المؤلفون: Manohar Nandanwar, Atul Kansagara, Sangita Gupta, Anasuya Patel, Muftedar Ahmed Patel, Ravindra Yeole, Deepak Thorve, Mahesh Patel

المصدر: Journal of Applied Toxicology. 42:1354-1370

مصطلحات موضوعية: Mice, Dogs, Administration, Oral, Animals, Humans, Quinolones, Toxicology, Quinolizines, Anti-Bacterial Agents, Fluoroquinolones, Rats

الوصف: Fluoroquinolone (FQ) antibacterials have drawn heightened attention from various international regulatory agencies due to their class-specific side effects. Levonadifloxacin is a novel broad spectrum benzoquinolizine FQ active against methicillin-resistant Staphyloccocus aureus (MRSA). Owing to FQ-associated safety concerns, extensive preclinical safety pharmacology (central nervous system and cardiac safety) and toxicology studies (subacute repeat-dose toxicity, genotoxicity, phototoxicity and chondrotoxicity) of levonadifloxacin were performed at relatively high doses. Intravenous (IV) and oral studies were conducted using WCK 771 (l-arginine salt of levonadifloxacin) and WCK 2349 (l-alanine ester prodrug of levonadifloxacin), respectively. Safety pharmacology studies following single dose revealed no adverse effects on central nervous system (including seizure) in mice and cardiovascular system (hERG and monkey telemetry). In repeat-dose toxicity studies, except for IV bolus dosing related effects in rat (hyperactivity, mild convulsion, polypnoea and injection site irritation) and dog (emesis and salivation), no other adverse findings limiting the dosing duration were observed. No major biochemical, haematological, gross or histopathological changes suggestive of damage to vital organs were observed in either WCK 771- or WCK 2349-treated groups. WCK 771 and WCK 2349 were found to be nongenotoxic; however, they showed weak phototoxicity that was comparable with levofloxacin. WCK 771 showed chondrotoxicity in the Beagle dog pups on repeat-dose administration; however, the severity level was lower than ofloxacin. Overall, preclinical safety studies helped establish wider safety margin for WCK 771 and WCK 2349 that supports administration of higher therapeutic doses in humans by both IV and oral routes, thereby enabling safe anti-MRSA treatment.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e4a3cc16f63b82959497190d75c3f028Test
https://doi.org/10.1002/jat.4300Test

المؤلفون: Sangita Gupta, Ulka Sakhalkar, Avinash Karade, Parag Ghorpade, Yasmeen Sidhu, Anuka Sharma, Manohar Nandanwar, Muftedar Ahmed Patel, Atul Kansagara, Vijay Sharma

المصدر: J Diabetes Metab Disord

مصطلحات موضوعية: Contraction (grammar), integumentary system, business.industry, Endocrinology, Diabetes and Metabolism, Growth factor, medicine.medical_treatment, Inflammation, medicine.disease, Streptozotocin, Diabetes mellitus, Anesthesia, Internal Medicine, Sprague dawley rats, Medicine, medicine.symptom, business, Wound healing, Non diabetic, medicine.drug, Research Article

الوصف: BACKGROUNDS: The investigation of wound healing potential of human GFC (growth factor concentrate) was undertaken in diabetic and non-diabetic rats. Primarily, GFC is the combination of several growth factors present in blood which has potential of wound healing. In present study, WCK-GFC kit, a single step optimized kit was used for obtaining human GFC. METHODS: Diabetes in rats was induced by intraperitoneal single injection of 40 mg/kg streptozotocin (STZ). The full thickness circular wounds of 2 cm(2) area were created using sterilized stainless steel biopsy punch. Non-diabetic wounds were topically treated with 100µL and 300µL of GFC, while diabetic wounds were treated with 300µL of GFC. The standard of care treatment groups were included, wherein the non-diabetic and diabetic wound were topically treated with Nadoxin and Z-AD-G skin cream, respectively. The percentage of wound contraction was measured on weekly intervals. At the end of study duration, tissues from wound were collected for histopathological evaluation. RESULTS: Both diabetic and non-diabetic GFC treated rats exhibited a significantly higher rate of wound contraction on day 8 and 15 compared to normal untreated control group and standard-of-care treated rats. Wound healing was induced by GFC through rapid re-epithelialization. On comparing wound healing with standard-of care agent, the GFC treated wounds demonstrated a faster remodeling phase, a better organization and lower inflammation. CONCLUSIONS: The current study demonstrates that topically applied GFC promotes healing of wounds, with enhanced wound contraction in both non-diabetic and diabetic rats.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f41b7205d92383ad2a545717550388a8Test
https://pubmed.ncbi.nlm.nih.gov/34900810Test

المؤلفون: Rajesh Chavan, Muftedar Ahmed Patel, Anasuya Patel, Atul Kansagara, Ravindra D. Yeole, Manohar Nandanwar, Mahesh Patel

المصدر: Regulatory toxicology and pharmacology : RTP. 122

مصطلحات موضوعية: Male, CYP2D6, Ketolides, CYP3A, medicine.drug_class, Antibiotics, 010501 environmental sciences, Pharmacology, Toxicology, 030226 pharmacology & pharmacy, 01 natural sciences, Cell Line, Rats, Sprague-Dawley, 03 medical and health sciences, Lactones, 0302 clinical medicine, Dogs, In vivo, medicine, Animals, Cytochrome P-450 CYP3A, Humans, Rats, Wistar, Ketolide, 0105 earth and related environmental sciences, Phospholipidosis, Dose-Response Relationship, Drug, business.industry, General Medicine, In vitro, Anti-Bacterial Agents, Rats, Liver, Toxicity, Cytochrome P-450 CYP3A Inhibitors, Female, business, medicine.drug

الوصف: Ketolide antibiotics are known to cause hepatic injury. Nafithromycin, a novel lactone ketolide was therefore assessed for hepatic safety through range of preclinical in vitro (metabolic stability, CYP inhibition/induction assays) and in vivo (mass balance and repeat dose toxicity) studies. Repeat-dose toxicity studies in rat and dog revealed that nafithromycin did not cause adverse hematological, biochemical and histopathological changes suggestive of systemic or hepatobiliary safety concern at exposures 3-8 fold higher than targeted therapeutic exposures. The only histological finding noticed was reversible phospholipidosis, mainly in lung and lymphoid organs but not in liver, indicating lower nafithromycin accumulation in liver. This observation was corroborated with lack of biologically relevant elevation of hepatic enzymes linked to hepatic injury. In vitro studies showed that nafithromycin undergoes moderate CYP3A mediated metabolism. Unlike other ketolides, nafithromycin and its metabolites showed weak inhibition of CYP3A isoform and lacked CYP2D6 inhibition. Due to hydrophilic nature, nafithromycin in addition to hepatic clearance is also eliminated unchanged by kidneys in significant amount, thereby minimizing hepatic burden. Based on the scientifically integrated evidences such as moderate metabolism, weak CYP inhibition, lack of CYP induction, minimal accumulation in liver, nafithromycin showed promising hepatic safety profile suitable for its intended community-based usage.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0f64122bc60e300c5c1a389fb0f94a6dTest
https://pubmed.ncbi.nlm.nih.gov/33587936Test