Updates on Pityriasis Rubra Pilaris: A Scoping Review.

Pityriasis rubra pilaris (PRP) is a rare, inflammatory papulosquamous skin disease with unknown exact etiology. Historically, PRP has been challenging to diagnose, especially during the acute phase, and to treat, due to its unclear pathogenesis. To better inform clinical practice, a literature review was conducted employing a broad search strategy to capture PRP-related published studies between January 1, 2012 to October 31, 2022. Two hundred twenty-one studies were identified, which were categorized into 9 themes: (1) potential causes and triggering factors, (2) comorbidities, (3) diagnostic difficulties, (4) genetics, (5) clinical manifestations and laboratory values, (6) treatment, (7) treatment-related adverse events, (8) quality of life, and (9) other. COVID-19 infection, COVID-19 vaccination, and malignancy were the most commonly reported potential triggering factors. Misdiagnosis is very common during the early acute stages. Pathogenesis and genetic studies have further implicated caspase recruitment domain family member 14 (CARD14) mutations in the development of familial PRP (Type V) and have underlined the overlap between psoriasis and PRP. To date, there are currently no specific and validated scoring systems or tools to assess the severity of PRP. While large, randomized trials are still lacking, biologic agents remain the most effective therapy.

Treatment Options for Juvenile Pityriasis Rubra Pilaris.

Pityriasis rubra pilaris represents a group of familial and acquired disorders of cornification that affect both adult and pediatric patients. Treatment options are difficult to assess through clinical trials, given the rarity of the disorder and its tendency for spontaneous remission. Case reports and case series are therefore the primary means of assessment. Because of the heterogeneity of the disease, there is no universal approach to treatment, and multiple agents may need to be trialed to achieve disease control. At present, topicals are used for most pediatric patients, though monotherapy with topicals is only effective for less severe disease. Despite concerns over their side-effect profiles, oral retinoids are generally accepted as a first-line systemic therapy. However, interleukin-17 inhibitors and ustekinumab, an interleukin-12 and interleukin-23 inhibitor, may soon become first-line systemic treatment as well, given their efficacy and relative safety in trials thus far. Ustekinumab, in particular, is emerging as a first-line agent for patients with pityriasis rubra pilaris with CARD14 gene variations. When these therapies fail, second-line and adjunctive therapies to consider include tumor necrosis factor-alpha inhibitors, methotrexate, and phototherapy. However, further investigation is necessary to assess the safety and efficacy of many of these agents in juvenile pityriasis rubra pilaris.

Successful treatment with ustekinumab in CARD14-associated papulosquamous eruption in a Brazilian child.

CARD14-associated papulosquamous eruption (CAPE) was proposed in 2018 to describe the clinical features of psoriasis and pityriasis rubra pilaris with CARD 14 mutations. We report a 5-month-old female infant who developed CAPE-associated erythroderma. Although she did not respond to conventional therapies, she responded well to ustekinumab treatment at the age of 4 years.

Generalized Pustular Psoriasis: A Review of the Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment.

Generalized pustular psoriasis (GPP) is a rare severe variant of psoriasis that is characterized by the abrupt widespread onset of small pustules accompanied by systemic manifestations of inflammation. It can arise in patients with a history of psoriasis as well as in those without, sometimes due to medication initiation or withdrawal, pregnancy, or infection. Generalized pustular psoriasis is thought to be driven primarily by innate immunity and unrestrained IL-36 cytokine activity. Recent genetic analyses have identified 3 genetic mutations that are associated with GPP-IL36RN, CARD14, and AP1S3-though these mutations only account for a minority of cases. There are many cutaneous pustular diseases that must be ruled out in the evaluation of a patient with suspected GPP, especially acute generalized exanthematous pustulosis (AGEP), and histologic analysis is the cornerstone of diagnosis. Although the quality of evidence to generate treatment recommendations for GPP is limited, management often includes utilization of systemic agents and/or biologics, usually with adjunctive topical treatment. Accumulating evidence suggests that biologic agents, especially infliximab, may be considered as first-line treatment of GPP, especially in severe acute cases, due to their abrupt onset of action and favorable side-effect profiles compared with oral systemic agents.

Inhaled mosliciguat (BAY 1237592): targeting pulmonary vasculature via activating apo-sGC.

BACKGROUND: Oxidative stress associated with severe cardiopulmonary diseases leads to impairment in the nitric oxide/soluble guanylate cyclase signaling pathway, shifting native soluble guanylate cyclase toward heme-free apo-soluble guanylate cyclase. Here we describe a new inhaled soluble guanylate cyclase activator to target apo-soluble guanylate cyclase and outline its therapeutic potential. METHODS: We aimed to generate a novel soluble guanylate cyclase activator, specifically designed for local inhaled application in the lung. We report the discovery and in vitro and in vivo characterization of the soluble guanylate cyclase activator mosliciguat (BAY 1237592). RESULTS: Mosliciguat specifically activates apo-soluble guanylate cyclase leading to improved cardiopulmonary circulation. Lung-selective effects, e.g., reduced pulmonary artery pressure without reduced systemic artery pressure, were seen after inhaled but not after intravenous administration in a thromboxane-induced pulmonary hypertension minipig model. These effects were observed over a broad dose range with a long duration of action and were further enhanced under experimental oxidative stress conditions. In a unilateral broncho-occlusion minipig model, inhaled mosliciguat decreased pulmonary arterial pressure without ventilation/perfusion mismatch. With respect to airway resistance, mosliciguat showed additional beneficial bronchodilatory effects in an acetylcholine-induced rat model. CONCLUSION: Inhaled mosliciguat may overcome treatment limitations in patients with pulmonary hypertension by improving pulmonary circulation and airway resistance without systemic exposure or ventilation/perfusion mismatch. Mosliciguat has the potential to become a new therapeutic paradigm, exhibiting a unique mode of action and route of application, and is currently under clinical development in phase Ib for pulmonary hypertension.

Inflammatory linear verrucous epidermal nevus (ILVEN) encompasses a spectrum of inflammatory mosaic disorders.

BACKGROUND: Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare skin disease characterized by pruritic erythematous scaly plaques distributed along the lines of Blaschko. Two cases of ILVEN with CARD14 mutations and one case with a GJA1 mutation have been previously reported. OBJECTIVE: To elucidate the genetic cause of a cohort of patients diagnosed based on clinical and histopathological evaluation with ILVEN. METHODS: We recruited patients diagnosed with ILVEN based on clinical and histopathological criteria. Exome sequencing of affected skin with or without blood/saliva was performed and germline and somatic pathogenic variants were identified. RESULTS: Five patients were enrolled. All had skin lesions from birth or early childhood. Two patients developed psoriasis vulgaris after the diagnosis of ILVEN. The first had a germline heterozygous CARD14 mutation and a post-zygotic hotspot mutation in KRT10. The histopathologic evaluation did not show epidermolytic hyperkeratosis. The second had a post-zygotic hotspot mutation in HRAS. Her ILVEN became itchy once psoriasis developed. One patient was re-diagnosed with linear porokeratosis based on a germline mutation in PMVK and a post-zygotic second-hit mutation. Two patients were re-diagnosed with congenital hemidysplasia with ichthyosiform nevus and limb defect nevus based on germline NSDHL mutations. CONCLUSION: ILVEN is a clinical descriptor for a heterogenous group of mosaic inflammatory disorders. Genetic analysis has the potential to more precisely categorize ILVEN and permits pathogenesis-directed therapies in some cases.

Pustular psoriasis of pregnancy: Clinical and genetic characteristics in a series of eight patients and review of the literature.

Pustular psoriasis of pregnancy (PPP) can lead to life-threatening complications. The objective of this study is to report clinical and genetic spectrum, prognostic factors and management options. A retrospective study was designed including eight PPP patients. Clinical data were collected, and performed genetic and statistical analysis to identify factors associated with fetal complications, resistance to treatment and post-partum flare extension. A systematic review of the literature was also carried out. Eight Tunisian patients, with a mean age of 23 ± 3.3 years, were included. They presented 14 flares (F) during pregnancies and one flare after delivery. Additional GPP flares outside pregnancy periods were noted in 2/8 of patients. The mean duration of PPP flares was 16.66 ± 7.8 weeks. The first flare occurred at a gestational age of 26 ± 5 weeks. Only 2/8 studied patients presented a homozygous mutation c.80 T > C (p.L27P) in IL36RN gene. Used treatments were topical steroids (n = 12F), systemic steroids (n = 5F), ciclosporin (n = 1F), UVB (n = 1F) and acitretin (in post-partum n = 6F). Complications were oligoamnios (n = 2), intra-uterine growth retardation (n = 1), fetal death in utero (n = 1), prematurity (n = 3), low weight at birth (n = 2). A significant association was found between (i) occurrence of fetal complications and early gestational age at the onset (p = 0.036), (ii) resistance to topical steroids and body surface affected area (p = 0.008), (iii) presence of mutation c.80 T > C in PPP flares and low serum levels of calcium (p = 0.01). Our systematic review of the literature identified 39 patients with 41 flares of PPP. Only 7/39 patients presented a causative mutation in IL36RN and CARD14 genes. PPP is characterized by a phenotypic heterogeneity and can be associated to IL36RN mutations. Its early onset can be associated with fetal complications. Systemic steroids and cyclosporine remain the most used therapies.

Therapeutic augmentation of NO-sGC-cGMP signalling: lessons learned from pulmonary arterial hypertension and heart failure.

The nitric oxide (NO)-guanylate cyclase (GC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular, pulmonary and renal function. Phosphodiesterase-5 inhibitors (PDE-5i) inhibit cGMP degradation, whereas both soluble guanylate cyclase (sGC) stimulators and sGC activators directly increase sGC. PDE-5i (e.g. sildenafil, tadalafil) and sGC stimulators (e.g. riociguat, vericiguat) have been extensively used in pulmonary artery hypertension (PAH) and heart failure (HF). PDE-5i have also been used in end-stage HF before and after left ventricular (LV) assist device (LVAD) implantation. Augmentation of NO-GC-cGMP signalling with PDE-5i causes selective pulmonary vasodilation, which is highly effective in PAH but may have controversial, potentially adverse effects in HF, including pre-LVAD implant due to device unmasking of PDE-5i-induced RV dysfunction. In contrast, retrospective analyses have demonstrated that PDE-5i have beneficial effects when initiated post LVAD implant due to the improved haemodynamics of the supported LV and the pleiotropic actions of these compounds. sGC stimulators, in turn, are effective both in PAH and in HF due to their balanced pulmonary and systemic vasodilation, and as such they are preferable to PDE-5i if the use of a pulmonary vasodilator is needed in HF patients, including those listed for LVAD implantation. Regarding the effectiveness of PDE-5i and sGC stimulators when initiated post LVAD implant, these two groups of compounds should be tested in a randomized control trial.

Riociguate para o tratamento da hipertensão pulmonar tromboembólica crônica (HPTEC) inoperável, persistente ou recorrente após tratamento cirúrgico / Riociguate for the treatment of hypertension chronic pulmonary thromboembolism (CTEPH) inoperable, persistent or recurrent after surgical treatment

INTRODUÇÃO: Este Relatório tem como objetivo analisar as evidências apresentadas pelo demandante acerca de eficácia, segurança, custo-efetividade e impacto orçamentário do riociguate para o tratamento de hipertensão pulmonar tromboembólica crônica (HPTEC) inoperável ou persistente/recorrente em adultos com vistas à incorporação ao Sistema Único de Saúde (SUS). A hipertensão pulmonar (HP) corresponde a um grupo de condições clínicas que se apresentam como elevação anormal da pressão na circulação pulmonar. Conforme o VI Simpósio Mundial de Hipertensão Pulmonar, a definição de HP incluiu uma medida de pressão arterial pulmonar média (PAPm) > 20 mmHg que, juntamente com outros critérios, definirão o grau da HP 1,2 . A HPTEC é um subtipo de hipertensão pulmonar pertencente ao Grupo 4. Tratase de uma doença debilitante independentemente da faixa etária dos pacientes, levando a dependência de cuidados. Dada sua incidência, essa doença também é classificada como rara3,4 . A HPTEC é definida como a persistência de trombos organizados n

Guanylate cyclase-C agonists as peripherally acting treatments of chronic visceral pain.

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain and altered bowel habit that affects ~11% of the global population. Over the past decade, preclinical and clinical studies have revealed a variety of novel mechanisms relating to the visceral analgesic effects of guanylate cyclase-C (GC-C) agonists. Here we discuss the mechanisms by which GC-C agonists target the GC-C/cyclic guanosine-3',5'-monophosphate (cGMP) pathway, resulting in visceral analgesia as well as clinically relevant relief of abdominal pain and other sensations in IBS patients. Due to the preponderance of evidence we focus on linaclotide, a 14-amino acid GC-C agonist with very low oral bioavailability that acts within the gut. Collectively, the weight of experimental and clinical evidence supports the concept that GC-C agonists act as peripherally acting visceral analgesics.

Eficácia e segurança de Riociguate comparado ao placebo e a medicamentos disponíveis no sus para tratamento de hipertensão pulmonar tromboembólica crônica: revisão rápida de evidências / Effectiveness and safety of Riociguate compared to placebo and drugs available in brazilian public health for treatment of chronic thromboembolic pulmonary hypertension: rapid response review of evidence

Tecnologia: Riociguate e outros medicamentos de controle da hipertensão pulmonar. Indicação: Tratamento de Hipertensão Pulmonar Tomboembólica Crônica (HPTEC). Pergunta: Há superioridade em eficácia e segurança do riociguate, comparado a medicamentos disponíveis no SUS, no tratamento de HPTEC inoperável ou operada com hipertensão pulmonar residual? Métodos: Revisão rápida de evidências (overview) de revisões sistemáticas, com levantamento bibliográfico realizado na base de dados PUBMED, utilizando estratégia estruturada de busca. A qualidade metodológica das revisões sistemáticas foi avaliada com AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews). Resultados: Foram selecionadas 4 e incluídas 2 revisões sistemáticas. Conclusão: Comparado ao placebo, em tratamento de curto prazo de HPTEC, riociguate melhora a tolerância ao exercício, aumenta a chance de melhora da classificação funcional e tem similar risco de eventos adversos sérios, porém não reduz a mortalidade. Treprostinil tem efeitos similares a riociguate. Entretanto, ambrisentana, bosentana, macitentana ou sildenafila não diferem do placebo no tratamento de HPTEC

Technology: Riociguat and other drugs to control pulmonary hypertension. Indication: Treatment of chronic thromboembolic pulmonary hypertension (CTEPH). Question: Is riociguat more effective and safe than other drugs available in the Brazilian Public Health System for the treatment of inoperable or recurrent CTEPH? Methods: Rapid review of evidence (overview) from systematic reviews, with a bibliographic search in the PUBMED database, using a structured strategy. The methodological quality of systematic reviews was assessed with AMSTAR-2 (Methodological Quality Assessment of Systematic Reviews). Results: Four systematic reviews were selected and two included in this study. Conclusion: Compared to placebo, in the short-term treatment of CTEPH, riociguat improves exercise tolerance, increases the chance of improving functional classification, and has a similar risk of serious adverse events, but does not reduce mortality. Treprostinil has similar effects to riociguat. However, ambrisentan, bosentan, macitentan or sildenafil do not differ from placebo in the treatment of CTEPH

Informe de evaluación científica en la evidencia disponible: hipertensión arterial pulmonar / Scientific evaluation report on the available evidence: pulmonary arterial hypertension

INTRODUCCIÓN: La Hipertensión Arterial Pulmonar (HAP) es una enfermedad crónica y progresiva, de baja prevalencia, pero con un alto impacto debido a su curso grave y potencialmente letal. Esta condición de salud implica una sustantiva pérdida de capacidad física y sobrecarga del ventrículo derecho, resultando en falla cardiaca y mortalidad temprana. Desde el punto de vista hemodinámico, la HAP se define como el aumento de la presión media de la arteria pulmonar ≥ 25 mmHg, (PAPm ≥ 25 mmHg) con presión capilar pulmonar ≤ 15 mmHg. La Organización Mundial de la Salud la ha clasificado en 5 grupos en base a criterios fisiopatológicos, hemodinámicos y estrategias de manejo. El grupo 1 es aquel en que la hipertensión pulmonar se caracteriza por hipertensión precapilar y resistencia vascular pulmonar y no se explica por enfermedades cardiacas, pulmonares o enfermedad tromboembólica. Por su parte, el grupo 4 denominado hipertensión pulmonar tromboembólica crónica es una enfermedad producida por el remodelado obstructivo de la arteria pulmonar como consecuencia de tromboembolia en grandes vasos. En el caso de HAP grupo 1, se indica que las estimaciones más bajas de prevalencia son 15 por millón de adultos, mientras que las tasas de incidencias más bajas son de 2,4 casos por millón de adultos al año. Por otro lado, se estima para HAP grupo 4 una prevalencia de 3,2 por millón y una incidencia de 0,9 por millón de personas. Este informe evalúa el uso de macitentán y riociguat para el tratamiento de pacientes adultos con HAP (Grupo 1 y 4). Esta condición de salud cuenta con cobertura para los medicamentos iloprost inhalatorio, ambrisentán y bosentán en el contexto de Ley N° 20.850 (Ley Ricarte Soto) para pacientes con Hipertensión Arterial Pulmonar Grupo I. TECNOLOGÍAS SANITARIA DE INTERÉS: Macitentán es un antagonista dual de los receptores de la endotelina que se administra por vía oral. Riociguat es un estimulador de la guanilato-ciclasa soluble (GCs), un enzima presente en el sistema cardiopulmonar y el receptor del óxido nítrico (NO). EFICACIA DE LOS TRATAMIENTOS: Macitentán - HAP Grupo 1: No se identificó evidencia directa que evaluara el efecto de macitentán en comparación con el mejor tratamiento disponible (bosentán) en personas con hipertensión arterial pulmonar grupo 1, por lo que se recurrió a comparaciones indirectas, seleccionándose una revisión sistemática que utilizó la técnica metaanálisis en red para comparar ambos fármacos. De acuerdo a esta evidencia, el uso de macitentán podría ser menos efectivo que bosentán en reducir la mortalidad, en reducir el empeoramiento clínico, en mejorar el test de caminata en 6 minutos y podría asociarse a menos efectos adversos severos que bosentán, pero la certeza de la evidencia es baja. Riociguat - HAP Grupo 1: No se identificó evidencia directa que evaluaba el efecto de riociguat en comparación con el mejor tratamiento disponible (bosentán) en personas con hipertensión arterial pulmonar grupo 1, por lo que se recurrió a comparaciones indirectas, seleccionándose una revisión sistemática que utilizó la técnica metaanálisis en red para comparar ambos fármacos. De acuerdo a esta evidencia, no está claro si existen diferencias en mortalidad, en empeoramiento clínico, en el test de caminata en 6 minutos y en la mejoría en capacidad funcional entre riociguat y antagonistas de endotelina, porque la certeza de la evidencia es muy baja. Además, riociguat podría tener menos efectos adversos severos que los antagonistas de endotelina, pero la certeza de la evidencia es baja. Riociguat - HAP: Grupo 4 Se identificó un ensayo clínico que comparaba riociguat con placebo en personas con hipertensión arterial pulmonar grupo 4. De acuerdo a esta evidencia, riociguat aumenta levemente el número de metros en test de marcha de 6 minutos y probablemente mejora la funcionalidad, esto con una calidad de evidencia alta y moderada, respectivamente. ALTERNATIVAS DISPONIBLES: Terapia Farmacológica: Después de ser realizado el diagnóstico de HAP, el paciente recibe un tratamiento dependiendo de su capacidad funcional, etiología y estratificación del riesgo. De esta forma, los pacientes reciben diversos medicamentos de acuerdo criterios establecidos. Entre los medicamentos se puede citar a Ambrisentan, Bosentan e Iloprost, los cuales se encuentran actualmente cubiertos por Ley 20.850 para Grupo 1 de HAP (10). Tratamiento no farmacológico: Tienen como objetivo, de manera coadyuvante, beneficiar la calidad de vida y sobrevida de pacientes. Entre las medidas que se recomienda se encuentran: rehabilitación, terapia anticoagulante, terapia diurética, oxigenoterapia y apoyo psicológico, entre otras. Cirugía: En caso de que los pacientes resulten refractarios a terapias farmacológicas o en ciertos subgrupos de pacientes Hipertensión Arterial Pulmonar, se plantea como alternativa terapéutica el trasplante de pulmón, trasplante de pulmón/corazón y la tromboendarterectomía pulmonar. RESULTADOS DE LA BÚSQUEDA DE EVIDENCIA: Se identificaron múltiples revisiones sistemáticas evaluando la intervención de interés, sin embargo, ninguna de ellas identificó ensayos que aborden la comparación pertinente a este informe (ambrisentán o bosentán). Tampoco se identificaron ensayos relevantes en la búsqueda adicional, por lo tanto, se llevó a cabo una estimación del efecto mediante evidencia indirecta, a partir de la mejor revisión sistemática disponible con metaanálisis en red, para responder la pregunta CONCLUSIÓN: Para dar cumplimiento al artículo 28° del Reglamento que establece el proceso destinado a determinar los diagnósticos y tratamientos de alto costo con Sistema de Protección Financiera, según lo establecido en los artículos 7°y 8° de la ley N°20.850, aprobado por el decreto N°13 del Ministerio de Salud, se concluye que el presente informe de evaluación se considera favorable, de acuerdo a lo establecido en el Título III. de las Evaluaciones Favorables de la Norma Técnica N° 0192 de este mismo ministerio.

Informe de evaluación científica en la evidencia disponible: hipertensión arterial pulmonar / Scientific evaluation report on the available evidence: pulmonary arterial hypertension

INTRODUCCIÓN: La Hipertensión Arterial Pulmonar (HAP) es una enfermedad crónica y progresiva, de baja prevalencia pero con un alto impacto debido a su curso grave y potencialmente letal. La HAP se define desde el punto de vista hemodinámico invasivo como el aumento de la presión media de la arteria pulmonar ≥ 25 mmHg, (PAPm ≥ 25 mmHg) con presión capilar pulmonar ≤ 15 mmHg. Se estima para la HAP un promedio de sobrevida de 2,8 años o una sobrevida promedio de 40% a dos años en pacientes adultos, y de 10 meses en población pediátrica sin tratamiento. Una de las características de la HAP es que es una condición poco reconocida, cuyo diagnóstico suele ser tardío, siendo los síntomas más comunes: disnea, dolor torácico, fatiga y síncope. Actualmente, la HAP se encuentra considerada dentro de las condiciones de salud que cubre el Sistema de Protección Financiera para Diagnóstico y Tratamientos de Alto Costo (Ley 20.850). En particular, se entrega cobertura para los medicamentos Ambrisentan, Bosentán e Iloprost para pacientes con HAP del Grupo 1 de la OMS. Por lo expuesto en el párrafo anterior, se evalúa la potencial extensión de cobertura de Ambrisentan y Bosentan a otros grupos de pacientes, y la incorporación de los medicamentos Macitentan y Riociguat. TECNOLOGÍAS SANITARIA DE INTERÉS: Ambrisentan: Ambrisentan cuenta con registro en el Instituto de Salud Pública (ISP) e indicación para el tratamiento de pacientes adultos con hipertensión arterial pulmonar (HAP) clasificados como clase funcional II y III de la Organización Mundial de la Salud (OMS), para mejorar su capacidad para realizar ejercicio. Bosentan: Bosentan cuenta con registro en ISP e indicación para el tratamiento de la hipertensión arterial pulmonar (HAP) para mejorar los síntomas y la capacidad de ejercicio en pacientes con grado funcional III. Macitentan: Etanercept cuenta con registro en ISP y está indicado para el tratamiento a largo plazo de la hipertensión arterial pulmonar (HAP) en pacientes adultos clasificados como clase funcional (CF) II a III de la Organización Mundial de la Salud (OMS). Riociguat: Riociguat está indicado en el tratamiento de pacientes adultos en Clase Funcional (CF) II a III de la OMS con Hipertensión Arterial Tromboembólica Crónica inoperable o persistente/recurrente después de tratamiento quirúrgico. También está indicado para en el tratamiento de pacientes adultos con hipertensión arterial pulmonar (HAP) en Clase Funcional (CF) II a III de la OMS. EFICACIA DE LOS TRATAMIENTOS: Para Ambrisentan no se cuenta con evidencia de eficacia/efectividad para pacientes distintos al Grupo 1 de OMS, esto de acuerdo a la metodología de búsqueda empleada. En el caso de Bosentan, se encuentra evidencia de eficacia para el Grupo 3 (HAP asociada a Enfermedad Pulmonar Obstructiva) y para el Grupo 4 (HAP Tromboembólica Crónica). En general, la evidencia es calificada como de baja calidad. En la mayor parte de los outcomes, no hay una diferencia relevante entre los grupos en tratamiento y control para ambos tipos de pacientes (Grupo 3 y Grupo 4). Para Macitentan solo se encuentra evidencia de eficacia para pacientes del Grupo 1 de OMS. El uso de Macitentan probablemente aumenta levemente el número de metros recorridos en test de marcha de 6 minutos, genera una mejora de la funcionalidad, disminuye la resistencia vascular pulmonar y reduce el número de pacientes con empeoramiento clínico. Por último, para Riociguat se encuentra evidencia de eficacia para HAP Grupo 1, Grupo 2 (HAP debido a Cardiopatía Izquierda) y a Grupo 4. Tanto para el Grupo 1 como Grupo 2, la evidencia es calificada como baja o muy baja y los efectos de Riociguat en relación a placebo resultan inciertos. Para el Grupo 4, Riociguat aumenta levemente el número de metros en test de marcha de 6 minutos y probablemente mejora la funcionalidad, esto con una calidad de evidencia alta y moderada, respectivamente. ALTERNATIVAS DISPONIBLES: Terapia Farmacológica: Después de ser realizado el diagnóstico de HAP, el paciente recibe un tratamiento dependiendo de su capacidad funcional, etiología y estratificación del riesgo. De esta forma, los pacientes reciben diversos medicamentos de acuerdo criterios establecidos. Entre los medicamentos se puede citar a Ambrisentan, Bosentan e Iloprost. Tratamiento no farmacológico: Tienen como objetivo, de manera coadyuvante, beneficiar la calidad de vida y sobrevida de pacientes. Entre las medidas que se recomienda se encuentran: rehabilitación, terapia anticoagulante, terapia diurética, oxigenoterapia y apoyo psicológico, entre otras. Cirugía: En caso de que los pacientes resulten refractarios a terapias farmacológicas o en ciertos subgrupos de pacientes Hipertensión Arterial Pulmonar, se plantea como alternativa terapéutica el trasplante de pulmón, trasplante de pulmón/corazón y la tromboendarterectomía pulmonar. RESULTADOS DE LA BÚSQUEDA DE EVIDENCIA: Los resultados de la recopilación de la evidencia son presentados para cada una de las tecnologías evaluadas. La información presentada fue extraída de 22 revisiones sistemáticas publicadas entre los años 2008 a 2017, que evaluaron el tratamiento para la Hipertensión Arterial Pulmonar para los cuatro medicamentos en evaluación. En el caso de Ambrisentan, en las seis revisiones sistemáticas encontradas, en ninguno de los estudios primarios considerados se pudo identificar pacientes que no fueran del Grupo 1 de la OMS1. Por tanto, no se logra con la metodología utilizada en este tipo resúmenes identificar evidencia de eficacia/efectividad de Ambrisentan en pacientes con Hipertensión Arterial Pulmonar Grupo 2 al 5. En definitiva, no se cuenta con datos de eficacia/efectividad para extender la cobertura de Ambrisentan a otro grupo de pacientes. CONCLUSIÓN: Los tratamientos Ambisentan y Bosentan no resultan favorable dado que no se considera que la evidencia de eficacia respalde su utilización. Por ende, no siguen en análisis en las etapas posteriores. Por otra parte, Riociguat y Macitentan se consideran favorables. Para dar cumplimiento al artículo 28° del Reglamento que establece el proceso destinado a determinar los diagnósticos y tratamientos de alto costo con Sistema de Protección Financiera, según lo establecido en los artículos 7°y 8° de la ley N°20.850, aprobado por el decreto N°13 del Ministerio de Salud, se concluye que el presente informe de evaluación considera favorables los tratamientos riociguar y macitentan, de acuerdo a lo establecido en el Título III. de las Evaluaciones Favorables de la Norma Técnica N° 0192 de este mismo ministerio.

[Diagnosis and treatment of pulmonary hypertension]. / Diagnostiek en behandeling van pulmonale hypertensie.

Pulmonary hypertension is defined as a mean pulmonary artery pressure of more than 25 mmHg. There are many possible causes of pulmonary hypertension; pulmonary hypertension has a poor prognosis, irrespective of the underlying cause. The most frequent causes of pulmonary hypertension are left heart failure and lung disease. The diagnostic work up of pulmonary hypertension starts with investigations into left heart failure and lung disease. If these reveal no cause, ventilation perfusion scintigraphy should be carried out so that chronic thrombo-embolic pulmonary hypertension can be demonstrated or excluded. In most cases, chronic thrombo-embolic pulmonary hypertension can be treated curatively by means of pulmonary endarterectomy. If chronic thrombo-embolic pulmonary hypertension is also ruled out, then we speak of pulmonary arterial hypertension. Prostacyclins, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and soluble guanylyl cyclase stimulators have been shown to be effective in patients with pulmonary arterial hypertension. This condition should be treated at specialist centres.

Pulmonary arterial hypertension in adults: novel drugs and catheter ablation techniques show promise? Systematic review on pharmacotherapy and interventional strategies.

This systematic review aims to provide an update on pharmacological and interventional strategies for the treatment of pulmonary arterial hypertension in adults. Currently US Food and Drug Administration approved drugs including prostanoids, endothelin-receptor antagonists, phosphodiesterase type-5 inhibitors, and soluble guanylate-cyclase stimulators. These agents have transformed the prognosis for pulmonary arterial hypertension patients from symptomatic improvements in exercise tolerance ten years ago to delayed disease progression today. On the other hand, percutaneous balloon atrioseptostomy by using radiofrequency perforation, cutting balloon dilatation, or insertion of butterfly stents and pulmonary artery catheter-based denervation, both associated with very low rate of major complications and death, should be considered in combination with specific drugs at an earlier stage rather than late in the progression of pulmonary arterial hypertension and before the occurrence of overt right-sided heart failure.

From Escherichia coli heat-stable enterotoxin to mammalian endogenous guanylin hormones.

The isolation of heat-stable enterotoxin (STa) from Escherichia coli and cholera toxin from Vibrio cholerae has increased our knowledge of specific mechanisms of action that could be used as pharmacological tools to understand the guanylyl cyclase-C and the adenylyl cyclase enzymatic systems. These discoveries have also been instrumental in increasing our understanding of the basic mechanisms that control the electrolyte and water balance in the gut, kidney, and urinary tracts under normal conditions and in disease. Herein, we review the evolution of genes of the guanylin family and STa genes from bacteria to fish and mammals. We also describe new developments and perspectives regarding these novel bacterial compounds and peptide hormones that act in electrolyte and water balance. The available data point toward new therapeutic perspectives for pathological features such as functional gastrointestinal disorders associated with constipation, colorectal cancer, cystic fibrosis, asthma, hypertension, gastrointestinal barrier function damage associated with enteropathy, enteric infection, malnutrition, satiety, food preferences, obesity, metabolic syndrome, and effects on behavior and brain disorders such as attention deficit, hyperactivity disorder, and schizophrenia.

From Escherichia coli heat-stable enterotoxin to mammalian endogenous guanylin hormones

The isolation of heat-stable enterotoxin (STa) from Escherichia coli and cholera toxin from Vibrio cholerae has increased our knowledge of specific mechanisms of action that could be used as pharmacological tools to understand the guanylyl cyclase-C and the adenylyl cyclase enzymatic systems. These discoveries have also been instrumental in increasing our understanding of the basic mechanisms that control the electrolyte and water balance in the gut, kidney, and urinary tracts under normal conditions and in disease. Herein, we review the evolution of genes of the guanylin family and STa genes from bacteria to fish and mammals. We also describe new developments and perspectives regarding these novel bacterial compounds and peptide hormones that act in electrolyte and water balance. The available data point toward new therapeutic perspectives for pathological features such as functional gastrointestinal disorders associated with constipation, colorectal cancer, cystic fibrosis, asthma, hypertension, gastrointestinal barrier function damage associated with enteropathy, enteric infection, malnutrition, satiety, food preferences, obesity, metabolic syndrome, and effects on behavior and brain disorders such as attention deficit, hyperactivity disorder, and schizophrenia.

[New directions in the therapy of pulmonary arterial hypertension]. / Nowe kierunki w leczeniu tetniczego nadcisnienia plucnego.

Recent years are the time of dynamic development of pulmonary arterial pressure pharmacotherapy. By introducing the goal oriented therapy the survival in this group of patients has significantly increased. Apart from the pharmacotherapy used according to the ESC guidelines, new attempts of interventional treatment based on denervation of pulmonary artery have also been taken. Constantly, the new clinical trials (tests?) of drugs acting via new metabolic pathways have been conducted. They include for example: soluble guanylate cyclase stimulators, tyrosine kinase inhibitors, serotonin receptors inhibitors, Rhokinase inhibitors, VIP analogues. One of the newmedicines is riociguat, the effectiveness and safety of which have been confirmed in the PATENT and CHEST study. However, the small number and clinical diversity in the group of the PAH patients cause significant difficulties with the extrapolation of the results of trials according to the guidelines of the therapy.

Modulation of soluble guanylate cyclase for the treatment of erectile dysfunction.

Nitric oxide (NO) is the principal mediator of penile erection, and PDE-5 inhibitors are the first-line agents used to treat erectile dysfunction (ED). When NO formation or bioavailability is decreased by oxidative stress and PDE-5 inhibitors are no longer effective, a new class of agents called soluble guanylate cyclase (sGC) stimulators like BAY 41-8543 will induce erection. sGC stimulators bind to the normally reduced, NO-sensitive form of sGC to increase cGMP formation and promote erection. The sGC stimulators produce normal erectile responses when NO formation is inhibited and the nerves innervating the corpora cavernosa are damaged. However, with severe oxidative stress, the heme iron on sGC can be oxidized, rendering the enzyme unresponsive to NO or sGC stimulators. In this pathophysiological situation, another newly developed class of agents called sGC activators can increase the catalytic activity of the oxidized enzyme, increase cGMP formation, and promote erection. The use of newer agents that stimulate or activate sGC to promote erection and treat ED is discussed in this brief review article.