Improving the relaxing effect of terbutaline with phosphodiesterase inhibitors: Studies on pregnant rat uteri in vitro

Abstract

The previous findings led us to conclude that the combined administration of PDE4 inhibitors with β(2)-agonists is of therapeutic value for the inhibition for uterine contractions, especially in the case of genital inflammation, which often triggers preterm birth. Combination therapy in general is associated with lesser side-effects, as a consequence of lower effective doses of each drug.

Uterus‐relaxing effect of β2‐agonists in combination with phosphodiesterase inhibitors: Studies on pregnant rat in vivo and on pregnant human myometrium in vitro

“…On the other hand, the potential beneficial effect of the PDE4 selective inhibitor rolipram as a tocolytic agent has not yet been confirmed. We earlier provided evidence that rolipram potentiates the tocolytic effect of terbutaline both in intact and in LPS‐treated pregnant rats, due to the higher cAMP levels 25 . In the present study, we set out to investigate their effects on pregnant rats in vivo .…”

“…We earlier provided evidence that rolipram potentiates the tocolytic effect of terbutaline both in intact and in LPS-treated pregnant rats, due to the higher cAMP levels. 25 In the present study, we set out to investigate their effects on pregnant rats in vivo. Detection of the myometrial activity in vivo is accompanied by the benefit of allowing studies of the efficacy of these drugs according to the principles of integrative pharmacology.…”

Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade

“…PDE-4 inhibitors are not only uterus-relaxant agents; they have also been shown to function as anti-inflammatory drugs in uterine tissues, which is important because inflammation provokes spontaneous uterine contractions [14,39,40]. Interestingly, all of the results obtained in the in vitro functional study of rolipram and thalidomide analogs as inhibitors of uterine contractions resembled those intended to evaluate the relaxant effect of diverse PDE-4 inhibitors on the spontaneous contraction of pregnant human myometrium [34,35,41], on tonic KCl-induced contractions in pregnant rat myometrium [42], and on in vivo spontaneous contractions in pregnant rats [38].…”

Relaxant and anti-inflammatory effect of two thalidomide analogs as PDE-4 inhibitors in pregnant rat uterus

“…As commented, salbutamol or terbutaline are, without any significant clinical benefit, commonly used as tocolytic agents, but are often associated with severe fetal and maternal side effects [1516]. The down-regulation of proinflammatory cytokines synthesis and the increase of cAMP through the combination of tocolytics and PDE-4 inhibitors may dampen the inflammatory cascade, which leads to premature contractions [1749]. Recent clinical trials with apremilast, one of main thalidomide analogs designed as PDE-4-inhibitor for inflammatory disorders, has been approved for the treatment of autoimmune diseases, such as psoriasis and psoriatic arthritis [50].…”