Formulation Development and In Vitro Characterization of Oral Floating in Situ Gelling Liquid System of Losartan Potassium

The Losartan potassium oral In situ gel F1.F2.F3.F4.F5.F6.F7 and F8 was developed using gelling agents such as Gellan gum, Iota carrageenan and HPMC K4M. • Physical compatibility study showed that the drug and excipients are physically compatible with each other. • Chemical compatibility study was performed using FT-IR spectroscopy and its studies revealed that there was no change in major peaks, thus confirming no interaction between the drug and excipients. • Calibration curve of Losartan potassium was constructed in simulated gastric fluid of pH 1.2 and it obeys Beer Lambert’s law. • 8 formulations of Losartan potassium In situ gel was prepared using varying concentrations of different polymers such as Gellan gum, Iota carrageenan along with HPMC K4M as the release retardants. • The prepared formulations (F1- F8) were evaluated for physical appearance, pourability, pH, viscosity, In vitro gelation study, In vitro buoyancy study, density, gel strength, percentage water uptake, drug content and In vitro drug release. • All the formulations had good physical appearance. • All the formulations except F3 exhibited good gelling capacity. The gel that was formed dispersed rapidly in the formulation F3 containing only Iota carrageenan as the main polymer. • All the formulations showed floating lag time of less than 1 minute and duration of floating are greater than 12 hours. • All the formulation exhibited lower density than the density of gastric fluid (⁓ 1.004 gcmˉ3). • Formulations F7 and F8 showed higher gel strength when compared to the other formulations. • The percentage water uptake was higher for formulations F7 and F8 due to the presence of combination of polymers Gellan gum and Iota carrageenan. • The percentage drug content of all the formulations was in the range of 87.5 – 92.74 % indicating uniform distribution of drugs. • In vitro drug release study showed that only the formulations F7 and F8 released 98.24 % and 98.64 % of drug respectively at the end of 12 hours, while the other formulations showed more than 90 % of drug release even before the period of 12 hours. • The In vitro release kinetics study of the optimized formulation F8 showed that the formulation followed Zero order kinetics and Non- fickian diffusion mechanism. • The stability studies indicated that the optimized formulation F8 was stable and did not show any significant changes in the physical appearance, pH, gelling capacity, floating time, viscosity, drug content and In vitro drug release at the end of 3 months. The overall results indicate that the formulation of Losartan potassium as oral floating In situ gel provides controlled release of the drug. This may improve the patient compliance due to ease of administration and reduction in dosing frequency. Hence, the developed formulation can be used as an alternative to the conventional dosage form for the treatment of Hypertension in patients. FUTURE PLANS: ❖ Scale-up studies of the optimized formulation ❖ In vivo and In vitro- In vivo correlation studies ❖ To perform Bioequivalence studie

Misdiagnosis and clinical significance of non-tuberculous mycobacteria in Western Kenya in the era of human immunodeficiency virus epidemic

Objectives: To determine and document the role of non-tuberculous mycobacteria (NTM) in TB-like disease morbidity and demonstrate the confusion they cause in the diagnosis of TB in western Kenya.Design: A cross-sectional study.Setting: One provincial and nine District hospitals in western Kenya.Subjects: Tuberculosis suspects.Interventions: Sputa from 872 tuberculosis suspects underwent microscopy and culture on solid and liquid media. The growth was identified using the Hain’s GenoType® Mycobacterium CM and GenoType® Mycobacterium AS kits. Consenting clients were screened for HIV infection using Trinity Biotech Uni-GoldTM test and positive cases were confirmed with the enzyme linked immunosorbent assay. A questionnaire was used to obtain demographic data.Main outcome measures: ZN smear positivity / negativity; Culture positivity or negativity; Mycobacterium species isolates (tuberculous or non-tuberculous); HIV status.                                                      Results: Sputa from 39.1% (341/872) of the participants were ZN smear positive, of these 53.1% (181/341) were culture positive. Only 3.8% (20/531) of the ZN smear negatives were culture positive. In total 41.4% (361/872) participants were infected with mycobacteria, of which 44.3% (160/361) were culture negative and 55.7% (201/361) were culture positive. The culture positives yielded 92.5% M. tuberculosis complexand 7.5% NTM. The overall prevalence of the NTM disease was 1.72% (15/872).                                                                            Conclusion: A low prevalence of NT M pulmonary disease in western Kenya is reported in this study, but some the NTM disease cases could have been misdiagnosed as TB cases

Smoking and life expectancy among HIV-infected individuals on antiretroviral therapy in Europe and North America.

BACKGROUND: Cardiovascular disease and non-AIDS malignancies have become major causes of death among HIV-infected individuals. The relative impact of lifestyle and HIV-related factors are debated. METHODS: We estimated associations of smoking with mortality more than 1 year after antiretroviral therapy (ART) initiation among HIV-infected individuals enrolled in European and North American cohorts. IDUs were excluded. Causes of death were assigned using standardized procedures. We used abridged life tables to estimate life expectancies. Life-years lost to HIV were estimated by comparison with the French background population. RESULTS: Among 17 995 HIV-infected individuals followed for 79 760 person-years, the proportion of smokers was 60%. The mortality rate ratio (MRR) comparing smokers with nonsmokers was 1.94 [95% confidence interval (95% CI) 1.56-2.41]. The MRRs comparing current and previous smokers with never smokers were 1.70 (95% CI 1.23-2.34) and 0.92 (95% CI 0.64-1.34), respectively. Smokers had substantially higher mortality from cardiovascular disease, non-AIDS malignancies than nonsmokers [MRR 6.28 (95% CI 2.19-18.0) and 2.67 (95% CI 1.60-4.46), respectively]. Among 35-year-old HIV-infected men, the loss of life-years associated with smoking and HIV was 7.9 (95% CI 7.1-8.7) and 5.9 (95% CI 4.9-6.9), respectively. The life expectancy of virally suppressed, never-smokers was 43.5 years (95% CI 41.7-45.3), compared with 44.4 years among 35-year-old men in the background population. Excess MRRs/1000 person-years associated with smoking increased from 0.6 (95% CI -1.3 to 2.6) at age 35 to 43.6 (95% CI 37.9-49.3) at age at least 65 years. CONCLUSION: Well treated HIV-infected individuals may lose more life years through smoking than through HIV. Excess mortality associated with smoking increases markedly with age. Therefore, increases in smoking-related mortality can be expected as the treated HIV-infected population ages. Interventions for smoking cessation should be prioritized

CD4 cell count and the risk of AIDS or death in HIV-Infected adults on combination antiretroviral therapy with a suppressed viral load: a longitudinal cohort study from COHERE.

BACKGROUND: Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load. METHODS AND FINDINGS: Using data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger), we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements 500 copies/µl, the first of two consecutive measurements between 50-500 copies/µl, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell count and a new AIDS event or death or death alone. 75,336 patients contributed 104,265 suppression episodes and were suppressed while on cART for a median 2.7 years. The mortality rate was 4.8 per 1,000 years of viral suppression. A higher CD4 cell count was always associated with a reduced risk of a new AIDS event or death; with a hazard ratio per 100 cells/µl (95% CI) of: 0.35 (0.30-0.40) for counts <200 cells/µl, 0.81 (0.71-0.92) for counts 200 to <350 cells/µl, 0.74 (0.66-0.83) for counts 350 to <500 cells/µl, and 0.96 (0.92-0.99) for counts ≥500 cells/µl. A higher CD4 cell count became even more beneficial over time for patients with CD4 cell counts <200 cells/µl. CONCLUSIONS: Despite the low mortality rate, the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression. A higher CD4 cell count was associated with the greatest benefit for patients with a CD4 cell count <200 cells/µl but still some slight benefit for those with a CD4 cell count ≥500 cells/µl

Morbidity and Risk of Subsequent Diagnosis of HIV: A Population Based Case Control Study Identifying Indicator Diseases for HIV Infection

BACKGROUND: Early identification of persons with undiagnosed HIV infection is an important health care issue. We examined associations between diseases diagnosed in hospitals and risk of subsequent HIV diagnosis. METHODS: In this population-based case control study, cases were persons with incident HIV infection diagnosed in Denmark between 1 January 1995 and 1 June 2008. Risk-set sampling was used to identify 19 age- and gender-matched population controls for each HIV case, using the HIV diagnosis date as the index date for both cases and controls. Prior hospital diagnoses obtained from Danish medical databases were first categorized into 22 major disease categories (excluding AIDS-defining diseases except tuberculosis) and then subdivided into 161 subcategories, allowing us to examine specific diseases as potential HIV indicators by conditional logistic regression. RESULTS: The study included 2,036 HIV cases and 35,718 controls. Persons with the following disease categories had a high risk of HIV diagnosis during the subsequent 5-year period: sexually transmitted infections and viral hepatitis (adjusted odds ratio [aOR] = 12.3, 95% CI: 9.60-15.7), hematological diseases (aOR = 4.28, 3.13-5.85), lower respiratory tract infections (aOR = 3.98, 3.14-5.04)), CNS infections (aOR = 3.44, 1.74-6.80), skin infections (aOR = 3.05, 2.47-3.75), other infections (aOR = 4.64, 3.89-5.54), and substance abuse (aOR = 2.60, 2.06-3.29). Several specific diseases were associated with aORs >20 including syphilis, hepatitis A, non "A" viral hepatitis, herpes zoster, candida infection, endocarditis, thrombocytopenia, and opioid abuse. CONCLUSIONS: Targeted testing for HIV in patients diagnosed with diseases associated with HIV may lead to earlier treatment and thereby reduced morbidity, mortality and HIV transmission

Phase II randomised discontinuation trial of brivanib in patients with advanced solid tumours

Background: Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]). Patients and methods: During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours. Results: A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio [HR]: 0.58, p Z 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval [CI]: 1.4e4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3e1.6) for placebo (HR Z 0.64, 95% CI: 0.38e1.07; p Z 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6e4.2) months for brivanib and 2.0 months (95% CI: 1.2e2.7) for placebo (HR: 0.56, 95% CI: 0.26e1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6e4.2) and was 2.0 months (95% CI: 1.2e2.7) in those randomised to placebo (HR Z 0.54, 95% CI: 0.25e1.17; p Z 0.11). Conclusion: Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib

Maternal bereavement shortly before or during pregnancy and risk of postpartum psychotic illness: a population-based study from Denmark and Sweden

Publisher's version (útgefin grein)Purpose: Postpartum psychosis is a rare but severe complication following childbirth, with unknown etiology. This study investigated whether the death of a close family member — a source of severe stress — the year before or during pregnancy was associated with an increased risk of psychotic illness in the postpartum period among women without and with a history of psychiatric disorder. Methods: We studied live births in Denmark during 1978-2008 and births in Sweden during 1973-2006 (n=5,246,978). Information on death of women’s relatives and partners and sociodemographic, health-, and pregnancy-related factors was obtained through linkage with nationwide registries. Results: The death of a close relative the year before or during pregnancy was not associated with psychotic illness during the first 90 days postpartum among women without (adjusted HR 1.02, 95% CI 0.76-1.37) or with a history of psychiatric disorder (HR 0.96, 95% CI 0.74-1.25). Similarly, there was no association between bereavement and risk of postpartum psychosis according to the timing of the loss (the year before or during pregnancy), the relative’s cause of death (natural or unnatural), or the woman’s relationship to the deceased (parent/sibling or partner/older child). Conclusions: Death of a close relative, one of the most severe sources of stress, before or during pregnancy was not associated with postpartum psychosis. Therefore, these data do not support the hypothesis that severely stressful life events, such as bereavement around the time of pregnancy, are associated with postpartum psychosis. © 2019 Warselius et al.This work was supported by the Swedish Society of Medicine (grant SLS588081 to KDL), Karolinska Institutet Research Foundation (grant 2016fobi50733 to KDL), Swedish Council for Working Life and Social Research (grant 2015-00837 to KDL), Danish Council for Independent Research (grant DFF-6110-00019 to JL), Karen Elise Jensens Fond (grant 2016 to JL), Nordic Cancer Union (grants 176673, 186200, and R217-A13234-18-S65 to JL), Novo Nordisk Fonden (grant NNF18OC0052029 to JL), TrygFonden (grants 904414 and 15199 to CO), and the Lundbeck Foundation (grant R155-2012-11280 to MV). The funders were not involved in the design of the study, analyses, interpretation of the results, writing of the manuscript, or decision to submit the manuscript for publication.Peer Reviewe

The HIV continuum of care in European Union countries in 2013: data and challenges

BACKGROUND: UNAIDS has set a 90-90-90 target to curb the HIV epidemic by 2020, but methods used to assess whether countries have reached this target are not standardised, hindering comparisons. METHODS: Through a collaboration formed by the European Centre for Disease Prevention and Control (ECDC) with European HIV cohorts and surveillance agencies, we constructed a standardised, four-stage continuum of HIV care for 11 European Union (EU) countries for 2013. Stages were defined as: 1) number of people living with HIV (PLHIV) in the country by end of 2013; 2) proportion of stage 1 ever diagnosed; 3) proportion of stage 2 ever initiated ART; and 4) proportion of stage 3 who became virally-suppressed (≤200 copies/mL). Case surveillance data were used primarily to derive stages 1 (using back-calculation models) and 2, and cohort data for stages 3 and 4. RESULTS: In 2013, 674,500 people in the 11 countries were estimated to be living with HIV, ranging from 5,500 to 153,400 in each country. Overall HIV prevalence was 0.22% (range 0.09%-0.36%). Overall proportions, of each previous stage, were 84% diagnosed, 84% on ART, and 85% virally-suppressed (60% of PLHIV). Two countries achieved ≥90% for all stages, and over half had reached ≥90% for at least one stage. CONCLUSIONS: EU countries are nearing the 90-90-90 target. Reducing the proportion undiagnosed remains the greatest barrier to achieving this target, suggesting further efforts are needed to improve HIV testing rates. Standardising methods to derive comparable continuums of care remains a challenge