ABSTRACT
In the present study, we describe how a nonstoichiometric ratio of the isomers of 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT) produce a broad-spectrum of antiemetic effects in cats and shrews. Determination of the receptor profile of the isomers and testing them separately in cats revealed superior antiemetic effects but severe defensive behavior with the R isomer compared with the S isomer. Differing ratios yielded the best results with the 1:8 (R-S) ratio producing a drug more potent than DPAT and with negligible defensive behavior side effects. Studies with selective 5-HT1D ligands led to the conclusion that this site contributes antiemetic efficacy but is not related to defensive behavior, which is most likely a consequence of 5-HT7 receptor activation. ETI-385 was effective in preventing emetic responses to provocative motion, drugs acting at the chemical trigger zone and cisplatin in both cats and shrews. The results support a clinical trial of this drug for antiemetic effects.
Subject(s)
Antiemetics/therapeutic use , Motion Sickness/drug therapy , Motor Activity/drug effects , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT1D/metabolism , Serotonin 5-HT1 Receptor Agonists/therapeutic use , 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , 8-Hydroxy-2-(di-n-propylamino)tetralin/therapeutic use , Animals , Antiemetics/pharmacology , Cats , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Isomerases , Motion Sickness/etiology , Serotonin Agents/pharmacology , Serotonin Agents/therapeutic useABSTRACT
The law of toxic substances dates back to Medieval England, but the present comprehensive federal regulatory scheme was developed over the past two decades. This article presents a brief overview of the federal law of air and water pollution, solid waste control, and the regulation of chemicals.