title: Diacerein-thymol prodrug: in vivo release and pharmacological screening in experimental models of osteoarthritis in Wistar rats.
abstract: We have reported the synthesis, characterization, in vitro release profile and preliminary pharmacological investigations of an antioxidant mutual prodrug of diacerein with thymol in our earlier communication. The present work reports the results of in vivo release studies and extensive pharmacological evaluation of this prodrug in collagenase- induced osteoarthritis and monosodium iodoacetate- induced hyperalgesia in Wistar rats. In vivo release was thoroughly studied in Wistar rats upon oral administration of the prodrug. In rat blood, release of 92.7% of diacerein and 20.5% of thymol was observed. From these studies we hypothesized that activation of prodrug could be mediated by physiological pH of blood (7.4) and serum esterases. Pharmacological screening of prodrug in collagenase and monoiodoacetate-induced osteoarthritis at a dose of 6.8 mg/kg, (BID) exhibited significant reduction in knee diameter (p<0.001), increase in paw withdrawal latency (p<0.001), and locomotor activity (p<0.001) with significantly higher anti-inflammatory and anti-osteoarthritic activities as compared to parent drug. The biochemical studies indicated a significant step-up in glucosaminoglycan level (p<0.001) and reduction in the C-reactive protein (p<0.001) and sulfated alkaline phosphatase levels (p<0.001). The histopathological and radiological studies confirmed the additive anti-osteoarthritic effect of prodrug as compared to plain diacerein. Antioxidant potential of prodrug was significantly more (p<0.001) while ulcer index was significantly lower (p<0.01) than diacerein. Interestingly, the diarrhea observed in diacerein- treated animals was not evident in animalstreated with prodrug, thymol and their physical mixture. Our findings indicate promising potential of this antioxidant prodrug to be used for long-term and safer management of OA.
authors: Dipmala
authors: D
authors: Patil
authors: Department of Pharmaceutical Chemistry, Bharati Vidyapeeth University, Poona College of Pharmacy, Pune-411038, Maharashtra, India. suneeladhaneshwar@rediffmail.com.
authors: Suneela
authors: S
authors: Dhaneshwar
authors: Parag
authors: P
authors: Kadam
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology; D017364:Collagenases; D004353:Drug Evaluation, Preclinical; D006863:Hydrogen-Ion Concentration; D007461:Iodoacetates; D007596:Joints / Q000473:pathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010003:Osteoarthritis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D010147:Pain Measurement / Q000187:drug effects; D011355:Prodrugs; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced; D013943:Thymol / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000880:Anthraquinones; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D007461:Iodoacetates; D011355:Prodrugs; D013943:Thymol; C025292:diacerein; D017364:Collagenases