RESUMEN
The term pulmonary arterial hypertension comprises a group of pulmonary vascular diseases of different etiologies that are characterized by similar precapillary vascular remodeling processes and result in exertional dyspnea and right heart insufficiency. The specific pharmacological treatment approach considers the risk of mortality and phenotypical properties and includes treatment with phosphodiesterase type 5 inhibitors, endothelin receptor antagonists and prostanoids, as well as with more novel substances, such as a soluble guanylyl cyclase stimulator and an oral prostacyclin receptor agonist. The prognosis of the disease is mainly determined by the right heart insufficiency for which there is currently no specific pharmacological treatment. Lung transplantation may be offered as a last option. This review provides an overview of the current European guidelines from 2015 and the recommendations of the Cologne Consensus Conference for pulmonary hypertension from 2016.
Asunto(s)
Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/tratamiento farmacológico , Antihipertensivos/efectos adversos , Antihipertensivos/uso terapéutico , Disnea/diagnóstico , Disnea/tratamiento farmacológico , Disnea/etiología , Antagonistas de los Receptores de Endotelina/efectos adversos , Antagonistas de los Receptores de Endotelina/uso terapéutico , Guanilato Ciclasa , Humanos , Hipertensión Pulmonar/etiología , Inhibidores de Fosfodiesterasa 5/efectos adversos , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Pronóstico , Prostaglandinas/efectos adversos , Prostaglandinas/uso terapéutico , Receptores de Epoprostenol/agonistas , Factores de Riesgo , Remodelación Vascular/fisiología , Disfunción Ventricular Derecha/diagnóstico , Disfunción Ventricular Derecha/tratamiento farmacológico , Disfunción Ventricular Derecha/etiologíaRESUMEN
Pulmonary hypertension (PH) is a chronic progressive disease of the pulmonary circulation of multifactorial causes. The current diagnostic classification of PH distinguishes five main groups, which have as a common feature an increased pulmonary arterial pressure and pulmonary resistance. The classification differentiates pulmonary arterial hypertension (PAH), PH due to left heart disease, PH in lung diseases and/or hypoxia, chronic thromboembolic pulmonary hypertension (CTEPH), and PH with unclear/multifactorial mechanisms. Recent advances in basic research with the approval of new drugs and the establishment of therapeutic strategies, mainly in PAH and CTEPH, require a differentiated view of the disease, a careful diagnosis and initiation of therapy, and regular follow-ups. In this article, we provide an overview of the complex drug therapy currently available for PAH patients.
Asunto(s)
Antihipertensivos/administración & dosificación , Antagonistas de los Receptores de Endotelina/administración & dosificación , Hipertensión Pulmonar/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5/administración & dosificación , Prostaglandinas/administración & dosificación , Receptores Citoplasmáticos y Nucleares/agonistas , Medicina Basada en la Evidencia , Guanilato Ciclasa , Humanos , Hipertensión Pulmonar/diagnóstico , Guanilil Ciclasa Soluble , Resultado del TratamientoRESUMEN
Lung cancer is the leading cause of cancer death worldwide. Recent data suggest that cyclic nucleotide phosphodiesterases (PDEs) are relevant in various cancer pathologies. Pathophysiological role of phosphodiesterase 4 (PDE4) with possible therapeutic prospects in lung cancer was investigated. We exposed 10 different lung cancer cell lines (adenocarcinoma, squamous and large cell carcinoma) to hypoxia and assessed expression and activity of PDE4 by real-time PCR, immunocytochemistry, western blotting and PDE activity assays. Expression and activity of distinct PDE4 isoforms (PDE4A and PDE4D) increased in response to hypoxia in eight of the studied cell lines. Furthermore, we analyzed various in silico predicted hypoxia-responsive elements (p-HREs) found in in PDE4A and PDE4D genes. Performing mutation analysis of the p-HRE in luciferase reporter constructs, we identified four functional HRE sites in the PDE4A gene and two functional HRE sites in the PDE4D gene that mediated hypoxic induction of the reporter. Silencing of hypoxia-inducible factor subunits (HIF1α and HIF2α) by small interfering RNA reduced hypoxic induction of PDE4A and PDE4D. Vice versa, using a PDE4 inhibitor (PDE4i) as a cyclic adenosine monophosphate (cAMP) -elevating agent, cAMP analogs or protein kinase A (PKA)-modulating drugs and an exchange protein directly activated by cAMP (EPAC) activator, we demonstrated that PDE4-cAMP-PKA/EPAC axis enhanced HIF signaling as measured by HRE reporter gene assay, HIF and HIF target genes expression ((lactate dehydrogenase A), LDHA, (pyruvate dehydrogenase kinase 1) PDK1 and (vascular endothelial growth factor A) VEGFA). Notably, inhibition of PDE4 by PDE4i or silencing of PDE4A and PDE4D reduced human lung tumor cell proliferation and colony formation. On the other hand, overexpression of PDE4A or PDE4D increased human lung cancer proliferation. Moreover, PDE4i treatment reduced hypoxia-induced VEGF secretion in human cells. In vivo, PDE4i inhibited tumor xenograft growth in nude mice by attenuating proliferation and angiogenesis. Our findings suggest that PDE4 is expressed in lung cancer, crosstalks with HIF signaling and promotes lung cancer progression. Thus, PDE4 may represent a therapeutic target for lung cancer therapy.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/fisiología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias Pulmonares/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , AMP Cíclico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Humanos , Ratones , Ratones Desnudos , Inhibidores de Fosfodiesterasa 4/farmacología , ARN Interferente Pequeño/farmacología , Transducción de Señal/efectos de los fármacos , Trasplante HeterólogoRESUMEN
Inflammation underlies a wide variety of physiological and pathological processes. Acute inflammation is the initial response of the body to harmful stimuli. Chronic inflammation, by contrast, is a prolonged, dysregulated and maladaptive response that involves active inflammation, tissue destruction and attempts at tissue repair. Over the past few years, such persistent inflammation has been shown to be associated with pulmonary hypertension (PH). Substantial advances in basic and experimental science have illuminated the role of inflammation and the underlying cellular and molecular mechanisms that contribute to PH. This review summarizes the experimental and clinical evidence for inflammation in various types of PH. In addition, it assesses the current state of knowledge regarding the inducers/triggers of chronic inflammation and infection, as well as the inflammatory mediators and cells that are involved in PH. Infiltration of inflammatory cells, such as dendritic cells, macrophages, mast cells, T-lymphocytes and B-lymphocytes, in the vascular lesions and an elevation of serum/tissue concentrations of proinflammatory cytokines and chemokines and their contribution to pulmonary vascular remodelling are reported in detail. We review the data supporting the use of inflammatory markers as prognostic and predictive factors in PH. Finally, we consider how new insights into inflammation in PH may identify innovative therapeutic strategies.
Asunto(s)
Enfermedades Transmisibles/complicaciones , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/inmunología , Neumonía/inmunología , Inmunidad Adaptativa , Animales , Linfocitos B/inmunología , Humanos , Hipertensión Pulmonar/fisiopatología , Inmunidad Innata , Mediadores de Inflamación/inmunología , Neumonía/complicaciones , Linfocitos T/inmunologíaRESUMEN
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterised by vasoconstriction and remodelling of the pulmonary vasculature. The serotonin (5-hydroxytryptamine (5-HT)) pathway has been shown to play a major role in the pathogenesis of PAH, but pharmacological modulation of this pathway for treatment of PAH is, to date, at a pre-clinical level. Terguride is a 5-HT receptor (5-HTR) antagonist that is well tolerated and clinically approved for ovulation disorders. Immunohistochemistry against 5-HTR(2A/B) on human lungs revealed their localisation to the vascular smooth muscle layer and quantitative RT-PCR showed 5-HTR(2B) upregulation in pulmonary artery smooth muscle cells (PASMC) isolated from PAH patients. Proliferation and migration of cultured primary human PASMC were dose-dependently blocked by terguride. Therapeutic 5-HT signalling inhibition was 1) demonstrated in isolated, ventilated and perfused rat lungs and 2) by chronic terguride treatment of rats with monocrotaline (MCT)-induced pulmonary hypertension in a preventive or curative approach. Terguride inhibited proliferation of PASMCs and abolished 5-HT-induced pulmonary vasoconstriction. Chronic terguride treatment prevented dose-dependently the development and progression of MCT-induced PAH in rats. Thus, terguride represents a valuable novel therapeutic approach in PAH.
Asunto(s)
Agonistas de Dopamina/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Lisurida/análogos & derivados , Pulmón/efectos de los fármacos , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Adulto , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Femenino , Humanos , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/patología , Lisurida/uso terapéutico , Pulmón/patología , Pulmón/fisiopatología , Trasplante de Pulmón , Masculino , Monocrotalina/farmacología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/patología , Músculo Liso Vascular/fisiopatología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , RatasRESUMEN
Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism to optimise lung gas exchange. We aimed to decipher the proposed oxygen sensing mechanism of mitochondria in HPV. Cytochrome redox state was assessed by remission spectrophotometry in intact lungs and isolated pulmonary artery smooth muscle cells (PASMC). Mitochondrial respiration was quantified by high-resolution respirometry. Alterations were compared with HPV and hypoxia-induced functional and molecular readouts on the cellular level. Aortic and renal arterial smooth muscle cells (ASMC and RASMC, respectively) served as controls. The hypoxia-induced decrease of mitochondrial respiration paralleled HPV in isolated lungs. In PASMC, reduction of respiration and mitochondrial cytochrome c and aa3 (complex IV), but not of cytochrome b (complex III) matched an increase in matrix superoxide levels as well as mitochondrial membrane hyperpolarisation with subsequent cytosolic calcium increase. In contrast to PASMC, RASMC displayed a lower decrease in respiration and no rise in superoxide, membrane potential or intracellular calcium. Pharmacological inhibition of mitochondria revealed analogous kinetics of cytochrome redox state and strength of HPV. Our data suggest inhibition of complex IV as an essential step in mitochondrial oxygen sensing of HPV. Concomitantly, increased superoxide release from complex III and mitochondrial membrane hyperpolarisation may initiate the cytosolic calcium increase underlying HPV.
Asunto(s)
Citocromos/metabolismo , Hipoxia/metabolismo , Pulmón/metabolismo , Mitocondrias/metabolismo , Músculo Liso Vascular/metabolismo , Consumo de Oxígeno/fisiología , Animales , Aorta/citología , Respiración de la Célula/fisiología , Células Cultivadas , Citocromos b/metabolismo , Citocromos c/metabolismo , Complejo IV de Transporte de Electrones/metabolismo , Femenino , Pulmón/irrigación sanguínea , Masculino , Potencial de la Membrana Mitocondrial/fisiología , Músculo Liso Vascular/citología , Oxidación-Reducción , Circulación Pulmonar/fisiología , Conejos , Arteria Renal/citología , Espectrofotometría , Superóxidos/metabolismo , Vasoconstricción/fisiologíaRESUMEN
We assessed the therapeutic potential of riociguat, a novel soluble guanylate cyclase stimulator, in adults with chronic thromboembolic pulmonary hypertension (CTEPH; n = 42) or pulmonary arterial hypertension (PAH; n = 33) in World Health Organization (WHO) functional class II/III. In this 12-week, multicentre, open-label, uncontrolled phase II study, patients received oral riociguat 1.0-2.5 mg t.i.d. titrated according to systemic systolic blood pressure (SBP). Primary end-points were safety and tolerability; pharmacodynamic changes were secondary end-points. Riociguat was generally well tolerated. Asymptomatic hypotension (SBP <90 mmHg) occurred in 11 patients, but blood pressure normalised without dose alteration in nine and after dose reduction in two. Median 6-min walking distance increased in patients with CTEPH (55.0 m from baseline (390 m); p<0.0001) and PAH (57.0 m from baseline (337 m); p<0.0001); patients in functional class II or III and bosentan pre-treated patients showed similar improvements. Pulmonary vascular resistance was significantly reduced by 215 dyn·s·cm(-5) from baseline (709 dyn·s·cm(-5); p<0.0001). 42 (56%) patients were considered to have experienced drug-related adverse events (AEs; 96% mild or moderate). Dyspepsia, headache and hypotension were the most frequent AEs. Study discontinuation because of AEs was 4%. These preliminary data show that riociguat has a favourable safety profile and improves exercise capacity, symptoms and pulmonary haemodynamics in CTEPH and PAH. Randomised controlled trials are underway.
Asunto(s)
Antihipertensivos/farmacología , Hipertensión Pulmonar/tratamiento farmacológico , Pirazoles/farmacología , Pirimidinas/farmacología , Tromboembolia/tratamiento farmacológico , Administración Oral , Anciano , Antihipertensivos/uso terapéutico , Ejercicio Físico , Femenino , Guanilato Ciclasa/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del TratamientoRESUMEN
An accumulating body of evidence incriminates Rho kinase (ROCK) in the pathogenesis of pulmonary hypertension (PH). The therapeutic efficacy of azaindole-1, a novel highly selective and orally active ROCK inhibitor, has not yet been investigated in PH. This study aimed to investigate the effects of azaindole-1 on 1) acute hypoxic pulmonary vasoconstriction (HPV), 2) proliferation of pulmonary arterial smooth muscle cells (PASMCs) and 3) animal models of PH. Azaindole-1 significantly inhibited HPV in isolated, ventilated and buffer-perfused murine lungs and proliferation of primary rat PASMCs in vitro. Azaindole-1 was administered orally from 21 to 35 days after monocrotaline (MCT) injection in rats and hypoxic exposure in mice. Azaindole-1 (10 and 30 mg per kg body weight per day in rats and mice, respectively) significantly improved haemodynamics and right ventricular hypertrophy. Moreover, the medial wall thickness and muscularisation of peripheral pulmonary arteries were ameliorated. Azaindole-1 treatment resulted in a decreased immunoreactivity for phospho-myosin phosphatase target subunit 1 and proliferating cell nuclear antigen in pulmonary vessels of MCT-injected rats, suggesting an impaired ROCK activity and reduced proliferating cells. Azaindole-1 provided therapeutic benefit in experimental PH, and this may be attributable to its potent vasorelaxant and antiproliferative effects. Azaindole-1 may offer a useful approach for treatment of PH.
Asunto(s)
Compuestos de Azabiciclo/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Indoles/uso terapéutico , Animales , Proliferación Celular , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Hemodinámica , Pulmón/patología , Masculino , Ratones , Ratas , Ratas Sprague-Dawley , Telemetría/métodos , Sales de Tetrazolio/farmacología , Tiazoles/farmacología , Timidina/química , Resultado del Tratamiento , Quinasas Asociadas a rho/antagonistas & inhibidoresRESUMEN
Lipoxygenase, cyclo-oxygenase and cytochrome P450 (CYP) products of arachidonic acid (AA) are implicated in pulmonary vasoregulation. The CYP-mediated epoxyeicosatrienoates (EETs) have been described previously as the predominant eicosanoids in human lungs upon stimulation with the Ca(2+) ionophore A23187. In this study, we challenged perfused human lungs with two microbial agents: Escherichia coli haemolysin (ECH) and formyl-methionyl-leucyl-phenylalanine (fMLP). Both stimuli elicited pronounced generation of leukotrienes (LTs), hydroxyeicosatetraenoic acids (HETEs), prostanoids (PTs) and EETs/dihydroxyeicosatrienoic acids (DHETs), as assessed by liquid chromatography-mass spectrometry, paralleled by pulmonary artery pressor response and lung oedema formation. The maximum buffer concentrations of EETs/DHETs surpassed those of LTs plus HETEs and PTs by a factor of four (ECH) or three (AA/fMLP). Dual 5-lipoxygenase/cyclo-oxygenase inhibition caused pronounced reduction of AA/fMLP-induced LT/PT synthesis and oedema formation but only limited attenuation of pulmonary vasoconstriction, while inhibition of CYP epoxygenase clearly attenuated AA/fMLP-induced EET/DHET synthesis and vasoconstriction but not oedema formation, suggesting a major contribution of LTs/PTs to vascular leakage and of EETs/DHETs to pressor response. Consequently, generation of EETs/DHETs is greater than that of LTs plus HETEs and PTs in ex vivo perfused human lungs upon microbial challenge suggesting a substantial contribution of these mediators to inflammatory-infectious pulmonary injury.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/metabolismo , Eicosanoides/metabolismo , Proteínas de Escherichia coli/farmacología , Proteínas Hemolisinas/farmacología , Ácidos Hidroxieicosatetraenoicos/metabolismo , Pulmón/metabolismo , N-Formilmetionina Leucil-Fenilalanina/farmacología , Animales , Ácido Araquidónico/metabolismo , Permeabilidad Capilar/efectos de los fármacos , Permeabilidad Capilar/fisiología , Sistema Enzimático del Citocromo P-450/metabolismo , Epóxido Hidrolasas/metabolismo , Humanos , Leucotrieno B4/metabolismo , Leucotrieno E4/metabolismo , Lipooxigenasa/metabolismo , Pulmón/irrigación sanguínea , Pulmón/microbiología , Perfusión , Prostaglandinas/metabolismo , Circulación Pulmonar/fisiología , Conejos , Vasoconstricción/fisiologíaRESUMEN
Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism of the lung matching blood perfusion to ventilation during local alveolar hypoxia. HPV thus optimizes pulmonary gas exchange. In contrast chronic and generalized hypoxia leads to pulmonary vascular remodeling with subsequent pulmonary hypertension and right heart hypertrophy. Among other non-selective cation channels, the family of classical transient receptor potential channels (TRPC) has been shown to be expressed in pulmonary arterial smooth muscle cells. Among this family, TRPC6 is essential for the regulation of acute HPV in mice. Against this background, in this chapter we give an overview about the TRPC family and their role in HPV.
Asunto(s)
Hipoxia/metabolismo , Pulmón , Isoformas de Proteínas/metabolismo , Arteria Pulmonar/fisiología , Canales de Potencial de Receptor Transitorio/metabolismo , Vasoconstricción/fisiología , Animales , Calcio/metabolismo , Humanos , Pulmón/irrigación sanguínea , Pulmón/metabolismo , Filogenia , Isoformas de Proteínas/química , Isoformas de Proteínas/clasificación , Isoformas de Proteínas/genética , Estructura Secundaria de Proteína , Transducción de Señal/fisiología , Canales de Potencial de Receptor Transitorio/química , Canales de Potencial de Receptor Transitorio/clasificación , Canales de Potencial de Receptor Transitorio/genéticaRESUMEN
This study aimed to describe health care provision, resource consumption and related costs, as well as treatment patterns and quality of life in adult patients with pulmonary arterial hypertension (PAH) in Germany. Data for this retrospective and prospective cost-of-illness-study were derived from hospitals, general practitioners and patients. Costs were evaluated from the perspective of third party payer and patient. Quality of life data were collected by using three validated instruments. A total of 167 patients were enrolled at 10 hospitals. Time period from first occurrence of symptoms to confirmed diagnosis of PAH was 2.3 years on average. Mean number of GP visits was 1.5 per patient per month, and within 15 months, inpatient stays were reported for 50% of patients. The ratio of combination therapy to single-drug therapy for endothelin receptor antagonists, phosphodiesterase-5-inhibitor and prostacyclin analogues increased significantly during 15 months. Treatment costs were, on average, euro47,400 per patient per year, arising mainly from drugs. Compared to the general population, quality of life of PAH patients was considerably impaired. This is the first study which evaluated aspects of the medical and economic consequences of PAH based on a large cohort of PAH patients in Germany.
Asunto(s)
Hipertensión Pulmonar/economía , Inhibidores de Fosfodiesterasa/economía , Adulto , Anciano , Análisis Costo-Beneficio , Femenino , Alemania/epidemiología , Gastos en Salud , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/epidemiología , Masculino , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa/uso terapéutico , Estudios RetrospectivosRESUMEN
Anti-neutrophil cytoplasmic antibodies (c-ANCA) targeting proteinase 3 (PR3) are implicated in the pathogenesis of Wegener's granulomatosis (WG). Fulminant disease can present as acute lung injury (ALI). In this study, a model of ALI in WG was developed using isolated rat lungs. Isolated human polymorphonuclear leukocytes (PMNs) were primed with tumour necrosis factor (TNF) to induce surface expression of PR3. Co-perfusion of TNF-primed neutrophils and monoclonal anti-PR3 antibodies induced a massive weight gain in isolated lungs. This effect was not observed when control immunoglobulin G was co-perfused with TNF-primed PMNs. The c-ANCA-induced oedema formation was paralleled by an increase in the capillary filtration coefficient as a marker of increased pulmonary endothelial permeability. In contrast, pulmonary artery pressure was not affected. In the presence of the oxygen radical scavenger superoxide dismutase and a NADPH oxidase inhibitor, c-ANCA-induced lung oedema could be prevented. Inhibition of neutrophil elastase was equally effective in preventing c-ANCA-induced lung injury. In conclusion, anti-PR3 antibodies induced neutrophil mediated, elastase- and oxygen radical-dependent ALI in the isolated lung. This experimental model supports the hypothesis of a pathogenic role for c-ANCA in WG and offers the possibility of the development of therapeutic strategies for the treatment of lung injury in fulminant WG.
Asunto(s)
Lesión Pulmonar Aguda/inmunología , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Granulomatosis con Poliangitis/inmunología , Neutrófilos/inmunología , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/prevención & control , Animales , Anticuerpos Anticitoplasma de Neutrófilos/farmacología , Anticuerpos Monoclonales/farmacología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Granulomatosis con Poliangitis/tratamiento farmacológico , Granulomatosis con Poliangitis/prevención & control , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina G/farmacología , Elastasa de Leucocito/antagonistas & inhibidores , Mieloblastina/inmunología , NADPH Oxidasas/antagonistas & inhibidores , Activación Neutrófila/inmunología , Edema Pulmonar/inmunología , Edema Pulmonar/prevención & control , Ratas , Superóxido Dismutasa/análisis , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Pulmonary arterial hypertension is a life-threatening, vasculoproliferative disease of the lung, which is characterized by vasoconstriction and remodeling of small pulmonary arteries. Drugs for the treatment of PAH mainly address the increased vascular tone. Substances like prostacyclin, endothelin-receptor-antagonists and phosphodiesterase-5-inhibitors have been approved for the treatment of PAH and represent the current therapeutic options. The development of a causal treatment aiming a normalization of the vessel wall structure is the current focus of research. The key events in disease progression are represented by increased proliferation, migration and a resistance to apoptosis of pulmonary vascular cells. Therefore, new non-vasoactive drugs are investigated in relevant preclinical animal models of pulmonary arterial hypertension. Some of these substances, like tyrosine kinase inhibitors, elastase inhibitors and phosphodiesterase-1-inhibitors, could not only attenuate (anti-remodeling) but reverse (reverse-remodeling) the disease. Additionally, new vasodilators, like soluble guanylate cyclase stimulators and activators, addressing well-known and new signaling pathways are currently under investigation. Taken together, with increasing insight into the pathology of PAH, several novel drug targets and treatments have emerged which may improve the management of patients and which efficacy is currently addressed in preclinical studies and clinical trials.
Asunto(s)
Hipertensión Pulmonar/tratamiento farmacológico , Arteria Pulmonar/fisiopatología , Animales , Progresión de la Enfermedad , Antagonistas de los Receptores de Endotelina , Epoprostenol/farmacología , Epoprostenol/uso terapéutico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipertensión Pulmonar/patología , NADPH Oxidasas/metabolismo , Elastasa Pancreática/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa 5 , Fosfodiesterasa I/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/patología , Especies Reactivas de Oxígeno/metabolismo , Antagonistas de la Serotonina/uso terapéutico , Transducción de Señal/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Vasodilatadores/uso terapéutico , Quinasas Asociadas a rho/antagonistas & inhibidoresRESUMEN
Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD) and of interstitial lung diseases (ILD) such as idiopathic pulmonary fibrosis and sarcoidosis. When present in these patients, PH is usually mild to moderate. When severe PH is diagnosed in COPD and ILD patients, other potentially better treatable underlying causes should be ruled out. In COPD patients, PH is associated with an increased risk of severe exacerbations and a reduced life expectancy. Similarly, in patients with ILD, the presence of PH correlates with a poor prognosis. Doppler echocardiography is the best non-invasive method for the diagnosis of PH, but is frequently inaccurate in patients with advanced lung diseases. Thus, when clinical suspicion remains high, right heart catheterization in a reference center is required to ultimately confirm the presence of PH. Treatment of PH in COPD and ILD is primarily based on long term oxygen therapy. Drugs approved for pulmonary arterial hypertension, such as prostanoids, phosphodiesterase inhibitors, and endothelin receptor antagonists, may represent promising options for COPD and ILD patients, however, their use may be hampered by potentially deleterious effects on gas exchange and their efficacy yet remains to be proven in appropriately designed and controlled clinical trials. Lung transplantation may be considered in all patients with an advanced disease.
Asunto(s)
Hipertensión Pulmonar/etiología , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Cateterismo Cardíaco , Ecocardiografía Doppler , Antagonistas de los Receptores de Endotelina , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/terapia , Trasplante de Pulmón , Terapia por Inhalación de Oxígeno , Inhibidores de Fosfodiesterasa/efectos adversos , Inhibidores de Fosfodiesterasa/uso terapéutico , Pronóstico , Prostaglandinas/efectos adversos , Prostaglandinas/uso terapéutico , Fibrosis Pulmonar/complicaciones , Intercambio Gaseoso Pulmonar/efectos de los fármacos , Factores de Riesgo , Sarcoidosis Pulmonar/complicacionesRESUMEN
During the last years, therapeutic options for the treatment of pulmonary arterial hypertension (PAH) have significantly improved. However, the therapeutic concept depends on the etiology of the disease, so that an exact classification is mandatory. Currently, three substance classes are approved for the treatment of PAH (Group I of the Venice Classification): Endothelin receptor antagonists, phosphodiesterase type-5 inhibitors, and prostanoids. After the World Conference in Dana Point (2008), recent changes in therapeutic strategies comprise the early treatment of the disease, as well as the increased importance of an early use of combination therapy if treatment goals are not met. Several new substances are currently evaluated in clinical trials. The soluble guanylate cyclase (sGC) stimulators achieve potent, NO-independent vasodilation. Another promising pathophysiological approach is currently evaluated by the use of tyrosine kinase inhibitors - anti-proliferative drugs which inhibit or even may reverse the pulmonary vascular remodeling process. Serotonin receptor antagonists are also reported to have anti-proliferative, anti-thrombotic and anti-fibrotic effects. Other forms of pulmonary hypertension (Groups II-V) are strictly separated from PAH. Evidence on treatment with PAH specific agents is strongly needed for these groups. Patients with non-PAH pulmonary hypertension should be referred to PAH expert centers, and preferably treated in controlled studies.
Asunto(s)
Antihipertensivos/uso terapéutico , Antagonistas de los Receptores de Endotelina , Hipertensión Pulmonar/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5 , Inhibidores de Fosfodiesterasa/uso terapéutico , Prostaglandinas/uso terapéutico , Antihipertensivos/clasificación , Quimioterapia Combinada , Endarterectomía , Guanilato Ciclasa/efectos de los fármacos , Guanilato Ciclasa/metabolismo , Insuficiencia Cardíaca/complicaciones , Humanos , Hipertensión Pulmonar/clasificación , Hipertensión Pulmonar/etiología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Embolia Pulmonar/complicaciones , Embolia Pulmonar/cirugía , Fibrosis Pulmonar/complicaciones , Antagonistas de la Serotonina/farmacología , Antagonistas de la Serotonina/uso terapéutico , Vasodilatadores/farmacología , Vasodilatadores/uso terapéuticoRESUMEN
Current international guidelines on the treatment of pulmonary arterial hypertension (PAH) are compiled by the European Society of Cardiology and the American College of Chest Physicians. The classification of pulmonary hypertension and guidelines on diagnosis and therapy were last adopted at the 4th World Congress of PAH in Dana Point (California) in the year 2008. Based on these guidelines this article presents an overview of the current therapy recommendations for patients with PAH corresponding to group 1 of the diagnostic WHO classification of pulmonary hypertension. Here it is recommended that diagnostic and therapy should be carried out in an expert centre. The therapy forms for PAH can be classified into basic therapy (e. g. oral anticoagulants, diuretics and oxygen therapy) and specific therapy (e. g. phosphodiesterase-5 inhibitors, endothelin receptor antagonists and prostanoids). Finally, some new substances will be presented which have already progressed relatively far in the clinical development.
Asunto(s)
Anticoagulantes/uso terapéutico , Antihipertensivos/uso terapéutico , Diuréticos/uso terapéutico , Hipertensión Pulmonar/terapia , Terapia por Inhalación de Oxígeno/métodos , HumanosRESUMEN
Pathological vascular remodelling is a key contributor to the symptomatology of pulmonary arterial hypertension (PAH), and reversing this process may offer the best hope for improving this debilitating condition. The vascular remodelling process is believed to be due to endothelial cell dysfunction and to involve altered production of endothelial cell-derived vasoactive mediators. The observation that circulating plasma levels of the vasoactive peptide endothelin (ET)-1 are raised in patients with PAH, and that ET-1 production is increased in the pulmonary tissue of affected individuals, makes it a particularly interesting target for a therapeutic intervention in PAH. Clinical trials with ET receptor antagonists (ETRAs) show that they provide symptomatic benefit in patients with PAH, thereby proving the clinical relevance of the ET system as a therapeutic target. In this paper, we review the role of ET-1 together with the available data on the roles of the specific ET receptors and ETRAs in PAH. In particular, we discuss the possible role of ET receptor selectivity in the vascular remodelling process in PAH and whether selective ET(A) or nonselective ET(A)/ET(B) blockade offers the greatest potential to improve symptoms and alter the clinical course of the disease.
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Antihipertensivos/uso terapéutico , Antagonistas de los Receptores de Endotelina , Endotelina-1/fisiología , Hipertensión Pulmonar/tratamiento farmacológico , Antihipertensivos/farmacología , Humanos , Hipertensión Pulmonar/fisiopatología , Ensayos Clínicos Controlados Aleatorios como Asunto , Vasodilatación/efectos de los fármacosRESUMEN
Pulmonary hypertension (PH) is associated with impaired production of the vasodilator nitric oxide (NO). Riociguat (BAY 63-2521; Bayer Healthcare AG, Wuppertal, Germany) acts directly on soluble guanylate cyclase, stimulating the enzyme and increasing sensitivity to low NO levels. The present study evaluates riociguat safety, tolerability and efficacy in patients with moderate-to-severe PH (pulmonary arterial hypertension, distal chronic thromboembolic PH or PH with mild to moderate interstitial lung disease). The optimal tolerated dose was identified by incremental dosing in four patients with PH; pharmacodynamic and pharmacokinetic parameters were assessed following single-dose administration (2.5 mg or 1 mg) in 10 and five patients with PH, respectively. All subjects (n = 19) were analysed for safety and tolerability. Riociguat had a favourable safety profile at single doses < or =2.5 mg. It significantly improved pulmonary haemodynamic parameters and cardiac index in patients with PH in a dose-dependent manner, to a greater extent than inhaled NO. Although riociguat also had significant systemic effects and showed no pulmonary selectivity, mean systolic blood pressure remained >110 mmHg. The present report is the first to describe the use of riociguat in patients with pulmonary hypertension. The drug was well-tolerated and superior to nitric oxide in efficacy and duration. Riociguat, therefore, has potential as a novel therapy for pulmonary hypertension and warrants further investigation.
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Guanilato Ciclasa/biosíntesis , Guanilato Ciclasa/fisiología , Pirimidinas/farmacología , Receptores Citoplasmáticos y Nucleares/biosíntesis , Receptores Citoplasmáticos y Nucleares/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/enzimología , Hipertensión Pulmonar/fisiopatología , Masculino , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo II/farmacología , Oxidación-Reducción , Circulación Pulmonar/fisiología , Pirimidinas/farmacocinética , Guanilil Ciclasa Soluble , Resultado del TratamientoRESUMEN
The prognosis for patients with pulmonary hypertension remains poor despite recent treatment advances, and there is a need for therapies with new modes of action. Nitric oxide (NO) is an endogenous vasodilator, the levels of which are regulated throughout the lung to ensure preferential perfusion of well-ventilated regions. Drugs that act in synergy with endogenous NO would therefore promote pulmonary vasodilation while maintaining optimal gas exchange. Riociguat is an oral stimulator of the NO receptor soluble guanylate cyclase. It synergises with NO and has demonstrated vasodilatory and antiremodelling properties in preclinical studies. Riociguat has been shown to have a favourable safety profile in healthy volunteers and in patients with pulmonary hypertension. Pharmacokinetic analyses have revealed substantial interindividual variation, suggesting that individual dose titration will be required. In a proof-of-concept study of patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension, riociguat improved cardiopulmonary haemodynamics from baseline. It also caused systemic vasodilation, which was well tolerated but should be monitored in future studies. Dose titration of riociguat should promote pulmonary vasodilation while maintaining control of systemic effects, and has been investigated in a phase-II study of patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Preliminary results indicate that phase-III trials are warranted.
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Guanilato Ciclasa/metabolismo , Hipertensión Pulmonar/tratamiento farmacológico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Vasodilatadores/uso terapéutico , Activación Enzimática , HumanosRESUMEN
Different routes for the in vivo administration of synthetic siRNA complexes targeting lung tumors were compared, and siRNA complexes were administered for the inhibition of hypoxia-inducible factor (HIF-1alpha and HIF-2alpha). Intravenous jugular vein injection of siRNA proved to be the most effective means of targeting lung tumor tissue in the Lewis lung carcinoma (LLC1) model. In comparison, intraperitoneal injection of siRNA was not suitable for targeting of lung tumor and intratracheal administration of siRNA exclusively targeted macrophages. Inhibition of HIF-1alpha and HIF-2alpha by siRNA injected intravenously was validated by immunohistofluorescent analysis for glucose-transporter-1 (GLUT-1), a well-established HIF target protein. The GLUT-1 signal was strongly attenuated in the lung tumors of mice treated with siRNA-targeting HIF-1alpha and HIF-2alpha, compared with mice treated with control siRNA. Interestingly, injection of siRNA directed against HIF-1alpha and HIF-2alpha into LLC1 lung tumor-bearing mice resulted in prolonged survival. Immunohistological analysis of the lung tumors from mice treated with siRNA directed against HIF-1alpha and HIF-2alpha displayed reduced proliferation, angiogenesis and apoptosis, cellular responses, which are known to be affected by HIF. In conclusion, intravenous jugular vein injection of siRNA strongly targets the lung tumor and is effective in gene inhibition as demonstrated for HIF-1alpha and HIF-2alpha.