RESUMEN
Pulmonary arterial (PA) hypertension (PAH) is a severe cardiopulmonary disease that may be triggered by exposure to drugs such as dasatinib or facilitated by genetic predispositions. The incidence of dasatinib-associated PAH is estimated at 0.45%, suggesting individual predispositions. The mechanisms of dasatinib-associated PAH are still incomplete. We discovered a KCNK3 gene (Potassium channel subfamily K member 3; coding for outward K+ channel) variant in a patient with dasatinib-associated PAH and investigated the impact of this variant on KCNK3 function. Additionally, we assessed the effects of dasatinib exposure on KCNK3 expression. In control human PA smooth muscle cells (hPASMCs) and human pulmonary endothelial cells (hPECs), we evaluated the consequences of KCNK3 knockdown on cell migration, mitochondrial membrane potential, ATP production, and in vitro tube formation. Using mass spectrometry, we determined the KCNK3 interactome. Patch-clamp experiments revealed that the KCNK3 variant represents a loss-of-function variant. Dasatinib contributed to PA constriction by decreasing KCNK3 function and expression. In control hPASMCs, KCNK3 knockdown promotes mitochondrial membrane depolarization and glycolytic shift. Dasatinib exposure or KCNK3 knockdown reduced the number of caveolae in hPECs. Moreover, KCNK3 knockdown in control hPECs reduced migration, proliferation, and in vitro tubulogenesis. Using proximity labeling and mass spectrometry, we identified the KCNK3 interactome, revealing that KCNK3 interacts with various proteins across different cellular compartments. We identified a novel pathogenic variant in KCNK3 and showed that dasatinib downregulates KCNK3, emphasizing the relationship between dasatinib-associated PAH and KCNK3 dysfunction. We demonstrated that a loss of KCNK3-dependent signaling contributes to endothelial dysfunction in PAH and glycolytic switch of hPASMCs.
Asunto(s)
Dasatinib , Células Endoteliales , Canales de Potasio de Dominio Poro en Tándem , Dasatinib/farmacología , Dasatinib/efectos adversos , Humanos , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Canales de Potasio de Dominio Poro en Tándem/genética , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Movimiento Celular/efectos de los fármacos , Hipertensión Arterial Pulmonar/inducido químicamente , Hipertensión Arterial Pulmonar/genética , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/patología , Masculino , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Arteria Pulmonar/efectos de los fármacos , Proteínas del Tejido NerviosoRESUMEN
BACKGROUND: Pulmonary arterial hypertension (PAH) has been described in patients treated with proteasome inhibitors (PIs). Our objective was to evaluate the association between PIs and PAH. METHODS: Characteristics of incident PAH cases previously treated with carfilzomib or bortezomib were analysed from the French pulmonary hypertension registry and the VIGIAPATH programme from 2004 to 2023, concurrently with a pharmacovigilance disproportionality analysis using the World Health Organization (WHO) global database (VigiBase) and a meta-analysis of randomised controlled trials. RESULTS: 11 incident cases of PI-associated PAH were identified (six with carfilzomib and five with bortezomib) with a female:male ratio of 2.7:1, a median age of 61â years, and a median delay between PI first exposure and PAH of 6â months. Four patients died (two from right heart failure, one from respiratory distress and one from an unknown cause). At diagnosis, six were in New York Heart Association Functional Class III/IV with severe haemodynamic impairment (median mean pulmonary arterial pressure 39â mmHg, cardiac index 2.45 L·min-1·m-2 and pulmonary vascular resistance 7.2â WU). In the WHO pharmacovigilance database, 169 cases of PH associated with PI were reported since 2013 with significant signals of disproportionate reporting (SDR) for carfilzomib, regardless of the definition of cases or control group. However, SDR for bortezomib were inconsistent. The systematic review identified 17 clinical trials, and carfilzomib was associated with a significantly higher risk of dyspnoea, severe dyspnoea and PH compared with bortezomib. CONCLUSION: PIs may induce PAH in patients undergoing treatment, with carfilzomib emitting a stronger signal than bortezomib, and these patients should be monitored closely.
Asunto(s)
Bortezomib , Oligopéptidos , Inhibidores de Proteasoma , Hipertensión Arterial Pulmonar , Humanos , Persona de Mediana Edad , Bortezomib/efectos adversos , Bortezomib/uso terapéutico , Francia/epidemiología , Oligopéptidos/efectos adversos , Oligopéptidos/uso terapéutico , Farmacovigilancia , Inhibidores de Proteasoma/efectos adversos , Inhibidores de Proteasoma/uso terapéutico , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/inducido químicamente , Ensayos Clínicos Controlados Aleatorios como Asunto , Sistema de RegistrosRESUMEN
Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by the dysfunction of pulmonary endothelial cells (ECs) and obstructive vascular remodeling. cAbl (non-receptor tyrosine kinase c-Abelson) plays central roles in regulating cell-cycle arrest, apoptosis, and senescence after cellular stress. We hypothesized that cAbl is downactivated in experimental and human PAH, thus leading to reduced DNA integrity and angiogenic capacity of pulmonary ECs from patients with PAH (PAH-ECs). We found cAbl and phosphorylated cAbl concentrations to be lower in the endothelium of remodeled pulmonary vessels in the lungs of patients with PAH than in control subjects. Similar observations were obtained for the lungs of Sugen + hypoxia and monocrotaline rats with established pulmonary hypertension. These in situ abnormalities were also replicated in vitro, with cultured PAH-ECs displaying lower cAbl expression and activity and an altered DNA damage response and capacity of tube formation. Downregulation of cAbl by RNA interference in control ECs or its inhibition with dasatinib resulted in genomic instability and the failure to form tubes, whereas upregulation of cAbl with 5-(1,3-diaryl-1H-pyrazol-4-yl) hydantoin reduced DNA damage and apoptosis in PAH-ECs. Finally, we establish the existence of cross-talk between cAbl and bone morphogenetic protein receptor type II. This work identifies the loss of cAbl signaling as a novel contributor to pulmonary EC dysfunction associated with PAH.
Asunto(s)
Células Endoteliales , Hipertensión Arterial Pulmonar , Animales , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Hipertensión Pulmonar Primaria Familiar/metabolismo , Humanos , Monocrotalina , Proteínas Tirosina Quinasas/metabolismo , Arteria Pulmonar/metabolismo , RatasRESUMEN
Since the 1960s, several drugs have been linked to the onset or aggravation of pulmonary arterial hypertension (PAH): dasatinib, some amphetamine-like appetite suppressants (aminorex, fenfluramine, dexfenfluramine, benfluorex) and recreational drugs (methamphetamine). Moreover, in numerous cases, the implication of other drugs with PAH have been suggested, but the precise identification of iatrogenic aetiologies of PAH is challenging given the scarcity of this disease and the potential long latency period between drug intake and PAH onset. In this context, we used the World Health Organization's pharmacovigilance database, VigiBase, to generate new hypotheses about drug associated PAH. METHODS: We used VigiBase, the largest pharmacovigilance database worldwide to generate disproportionality signals through the Bayesian neural network method. All disproportionality signals were further independently reviewed by experts in pulmonary arterial hypertension, pharmacovigilance and vascular pharmacology and their plausibility ranked according to World Health Organization causality categories. RESULTS: We included 2184 idiopathic PAH cases, yielding a total of 93 disproportionality signals. Among them, 25 signals were considered very likely, 15 probable, 28 possible and 25 unlikely. Notably, we identified 4 new protein kinases inhibitors (lapatinib, lorlatinib, ponatinib and ruxolitinib), 1 angiogenesis inhibitor (bevacizumab), and several chemotherapeutics (etoposide, trastuzumab), antimetabolites (cytarabine, fludarabine, fluorouracil, gemcitabine) and immunosuppressants (leflunomide, thalidomide, ciclosporin). CONCLUSION: Such signals represent plausible adverse drug reactions considering the knowledge of iatrogenic PAH, the drugs' biological and pharmacological activity and the characteristics of the reported case. Although confirmatory studies need to be performed, the signals identified may help clinicians envisage an iatrogenic aetiology when faced with a patient who develops PAH.
Asunto(s)
Farmacovigilancia , Hipertensión Arterial Pulmonar , Humanos , Hipertensión Arterial Pulmonar/inducido químicamente , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/epidemiología , Sistemas de Registro de Reacción Adversa a Medicamentos , Teorema de Bayes , Bases de Datos Factuales , Organización Mundial de la Salud , Enfermedad IatrogénicaRESUMEN
Tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl oncoprotein revolutionised the treatment of chronic myelogenous leukaemia. Following the success of imatinib, second- and third-generation molecules were developed. Different profiles of kinase inhibition and off-target effects vary between TKIs, which leads to a broad spectrum of potential toxicities.Pulmonary complications are most frequently observed with dasatinib but all other Bcr-Abl TKIs have been implicated. Pleural effusions are the most frequent pulmonary complication of TKIs, usually associated with dasatinib and bosutinib. Pulmonary arterial hypertension is an uncommon but serious complication of dasatinib, which is often reversible upon discontinuation. Bosutinib and ponatinib have also been associated with pulmonary arterial hypertension, while imatinib has not. Rarely, interstitial lung disease has been associated with TKIs, predominantly with imatinib.Mechanistically, dasatinib affects maintenance of normal pulmonary endothelial integrity by generating mitochondrial oxidative stress, inducing endothelial apoptosis and impairing vascular permeability in a dose-dependent manner. The mechanisms underlying other TKI-related complications are largely unknown. Awareness and early diagnosis of the pulmonary complications of Bcr-Abl TKIs is essential given their seriousness, potential reversibility, and impact on future treatment options for the underlying chronic myelogenous leukaemia.
Asunto(s)
Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Antineoplásicos/efectos adversos , Dasatinib/efectos adversos , Proteínas de Fusión bcr-abl/uso terapéutico , Humanos , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
BACKGROUND: Viral respiratory infections are the main causes of asthma exacerbation. The susceptibility of patients with asthma to develop an exacerbation when they present with severe pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is unknown. The objective of this study was to investigate the characteristics and outcomes of asthmatic patients with coronavirus disease 2019 (COVID-19) pneumonia who required hospitalisation during the spring 2020 outbreak in Paris, France. METHODS: A prospective cohort follow-up was carried out from 15 March to 15 April 2020 in Bicêtre Hospital, University Paris-Saclay, France. All hospitalised patients with a SARS-CoV-2 infection who reported a history of asthma were included. RESULTS: Among 768 hospitalised patients, 37 (4.8%) reported a history of asthma, which had been previously confirmed by a pulmonologist in 85% of cases. These asthmatic patients were mainly female (70%) and nonsmokers (85%), with a median age of 54â years (interquartile range (IQR) 42-67â years). None of them presented with an asthma exacerbation. 22 (59%) had major comorbidities and 31 (84%) had a body mass index ≥25â kg·m-2. The most common comorbidities were obesity (36%), hypertension (27%) and diabetes (19%). All patients had a confirmed diagnosis of COVID-19 pneumonia on computed tomography of the chest. Eosinopenia was a typical biological feature with a median count of 0â cells·mm-3 (IQR 0-0â cells·mm-3). 11 patients (30%) were admitted into the intensive care unit, with three deaths (8.1%) occurring in the context of comorbidities. CONCLUSION: Asthma patients were not overrepresented among those with severe pneumonia due to SARS-CoV-2 infection who required hospitalisation. The worst outcomes were observed mainly in patients with major comorbidities.
Asunto(s)
Asma/complicaciones , Asma/terapia , Betacoronavirus , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/terapia , Hospitalización , Neumonía Viral/complicaciones , Neumonía Viral/terapia , Adulto , Anciano , Antiasmáticos/uso terapéutico , Asma/diagnóstico , COVID-19 , Estudios de Cohortes , Infecciones por Coronavirus/diagnóstico , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Pandemias , Neumonía Viral/diagnóstico , SARS-CoV-2RESUMEN
Atrial fibrillation (AF) accounts for up to one third of strokes, one of the lead mortality causes worldwide. The European Society of Cardiology guidelines recommend opportunistic screening as a means to increase the odds of early detection and institution of appropriate treatment according to risk factors identified. However, in most countries there are various barriers to effective uptake of screening, including low awareness. The Atrial Fibrillation Association is a patient association engaged with raising awareness of AF. Establishing a partnership with the International Pharmacists for Anticoagulation Care Taskforce, we set as goals to test a model for raising awareness of AF involving pharmacists globally; and to identify barriers and enablers to its implementation. A cross-sectional study was conducted during the Arrhythmia Alliance World Heart Rhythm Week. Pharmacists from 10 countries invited individuals (≥ 40 years; without anticoagulation therapy of AF) to participate in the awareness campaign. Participants agreeing were engaged in the early detection of AF (EDAF) using pulse palpation. Individuals with rhythm discrepancies were referred and prospectively assessed to have information on the proportion of confirmed diagnosis, leading to estimate the detection rate. Interviews with country coordinators explored barriers and enablers to implementation. The study involved 4193 participants in the awareness campaign and 2762 in the EDAF event (mean age 65.3 ± 13.0), of whom 46.2% individuals were asymptomatic, recruited across 120 sites. Most common CHA2DS2-VASc risk factor was hypertension. Among 161 patients referred to physician, feedback was obtained for 32 cases, of whom 12 new arrhythmia diagnoses were confirmed (5 for AF, 2 for atrial flutter), all among elders (≥ 65 years). Qualitative evaluation suggested a local champion to enable pharmacists' success; technology enhanced engagement amongst patients and increased pharmacists' confidence in referring to physicians; interprofessional relationship was crucial in success. This study suggests pharmacists can contribute to greater outreach of awareness campaigns. Effective communication pathways for inter-professional collaboration were suggested enablers to gain full benefits of EDAF.
Asunto(s)
Fibrilación Atrial/diagnóstico , Educación en Salud/métodos , Farmacéuticos , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Diagnóstico Precoz , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Internacionalidad , Masculino , Persona de Mediana EdadRESUMEN
The pathophysiology of pulmonary arterial hypertension (PAH) induced by protein kinase inhibitors (PKIs) remains unclear. To gain knowledge into this rare and severe pathology we performed a study combining a pharmacovigilance approach and the pharmacodynamic properties of PKIs.A disproportionality analysis on the World Health Organization pharmacovigilance database VigiBase using the reporting odds ratio (ROR) and 95% confidence interval was first performed. Then, we identified the most relevant cellular targets of interest through a systematic literature review and correlated the pharmacovigilance signals with the affinity for the different PKIs. We further performed a hierarchical cluster analysis to assess patterns of binding affinity.A positive disproportionality signal was found for dasatinib, bosutinib, ponatinib, ruxolitinib and nilotinib. Five non-receptor protein kinases significantly correlate with disproportionality signals: c-Src (r=0.79, p=0.00027), c-Yes (r=0.82, p=0.00015), Lck (r=0.81, p=0.00046) and Lyn (r=0.80, p=0.00036), all belonging to the Src protein kinase family, and TEC (r=0.85, p=0.00006). Kinases of the bone morphogenetic protein signalling pathway also seem to play a role in the pathophysiology of PKI-induced PAH. Interestingly, the dasatinib affinity profile seems to be different from that of other PKIs in the cluster analysis.The study highlights the potential role of the Src protein kinase family and TEC in PAH induced by PKIs. This approach combining pharmacovigilance and pharmacodynamics data allowed us to generate some hypotheses about the pathophysiology of the disease; however, the results have to be confirmed by further studies.
Asunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Farmacovigilancia , Inhibidores de Proteínas Quinasas/efectos adversos , Hipertensión Arterial Pulmonar/epidemiología , Adulto , Anciano , Bases de Datos Factuales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Hipertensión Arterial Pulmonar/inducido químicamente , Hipertensión Arterial Pulmonar/inmunología , Revisiones Sistemáticas como Asunto , Organización Mundial de la Salud , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/inmunologíaRESUMEN
This study aimed to describe the long-term outcomes of pulmonary arterial hypertension (PAH) induced by dasatinib.21 incident, right heart catheterisation-confirmed cases of dasatinib-induced PAH were identified from the French Pulmonary Hypertension Registry. Clinical and haemodynamic variables were compared from baseline to last follow-up (median (range) 24 (1-81)â months).Median age was 52â years and 15 patients were female (71%). 19 patients received dasatinib for chronic myelogenous leukaemia for a median (range) duration of 42â (8-74)â months before PAH diagnosis. No bone morphogenic protein receptor-2 (BMPR2) mutations were found in the 10 patients tested. Dasatinib was uniformly discontinued and 11 patients received PAH medications. Four patients died during follow-up. New York Heart Association functional class improved from 76% in class III/IV to 90% in class I/II (p<0.01). Median (range) 6-min walk distance improved from 306â (0-660) to 430â (165-635)â m (p<0.01). Median (range) mean pulmonary arterial pressure improved from 45â (30-70) to 26â (17-50)â mmHg (p<0.01) and pulmonary vascular resistance from 6.1â (3.2-27.3) to 2.6â (1.2-5.9)â Wood units (p<0.01). Patients treated with PAH medications had worse baseline haemodynamics but similar long-term outcomes to untreated patients. PAH persisted in 37% of patients.Dasatinib-induced PAH frequently improves after discontinuation but persisted in over one-third of patients, therefore systematic follow-up is essential.
Asunto(s)
Dasatinib/efectos adversos , Hipertensión Pulmonar/inducido químicamente , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Adolescente , Adulto , Anciano , Femenino , Estudios de Seguimiento , Francia , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Sistema de Registros , Estudios Retrospectivos , Resistencia Vascular , Adulto JovenRESUMEN
PURPOSE OF REVIEW: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of several neoplastic conditions; however, pulmonary arterial hypertension (PAH) has been reported as a complication of TKIs, predominantly with dasatinib. Recent studies have elucidated the potential mechanisms of TKI-induced PAH and have better clarified the long-term outcomes. RECENT FINDINGS: In addition to the known association between dasatinib and PAH, several other TKIs have recently been reported to cause PAH, including ponatinib, bosutinib and lapatinib. Dasatinib causes direct pulmonary artery endothelial cell toxicity through the production of mitochondrial reactive oxygen species, but likely requires the presence of a second risk factor to cause PAH. Symptoms and haemodynamic abnormalities frequently resolve after discontinuation of the TKI, but PAH persists in over a third of patients and can reoccur when other TKIs are used, which warrants close follow-up. Rare fatal cases have occurred; therefore, treatment with PAH-specific therapy is recommended for patients with right heart failure or persistent PAH after discontinuation of the TKI. SUMMARY: PAH is a rare but important complication of several TKIs. Management includes discontinuation of the TKI, close follow-up and PAH-specific therapy in severe cases.
Asunto(s)
Antineoplásicos/efectos adversos , Hipertensión Pulmonar , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Humanos , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/prevención & control , Administración del Tratamiento Farmacológico , Selección de Paciente , Arteria Pulmonar/efectos de los fármacosRESUMEN
BACKGROUND: Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension characterized by the obstruction of small pulmonary veins and a dismal prognosis. PVOD may be sporadic or heritable because of biallelic mutations of the EIF2AK4 gene coding for GCN2. Isolated case reports suggest that chemotherapy may be a risk factor for PVOD. METHODS AND RESULTS: We reported on the clinical, functional, and hemodynamic characteristics and outcomes of 7 cases of PVOD induced by mitomycin-C (MMC) therapy from the French Pulmonary Hypertension Registry. All patients displayed squamous anal cancer and were treated with MMC alone or MMC plus 5-fluoruracil. The estimated annual incidence of PVOD in the French population that have anal cancer is 3.9 of 1000 patients, which is much higher than the incidence of PVOD in the general population (0.5/million per year). In rats, intraperitoneal administration of MMC induced PVOD, as demonstrated by pulmonary hypertension at right-heart catheterization at days 21 to 35 and major remodeling of small pulmonary veins associated with foci of intense microvascular endothelial-cell proliferation of the capillary bed. In rats, MMC administration was associated with dose-dependent depletion of pulmonary GCN2 content and decreased smad1/5/8 signaling. Amifostine prevented the development of MMC-induced PVOD in rats. CONCLUSIONS: MMC therapy is a potent inducer of PVOD in humans and rats. Amifostine prevents MMC-induced PVOD in rats and should be tested as a preventive therapy for MMC-induced PVOD in humans. MMC-induced PVOD in rats represents a unique model to test novel therapies in this devastating orphan disease.
Asunto(s)
Antibióticos Antineoplásicos/efectos adversos , Modelos Animales de Enfermedad , Mitomicina/efectos adversos , Enfermedad Veno-Oclusiva Pulmonar/inducido químicamente , Enfermedad Veno-Oclusiva Pulmonar/diagnóstico , Adulto , Animales , Neoplasias del Ano/diagnóstico , Neoplasias del Ano/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Ratas , Ratas Wistar , Sistema de RegistrosRESUMEN
Sofosbuvir and daclatasvir are direct-acting antiviral drugs used to treat chronic hepatitis C virus infection. In 2015, the Food and Drug Administration and European Medical Agency warned that bradycardia could occur when amiodarone was administered in combination with sofosbuvir, but no case reports had been published. We report extreme bradycardia within 2 hrs after intake of sofosbuvir and daclatasvir by 2 patients receiving amiodarone. The first patient had a cardiac asystole 30 min after receiving sofosbuvir and daclatasvir. Amiodarone, sofosbuvir, and daclatasvir treatment were stopped; after 10 days, the cardiac evaluation was normal and patient was discharged. The second patient was taking amiodarone and propranolol; 2 hrs after receiving sofosbuvir and daclatasvir, he had an extreme sinus node dysfunction (heart rate of 27beats/min). Amiodarone and propranolol were stopped, but the patient continued receiving sofosbuvir and daclatasvir for 3 days and sinus bradycardia was recorded each day, 2 hrs after intake of these drugs. When he stopped taking the drugs, no bradycardia was observed. Administration of sofosbuvir and daclatasvir on day 13 induced bradycardia 2 hrs after intake. However, no bradycardia occurred following a rechallenge 8 weeks after the patient stopped taking amiodarone. These observations indicate that patients treated with amiodarone should be continuously monitored within the first 48 hrs following the initiation of sofosbuvir and daclatasvir.
Asunto(s)
Amiodarona/administración & dosificación , Bradicardia/inducido químicamente , Quimioterapia Combinada/efectos adversos , Electrocardiografía , Imidazoles/efectos adversos , Sofosbuvir/efectos adversos , Antivirales/administración & dosificación , Antivirales/efectos adversos , Bradicardia/diagnóstico , Carbamatos , Femenino , Humanos , Imidazoles/administración & dosificación , Masculino , Persona de Mediana Edad , Pirrolidinas , Sofosbuvir/administración & dosificación , Factores de Tiempo , Valina/análogos & derivados , Vasodilatadores/administración & dosificaciónRESUMEN
Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents.
Asunto(s)
Antineoplásicos Alquilantes/efectos adversos , Ciclofosfamida/efectos adversos , Hemodinámica/efectos de los fármacos , Hipertensión Pulmonar , Venas Pulmonares , Animales , Antineoplásicos Alquilantes/uso terapéutico , Ciclofosfamida/uso terapéutico , Modelos Animales de Enfermedad , Femenino , Humanos , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Masculino , Ratones , Venas Pulmonares/metabolismo , Venas Pulmonares/patología , Venas Pulmonares/fisiopatología , Conejos , RatasRESUMEN
PURPOSE OF REVIEW: Pulmonary adverse effects of interferon (IFN) therapies are rare but can be life threatening. This article proposes to review clinical and experimental data suggesting a causal link between interferon exposure and pulmonary arterial hypertension (PAH). RECENT FINDINGS: Interferon has recently been added to the list of possible risk factors for PAH. This was justified by the reporting of many cases of pulmonary hypertension potentially associated with IFN-α or IFN-ß exposure. Some of them were reversible after cessation of interferon exposure, especially in patients without concomitant risk factors for pulmonary hypertension. In contrast, it remains a challenge to definitively confirm the causal role of IFN-α in patients treated for hepatitis C viral infection because of frequent concomitant PAH risk factors such as portal hypertension and/or HIV infection. In these patients, temporal and clinical arguments suggest that interferon may potentially act as an additional trigger for PAH. Moreover, the information obtained from clinical experience with interferon therapy has been enriched by basic science research on this topic suggesting that interferon is involved in both human and experimental pulmonary hypertension. SUMMARY: Many clinical and experimental data corroborate the link between interferon exposure and the risk to develop PAH.
Asunto(s)
Antivirales/efectos adversos , Hipertensión Pulmonar/inducido químicamente , Interferón-alfa/efectos adversos , Interferón beta/efectos adversos , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Factores de RiesgoRESUMEN
Isolated cases of pulmonary arterial hypertension (PAH) in patients treated with interferon (IFN) α or ß have been reported in the literature. The aim of this study was to describe all consecutive cases of PAH patients with a history of IFN exposure identified in the French reference centre for severe pulmonary hypertension between 1998 and 2012. A total of 53 patients with PAH and a history of IFN therapy were identified. 48 patients had been treated with IFNα for chronic hepatitis C. Most of them had portal hypertension (85%) and 56% had HIV co-infection. Five additional patients had been treated with IFNß for multiple sclerosis. The diagnosis of PAH was made within 3 years after IFN therapy in 66% of patients. Repeated haemodynamic assessment was available in 13 out of 16 patients exposed to IFN after the diagnosis of PAH. Increased pulmonary vascular resistance >20% was observed in 11 out of 13 cases (median 43% increase; IQR 32-67%). In five of these patients, IFN withdrawal resulted in spontaneous haemodynamic improvement. This retrospective analysis suggests that IFN therapy may trigger PAH. However, most of these patients had other risk factors for PAH. A prospective case-control study is necessary to definitively establish a link between IFN exposure and PAH.
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Antivirales/uso terapéutico , Hipertensión Pulmonar/epidemiología , Factores Inmunológicos/uso terapéutico , Interferón-alfa/uso terapéutico , Interferón beta/uso terapéutico , Adulto , Estudios de Cohortes , Coinfección/epidemiología , Femenino , Francia/epidemiología , Infecciones por VIH/epidemiología , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/epidemiología , Humanos , Hipertensión Portal/epidemiología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/epidemiología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/tratamiento farmacológico , Estudios Retrospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
BACKGROUND: The outcome of patients suffering from pulmonary arterial hypertension (PAH) are predominantly determined by the response of the right ventricle to the increase afterload secondary to high vascular pulmonary resistance. However, little is known about the effects of the current available or experimental PAH treatments on the heart. Recently, inflammation has been implicated in the pathophysiology of PAH. N-acetylcysteine (NAC), a well-known safe anti-oxidant drug, has immuno-modulatory and cardioprotective properties. We therefore hypothesized that NAC could reduce the severity of pulmonary hypertension (PH) in rats exposed to monocrotaline (MCT), lowering inflammation and preserving pulmonary vascular system and right heart function. METHODS: Saline-treated control, MCT-exposed, MCT-exposed and NAC treated rats (day 14-28) were evaluated at day 28 following MCT for hemodynamic parameters (right ventricular systolic pressure, mean pulmonary arterial pressure and cardiac output), right ventricular hypertrophy, pulmonary vascular morphometry, lung inflammatory cells immunohistochemistry (monocyte/macrophages and dendritic cells), IL-6 expression, cardiomyocyte hypertrophy and cardiac fibrosis. RESULTS: The treatment with NAC significantly decreased pulmonary vascular remodeling, lung inflammation, and improved total pulmonary resistance (from 0.71 ± 0.05 for MCT group to 0.50 ± 0.06 for MCT + NAC group, p < 0.05). Right ventricular function was also improved with NAC treatment associated with a significant decrease in cardiomyocyte hypertrophy (625 ± 69 vs. 439 ± 21 µm2 for MCT and MCT + NAC group respectively, p < 0.001) and heart fibrosis (14.1 ± 0.8 vs. 8.8 ± 0.1% for MCT and MCT + NAC group respectively, p < 0.001). CONCLUSIONS: Through its immuno-modulatory and cardioprotective properties, NAC has beneficial effect on pulmonary vascular and right heart function in experimental PH.
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Acetilcisteína/uso terapéutico , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/tratamiento farmacológico , Monocrotalina/toxicidad , Acetilcisteína/farmacología , Animales , Células Cultivadas , Hipertensión Pulmonar/patología , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Ratas , Ratas Sprague-Dawley , Resultado del TratamientoRESUMEN
Introduction: Pulmonary arterial hypertension (PAH) is a rare and severe disease for which most of the evidence about prognostic factors, evolution and treatment efficacy comes from cohorts, registries and clinical trials. We therefore aimed to develop and validate a new PAH identification algorithm that can be used in the French healthcare database "Système National des Données de Santé (SNDS)". Methods: We developed and validated the algorithm using the Grenoble Alpes University Hospital medical charts. We first identified PAH patients following a previously validated algorithm, using in-hospital ICD-10 (10th revision of the International Statistical Classification of Diseases) codes, right heart catheterisation procedure and PAH-specific treatment dispensing. Then, we refined the latter with the exclusion of chronic thromboembolic pulmonary hypertension procedures and treatment, the main misclassification factor. Second, we validated this algorithm using a gold standard review of in-hospital medical charts and calculated sensitivity, specificity, positive and negative predictive value (PPV and NPV) and accuracy. Finally, we applied this algorithm in the French healthcare database and described the characteristics of the identified patients. Results: In the Grenoble University Hospital, we identified 252 unique patients meeting all the algorithm's criteria between 1 January 2010 and 30 June 2022, and reviewed all medical records. The sensitivity, specificity, PPV, NPV and accuracy were 91.0%, 74.3%, 67.9%, 93.3% and 80.6%, respectively. Application of this algorithm to the SNDS yielded the identification of 9931 patients with consistent characteristics compared to PAH registries. Conclusion: Overall, we propose a new PAH identification algorithm developed and adapted to the French specificities that can be used in future studies using the French healthcare database.
RESUMEN
INTRODUCTION: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are life-threatening conditions that can progress to death without treatment. Although strong medication adherence (MA) is known to enhance outcomes in chronic illnesses, its association with PAH and CTEPH was sporadically explored. This study aims to examine the MA of patients with PAH or CTEPH, identify factors associated with low adherence and explore the resulting outcomes. METHODS: A systematic review was conducted by searching multiple databases (Medline, Embase, Cochrane Central, ClinicalTrials.gov, Scopus, Web of Science and Google Scholar) from 6 March 1998 to 6 July 2023. We included studies reporting MA as primary or secondary end-points. Study selection, data extraction and methodological quality assessment were performed in duplicate. RESULTS: 20 studies involving 22 675 patients met the inclusion criteria. Heterogeneity was observed, particularly in the methods employed. MA means ranged from 0.62 to 0.96, with the proportion of patients exhibiting high MA varying from 40% (95% CI 35-45%) to 94% (95% CI 88-97%). Factors associated with low adherence included increased treatment frequency, time since diagnosis and co-payment. High MA seems to be associated with reduced hospitalisation rates, inpatient stays, outpatient visits and healthcare costs. CONCLUSIONS: This systematic review underscores the heterogeneity of MA across studies. Nevertheless, the findings suggest that high MA could improve patients' clinical outcomes and alleviate the economic burden. Identifying factors consistently associated with poor MA could strengthen educational efforts for these patients, ultimately contributing to improved outcomes.
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Antihipertensivos , Cumplimiento de la Medicación , Embolia Pulmonar , Humanos , Antihipertensivos/uso terapéutico , Resultado del Tratamiento , Enfermedad Crónica , Factores de Riesgo , Embolia Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/diagnóstico , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/diagnóstico , Hipertensión Arterial Pulmonar/fisiopatología , Femenino , Masculino , Persona de Mediana EdadRESUMEN
Background: Despite its known cardiac and lung toxicities, the chemotherapy drug gemcitabine has only rarely been associated with pulmonary hypertension (PH), and the underlying mechanism remains unclear. The objective of the present study was to assess the association between gemcitabine and PH. Methods: We identified incident cases of precapillary PH confirmed by right heart catheterisation in patients treated with gemcitabine from the French PH Registry between January 2007 and December 2022. The aetiology, clinical, functional, radiological and haemodynamic characteristics of PH were reviewed at baseline and during follow-up. A pharmacovigilance disproportionality analysis was conducted using the World Health Organization (WHO) pharmacovigilance database. Results: We identified nine cases of pulmonary arterial hypertension, either induced (in eight patients) or exacerbated (in one patient) by gemcitabine. Patients exhibited severe precapillary PH, with a median mean pulmonary arterial pressure of 40 (range 26-47) mmHg, a cardiac index of 2.4 (1.6-3.9) L·min-1·m-2 and a pulmonary vascular resistance of 6.3 (3.1-12.6) Wood units. The median time from the initiation of gemcitabine to the onset of PH was 7 (4-50) months, with patients receiving a median of 16 (6-24) gemcitabine injections. Six patients showed clinical improvement upon discontinuation of gemcitabine. In the WHO pharmacovigilance database, we identified a significant signal with 109 cases reporting at least one adverse event related to PH with gemcitabine. Conclusion: Both clinical cases and pharmacovigilance data substantiate a significant association between gemcitabine use and the onset or worsening of precapillary PH. The observed improvement following the discontinuation of treatment underscores the importance of PH screening in gemcitabine-exposed patients experiencing unexplained dyspnoea.