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Medical Mycology May 2012Candidemia remains a major cause of morbidity and mortality, especially in immunocompromised patients. A strategy of reducing virulence and virulence factors of Candida...
Candidemia remains a major cause of morbidity and mortality, especially in immunocompromised patients. A strategy of reducing virulence and virulence factors of Candida spp. is an attractive approach for the treatment of serious infections caused by these yeasts. Recently, farnesol has been reported to be a quorum-sensing autoinducer, as well as a virulence factor of C. albicans. In the present study, we examined the effects of pravastatin, a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor on the in vitro production of farnesol. In addition, the synergistic effects of pravastatin with fluconazole (FLC) were examined in a mouse model of systemic infections. In vitro experiments demonstrated that pravastatin had synergistic activity with FLC as judged by fractional inhibitory concentration index (FICI) and suppression of farnesol production at sub-minimum inhibitory concentrations. Furthermore, significant improvement of survival in systemic infection models was shown with pravastatin supplementation. The survival benefits of pravastatin were correlated with reductions of fungal burden. These data suggest the potential of pravastatin as a supportive therapy against C. albicans infections. Synergistic antifungal activity and suppression of HMG-CoA reductase-associated Candida virulence factors, including farnesol, may explain, at least in part, the in vivo efficacy of pravastatin.
Topics: Animals; Antifungal Agents; Candida albicans; Candidiasis; Colony Count, Microbial; Disease Models, Animal; Farnesol; Female; Mice; Mice, Inbred C3H; Pravastatin; Survival Analysis; Virulence Factors
PubMed: 21954955
DOI: 10.3109/13693786.2011.610037 -
Journal of Pharmaceutical Sciences Jul 2018Herein, we aimed to prepare porous granules of pravastatin and evaluate their applicability to orally disintegrating tablets (ODTs). Pravastatin solid dispersion...
Herein, we aimed to prepare porous granules of pravastatin and evaluate their applicability to orally disintegrating tablets (ODTs). Pravastatin solid dispersion granules (PSDGs-A) were prepared by dispersing pravastatin sodium in D-mannitol (the dispersion medium) in the presence of ammonium bicarbonate (the sublimation agent) using a spray-drying process. The PSDGs-A were round, irregularly shaped, mesoporous agglomerates with appropriate particle size, bulk density, and flowability for the tableting process. The mesopore formation in PSDGs-A resulted from the complete sublimation of ammonium bicarbonate during spray-drying and resulted in a notably high surface area. When the PSDGs-A were blended with ODT excipients and then directly compressed into ODTs (PSDGs-A-ODTs), they were readily incorporated into ODTs without tableting problems and had desirable ODT characteristics. They demonstrated rapid disintegration times because of the fast water uptake of mesoporous PSDGs-A caused by their high surface area. This rapid disintegration of PSDGs-A-ODTs was reflected also by their quick initial dissolution. The mesoporous PSDGs-A prepared with ammonium bicarbonate using the spray-drying process can be used to develop pravastatin ODTs. This spray-dried, mannitol-based solid dispersion of drugs using sublimation solids is a potential formulation technology for ODT product development.
Topics: Administration, Oral; Anticholesteremic Agents; Bicarbonates; Desiccation; Drug Compounding; Excipients; Mannitol; Porosity; Pravastatin; Solubility; Tablets; Water
PubMed: 29530714
DOI: 10.1016/j.xphs.2018.03.003 -
Circulation Aug 2002
Topics: Advisory Committees; Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Drug Packaging; Drug Therapy, Combination; Humans; Hypertension; Pravastatin
PubMed: 12187915
DOI: No ID Found -
Journal of Cellular Physiology Jul 2019New onset of diabetes is associated with the use of statins. We have recently demonstrated that pravastatin-treated hypercholesterolemic LDL receptor knockout (LDLr )...
New onset of diabetes is associated with the use of statins. We have recently demonstrated that pravastatin-treated hypercholesterolemic LDL receptor knockout (LDLr ) mice exhibit reductions in insulin secretion and increased islet cell death and oxidative stress. Here, we hypothesized that these diabetogenic effects of pravastatin could be counteracted by treatment with the antioxidant coenzyme Q (CoQ ), an intermediate generated in the cholesterol synthesis pathway. LDLr mice were treated with pravastatin and/or CoQ for 2 months. Pravastatin treatment resulted in a 75% decrease of liver CoQ content. Dietary CoQ supplementation of pravastatin-treated mice reversed fasting hyperglycemia, improved glucose tolerance (20%) and insulin sensitivity (>2-fold), and fully restored islet glucose-stimulated insulin secretion impaired by pravastatin (40%). Pravastatin had no effect on insulin secretion of wild-type mice. In vitro, insulin-secreting INS1E cells cotreated with CoQ were protected from cell death and oxidative stress induced by pravastatin. Simvastatin and atorvastatin were more potent in inducing dose-dependent INS1E cell death (10-15-fold), which were also attenuated by CoQ cotreatment. Together, these results demonstrate that statins impair β-cell redox balance, function and viability. However, CoQ supplementation can protect the statins detrimental effects on the endocrine pancreas.
Topics: Animals; Cell Line; Cell Survival; Diabetes Mellitus; Dietary Supplements; Female; Glucose Tolerance Test; Hydrogen Peroxide; Hypercholesterolemia; Insulin; Insulin-Secreting Cells; Liver; Mice; Mice, Knockout; Pravastatin; Receptors, LDL; Ubiquinone
PubMed: 30536661
DOI: 10.1002/jcp.27932 -
Clinical Pharmacology and Therapeutics Jun 2019This study investigated the impact of SLCO1B1 genotype on pravastatin systemic exposure in children and adolescents with hypercholesterolemia. Participants (8-20 years)...
This study investigated the impact of SLCO1B1 genotype on pravastatin systemic exposure in children and adolescents with hypercholesterolemia. Participants (8-20 years) with at least one allelic variant of SLCO1B1 c.521T>C (521TC, n = 15; 521CC, n = 2) and wild-type controls (521TT, n = 15) completed a single oral dose pharmacokinetic study. Interindividual variability of pravastatin acid (PVA) exposure within SLCO1B1 genotype groups exceeded the approximately twofold difference in mean PVA exposure observed between SLCO1B1 genotype groups (P > 0.05, q > 0.10). The 3'α-iso-pravastatin acid and lactone isomer formation in the acidic environment of the stomach prior to absorption also was variable and affected PVA exposure in all genotype groups. The SLCO1B1 c.521 gene variant contributing to variability in systemic exposure to PVA in our pediatric cohort was comparable to previous studies in adults. However, other demographic and physicochemical factors seem to also contribute to interindividual variability in the dose-exposure relationship.
Topics: Adolescent; Child; Female; Genetic Variation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Liver-Specific Organic Anion Transporter 1; Male; Pravastatin
PubMed: 30549267
DOI: 10.1002/cpt.1330 -
Pharmacotherapy 1995A new animal model of hyperlipidemia is being developed using the nonionic surfactant poloxamer 407 (P-407). We investigated the impact of pravastatin on P-407-induced... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
A new animal model of hyperlipidemia is being developed using the nonionic surfactant poloxamer 407 (P-407). We investigated the impact of pravastatin on P-407-induced hyperlipidemia. Twenty rats received P-407 300 mg intraperitoneally to induce hyperlipidemia, and 20 control rats received saline injection. Pravastatin was administered orally to an equal number of rats in both groups using three different regimens. A fourth group did not receive pravastatin. At 24 hours after injection, total cholesterol levels in two of the pravastatin groups were 28% and 34% lower than those in animals that did not receive pravastatin (p < or = 0.01). At 48 hours, triglyceride levels were significantly lower in all pravastatin groups (21-44%) versus animals not receiving pravastatin. Pravastatin diminished the effects of P-407 on lipoproteins. This new animal model may be useful in screening for investigational antihyperlipidemic agents.
Topics: Animals; Cholesterol; Hyperlipidemias; Injections, Intraperitoneal; Lipids; Male; Poloxalene; Pravastatin; Rats; Rats, Wistar; Tablets; Time Factors; Triglycerides
PubMed: 7739951
DOI: No ID Found -
Coronary Artery Disease Nov 2002Previous studies suggested that hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) promotes collateral circulation in ischemic limbs of rabbits. The present... (Clinical Trial)
Clinical Trial
BACKGROUND
Previous studies suggested that hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) promotes collateral circulation in ischemic limbs of rabbits. The present study was designed to determine the association between treatment with pravastatin and the development of coronary collateral circulation as assessed by the Rentrop Score in patients with coronary artery disease (CAD) in a case-control study.
DESIGN
The study included patients who had one (1-V), two (2-V) or three (3-V) significantly stenosed vessels. Patients who did and did not receive pravastatin were defined as case participants (n = 42) and control participants (n = 100), respectively.
RESULTS
The case participants included a higher percentage of 3-V patients with a Rentrop Score 1 compared to the control participants but there was no difference among 1-V and 2-V patients, suggesting that pravastatin was associated with coronary collateral circulation independent of the number of stenosed vessels. Patients with 3-V disease who were treated with pravastatin were most likely [odds ratio (confidence interval), 17.4 (4.4-115)] to develop collateral circulation, as assessed by multiple logistic regression analysis.
CONCLUSIONS
Treatment with pravastatin was associated with the development of collateral circulation in patients with CAD, suggesting that such action constitutes part of the pleiotropic effects of statin.
Topics: Aged; Anticholesteremic Agents; Collateral Circulation; Coronary Circulation; Coronary Disease; Female; Humans; Male; Pravastatin
PubMed: 12488647
DOI: 10.1097/00019501-200211000-00005 -
Molecules (Basel, Switzerland) Aug 2021Dihydro analogues are known byproducts of the fermentative production of statins and cannot be detected with existing pharmacopoeia analysis methods. We detected...
Dihydro analogues are known byproducts of the fermentative production of statins and cannot be detected with existing pharmacopoeia analysis methods. We detected dihydropravastatin in most commercial formulations of pravastatin with LC-MS, in some cases in levels requiring identification. In fermentation broth samples of the single step production of pravastatin, we detected and identified for the first time 4a,5-dihydropravastatin, and confirmed that after several recrystallization steps this impurity can be fully removed from the pravastatin powder.
Topics: Anticholesteremic Agents; Chromatography, Liquid; Drug Contamination; Mass Spectrometry; Pravastatin
PubMed: 34361838
DOI: 10.3390/molecules26154685 -
Pharmacoepidemiology and Drug Safety Feb 2010To assess the influence of pravastatin therapy on cancer morbidity and mortality by a meta-analysis of individual patient data (IPD) from three independent Japanese... (Meta-Analysis)
Meta-Analysis
PURPOSE
To assess the influence of pravastatin therapy on cancer morbidity and mortality by a meta-analysis of individual patient data (IPD) from three independent Japanese large-scale clinical trials.
METHODS
We conducted a meta-analysis of IPD collected from three large-scale prospective studies, the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study, Kyushu Lipid Intervention Study (KLIS), and Hokuriku Lipid Coronary Heart Disease Study-Pravastatin Atherosclerosis Trial (Holicos-PAT), which compared cardiovascular outcomes with pravastatin therapy and non-statin therapy in Japanese patients with hypercholesterolemia over a follow-up period of >or=4 years. The incidence of cancer or cancer death in the pravastatin and non-statin therapy groups was compared by multivariate Cox proportional hazard models stratified by trial. Subgroup analyses by sex and age were also conducted using the same methods.
RESULTS
In a total of 13 724 patients (mean age, 58 years; women, 48%) included in the analyses, pravastatin was not associated with an increased risk of developing cancer (hazard ratio [HR], 0.99; 95% confidence interval [95%CI], 0.81-1.19). Similarly, pravastatin therapy did not statistically affect cancer death (HR, 0.86; 95%CI, 0.61-1.21). Moreover, in subgroups analyses, no influence was observed on cancer incidence or death in relation to sex and age.
CONCLUSION
Pravastatin did not increase the rate of cancer incidence or cancer death in a large population of Japanese patients followed for >70,000 patient-years.
Topics: Anticholesteremic Agents; Controlled Clinical Trials as Topic; Female; Humans; Japan; Male; Middle Aged; Neoplasms; Pravastatin; Risk Factors
PubMed: 19856484
DOI: 10.1002/pds.1870 -
Author's reply re: Pravastatin to ameliorate early onset pre-eclampsia: promising but not there yet.BJOG : An International Journal of... May 2020
Topics: Female; Humans; Pravastatin; Pre-Eclampsia; Pregnancy
PubMed: 32154980
DOI: 10.1111/1471-0528.16158