Dovepress Treatment of Raynaud’s phenomenon Table 2 Summary of bosentan clinical trials on Raynaud’s phenomenon (RP) Patients Study design Treatment Outcomes 122 patients Randomized Bosentan 62.5 mg Fewer new digital ulcers per patient with bosentan secondary RP double-blind twice daily × 4 weeks, (primary study outcome; mean of 1.4 new ulcers placebo-controlled then 125 mg twice per patient on bosentan vs 2.7 new ulcers per patient daily × 12 weeks on placebo [P = 0.0083]) No difference in percentage of patients with new digital ulcers, time to first ulcer, ulcer healing, or functional improvement 188 patients Randomized Bosentan 62.5 mg Fewer new digital ulcers per patient with bosentan secondary RP double-blind twice daily × 4 weeks, (primary study outcome; mean of 1.9 new ulcers placebo-controlled then 125 mg twice per patient on bosentan vs 2.7 new ulcers per patient daily × 20–32 weeks on placebo [P = 0.035]) No difference in time to healing of cardinal ulcer, time to healing of all digital ulcers, and percent with complete healing References 42 44 of ulcers was reported in 65% of patients after a median of 25 weeks (range 8 to 26 weeks).46 Reduction in ulcers, improved ulcer healing, and improvement in RP frequency and severity have also been reported in several case series and case reports including patients with systemic sclerosis.47–53 while another case series observed no improvement in RP activity, microvascular blood flow, systolic finger pressures, or disability scores.54 Bosentan toxicities include serious liver injury and major birth defects. In the United States bosentan is only approved by the Food and Drug Administration for use in the treatment of pulmonary arterial hypertension and is only available through a limited distribution system. Phosphodiesterase type 5 inhibitors Nitric oxide vasodilates and inhibits platelet activation by generating cyclic guanosine 5′-monophosphate.55 cGMP is hydrolyzed by phosphodiesterases, particularly the cGMP- specific phosphodiesterase-5 isoenzyme. Sildenafil, tadalafil, and vardenafil are selective inhibitors of cGMP-specific phosphodiesterase type 5 which increases cGMP, resulting in enhanced cGMP-dependent microvascular and macrovascu- lar dilation.5,55 The use of PDE5 inhibitors is being explored in patients with RP because of their potential effects on the microvascular and macrovascular circulation. Several small studies have assessed sildenafil, tadalafil, and vardenafil in the treatment of RP (study designs and key results are summarized in Table 3). These studies include a single-dose crossover study with sildenafil and alpha-tocopherol,56 a small study comparing tadalafil and pentoxifylline,57 two crossover studies comparing sildenafil and placebo,5,58 two crossover studies comparing tadalafil and Vascular Health and Risk Management 2010:6 placebo,59,60 and open-label uncontrolled studies of sildenafil, tadalafil, and vardenafil.61–64 Several of these studies have only been presented in meeting abstracts or as letters.56–62,64 A randomized, double-blind, crossover study compared the physiologic effects of single-dose sildenafil and alpha- tocopherol in 15 patients with RP. Following sildenafil, basal forearm blood flow and plasma cGMP were increased, and systolic and diastolic blood pressure were reduced. Alpha- tocopherol had no effect on any of these parameters.56 Clinical and blood flow effects of vardenafil have been assessed in 40 patients with primary or secondary RP in an open-label pilot study. Laser-Doppler measurements revealed improved digital blood flow in 70% of patients. Among those respond- ing, peripheral blood flow was increased at room temperature and in a cold-exposure test at both 1 hour and 2 weeks after initiation of vardenafil. Symptomatic improvement was also observed, along with a reduction in the duration, frequency, and severity of attacks.63 Objective digital temperature responses following a mild cold challenge were observed in 3 of 5 patients treated with single dose of sildenafil in another open-label uncontrolled study. Subjective responses were also observed.64 Symptomatic improvement has been reported in several open-label studies. Primarily subjective endpoints were assessed in an open-label uncontrolled study of sildenafil in 10 female patients. Sildenafil 25 mg 3 times daily for 6 weeks was initiated following 5 days of intravenous iloprost therapy. Six of 10 patients demonstrated symptomatic improvement and five experienced ulcer healing. Among the six demon- strating clinical improvement, four showed an increase in finger skin temperature on thermography.61 Healing was also observed with sildenafil in an open-label study enrolling submit your manuscript | www.dovepress.com Dovepress 171