783 The effects of reduced physical activity on the lipid profile in patients with high cardiovascular risk during COVID-19 lockdown

Aims The COVID-19 pandemic is a serious global health problem. In Italy, to limit the infections, the government ordered lockdown from March 2020. This measure, designed to contain the virus, led to serious limitations on the daily life of the individuals it affected, and in particular in the limitation of physical exercise. The aim of this study was to evaluate the effects of reduced physical activity on the lipid profile in patients with high cardiovascular risk. Methods and results We enrolled 38 dyslipidaemic patients, 56% male, with an age range of 44–62 years, considered to be at high cardiovascular risk. All patients were prescribed statin drug therapy (atorvastatin 40 mg) and a vigorous physical activity program four times a week, 1 h per session. In addition, a personalized Mediterranean diet was prescribed to all the patients. Total cholesterol, LDL, HDL, and triglycerides were measured in patients at T0 before lockdown and at T1 during lockdown. Data showed a significant increase (P < 0.01) in total cholesterol (+6.8%) and LDL (+15.8%). Furthermore, the analysis of the data revealed a reduction in HDL (−3%) and an increase in triglycerides (+3.2%), although both were not significant (P > 0.05). Of the 14 patients who were all in perfect therapeutic range at T0, only 4 (28%) had LDL <70 mg/dL at T1. Conclusions Our study showed that the reduction in physical activity during lockdown led to an increase in LDL levels, and therefore, in the risk of ischaemic heart disease in dyslipidaemic patients with high cardiovascular risk.

Comparison of ten biochemical laboratory tests before and after treatment by statins

Results of 10 biochemical tests of 172 patient data (among them 84 men data and 88 women data, resp.) before and after administration of statins were thoroughly studied. All monitored patients are characterized by disorders of lipoprotein metabolism or other kind of dislipidaemia. The calculations were performed using four chemometrical methods facilitating quantification and visualization of the statin effect upon most important biochemical parameters, mainly lipid markers, and allowing classification of the patient blood samples taking into account whether the patient has been or has not been medicated by a statin drug.

A Novel Statin Compound from Monacolin J Produced Using CYP102A1-Catalyzed Regioselective C-Hydroxylation

Statins inhibit the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), which is the rate-limiting enzyme in cholesterol biosynthesis. Statin therapy reduces morbidity and mortality in those who are at high risk of cardiovascular disease. Monacolin J is a statin compound, which is an intermediate in the lovastatin biosynthesis pathway, in the fungus Aspergillus terreus. It is also found in red yeast rice, which is made by culturing rice with the yeast Monascus purpureus. Monacolin J has a hydroxyl substituent at position C’-8 of monacolin L. Here, a new statin derivative from monacolin J was made through the catalysis of CYP102A1 from Bacillus megaterium. A set of CYP102A1 mutants of monacolin J hydroxylation with high catalytic activity was screened. The major hydroxylated product was C-6′a-hydroxymethyl monacolin J, whose structure was confirmed using LC–MS and NMR analysis. The C-6′a-hydroxymethyl monacolin J has never been reported before. It showed a greater ability to inhibit HMG-CoA reductase than the monacolin J substrate itself. Human liver microsomes and human CYP3A4 also showed the ability to catalyze monacolin J in producing the same product of the CYP102A1-catalyzed reaction. This result motivates a new strategy for the development of a lead for the enzymatic and chemical processes to develop statin drug candidates.

The Effects of Reduced Physical Activity on the Lipid Profile in Patients with High Cardiovascular Risk during COVID-19 Lockdown

Background: The COVID-19 pandemic is a serious global health problem. In Italy, to limit the infections, the government ordered lockdown from March 2020. This measure, designed to contain the virus, led to serious limitations on the daily life of the individuals it affected, and in particular in the limitation of physical exercise. The aim of this study was to evaluate the effects of reduced physical activity on the lipid profile in patients with high cardiovascular risk. Methods: We enrolled 38 dyslipidemic patients, 56% male, with an age range of 44–62 years, considered to be at high cardiovascular risk. All patients were prescribed statin drug therapy (atorvastatin 40 mg) and a vigorous physical activity program four times a week, 1 h per session. In addition, a personalized Mediterranean diet was prescribed to all the patients. Total cholesterol, LDL, HDL and triglycerides were measured in patients at T0 before lockdown and at T1 during lockdown. Results: Data showed a significant increase (p < 0.01) in total cholesterol (+6,8%) and LDL (+15,8%). Furthermore, the analysis of the data revealed a reduction in HDL (−3%) and an increase in triglycerides (+3,2%), although both were not significant (p > 0.05). Conclusions: Our study showed that the reduction in physical activity during lockdown led to an increase in LDL levels, and therefore, in the risk of ischemic heart disease in dyslipidemic patients with high cardiovascular risk.

Leveraging national claim and hospital big data integration: a cohort study on a statin-drug interaction use case. (Preprint)

BACKGROUND Linking different sources of medical data is a promising approach to analyse care trajectories. The INSHARE project aim was to provide the blueprint of a technological platform that facilitates integration, sharing and reuse of data from two sources: the eHOP clinical data warehouse (CDW) of Rennes academic hospital, and a dataset extracted from the French national claim data warehouse (SNDS). OBJECTIVE Using a pharmacovigilance use case based on statin consumption and statin-drug interactions, the present work demonstrates how the INSHARE platform can support big data analytical tasks in the health field. METHODS A Spark distributed cluster-computing framework was used for the record linkage procedure and all the analyses. A semi-deterministic record-linkage method based on the variables common between the chosen data sources was developed to identify all patients discharged after at least one hospital stay at Rennes academic hospital between 2015 and 2017. The use case study focused on a cohort of patients treated with statins prescribed by their general practitioner and/or during their hospital stay. RESULTS The whole process (record-linkage procedure and use case analyses) required 88 minutes. Among the 161,532 and 164,316 patients from the SNDS dataset and eHOP CDW, respectively, 159,495 patients were successfully linked (98.7% and 97.0% of patients from SNDS and eHOP CDW, respectively). Among the 16,806 patients with at least one statin delivery, 8,293 patients started the consumption before and continued during the hospital stay, 6,382 patients stopped statin consumption at hospital admission, and 2,131 patients initiated taking statins in hospital. Statin-drug interactions occurred more frequently during hospitalization than in the community (36.4% and 22.2%, respectively). Only 121 patients had the most severe level of statin-drug interaction. Hospital stay burden (length of stay and in-hospital mortality) was more severe in patients with statin-drug interactions during hospitalization. CONCLUSIONS This study demonstrates the added value of combining and re-using clinical and claim data to provide large-scale measures of drug-drug interaction prevalence and care pathways outside hospitals. It builds the path to move the current healthcare system towards a Learning Health System using knowledge generated from research on real-world health data.

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

PREPARATION OF SPRAY DRIED COAMORPHOUS SOLIDS TO IMPROVE THE SOLUBILITY AND DISSOLUTION RATE OF ATORVASTATIN CALCIUM

Atorvastatin calcium (AC) is a statin drug used to lower cholesterol. Its crystalline form is usually found in the market with low solubility properties. The amorphization of crystalline AC is a technique used to increase its solubility however; the amorphous form has less thermodynamic stability. Therefore, to increase the solubility properties of its crystalline form, an AC coamorphous solid was prepared. This coamorphous solid was prepared using spray drying techniques, and coformers such as isonicotinamide (INA) and maleic acid (MA). Furthermore, characterization was carried out using powder X-ray diffraction, differential scanning calorimetry, fourier transform infrared spectroscopy, and scanning electron microscopy, while the solubility properties test was conducted using the shake-flask and paddle method. The results showed that the spray-dried solids were coamorphous with single-phase homogeneous systems. Furthermore, the coamorphous solids, AC-INA and AC-MA were found to have a higher Tg than the melting points of other components, and formed intermolecular interactions between them. The higher Tg and presence of intermolecular interactions indicate that coamorphous solids are more stable than the amorphous form. Therefore, the results of the solubility and dissolution test showed that the coamorphous solid of AC-INA and AC-MA have better solubility properties compared to the AC crystalline form.

Production of a Human Metabolite of Atorvastatin by Bacterial CYP102A1 Peroxygenase

Atorvastatin is a widely used statin drug that prevents cardiovascular disease and treats hyperlipidemia. The major metabolites in humans are 2-OH and 4-OH atorvastatin, which are active metabolites known to show highly inhibiting effects on 3-hydroxy-3-methylglutaryl-CoA reductase activity. Producing the hydroxylated metabolites by biocatalysts using enzymes and whole-cell biotransformation is more desirable than chemical synthesis. It is more eco-friendly and can increase the yield of desired products. In this study, we have found an enzymatic strategy of P450 enzymes for highly efficient synthesis of the 4-OH atorvastatin, which is an expensive commercial product, by using bacterial CYP102A1 peroxygenase activity with hydrogen peroxide without NADPH. We obtained a set of CYP102A1 mutants with high catalytic activity toward atorvastatin using enzyme library generation, high-throughput screening of highly active mutants, and enzymatic characterization of the mutants. In the hydrogen peroxide supported reactions, a mutant, with nine changed amino acid residues compared to a wild-type among tested mutants, showed the highest catalytic activity of atorvastatin 4-hydroxylation (1.8 min−1). This result shows that CYP102A1 can catalyze atorvastatin 4-hydroxylation by peroxide-dependent oxidation with high catalytic activity. The advantages of CYP102A1 peroxygenase activity over NADPH-supported monooxygenase activity are discussed. Taken together, we suggest that the P450 peroxygenase activity can be used to produce drugs’ metabolites for further studies of their efficacy and safety.