Rifampin- and Silymarin-Mediated Pharmacokinetic Interactions of Exogenous and Endogenous Substrates in a Transgenic OATP1B Mouse Model.

Organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3, encoded by the SLCO gene family of the solute carrier superfamily, are involved in the disposition of many exogenous and endogenous compounds. Preclinical rodent models help assess risks of pharmacokinetic interactions, but interspecies differences in transporter orthologs and expression limit direct clinical translation. An OATP1B transgenic mouse model comprising a rodent Slco1a/1b gene cluster knockout and human SLCO1B1 and SLCO1B3 gene insertions provides a potential physiologically relevant preclinical tool to predict pharmacokinetic interactions. Pharmacokinetics of exogenous probe substrates, pitavastatin and pravastatin, and endogenous OATP1B biomarkers, coproporphyrin-I and coproporphyrin-III, were determined in the presence and absence of known OATP/Oatp inhibitors, rifampin or silymarin (an extract of milk thistle [Silybum marianum]), in wild-type FVB mice and humanized OATP1B mice. Rifampin increased exposure of pitavastatin (4.6- and 2.8-fold), pravastatin (3.6- and 2.2-fold), and coproporphyrin-III (1.6- and 2.1-fold) in FVB and OATP1B mice, respectively, but increased coproporphyrin-I AUC0-24h only (1.8-fold) in the OATP1B mice. Silymarin did not significantly affect substrate AUC, likely because the silymarin flavonolignan concentrations were at or below their reported IC50 values for the relevant OATPs/Oatps. Silymarin increased the Cmax of pitavastatin 2.7-fold and pravastatin 1.9-fold in the OATP1B mice. The data of the OATP1B mice were similar to those of the pitavastatin and pravastatin clinical data; however, the FVB mice data more closely recapitulated pitavastatin clinical data than the data of the OATP1B mice, suggesting that the OATP1B mice are a reasonable, though costly, preclinical strain for predicting pharmacokinetic interactions when doses are optimized to achieve clinically relevant plasma concentrations.

The role of pravastatin in preventing preeclampsia in high-risk pregnant women: a meta-analysis with trial sequential analysis.

OBJECTIVE: We aimed to perform a systematic review and meta-analysis of randomized controlled trials to evaluate the prophylactic use of pravastatin in pregnant women with high-risk of preeclampsia. DATA SOURCES: PubMed, Embase, Cochrane Central, and Web of Science were searched from inception to August 2023 with no language or filters restriction. The references from included studies, previous systematic reviews, and meta-analyses were manually searched for any additional studies. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials comparing pravastatin in any dose with placebo or no treatment in pregnant women with high risk for preeclampsia and up to 20 weeks of gestation were included in this meta-analysis. METHODS: We used RStudio version 4.2.2 with random effects models to compute pooled risk ratios for prespecified outcomes data. The quality assessment was conducted using version 2 of the Cochrane Risk of Bias Assessment Tool. We also performed a trial sequential analysis to evaluate the reliability of our findings. RESULTS: We included 3 randomized controlled trials comprising 213 patients, of whom 106 (49.8%) were allocated to the pravastatin group. There was no significant effect of pravastatin on the incidence of preeclampsia (risk ratio, 0.62; 95% confidence interval, 0.33-1.14; P=.12). CONCLUSION: Our study was unable to demonstrate the benefit of pravastatin for preventing preeclampsia in high-risk pregnant women. Nevertheless, these findings comprised only preliminary studies with a small number of subjects, highlighting the need of well-designed, and adequately powered clinical trials.

Papel das estatinas na modulação da função endotelial vasomotora na hipertensão e doença coronariana / The role of statins in the modulation of endothelium vasomotor function in hypertension and coronary artery disease

o benefício em longo prazo do tratamento com estatinas naprevenção de eventos coronarianos primários e secundários éindiscutível. Embora uma parte deste benefício esteja ligadaao efeito sobre a redução da circulação de lipoproteínasaterogênicas, outros mecanismos, como a modulação datrombogênese, a redução da inflamação e melhora da funçãoendotelial, têm sido investigados. O efeito da estatina sobrea função endotelial está ligado à sua inibição da produçãode superóxido e sua regulação positiva da síntese do óxidonítrico (NOS) no endotélio. Na prática clínica, o benefíciona função do endotélio depois do tratamento com estatinatem sido observado em uma ampla variedade de condiçõesque incluem a hipertensão arterial sistêmica, doença arterialcrônica e síndrome coronariana aguda. Esta breve revisãoincidirá sobre as principais conclusões relacionadas à terapiacom estatina sobre o tônus arterial sistêmico e doença arterialcoronariana aguda e crônica...

The long-term benefit of statin treatment on the prevention of primary and secondary coronary events is undisputed. Although a proportion of this effect has been linked to its reduction of circulating atherogenic lipoproteins, other mechanisms have been studied such as modulation of thrombogenesis, reduction of inflammation, and improvement of endothelia! function. Its favorable effect on endothelial function is tied to its inhibition of superoxide production and its positive regulation of nitric oxide synthase (NOS) in the endothelium. In the clinica! setting, the gain in endothelia! function after statin treatment has been observed in a wide range of conditions that include systernic hypertension, chronic arterial disease, and acute coronary syndrome. This brief review will focus on the main findings related to statin therapy on the systernic arterial tone and both acute and chronic coronary artery disease...

Efeitos da pravastatina nas lipoproteínas, Lp(a), apo B e apo A-I em pacientes com hipercolesterolemia primária / Effects of Pravastatin on Lipoproteins, Lp(a), apo B and apo A-I in Patients with Primary Hypercholesterolemia

PURPOSE--To evaluate the effects of pravastatin on lipoproteins, Lp (a), apo B and apo A-I and its tolerability in primary hypercholesterolemic patients in our outpatient lipid clinic. METHODS--Twenty-two primary hypercholesterolemic patients were evaluated. They had all been treated previously with other hypocholesterolemic drugs, including the statins, forming a specific and homogeneous group with hypercholesterolemia and definite coronary risk. After 7 weeks with American Heart Association phase I diet and placebo drug, pravastatin was administered during 12 weeks. All patients received an initial daily dose of 10 mg for six weeks. After this period, this dose was increased to 20 mg. The levels of cholesterol, triglycerides, high-density lipoprotein, lipoprotein (a) and apolipoproteins A-1 and B were determined. RESULTS--No changes occurred with diet and placebo, but pravastatin at a daily dose of 10 mg, reduced significantly cholesterol level (7.22 per cent) LDL-cholesterol (13.08 per cent) and increased HDL-cholesterol (7.8 per cent). The results were better with 20 mg, achieving a reduction of (28.21 per cent) in cholesterol, (36.88 per cent) in LDL-cholesterol, (17.06 per cent) in apo B level and an increase of (10.06 per cent) in HDL-cholesterol. The smaller effect observed with the more commonly used dosage (10 mg/day) was most probably due to the characteristics of the sample with already established hypercholesterolemia, being thus dependent of higher concentrations of medications, as observed in previous treatments in our outpatient clinic. Side affects with this drug were rare. No biochemical changes were observed that would interrupt the continuation of therapy. CONCLUSION--Pravastatin was well tolerated and promoted favorable changes in the total cholesterol, LDL, apo B and cholesterol/HDL and LDL/HDL ratios of primary hypercholesterolemic patients

Estudio multicéntrico nacional de pravastatin en la hipercolesterolemia primaria / Argentine multicentric study with pravastatin in primary hypercholesterolemia

Para evaluar la eficacia y la seguridad de 10mg/día de pravastatin en el tratamiento de la hipercolesterolemia primaria, 564 pacientes (con colesterolemia mayor de 240 mg/día al cabo de 4 semanas de dieta) fueron tratados durante 8 semanas. El perfil lipídico mejoró significativamente (p< 0,01) tanto a las 4 como a las 8 semanas de tratamiento. Sólo 42 pacientes (7,4 por ciento) presentaron efectos colaterales y no hubo cambios significativos en los parámetros no lipídicos. En conclusión, el pravastatin resultó ser una droga eficaz y segura para el tratamiento de la hipercolesterolemia primaria