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1.
Int Heart J ; 61(2): 413-418, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32224603

RESUMO

Anticentriole autoantibodies-positive systemic sclerosis (SSc) has been reported to develop pulmonary arterial hypertension (PAH) at a high rate. In this report, we describe two patients with anticentriole antibodies-positive SSc-PAH who were treated with pulmonary vasodilators. Both cases were elderly women with poor physical conditions and clinical findings of SSc. Case 1 was resistant to combination therapy with pulmonary vasodilators; in Case 2, hemodynamic improvement was obtained by upfront combination therapy at an early stage. Because anticentriole antibodies-positive SSc-PAH rapidly deteriorates, careful hemodynamic observation and timely aggressive use of pulmonary vasodilators should be considered.


Assuntos
Anticorpos Antinucleares/imunologia , Centríolos/imunologia , Antagonistas dos Receptores de Endotelina/uso terapêutico , Escleroderma Sistêmico/imunologia , Vasodilatadores/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Bosentana/uso terapêutico , Cateterismo Cardíaco , Quimioterapia Combinada , Epoprostenol/análogos & derivados , Epoprostenol/uso terapêutico , Feminino , Volume Expiratório Forçado , Humanos , Mesilato de Imatinib/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , /etiologia , Capacidade de Difusão Pulmonar , Pirimidinas/uso terapêutico , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Citrato de Sildenafila/uso terapêutico , Sulfonamidas/uso terapêutico , Tadalafila/uso terapêutico , Tomografia Computadorizada por Raios X
2.
Clin Drug Investig ; 39(11): 1117-1123, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31435905

RESUMO

BACKGROUND: The orally active dual endothelin receptor antagonist aprocitentan targets a novel pathway in the treatment of hypertension and could be a key player in the treatment of salt/volume-dependent hypertension. Its pharmacokinetic profile supports a once-daily dosing strategy. OBJECTIVE: As hypertensive patients may also experience concomitant renal disease, the objectives of this study were to evaluate the pharmacokinetics and tolerability of aprocitentan in subjects with severe renal function impairment (SRFI) and compare these with matched healthy subjects. DESIGN, SETTING, PARTICIPANTS: In this open-label, single-center, phase 1 study (NCT03165071) eight subjects with SRFI (mean estimated glomerular filtration rate [eGFR] 21.9 mL/min/1.73 m2) and eight healthy subjects (mean eGFR 94.9 mL/min/1.73 m2) received a single dose of 50 mg of aprocitentan followed by an observation period of up to 17 days. Plasma pharmacokinetic parameters of aprocitentan were derived by noncompartmental analysis of the plasma concentration-time profiles. Differences in pharmacokinetic parameters were explored using geometric means ratio (GMR) and 90% confidence intervals (CIs) with SRFI subjects as test group and healthy subjects as reference group. Safety and tolerability evaluations included adverse events (AEs), electrocardiograms, vital signs, and clinical laboratory tests. RESULTS: All 16 subjects received aprocitentan and completed the study. The pharmacokinetics of aprocitentan were similar in SRFI and healthy subjects with maximum plasma concentrations reached at 7.6 h and 5.0 h, respectively. Maximum plasma concentrations did not differ as indicated by a GMR (90% CI) of 1.04 (0.85-1.28). Due to a slightly lower observed clearance in SRFI subjects, half-life was longer (53.2 h compared to 47.4 h in healthy subjects), while exposure expressed as area under the curve was 34% higher (GMR 90% CI 1.13-1.58). There were no differences in plasma protein binding (> 99% bound). Aprocitentan was well tolerated in subjects with SRFI with no notable difference compared to healthy subjects. CONCLUSIONS: Based on these single-dose results, subjects with mild, moderate, or severe renal function can be included in clinical studies without the need for dose adjustment.


Assuntos
Antagonistas dos Receptores de Endotelina/farmacocinética , Rim/efeitos dos fármacos , Pirimidinas/farmacocinética , Insuficiência Renal/metabolismo , Sulfonamidas/farmacocinética , Adulto , Antagonistas dos Receptores de Endotelina/uso terapêutico , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Humanos , Rim/fisiologia , Masculino , Pessoa de Meia-Idade , Pirimidinas/uso terapêutico , Insuficiência Renal/tratamento farmacológico , Sulfonamidas/uso terapêutico
3.
Heart Surg Forum ; 22(3): E213-E214, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31237545

RESUMO

BACKGROUND: Increased pulmonary vascular resistance index (PVR) leads to several complications in patients after a Fontan operation. This increase is mainly attributed to the overexpression of endothelin-1 for a long duration after the Fontan procedure. Here, we describe the case of a 3-year-old boy with a failed Fontan operation who was treated with bosentan, an endothelin-1 receptor blocker. CASE REPORT: Cardiac catheterization was performed, which showed a main pulmonary artery pressure (MPAP) of 19 mmHg and PVRI of 5.6 woods/m2. Oral bosentan regimen at a dose of 31.25 mg was initiated twice a day. The treatment was continued as pleural effusion and ascites persisted. No adverse events were observed, and the treatment was well tolerated. Pleural effusion disappeared, and ascites decreased markedly after 4 weeks, whereas the MPAP was 15 mmHg and the PVRI was 4.3 woods/m2. After 3 months of bosentan therapy, the MPAP was 12 mmHg and the PVRI was 4.1 woods/m2. CONCLUSION: We observed that bosentan reduces the PVRI and complications such as pleural effusion and ascites after a failed Fontan procedure.


Assuntos
Bosentana/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Técnica de Fontan/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Atresia Tricúspide/cirurgia , Resistência Vascular , Pré-Escolar , Humanos , Masculino , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/fisiopatologia , Falha de Tratamento , Atresia Tricúspide/complicações , Atresia Tricúspide/fisiopatologia
4.
Health Qual Life Outcomes ; 17(1): 103, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31200710

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) remains a life-threatening condition, despite modern therapies. We prospectively investigated the therapeutic health-related quality of life (HRQOL) effects of goal-oriented sequential combination therapy based on exercise capacity in patients newly diagnosed with PAH. METHODS: To examine the changes in HRQOL in PAH patients, we treated 30 patients newly diagnosed with PAH with goal-oriented sequential combination therapy based on exercise capacity. We monitored exercise capacity by cardiopulmonary exercise testing and observed the benefit of using a peak VO2 cut-off of 15 mL/kg/min to guide combination therapy. First-line treatment was an endothelin receptor antagonist (ERA); second-line treatment was the addition of a phosphodiesterase-5 inhibitor (PDE-5I). At baseline and at 3, 6, and 12 months, HRQOL was evaluated by using the eight-item Medical Outcomes Survey Short Form Health Survey. RESULTS: At 12 months, 100% of PAH patients were receiving an ERA, and 82% an ERA + PDE-5I. The mean physical component summary (PCS) score was 33.5 at baseline, 41.2 at 3 months, 40.8 at 6 months, and 42.0 at 12 months, and the mean mental component summary (MCS) scores were 45.6, 47.0, 50.0, and 50.1, respectively. PCS score was significantly greater at 3 months than at baseline (P = 0.035). MCS score was comparable at 3 months and at baseline, but was significantly greater at 6 and 12 months than at baseline (P = 0.033, P = 0.028, respectively). Thus, PCS score improved soon after initiation of therapy, and MCS score improved later. CONCLUSIONS: Together, these results suggest that goal-oriented sequential combination therapy based on exercise capacity improves HRQOL in patients with PAH.


Assuntos
Antagonistas dos Receptores de Endotelina/uso terapêutico , Exercício , Hipertensão Pulmonar , Inibidores da Fosfodiesterase 5/uso terapêutico , Qualidade de Vida , Adulto , Terapia Combinada , Tolerância ao Exercício , Feminino , Humanos , Hipertensão Pulmonar/psicologia , Hipertensão Pulmonar/terapia , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
5.
Medicine (Baltimore) ; 98(20): e15632, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31096477

RESUMO

BACKGROUND: It is commonly reported a limitation of therapeutic strategy in Eisenmenger syndrome (ES) historically. This qualitative systematic review is conducted to evaluate the safety and efficacy of pulmonary arterial hypertension-specific drug therapy (PAH-SDT) for ES patients for a clinical therapeutic strategy based on evidence. METHODS: PubMed, EMBASE, and the Cochrane Library databases have been systematically reviewed up to January 2019. Two reviewers independently conducted a literature search, quality evaluation, and data extraction. The occurrence of death, deterioration, and adverse events (AEs) has respectively been described as a count or percentage. Meta-analysis was conducted by Stata 15.1, and weighted mean differences (WMD) with 95% confidence intervals (CI) were recorded for continuous data. Randomized-effect model or fixed-effect model was applied according to the heterogeneity test. RESULTS: Fifteen citations recruiting 456 patients associated with ES were eventually pooled, which involved 4 RCTs, 6 prospective studies, and 5 retrospective studies. Within the first year, it indicated PAH-SDT significantly ameliorated exercise capacity in 6-minute walk distance (6MWD) (I = 60.5%; WMD: 53.86 m, 95% CI [36.59, 71.13], P < .001), functional class (FC) (WMD = -0.71, 95% CI [-0.98, -0.44], P < .001) and Borg dyspnea index (WMD = -1.28, 95% CI [-1.86, -0.70], P < .001), in addition to hemodynamics, especially mean pulmonary arterial pressure by 5.70 mmHg (WMD = -5.70 mmHg, 95% CI [-8.19, -3.22], P < .001) and pulmonary vascular resistance by 4.20 wood U (WMD: -4.20, 95% CI [-7.32, -1.09], P = .008), but unsatisfactory effects in oxygen saturation at exercise (P = .747). In a prolonged medication, bosentan, a dual ERA, has been proved acting an important role in improving exercise tolerance of patients with ES (6MWD: I = 47.5%; WMD: 88.68 m, 95% CI [54.05, 123.3], P < .001; FC: I = 0.0%; WMD = -0.65, 95% CI [-1.10, -0.19], P = .006). While a nonsignificant change of 6MWD was noted in a long-term therapy of ambrisentan (P = .385). There existed rare evidence about the efficacy and safety of macitentan, phosphodiesterase-5 inhibitors (PDE5i), and prostanoids in a prolonged medication. Most AEs were recorded as mild to moderate with PAH-SDT, but about 4.3% individuals treated with endothelin receptor antagonists (ERAs) suffered from serious ones, and 3.9% suffered from death. CONCLUSIONS: This systematic review and meta-analysis proved PAH-SDT as a safe and effective role in ES in an early stage. However, in a long-term treatment, bosentan has been supported for a lasting effect on exercise tolerance. A further multicenter research with a large sample about pharmacotherapy of ES is necessary.


Assuntos
Anti-Hipertensivos/uso terapêutico , Complexo de Eisenmenger/tratamento farmacológico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Inibidores da Fosfodiesterase 5/uso terapêutico , Prostaglandinas/uso terapêutico , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Bosentana/uso terapêutico , Antagonistas dos Receptores de Endotelina/administração & dosagem , Antagonistas dos Receptores de Endotelina/efeitos adversos , Tolerância ao Exercício/efeitos dos fármacos , Hemodinâmica , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Oxigênio/sangue , Fenilpropionatos/uso terapêutico , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Fosfodiesterase 5/efeitos adversos , Prostaglandinas/administração & dosagem , Prostaglandinas/efeitos adversos , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico
6.
Nagoya J Med Sci ; 81(1): 19-30, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30962652

RESUMO

Pulmonary hypertension (PH) is a hemodynamic state that is characterized by a resting mean pulmonary artery pressure ≧ 25 mmHg. The common forms of PH are pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), PH caused by left-heart disease, and PH due to lung disease. Previously regarded as untreatable, the treatment of PAH has dramatically advanced since the introduction of the drug epoprostenol in 1999, with three-year survival rates improving from 30%-40% to over 85%. Drugs available for the specific treatment of PAH include endothelin-receptor antagonists, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, prostacyclin analogs, and prostacyclin-receptor agonists. In the past decade, management and treatment of CTEPH have also improved. While pulmonary endarterectomy used to be the only option for the treatment of CTEPH, newer treatments include a soluble guanylate cyclase stimulator, which has proven to be an efficacious targeted therapy. Other cases benefit from balloon pulmonary angioplasty.


Assuntos
Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/fisiopatologia , Animais , Endarterectomia , Antagonistas dos Receptores de Endotelina/uso terapêutico , Humanos , Hipertensão Pulmonar/cirurgia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Embolia Pulmonar
9.
Trials ; 20(1): 164, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30871594

RESUMO

BACKGROUND: Axonal degeneration is related to long-term disability in patients with multiple sclerosis (MS). The underlying mechanism remains ill understood but appears to involve axonal energetic dysfunction. A globally impaired cerebral blood flow (CBF) has been observed in the normal-appearing white matter (NAWM) of patients with MS, which is probably related to astrocytic overexpression of endothelin-1 (ET-1). Cerebral hypoperfusion has been associated with reduced mitochondrial activity and disabling symptoms (e.g. fatigue and cognitive decline) of MS. Countering this process could therefore be beneficial in the disease course. Short-term CBF restoration with a single 62.5-mg dose of the ET-1 receptor antagonist bosentan has already been demonstrated in patients with MS. METHODS: The ROCHIMS study is a proof-of-concept double-blind randomized clinical trial in which patients with relapsing-remitting MS will receive either 62.5 mg bosentan or matching placebo twice daily during 28 ± 2 days. Clinical evaluation and brain magnetic resonance imaging (MRI) will be performed at baseline and treatment termination. Based on previous work, we expect a global increase of CBF in the individuals treated with bosentan. The primary outcome measure is the change of N-acetyl aspartate in centrum semiovale NAWM, which is a marker of regional axonal mitochondrial activity. Other parameters of interest include changes in fatigue, cognition, motor function, depression, and brain volume. DISCUSSION: We hypothesize that restoring cerebral hypoperfusion in MS patients improves axonal metabolism. Early positive effects on fatigue and cognitive dysfunction related to MS might additionally be detected. There is a medical need for drugs that can slow down the progressive axonal degeneration in MS, making this an important topic of interest. TRIAL REGISTRATION: Clinical Trials Register, EudraCT 2017-001253-13 . Registered on 15 February 2018.


Assuntos
Bosentana/uso terapêutico , Circulação Cerebrovascular/efeitos dos fármacos , Antagonistas dos Receptores de Endotelina/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Bélgica , Bosentana/efeitos adversos , Método Duplo-Cego , Antagonistas dos Receptores de Endotelina/efeitos adversos , Humanos , Imagem por Ressonância Magnética , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Esclerose Múltipla Recidivante-Remitente/psicologia , Estudo de Prova de Conceito , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia Doppler Transcraniana
10.
Ther Adv Respir Dis ; 13: 1753466618823440, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30736726

RESUMO

Macitentan (10 mg once daily orally), a dual endothelin receptor antagonist (ERA) developed by modifying the structure of bosentan to increase the efficacity and safety, is approved for the treatment of pulmonary arterial hypertension (PAH). The pivotal SERAPHIN trial, (a landmark trial in the history of PAH trials because of the large number of included patients, the long-term follow up and the first trial with morbidity/mortality as the primary endpoint) showed a reduction of the risk of a morbidity or mortality event by 45% over the treatment time compared with placebo. The positive effect on the primary endpoint was observed whether or not the patient was already on PAH therapy. There has been no direct comparison between macitentan and other ERAs, which were approved based on improved exercise capacity, but preclinical and clinical data suggest better pharmacological and safety profiles. Further analyses of the SERAPHIN trial investigated the predictive value of different indices and events on long-term outcome and mortality. The efficacy in children, the long-term effects and safety of macitentan and its place in combination therapy compared with other ERAs are still under investigation. This review presents the preclinical evidence of superiority of macitentan compared with other ERAs, and the available clinical trial data. The place of macitentan in the therapeutic algorithm for PAH treatment, post-marketing experience and future perspectives are discussed.


Assuntos
Antagonistas dos Receptores de Endotelina/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Antagonistas dos Receptores de Endotelina/efeitos adversos , Antagonistas dos Receptores de Endotelina/farmacologia , Tolerância ao Exercício/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/mortalidade , Hipertensão Pulmonar/fisiopatologia , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , Resultado do Tratamento
11.
Cochrane Database Syst Rev ; 1: CD012621, 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30701543

RESUMO

BACKGROUND: Pulmonary hypertension (PH) comprises a group of complex and heterogenous conditions, characterised by elevated pulmonary artery pressure, and which left untreated leads to right-heart failure and death. PH includes World Health Organisation (WHO) Group 1 pulmonary arterial hypertension (PAH); Group 2 consists of PH due to left-heart disease (PH-LHD); Group 3 comprises PH as a result of lung diseases or hypoxia, or both; Group 4 includes PH due to chronic thromboembolic occlusion of pulmonary vasculature (CTEPH), and Group 5 consists of cases of PH due to unclear and/or multifactorial mechanisms including haematological, systemic, or metabolic disorders. Phosphodiesterase type 5 (PDE5) inhibitors increase vasodilation and inhibit proliferation. OBJECTIVES: To determine the efficacy of PDE5 inhibitors for pulmonary hypertension in adults and children. SEARCH METHODS: We performed searches of CENTRAL, MEDLINE, Embase, CINAHL, and Web of Science up to 26 September 2018. We handsearched review articles, clinical trial registries, and reference lists of retrieved articles. SELECTION CRITERIA: We included randomised controlled trials that compared any PDE5 inhibitor versus placebo, or any other PAH disease-specific therapies, for at least 12 weeks. We include separate analyses for each PH group. DATA COLLECTION AND ANALYSIS: We imported studies identified by the search into a reference manager database. We retrieved the full-text versions of relevant studies, and two review authors independently extracted data. Primary outcomes were: change in WHO functional class, six-minute walk distance (6MWD), and mortality. Secondary outcomes were haemodynamic parameters, quality of life/health status, dyspnoea, clinical worsening (hospitalisation/intervention), and adverse events. When appropriate, we performed meta-analyses and subgroup analyses by severity of lung function, connective tissue disease diagnosis, and radiological pattern of fibrosis. We assessed the evidence using the GRADE approach and created 'Summary of findings' tables. MAIN RESULTS: We included 36 studies with 2999 participants (with pulmonary hypertension from all causes) in the final review. Trials were conducted for 14 weeks on average, with some as long as 12 months. Two trials specifically included children.Nineteen trials included group 1 PAH participants. PAH participants treated with PDE5 inhibitors were more likely to improve their WHO functional class (odds ratio (OR) 8.59, 95% confidence interval (CI) 3.95 to 18.72; 4 trials, 282 participants), to walk 48 metres further in 6MWD (95% CI 40 to 56; 8 trials, 880 participants), and were 22% less likely to die over a mean duration of 14 weeks (95% CI 0.07 to 0.68; 8 trials, 1119 participants) compared to placebo (high-certainty evidence). The number needed to treat to prevent one additional death was 32 participants. There was an increased risk of adverse events with PDE5 inhibitors, especially headache (OR 1.97, 95% CI 1.33 to 2.92; 5 trials, 848 participants), gastrointestinal upset (OR 1.63, 95% CI 1.07 to 2.48; 5 trials, 848 participants), flushing (OR 4.12, 95% CI 1.83 to 9.26; 3 trials, 748 participants), and muscle aches and joint pains (OR 2.52, 95% CI 1.59 to 3.99; 4 trials, 792 participants).Data comparing PDE5 inhibitors to placebo whilst on other PAH-specific therapy were limited by the small number of included trials. Those PAH participants on PDE5 inhibitors plus combination therapy walked 19.66 metres further in six minutes (95% CI 9 to 30; 4 trials, 509 participants) compared to placebo (moderate-certainty evidence). There were limited trials comparing PDE5 inhibitors directly with other PAH-specific therapy (endothelin receptor antagonists (ERAs)). Those on PDE5 inhibitors walked 49 metres further than on ERAs (95% CI 4 to 95; 2 trials, 36 participants) (low-certainty evidence). There was no evidence of a difference in WHO functional class or mortality across both treatments.Five trials compared PDE5 inhibitors to placebo in PH secondary to left-heart disease (PH-LHD). The quality of data were low due to imprecision and inconsistency across trials. In those with PH-LHD there were reduced odds of an improvement in WHO functional class using PDE5 inhibitors compared to placebo (OR 0.53, 95% CI 0.32 to 0.87; 3 trials, 285 participants), and those using PDE5 inhibitors walked 34 metres further compared to placebo (95% CI 23 to 46; 3 trials, 284 participants). There was no evidence of a difference in mortality. Five trials compared PDE5 inhibitors to placebo in PH secondary to lung disease/hypoxia, mostly in COPD. Data were of low quality due to imprecision of effect and inconsistency across trials. There was a small improvement of 27 metres in 6MWD using PDE5 inhibitors compared to placebo in those with PH due to lung disease. There was no evidence of worsening hypoxia using PDE5 inhibitors, although data were limited. Three studies compared PDE5 inhibitors to placebo or other PAH-specific therapy in chronic thromboembolic disease. There was no significant difference in any outcomes. Data quality was low due to imprecision of effect and heterogeneity across trials. AUTHORS' CONCLUSIONS: PDE5 inhibitors appear to have clear beneficial effects in group 1 PAH. Sildenafil, tadalafil and vardenafil are all efficacious in this clinical setting, and clinicians should consider the side-effect profile for each individual when choosing which PDE5 inhibitor to prescribe.While there appears to be some benefit for the use of PDE5 inhibitors in PH-left-heart disease, it is not clear based on the mostly small, short-term studies, which type of left-heart disease stands to benefit. These data suggest possible harm in valvular heart disease. There is no clear benefit for PDE5 inhibitors in pulmonary hypertension secondary to lung disease or chronic thromboembolic disease. Further research is required into the mechanisms of pulmonary hypertension secondary to left-heart disease, and cautious consideration of which subset of these patients may benefit from PDE5 inhibitors. Future trials in PH-LHD should be sufficiently powered, with long-term follow-up, and should include invasive haemodynamic data, WHO functional class, six-minute walk distance, and clinical worsening.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Adulto , Criança , Antagonistas dos Receptores de Endotelina/uso terapêutico , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/mortalidade , Números Necessários para Tratar , Inibidores da Fosfodiesterase 5/efeitos adversos , Placebos/uso terapêutico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Teste de Caminhada
12.
Hepatol Int ; 13(1): 25-39, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30302735

RESUMO

The process of wound healing in response to chronic liver injury leads to the development of liver fibrosis. Regardless of etiology, the profound impact of the degree of liver fibrosis on the prognosis of chronic liver diseases has been well demonstrated. While disease-specific therapy, such as treatments for viral hepatitis, has been shown to reverse liver fibrosis and cirrhosis in both clinical trials and real-life practice, subsets of patients do not demonstrate fibrosis regression. Moreover, where disease-specific therapies are not available, the need for antifibrotics exists. Increased understanding into the pathogenesis of liver fibrosis sets the stage to focus on antifibrotic therapies attempting to: (1) Minimize liver injury and inflammation; (2) Inhibit liver fibrogenesis by enhancing or inhibiting target receptor-ligand interactions or intracellular signaling pathways; and (3) Promote fibrosis resolution. While no antifibrotic therapies are currently available, a number are now being evaluated in clinical trials, and their use is becoming closer to reality for select subsets of patients.


Assuntos
Cirrose Hepática/tratamento farmacológico , Imunidade Adaptativa/fisiologia , Adipocinas/fisiologia , Amidas/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Antagonistas de Receptores de Canabinoides/uso terapêutico , Comunicação Celular/fisiologia , Transdiferenciação Celular/fisiologia , Senescência Celular/efeitos dos fármacos , Antagonistas dos Receptores de Endotelina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Epigênese Genética/fisiologia , Células Epiteliais/fisiologia , Matriz Extracelular/patologia , Galectinas/antagonistas & inibidores , Células Estreladas do Fígado/fisiologia , Humanos , Imunidade Inata/fisiologia , Integrinas/fisiologia , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , NF-kappa B/fisiologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/fisiologia , Piridinas/uso terapêutico , Receptores CCR/antagonistas & inibidores , Receptores de Canabinoides/fisiologia , Sistema Renina-Angiotensina/fisiologia , Transdução de Sinais/fisiologia , Receptores Toll-Like/fisiologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/fisiologia
13.
J Am Assoc Nurse Pract ; 31(1): 72-77, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30475252

RESUMO

BACKGROUND AND PURPOSE: Eisenmenger syndrome (ES) is a rare condition caused by a right-to-left cyanotic shunt. To date, only heart-lung transplant has been shown to be curative. Bosentan is the only medication studied with a double-blind placebo-controlled randomized trial for management of this condition. The intent of this article is to explore the literature surrounding bosentan in ES and assess its efficacy. METHODS: A literature review was conducted with no limitation on date. Titles were scanned for applicability, and abstracts of those articles found to be pertinent were reviewed. Those articles considered relevant based on the abstract were read in entirety. CONCLUSIONS: Eisenmenger syndrome remains incurable except through heart-lung transplant. Although no specific medical treatment or algorithm exists, three pharmacological classes show promise in disease management: endothelin receptor antagonists, phosphodiesterase inhibitors, and prostacyclins. Combined therapy with these agents may improve cardiopulmonary function. Bosentan has not been proven as a monotherapy for ES and is not appropriate in all patients as side effects are commonly reported. IMPLICATIONS FOR PRACTICE: Further study is required to assess efficacy of combination therapy and utilization as a bridge to transplant or surgical correction of the underlying defect.


Assuntos
Anti-Hipertensivos/uso terapêutico , Bosentana/uso terapêutico , Complexo de Eisenmenger/tratamento farmacológico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
Circulation ; 139(1): 51-63, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30586694

RESUMO

BACKGROUND: Eisenmenger syndrome describes congenital heart disease-associated severe pulmonary hypertension accompanied by right-to-left shunting. The multicenter, double-blind, randomized, placebo-controlled, 16-week, phase III MAESTRO study (Macitentan in Eisenmenger Syndrome to Restore Exercise Capacity) evaluated the efficacy and safety of the endothelin receptor antagonist macitentan in patients with Eisenmenger syndrome. METHODS: Patients with Eisenmenger syndrome aged ≥12 years and in World Health Organization functional class II-III were randomized 1:1 to placebo or macitentan 10 mg once daily for 16 weeks. Patients with complex cardiac defects, Down syndrome and background PAH therapy were eligible. The primary end point was change from baseline to week 16 in 6-minute walk distance. Secondary end points included change from baseline to week 16 in World Health Organization functional class. Exploratory end points included NT-proBNP (N-terminal pro-B-type natriuretic peptide) at end of treatment expressed as a percentage of baseline. In a hemodynamic substudy, exploratory end points included pulmonary vascular resistance index (PVRi) at week 16 as a percentage of baseline. RESULTS: Two hundred twenty six patients (macitentan n=114; placebo n=112) were randomized. At baseline, 60% of patients were in World Health Organization functional class II and 27% were receiving phosphodiesterase type-5 inhibitors. At week 16, the mean change from baseline in 6-minute walk distance was 18.3 m and 19.7 m in the macitentan and placebo groups (least-squares mean difference, -4.7 m; 95% confidence limit (CL), -22.8, 13.5; P=0.612). World Health Organization functional class improved from baseline to week 16 in 8.8% and 14.3% of patients in the macitentan and placebo groups (odds ratio, 0.53; 95% CL, 0.23, 1.24). NT-proBNP levels decreased with macitentan versus placebo (ratio of geometric means, 0.80; 95% CL, 0.68, 0.94). In the hemodynamic substudy (n=39 patients), macitentan decreased PVRi compared with placebo (ratio of geometric means, 0.87; 95% CL, 0.73, 1.03). The most common adverse events with macitentan versus placebo were headache (11.4 versus 4.5%) and upper respiratory tract infection (9.6 versus 6.3%); a hemoglobin decrease from baseline of ≥2 g/dL occurred in 36.0% versus 8.9% of patients. Five patients (3 macitentan; 2 placebo) prematurely discontinued treatment and 1 patient died (macitentan group). CONCLUSIONS: Macitentan did not show superiority over placebo on the primary end point of change from baseline to week 16 in exercise capacity in patients with Eisenmenger syndrome. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01743001.


Assuntos
Anti-Hipertensivos/uso terapêutico , Complexo de Eisenmenger/complicações , Antagonistas dos Receptores de Endotelina/uso terapêutico , Tolerância ao Exercício/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Artéria Pulmonar/efeitos dos fármacos , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/efeitos adversos , Biomarcadores/sangue , Criança , Método Duplo-Cego , Síndrome de Down/complicações , Complexo de Eisenmenger/diagnóstico por imagem , Complexo de Eisenmenger/fisiopatologia , Antagonistas dos Receptores de Endotelina/efeitos adversos , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Artéria Pulmonar/fisiopatologia , Pirimidinas/efeitos adversos , Recuperação de Função Fisiológica , Sulfonamidas/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Teste de Caminhada , Adulto Jovem
15.
World Neurosurg ; 123: 418-424.e3, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30508597

RESUMO

OBJECTIVE: Clazosentan, an endothelin receptor antagonist, reduced vasospasm and delayed ischemic neurologic deficit (DIND) but did not improve outcome after subarachnoid hemorrhage (SAH) in clinical trials. However, a lack of dose-dependent analysis and potential overestimation of clazosentan's effect are concerning. We used stratified analysis and trial sequential analysis (TSA) of existing data to investigate the effects of clazosentan on SAH outcome. METHODS: Studies from PubMed, Embase, and Cochrane were reviewed for eligibility. Primary outcomes were DIND requiring rescue therapy, all-cause mortality, and vasospasm-related morbidity at 6 weeks. Secondary outcomes were moderate-to-severe angiographic vasospasm, new cerebral infarction, and poor clinical outcome at 3 months. TSA was performed to assess the required information size and the α-spending monitoring boundary effect of relative risk (RR) reduction. A stratified analysis of clazosentan dosage was performed. RESULTS: Five studies (N = 2317) were included. Clazosentan significantly reduced the risk of DIND requiring rescue therapy (RR, 0.625; 95% confidence interval [CI], 0.462-0.846) and vasospasm (RR, 0.543; 95% CI, 0.464-0.635), but did not significantly affect mortality or vasospasm-related morbidity (RR, 0.775; 95% CI, 0.578-1.039), new cerebral infarction (RR, 0.604; 95% CI, 0.383-0.952), or outcome (RR, 1.131; 95% CI, 0.959-1.334). TSA revealed that the studies were underpowered to evaluate the effects of clazosentan on mortality and vasospasm-associated morbidity. We found 10-15 mg/h of clazosentan administration was associated with lower rates of vasospasm and new cerebral infarctions compared with 5 mg/h. CONCLUSIONS: Clazosentan reduced the risk of DIND requiring rescue therapy and moderate-to-severe vasospasm. Further meta-analyses based on individual patient data with different clazosentan doses and more refined outcome measures are necessary to clarify clazosentan's efficacy in improving post-SAH outcome.


Assuntos
Dioxanos/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Hemorragia Subaracnóidea/tratamento farmacológico , Sulfonamidas/uso terapêutico , Tetrazóis/uso terapêutico , Bases de Dados Bibliográficas/estatística & dados numéricos , Humanos , Resultado do Tratamento
16.
Can Respir J ; 2018: 1015239, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30581511

RESUMO

Objectives: Although many studies have reported on the cost-effectiveness of bosentan for treating pulmonary arterial hypertension (PAH), a systematic review of economic evaluations of bosentan is currently lacking. Objective evaluation of current pharmacoeconomic evidence can assist decision makers in determining the appropriate place in therapy of a new medication. Methods: Systematic literature searches were conducted in English-language databases (MEDLINE, EMBASE, EconLit databases, and the Cochrane Library) and Chinese-language databases (China National Knowledge Infrastructure, WanFang Data, and Chongqing VIP) to identify studies assessing the cost-effectiveness of bosentan for PAH treatments. Results: A total of 8 published studies were selected for inclusion. Among them were two studies comparing bosentan with epoprostenol and treprostinil. Both results indicated that bosentan was more cost-effective than epoprostenol, while the results of bosentan and treprostinil were not consistent. Four studies compared bosentan with other endothelin receptor antagonists, which indicated ambrisentan might be the drug of choice for its economic advantages and improved safety profile. Only two economic evaluations provided data to compare bosentan versus sildenafil, and the results favored the use of sildenafil in PAH patients. Four studies compared bosentan with conventional, supportive, or palliative therapy, and whether bosentan was cost-effective was uncertain. Conclusions: Bosentan may represent a more cost-effective option compared with epoprostenol and conventional or palliative therapy. There was unanimous agreement that bosentan was not a cost-effective front-line therapy compared with sildenafil and other endothelin receptor antagonists. However, high-quality cost-effectiveness analyses that utilize long-term follow-up data and have no conflicts of interest are still needed.


Assuntos
Bosentana/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Anti-Hipertensivos/economia , Anti-Hipertensivos/uso terapêutico , Bosentana/economia , Análise Custo-Benefício , Antagonistas dos Receptores de Endotelina/economia , Epoprostenol/análogos & derivados , Epoprostenol/uso terapêutico , Humanos , Fenilpropionatos/economia , Fenilpropionatos/uso terapêutico , Piridazinas/economia , Piridazinas/uso terapêutico , Citrato de Sildenafila/uso terapêutico , Vasodilatadores/economia , Vasodilatadores/uso terapêutico
17.
Swiss Med Wkly ; 148: w14677, 2018 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-30378090

RESUMO

BACKGROUND: Sarcoidosis is a disorder of unknown aetiology. Most patients have steroid-responsive disease, but side effects and steroid resistance may necessitate alternative treatments. Endothelin has in-vitro fibrogenic activity and the endothelin system is activated in sarcoidosis. OBJECTIVES: We studied the efficacy and safety of the endothelin receptor antagonist bosentan in sarcoidosis patients. METHODS: In a prospective 12-month, double-blind, 1:1-randomised, placebo-controlled phase II trial, we assessed the effect of bosentan in patients with steroid-resistant sarcoidosis and with impaired exercise capacity and/or resting lung function. Primary endpoints were safety and overall response rate of total lung capacity, diffusion capacity, peak oxygen uptake, 6-minute walking distance and chest computed tomography score. Secondary endpoints included adverse events and quality of life. MAIN RESULTS: Twenty patients were randomised. Three patients discontinued the study medication prematurely. No serious drug-related adverse events occurred. At 12 months no statistically significant differences were observed in the primary endpoints including total lung capacity, diffusion capacity, 6-minute walking distance, peak oxygen uptake, and computed tomography-score. Sixty-three percent of the patients treated with bosentan showed an increase of 10% in at least one of the primary endpoints, compared with 67% in the placebo group (p = 1). CONCLUSIONS: There is no evidence to support efficacy of bosentan as an antifibrotic treatment for patients with steroid-resistant pulmonary sarcoidosis. Bosentan was well tolerated and no drug-related adverse effects were observed within the study population. TRIAL REGISTRATION: ISRCTN registry, ISRCTN73579020.


Assuntos
Bosentana/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Testes de Função Respiratória/estatística & dados numéricos , Sarcoidose Pulmonar/tratamento farmacológico , Adulto , Método Duplo-Cego , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Oxigênio/análise , Estudos Prospectivos , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Resultado do Tratamento
18.
Vasc Health Risk Manag ; 14: 253-264, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30323613

RESUMO

Pulmonary arterial hypertension, a disease largely neglected until a few decades ago, is presently the object of intense studies by several research teams. Despite considerable progress, pulmonary arterial hypertension remains a major clinical problem, because it is not always easy to diagnose, treat, and prevent. The disease was considered incurable until the late 1990s, when Epoprostenol was introduced as the first tool against this illness. More recently, therapy for pulmonary arterial hypertension gained momentum after publication of the SERAPHIN and AMBITION trials, which also highlighted the importance of upfront therapy. This review also focuses on recent substudies from these trials and progress in drugs targeting the endothelin pathway. Future perspectives with regard to endothelin-receptor antagonists are also discussed.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Antagonistas dos Receptores de Endotelina/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Artéria Pulmonar/efeitos dos fármacos , Receptores de Endotelina/efeitos dos fármacos , Animais , Anti-Hipertensivos/efeitos adversos , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Antagonistas dos Receptores de Endotelina/efeitos adversos , Endotelinas/metabolismo , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/fisiopatologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Receptores de Endotelina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
20.
Clin Dermatol ; 36(4): 498-507, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30047433

RESUMO

Raynaud's phenomenon (RP) is a transient, acral, vasospastic phenomenon that manifests with characteristic color changes. This vasospasm, classically triggered by cold temperatures, may also be driven by shifts in temperature, climate, or emotional state. Primary RP (PRP) is a common condition without severe sequelae. Secondary RP (SRP), which may be driven by vascular, autoimmune, hematologic, or endocrine etiologies, can result in digital ulceration, irreversible ischemia and necrosis, and secondary infection. This review delineates the clinical manifestations of both primary and secondary RP, as well as the current understanding of RP epidemiology and pathogenesis. Proper examination, including nailfold capillary microscopy, and laboratory workup for secondary causes of RP are also discussed. The traditional armamentarium of therapies used for RP, as well as newer medical and surgical options, is also summarized with particular regard to the clinical evidence for their efficacy.


Assuntos
Doença de Raynaud/diagnóstico , Doença de Raynaud/terapia , Administração Cutânea , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anticoagulantes/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Toxinas Botulínicas Tipo A/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Epoprostenol/uso terapêutico , Humanos , Hipertermia Induzida , Fármacos Neuromusculares/uso terapêutico , Nitroglicerina/administração & dosagem , Educação de Pacientes como Assunto , Inibidores da Fosfodiesterase 5/uso terapêutico , Doença de Raynaud/complicações , Doença de Raynaud/epidemiologia , Inibidores de Captação de Serotonina/uso terapêutico , Simpatectomia , Vasodilatadores/uso terapêutico
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