OBJECTIVE Niacin is an effective treatment for dyslipidemia due to its favorable effects on multiple lipid parameters. Clinical utility of niacin is sometimes limited, however, because of cutaneous flushing. A once-daily, extended-release (ER) niacin formulation has been shown to significantly reduce flushing compared to immediate-release niacin. An optimized (reformulated) version of niacin ER has recently been developed and was shown in a previous study to significantly reduce flushing intensity (severity) compared to the non-optimized (commercial) formulation. The current study was designed to evaluate the effect of aspirin on various indices of flushing when administered with the optimized niacin ER formulation. METHOD This was a randomized, double-blind, double-dummy, placebo-controlled flush provocation crossover study in healthy males. To increase the probability of flushing, subjects received a single dose of reformulated niacin ER 2,000 mg, which is the upper limit of the approved dosage range. Subjects received 650 mg aspirin orally either 30 minutes before or concomitantly with niacin ER, or placebo with niacin ER, in 3-way crossover fashion. The primary endpoint was the number of subjects who reported at least one flushing event. Secondary endpoints included the perceived intensity and duration of flushing symptoms. RESULTS In the 148 men who completed all treatments, aspirin significantly reduced flushing incidence (the primary endpoint) following administration of niacin ER compared with placebo. Among subjects receiving placebo, 77% of subjects reported flushing with niacin ER. Among subjects receiving aspirin, 53-61% of subjects reported flushing (pretreatment and concomitant treatment, respectively, both p < 0.001 compared with placebo) with niacin ER. Aspirin also significantly reduced intensity and duration of flushing (by 30-40%) compared with no aspirin. The two aspirin-containing treatments (i.e. pre- or concomitant treatment) were similar in their effects on flushing incidence, intensity and duration. Median intensity on a 100 mm visual analogue scale (VAS) was reduced from 33 mm with placebo to 19-23 mm with aspirin. Median duration was reduced from approximately 1 hour with placebo to 37-48 minutes with aspirin. CONCLUSION Aspirin significantly reduced the incidence, intensity and duration of flushing associated with reformulated niacin ER. These results support the administration of aspirin prophylactically to decrease niacin-induced cutaneous flushing and to improve patient adherence and acceptability of chronic niacin treatment at therapeutic doses.

Background: Diabetic dyslipidemia is characterized by high triglyceride levels; low high-density lipoprotein cholesterol levels; small, dense low-density lipoprotein particles; and high free fatty acid levels. Niacin reduces concentrations of triglyceride-rich and small low-density lipoprotein particles while increasing high-density lipoprotein cholesterol levels. It also lowers levels of free fatty acids and lipoprotein(a). However, the use of niacin in patients with diabetes has been discouraged because high doses can worsen glycemic control. We evaluated the efficacy and safety of once-daily extended-release (ER) niacin in patients with diabetic dyslipidemia.

L'invention concerne une methode de prevention ou de reduction du risque d'apparition de maladies cardio-vasculaires par l'administration d'un inhibiteur de proteine de transfert microsomale (MTP) seul ou en combinaison avec un autre medicament reduisant le cholesterol tel qu'un inhibiteur de la HMG CoA-reductase, dont la pravastatine, a un patient qui peut presenter ou non un ou plusieurs facteurs de risque pour un accident coronaire et/ou cerebro-vasculaire tel que l'hypercholesterolemie.

Recent landmark studies using hydroxy-methyl-glutaryl-Co-enzyme A reductase inhibitors (HMG-CoA reductase inhibitors or statins), specifically, pravastatin and simvastatin, have led to dramatic changes in medical practice. These clinical trials have demonstrated that clinicians can impact coronary morbidity and mortality in primary (pravastatin) and secondary (pravastatin, simvastatin) prevention settings, including post-infarct patients with ‘normal’ cholesterol levels (pravastatin). The clinical benefit can be seen irrespective of risk factors at baseline and in women, the elderly and diabetics.

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, multicenter, 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 less than or equal to 0.001 versus placebo for all reductions), and significant increases in high-density lipoprotein cholesterol (4.4%) (P less than or equal to 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.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are more efficacious than older lipid-lowering agents and therefore may be more effective in reducing the incidence of coronary events. The objective of this prespecified analysis was to examine in coronary patients the effect of the lipid-lowering agent pravastatin on 3-year rates of coronary event incidence, all-cause mortality, and nonfatal myocardial infarction (MI), and to determine whether any observed benefit was also evident in patients > or = 65 years of age. The design of this analysis was to pool the data from 2 concurrent 3-year placebo-controlled clinical trials of pravastatin monotherapy in coronary patients (Pravastatin Limitation of Atherosclerosis in the Coronary Arteries [PLAC I] and the Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries [PLAC II]). This pooled database included 559 coronary patients with moderately elevated levels of low density lipoprotein cholesterol (between the 60th and 90th percentiles for age and gender in the United States). Over the 3 years of follow-up, use of pravastatin was associated with a 55% reduction in coronary incidence (p = 0.014). Pravastatin was also associated with a 67% reduction in nonfatal MI (p = 0.006). Eleven placebo patients died over the 3 years of follow-up compared with 7 in the pravastatin groups (a 40% reduction). Among older patients (age > or = 65 years), pravastatin therapy was associated with a 79% reduction in coronary event incidence (95% confidence interval [CI] 33-100%) and with a 86% reduction in nonfatal myocardial infarction (CI, 35-100%).(ABSTRACT TRUNCATED AT 250 WORDS)

The relative surface concentrations of octadecyltrichlorosilane (OTS) deposited on glass substrates in the presence of 11 different solvents were evaluated by X-ray photoelectron spectroscopy, with supporting evidence from contact angle measurements. The density of the observed OTS films cannot be explained entirely on the geometrical similarities or differences between the solvent and the octadecyl moiety, as it was observed that n-pentane produces an OTS film much sparser than that of hexadecane or toluene. A new mechanism involving extraction of surface moisture into the bulk solvent, followed by OTS hydrolysis and subsequent deposition, is proposed. Aromatic solvents (benzene and toluene) which are capable of extracting significant amounts of water from the substrate surface yield the densest OTS films, indicating a preference for OTS hydrolysis in the bulk solvent phase rather than at the substrate surface. A novel protocol was developed to quantitate the surface water extracting capacities of pentane and toluene. Dehydrated silica powder was rehydrated with D2O, followed by extraction with solvent, and the dissolved heavy water was trapped by treatment with phenyllithium to form deuterobenzene. The ratio of mass 79 (deuterobenzene) to mass 78 (benzene), determined by GC-MS, enables the quantitation of extracted D2O. The results show that toluene can extract significant amounts of D2O from the silica surface, whereas n-pentane is much less effective. OTS dissolved in anhydrous toluene only reacts with the surface silanol groups, producing a low density film. However, the same toluene, when spiked with a small quantity of D2O, forms an OTS film nearly twice as dense as that obtained under anhydrous conditions. The optimum quantity of moisture for the formation of a closely-packed monolayer is about 0.15 mg/100 mL of solvent.

The pharmacokinetics and pharmacodynamics of pravastatin 20 mg administered twice daily when taken with or one hour before meals were evaluated in 24 hypercholesterolemic men in an 8-week, open-label, randomized, two-way crossover study. The bioavailability of pravastatin was reduced significantly (p < or = 0.001) when it was taken with meals (AUC dropped 31% and Cmax dropped 49%), and mean Tmax increased 50% (p < or = 0.01). The mean elimination t1/2 was unaffected by taking pravastatin with food. However, reductions in mean total cholesterol and low density lipoprotein cholesterol were identical whether pravastatin was given with or before meals. In both treatment groups, total cholesterol and low-density lipoprotein cholesterol were significantly reduced from baseline (p < 0.001). These results indicate that although the bioavailability of pravastatin is reduced when taken with meals, the lipid-lowering efficacy of pravastatin is not altered. It can be concluded that pravastatin can be ingested without regard to meal time.

Pravastatin is a new lipid-lowering drug belonging to the class of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors. Since 1986, more than 15,000 patients have received pravastatin in sponsored clinical research trials with more than 21,000 cumulative patient-years of exposure to the drug. Analysis of long-term follow-up data from 1142 patients participating between 1986 and 1990 in six core randomized clinical trials in the United States confirms the favorable safety profile of pravastatin. Rash, gastrointestinal complaints, musculoskeletal pain, and elevations in liver transaminase levels, whether or not attributed to treatment, were the most common reasons for patients withdrawing from these trials. Ophthalmologic monitoring revealed no adverse effects on the crystalline lens. Safety assessments continue for two core trials in more than 400 patients with up to 7 years of continuous follow-up. The effects of pravastatin on serum cholesterol levels are not influenced by the age, sex, weight, or initial cholesterol level of the patient. Vitamin E, A, and D metabolism remain normal during treatment. Combination therapy with pravastatin and bile-acid-binding resins or niacin is well tolerated, with additive effects on low-density lipoprotein cholesterol. There is limited experience with the combination of pravastatin and gemfibrozil or cyclosporine. An ongoing arteriosclerosis research program with more than 21,000 patients enrolled will further define the long-term safety of pravastatin and its effects on atherosclerosis progression, as well as its role in the primary and secondary prevention of coronary heart disease.

Epidemiologic evidence linking elevated cholesterol concentrations and coronary heart disease (CHD) through the eighth decade of life provides a rationale for lowering cholesterol concentrations to reduce morbidity and mortality from CHD. Pravastatin, a well tolerated HMG CoA reductase inhibitor with a convenient once-daily dosing regimen, has been shown to effectively lower total and low density lipoprotein (LDL) cholesterol. Individual data from more than 1800 hypercholesterolemic patients enrolled in six double-blind, randomized, multicenter studies were pooled and then analyzed to compare the safety and efficacy of pravastatin in the elderly (i.e., patients at least 65 years old) and the non-elderly. In short-term studies (8-16 weeks), response was dose-related and similar in elderly and non-elderly subjects. Pravastatin 20 or 40 mg daily lowered total cholesterol 19-25%, LDL-cholesterol 25-33%, and triglycerides 14-23%; high density lipoprotein (HDL) cholesterol increased 5-10%. During long-term studies, improvements were sustained for more than 24 months in both the non-elderly and elderly. The incidences of adverse drug events and laboratory abnormalities were similar in the elderly and non-elderly patients in all groups (active treatment control with resin, pravastatin alone, or combination therapy). In short-term studies, treatment was discontinued because of adverse events in < 1% of all patients treated with pravastatin (all doses) or placebo. The frequency and profile of adverse events were similar among patients treated with pravastatin or placebo. In long-term studies, treatment was discontinued in 0.4% of patients in the pravastatin group and in 0.3% of the patients in the bile-acid-binding resin group. If drug therapy is warranted, pravastatin appears to be safe and effective for long-term use in elderly patients with hypercholesterolemia.