-
The American Journal of Cardiology Jul 1996
Clinical Trial Comparative Study Randomized Controlled Trial
Topics: Anticholesteremic Agents; Drug Administration Schedule; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Pravastatin
PubMed: 8712106
DOI: 10.1016/s0002-9149(96)90321-5 -
International Journal of Pharmaceutics Dec 2015Wiechers' programme "Formulating for Efficacy" initiated a new strategy to optimise the oil phase of topical formulations in order to achieve optimal transdermal drug...
Wiechers' programme "Formulating for Efficacy" initiated a new strategy to optimise the oil phase of topical formulations in order to achieve optimal transdermal drug delivery. This new approach uses the "Delivery Gap Theory" on any active pharmaceutical ingredients (APIs) to test if it could enhance transdermal drug delivery. The aim of the study was to formulate six different semi-solid formulations (three creams and three emulgels) with 2% pravastatin as the API in order to investigate the "Delivery Gap Principle", by determining which formulation would deliver pravastatin best to the target-site (system circulation). The three cream- and three emulgel formulations had different polarities, i.e. a formulation with polarity equal to that of the stratum corneum (optimised), a non-polar (lipophilic)- and a polar (hydrophilic)-formulation. Franz cell diffusion studies were executed over 12h and the optimised emulgel (2.578μg/cm(2)) had the highest median amount per area obtained. Tape stripping followed the diffusion studies and in the stratum corneum-epidermis, the hydrophilic emulgel (1.448μg/ml) contained the highest median pravastatin concentration and the epidermis-dermis the optimised emulgel (0.849μg/ml) depicted the highest pravastatin concentration. During this study, it was observed that when both emulgel and cream formulations were compared; the emulgels enhanced the delivery of pravastatin more than the creams.
Topics: Administration, Cutaneous; Chemistry, Pharmaceutical; Diffusion; Ointments; Pravastatin
PubMed: 26505148
DOI: 10.1016/j.ijpharm.2015.10.034 -
Shock (Augusta, Ga.) Jan 2020In septic patients, adequate microvascular oxygenation (μHBO2) of the intestine is vital for their outcome. Recent studies suggest that statins can ameliorate septic...
INTRODUCTION
In septic patients, adequate microvascular oxygenation (μHBO2) of the intestine is vital for their outcome. Recent studies suggest that statins can ameliorate septic microcirculation in a variety of tissues. However, the effect on intestinal microvascular oxygenation and blood flow is largely unknown. Furthermore, there are indications that statin therapy might not be beneficial in the presence of hypercapnia, as observed in septic acute respiratory distress syndrome (ARDS) patients. Therefore, the present study explores the effect of pravastatin with and without additional moderate acute hypercapnia on intestinal microvascular oxygenation and blood flow in experimental sepsis.
METHODS
Forty male Wistar rats were randomized into four groups. Half of the animals received 0.2 mg • kg pravastatin s.c., the other half received the same volume as vehicle (NaCl 0.9%). After 18 h, colon ascendens stent peritonitis surgery was conducted in all animals to induce sepsis. Twenty-four hours after surgery, baseline was established and the animals were subjected to either 120 min of normocapnic (pCO2 40 ± 6 mm Hg) or moderate hypercapnic (pCO2 72 ± 10 mm Hg) ventilation. Microcirculatory oxygenation (μHBO2) and perfusion (μflow) of the colon were continuously recorded using tissue reflectance spectrophotometry and laser Doppler, respectively.
RESULTS
In normocapnic septic animals μHBO2 decreased over time (-8.4 ± 8.7%; P < 0.05 vs. baseline), whereas after pravastatin pretreatment μHBO2 remained constant (-1.9 ± 5.7% vs. baseline). However, in hypercapnic septic animals pretreated with pravastatin μHBO2 declined significantly over time (-8.9 ± 11.8%; P < 0.05 vs. baseline) and was significantly lower compared with normocapnic pravastatin-pretreated animals. μflow did not change over time in any group.
CONCLUSION
Pravastatin pretreatment ameliorates the intestinal microvascular oxygenation in sepsis and thus seems to prevent intestinal hypoxia. Furthermore, we demonstrated that additional hypercapnia abolishes this effect, indicating why septic ARDS patients might not benefit from pravastatin therapy.
Topics: Animals; Gastric Mucosa; Hemodynamics; Hypercapnia; Male; Microcirculation; Oxygen; Pravastatin; Rats; Rats, Wistar; Sepsis
PubMed: 30724816
DOI: 10.1097/SHK.0000000000001323 -
Atherosclerosis Jun 1993Epidemiologic evidence linking elevated cholesterol concentrations and coronary heart disease (CHD) through the eighth decade of life provides a rationale for lowering... (Meta-Analysis)
Meta-Analysis
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.
Topics: Adult; Age Factors; Aged; Cholesterol; Female; Humans; Hypercholesterolemia; Male; Middle Aged; Pravastatin; Triglycerides
PubMed: 8216507
DOI: 10.1016/0021-9150(93)90105-4 -
Contact Dermatitis Apr 1994
Topics: Drug Eruptions; Humans; Male; Middle Aged; Patch Tests; Pravastatin
PubMed: 8033551
DOI: 10.1111/j.1600-0536.1994.tb00651.x -
JCI Insight Apr 2018Preeclampsia (PE), associates with long-term increased risk for cardiovascular disease in women, suggesting that PE is not an isolated disease of pregnancy. It is not...
Preeclampsia (PE), associates with long-term increased risk for cardiovascular disease in women, suggesting that PE is not an isolated disease of pregnancy. It is not known if increased risk for long-term diseases is due to PE-specific factors or to prepregnancy renal and cardiovascular risk factors. We used a mouse model in which a WT female with normal prepregnancy health develops PE to investigate if preeclampsia causes long-term cardiovascular consequences after pregnancy for mothers and offspring. Mothers exhibited endothelial dysfunction and hypertension after PE and had glomerular injury that not only persisted but deteriorated, leading to fibrosis. Left ventricular (LV) remodeling characterized by increased collagen deposition and MMP-9 expression and enlarged cardiomyocytes were also detected after PE. Increased LV internal wall thickness and mass, increased end diastolic and end systolic volumes, and increased stroke volume were observed after PE in the mothers. Placenta-derived bioactive factors that modulate vascular function, markers of metabolic disease, vasoconstrictor isoprostane-8, and proinflammatory mediators were increased in sera during and after a preeclamptic pregnancy in the mother. Offspring of PE mice developed endothelial dysfunction, hypertension, and signs of metabolic disease. Microglia activation was increased in the neonatal brains after PE, suggesting neurogenic hypertension in offspring. Prevention of placental insufficiency with pravastatin prevented PE-associated cardiovascular complications in both mothers and offspring. In conclusion, factors that develop during PE have long-term, cardiovascular effects in the mother and offspring independent of prepregnancy risk factors.
Topics: Animals; Cardiovascular Diseases; Disease Models, Animal; Endothelin-1; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Male; Mice; Mice, Inbred C57BL; Placenta; Pravastatin; Pre-Eclampsia; Pregnancy; Risk Factors; Vascular Remodeling
PubMed: 29669946
DOI: 10.1172/jci.insight.120147 -
Journal of Pharmaceutical Sciences Feb 2022Pravastatin is currently under evaluation for prevention of preeclampsia. Factors contributing to placental disposition of pravastatin are important in assessment of...
Pravastatin is currently under evaluation for prevention of preeclampsia. Factors contributing to placental disposition of pravastatin are important in assessment of potential undesirable fetal effects. The purpose of this study was to identify the uptake transporters that contribute to the placental disposition of pravastatin. Our data revealed the expression of organic anion transporting polypeptide 1A2 (OATP1A2) and OATP2A1 in the apical, and OATP2B1 and OATP5A1 in the basolateral membranes of the placenta, while organic anion transporter 4 (OAT4) exhibited higher expression in basolateral membrane but was detected in both membranes. Preloading placental membrane vesicles with glutarate increased the uptake of pravastatin suggesting involvement of glutarate-dependent transporters such as OAT4. In the HEK293 cells overexpressing individual uptake transporters, OATP2A1, OATP1A2 and OAT4 were determined to accept pravastatin as a substrate at physiological pH, while the uptake of pravastatin by OATP2B1 (known to interact with pravastatin at acidic pH) and OATP5A1 was not detected at pH 7.4. These findings led us to propose that OATP1A2 and OATP2A1 are responsible for the placental uptake of pravastatin from the maternal circulation, while OAT4 mediates the passage of the drug across placental basolateral membrane in the fetal-to-maternal direction.
Topics: Biological Transport; Female; HEK293 Cells; Humans; Organic Anion Transporters; Placenta; Pravastatin; Pregnancy
PubMed: 34597623
DOI: 10.1016/j.xphs.2021.09.035 -
European Review For Medical and... Dec 2020The aim of this study was to explore the effects of pravastatin on oxidative stress and placental trophoblastic cell apoptosis in preeclampsia rats via the interleukin...
OBJECTIVE
The aim of this study was to explore the effects of pravastatin on oxidative stress and placental trophoblastic cell apoptosis in preeclampsia rats via the interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) signaling pathway.
MATERIALS AND METHODS
Experimental rats were randomly assigned into three groups, including control group (C group), model group (M group) and pravastatin group (P group). The rat model of preeclampsia was successfully established. Blood pressure, urinary protein and nitric oxide (NO) as well as oxidative stress indicators in rats were detected at 7, 14 and 21 d, respectively. The content of serum IL-6 was determined via enzyme-linked immunosorbent assay (ELISA). The messenger ribonucleic acid (mRNA) expression of IL-6 in the placenta of rats in each group was detected using quantitative polymerase chain reaction (qPCR). Western blotting (WB) was used to determine the protein expression level of STATs in the placental tissues of rats. In addition, cell counting kit (CCK)-8 assay was conducted to detect the proliferation of rat placental trophoblasts.
RESULTS
The content of serum NO was (14.32±2.32) μM in M group, (28.37±3.32) μM in C group and (22.54±3.12) μM in P group, respectively. It was significantly elevated in P group compared with M group (p<0.05). Blood pressure in M group was evidently higher than that in C group at 14 and 21 d (p<0.05). However, P group exhibited distinctly lower blood pressure than M group (p<0.05). No statistically significant differences were observed in the urinary protein of rats among all the three groups at 7 d (p>0.05). At 14 and 21 d, the content of urinary protein in M group was considerably higher than that in C group (p<0.05). However, P group had distinctly lower urinary protein content than M group (p<0.05). Compared with C group, the content of malondialdehyde (MDA) and advanced oxidation protein products (AOPP) rose significantly in M group, whereas the content of superoxide dismutase (SOD) declined remarkably (p<0.05). In comparison with M group, P group exhibited declined MDA and AOPP content and increased SOD content, with statistically significant differences between the two groups (p<0.05). The expression level of serum IL-6 in rats in M group was markedly higher than that in C group (p<0.05). Meanwhile, the expression level of serum IL-6 evidently declined in P group compared with M group (p<0.05). Compared with C group, the protein expressions of phosphorylated STAT1 (p-STAT1) and p-STAT3 were considerably up-regulated in M group (p<0.01). However, they decreased prominently in P group in comparison with M group (p<0.01). C group exhibited a remarkably worse proliferation ability of rat placental trophoblasts than C group (p<0.01). In comparison with M group, the proliferation ability of rat placental trophoblasts was evidently enhanced in P group (p<0.05). Flow cytometry results indicated that the apoptosis of trophoblastic cells increased significantly in M group compared with that in C group (p<0.01). However, it significantly declined in P group in comparison with M group (p<0.05).
CONCLUSIONS
Pravastatin can repress the IL-6/STAT3 signaling pathway to alleviate oxidative stress, improve preeclampsia and decrease the apoptosis of placental trophoblastic cells in preeclampsia rats.
Topics: Animals; Apoptosis; Female; Injections, Intraperitoneal; Interleukin-6; Male; Oxidative Stress; Pravastatin; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor; Signal Transduction; Trophoblasts
PubMed: 33378046
DOI: 10.26355/eurrev_202012_24199 -
Journal of Pharmacological Sciences Mar 2007We have reported that chronically administered pravastatin prevented coronary artery reperfusion-induced lethal ventricular fibrillation (VF) in anesthetized rats... (Comparative Study)
Comparative Study
We have reported that chronically administered pravastatin prevented coronary artery reperfusion-induced lethal ventricular fibrillation (VF) in anesthetized rats without lowering the serum cholesterol level. The present study was undertaken to evaluate whether pravastatin prevents ischemia-induced lethal VF, simultaneously examining myeloperoxidase (MPO) activity in ischemic myocardial tissues. Anesthetized rats were subjected to 30-min ischemia and 60-min reperfusion after chronic administration of pravastatin (0.02, 0.2, and 2 mg/kg), fluvastatin (2 and 4 mg/kg), or vehicle for 22 days, orally, once daily. ECG and blood pressure were continually recorded, and MPO was measured by a spectrophotometer. Pravastatin and fluvastatin significantly (P<0.05) decreased MPO activities, but only pravastatin decreased the incidence of ischemia-induced lethal VF. Both statins had no significant effects on body weight, blood pressure, heart rate, and QT interval as we reported earlier. Our results prove further that pravastatin has benefits to decrease cardiovascular mortality beyond its cholesterol-lowering effect. Pravastatin is more potent than fluvastatin in prevention of arrhythmias. A decrease in the neutrophil infiltration may be partly involved in the inhibitory effect of pravastatin on the ischemia-induced VF.
Topics: Administration, Oral; Anesthesia; Animals; Arrhythmias, Cardiac; Coronary Vessels; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatty Acids, Monounsaturated; Fluvastatin; Hydroxymethylglutaryl CoA Reductases; Indoles; Ischemia; Male; Peroxidase; Pravastatin; Rats; Rats, Sprague-Dawley
PubMed: 17341842
DOI: 10.1254/jphs.fp0061235 -
International Journal of Molecular... Nov 2022Radiation-induced gastrointestinal (GI) damage is one of the critical factors that serve as basis for the lethality of nuclear accidents or terrorism. Further, there are...
Radiation-induced gastrointestinal (GI) damage is one of the critical factors that serve as basis for the lethality of nuclear accidents or terrorism. Further, there are no Food and Drug Administration-approved agents available to mitigate radiation-induced intestinal injury. Although pravastatin (PS) has been shown to exhibit anti-inflammatory and epithelial reconstructive effects following radiation exposure using mouse and minipig models, the treatment failed to improve the survival rate of high-dose irradiated intestinal injury. Moreover, we previously found that metformin (MF), a common drug used for treating type 2 diabetes mellitus, has a mitigating effect on radiation-induced enteropathy by promoting stem cell properties. In this study, we investigated whether the combined administration of PS and MF could achieve therapeutic effects on acute radiation-induced intestinal injury in mouse and minipig models. We found that the combined treatment markedly increased the survival rate and attenuated histological damage in a radiation-induced intestinal injury mouse model, in addition to epithelial barrier recovery, anti-inflammatory effects, and improved epithelial proliferation with stem cell properties. Furthermore, in minipig models, combined treatment with PS and MF ameliorates gross pathological damage in abdominal organs and attenuated radiation-induced intestinal histological damage. Therefore, the combination of PS and MF effectively alleviated radiation-induced intestinal injury in the mouse and minipig models. We believe that the combined use of PS and MF is a promising therapeutic approach for treating radiation-induced intestinal injury.
Topics: Mice; Animals; Swine; Swine, Miniature; Pravastatin; Metformin; Diabetes Mellitus, Type 2; Intestines; Radiation Injuries; Intestinal Diseases
PubMed: 36499155
DOI: 10.3390/ijms232314827