The Anti-Inflammation and Anti-Nociception Effect of Ketoprofen in Rats Could Be Strengthened Through Co-Delivery of a H2S Donor, S-Propargyl-Cysteine
Yue Yu, Qinyan Yang, Zhou Wang, Qian Ding, Meng Li, Yudong Fang, Qida He, Yi Zhun Zhu
Abstract
Purpose: Ketoprofen (KETO) is a traditional non-steroidal anti-inflammatory drug (NSAIDs) with good analgesic and antipyretic effects. However, as NASIDs, the toxicity of KETO towards gastrointestinal (GI) system might limit its clinical use. S-propargyl-cysteine (SPRC) is an excellent endogenous H 2 S donor showed wide application in the field of anti-inflammation, anti-oxidative stress, or even the protection of cardiovascular system through the elevation of endogenous H 2 S concentration. As recently studies reported, co-administration of H 2 S donor might potentially mitigate the GI toxicity and relevant side effects induced by series of NSAIDs. Methods: In this study, we established a SPRC and KETO co-encapsulated poly (lactic-co-glycolic acid) microsphere ( [email protected] ), and its particle size, morphology, storage stability and in vitro release profile were firstly investigated. The elevation of endogenous H 2 S level of [email protected] was then calculated, and the pharmacodynamic study (anti-inflammation and analgesic effects) of [email protected] , SPRC, and KETO towards adjuvant induced arthritis (AIA) in rats were also studied. Finally, to test the potential side effect, the heart, liver, spleen, lung, kidney, stomach, small intestine, and large intestine were resected from rats and examined by H&E staining. Results: A monodispersed [email protected] could be observed under the SEM, and particle size was calculated around 25.12 μm. The loading efficiency (LE) for SPRC and KETO were 6.67% and 2.64%, respectively, while the encapsulation efficiency (EE) for SPRC and KETO were 37.20% and 68.28%, respectively. [email protected] showed a sustained release of SPRC and KETO in vitro, which was up-to 15 days. [email protected] could achieve a long-term elevation of the H 2 S concentration in vivo, while SPRC showed an instant H 2 S elevation and metabolize within 6 h. Interestingly, the KETO did not show any influence on the H 2 S concentration in vivo. After establishment of AIA model, neither SPRC nor KETO showed scarcely anti-inflammation and anti-nociception effect, while conversely, [email protected] showed an obvious mitigation towards paw edema and pain in AIA rats, which indicated an improved anti-inflammation and anti-nociception effect when co-delivery of SRC and KETO. Besides, low stimulation towards major organs in rats observed in any experimental group. Conclusion: A monodispersed was successfully prepared in this study, and [email protected] showed a sustained SPRC and KETO release in vitro and H 2 S release in vivo. In the pharmacodynamics study, [email protected] not only exhibited an excellent anti-inflammation and analgesic effects in AIA rats but also showed low stimulation towards rats. Keywords: H 2 S donor, ketoprofen, adjuvant induced arthritis, anti-inflammation, analgesic effect