Impact of Genetic Polymorphisms in NF-ĸB2 and TRAF3 Genes on Response to Bortezomib-Based Therapy in Multiple Myeloma Patients.

BACKGROUND: Multiple myeloma (MM), being the second most common hematological malignancy, has garnered significant attention. The ubiquitin proteasomal pathway (UPP), crucial for normal cell function, plays a pivotal role in myeloma pathophysiology, especially with the advent of bortezomib (BTZ). Dysregulation of the UPP has implications ranging from developmental abnormalities to cancer. OBJECTIVES: This study aimed to delineate the clinical characteristics of newly diagnosed multiple myeloma patients and investigate the influence of single nucleotide polymorphisms (SNPs) in NF-ĸB2 and TRAF3 genes on the risk and treatment response to bortezomib-based chemotherapy. MATERIALS AND METHODS: Conducted at JIPMER, Pondicherry, this prospective study enrolled 184 participants, comprising cases and controls. DNA extraction from peripheral blood samples was followed by SNP analysis through Real-time Polymerase Chain Reaction. Patients were categorized into Good and Poor responders, and SNP associations with treatment response, response rates, and survival outcomes were assessed using chi-square and Kaplan-Meier analyses. RESULTS: The median age of participants was 55 years, with backache being the most prevalent symptom (66.3%). Hypercalcemia (22%), renal failure (8.7%), and bone fractures (45.7%) were also observed, alongside high prevalence of anemia. Notably, the frequency of the TRAF3 rs12147254 A allele was lower in cases compared to controls (31% vs. 49%, P-value=0.002). Poor responders exhibited higher frequencies of the GA+AA genotypes in TRAF3 rs12147254 (OR-3.882(1.629-9.251), P-value-0.002) and NFKB2 rs1056890 (OR-3.308(1.366-8.012), P-value-0.008) when compared to good responders. The GA+AA genotype in TRAF3 rs11160707 SNP correlated with improved progression-free survival. CONCLUSION: The study findings underscore a significant association between genetic polymorphisms and treatment response outcomes, suggesting their utility in prognostic determinations and clinical outcomes prediction in multiple myeloma patients.

A cross-sectional study evaluating the knowledge, attitude, and practice of evidence-based medicine among resident doctors of a health-care Institution of National Importance in India.

Background and Objectives: Evidence-based medicine (EBM) promotes the integration of updated- best evidence with patient preferences and medical expertise for clinical decision-making. Despite the availability of high-quality evidence such as systematic review and meta-analysis, some clinicians manage their patients based on past experiences and expert opinion. Thus, this study was proposed to assess the knowledge, attitude, and practice of EBM among resident doctors at a tertiary care hospital in India. Participants and Methods: This cross-sectional questionnaire-based study was conducted among senior residents and final-year postgraduates (PGs) who were independently involved in clinical decision-making. By convenience sampling method, the participants were recruited, and the validated EBM Questionnaire (EBMQ) was distributed online for assessing the knowledge, attitude, and practice of EBM. Descriptive statistics were represented as frequency and proportions. Results: A total of 102 resident doctors participated with male preponderance (74.5%). Nearly, 96 (94.1%) participants were already practicing EBM and 21.6% had undergone EBM training. Textbooks (50%) were the most often referred sources for EBM information. Specific EBM databases such as MEDLINE and Cochrane were also utilized by 37.3% of participants. More than 70% of participants understood the terms such as a randomized controlled trial, case-control study, and P value. A higher proportion (80.4%) of participants showed a positive attitude about patient care improved by EBM. Conclusions: The majority of the resident doctors exhibited good knowledge and a positive attitude toward applying EBM in clinical decision-making. Periodic training through workshops or courses and integration of EBM with the PG curriculum would potentially enhance the EBM practice.

Usage Pattern of Fixed-dose Combinations at ICMR Network of Rational Use of Medicine Centres across India: Recommendations for Policymakers and Prescribers.

AIM: Irrational use of medicines is a global problem. In India, one contributing factor is the availability of a large number of fixed-dose combinations (FDCs). To improve rational use and to strengthen policies, it is important to assess the usage patterns and rationality of FDCs. METHODS: This study was conducted as part of a 1-year prospective cross-sectional analysis of prescriptions in the outpatient clinics of broad specialities from 13 tertiary care hospitals across India. Five most commonly prescribed FDCs in each center were analyzed. In addition, all the prescribed FDCs were classified as per the Kokate Committee classification and it was noted whether any of the FDCs were irrational or banned as per the reference lists released by regulatory authorities. RESULTS: A total of 4,838 prescriptions were analyzed. Of these, 2,093 (43.3%) prescriptions had at least one FDC. These 2,093 prescriptions had 366 different FDCs. Of the 366 FDCs, 241 were rational; 10 were irrational; 14 required further data generation; and the remaining 96 FDCs could not be categorized into any of the above. Vitamins and minerals/supplements, antibacterial for systemic use, and drugs for gastroesophageal reflux disease (GERD) and peptic ulcer were the most used FDCs. CONCLUSION: Based on the finding that some prescriptions contained irrational FDCs, it is recommended that a rigorous, regular, and uniform method of evaluation be implemented to approve/ban FDCs and that prescribers be periodically notified about the status of the bans.

Peroxisome Proliferator-Activated Receptor α and γ Gene Polymorphisms among South Indian Patients with Diabetic Dyslipidaemia.

Background: Peroxisome proliferator-activated receptors (PPAR) α and γ genes play an important role in dyslipidaemia of T2DM. Aims: To estimate the frequency distribution of PPAR α and γ gene polymorphisms in South Indian T2DM patients with dyslipidaemia compared to healthy controls. Normative frequencies of SNPs were established and compared with data for 1000 genome populations. Methods: Eligible 382 cases and 336 age and sex-matched controls were enrolled. Six SNPs in PPARα [rs1800206 C>G (Leu162Val), rs4253778 G>C, rs135542 T>C] and PPARγ [rs3856806 (C>T), rs10865710 (C>G), rs1805192 C>G (Pro12Ala)] genes were selected for genotyping. Results: The allele and gene frequencies did not significantly differ between the diabetic dyslipidaemia cases and healthy controls. However, they were significantly different from that of 1000 genome populations except for rs1800206 C>G (Leu162Val) and rs1805192 C>G (Pro12Ala). Conclusion: The studied polymorphisms in PPARα and PPARγ genes are not associated with diabetic dyslipidaemia among South Indian patients.

An observational multi-centric COVID-19 sequelae study among health care workers.

Background: India has seen more than 43 million confirmed cases of COVID-19 as of April 2022, with a recovery rate of 98.8%, resulting in a large section of the population including the healthcare workers (HCWs), susceptible to develop post COVID sequelae. This study was carried out to assess the nature and prevalence of medical sequelae following COVID-19 infection, and risk factors, if any. Methods: This was an observational, multicenter cross-sectional study conducted at eight tertiary care centers. The consenting participants were HCWs between 12 and 52 weeks post discharge after COVID-19 infection. Data on demographics, medical history, clinical features of COVID-19 and various symptoms of COVID sequelae was collected through specific questionnaire. Finding: Mean age of the 679 eligible participants was 31.49 ± 9.54 years. The overall prevalence of COVID sequelae was 30.34%, with fatigue (11.5%) being the most common followed by insomnia (8.5%), difficulty in breathing during activity (6%) and pain in joints (5%). The odds of having any sequelae were significantly higher among participants who had moderate to severe COVID-19 (OR 6.51; 95% CI 3.46-12.23) and lower among males (OR 0.55; 95% CI 0.39-0.76). Besides these, other predictors for having sequelae were age (≥45 years), presence of any comorbidity (especially hypertension and asthma), category of HCW (non-doctors vs doctors) and hospitalisation due to COVID-19. Interpretation: Approximately one-third of the participants experienced COVID sequelae. Severity of COVID illness, female gender, advanced age, co-morbidity were significant risk factors for COVID sequelae. Funding: This work is a part of Indian Council for Medical Research (ICMR)- Rational Use of Medicines network. No additional financial support was received from ICMR to carry out the work, for study materials, medical writing, and APC.

Phase II study of sodium valproate in combination with oral etoposide in platinum-resistant ovarian cancer.

Patients with platinum-resistant ovarian cancer (PROC) have limited therapeutic options and poor survival. There is a need for the development of newer therapies. Sodium valproic acid (VPA) is a short-chain fatty acid histone deacetylase (HDAC) inhibitor with antitumor activity in preclinical models of PROC. Synergism with conventional cytotoxic agents like etoposide has been demonstrated. In this prospective, single-arm, open-label, phase 2 study, we included patients ≥ 18 years with histologically or cytologically confirmed PROC and Eastern Cooperative Oncology Group performance status (ECOG-PS) 0-3. Patients received oral VPA 60 mg/kg/day in three divided doses for 3 days (D1-D3), followed by oral etoposide 50 mg once daily for two consecutive weeks (D4-D17). Serum samples were collected to assess peak VPA drug levels. The primary endpoint was the overall response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. We sought to show an improvement in response rate from 25% (historically with oral etoposide) to 40% with the addition of VPA. 27 patients were enrolled in the study, and 18 [median age: 52 (45-59) years; serous histology:17 (94%); ECOG-PS 2 or 3: 14 (78%)] were evaluable for the response after 4 months. Nine patients were lost from follow-up before achieving the primary endpoint (mainly due to Covid-related lockdown issues). The median number of prior lines of treatment was 2 (1-3). ORR was 0% according to GCIG criteria. The disease was stable in two patients [clinical benefit rate (CBR) of 11%]. The median OS and PFS were 7 months and 2 months, respectively. Grade ≥ 3 adverse events were reported in 6 (33%) patients. The addition of valproic acid to oral etoposide in patients with PROC and poor general condition was not helpful and failed to improve responses compared to those historically achieved with single-agent etoposide. However, further phase 2 randomized controlled trials with larger sample size can be done to confirm the findings.

Identification of Differentially Expressed Mirna by Next Generation Sequencing in Locally Advanced Breast Cancer Patients of South Indian Origin.

PURPOSE: miRNAs are known to be aberrantly expressed in the serum, tissue, and Peripheral Blood Mononuclear Cells (PBMC) of cancer patients and could serve as potential noninvasive diagnostic markers for breast cancer. The aim of this study was to identify the differentially expressed miRNA using next-generation sequencing (NGS) from the paired PBMC samples from breast cancer patients and age-matched healthy individuals and explore their functional significance. METHODS: In this study, PBMCs were employed for the detection of miRNAs by NGS in locally advanced breast cancer (LABC) women of South Indian origin who were divided into three age groups, (a) 40yrs-50yrs (b) 50yrs-60yrs and (c) 60yrs-70yrs, compared with age-matched control groups. RESULTS: Four miRNAs (hsa-miR-192-5p, hsa-miR-24-2-2p, hsa-miR-3609, and hsa-miR-664b-3p) were found to be differentially expressed among LABC patients compared with age matched healthy women of the South Indian population. While miR-24-2-5p, miR3609, and miR-664b-3p were down-regulated, miR-192-5p was up-regulated. Gene Ontology (GO) annotations implicated miRNA with signaling pathways in peripheral nerve synapses, glutamatergic synapse, and cell morphogenesis, all of which play a pivotal role in the manifestation of cancer. CONCLUSION: Four miRNAs- 3 (While miR-24-2-5p, miR3609, and miR-664b-3p) downregulated and one upregulated (miR-192-5p) were identified as potential biomarkers for patients with locally advanced breast cancer. These markers could be validated in studies with a larger sample size.

Use of drugs not listed in the National List of Essential Medicines: Findings from a prescription analysis by the Indian Council of Medical Research-Rational Use of Medicines Centres Network in tertiary care hospitals across India.

BACKGROUND: The concept of listing essential medicines can lead to improved supply and access, more rational prescribing, and lower costs of drugs. However, these benefits hinge on the prescription of drugs from an Essential Medicines List (EML). Several studies have highlighted the problem of underutilization of EMLs by prescribers. Therefore, as part of prescription research by the Indian Council of Medical Research-Rational Use of Medicines Centres Network, we evaluated the extent of prescription of drugs not listed in the National List of Essential Medicines (NLEM). MATERIALS AND METHODS: Prescriptions of outpatients from participating centers were included after obtaining verbal/written informed consent as approved by the Ethics Committee, and evaluated for prescription of drugs from the NLEM 2015. RESULTS: Analysis of 4838 prescriptions from 13 tertiary health-care institutes revealed that 2677 (55.33%) prescriptions had at least one non-NLEM drug prescribed. In all, 5215 (31.12%) of the total 16,758 drugs prescribed were not in NLEM. Of these, 2722 (16.24%) were single drugs and 2493 (14.88%) were fixed-dose combinations (FDCs). These comprised 700 different drug products - 346 single drugs and 354 FDCs. The average number of non-NLEM drugs prescribed per prescription was 1.08, while the average number of all drugs prescribed was 3.35 per prescription. It was also found that some of the non-NLEM drugs prescribed had the potential to result in increased cost (for example, levocetirizine), increased adverse effects (dextromethorphan), and less effectiveness (losartan) when compared to their NLEM counterparts. Nonavailability of an essential drug (oral hydroxocobalamin) was another important finding of our study. CONCLUSION: This study highlights the extent and pattern of drugs prescribed from outside the NLEM at the tertiary health-care level and the need for training and enhanced awareness among prescribers for greater utilization of the NLEM.

Perceptions about controlled human infection model (CHIM) studies among members of ethics committees of Indian medical institutions: A qualitative exploration.

Introduction: Controlled Human Infection Model (CHIM) studies provide a unique platform for studying the pathophysiology of infectious diseases and accelerated testing of vaccines and drugs in controlled settings. However, ethical issues shroud them as the disease-causing pathogen is intentionally inoculated into healthy consenting volunteers, and effective treatment may or may not be available. We explored the perceptions of the members of institutional ethics committees (IECs) in India about CHIM studies. Methods: This qualitative exploratory study, conducted across seven sites in India, included 11 focused group discussions (FGD) and 31 in-depth interviews (IDI). A flexible approach was used with the aid of a topic guide. The data were thematically analyzed using grounded theory and an inductive approach. Emerging themes and sub-themes were analyzed, and major emergent themes were elucidated. Results: Seventy-two IEC members participated in the study including 21 basic medical scientists, 29 clinicians, 9 lay people, 6 legal experts and 7 social scientists. Three major themes emerged from this analysis-apprehensions about conduct of CHIM studies in India, a perceived need for CHIM studies in India and risk mitigation measures needed to protect research participants and minimize the associated risks. Conclusion: Development of a specific regulatory and ethical framework, training of research staff and ethics committee members, and ensuring specialized research infrastructure along with adequate community sensitization were considered essential before initiation of CHIM studies in India.

Assessment of medicine use based on WHO drug-use indicators in public health facilities of the South Indian Union Territory.

OBJECTIVE: To assess medicine use based on World Health Organization (WHO) core drug-use indicators in selected public health facilities of the South Indian Union Territory. METHODS: A prospective cross-sectional study was conducted for period of one year (from March 2019 to February 2020) in 10 selected public health facilities based on the WHO document How to investigate drug use in health facilities. Total 900 prescriptions were analysed to study prescribing, patient care and health facility indicators. The results were compared with the WHO standard measures. RESULTS: The overall average number of drugs per prescription was 3.2. Percentage of prescriptions with antibiotics and injections were found to be 36.6 and 11.4%, respectively. Percentage of drugs prescribed by generic name was 74.6%. Percentage of drugs prescribed from the National List of Essential Medicine was 93.3%. Average consultation and dispensing time were found to be 3.9 minutes and 49.3 seconds, respectively. The percentage of drugs dispensed in this study was 98.5 and 61.6% of medicines were properly labelled; 76.7% of patients had correct knowledge of each medicine dispensed to them. Mean availability of key essential medicine was 73.4%. CONCLUSION: Indicators such as percentage of drugs prescribed from the National List of Essential Medicine, availability of copy of essential medicine list and percentage of drugs dispensed were found to be as per WHO optimal value. Indicators such as average number of drugs per prescription, average consultation and dispensing time and percentage of medicines labelled were found below optimal value and need to be improved.

Association of genetic polymorphisms in vitamin D receptor (ApaI, TaqI and FokI) with vitamin D and glycemic status in type 2 diabetes patients from Southern India.

OBJECTIVES: To evaluate the association of VDR polymorphisms (FokI, TaqI and ApaI) with vitamin D levels and glycemic status in type 2 diabetes patients from Southern India. METHODS: In this observational study, genotype frequencies and vitamin D levels of 200 cases (type 2 diabetes patients) were compared with 300 controls (unrelated anonymised stored samples of healthy volunteers) from south India. Serum 25 (OH) D levels were measured by immunoassay technique, glycated hemoglobin (HbA1c) was measured using HPLC and genotyping of VDR polymorphisms were carried out using Real time Polymerase Chain Reaction (RT PCR). RESULTS: About 69.2% of type 2 diabetes patients were found to have vitamin D deficiency. FokI polymorphism showed variations in serum 25 (OH) D levels, with AA and AG genotypes having significantly lower serum 25 (OH) D levels as compared to GG [13.24 (8.4) ng/ml, 15.02 (7.07) ng/ml and 20.67 (13.64) ng/ml respectively]. There was no difference in HbA1c levels with respect to the vitamin D levels and VDR polymorphisms. CONCLUSIONS: AA and AG genotypes of FokI polymorphisms are associated with low serum 25 (OH) D levels. However there was no association between VDR polymorphisms and glycemic status in south Indian type 2 diabetes patients.

Association of genetic polymorphisms in vitamin D receptor (ApaI, TaqI and FokI) with vitamin D and glycemic status in type 2 diabetes patients from Southern India.

OBJECTIVES: To evaluate the association of VDR polymorphisms (FokI, TaqI and ApaI) with vitamin D levels and glycemic status in type 2 diabetes patients from Southern India. METHODS: In this observational study, genotype frequencies and vitamin D levels of 200 cases (type 2 diabetes patients) were compared with 300 controls (unrelated anonymised stored samples of healthy volunteers) from south India. Serum 25 (OH) D levels were measured by immunoassay technique, glycated hemoglobin (HbA1c) was measured using HPLC and genotyping of VDR polymorphisms were carried out using Real time Polymerase Chain Reaction (RT PCR). RESULTS: About 69.2% of type 2 diabetes patients were found to have vitamin D deficiency. FokI polymorphism showed variations in serum 25 (OH) D levels, with AA and AG genotypes having significantly lower serum 25 (OH) D levels as compared to GG [13.24 (8.4) ng/ml, 15.02 (7.07) ng/ml and 20.67 (13.64) ng/ml respectively]. There was no difference in HbA1c levels with respect to the vitamin D levels and VDR polymorphisms. CONCLUSIONS: AA and AG genotypes of FokI polymorphisms are associated with low serum 25 (OH) D levels. However there was no association between VDR polymorphisms and glycemic status in south Indian type 2 diabetes patients.

Impact of Therapeutic Drug Monitoring on Once-Daily Regimen of Amikacin in Patients With Urinary Tract Infection: A Prospective Observational Study.

BACKGROUND: Amikacin is a semisynthetic antibiotic used in the treatment of gram-negative bacterial infections and has a narrow therapeutic index. Although therapeutic drug monitoring is recommended for amikacin, it is not routinely performed because of the use of a less toxic once-daily regimen. Only few studies have evaluated the role of therapeutic drug monitoring in patients treated with amikacin. The objective of our study was to find an association between the pharmacokinetic parameters of amikacin and the time required for a clinical cure, creatinine clearance, and frequency of ototoxicity in patients with urinary tract infection treated for 7 or more days. METHODS: A prospective study was conducted on patients with urinary tract infections who were administered amikacin for 7 or more days. Blood samples were obtained from the patients to measure the maximum drug concentration (Cmax) and trough concentration (Ctrough). Minimum inhibitory concentration (MIC) values were determined for patients with positive urine cultures. Serum creatinine levels were estimated every 3 days. The auditory assessment was performed using pure tone audiometry at baseline and weekly until the patients were discharged. Levels of amikacin were analyzed using a validated liquid chromatography-tandem mass spectrometry method. RESULTS: Of 125 patients analyzed, the median time required for a clinical cure was less in the group of patients who achieved a Cmax/MIC ratio ≥8 than it was in those who did not achieve this level [7 versus 8 days (P = 0.02)]. The Ctrough of amikacin was associated with the change in serum creatinine level (P = 0.01) and the incidence of nephrotoxicity (P = 0.004). CONCLUSIONS: In patients receiving short-term amikacin therapy, Cmax/MIC value can be used to predict the time required for a clinical cure. Ctrough can be used to predict the occurrence of nephrotoxicity in patients receiving amikacin therapy.

Influence of ABCB-1, ERCC-1 and ERCC-2 gene polymorphisms on response to capecitabine and oxaliplatin (CAPOX) treatment in colorectal cancer (CRC) patients of South India.

WHAT IS KNOWN AND OBJECTIVE: High interindividual response variability was reported with capecitabine and oxaliplatin (CAPOX) regimen in colorectal cancer (CRC). The single nucleotide polymorphisms (SNPs) of the genes related to drug efflux transport (ABCB1) and DNA repair (ERCC) could result in altered tumour response. Hence, this study was designed to assess the influence of ABCB1, ERCC-1 and ERCC-2 gene polymorphisms on tumour response to CAPOX treatment in CRC patients of South Indian origin. PATIENTS AND METHODS: A total of 145 newly diagnosed CRC patients were included in the final analysis. Response to CAPOX treatment in the adjuvant setting was assessed in terms of disease-free survival rate (DFSR) and overall survival rate (OSR) at 3 years, whereas in the palliative setting, the response was assessed as progression-free survival rate (PFSR) and OSR at 3 years. Five millilitres of the venous blood sample was collected from each patient for genomic DNA extraction by the manual phenol-chloroform method. Genotyping and allelic discrimination analysis were done using real-time PCR (RT-PCR). RESULTS AND DISCUSSION: With ABCB1 gene polymorphism rs1045642 (A > G), patients with AG/GG genotype showed better DFSR [P value = .02, OR = 2 (CI: 1.5-3)] and PFSR [P value = .02, OR = 1.6 (CI: 1.1-2.5)] when compared to AA genotype in the adjuvant and palliative settings, respectively. Similarly with rs1128503 (A > G) polymorphism, patients with AG/GG genotype were found to have better DFSR [P value = .02, OR = 1.9 (CI: 1.3-3)] and PFSR [P value = .01, OR = 2 (CI: 1.1-3.7)] when compared to AA genotype. However, we did not find any association between CAPOX response and ABCB1 gene polymorphisms in a binary logistic regression when non-genetic predictors were considered for analysis. We did not find any association with ERCC1 (rs11615 A > G) and ERCC2 (rs13181 T > G) gene polymorphisms with respect to CAPOX response in either of the treatment settings. WHAT IS NEW AND CONCLUSION: The response to CAPOX treatment was found to be influenced by the ABCB1 gene variants (rs1128503 and rs1045642), thereby strengthening their predictive role. No association was found between ERCC1 (rs11615 A > G), ERCC2 (rs13181 T > G) gene polymorphisms and tumour response to CAPOX treatment in CRC patients of South Indian origin.

Nitric Oxide in the Prevention of Pre-eclampsia (NOPE): A Double-Blind Randomized Placebo-Controlled Trial Assessing the Efficacy of Isosorbide Mononitrate in the Prevention of Pre-eclampsia in High-Risk Women.

INTRODUCTION: Pre-eclampsia contributes to maternal and fetal morbidity and mortality all over the world. Endothelial dysfunction is postulated to be the crux of the pathogenesis. Recent meta-analysis of aspirin trials showed aspirin to be effective when started early in pregnancy (at ≤ 16-week gestation). We aimed to study the effect of low-dose prophylactic isosorbide mononitrate (ISMN) 20 mg/day on the incidence of hypertensive diseases in high-risk women receiving standard aspirin prophylaxis. METHODS: Design: Randomized double-blind placebo-controlled parallel-arm superiority trial. Setting: Antenatal clinic of a tertiary teaching hospital, South India. Participants and methods: One hundred women fulfilling NICE guideline criteria for aspirin prophylaxis recruited at 12-16 weeks were randomized to receive either 20 mg/day of ISMN or placebo, in addition to 75 mg/day of oral aspirin from recruitment till delivery. Main outcome measure: Rate of hypertensive disorder of pregnancy (HDP). Sample Size: One hundred women (50 in each arm) to detect a decrease of HDP from 20% in the placebo group to 5% in the ISMN group with a power of 80% and at 0.05. RESULTS: One hundred women (50 in each arm) participated and completed the trial. Intention to treat analysis of these 100 women showed that the groups were comparable in terms of age, BMI, parity, and vascular indices (such as mean arterial pressure, uterine artery pulsatility index, flow-mediated vasodilatation index, brachial-ankle pulse wave velocity, Ankle-Brachial Index, brachial arterial stiffness index, and ankle arterial stiffness index). The rate of hypertensive disorders (gestational hypertension, pre-eclampsia, or superimposed pre-eclampsia) was not significantly different between the groups (14/50, 28% in ISMN vs. 12/50, 24% in placebo group; p = 0.7). The mean gestational age at diagnosis of hypertensive disease (35.4 vs. 36 weeks, ISMN vs. placebo groups, p = 0.7) or the rate of severe disease (8/50, 16% in ISMN vs. 7/50, 14% in the placebo group; p = 0.9) did not differ significantly between the two groups. Stillbirths (1 vs. 2), NICU admission rates (18 vs. 10%), and neonatal mortality (2 vs. 2) were also similar between the groups. CONCLUSION: The results of the randomized controlled trial of nitric oxide in the prevention of pre-eclampsia (NOPE) showed that in high-risk women receiving standard aspirin prophylaxis from less than 16 weeks, there is no significant reduction in the incidence of hypertensive disorders of pregnancy in the ISMN group, to the desired extent. There was no significant effect on the severity of disease, gestational age at diagnosis of disease or maternal-perinatal morbidity due to low-dose isosorbide mononitrate.

Screening of herbal medicines for potential allopathic antidiabetic adulterants: An analytical study.

BACKGROUND: There are several reports worldwide on adulteration of herbal medicines (HMs) with allopathic drugs. In India, only a few studies have reported adulteration of HMs with antidiabetics and there are no systematic studies. AIMS: To develop a rapid and validated method for detection of allopathic antidiabetic adulterants and to explore the extent of adulteration in HMs sold in South India. MATERIALS AND METHODS: Standards and solvents were purchased from Sigma-Aldrich. Different brands of antidiabetic HM samples with manufacturing licenses were procured from dispensaries. Spiked drug free psyllium husk as solid and flask seed oil as liquid herbal matrices were used for method development. The spiked matrices with different concentrations were extracted with methanol and subjected to centrifugation. The supernatant was collected and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Isocratic elution was carried on a C18 column with 0.1% (v/v) formic acid:methanol (3:7, v/v) as a mobile phase. All drugs were monitored for two ion products in positive electrospray ionization mode using multiple reaction monitoring scans. RESULTS: The retention time was 9 min. Limit of detection is 10 Pictograms (pg) for all analytes except for metformin, which was 370 pg. Recoveries of analytes range from 96% to 117%. Forty different brands of antidiabetic HMs were analyzed. Adulterant peaks were not observed in the mass chromatograms of HMs. CONCLUSIONS: A single-run method was developed by LC-MS/MS for the detection of proposed antidiabetics in HMs from licensed manufacturing units and online sold HMs across herbal dispensaries in Puducherry union territory, India. None of the HMs was found to be adulterated with proposed allopathic antidiabetic adulterants.

Lack of effect of the SLC47A1 and SLC47A2 gene polymorphisms on the glycemic response to metformin in type 2 diabetes mellitus patients.

Background This work aimed to evaluate the influence of single nucleotide polymorphisms (SNPs) in the SLC47A1 (922-158G>A; rs2289669) and SLC47A2 (-130G>A; rs12943590) genes on the relative change in HbA1c in type 2 diabetes mellitus (T2DM) patients of South India who are taking metformin as monotherapy. It also aims to study the effects of these SNPs on the dose requirement of metformin for glycemic control and the adverse effects of metformin. Methods Diabetes patients on metformin monotherapy were recruited based on the eligibility criteria (n=105). DNA was extracted and genotyping was performed with a real-time PCR system using TaqMan® SNP genotyping assay method. The HbA1c levels were measured using Bio-Rad D-10™ Hemoglobin Analyzer. Results After adjusting for multiple comparisons (Bonferroni correction) the difference found in the glycemic response between the "GG" genotype and "AG/AA" genotype groups of the SLC47A2 gene was not significant (p=0.027; which was greater than the critical value of 0.025). Patients with "GG" genotype showed a 5.5% decrease in HbA1c from baseline compared to those with the "AG/AA" genotype (0.1% increase). The SNP in the SLC47A1 gene also did not influence the glycemic response to metformin (p=0.079). The median dose requirements based on the genotypes of the rs12943590 variant (p=0.357) or rs2289669 variant (p=0.580) were not significantly different. Similarly, there was no significant difference in the occurrence of adverse effects across the genotypes in both the SLC47A1 (p=0.615) and SLC47A2 (p=0.309) genes. Conclusions The clinical response to metformin was not associated with the SNPs in the SLC47A1 and SLC47A2 genes coding for the multidrug and toxin extrusion protein (MATE) transporters. Furthermore, the studied SNPs had no influence on the dose requirement or adverse effects of metformin.

Genetic polymorphisms in cyclin H gene are associated with oxaliplatin-induced acute peripheral neuropathy in South Indian digestive tract cancer patients.

PURPOSE: Digestive tract cancer patients treated with oxaliplatin are often associated with the development of peripheral neuropathy. The aim of the present study is to identify the influence of single-nucleotide polymorphisms (SNPs) in genes involved in oxaliplatin metabolism, cell cycle control, detoxification or excretion pathways with the development of oxaliplatin-induced acute peripheral neuropathy (acute OXAIPN) and its severity among digestive tract cancer patients treated with oxaliplatin-based chemotherapy. PATIENTS AND METHODS: A total of 228 digestive tract cancer patients undergoing with the oxaliplatin-based chemotherapy between November 2014 and December 2016 were included in the current study. Genomic DNA was extracted from peripheral blood by standard phenol-chloroform method. Genotyping of five SNPs in four genes [GSTP1 (rs1965), ABCG2 (rs3114018), CCNH (rs2230641, rs3093816), AGXT (rs4426527)] was carried out by Real-Time TaqMan SNP genotyping assay. RESULTS: We found that the two genetic variants rs2230641 and rs3093816 in cyclin H (CCNH) gene were significantly associated with both the incidence and severity of acute OXAIPN. For CCNH-rs2230641 (AA vs AG+GG; dominant model) Incidence: OR 2.62, 95% CI 1.44-4.75, p = 0.001, severity; OR 4.64, 95% CI 1.58-13.62, p = 0.002. For CCNH-rs3093816 (AA vs AG+GG; dominant model); incidence: OR 3.43, 95% CI 1.57-7.50, p = 0.001; severity: OR 2.36, 95% CI 1.05-5.30, p = 0.033. CONCLUSIONS: The results of the present study found significant association between CCNH polymorphisms and acute OXAIPN development. However, further studies are warranted from independent groups to validate our study results.