Study on development and tissue permeation of different formulations of Fasudil.

OBJECTIVE: The study is intended to formulate Fasudil loaded vesicular system for application in the management of angina. MATERIALS AND METHODS: Fasudil was made into a complex with phospholipid, and other different formulations were made, including Fasudil solution, liposomal form, and Fasudil loaded into the gel. A drug characterization study was conducted and noted. Drug release was quantified and analyzed and, finally, inoculated in Sprague-Dawley rats. These rats underwent anginal induction, and each formulation's effect on angina was evaluated. RESULTS: Drug solution (F-Phos) and F-Phos-Lipo (liposomal dispersion form of the drug) have shown that more than half percent of them have been released within 1.5 hours, and the rapid release occurred from liposomal dispersion in the first hour. The study determined the viscosity of the different formulations, which was significantly (p<0.05) higher than the theoretical sum of the viscosity of each formulation. The study found that the F-Phos-Lipo+P-407HMS formulation is the most effective as its application has the minimum infarct area percentage compared to the other formulations and can also reduce creatine kinase levels significantly as compared to the different formulations (p<0.05). CONCLUSIONS: The study concluded that the typical gel formulation (liposomal Fasudil dispersed in hydroxypropyl methylcellulose solution, which is added to blank poloxamer 407) had been shown to have significantly anti-anginal properties, including easy administration, its application on the infarct area percentage and subsequently its pharmacological effect on the cardiac tissue.

In silico elucidation of plausible anti-obesity activity by Withaferin-A compound targeting alpha-amylase.

OBJECTIVE: The study aimed to evaluate the Withaferin-A against the drug target α-amylase, revealing its plausible mode of action and molecular-level interactions essential for this specific target inhibitory potential computational approach. MATERIALS AND METHODS: In this scenario, we used computational methods, including docking, molecular dynamics simulation, and model-building simulations, to elucidate the atomic-level details responsible for the inhibitory potential of Withaferin-A derived from W. somnifera. The studio visualizer software was used for the visualization of ligands, structures of the receptor, bond length, and rendering of the image. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics of phytochemicals were investigated. Crystal structure of protein receptors and ligands were generated. Semi-flexible docking was done using Autodock software. Docking was performed using the Lamarckian Genetic Algorithm (LGA). Molecular descriptors were evaluated, and the pharmacological properties of the phytochemicals were explored. Molecular dynamic simulations were analyzed at the atomic level. All the simulations were conducted under the same temperature, pressure, and volume circumstances over the simulated time scale. RESULTS: Withaferin-A has shown a strong binding affinity towards α-amylase as demonstrated with -9.79 Kcal/mol with 66.61 estimated nanomolecular IC50 value for plausible anti-obesity activity. Molecular-level relationships and knowledge obtained from this study indicate solid interactions with TYR59, ASP197, and HIS299 residues which are of high importance for future works related to computational screening of target-specific α-amylase inhibitors. The results from the analysis have revealed potential molecular-level interactions useful for further designing/discovering novel α-amylase inhibitors. CONCLUSIONS: The framework of the studied phytochemicals enables the rapid development of subsequent modifications that could result in more lead-like compounds with better inhibitory efficacy and selectivity for α-amylase.

Significance of Orlistat in management of dyslipidemia, systolic blood pressure and body mass index.

OBJECTIVE: The current study intends to find out the efficacy of Orlistat in the management of hyperlipidemia, Systolic Blood Pressure (SBP) and Body Mass Index (BMI). MATERIALS AND METHODS: This retrospective study has evaluated the lipid profiles of the patients, who have been using metformin therapy for Type 2 diabetes. The study has obtained data regarding the parameters like triglyceride, Total cholesterol (TC), LDL cholesterol, HDL cholesterol and LDL/HDL ratio, systolic blood pressure and Body Mass Index (BMI). Random distribution of patients was done into placebo and Orlistat groups. The placebo group received only metformin, and patients in the Orlistat group received Orlistat along with metformin. After 24 weeks, the follow-up study was done, and statistical analysis was conducted. RESULTS: The study found that the Orlistat group has significant improvement (p<0.05) more improvement in LDL cholesterol, HDL cholesterol, Total cholesterol, LDL/HDL Ratio and Triglycerides, while BMI and systolic blood pressure did not show a significant difference between placebo and Orlistat group. CONCLUSIONS: This study has concluded that Orlistat can be used for significant improvement in lipid profile. The study also found that Orlistat may not have a significant effect on reducing BMI and blood pressure without adequate lifestyle modification.

Design, in silico study, synthesis and in vitro evaluation of some N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine derivatives as potential pancreatic lipase inhibitors for anti-obesity activity.

OBJECTIVE: The aim of the study is to design N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine derivatives and evaluate its anti-obesity activity. MATERIALS AND METHODS: A few pyrazole-fused benzimidazole derivatives were designed as potential Pancreatic Lipase (PL) inhibitors. The designed N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine derivatives have been screened using the Lipinski rule of five, ADMET analysis, acute toxicity prediction, and molecular docking. Later on, the derivatives which possess the most drug-likeness properties and displayed the most potent inhibition of the enzyme in molecular docking were synthesized. Then, in vitro enzyme assay was performed. RESULTS: Orlistat used as the standard exhibited 91±1.68% inhibition of the enzyme, displayed binding affinity (BA) of only -4.5 kcal/mol with Pancreatic Lipase (PL), and made only one salt bridge attractive charge and carbon-hydrogen bond with ASP79 and TRP252, respectively. Compound 9 displayed the most potent activity (93±1.12% inhibition of P.L. and -9.5 kcal/mol BA). It has formed five conventional H- bonds with GLU253, ILE78, ASP79, PHE258, and one Pi-donor H- bond with ILE78. From the present investigation, we hereby reported (E)-N2-((naphthalene-1-yl)methylene)-N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine as most potent PL inhibitor for the treatment of obesity, which can be further optimized by undergoing more studies using in vivo and in vitro models. CONCLUSIONS: (E)-N2-((naphthalene-1-yl)methylene)-N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine as most potent PL inhibitor for the treatment of obesity which can be further optimized better using more in vivo and in vitro models. PL plays a critical role in digesting dietary fat. Therefore, PL inhibitors are verified as a potential therapy for treating obesity.

Prevalence of cardiovascular disease and osteoarthritis in obese population of Hail region, Saudi Arabia.

OBJECTIVE: The aim of the study was to analyze if there was a link between chronic diseases, like cardiovascular disease (CVD) and osteoarthritis (OA), and obesity in the population of Saudi Arabia's Hail region. MATERIALS AND METHODS: The study was conducted over 12 months using an observational cross-sectional survey on 172 patients from five clinics in Hail, Saudi Arabia. A total of 172 individuals with obesity (BMI ≥ 30) finally participated in this research. The study evaluated sociodemographic variables via an electronic questionnaire with voluntary participation. RESULTS: The study found a 76% prevalence of joint pain and 77.9% prevalence of cardiovascular abnormalities. Patients with CVD were older (58±23 vs. 56±12 years) than those with OA. CVD cases were found in 42 (31.3%) males and 92 (68.7%) females, whereas OA cases were recognized in 24 (18.5%) males and 106 (81.5%) females. The occurrence of various CVDs among our participants was 43 (32%) for high cholesterol, 64 (48%) for hypertension, and 27 for both high cholesterol and hypertension (20%). Definite osteophytes were found in 28 of 24 male knees (14 right and 14 left knees) and 175 of 106 female knees (88 right knees and 87 left knees). CONCLUSIONS: The prevalence of obesity in the Hail region has continued to be a risk factor for CVD and OA in 2019 and 2020. The Saudi population has shown a higher prevalence of radiographic evidence of OA of the knee and associated symptoms than western civilizations, and preventive interventions are desperately needed in order to minimize overweight and obesity.

Comparative analysis between mono approach and multi approaches in managing T2DM: a survey-based study.

OBJECTIVE: The aim of the study was to analytically compare the therapeutic effect of the addition of diet modification and regular exercise to oral agents. MATERIALS AND METHODS: This cross-sectional study surveyed 1248 participants via online and offline modes by employing a questionnaire about an individual's management of diabetes. Group 1 patients follow Single Approach Management for Type 2 Diabetes Mellitus (T2DM), while Group 2 and Group 3 patients follow Multi-Approach Management for T2DM. Based on the answers, the participants were classified into three groups. The diagnostic criteria of Diabetes Mellitus Type-2 in this study were done by determining morning Fasting Blood Sugar (FBS) and glycated Hemoglobin (HbA1c). RESULTS: The current study found 656 single oral agent users and 592 combination regimens users among all the study participants. The study also found that, among all participants, 511 patients were on mild to moderate diet modification while 325 patients were on moderate to severe diet modification. The study also noted that 232 males and 215 females took Complementary and Alternative Medicines (CAM). Of 447 patients, 12 showed menstrual abnormalities (2.6%), and 18 had mild diarrhoea (4%). The study also found that there is a vital significance of lowering FBS and HbA1c with the management strategies (p=0.000). The study showed a strong association between group 3 and improved FBS and HbA1c (p=0.000). CONCLUSIONS: This study reveals that diet modification and regular exercise improve FBS and HbA1c levels significantly. Hence, diet modification and exercise can be added as adjuvants and should be incorporated into the management guidelines of T2DM.

Effect of methacrylonitrile on membrane bound enzymes of rat brain.

Methacrylonitrile (MeAN) is a plastic monomer. Its effect on membrane bound enzymes like Na+K+ -ATPase, Ca2+ -ATPase, Mg2+ -ATPase, NADH dehydrogenase, alkaline phosphatase (ALP) and various elements like sodium (Na+), potassium (K+), and calcium (Ca2+) in rat brain were studied. Administration of 50 mg/kg body weight/day (0.25 LD50) and 100 mg/kg body weight/day (0.5 LD50) by gavage to rats for 7 days resulted in a significant decrease in activities of Na+K+ -ATPase, Ca2+ -ATPase, Mg2+ -ATPase, and NADH dehydrogenase. A significant reduction in calcium content, potassium content and a significant increase in sodium content and alkaline phosphatase activity in MeAN treated animals were observed. Inhibition of membrane bound enzymes occurred due to either direct effect of MeAN or indirect effect of changes in ionic homeostasis in MeAN treated animals.

Brain lipid peroxidation and antioxidant status after acute methacrylonitrile intoxication.

The status of brain antioxidant enzymes and glutathione in methacrylonitrile (MeAN)-intoxicated Wistar rats was correlated with the levels of lipid peroxidation products. Optimum changes were observed 30 min and 60 min after oral administration of MeAN at dosages of 50 mg/kg body weight per day (0.25 LD50) and 100 mg/kg body weight per day (0.5 LD50). An increase in lipid peroxidation products, decrease in the activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione reductase (GR), glutathione S-transferase (GST), and decrease in reduced glutathione (GSH) were observed. These studies suggest that the membrane lipid peroxidation observed in MeAN intoxication is related, in part, to a compromised antioxidant defense system.