The Chemical Genetic Interactions of Statin Drugs with Their Target Genes in Saccharomyces cerevisiae

<p>Statins, competitive inhibitors of the rate limiting cholesterol/ergosterol enzymes HMG-CoA reductase (HMG1 and HMG2), are the most widely prescribed human therapeutic drugs. They are effective in lowering cholesterol levels in atherosclerosis and related syndromes. However, statins exhibit a range of pleiotropic side effects whose mechanisms are poorly understood. This study investigates statin pleiotropy by analysis of genetic interaction networks in yeast, Saccharomyces cerevisiae, which shows high homology to mammalian pathways affected by statins. Synthetic genetic array (SGA) analysis allows elucidation of functional genetic networks of genes of interest ("query genes") by measurement of genetic epistasis in double mutants of the query gene with the genome - wide deletion mutant array of ~4800 non-essential strains. Chemicalgenetic profiling is similar where a SMP may effectively replace the query gene in genome wide epistatic analysis. The genetic interaction networks resulting from use of HMG1 and HMG2 as query genes for SGA analysis were compared to the chemical-genetic profiles of atorvastatin, cerivastatin and lovastatin. The genes ARV1, BTS1, OPI3 displaying phenotypic enhancements (i.e. their deletion caused major growth inhibition) with statins became essential in the presence of all the statins. Two mitochondrial genes, COX17 and MMM1, showed phenotypic suppressions (i.e. their deletion allowed better growth) in common to all three statin drugs. An attractive hypothesis is that major pleiotropic effects of statins could be due to variation in function or expression of these enhancing or suppressing genes. Other processes compensating statin use were also elucidated. For example, when HMG1 and its epistatically interacting genes are shut down by deletion coupled with inhibition of HMG2 with statin, there is strong evidence that the cell attempts to maintain membrane/lipid homeostasis via anterograde and retrograde transport mechanisms, including the mobilisation of lipid storage droplets. To aid refinement of genetic analysis in this and future studies, a more direct phenotypic assay was developed for quantifying ergosterol. Such an assay may be used as a phenotype to map the effect of up - and downstream - genes, or network genes affecting ergosterol levels. This assay was used to quantify ergosterol in a drug - resistant mutant developed by others aiding confirmation of the drug target.</p>

The Chemical Genetic Interactions of Statin Drugs with Their Target Genes in Saccharomyces cerevisiae

<p>Statins, competitive inhibitors of the rate limiting cholesterol/ergosterol enzymes HMG-CoA reductase (HMG1 and HMG2), are the most widely prescribed human therapeutic drugs. They are effective in lowering cholesterol levels in atherosclerosis and related syndromes. However, statins exhibit a range of pleiotropic side effects whose mechanisms are poorly understood. This study investigates statin pleiotropy by analysis of genetic interaction networks in yeast, Saccharomyces cerevisiae, which shows high homology to mammalian pathways affected by statins. Synthetic genetic array (SGA) analysis allows elucidation of functional genetic networks of genes of interest ("query genes") by measurement of genetic epistasis in double mutants of the query gene with the genome - wide deletion mutant array of ~4800 non-essential strains. Chemicalgenetic profiling is similar where a SMP may effectively replace the query gene in genome wide epistatic analysis. The genetic interaction networks resulting from use of HMG1 and HMG2 as query genes for SGA analysis were compared to the chemical-genetic profiles of atorvastatin, cerivastatin and lovastatin. The genes ARV1, BTS1, OPI3 displaying phenotypic enhancements (i.e. their deletion caused major growth inhibition) with statins became essential in the presence of all the statins. Two mitochondrial genes, COX17 and MMM1, showed phenotypic suppressions (i.e. their deletion allowed better growth) in common to all three statin drugs. An attractive hypothesis is that major pleiotropic effects of statins could be due to variation in function or expression of these enhancing or suppressing genes. Other processes compensating statin use were also elucidated. For example, when HMG1 and its epistatically interacting genes are shut down by deletion coupled with inhibition of HMG2 with statin, there is strong evidence that the cell attempts to maintain membrane/lipid homeostasis via anterograde and retrograde transport mechanisms, including the mobilisation of lipid storage droplets. To aid refinement of genetic analysis in this and future studies, a more direct phenotypic assay was developed for quantifying ergosterol. Such an assay may be used as a phenotype to map the effect of up - and downstream - genes, or network genes affecting ergosterol levels. This assay was used to quantify ergosterol in a drug - resistant mutant developed by others aiding confirmation of the drug target.</p>

Oral Lipid-Lowering Treatments Beyond Statins: Too Old and Outdated or Still Useful?

Purpose of Review For many years, the lipid-lowering armamentarium consisted of statins and/or ezetimibe and/or bile acid sequestrants and/or fibrates. Now, with the availability of new drugs mostly injectables, the field has changed and the role of oral non-statin drugs (including bempedoic acid) must be reevaluated. Recent Findings Ezetimibe remains a very important combination partner for statins with continuously increasing treatment numbers. Bempedoic acid is another interesting combination partner for statin/ezetimibe or ezetimibe alone but lacks in contrast to ezetimibe evidence from outcome trials. The role of fibrates is less clear as they have shown disappointing results in outcome trials but may still be used in selected, high-risk patients with combined dyslipidemia. Bile acid sequestrants are now rarely used as there are stronger, better tolerable ways to lower LDL-cholesterol. Summary With the introduction of new injectable lipid-lowering drugs, some oral drugs such as ezetimibe and bempedoic acid still have an important spot in our treatment algorithm others such as fibrates have a less clear role while again others are now rarely used.

Repurposing Statin Drugs to Decrease Toxicity and Improve Survival Outcomes in Head and Neck Cancer

Objective The rising incidence of head and neck squamous cell carcinoma (HNSCC) calls for the assessment and improvement of currently available therapies that may enhance the therapeutic ratio in these patients. Statin drugs are one of the most widely used drug classes in the world for their lipid-lowering properties. As such, statins have been widely studied and found to possess pleiotropic effects that may make them effective in cancer treatment and toxicity mitigation. The aim of this review is to examine the potential use of statin drugs as adjunctive therapy in patients with HNSCC. Data Sources PubMed. Review Methods Any preclinical or clinical articles pertaining to the effects of statin drugs on treatment-related toxicity or survival outcomes in patients with head and neck cancer were included in this narrative review. Conclusions Emerging data suggest that statins may improve survival and reduce toxicities associated with chemotherapy and radiotherapy in patients with head and neck cancer, by mechanisms that are poorly understood at present. Implications for Practice Given their affordability and safety, statins deserve further study as a tool to improve oncologic outcomes and enhance survivorship in patients with HNSCC.

A simple HPLC method containing greener modifier and slighter temperature elevated for simultaneous determination of three statin drugs in tablets

Statins drugs are thought to be among the most prescribed drugs worldwide for the treatment of hypercholesterolaemia. A simple and reliable RP-HPLC method has been successfully employed for simultaneously separating and qualifying three statin drugs including atorvastatin, rosuvastatin and simvastatin in pharmaceutical tablets. The optimal conditions were mobile phase 50:50 (v/v) (formic acid pH 2.50: ETOH), column temperature 40.00 °C, detection wavelength 238.00 nm, and flow rate 1.00 mL/min. The proposed method has been validated based on the ICH guidelines in terms of linearity, precision, accuracy, and limit of detection and limit of quantification. The linear range investigated 2.0–80.0, 4.0–100.00, and 12.00–120.00 µg/mL for rosuvastatin, atorvastatin and simvastatin respectively with coefficients of determination (R2) within the range of 0.9993–0.9995. The LOD and LOQ for rosuvastatin, atorvastatin and simvastatin were (1.57, 4.76 µg/mL), (1.87, 5.66 µg/mL), (3.46, 10.49 µg/mL) respectively. In addition, in order to evaluate the feasibility of the method developed, it was employed towards the quantification of the pharmaceutical tablets for the analytes investigated and excellent recovery was obtained.

PENGARUH KRONOFARMAKOLOGI TERHADAP KADAR KOLESTEROL TOTAL DAN TRIGLISERIDA DALAM DARAH PASIEN PENGGUNA OBAT GOLONGAN STATIN DAN FIBRAT

ABSTRACT Chronopharmacology is a therapy based on circadian rhythms that can be said to be relevant if the risk and symptoms of the disease are predicted to vary over time. This study aims to determine the effect of chronopharmacology on total cholesterol and triglyceride levels in the blood of patients with fibrates and statin groups, so that patients with certain diseases are encouraged to take drugs according to the organ picket hours or circadian rhythms. This study was an observational descriptive study with a cross sectional study design involving 18 patients. Primary data were obtained through interviews and checking total cholesterol and triglyceride levels while secondary data were obtained from the patient's medical record. Based on the results of the analysis using SPSS for statin drug use in the morning and at night getting a value of P = 0.003. whereas for drug use in the fibrat group in the morning and evening, P = 0.083 was obtained. Based on the results of the research that has been done, it can be concluded from 18 patients using statins and fibrates in RSUD Dr. Soekardjo Tasikmlaya, for the use of statin drugs at night is more beneficial, but in the use of fibrates in the morning or evening the same effectiveness. Keyword : chronopharmacology, statin, fibrat

Aspirin and Statin Use and the Risk of Gallbladder Cancer

Aspirin and statin drugs have been associated with reduced risk of several gastrointestinal cancers, but their association with gallbladder cancer (GBC) has not been well established. We evaluated the association of aspirin and statins with the risk of GBC. Patients with GBC managed at Mayo Clinic between 2000 and 2019 were matched 1:2 with a general patient pool by age and sex. Univariable and multivariable logistic regression models were used to assess associations between GBC and aspirin or statin use. The analysis included 795 cases and 1590 controls, with a median age of 67 years. Aspirin or statin use alone or in combination was higher in controls (p < 0.001). Univariate analysis showed that the use of aspirin [odds ratio (OR): 0.11; 95%CI: 0.08–0.15] or statins (OR: 0.29; 95%CI: 0.20–0.40) and their combined use (OR: 0.18; 95%CI: 0.13–0.24) was associated with lower risk of GBC. Multivariable analysis revealed that aspirin (OR: 0.12; 95%CI: 0.09–0.16) and combined statins and aspirin (OR: 0.46; 95%CI: 0.31–0.67) were associated with lower risk of GBC. Aspirin alone or in combination with statins is associated with a strongly reduced risk of GBC. Further prospective studies are needed to confirm these results and to elucidate their mechanisms.

Assimilation of Cholesterol by Monascus purpureus

Monascus purpureus, a filamentous fungus known for its fermentation of red yeast rice, produces the metabolite monacolin K used in statin drugs to inhibit cholesterol biosynthesis. In this study, we show that active cultures of M. purpureus CBS 109.07, independent of secondary metabolites, use the mechanism of cholesterol assimilation to lower cholesterol in vitro. We describe collection, extraction, and gas chromatography-flame ionized detection (GC-FID) methods to quantify the levels of cholesterol remaining after incubation of M. purpureus CBS 109.07 with exogenous cholesterol. Our findings demonstrate that active growing M. purpureus CBS 109.07 can assimilate cholesterol, removing 36.38% of cholesterol after 48 h of incubation at 37 °C. The removal of cholesterol by resting or dead M. purpureus CBS 109.07 was not significant, with cholesterol reduction ranging from 2.75–9.27% throughout a 72 h incubation. Cholesterol was also not shown to be catabolized as a carbon source. Resting cultures transferred from buffer to growth media were able to reactivate, and increases in cholesterol assimilation and growth were observed. In growing and resting phases at 24 and 72 h, the production of the mycotoxin citrinin was quantified via high-performance liquid chromatography-ultraviolet (HPLC-UV) and found to be below the limit of detection. The results indicate that M. purpureus CBS 109.07 can reduce cholesterol content in vitro and may have a potential application in probiotics.

Pharmacoeconomic Analysis of Therapy with Generic Statin Drugs in Patients with High and Very High Cardiovascular Risk (According to the Study PRIORITY)

Aim. To perform a pharmacoeconomical assessment of the use of generic statin drugs in patients with high and very high cardiovascular risk (CVR) in real clinical practice based on the data of the study PRIORITY.Material and methods. The PRIORITY study included 298 patients with high (29; 9.7%) and very high (269, 90.3%) CVR. All patients were recommended to take the reproduced drugs of atorvastatin and rosuvastatin in an individually prescribed dose. After 1 month (B1), if the target level of lowdensity lipoprotein cholesterol (LDL-C) was not reached, the statin dose was titrated. After 3 months of follow-up (B3), the hypolipidemic effect of statin therapy was evaluated. 295 people completed the study, 285 patients had the results of the lipid profile. To perform a pharmacoeconomic analysis and evaluate the “cost/effectiveness” ratio, we used the prices of generic statins in one of the online pharmacies. The effectiveness of statins was determined by the LDL-C reduction, as well as by the percentage of achieving the target LDL-C level.Results. At the first stage of the pharmacoeconomic analysis, the criterion for the effectiveness of 3-month lipid-lowering therapy was a decrease in LDL-C level by 1 mmol/l. The median and interquartile range of the ratio “cost/effectiveness” indicator for atorvastatin was 658.2 (431.5; 1257.1) RUB/mmol/l, and for rosuvastatin – 621.0 (390.7; 940.6) RUB/mmol/l (p=0.45). The results of a comparative assessment of the “cost/effectiveness” ratio (with the abovementioned effectiveness indicator) in subgroups of patients with high and very high CVR, with the achievement and nonachievement of the target level of LDL-C, adherent and non-adherent to statins, revealed the economic advantage of statins in groups of adherent patients (p=0.35), high-risk patients (p<0.0001) and individuals who reached the target level of LDL-C (p=0.002) when compared with the corresponding comparison groups. Despite the revealed high effectiveness of rosuvastatin at doses of 20-40 mg/day (assessed by the cost/effectiveness of achieving the target values of LDL-C for specific doses of statins), calculation of the “cost/effectiveness” ratio for each reproduced statin, in general, showed a higher economic effectiveness of atorvastatin.Conclusion. Pharmacoeconomic analysis of therapy with generic statin drugs, performed according to the data of the non-randomized uncontrolled study, allows to justify the economic efficiency and advantages of these drugs in various subgroups of patients who need statin therapy.

Non-statin lipid-lowering therapy in coronary atherosclerosis regression: a meta-analysis and meta-regression

Introduction Several studies have investigated the association between non-statin lipid-lowering therapy and regression of atherosclerosis. However, the studies were mostly small and their results were not always robust. Objectives (1) to define if a dual lipid-lowering therapy (statin ± non-statin drugs) is associated with coronary atherosclerosis regression, estimated by intravascular ultrasound (IVUS); (2) to assess the association between dual lipid-lowering-induced changes in LDL-C and non-HDL-C levels and atherosclerosis regression. Methods We performed a meta-analysis including trials of non-statin lipid-lowering therapy, reporting C-LDL, non-HDL-C and total atheroma volume (TAV) with a minimum of 6 months of follow-up. The primary endpoint was defined as the change in TAV measured from baseline to follow-up, comparing groups of subjects on statins alone versus combination of statin and non-statin drugs. The random-effects model and meta-regression were performed. Results Eight eligible trials of non-statin lipid-lowering drugs (1759 patients) were included. Overall, the dual lipid-lowering therapy was associated with a significant reduction in TAV [−3.5 mm3 (95% CI: −4.5 to −2.6)]; I2=11%]. In the analysis stratified according to the lipid-lowering drug class (ezetimibe or PCSK9 inhibitors), the findings were similar. In a meta-regression, a 10% decrease in LDL-C or non-HDL-C levels, was associated, respectively, with 0.92 mm3 and 1.05 mm3 regressions in TAV. Conclusion Our data suggest the addition of ezetimibe or PCSK9 inhibitors to statin therapy results in significantly increased regression of TAV. When the LDL-C and non-HDL-C levels reached were lower, the observed effect was also greater. Forest Plot by Drugs Group Funding Acknowledgement Type of funding source: None