Drug‐disease interactions: reduced β‐adrenergic and potassium channel antagonist activities of sotalol in the presence of acute and chronic inflammatory conditions in the rat

Abstract

1 In¯ammation may in¯uence response to pharmacotherapy. 2 We investigated the eect of in¯ammation on response to sotalol, a b-adrenergic receptor and potassium channel antagonist. Racemic sotalol (40 mg kg 71) was administered to healthy, acutely (interferona 2a-induced) and chronically (Mycobacterium butyricum-induced adjuvant arthritis) in¯amed male Sprague-Dawley rats (n=4 ± 6/group). Another group of interferon-treated rats received 3 mg kg 71 of anti-TNF antibody in¯iximab. Electrocardiogram (ECG) recorded and plasma sotalol concentration monitored for 6 h. The study was repeated in acutely in¯amed rats following administration of stereochemically pure individual sotalol enantiomers [40 mg kg 71 S (potassium channel blocker) or 20 mg kg 71 R (b-adrenergic/potassium channel blocker)]. 3 Chronic arthritis was readily evident. Acute arthritis was associated with elevated segmented neutrophils and increased plasma nitrite and tumour necrosis factor (TNF) concentrations. Sotalol aected ECG in all rats. In both in¯amed groups, however, response to sotalol in prolongation of QT interval (potassium channel sensitivity) was reduced. The eect of PR interval (b-adrenergic activity) was also reduced following administration of the racemate and R-enantiomer. No signi®cant dierences in pharmacokinetics were observed between control and in¯amed rats. 4 In¯iximab reduced nitrite and TNF concentrations and reversed the eect of acute in¯ammation on both PR and QT intervals. 5 The reduced electrocardiographic responses to sotalol is likely due to the in¯uence of in¯ammation on the action of the drug on both b-adrenergic and potassium channel receptors secondary to over-expression of pro-in¯ammatory cytokines and/or nitric oxide. 6 Our observation may have therapeutic consequences in all conditions where in¯ammatory mediators are increased.

Tumor necrosis factor-α in a porcine bronchial model of obliterative bronchiolitis1

“…We chose to study the effect of this drug in our model because protein coding sequences of human and pig TNF-␣ share a considerable degree of homology (86%) (23). Furthermore, in previous experiments in different pig and rat models, infliximab has shown anti-inflammatory effects (24,25). In lung diseases, infliximab has been successfully tried in individual patient cases in rheumatoid arthritis-associated pulmonary fibrosis (26).…”

Disease–drug interaction: Reduced response to propranolol despite increased concentration in the rat with inflammation

“…10,14,15 Its prolongation is dose dependent and is measurable after a single dose. Changes in the receptor activities are reflected on PR interval without physical or pharmacological stimulation.…”

“…This parameter has been shown to be a sensitive and reproducible measure of both b-adrenergic and calcium channel receptors functions without a need for cardiac stimulation. 10,14,15 …”

Perioperative Infliximab Application Ameliorates Acute Rejection Associated Inflammation After Intestinal Transplantation

“…Inhibition of TNF-a with infliximab has become a therapeutic option in chronic inflammatory bowel diseases (29,30), psoriasis (31), rheumatoid arthritis (32) and OKT-3-and steroid-resistant acute rejection after SBTx (10,13,14). The use of infliximab (chimeric antibody for human therapy) in animal models regarding specific TNFa-inhibition has been described previously (33)(34)(35). Our own preliminary experiments revealed an efficient reduction of TNF-a in the serum of rats after LPS-induced acute peritonitis.…”