Background and aim: This study investigated the pharmacological influence under experimental conditions of the fixed-ratio combination of a modulator of the renin angiotensin system (candesartan) and an adjuvant in pain therapy (clomipramine) using nociception models with chemical and thermal stimuli.
Methods: The nociception models used were: the formalin test, the hot plate test (52.5 ± 0.2°C, 30, 60, 90, 120 minutes) and the Zymosan-induced constrictive abdominal response
The investigations were conducted on groups of 10 Swiss male mice weighing 20.00-30.00g, treated orally with dose sequences of the administered substances alone and in combination. Combination analysis was performed using the composite additive method. All experiments have been made in accordance with the bioethical rules and regulations (EU Directive 63/2010).
Results: The binary candesartan-clomipramine combination was found to be synergistic for both phases of the formalin test (Phase I: Zmix = 0.16 ± 0.02 mg / kg, γ = 0.271, tcalc = 6.13, ttab = 3.83, p <0.001; : Zmix = 0.20 ± 0.04 mg / kg, γ = 0.338, tcalc = 4.64, ttab = 3.89, p <0.01) for the dose sequence used and the ratio (f = 0.5, p1 = , p2 = 0.266). The synergism was demonstrated by the left shift of the additive composite line compared to the regression line of the combination).
Conclusion: The synergism of the combination can be explained by reducing the pro-inflammatory effects of angiotensin II and the positive regulation of TNF-alpha, and the addition of clomipramine effects on the 5HT2 and 5HT3 receptors.

DEMONSTRATION OF THE ANTINOCICEPTIVE ACTION OF THE FIXED COMBINATION OF CANDESARTAN-CLOMIPRAMINE