Depression among Tuberculosis patients and its association with treatment outcomes in district Srinagar.

BACKGROUND: Tuberculosis (TB) is among the top 10 causes of death worldwide and there are estimated 10.4 million new (incident) patients, of which about one fourth are in India. There has been calls for rigorous investigations and interventions that may address other factors known to have effect on adherence of treatment like Depression but the amount of research into comorbidity is surprisingly low. The aim of the study was to assess magnitude and impact of depression among TB patients and determine the treatment outcomes of TB in District Srinagar. METHODS: In this prospective study the adults with newly diagnosed TB were recruited within one month of initiating treatment and were followed upto the end of treatment. Data collection was done at three time-points: baseline, after 2 months and after 6 months of treatment initiation. The sample size of 200 was calculated using OpenEpi, V3 and identified 202 TB patients were interviewed in their local language and PHQ-9 scale was used to measure Depression. RESULTS: The prevalence of Depression at baseline was 50.5% with CI (43.7%-57.3%). After two months of treatment the prevalence reduced to 9.4% with CI (5.9%-14.0%) and at the end of treatment to 2.5% with CI (0.91%-5.4%). Association between Depression in TB patients and treatment failure was found to be small to medium as revealed by Cramer's V test (0.29-0.59). Binary logistic regression estimated that at baseline TB patients with Depression were at 4.46 times at more risk of treatment failure than patients without Depression and those patients who continued Depression even after intensive phase were 34.5 times at higher risk. CONCLUSION: Our findings indicate Depression is associated with poor treatment outcome in these patients, despite TB treatment. TB treatment strategies should consider screening and managing the psychologically distressed individuals among TB patients.

Exploring Derivatives of Quinazoline Alkaloid l-Vasicine as Cap Groups in the Design and Biological Mechanistic Evaluation of Novel Antitumor Histone Deacetylase Inhibitors.

l-Vasicine is a quinazoline alkaloid with an electron dense ring and additional functionalities in its structure. Employing target oriented synthesis (TOS) based on in silico studies, molecules with significant docking scores containing different derivatives of l-vasicine as caps were synthesized. Interestingly, one molecule, i.e., 4a, which contained 3-hyroxypyrrolidine as a cap group and a six carbon long aliphatic chain as a linker was found to inhibit HDACs. 4a showed more specificity toward class I HDAC isoforms. Also 4a was found to be less cytotoxic toward normal cell lines as compared to cancer cell lines. 4a inhibited cancer cell growth and induced cell death by various mechanisms. However, 4a was found to induce cell death independent of ROS generation, and unlike many natural product based HDAC inhibitors, 4a was found to be nontoxic under in vivo conditions. Importantly, we for the first time report the possibility of using a 3-hydroxypyrrolidine cap for the synthesis of HDAC inhibitors with good potency.

Synthesis of Ofornine mimics from natural product l-vasicine as anti-hypertensive agents.

We report the chemical synthesis of Ofornine mimics from l-vasicine, structure-activity relationship studies and their in vivo screening for anti-hypertensive action in Wistar rats. It was observed that most of the analogs possessed anti-hypertensive effect; however, the duration of the effect was variable and mostly transient. The results demonstrated that the analogs 12, 13, 14, 15, and 16 showed a sharp and significant decrease in systolic and diastolic blood pressure for 30-60min after intravenous administration. Analog (S)-(3-hydroxypyrrolidin-1-yl)(2-(pyridin-4-ylamino)phenyl)methanone (8) showed a significant decrease in blood pressure in a dose dependent manner whose maximal response lowered to 79.29±4.26mmHg of SBP and 62.55±2.9 of DBP at 10mg/kg intravenous dose. Further, the significant anti-hypertensive effect of 8 lasted for about 2.5h at 10mg/kg dose. We also evaluated the acute toxicity of the analog 8 as per the OECD guidelines and the compound was found to be safe up to the dose of 2000mg/kg body weight. These preclinical findings suggest that the analog 8 could be considered as a promising lead and a durable anti-hypertensive drug candidate and deserves further investigation. The SAR studies clearly showed that the amide, hydroxyl and pyridine ring plays important role in showing the activity.

Synthesis and immunopotentiating activity of novel isoxazoline functionalized coumarins.

A novel series (13) of isoxazoline functionalized coumarins was synthesized through 1,3-dipolar cyclization of nitrile oxides with Allylated coumarins. Synthesis of effective and target selective immunostimulators through conjugation of diversely substituted isoxazolines and 7-hydroxycoumarins is the focus of the present article. The proposed synthetic scheme was observed to be highly regiospecific yielding attempted conjugates in good yield (>90%). Kinetic resolution of the racemates was carried out by employing lipase B from Candida antarctica (CALB). The synthesized compounds were screened in vitro and in vivo for their biological activities viz. toxicity and impact on splenocyte proliferation (T- and B-cell proliferation), antibody production (HA titre), delayed-type hypersensitivity reaction (DTH), T-cell subtypes (CD4 and CD8), cytokine production (IL-2, IFN-γ, and IL-4) and NO (macrophage) production. Our results establish that isoxazoline functionalized coumarins exhibit excellent immune potentiating activity especially compounds 2, 4 and 8 whose activity is more than that of Levimasole as standard. The structure activity relations are explained in light of the structural/functional aspects of tested compounds. To the best of our knowledge the presented work is first of its kind and is presaged to prove very useful for the design and synthesis of bis-heterocycle based novel, therapeutically selective and effective immunopotentiators.

Bioactive thiazole and benzothiazole derivatives.

The heterocycles are the versatile compounds existing in almost all natural products and synthetic organic compounds, usually associated with one or the other biological activity. Among the heterocycles the thiazoles and benzothiazoles occupy a prominent position. They possess a broad range of biological activities and are found in many potent biologically active molecules and drugs such as vitamin thiamine, sulfathiazol (antimicrobial drug), ritonavir (antiretroviral drug), abafungin (antifungal drug) and tiazofurin (antineoplastic drug). The thiazole moiety is abundantly found in natural products while benzothiazole moiety is rare. In this review we disclose the literature reports of thiazoles and benzothiazoles possessing different biological activities.

Synthesis of single-enantiomer bioactive molecules: a brief overview.

Chiral-center enantiomers have been shown to differ significantly in biological activity, pharmacodynamics, pharmacokinetics and toxicity. New developments in the stereoselective organic synthesis have enriched the vast literature of synthetic methodologies applicable to access natural products as well as bioactive molecules. These compounds also include new drugs, drug candidates and reagents used to explore biological processes. The article reviews the synthesis of optically pure drugs, biologically active intermediates and amino alcohols by using different methods.

2,3-Unsaturated allyl glycosides as glycosyl donors for selective α-glycosylation.

In the presence of NBS and a catalytic amount of a Lewis acid, 2,3-unsaturated allyl glycosides [6-(allyloxy)-3,6-dihydro-2-(hydroxymethyl)-2H-pyran-3-ol] have been successfully used as versatile glycosyl donors for the stereoselective α-glycosylation of a variety of alcohols comprising sensitive functions such as acetonide, keto, nitro, and ester in 50-90% yields. The methodology offers an equally facile alternative to 4-pentenyl replacement in unsaturated sugars.

Attitudes and experiences of community pharmacists towards paediatric off-label prescribing: a prospective survey.

AIM: To identify community pharmacist experiences of, and attitudes towards paediatric off-label prescribing. METHODS: A prospective questionnaire-based study, with a 21-item questionnaire issued to 1500 randomly selected community pharmacies throughout the UK during 2005 on three separate occasions. RESULTS: Four hundred and eighty-two (32.1%) completed questionnaires were returned. Over 70% of respondents were familiar with the concept of off-label prescribing, primarily through dispensing experience rather than education, although only 40% were aware of having dispensed a paediatric off-label prescription within the previous month. The reasons given for a prescription being off label were younger age than recommended (84.6%, 297/351), primarily for antihistamines, analgesics and beta(2)-agonists, and higher (73.9%, 229/310) or lower than (41%, 103/258) recommended dose, primarily antibiotics and analgesics. Over 60% of respondents had been asked by the public to sell paediatric over-the-counter medicines, such as antihistamines, analgesics and steroid preparations for off-label use. The majority of respondents used the British National Formulary or the Pack Insert rather than specialist formularies or guidelines as a source of specialist paediatric information. Although 78% of respondents believed they had a responsibility to inform the prescriber that a medicine was off label, only 66% believed that they had a similar responsibility to inform parents. CONCLUSION: The community pharmacists who responded to this questionnaire appear to be aware of and concerned by the issues which surround paediatric off-label prescribing. Despite this, most gained relevant knowledge through work experience rather than undergraduate or postgraduate training or professional development.