-
Journal of Controlled Release :... Aug 2022Oral administration of cholesterol-lowering statins, HMG-CoA reductase inhibitors, is associated with beneficial effects on eye conditions. This work aims to design...
Oral administration of cholesterol-lowering statins, HMG-CoA reductase inhibitors, is associated with beneficial effects on eye conditions. This work aims to design contact lenses (CLs) that can sustainedly deliver pravastatin and thus improve the ocular efficacy while avoiding systemic side effects of statins. Bioinspired hydrogels were prepared with monomers that resemble hydrophobic (ethylene glycol phenyl ether methacrylate) and amino (2-aminoethyl methacrylamide hydrochloride) functionalities of the active site of HMG-CoA. Best performing CLs loaded >6 mg/g, in vitro fulfilled the release demands for daily wearing, and showed anti-inflammatory activity (lowering TNF-α). High hydrostatic pressure sterilization preserved the stability of both the drug and the hydrogel network. Ex vivo tests revealed the ability of pravastatin to accumulate in cornea and sclera and to penetrate through transscleral route. In vivo tests (rabbits) confirmed that, compared to eye drops and for the same dose, CLs provided significantly higher pravastatin levels in tear fluid within 1 to 7 h of wearing. Moreover, after 8 h wearing pravastatin was present in cornea, sclera, aqueous humour and vitreous humour. Strong correlations between percentages of drug released in vitro and in vivo were found. Effects of volume and proteins on release rate and Levy plots were identified.
Topics: Animals; Contact Lenses; Cornea; Drug Delivery Systems; Hydrogels; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ophthalmic Solutions; Pravastatin; Rabbits
PubMed: 35688348
DOI: 10.1016/j.jconrel.2022.06.001 -
Current Opinion in Pediatrics Apr 2015Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, affecting one in 500 individuals. The cardinal manifestation of ADPKD... (Review)
Review
PURPOSE OF REVIEW
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, affecting one in 500 individuals. The cardinal manifestation of ADPKD is progressive cystic dilatation of renal tubules with kidney enlargement and progression to end-stage renal disease in approximately half of cases by 60 years of age. Although previously considered a condition of adults, it is clear that children and young adults are subject to the complications of ADPKD.
RECENT FINDINGS
It has been increasingly recognized that interventions early in life are necessary in order to confer the best long-term outcome in this common condition. Therefore, it is imperative for pediatricians to recognize the manifestations and complications of this disease. Until recently ADPKD management focused on general principles of chronic kidney disease. However, several recent clinical trials in children and adults with ADPKD have focused on disease-specific therapies.
SUMMARY
This review will highlight the clinical manifestations, diagnosis, and appropriate management of ADPKD in childhood and will review recent relevant clinical trials in children and adults with this condition.
Topics: Blood Pressure; Child; Child, Preschool; Diet, Sodium-Restricted; Disease Progression; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Polycystic Kidney, Autosomal Dominant; Pravastatin; Prognosis; Renal Dialysis; Ultrasonography
PubMed: 25635587
DOI: 10.1097/MOP.0000000000000195 -
Wound Repair and Regeneration :... Jul 2020Hypertrophic scar is an important clinical problem with limited therapeutic options. Aside from their roles as 3-hydroxy-3-methylglutaryl-coenzyme A reductase...
Hypertrophic scar is an important clinical problem with limited therapeutic options. Aside from their roles as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, statins have also been demonstrated to decrease scarring by reducing connective tissue growth factor (CTGF) expression. However, poor penetrative ability limits their utility as topical treatments for hypertrophic scar. Here, we aim to develop novel statin formulations using liposomes to enhance dermal penetrative ability and to evaluate their efficacy against formation of hypertrophic scar utilizing our validated rabbit ear hypertrophic scar model. Liposomal simvastatin or pravastatin were compounded using a novel, flexible liposomal formulation and applied topically to rabbit ear hypertrophic scars daily from postoperation day (POD) 14 until POD 25. Scar color, including erythema and melanin, was measured using reflectance spectrophotometry on POD 28, and scar tissue was harvested for evaluation of scar elevation index as well as gene and protein expression. Human foreskin fibroblasts were also treated with statin formulations and CCN2 expression was determined by quantitative PCR. Both simvastatin and pravastatin were efficiently encapsulated in liposomes, forming nanometer-scale particles possessing highly negative charges. Topical treatment with liposomal simvastatin and pravastatin at 6.5% concentration significantly reduced scar elevation index and decreased type I/III collagen content and myofibroblast persistence in the wound. The erythema/vascularity of scars was reduced by liposomal statin treatment, with concomitant decrease of CD31 expression as measured histologically. Expression levels of transcripts encoding CTGF, collagen I, and collagen III collagen in scar tissue were also decreased by liposomal pravastatin treatment, as were myofibroblast persistence and the type I/III collagen ratio as assessed by immunofluorescence and picrosirus red staining, respectively. Treatment of human foreskin fibroblasts with simvastatin or with liposome-encapsulated pravastatin resulted in decreased expression of transcript encoding CTGF. Overall, our novel statin formulations encapsulated in liposomes were successfully delivered through topical application, significantly reducing hypertrophic scarring in a rabbit ear model.
Topics: Animals; Cicatrix, Hypertrophic; Collagen Type I; Collagen Type III; Connective Tissue Growth Factor; Ear, External; Erythema; Fibroblasts; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro Techniques; Liposomes; Melanins; Platelet Endothelial Cell Adhesion Molecule-1; Pravastatin; Rabbits; Simvastatin; Skin; Spectrophotometry
PubMed: 32428986
DOI: 10.1111/wrr.12811 -
AIDS (London, England) Mar 2017Persistent immune activation is thought to contribute to increased cardiovascular disease risk in HIV and statins may help modulate systemic immune activation. We aimed... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Persistent immune activation is thought to contribute to increased cardiovascular disease risk in HIV and statins may help modulate systemic immune activation. We aimed to compare the effects of two key statins on markers of systemic immune activation and arterial inflammation in the HIV population.
DESIGN
Double-blind, active-controlled, parallel-group comparative trial performed in 45 sites.
METHODS
Two hundred and fifty-two antiretroviral therapy-treated HIV-infected participants with dyslipidemia were randomized (1 : 1) to pitavastatin 4 mg daily vs. pravastatin 40 mg daily in the HIV-infected patieNts and TREatment with PItavastatin vs. pravastatin for Dyslipidemia (INTREPID) trial. In this analysis of the INTREPID trial, we assessed markers of immune activation and arterial inflammation using a modified intent-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01301066).
RESULTS
One hundred and twenty-six participants were randomized to receive pitavastatin and 126 to pravastatin. Ninety-nine participants in the pitavastatin group and 91 participants in the pravastatin group completed the study. Median age was 50 (45, 56) years [median (interquartile range)]. Baseline, low-density lipoprotein-cholestrol (LDL-C) was 153 (135, 171) mg/dl, log HIV-1 viral load was 1.1 ± 0.2 copies/ml, and CD4 cell count was 580 (439, 794) cells/μl. At week 52, the pitavastatin group had a significantly greater reduction (% change) compared with pravastatin in soluble CD14 (sCD14), (-10.0 vs. 0.6%, P = 0.02), oxidized LDL (oxLDL) (-26.9 vs. -17.5%, P = 0.02), and lipoprotein-associated phospholipase 2 (Lp-PLA2) (-26.6 vs. -15.5%, P = 0.005) (pitavastatin vs. pravastatin).
CONCLUSION
Fifty-two weeks of pitavastatin 4 mg daily (vs. pravastatin 40 mg daily) led to a greater reduction in select markers of immune activation and arterial inflammation (sCD14, oxLDL, and LpPLA2) among HIV-infected participants. Further work is needed to assess whether immune-modulatory effects of pitavastatin reduce cardiovascular disease risk in HIV.
Topics: Anticholesteremic Agents; Arteritis; Biomarkers; Double-Blind Method; HIV Infections; Humans; Immunologic Factors; Pravastatin; Quinolines; Treatment Outcome
PubMed: 28252528
DOI: 10.1097/QAD.0000000000001427 -
Current Pharmaceutical Biotechnology 2019Statins are drugs used for people with abnormal lipid levels (hyperlipidemia) and are among the best-selling medications in the United States. Thus, the aspects related... (Review)
Review
Statins are drugs used for people with abnormal lipid levels (hyperlipidemia) and are among the best-selling medications in the United States. Thus, the aspects related to the production of these drugs are of extreme importance for the pharmaceutical industry. Herein, we provide a non-exhaustive review of fungal species used to produce statin and highlighted the major factors affecting the efficacy of this process. The current biotechnological approaches and the advances of a metabolic engineer to improve statins production are also emphasized. The biotechnological production of the main statins (lovastatin, pravastatin and simvastatin) uses different species of filamentous fungi, for example Aspergillus terreus. The statins production is influenced by different types of nutrients available in the medium such as the carbon and nitrogen sources, and several researches have focused their efforts to find the optimal cultivation conditions. Enzymes belonging to Lov class, play essential roles in statin production and have been targeted to genetic manipulations in order to improve the efficiency for Lovastatin and Simvastatin production. For instance, Escherichia coli strains expressing the LovD have been successfully used for lovastatin production. Other examples include the use of iRNA targeting LovF of A. terreus. Therefore, fungi are important allies in the fight against hyperlipidemias. Although many studies have been conducted, investigations on bioprocess optimization (using both native or genetic- modified strains) still necessary.
Topics: Animals; Biotechnology; Fermentation; Fungi; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Lovastatin; Metabolic Engineering; Pravastatin
PubMed: 31333127
DOI: 10.2174/1389201020666190718165746 -
Cells Aug 2019Statins and fibrates are widely used for the management of hypertriglyceridemia but they also have limitations, mostly due to pharmacokinetic interactions or side...
Statins and fibrates are widely used for the management of hypertriglyceridemia but they also have limitations, mostly due to pharmacokinetic interactions or side effects. It is conceivable that some adverse events like liver dysfunction or gastrointestinal discomfort are caused by mitochondrial dysfunction. Data about the effects of statins and fibrates on mitochondrial function in different organs are inconsistent and partially contradictory. The aim of this study was to investigate the effect of pravastatin (statin) and gemfibrozil (fibrate) on hepatic and colonic mitochondrial respiration in tissue homogenates. Mitochondrial oxygen consumption was determined in colon and liver homogenates from 48 healthy rats after incubation with pravastatin or gemfibrozil (100, 300, 1000 μM). State 2 (substrate dependent respiration) and state 3 (adenosine diphosphate: ADP-dependent respiration) were assessed. RCI (respiratory control index)-an indicator for coupling between electron transport chain system (ETS) and oxidative phosphorylation (OXPHOS) and ADP/O ratio-a parameter for the efficacy of OXPHOS, was calculated. Data were presented as a percentage of control (Kruskal-Wallis + Dunn's correction). In the liver both drugs reduced state 3 and RCI, gemfibrozil-reduced ADP/O (complex I). In the colon both drugs reduced state 3 but enhanced ADP/O. Pravastatin at high concentration (1000 µM) decreased RCI (complex II). Pravastatin and gemfibrozil decrease hepatic but increase colonic mitochondrial respiration in tissue homogenates from healthy rats.
Topics: Animals; Cell Respiration; Colon; Dose-Response Relationship, Drug; Gemfibrozil; Liver; Male; Mitochondria; Oxygen; Pravastatin; Rats; Rats, Wistar
PubMed: 31461874
DOI: 10.3390/cells8090983 -
Frontiers in Immunology 2021Intestinal ischemia/reperfusion (I/R) injury is a grave condition with high morbidity and mortality. We previously confirmed that intestinal I/R induces intestinal flora...
Gut Microbial Metabolite Pravastatin Attenuates Intestinal Ischemia/Reperfusion Injury Through Promoting IL-13 Release From Type II Innate Lymphoid Cells IL-33/ST2 Signaling.
Intestinal ischemia/reperfusion (I/R) injury is a grave condition with high morbidity and mortality. We previously confirmed that intestinal I/R induces intestinal flora disorders and changes in metabolites, but the role of different metabolites in intestinal I/R injury is currently unclear. Based on targeted metabolic sequencing, pravastatin (PA) was determined to be a metabolite of the gut microbiota. Further, intestinal I/R model mice were established through superior mesenteric artery obstruction. In addition, a co-culture model of small intestinal organoids and type II innate lymphoid cells (ILC2s) was subjected to hypoxia/reoxygenation (H/R) to simulate an intestinal I/R model. Moreover, correlation analysis between the PA level in preoperative feces of patients undergoing cardiopulmonary bypass and the indices of postoperative intestinal I/R injury was carried out. IL-33-deficient mice, ILC2-deleted mice, and anti-IL-13 neutralizing antibodies were also used to explore the potential mechanism through which PA attenuates intestinal I/R injury. We demonstrated that PA levels in the preoperative stool of patients undergoing cardiopulmonary bypass were negatively correlated with the indices of postoperative intestinal I/R injury. Furthermore, PA alleviated intestinal I/R injury and improved the survival of mice. We further showed that PA promotes IL-13 release from ILC2s by activating IL-33/ST2 signaling to attenuate intestinal I/R injury. In addition, IL-13 promoted the self-renewal of intestinal stem cells by activating Notch1 and Wnt signals. Overall, results indicated that the gut microbial metabolite PA can attenuate intestinal I/R injury by promoting the release of IL-13 from ILC2s IL-33/ST2 signaling, revealing a novel mechanism of and therapeutic strategy for intestinal I/R injury.
Topics: Animals; Disease Models, Animal; Gastrointestinal Microbiome; Humans; Immunity, Innate; Interleukin-1 Receptor-Like 1 Protein; Interleukin-13; Interleukin-33; Intestinal Diseases; Lymphocytes; Male; Mice; Mice, Knockout; Pravastatin; Reperfusion Injury
PubMed: 34650552
DOI: 10.3389/fimmu.2021.704836 -
Expert Opinion on Investigational Drugs Aug 2016
Topics: Animals; Drug Design; Female; Humans; Pre-Eclampsia; Pregnancy
PubMed: 27253272
DOI: 10.1080/13543784.2016.1196185 -
Current Vascular Pharmacology 2023Hypertriglyceridemia, is commonly found in patients with diabetes. Xuezhikang, an extract of red yeast rice, is effective in reducing cardiovascular events in Chinese...
BACKGROUND
Hypertriglyceridemia, is commonly found in patients with diabetes. Xuezhikang, an extract of red yeast rice, is effective in reducing cardiovascular events in Chinese patients with diabetes and coronary heart disease (CHD). Xuezhikang has been reported to significantly decrease the level of triglycerides (TG), a potential causal risk factor for myocardial infarction. On the basis of a similar reduction in low-density lipoprotein cholesterol, this study will evaluate the effect of xuezhikang on TG levels compared with pravastatin in patients with type 2 diabetes mellitus (T2DM) and dyslipidemia.
METHODS
This is an open-label, multicenter, randomized controlled study to assess the effects of xuezhikang (1.2 g/day) and pravastatin (20 mg/day) on TG and other blood lipid parameters in patients with T2DM and dyslipidemia. A total of 114 patients will be enrolled and randomly assigned 1:1 to receive xuezhikang or pravastatin treatment for 6 weeks.
RESULT
The primary outcome measure is the change from baseline in fasting TG levels after 6 weeks. The change from baseline in other fasting and postprandial lipid parameters, and glucose profiles at 1, 2, and 4 h after a nutritious breakfast will also be explored.
CONCLUSION
This study will evaluate the effect of a 6-week treatment with xuezhikang compared with pravastatin on fasting and postprandial TG levels and other blood lipid parameters in patients with T2DM and dyslipidemia without atherosclerotic cardiovascular disease (ASCVD). The results will provide more information on optimizing the lipid control of patients with diabetes in the primary prevention of ASCVD.
Topics: Humans; Atherosclerosis; Diabetes Mellitus, Type 2; Dyslipidemias; Lipids; Multicenter Studies as Topic; Pravastatin; Randomized Controlled Trials as Topic; Triglycerides
PubMed: 36998136
DOI: 10.2174/1570161121666230328110215 -
Physiological Reports Jan 2021Atherosclerosis is the main cause of the cardiovascular disease (CVD). Elevated blood cholesterol and inflammation of the endothelium are two major mechanisms...
OBJECTIVE
Atherosclerosis is the main cause of the cardiovascular disease (CVD). Elevated blood cholesterol and inflammation of the endothelium are two major mechanisms contributing to the establishment of atherosclerotic plaques. Statins, such as pravastatin, are blood-cholesterol lowering drugs commonly prescribed for patients with or at risk for CVDs. In addition to lowering blood cholesterols, statins have recently been shown to improve endothelial function in both hyper- and normocholesterolemic patients with atherosclerosis. To understand the molecular mechanisms underlying the endothelial function improvement by statins, we assessed the RNA profile of pravastatin-treated endothelial cells, particularly their mRNAs and long non-coding RNAs (lncRNAs).
METHODS
Human umbilical vein endothelial cells (HUVECs) treated with pravastatin (10 µM) for 24 hr were profiled for lncRNAs and mRNAs using the Arraystar Human lncRNA Expression Microarray V3.0.
RESULTS
Of the 30,584 different lncRNAs screened, 95 were significantly upregulated, while 86 were downregulated in HUVECs responding to pravastatin. LINC00281 and BC045663 were the most upregulated (~8-fold) and downregulated (~3.5-fold) lncRNAs, respectively. Of the 26,106 different mRNAs screened in the pravastatin-treated HUVEC samples, 190 were significantly upregulated, while 90 were downregulated. Assigning the differentially expressed genes by bioinformatics into functional groups revealed their molecular signaling involvement in the following physiological processes: osteoclast differentiation, Rap1 signaling pathway, hematopoiesis, immunity, and neurotrophin signaling pathway.
CONCLUSIONS
This is the first lncRNA and mRNA expression profiling of pravastatin-mediated changes in human endothelial cells. Our results reveal potential novel targets and mechanisms for pravastatin-mediated vascular protection in atherosclerosis.
Topics: Endothelium; Gene Expression Profiling; Gene Expression Regulation; Human Umbilical Vein Endothelial Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pravastatin; RNA, Long Noncoding; RNA, Messenger; Shelterin Complex; Signal Transduction; Telomere-Binding Proteins
PubMed: 33369888
DOI: 10.14814/phy2.14661