Interactions between diabetic and hypertensive drugs: a pharmacogenetics approach.

Diabetes is known to increase susceptibility to hypertension due to increase in inflammation, oxidative stress, and endothelial dysfunction, leading to vascular stiffness. The polytherapy might lead to several drug-drug interactions (DDIs), which cause certain life-threatening complications such as diabetic nephropathy and hypoglycaemia. So, in this review we focused on drug-drug interactions and impact of genetic factors on drug responses for better disease management. Drug-drug interactions (DDIs) may act either synergistically or antagonistically. For instance, a combination of metformin with angiotensin II receptor antagonist or angiotensin-converting enzyme inhibitors (ACEIs) synergistically improves glucose absorption, whereas the same hypertensive drug combination with sulphonylurea might cause severe hypoglycaemia sometimes. Thiazolidinediones (TDZs) can cause fluid retention and heart failure when taken alone, but a combination of angiotensin II receptor antagonist with TZDs prevents these side effects. Interindividual genetic variation affects the DDI response. We found two prominent genes, GLUT4 and PPAR-γ, which are common targets for most of the drug. So, all of these findings established a connection between drug-drug interaction and genetics, which might be used for effective disease management.

Genetic Variants and Drug Efficacy in Tuberculosis: A Step toward Personalized Therapy.

Tuberculosis (TB) continues to be a major infectious disease affecting individuals worldwide. Current TB treatment strategy recommends the standard short-course chemotherapy regimen containing first-line drug, i.e., isoniazid, rifampicin, pyrazinamide, and ethambutol to treat patients suffering from drug-susceptible TB. Although Mycobacterium tuberculosis , the causing agent, is susceptible to drugs, some patients do not respond to the treatment or treatment may result in serious adverse reactions. Many studies revealed that anti-TB drug-related toxicity is associated with genetic variations, and these variations may also influence attaining maximum drug concentration. Thus, inter-individual diversities play a characteristic role by influencing the genes involved in drug metabolism pathways. The development of pharmacogenomics could bring a revolution in the field of treatment, and the understanding of germline variants may give rise to optimized targeted treatments and refine the response to standard therapy. In this review, we briefly introduced the field of pharmacogenomics with the evolution in genetics and discussed the pharmacogenetic impact of genetic variations on genes involved in the activities, such as anti-TB drug transportation, metabolism, and gene regulation.

Determinants in Tailoring Antidiabetic Therapies: A Personalized Approach.

Diabetes has become a pandemic as the number of diabetic people continues to rise globally. Being a heterogeneous disease, it has different manifestations and associated complications in different individuals like diabetic nephropathy, neuropathy, retinopathy, and others. With the advent of science and technology, this era desperately requires increasing the pace of embracing precision medicine and tailoring of drug treatment based on the genetic composition of individuals. It has been previously established that response to antidiabetic drugs, like biguanides, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and others, depending on variations in their transporter genes, metabolizing genes, genes involved in their action, etc . Responsiveness of these drugs also relies on epigenetic factors, including histone modifications, miRNAs, and DNA methylation, as well as environmental factors and the lifestyle of an individual. For precision medicine to make its way into clinical procedures and come into execution, all these factors must be reckoned with. This review provides an insight into several factors oscillating around the idea of precision medicine in type-2 diabetes mellitus.

Circulating microRNA-126 as an Independent Risk Predictor of Coronary Artery Disease: A Case-Control Study.

CONTEXT: Circulating microRNAs (miR) have revolutionized the field of molecular biology owing to their potential as a diagnostic as well as a prognostic biomarker of cardiovascular disease and dysfunctions. The present study aims to identify the circulating miR-126 and -122 as an independent risk predictors of coronary artery disease cases. METHODS AND MATERIAL: Blood samples were collected from coronary artery disease cases (n=100) and non-CAD cases (n=100). Serum RNA was isolated by Trizol method. MiR levels were measured by quantitative real-time polymerase chain reaction with the specific primer probe set. RESULTS: MiR-126 levels were significantly down-regulated in CAD cases compared to non-CAD cases (controls) (80.0% vs. 39.0%, χ2=14.95, p<0.001). The level of miR-122 was significantly up-regulated in CAD cases in comparison to its non-CAD variant (14.0% vs. 63.0%, χ2=21.23, p<0.001). Multivariate analysis found chest pain (OR=37.07, 95% CI=3.21-169.04, p=0.017) and miR-126 (OR=0.01, 95% CI=0.00-0.63, p=0.030) as independent risk predictors of CAD. CONCLUSION: The results of our study show the potential of circulating miR-126 as a novel non-invasive biomarker in the risk prediction of CAD. Further unraveling of the role of miR-122 and miR-126 in the pathogenesis and progression of CAD will add to our understanding of the disease process leading to a new diagnostic approach. HIGHLIGHTS: Mir-122 and -126 significantly differentiate non CAD cases from angiographically proven CAD casesChest pain and miR-126 might work as an independent risk predictor of coronary artery disease.

Regulation of miR-126 and miR-122 Expression and Response of Imatinib Treatment on Its Expression in Chronic Myeloid Leukemia Patients.

BACKGROUND: MicroRNAs (miRNAs) have been observed to exhibit altered expression patterns in chronic myeloid leukemia (CML). Therefore, this study was aimed to evaluate the clinical importance of miR-126 and miR-122 expression in concert to imatinib response in CML patients. METHODS: The present study included 100 CML and 100 healthy subjects. The expression of the 2 miRNAs was performed using TaqMan probe chemistry, and snU6 was used as internal control. RESULTS: The expression of miR-126 and miR-122 was downregulated in CML patients, with a mean fold change ± SD 0.20 ± 0.33 and 0.22 ± 0.37, respectively. While the expression of both miRNAs was analysed before and after imatinib treatment, it was observed that the expression levels of both were increased after imatinib treatment by 26.25-fold (5.33 against 0.20) and 13.95-fold (3.07 against 0.22) and the increase was statistically significant (p < 0.0001 and p < 0.0001, respectively). The expression of miR-126 was not conclusive when compared in different clinical stages of the CML disease as it showed a decreased expression in patients with accelerated phase compared to chronic phase (mean fold change = 0.03 and 0.27, respectively), but patients with chronic phase and blastic phase had comparable expression (mean fold change = 0.27 and 0.24, respectively). We also observed an increased expression of both miRNAs after imatinib therapy in each clinical phase. CONCLUSION: The study concludes that expression of miR-126 and miR-122 increases after imatinib treatment in CML patients and that miR-126 defines the good responders of imatinib therapy.

Hematological and serum biochemistry parameters as a prognostic indicator of severally ill versus mild Covid-19 patients: A study from tertiary hospital in North India.

BACKGROUND/OBJECTIVES: In, India coronavirus disease (COVID-19) cases are on the rise in terms of the total number of cases. Findings on clinical and hematological parameters alone carry no significance apart from telling patients present status and hence are diminutive. This study aims to assess the hematological and serum biochemistry parameters and correlate them with the presenting symptoms and severity of disease which can help predict the need for intensive care unit (ICU) care, help in triage, assess the severity of the disease which will help clinicians decide their future course of action and further improve patients clinical outcome. METHODS: A total of 200 COVID-19 positive patients were included. Hematological and serum biochemistry parameters were recorded for the patients at the time of admission and categorized as mild, moderate, and severely ill based on clinical status and then admitted into various wards. RESULTS: Total leucocyte count (TLC) was significantly different and higher in severely ill patients (13,200 ± 6,999.2) compared to cases presented with mild and moderate symptoms (12,100 ± 6,488.41& 8,788.20 ± 4,954.32, p = 0.001). The mean difference of TLC, Neutrophil% (N%), Lymphocyte% (L%) and Monocyte (M%) was significantly different between mild and moderate symptoms cases (p = 0.030, p = 0.002, p = 0.004 & p = 0.003). Between groups comparison of moderate vs. severely ill cases showed a significant difference in TLC (p = 0.000), N% (p = 0.000), L% (0.000), and L/N ratio (p = 0.002). The serum ionic calcium (Ca), random blood sugar (RBS), C-reactive protein (CRP), fibrinogen, prothrombin (PT), International Normalized Ratio (INR), ferritin, and Lactate Dehydrogenase (LDH) level also differed significantly between mild, moderate and severely ill cases (p = 0.001, p=<0.001, p = 0.002, p=<00.1, p = 0006, p = 0.005, p=<0.001 and p=<0.001) respectively. Comparison of the mild vs. severely ill cases showed a significant difference in urea, fibrinogen, and procalcitonin (PCT) level (p = 0.005, p = 0.000 & p = 0.048) respectively. CONCLUSION: The preliminary findings of this study suggest hematological and serum biochemistry parameters could be used as a screening tool to identify patients requiring intensive care and thus allowing clinical stratification and triage at the time of presentation.

Circulating microRNA-126 &122 in patients with coronary artery disease: Correlation with small dense LDL.

BACKGROUND: Coronary artery disease (CAD) and stroke are major causes of cardiovascular diseases related deaths. Conventional risk factors cannot explain the changes in atherosclerosis. New and useful diagnostic markers are required. MicroRNAs are small, noncoding RNA that regulate the gene expression implicated in the pathogenesis of various cardiovascular diseases. Endothelial dysfunction is involved in the early event of the atherosclerosis process. AIMS: The current study was designed to evaluate the vascular endothelium-enriched miRNAs would be altered in CAD patients. METHODS: Circulating miR-126 & 122 levels were measured in serum from 78 CAD patients and 60 non CDA patients by qRT-PCR analysis. RESULTS: MiR-122 was significantly down regulated in CAD patients (p = 0.001), however the level of miR-126 did not show any change (p = 0.507). Remarkably, the level of miR-126 was significantly decreased in patients with CAD and high small dense low density lipoprotein (sdLDL) level. The level of miR-126 was significantly increased when sdLDL was higher in patients with risk factors for CAD but did not have angiographically significant CAD. CONCLUSION: . In CAD patient's, miR-126 level was lowered compared to non CAD patients, however the difference was not significant (0.507). However we found a direct relationship between endothelium-enriched miR-126 and sdLDL in patients with or without CAD. Our finding suggests that miR-126 may have a potential role in sdLDL cholesterol metabolism. Mir-122 plays a role in cholesterol biosynthesis and deteriorates the cardiovascular system through the process of inflammation, apoptosis, oxidative stress and ECM deposition in a number of cardiovascular diseases.

microRNA-21 Expression as Prognostic and Therapeutic Response Marker in Chronic Myeloid Leukaemia Patients.

Background: Chronic myeloid leukaemia (CML) is a myeloproliferative disorder categorized by malignant transformation of a single stem cell of hematopoietic cells. microRNAs (miRNAs) belong to transcription regulators in hematopoiesis and their altered expression associates with pathogenesis of CML. Aim: Current study aimed to access the miR-21 expression profile in CML patients and therapy response as well as its prognostic significance. Methods: 100 CML cases, 100 controls were included in study and miR-21 expression was analyzed. Overall 9.22 mean fold increased expression was observed in CML patients before treatment. Results: Patients with different CML phases such as chronic phase, accelerated phase and blast crisis showed 7.16, 10.30 and 13.20 fold increased expression respectively. Overall 3.57 mean fold expression was observed in imatinib treated patients suggested more than 5 fold decreased expression in CML patients. Prognostic significance was calculated and observed that miR-21 expression at 7.29 fold cutoff, 75% sensitivity and 50% specificity was observed (AUC=0.75, p<0.0001). Study observed miR-21 overexpression in CML patients as well as gradually increased expression with advancement of disease. Conclusion: miR-21 overexpression represented molecular prognostic marker and predictive tool enabling efficient monitoring of drug response and therapy outcomes in CML patients.