Digoxin and digoxin derivative induced arrhythmias: in vitro binding and in vivo abolition of arrhythmias by digoxin immune Fab (DIGIBAND).

OBJECTIVE: The aim was to compare the binding characteristics of a highly purified digoxin specific antigen binding fragment (digoxin immune Fab: DIGIBIND) with digoxin and with two commonly used derivatives of digoxin, beta methyl digoxin and beta acetyl digoxin, and to assess its ability to abolish the arrhythmogenic effects of these digitalis glycosides. METHODS: The binding characteristics of DIGIBIND with digoxin, beta methyl digoxin, and beta acetyl digoxin were assessed in vitro by measuring their ability to inhibit the binding of DIGIBIND to 3H-digoxin. From these studies the affinities of the interactions between DIGIBIND and these glycosides, and the binding capacity of DIGIBIND for each of these glycosides, could be measured. The ability of DIGIBIND to abolish the arrhythmogenic effects of digoxin, beta methyl digoxin, and beta acetyl digoxin was assessed using an in vivo anaesthetised guinea pig model (n = 36, weight 300-400 g), in which these glycosides were infused intravenously (50 micrograms.kg-1 x min-1) until the onset of ventricular arrhythmias, at which point the total amount of glycoside given was calculated. A single bolus dose of either vehicle or DIGIBIND was then given intravenously, and the time to restoration of normal cardiac rhythm noted. After the administration of DIGIBIND, a second infusion of the same glycoside was given to reinitiate the ventricular arrhythmias. The time to onset of the arrhythmias was noted, and the additional amount of glycoside given calculated. RESULTS: In vitro studies showed the binding of DIGIBIND to 3H-digoxin to be inhibited by digoxin and by the two derivatives. The affinities of these interactions with DIGIBIND were significantly different, that for digoxin being some twofold greater than that for beta methyl digoxin and beta acetyl digoxin. The ED50 concentrations were 14.1 (95% CI 12.2, 15.2), 29.2(26.1, 32.7), and 36.2(33.0, 39.8) nM, respectively. However, there were no significant differences between these glycosides in their binding capacities. The in vivo studies showed that intravenous infusion of digoxin, beta methyl digoxin, or beta acetyl digoxin induced similar ventricular arrhythmias. The onset of the arrhythmias was clearly discernible, and required a significantly lower dose of digoxin compared with that of beta methyl digoxin and beta acetyl digoxin. These doses were 667(SEM 55), 868(33), and 854(40) nmol.kg-1, respectively. Termination of the infusion had no effect on the arrhythmias, and in those animals which received a bolus intravenous injection of saline there was no return to normal cardiac rhythm. By contrast, in animals which received a bolus intravenous injection of DIGIBIND, there was complete abolition of the arrhythmias within 4-6 min. Although the dose of DIGIBIND given to abolish digoxin induced arrhythmias was approximately 25% less than that given to abolish beta methyl digoxin and beta acetyl digoxin induced arrhythmias (p < 0.05), the time to restoration of normal cardiac rhythm after DIGIBIND was not significantly different for digoxin compared with beta methyl digoxin and beta acetyl digoxin, at 4.6(0.9), 4.9(0.8), and 5.7(0.8) min, respectively. To reinitiate the arrhythmias in those animals which had received DIGIBIND, a dose of glycoside was required which was not significantly different from that given prior to the DIGIBIND. This observation therefore confirmed the stoichiometric relationship between DIGIBIND and each of the glycosides in respect of the neutralising action of DIGIBIND in abolishing the arrhythmogenic effects of these agents. CONCLUSIONS: Although there is some small difference in the affinities of the binding interactions, there is no difference in the binding capacities of DIGIBIND for digoxin, beta methyl digoxin, or beta acetyl digoxin in vitro. These binding interactions are manifest as the ability of DIGIBIND to abolish the arrhythmogenic effects of digoxin and the two derivatives in vivo.

Concentraciones séricas de digoxina en niños tratados con beta metil digoxina / Serum digoxin in children treated with ß methyl digoxin

Se midieron concentraciones séricas de digoxina con el método de inmunofluorescencia polarizada (TDxII System Abbot Diagnostic Inc.) en 59 muestras de sangre tomadas de 53 pacientes pediátricos en tratamiento de mantención oral con ß metildigoxina. Se consideró como margen terapéutico las concentraciones séricas entre 0,9 y 2,25 ng/ml plasma. Se midió, además, Na, K y cratinina plasmática. En 8 muestras la concentración sérica fue inferior mínimo terapéutico de 0,9 ng/ml, la dosis de mantención fluctuaba entre 1,3 y 8,6 *g*kg*día (promedio 5,6 ñ 2,8) y entre ellos no hubo casos de toxicidad. En 36 muestras la concentración sérica estaba dentro de los márgenes establecidos como terapéuticos, las dosis de mantención de metildigoxina habían variado entre 5 y 12,5 *g*kg*día (promedio de 8,9 ñ 2,0) y entre ellos se detectó un caso de toxicidad, con concentración sérica de 2,0 ng/ml. En 15 muestras la concentración sérica superó la máxima del margen terapéutico establecido y 11 de ellas (73%) coincidieron con signos de toxicidad cardíacos y, o, digestivos en los respectivos pacientes. En 6 de estos 11 casos había coincidentemente insuficiencia renal aguda, que en 4/6 era subclínica y en 2/4 prerrenal. En el total de los 12 casos que presentaron toxicidad a partir de concentración sérica de 2,4 ng/ml, por lo que el margen terapéutico escogido para ésta parece adecuado; en niños los signos de toxicidad deben buscarse siempre y en los casos críticos o si se sospecha la posibilidad de insuficiencia renal, en el curso del tratamiento, conviene determinar dicha concentración sérica. En la práctica clínica los signos de toxicidad son predominantemente digestivos. La dosis de mantención con metildigoxina entre 7 y 10 *g*kg*día es razonablemente segura