Levien over 11 weeks during the winter. Patients received a continu- ous 5-day intravenous infusion of N-acetylcysteine starting with a 2-hour loading dose of 150 mg/kg followed by a dose of 15 mg/kg/hour. The primary outcome measures were the frequency and severity of RP attacks, and the number of digital ulcers. Frequency and severity of RP attacks were both reduced. Frequency was reduced from 21.2 RP attacks per week at baseline to 10.7 attacks per week from days 5 to 19, 12.1 per week from days 20–33, and 14.1 per week from days 34 to 61. Severity scores declined from 5.5 at baseline to 3.4 at days 5 to 19, 2.9 at days 20 to 33, and 3.1 at days 34 to 61. Digital ulcers were reduced at least 50% in 80% of patients at day 33 after the infusion, with 53% demonstrating complete ulcer healing. In a cold challenge test assessed by photoelectric plethysmography, mean recovery time fell by approximately 70%.94 In a subsequent assessment of the long- term use of N-acetylcysteine in patients with RP secondary to systemic sclerosis, patients treated with an intravenous dose of 15 mg/kg/hour for 5 consecutive hours every 2 weeks from October to May for 2 years demonstrated increased global hand perfusion, reduced plasma adrenomedullin levels, and reduced frequency and severity of RP attacks. Frequency of RP declined from 23.2 per week at baseline to 13.2 per week after 2 weeks of treatment (43.1% decline) and to 10.8 per week during the last 4 weeks of follow-up (53.4% decline). RP severity scores declined approximately 40%. Adreno- medullin is a potent vasodilator endothelial-derived peptide which levels increased in patients with systemic sclerosis. N-acetylcysteine seemed to act as a vasodilator, perhaps via modulation of adrenomedullin levels.95 Statins The observed effects of the statins on endothelial function prompted assessment of statins in the therapy of RP associ- ated with systemic sclerosis. One randomized study enrolled 84 patients with RP secondary to systemic sclerosis despite Dovepress ongoing vasodilator therapy. Patients received atorvastatin 40 mg per day (56 patients) or placebo (28 patients) for 4 months. The primary outcome was the number of digital ulcers, which declined from 3.3 at baseline to 2.4 at 4 months in the atorvastatin group compared with a reduction from 3.4 at baseline to 3 at 4 months in the placebo group (P = 0.001). Patients in the atorvastatin group had a mean of 1.6 new ulcers compared with 2.5 new ulcers per patient in the pla- cebo group (P = 0.003). Patients in the atorvastatin group also demonstrated improvement in the Scleroderma Health Assessment Questionnaire Disability Index (SHAQ-DI; P = 0.001), VAS for RP severity (P = 0.005), VAS for digital ulcer severity (P = 0.001), and VAS pain scales (P = 0.004) compared with the placebo group. Endothelial markers of activation that improved from baseline in the statin group compared with the placebo group included IL-6, TNF-alpha, ET-1, nitric oxide, thrombomodulin, soluble E-selectin, von Willebrand factor, monocyte chemoattractant, fibrinogen, high sensitivity C-reactive protein, erythrocyte sedimentation rate, lipid peroxide, and malonylaldehyde.96 Botulinum toxin-A Decreased pain and numbness, decreased frequency of vasospastic attacks, healing of digital ulcers, and increased blood flow was observed in three case series and a case report assessing interdigital injections of botulinum toxin in patients with primary and secondary RP.97–100 A dual mechanism of action has been suggested: inhibition of vasospasm by blocking cold-induced vasoconstriction and by preventing recruitment of alpha2 receptors to vascular smooth muscle in cold conditions.98 Placebo-controlled studies are necessary to confirm the activity of botulinum toxin in RP. Conclusion In patients with primary RP, nonpharmacologic lifestyle modifications remain the first-line therapy. Calcium channel Table 4 Newer therapies with demonstrated efficacy in Raynaud’s phenomenon Agents Class Route RP population MQX-503 Nitrate Topical Primary and secondary iloprost Prostaglandin analog intravenous Secondary Bosentan Sildenafil Tadalafil endothelin receptor antagonist Phosphodiesterase type 5 inhibitor Phosphodiesterase type 5 inhibitor Oral Oral Oral 174 submit your manuscript | www.dovepress.com Dovepress Secondary Secondary Secondary Effect Reduced attack severity Reduced duration, frequency, and severity of attacks; improved ulcer healing Reduced number of new digital ulcers Reduced duration, frequency, and severity of attacks; improved ulcer healing Reduced duration, frequency, and severity of attacks; improved ulcer healing Vascular Health and Risk Management 2010:6