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2.
BMJ Open Respir Res ; 7(1)2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33239407

RESUMO

INTRODUCTION: Family history is a risk factor for chronic obstructive pulmonary disease (COPD). We previously developed a COPD risk score from genome-wide genetic markers (Polygenic Risk Score, PRS). Whether the PRS and family history provide complementary or redundant information for predicting COPD and related outcomes is unknown. METHODS: We assessed the predictive capacity of family history and PRS on COPD and COPD-related outcomes in non-Hispanic white (NHW) and African American (AA) subjects from COPDGene and ECLIPSE studies. We also performed interaction and mediation analyses. RESULTS: In COPDGene, family history and PRS were significantly associated with COPD in a single model (PFamHx <0.0001; PPRS<0.0001). Similar trends were seen in ECLIPSE. The area under the receiver operator characteristic curve for a model containing family history and PRS was significantly higher than a model with PRS (p=0.00035) in NHWs and a model with family history (p<0.0001) alone in NHWs and AAs. Both family history and PRS were significantly associated with measures of quantitative emphysema and airway thickness. There was a weakly positive interaction between family history and the PRS under the additive, but not multiplicative scale in NHWs (relative excess risk due to interaction=0.48, p=0.04). Mediation analyses found that a significant proportion of the effect of family history on COPD was mediated through PRS in NHWs (16.5%, 95% CI 9.4% to 24.3%), but not AAs. CONCLUSION: Family history and the PRS provide complementary information for predicting COPD and related outcomes. Future studies can address the impact of obtaining both measures in clinical practice.

3.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 184-191, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093782

RESUMO

Sarcoidosis-Associated Pulmonary Hypertension (SAPH) is a common finding in patients with chronic sarcoidosis and is associated with increased mortality. The optimal treatment for SAPH is not known; however, therapies approved for Group 1 pulmonary hypertension have improved hemodynamics and functional status. Prostanoids, including epoprostenol, have been therapeutic in short-term studies of SAPH, but long-term efficacy is unknown. In this study, we evaluated the long-term effect of epoprostenol therapy in 12 patients with SAPH. Hemodynamic assessment after an average of 4.1 years of epoprostenol therapy demonstrated significant improvement in mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output; furthermore, patients demonstrated improved NYHA functional class. To evaluate further the long-term effect of epoprostenol, we compared survival of SAPH patients to a cohort of hemodynamically matched patients from the same center treated with epoprostenol for Idiopathic Pulmonary Arterial Hypertension (IPAH). Interestingly, there was no difference in survival, despite the additional systemic disease burden of the SAPH subjects. Subgroup analysis by Scadding stage demonstrated that Scadding stages 1-3 had improved survival compared to Scadding stage 4. These observations suggest that epoprostenol is an effective long-term therapy for patients with SAPH; it improves hemodynamics, functional class, and provides survival similar to that seen in a hemodynamically-matched cohort of IPAH patients. Furthermore, we identify a subgroup of SAPH patients (nonfibrotic lung disease Scadding 1-3) who may derive significant benefit from prostanoid therapy. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 184-191).


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Epoprostenol/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Artéria Pulmonar/efeitos dos fármacos , Sarcoidose/complicações , Adulto , Anti-Hipertensivos/efeitos adversos , Débito Cardíaco/efeitos dos fármacos , Doença Crônica , Epoprostenol/efeitos adversos , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/fisiopatologia , Estudos Retrospectivos , Sarcoidose/diagnóstico , Sarcoidose/tratamento farmacológico , Fatores de Tempo , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacos
4.
EBioMedicine ; 61: 103026, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33039714

RESUMO

BACKGROUND: Prognostic tools are required to guide clinical decision-making in COVID-19. METHODS: We studied the relationship between the ratio of interleukin (IL)-6 to IL-10 and clinical outcome in 80 patients hospitalized for COVID-19, and created a simple 5-point linear score predictor of clinical outcome, the Dublin-Boston score. Clinical outcome was analysed as a three-level ordinal variable ("Improved", "Unchanged", or "Declined"). For both IL-6:IL-10 ratio and IL-6 alone, we associated clinical outcome with a) baseline biomarker levels, b) change in biomarker level from day 0 to day 2, c) change in biomarker from day 0 to day 4, and d) slope of biomarker change throughout the study. The associations between ordinal clinical outcome and each of the different predictors were performed with proportional odds logistic regression. Associations were run both "unadjusted" and adjusted for age and sex. Nested cross-validation was used to identify the model for incorporation into the Dublin-Boston score. FINDINGS: The 4-day change in IL-6:IL-10 ratio was chosen to derive the Dublin-Boston score. Each 1 point increase in the score was associated with a 5.6 times increased odds for a more severe outcome (OR 5.62, 95% CI -3.22-9.81, P = 1.2 × 10-9). Both the Dublin-Boston score and the 4-day change in IL-6:IL-10 significantly outperformed IL-6 alone in predicting clinical outcome at day 7. INTERPRETATION: The Dublin-Boston score is easily calculated and can be applied to a spectrum of hospitalized COVID-19 patients. More informed prognosis could help determine when to escalate care, institute or remove mechanical ventilation, or drive considerations for therapies. FUNDING: Funding was received from the Elaine Galwey Research Fellowship, American Thoracic Society, National Institutes of Health and the Parker B Francis Research Opportunity Award.


Assuntos
Infecções por Coronavirus/diagnóstico , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Pneumonia Viral/diagnóstico , Adulto , Idoso , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Prognóstico , Fatores de Tempo
5.
Chronic Obstr Pulm Dis ; 7(4): 346-361, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32877963

RESUMO

Background: Risk factor identification is a proven strategy in advancing treatments and preventive therapy for many chronic conditions. Quantifying the impact of those risk factors on health outcomes can consolidate and focus efforts on individuals with specific high-risk profiles. Using multiple risk factors and longitudinal outcomes in 2 independent cohorts, we developed and validated a risk score model to predict mortality in current and former cigarette smokers. Methods: We obtained extensive data on current and former smokers from the COPD Genetic Epidemiology (COPDGene®) study at enrollment. Based on physician input and model goodness-of-fit measures, a subset of variables was selected to fit final Weibull survival models separately for men and women. Coefficients and predictors were translated into a point system, allowing for easy computation of mortality risk scores and probabilities. We then used the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) cohort for external validation of our model. Results: Of 9867 COPDGene participants with standard baseline data, 17.6% died over 10 years of follow-up, and 9074 of these participants had the full set of baseline predictors (standard plus 6-minute walk distance and computed tomography variables) available for full model fits. The average age of participants in the cohort was 60 for both men and women, and the average predicted 10-year mortality risk was 18% for women and 25% for men. Model time-integrated area under the receiver operating characteristic curve statistics demonstrated good predictive model accuracy (0.797 average), validated in the external cohort (0.756 average). Risk of mortality was impacted most by 6-minute walk distance, forced expiratory volume in 1 second and age, for both men and women. Conclusions: Current and former smokers exhibited a wide range of mortality risk over a 10- year period. Our models can identify higher risk individuals who can be targeted for interventions to reduce risk of mortality, for participants with or without chronic obstructive pulmonary disease (COPD) using current Global initiative for obstructive Lung Disease (GOLD) criteria.

7.
J Community Hosp Intern Med Perspect ; 10(2): 93-98, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32850043

RESUMO

Background: Despite its proven utility, integration of point-of-care ultrasound (POCUS) into internal medicine (IM) residency training has been inconsistent. Due to their unique constraints, community-based teaching hospitals may face particular challenges in providing POCUS training to IM residents. Objectives: To evaluate short-term educational outcomes of an academic center's POCUS curriculum following its adaptation and delivery to IM residents at a community-based teaching hospital. Methods: A needs assessment (NA) regarding POCUS training was distributed to PGY-2 and PGY-3 IM residents at a community-based teaching hospital in 2017. Based on the NA results, a POCUS curriculum from an academic center was modified and a revised course was offered to the same residents. Participants completed cognitive assessments before and after three of the four didactic sessions. Observed placement of an ultrasound-guided peripheral IV before and after the training program comprised the skills assessment. Results: 17 of 28 (61%) residents completed the NA; eleven participated in the course. Of 33 possible quiz pairs, 15 (45%) were completed. Average quiz scores rose after the first and third sessions. Skills assessment scores increased after course completion. Conclusion: Adaptation of POCUS curricula from academic centers may be a feasible instructional strategy for community-based IM residency programs.

8.
Lancet Respir Med ; 8(7): 696-708, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32649918

RESUMO

BACKGROUND: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. METHODS: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC <0·7 and FEV1 <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth. FINDINGS: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern. INTERPRETATION: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth. FUNDING: US National Institutes of Health, Wellcome Trust.


Assuntos
Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Volume Expiratório Forçado , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Fatores de Risco , Capacidade Vital
9.
Chest ; 158(5): 2130-2135, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32710891
10.
Chest ; 158(3): 952-964, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32353417

RESUMO

BACKGROUND: COPD is a leading cause of mortality. RESEARCH QUESTION: We hypothesized that applying machine learning to clinical and quantitative CT imaging features would improve mortality prediction in COPD. STUDY DESIGN AND METHODS: We selected 30 clinical, spirometric, and imaging features as inputs for a random survival forest. We used top features in a Cox regression to create a machine learning mortality prediction (MLMP) in COPD model and also assessed the performance of other statistical and machine learning models. We trained the models in subjects with moderate to severe COPD from a subset of subjects in Genetic Epidemiology of COPD (COPDGene) and tested prediction performance in the remainder of individuals with moderate to severe COPD in COPDGene and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We compared our model with the BMI, airflow obstruction, dyspnea, exercise capacity (BODE) index; BODE modifications; and the age, dyspnea, and airflow obstruction index. RESULTS: We included 2,632 participants from COPDGene and 1,268 participants from ECLIPSE. The top predictors of mortality were 6-min walk distance, FEV1 % predicted, and age. The top imaging predictor was pulmonary artery-to-aorta ratio. The MLMP-COPD model resulted in a C index ≥ 0.7 in both COPDGene and ECLIPSE (6.4- and 7.2-year median follow-ups, respectively), significantly better than all tested mortality indexes (P < .05). The MLMP-COPD model had fewer predictors but similar performance to that of other models. The group with the highest BODE scores (7-10) had 64% mortality, whereas the highest mortality group defined by the MLMP-COPD model had 77% mortality (P = .012). INTERPRETATION: An MLMP-COPD model outperformed four existing models for predicting all-cause mortality across two COPD cohorts. Performance of machine learning was similar to that of traditional statistical methods. The model is available online at: https://cdnm.shinyapps.io/cgmortalityapp/.

11.
BMC Pulm Med ; 20(1): 123, 2020 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366316

RESUMO

BACKGROUND: Previous studies have established a higher prevalence of vitamin D deficiency in patients with COPD, but the relationship between vitamin D levels and COPD exacerbations remains controversial. In addition, the effect of vitamin D levels on imaging characteristics remains mostly unexplored. Using cross-sectional and longitudinal follow up data from the COPDGene Study, we assessed the association between vitamin D levels on respiratory symptoms, exacerbations, and imaging characteristics. We hypothesized that vitamin D deficiency will be associated with worse respiratory-related outcomes. METHODS: Current and former smokers between ages 45-80 were enrolled the COPDGene Study. Subjects completed questionnaires, spirometry, six-minute walk test, and chest computed tomography scans. A subset of subjects had measurement of serum concentration of 25-hydroxyvitamin D (25(OH)D). Vitamin D deficiency was defined as serum concentration less than 20 ng/mL. Longitudinal follow up was conducted via a web-based or telephone questionnaire. RESULTS: Vitamin D levels were measured on 1544 current and former smokers, of which 981 subjects had sufficient vitamin D levels and 563 subjects had vitamin D deficiency. Subjects with vitamin D deficiency were younger with increased likelihood of being African American, being current smokers, having a lower percent predicted FEV1, and having COPD. Vitamin D deficiency was associated with worse quality of life, increased dyspnea, decreased exercise tolerance, and increased frequency of severe exacerbations. Vitamin D deficiency was also associated with increased segmental airway wall thickness on chest CT scans. CONCLUSION: Vitamin D deficiency was associated with increased respiratory symptoms, decreased functional status, increased frequency of severe exacerbations, as well as airway wall thickening on chest CT scans. Further research is needed to determine the potential impact of vitamin D supplementation to improve disease outcomes.

12.
Chronic Obstr Pulm Dis ; 7(2): 86-98, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32324980

RESUMO

Background: Apparent increased female susceptibility to chronic obstructive pulmonary disease (COPD) suggests sex hormones modulate disease pathogenesis. Little is known about associations between multiparity and lung function in smokers. Research Question: We hypothesized that multiparity is associated with lung function and measures of emphysema and airway disease. Study Design and Methods: Utilizing female participants from the 5-year follow up of the COPD Genetic Epidemiology (COPDGene®) study we performed multivariable linear regressions to assess the effect of multiparity and number of pregnancies on forced expiratory volume in 1 second (FEV1) percentage of predicted (% predicted), FEV1/forced vital capacity (FVC), percent emphysema on computed tomography (CT) scans, and Pi10, a measure of airway thickening. We sampled never smokers and those with lower smoking exposure from the National Health and Nutrition Examination Survey (NHANES) 2011-2012 dataset. Results: We included 1820 participants from COPDGene® and 418 participants from NHANES (321 never smokers, 97 ever smokers). In COPDGene®, multiparity (beta coefficient [ß] = -3.8, 95% confidence interval [CI]: [-6.5, -1.1], p = 0.005) and higher number of pregnancies were associated with lower FEV1 % predicted. Multiparity was not associated with percent emphysema or Pi10. In individuals with no or mild obstruction, multiparity was associated with lower FEV1 % predicted. There was an interaction with multiparity and age on FEV1 % predicted (p = 0.025). In NHANES, there was no association between multiparity and FEV1 % predicted in never smokers or the lower smoking exposure group. Interpretation: Multiparity was associated with lower FEV1 % predicted in current and former smokers in COPDGene® study participants. These preliminary results emphasize the importance of smoking abstinence in women of child-bearing age.

14.
J Scleroderma Relat Disord ; 3(3): 242-248, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30498788

RESUMO

Objective: Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are major causes of mortality in systemic sclerosis (SSc). We used a previously identified microarray biomarker to determine if SSc-PAH and SSc-ILD patients demonstrate distinct gene expression profiles. Methods: PBMCs were collected from healthy controls (n=10), SSc (SSc) patients without pulmonary hypertension [SSc-noPAH, n=39], and SSc-PAH patients (n=21; mPAP≥25, PCWP≤15, PVR≥3WU) diagnosed by right heart catheterization (RHC). SSc-ILD patients were defined as those with evidence of fibrosis on chest CT and significant restriction (FVC<70% predicted, n = 11). SSc-PAH biomarker included 69 genes selected by unbiased statistical screening of 3 publicly available microarray studies. RNA levels were measured by Nanostring. Gene expression levels that were significantly correlated with PAH (multiple statistical measures) were chosen as inputs into a forward selection logistic regression model. Results: When ILD patients were included (n=64), 4 genes (S100P, CD8B1, CCL2, TIMP1) and male sex predicted PAH with a high level of accuracy (AUC = 0.83). Without ILD patients (n=53), 2 genes (THBS1, CD8B1) and male sex predicted PAH with a high level of accuracy (AUC = 0.80). When examining SSc patients with borderline elevated pulmonary pressures (mPAP = 21-24 mmHg), gene expression changes closely resembled the SSc-PAH group, except for THBS1. Conclusion: SSc-PAH and SSc-ILD have similar, but distinct, gene expression profiles. Many gene expression changes occur early in the disease course, potentially allowing for early detection. THBS1 appears to be an important mediator in the development of PAH-predominant phenotype. Further prospective investigation is warranted.

16.
Expert Opin Drug Metab Toxicol ; 12(12): 1513-1520, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27756196

RESUMO

INTRODUCTION: Management of pulmonary arterial hypertension (PAH) remains challenging even in the contemporary era. Intravenous prostacyclin therapy, while associated with decreased mortality, has practical limitations and requires significant lifestyle modifications. The recently approved long-acting oral IP prostacyclin receptor agonist for treatment of PAH, selexipag, is a non-prostanoid agent that vasodilates, impacts remodeling (anti-proliferative), reduces endothelial cell dysfunction, inhibits platelet aggregation (anti-thrombotic), and increases right heart inotropy. Areas covered: This review discusses the limitations of non-oral prostacyclin therapy for PAH and describes the factors which led to successful development of selexipag in in vitro and preclinical studies. We review the pharmacokinetics and pharmacodynamics of selexipag. We further discuss the methodology and results of phase II and III trials, which led to approval of selexipag for PAH management. Expert opinion: As compared to previously developed oral prostacyclins, selexipag has limited adverse effects despite similar or better efficacy. Its final place in the treatment paradigm is not yet clear but it does represent a significant advance in the area of oral PAH therapy.


Assuntos
Acetamidas/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Hipertensão Pulmonar/tratamento farmacológico , Pirazinas/administração & dosagem , Acetamidas/farmacocinética , Acetamidas/farmacologia , Administração Oral , Animais , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Preparações de Ação Retardada , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Hipertensão Pulmonar/mortalidade , Pirazinas/farmacocinética , Pirazinas/farmacologia , Resultado do Tratamento
18.
J Allergy Clin Immunol ; 137(5): 1390-1397.e6, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26792209

RESUMO

BACKGROUND: Recent studies have used cluster analysis to identify phenotypic clusters of asthma with differences in clinical traits, as well as differences in response to therapy with anti-inflammatory medications. However, the correspondence between different phenotypic clusters and differences in the underlying molecular mechanisms of asthma pathogenesis remains unclear. OBJECTIVE: We sought to determine whether clinical differences among children with asthma in different phenotypic clusters corresponded to differences in levels of gene expression. METHODS: We explored differences in gene expression profiles of CD4(+) lymphocytes isolated from the peripheral blood of 299 young adult participants in the Childhood Asthma Management Program study. We obtained gene expression profiles from study subjects between 9 and 14 years of age after they participated in a randomized, controlled longitudinal study examining the effects of inhaled anti-inflammatory medications over a 48-month study period, and we evaluated the correspondence between our earlier phenotypic cluster analysis and subsequent follow-up clinical and molecular profiles. RESULTS: We found that differences in clinical characteristics observed between subjects assigned to different phenotypic clusters persisted into young adulthood and that these clinical differences were associated with differences in gene expression patterns between subjects in different clusters. We identified a subset of genes associated with atopic status, validated the presence of an atopic signature among these genes in an independent cohort of asthmatic subjects, and identified the presence of common transcription factor binding sites corresponding to glucocorticoid receptor binding. CONCLUSION: These findings suggest that phenotypic clusters are associated with differences in the underlying pathobiology of asthma. Further experiments are necessary to confirm these findings.


Assuntos
Asma/genética , Hipersensibilidade Imediata/genética , Adolescente , Asma/sangue , Asma/imunologia , Asma/fisiopatologia , Linfócitos T CD4-Positivos/metabolismo , Criança , Eosinófilos/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Imunoglobulina E/sangue , Masculino , Fenótipo , Ensaios Clínicos Controlados Aleatórios como Assunto , Espirometria , Transcriptoma
19.
Pulm Circ ; 5(4): 730-3, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26697182

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive disease marked by the irreversible pulmonary vascular changes of vasoconstriction, thrombosis, and proliferation of smooth muscle and endothelial cells. The untreated clinical course is characterized by progressive dyspnea and a median survival of less than 3 years. Many of these patients are of child-bearing age; however, pregnancy leads to physiologic changes that are particularly poorly tolerated in PAH, conferring a 30%-56% mortality. We present a case of PAH that spontaneously resolved after termination of pregnancy and recurred during each of two subsequent pregnancies. To our knowledge, this case is unique, because no cases of spontaneous resolution of idiopathic PAH have been reported in adults, nor have there been any reports of pulmonary hypertension that is isolated to the gestational period.

20.
Expert Opin Investig Drugs ; 24(12): 1571-96, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26484967

RESUMO

INTRODUCTION: Despite the development of new therapies, pulmonary arterial hypertension (PAH) has a median survival of 6 - 7 years. This is likely because the currently approved therapies affect predominantly pulmonary vasoconstriction. The past two decades have witnessed greater insights into the pathogenesis of PAH, from the role of inflammation to molecular signaling and epigenetics. Multiple pharmacological agents targeting these newly identified pathways are currently being investigated in preclinical and early clinical studies. AREAS COVERED: Herein, the authors review the modalities targeting recently identified molecular targets in PAH. These include: prostaglandin receptor agonists, agents that alter the cyclic adenosine monophosphate and cyclic guanosine monophosphate pathways, vasoactive peptides, receptor tyrosine kinase inhibitors, Rho-kinase inhibitors, serotonin pathway inhibitors, anti-inflammatory agents, antioxidants, agents that alter nitric oxide signaling, various cardiac medications, mitochondrial metabolism modifying agents, epigenetic agents and cell-based therapies. The authors also address the gaps in the knowledge and explain why certain agents may or may not be promising PAH pharmacotherapeutics. EXPERT OPINION: Newer agents target multiple pathways including vasoconstriction, cellular proliferation and inflammatory response. And while only a few of the current investigational drugs will likely be further developed, the authors expect that the next two decades will bring some major breakthroughs in PAH management.


Assuntos
Anti-Hipertensivos/uso terapêutico , Drogas em Investigação/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Animais , Anti-Hipertensivos/farmacologia , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Drogas em Investigação/farmacologia , Humanos , Hipertensão Pulmonar/fisiopatologia , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos
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