Rheumatol Int DOI 10.1007/s00296-014-3025-z
Short Communication
Effects of phosphodiesterase type 5 inhibitors on Raynaud’s phenomenon Yasuyuki Kamata · Seiji Minota
Received: 1 March 2014 / Accepted: 13 April 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Raynaud’s phenomenon (RP) is commonly observed in fingers and toes of patients with connective tissue diseases (CTDs). However, existing vasodilators have very limited efficacy. In this study, phosphodiesterase type 5 inhibitors (PDE-5Is) were administered to evaluate efficacy on RP. Three patients with mixed connective tissue disease and three patients with systemic sclerosis having RP were enrolled. Oral sildenafil, vardenafil, or tadalafil was administered. The fingertip temperature was measured by thermography before and 120 min after administration. To evaluate longer effects, vardenafil was administered daily for 12 weeks; the fingertip temperature was measured by thermography before and 12 weeks after administration. As compared with the pre-administration of sildenafil, vardenafil, and tadalafil, the mean fingertip temperature increased by 2.17, 3.47, and 3.59 °C, respectively, in 120 min. In the 12-week trial with vardenafil in 3 patients, the mean fingertip temperature increased by 3.04, 7.96, and 3.32 °C from baseline in each patient. PDE-5Is significantly increased fingertip temperature within 120 min, and the effect of vardenafil lasted for 12 weeks under daily use. PDE-5Is were safe and would be an effective treatment for RP with CTDs. Keywords Connective tissue diseases · Raynaud’s phenomenon · Sildenafil · Tadalafil · Vardenafil
Y. Kamata (*) · S. Minota Division of Rheumatology and Clinical Immunology, Jichi Medical University, 3311‑1 Yakushiji, Shimotsuke‑shi, Tochigi‑ken 329‑0498, Japan e-mail: [email protected] S. Minota e-mail: [email protected]
Introduction Raynaud’s phenomenon (RP) is commonly observed in fingers and toes of patients with connective tissue diseases (CTDs). Without successful treatment, ulceration and necrosis often ensue and a mandatory amputation is not infrequent in severe cases [1]. Glucocorticoids and immunosuppressants are usually ineffective in this setting. Vasodilators such as calcium channel blockers and prostaglandins have been used most frequently in these patients [2–4]. However, these drugs have very limited effects. Nitric oxide produced in vascular endothelial cells plays an important role in vasodilation. Nitric oxide acts on vascular smooth muscle cells, activating guanylate cyclase and producing cyclic guanosine monophosphate (cGMP) from guanosine triphosphate. By activating cGMP-dependent protein kinase, cGMP induces relaxation in vascular smooth muscle and vasodilation. Phosphodiesterase type 5 (PDE-5) rapidly hydrolyzes cGMP to 5’GMP and terminates vasodilation. PDE-5 inhibitors (PDE-5Is) continue and enhance vasodilation by inhibiting hydrolysis of cGMP [5–7]. Because PDE-5 is abundant in vascular smooth muscle cells and lung tissues, it is highly probable that the administration of PDE-5Is induces vasodilation in lung, fingers, and toes [7–13]. In this study, PDE-5Is were administered in patients with RP associated with CTDs, and their effect was assessed by measuring surface temperatures of the fingers. This is a pilot study that compared three kinds of PDE-5 inhibitor (PDE-5I). Because this study was performed prospectively, the inclusion criteria were not so stringent and the number of the patients included was small.
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Table 1 Clinical features of six patients
Rheumatol Int Patient
Age
Sex
Diagnosis
Duration of Raynaud’s phenomenon (years)
Prednisolone (mg/day)
1 2 3 4 5
46 38 61 28 67
F M F F M
SSc SSc SSc MCTD MCTD
11 7 14 1 13
0 15 0 5 10
6
26
F
MCTD
19
0
Patients and methods The six patients were all we treated with PDE-5I. No patient dropped out. All patients had Reynaud’s phenomenon more than several times daily. They were severe enough in Raynaud’s phenomenon, pain and numbness and conventional therapy such as calcium channel blockers was not effective. Patient 1 was a 46-year-old woman with systemic sclerosis (SSc) of an 11-year history of RP. Patient 2 was a 38-year-old man with SSc of a 7-year history of RP. Patient 3 was a 61-year-old woman with SSc of a 14-year history of RP. Patient 4 was a 28-year-old woman with mixed connective tissue disease (MCTD) of a 1-year history of RP. Patient 5 was a 67-year-old man with MCTD of a 13-year history of RP. Patient 6 was a 26-year-old woman with MCTD of a 19-year history of RP (Table 1). All patients were non-smoker. The dose of prednisolone for the underlying diseases was between 0 and 15 mg/day with a mean dose of 5 mg/day, and the dose was not changed for ≥3 months prior to start of the study (Table 1). None of them received other oral vasodilators. No other hormones including sex hormone derivatives were given. The participants received lactose in capsule as a placebo in a room whose temperature was fixed to 25 ± 1 °C and were kept at rest for 60 min. Then, skin temperatures were measured by thermography and used as pre-treatment values. The participants were given one of the 3 drugs, sildenafil 50 mg, vardenafil 10 mg, or tadalafil 10 mg, with their names undisclosed. The dose of each drug employed here was the same as that used for erectile dysfunction in men. The surface temperature of the fingertips was measured by thermography (TH3106ME; NEC San-ei Instruments, Tokyo, Japan) at 0, 60, and 120 min after oral administration of PDE-5I. The participants were advised not to take food before test to minimize food effect on drug absorption from intestine. Sildenafil, vardenafil, or tadalafil was tried in the same patient on different days, at least 3 days apart to prevent the effect of earlier drug. To observe the long-term effect of PDE-5I, 10 mg of vardenafil was administered daily for 12 weeks in Patients
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1, 2, and 6. For evaluation, the surface temperature of the fingertips was measured by thermography before and 12 weeks after administration. The ethics committee of Jichi Medical University approved this study, and all the participants gave us written consent to the short-term study. Only Patient 1, 2, and 6 gave us consent to the long-term study. Statistical analysis Statistical analysis was performed using the Wilcoxon signed rank test. A p value
Short Communication
Effects of phosphodiesterase type 5 inhibitors on Raynaud’s phenomenon Yasuyuki Kamata · Seiji Minota
Received: 1 March 2014 / Accepted: 13 April 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Raynaud’s phenomenon (RP) is commonly observed in fingers and toes of patients with connective tissue diseases (CTDs). However, existing vasodilators have very limited efficacy. In this study, phosphodiesterase type 5 inhibitors (PDE-5Is) were administered to evaluate efficacy on RP. Three patients with mixed connective tissue disease and three patients with systemic sclerosis having RP were enrolled. Oral sildenafil, vardenafil, or tadalafil was administered. The fingertip temperature was measured by thermography before and 120 min after administration. To evaluate longer effects, vardenafil was administered daily for 12 weeks; the fingertip temperature was measured by thermography before and 12 weeks after administration. As compared with the pre-administration of sildenafil, vardenafil, and tadalafil, the mean fingertip temperature increased by 2.17, 3.47, and 3.59 °C, respectively, in 120 min. In the 12-week trial with vardenafil in 3 patients, the mean fingertip temperature increased by 3.04, 7.96, and 3.32 °C from baseline in each patient. PDE-5Is significantly increased fingertip temperature within 120 min, and the effect of vardenafil lasted for 12 weeks under daily use. PDE-5Is were safe and would be an effective treatment for RP with CTDs. Keywords Connective tissue diseases · Raynaud’s phenomenon · Sildenafil · Tadalafil · Vardenafil
Y. Kamata (*) · S. Minota Division of Rheumatology and Clinical Immunology, Jichi Medical University, 3311‑1 Yakushiji, Shimotsuke‑shi, Tochigi‑ken 329‑0498, Japan e-mail: [email protected] S. Minota e-mail: [email protected]
Introduction Raynaud’s phenomenon (RP) is commonly observed in fingers and toes of patients with connective tissue diseases (CTDs). Without successful treatment, ulceration and necrosis often ensue and a mandatory amputation is not infrequent in severe cases [1]. Glucocorticoids and immunosuppressants are usually ineffective in this setting. Vasodilators such as calcium channel blockers and prostaglandins have been used most frequently in these patients [2–4]. However, these drugs have very limited effects. Nitric oxide produced in vascular endothelial cells plays an important role in vasodilation. Nitric oxide acts on vascular smooth muscle cells, activating guanylate cyclase and producing cyclic guanosine monophosphate (cGMP) from guanosine triphosphate. By activating cGMP-dependent protein kinase, cGMP induces relaxation in vascular smooth muscle and vasodilation. Phosphodiesterase type 5 (PDE-5) rapidly hydrolyzes cGMP to 5’GMP and terminates vasodilation. PDE-5 inhibitors (PDE-5Is) continue and enhance vasodilation by inhibiting hydrolysis of cGMP [5–7]. Because PDE-5 is abundant in vascular smooth muscle cells and lung tissues, it is highly probable that the administration of PDE-5Is induces vasodilation in lung, fingers, and toes [7–13]. In this study, PDE-5Is were administered in patients with RP associated with CTDs, and their effect was assessed by measuring surface temperatures of the fingers. This is a pilot study that compared three kinds of PDE-5 inhibitor (PDE-5I). Because this study was performed prospectively, the inclusion criteria were not so stringent and the number of the patients included was small.
13
Table 1 Clinical features of six patients
Rheumatol Int Patient
Age
Sex
Diagnosis
Duration of Raynaud’s phenomenon (years)
Prednisolone (mg/day)
1 2 3 4 5
46 38 61 28 67
F M F F M
SSc SSc SSc MCTD MCTD
11 7 14 1 13
0 15 0 5 10
6
26
F
MCTD
19
0
Patients and methods The six patients were all we treated with PDE-5I. No patient dropped out. All patients had Reynaud’s phenomenon more than several times daily. They were severe enough in Raynaud’s phenomenon, pain and numbness and conventional therapy such as calcium channel blockers was not effective. Patient 1 was a 46-year-old woman with systemic sclerosis (SSc) of an 11-year history of RP. Patient 2 was a 38-year-old man with SSc of a 7-year history of RP. Patient 3 was a 61-year-old woman with SSc of a 14-year history of RP. Patient 4 was a 28-year-old woman with mixed connective tissue disease (MCTD) of a 1-year history of RP. Patient 5 was a 67-year-old man with MCTD of a 13-year history of RP. Patient 6 was a 26-year-old woman with MCTD of a 19-year history of RP (Table 1). All patients were non-smoker. The dose of prednisolone for the underlying diseases was between 0 and 15 mg/day with a mean dose of 5 mg/day, and the dose was not changed for ≥3 months prior to start of the study (Table 1). None of them received other oral vasodilators. No other hormones including sex hormone derivatives were given. The participants received lactose in capsule as a placebo in a room whose temperature was fixed to 25 ± 1 °C and were kept at rest for 60 min. Then, skin temperatures were measured by thermography and used as pre-treatment values. The participants were given one of the 3 drugs, sildenafil 50 mg, vardenafil 10 mg, or tadalafil 10 mg, with their names undisclosed. The dose of each drug employed here was the same as that used for erectile dysfunction in men. The surface temperature of the fingertips was measured by thermography (TH3106ME; NEC San-ei Instruments, Tokyo, Japan) at 0, 60, and 120 min after oral administration of PDE-5I. The participants were advised not to take food before test to minimize food effect on drug absorption from intestine. Sildenafil, vardenafil, or tadalafil was tried in the same patient on different days, at least 3 days apart to prevent the effect of earlier drug. To observe the long-term effect of PDE-5I, 10 mg of vardenafil was administered daily for 12 weeks in Patients
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1, 2, and 6. For evaluation, the surface temperature of the fingertips was measured by thermography before and 12 weeks after administration. The ethics committee of Jichi Medical University approved this study, and all the participants gave us written consent to the short-term study. Only Patient 1, 2, and 6 gave us consent to the long-term study. Statistical analysis Statistical analysis was performed using the Wilcoxon signed rank test. A p value
