Effect of the new H1-antagonist ReN1869 on capsaicin-induced hyperalgesia in human skin/Human phase-I trial using somatosensory evoked potentials induced by a CO2 laser.

Extensive pre-clinical investigations have shown that the tricyclic compound ReN1869 ((R)-1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidine carboxylic acid, CAS 170149-99-2) is a potent H1-antagonist with pronounced antinociceptive properties. In this human phase-I trial the effect of different acute and multiple doses of ReN1869 on capsaicin induced neurogenic inflammation and hyperalgesia was investigated. Twenty-one healthy male subjects were enrolled in this randomised, double-blind, three-period, crossover trial design--consisting of acute and one week b.i.d. oral administration of 25 and 50 mg doses of ReN1869 and matching placebo--separated by 3 week washout periods. Capsaicin solution (1%) (INCI: Capsicum frutescens--containing capsaicinoides from Capsicum annuum annuum, CAS 84603-55-4) was applied in an occlusive mode for 30 min on the skin of the back in all three acute and subchronic medication periods to induce neurogenic inflammation. When the nociceptive laser pulses were applied to the capsaicin pre-treated skin, ReN1869 exerted a highly significant reduction of the pain response--as predominantly detected by suppression of the (central) P2-component in the laser-induced somatosensory evoked potentials (LSEPs) from Vertex-EEG. The primary efficacy endpoint, the N1/P2 peak to peak amplitude, was significantly reduced with the administration of ReN1869--primarily by a suppression of the P2-component of the LSEP. This suppression was dose-dependent and was more pronounced after a one week treatment (subchronic mode) with ReN1869 than after the first dose (acute mode). In contrast to the (central) P2-component there was no significant effect on the (peripheral) N1-component of the LSEPs taken from capsaicin-treated skin. As ReN1869 had no significant effect when the laser pulses were applied to normal skin, and the compound's effect was mainly restricted to the (central) P2-component, when LSEPs were taken from capsaicin treated skin, it can be concluded that ReN1869 exerts its positive effect to reduce capsaicin-induced hyperalgesia by a primarily central mechanism.