Search

The present study aims to investigate the anti-inflammatory potential of the leaf hydroalcoholic extract of Piper betleoides C. DC., also known as "Jangli Paan" in Northeast India, using lipopolysaccharide (LPS)-treated both cell culture (RAW264.7, macrophage cells) and animal (albino rat) model of inflammation. Treatment with leaf hydroalcoholic extract of Piper betleoides (PBtE) dose-dependently (5, 10, and 20 µg/mL) decreased the secretion of pro-inflammatory (TNF-α, IL-6, and MCP-1) and increased anti-inflammatory (IL-4 and IL-10) cytokines in LPS-treated macrophages. Similarly, treatment with PBtE also prevented the alternation in mRNA expression of inflammatory markers (TNF-α, CCL-2, IL-6, and IL-10) in LPS-treated macrophages. Dose-dependent supplementation with PBtE further reduced the production of intracellular ROS and increased the phagocytosis efficacies in LPS-treated cells. Further in vivo studies demonstrated that treatment with PBtE dose-dependently (50, 100, and 200 mg/kg body weight) prevented the dysregulation of the secretion of inflammatory cytokines (TNF-α, IL-4, IL-6, and IL-10) and reduced the circulatory levels of prostaglandin (PGE2) and nitric oxide products (nitrite) in LPS-treated animals. In addition, alternation of blood cell profiling and the liver as well as kidney dysfunctions were also prevented by the treatment with PBtE in LPS-treated rats. The anti-inflammatory potential of PBtE was comparable to those seen in sodium diclofenac (positive control) treated group. LC-MS analyses showed piperine, piperlongumine, piperolactam-A, and dehydropipernonaline and GC-MS analyses demonstrated phytol, caryophyllene, and falcarinol as the phytochemicals present in Piper betleoides, which might play an important role in preventing inflammation and associated pathophysiology. Different treatments didn't cause any toxicity in cell culture and animal models. This study for the first time demonstrated the promising anti-inflammatory potential of the leaf hydroalcoholic extract of Piper betleoides., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: To compare the efficacy and safety of a fixed-dose combination of aspirin and pantoprazole with that of aspirin alone for the prevention of gastro duodenal mucosal damage in patients taking aspirin for secondary prevention of cardiovascular disease or cerebrovascular disease., Methods: This was a comparative, double-blind, double-dummy, randomized, multicenter, phase III study conducted in patients taking aspirin ≤150 mg daily for ≥3 to ≤6 months and expected to require daily aspirin therapy for at least 6 months for the secondary prevention of cardiovascular disease or cerebrovascular disease., Results: A total of 240 patients were randomized to receive either a fixed-dose combination of aspirin 150 mg and pantoprazole 20 mg or aspirin 150 mg alone in a 2:1 ratio. The proportion of non-responders (patients experiencing gastroduodenal events) was 9.7 % in the test group (fixed-dose combination of aspirin 150 mg and pantoprazole 20 mg) compared to 19.7 % in the comparator group (aspirin 150 mg) at week 12, while the proportions were 11.0 % in the test group and 22.4 % in the comparator group at the end of 24 weeks of treatment (p-value was <0.05 at week 12 and 24). GI injuries were significantly less in test group as compared to comparator group. Both drugs were well tolerated by all patients., Conclusion: The fixed-dose combination of aspirin 150 mg and pantoprazole 20 mg was found to be more efficacious and safer compared to aspirin 150 mg alone for the prevention of gastroduodenal mucosal damage in patients receiving aspirin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier, a division of RELX India, Pvt. Ltd.)

Purpose: To analyze the medical management of primary open-angle glaucoma (POAG) and ocular hypertension (OHT) and the placement of fixed-drug combination drugs (FDC) in the treatment paradigm at a tertiary eye care center in South India., Methods: Retrospective study (January 2011-December 2015) of newly diagnosed POAG and OHT patients (≥18 years) with ≥5 years follow-up. Primary outcome included percentage use of different antiglaucoma drugs (at initiation) and FDCs at the first, second, and third progression (sequencing). Secondary outcomes: Percentage discontinuation for different FDCs, efficacy parameters (decrease in intraocular pressure (IOP)/visual field), adverse events, and the median number of antiglaucoma medications (AGMs) after 5 years., Results: Three hundred and seventy eyes (198 patients) were analyzed; 84% of them had POAG. Prostaglandin analogs (PGAs) were the most common (66.2%). FDCs were started in 48 eyes (12.9%), with brimonidine + timolol combination being the most common. FDC usage at subsequent modifications was 10.1%, 24.04%, and 30.0%. Beta-blockers and PGAs were the most frequently prescribed AGMs in our practice pattern, with β-blockers being the most consistent one., Conclusion: This study is a fairly large study with a minimum of a 5-year follow-up of patients with POAG and OHT and gives insights into the treatment patterns, use of FDCs, and the need for multiple medications over time., (Copyright © 2024 Copyright: © 2024 Indian Journal of Ophthalmology.)

Aim: The present study compared the safety, efficacy, and tolerability of the new fixed-dose combination (FDC) of telmisartan 40 mg + bisoprolol 5 mg (TBP) tablets with the existing comparator FDC telmisartan 40 mg + metoprolol succinate ER 50 mg (TMS) tablets in patients with stage 1 and stage 2 hypertension., Methodology: The multicentric, double-blind, parallel-group, comparative, prospective, phase-III clinical study involved 264 subjects with stage 1 and stage 2 hypertension from 10 centres across India. The selected subjects were randomized into two groups: group A received the TMS and group B received the new FDC TBP. The primary endpoint was the mean change in seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) from baseline to week 12 in both the control and study arms. The secondary endpoint was achieving the target of SeSBP <140 mmHg and SeDBP <90 mmHg from baseline to week 12 in both groups. Safety and tolerability parameters were evaluated in both groups based on adverse effects (AEs) reported by the patients and the physician., Results: Both treatment groups exhibited a reduction in BP after 2 weeks of treatment, which was sustained until 12 weeks. The mean change in SeSBP and SeDBP at weeks 2, 6, and 12 compared to the previous visit showed statistical significance (p < 0.001) in all cases for both groups A and B. The mean changes in SeSBP and SeDBP from baseline to study end were numerically higher in group B than in group A. The mean difference in SeSBP from baseline to study end was significantly higher in group B compared to group A (p = 0.029). By week 12, 88.28 % and 89.84 % of subjects in group B achieved SeSBP <140 mmHg and SeDBP <90 mmHg respectively, while 86.71 % and 91.40 % of subjects in group A achieved the same targets. Reported AEs were mostly mild to moderate in both treatment groups, and no serious AEs or deaths were reported. Tolerability was rated as 'excellent' by 93.75 % of subjects in group B and 91.40 % of subjects in group A., Conclusion: Both the new FDC TBP and the existing comparator TMS combination therapy have comparable efficacy, tolerability, and safety for the management of stage 1 and stage 2 hypertension., Trial Registry Name: Clinical Trials Registry of India (CTRI) TRIAL REGISTRATION NO: CTRI/2021/11/037,926 PROTOCOL NO: MLBTL/05/2021 PROTOCOL URL: https://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=62069&EncHid=&userName=bisoprolol., Competing Interests: Declaration of competing interest The authors Dr. Manjula S and Dr. Krishna Kumar M are employees of Micro Labs Limited., (Copyright © 2024 Cardiological Society of India. Published by Elsevier, a division of RELX India, Pvt. Ltd. All rights reserved.)

Objective: This work was undertaken to evaluate the protective effect of Arsenicum album 30C against COVID-19., Design: The work was designed as a prospective parallel cluster cohort study., Intervention: Participants were enrolled in a homeopathy intervention (HI) cohort (who received Arsenicum album ) or in a non-intervention (NI) cohort (who received no systematic intervention) from COVID-19 containment areas of Delhi. Individuals of age 5 years or above were given four medicated pills of Arsenicum album 30C, while those from 1 to 5 years old were given two medicated pills in each dose., Results: The analysis included 10,180 individuals residing in 11 COVID-19 containment areas in Delhi, out of which 6,590 individuals were in the HI cohort and 3,590 individuals were in the NI cohort. The overall protective effect of Arsenicum album 30C was 83.43% (95% confidence interval [CI], 76.77 to 88.17): 45 cases per 6,590 (8.34 per 10,000 person-weeks) in the Arsenicum album 30C group versus 143 cases per 3,590 (45.01 per 10,000 person-weeks) in the NI cohort. The protective effect of Arsenicum album 30C against laboratory confirmed COVID-19 was 74.40% (95% CI, 55.08 to 85.41): 18 cases per 6,590 (3.32 per 10,000 person-weeks) in the Arsenicum album 30C group versus 38 cases per 3,590 (11.85 per 10,000 person-weeks) in the NI cohort., Conclusion: The   use of Arsenicum album 30C was associated with some protection against probable and laboratory-confirmed COVID-19 in a containment-zone setting. Randomized controlled trials are needed to confirm or refute these results., Competing Interests: None declared., (Faculty of Homeopathy. This article is published by Thieme.)

Root-knot nematode, Meloidogyne incognita is one of the most destructive nematodes worldwide. Essential oils (EOs) are being extensively utilized as eco-benign bionematicides, although the precise mechanism of action remains unclear. Pogostemon cablin Benth. is well-known as "Patchouli". It is native to South East Asia and known for ethno-pharmacological properties. In this study, chemical composition and potential nematicidal effect of EOs hydrodistilled from the leaves of P. cablin grown at three different locations in India were comprehensively investigated to correlate their mechanism of action for target specific binding affinities toward nematode proteins. Aromatic volatile Pogostemon essential oils (PEO) from Northern India (PEO-NI), Southern India (PEO-SI) and North Eastern India (PEO-NEI) were analyzed by Gas Chromatography-Mass Spectrometry (GC/MS) to characterize forty volatile compounds. Maximum thirty-three components were identified in PEO-NEI. Sesquiterpenes were predominant with higher content of α-guaiene (2.3-24.4 %), patchoulol (6.1-32.7 %) and α-bulnesene (5.9-27.1 %). Patchoulol was the major component in PEO-SI (32.7±1.2 %) and PEO-NEI (29.2±1.1 %), while α-guaiene in PEO-NI (24.4±1.2 %). In vitro nematicidal assay revealed significant nematicidal action (LC 50 44.6-87.0 μg mL -1 ) against juveniles of M. incognita within 24 h exposure. Mortality increases with increasing time to 48 h (LC 50 33.6-71.6 μg mL -1 ) and 72 h (LC 50 27.7-61.2 μg mL -1 ). Molecular modelling and in silico studies revealed multi-modal inhibitive action of α-bulnesene (-22 to -13 kJ mol -1 ) and α-guaiene (-22 to -12 kJ mol -1 ) against three target proteins namely, acetyl cholinesterase (AChE), odorant response gene-1 (ODR1), odorant response gene-3 (ODR3). Most preferable binding mechanism was observed against AChE due to pi-alkyl, pi-sigma, and hydrophobic interactions. Structure nematicidal activity relationship suggested the presence of hydroxy group for nematicidal activity is nonessential, rather highly depends on synergistic composition of sesquiterpene hydrocarbons., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

Aims: To evaluate the dose-effect association between COVID-19 vaccination and probability of turning RT-PCR positive and to assess the correlation between disease severity and vaccination status., Methods: A single centre cross-sectional study was conducted amongst 583 individuals presenting to COVID-19 testing clinic and 55 hospitalized COVID-19 patients. Vaccination status was assessed by the number of doses and duration since the last dose. Disease severity was evaluated by the requirement of hospitalisation and ICU admission/death. The association between the vaccination status and development of disease and its severity were statistically analyzed., Results: The mean age of the population was 36.6 years and 82.6% had no comorbidities. The odds of turning RT-PCR positive was 0.17(95% CI: 0.11-0.27) among the clinical suspects who had taken both doses of the vaccine at least 14 days before (fully vaccinated). The odds of hospitalisation was 0.12(95% CI: 0.03-0.45) and ICU admission/death was 0.07(95% CI: 0.01-0.36) among fully vaccinated individuals. The protective role of vaccination was observed to start 14 days after receiving the first dose., Conclusions: COVID-19 vaccination provides dose-dependent protection against the development of the disease. It also lowers the risk of hospitalisation and ICU admission/death in RT-PCR positive patients in a dose-dependent manner., Competing Interests: Declaration of competing interest There is no conflicts of interest between the authors., (Copyright © 2021 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear., Methods: The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol., Discussion: The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society., (© 2021 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Aims: To study the feasibility of diabetes education through telemedicine in patients with diabetes mellitus (DM) hospitalized for coronavirus disease 2019 (COVID-19) management., Methods: This was a prospective study of 100 patients with DM who were admitted in a COVID isolation ward for management of COVID-19. Patients managed with multiple subcutaneous insulin injections were eligible. During teleconsultation, diabetes education including insulin injection technique was given by a diabetes educator via a phone call (audio and video) during hospitalization. They were also re-assessed after 2 weeks of discharge from the hospital via teleconsultation or in-person., Results: Out of 100 patients, 72.0% had prior history of diabetes while 28.0% were newly diagnosed. The median age of our cohort was 56 years and median duration of diabetes was 7.0 years. Telemedicine as a mode of consult for diabetes education was accepted by 96.0% of patients during hospitalization. At 2 weeks' follow-up, 77.0% patients were following insulin instructions correctly and were satisfied with this mode of consultation., Conclusion: Diabetes education using telemedicine as a technology is feasible, acceptable, and effective in the management of most patients with DM. Telemedicine appears to be an effective way to replace routine visits in special situations., (Copyright © 2021 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed for extensive data for differing dosage forms and routes for dexamethasone (DEX) and betamethasone (BET) in 48 healthy nonpregnant Indian women in a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM) where each woman enrolled in a two-period cross-over study. Plasma concentrations collected over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs. Overall, BET exhibited slower clearance, similar volume of distribution, faster absorption, and longer persistence than DEX with BET acetate producing extremely slow absorption but full bioavailability of BET. Six biomarkers were assessed over a 24-h baseline period with four showing circadian rhythms with complex baselines. These baselines and the strong responses seen after drug dosing were fitted with various indirect response models using the Laplace estimation methods in NONMEM 7.4. Both the PK and six biomarker responses were well-described with modest variability likely due to the homogeneous ages, weights, and ethnicities of the women. The drugs either inhibited or stimulated the influx processes with some models requiring joint inclusion of drug effects on circadian cortisol suppression. The biomarkers and order of sensitivity (lowest IC 50 /SC 50 to highest) were: cortisol, T-helper cells, basophils, glucose, neutrophils, and T-cytotoxic cells. DEX sensitivities were generally greater than BET with corresponding mean ratios for these biomarkers of 2.86, 1.27, 1.72, 1.27, 2.69, and 1.06. Overall, the longer PK (e.g. half-life) of BET, but lesser PD activity (e.g. higher IC 50 ), produces single-dose response profiles that appear quite similar, except for the extended effects from BET-PA. This comprehensive population modeling effort provides the first detailed comparison of the PK profiles and six biomarker responses of five commonly used dosage forms of DEX and BET in healthy women.

The study aims to estimate the prevalence of hydroxychloroquine (HCQ) retinopathy in a cohort of Indian patients and analyse the associated factors. Adult patients with rheumatological disorders aged ≥ 18 years using HCQ for more than 5 years and/or having received a cumulative dose > 400 g were included. Demographic and clinical data were collected and all underwent ophthalmological tests which included Humphrey automated visual fields (AVF) and spectral domain optical coherence tomography (SD-OCT). The various clinical characteristics of the patients were compared. The study included 110 patients with a mean age of 43.5 ± 10.1 years and predominantly females. Eleven patients (10%) were diagnosed with definite HCQ retinopathy. The mean daily dose of HCQ (mg/kg of real body weight) was significantly different in the groups with and without retinopathy (5.7 ± 0.9 vs 5.1 ± 0.8, p = 0.04). Patients with retinopathy had significantly more colour vision abnormalities (odds of 16.9; confidence interval 4.1-69.1, p = 0.0001) and higher prevalence of both parafoveal and perifoveal thinning (p < 0.0001). Age, gender, duration of HCQ use, cumulative HCQ dose and body mass index were not found to be associated with retinopathy. Four out of 11 patients had abnormalities only on 30-2 protocol for AVF testing, two had abnormalities only on 10-2 protocol, whereas five patients had abnormalities on both protocols. SD-OCT abnormalities were present in all patients with retinopathy. Hydroxychloroquine retinopathy was prevalent in the study cohort and significantly associated with a higher daily dose of HCQ (mg/kg real body weight).

Background and Aims: Insulin therapy is an integral part of diabetes management. However, reliable and easily accessible information on a number of basic facts concerning insulin therapy, including storage of insulin, managing insulin therapy during travel, nuances of insulin use while driving, and dose adjustments during sick days is lacking. This document aims to make readily available, reliable, and easy to implement information on these essential but relatively less discussed aspects of insulin therapy., Method: Literature search was performed using PubMed and Cochrane Library from inception till 1 st of July 2019. The relevant topics were reviewed by a panel of 5 specialists and 23 contributing physicians and endocrinologists, who had assembled at Bengaluru, India for the 13th National Insulin Summit. After a thorough review of the literature, and following detailed discussions, the committee arrived at these recommendations., Results: Unopened vials and cartridges of insulin should be stored at 2 °C-8 °C in a refrigerator and protected from direct sunlight. For opened vials and in-use cartridges, manufacturer's instructions must be followed at all times. While traveling by air, dose adjustments are required only when flying across more than five time zones in the east or west directions. Insulin therapy should not be omitted or stopped during an acute illness; rather the doses need careful adjustments based on self-monitoring of blood glucose., Conclusion: Recommendations and guidelines, covering many common aspects of insulin therapy are readily available. This consensus document aims to make recommendations for those essential aspects of insulin therapy that are crucial for its success but are relatively less known and less discussed., Competing Interests: Declaration of competing interest Declares that there is no conflict of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Background: The pharmacokinetics of primaquine [PQ] have been the subject of studies in both adults and healthy participants. However, there is no study on its pharmacokinetics in a setting of undernourishment. In India, there is evidence to show considerable malnourishment in children that in turn can affect drug pharmacokinetics. Given that the country is moving towards malaria elimination, the present study was planned with the objective of comparing pharmacokinetics of the drug in undernourished children relative to normally nourished children., Materials and Methods: After Institutional Ethics Committee approval, children of either gender between the ages of 5 and 12 years and smear-positive for Plasmodium vivax malaria were included. Nourishment status was determined using the Indian Academy of Pediatrics classification of protein energy malnutrition based on Khadilkar's growth charts. Twelve children each were enrolled in the two groups. PQ was given in the dose of 0.3 mg/kg/d and blood collections were made at 0, 1, 2, 3, 4, 6, 8 and 24 hours post-dosing. Levels were estimated by high-performance liquid chromatography. Chloroquine in the dose of 25 mg/kg was given over three days along with supportive care., Results: Of the 24 children, there were 17 boys and 7 girls. There was a statistically significant difference in the body weight between the undernourished and the normally nourished children [21.5 ± 5.52 vs. 28.8 ± 8.84, P < 0.05]. PQ levels showed wide inter-individual variation in both groups. No significant difference was seen in any pharmacokinetic parameter between the two groups., Discussion: This study adds to the limited body of evidence on the pharmacokinetics of PQ in children with malaria and indicates that the dosing of primaquine could potentially be independent of the nourishment status., Competing Interests: None

Zingiberaceae plants are well known for their use in ethnomedicine. Curcuma mutabilis Škorničk., M. Sabu & Prasanthk., is an endemic Zingiberaceae species from Western Ghats of Kerala, India. Here, we report for the first time, the anticancer potential of petroleum ether extract from C. mutabilis rhizome (CMRP) and a novel labdane diterpenoid, (E)-14, 15-epoxylabda-8(17), 12-dien-16-al (Cm epoxide) isolated from it. CMRP was found to be a mixture of potent bioactive compounds including Cm epoxide. Both the extract and the compound displayed superior antiproliferative activity against several human cancer cell lines, without any display of cytotoxicity towards normal human cells such as peripheral blood derived lymphocytes and erythrocytes. CMRP treatment resulted in phosphatidylserine externalization, increase in the levels of intracellular ROS, Ca 2+ , loss of mitochondrial membrane potential as well as fragmentation of genomic DNA. Analyses of transcript profiling and immunostained western blots of extract-treated cancer cells confirmed induction of apoptosis by both intrinsic and extrinsic pathways. The purified compound, Cm epoxide, was also found to induce apoptosis in many human cancer cell types tested. Both CMRP and the Cm epoxide were found to be pharmacologically safe in terms of acute toxicity assessment using Swiss albino mice model. Further, molecular docking interactions of Cm epoxide with selected proteins involved in cell survival and death were also indicative of its druggability. Overall, our findings reveal that the endemic C. mutabilis rhizome extract and the compound Cm epoxide isolated from it are potential candidates for development of future cancer chemotherapeutics.

The drug resistance of Plasmodium vivax in clinical cases remains largely unknown till date because of the difficulty in diagnosing the resistant P. vivax strains. The present study was undertaken to determine the prevalence of mutant alleles in drug resistance genes viz P. vivax multi-drug resistance (pvmdr-1), chloroquine resistance transporter (pvcrt-o), dihydrofolate reductase (pvdhfr) and dihydropteroate synthase (pvdhps) along with in vitro chloroquine (CQ) sensitivity in P. vivax clinical isolates. During August-October 2017 a total of 86 samples of the febrile patients were screened and 31 samples were found to be positive for P. vivax in Safdarjung hospital, New Delhi. Sequence genotyping of the drug resistance genes was carried out in these P. vivax samples and in vitro CQ susceptibility for 23 isolates was determined by the schizont maturation assay (SMA). The CQ inhibitory concentrations (IC 50 ) for the clinical isolates was found to be in the range of 25.6-176.7 nM. All the 31 clinical isolates analyzed for pvmdr-1 gene, showed mutant alleles and in only two isolates novel mutations at 861 and 898 codons were observed. Sequence analysis of pvcrt-o, pvdhfr and pvdhps genes revealed wild type genotypes in all the 31 studied isolates. The presence of mutations in pvmdr-1 gene and the increase in the CQ IC 50 value indicates the possibility of shift in drug tolerance where CQ with primaquine (PQ) is still the first line of treatment for P. vivax malaria in the country. The regular molecular surveillance in P. vivax would provide useful information for the policy makers of the malaria control programme., (Copyright © 2020. Published by Elsevier Inc.)

Background: Warfarin is primarily metabolized by cytochrome P450 2C9 (CYP2C9) enzyme, which is encoded by the CYP2C9 gene. CYP2C9*2 and CYP2C9*3 variants significantly influence warfarin metabolism and subsequently the required dose of warfarin., Objectives: The current retrospective study was aimed to determine the influence of CYP2C9 variants on warfarin metabolic ratio (MR, warfarin/7-hydroxy warfarin) and warfarin maintenance therapy in 210 patients (mean age 44.6±11.6 (SD) years; male to female ratio 81:129)., Methods: High-performance liquid chromatography (HPLC) with UV detector was used to measure plasma concentrations of warfarin and 7-hydroxy warfarin. Plasma samples were collected 12 h after the previous dose of warfarin was administered. CYP2C9 variants (rs1799853 and rs1057910) were identified using real-time polymerase chain reaction allele-discrimination method., Results: The mean daily maintenance dose of warfarin was 4.6±1.8 (SD) mg. The mean plasma warfarin and 7-hydroxy warfarin concentrations were 3.7±1.6 (SD) μg/mL and 1.1±0.54 (SD) μg/mL, respectively. Patients carrying other CYP2C9 variants required 39% lower warfarin maintenance dose 3.3±1.2(SD)mg than CYP2C9*1*1 carrier 4.9±1.8(SD)mg, (p<0.0001). MRs differed significantly between CYP2C9 variant carriers (8.1±5.1) and normal genotype carriers (4.8±3.9) (p<0.0001). Probit analysis identified an MR value of 7.6 as the anti-mode (sensitivity of 84% and specificity of 55%) to differentiate poor and intermediate metabolizers (carriers of any CYP2C9*2 or CYP2C9*3 variants) from normal metabolizers (CYP2C9*1*1 genotype)., Conclusion: The present study results provide, insights on the effect of CYP2C9 genetic polymorphisms on inter-individual variability in warfarin metabolism and emphasizes utility of phenotyping in a setting of genotype-guided dosing of warfarin in South Indian population., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Mercury (Hg) is a toxic heavy metal, and the reported effects of exposure on liver function continue to be inconsistent. The objective of our study was to identify correlations between high blood Hg levels and liver enzymes in a pan-India population including adults ≥19 years of age. This retrospective study analyzed the data from 95,398 individuals tested for blood Hg levels and liver enzymes in our national laboratory. Testing for blood Hg was done by inductively coupled plasma-mass spectrometry, while testing for liver enzymes-aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), and gamma-glutamyl transferase-was done by automated photometry systems. Data from all the individuals inclusive of 52,497 males and 42,901 females were studied. The frequency of high blood Hg levels (>5 µg/L) was found to be 0.6%, and the difference between males and females was not found to be significant. Further correlation by linear regression analysis found no relationship between high blood Hg levels and liver enzymes among females. However, among males, there was a significant correlation between high blood Hg levels, and increased AST as well as ALT. Our report suggested that for males but not females, Hg exposure may be one of the differentials for elevated liver enzymes.

With the increasing emergence of drug resistance in enterococci, there have been very limited data on the efficacy of orally available nitrofurantoin and fosfomycin on enterococci causing urinary tract infections (UTIs), particularly for multidrug-resistant (MDR) strains. This study aimed to determine the in vitro effectiveness of these two drugs against the MDR enterococci. A total of 514 phenotypically and genotypically confirmed isolates of enterococci (239, 46.5% Enterococcus faecalis and 275, 53.5% Enterococcus faecium ) showed E. faecalis as significantly more resistant ( p  < 0.05) to ciprofloxacin and high strength gentamicin. Vancomycin resistance was seen in 37 (7.2%) isolates. Of these, 114 (22.18%) isolates (51, 44.73% E. faecalis and 63, 55.26% E. faecium ) were MDR. Nitrofurantoin minimum inhibitory concentrations (MICs) for the MDR enterococci varied from 1 to 128 μg/mL (MIC 50 8 μg/mL, MIC 90 64 μg/mL for E. faecalis ), while fosfomycin MICs for the MDR E. faecalis , including vancomycin resistant enterococci (VRE) were in susceptible range (≤64 μg/mL, MIC 50 8 μg/mL, MIC 90 16 μg/mL). An efficacy ratio of ≥8 for nitrofurantoin was observed in the 39 (76.5%) MDR E. faecalis and 44 (69.8%) MDR E. faecium isolates as against the 50 (98%) E. faecalis isolates for fosfomycin. Although nitrofurantoin has been widely prescribed for the treatment of UTIs for the past several years, it was still found to be active in vitro against the urinary isolates of MDR enterococci, including VRE. As for fosfomycin, it holds robust potential to be used against the urinary MDR enterococci and VRE ( E. faecalis ).

A hallmark of mortality and morbidity, malaria is affecting nearly half of the world's population. Emergence of drug-resistant strains of malarial parasite prompts identification and evaluation of medicinal plants and their constituents that may hold the key to a new and effective anti-malarial drug. In this context, nineteen methanolic extracts from seventeen medicinal plants were evaluated for anti-plasmodial potential against Plasmodium falciparum strain 3D7 (Chloroquine (CQ) sensitive) and INDO (CQ resistant) using fluorescence based SYBR-Green assay and for cytotoxic effects against mammalian cell lines. Leaf extract of two plants showed promising in vitro anti-malarial activity (Pf3D7 IC 50  ≤ 10 μg/ml); one plant extract showed good activity (Pf3D7 IC 50  = 10.1-20 μg/ml); seven were moderately active (IC 50  = 20.1-50 μg/ml), four plant extracts showed poor activity (PfD7 IC 50  = 50.1-100 μg/ml) and five extracts showed no activity up to IC 50  = 100 μg/ml. Further, six extracts were found equipotent to PfINDO (resistance index ranging 0.4-2) and relatively nontoxic to mammalian cell lines HEK293 (cytotoxicity index ranging 1.4-12.5). Based on good resistance and selectivity indices, three extracts were evaluated for in vivo activity in Plasmodium berghei ANKA infected mice at a dose of 500 mg/kg and they showed significant suppression of P. berghei parasitemia. Further, these active plant extracts were fractionated using silica-gel chromatography and their fractions were evaluated for anti-plasmodial action. Obtained fractions showed enrichment in antimalarial activity. Active fractions were analyzed by gas chromatography and mass-spectrometery. Results suggests that the three active plant extracts could serve as potent source of anti-malarial agent and therefore require further analysis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Peri-operative glucocorticoids are routinely administered to patients undergoing trans-sphenoidal surgery for non-functional pituitary adenomas (NFPA) irrespective of hypothalamus-pituitary-adrenal (HPA) axis status., Purpose: Evaluation of HPA axis before and 12 weeks after endoscopic trans-sphenoidal adenomectomy (E-TSA) utilizing low-dose (1 μg) ACTH stimulation test (LDACTH) to determine the need for glucocorticoid administration in patients with NFPA. We also determined the factors that can predict occurrence of hypocortisolism at 12 weeks after surgery., Methods: Sixty-three consecutive patients with NFPA requiring surgical excision were enrolled in this study. Glucocorticoids were administered to patients with demonstrable hypocortisolism [preoperative peak cortisol < 16 μg/dL during LDACTH test, postoperative day 3 (POD-3) 0800 hrs Cortisol < 8 μg/dL or stimulated cortisol (LDACTH) < 16 μg/dL at 12 weeks]., Results: Hypocortisolism was present in 43 patients (68.2%) pre-operatively and persisted in 33 patients (52.4%) on POD-3. Thirty-three patients (52.4%) had hypocortisolism at 12 weeks after surgery. Eleven patients (17.4%) did not require glucocorticoids during the entire study period and 30 patients (47.6%) did not require glucocorticoids after 3 months. None of the patients developed adrenal crisis during the study. Hypocortisolism on the third post-operative day was the single significant predictor of hypocortisolism at 12 weeks after the surgery. There was a significant correlation between POD-3 0800 hrs cortisol ≥ 8μg/dL and stimulated cortisol (LDACTH) ≥16μg/dL at 12 weeks (r = 0.62, p < 0.0001). POD-3 0800 hrs cortisol ≥ 8 μg/dL had 73% sensitivity and 79% specificity in predicting eucortisolism at 12 weeks., Conclusions: HPA function is preserved in significant proportion of NFPA patients undergoing E-TSA. Perioperative glucocorticoids should be given only in patients with demonstrable preoperative hypocortisolism on 1 μg ACTH test. Postoperative day 3 0800 hrs cortisol is a reasonable predictor of HPA axis status at 12 weeks after surgery.

Background: High-dose methotrexate (HDMTX) is recommended to be administered with serial monitoring of methotrexate (MTX) levels, which may not be universally feasible in resource-limited settings. In this study, we evaluated the overall experience of administration of HDMTX at our center by monitoring a single drug level at 54 h from the start of MTX infusion., Methods: This retrospective study was performed at a tertiary level hospital in north India, over a 5-year period (2011-2015). All patients <18 years of age with newly diagnosed acute lymphoblastic leukemia (ALL) and T-non-Hodgkin lymphoma (T-NHL) were enrolled in the study. Details of HDMTX and all significant toxicities requiring prolonged or repeat hospitalization were retrieved from the medical records. All eligible patients received HDMTX as per the recommendations followed by at least three doses of leucovorin rescue, before drug levels were sent at 54 h. Subsequent leucovorin doses were adjusted accordingly., Results: The records of 598 cycles of HDMTX in 184 patients were reviewed. A total of 531 of 598 cycles (88.7%) were managed with monitoring only a single plasma drug level at 54 h from the beginning of infusion. Delayed MTX clearance was seen in 260 of 598 cycles (43.5%). Only three episodes (0.5%) were associated with significant toxicity. There were no deaths., Conclusions: The strategy of monitoring MTX concentration at 54 h was safe in our cohort. Although recommended, dynamic monitoring of plasma drug levels may not always predict toxicity., (© 2020 Wiley Periodicals, Inc.)

Aims: Macrophage activation syndrome (MAS) is a dreaded complication of systemic inflammatory diseases and is most commonly seen in systemic juvenile idiopathic arthritis (sJIA). We evaluate the clinical features, laboratory findings and outcomes in pediatric MAS, assess the response to different pharmacological therapies, and finally identify possible factors associated with an unfavorable outcome., Methods: This is a retrospective analysis of data from patients diagnosed as having MAS, admitted between July 2008 and April 2018 into the Department of Pediatric Rheumatology, Institute Of Child Health Kolkata. The data noted were the clinical and laboratory features, treatment details, responses to therapy and outcomes., Results: Thirty-one patients were diagnosed as having MAS. Primary illness was sJIA in 26 (84%), systemic lupus erythematosus in 4 (13%) and Kawasaki disease (KD) in 1 (3%). All had fever with varying degrees of multisystemic involvement. Hyperferritinemia was universally present. Pulse methylprednisolone with cyclosporine was used for treating the majority. Ten patients (32%) expired., Conclusion: Macrophage activation syndrome is a near fatal complication with protean manifestations and multiorgan dysfunction. Hyperferritinemia is characteristic, higher values being associated with increased mortality. Cases resistant to steroids and cyclosporine had a poor prognosis. Late presentations with multiorgan dysfunction were associated with the poorest outcomes., (© 2020 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objectives: The objectives of this study were to determine the relationship between genetic polymorphisms in gene encodings for CYP3A4 and carbamazepine (CBZ)-induced dose-related side effects in North Indian people with epilepsy., Patients and Methods: The current prospective study included 37 patients with CBZ-induced dose-related side effects and 102 patients who did not experience side effects while on CBZ. The genotyping for CYP3A4 allele (CYP3A4*16) was done using real-time polymerase chain reaction (RT-PCR) in Applied Biosystems 7500 RT-PCR System (USA). CBZ was administered in all patients at a dose varying from 15 to 20 mg/kg daily., Results: Various demographic variables were comparable between the groups except that control of seizures was far better in controls. After testing, it was found that none of our patients had the presence of CYP3A4*16 allele., Conclusion: CYP3A4*16 allele is not represented significantly in North Indian people with CBZ-induced dose-related side effects., Competing Interests: None

The dose of Anti Snake Venom (ASV) in hemotoxic snake bite depends on the amount of venom injected and species of snake. All trials in South East Asia have studied different doses of ASV, wherein the ASV in high dose group itself was lower than the dose that is recommended in Indian National protocol. These studies favored low dose protocol, as there was no difference in mortality and morbidity between the groups. So, this study intended to assess the efficacy of National protocol in reducing morbidity and mortality in hemotoxic snake bite in comparison to current protocol followed in institution. This was an open label randomized trial of 140 hemotoxic snakebite patients. Group A received national protocol: initial dose of 100 ml followed by 100 ml 6th hourly till 20-min Whole Blood Clotting Time (20WBCT) was negative or 300 ml of ASV was given, whichever was earlier. Group B received 70 ml followed by 30 ml every 6th hourly until two consecutive 20WBCT were negative. There was no statistical difference in the amount of ASV required in both the groups. Mortality and acute kidney injury were higher in group A (statistically not significant), probably due to sicker patients in that group. There was no relapse of clotting time abnormality in both the groups. In a significant number of patients (12%), clotting time was persistently prolonged till death. We found that the use of National ASV dosing protocol did not decrease the mortality and morbidity., Competing Interests: Declaration of competing interest We have not taken any financial grant or services from the government, commercial or any private foundation. We don't have any relationships, conditions or circumstances that present a potential conflict of interest. We also declare that we don't have conflict of interest with each other., (Copyright © 2020 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

Background: Government of India's Revised National TB Control Programme (RNTCP) has begun implementing daily fixed dose combination (FDC) anti-TB treatment regimen for drug sensitive TB patients in which ethambutol is given for six months. Prolonged ethambutol use is known to cause ocular adverse drug events (ADE)., Objectives: To assess the magnitude of ocular ADEs in adult drug sensitive TB patients initiated on daily FDCs and to describe the demographic and clinical profile of patients with ocular ADEs., Methods: We conducted a retrospective cohort study involving review of RNTCP records of all adult (age >14 years) drug sensitive TB patients initiated on daily FDCs between1 st January 2018 and 31st July 2018 in Thiruvananthapuram district, Kerala State, India., Results: 714 patients were initiated on daily FDCs during the study period. It was unknown whether all patients had undergone assessment for ocular ADEs. However, of these 714 patients, 8 patients (1.1%) were documented to have had ocular ADEs. Seven of these 8 patients had received ethambutol more than 15 mg/kg body weight and had developed ocular symptoms (decreased/blurring of vision) 3 months after TB treatment initiation. Ethambutol was stopped in all these 8 patients. In 5 patients it was recorded that ocular ADEs had resolved following stoppage of ethambutol and in the remaining it was unknown., Conclusion: The study confirms the occurrence of ocular ADEs among drug sensitive TB patients on daily FDCs and recommends strengthening of systems for assessing, documenting and managing ocular ADE., Competing Interests: Conflicts of interest The authors have none to declare., (Copyright © 2020 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

High-dose betamethasone and dexamethasone are standard of care treatments for women at risk of preterm delivery to improve neonatal respiratory and mortality outcomes. The dose in current use has never been evaluated to minimize exposures while assuring efficacy. We report the pharmacokinetics and pharmacodynamics (PDs) of oral and intramuscular treatments with single 6 mg doses of dexamethasone phosphate, betamethasone phosphate, or a 1:1 mixture of betamethasone phosphate and betamethasone acetate in reproductive age South Asian women. Intramuscular or oral betamethasone has a terminal half-life of 11 hours, about twice as long as the 5.5 hours for oral and intramuscular dexamethasone. The 1:1 mixture of betamethasone phosphate and betamethasone acetate shows an immediate release of betamethasone followed by a slow release where plasma betamethasone can be measured out to 14 days after the single dose administration, likely from a depo formed at the injection site by the acetate. PD responses were: increased glucose, suppressed cortisol, increased neutrophils, and suppressed basophils, CD3CD4 and CD3CD8 lymphocytes. PD responses were comparable for betamethasone and dexamethasone, but with longer times to return to baseline for betamethasone. The 1:1 mixture of betamethasone phosphate and betamethasone acetate caused much longer adrenal suppression because of the slow release. These results will guide the development of better treatment strategies to minimize fetal and maternal drug exposures for women at risk of preterm delivery., (© 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

To compare the efficacy of low dose fentanyl infusion and 24% oral sucrose in providing optimal pain relief during laser for retinopathy of prematurity (ROP), we enrolled fifty-eight spontaneously breathing preterm infants undergoing laser. The preterm infants were randomized to either fentanyl infusion (1 mcg/kg/hr) or 24% oral sucrose (2 ml). We evaluated and compared the proportion of time spent crying during the procedure, salivary cortisol before and after the procedure, premature infant pain profile- revised (PIPP-R) scores during the procedure, apnoea during and after the procedure, need for mechanical ventilation, and feed intolerance and urinary retention 24 h after the procedure between the two groups. We found that the proportion of time spent crying during the procedure was significantly less in the fentanyl group [62.5% (50.7-74.2) vs 73.8% (55.6-83.4); P = 0.02]. Average PIPP-R score during the procedure was significantly less in the fentanyl group [7.2 vs 9.0; (mean difference of - 1.8; P = 0.01)]. There was no difference in other outcomes between the two groups.Conclusion: During laser for ROP, low dose fentanyl infusion was found to be efficacious in reducing pain as compared with 24% sucrose.What is Known:• Preterm infants undergoing laser photocoagulation for ROP suffer significant amount of pain.• Standard of care for pain relief in infants undergoing laser therapy in developed countries is general anesthesia (GA) or combination of sedation, analgesia, and paralysis (SAP).What is New:• During laser photocoagulation for ROP, fentanyl infusion at low dose (1 mcg/kg/hr) is efficacious in reducing pain as compared to 24% oral sucrose.

Aim: A significant proportion of patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are either steroid dependent or steroid resistant, requiring long-term calcineurin inhibitors (CNI) use. Rituximab has more favourable safety profile. The present study was undertaken to evaluate the efficacy and safety of rituximab in CNI-dependent patients., Methods: This was a prospective observational study conducted from July 2014 to February 2018. Steroid-dependent nephrotic syndrome or steroid-resistant nephrotic syndrome (biopsy proven MCD/FSGS), who were CNI dependent were enrolled. Mean age at enrolment was 22.77 ± 7.45 years. All patients received rituximab at a dose of 375 mg/m 2 at entry in the study. CD-19 levels were monitored monthly and patients having CD-19 levels >5/μL and/or > 1% received additional low-dose (100 mg) of rituximab., Results: A total of 24 patients were followed up for 12 months. At the end of 6 and 12 months, 87.5% and 79.16% of the patients achieved remission, respectively. Eight (33.33%) patients developed relapse. The mean dose of rituximab in the first year was 791 mg. The average cost of rituximab in the first year was 487.17$. Rituximab was well-tolerated, with mild infusion reactions, respiratory tract infection and oral candidiasis in 5 (20.83%), 5 (20.83%) and 1 (4.17%) patient, respectively., Conclusions: CD-19 targeted rituximab is a safe and cost-effective agent in remission maintenance in adults with CNI dependent. Over three-fourths of the patients with CNI-dependent podocytopathy maintain clinical remission with CD-19 targeted rituximab therapy., (© 2018 Asian Pacific Society of Nephrology.)

Polyaromatic hydrocarbons are a group of chemical pollutants which cause a significant threat to the living organisms in estuaries and marine ecosystems. We report the effect of chrysene, a major PAH pollutant found in Cochin Estuary along the southwest coast of India, on the neuroendocrine and immune gene expression of the post larvae (PL-25) of Penaeus monodon. The PL- 25 of P. monodon were administered with feed coated with increasing concentrations of chrysene (1, 2 and 3 µg/g) for 10 days and the gene expression was studied on 7th, 11th and 15th day. The PL exposed to chrysene showed moulting stress and changes in the levels of moult-inhibiting hormone I (MIH I) indicated by irregular moulting in the experimental tanks. At the molecular level, the higher concentration of chrysene induced two-fold upregulation of neuroendocrine (MIH I) and downregulation of immune (ProPO and crustin) gene on the 7th day of exposure. The expression of MIH I gene reduced on withdrawing the experimental feed (on 11th day), while continued downregulation of ProPO and crustin were observed on the 11th day. The results of the present study indicate that the microgram levels of PAH can impinge the neuroendocrine and immune system of the P. monodon, which may induce morbidity and mortality to the larvae in polluted coastal ecosystems. Therefore, more attention may be given to avoid PAH pollution in the estuaries to maintain a healthy ecosystem and to protect the animals from extinction.

Severe alcoholic hepatitis (SAH) is often a progressive disease with high mortality and limited steroid responsiveness. Management options of steroid nonresponsive SAH (day 7 Lille score > 0.45) are limited. We assessed the efficacy and safety of granulocyte colony-stimulating factor (G-CSF) in steroid nonresponders. A randomized, double-blind, single-center trial (NCT01820208) was conducted between March 2013 and June 2016 in patients with histologically proven SAH, nonresponsive to 40 mg/day of prednisolone were randomized to G-CSF (12 doses, 300 μg each in 28 days) or placebo. Responders were continued with prednisolone. Of the 430 patients with SAH, 132 received steroid therapy. Of these, 33 (25%) were nonresponders and were randomized to G-CSF or placebo (14 in each group after exclusions). The baseline characteristics of both groups were comparable. The 28-day mortality was comparable between the groups (21.4%, G-CSF; 28.6%, placebo; P = 0.69). At 90 days, in the G-CSF but not in the placebo group, the Model for End-Stage Liver Disease reduced from 24.6 ± 3.9 to 19.4 ± 3.7 (P = 0.002) and Maddrey's discriminant function from 74.8 ± 22.8 to 57.4 ± 31 (P = 0.26). Infections were less common (28% versus 71%; P < 0.001) with lower 90-day mortality (35.7% versus 71.4%; P = 0.04) in the G-CSF than in the placebo group. On Cox regression analysis, receiving G-CSF (hazard ratio, 0.37; SD, 0.14-0.98; P = 0.04), and high baseline serum creatinine (hazard ratio, 4.12; SD, 1.7-10.3; P = 0.002) predicted day-90 outcomes in steroid nonresponsive SAH. Patients tolerated G-CSF without any major adverse events. Conclusion: Approximately one-quarter of patients with SAH do not respond to corticosteroid therapy. Administration of G-CSF is safe and helps to reduce the disease severity and 90-day mortality in these patients., (© 2019 by the American Association for the Study of Liver Diseases.)

Weight estimation in pediatric emergencies is often required for calculation of drug dosages, fluid therapy and defibrillation. The 'gold standard' of actually weighing the patient is not practically possible in emergency conditions. The aim of this study is to validate common age-based formulae (APLS, Luscombe and Argall's) and their accuracy in estimating weight of under 5-y-old Indian children by secondary data analysis from a cross-sectional study conducted by the National Nutrition Monitoring Bureau (NNMB), National Institute of Nutrition, Hyderabad, in 10 states of India in 2011-12 among under five-year-old children. Their measured weights were compared to their estimated weights as calculated using the APLS formula, the Luscombe and Argall formulae. There is a need to adjust the formulae for accurate estimation of weight among Indian children as all the three age-based weight formulae namely APLS, Argyll and Luscombe overestimated the weight among the Indian children.

A desperate situation may evoke a fundamental question or suggestion of a radical solution. Hence, let us first examine whether the current situation of maternal anemia in India is really desperate and therefore merits a search for a "magic bullet" as a cure.

Background & Objectives: Survival of patients with multiple myeloma (MM) has improved in the past two decades following use of novel agents and autologous stem cell transplantation. To determine predictors of long-term outcome, data of MM patients who underwent autologous stem cell transplantation (ASCT) at a tertiary care centre in north India were retrospectively analyzed., Methods: Between 1995 and 2016, 349 MM patients underwent ASCT. Patients' median age was 52 yr, ranging from 29 to 68 yr, 68.2 per cent were males. Thirty three per cent patients had international staging system (ISS) Stage III and 68.5 per cent had received novel agents-based induction. High-dose melphalan (200 mg/m 2 ) was used for conditioning; patients with renal insufficiency (estimated glomerular filtration rate <40 ml/min) received melphalan 140-150 mg/m 2 ., Results: Post-transplant, 317 of 349 (90.8%) patients responded; complete [complete response (CR)] -213 (61%)], very good partial response (VGPR) -62 (17.8%) and PR in 42 (12%)]. Induction with novel agents, pre-transplant chemosensitive disease, transplant in first remission and serum albumin (≥3.5 g/dl) were predictors of significant response. At a median follow up of 73 months, median overall survival (OS) was 90 months [95% confidence interval (CI) 70.8-109.2], and progression-free survival (PFS) was 41 months (95% CI 33.0-49.0). On multivariate analysis, achievement of CR post-transplant, transplant in first remission, ISS Stages I and II (vs. III), absence of extramedullary disease and serum albumin ≥3.5 g/dl were predictors of prolonged OS. For PFS, achievement of post-transplant CR and transplant in first remission were predictors of superior outcome., Interpretation & Conclusions: Treatment with novel agents, achievement of complete remission post-transplant, ISS Stages I and II, absence of extramedullary disease and transplant in first remission were predictors of long-term survival for patients with MM., Competing Interests: None

Synthetic chemical pesticides can enhance crop yields but also have undesired effects. Alternative 'botanical insecticides' may also have non-target effects on pollinators and biocontrol services. Employing action thresholds (ATs) can reduce pesticide (whether synthetic or botanical) use compared to fixed-interval applications. Here the azadirachtin-based botanical formulation NeemAzal and a neem seed extract (NSE) were evaluated in field spraying trials alongside commonly-used synthetics (Voliam Flexi [chlorentraniliprole plus thiamethoxam] and imidacloprid) in developing ATs for the regular and cosmopolitan cauliflower pests Brevicoryne brassicae, Plutella xylostella and Spodoptera litura. We considered the size of the S. litura larvae infesting the crop in order to derive ATs. ATs per plant were higher for NeemAzal (0.55 larvae for P. xylostella and 3 larvae for large-sized S. litura) than for Voliam Flexi (0.30 larvae for P. xylostella and 0.80 larvae for S. litura) but were similar for B. brassicae (50 individuals). Higher ATs when using azadirachtin were associated with the diverse modes of action of botanicals, for instance NeemAzal and NSE deterred oviposition of S. litura. Although the exact values of ATs are likely to have regional limits, our approach can be applied for determining ATs against common lepidopteran and aphid pests in many other vegetable crop agro-ecosystems.

Aims: Pharmacokinetic studies in the past have shown inadequate antituberculosis drug levels in children with the currently available dosing regimens. This study attempted to investigate the pharmacokinetics of isoniazid and rifampicin, when used in children, and to optimize their dosing regimens., Methods: Data were collected from 41 children, aged 2-16 years, who were being treated with antituberculosis drugs for at least 2 months. Concentration measurements were done for 6 h and analysed using a nonlinear, mixed-effects model., Results: Isoniazid pharmacokinetics were described by a one-compartment disposition model with a transit absorption model (fixed, n = 5). A mixture model was used to identify the slow and fast acetylator subgroups. Rifampicin was described by a one-compartment disposition model with a transit absorption model (fixed, n = 9). Body weight was added to the clearance and volume of distribution of both the drugs using an allometric function. Simulations with the isoniazid model showed that 84.9% of the population achieved therapeutic peak serum concentration with the planned fixed-dose combination regimen. Simulations with the rifampicin model showed that only about 28.8% of the simulated population achieve the therapeutic peak serum concentration with the fixed-dose combination regimen. A novel regimen for rifampicin, with an average dose of 35 mg kg -1 , was found to provide adequate drug exposure in most children., Conclusions: The exposure to isoniazid is adequate with present regimens. For rifampicin, a novel dosing regimen was developed to ensure adequate drug concentrations in children. However, further studies are required to assess the dose-effect relationship of higher doses of rifampicin., (© 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Botulinum A exotoxin is an established treatment for glabellar frown lines, crow's feet, and horizontal furrows of the forehead. The glabella is probably the most common site for botulinum toxin treatment in Asians. Five glabellar contraction patterns have been classified in earlier studies based on eyebrow approximation, depression, and elevation. Unfortunately, this was found to be confusing by many practitioners. Indians, as all Asians, have smaller muscles compared to the European population, and there is no consensus on the optimal dosage per injection site or concentration of toxin to be used., Aims: (a) Identification and classification of glabellar wrinkle patterns in Indians. (b) Optimization of the minimal effective dose of toxin per site., Materials and Methods: Retrospective photographic analysis of 200 patients who received botulinum toxin for the first time to treat glabellar wrinkles was conducted. The wrinkle patterns were identified and classified by the authors based on the prevalence of perpendicular and transverse glabellar lines, nasal, and forehead wrinkles., Results: Six patterns were identified: (1) 11 (2) U (3) Pi (4) X (5) W (6) I. The relevant muscles were identified and doses optimized for those sites., Limitations: The doses mentioned in this study are not universal for all patients and toxin units would have to be altered and individualized according to the bulk of the facial muscles and individual needs., Conclusion: The investigators classification, injection patterns, and dosage may provide valuable guidance to facial esthetic treatment., Competing Interests: None

Aim: Sofosbuvir is a key agent for HCV treatment. It is not recommended for patients with chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR) <30 mL/min. We report real-life experience of treating a cohort of CKD patients with eGFR <30 mL/min using daclatasvir and half-daily dose of sofosbuvir., Methods: Adults patients who (i) had eGFR<30 mL/min and detectable HCV RNA and (ii) were treated with interferon and ribavirin free, DAA based regimens were included. All patients were treated with daily doses of daclatasvir 60 mg and sofosbuvir 200 mg. The planned duration of treatment was 12 weeks, except for 24 weeks in those with either clinical evidence of cirrhosis or on immunosuppressive drugs. The end-points of the study were: (i) 12 weeks of follow-up after treatment completion, (ii) treatment discontinuation, or (iii) death or loss to follow-up., Results: Thirty-six (88%) among 41 included patients (median [range] age: 48 [19-75] years; 25 [61%] male; genotype 1/3/4 were 17/ 22/2; cirrhosis 5) completed the treatment, two discontinued and three died during treatment. On an intention-to-treat basis, HCV RNA were undetectable at 4 weeks of treatment, treatment completion and after 12 weeks of follow-up in 40/41 (97.6%), 37/41 (90.2%) and 37/41 (90.2%), respectively. None of the patients had a relapse., Conclusions: Daclatasvir and half-daily dose of sofosbuvir was effective against genotype 1 and 3 HCV infection in patients with eGFR <30 mL/min. This combination could be a pangenotypic treatment option for such patients., (© 2018 Asian Pacific Society of Nephrology.)

Objective: This study evaluated whether use of different spasmolytic regimens (nitroglycerin or verapamil) administered soon after sheath insertion affects postprocedure radial artery occlusion (RAO) in patients who underwent transradial catheterization., Methods and Results: We performed a post hoc analysis of a randomized trial evaluating the use of 500 μg intra-arterial nitroglycerin just before sheath removal in 1706 patients undergoing transradial catheterization. Patients who received 200 μg or 300 μg nitroglycerin after sheath placement (group A; n = 688) were compared with patients who received 5 mg verapamil after sheath placement (group B; n = 1018). The primary endpoint was RAO diagnosed by Doppler ultrasound examination at 1 calendar day after the procedure. Logistic regression was used to determine predictors of RAO. RAO occurred in 16.0% of group A and 5.4% of group B. After adjustment for potential confounders, neither the use of verapamil nor nitroglycerin was associated with RAO (odds ratio [OR], 1.24; 95% confidence interval [CI], 0.51-3.02; P=.62). Radial artery compression >4 hours was the strongest predictor of RAO (OR, 5.41; 95% CI, 2.31-12.65; P<.001)., Conclusions: In this study, the use of verapamil or nitroglycerin as a spasmolytic regimen was not associated with RAO. Given the strong association between duration of radial compression and RAO, further studies are needed to determine the interaction between vasodilator agents and compression protocols on RAO.

Objective: Warfarin is the most commonly prescribed oral anticoagulant, although having a narrow therapeutic index and wide interindividual variability. The aim of this study was to replicate the utility of VKORC1 (-1639G>A) rs9923231 genotyping in predicting the mean daily dose and to evaluate its ability to categorize warfarin-treated patients to high-, intermediate-, or low-dose categories in the South Indian population., Materials and Methods: A cohort of 222 warfarin-treated patients was genotyped using restriction fragment length polymorphism method. The influence of the rs9923231 polymorphism on the variations in the mean daily dose was compared using one-way analysis of variance and linear regression analysis. Discriminatory ability of the rs9923231 polymorphism to group the patients into ordered dose categories was assessed by estimating the proportional odds ratios using the ordered logit regression analysis., Results: The frequency of AA genotype and A allele in the study sample was found to be 1.8% and 9.23%, respectively, which was similar to reports from other South Indian populations. The mean daily dose required to achieve the optimum international normalized ratio was significantly lower in AA homozygous genotype carriers (3.99 ± 1.67 mg/day) and GA heterozygous (4.26 ± 1.57 mg/day) compared to the GG genotype carriers (5.51 ± 2.13 mg/day), p = 0.003. The A allele carriers (GA+AA genotypes) had a 3.23 higher odds of being grouped as a low-dose requiring category compared to non-carriers (95% CI 1.49-6.98, p = 0.003)., Conclusions: These preliminary results strongly support the use of VKORC1 (-1639G>A) rs9923231 polymorphism for genetically guided initial warfarin dosing in South Indian patients with heart valve replacements., (Copyright © 2018 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Background: Although conventional 60 mg of prasugrel allows for rapid and potent platelet inhibition within 30 min after loading dose, the efficacy and safety of lower doses of prasugrel in Indian patients has not yet been investigated., Objective: The study sought to compare the efficacy of a lower loading dose of prasugrel with conventional loading dose of prasugrel in Indian patients., Material and Methods: Three hundred thirty-two Indian patients undergoing elective percutaneous coronary intervention (PCI) were enrolled in the study. Participants were randomly administered loading doses of prasugrel 60 mg (group A, n = 166) or 30 mg (group B, n = 166) before undergoing elective PCI in a 1:1 manner. Primary efficacy end point was composite of in-hospital death and stent thrombosis at 96 h, while safety end point was in-hospital bleeding., Results: The two groups did not differ in their baseline characteristics. The primary efficacy end point was 0.6% in both the conventional 60 mg loading dose (LD) and lower 30 mg LD groups (p = not significant). Minor bleeding was significantly less in group B [Bleeding Academic Research Consortium 1, A = 6.63% vs B = 1.81%, odds ratio (OR) = 3.86, 95% confidence interval (CI) = 1.06-14.08, P = 0.05]. Major bleeding was higher in group A (A = 3.61%, vs B = 1.81%, OR = 2.04, 95% CI = 0.50-8.29, P = 0.50)., Conclusion: In Indian patients, 30 mg of prasugrel loading is as effective as 60 mg of prasugrel with significantly less minor bleeding., (Copyright © 2018 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Context: The importance of phytochemicals/natural products as potential therapeutic agents in the present context is gaining a lot of importance. India with a rich heritage of such preparations needs evaluation as potent drugs. Explant culture system is a method, which is sensitive, reliable, reproducible and is capable of mimicking the in situ conditions maintaining the tissue in sufficiently high level of integration., Aim: The current study aimed to test the antioxidant activity of test compounds, namely, traditional aqueous (4212) and aqueous-methanolic (4308) extracts of Rasna panchaka using liver explant cultures., Materials and Methods: Dose-response optima of extracts (0.2-10 μg/mL) were determined using mouse liver explant culture system up to 48 h. The antioxidant property of extracts was assessed by primary oxidative defense parameters, namely, superoxide-dismutase (SOD), catalase, reduced glutathione (GSH), and malondialdehyde (MDA)., Results: The results indicated that the cellular architecture of the cultured tissue was well conserved in the first 6 h with a gradual display of specific changes in the next 24 h. There was a significant increase in MDA levels in experimental groups indicating the oxidative stress induction in explants. A dose of 2.0 μg/mL extracts have shown statistically significant ( P < 0.05) protection against oxidative stress. MDA levels, a measure of lipid peroxidation, were significantly ( P < 0.01) reduced by 50% in extract treated explants compared to control. This effect was accompanied by the increase in the first defense enzymes SOD (50%) and catalase (18%) with no change in reduced GSH levels., Conclusion: The study enforces the importance of "explant culture system," as it not only reduces the use of nonclinical/animal model but also is rapid and sensitive. Further, results of the current study also suggest that aqueous-methanolic extract of Rasna panchaka is having superior antioxidant activity compared to traditional water extract., Competing Interests: There are no conflicts of interest.

This work aimed to evaluate the once-daily antituberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin, and pyrazinamide concentration-time profiles and treatment outcome were obtained from 161 Indian children with drug-sensitive tuberculosis undergoing thrice-weekly dosing as per previous Indian pediatric guidelines. The exposure-response relationships were established using a population pharmacokinetic-pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome. Consequently, children with low body weight (4-7 kg) and/or HIV infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (P unfavorable ). Model-based simulation of optimized (P unfavorable ≤ 5%) rifampin once-daily doses were suggested per treatment weight band and HIV coinfection status (33% and 190% dose increase, respectively, from the new Indian guidelines). The established dose-exposure-response relationship could be pivotal in the development of future pediatric tuberculosis treatment guidelines., (© 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The alarming health issues especially the unusually high number of cancer cases in agriculture community of Bathinda district of Punjab (India) is a serious concern. There is limited knowledge about the role of gene-environment interactions in oncogenesis prevalent in this area. The aim of this study was to evaluate the association of oxidative stress with CYP1A2, CYP2B6, CYP2C9, CYP3A4, and PON1 genetic variation in the pesticide-exposed (occupationally) population of Bathinda district of Punjab (India). This study demonstrated significantly elevated relative risk (RR) of lower antioxidant defense mechanism (Glutathione, Catalase, Superoxide Dismutase, Glutathione peroxidases, and Glutathione Reductase) in occupationally pesticide-exposed group (n = 120) as compared with unexposed group (n = 84) from Bathinda district of Punjab (India). Our data shows pesticide exposure to be a major risk factor leading to increased oxidative stress inside the body. Gas chromatographic analysis revealed the residues of organophosphates (chlorpyriphos, dichlorvos, ethoprophos) and herbicides (atrazine, butachlor, alachlor, metolachlor) in the blood samples of the exposed population. In vitro results showed a dose dependent decrease in cell viability following treatment of pesticides detected in blood samples in hPBMCs and A549 cell line. Genetic variation analysis revealed missense mutations in CYP2B6 (2 mutations), CY3A4 (1 mutation), and CYP2C9 (2 mutations). The observed mutations have been predicted to cause structural and conformation change in protein structure which could result in altered stability. In first of its kind of study, our data reveal oxidative stress and pesticide residue accumulation inside the body to be the major reasons for health concerns in Bathinda district.

Objectives: Currently, recommended high-dose oxytocin regimen for the prevention of postpartum hemorrhage (PPH) following cesarean delivery (CD) is associated with maternal side effects frequency of which is greater with a higher cumulative dose and rapid administration of oxytocin. Here, we evaluated the efficacy of single-dose intravenous oxytocin over 2-4 h (total = 10 units) with oxytocin maintenance infusion for 8-12 h (total = 30 units) in postoperative CD women for the prevention of PPH., Methods: The current double-blinded randomized controlled trial was carried out in a tertiary care institute in Southern India. The primary outcome measures included the following: (a) the need for additional uterotonics to control PPH and (b) significant deterioration of vital signs as assessed by pulse rate and blood pressure in the postoperative period. The secondary outcome measures were as follows: (a) significant difference (≥10% between preoperative and postoperative packed cell volume) and (b) need for blood transfusion., Results and Conclusions: Two hundred and seventy-one women were randomized into Group A (oxytoci n = 10 units; n = 135) and Group B (oxytoci n = 30 units; n = 136). Both the groups were comparable with regard to demographic characteristics. There was no difference in any of primary or secondary outcome measures in the two groups. Thus, low-dose oxytocin regimen is as effective as high-dose oxytocin regimen in the prevention of PPH in postoperative CD women., Competing Interests: There are no conflicts of interest.

Childhood blindness due to corneal ulceration has historically been prevalent among poor Indian children. To tackle this situation the National Institute of Nutrition (NIN), Hyderabad, India, launched (after field-testing) massive dose based national vitamin A (Vit-A) prophylaxis program. Over a period of time reduction in childhood mortality was also hailed as a beneficial effect of the program. Data from the Indian Council for Medical Research (ICMR) indicate that in most Indian states there has been a gradual reduction in the prevalence of Bitot's spots. However, it was not attributed to the prophylaxis program because of its low and patchy coverage. It was, rather, attributed to the control of malnutrition, along with measles vaccination and improvement in healthcare access. Various studies have concluded that massive dose vitamin A prophylaxis does not reduce childhood mortality; this may have been due to the Hawthorne effect; whereby beneficial effects arose from frequent contact of health workers with community members. Paradoxically, harmful effects of massive doses of Vit-A are documented, e.g. acute toxicity in certain groups of children, ranging from increased intracranial pressure, mental retardation (postnatal period), and even death. Vit-A also intensifies bone demineralization, and increased levels can lead to calcium deficiency and, hence, growth retardation in vulnerable children. According to the present authors, for children who have Bitot's spots or who have just recovered from an attack of measles, the best approach is to give Vit-A in therapeutic doses along with adequate daily intake of vegetables and fruits. Public-spirited citizens, along with the scientific community, must ensure the scrapping of the universal massive dose Vit-A prophylaxis approach, to avoid Vit-A toxicity and reduce economic burden to the health system., (Copyright © 2017 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Introduction: Cataract is any opacification in lens or its capsule, which accounts for about 50% of treatable blindness worldwide. The prevalence of cataract in India is about 62.6%. The incidence of post operative endophthalmitis ranges from 0.05% - 0.14% and so the use of post-operative antibiotics and steroids is necessary to control infection and prevent inflammation. Fixed drug combinations not only cut the cost but also the dosage and improve the compliance of patients in the immediate post operative period. In this regard, the present study was conducted with the aim of studying the efficacy of using fixed drug combination (Difluprednate and Moxifloxacin) in reducing ocular inflammation and pain in post-operative patients undergoing cataract surgery., Methodology: Study design: Prospective interventional study, in which 749 eyes underwent SICS with IOL. All of them were treated with Difluprednate and Moxifloxacin, combination eye drops postoperatively 4 times a day, and reviewed on day 1, 5 and once in two weeks up to 6 weeks., Results: Out of 749 eyes, 730 were normal, 10 eyes had minimal raise in IOP in the range of 21 mmHg-31mmHg (considering 21mmHg as baseline) which decreased without any intervention within 3 weeks and only 9 eyes had raise in IOP of more than 31mmHg, which did not decrease in spite of discontinuing the drops and needed anti-glaucoma treatment., Conclusion: Our study clearly shows that fixed drug combination of antibiotic and steroid does not cause raised IOP in about 97% of cases of SICS in the post-operative period and also improves the compliance of the patients., (© NEPjOPH.)

Ethnopharmacological Relevance: 'Ubtan' is a traditional herbal formulation in the Indian system of medicine being used in India and its subcontinent for a long time. Several commercial skin care formulations are marketed throughout this region as the name of Ubtan. Therefore, it is worthwhile to evaluate Ubtan in respect of its efficacy as skin care formulation., Aim of the Study: The present study was designed for the preparation of Ubtan and standardization through the chromatographic techniques by using suitable phyto-markers. Further, its antioxidant, sun protection factor (SPF) and anti-tyrosinase potential have been explored., Materials and Methods: Four in-house formulations (UF-1, UF-2, UF-3 and UF-4) were prepared by mixing a varied quantity of each powdered plants, i.e. turmeric (Curcuma longa L.), Chickpea (Cicer arietinum L.) and sandalwood (Santalum album L.). Optimization of the formulations was made by evaluating its biological activity through in vitro assay. Evaluation of physicochemical properties of the optimized formulation (UF-1) has been carried out by analysis of pH, flow properties and stability. Moreover, RP-HPLC (reverse phase - high performance liquid chromatography) and HPTLC (high performance thin layer chromatography) standardization of UF-1 was performed for its quantitative and qualitative analysis., Results: Ubtan formulations (UF-1to UF-4) showed free radical scavenging and ferric reducing potential. It may be due to its high phenolic and flavonoid content. Statistically, significant Pearson's correlation (r) was confirmed the positive correlation between phenolic content and SPF of the formulations. The tyrosinase inhibition study indicated that the formulations showed both diphenolase and monophenolase inhibitory activity. Among four formulations, UF-1 showed notable biological activity (p<0.05). The content of curcumin and ascorbic acid was found to be 1.6% and 2.1% w/w respectively in UF-1 through RP-HPLC estimation. Physiochemical properties of the UF-1 exhibited good flow rate and aqueous solubility. From the stability studies, it can be anticipated that the UF-1 was stable at 40°C for longer periods. Microbial load count and heavy metal content (lead-Pb, arsenic-As, mercury-Hg and cadmium-Cd) of the formulation was also within the permissible limit of a pharmacopeial standard., Conclusion: This scientific exploration helps to set the quality and safety standard of traditional cosmetic formulation, Ubtan and its further use as an herbal skin care product., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Canagliflozin, an orally active selective inhibitor of sodium glucose cotransporter 2, has been approved in several countries for the treatment of type 2 diabetes mellitus. This study assessed the pharmacokinetic (PK) and pharmacodynamic (PD) properties and tolerability of single-dose canagliflozin 200 or 300 mg in healthy Indian participants., Methods: In this Phase 1, single-center, open-label, 2-period crossover study, healthy adult participants were randomly assigned to receive a single dose of canagliflozin 200 mg in period 1, followed by canagliflozin 300 mg in period 2, or vice versa. The 2 periods were separated by a washout interval of 14 days. The PK and PD properties and tolerability of canagliflozin were assessed at prespecified time points., Findings: Of 15 randomized participants, 14 completed the study. After the administration of single doses of 200 and 300 mg, the mean (SD) Cmax values were 1792 (430) ng/mL and 2789 (941) ng/mL, respectively; AUC0-∞, values were 18,706 (3818) ng·h/mL and 28,207 (5901) ng·h/mL, respectively. The Tmax and t½ of canagliflozin were independent of dose (Tmax, 1.5 hours at both doses; t½, 13.0 and 12.6 hours with 200 and 300 mg). Over the first 4 hours, mean (SD) renal threshold for glucose (RTG) values were 60.8 (8.90) and 61.2 (7.04) mg/dL with the 200- and 300-mg doses, respectively. No effect on plasma glucose concentrations over 0 to 4 hours relative to baseline was observed with either dose. The only treatment-emergent adverse event (TEAE) reported in >1 participant was dizziness (2 participants with the 200-mg dose). None of the participants in the 300-mg group reported any TEAEs. No deaths, discontinuations due to TEAEs, or hypoglycemic episodes were reported., Implications: The mean plasma exposure (Cmax and AUC) to canagliflozin increased in a dose-dependent manner after the administration of single-dose oral canagliflozin 200 and 300 mg in these healthy Indian participants. The Tmax and t½ of canagliflozin appeared to be independent of dose. Overall, PK characteristics were consistent with previous findings in other ethnic populations. The reductions in RTG with canagliflozin were similar to those reported in Western participants, whereas the amount of urinary glucose excretion was somewhat less than those previously observed in studies in Western participants. Canagliflozin was generally well tolerated in these healthy Indian participants. ClinicalTrials.gov identifier: NCT01748526., (Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.)