Quantitative analysis of quinidine analogs using ion-pairing HPLC.

Quinidine, a useful antiarrhythmic compound, is usually contaminated with dihydroquinidine, a compound that itself shows potent antiarrhythmic activity. Complete hydrogenation of quinidine followed by conversion to dihydroquinidine derivatives was explored as a basis for eliminating the analytical problems inherent in the quality control of quinidine products and for determining their pharmacological potency and pharmacokinetic parameters without interfering impurities. Attempts to resolve the quinidine analogs, dihydrocupreidine, and its benzoyloxy ester failed with normal and reversed-phase chromatography. Ion-pairing chromatography using n-octanesulfonate in methanol:water proved successful. Using 9-hydroxy-4-methoxy acridine as internal standard, separation and quantitation of the dihydroquinidine analogs from spiked plasma samples was achieved with 92 to 95% efficiency.

Hemodynamic properties of a new quinidine analog, cupreidine (6'-hydroxycinchonine).

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.

A comparative study on the antiarrhythmic activity and acute toxicity of quinidine and four new analogs in mice.

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.

Partial synthesis of 6'-hydroxycinchonine and its antiarrhythmic activity in mice.

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.

Synthesis and preliminary antimicrobial screening of two thiosulfonates.

Tetramethylene bis(methanethiosulfonate), the S-ester analog of busulfan, was prepared by reacting 1,4-dibromobutane with potassium methanethiosulfonate. 2,4-Dichlorophenyl methanethiosulfonate was prepared by reacting sodium methanesulfinate with 2,4-dichlorobenzenesulfenyl chloride. Neither compound showed antifungal activity against Microsporum audouini or Trichophyton mentagrophytes. Although tetramethylene bis(methanethiosulfonate) was more active against Staphylococcus aureus than was 2,4-dichlorophenyl methanethiosulfonate, neither compound was as active as the streptomycin control.

Effect of cyanoketone on digitoxin-induced mortality and hepatic mixed function oxidases in rats.

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.