Unfavourable outcomes among patients with MDR-TB on the standard 24-month regimen in Maharashtra, India.

Setting: Patients with multidrug-resistant tuberculosis (MDR-TB) registered for treatment (2011-2012 cohort) using the standard 24-month regimen, under the Revised National TB Control Programme's programmatic management of drug-resistant TB (PMDT), Maharashtra, India. Objectives: To assess the treatment outcomes and the timing and risk factors for unfavourable treatment outcomes, with a focus on death and loss to follow-up (LTFU). Method: This was a retrospective cohort study involving a review of PMDT records. Treatment outcomes were reported on 31 December 2014. Results: Of 4024 patients, treatment success was recorded in 1168 (29%). Unfavourable outcomes occurred in 2242 (56%), of whom 857 (21%) died and 768 (19%) were lost to follow-up. Treatment outcomes were missing on record review for 375 (9%) patients, and 239 (6%) were still undergoing treatment. Half of LTFU occurred within 3 months, and more than four fifths of deaths occurred after 6 months of treatment. Human immunodeficiency virus infection, being underweight, age ⩾ 15 years, male sex and pulmonary TB were the main risk factors for death, LTFU or other unfavourable treatment outcomes. Conclusion: The study found poor treatment outcomes in patients with MDR-TB registered for treatment in Maharashtra, India. Interventions are required to address the high rates of LTFU and death.

Contexte: Les patients atteints d'une tuberculose multi-résistante (TB-MDR) enregistrés en vue d'un traitement (cohorte de décembre 2011) recourant au protocole standard de 24 mois de la prise en charge programmatique de la TB pharmacorésistante (PMDT) sous l'égide du Programme national révisé de lutte contre la TB, à Maharashtra, Inde.Objectifs: Evaluer les résultats du traitement, et le timing et les facteurs de risque de résultats défavorables du traitement en particulier, le décès et les pertes de vue.Méthode: Etude rétrospective de cohorte impliquant la revue des dossiers du PMDT. Les résultats du traitement ont été rapportés au 31 décembre 2014.Résultats: Sur 4024 patients, 1168 (29%) patients ont connu un succès, tandis que 2242 (56%) ont eu un résultat défavorable : 857 (21%) sont décédés et 768 (19%) ont été perdus de vue. Les résultats du traitement ont été manquants lors de la revue des dossiers pour 375 (9%) patients et 239 (6%) patients étaient toujours sous traitement. La moitié des pertes de vue est survenue dans les 3 mois et plus de quatre décès sur cinq sont survenus après 6 mois de traitement. Le virus de l'immunodéficience humaine, la maigreur, l'âge ⩾ 15 ans, le sexe masculin et la TB pulmonaire ont été des facteurs de risque de décès ou de perte de vue ou de résultat défavorable du traitement.Conclusion: Cette étude a découvert des résultats médiocres du traitement chez des patients atteints de TB-MDR enregistrés pour traitement à Maharashtra, Inde. Des interventions sont requises pour combattre ce taux élevé de pertes de vue et de décès.

Marco de referencia: Los pacientes con diagnóstico de tuberculosis multidrogorresistente (TB-MDR) registrados para tratamiento (cohorte de 2011 y 2012) con el régimen normalizado de 24 meses del tratamiento programático de la TB farmacorresistente (PMDT, por su equivalente en inglés) en el marco del Programa Nacional Revisado contra la TB en Maharashtra, en la India.Objetivos: Evaluar los desenlaces terapéuticos, la evolución cronológica y los factores de riesgo de alcanzar un desenlace desfavorable, en especial la muerte y la pérdida durante el seguimiento.Método: Un estudio retrospectivo de cohortes con análisis de los registros del PMDT. Los desenlaces terapéuticos se notificaron el 31 de diciembre del 2014.Resultados: De los 4024 pacientes tratados, 1168 alcanzaron el éxito terapéutico (29%). Se observaron desenlaces desfavorables en 2242 pacientes (56%), así: 857 fallecieron (21%) y 768 se perdieron durante el seguimiento (19%). En el examen de los registros, faltaba el desenlace terapéutico de 375 pacientes (9%) y 239 estaban aun recibiendo tratamiento (6%). La mitad de las pérdidas durante el seguimiento ocurrió durante los primeros 3 meses y más de cuatro quintos de las muertes ocurrieron después de 6 meses de tratamiento. Los factores que se asociaron con la muerte, la pérdida durante el seguimiento u otros desenlaces desfavorables fueron la infección por el virus de la inmunodeficiencia humana, el peso insuficiente, la edad ⩾ 15 años, el sexo masculino y la TB de localización pulmonar.Conclusión: En el presente estudio se observaron desenlaces terapéuticos deficientes en los pacientes registrados en tratamiento por TB-MDR en Maharashtra, en la India. Es necesario introducir intervenciones que aborden la alta tasa de pérdida durante el seguimiento y de muertes.

Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors.

BACKGROUND: Nivolumab 3 mg/kg every 2 weeks (Q2W) has shown benefit versus the standard of care in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). However, flat dosing is expected to shorten preparation time and improve ease of administration. With knowledge of nivolumab safety, efficacy, and pharmacokinetics across a wide dose range in body weight (BW) dosing, assessment of the benefit-risk profile of a 240-mg flat dose relative to the approved 3-mg/kg dose was approached by quantitative clinical pharmacology. PATIENTS AND METHODS: A flat dose of 240 mg was selected based on its equivalence to the 3-mg/kg dose at the median BW of ∼80 kg in patients in the nivolumab program. The benefit-risk profile of nivolumab 240 mg was evaluated by comparing exposures at 3 mg/kg Q2W and 240 mg Q2W across BW and tumor types; clinical safety at 3 mg/kg Q2W by BW and exposure quartiles in melanoma, NSCLC, and RCC; and safety and efficacy at 240 mg Q2W relative to 3 mg/kg Q2W in melanoma, NSCLC, and RCC. RESULTS: The median nivolumab exposure and its distribution at 240 mg Q2W were similar to 3 mg/kg Q2W in the simulated population. Safety analyses did not demonstrate a clinically meaningful relationship between BW or nivolumab exposure quartiles and frequency or severity of adverse events. The predicted safety and efficacy were similar across nivolumab exposure ranges achieved with 3 mg/kg Q2W or 240 mg Q2W flat dose. CONCLUSION: Based on population pharmacokinetic modeling, established flat exposure-response relationships for efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab 240 mg Q2W was comparable to 3 mg/kg Q2W. The quantitative clinical pharmacology approach provided evidence for regulatory decision-making on dose modification, obviating the need for an independent clinical study.

Chemotherapy of leishmaniasis part XIII: design and synthesis of novel heteroretinoid-bisbenzylidine ketone hybrids as antileishmanial agents.

Some novel heteroretinoid-bisbenzylidine ketone hybrids have been synthesized and evaluated for their in vitro antileishmanial activity against intramacrophagic amastigotes of Leishmania donovani. Among all the nine synthetic compounds, five compounds (7c, 7d and 7f-h) have shown significant (less than 7µM) activity against intramacrophagic amastigotes. The IC50 values of these compounds were found better than the reference drugs sodium stibogluconate (SSG) and miltefosine. This study helped us in identifying the new class of compounds that could be exploited as potent antileishmanial agents.

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND:Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.RESULTS:During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32).

Design, synthesis and biological evaluation of aryl pyrimidine derivatives as potential leishmanicidal agents.

A series of substituted aryl pyrimidine derivatives was synthesized and evaluated in vitro for their antileishmanial potential against intracellular amastigotes of Leishmania donovani using reporter gene luciferase assay. Among all, 8 compounds showed promising IC50 values ranging from 0.5 to 12.9 µM. Selectivity indices (S.I.) of all these compounds are far better than reference drugs, sodium stibogluconate (SSG) and miltefosine. On the basis of good S.I., compounds were further screened for their in vivo antileishmanial activity against L. donovani/hamster model. Compounds 2d, 4a and 4b have shown significant inhibition of parasitic multiplication that is 88.4%, 78.1% and 78.2%, respectively at a daily dose of 50 mg/kg × 5 days, when administered intraperitoneally. Compound 2d is most promising one, which may provide a new lead that could be exploited as a new antileishmanial agent.

Synthesis and biological evaluation of a novel series of aryl S,N-ketene acetals as antileishmanial agents.

A series of aryl S,N-ketene acetals 7(a-f) was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. All the 6 compounds exhibited significant in vitro activity against intracellular amastigotes of L. donovani with IC50 values ranging from 1.2 to 3.5 µM and were found promising as compared with reference drugs, sodium stibogluconate (SSG) and paromomycin. On the basis of good selectivity indices (SI), they were further tested for their in vivo potential against L. donovani/hamster model. Two compounds 7a and 7b showed significant inhibition of parasite multiplication, 72% and 83%, respectively. These compounds were comparable with SSG and superior to paromomycin. Preliminary in vitro metabolic investigations were also performed to assess the metabolic stability and in vitro hepatic intrinsic clearance (Clint) of compound 7b in hamster liver microsomes.

Chemotherapy of leishmaniasis. Part XII: design, synthesis and bioevaluation of novel triazole integrated phenyl heteroterpenoids as antileishmanial agents.

A novel series of triazole integrated phenyl heteroterpenoids have been synthesized and screened for their in vitro activity against intracellular amastigote form of Leishmania donovani. Among all tested compounds, compound 3a was found to be the most active with IC50 6.4µM and better selectivity index (SI) 18 as compared to reference drugs, miltefosine and miconazole. When evaluated in vivo in L. donovani/hamster model, 3a has exhibited 79±11% inhibition of parasite multiplication at 50mgkg(-1)×5days on day 7 post treatment.

Chemotherapy of leishmaniasis part X: synthesis and bioevaluation of novel terpenyl heterocycles.

Some novel α and ß ionone based chalcones and their dihydropyrazolidines/pyrazolidines have been synthesized and evaluated for their in vitro and in vivo antileishmanial activities against Leishmania donovani. Amongest all, one compound (4d) exhibited significant in vitro activity against intracellular amastigotes of Leishmania donovani with IC(50) values of 7.49 µM and was found promising as compared to reference drug, miltefosine. On the basis of good Selectivity Index (S.I.), the compound was further tested for its in vivo response against Leishmania donovani/hamster model and has shown significant inhibition of parasite multiplication (81%). The present study has helped us in identifying a new lead that could be exploited as a potential antileishmanial agent.

Chemotherapy of leishmaniasis. Part IX: synthesis and bioevaluation of aryl substituted ketene dithioacetals as antileishmanial agents.

A new series of aryl substituted ketene dithioacetals 6a-h was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. Two compounds exhibited significant in vitro activity against intracellular amastigotes of L. donovani with IC(50) values 3.56 and 5.12 µM and were found promising as compared with reference drug, miltefosine. On the basis of good Selectivity Indices (S.I.), they were further tested for their in vivo response against L. donovani/hamster model and showed significant inhibition of parasite multiplication 78% and 83%, respectively. These compounds were better than the existing antileishmanials in respect to IC(50) and SI values, but were less active than miltefosine in vivo.

Chemotherapy of leishmaniasis. Part XI: synthesis and bioevaluation of novel isoxazole containing heteroretinoid and its amide derivatives.

Novel isoxazole containing heteroretinoid (4) and its amide derivatives (5a-j) have been synthesized and evaluated for their in vivo antileishmanial activity against Leishmania donovani in hamsters. Compounds 3, 5a, 5d, 5k and 5l inhibited 70-76% parasite growth at 50 mg kg(-1) ×5 days. The present study has helped us in identifying a new lead that could be exploited as a potential antileishmanial agent.

Serum ferritin-a novel risk factor in acute myocardial infarction.

BACKGROUND: A possible association between body iron status and risk of coronary heart disease (CHD) has been found to be controversial from the data obtained from various studies. OBJECTIVES: To study the relationship of serum ferritin with acute myocardial infarction (AMI) in univariate and multivariate analysis and to assess the relationship of high serum ferritin with established conventional risk factors. METHODS: Hospital based case-control study of 75 cases of AMI, and 75 age and equal number of age, and gender-matched controls without having AMI in the age group of 30-70 years. RESULTS: Median serum ferritin levels were significantly higher in cases (220 µg/L) than controls (155 µg/L) (P ≤ 0.0001. In univariate analysis in addition to ferritin > 200 µg/L (odds ratio [OR] 6.71, 95% confidence interval [CI] = 3.22-12.89, P<0.05), diabetes (OR=7.68, 95% CI=2.95-19.13, P<0.05), hypertension (HTN) (OR=2.36, 95% CI=1.02-5.14, P<0.05) high-density lipoprotein (HDL) < 35 mg/dL (OR = 11.9, 95% CI = 2.66-52.57, P<0.05) and smoking (OR=2.17, 95% CI = 1.12-3.87, P< 0.05) were found to be significantly associated with AMI. After controlling for all conventional risk factors, in multiple logistic regression analysis, high ferritin was significantly associated with AMI. (adjusted OR=5.72, 95% CI=2.16-15.17, P < 0.001). Serum ferritin was significantly higher in diabetics than non-diabetics (P < 0.01). CONCLUSION: High serum ferritin is strongly and independently associated with AMI.

The incidence of hypoglycaemia in Muslim patients with type 2 diabetes treated with sitagliptin or a sulphonylurea during Ramadan: a randomised trial.

AIMS: To compare the incidence of symptomatic hypoglycaemia in fasting Muslim patients with type 2 diabetes treated with sitagliptin or a sulphonylurea during Ramadan. METHODS: Patients with type 2 diabetes (age ≥ 18 years) who were treated with a stable dose of a sulphonylurea with or without metformin for at least 3 months prior to screening, who had an HbA(1c) < 10% and who expressed their intention to daytime fast during Ramadan were eligible for this open-label study. Patients were randomised in a 1 : 1 ratio to either switch to sitagliptin 100 mg qd or to remain on their prestudy sulphonylurea. Patients completed daily diary cards to document information on hypoglycaemic symptoms and complications. The primary end-point was the overall incidence of symptomatic hypoglycaemia recorded during Ramadan. RESULTS: Of the 1066 patients randomised, 1021 (n = 507 for sitagliptin and n = 514 for sulphonylurea) returned at least one completed diary card and were included in the analysis. The proportion of patients who recorded one or more symptomatic hypoglycaemic events during Ramadan was lower in the sitagliptin group (6.7%) compared with the sulphonylurea group (13.2%). The risk of symptomatic hypoglycaemia was significantly decreased with sitagliptin relative to sulphonylurea treatment (Mantel-Haenszel relative risk ratio [95% CI] = 0.51 [0.34, 0.75]; p < 0.001). There were no reported events that required medical assistance (i.e. visits to physician or emergency room or hospitalisations) or were considered severe (i.e. events that caused loss of consciousness, seizure, coma or physical injury) during Ramadan. CONCLUSIONS: In Muslim patients with type 2 diabetes who observed the fast during Ramadan, switching to a sitagliptin-based regimen decreased the risk of hypoglycaemia compared with remaining on a sulphonylurea-based regimen. The incidence of hypoglycaemia was lower with gliclazide relative to the other sulphonylurea agents and similar to that observed with sitagliptin.

Clinical and statistical assessment of suicidal ideation and behavior in pharmaceutical trials.

In the past two decades, the potential association between the risk of suicidal ideation and behavior and the clinical use of pharmaceutical products has been debated among industry, regulators, and academia. A better understanding of the possible effects-favorable, unfavorable, or neutral-of pharmaceuticals on the risk of suicidal ideation and behavior may be required, especially for trials typically designed for other primary objectives. Here, a cross-industry statistical team provides recommendations that address the assessment, statistical analysis, interpretation, and utility of suicide-related data in pharmaceutical clinical trials. These recommendations are to evaluate suicidal ideation, suicidal behavior, and the two combined as end points; utilize standard scales to collect data prospectively; and analyze the data using several statistical methods. A more accurate assessment of the potential association between the use of pharmaceutical products and risk of suicide-related events will contribute to estimating the benefit/risk ratio and result in safer medicines for patients.

Association of impaired cognitive functions with cardiovascular risk factors in elderly Indian population.

BACKGROUND: The prevalence of dementia is projected to rise dramatically in future with increasing life expectancy. Though dementia itself is not treatable in majority of cases, modification of co-morbid medical conditions may influence onset and rate of decline of cognitive functions. OBJECTIVE: To determine the prevalence of dementia in elderly by assessing cognitive function and to assess the association of cardiovascular risk factors with cognitive functions. STUDY DESIGN: Cross sectional analytical study. PARTICIPANTS: 400 consecutive elderly subjects > 65 years attending Geriatric OPD, Dept. of Medicine, Indira Gandhi Government Medical College, Nagpur, were recruited and assessed for cognitive functions by applying Mini Mental Status examination Score (MMSE). Relationships between cardiovascular risk factors and impaired cognitive score were determined. RESULTS: Prevalence of impaired cognitive function (MMSE Score < 25) was 33.25% (133 cases), while that of dementia (MMSE < 23) was 3.25 % (13 cases) in this elderly population. Impaired cognitive function was higher in those with low education and low socioeconomic status, (p = < 0.001). Increasing age, Female gender, alcohol intake and high cholesterol were found to be independently associated with impaired cognitive score in multiple logistic regression (p = < 0.001). Hypertension, diabetes mellitus, smoking and obesity were not associated with impaired cognitive score. CONCLUSION: Prevalence of cognitive impairment rises significantly as the age advances and is associated with alcohol intake and high cholesterol.

A one-year study to assess the safety and efficacy of the CB1R inverse agonist taranabant in overweight and obese patients with type 2 diabetes.

AIM: To evaluate the efficacy and safety of taranabant in overweight and obese patients with type 2 diabetes mellitus (T2DM). METHODS: This was a multicenter, double-blind, randomized, placebo-controlled study in overweight and obese patients with T2DM (ages > or = 18 and < or = 75 years) with a BMI > or = 27 kg/m(2) and < or = 43 kg/m(2) and HbA1c > or =7.0 and < or = 10.0%, who were either not on an antihyperglycaemic agent or on a stable dose of metformin (> or = 1500 mg/day). After a 2-week placebo run-in, patients were randomized to placebo (N = 156) or taranabant 0.5-mg (N = 155), 1-mg (N = 157), or 2-mg (N = 155) once daily for 52 weeks. Primary efficacy endpoints were changes from baseline in body weight (BW) and HbA1c at Week 36, with results at Week 52 being key secondary endpoints. RESULTS: In the all-patients-treated population, using a last-observation-carried-forward analysis, reductions in BW were -2.5, -3.7, -4.5 and -5.1 kg at Week 36 and -2.4, -4.0, -4.6 and -5.3 kg at Week 52 in the placebo, 0.5-, 1- and 2-mg groups, respectively (all doses significant vs. placebo at both time points). The proportion of patients who lost > or = 5 and > or = 10% of their baseline BW was significantly greater in the 1- and 2-mg groups vs. placebo at Week 36 and all taranabant groups vs. placebo at Week 52. Reductions in HbA1c were -0.40, -0.47, -0.68 and -0.71% at Week 36 and -0.30, -0.43, -0.65 and -0.64% at Week 52, in the placebo, 0.5-, 1- and 2-mg groups, respectively (1- and 2-mg doses significant vs. placebo at both time points). After 52 weeks, the incidences of adverse experiences classified in the gastrointestinal (diarrhoea, nausea, vomiting), nervous system-related (dizziness, sensory-related), and psychiatric (irritability, depression-related) organ systems were numerically higher or statistically significantly higher in all taranabant groups compared with the placebo group. CONCLUSIONS: After 36 and 52 weeks, treatment with taranabant at the 1- and 2-mg doses led to clinically significant weight loss and improvement in glycaemic parameters in overweight and obese patients with T2DM that was associated with dose-related increases in adverse experiences. Based on these data and data from other Phase III clinical studies, it was determined that the overall safety and efficacy profile of taranabant did not support further development for the treatment of obesity.

A clinical trial assessing the safety and efficacy of the CB1R inverse agonist taranabant in obese and overweight patients: low-dose study.

OBJECTIVE: To evaluate the weight loss efficacy, safety and tolerability of taranabant, a CB1R inverse agonist, in obese and overweight patients. DESIGN: Multicenter, double-blind, randomized, placebo-controlled study. SUBJECTS: Patients >or=18 years old, BMI 27-43 kg m(-2), were randomized to placebo (n=209) or taranabant 0.5 mg (n=207), 1 mg (n=208) or 2 mg given orally once daily (n=417) for 52 weeks. MEASUREMENTS: Key efficacy measurements included body weight (BW), waist circumference (WC), lipid endpoints and glycemic endpoints. RESULTS: Based on a last observation carried forward analysis of the all-patients-treated population, mean change in BW for taranabant 0.5, 1, and 2 mg and placebo was -5.4, -5.3, -6.7 and -1.7 kg, respectively (P<0.001 for all doses vs placebo). The proportions of patients who lost at least 5 and 10% of their baseline BW at week 52 were significantly higher for all taranabant doses vs placebo (P<0.001 for all doses). Reductions in WC, percentage of body fat, and triglycerides were significant for taranabant 2 mg and in triglycerides for taranabant 1 mg vs placebo. There was no effect of taranabant vs placebo on other lipid or glucose-related endpoints. Incidences of adverse experiences classified in the gastrointestinal (diarrhea and nausea), nervous system (dizziness/dizziness postural), psychiatric-related (irritability and anger/aggression) and vascular (flushing/hot flush) organ systems were higher and statistically significant in the taranabant 2-mg group compared with the placebo group. Irritability was higher and statistically significant in all taranabant groups compared with the placebo group. CONCLUSION: All three doses of taranabant-induced clinically meaningful and statistically significant weight loss. Incidences of adverse experiences in organ systems known to express CB1R were higher in taranabant groups.

A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: a high-dose study.

OBJECTIVE: To evaluate the efficacy, safety and tolerability of taranabant in obese and overweight patients. DESIGN: Double-blind, randomized, placebo-controlled study. SUBJECTS: Patients were >or=18 years old, with body mass index of 27-43 kg m(-2), and 51% with metabolic syndrome (MS) randomized to placebo (N=417) or taranabant 2 mg (N=414), 4 mg (N=415) or 6 mg (N=1256) for 104 weeks. MEASUREMENTS: Key efficacy measurements included body weight, waist circumference (WC), lipid and glycemic end points. RESULTS: On the basis of risk/benefit assessments, the 6-mg dose was discontinued during year 1 (patients on 6 mg were down-dosed to 2 mg or placebo) and the 4-mg dose was discontinued during year 2 (patients on 4 mg were down-dosed to 2 mg). Changes from baseline in body weight at week 52 (all-patients-treated population, last observation carried forward analysis) were -2.6, -6.6 and -8.1 kg, respectively, for placebo and taranabant 2 and 4 mg (both doses P<0.001 vs placebo). For patients who completed year 1, changes from baseline in body weight at week 104 were -1.4, -6.4 and -7.6 kg for placebo and taranabant 2 and 4 mg, respectively (both doses P<0.001 vs placebo). The proportions of patients at weeks 52 and 104 who lost at least 5 and 10% of their baseline body weight were significantly higher and the proportions of patients who met criteria for MS were significantly lower for taranabant 2 and 4 mg vs placebo. The incidence of adverse experiences classified in the gastrointestinal, nervous, psychiatric, cutaneous and vascular organ systems were generally observed to be dose related with taranabant vs placebo. CONCLUSION: Taranabant at the 2- and 4-mg dose was effective in achieving clinically significant weight loss over 2 years and was associated with dose-related increases in adverse experiences. On the basis of these and other data, an assessment was made that the overall safety and efficacy profile of taranabant did not support its further development for the treatment of obesity.

Potent and selective agonism of the melanocortin receptor 4 with MK-0493 does not induce weight loss in obese human subjects: energy intake predicts lack of weight loss efficacy.

MK-0493 is a novel, potent, and selective agonist of the melanocortin receptor 4 (MC4R), one of the best-validated genetic targets and considered one of the most promising for the development of antiobesity therapeutics. An ad libitum energy-intake model was qualified with excellent reproducibility: the geometric mean ratio (GMR) with 95% confidence interval (CI) for total energy intake over a period of 24 h for 30 mg sibutramine/placebo was 0.82 (0.76, 0.88), and for 10 mg sibutramine/placebo it was 0.98 (0.91, 1.05). MK-0493 showed a small and marginally significant effect on 24-h energy intake, whereas 30 mg of sibutramine caused a significant reduction in total 24-h energy intake; specifically, the GMR (95% CI) for 30 mg sibutramine/placebo was 0.79 (0.74, 0.85). MK-0493 was associated with modest weight reduction from baseline but had only small, statistically insignificant effects relative to placebo after 12 weeks in a fixed-dose study and also after 18 weeks of stepped-titration dosing. We conclude that agonism of MC4R is not likely to represent a viable approach to the development of antiobesity therapeutics.

Clinical profile of chikungunya fever in patients in a tertiary care centre in Maharashtra, India.

BACKGROUND & OBJECTIVE: In India a chikungunya fever outbreak started in December 2005 when the country experienced more than 13 lakhs of chikungunya infected cases. We undertook this study to study detailed clinical profile of chikungunya fever in both indoor and outdoor patients in a tertiary care hospital in Nagpur, Maharashtra in 2006. METHODS: Suspected cases of chikungunya fever (n=405) during the period of July to September 2006, having clinical triad of fever, arthralgia and/or rashes were included in the study. Clinical profile was studied in all the cases. Of the 405 samples collected, 166 were tested for serum CHIK IgM antibodies. RESULTS: Of the 166 samples tested for CHIKV IgM antibodies, 87 (52.4%) were positive (confirmed cases). Male: female ratio was 2.3:1. Fever and arthralgia were present in all cases. Rash was present in 27 (31%) confirmed and 38 (12%) suspected cases. Lymphadenopathy was present in 12 (13.8 %) confirmed and 4 of suspected cases. Chronic polyarthritis was seen in 22 (25.3%) confirmed and 75 (23.6%) suspected cases. Neurological manifestations were observed in 08 (9%) confirmed and 10 (3.14%) suspected cases. Mortality was 7 (2.2%) in 318 suspected cases and 3 (3.4%) in 87 confirmed cases. INTERPRETATION & CONCLUSION: Our findings showed that about half of the serum samples for CHIKV IgM antibody tested positive from cases suspected to have chikungunya fever. Fever, joint pain and headache were major symptoms. Certain rare manifestations like lymphodenopathy, oral ulcers and encephalitis were also seen. Mortality in confirmed cases was about 3.4 per cent.