A 1-Month Exploratory Combination Safety and Toxicity Study of Co-Administration of Sitagliptin and Telmisartan in Male Wistar Han Rats.

Diabetes and hypertension often coexist and need complex pharmacological management. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is widely used for glycemic control, and telmisartan, an angiotensin II receptor blocker, is the preferred treatment for hypertension. Thus, we have conducted a 1-month exploratory combination safety and toxicity study in male Wistar Han rats.

Evaluating Solvent Safety in Chromosome Aberration Assays for Genetic Toxicology.

The chromosome aberration test (CAT) is a widely used in vitro assay for detecting structural chromosomal damage induced by clastogenic chemicals. It plays a crucial role in genetic toxicology, helping assess the potential genotoxic effects of pharmaceutical compounds, environmental contaminants, and industrial chemicals. This test is particularly valuable in regulatory studies, as chromosomal aberrations are linked to mutagenicity, carcinogenicity, and hereditary diseases.

Preclinical safety, tolerability and pharmacokinetics of a novel cyclobenzaprine hydrochloride nasal spray.

These studies examined the effects of repeated intranasal administration of Cyclobenzaprine hydrochloride in rats and dogs. In rats, doses up to 1.05 mg/animal/day over 28 days showed no mortality or toxicity.

Targeting TRPC6 in podocytopathies: Why clinical translation remains a challenge?

Podocytopathies, driven by injury to glomerular podocytes, are a major cause of proteinuric kidney diseases like focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease (DKD). The transient receptor potential canonical 6 (TRPC6) channel, expressed in podocytes, is critical for maintaining the glomerular filtration barrier. Dysregulation of TRPC6 activity-whether due to gain-of-function mutations or pathological activation-induces excessive calcium influx, leading to podocyte cytoskeletal disruption, oxidative stress, and apoptosis.

Strain-specific mutagenicity of NDMA and CPNP: insights from TA1535, TA100, and WP2 uvrA (pKM101) under metabolic activation.

The Ames test is a critical assay for assessing the mutagenic potential of chemical compounds; however, its conventional version (OECD TG 471) falls short in detecting nitrosamine mutagenicity due to insufficient metabolic activation. Given the ubiquity of nitrosamines as environmental contaminants and drug impurities, an enhanced protocol incorporating 30 % v/v hamster and rat liver S9 fractions with a 30-minute pre-incubation is warranted. This study streamlined the enhanced Ames test by evaluating the sensitivity of S.

Evaluation of Repeat Dose Toxicity and Embryo-Fetal Developmental Toxicity of Novel Glucokinase Activator ZYGK1 in Wistar Rats.

ZYGK1 is a novel small molecule glucokinase (GK) activator. The purpose of this study was to assess the repeated dose toxicity of ZYGK1 in male and female Wistar rats and its effect on pregnancy and embryo-fetal development in pregnant female Wistar rats. ZYGK1 was administered by oral gavage to rats at 15, 30, 60, and 120 mg/kg, once a day, for 28 consecutive days.

Comparative Analysis of TA102 and WP2 uvrA(pKM101) Strains in Detecting Nitrosamine Mutagens in the Enhanced Ames Test.

The Ames test is a fundamental assay for evaluating chemical mutagenicity, particularly for nitrosamines, which are widespread environmental and pharmaceutical contaminants. To improve sensitivity, regulatory agencies have endorsed the enhanced Ames test (EAT), which incorporates five tester strains, a 30-min pre-incubation step, and metabolic activation using both rat and hamster liver S9 fractions. While Salmonella typhimurium TA102 is known for its sensitivity to oxidative mutagens, its performance under EAT conditions has not been fully characterized.

Investigating the Genotoxic Potential of Pioglitazone in Hyperglycemic Conditions Using Chromosome Aberration and GADD45α Markers in TK6 Cells.

Hyperglycemia significantly increases the production of reactive oxygen species (ROS), leading to amplified DNA damage and a higher potential for mutations. Pioglitazone, a thiazolidine-class oral antidiabetic drug, enhances insulin sensitivity but also raises concerns about cancer risk due to ROS-induced genotoxic effects. We hypothesized and evaluated the genotoxic potential of pioglitazone under hyperglycemic conditions using TK6 cells.

Inhalation safety and tolerability of a novel fixed-dose combination of glycopyrronium-vilanterol powder in Wistar rats.

Fixed-dose combinations (FDCs) offer therapeutic benefits like enhanced efficacy, reduced adverse effects, and better patient compliance, making them cost-effective. They are particularly effective in managing chronic obstructive pulmonary disease (COPD). Combining a long-acting muscarinic antagonist with a long-acting beta-agonist improves lung function, reduces the need for rescue bronchodilators, alleviates respiratory symptoms, and enhances the overall quality of life in COPD patients.

Discovery of ZYDG2: A potent, selective, and safe GPR40 agonist for treatment of type 2 diabetes.

GPR40/FFA1 receptor, predominantly expressed in pancreatic β-cells, mediates glucose-stimulated insulin secretion by free fatty acids. Fasiglifam-GPR40 agonist was terminated in phase III clinical trials due to adverse liver effects. ZYDG2 is identified as a novel, potent and selective agonist for GPR40, exhibiting EC of 41 nM and 17 nM in cell-based functional inositol 1-phosphate-ELISA assay and Ca mobilization assay, respectively.

Pharmacological effect of ZYGK1, a novel glucokinase activator, in hyperglycemic and sulfonylurea-resistant type 2 diabetes in mice models.

Objectives: Type 2 diabetes is caused due to inadequate glucose utilization in the liver and pancreas due to insulin resistance. Glucokinase enzyme plays a key role in metabolism of glucose and insulin release and hence glucokinase activation can be a useful therapeutic target for treatment of type 2 diabetes.

Methods: Present study was conducted to investigate the effect of a novel glucokinase activator ZYGK1 in the preclinical models of diabetes in mice.

Assessing the impact of different solvents in the bacterial reverse mutation test.

The bacterial reverse mutation test is essential for identifying the mutagenic potential of chemicals. The solubility of the test substance is vital for achieving the recommended assay concentration. Preferred solvents like dimethyl sulfoxide and water are chosen for their compatibility and historical data.

Selection of solvent and positive control concentration for enhanced Ames test conditions for N-nitrosamine compounds.

The Ames test is a widely used bacterial mutagenicity assay to evaluate the potential of chemical compounds to induce mutations. In recent years, there has been growing concern regarding the presence of N-nitrosamines in pharmaceuticals, food, and other consumer products. N-Nitrosamines are probable mutagens and carcinogens.

A novel selective NLRP3 inhibitor shows disease-modifying potential in animal models of Parkinson's disease.

Pathological activation of the Nod-like receptor family pyrin domain containing protein 3 (NLRP3) inflammasome signaling underlies many autoimmune and neuroinflammatory conditions. Here we report that, a rationally designed, novel, orally active, selective NLRP3 inflammasome inhibitor, Usnoflast (ZYIL1), showed potent inhibition of ATP, Nigericin and monosodium urate-mediated interleukin (IL)-1β release in THP-1 cells and human PBMC. In isolated microglia cells, the IC of ZYIL1 mediated inhibition of IL-1β was 43 nM.

HIF Stabilizer Desidustat Protects against Complement-Mediated Diseases.

Complement cascade is a defence mechanism useful for eliminating pathogenic microorganisms and damaged cells. However, activation of alternative complement system can also cause inflammation and promote kidney and retinal disease progression. Inflammation causes tissue hypoxia, which induces hypoxia-inducible factor (HIF) and HIF helps the body to adapt to inflammation.

Safety Assessment of a Novel Intravenous Diclofenac Sodium Formulation Following 28-Day Repeated Administration in Wistar Rats.

These toxicity studies aimed to assess the safety and tolerability of a novel intravenous diclofenac sodium (37.5 mg/mL) formulation containing povidone K12 (80 mg/mL) as the key excipient in Wistar rats. This formulation was tested at doses of 3, 7, and 15 mg/kg/day and was administered daily for 28 days by intravenous route.

A Retrospective Comparison of Electrocardiographic Parameters in Ketamine and Tiletamine-Zolazepam Anesthetized Indian Rhesus Monkeys ().

Electrocardiographic evaluation is performed in rhesus monkeys to establish the cardiovascular safety of candidate molecules before progressing to clinical trials. These animals are usually immobilized chemically by ketamine (KTM) and tiletamine-zolazepam (TZ) to obtain a steady-state heart rate and to ensure adequate human safety. The present study aimed to evaluate the effect of these anesthetic regimens on different electrocardiographic parameters.

Comparison of different QT correction methods for nonclinical safety assessment in ketamine-anesthetized Indian rhesus monkeys ().

Rhesus monkeys are a non-rodent species employed in the preclinical safety evaluation of pharmaceuticals and biologics. These nonhuman primate species have been increasingly used in biomedical research because of the similarity in their ionic mechanisms of repolarization with humans. Heart rate and QT interval are two primary endpoints in determining the pro-arrhythmic risk of drugs.

Design, synthesis and biological evaluation of novel pyrazolo-pyrimidin-amines as potent and selective BTK inhibitors.

To discover the best-in-class Bruton's Tyrosine Kinase (BTK) inhibitors, for th treatment of autoimmune disorders like cancer (B-Cell Lymphoma (BCL)) and rheumatoid arthritis (RA), in the present investigation, novel structural optimizations were carried out. Introduction of novel bicyclic amine linkers and aromatic backbone led to series of compounds 9a-h and 14a-u. Compound 14b was found to be potent, orally bioavailable, selective and irreversible BTK inhibitor.

Hematological and biochemical reference intervals of wild-caught and inhouse adult Indian rhesus macaques (Macaca mulatta).

Background: Nonhuman primates are used for research purposes such as studying diseases and drug discovery and development programs. Various clinical pathology parameters are used as biomarkers of disease conditions in biomedical research. Detailed reports of these parameters are not available for Indian-origin rhesus macaques.

Discovery of diaminopyrimidine-carboxamide derivatives as JAK3 inhibitors.

Selective inhibition of janus kinase (JAK) has been identified as an important strategy for the treatment of autoimmune disorders. Optimization at the C2 and C4-positions of pyrimidine ring of Cerdulatinib led to the discovery of a potent and orally bioavailable 2,4-diaminopyrimidine-5-carboxamide based JAK3 selective inhibitor (11i). A cellular selectivity study further confirmed that 11i preferentially inhibits JAK3 over JAK1, in JAK/STAT signaling pathway.

Influence of estrous stages on electrocardiography, clinical pathology and ovarian weight of experimental beagle dogs: a retrospective analysis.

Estrous cycle is a repetitive phenomenon occurring during the reproductive life of a female dog. The duration of the canine estrous cycle is considerably longer than one in the most of the other animals and is broadly grouped into follicular phase (proestrus and estrus), luteal phase (diestrus) and non-seasonal anestrus. Dogs in the same stage of cycle can be inadvertently assigned to same group during routine safety and metabolic studies leading to possible erroneous interpretation of test-item related effects.

Non-clinical safety evaluation of a novel pharmaceutical salt, rosuvastatin ethanolamine, in Wistar rats.

Rosuvastatin, a second generation 3-Hydroxy-3-Methyl Glutaryl Coenzyme-A reductase inhibitor, is widely used for the management of hypercholesterolemia. Rosuvastatin ethanolamine, developed by Cadila Healthcare Ltd., is a novel, chemically stable, and pharmaceutically acceptable salt, having better physiochemical properties than commercially available Rosuvastatin salt.

Identification and preclinical characterization of a novel and potent poly (ADP-ribose) polymerase (PARP) inhibitor ZYTP1.

Purpose: Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in the detection and repair of DNA damage. Studies have shown that inhibition of PARP and Tankyrase (TNKS) has significant antitumor effect in several types of cancers including BRCA-negative breast cancers.

Methods: Identification of ZYTP1, a novel PARP inhibitor, through a battery of in vitro assays and in vivo studies.