Studies on synthesis, stability, release and pharmacodynamic profile of a novel diacerein-thymol prodrug

被引:32
作者
Dhaneshwar, Suneela [1 ]
Patel, Vriha [1 ]
Patil, Dipmala [1 ]
Meena, Gourav [2 ]
机构
[1] Bharati Vidyapeeth Deemed Univ, Poona Coll Pharm, Dept Pharmaceut Chem, Pune 411038, Maharashtra, India
[2] Bharati Vidyapeeth Deemed Univ, Poona Coll Pharm, Dept Pharmacol, Pune 411038, Maharashtra, India
关键词
Co-drug; Diacerein; Antioxidant; IL-1-beta inhibitor; Thymol; Osteoarthritis; Ulcerogenicity; Oxidative stress; ARTICULAR-CARTILAGE; NITRIC-OXIDE; MUTUAL PRODRUG; II COLLAGEN; OSTEOARTHRITIS; GLUCOCORTICOIDS; CHONDROCYTES; INHIBITION; EXPRESSION; CYTOKINES;
D O I
10.1016/j.bmcl.2012.11.016
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 beta 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. (C) 2012 Elsevier Ltd. All rights reserved.
引用
收藏
页码:55 / 61
页数:7
相关论文
共 37 条
[1]  
Abdulrahman L., 2010, JKAU SCI, V22, P239
[2]   ANTIOXIDANT ACTIONS OF THYMOL, CARVACROL, 6-GINGEROL, ZINGERONE AND HYDROXYTYROSOL [J].
AESCHBACH, R ;
LOLIGER, J ;
SCOTT, BC ;
MURCIA, A ;
BUTLER, J ;
HALLIWELL, B ;
ARUOMA, OI .
FOOD AND CHEMICAL TOXICOLOGY, 1994, 32 (01) :31-36
[3]   Long-term NSAID treatment directly decreases COX-2 and mPGES-1 production in the articular cartilage of patients with osteoarthritis [J].
Alvarez-Soria, M. A. ;
Herrero-Beaumont, G. ;
Moreno-Rubio, J. ;
Calvo, E. ;
Santillana, J. ;
Egido, J. ;
Largo, R. .
OSTEOARTHRITIS AND CARTILAGE, 2008, 16 (12) :1484-1493
[4]  
[Anonymous], 2007, INDIAN PHARMACOPOIEA, VI, P241
[5]   The protective effect of OP-1 on articular cartilage in the development of osteoarthritis [J].
Badlani, N. ;
Inoue, A. ;
Healey, R. ;
Coutts, R. ;
Amiel, D. .
OSTEOARTHRITIS AND CARTILAGE, 2008, 16 (05) :600-606
[6]   INHIBITION OF CARTILAGE PROTEOGLYCAN SYNTHESIS BY INTERLEUKIN-I [J].
BENTON, HP ;
TYLER, JA .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1988, 154 (01) :421-428
[7]   Anti-inflammatory activity of thymol: Inhibitory effect on the release of human neutrophil elastase [J].
Braga, Pier Carlo ;
Dal Sasso, Monica ;
Culici, Maria ;
Bianchi, Tiziana ;
Bordoni, Luca ;
Marabini, Laura .
PHARMACOLOGY, 2006, 77 (03) :130-136
[8]  
Buckwalter JA, 1998, AAOS INSTR COURS LEC, V47, P487
[9]   ROLE OF DIRECT TISSUE CONTACT IN THE PRODUCTION OF GASTRO-INTESTINAL ULCERS BY ANTI-INFLAMMATORY DRUGS IN RATS [J].
CIOLI, V ;
ROSSI, V ;
PUTZOLU, S ;
BARCELLONA, PS ;
CORRADINO, C .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1979, 50 (02) :283-289
[10]   A TOXICOLOGICAL AND PHARMACOLOGICAL STUDY OF IBUPROFEN GUAIACOL ESTER (AF-2259) IN THE RAT [J].
CIOLI, V ;
PUTZOLU, S ;
ROSSI, V ;
CORRADINO, C .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1980, 54 (02) :332-339