Efficacy of Rho kinase inhibitor fasudil in secondary Raynaud's phenomenon

Abstract

Objective: The RhoA/Rho kinase pathway plays a pivotal role in cold-induced vasoconstriction, vascular smooth muscle cells function, and vascular homeostasis. This study evaluates the efficacy of fasudil, a RhoA/Rho kinase inhibitor, to reverse cold-induced vasospasm in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc; scleroderma).

Methods: This is a single-center, double-blind, placebo-controlled, randomized, 3-period crossover study of oral fasudil (40 mg or 80 mg) or placebo administered 2 hours before a standardized cold challenge. The fall in skin temperature after the cold challenge and time to recover 50% and 70% of prechallenge digital skin temperature were used as primary outcomes. Digital blood flow assessed by laser Doppler, time to minimum skin temperature, and rate of skin cooling were also measured.

Results: A total of 17 patients with SSc and RP completed the study. After the cold challenge, skin temperatures and the average time (minutes) to recover 50% (7.9 minutes for placebo, 7.5 minutes for fasudil 40 mg, and 8.2 minutes for fasudil 80 mg; P = 0.791) and 70% (18.2 minutes for placebo, 15.0 minutes for fasudil 40 mg, and 17.1 minutes for fasudil 80 mg; P = 0.654) of prechallenge skin temperature were not significantly different across the 3 groups. The digital blood flow measurements were higher in fasudil-treated groups than placebo, but differences were not significant (P = 0.693).

Conclusion: Fasudil administered at a single oral dose of 40 mg or 80 mg was not associated with significant benefit in terms of the skin temperature recovery time and the digital blood flow after the cold challenge.

Copyright © 2012 by the American College of Rheumatology.

Figures

Figure 1. Temperature and digital blood flow curves following single dose fasudil administration versus placebo in SSc patients with Raynaud’s phenomenon

* Perfusion units (PU) calculated by the instrument accounting for erythrocyte density and velocity in the sampled volume. CC = cold-challenge; pre-CC = skin temperature measured right before the beginning of the CC; end-CC = skin temperature measured at the end of the CC (CC stopped when digital skin temperature reached 12 °C or the patient could no longer tolerate the cold). (A) Recovery of digital skin temperature after cold challenge (CC) according to treatment group. Values are expressed as percentage of range from baseline (100%) to minimum digital skin temperature after CC (0%). Times to recover to 50% and 70% (dotted lines) represent the primary outcome. (B) Mean digital blood flow during and after the cold-challenge (CC) measured with Laser Doppler perfusion imaging according to treatment group (values are reported in Table 2).