Aspirin reduces cutaneous flushing after administration of an optimized extended-release niacin formulation.

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.

High surface density immobilization of oligonucleotide on silicon.

Oligonucleotide (11-mer) molecules are immobilized on silicon in high surface population using either a permanent thioether bond or a chemo-selectively reversible disulfide bond to the surface thiol functionality. Substrate hydroxy groups are first silanized with an 11 carbon trichlorosilane containing a terminal, protected thiol moiety. Oligonucleotide modified with a tether possessing a terminal thiol group is further derivatized with a water-soluble, halobenzylic bifunctional reagent, which allows the complete conjugate to be attached to the surface through a permanent thioether bond. Alternatively, the oligonucleotide-tether complex can be combined with a pyridyldisulfide compound, which, in turn, facilitates the formation of a reversible disulfide bond with surface thiol. The amount of immobilized oligonucleotide was determined by radiochemical labeling with 32P. Additional verification of surface amounts was obtained from X-ray photoelectron spectroscopic analysis of substrates. The results of the immobilization protocols are compared with the oligonucleotide surface population achieved through the conventional silanizing agent, mercaptopropyltrimethoxysilane. Finally, a preliminary confirmation of duplex formation of a TTU-attached 25-mer with its complementary strand is outlined.

Pentafluorinated probes for the X-ray photoelectron spectroscopic study of immobilized bifunctional silanes.

Bifunctional silanes constitute valuable linking agents for attachment of biomolecules at high levels of surface population density through the formation of thioether or disulfide bonds. Three such compounds, 1-((trifluoroacetyl)-thio)-11-(trichlorosilyl)undecane, 1-bromo-11-(trichlorosilyl)undecane, and 1-((bromoacetyl)oxy)-11-(trichlorosilyl)undecane, are discussed in terms of their surface chemistry on silicon wafers. To examine the electrophilic and nucleophilic generation of sulfur-containing linkages, three new probes, N'-(pentafluorophenyl)iodoacetohydrazide, N'-(pentafluorophenyl)-3-(2-pyridylthio)propriono-hydrazide, and N'-(pentafluorophenyl)mercaptoacetohydrazide, are introduced with respect to their reactions with silanized surfaces (studied by X-ray photoelectron spectroscopy). Thiol-functionalized surfaces obtained by silanization act as nucleophiles toward the probes. In air, low yields of conjugation are exhibited which are attributed to the unavailability of thiol groups because of intramolecular disulfide group formation instigated by oxygen or by disulfide exchange with the proprionyl probe. The behavior of electrophilic silanized surfaces toward the mercaptoacetyl-containing probe is governed by the nature of the leaving group and by steric factors.

Surface immobilized biochemical macromolecules studied by scanning Kelvin microprobe.

The measurement of work function is a particularly effective method for the characterization of surfaces because of the sensitivity of the parameter to interfacial structure, modification and overall chemistry. Accordingly, techniques for the analysis of work function offer a powerful tool for monitoring surface chemical changes, especially for situations involving the immobilization of new moieties at the interface. In the present paper, we describe the performance of a new, modified scanning Kelvin microprobe which is capable of the tandem measurement of contact potential and surface topography with resolutions of 1 mV and 10 nm, respectively. The lateral resolution is 1 micron. The instrument has been applied to the study of substrates modified by the attachment of biochemical macromolecules such as oligonucleotides and DNA. This preliminary work confirms the great potential of the technique in the study of biocompatibility, macromolecular structure and microarray devices.

Acoustic waves and the real-time study of biochemical macromolecules at the liquid/solid interface.

The adsorption of the proteins, bovine serum albumin, fibrinogen, avidin and neutravidin (non-glycosylated form of avidin) to a variety of surfaces imposed on thickness shear mode sensors in examined in a flow-injection analysis format. In all cases, adsorption of these moieties was essentially irreversible, although the magnitude of adsorption was dependent on surface free energy and functional group chemistry. Also described is the direct, real-time detection of the binding of peptides to HIV-1 TAR RNA bound on a thickness-shear mode (TSM) sensor surface. The results clearly indicate that responses are discriminatory for two different peptides. In order to provide a theoretical backcloth for the experimental measurements, a new model for the operation of the TSM in liquids is presented.

Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events. PLAC I investigation.

OBJECTIVES: This study was designed to evaluate the effect of pravastatin on progression of coronary atherosclerosis and ischemic events in patients with coronary artery disease and mild to moderate hyperlipidemia. BACKGROUND: Few clinical trial data support the use of lipid-lowering therapy in patients with coronary artery disease and mild to moderate elevations in cholesterol levels. METHODS: Four hundred eight patients (mean age 57 years) with coronary artery disease and low density lipoprotein (LDL) cholesterol > or = 130 mg/dl (3.36 mmol/liter) but < 190 mg/dl ([4.91 mmol/liter]) despite diet were randomized in a 3-year study to receive pravastatin or placebo. Atherosclerosis progression was evaluated by quantitative coronary arteriography. RESULTS: Baseline mean LDL cholesterol was 164 mg/dl (4.24 mmol/liter). Pravastatin decreased total and LDL cholesterol and triglyceride levels by 19%, 28% and 8%, respectively, and increased high density lipoprotein cholesterol by 7% (p < or = 0.001 vs. placebo for all lipid variables). Progression of atherosclerosis was reduced by 40% for minimal vessel diameter (p = 0.04), particularly in lesions < 50% stenosis at baseline. There was a consistent although not statistically significant effect on mean diameter and percent diameter stenosis. There were also fewer new lesions in those assigned pravastatin (p < or = 0.03). Myocardial infarction was reduced during active treatment (8 in the pravastatin group, 17 in the placebo group; log-rank test, p < or = 0.05; 60% risk reduction), with the benefit beginning to emerge after 1 year. CONCLUSIONS: In patients with coronary artery disease and mild to moderate cholesterol elevations, pravastatin reduces progression of coronary atherosclerosis and myocardial infarction. The time course of event reduction increases the potential for a relatively rapid decrease in the clinical manifestations of coronary artery disease with lipid lowering.

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.

Reduction in coronary events during treatment with pravastatin. PLAC I and PLAC II Investigators. Pravastatin Limitation of Atherosclerosis in the Coronary Arteries.

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)

Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II)

We randomized 151 coronary patients to placebo or pravastatin and treated them for 3 years. B-mode ultrasound quantification of carotid artery intimal-medial thickness (IMT) was obtained at baseline and sequentially during this period. The primary outcome was the change in the mean of the maximal IMT measurements across time. Effects on individual carotid artery segments (common, bifurcation, and internal carotid) and on clinical events were also investigated. Plasma concentrations of total cholesterol were lower with active treatment than with placebo (4.80 vs 6.07 mmol/L [186 vs 235 mg/dl], respectively) as were concentrations of low-density lipoprotein cholesterol (3.11 vs 4.30 mmol/L [120 vs 167 mg/dl], respectively). Plasma concentrations of high-density lipoprotein2 cholesterol were higher with active treatment (0.16 vs 0.14 mmol/L [6.1 vs 5.5 mg/dl], respectively). Active treatment resulted in a nonsignificant 12% reduction in progression of the mean-maximum IMT (from 0.068 to 0.059 mm/year) and a statistically significant 35% reduction in IMT progression in the common carotid. Active treatment was also associated with a reduction in fatal and nonfatal coronary events [corrected] (p = 0.09) and of any fatal event plus nonfatal myocardial infarction (p = 0.04).

A multinational study of the effects of low-dose pravastatin in patients with non-insulin-dependent diabetes mellitus and hypercholesterolemia. Pravastatin Multinational Study Group for Diabetes.

This multinational, 16-week, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of low-dose pravastatin in 325 patients with non-insulin-dependent diabetes mellitus (NIDDM) and hypercholesterolemia [serum total cholesterol concentrations of 5.2-7.8 mmol/l (200 to 300 mg/dl)]. Patients were randomized to receive pravastatin 10 mg or matching placebo with doubling of the dose after 8 weeks if predefined target levels for total cholesterol [(i.e., < 5.2 mmol/l (200 mg/dl) or > 15% decrease from baseline] had not been achieved. At Week 16, pravastatin-treated patients showed a 21.4% decrease in serum low-density lipoprotein cholesterol (LDL-C) and a 13.5% reduction in serum total cholesterol (TC) concentrations (p < 0.001 compared with placebo). Levels of triglycerides (TG) were reduced 9.6% during pravastatin treatment (p < 0.05 compared with placebo) while high-density lipoprotein cholesterol (HDL-C) levels were increased 4.4% (p = NS). Adverse events and laboratory test abnormalities were similar among patients treated with pravastatin or placebo. Glycosylated hemoglobin (HbA1C) levels remained unchanged. The results of this study demonstrate that low-dose pravastatin is effective and well tolerated for lowering elevated cholesterol concentrations during short-term treatment of patients with NIDDM and hypercholesterolemia.

Efficacy and safety of pravastatin in the long-term treatment of elderly patients with hypercholesterolemia.

PURPOSE: Elevated cholesterol levels are a major risk factor for coronary heart disease, which remains a significant problem in patients beyond age 65 years. Because drug therapy for the control of hypercholesterolemia in elderly patients is frequently considered to be indicated, we investigated the efficacy and safety of pravastatin in the treatment of elderly subjects with primary hypercholesterolemia. PATIENTS AND METHODS: In this 96-week, multicenter, double-blind, placebo-controlled study, 142 subjects (95 women, 47 men) 64 to 90 years of age with elevated cholesterol levels despite dietary intervention were randomized to receive pravastatin 20 mg at bedtime or matching placebo (2:1). Dosage could be doubled after 8 weeks, a bile acid-binding resin could be added after 16 weeks, and nicotinic acid or probucol could be added after 32 weeks, as needed, to adequately lower the low-density lipoprotein cholesterol (LDL-C) levels. RESULTS: Significant reductions in the levels of LDL-C (-30.9%), total cholesterol (Total-C; -21.9%), and triglycerides (TG; -16.7%) and significant increases in the levels of high-density lipoprotein cholesterol (HDL-C; 11.3%) were noted in the group receiving pravastatin treatment at 16 weeks (P < or = 0.001 compared with baseline, P < or = 0.01 compared with placebo). The cholesterol-lowering effects of pravastatin were sustained throughout the 96 weeks of the trial. Pravastatin was well tolerated, with an overall incidence of adverse events nearly identical to that of placebo. CONCLUSIONS: In this study, pravastatin was well tolerated and effective in lowering LDL-C, Total-C, and TG and in raising HDL-C during long-term treatment of elderly patients with primary hypercholesterolemia.

Design and recruitment in the United States of a multicenter quantitative angiographic trial of pravastatin to limit atherosclerosis in the coronary arteries (PLAC I).

The present study was designed to test the effect of pravastatin, a new, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on the progression of coronary artery disease in patients with moderate hypercholesterolemia. Angiographic entry criteria included the presence of > or = 1 stenosis > or = 50% in a major epicardial coronary artery, and certification of film quality through the core angiography laboratory. Patients qualified for randomization if after diet stabilization their low density lipoprotein cholesterol concentrations were > or = 130 and < 190 mg/dl, and triglycerides were < or = 350 mg/dl. Pravastatin (40 mg) or placebo is administered once daily at bedtime. Arteriography will be repeated at the end of 3 years of treatment. The primary end point of the study is the change in absolute mean coronary artery diameter. During a 30-month recruitment period, 44,145 patients were screened, and 408 were randomized. The most frequent reason for excluding patients during the screening and dietary lead-in periods was a low serum cholesterol level. A large proportion of patients with documented coronary artery disease have cholesterol concentrations that are considered to be normal or only modestly increased. Adherence to strict standards of quality control for digital analysis of angiograms ensures that baseline angiograms can be interpreted at the end of 3-year follow-up.

Effect of food on pravastatin pharmacokinetics and pharmacodynamics.

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 experience in elderly and non-elderly patients.

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.

Long-term experience with pravastatin in clinical research trials.

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.

Segurança da pravastatina em ensaios clínicos a longo prazo realizados nos Estados Unidos / Pravastatin safety in long term clinical trials in United States

A segurança da pravastatina, um inibidor seletivo hidrofílico da HMG-CoA redutase, foi avaliada em 1.142 pacientes adultos hipercolesterolêmicos em seis ensaios clínicos multicêntricos realizados nos Estados Unidos. Todos os ensaios foram aleatórios, duplo-cegos e controlados por placebo ao menos nas primeiras oito a 16 semanas, mantendo-se a seguir o tratamento a longo prazo com pravastatina em esquema duplo-cego ou aberto, com ou sem outras drogas redutoras de lipídios; o controle ativo primário foi a resina biliar de ligaçao a ácidos. Nao houve diferenças entre os grupos de pravastatina e placebo com relaçao às taxas globais de reaçoes adversas atribuíveis à droga. Somente erupçoes cutâneas (rash) ocorreram com maior freqúência estatística (p < 0,01) nos pacientes tratados com pravastina. Essas erupçoes geralmente eram leves e transitórias e somente 1,3 por cento dos casos relatados em pacientes tratados com pravastatina estavam possivelmente relacionados à terapia. Durante um período médio de tratamento de 18 meses, as razoes mais freqüentes para a interrupçao da administraçao de pravastatina foram queixas abdominais leves (1,4 por cento dos pacientes) e aumentos assintomáticos das transaminases hepáticas (1,0 por cento dos pacientes). Os valores médios de ALAT e ASAT aumentaram ligeiramente, atingindo um patamar estável após as primeiras oito semanas de terapia. Nenhuma ocorrência de enzimas hepáticas anormais entre os pacientes tratados com pravastina foi associada a doença clínica. Aumentos semelhantes das transaminases hepáticas também foram observados nos pacientes tratados com resina. Em geral, a pravastatina foi bem tolerada e aparentemente nao afetou os músculos esqueléticos, o sono ou o desenvolvimento de catarata.

Intentional poisoning of children--an overlooked category of child abuse: report of seven cases and review of the literature.

Seven instances of child abuse due to poisoning are reported; two of the children died. Forty-one cases of this form of poisoning are found in the literature. Of the total of 48 children, eight (17%) died as a result of the incident; and one was mentally retarded. The seven different agents described here are alcohol, glutethimide (Doriden), propoxyphene hydrochloride (Darvon), diazepam, insulin, lye, and pepper, constituting 27 different types of poison used by abusing guardians. The most common cause of abuse reported is excessive salt ingestion with water restriction. Excessive ingestion of water is the second most common cause. Barbiturates and tranquilizers are also frequent agents. In 30% of the cases, poisoning persists even after hospitalization. Child abuse by battering is associated in 20% of the cases. The need for a high index of suspicion of abuse in bizarre presentations of children for medical care when the etiology is obscure is emphasized.