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Contemporary Clinical Trials Feb 2024Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development and continued growth of multiple cysts in the kidneys leading to ultimate loss... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development and continued growth of multiple cysts in the kidneys leading to ultimate loss of kidney function in most patients. Currently, tolvaptan is the only agency approved therapy to slow kidney disease advancement in patients with faster progressing disease underscoring the need for additional ADPKD therapies suitable for all patients. We previously showed that pravastatin slowed kidney disease progression in children and young adults with ADPKD. However, the intervention has not been tested in an adult cohort.
AIMS
The aim of the study is to conduct a single center, randomized, placebo-controlled double-blinded clinical trial to determine the efficacy of pravastatin on slowing kidney disease progression in adult patients with early stage ADPKD.
METHODS
One hundred and fifty adult patients with ADPKD and eGFR ≥60 ml/min/1.73m will be enrolled in the study and randomized to receive 40 mg/day pravastatin or placebo for a period of 2-years.
OUTCOMES
The primary outcome of the trial is change in total kidney volume assessed by magnetic resonance imaging (MRI). Secondary outcomes include change in kidney function by iothalamate GFR and renal blood flow and markers of inflammation and oxidative stress.
CONCLUSION
This study will assess the kidney therapeutic benefits of pravastatin in adult patients with ADPKD. The recruitment goal of 150 subjects was attained and the study is ongoing.
REGISTRATION
This study is registered on Clinicaltrials.gov # NCT03273413.
Topics: Young Adult; Child; Humans; Adult; Polycystic Kidney, Autosomal Dominant; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pravastatin; Double-Blind Method; Disease Progression; Glomerular Filtration Rate
PubMed: 38151173
DOI: 10.1016/j.cct.2023.107423 -
Journal of Ovarian Research Nov 2023High-grade serous carcinoma (HGSC) is the most common and aggressive subtype of epithelial ovarian cancer, characterized by gain-of-function TP53 mutations originating...
High-grade serous carcinoma (HGSC) is the most common and aggressive subtype of epithelial ovarian cancer, characterized by gain-of-function TP53 mutations originating in the fallopian tube epithelium. Therapeutic intervention occurs at advanced metastatic disease, due to challenges in early-stage diagnosis, with common disease recurrence and therapy resistance despite initial therapy success. The mevalonate pathway is exploited by many cancers and is potently inhibited by statin drugs. Statins have shown anti-cancer activity in many, but not all cancers. Here, we investigated the role of p53 status in relation to mevalonate pathway signaling in murine oviductal epithelial (OVE) cells and identified OVE cell sensitivity to statin inhibition. We found that p53 mutant and Trp53 knockout OVE cells have increased mevalonate pathway signaling compared to p53 wild-type OVE cells. Through orthotopic implantation to replicate the fallopian tube origin of HGSC, p53 mutant cells upregulated the mevalonate pathway to drive progression to advanced-stage ovarian cancer, and simvastatin treatment abrogated this effect. Additionally, simvastatin was more efficacious at inhibiting cell metabolic activity in OVE cells than atorvastatin, rosuvastatin and pravastatin. In vitro, simvastatin demonstrated potent effects on cell proliferation, apoptosis, invasion and migration in OVE cells regardless of p53 status. In vivo, simvastatin induced ovarian cancer disease regression through decreased primary ovarian tumor weight and increased apoptosis. Simvastatin also significantly increased cytoplasmic localization of HMG-CoA reductase in ovarian tumors. Downstream of the mevalonate pathway, simvastatin had no effect on YAP or small GTPase activity. This study suggests that simvastatin can induce anti-tumor effects and could be an important inhibitor of ovarian cancer progression.
Topics: Female; Mice; Animals; Humans; Fallopian Tubes; Simvastatin; Tumor Suppressor Protein p53; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mevalonic Acid; Epithelial Cells; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial
PubMed: 37986175
DOI: 10.1186/s13048-023-01307-x -
Current Medicinal Chemistry Aug 2023The literature suggests that statins may increase superoxide dismutase (SOD) levels by different mechanisms. These effects may contribute to the antioxidant and...
BACKGROUND AND OBJECTIVE
The literature suggests that statins may increase superoxide dismutase (SOD) levels by different mechanisms. These effects may contribute to the antioxidant and anti-inflammatory effects of statins, which are thought to be beneficial in preventing cardiovascular events. However, there are also conflicting results concerning the effect of statins on SOD levels. The goal of this systematic review was to evaluate the effect of statin therapy on SOD activity.
METHODS
This systematic review was performed based on the PRISMA statement. The terms ("statin" or "HMG-CoA reductase inhibitor" OR "lipid-lowering agents" OR "Atorvastatin" OR "Simvastatin" OR "Pravastatin" OR "Fluvastatin" OR "Lovastatin") AND ("superoxide dismutase" OR "SOD" OR "anti-oxidative" OR "oxidative stress") were searched in database systems Google Scholar, PubMed/MEDLINE, and Scopus from inception to April 2022.
RESULTS
A total of 14 controlled clinical trials - 10 randomized and 4 non-randomized - were found to be eligible. Four studies measured SOD levels in plasma, six in serum, two in red blood cells, one in venous blood, and one on both red blood cells and venous blood matrices. Seven clinical trials used atorvastatin, six used simvastatin, and four used rosuvastatin. Six studies reported an increase in SOD activity, seven found no significant changes, and one showed a reduced SOD activity.
CONCLUSION
Our systematic review suggests that treatment with statins has a positive effect on SOD activity. However, evidence from further randomized controlled trials is required to confirm the potential antioxidant effect of statin therapy.
PubMed: 37653630
DOI: 10.2174/0929867331666230831145809 -
Therapie 2024Immune-mediated necrotizing myopathy (IMNM) is a form of statin myopathy characterized by the presence of antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A...
INTRODUCTION
Immune-mediated necrotizing myopathy (IMNM) is a form of statin myopathy characterized by the presence of antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti HMGCR).
OBJECTIVES
The aim of this study was to investigate the relationship between the different statins and the risk of IMNM.
METHODS
A two-time approach was used. First, we performed a descriptive analysis of the French national pharmacovigilance database (FNPV) for the period from 1985 to december2020. To identify relevant cases, we used Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) related to IMNM. We performed a quantitative and qualitative review of individual case safety reports (ICSRs) recorded in the french vigilance spontaneous reporting system. In a second time, we performed a comparative analysis with the World Health Organization global individual case safety reports database (Vigibase). The association between IMNM and statins exposure was assessed by calculating the reporting odds ratio (ROR) and its 95% confidence interval.
RESULTS
After analysis, a total of 25 ICSRs were related to IMNM in the FNPV. The suspected statins were atorvastatin (n=21), simvastatin (n=2), pravastatin (n=1) and rosuvastatin (n=1). In Vigibase, 567 notifications were identified. A significant ROR value was found for atorvastatin, pitavastatin, simvastatin, pravastatin and rosuvastatin.
CONCLUSION
Atorvastatin presents the highest risk of IMNM. Our data suggest that the occurrence of IMNM is a class effect.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Muscular Diseases; Pharmacovigilance; Male; Female; Middle Aged; Aged; France; Hydroxymethylglutaryl CoA Reductases; Adult; Adverse Drug Reaction Reporting Systems; Necrosis; Databases, Factual; Atorvastatin; Aged, 80 and over
PubMed: 37625939
DOI: 10.1016/j.therap.2023.07.005 -
European Journal of Preventive... Jun 2024Clinical guidelines often recommend treating individuals based on their cardiovascular risk. We revisit this paradigm and quantify the efficacy of three treatment... (Randomized Controlled Trial)
Randomized Controlled Trial
The potential benefit of statin prescription based on prediction of treatment responsiveness in older individuals: an application to the PROSPER randomized controlled trial.
AIMS
Clinical guidelines often recommend treating individuals based on their cardiovascular risk. We revisit this paradigm and quantify the efficacy of three treatment strategies: (i) overall prescription, i.e. treatment to all individuals sharing the eligibility criteria of a trial; (ii) risk-stratified prescription, i.e. treatment only to those at an elevated outcome risk; and (iii) prescription based on predicted treatment responsiveness.
METHODS AND RESULTS
We reanalysed the PROSPER randomized controlled trial, which included individuals aged 70-82 years with a history of, or risk factors for, vascular diseases. We conducted the derivation and internal-external validation of a model predicting treatment responsiveness. We compared with placebo (n = 2913): (i) pravastatin (n = 2891); (ii) pravastatin in the presence of previous vascular diseases and placebo in the absence thereof (n = 2925); and (iii) pravastatin in the presence of a favourable prediction of treatment response and placebo in the absence thereof (n = 2890). We found an absolute difference in primary outcome events composed of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke, per 10 000 person-years equal to: -78 events (95% CI, -144 to -12) when prescribing pravastatin to all participants; -66 events (95% CI, -114 to -18) when treating only individuals with an elevated vascular risk; and -103 events (95% CI, -162 to -44) when restricting pravastatin to individuals with a favourable prediction of treatment response.
CONCLUSION
Pravastatin prescription based on predicted responsiveness may have an encouraging potential for cardiovascular prevention. Further external validation of our results and clinical experiments are needed.
TRIAL REGISTRATION
ISRCTN40976937.
Topics: Humans; Aged; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Female; Aged, 80 and over; Cardiovascular Diseases; Risk Assessment; Pravastatin; Treatment Outcome; Age Factors; Drug Prescriptions; Heart Disease Risk Factors; Time Factors; Decision Support Techniques
PubMed: 38085032
DOI: 10.1093/eurjpc/zwad383 -
Biomolecules Nov 2023Despite the development of modern drugs, drug resistance in oncology remains the main factor limiting the curability of patients. This paper shows the use of a group of...
Despite the development of modern drugs, drug resistance in oncology remains the main factor limiting the curability of patients. This paper shows the use of a group of hydrophobic statins to inhibit drug resistance (Pgp protein). In a chemoresistance melanoma cell model, viability, necroptosis with DNA damage, the absorption of the applied pharmaceuticals, and the functional activity of the ABCB1 drug transporter after administration of docetaxel or docetaxel with a selected hydrophobic statin were studied. Taxol-resistant human melanoma cells from three stages of development were used as a model: both A375P and WM239A metastatic lines and radial growth phase WM35 cells. An animal model ( SCID) was developed for the A375P cell line. The results show that hydrophobic statins administered with docetaxel increase the accumulation of the drug in the tumor cell a.o. by blocking the ABCB1 channel. They reduce taxol-induced drug resistance. The tumor size reduction was observed after the drug combination was administrated. It was shown that the structural similarity of statins is of secondary importance, e.g., pravastatin and simvastatin. Using cytostatics in the presence of hydrophobic statins increases their effectiveness while reducing their overall toxicity.
Topics: Animals; Mice; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Docetaxel; Melanoma; Drug Resistance, Neoplasm; Paclitaxel; Cell Line, Tumor
PubMed: 38136555
DOI: 10.3390/biom13121682 -
Cardiovascular & Hematological Agents... Jul 2023Advances in organ transplantation were made after the discovery of the pure form of cyclosporine by Dr Jean Borel in the 1970s. In fact, in clinical practice achieving a...
BACKGROUND
Advances in organ transplantation were made after the discovery of the pure form of cyclosporine by Dr Jean Borel in the 1970s. In fact, in clinical practice achieving a delicate balance in circulating immunosuppressive necessitate focus on the difficult task of post-transplant therapeutic drug monitoring.
OBJECTIVE
The purpose of this study was to determine the pharmacologic properties of cyclosporine-tacrolimus, detection methods, and the effects on the activity of cytochrome P450 enzymes when prescribing the most efficient treatments in forms of polypharmacy for the recipients of heart transplantation.
METHODS
Scientific literature on the interactions of tacrolimus and cyclosporine with human cytochrome P450 enzymes was searched using PUBMED.Gov (https://pubmed.ncbi.nlm.nih.gov/), Web of Science, and Scopus.
RESULTS
Prescription immunosuppressive drugs based on polypharmacy accompanied by induction agents could result in hidden neurotoxicity and nephrotoxicity. A literature search shows that cyclosporine prescription with antihypertensives drugs needs close monitoring. Co-administration of tacrolimus and diltiazem or verapamil needs a decrease in the tacrolimus dose by 20-50%. Vigilant attention to the lowest possible statin dose is needed when coadministered with fluvastatin or pravastatin. Polypharmacy based on ticlopidine, clopidogrel, and cyclosporine or tacrolimus needs monitoring of immunosuppressive drug levels for several months. A prescription with clotrimazole or fluconazole needs close monitoring, and itraconazole or ketoconazole needs to reduce the initial dose by 50%. Combination with nefazodone needs to be avoided, and alternative drugs such as sertraline or citalopram could be prescribed in addition to further monitoring consideration. In prescription with phenytoin, the bound and free phenytoin levels need close monitoring.
CONCLUSION
Polypharmacy based on tacrolimus or cyclosporine needs vigilant therapeutic drug monitoring due to the cytochrome P450 enzymes associated with biochemical variables in metabolic pathways. Further attention to polypharmacy should be given to circulate drugs that could hide pharmacokinetics interactions associated with infections, malignancies, chronic kidney disease, and rejection after organ transplantation.
PubMed: 37496131
DOI: 10.2174/1871525721666230726150021 -
Oral Diseases Mar 2024This study evaluated antimicrobial activity of atorvastatin, pravastatin, rosuvastatin, and simvastatin against oral bacteria, and the interaction of simvastatin with...
OBJECTIVES
This study evaluated antimicrobial activity of atorvastatin, pravastatin, rosuvastatin, and simvastatin against oral bacteria, and the interaction of simvastatin with standard antimicrobials (amoxicillin and metronidazole).
METHODS
Minimal inhibitory concentration assays were performed with Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum, Actinomyces odontolyticus, Streptococcus oralis, Streptococcus mitis, Streptococcus salivarius, Streptococcus sanguinis, and Streptococcus gordonii; checkerboard microdilution assays between simvastatin and standard antimicrobials; monospecies and multispecies biofilms.
RESULTS
Simvastatin showed the best antimicrobial activity against most species (MIC range from 3.12 to 25 μg/ml), highlighting the sensitivity of P. gingivalis. In the checkerboard assay, synergistic interaction was found between simvastatin and amoxicillin against S. oralis and S. sanguinis. P. gingivalis biofilm was inhibited by simvastatin at 10 and 50× Minimal inhibitory concentration, with similar effects to metronidazole. For multispecies biofilm, SMV reduced the biofilm metabolic activity (79%) and total counts (87%), comparable to amoxicillin. Simvastatin also reduced bacterial counts of Veilonnella parvula, P. gingivalis, Streptococcus mutans, Actinomyces naeslundii, P. intermedia, and Capnocytophaga ochracea in the multispecies biofilm.
CONCLUSIONS
Simvastatin showed antimicrobial and antibiofilm activity against oral bacteria and may contribute to the control of dysbiosis, and may be considered in clinical studies as an adjuvant in the treatment of periodontitis.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin; Metronidazole; Dysbiosis; Biofilms; Porphyromonas gingivalis; Amoxicillin; Anti-Infective Agents; Fusobacterium nucleatum
PubMed: 36416468
DOI: 10.1111/odi.14446 -
Toxicology Mechanisms and Methods Feb 2024An increased risk of new-onset diabetes mellitus has been recently reported for statin therapy, and experimental studies have shown reduced glucose-stimulated insulin...
An increased risk of new-onset diabetes mellitus has been recently reported for statin therapy, and experimental studies have shown reduced glucose-stimulated insulin secretion (GSIS) and mitochondrial dysfunction in beta cells with effects differing among agents. Organic anion transporting polypeptide (OATP) 2B1 contributes to hepatic uptake of rosuvastatin, atorvastatin and pravastatin, three known substrates. Since OATP2B1 is present in beta cells of the human pancreas, we investigated if OATP2B1 facilitates the local accumulation of statins in a rat beta cell model INS-1 832/13 (INS-1) thereby amplifying statin-induced toxicity. OATP2B1 overexpression in INS-1 cells adenoviral transduction showed 2.5-, 1.8- and 1.4-fold higher cellular retention of rosuvastatin, atorvastatin and pravastatin, respectively, relative to LacZ control, while absolute intracellular concentration was about twice as high for the lipophilic atorvastatin compared to the more hydrophilic rosuvastatin and pravastatin. After 24 h statin treatment at high concentrations, OATP2B1 enhanced statin toxicity involving activation of intrinsic apoptosis (caspase 3/7 activation) and mitochondrial dysfunction (NADH dehydrogenase activity) following rosuvastatin and atorvastatin, which was partly reversed by isoprenoids. OATP2B1 had no effect on statin-induced reduction in GSIS, mitochondrial electron transport chain complex expression or caspase 9 activation. We confirmed a dose-dependent reduction in insulin secretion by rosuvastatin and atorvastatin in native INS-1 with a modest change in cellular ATP. Collectively, our results indicate a role of OATP2B1, which is abundant in human beta cells, in statin accumulation and statin-induced toxicity but not insulin secretion of rosuvastatin and atorvastatin in INS-1 cells.
Topics: Humans; Rats; Animals; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Rosuvastatin Calcium; Pravastatin; Mitochondrial Diseases
PubMed: 37771097
DOI: 10.1080/15376516.2023.2262568 -
Mikrochimica Acta Oct 2023A sol-gel Carbowax 20 M/3-[(3-Cholamidopropyl) dimethyl ammonio]-1-propanesulfonate composite sorbent-based capsule phase microextraction device has been fabricated and...
Fabricating a designer capsule phase microextraction platform based on sol-gel Carbowax 20M-zwitterionic ionic liquid composite sorbent for the extraction of lipid-lowering drugs from human urine samples.
A sol-gel Carbowax 20 M/3-[(3-Cholamidopropyl) dimethyl ammonio]-1-propanesulfonate composite sorbent-based capsule phase microextraction device has been fabricated and characterized for the determination of four statins (pravastatin, rosuvastatin, pitavastatin, and atorvastatin) in human urine. The presence of ionizable carboxyl functional groups in statins requires pH adjustment of the sample matrix to ensure that the target molecules are in their protonated form (pH should be 2 units below their pK values) which not only is cumbersome but also risks unintended contamination of the sample. This challenge was addressed by introducing zwitterionic ionic liquid in addition to neutral, polar Carbowax 20 M polymer in the sol-gel-derived composite sorbent. As such, the composite zwitterionic multi-modal sorbent can simultaneously extract neutral, cationic, and anionic species. This particular attribute of the composite sorbent eliminates the necessity of the matrix pH adjustment and consequently simplifies the overall sample preparation workflow. Various experimental parameters such as the sample amount, extraction time, salt addition, stirring rate, and elution solvent type that may affect the extraction performance of the statins were investigated using a central composite design and the one-parameter-at-a-time approach. The analytes and the internal standard were separated on a Ccolumn with gradient elution using phosphate buffer (20 mM, pH 3) and acetonitrile as mobile phase. The analytes were detected at 237 nm. The method was validated, and linearity was observed in the range 0.10-2.0 μg mL for all compounds. The method precision was better 9.9% and 10.4% for intra-day and inter-day, respectively, while the relative recoveries were acceptable, ranging between 83.4 and 116% in all cases. Method greenness was assessed using the ComplexGAPI index. Finally, the method's applicability was demonstrated in the determination of the statins in authentic human urine after oral administration of pitavastatin and rosuvastatin-containing tablets.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Polyethylene Glycols; Ionic Liquids; Rosuvastatin Calcium; Lipids
PubMed: 37796344
DOI: 10.1007/s00604-023-05998-3