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European Journal of Pharmaceutical... Jun 2021We investigated the effects of mineral oil on statin pharmacokinetics and inflammatory markers in animal models. A new synthesis strategy produced regioisomers that...
We investigated the effects of mineral oil on statin pharmacokinetics and inflammatory markers in animal models. A new synthesis strategy produced regioisomers that facilitated the characterization of the main metabolite (M1) of atorvastatin, a lipophilic statin, in C57BL/6NCrl mice. The chemical structure of M1 in mice was confirmed as ortho-hydroxy β-oxidized atorvastatin. Atorvastatin and M1 pharmacokinetics and inflammatory markers were assessed in C57BL6/J mice given atorvastatin 5 mg/kg/day or 10 mg/kg/day, as a single dose or for 21 days, with or without 10 µL or 30 µL mineral oil. No consistent differences in plasma exposure of atorvastatin or M1 were observed in mice after single or repeat dosing of atorvastatin with or without mineral oil. However, mice administered atorvastatin 10 mg/kg with 30 µL mineral oil for 21 days had significantly increased plasma levels of serum amyloid A (mean 9.6 µg/mL vs 7.9 µg/mL without mineral oil; p < 0.01) and significantly increased proportions of C62L B cells (mean 18% vs 12% without mineral oil; p = 0.04). There were no statistically significant differences for other inflammatory markers assessed. In dogs, pharmacokinetics of atorvastatin, its two hydroxy metabolites and pravastatin (a hydrophilic statin) were evaluated after single administration of atorvastatin 10 mg plus pravastatin 40 mg with or without 2 g mineral oil. Pharmacokinetics of atorvastatin, hydroxylated atorvastatin metabolites or pravastatin were not significantly different after single dosing with or without mineral oil in dogs. Collectively, the results in mice and dogs indicate that mineral oil does not affect atorvastatin or pravastatin pharmacokinetics, but could cause low-grade inflammation with chronic oral administration, which warrants further investigation.
Topics: Animals; Atorvastatin; Dogs; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice; Mice, Inbred C57BL; Mineral Oil; Pravastatin; Pyrroles
PubMed: 33667667
DOI: 10.1016/j.ejps.2021.105776 -
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 -
BMC Pregnancy and Childbirth Nov 2019Pravastatin, a known inducer of endothelial nitric-oxide synthase (eNOS) was demonstrated in human placenta, however the exact mechanism of it's action is not fully...
BACKGROUND
Pravastatin, a known inducer of endothelial nitric-oxide synthase (eNOS) was demonstrated in human placenta, however the exact mechanism of it's action is not fully understood. Since placental NO (nitric oxide) synthesis is of primary importance in the regulation of placental blood flow, we aimed to clarify the effects of pravastatin on healthy (n = 6) and preeclamptic (n = 6) placentas (Caucasian participants).
METHODS
The eNOS activity of human placental microsomes was determined by the conversion rate of C14 L-arginine into C14 L-citrulline with or without pravastatin and Geldanamycin. Phosphorylation of eNOS (Ser1177) was investigated by Western blot. Microsomal arginine uptake was measured by a rapid filtration method.
RESULTS
Pravastatin significantly increased total eNOS activity in healthy (28%, p<0.05) and preeclamptic placentas (32%, p<0.05) using 1 mM Ca promoting the dissociation of a eNOS from it's inhibitor caveolin. Pravastatin and Geldanamycin (Hsp90 inhibitor) cotreatment increased microsomal eNOS activity. Pravastatin treatment had no significant effects on Ser1177 phosphorylation of eNOS in either healthy or preeclamptic placentas. Pravastatin induced arginine uptake of placental microsomes in both healthy (38%, p < 0.05) and preeclamptic pregnancies (34%, p < 0.05).
CONCLUSIONS
This study provides a novel mechanism of pravastatin action on placental NO metabolism. Pravastatin induces the placental microsomal arginine uptake leading to the rapid activation of eNOS independently of Ser1177 phosphorylation. These new findings may contribute to better understanding of preeclampsia and may also have a clinical relevance.
Topics: Adult; Arginine; Benzoquinones; Case-Control Studies; Citrulline; Enzyme Inhibitors; Female; Humans; Lactams, Macrocyclic; Microsomes; Nitric Oxide Synthase Type III; Placenta; Pravastatin; Pre-Eclampsia; Pregnancy
PubMed: 31747921
DOI: 10.1186/s12884-019-2507-0 -
Journal of Clinical Oncology : Official... May 2017
Topics: Double-Blind Method; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lung Neoplasms; Pravastatin; Small Cell Lung Carcinoma
PubMed: 28475851
DOI: 10.1200/JCO.2016.72.0870 -
Tidsskrift For Den Norske Laegeforening... Jan 2004Previous studies of treatment with statins have included few subjects aged 70 years or above. While the absolute risk of cardiovascular disease in the elderly is very... (Comparative Study)
Comparative Study Review
BACKGROUND
Previous studies of treatment with statins have included few subjects aged 70 years or above. While the absolute risk of cardiovascular disease in the elderly is very high, the benefits of treatment may be reduced by adverse events, polypharmacy and competing risks.
MATERIAL AND METHODS
A statistician and a clinician reviewed the Pravastatin in elderly individuals at risk of vascular disease (PROSPER) study and compared the results with subgroup analyses of previous studies.
RESULTS
Subgroup analyses of previous studies showed that treatment with statins reduces cardiovascular events among patients with coronary heart disease aged > or = 65 years. The Heart Protection Study (HPS) included elderly with known atherosclerotic disease, while only 44% of subjects in the PROSPER study had such disease. Among subjects aged 70 or above the difference in events between the groups that received a statin or placebo was 6.1% in the HPS study and 2.1% in the PROSPER study (numbers needed to treat were 6 and 48, respectively). The studies gave conflicting results with regard to stroke and cancer.
INTERPRETATION
Elderly people with cardiovascular disease may benefit from treatment with statins. We do not have data that show that statins reduce total mortality among the elderly.
Topics: Aged; Aged, 80 and over; Anticholesteremic Agents; Cardiovascular Diseases; Cohort Studies; Humans; Pravastatin; Prospective Studies; Risk Factors
PubMed: 14743228
DOI: No ID Found -
Journal of Reconstructive Microsurgery Oct 2022Radiation-associated soft tissue injury is a potentially devastating complication for head and neck cancer patients. The damage can range from minor sequelae such as... (Review)
Review
BACKGROUND
Radiation-associated soft tissue injury is a potentially devastating complication for head and neck cancer patients. The damage can range from minor sequelae such as xerostomia, which requires frequent daily maintenance, to destructive degenerative processes such as osteoradionecrosis, which can contribute to flap failure and delay or reverse oral rehabilitation. Despite the need for effective radioprotectants, the literature remains sparse, primarily focused on interventions beyond the surgeon's control, such as maintenance of good oral hygiene or modulation of radiation dose.
METHODS
This narrative review aggregates and explores noninvasive, systemic treatment modalities for prevention or amelioration of radiation-associated soft tissue injury.
RESULTS
We highlighted nine modalities with the most clinical potential, which include amifostine, melatonin, palifermin, hyperbaric oxygen therapy, photobiomodulation, pentoxifylline-tocopherol-clodronate, pravastatin, transforming growth factor-β modulators, and deferoxamine, and reviewed the benefits and limitations of each modality. Unfortunately, none of these modalities are supported by strong evidence for prophylaxis against radiation-associated soft tissue injury.
CONCLUSION
While we cannot endorse any of these nine modalities for immediate clinical use, they may prove fruitful areas for further investigation.
Topics: Amifostine; Deferoxamine; Fibroblast Growth Factor 7; Humans; Melatonin; Pravastatin; Soft Tissue Injuries; Transforming Growth Factors
PubMed: 35213927
DOI: 10.1055/s-0042-1742731 -
The American Journal of Medicine Dec 2019Impairment in domain-specific cognitive function is associated with the increased risk of mortality. We prospectively evaluated the association of executive function and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Impairment in domain-specific cognitive function is associated with the increased risk of mortality. We prospectively evaluated the association of executive function and memory with the risk of long-term mortality in dementia-free older subjects. Moreover, we investigated the role of structural brain abnormalities in this association.
METHODS
We included 547 dementia-free participants (mean age 78 years, 56.5% male) from the nested magnetic resonance imaging sub-study of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Cox proportional hazard models were used to model 10-year risk of all-cause, cardiovascular, and noncardiovascular mortality in relation to performance in executive function and memory. Moreover, we evaluated the role of total brain parenchymal volume, cerebral blood flow, white matter hyperintensity, and the presence of microbleeds and infarcts in the link between cognitive function and mortality.
RESULTS
In the multivariable model, lower performance in executive function was associated with greater risk of all-cause (hazard ratio [HR] 1.49; 95% confidence interval [CI], 1.31-1.70), cardiovascular (HR 1.69; 95% CI, 1.36-2.11), and noncardiovascular (HR 1.36; 95% CI, 1.15-1.62) mortality. Similarly, poorer performance in memory tests associated with higher risk of all-cause (HR 1.47; 95% CI, 1.29-1.68), cardiovascular (HR 1.45; 95% CI, 1.15-1.83), and noncardiovascular (HR 1.49; 95% CI, 1.27-1.76) mortality. The associations were similar in subjects with various levels of brain structural abnormalities and cerebral blood flow (all P for interaction ≫ .05).
CONCLUSIONS
Poorer performance in both executive function and memory tests associates with all-cause, cardiovascular, and noncardiovascular mortality in elderly individuals. This association is independent of cardiovascular risk factors and diseases, brain structural abnormalities, and cerebral blood flow.
Topics: Aged; Aged, 80 and over; Cardiovascular Diseases; Cause of Death; Cerebrovascular Circulation; Cognition; Dementia; Executive Function; Female; Geriatric Assessment; Humans; Internationality; Magnetic Resonance Imaging; Male; Memory; Multivariate Analysis; Neuropsychological Tests; Pravastatin; Proportional Hazards Models; Prospective Studies; Survival Analysis
PubMed: 31228412
DOI: 10.1016/j.amjmed.2019.06.001 -
Journal of Internal Medicine Nov 1998To evaluate the effect of diet and drug intervention separately and combined in the treatment of primary hypercholesterolemia. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
OBJECTIVE
To evaluate the effect of diet and drug intervention separately and combined in the treatment of primary hypercholesterolemia.
DESIGN
The study was conducted as a randomized, placebo-controlled factorial trial, double-blinded for drug intervention.
SETTING
Subjects were recruited from a population-based cholesterol screening programme.
SUBJECTS
215 middle-aged men with primary hypercholesterolemia, free from cardiovascular disease.
INTERVENTIONS
Subjects were randomized to one of four intervention groups: (1) placebo and US National Cholesterol Education Program step 1 diet; (2) placebo and step 2 diet; (3) pravastatin 20 mg day-1 and step 1 diet; or (4) pravastatin 20 mg day-1 and step 2 diet. The intervention period was 6 months.
MAIN OUTCOME MEASUREMENTS
Efficacy measurements included: serum total cholesterol, HDL cholesterol, triglycerides, apolipoproteins A1 and B. LDL cholesterol was calculated. For safety, values of ALAT, ASAT and CK were measured.
RESULTS
In the group receiving the step 1 diet only, lipid values were stable during the study period. In the placebo group on the step 2 diet, total cholesterol decreased by 6.3% (0.47 mmol L-1 (95% CI: 0.28, 0.67)) during 6 months. In the group receiving both pravastatin and the step 1 diet, there was a mean reduction in serum total cholesterol of 19.4% (1.46 mmol L-1 (95% CI: 1.20, 1.72)). In the group treated with pravastatin and the step 2 diet, the 6 months of data show a reduction of 20.7% (1.55 mmol L-1 (95% CI: 1.30, 1.80)).
CONCLUSIONS
If drug therapy with a HMG-CoA reductase inhibitor is considered necessary, a step 2 diet has no additional lipid-lowering effect compared with a step 1 diet in men with primary hypercholesterolaemia. However, favourable 'side-effects' of a lipid-lowering diet, such as weight loss and lowering of blood pressure, may still warrant a low-fat diet in these cases.
Topics: Anticholesteremic Agents; Blood Pressure; Body Weight; Combined Modality Therapy; Double-Blind Method; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipids; Male; Middle Aged; Patient Compliance; Pravastatin; Treatment Outcome
PubMed: 9845852
DOI: 10.1046/j.1365-2796.1998.00350.x -
Journal of Pharmacological Sciences Feb 2004We have elucidated the interactions of human and rat organic anion transporters (hOATs and rOATs) with pravastatin and cimetidine. Pravastatin inhibited hOAT1/rOAT1,... (Comparative Study)
Comparative Study
We have elucidated the interactions of human and rat organic anion transporters (hOATs and rOATs) with pravastatin and cimetidine. Pravastatin inhibited hOAT1/rOAT1, hOAT2/rOAT2, hOAT3/rOAT3, and hOAT4. The mode of inhibition was noncompetitive for hOAT1 and hOAT2, whereas it was competitive for hOAT3 and hOAT4. Cimetidine also inhibited hOAT1/rOAT1, hOAT3/rOAT3, and hOAT4. The mode of inhibition was a combination of competitive and noncompetitive manners for hOAT1, whereas it was competitive for hOAT3. The effects of OAT inhibitors on OAT1, OAT2, and OAT3 exhibited some but not so remarkable interspecies differences between humans and rats. In conclusion, we have characterized pravastatin and cimetidine as OAT inhibitors.
Topics: Animals; Cimetidine; Humans; Organic Anion Transporters; Pravastatin; Rats
PubMed: 14978359
DOI: 10.1254/jphs.94.197 -
Journal of Internal Medicine May 1998Lipid-lowering drugs as 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors and cholestyramine are effective in reducing cardiovascular morbidity both... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
OBJECTIVES
Lipid-lowering drugs as 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors and cholestyramine are effective in reducing cardiovascular morbidity both in primary and secondary prevention. Patient compliance is an important determinant of the outcome of therapy. This study was designed to compare compliance with tolerance and lipid-lowering effectiveness of pravastatin and/or cholestyramine in primary care.
DESIGN
Nine hundred and eighty nine women and 1047 men were randomized to treatment at 100 primary-care centres in Sweden. After dietary intervention, an eligible patient was randomly assigned to one of four programs of daily treatment: group Q, 16 g cholestyramine, group QP, 8 g cholestyramine and 20 mg pravastatin, group P20, 20 mg pravastatin or group P40, 40 mg pravastatin.
RESULTS
In group Q, group QP, group P20 and group P40 the reductions in low density lipoprotein (LDL)-cholesterol were 26%, 36%, 27% and 32%. The dose actually taken was 91-95% of the prescribed for the pravastatin treatment groups and 77-88% for the cholestyramine groups. In the pravastatin and cholestyramine groups 76-78% and 44-53%, respectively, completed the trial. Only 8-27% of the patients reached a serum cholesterol target level of 5.2 mmol L-1. There was no difference in lipid-lowering effect between women and men.
CONCLUSION
Pravastatin alone is efficacious and compliance is high, independent of dose. Combined treatment with cholestyramine and pravastatin had a better cholesterol lowering effect (although not statistically significant) than 40 mg pravastatin. Despite this, only 8-27% of the patients actually reached a serum cholesterol level of 5.2 mmol L-1. No unexpected serious adverse events were detected in any of the treatment groups. As predicted, the gastrointestinal disturbances were more common on cholestyramine treatment. These two factors suggest that an increase in the dosage of the HMG-CoA reductase inhibitor may be appropriate. Results from other studies indicate that there also might be other positive effects of statin treatment beyond cholesterol lowering.
Topics: Adult; Aged; Anticholesteremic Agents; Cholestyramine Resin; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipids; Male; Middle Aged; Patient Compliance; Pravastatin; Primary Health Care; Sex Factors; Sweden; Treatment Outcome
PubMed: 9651560
DOI: 10.1046/j.1365-2796.1998.00294.x