Efficacy and tolerability of a selective α_2C‐adrenergic receptor blocker in recovery from cold‐induced vasospasm in scleroderma patients: A single‐center, double‐blind, placebo‐controlled, randomized crossover study

Abstract

Objective. OPC-28326 is a selective ␣-adrenergic antagonist with preferential binding to the ␣ 2C -adrenergic receptor (␣ 2C -AR) subtype. This study observed the effect of OPC-28326 on skin temperature and digital blood flow following an acute cold challenge in patients with Raynaud's phenomenon secondary to scleroderma.Methods. The study was designed as a singlecenter, double-blind, placebo-controlled, randomized, 3-period crossover study of OPC-28326 (oral doses of 10 mg or 40 mg) or placebo. The primary outcome measures were the time to recover 50% and 70% of the fall (induced by cold challenge) in baseline digital skin temperature.Results. Twelve of 13 enrolled patients completed the study. The mean time to achieve 50% and 70% recovery of the change in prechallenge digital skin temperature was shorter after the OPC-28326 40-mg dose than after placebo (50% recovery at 5.8 minutes versus 10.0 minutes [P ‫؍‬ 0.02]; 70% recovery at 13.8 minutes versus 19.5 minutes [P ‫؍‬ 0.01]). These recovery times tended to be shorter in the 10 mg OPC-28326 group as well, but the difference versus placebo was not significant (50% recovery at 9.0 minutes versus 10.0 minutes [P ‫؍‬ 0.65]; 70% recovery at 15.3 minutes versus 19.5 minutes [P ‫؍‬ 0.07]). Total digital blood flow tended to be lower prior to the cold challenge and after administration of 40 mg OPC-28326, as compared with that after placebo, but the difference was not significant. Symptoms that were potentially drug-related were reported more frequently with 40 mg OPC-28326 than with 10 mg OPC-28326 or with placebo, but none were serious or sustained.Conclusion. OPC-28326 at doses of 10 mg and 40 mg was well tolerated during this study. The shorter time to skin temperature recovery after 40 mg OPC-28326 suggests that selective ␣ 2C -AR blockade improves digital skin perfusion during recovery from cooling in patients with Raynaud's phenomenon secondary to scleroderma.

Raynaud’s phenomenon and digital ischaemia - pharmacologic approach and alternative treatment options

“…To date, there is no sympatholytic agent that satisfactorily prevents patients from experiencing RP episodes. It has been argued that cold-induced vasoconstriction of digital arteries is mainly mediated via alpha-2C-adrenergic receptors, which are not specifi cally blocked by the available alpha-1-adrenergic receptor antagonists [37]. However, a specifi c alpha-2C agent is not yet available.…”

“…With regard to vasculitis, secondary RP occurs more frequently in thrombangiitis obliterans (Buerger's disease) and in small and medium-sized vessel vasculitis than in largevessel vasculitis [ESM 2,[36][37][38][39][40], and it often predicts a more progressive course of the disease. In particular, patients with secondary RP related to connective tissue diseases (CTD) are at high risk for developing digital skin ulcers.…”

Drug Treatment of Raynaud’s Phenomenon

“…4 ) OPC-28326 is a selective alpha-adrenergic antagonist with preferential binding to the alpha (2C)-adrenergic receptor (alpha(2C)-AR) subtype. It was studied in 13 secondary RP patients with SSc in a double-blind, placebo-controlled, randomized, 3-period crossover study of OPC-28326 (oral doses of 10 mg or 40 mg) or placebo [ 100 ]. Digital skin perfusion was improved with the drug.…”

Management of Raynaud’s Phenomenon in the Patient with Connective Tissue Disease

“…& None of the available sympatholytic agents specifically inhibits the α 2c -adrenergic receptor, now considered to be the major mediator through which cold-induced digital vasoconstriction is triggered. A laboratory-based study using a specific α 2c -adrenergic receptor antagonist shows some promise (see "Emerging Therapies") [47]. Prazosin Standard dosage 1 mg three times daily.…”