Using isolated enzyme systems and in vitro human or canine cell models, the efficacy and specificity of Oclacitinib are assessed against members of the JAK family and the cytokines that initiate JAK activation in cells. The compound inhibits JAK1, JAK2, JAK3, and TYK2 with 50% inhibitory concentrations (IC50's) of 10, 18, 99, and 84 nM, respectively. Oclacitinib demonstrates its highest potency against JAK1, with 1.8-fold greater selectivity for JAK1 over JAK2 and 9.9-fold greater selectivity over JAK3. It inhibits members of the JAK family at concentrations ranging from 10 to 99 nM and shows no inhibition against a set of 38 unrelated kinases (IC50's > 1000 nM). Additionally, Oclacitinib blocks the activity of JAK1-dependent cytokines critical for allergic responses and inflammation (IL-2, IL-4, IL-6, and IL-13) and pruritus (IL-31), with IC50 values between 36 and 249 nM. It has minimal impact on cytokines that do not activate the JAK1 enzyme (erythropoietin, granulocyte/macrophage colony-stimulating factor, IL-12, IL-23; IC50's > 1000 nM) [1]. Topical application of Tofacitinib (0.1%) and Oclacitinib (0.1%) significantly decreases cell migration from mouse ear explants compared to vehicle-treated ears (all P < 0.05). Additionally, the number of MHC class II positive cells (Langerhans cells) is substantially reduced in epidermis treated with vehicle compared to those treated with each JAK inhibitor (all P < 0.01) [2].
体内研究
Scratching episodes are significantly fewer in the high-dose Oclacitinib group compared to the vehicle-only group (P<0.01)[2].
Client-owned dogs (n=436) suffering from moderate to severe pruritus, as assessed by owners, and diagnosed with allergic dermatitis are enrolled. These dogs are randomly allocated to either receive Oclacitinib at 0.4-0.6 mg/kg orally twice daily or a placebo that looks the same as the active medication. The severity of pruritus is evaluated using an enhanced 10 cm visual analog scale (VAS) from day 0 to day 7, and the severity of dermatitis is assessed on days 0 and 7. Dogs may remain in the study for a period of up to 28 days. Oclacitinib shows a rapid onset of action, with effects evident within 24 hours[3].
体外研究
Using isolated enzyme systems and in vitro human or canine cell models, the efficacy and specificity of Oclacitinib are assessed against members of the JAK family and the cytokines that initiate JAK activation in cells. The compound inhibits JAK1, JAK2, JAK3, and TYK2 with 50% inhibitory concentrations (IC50's) of 10, 18, 99, and 84 nM, respectively. Oclacitinib demonstrates its highest potency against JAK1, with 1.8-fold greater selectivity for JAK1 over JAK2 and 9.9-fold greater selectivity over JAK3. It inhibits members of the JAK family at concentrations ranging from 10 to 99 nM and shows no inhibition against a set of 38 unrelated kinases (IC50's > 1000 nM). Additionally, Oclacitinib blocks the activity of JAK1-dependent cytokines critical for allergic responses and inflammation (IL-2, IL-4, IL-6, and IL-13) and pruritus (IL-31), with IC50 values between 36 and 249 nM. It has minimal impact on cytokines that do not activate the JAK1 enzyme (erythropoietin, granulocyte/macrophage colony-stimulating factor, IL-12, IL-23; IC50's > 1000 nM) [1].
Topical application of Tofacitinib (0.1%) and Oclacitinib (0.1%) significantly decreases cell migration from mouse ear explants compared to vehicle-treated ears (all P < 0.05). Additionally, the number of MHC class II positive cells (Langerhans cells) is substantially reduced in epidermis treated with vehicle compared to those treated with each JAK inhibitor (all P < 0.01) [2].
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