sildenafil-citrate and Connective-Tissue-Diseases

Pulmonary hypertension (PH) is a common complication of connective tissue disease. While there are no reliable epidemiological data, the prevalence of systemic sclerosis (SSc) has been estimated as being 8-12%. Mixed connective tissue disease (MCTD) and systemic lupus erythematodes (SLE) are thought to have a lower prevalence. PH associated with SSc has a poor prognosis, a two-year survival rate of approximately 50%, if untreated. Systematic literature search for studies of PH and CTD between 02/2007 and 02/2008 found 38 articles, a selection of which is reviewed here. One epidemiological study showed that nowadays PH is together with interstitial pulmonary fibrosis the most common cause of death in patients with SSc. Before the introduction of angiotensin- converting enzyme inhibitors the most frequent cause of death was acute renal crisis. Investigations of the pathogenesis of PH in CTD revealed that in patients with a severe, treatment-resistant course there is frequent histological evidence of pulmonary veno-occlusive disease. A prospective study on diagnosis revealed that transthoracic echocardiography (TTE) is better than magnetic resonance imaging or pulmonary function tests especially in screening for PH in patients with SSc, because of its high specificity and good predictive value at higher pulmonary pressures. But because of the low sensitivity of TTE right heart catheterization is the gold standard for verifying PH also in patients with SSc. A therapeutic uncontrolled trial indicated that treatment with bosentan combined with sildenafil results in clinical stabilization, but patients with idiopathic PHT responded better.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Connective Tissue Diseases; Drug Therapy, Combination; Echocardiography; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging; Piperazines; Prevalence; Prognosis; Purines; Respiratory Function Tests; Sensitivity and Specificity; Sildenafil Citrate; Sulfonamides; Sulfones; Survival Rate; Vasodilator Agents

Pulmonary arterial hypertension associated with connective tissue disease (PAH-CTD) is difficult to manage, and has a poor prognosis. The phosphodiesterase-5 inhibitor sildenafil citrate enhances vasodilatation, has antiproliferative effects, and is effective in the treatment of PAH. We examined the efficacy and safety of oral sildenafil in patients with PAH-CTD.. In a 12-week, double-blind study (SUPER-1), 278 patients with PAH were randomized to oral placebo, sildenafil 20 mg, sildenafil 40 mg, or sildenafil 80 mg 3 times daily (tid). In a post-hoc subgroup analysis of 84 patients with PAH-CTD, exercise capacity, hemodynamic measures, World Health Organization functional class, and tolerability were assessed.. Forty-five percent of the patients had scleroderma, 23% had systemic lupus erythematosus, and the rest (32%) were categorized as other. Patients were predominantly functional class II (38%) or III (61%) at baseline. Sildenafil-treated patients exhibited mean increases in 6-minute walk distance at Week 12 of 42 m (95% CI 20, 64) for 20 mg, 36 m (95% CI 14, 58) for 40 mg, and 15 m (95% CI -24, 54) for 80 mg, while placebo-treated patients exhibited a mean decrease of 13 m (95% CI -36, 10). Improvement of at least 1 functional class occurred in 29%-42% of sildenafil-treated patients, compared to 5% for placebo. Significant improvements in mean pulmonary arterial pressure and pulmonary vascular resistance were observed with sildenafil 20 mg, and sildenafil was generally well tolerated.. In patients with PAH-CTD, sildenafil improves exercise capacity, hemodynamic measures (at the 20 mg dose), and functional class after 12 weeks of treatment.

Topics: Adult; Aged; Connective Tissue Diseases; Double-Blind Method; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Vasodilatory therapy of Raynaud's phenomenon represents a difficult clinical problem because treatment often remains inefficient and may be not tolerated because of side effects.. To investigate the effects of sildenafil on symptoms and capillary perfusion in patients with Raynaud's phenomenon, we performed a double-blinded, placebo-controlled, fixed-dose, crossover study in 16 patients with symptomatic secondary Raynaud's phenomenon resistant to vasodilatory therapy. Patients were treated with 50 mg sildenafil or placebo twice daily for 4 weeks. Symptoms were assessed by diary cards including a 10-point Raynaud's Condition Score. Capillary flow velocity was measured in digital nailfold capillaries by means of a laser Doppler anemometer. While taking sildenafil, the mean frequency of Raynaud attacks was significantly lower (35+/-14 versus 52+/-18, P=0.0064), the cumulative attack duration was significantly shorter (581+/-133 versus 1046+/-245 minutes, P=0.0038), and the mean Raynaud's Condition Score was significantly lower (2.2+/-0.4 versus 3.0+/-0.5, P=0.0386). Capillary blood flow velocity increased in each individual patient, and the mean capillary flow velocity of all patients more than quadrupled after treatment with sildenafil (0.53+/-0.09 versus 0.13+/-0.02 mm/s, P=0.0004). Two patients reported side effects leading to discontinuation of the study drug.. Sildenafil is an effective and well-tolerated treatment in patients with Raynaud's phenomenon.

Topics: Adult; Aged; Blood Flow Velocity; Connective Tissue Diseases; Cross-Over Studies; Double-Blind Method; Drug Resistance; Female; Humans; Male; Middle Aged; Patient Selection; Piperazines; Purines; Raynaud Disease; Scleroderma, Systemic; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilation; Vasodilator Agents

Hemodynamic assessment during exercise may unmask an impaired functional reserve of the right ventricle and the pulmonary vasculature in patients with connective tissue disease. We assessed the effect of intravenous sildenafil on the hemodynamic response to exercise in patients with connective tissue disease.. In this proof-of-concept study, patients with connective tissue disease and mean pulmonary arterial pressure (mPAP) >20 mm Hg were subjected to a supine exercise hemodynamic evaluation before and after administration of intravenous sildenafil 10 mg.. Ten patients (four with moderately elevated mPAP 21-24 mm Hg; six with mPAP >25 mm Hg) underwent hemodynamic assessment. All of them showed markedly abnormal exercise hemodynamics. Intravenous sildenafil was well tolerated and had significant hemodynamic effects at rest and during exercise, although without pulmonary selectivity. Sildenafil reduced median total pulmonary resistance during exercise from 6.22 (IQR 4.61-8.54) to 5.24 (3.95-6.96) mm Hg·min·L-1 (p = 0.005) and increased median pulmonary arterial capacitance during exercise from 1.59 (0.93-2.28) to 1.74 (1.12-2.69) mL/mm Hg (p = 0.005).. In patients with connective tissue disease who have an abnormal hemodynamic response to exercise, intravenous sildenafil improved adaption of the right ventricular-pulmonary vascular unit to exercise independent of resting mPAP. The impact of acute pharmacological interventions on exercise hemodynamics in patients with pulmonary vascular disease warrants further investigation.. Clinicaltrials.gov NCT01889966.

Topics: Aged; Arterial Pressure; Connective Tissue Diseases; Exercise; Exercise Test; Female; Hemodynamics; Humans; Injections, Intravenous; Male; Middle Aged; Sildenafil Citrate; Vasodilator Agents

Raynaud's phenomenon is a microvascular disorder that results in exaggerated vasoconstriction over vasodilatation secondary to an alteration in autonomic control. Though benign, it can result in severe ulceration and ultimately gangrene associated with disfiguration and permanent deformity. We present a case of severe secondary Raynaud's phenomenon in a black-African patient from a resource-limited setting, with focus on the difficulties encountered in the diagnosis and treatment.. A 43-year-old female Cameroonian farmer with a 7-year history of episodic paresthesia in her fingers and toes (when exposed to cold) presented to our emergency department with severe pain, ulceration, and "darkening" of her fingertips over a period of 2 days. An examination revealed bilateral ulceration and dry gangrene of her fingers and toes, based on which a diagnosis of secondary Raynaud's phenomenon due to a connective tissue disease was proposed. Results of paraclinical investigations were normal. Lifestyle modification along with a calcium channel blocker and phosphodiesterase type 5 inhibitor provided significant relief.. An early diagnosis and knowledge on appropriate treatment of Raynaud's phenomenon is of vital importance to prevent permanent tissue damage and disability. Relying on biphasic color change for the diagnosis of Raynaud's phenomenon in black Africans can be potentially misleading.

Topics: Adult; Analgesics, Opioid; Anti-Bacterial Agents; Black People; Calcium Channel Blockers; Cloxacillin; Connective Tissue Diseases; Directive Counseling; Female; Fingers; Gangrene; Humans; Life Style; Microcirculation; Nifedipine; Phosphodiesterase 5 Inhibitors; Raynaud Disease; Risk Reduction Behavior; Severity of Illness Index; Sildenafil Citrate; Toes; Tramadol; Treatment Outcome

Pulmonary arterial hypertension (PAH) can be a complication in patients with connective tissue disease (CTD). Although the phosphodiesterase-5 inhibitor sildenafil shows evidence of efficacy and tolerability among patients with PAH associated with CTD in clinical trials, no studies have examined the association between its use and health care resource utilization in clinical practice. The objective of this study was to assess the associations between the use of sildenafil and health care resource utilization, specifically days of hospitalization, in a population with PAH associated with CTD.. A retrospective, matched, case-control analysis was conducted using data from a commercial claims database. Patients with a claim dated between 2003 and 2009 were selected. Cases and controls were matched on age, sex, and baseline total days of hospitalization. A longitudinal, zero-inflated, negative binomial model was used for analyzing the data after control for age, sex, region, Charlson comorbidity score, and use of PAH-specific medication other than sildenafil.. A total of 420 individuals, 210 cases and 210 controls, were included in the sample. The sample was 85.71% women, and the mean age was 57.6 years. Estimates for variances of an intercept random effect (5.08 × 10(-13)) and for a time-variable random effect (2.84 × 10(-16)) were both essentially zero. Thus a zero-inflated negative binomial model without random effects was used. When individuals were not using sildenafil, each 1-month interval was associated with a 2.8% increase in the mean number of days of hospitalization. In contrast, when individuals were using sildenafil, each 1-month interval was associated with a decrease of 3.3% in days of hospitalization.. In this data analysis of the association between sildenafil use and days of hospitalization among individuals with PAH associated with CTD in a large-scale population, sildenafil use in the treatment of PAH associated with CTD was associated with reduced days of hospitalization during the year after the initiation of treatment.

Topics: Adult; Aged; Connective Tissue Diseases; Female; Health Resources; Hospitalization; Humans; Hypertension, Pulmonary; Length of Stay; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Retrospective Studies; Sildenafil Citrate; United States; Vasodilator Agents

Pulmonary arterial hypertension is a severe disease with a complex pathogenesis, for which combination therapy is an attractive option.This study aimed to assess the impact of sequential combination therapy on both short-term responses and long-term outcomes in a real-world setting.Patients with idiopathic/heritable pulmonary arterial hypertension, or pulmonary arterial hypertension associated with congenital heart disease or connective tissue disease and who were not meeting treatment goals on either first-line bosentan or sildenafil monotherapy, were given additional sildenafil or bosentan and assessed after 3-4 months. Double combination therapy significantly improved clinical and haemodynamic parameters, independent of aetiology or the order of drug administration. Significant improvements in functional class were observed in patients with idiopathic/heritable pulmonary arterial hypertension. The 1-, 3- and 5-year overall survival estimates were 91%, 69% and 59%, respectively. Patients with pulmonary arterial hypertension associated with connective tissue disease had significantly poorer survival rates compared to other aetiologies (p<0.003).The favourable short-term haemodynamic results and good survival rates, observed in patients receiving both bosentan and sildenafil, supports the use of sequential combination therapy in patients failing on monotherapy in a real-world setting.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Bosentan; Cause of Death; Child; Connective Tissue Diseases; Drug Therapy, Combination; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Italy; Kaplan-Meier Estimate; Male; Middle Aged; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Survival Rate; Treatment Outcome; Vasodilator Agents; Young Adult

To investigate the effect of sildenafil on the survival of patients with pulmonary arterial hypertension (PAH) associated with connective tissue diseases (CTD), who have been followed up at the Rheumatology Expert Center.. A total of 16 patients (all women) with PAH associated with CTD, who had been admitted to the V. A. Nasonova Research Institute of Rheumatology in 2013-2015, were examined. PAH corresponded to Functional Class II in the majority of the patients. After the diagnosis was verified by catheterization of the right heart and pulmonary artery, all the patients received original sildenafil (a phosphodiesterase type 5 inhibitor, a potent vasodilator, the efficiency of which was proven in patients with PAH) at a dose of 20 mg thrice daily. Survival rates and time to clinical deterioration were estimated during a prospective follow-up).. Three-year survival rates were 94% in the study group and 25% in the group of historical control (p < 0.05). The time to clinical deterioration was associated with the duration of the follow-up and hemodynamic parameters (right atrial pressure and changes in vascular resistance within 4 months after therapy initiation).. The administration of sildenafil substantially improves survival in patients with PAH associated with CTD as compared with the historical control. The identification of poor prognostic factors in this cohort of patients and early diagnosis will favor the personification of therapy for the fatal manifestation of CTD.. Цель исследования. Изучить влияние силденафила на выживаемость пациентов с легочной артериальной гипертонией (ЛАГ), ассоциированной с системными заболеваниями соединительной ткани (СЗСТ), наблюдаемыми в ревматологическом экспертном центре. Материалы и методы. Обследовали 16 женщин с ЛАГ-СЗСТ, госпитализированных в ФГБНУ НИИР им. В.А.Насоновой в 2013-2015 гг. У большинства ЛАГ соответствовала II функциональному классу. После подтверждения диагноза при катетеризации правых отделов сердца и легочной артерии все пациентки получали оригинальный силденафил (ингибитор фосфодиэстеразы 5-го типа, мощный вазодилататор, эффективность которого доказана у пациентов с ЛАГ) 20 мг 3 раза в день. В процессе проспективного наблюдения оценивали выживаемость и время наступления клинического ухудшения. Результаты. Трехлетняя выживаемость в обследуемой группе составила 94%, в то время как в группе 'исторического' контроля - 25% (р<0,05). Время до наступления клинического ухудшения связано с длительностью наблюдения и гемодинамическими параметрами (давление в правом предсердии и динамика легочного сосудистого сопротивления в течение 4 мес от начала терапии). Заключение. Применение силденафила существенно улучшает выживаемость пациенток ЛАГ-СЗСТ по сравнению с 'историческим' контролем. Выявление факторов неблагоприятного прогноза у данной категории больных, а также ранняя диагностика будут способствовать персонификации терапии этого фатального проявления СЗСТ.

Topics: Adult; Aged; Comorbidity; Connective Tissue Diseases; Female; Humans; Hypertension, Pulmonary; Middle Aged; Phosphodiesterase 5 Inhibitors; Prospective Studies; Sildenafil Citrate; Treatment Outcome