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360 Digitoxin-(23-14C)
Abstracts control experiments that the lethal dose ofbarbituric acid is mathematically proportional to the dose If an effective which halves the cardiac output. glycoside is added to the venous storage vessel at this time, the life-span of the preparation increases and with it the dose of barbituric acid required to cause death. The difference between the lethal barbiturate dose in control experiments and in experiments with various doses of the glycosides used was designated the survival time. Within a certain range of dosages there is a linear relationship between them and the logarithms of the glycosides administered. As the addition of glycosides in all preparations was carried out at the time when the same degree of insufficiency had been reached, the effect of equal doses on different preparations can easily be compared. The relative effectiveness of individual glycosides can be statistically calculated by analysis of variance. An account is given of the peroral, intramuscular and intraperitoneal resorption of heart-glycosides as preliminary treatment of the animals at various periods.
359
A
Comparison of Some Properties of gStrophantin and Convallatoxin on the Heart Lung Preparation of the Cat. K. P.&vEK, \.. DITTERTOV~~ and F. V. SELECK+ (Czechoslovakia) .
Heart-lung preparations of cats were damaged by means of phenobarbital sodium and the effects of g-strophanthin and convallatoxin on the damaged hearts was compared. The decreased minute volume and cardiac output was restored by both drugs, but convallatoxin acted much more rapidly and its negative chronotrophic potency was more marked. The same occurred with the blood pressure, the lowered pressure due to the barbiturate being restored to normal by both drugs but again convallatoxin acted the more rapidly. The increased venous pressure was decreased by both drugs in a like manner. For therapeutic use. lower doses of convallatoxin than of g-strophanthin arc necessary but even so disturbances of cardiac action and cardiac arrest are produced by lower doses of convallatoxin than g-strophanthin. The comparative value of both glycosides will br discussed.
360 Digitoxin-(23-l%).
G. RABITZSCI~ (Germany).
The preparation of i4C-labelled cardenolide glycosides was previously done either by the biological method (digitoxin-U-t4C)t1’ or by partial synthesis of the monoglucoside from inactive aglycone and n-glucose-U-14C.‘z’ The labelling of the biologically less important part of the molecule makes this compound less suitable for the examination of pharmacological questions. Therefore, the possibility of labelling a native glycoside specifically
107
of Papers
with “C in the aglycone moiety was investigated, using digitoxin (digitoxigenin-(IJ-n)-tridigitoxoside). After blocking the digitoxose hydroxyl groups the labelling of the steroid skeleton of the intact glycoside is done by ozonolytic degradation of the lactone ring to the ketolacetate, (*I followed by resynthesis to the unsaturated lactone with ethyl bromoacetatct4C according to Reformatzky. The separation of the heterogeneous reaction product is performed by thin-layer and column chromatography with silica gel. Studies on the binding of this compound and its aglycone to heart muscle are in progress in this laboratory. -__ 1. OKITA et al. (1954). 2. TURBA and SCHOLTISSE~~ (19%).
361 The Relationship between Molecular Structure and Pharmacological Activity in Derivatives of Digitoxigenin and Digoxigenin. A, STAFFORD and S. E. WRIGHT (Australia). hlost of the present knowledge about structural requirements for cardiac glycoside-like activity is derived from measurement of lethal doses in the cat. This work was done to see whether similar structure activity relations hold for the positive inotropic effects. Oxidation or acctylation of the 3-OH of digitouigenin or the 3- and 12-OH of digoxigenin caused a reduction in toxicity in the cat, guinea pig and isolated embryonic chick heart to l/10-1/12 of that of the parent aglycone without altering qualitatively the electrocardiographic changes. The concentrations required to produce positive inotropic effects on the isolated cat papillary muscle and guinea-pig heart were 2-20 times higher than for the parent compounds but even at their most effective concentrations they produced a significantly smaller increase in the force of contraction. Removal of the 14-OH and formation of a tram C-D ring junction resulted in compounds with no demonstrable toxicity in the cat or guinea-pig, l/20-1/50 of the activity of digitoxigenin or digoxigenin on the embryo chick heart, and only a negative inotropic action on the isolated guinea-pig heart and cat papillary muscle. Hydrogenation of the lactone ring reduced toxicity both in the cat and the guinea-pig and reduced the positive inotropic activity to l/50-1/100 of the parent compound. These results suggest that positive inotropic activity in the cardiac glycosidrs parallels their toxicity.
362 The Therapeutic-Toxic Ratio in Digitalization. P. SZEKELY and N. A. \VYNNE (United Kingdom). The therapeutic and toxic effects of digitalis have been studied in man and in the experimental animal
359
A
Comparison of Some Properties of gStrophantin and Convallatoxin on the Heart Lung Preparation of the Cat. K. P.&vEK, \.. DITTERTOV~~ and F. V. SELECK+ (Czechoslovakia) .
Heart-lung preparations of cats were damaged by means of phenobarbital sodium and the effects of g-strophanthin and convallatoxin on the damaged hearts was compared. The decreased minute volume and cardiac output was restored by both drugs, but convallatoxin acted much more rapidly and its negative chronotrophic potency was more marked. The same occurred with the blood pressure, the lowered pressure due to the barbiturate being restored to normal by both drugs but again convallatoxin acted the more rapidly. The increased venous pressure was decreased by both drugs in a like manner. For therapeutic use. lower doses of convallatoxin than of g-strophanthin arc necessary but even so disturbances of cardiac action and cardiac arrest are produced by lower doses of convallatoxin than g-strophanthin. The comparative value of both glycosides will br discussed.
360 Digitoxin-(23-l%).
G. RABITZSCI~ (Germany).
The preparation of i4C-labelled cardenolide glycosides was previously done either by the biological method (digitoxin-U-t4C)t1’ or by partial synthesis of the monoglucoside from inactive aglycone and n-glucose-U-14C.‘z’ The labelling of the biologically less important part of the molecule makes this compound less suitable for the examination of pharmacological questions. Therefore, the possibility of labelling a native glycoside specifically
107
of Papers
with “C in the aglycone moiety was investigated, using digitoxin (digitoxigenin-(IJ-n)-tridigitoxoside). After blocking the digitoxose hydroxyl groups the labelling of the steroid skeleton of the intact glycoside is done by ozonolytic degradation of the lactone ring to the ketolacetate, (*I followed by resynthesis to the unsaturated lactone with ethyl bromoacetatct4C according to Reformatzky. The separation of the heterogeneous reaction product is performed by thin-layer and column chromatography with silica gel. Studies on the binding of this compound and its aglycone to heart muscle are in progress in this laboratory. -__ 1. OKITA et al. (1954). 2. TURBA and SCHOLTISSE~~ (19%).
361 The Relationship between Molecular Structure and Pharmacological Activity in Derivatives of Digitoxigenin and Digoxigenin. A, STAFFORD and S. E. WRIGHT (Australia). hlost of the present knowledge about structural requirements for cardiac glycoside-like activity is derived from measurement of lethal doses in the cat. This work was done to see whether similar structure activity relations hold for the positive inotropic effects. Oxidation or acctylation of the 3-OH of digitouigenin or the 3- and 12-OH of digoxigenin caused a reduction in toxicity in the cat, guinea pig and isolated embryonic chick heart to l/10-1/12 of that of the parent aglycone without altering qualitatively the electrocardiographic changes. The concentrations required to produce positive inotropic effects on the isolated cat papillary muscle and guinea-pig heart were 2-20 times higher than for the parent compounds but even at their most effective concentrations they produced a significantly smaller increase in the force of contraction. Removal of the 14-OH and formation of a tram C-D ring junction resulted in compounds with no demonstrable toxicity in the cat or guinea-pig, l/20-1/50 of the activity of digitoxigenin or digoxigenin on the embryo chick heart, and only a negative inotropic action on the isolated guinea-pig heart and cat papillary muscle. Hydrogenation of the lactone ring reduced toxicity both in the cat and the guinea-pig and reduced the positive inotropic activity to l/50-1/100 of the parent compound. These results suggest that positive inotropic activity in the cardiac glycosidrs parallels their toxicity.
362 The Therapeutic-Toxic Ratio in Digitalization. P. SZEKELY and N. A. \VYNNE (United Kingdom). The therapeutic and toxic effects of digitalis have been studied in man and in the experimental animal