AmBisome Monotherapy and Combination AmBisome-Miltefosine Therapy for the Treatment of Visceral Leishmaniasis in Patients Coinfected With Human Immunodeficiency Virus in India: A Randomized Open-Label, Parallel-Arm, Phase 3 Trial.

BACKGROUND: Visceral leishmaniasis (VL) in patients with human immunodeficiency virus (HIV) presents an increasingly important patient cohort in areas where both infections are endemic. Evidence for treatment is sparce, with no high-quality studies from the Indian subcontinent. METHODS: This is a randomized, open-label, parallel-arm, phase 3 trial conducted within a single hospital in Patna, India. One hundred and fifty patients aged ≥18 years with serologically confirmed HIV and parasitologically confirmed VL were randomly allocated to 1 of 2 treatment arms, either a total 40 mg/kg intravenous liposomal amphotericin B (AmBisome; Gilead Pharmaceuticals) administered in 8 equal doses over 24 days or a total 30 mg/kg intravenous AmBisome administered in 6 equal doses given concomitantly with a total 1.4 g oral miltefosine administered through 2 daily doses of 50 mg over 14 days. The primary outcome was intention-to-treat relapse-free survival at day 210, defined as absence of signs and symptoms of VL or, if symptomatic, negative parasitological investigations. RESULTS: Among 243 patients assessed for eligibility, 150 were recruited between 2 January 2017 and 5 April 2018, with no loss to follow-up. Relapse-free survival at day 210 was 85% (64/75; 95% CI, 77-100%) in the monotherapy arm, and 96%, (72/75; 90-100%) in the combination arm. Nineteen percent (28/150) were infected with concurrent tuberculosis, divided equally between arms. Excluding those with concurrent tuberculosis, relapse-free survival at day 210 was 90% (55/61; 82-100%) in the monotherapy and 97% (59/61; 91-100%) in the combination therapy arm. Serious adverse events were uncommon and similar in each arm. CONCLUSIONS: Combination therapy appears to be safe, well tolerated, and effective, and halves treatment duration of current recommendations. CLINICAL TRIALS REGISTRATION: Clinical Trial Registry India (CTRI/2015/05/005807; the protocol is available online at https://osf.io/avz7r).

Assessment of mass drug administration for lymphatic filariasis elimination in the Armori and Chamorshi blocks of Gadchiroli District, Maharashtra: A cross-sectional study.

Context: Medical colleges regularly examine mass drug administration (MDA) programs to determine their effectiveness and pinpoint areas for development. These analyses frequently show a discrepancy between the program's coverage and actual drug use. This study was conducted in the Chamorshi and Armori blocks of the Gadchiroli District in Maharashtra. Aim: This study aimed to find out the coverage and compliance of MDA in the Chamorshi and Armori blocks of Gadchiroli, Maharashtra. Settings and Design: This study was a cross-sectional study. Materials and Methods: Thirty houses from each of the three randomly chosen villages and a ward were surveyed in each implementing unit. Thus, a total of 120 households' worth of data were gathered and examined. Information was gathered from each individual in the chosen home at the individual level. Statistical Analysis Used: Data were collected and duly filled out on questionnaire forms, which were then entered in Microsoft (MS) Excel. Statistical Package for the Social Sciences (SPSS) version 16.0 (Chicago) was used as a statistical tool in the analysis. Results: Consumption rates in rural areas were much higher than in urban areas. A minimum consumption rate was found in the 2- to 5-year-old age range. Conclusions: In this study, the percentage of coverage and compliance rates was 89.5% and 99.4% and 90.81% and 99.2% for the Armori and Chamorshi blocks, respectively. In comparison, coverage was better in rural areas than in urban areas. The MDA program must therefore be significantly strengthened in urban areas, particularly by guaranteeing improved compliance through monitored drug consumption.

Comprehensive Management of Polycystic Ovary Syndrome: Effect of Pharmacotherapy, Lifestyle Modification, and Enhanced Adherence Counseling.

Introduction Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of childbearing age in India, which often presents as menstrual irregularities, infertility, acanthosis nigricans, etc. Metabolic disturbances associated with PCOS predispose patients to cardiovascular diseases, which may be avoided by effective management. The aim of the current study was to evaluate the role of lifestyle modification (LSM) and metformin in PCOS management. Methods This is a retrospective cohort study conducted among 130 PCOS patients who attended the outpatient department of the tertiary care hospital in central India from October 2019 to March 2020. The study describes the effect of a combined package of LSM (physical exercise and dietary changes) and metformin on anthropometric, clinical, and biochemical parameters at three and six months. Results Out of the total 130 women, 12 were lost to follow-up and were omitted from further analysis. At six months of the treatment package (LSM, metformin, and enhanced adherence counseling (EAC)), a significant decrease was seen in body mass index, blood sugar, follicle-stimulating hormone, luteinizing hormone, and insulin. Following the intervention, the menstruation cycle became regular in 91% of the women while volume, theca, and appearance of polycystic ovaries on ultrasound decreased in 86% of women. Insulin resistance (IR) and hyperinsulinemia are the major causes of pathophysiological changes associated with PCOS. Metformin along with LSM primarily acts by decreasing IR, while EAC ensures treatment compliance. Conclusion Metformin along with LSM in the form of calories restricted, high-protein diet, and physical activity reduce IR and hyperandrogenaemia, resulting in improved anthropometric, glycemic indices, hormonal profiles, and features of hyperandrogenaemia. The combined therapy is beneficial to 85-90% of women with PCOS.

Angiogenic footprints in diabetic retinopathy: opportunities for drug development.

Diabetic retinopathy is one of the withering disorders that has been making the lives of patients miserable. Arising as a result of chronic high blood sugar levels in diabetes patients, retinopathy has become a major reason causing permanent blindness, retinal detachment, vitreous humor, rage, or glaucoma among patients. Angiogenesis being the major culprit behind the development of this condition is the growth of new blood vessels from the earlier ones existing. The abnormal growth and poor development of blood vessels also lead to aggravation of the conditions, with vascular endothelial growth factor (VEGF) playing a major role in the process. Various anti-angiogenic therapies or anti-VEGF therapies are being explored for the treatment of this condition. 4 widely explored drugs being-Bevacizumab, pegaptanib sodium, ranibizumab, and aflibercept. The review article tries to summarize studies illustrating the efficacy of these drugs in the treatment of diabetic retinopathy along with some of the herbal therapeutic paradigms displaying anti-angiogenic action that is being used to treat this condition.

Visceral Leishmaniasis-HIV Coinfection as a Predictor of Increased Leishmania Transmission at the Village Level in Bihar, India.

Background: Visceral leishmaniasis (VL) is on the verge of being eliminated as a public health problem in the Indian subcontinent. Although Post-kala-azar dermal leishmaniasis (PKDL) is recognized as an important reservoir of transmission, we hypothesized that VL patients co-infected with Human Immunodeficiency Virus (HIV) may also be important reservoirs of sustained leishmania transmission. We therefore investigated to what extent cases of PKDL or VL-HIV are associated with VL incidence at the village level in Bihar, India. Methods: VL, VL-HIV, and PKDL case data from six districts within the highly VL-endemic state of Bihar, India were collected through the Kala-Azar Management Information System for the years 2014-2019. Multivariate analysis was done using negative binomial regression controlling for year as a fixed effect and block (subdistrict) as a random effect. Findings: Presence of VL-HIV+ and PKDL cases were both associated with a more than twofold increase in VL incidence at village level, with Incidence Rate Ratios (IRR) of 2.16 (95% CI 1.81-2.58) and 2.37 (95% CI 2.01-2.81) for VL-HIV+ and PKDL cases respectively. A sensitivity analysis showed the strength of the association to be similar in each of the six included subdistricts. Conclusions: These findings indicate the importance of VL-HIV+ patients as infectious reservoirs for Leishmania, and suggest that they represent a threat equivalent to PKDL patients towards the VL elimination initiative on the Indian subcontinent, therefore warranting a similar focus.

Optimizing Village-Level Targeting of Active Case Detection to Support Visceral Leishmaniasis Elimination in India.

Background: India has made major progress in improving control of visceral leishmaniasis (VL) in recent years, in part through shortening the time infectious patients remain untreated. Active case detection decreases the time from VL onset to diagnosis and treatment, but requires substantial human resources. Targeting approaches are therefore essential to feasibility. Methods: We analyzed data from the Kala-azar Management Information System (KAMIS), using village-level VL cases over specific time intervals to predict risk in subsequent years. We also graphed the time between cases in villages and examined how these patterns track with village-level risk of additional cases across the range of cumulative village case-loads. Finally, we assessed the trade-off between ACD effort and yield. Results: In 2013, only 9.3% of all villages reported VL cases; this proportion shrank to 3.9% in 2019. Newly affected villages as a percentage of all affected villages decreased from 54.3% in 2014 to 23.5% in 2019, as more surveillance data accumulated and overall VL incidence declined. The risk of additional cases in a village increased with increasing cumulative incidence, reaching approximately 90% in villages with 12 cases and 100% in villages with 45 cases, but the vast majority of villages had small cumulative case numbers. The time-to-next-case decreased with increasing case-load. Using a 3-year window (2016-2018), a threshold of seven VL cases at the village level selects 329 villages and yields 23% of cases reported in 2019, while a threshold of three cases selects 1,241 villages and yields 46% of cases reported in 2019. Using a 6-year window increases both effort and yield. Conclusion: Decisions on targeting must consider the trade-off between number of villages targeted and yield and will depend upon the operational efficiencies of existing programs and the feasibility of specific ACD approaches. The maintenance of a sensitive, comprehensive VL surveillance system will be crucial to preventing future VL resurgence.

Impact of IRS: Four-years of entomological surveillance of the Indian Visceral Leishmaniases elimination programme.

BACKGROUND: In 2005, Bangladesh, India and Nepal agreed to eliminate visceral leishmaniasis (VL) as a public health problem. The approach to this was through improved case detection and treatment, and controlling transmission by the sand fly vector Phlebotomus argentipes, with indoor residual spraying (IRS) of insecticide. Initially, India applied DDT with stirrup pumps for IRS, however, this did not reduce transmission. After 2015 onwards, the pyrethroid alpha-cypermethrin was applied with compression pumps, and entomological surveillance was initiated in 2016. METHODS: Eight sentinel sites were established in the Indian states of Bihar, Jharkhand and West Bengal. IRS coverage was monitored by household survey, quality of insecticide application was measured by HPLC, presence and abundance of the VL vector was monitored by CDC light traps, insecticide resistance was measured with WHO diagnostic assays and case incidence was determined from the VL case register KAMIS. RESULTS: Complete treatment of houses with IRS increased across all sites from 57% in 2016 to 70% of houses in 2019, rising to >80% if partial house IRS coverage is included (except West Bengal). The quality of insecticide application has improved compared to previous studies, average doses of insecticide on filters papers ranged from 1.52 times the target dose of 25mg/m2 alpha-cypermethrin in 2019 to 1.67 times in 2018. Resistance to DDT has continued to increase, but the vector was not resistant to carbamates, organophosphates or pyrethroids. The annual and seasonal abundance of P. argentipes declined between 2016 to 2019 with an overall infection rate of 0.03%. This was associated with a decline in VL incidence for the blocks represented by the sentinel sites from 1.16 per 10,000 population in 2016 to 0.51 per 10,000 in 2019. CONCLUSION: Through effective case detection and management reducing the infection reservoirs for P. argentipes in the human population combined with IRS keeping P. argentipes abundance and infectivity low has reduced VL transmission. This combination of effective case management and vector control has now brought India within reach of the VL elimination targets.

Development and Evaluation of Active Case Detection Methods to Support Visceral Leishmaniasis Elimination in India.

As India moves toward the elimination of visceral leishmaniasis (VL) as a public health problem, comprehensive timely case detection has become increasingly important, in order to reduce the period of infectivity and control outbreaks. During the 2000s, localized research studies suggested that a large percentage of VL cases were never reported in government data. However, assessments conducted from 2013 to 2015 indicated that 85% or more of confirmed cases were eventually captured and reported in surveillance data, albeit with significant delays before diagnosis. Based on methods developed during these assessments, the CARE India team evolved new strategies for active case detection (ACD), applicable at large scale while being sufficiently effective in reducing time to diagnosis. Active case searches are triggered by the report of a confirmed VL case, and comprise two major search mechanisms: 1) case identification based on the index case's knowledge of other known VL cases and searches in nearby houses (snowballing); and 2) sustained contact over time with a range of private providers, both formal and informal. Simultaneously, house-to-house searches were conducted in 142 villages of 47 blocks during this period. We analyzed data from 5030 VL patients reported in Bihar from January 2018 through July 2019. Of these 3033 were detected passively and 1997 via ACD (15 (0.8%) via house-to-house and 1982 (99.2%) by light touch ACD methods). We constructed multinomial logistic regression models comparing time intervals to diagnosis (30-59, 60-89 and ≥90 days with <30 days as the referent). ACD and younger age were associated with shorter time to diagnosis, while male sex and HIV infection were associated with longer illness durations. The advantage of ACD over PCD was more marked for longer illness durations: the adjusted odds ratios for having illness durations of 30-59, 60-89 and >=90 days compared to the referent of <30 days for ACD vs PCD were 0.88, 0.56 and 0.42 respectively. These ACD strategies not only reduce time to diagnosis, and thus risk of transmission, but also ensure that there is a double check on the proportion of cases actually getting captured. Such a process can supplement passive case detection efforts that must go on, possibly perpetually, even after elimination as a public health problem is achieved.

Role of 7,8-dimethoxycoumarin in anti-secretary and anti-inflammatory action on pyloric ligation-induced gastritis in rats.

The present study was designed to investigate the effect of 7,8-dimethoxycoumarin (DMC) isolated from ethyl acetate extract of Citrus decumana peels on gastritis in rats. Isolation of 7,8-DMC from ethyl acetate extract of C. decumana peels was done by column and preparative thin layer chromatography using different solvents on polarity basis. Furthermore, effect of 7,8-DMC (50, 75, and 100 mg/kg, i.p.) in pyloric ligation-induced gastritis was studied in rats. The highest dose of 7,8-DMC showed significant decrease in the gastric volume, total acidity, ulcerative index, thiobarbituric acid reactive species levels, and myeloperoxidase activity, whereas there was an increase in the glutathione level. However, the lowest and medium doses did not produce significant results as compared to omeprazole and N-acetyl cysteine-treated groups. Compound 7,8-DMC (100 mg/kg) showed ameliorative effect on gastric inflammation and may be used as a therapeutic agent in the treatment of gastritis.

Antioxidant, anti-inflammatory and analgesic potential of the Citrus decumana L. peel extract.

The present study was designed to investigate the antioxidant, anti-inflammatory and analgesic potential of Citrus decumana peel extract. Antioxidant activity of Citrus decumana peel extract in four solvent systems was evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH(.)) and hydrogen peroxide (H(2)O(2)) radical scavenging methods. Ethyl acetate peel extract of Citrus decumana (EtCD) was studied for its anti-inflammatory and analgesic activities at a dose level of 100, 200 and 300 mg/kg. Anti-inflammatory activity was performed using carrageenan-induced paw edema in rats. Analgesic activity was evaluated for its central and peripheral pharmacological actions in mice. EtCD showed significant antioxidant activity in a dose-dependent manner when compared with ascorbic acid. EtCD at the dose of 300 mg/kg produced significant decrease in paw volume and pain when compared with reference drug diclofenac and morphine, respectively. The Citrus decumana peel extract may be useful as a natural antioxidant in the treatment of inflammation and pain.

Genotyping and outcomes of presumptive second line ART failure cases switched to third line or maintained on second line ART in Mumbai, India.

BACKGROUND: HIV programs are increasingly confronted with failing antiretroviral therapy (ART), including second-line regimens. WHO has provided guidelines on switching to third-line ART. In a Médecins Sans Frontières clinic in Mumbai, India, receiving referred presumptive second-line ART failure cases, an evidence-based protocol consisting of viral load (VL) testing, enhanced adherence counselling (EAC) and genotype for switching was implemented. OBJECTIVE: To document the outcome and genotype of presumptive second-line ART failure cases switched to third-line or maintained on second-line ART. DESIGN: Retrospective cohort study of patients referred between January 2011 and September 2017. RESULTS: The cases (n = 120) were complex with median 9.2 years of ART exposure, poor adherence at baseline, and exposure to multiple ART regimens other than recommended by WHO. Out of 90 evaluated cases, 39(43%) were maintained on second-line ART. Forty-nine (54%) were ever switched to third-line ART. Twelve months virological suppression was 72% in the second-line and 93% in the third-line ART cohort, while retention in care was 80% and 94% respectively. Genotyping showed 62% resistance for PIs, and 52% triple class resistance to NRTIs, NNRTIs and PIs. Resistance was noted for the new class of integrase inhibitors, and for different drugs without any documented previous exposure to the same drug. CONCLUSION: Adopting WHO guidelines on switching ART regimens and provision of EAC can prevent unnecessary switching/exposure to third-line ART regimens. Genotyping is urgently required in national HIV programs, which currently use only the exposure history of patients for switching to third-line ART regimens.

Study on antioxidant potential of Murraya koenigii leaves in Wistar rats.

The antioxidant activity of Murraya koenigii (L.) Spreng (Family: Rutaceae), leaves was investigated in male wistar rats. Potassium dichromate was used to induce oxidative stress. The traditional medical literature describes its potential role as a source of many vitamins, flavonoids, phenols and domestic remedy for many human disorders. The whole plant is considered to be tonic, antidiarrhoeal, febrifuge, blood purifier and as stomachic. In the present study animals were divided into four groups Group I (Control), Group II (Potassium dichromate), Group III (Murraya koenigii + Potassium dichromate) and Group IV (Murraya koenigii). in vivo antioxidant activity of Murraya koenigii inhibited the toxicity of potassium dichromate. The GSH content in liver (1.79 +/- 0.019) and kidney (1.967 +/- 0.013) of Group IV rats significantly (p < 0.05) increased whereas, hepatic malondialdehyde content in liver (2.44 +/- 0.29) and kidney (2.34 +/- 0.057) was significantly (p < 0.05) reduced as compare to control. However, Chromate significantly (p < 0.05) decreased the reduced glutathione (GSH) content and increases hepatic malondialdehyde (MDA) content in both liver and kidney as compared to control. Further post treatment with Murraya koenigii (Group III) significantly (p<0.05) increase the GSH content in liver (1.54 +/- 0.013) and kidney (1.27 +/- 0.011) as compared to Group II whereas, hepatic malondialdehyde content in liver (4.24 +/- 0.71) and kidney (3.86 +/- 0.038) was significantly (p<0.05) reduced as compare to Group II(Potassium dichromate) These results clearly indicate that Murraya koenigii leaves have significant potential as a natural antioxidant agents.

A Phytopharmacological Review on a Medicinal Plant: Juniperus communis.

Juniperus communis is a shrub or small evergreen tree, native to Europe, South Asia, and North America, and belongs to family Cupressaceae. It has been widely used as herbal medicine from ancient time. Traditionally the plant is being potentially used as antidiarrhoeal, anti-inflammatory, astringent, and antiseptic and in the treatment of various abdominal disorders. The main chemical constituents, which were reported in J. communis L. are α-pinene, ß-pinene, apigenin, sabinene, ß-sitosterol, campesterol, limonene, cupressuflavone, and many others. This review includes the last 20 years journals and various books update on this plant, representing its pharmacological activity and health benefits against various diseases.