Cupreidine 96'-hydroxycinchonine) is a recently synthesized analog of quinidine (6'-methoxycinchonine). Previous studies in mice have shown that quinidine and cupreidine have equivalent antiarrhythmic potencies, whereas the acute toxicity of cupreidine is about 50% less than that of quinidine. Many of the serious adverse effects of quinidine are due to undesirable cardiovascular properties. We have, therefore, compared the effects of the two drugs on blood pressure, heart rate, and peripheral vasodilation in rats, and on myocardial contractility in isolated rabbit hearts at a series of comparable doses. Quinidine produces a more marked bradycardia and depression of blood pressure than does cupreidine. The vasodilation produced by intraarterial administration of quinidine was significantly greater than cupreidine. Furthermore, quinidine elicited a greater negative inotropic effect. Cupreidine exhibited a much more favorable hemodynamic profile than quinidine with regard to the properties that were examined. These results, coupled with the fact that cupreidine has significant antiarrhythmic activity and a lower acute toxicity profile, suggest that this drug may be useful in the therapy of cardiac arrhythmias.

We have compared the ED50 value for antiarrhythmic activity and the acute toxicities in mice of quinidine and 4 recently synthesized analogs. For the ED50 studies, groups of mice were treated intravenously with equally spaced logarithmic doses of 6'-methoxycinchonine (quinidine), 6'-hydroxycinchonine (cupreidine), 6'-isovaleryloxycinchonine, 6'-acetyloxycinchonine and 6'-benzoyloxycinchonine. For the actue toxicity studies, mice were treated intraperitoneally with quinidine and the 4 analogs. Mice were observed over a 24-h period, and thereafter for each additional 24-h period for a total of 120 h. Tests for parallelism of acute toxicity indicated that with the exception of the 6'-isovaleryloxy derivative the drug treatment regression lines were parallel to that of quinidine (P > 0.05). The results indicated decreases of 50% (843 mumol/kg), 52% (857 mumol/kg), and 61% (910 mumol/kg) in the acute toxicities of the 6'-acetyloxy, 6'-hydroxy, and 6'-benzoyloxycinchonine, respectively. The 6'-acetyloxy (18.5 mumol/kg) and 6'-benzoyloxy (14.6 mumol/kg) derivatives had significantly lower ED50 values than quinidine (60.1 mumol/kg). The results suggest that the 6'-acetyloxy and 6'-benzoyloxy derivatives may have much greater antiarrhythmic effectiveness than quinidine.

Journal Article The antiarrhythmic activities of 6′-hydroxycinchonine, 6’-benzyloxycin-chonine and 6′-allyloxycinchonine compared with quinidine in mice Get access P U Nwangwu, P U Nwangwu College of Pharmacy, University of Nebraska Medical Center, 42nd and Dewey Avenue, Omaha, Nebraska 68105, Canada Search for other works by this author on: Oxford Academic Google Scholar T L Holcslaw, T L Holcslaw College of Pharmacy, University of Nebraska Medical Center, 42nd and Dewey Avenue, Omaha, Nebraska 68105, Canada Search for other works by this author on: Oxford Academic Google Scholar H Rosenberg, H Rosenberg College of Pharmacy, University of Nebraska Medical Center, 42nd and Dewey Avenue, Omaha, Nebraska 68105, Canada Search for other works by this author on: Oxford Academic Google Scholar L D Small, L D Small College of Pharmacy, University of Nebraska Medical Center, 42nd and Dewey Avenue, Omaha, Nebraska 68105, Canada Search for other works by this author on: Oxford Academic Google Scholar S J Stohs S J Stohs College of Pharmacy, University of Nebraska Medical Center, 42nd and Dewey Avenue, Omaha, Nebraska 68105, Canada Correspondence: College of Pharmacy, University of Nebraska Medical Center, 42nd and Dewey Avenue, Omaha, Nebraska 68105, Canada Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 31, Issue 1, September 1979, Pages 488–489, https://doi.org/10.1111/j.2042-7158.1979.tb13566.x Published: 12 April 2011 Article history Received: 11 August 1978 Published: 12 April 2011

The synthesis of 6'-hydroxycinchonine [8R,9S)-cinchonan-6',9-diol] was achieved by demethylating quinidine with boron tribromide in dichloromethane at -75 degrees C. The antiarrhythmic activities of 6'-hydroxycinchonine and quinidine were compared following the infusion of aconitine into the tail veins of mice to induce arrhythmias. Comparative ED50 and LD50 studies for quinidine and 6'-hydroxycinchonine revealed equivalent antiarrhythmic potencies for the two drugs but a smaller acute toxicity for 6'-hydroxycinchonine.

Cyanoketone pretreatment protected female rats against digitoxin-induced mortality. Cyanoketone also acts as an inducer of hepatic mixed function oxidases, increasing cytochrome P-450 content and enhancing aniline hydroxylase and aminopyrine demethylase activities. The protective effect of cyanoketone against digitoxin toxicity may be due to the enhanced conversion of the glycoside to more polar metabolites which are more readily excretable.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAlkyl ThiolsulfinatesLaVerne D. Small, John Hays Bailey, and Chester J. CavallitoCite this: J. Am. Chem. Soc. 1947, 69, 7, 1710–1713Publication Date (Print):July 1, 1947Publication History Published online1 May 2002Published inissue 1 July 1947https://pubs.acs.org/doi/10.1021/ja01199a040https://doi.org/10.1021/ja01199a040research-articleACS PublicationsRequest reuse permissionsArticle Views779Altmetric-Citations182LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts