Photoangioplasty for human peripheral atherosclerosis: results of a phase I trial of photodynamic therapy with motexafin lutetium (Antrin).

BACKGROUND: In photoangioplasty, light activation of a photosensitive drug offers the potential for treatment of long segments of vascular disease. This is a brief description of a study designed to evaluate the safety and tolerability of a new photosensitizer, Antrin (motexafin lutetium), in the endovascular treatment of atherosclerosis. METHODS AND RESULTS: An open-label, single-dose, escalating drug- and light-dose study was performed in patients with atherosclerotic peripheral arterial insufficiency. Clinical evaluation, serial quantitative angiography, and intravascular ultrasonography were performed. Therapy was well tolerated, and only minor side effects were observed. Treatment produced no deleterious vascular effects. Although this study was not designed to examine clinical efficacy, several secondary end points suggested a favorable therapeutic effect. CONCLUSIONS: This phase I study demonstrates that photoangioplasty with motexafin lutetium is well tolerated and safe. Preliminary efficacy data suggest a future role for the treatment of flow-limiting atherosclerosis.

Pharmacokinetics and pharmacodynamics of pravastatin alone and with cholestyramine in hypercholesterolemia.

The pharmacokinetics, pharmacodynamics, and safety of pravastatin, a new selective 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, were evaluated during monotherapy and with subsequent concomitant cholestyramine therapy in 33 patients with primary hypercholesterolemia in this randomized study. After 4 weeks, pravastatin monotherapy (5 mg, 10 mg, and 20 mg twice daily) significantly decreased total cholesterol by 17% to 24% (p less than 0.001 versus baseline) and low-density lipoprotein cholesterol by 23% to 35% (p less than 0.001). High-density lipoprotein cholesterol increased by 8% to 9%, and triglycerides decreased by 6% to 9%. The area under the serum concentration-time curve and maximum serum concentration of pravastatin showed dose-proportionality; time to maximum serum concentration and serum elimination half-life were independent of dose. When added to pravastatin therapy, cholestyramine enhanced the lipid-lowering effects of pravastatin. After 4 weeks of combination therapy, total cholesterol was reduced by 32% to 38% (p less than 0.001 versus baseline), and low-density lipoprotein cholesterol was reduced by 47% to 56% (p less than 0.001). High-density lipoprotein cholesterol increased by 11% to 18% (p less than 0.05). Pravastatin was well tolerated; no clinical adverse events directly attributable to the drug were reported.

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.

Comparative pharmacokinetics and pharmacodynamics of pravastatin and lovastatin.

The oral bioavailability of two HMG-CoA reductase inhibitors, pravastatin and lovastatin, was investigated in this randomized, two-way crossover study. Twenty healthy men were randomly assigned to treatment with a 40-mg dose of pravastatin or lovastatin once daily for 1 week; steady state kinetics were assessed after the last dose. After 1 week of washout, each subject received the alternate treatment. Serum specimens were assayed by gas chromatography/mass spectrometry (GC/MS) for intact pravastatin or lovastatin acid and by bioassay for active inhibitor concentration and, after hydrolysis of lactones, for total inhibitor concentration. The systemic bioavailabilities of total (active plus potentially active) inhibitors for the two drugs were different, with the mean AUC value for lovastatin being 50% higher than that of pravastatin (mean +/- SEM AUC0-24 values of 285 +/- 25 and 189 +/- 13 ng-equiv x hr/mL, respectively, P less than .0001). Pravastatin, which is administered as the monosodium salt, is present in the systemic circulation as the open acid; lovastatin, which is administered as the lactone, is present as both open-acid active metabolites (62%) and closed-ring lactone metabolites (38%), which are potentially active. Based on mean AUC values, pravastatin accounted for 75% of the active inhibitors from a pravastatin dose. Lovastatin acid accounted for just 25% of the active inhibitors from a lovastatin dose, with the remainder due to other active metabolites. Significant decreases from baseline in total and low-density lipoprotein (LDL) cholesterol were observed during the first treatment leg for both pravastatin and lovastatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative efficacy of once-daily versus twice-daily pravastatin in primary hypercholesterolemia.

The efficacy of once-daily versus twice-daily dosing of pravastatin was determined in men with primary hypercholesterolemia. The same group of patients was used in the two studies. In the once-daily study, 18 patients took 20 mg of pravastatin at bedtime for four weeks and then 40 mg of pravastatin for an additional four weeks. In the twice-daily study, 22 patients took 10 mg or 20 mg of pravastatin twice daily for four weeks. Total cholesterol was reduced 18% in the 20-mg once-daily group, 20% in the 10-mg twice-daily group, 23% in the 40-mg once-daily group, and 24% in the 20-mg twice-daily group; the respective reductions in low-density cholesterol were 27%, 28%, 32%, and 34%. All these reductions were statistically significant; no between-group differences were significant. Pravastatin was well tolerated and no patients dropped out because of side effects.

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.

Pharmacokinetic interaction between propranolol and the HMG-CoA reductase inhibitors pravastatin and lovastatin.

1. Single oral 20 mg doses of the HMG-CoA reductase inhibitors pravastatin and lovastatin, with and without concomitant propranolol (40 mg twice daily), were administered to 16 healthy male subjects participating in a randomized, four-way crossover study. 2. Serum concentrations of total and active inhibitors were measured by bioassay and concentrations of pravastatin, two pravastatin metabolites and lovastatin acid were measured by gas chromatography/mass spectrometry. 3. Coadministration of propranolol with pravastatin reduced the mean area under the serum concentration-time curve (AUC) of total inhibitors by 23%, of active inhibitors by 20% and of pravastatin by 16%. 4. Coadministration of propranolol with lovastatin also resulted in decreases in the mean serum AUC of total inhibitors by 18%, of active inhibitors by 12% and of lovastatin acid by 13%. 5. These decreases in systemic drug concentrations may reflect enhanced drug first-pass hepatic clearance in the presence of propranolol. 6. The clinical significance of these changes is likely to be small.

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.