title: Studies on synthesis, stability, release and pharmacodynamic profile of a novel diacerein-thymol prodrug.
abstract: Involvement of oxidative stress, leading to chondrocyte senescence and cartilage ageing has been implicated in the pathogenesis of osteoarthritis (OA). New efforts to prevent the development and progression of OA include strategies and interventions aimed at reducing oxidative damage in articular cartilage using antioxidants as adjuncts to conservative therapy. Diacerein is an anthraquinone derivative with a marked disease modifying effect on OA owing to IL-1 β inhibition. In the present work an attempt was made at design and development of a co-drug of diacerein with antioxidant thymol. Structural elucidation was carried out by spectral analysis. When release kinetics of prodrug was studied in phosphate buffer (pH 7.4) and small intestinal homogenates of rats, 91% and 94% diacerein was available respectively at the end of 4.5 h. Chemical linkage of thymol with diacerein improved its lipophilicity and hence bioavailability. Screening of prodrug in Freud's adjuvant-induced arthritis and ulcerogenic potential by Rainsford's cold stress model exhibited significant reduction in paw volume, joint diameter and ulcer index with superior anti-inflammatory/anti-arthritic activities than the standards. Results of histopathology of tibio-tarsal joint indicated that animals treated with diacerein exhibited moderate synovitis while thymol and physical mixture-treated animals showed mild synovitis. Interestingly in prodrug-treated animals synovitis was not observed. The results of this study underline the promising potential of co-drug of diacerein and thymol in the management of OA.
authors.affiliation: Department of Pharmaceutical Chemistry, Bharati Vidyapeeth Deemed University, Poona College of Pharmacy, Pune 411038, Maharashtra, India. suneeladhaneshwar@rediffmail.com
authors.forename: Suneela
authors.initials: S
authors.lastname: Dhaneshwar
authors.forename: Vriha
authors.initials: V
authors.lastname: Patel
authors.forename: Dipmala
authors.initials: D
authors.lastname: Patil
authors.forename: Gourav
authors.initials: G
authors.lastname: Meena
mesh_terms: D000818:Animals; D000843:Ankle Joint / Q000473:pathology; D000880:Anthraquinones / Q000737:chemistry* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D006207:Half-Life; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013943:Thymol / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D000880:Anthraquinones; D000893:Anti-Inflammatory Agents; D011355:Prodrugs; D013943:Thymol; C025292:diacerein