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Diacerein-thymol prodrug: in vivo release and pharmacological screening in experimental models of osteoarthritis in Wistar rats.
Inflamm Allergy Drug Targets. 2015; 13(6):393-405.IA

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+Show Affiliations

No affiliation info availableDepartment of Pharmaceutical Chemistry, Bharati Vidyapeeth University, Poona College of Pharmacy, Pune-411038, Maharashtra, India. suneeladhaneshwar@rediffmail.com.No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

25675406

Citation

Patil, Dipmala, et al. "Diacerein-thymol Prodrug: in Vivo Release and Pharmacological Screening in Experimental Models of Osteoarthritis in Wistar Rats." Inflammation & Allergy Drug Targets, vol. 13, no. 6, 2015, pp. 393-405.
Patil D, Dhaneshwar S, Kadam P. Diacerein-thymol prodrug: in vivo release and pharmacological screening in experimental models of osteoarthritis in Wistar rats. Inflamm Allergy Drug Targets. 2015;13(6):393-405.
Patil, D., Dhaneshwar, S., & Kadam, P. (2015). Diacerein-thymol prodrug: in vivo release and pharmacological screening in experimental models of osteoarthritis in Wistar rats. Inflammation & Allergy Drug Targets, 13(6), 393-405.
Patil D, Dhaneshwar S, Kadam P. Diacerein-thymol Prodrug: in Vivo Release and Pharmacological Screening in Experimental Models of Osteoarthritis in Wistar Rats. Inflamm Allergy Drug Targets. 2015;13(6):393-405. PubMed PMID: 25675406.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Diacerein-thymol prodrug: in vivo release and pharmacological screening in experimental models of osteoarthritis in Wistar rats. AU - Patil,Dipmala, AU - Dhaneshwar,Suneela, AU - Kadam,Parag, PY - 2014/11/20/received PY - 2015/01/01/revised PY - 2015/02/08/accepted PY - 2015/2/13/entrez PY - 2015/2/13/pubmed PY - 2016/3/15/medline SP - 393 EP - 405 JF - Inflammation & allergy drug targets JO - Inflamm Allergy Drug Targets VL - 13 IS - 6 N2 - 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. SN - 2212-4055 UR - https://www.unboundmedicine.com/medline/citation/25675406/Diacerein_thymol_prodrug:_in_vivo_release_and_pharmacological_screening_in_experimental_models_of_osteoarthritis_in_Wistar_rats_ L2 - http://www.eurekaselect.com/128425/article DB - PRIME DP - Unbound Medicine ER -