Abraham W M, Ahmed A, Cortes A, Sielczak M, Wantanabe A
Department of Research, Mount Sinai Medical Center, Miami Beach, Florida 33140, USA.
Pulm Pharmacol. 1996 Feb;9(1):49-58. doi: 10.1006/pulp.1996.0006.
We studied the effect of a new antiallergic compound, TYB-2285 (3,5-bis(acetoxyacetylamino)-4-chlorobenzonitrile), on antigen-induced early and late bronchoconstriction and airway responsiveness in conscious allergic sheep. The same general protocol was used for all studies, except that the dosage and time of TYB-2285 treatment was varied. The basic protocol consisted of determining airway responsiveness to inhaled carbachol, then measuring the airway responses to Ascaris suum antigen challenge followed 1 day later by a post challenge assessment of airway responsiveness. Specific lung resistance (SRL) was used to measure the airway responses to antigen and carbachol and the concentration of carbachol that caused a 400% increase in SRL (PC400) was used as a measure of airway responsiveness. All protocols were of crossover design, such that each sheep served as its own control and each protocol employed six to eight animals. In all instances, TYB-2285 or vehicle control (methylcellulose) was given orally. When TYB-2285 (100 mg/kg) was given at 16 and 2 h before the challenge, the early response, the late response and the post antigen-induced airway hyperresponsiveness (AHR) as indicated by a decrease in the PC400 was inhibited significantly. TYB-2285 (100 mg/kg), when given 1 h after challenge, inhibited the late response and AHR significantly. TYB-2285 (100 mg/kg), when given 8 h after the challenge, also inhibited the antigen-induced AHR. When animals were given TYB-2285 (100 mg/kg) at 32, 56 and 80 h after the challenge, the antigen-induced AHR that persisted (for 1 week) in the control trial was reversed to the normal level. TYB-2285 (30 mg/kg), when given at 1, 32, 56 and 80 h after the challenge, inhibited late response slightly and reversed the persistent AHR to the normal level. At lower doses (3 and 10 mg/kg) there was no protection of the early response, the late response or AHR. Pretreatment with TYB-2285 (100 mg/kg) also prevented the antigen-induced influx of eosinophils in bronchoalveolar lavage obtained 24 h after segmental antigen challenge. TYB-2285 did not inhibit histamine or LTD4-induced bronchoconstriction nor did the active metabolites of TYB-2285, TC-286 and TC-326 inhibit acetylcholine-induced contraction of sheep tracheal smooth muscle. These results suggest that TYB-2285 has both antiallergic and antiinflammatory properties in the sheep model of allergic bronchoconstriction. The compound demonstrates both prophylactic and therapeutic activity and, therefore, may be potentially useful in the treatment of allergen-induced airway disease.
我们研究了一种新型抗过敏化合物TYB - 2285（3,5 - 双（乙酰氧基乙酰氨基）- 4 - 氯苯甲腈）对清醒过敏绵羊抗原诱导的早期和晚期支气管收缩以及气道反应性的影响。除了TYB - 2285的给药剂量和时间有所不同外，所有研究均采用相同的总体方案。基本方案包括测定气道对吸入卡巴胆碱的反应性，然后测量对猪蛔虫抗原激发的气道反应，1天后进行激发后气道反应性评估。使用比气道阻力（SRL）来测量气道对抗原和卡巴胆碱的反应，导致SRL增加400%的卡巴胆碱浓度（PC400）用作气道反应性的指标。所有方案均采用交叉设计，使得每只绵羊作为自身对照，每个方案使用6至8只动物。在所有情况下，口服给予TYB - 2285或载体对照（甲基纤维素）。当在激发前16小时和2小时给予TYB - 2285（100mg/kg）时，早期反应、晚期反应以及抗原诱导后气道高反应性（AHR，以PC400降低表示）均受到显著抑制。当在激发后1小时给予TYB - 2285（100mg/kg）时，显著抑制了晚期反应和AHR。当在激发后8小时给予TYB - 2285（100mg/kg）时，也抑制了抗原诱导的AHR。当在激发后32、56和80小时给予动物TYB - 2285（100mg/kg）时，在对照试验中持续存在（长达1周）的抗原诱导AHR恢复到正常水平。当在激发后1、32、56和80小时给予TYB - 2285（30mg/kg）时，轻微抑制了晚期反应，并将持续的AHR恢复到正常水平。在较低剂量（3和10mg/kg）时，对早期反应、晚期反应或AHR没有保护作用。用TYB - 2285（100mg/kg）预处理也可防止在节段性抗原激发24小时后支气管肺泡灌洗中抗原诱导的嗜酸性粒细胞流入。TYB - 2285不抑制组胺或白三烯D4诱导的支气管收缩，TYB - 2285的活性代谢产物TC - 286和TC - 326也不抑制乙酰胆碱诱导的绵羊气管平滑肌收缩。这些结果表明，在过敏性支气管收缩的绵羊模型中，TYB - 2285具有抗过敏和抗炎特性。该化合物具有预防和治疗活性，因此可能对治疗变应原诱导的气道疾病有潜在用途。
