The effect of a leukotriene D4 (LTD4) receptor antagonist, L-648,051, was investigated in digoxin-induced cardiac toxicity in isolated guinea-pig hearts (Langendorff preparation). Digoxin infusion (25 µg·ml–1, 0.5 ml·min–1) increased perfusion pressure and contractile force initially, but decreased them later. The onset of first ventricular premature beats (VPBs) matched the increase phase, but the decrease phase was accompanied by ventricular tachycardia (VT) and fibrillation (VF). In the presence of L-648,051 (5 µmol·l–1), the initial phase was similar to that observed with digoxin alone, but the marked reduction was inhibited. This drug increased the concentration of digoxin required for VBSs and cardiac arrest, but it could not prevent the formation of VT and VF. The duration of VT was significantly decreased by L-648,051. It is concluded that the leukotriene receptor antagonist might have beneficial effects on digoxin-induced arrhythmias. Whether this effect depends on direct or indirect actions is uncertain.

01 Mar 1993·Pulmonary Pharmacology

Leukotrienes and Histamine Mediate IgE-dependent Contractions of Human Bronchi: Pharmacological Evidence Obtained with Tissues from Asthmatic and Non-asthmatic Subjects

Article

Author: S E Dahlén ; T Björck

Isolated human bronchi were challenged with anti-human IgE or specific allergen. The mediators of allergic constriction were characterized by pharmacological interventions. Experiments were performed on more than 180 preparations obtained from 48 non-asthmatic subjects and on 44 bronchial preparations from six asthmatic subjects. Addition of antihistamines (mepyramine and metiamide) to the organ bath abolished the response to exogenous histamine, but failed to alter the dose-response relationship of the reaction to cumulative challenge with rising titres of anti-IgE. On the other hand, pretreatment with drugs which blocked the action (receptor antagonists FPL55712, L-648,051 and ICI 198,615) or formation (biosynthesis inhibitors: U-60,257 and MK886) of leukotrienes consistently resulted in clear-cut inhibition of the allergic constriction in bronchi from both asthmatic and non-asthmatic subjects. In the presence of the most effective inhibitors (ICI 198,615 and MK886), the response to anti-IgE was depressed by more than 60%. In contrast, the cyclooxygenase inhibitor indomethacin and the antagonist of platelet activating factor (PAF) WEB 2086, failed to alter the response, indicating that prostanoids and PAF do not mediate IgE-dependent constriction of human bronchi. After the leukotriene antagonist ICI 198,615 had rendered the bronchi insensitive to exogenous leukotrienes, the residual component of the contractile response to anti-IgE was completely abolished by addition of antihistamines. Similar abolition of the Schultz-Dale reaction in bronchi of two allergic asthmatic patients was noted when antihistamines were administered together with ICI 198,615 or MK886. In conclusion, the leukotrienes appear to be the major and singularly most important mediators of the contraction, whereas histamine accounts for its minor residual component.

01 Oct 1992·European Journal of PharmacologyQ3 · MEDICINE

Leukotriene receptors in the skin of rats differ from those of mouse skin or rat stomach strip

Q3 · MEDICINE

Article

Author: Yoshida Kenji ; Koda Akihide ; Miura Toru ; Inagaki Naoki ; Nagai Hiroichi ; Goto Shoichi

To compare the receptors for cysteinyl-leukotriene (cys-LT) in rat skin with those in other tissues, we investigated the effects of specific cys-LT receptor antagonists (FPL 55712, LY171883, MCI-826 and L-648051) on cys-LT-induced cutaneous reactions in rats and mice, and on cys-LT-induced contractile responses in rat stomach smooth muscle. We also studied the effects of these drugs on homologous passive cutaneous anaphylaxis. The four cys-LT receptor antagonists dose dependently inhibited cys-LT-induced cutaneous reactions in mouse ear, but failed to inhibit passive cutaneous anaphylaxis and the histamine-induced cutaneous reaction. In rats, only MCI-826 inhibited cys-LT-induced cutaneous reactions although the other three drugs failed to inhibit these reactions. In contrast, the cys-LT-induced contractile responses of rat stomach smooth muscle were inhibited by all these drugs in a concentration-dependent manner. These results suggest that cys-LT receptors in rat skin have an affinity different from that of receptors in mouse skin and rat stomach. They also suggest that cys-LTs are not involved in passive cutaneous anaphylaxis in mice and rats.

100 Deals associated with L-648051

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Indication	Highest Phase	Country/Location	Organization	Date
Arrhythmias, Cardiac	Phase 2	US	Merck GmbH	-
Asthma	Phase 2	-	Merck Sharp & Dohme Corp.	-
Asthma	Phase 2	US	Merck GmbH	-
Asthma	Phase 2	US	Merck GmbH	-
Asthma	Phase 2	-	Merck Sharp & Dohme Corp.	-

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