Chakravarthy Kalyan, Faltus Robert, Robinson Gain, Sevilla Raquel, Shin John, Zielstorff Mark, Byford Alan, Leccese Erica, Caniga Michael J, Hseih SuChun, Zhang Shuli, Chiu Chi-Sung, Zhang-Hoover Jie, Moy Lily Y, McLeod Robbie L, Stoffregen Dana, Zhang Weisheng, Murtaza Anwar, Cicmil Milenko
Discovery Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
BMC Musculoskelet Disord. 2014 Dec 4;15:409. doi: 10.1186/1471-2474-15-409.
The impact of anti-TNF, corticosteroid and analgesic therapy on inflammation and pain was evaluated in a novel mono-arthritic multi-flare rat Streptococcal Cell Wall (SCW) model using Etanercept, Dexamethasone and Buprenorphine.
Multiple flares of arthritis were induced with an intra-articular injection of SCW in the hind ankle on day 1, followed by intravenous challenges on days 21 and 42. Inflammation and pain were monitored in the hind paws. Cytokine profiling, cell phenotyping, bioluminescence imaging and histopathological evaluation were also performed.
Local injection of SCW caused a rapid onset of inflammation and pain in the injected ankle which resolved within 4 days (Flare 1). Intravenous injection 20 days after sensitization resulted in an increase in ankle diameter and pain, which partially resolved in 8 days (Flare 2). The subsequent intra-venous injection in the same animals 14 days after resulted in a more chronic disease with inflammation and pain persisting over a period of 10 days (Flare 3). In Flare 2, therapeutic administration of Dexamethasone inhibited paw swelling (95%; P<0.001) and pain (55%; P<0.05). Therapeutic administration of Buprenorphine inhibited pain (80%; P<0.001) without affecting paw swelling (0%). Prophylactic administration of Etanercept in Flare 2 inhibited paw swelling (≥60%; P<0.001) and pain by ≥30%. Expression of IL-1β, IL-6, MCP-1 and CINC was reduced by >50% (P<0.001). Treatment with Etanercept in Flare 3 inhibited paw swelling by 60% (P<0.001) and pain by 25%. Prior treatment with Etanercept in Flare 2 followed by re-administration in Flare 3 led to a complete loss in the efficacy of Etanercept. Systemic exposure of Etanercept corroborated with lack of efficacy. Dexamethasone inhibited inflammation and pain in both Flares 2 and 3 (P<0.001).
We established a novel multi-flare SCW arthritis model enabling drug intervention in different stages of disease. We show for the first time the evaluation of inflammation and pain simultaneously in this model. Etanercept and Dexamethasone inhibited inflammation, pain and proinflammatory cytokines in this model. Taken together, this model facilitates the assessment of anti-rheumatic agents targeting inflammation and pain in the multiple flare paradigm and offers a powerful tool for drug discovery.
在一种新型单关节炎多发作大鼠链球菌细胞壁（SCW）模型中，使用依那西普、地塞米松和丁丙诺啡评估了抗TNF、皮质类固醇和镇痛疗法对炎症和疼痛的影响。
在第1天通过后踝关节内注射SCW诱导多次关节炎发作，随后在第21天和第42天进行静脉激发。监测后爪的炎症和疼痛情况。还进行了细胞因子分析、细胞表型分析、生物发光成像和组织病理学评估。
局部注射SCW导致注射踝关节迅速出现炎症和疼痛，4天内消退（发作1）。致敏20天后静脉注射导致踝关节直径增加和疼痛，8天内部分消退（发作2）。在同一动物中，14天后再次静脉注射导致更慢性的疾病，炎症和疼痛持续10天（发作3）。在发作2中，地塞米松的治疗性给药抑制了爪肿胀（95%；P<0.001）和疼痛（55%；P<0.05）。丁丙诺啡的治疗性给药抑制了疼痛（80%；P<0.001），而不影响爪肿胀（0%）。在发作2中预防性给予依那西普抑制了爪肿胀（≥60%；P<0.001）和疼痛≥30%。IL-1β、IL-6、MCP-1和CINC的表达降低了>50%（P<0.001）。在发作3中用依那西普治疗抑制了爪肿胀60%（P<0.001）和疼痛25%。在发作2中先用依那西普治疗，然后在发作3中重新给药，导致依那西普的疗效完全丧失。依那西普的全身暴露与疗效缺乏相符。地塞米松在发作2和发作3中均抑制了炎症和疼痛（P<0.001）。
我们建立了一种新型多发作SCW关节炎模型，能够在疾病的不同阶段进行药物干预。我们首次在此模型中同时评估了炎症和疼痛。依那西普和地塞米松在该模型中抑制了炎症、疼痛和促炎细胞因子。综上所述，该模型有助于评估在多发作模式下针对炎症和疼痛的抗风湿药物，并为药物发现提供了一个强大的工具。
