risk of developing kernicterus, mostly associated with indirect bilirubin levels of around 25 mg/dl. Phototherapy is very useful in these patients but the only definitive treatment is liver transplantation.

Adolescent↗
PubMed2002

The anatomy of a clinical trial. The West of Scotland Coronary Prevention Study.

OBJECTIVE: Treatment of hyperlipidemia to reduce the risk of ischemic heart disease was, prior to the statin era, disappointingly limited in its ability to yield the benefits expected from the strong relationship known to exist between serum cholesterol and coronary death. Three primary prevention trials, using clofibrate, cholestyramine and gemfibrozil, had achieved modest reductions in fatal and nonfatal coronary events but none was able to extend life overall or even to reduce cardiovascular mortality; and combined analyses of the three raised disquiet over potential links between cholesterol reduction, cancer and aggressive or violent behaviour. The time was therefore ripe to determine whether statins could help prevent that first and all important myocardial infarction. METHODS: The West of Scotland Coronary Prevention Study recruited 6,595 45- to 64-year-old men with no history of prior myocardial infarction and with low-density lipoprotein cholesterol in the range 4-6 mmol/l (155-232 mg/dl). Subjects who had undergone coronary revascularisation or had been hospitalised for angina pectoris in the previous 12 months were excluded, as were those with significant electrocardiographic abnormalities. Participants were randomised to receive pravastatin 40 mg/day or matching placebo and were followed for an average of 4.9 years. RESULTS: Treatment with pravastatin reduced the combined risk of fatal and nonfatal myocardial infarction by 31%. Cardiovascular death overall fell by 32% and the need for coronary revascularisation procedures was reduced by 37%. All of these endpoint benefits were statistically significant. Because there was no increase in non-cardiovascular mortality, the reduction in death from any cause also proved to be statistically significant (p = 0.051 by log rank test and p = 0.037 after adjustment for baseline risk factors). CONCLUSIONS: The West of Scotland Coronary Prevention Study is the first to show that cholesterol reduction with pravastatin helps avoid the first myocardial infarction, reduces coronary mortality and extends life. Ongoing exploration of the study database continues to unearth additional surprisingly beneficial effects of the treatment and permits authoritative decision-making on the effective use of lipid-lowering drugs.

Aged↗
PubMed2004

Rosuvastatin-induced arrest in progression of renal disease.

Preclinical and limited clinical data suggest that statins decrease the progressive decline in renal function that occurs in patients with renal disease. Pooled analysis of data obtained from a population of hyperlipidemic patients enrolled in the rosuvastatin (Crestor) clinical development program permitted assessment of its effects on renal function both early and later in the course of treatment. Study participants were initially included in controlled clinical trials that evaluated the lipid-lowering efficacy and safety of rosuvastatin when compared with placebo or other lipid-lowering agents (i.e., atorvastatin, simvastatin, pravastatin, cholestyramine, fenofibrate or extended-release niacin). The median duration of treatment with the various doses of statins in these trials was approximately 8 weeks. Following completion of a controlled clinical trial, patients were permitted to enter an open-label extension trial and received rosuvastatin treatment. These data permitted assessment of renal function in a diverse group of over 10,000 patients who received rosuvastatin in its recommended dose range (5-40 mg) for up to 3.8 years. Mean serum creatinine concentrations were lower when compared with baseline both early and later in the course of rosuvastatin treatment. In contrast, no change in mean serum creatinine was observed with placebo. Mean glomerular filtration rates (GFR) predicted from the Modification of Diet in Renal Disease (MDRD) equation were higher when compared with baseline both early and later in the course of rosuvastatin treatment. No change in GFR was observed in the placebo group. Among patients who received long-term rosuvastatin treatment (> or =96 weeks), GFR was unchanged or tended to increase, rather than decrease, when compared with baseline irrespective of age, gender, hypertensive or diabetic status, level of renal function (GFR > or =60 vs. <60 ml/min/1.73 m(2)) at entry or urine dipstick protein status prior to or during the period of treatment. These findings suggest that rosuvastatin may arrest the progression of renal disease.

Aged↗
PubMed2006

Low-density lipoprotein-lowering medication and platelet function.

Elevated low-density lipoprotein (LDL) cholesterol (LDL-C) levels represent one of the most important risk factors for atherosclerosis and therefore cardiovascular morbidity and mortality. LDL-C operates at different levels and through various classic and non-classic mechanisms. In particular, increased or modified LDL enhances platelet function and increases sensitivity of platelets to several naturally occurring agonists. Agents that lower LDL-C in hypercholesterolemic patients have been shown to interfere with platelet function. Several studies, in fact, suggested that statins exert anti-thrombotic effects largely as a result of an anti-platelet activity. Among the other LDL-C-lowering agents those acting by interfering with cholesterol reabsorption from the gut (cholestyramine, colestipol) do not appear to interfere with platelet function, whereas peroxisome proliferator-activated receptor agonists (such as fibrates) can inhibit platelet function. The full potential of these drugs in vascular protection is only just being realized. Further studies are still needed to elucidate the full therapeutic benefits of these agents in plaque stabilization and thrombosis.

Anticholesteremic Agents↗
PubMed2007

Homozygous familial hypercholesterolemia with generalized arterial disease.

OBJECTIVE: This report describes the clinical features and management of an 11-year-old boy with end-stage homozygous familial hypercholesterolemia (hoFH) and generalized arterial disease. CLINICAL PRESENTATION AND INTERVENTION: The patient presented with recurrent anginal episodes. On examination, he was found to have multiple planar and tendinous xanthomas, an (LDL) cholesterol level of 24.6 mmol/l and family history of hypercholesterolemia. Resting electrocardiogram showed ST depression in the anterior and inferior leads. Coronary angiogram outlined 70% stenosis of the left main coronary, ostial stenosis of the right coronary artery and extensive atherosclerotic disease of the aorta and all its major branches. The lipid profile was grossly abnormal, but the other biochemical and hematological parameters were normal. The patient was managed with metoprolol 12.5 mg twice daily, nitroglycerin infusion, antithrombotics (aspirin 75 mg once daily and heparin infusion 150 units per hour), cholesterol-lowering drugs (simvastatin 10 mg once a day, cholestyramine 4 g twice a day) and analgesics. CONCLUSION: This case report emphasizes the need to diagnose early familial hypercholesterolemia in families with heart disease and the need to test the partners of affected persons so that the risk of conceiving children with hoFH can be counseled.

Child↗
PubMed1993

RG 12561 (dalvastatin): a novel synthetic inhibitor of HMG-CoA reductase and cholesterol-lowering agent.

RG 12561 (dalvastatin) is a prodrug which converts to its open hydroxyacid form in the body. The Na salt of RG 12561 (RG 12561-Na) is a potent inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway. It competitively inhibits rat liver HMG-CoA reductase with an IC50 value of 3.4 nmol/l. In the same assay, the IC50 values for other potent HMG-CoA reductase inhibitors, lovastatin-Na and pravastatin, were 2.3 and 8.9 nmol/l, respectively. In Hep G2 liver cells, RG 12561-Na, lovastatin-Na and pravastatin inhibited cholesterol biosynthesis from radiolabeled octanoate with IC50 values of 4 and 5 nmol/l and 1.1 mumol/l, respectively. In a rat ex vivo assay, orally administered RG 12561, lovastatin and pravastatin inhibited cholesterol biosynthesis in liver slices with ED50 values of 0.9, 0.5 and 12 mg/kg, respectively. In cholestyramine-fed hamsters, RG 12561 (0.1% in food for 18 days) reduced LDL cholesterol, whereas HDL was slightly increased. The reductions in the LDL/HDL ratio for RG 12561, RG 12561-Na, lovastatin and lovastatin-Na were 35, 76, 88 and 88%, respectively. At a higher dose, RG 12561 (0.4% in food) reduced serum cholesterol, LDL and LDL/HDL by 84, 97 and 91%, respectively. In WHHL rabbits, RG 12561 and lovastatin (5 mg/kg, b.i.d., 12 days) reduced serum cholesterol by 17 and 16%, respectively. These results demonstrate that RG 12561 is a potent cholesterol-lowering agent.

Analysis of Variance↗