Cardiovascular effects of N-methyl leukotriene C₄, a nonmetabolizable leukotriene C₄ analogue, and the antagonism of leukotriene-induced hypotension by Ro 23-3544, in the American bullfrog, Rana catesbeiana

Q4 · MEDICINE

Article

Author: Sun, Jimin ; Herman, Ceil A.

Although some leukotriene antagonists have been reported to block leukotriene (LT) C4 responses in vivo, it is difficult to determine whether those antagonists block the effect of LTC4 directly or act via blocking the action of LTD4, as LTC4 is metabolized to LTD4 rapidly in vivo. In this study, the dose–response curves of N-methyl LTC4 (NMLTC4), the nonmetabolizable LTC4 analogue, and the peptidoleukotrienes (LTC4, LTD4, and LTE4) were obtained in the absence and presence of the leukotriene antagonist Ro 23-3544 in cannulated frogs. The more potent effect of NMLTC4 suggests that receptors that preferentially bind LTC4 exist in frog vascular smooth muscle and the previously reported LTC4 effect is a combination of LTC4 and its less potent metabolite LTD4. The NMLTC4- and LTC4-induced hypotensive effects were antagonized by Ro 23-3544. Ro 23-3544 also antagonized the effects induced by high doses of LTD4 and LTE4. Ro 23-3544 had no effect on duration of response and did not affect heart rate responses to LTC4 at low dose of the antagonist. The data suggest that receptors that preferentially bind LTC4 in bullfrog vascular smooth muscle regulate the hypotensive effect and that they can be antagonized by Ro 23-3544.Key words: leukotriene receptors, N-methyl LTC4, Ro 23-3544, cardiovascular, bullfrog.

01 Jul 1992·Journal of Pharmaceutical SciencesQ3 · MEDICINE

Studies of in Vitro Skin Permeation and Retention of a Leukotriene Antagonist from Topical Vehicles with a Hairless Guinea Pig Model

Q3 · MEDICINE

Article

Author: Charan R. Behl ; J.D. Mouskountakis ; Saran Kumar ; Noel M. Meltzer ; A. Waseem Malick

A leukotriene antagonist [Ro 23-3544; 6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid; 1] was studied in vitro for its permeation through and retention in hairless guinea pig skin from various topical vehicles. Both the free acid and the sodium salt forms of the drug were used. The vehicles evaluated were polyethylene glycol 400, propylene glycol, dimethyl sulfoxide (DMSO), C12-C15 alcohol lactates, dimethyl isosorbide, butyrolactone, methylpyrrolidone, hexyl laurate, isopropyl myristate, and caprylic/capric triglyceride (Neobee M5). For the salt form of the drug, the highest permeability coefficient and retention were obtained from DMSO and methylpyrrolidone, respectively. For the acid form, however, the highest permeability coefficient and retention were obtained from hexyl laurate and DMSO, respectively. The highest permeation and retention values were not obtained from the same vehicle for either the salt or the acid form of the drug. This observation questions the validity of using permeation (flux) measurements to screen topical drugs and formulations. Although the precise reasons for this lack of correlation between permeation and retention are not known at this time, this study has shown that the solubility parameters of the drug and the vehicles used may play an important role. It seems logical to conduct skin retention studies rather than flux measurements in evaluating drug delivery from dermatological products.

01 Jan 1992·Archiv der Pharmazie

Thiophen als Strukturelement physiologisch aktiver Substanzen, 20. Mitt.: Ein Thiophenanalogon des Leukotrien D₄ Antagonisten Ro 23–3544

Article

Author: Koch A ; Binder D ; Rovenszky F ; Stroissnig H

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