García G, DeMora F, Ferrer L, Puigdemont A
Department de Farmacología i Terapèutica, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Am J Vet Res. 1997 Mar;58(3):293-7.
Because of the implication of histamine in canine atopic dermatitis, H1-antihistamines may provide a valid alternative to glucocorticoid therapy. In vitro study of these drugs prior to clinical testing can allow the most promising compounds to be selected for trials and render trials with drugs of doubtful efficacy unnecessary.
Isolated canine cutaneous mast cells.
Cells were preincubated with antihistamines at increasing concentrations and incubated with concanavalin A (1,000 micrograms/ml), calcium ionophore A23187 (1 microM), and substance P (100 microM). Compound 48/80 was not used because it proved to be cytotoxic.
Generally, significant prodegranulating effect was not observed for most of the studied agents. Only terfenadine increased spontaneous histamine release at concentrations > 30 microM. Cetirizine did not block histamine release at any of the studied concentrations. Ketotifen had a low inhibitory effect only at the highest concentration (100 microM) after concanavalin A- (23.6 +/- 2.8%) and calcium ionophore A23187- (29.8 +/- 3.0%) induced release. Terfenadine caused a concentration-dependent inhibitory effect after ionophore A23187- (48.1 +/- 2.2%) and concanavalin A- (28.9 +/- 2.3%) activation, but was inactive against substance P-induced release. In contrast, loratadine had potent dose-dependent inhibition of concanavalin A- and ionophore A23187-induced histamine release, with maximal effect of 85.6 +/- 3.1% and 62.6 +/- 4.7%, respectively, at 100 microM concentration. After substance P activation, histamine release was only slightly inhibited by loratadine (14.8 +/- 1.1%).
This study documents the behavior of isolated canine cutaneous mast cells in the presence of nonimmunologic stimulation. Using this in vitro method, we were able to determine that loratadine is the only antihistamine that has potent inhibition of histamine release from dog cutaneous mast cells without a substantial prodegranulating effect. Loratadine is, therefore, a good candidate for clinical testing.
鉴于组胺与犬特应性皮炎有关，H1抗组胺药可能是糖皮质激素治疗的有效替代方案。在临床试验前对这些药物进行体外研究，可挑选出最有前景的化合物进行试验，避免对疗效存疑的药物进行试验。
分离出的犬皮肤肥大细胞。
细胞先与浓度递增的抗组胺药预孵育，然后与伴刀豆球蛋白A（1000微克/毫升）、钙离子载体A23187（1微摩尔）和P物质（100微摩尔）共同孵育。未使用化合物48/80，因为它被证明具有细胞毒性。
一般来说，大多数研究药物未观察到明显的促脱颗粒作用。只有特非那定在浓度>30微摩尔时增加了组胺的自发释放。西替利嗪在任何研究浓度下均未阻断组胺释放。酮替芬仅在伴刀豆球蛋白A（23.6±2.8%）和钙离子载体A23187（29.8±3.0%）诱导释放后的最高浓度（100微摩尔）时有较低的抑制作用。特非那定在离子载体A23187（48.1±2.2%）和伴刀豆球蛋白A（28.9±2.3%）激活后产生浓度依赖性抑制作用，但对P物质诱导的释放无活性。相比之下，氯雷他定对伴刀豆球蛋白A和离子载体A23187诱导的组胺释放有强大的剂量依赖性抑制作用，在100微摩尔浓度时最大抑制率分别为85.6±3.1%和62.6±4.7%。在P物质激活后，氯雷他定仅轻微抑制组胺释放（14.8±1.1%）。
本研究记录了分离出的犬皮肤肥大细胞在非免疫刺激下的行为。使用这种体外方法，我们能够确定氯雷他定是唯一一种能有效抑制犬皮肤肥大细胞组胺释放且无明显促脱颗粒作用的抗组胺药。因此，氯雷他定是临床试验的良好候选药物。
