Intra-articular (IA) Ropivacaine Microparticle Suspensions Reduce Pain, Inflammation, Cytokine, and Substance P Levels Significantly More than Oral or IA Celecoxib in a Rat Model of Arthritis

Abstract

Current therapeutic treatment options for osteoarthritis entail significant safety concerns. A novel ropivacaine crystalline microsuspension for bolus intra-articular (IA) delivery was thus developed and studied in a peptidoglycan polysaccharide (PGPS)-induced ankle swelling rat model. Compared with celecoxib controls, both oral and IA, ropivacaine IA treatment resulted in a significant reduction of pain upon successive PGPS reactivation, as demonstrated in two different pain models, gait analysis and incapacitance testing. The reduction in pain was attended by a significant reduction in histological inflammation, which in turn was accompanied by significant reductions in the cytokines IL-18 and IL-1β. This may have been due to inhibition of substance P, which was also significantly reduced. Pharmacokinetic analysis indicated that the analgesic effects outlasted measurable ropivacaine levels in either blood or tissue. The results are discussed in the context of pharmacologic mechanisms both of local anesthetics as well as inflammatory arthritis.

Applicability of a Modified Rat Model of Acute Arthritis for Long-Term Testing of Drug Delivery Systems

“…Episodes of acute inflammation recurred spontaneously in between reactivation intervals, and the variability was high, something also observed in RA patients [21,22]. It is not clear to what extent comparable follow-up losses were encountered in the previous studies on the original PGPS rat model of arthritis, they do not report animal wellbeing or loss [11,12]. Here, we evaluated for the first time potential systemic effects occurring in the acute arthritis model.…”

“…Indeed, the inhibition of joint swelling in the current arthritis model by TAA-loaded PLGA microspheres appeared to be lost after 32 days, while the PEA platform continued to inhibit joint swelling. This important difference between drug delivery platforms would not have been observed in the original version of this arthritis model [11,12]. Therefore, the modified arthritis model is well suited to test DDS for an extended follow-up period with relatively small group sizes.…”

“…Additionally, in this adjusted arthritis model, we investigated the anti-inflammatory and analgesic effects of prolonged TAA release from two different drug delivery systems over 84 days. For this purpose, the recently developed and characterized polyesteramide (PEA) microsphere platform [9,10] releasing TAA was compared to the PLGA microsphere platform already evaluated in the original arthritis model [11,12]. We show here that the modified model of acute arthritis has good applicability for long-term testing of drug delivery systems, but also results in systemic inflammatory features such as hepatitis, splenitis and polyarthritis.…”

The effect of two drug delivery systems in ropivacaine cytotoxicity and cytokine release by human keratinocytes and fibroblasts

“…Ropivacaine can block TNF‐α signalling in endothelial cells, reducing the in‐vitro expression of adhesion molecules from human T‐lymphocyte . They also decreased inflammation in arthritis, leading to a significant reduction in tissue cytokine levels …”

“…[39,40] They also decreased inflammation in arthritis, leading to a significant reduction in tissue cytokine levels. [41] Cytokines are important mediators of local and systemic inflammatory response and are also involved in nociception and in the development of hyperalgesia. [42][43][44] TNF-a is directly involved in the inflammatory cascade activation by interacting with endothelial cells, which induces the production of adhesion molecules (ICAM, VCAM and E-selectin), allowing the penetration of granulocytes in the inflammation site.…”