Synthesis and antihistaminic activity of 3H-benzo [4,5] thieno [2,3-d][1,2,3] triazin-4-ones

AbstractIn the present study the antihistaminic activity of tricyclic benzothieno 1,2,3-triazine derivatives namely CP-3 (3-(phenyl)-5,6,7,8-tetrahydro,3H-benzo[4,5] thieno [2,3-d][1,2,3] triazin-4-one), CP-5 (3-(3-methyl phenyl)-5,6,7,8-tetrahydro,3H-benzo[4,5] thieno [2,3-d][1,2,3] triazin-4-one) and CP-8 (3-(4-chloro phenyl)-5,6,7,8-tetrahydro,3H-benzo[4,5] thieno [2,3-d][1,2,3] triazin-4-one) were evaluated using in vitro (isolated guinea pig ileum) and in vivo (bronchodilator activity in guinea pigs) models and the sedative potential of the test compounds were evaluated using actophotometer in mice. In in vitro antihistaminic study, the CP-3, CP-5, CP-8 and chlorpheniramine maleate (CPM) have shown a rightward shift in concentration response curve (CRC) of histamine with a change in EC50 values of histamine in all the four tissue preparations. The slope obtained in the schild plot indicated that CP-5, CP-8 and CPM were competitive in nature for H1-receptors. However, CP-3 has shown non-competitive antagonism. In in vivo antihistaminic study, the CP-3, CP-5, CP-8 and CPM have shown mean increase in exposition time against histamine challenge compared to control group (p<0.001). All the test drugs (10mg/kg) and CPM (2mg/kg) have offered a significant (p<0.001) protection against preconvulsive dyspnoea (PCD) compared to control. In conclusion, all the test drugs have shown very good antihistaminic activity and the test drugs have very little sedative action compared to CPM

Highly active antiretroviral therapy induced adverse drug reactions in Indian human immunodeficiency virus positive patients

Objective: To assess the incidence, severity pattern, causality, predictability and preventability of adverse drug reactions (ADRs) and to identify risk factors for adverse drug reactions in highly active antiretroviral therapy. Methods: Enrolled patients were intensively monitored for ADRs to highly active antiretroviral therapy. Predictability was assessed based on history of previous exposure to the drug or literature incidence of ADRs. Preventability was assessed using Schumock and Thornton criteria and severity was assessed using modified Hartwig and Siegel scale. Multivariate logistic regressions were used to identify the risk factors for ADRs. Results: Monitoring of 130 retropositive patients by active pharmacovigilance identified 74 ADRs from 57 patients. Anemia and hepatotoxicity were the most commonly observed ADRs. The organ system commonly affected by ADR was red blood cell (21.4%).The ADRs were moderate in 77% of cases. Type A reactions (77%) were more common. A total of 10.8% ADRs were definitely preventable. The incidence rate of ADRs (65.9%) was highest with Zidovudine + Lamivudine + Nevirapine combination. A total of 84% interruptions to highly active antiretroviral therapy were due to toxicity. CD4 less than 200 cells/ìl, female gender and tuberculosis were observed as risk factors for ADRs. Conclusion: Incidence of ADRs in intensively monitored patients was found to be 43.8%. Anemia in HIV patients is an influential risk factor for occurrence of ADRs. With the increasing access to antiretroviral in India, clinicians must focus on early detection and prevention of ADRs to highly active antiretroviral therapy.Objetivo: Evaluar la incidencia, gravedad, causalidad y preventabilidad de las reacciones adversas medicamentosas (RAM) e identificar los factores de riesgo de esas RAM en terapias de antiretrovirales altamente activos. Metodos: Se monitorizo intensamente a los pacientes incluidos a la busqueda de RAM. La predecibilidad se evaluo con base en la historia de exposiciones previas al medicamento o a la incidencia de RAM en la literatura. La preventabilidad se valoro usando los criterios de Schumock y Thornton y la gravedad se evaluo utilizando la escala modificada de Hartwig y Siegel. Se utilizaron regresiones logisticas multivariadas para identificar los factores de riesgo de RAM. Resultados: La monitorizacion retrospectiva de 130 pacientes mediante farmacovigilancia activa identifico 74 RAM de 57 pacientes. Anemia y hepatotoxicidad fueron las RAM mas comunmente observadas. El sistema comunmente afectado por las RAM fueron las celulas rojas sanguineas (21,4%). Las RAM fueron moderadas en el 77% de los casos. Las reacciones tipo A fueron las mas comunes. Un total del 10,8% de RAM fueron definitivamente prevenibles. La incidencia de RAM mas alta fue con la combinacion Zidovudina + Lamivudina + Nevirapina. Un 84% de las interrupciones de terapias antiretrovirales altamente activas fue debido a la toxicidad. Se observaron como factores de riesgo de RAM un CD4 en menos de 200 cel, el genero femenino y la tuberculosis. Conclusion: La incidencia de RAM en pacientes intensivamente monitorizados fue del 43,8%. La anemia en pacientes con VIH es u7n factor d e riesgo de influencia en la aparicion de RAM. Con el creciente uso de antiretrovirales en India, los clinicos deben centrar la atencion en la deteccion temprana y la prevencion de RAM de terapias antiretrovirales altamente activos

Catechin, an active constituent of green tea, preserves skeletal muscle activity in dexamethasone induced cachexia by increasing acetylcholine sensitivity in muscles of Wistar rats

314-321Chronic administration of glucocorticoids produces cachexia like symptoms such as muscular dystrophy, weight loss and skeletal muscle dysfunction. However, only limited options are available for treatment of this disease. One of the tea catechins, epigallocatechin-3-gallate attenuated skeletal muscle atrophy in cancer cachexia. In this context, we explored here (+)-catechin hydrate (catechin) for of its anticachectic activity in dexamethasone induced muscle dystrophy. Dosing of catechin at 100 mg/kg p.o. was continued for 5 days along with a daily dosing of dexamethasone at 0.6 mg/kg i.p. On the 6th day, animals were assessed for cachectic condition using changes in body weight, functional aspect of skeletal muscle such as muscle integrity, locomotor activity, handgrip strength, glucose uptake, responsiveness of skeletal muscle to acetylcholine, by estimating inflammatory parameters such as nitrite, myeloperoxidase in the gastrocnemius muscle and by evaluating plasma biochemical parameters such as triglycerides, total protein, albumin, creatinine, urea and IL-6 levels. Except for a few parameters, such as body weight, glucose uptake by hemi-diaphragm and triglyceride level, remaining parameters were significantly reversed by catechin treatment. The underlying mechanism of the myoprotective action of catechin has been postulated by the increased sensitivity of muscle to acetylcholine as demonstrated in this study, which might be responsible for prevention of muscle inflammation

The basics and advances of immunomodulators and antigen presentation: a key to development of potent memory response against pathogens

Introduction: Immunomodulators are agents, which can modulate the immune response to specific antigens, while causing least toxicity to the host system. Being part of the modern vaccine formulations, these compounds have contributed remarkably to the field of therapeutics. Despite the successful record maintained by these agents, the requirement of novel immunomodulators keeps increasing due to the increasing severity of diseases. Hence, research regarding the same holds great importance. Areas covered: In this review, we discuss the role of immunomodulators in improving performance of various vaccines used for counteracting most threatening infectious diseases, mechanisms behind their action and criteria for development of novel immunomodulators. Expert opinion: Understanding the molecular mechanisms underlying immune response is a prerequisite for development of effective therapeutics as these are often exploited by pathogens for their own propagation. Keeping this in mind, the present research in the field of immunotherapy focuses on developing immunomodulators that would not only enhance the protection against pathogen, but also generate a long-term memory response. With the introduction of advanced formulations including combination of different kinds of immunomodulators, one can expect tremendous success in near future

Vaccine with herbal adjuvant-A better cocktail to combat the infection

Cross-talk between microbe and the host makes important contribution to the subsequent course of infection. Edward Jenner and Louis Pasteur—Fathers of vaccinology have wisely thought of combating an infectious bug with the same bug in a non-infectious form. Then on, vaccines have taken a great toll as a prophylactic agent to improve the quality of human life. Vaccines are successful in controlling a substantial portion of the morbidity and mortality in the developing world. Though vaccines against few diseases like small pox, polio and cholera are highly successful, the stories of failed vaccines are far more. An ideal vaccine candidate should be able to elicit the correct response, either Th1 or Th2 to combat the infection along with a strong immune memory. Use of adjuvant in the vaccine preparation is a long standing practice. Despite major advances in our understanding of vaccine adjuvants, both old and new vaccines seem likely to depend on aluminium salts. However, these adjuvants can lead to serious adverse effects [1]. Herbal immuno-modulators are paving its way as a safe alternative [2-7]. These herbal modulators can be administered along with the vaccine to elicit a faster and stronger immune response. Various herbal preparations have been shown to exert strong immuno-modulatory properties like increase in the cytokine expression [6], enhanced activation of CD4 and CD8 T cells [4-6], enhanced NK cell activity [4], etc. The failure of various vaccines can be attributed to its inability to trigger a robust immune response necessary for protection due to subsequent exposure to an infectious agent. Use of herbal immuno-modulators perhaps might be helpful in overcoming the initial lag. For, e.g., Angelica sinensus polysaccharide (ASP) increased the production of IL-2 and IFNγ, while that of IL-4 was decreased [6]. Hence, in bacterial and viral infections, which need IFNγ for its clearance, can use ASP as an adjuvant along with the vaccine. Similarly, infections which need IL-4 for its clearance should be combined with herbal modulators favoring Th2 responses, like ginseng [3]. Herbs are usually considered to be safe. However, there is no database available which can summarize the immunological profile of the various herbs or polyherbs preparation. Hence, a note of caution is a must before choosing herbal immuno-modulators as an adjuvant

In vivo Evaluation of Two Thiazolidin-4-one Derivatives in High Sucrose Diet Fed Pre-diabetic Mice and Their Modulatory Effect on AMPK, Akt and p38 MAP Kinase in L6 Cells

We had previously demonstrated the anti-diabetic potential and pancreatic protection of two thiazolidin-4-one derivatives containing nicotinamide moiety (NAT-1 and NAT-2) in STZ-induced diabetic mice. However, due to the limitations of the STZ model, we decided to undertake a detailed evaluation of anti-diabetic potential of the molecules on a high sucrose diet (HSD) fed diabetic mouse model. Further, in vitro mechanistic studies on the phosphorylation of AMPK, Akt and p38 MAP kinase in L6 myotubes and anti-inflammatory studies in RAW264.7 mouse monocyte macrophage cells were performed.15 months of HSD induced fasting hyperglycaemia and impaired glucose tolerance in mice. Treatment with NAT-1 and NAT-2 (100 mg/kg) for 45 days significantly improved the glucose tolerance and lowered fasting blood glucose levels compared to untreated control. An improvement in the elevated triglycerides and total cholesterol levels, and favourable rise in HDL cholesterol were also observed with test drug treatment. Also, no major changes were observed in the liver (albumin, AST and ALT) and kidney (creatinine and urea) parameters. This was further confirmed in their respective histology profiles which revealed no gross morphological changes. In L6 cells, significant phosphorylation of Akt and p38 MAP kinase proteins were observed with 100 μM of NAT-1 and NAT-2 with no significant changes in phosphorylation of AMPK. The molecules failed to exhibit anti-inflammatory activity as observed by their effect on the generation of ROS and nitrite, and nuclear levels of NF-B in LPS-stimulated RAW264.7 cells. In summary, the molecules activated Akt and p38 MAP kinase which could have partly contributed to their anti-hyperglycaemic and hypolipidaemic activities in vivo