Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Synthesis of some substituted pyrazole derivatives as antiprotozoal agents

Compounds incorporating a pyrazole moiety have attracted a great deal of research owing to its therapeutic utility of the templates as useful drug molecule scaffolding. We report the synthesis of Pyrazoles moiety substituted with anilines at the fifth position of the ring as anti-protozoal lead moiety. All the compounds were screened for the anti-protozoal activity. The compounds 3a, 3-Amino-5phenylamino-4H-pyrazole-4-carboxylic acid ethyl ester and 3c 3-Amino-5-(-4- methoxy-phenyl amino)-4H-pyrazole-4-carboxylic acid ethyl ester showed better antimalarial as well as anti-leishmanial activity with IC50 value of 0.132ìmol/l and 0.150ìmol/l against P.falciparum and IC50 value of0.132ìmol/l and 0.168 ìmol/l against Leishmaniasis donovani. The result opens up new avenues in designing novel anti-protozoal drugs as dual inhibitor with utilization of pyrazole template as part of the pharmacophore

Emerging role of sphingosine-1-phosphate signaling in head and neck squamous cell carcinoma

Rajeev Nema,1 Supriya Vishwakarma,1 Rahul Agarwal,2 Rajendra Kumar Panday,3 Ashok Kumar11Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Bhopal, 2Jawaharlal Nehru Cancer Hospital & Research Centre, 3Navodaya Cancer Hospital, Indrapuri, Bhopal, IndiaAbstract: Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer type, with an annual incidence of approximately half a million people worldwide. It has a high recurrence rate and an extremely low survival rate. This is due to limited availability of effective therapies to reduce the rate of recurrence, resulting in high morbidity and mortality of patients with advanced stages of the disease. HNSCC often develops resistance to chemotherapy and targeted drug therapy. Thus, to overcome the problem of drug resistance, there is a need to explore novel drug targets. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid involved in inflammation, tumor progression, and angiogenesis. S1P is synthesized intracellularly by two sphingosine kinases (SphKs). It can be exported to the extracellular space, where it can activate a family of G-protein-coupled receptors. Alternatively, S1P can act as an intracellular second messenger. SphK1 regulates tumor progression, invasion, metastasis, and chemoresistance in HNSCC. SphK1 expression is highly elevated in advanced stage HNSCC tumors and correlates with poor survival. In this article, we review current knowledge regarding the role of S1P receptors and enzymes of S1P metabolism in HNSCC carcinogenesis. Furthermore, we summarize the current perspectives on therapeutic approaches for targeting S1P pathway for treating HNSCC.Keywords: head and neck squamous cell carcinoma, HNSCC, oral squamous cell carcinoma, OSCC, sphingosine-1-phosphate, S1P, sphingosine kinase 1, SphK1, S1P receptor, sphingolipi

Complete genome sequence analyses of an Indian cattle strain of bovine viral diarrhoea virus 2 (BVDV-2)

Not AvailableBovine viral diarrhea virus (BVDV) is a pestivirus which infects cattle worldwide causing substantial economic losses in cattle farming. BVDV is divided into two recognized species, BVDV-1 and BVDV-2 and one tentative species, BVDV-3. Since, complete genome sequence analysis can provide better insights into molecular epidemiology of BVD, we report here the first complete genome sequence analyses of an Indian BVDV-2 strain isolated from cattle. The full-genome of strain Ind 141353 contains 12285 nucleotides (nt) with a single large open reading frame which codes for 3898 amino acids. Phylogenetic analysis indicated that this strain belongs to the BVDV-2a subtype and has highest (93%) level of genetic identity with the Chinese cattle strain JZ05-1. It was inferred that although introduction from China is possible, introduction of BVDV-2 into Indian and Chinese cattle from a common trade source cannot be ruled out completely. The results in this study extend the spectrum of pestivirus molecular data and provide important insights into BVDV molecular epidemiology.Not Availabl