Inhibition of Leukotriene D4 and E4 in Guinea Pigs: The Impact of LY170680

The study focuses on the assessment of LY170680 as an inhibitor of leukotrienes C4, D4, and E4. In laboratory settings, LY170680 demonstrated strong, selective antagonism against LTD4 and LTE4, causing a concentration-dependent shift in response curves in guinea pig ileum and trachea, with pA2 values indicating its potency. It also acted as a moderate antagonist to LTC4-induced responses in guinea pig ileum but did not affect contractions caused by histamine, prostaglandins, or acetylcholine. Furthermore, LY170680 reduced the effects of LTC4 on trachea non-competitively.

When administered intravenously, LY170680 decreased the decline in lung compliance and the increase in total pulmonary resistance in anesthetized and ventilated guinea pigs, respectively, in a dose-dependent manner. It was also effective in reducing the response to antigen challenge in sensitized animals that had been pretreated with other medications. However, when taken orally, its effectiveness was moderate in preventing the increase in total pulmonary resistance induced by LTD4.

Inhalation of LY170680 was notably effective in preventing the increase in total pulmonary resistance caused by aerosolized LTD4, with a small amount delivered via nebulizer causing a significant shift in the dose-response curve. Additionally, inhaled LY170680 reduced the volume of trapped gas in the lungs after exposure to aerosolized leukotrienes, with a sustained effect for several hours. However, it did not impact gas trapping caused by histamine.