Grosios K, Wood J, Esser R, Raychaudhuri A, Dawson J
Oncology Research, Novartis Pharma AG, Basel, Switzerland.
Inflamm Res. 2004 Apr;53(4):133-42. doi: 10.1007/s00011-003-1230-4. Epub 2004 Mar 18.
To examine the effects of PTK787/ZK222584, a novel angiogenesis inhibitor, in a series of in vivo models of arthritis and inflammation.
The granulomatous air pouch and antigen-induced arthritis models were established in female OFA-1 mice. Female DBA/1LacJ mice were used for the collagen-induced arthritis model and male OFA rats were used for the carrageenan oedema and hyperalgesia tests.
PTK787/ZK222584 was administered p.o., once daily, at various concentrations. Diclofenac (3 mg/kg) and DUP697 (0.5 mg/kg) were also given p.o, once daily.
The anti-angiogenic effects of PTK787/ZK222584 were directly assessed in the granulomatous air pouch model using the carmine red assay. The anti-arthritic effects of this compound were further examined in the mouse antigen-induced and collagen-induced models of arthritis, using macroscopic observations (calliper measurements of joints) and histological scores (as assessed by degree of cellularity, cell infiltration and erosions and proteoglycan loss). All compounds were administered orally. PTK787/ZK222584 at 10, 30, 50 and 100 mg/kg and positive control compounds, diclofenac and DUP697 at 3 mg/kg and 0.5 mg/kg, respectively. In addition, the effects of PTK787/ZK222584 in the rat carrageenan oedema model and Randall Selitto hyperalgesia test were observed.
PTK787/ZK222584 treatment caused dose dependent reduction in the vascularity of the granulomatous air pouch model. It inhibited knee swelling by 40% in antigen-induced arthritis, at the dose of 30 mg/kg p.o., once daily (s.i.d). and inhibited both severity scores (by 51%) and global histological scores in mice with collagen-induced arthritis following oral treatment (45 mg/kg p.o.), as compared to control animals. PTK787/ZK222584 demonstrated no effects on inflammatory mediators in the VEGF-independent rat carrageenan model and displayed interesting analgesic activity in the Randall Selitto test in the acute setting.
The anti-arthritic effects of this specific, receptor tyrosine kinase inhibitor compound appear to be mediated by anti-angiogenic actions. This study represents a new indication for PTK787/ZK222584, namely, rheumatoid arthritis and further supports the belief that angiogenesis inhibition is likely to be beneficial in the therapy of this condition.
研究新型血管生成抑制剂PTK787/ZK222584在一系列关节炎和炎症体内模型中的作用。
在雌性OFA-1小鼠中建立肉芽肿性气囊和抗原诱导性关节炎模型。雌性DBA/1LacJ小鼠用于胶原诱导性关节炎模型，雄性OFA大鼠用于角叉菜胶水肿和痛觉过敏试验。
PTK787/ZK222584以不同浓度口服给药，每日一次。双氯芬酸（3 mg/kg）和DUP697（0.5 mg/kg）也口服给药，每日一次。
在肉芽肿性气囊模型中使用胭脂红试验直接评估PTK787/ZK222584的抗血管生成作用。在小鼠抗原诱导性和胶原诱导性关节炎模型中，通过宏观观察（关节卡尺测量）和组织学评分（根据细胞密度、细胞浸润、侵蚀程度和蛋白聚糖损失评估）进一步研究该化合物的抗关节炎作用。所有化合物均口服给药。PTK787/ZK222584的剂量为10、30、50和100 mg/kg，阳性对照化合物双氯芬酸和DUP697的剂量分别为3 mg/kg和0.5 mg/kg。此外，观察了PTK787/ZK222584在大鼠角叉菜胶水肿模型和Randall Selitto痛觉过敏试验中的作用。
PTK787/ZK222584治疗导致肉芽肿性气囊模型的血管生成呈剂量依赖性减少。在抗原诱导性关节炎中，以30 mg/kg口服给药，每日一次（s.i.d.），可使膝关节肿胀抑制40%。与对照动物相比，口服治疗（45 mg/kg）后，PTK787/ZK222584在胶原诱导性关节炎小鼠中可使严重程度评分（降低51%）和整体组织学评分（降低45%）均受到抑制。在不依赖VEGF的大鼠角叉菜胶模型中，PTK787/ZK222584对炎症介质无影响，在急性情况下的Randall Selitto试验中显示出有趣的镇痛活性。
这种特异性受体酪氨酸激酶抑制剂化合物的抗关节炎作用似乎是由抗血管生成作用介导的。本研究为PTK787/ZK222584提供了一个新的适应症，即类风湿性关节炎，并进一步支持了血管生成抑制可能对这种疾病的治疗有益的观点。
