Anti-Microbial Drug Metronidazole Promotes Fracture Healing: Enhancement in the Bone Regenerative Efficacy of the Drug by a Biodegradable Sustained-Release In Situ Gel Formulation.

Autor:	Duggal S; Division of Endocrinology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow 226031, India., Sharma S; Division of Endocrinology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow 226031, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India., Rai N; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow 226031, India., Chauhan D; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow 226031, India., Upadhyay V; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.; Division of Cancer Biology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow 226031, India., Srivastava S; Division of Cancer Biology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow 226031, India., Porwal K; Division of Endocrinology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow 226031, India., Kulkarni C; Division of Endocrinology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow 226031, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India., Trivedi AK; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.; Division of Cancer Biology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow 226031, India., Gayen JR; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow 226031, India., Mishra PR; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow 226031, India., Chattopadhyay N; Division of Endocrinology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow 226031, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India., Pal S; Division of Endocrinology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow 226031, India.; Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA.; Division of Medical Research, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology (SRM IST), Kattankulathur 603203, India.
Jazyk:	angličtina
Zdroj:	Biomedicines [Biomedicines] 2024 Jul 18; Vol. 12 (7). Date of Electronic Publication: 2024 Jul 18.
DOI:	10.3390/biomedicines12071603
Abstrakt:	Nitroimidazoles comprise a class of broad-spectrum anti-microbial drugs with efficacy against parasites, mycobacteria, and anaerobic Gram-positive and Gram-negative bacteria. Among these drugs, metronidazole (MTZ) is commonly used with other antibiotics to prevent infection in open fractures. However, the effect of MTZ on bone remains understudied. In this paper, we evaluated six nitroimidazole drugs for their impact on osteoblast differentiation and identified MTZ as having the highest osteogenic effect. MTZ enhanced bone regeneration at the femur osteotomy site in osteopenic ovariectomized (OVX) rats at the human equivalent dose. Moreover, in OVX rats, MTZ significantly improved bone mass and strength and improved microarchitecture compared to the vehicle-treated rats, which was likely achieved by an osteogenic mechanism attributed to the stimulation of the Wnt pathway in osteoblasts. To mitigate the reported neurological and genotoxic effects of MTZ, we designed an injectable sustained-release in situ gel formulation of the drug that improved fracture healing efficacy by 3.5-fold compared to oral administration. This enhanced potency was achieved through a significant increase in the circulating half-life and bioavailability of MTZ. We conclude that MTZ exhibits osteogenic effects, further accentuated by our sustained-release delivery system, which holds promise for enhancing bone regeneration in open fractures.
Databáze:	MEDLINE
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