Lack of arrhythmogenicity of aminophylline in dogs

Abstract

This study was designed to determine if doses of aminophylline up to 10 mg/kg given i.v. would produce ventricular arrhythmias in seven healthy dogs anaesthetized with fentanyl-droperidol-pentobarbital. Arrhythmias were sought by inspection of ECGs before and after attempts at provoking them with 5 micrograms/kg boluses of epinephrine given i.v., or by programmed electrical stimulation. After cumulative doses of 10 mg aminophylline/kg body weight, producing an estimated plasma concentration of greater than 30 micrograms/ml, no ventricular ectopia other than escape depolarizations were observed. We were unable to document an arrhythmogenic effect of aminophylline when given rapidly by the i.v. route. It is possible that the anaesthetic regimen reduced the arrhythmogenic property of aminophylline, or that arrhythmias might be produced in either obese or ill dogs; but it is unlikely that chronic administration of aminophylline would be more arrhythmogenic.

Pharmacokinetics of a modified, compounded theophylline product in dogs

“…In our study, no plasma drug concentration for any dog exceeded 20 μg/ml after a single oral dose of the MCT, and only two dogs had a predicted C MAX,SS above this concentration. However, these concentrations were well below those associated with any adverse effects in dogs (Hamlin & Sally 1993;Shibata et al, 2000). Therefore, we do not expect significant toxicity with a dosing regimen of 10 mg/kg q 12 hr.…”

“…It has been hypothesized that the short t 1/2,β of rapid re- It should be noted that theophylline products marketed as slow release or extended release in humans generally do not have extended-release properties in dogs (Bach et al, 2004;Koritz et al, 1986 Papich, 2014) because of the narrow therapeutic range (10-20 μg/ ml) and high incidence of dose-dependent adverse effects seen in humans (Barnes, 2010). In contrast, dogs may be more resistant to theophylline's adverse effects with mild and serious signs only occurring at plasma concentrations exceeding 37 and 90 μg/ml, respectively, without cumulative effects (Hamlin & Sally, 1993;Shibata, Wachi, Kagawa, Kojima, & Onodera, 2000). In our study, no plasma drug concentration for any dog exceeded 20 μg/ml after a single oral dose of the MCT, and only two dogs had a predicted C MAX,SS above this concentration.…”

Multidose pharmacokinetics and safety of a modified, compounded theophylline product in dogs

“…One dog had one ventricular premature contraction throughout the entire study, which theoretically could be caused by theophylline. However, the plasma drug concentration was low when this occurred (5.32 μg/ml), so this single ventricular arrhythmia is most likely due to normal variation given that other studies examining much higher plasma concentrations have failed to identify ventricular arrhythmogenicity of theophylline in dogs (Hamlin & Sally, 1993; Munsiff et al, 1988).…”

“…However, dogs are more resistant to the adverse effects of theophylline. In one toxicity study, dogs did not show adverse effects until plasma concentrations reached 37–60 μg/ml (Hamlin & Sally, 1993; Munsiff et al, 1988). Even then, the adverse effects observed were relatively mild, including sinus tachycardia and central nervous stimulation.…”

“…Even then, the adverse effects observed were relatively mild, including sinus tachycardia and central nervous stimulation. Furthermore, plasma concentrations up to 90 μg/ml did not appear to induce significant arrhythmias in awake canine patients (Hamlin & Sally, 1993; Munsiff et al, 1988). Taken together, these data suggest that the wider therapeutic target range of 5–30 μg/ml for theophylline may be more appropriate in dogs.…”