Floating tablets of hydralazine hydrochloride: optimization and evaluation

Hydralazine hydrochloride has a half-life of 2 to 4 hours with an oral bioavailability of 26-50%. Since hydralazine has a demethylating effect on various suppressor genes, it can be used in various types of cancer to support chemotherapy. The purpose of this study was to optimize and evaluate floating tablets of hydralazine hydrochloride designed to prolong the gastric residence time and to provide controlled release of the drug for 14 h. The floating tablets of hydralazine hydrochloride were prepared by the wet granulation method. Semi-synthetic polymers of hydroxy propyl methyl cellulose (HPMC K100M) and ethyl cellulose were used as the release retarding agents. A 2² factorial design was applied to systematically optimize the drug release profile. The concentrations of HPMC K100M and ethyl cellulose were optimized to provide controlled release of hydralazine for 14h. Non-Fickian diffusion release transport was confirmed as the release mechanism for the optimized formulation and the predicted values agreed well with the experimental values. Drug excipient compatibility studies were investigated by FTIR, DSC and XRD. These data indicate that there were no chemical interactions between the drug and the polymer. In vivo X-ray imaging showed floating tablet performance in rabbits.O cloridrato de hidralazina apresenta meia-vida de 2 a 4 horas, com biodisponibilidade oral de 26-50%. Uma vez que a hidralazina possui efeito desmetilante em vários genes supressores, ela pode ser utilizada para diversos tipos de câncer, em apoio à quimioterapia. O objetivo deste estudo foi o de avaliar e otimizar comprimidos flutuantes de cloridrato de hidralazina, planejados para prolongar o tempo de residência gástrica e proporcionar liberação controlada do fármaco por 14 h. Os comprimidos flutuantes de cloridrato de hidralazina foram preparados pelo método de granulação úmida. Polímeros semi-sintéticos de hidroxipropiletil celulose (HPMCK100M) e acetato de celulose foram utilizados como agente de retardamento de liberação. Aplicou-se planejamento fatorial 2² para otimizar sistematicamente o perfil de liberação do fármaco. As concentrações de HPMCK100M e de etilcelulose foram otimizadas para se obter liberação controlada de hidralazina durante 14 h. O transporte de liberação de difusão não-Fickiana foi confirmado como o mecanismo de liberação para a formulação otimizada e os valores previstos estiveram de acordo com os valores experimentais. Estudos de compatibilidade entre fármaco e excipiente foram realizados por FTIR, DSC e DRX. Estes dados indicaram que não havia interação química entre o fármaco e o polímero. Imagens de raios-X in vivo mostraram o desempenho dos comprimidos flutuantes em coelhos

Phosphoinositide 3-kinase inhibitor AS605240 ameliorates streptozotocin-induced Alzheimer’s disease like sporadic dementia in experimental rats

The quest for chemical entities able to curb the action of the phosphoinositide 3-kinase, (PI3K)/protein kinase B (AKT) signaling pathways is evolving as a potential therapeutic strategy for the treatment and/or prevention of neurodegenerative disorders including Alzheimer’s disease (AD). In this study, the effects of a PI3K inhibitor, AS605240 on cognitive dysfunction and antioxidative defense parameters against intra-cerebroventricular-streptozotocin (ICV-STZ)-induced rat model of sporadic AD was evaluated. ICV administration of a single dose of STZ (3 mg/kg) was performed to induce behavioral and biochemical changes in rats using the stereotaxic technique. Animals were administered with varying doses of AS605240 (5, 10 and 15 mg/kg) orally, 1 h before ICV-STZ on day 1 and continued once daily for four weeks. The behavioral parameters (passive avoidance and Morris water maze), antioxidative defense parameters, amyloid-beta (Aβ) protein expression by Western blotting and immunostaining technique were estimated in brain tissue. AS605240 dose-dependently and significantly (p < 0.05 and p < 0.01 and p < 0.001) improved ICV-STZ-induced cognitive impairment and attenuated the altered antioxidative related parameters including superoxide dismutase, lipid peroxidation, glutathione and nitrite levels. Further, the increased Aβ protein expression levels in brain tissue were markedly restored with AS605240 treatment. In conclusion, our study demonstrated that AS605240 exhibited immense potential in attenuating STZ-induced sporadic AD features in rats and may be developed as a therapeutic agent in the treatment and management of sporadic AD

Preclinical investigation of the acute effects of Trigonella foenum-graecum seed powder on blood glucose in normal and alloxan-induced diabetic rabbits

To investigate the blood glucose lowering effect of the seed powder of T. foenum-graecum Linn (Papilionaceae) in normal and alloxan-induced diabetic rabbits. The blood glucose lowering effect of the seed powder was determined in normal and alloxan-induced (100 mg/kg, i.v.) diabetic rabbits, after oral administration of doses of 50, 100 and 150 mg/kg body weight. Blood samples were collected from the marginal ear vein before and also at 4, 6, 8, 10, 12, 16, 18, 20 and 24 h after drug administration and blood glucose was analysed by Nelson-Somogyi's method using a visible spectrophotometer. The data was compared statistically by using Student's t-test. The seed powder of T. foenum-graecum produced a dose-dependent reduction in blood glucose of both normal and diabetic rabbits and comparable with that of standard drug, glibenclamide. The results indicate a prolonged action in reduction of blood glucose by T. foenum-graecum and the mode of action of the active compound (s) of T. foenum-graecum is probably mediated through enhanced secretion of insulin from the b-cells of Langerhans or through extrapancreatic mechanism. The present study clearly indicated a significant anti-diabetic activity with the seed powder of T. foenum-graecum and supported the traditional usage of the seed powder by Ayurvedic physicians for the control of diabetes

The global burden of adolescent and young adult cancer in 2019 : a systematic analysis for the Global Burden of Disease Study 2019

Background In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults. Findings There were 1.19 million (95% UI 1.11-1.28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59.6 [54.5-65.7] per 100 000 person-years) and high-middle SDI countries (53.2 [48.8-57.9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14.2 [12.9-15.6] per 100 000 person-years) and middle SDI (13.6 [12.6-14.8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23.5 million (21.9-25.2) DALYs to the global burden of disease, of which 2.7% (1.9-3.6) came from YLDs and 97.3% (96.4-98.1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe

Antidepressant effects of standardized extract of Commiphora mukul Engl. in olfactory bulbectomized rats

The objective of this work was to evaluate the effects of standardized hydroalcholic extract of Commiphora mukul (HECM) in animal model of chronic stress medicated depression, namely olfactory bulbectomy (OBX) model in rats. Effects of 14-day (subacute) oral pretreatment of HECM (50, 100 and 200 mg/kg) were evaluated on depression and stress related parameters on OBX rats. Separate groups for sham control, OBX control and positive controls namely imipramine (20 mg/kg), fluoxetine (30 mg/kg) and desipramine (15 mg/kg) were also maintained. Behavioral and physiological parameters in open field and elevated plus maze were recorded. HECM showed dose-dependent reversal of OBX-induced physiological effects such as reduction of body weight, body temperature, heart rate and serum sodium concentration. HECM also showed reversal effects on OBX induced food intake increase and hyperactivity in open field and elevated plus maze paradigm. In conclusion, HECM demonstrated restorative effects in OBX induced depression model in rats probably due to stress reliving mechanisms

Structure-based discovery of small molecule APC-Asef interaction inhibitors: In silico approaches and molecular dynamics simulations

Colorectal cancer, which is considered one of the leading causes of mortality worldwide, develops through the formation of benign polyps on the inner colon or rectum wall. Truncations in adenomatous polyposis coli (APC) gene lead to the spread of the disease in the entire colon region when combined with the guanine nucleotide exchange factor (GEF) Asef. A series of peptidomimetic agents were previously discovered as protein-protein interaction inhibitors that can target the APC-Asef interface. Structure-based virtual screening (SBVS), using a set of docking methods combined with molecular dynamics simulations, was carried out to identify new small drug-like agents. After the initial screening process, compounds with diverse chemical scaffolds and direct interaction with Arg549 and other active site residues were chosen and subjected to induce fit. The amide functional group found in the ligand hit structures showed strong interactions with Arg549, leading to observable conformational changes that allow suitable positioning within the peptide binding site. Furthermore, the pH-specific MD simulations of the top hit 838 within the APC-Asef binding site depicted significant interactions required for biochemical recognition in changing microenvironment. Predicted inhibitory constant (Ki) values and binding free energies of hits further described the significance of the amide group over the other chemical scaffolds. This combination of in silico approaches provides key insights for colorectal drug discovery programs targeting the APC-Asef interaction. [Figure not available: see fulltext.] © 2020, Springer-Verlag GmbH Germany, part of Springer Nature