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Effects of ReN1869, a CNS‐available antihistamine, on capsaicin‐ and histamine‐induced neurogenic inflammation in healthy subjects

ReN1869 (elsewhere referred to as NNC 05‐1869) is a new tricyclic compound which is chemically related to amitriptyline, but is without any significant interaction with other receptors except for the histamine H1‐receptor, where it functions as an antagonist. The compound exhibits antinociceptive effects in rodent models of chronic pain and is effective against inflammation of neurogenic origin. The present trial was designed to assess the effect of a single dose of ReN1869 in humans on neurogenic inflammation induced by capsaicin and histamine and on the concomitant itch and pain sensation. Twenty‐four healthy male subjects were enrolled in this randomized, double‐blind, two‐period, crossover trial consisting of a single oral dose of 95 mg ReN1869 and matching placebo. Thirty minutes after dosing the participants received, in a randomized order, either histamine (on the skin of the palmar forearm, prick test) before capsaicin (on the skin of the back) in both trial periods and capsaicin before histamine in both periods. Several pharmacodynamic tests were performed after the capsaicin/histamine application: laser somatosensory‐evoked potentials (Laser‐SEP), sensory and pain threshold to laser stimuli of increasing intensity, planimetry of areas of wheal and flare, pinprick hyperalgesia, brush‐evoked pain, allodynia, skin reflection spectrometry (colorimetry), and visual analog scale of itch. ReN1869 had significant effects on the histamine‐induced phenomena. No wheal could be evoked in 14/21 evaluated subjects in contrast to all placebo‐treated subjects. The area of flare was reduced by 80% and itching by 65%. The flare induced by capsaicin was only slightly (not significantly) reduced by ReN1869. However, ReN1869 strongly influenced Laser‐SEP evoked by nociceptive stimuli from the capsaicin‐treated skin area by a 25% reduction of the amplitude of the P2 component, whereas the N1 component was not affected. This observation reflects a central analgesic effect without a peripheral component. The dosing was well tolerated and no particular adverse events were related to the trial drug. Conclusively, ReN1869 represents a new class of antihistamines that has antiinflammatory properties (related to antihistaminergic effects) as well as central analgesic effects (probably mediated centrally through histamine H1 receptors). Drug Dev. Res. 57:193–199, 2002. © 2003 Wiley‐Liss, Inc.