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1.
Respir Res ; 24(1): 18, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36653855

RESUMO

BACKGROUND: Epoprostenol AS (Veletri®), a thermostable epoprostenol formulation, provides better drug stability and improved clinical use compared to previous epoprostenol formulations. This study aims to expand clinical experience in the use of Veletri®, especially regarding tolerability, safety and survival. METHODS: Pulmonary arterial hypertension (PAH) patients at high risk despite pretreatment with at least double oral combination therapy and with clinical indication for epoprostenol (Veletri®) treatment were consecutively included in this prospective, open label, observational, non-interventional study. Clinical data were assessed at baseline, after 3 and 6 months. Adverse events (AEs) and serious adverse events (SAEs) were documented. Survival from initiation of Veletri® was assessed at last patient out. RESULTS: Fifteen patients (60 ± 13.7 years, WHO functional class III (n = 10) or IV (n = 5), severely impaired right ventricular function, mean pulmonary arterial pressure 54.8 ± 8.9 mmHg, mean pulmonary vascular resistance 4.4 ± 0.7 (median 3.8) Wood Units) were enrolled and treated with a mean dosage of 7.9 ± 3.9 (median 7.5) ng/kg/min. Eleven patients completed the study (treatment withdrawal n = 1, death n = 3). After a mean follow-up of 19.1 ± 13.5 (median 18.0) months, seven patients died and three were listed for lung transplantation. Seven AEs (nausea n = 3, diarrhea n = 1, flushing n = 2, headaches n = 1) and three SAEs (catheter infection n = 2, catheter occlusion n = 1) were related to Veletri®. The 1- and 2-year survival rates were 73.3% and 52.4%, respectively. CONCLUSIONS: The study showed that safety and tolerability of epoprostenol AS (Veletri®) was comparable to previous prostacyclin formulations and was feasible for most patients. The maximum tolerable dosage was lower than dosages reported in the literature. In future applications/trials the up-titration process should be pushing for higher dosages of epoprostenol in the occurrence of side effects, as the achievement of a high and effective dosage is crucial for the clinical benefit of the patients. Survival was as expected in these prevalent severely impaired patients. Trial registration The study was registered in the EUPAS registry (EUPAS32492).


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Humanos , Epoprostenol/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/induzido quimicamente , Estudos Prospectivos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar Primária Familiar
2.
Wiad Lek ; 75(10): 2497-2500, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36472287

RESUMO

OBJECTIVE: The aim: To study the features of changes in the level of prostaglandins (I2 and F2α) in blood serum of patients GERD on the background of OH of the cervical and thoracic spine and obesity. PATIENTS AND METHODS: Materials and methods: The examined patients included 56 patients with GERD and OH of the cervical and thoracic spine. All patients had their blood serum prostaglandin (Pg) F2α and 6-keto prostaglandin F1α (blood prostacyclin - Pg I2) levels examined using the method of immunoassay analysis. RESULTS: Results: In all patients with GERD and OH an excessive body weight or obesity of varying degrees was found while analyzing anthropometric study results. The determination of prostaglandin F2α and prostacyclin (Pg I2) levels in blood serum in patients with GERD and OH and healthy individuals was performed. A more pronounced increase of Pg I2 and Pg F2α in blood serum in patients with GERD and OH with III degree obese was found and the smallest concentration of prostaglandines in blood serum was diagnosed in patients with excessive weight (p<0.05). CONCLUSION: Conclusions: 1. In patients with GERD and OH, an increase in levels of prostaglandins F2α and I2 in blood serum has been established. 2. The relationship between the duration of excess body weigh, obesity and the dynamics of the level of prostaglandin Pg I2 and F2α in blood serum in patients with GERD on the background of OH has been established.


Assuntos
Refluxo Gastroesofágico , Osteocondrose , Doenças da Coluna Vertebral , Humanos , Epoprostenol , Refluxo Gastroesofágico/diagnóstico , Obesidade/complicações , Prostaglandinas , Soro , Doenças da Coluna Vertebral/complicações
3.
J Pharmacol Exp Ther ; 383(1): 103-116, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36507843

RESUMO

Treprostinil palmitil (TP), a long-acting inhaled pulmonary vasodilator prodrug of treprostinil (TRE), has beneficial effects in a Sugen5416/hypoxia (Su/Hx) rat model of pulmonary arterial hypertension (PAH) that compare favorably to the oral phosphodiesterase 5 inhibitor (PDE5) sildenafil. In this study in male Sprague-Dawley rats, a dry powder formulation of TP (TPIP) was compared with inhaled and intravenous TRE and oral selexipag to evaluate inhibition of hemodynamic and pathologic changes in the lungs and heart induced by Su/Hx challenge. Su (20 mg/kg) was injected subcutaneously followed by 3 weeks of Hx (10% O2/balance N2) and then initiation of test article administration over 5 weeks with room air breathing. Hemodynamics and histopathology were measured at the end of the study. Su/Hx challenge approximately doubled the mean pulmonary arterial blood pressure (mPAP) and the Fulton index, decreased cardiac output (CO), doubled the wall thickness and muscularization of the small (10-50 µm) and medium (51-100 µm) sized pulmonary arteries, and increased the percentage of obliterated pulmonary blood vessels. Even though inhaled TRE (65 µg/kg, 4× daily), intravenous TRE (810 ng/kg/min), and oral selexipag (30 mg/kg, twice daily) provided some beneficial effects against the Su/Hx challenge, the overall benefit was generally greater with TPIP at high dose (117 µg/kg, once daily). These results demonstrate that TPIP compares favorably to inhaled and intravenous TRE and oral selexipag with respect to inhibition of the pathophysiological changes induced by Su/Hx challenge in rats. SIGNIFICANCE STATEMENT: Treprostinil palmitil (TP) is a long-acting pulmonary vasodilator prodrug of treprostinil (TRE) formulated for inhaled administration by dry powder [treprostinil palmitil inhalation powder (TPIP)]. Comparison of the activity of TPIP, inhaled and intravenous TRE, and oral selexipag in a Sugen5416/hypoxia (Su/Hx) rat model of pulmonary arterial hypertension demonstrated that each of these drugs exert protection against the hemodynamic and histopathological changes induced by the Su/Hx challenge, with the greatest effect on these changes produced by TPIP.


Assuntos
Hipertensão Pulmonar , Pró-Fármacos , Hipertensão Arterial Pulmonar , Masculino , Ratos , Animais , Hipertensão Arterial Pulmonar/tratamento farmacológico , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Ratos Sprague-Dawley , Administração por Inalação , Epoprostenol/farmacologia , Vasodilatadores , Hipóxia/tratamento farmacológico
4.
J Drugs Dermatol ; 21(11): 1249-1251, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36342724

RESUMO

Epoprostenol (Flolan) is a last-resort intravenous medication for the treatment of severe pulmonary arterial hypertension (PAH). Cutaneous adverse events of Flolan are well-known by pulmonologists, though lacking in dermatologic literature. We report a near erythrodermic appearing, yet asymptomatic eruption lasting 10 years in a woman with end-stage PAH treated with long-term intravenous epoprostenol. Non-pruritic, blanching, erythematous papules coalescing to plaques surrounded by a hypopigmented halo encompassed her entire torso, as well as bilateral upper and lower extremities. Additional findings included bright red palms and soles associated with pain and tingling while walking. Laboratory workup revealed thrombocytopenia and a slightly elevated erythrocyte sedimentation rate (ESR); connective tissue disease markers were negative. Skin biopsies were, surprisingly, largely unremarkable without an inflammatory infiltrate. The patient was trialed on topical clobetasol ointment without effect. Her striking, yet asymptomatic and non-inflammatory eruption was thought due to long-term use of epoprostenol, a last-resort synthetic prostacyclin used to treat severe PAH. As her cutaneous findings were not bothersome, her dose of Flolan was not lowered and her lower extremity pain was treated with gabapentin. With this case, we aim to increase awareness of the impressive “Flolan rash”, a persistent erythematous eruption well-known by pulmonologists, yet scarcely described in dermatologic literature. Significant Finding: We report a striking, yet asymptomatic and non-inflammatory skin eruption lasting 10 years presumed due to long-term use of epoprostenol for end-stage pulmonary arterial hypertension. Meaning: Cutaneous adverse events of intravenous epoprostenol are well-known by pulmonologists, though lacking in dermatologic or primary care literature. The extensive body surface involvement, and near erythroderma, associated with Flolan necessitates awareness by patients, dermatologists, and other healthcare providers outside of the field of pulmonology. J Drugs Dermatol. 2022;21(11):1249-1251. doi:10.36849/JDD.6821.


Assuntos
Exantema , Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Humanos , Feminino , Epoprostenol/efeitos adversos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Exantema/induzido quimicamente , Eritema/tratamento farmacológico , Dor/induzido quimicamente , Anti-Hipertensivos/efeitos adversos
5.
Commun Biol ; 5(1): 1192, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36344664

RESUMO

Pulmonary arterial hypertension (PAH) is an unmet clinical need. The lack of models of human disease is a key obstacle to drug development. We present a biomimetic model of pulmonary arterial endothelial-smooth muscle cell interactions in PAH, combining natural and induced bone morphogenetic protein receptor 2 (BMPR2) dysfunction with hypoxia to induce smooth muscle activation and proliferation, which is responsive to drug treatment. BMPR2- and oxygenation-specific changes in endothelial and smooth muscle gene expression, consistent with observations made in genomic and biochemical studies of PAH, enable insights into underlying disease pathways and mechanisms of drug response. The model captures key changes in the pulmonary endothelial phenotype that are essential for the induction of SMC remodelling, including a BMPR2-SOX17-prostacyclin signalling axis and offers an easily accessible approach for researchers to study pulmonary vascular remodelling and advance drug development in PAH.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Fatores de Transcrição SOXF , Humanos , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Epoprostenol/genética , Epoprostenol/metabolismo , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/genética , Fatores de Transcrição SOXF/genética , Fatores de Transcrição SOXF/metabolismo
6.
Ther Adv Respir Dis ; 16: 17534666221132735, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36314498

RESUMO

INTRODUCTION: Pulmonary arterial hypertension is a progressive haemodynamic disease with high morbidity and mortality. Of the different treatments available, the prostacyclin analogues are the drugs of choice for high-risk patients, with treprostinil being the most commonly used drug in Argentina. METHODOLOGY: The objective of this study is to perform a retrospective evaluation of the efficacy and safety of subcutaneous treprostinil in regular clinical practice in Argentina in 51 patients with pulmonary arterial hypertension after 12 months of follow-up. RESULTS: The results showed that treatment with subcutaneous treprostinil is associated with a significant improvement in different clinical efficacy parameters: 65% reduction in advanced functional class (p < 0.0001), 130-m increase in the 6-min walk test (p < 0.0001), 65% reduction in the pro B-type natriuretic peptide value (-531 pg/dL; p < 0.0001), significant reduction of 15.7% in pulmonary vascular resistance [-1.3 wood units (WU); p < 0.0001], improved cardiac index with an increase of 16.7% (+0.4 L/min/m2; p = 0.002), as well as a high survival rate (92%) and a 44% incidence of combined events (mortality, heart failure, syncope and/or lung transplantation), without a significant increase in previously reported adverse events. The risk stratification evaluation according to ESC/ERS guidelines showed a significant decrease in the proportion of patients at high risk after the treatment period (p = 0.004). CONCLUSIONS: These real-world results corroborate the efficacy and safety of subcutaneous treprostinil, even at high doses, and open up the possibility of improving its current use in clinical practice as a first-line therapy, especially in high-risk patient profiles.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Humanos , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Estudos Retrospectivos , Argentina , Anti-Hipertensivos , Epoprostenol , Hipertensão Pulmonar Primária Familiar , Resultado do Tratamento
7.
Biomolecules ; 12(10)2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36291611

RESUMO

We previously identified that NO derived from neuronal cells acts on glial cells and causes vasodilation in the healthy rat retina via the release of epoxyeicosatrienoic acids (EETs) and prostaglandins (PGs) by activation of the arachidonic acid cascade. However, it is not clear which PG types are involved in these responses. The aim of the present study was to identify prostanoid receptors involved in glial cell-derived vasodilation induced by NO in rat retina. Male Wistar rats were used to examine the effects of intravitreal pretreatment with indomethacin, a cyclooxygenase inhibitor; PF-04418948, a prostanoid EP2 receptor antagonist; and CAY10441, a prostanoid IP receptor antagonist, on the changes in the retinal arteriolar diameter induced by intravitreal administration of NOR3, an NO donor. Retinal arteriolar diameters were measured using ocular fundus images captured with a high-resolution digital camera in vivo. The increase in the retinal arteriolar diameter induced by intravitreal injection of NOR3 was significantly suppressed by intravitreal pretreatment with indomethacin and PF-04418948, but not by CAY10441. The dose of PF-04418948 and CAY10441 injected intravitreally in the present study significantly reduced the increase in the retinal arteriolar diameter induced by prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2), respectively. These results suggest that activation of the arachidonic acid cascade and subsequent stimulation of prostanoid EP2 receptors are involved in rat retinal vasodilatory responses evoked by NO-induced glial cell stimulation. Therefore, glial cell-derived PGE2, similar to EETs, may play an important role in retinal vasodilatory mechanisms.


Assuntos
Prostaglandinas , Vasodilatação , Animais , Ratos , Masculino , Óxido Nítrico/farmacologia , Epoprostenol/farmacologia , Ratos Wistar , Neuroglia , Retina , Dinoprostona , Inibidores de Ciclo-Oxigenase/farmacologia , Indometacina , Eicosanoides/farmacologia , Ácidos Araquidônicos/farmacologia
8.
Biomolecules ; 12(10)2022 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-36291709

RESUMO

The risk of thrombotic events dramatically increases with age and may be accelerated in women by the cessation of endogenous estrogen production at menopause. Patients at risk of thrombosis are prescribed dual anti-platelet therapy (DAPT; aspirin and a P2Y12 antagonist) and are encouraged to participate in regular physical activity, as these modalities improve nitric oxide and prostacyclin-mediated inhibition of platelet aggregation. METHODS: We assessed prostacyclin sensitivity as well as basal platelet reactivity with and without in vitro DAPT before and after an 8-week high-intensity exercise training program in 13 healthy, sedentary postmenopausal women. The training intervention consisted of three 1 h sessions per week. Isolated platelets were analyzed for thromboxane A2 receptor, thromboxane A2 synthase, cyclooxygenase-1, and prostacyclin receptor protein expression. Additionally, plasma 6-keto prostaglandin F1α and thromboxane B2 levels were determined. RESULTS: Exercise training made platelets more sensitive to the inhibitory effects of prostacyclin on thromboxane-, collagen-, and adenosine 5'-diphosphate (ADP)-induced aggregation, as well as thrombin-receptor activator peptide 6- and ADP-induced aggregation with DAPT. However, there was no change in protein expression from isolated platelets or plasma thromboxane B2 and prostacyclin levels following training. CONCLUSION: Together, these findings emphasize the importance of promoting physical activity as a tool for reducing thrombotic risk in postmenopausal women and suggest that training status should be considered when prescribing DAPT in this cohort.


Assuntos
Epoprostenol , Trombose , Humanos , Feminino , Epoprostenol/farmacologia , Ciclo-Oxigenase 1 , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Terapia Antiplaquetária Dupla , Óxido Nítrico/farmacologia , Trombina , Pós-Menopausa , Difosfatos , Receptores de Epoprostenol , Aspirina/farmacologia , Aspirina/uso terapêutico , Tromboxanos , Difosfato de Adenosina , Exercício Físico , Receptores de Tromboxanos , Estrogênios , Adenosina , Peptídeos
9.
Adv Ther ; 39(11): 5144-5157, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36070132

RESUMO

INTRODUCTION: Treprostinil is a prostacyclin vasodilator widely used for the treatment of pulmonary arterial hypertension (PAH) and, in its inhaled form, for pulmonary hypertension associated with interstitial lung disease (PH-ILD). Treprostinil palmitil inhalation powder (TPIP) is a dry powder formulation of treprostinil palmitil (TP), an ester prodrug of treprostinil. TPIP is designed to provide sustained release of treprostinil in the lung over a prolonged period, potentially enabling a once-daily (QD) dosing regimen and significantly higher tolerated doses compared with currently available treprostinil formulations. This phase 1 study assessed the safety, tolerability, and pharmacokinetics of TP and treprostinil following single and multiple QD administrations of TPIP in healthy volunteers. METHODS: Healthy adults (aged 18-45 years) were randomized to receive single or multiple QD inhalation doses of TPIP. Participants in the single-dose phase received TPIP 112.5, 225, 450, or 675 µg (n = 6/dose) or placebo (n = 2). Participants in the multiple-dose phase received TPIP 225 µg QD for 7 days (n = 6), 112.5 µg QD for 4 days followed by 225 µg QD for 3 days (n = 6), or placebo for 7 days (n = 4). RESULTS: Overall, 41 of 42 participants (97.6%) completed the study. In the single-dose phase, 70.8% (n = 17/24) of TPIP-treated participants experienced a treatment-emergent adverse event (TEAE) vs 0% (n = 0/2) of placebo-treated participants; the most common TEAEs (≥ 20%) were cough (45.8%), dizziness (29.2%), and throat irritation (20.8%). In the multiple-dose phase, 83.3% (n = 10/12) of TPIP-treated participants experienced a TEAE vs 50.0% of placebo-treated participants (n = 2/4); the most common TEAEs were cough (58.3% TPIP vs 50.0% placebo), headache (50.0% vs 0%), nausea (33.3% vs 0%), chest discomfort (33.3% vs 0%), and dizziness (25.0% vs 0%). Most TEAEs were mild; only seven patients experienced a moderate TEAE, and no severe or serious TEAEs occurred. In the multiple-dose phase, participants whose doses were titrated from TPIP 112.5 µg QD to 225 µg QD experienced fewer TEAEs than those who received 225 µg QD at treatment initiation (66.7% vs 100.0%), and all TEAEs with dose titration were mild. After a single dose of TPIP, treprostinil elimination t1/2 was 8.67-11.6 h and exposure was dose proportional, with mean (CV%) Cmax 78.4-717 pg/mL (38.6-72.9%) and AUC0-∞ 1090-5480 pg·h/mL (11.5-30.0%). At steady state (TPIP 225 µg), the mean (CV%) of Cmax, Cmin, and AUCτ were 193-228 pg/mL (32.9-46.4%), 17.6-22.8 ng/mL (43.7-64.4%), and 1680-1820 pg·h/mL (28.7-36.6%), respectively. The elimination t1/2 was 6.84-8.82 h after repeat dosing. No steady-state accumulation was observed. Plasma concentrations of TP were below the limit of quantification (100 pg/mL) at all time points measured. CONCLUSION: TPIP was well tolerated at the doses tested, and dose titration improved tolerability. Treprostinil pharmacokinetics were linear and supportive of a QD treatment regimen. These results support further development of TPIP in patients with PAH and PH-ILD.


Assuntos
Hipertensão Pulmonar , Pró-Fármacos , Adulto , Tosse , Preparações de Ação Retardada , Tontura , Relação Dose-Resposta a Droga , Método Duplo-Cego , Epoprostenol/efeitos adversos , Epoprostenol/análogos & derivados , Ésteres , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Pós , Vasodilatadores
10.
Zhonghua Jie He He Hu Xi Za Zhi ; 45(9): 930-935, 2022 Sep 12.
Artigo em Chinês | MEDLINE | ID: mdl-36097931

RESUMO

Pulmonary arterial hypertension is a progressive pulmonary vascular disease, which can cause right heart failure and even death in severe cases. Treprostinil is a stable prostacyclin analogue and a powerful drug for dilating pulmonary vessels. It can be administered in different ways, with a long half-life, good stability and is suited for diverse types of PAH. It is approved for the treatment of Group 1 PAH, but some studies show that treprostinil is effective in patients with Group 3 or Group 4 PAH. Therefore, this article will review the progress of evidence-based medicine evidence of traprostanil in the treatment of type 1, 3 and 4 pulmonary hypertension.


Assuntos
Hipertensão Pulmonar , Anti-Hipertensivos/uso terapêutico , Epoprostenol/análogos & derivados , Epoprostenol/uso terapêutico , Hipertensão Pulmonar Primária Familiar , Humanos , Hipertensão Pulmonar/tratamento farmacológico
11.
Int J Mol Sci ; 23(17)2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36077548

RESUMO

The prostacyclin analogue iloprost is used to treat vascular alterations and digital ulcers, the early derangements manifesting in systemic sclerosis (SSc), an autoimmune disease leading to skin and organ fibrosis. Bioindicator(s) of SSc onset and progress are still lacking and the therapeutic approach remains a challenge. The T helper 1 (Th1) chemokine interferon (IFN)γ-induced protein 10 (IP-10/CXCL10) associates with disease progression and worse prognosis. Endothelial cells and fibroblasts, under Th1-dominance, release CXCL10, further enhancing SSc's detrimental status. We analyzed the effect of iloprost on CXCL10 in endothelial cells, dermal fibroblasts, and in the serum of SSc patients. Human endothelial cells and dermal fibroblasts activated with IFNγ/Tumor Necrosis Factor (TNF)α, with/without iloprost, were investigated for CXCL10 secretion/expression and for intracellular signaling cascade underlying chemokine release (Signal Transducer and Activator of Transcription 1, STAT1; Nuclear Factor kappa-light-chain-enhancer of activated B cells, NF-kB; c-Jun NH2-terminal kinase, JNK: Phosphatidyl-Inositol 3-kinase (PI3K)/protein kinase B, AKT; Extracellular signal-Regulated Kinase 1/2, ERK1/2). CXCL10 was quantified in sera from 25 patients taking iloprost, satisfying the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 classification criteria for SSc, and in sera from 20 SSc sex/age-matched subjects without therapy, previously collected. In human endothelial cells and fibroblasts, iloprost targeted CXCL10, almost preventing IFNγ/TNFα-dependent cascade activation in endothelial cells. In SSc subjects taking iloprost, serum CXCL10 was lower. These in vitro and in vivo data suggest a potential role of iloprost to limit CXCL10 at local vascular/dermal and systemic levels in SSc and warrant further translational research aimed to ameliorate SSc understanding/management.


Assuntos
Iloprosta , Escleroderma Sistêmico , Quimiocina CXCL10/metabolismo , Quimiocinas/metabolismo , Células Endoteliais/metabolismo , Epoprostenol/metabolismo , Humanos , Iloprosta/metabolismo , Iloprosta/farmacologia , Iloprosta/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo
12.
Transplant Proc ; 54(6): 1664-1670, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35914967

RESUMO

Portopulmonary hypertension, a type of pulmonary arterial hypertension in the setting of cirrhotic or noncirrhotic portal hypertension, is associated with elevated morbidity and mortality during and after transplantation. Uncontrolled portopulmonary hypertension may prevent or delay listing for transplant candidates, and the prognosis without treatment and ultimately transplant is extremely poor. We present a 29-year-old White woman, who had a post-liver transplant at infancy due to biliary atresia. Later on, she developed extensive portal vein thrombosis and portopulmonary hypertension and underwent a multivisceral transplant (liver, stomach, pancreaticoduodenal complex, and small and large intestine). Preoperative mean pulmonary artery pressure was <30 mm Hg with a pulmonary vascular resistance of <300 dynes.s/cm5 on oral sildenafil and intravenous epoprostenol. Intraoperatively, management required comprehensive transfusion protocols, a careful balance between correcting blood loss and preventing thrombosis. Intravenous epoprostenol, sildenafil, milrinone, and inhaled nitric oxide were used to reduce elevated mean pulmonary artery pressure and right ventricular strain associated with vascular clamping, reperfusion, and massive fluid shifts. Nitric oxide and epoprostenol use unleashed antiplatelet effects on a patient already susceptible to coagulopathy. A multimodal and multidisciplinary approach continued throughout the surgery and in the postoperative period, which led to a successful outcome.


Assuntos
Hipertensão Portal , Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Adulto , Anti-Hipertensivos/uso terapêutico , Epoprostenol/uso terapêutico , Feminino , Humanos , Hipertensão Portal/complicações , Hipertensão Pulmonar/complicações , Milrinona , Óxido Nítrico , Citrato de Sildenafila/uso terapêutico
13.
EBioMedicine ; 81: 104106, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35779494

RESUMO

BACKGROUND: Persistent pulmonary hypertension (PH) causes significant mortality and morbidity in infants with congenital diaphragmatic hernia (CDH). Since pulmonary vascular abnormalities in CDH develop early during foetal development, we hypothesized that prenatal maternal administration of treprostinil, through its anti-remodelling effect, would improve the PH-phenotype in the nitrofen rat model of CDH. METHODS: In a dose-finding study in normal, healthy pregnant rats, we demonstrated target-range foetal plasma treprostinil concentrations without signs of toxicity. Next, an efficacy study was performed assessing the effects of treprostinil administration at 900 and 1500ng/kg/min from gestational day (GD) 16 until term (GD 21) in CDH and control pups. Pulmonary vascular and airway morphometry, lung mechanics, and expression patterns of genes implicated in the prostaglandin vasoactive pathway were studied. FINDINGS: In rats maternal administration of 1500ng/kg/min treprostinil reached target foetal concentrations, with no detrimental maternal or foetal side-effects. Prenatal exposure to 900 and 1500 ng/kg/min treprostinil reduced the medial wall thickness (%MWT) (CDH·900, 38.5± 8·4%; CDH.1500, 40·2±9·7%; CDH, 46·6±8·2%; both p < 0·0001) in rat pups with CDH, however increased the %MWT in normal foetuses (C.T.900, 36·6±11·1%; C.T.1500, 36·9±9·3%; C.P., 26·9±6·2%; both p < 0·001). Pulmonary airway development, lung hypoplasia and pulmonary function were unaffected by drug exposure. INTERPRETATION: In pregnant rats maternally administered treprostinil crosses the placenta, attains foetal target concentrations, and is well tolerated by both mother and foetuses. This report shows a significant reduction of pulmonary arteriole muscularization with prenatal treprostinil in a nitrofen rat model, supporting the promise of this treatment approach for PH of CDH. FUNDING: United Therapeutics Corporation provided treprostinil and financial support (ISS-2020-10879).


Assuntos
Hérnias Diafragmáticas Congênitas , Hipertensão Pulmonar , Pneumopatias , Animais , Modelos Animais de Doenças , Epoprostenol/análogos & derivados , Feminino , Hérnias Diafragmáticas Congênitas/etiologia , Hérnias Diafragmáticas Congênitas/genética , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Pulmão/metabolismo , Pneumopatias/metabolismo , Fenótipo , Gravidez , Ratos
14.
Genes (Basel) ; 13(7)2022 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-35885938

RESUMO

Traditional methods concerning type 2 diabetes (T2D) are limited to grouped cells instead of each single cell, and thus the heterogeneity of single cells is erased. Therefore, it is still challenging to study T2D based on a single-cell and network perspective. In this study, we construct a conditional cell-specific network (CCSN) for each single cell for the GSE86469 dataset which is a single-cell transcriptional set from nondiabetic (ND) and T2D human islet samples, and obtain a conditional network degree matrix (CNDM). Since beta cells are the key cells leading to T2D, we search for hub genes in CCSN of beta cells and find that ATP6AP2 is essential for regulation and storage of insulin, and the renin-angiotensin system involving ATP6AP2 is related to most pathological processes leading to diabetic nephropathy. The communication between beta cells and other endocrine cells is performed and three gene pairs with obvious interaction are found. In addition, different expression genes (DEGs) are found based on CNDM and the gene expression matrix (GEM), respectively. Finally, 'dark' genes are identified, and enrichment analysis shows that NFATC2 is involved in the VEGF signaling pathway and indirectly affects the production of Prostacyclin (PGI2), which may be a potential biomarker for diabetic nephropathy.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , ATPases Vacuolares Próton-Translocadoras , Biomarcadores , Diabetes Mellitus Tipo 2/patologia , Epoprostenol , Humanos , Insulina/genética , Insulina/metabolismo , Fatores de Transcrição NFATC , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/genética
15.
Biol Pharm Bull ; 45(8): 979-984, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35908907

RESUMO

Prostacyclin (PGI2) synthase (PGIS) and microsomal prostaglandin (PG) E synthase-1 (PGES-1) are PG terminal synthases which functionally couple with inducible cyclooxygenase-2 (COX-2) as their upstream enzymes to produce PGI2 and PGE2, respectively. Non-steroidal anti-inflammatory drugs exert their pharmacological effects by the inhibition of COX-2 and thereby suppression of the biosynthesis of these PGs. PGIS is abundantly expressed in vascular endothelial and smooth muscle cells and has been shown to be critical for regulation of platelet aggregation and vascular tone. In addition to its role in vascular regulation, PGIS has been shown to be expressed in inflammatory cells including macrophages, and the proinflammatory roles of PGIS has been demonstrated. On the other hand, several investigators have recently reported that PGIS functions as an anti-inflammatory mediator by macrophage polarization and have indicated that PGIS is an ambivalent regulator of inflammatory reactions. In this review, we summarize the current understanding of proinflammatory and anti-inflammatory functions of PGIS and discuss its potential as a novel anti-inflammatory therapeutic target.


Assuntos
Epoprostenol , Oxirredutases Intramoleculares , Ciclo-Oxigenase 2 , Sistema Enzimático do Citocromo P-450 , Prostaglandina-E Sintases
16.
J Heart Lung Transplant ; 41(9): 1285-1293, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35778258

RESUMO

BACKGROUND: It is unknown whether pulmonary arterial hypertension (PAH) risk stratification instruments could be helpful to support the decision to list a patient for lung transplantation (LT). Our aim was to evaluate contemporary risk assessment tools in a cohort of PAH patients listed for LT. METHODS: Consecutive PAH patients (without pulmonary veno-occlusive disease or unrepaired congenital heart disease) listed for LT at the French Pulmonary Hypertension Reference Center between January 2006 and December 2018 were included. At the time of listing, risk stratification was assessed using the ESC/ERS criteria, the REVEAL Lite 2 score and the COMPERA 2.0 method. The primary end point was overall survival after LT listing. Secondary outcome measures were mortality on waiting list and posttransplant survival. RESULTS: One hundred and two patients were enrolled (mean age 38 ± 13 years, 69% females). Overall survival after listing was 72%, 58% and 46% at 1, 3 and 5 years respectively. Survival after LT listing was lower in "high-risk" patients according to the ESC/ERS criteria (p = 0.0001) and the REVEAL Lite 2 score (p = 0.04). The COMPERA 2.0 method discriminated post-listing survival of patients at high-risk, intermediate-high and intermediate-low risk (p = 0.04). The proportion of patients requiring urgent transplantation and extracorporeal life support as a bridge to transplantation was higher in the "high-risk" patients. Posttransplant survival was significantly lower in "high-risk" patients according to the ESC/ERS criteria (p = 0.0004). CONCLUSIONS: High-risk PAH patients at the time of LT listing have poor outcomes, suggesting that LT should be considered earlier in the course of PAH remaining refractory to triple combination therapy with a parenteral prostacyclin.


Assuntos
Transplante de Pulmão , Hipertensão Arterial Pulmonar , Adulto , Epoprostenol , Hipertensão Pulmonar Primária Familiar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hipertensão Arterial Pulmonar/cirurgia , Estudos Retrospectivos , Medição de Risco
17.
BMJ Open Respir Res ; 9(1)2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35787522

RESUMO

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) greatly impacts quality of life and eventually leads to premature death from respiratory failure. Inhaled treprostinil was associated with improvements in forced vital capacity (FVC) and reduced exacerbations of underlying lung disease in post hoc analyses from a phase 3 study in patients with precapillary pulmonary hypertension due to interstitial lung disease. These results, combined with preclinical evidence of treprostinil's antifibrotic activity, support its investigation in the treatment of IPF. METHODS AND ANALYSIS: The TETON programme consists of two replicate, 52-week, randomised, double-blind placebo-controlled, phase 3 studies, each enrolling 396 subjects (NCT04708782, NCT05255991). Eligible subjects must have a diagnosis of IPF confirmed by central imaging review, along with an FVC ≥45%. Stable background use of pirfenidone or nintedanib is allowed. The primary endpoint is change in absolute FVC at week 52. Secondary endpoints include time to clinical worsening (first event of death, respiratory hospitalisation or ≥10% decline in % predicted FVC), time to first acute exacerbation of IPF, overall survival, change in % predicted FVC and change in the King's Brief Interstitial Lung Disease Questionnaire at week 52. Safety parameters include adverse events, hospitalisations, oxygenation and laboratory parameters. Patients who complete week 52 will be eligible to enter an open-label extension study. ETHICS AND DISSEMINATION: Studies will be conducted in accordance with the International Conference on Harmonisation Guideline for Good Clinical Practice, Declaration of Helsinki principles, and local regulatory, ethical and legal requirements. Results will be published in a peer-reviewed publication.


Assuntos
Fibrose Pulmonar Idiopática , Método Duplo-Cego , Epoprostenol/análogos & derivados , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Qualidade de Vida , Resultado do Tratamento
18.
Adv Ther ; 39(9): 3881-3895, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35781186

RESUMO

Interstitial lung diseases (ILD) encompasses a heterogeneous group of parenchymal lung diseases characterized by variable amounts of inflammation and fibrosis. The targeting of fibroblasts and myofibroblasts with antifibrotic treatments is a potential therapeutic target for these potentially fatal diseases. Treprostinil is unique among the prostacyclin mimetics in that it has distinct actions at additional prostaglandin receptors. Preclinical and clinical evidence suggests that treprostinil has antifibrotic effects through the activation of the prostaglandin E receptor 2 (EP2), the prostaglandin D receptor 1 (DP1), and peroxisome proliferator-activated receptors (PPAR). In vivo studies of EP2 and the DP1 have found that administration of treprostinil resulted in a reduction in cell proliferation, reduced collagen secretion and synthesis, and reduced lung inflammation and fibrosis. In vitro and in vivo studies of PPARß and PPARγ demonstrated that treprostinil inhibited fibroblast proliferation in a dose-dependent manner. Clinical data from a post hoc analysis of the INCREASE trial found that inhaled treprostinil improved forced vital capacity in the overall population as well as in idiopathic interstitial pneumonia and idiopathic pulmonary fibrosis subgroups. These preclinical and clinical findings suggest a dual benefit of treprostinil through the amelioration of both lung fibrosis and pulmonary hypertension.


Assuntos
Hipertensão Pulmonar , Fibrose Pulmonar Idiopática , Epoprostenol/análogos & derivados , Epoprostenol/farmacologia , Epoprostenol/uso terapêutico , Fibrose , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Fibrose Pulmonar Idiopática/tratamento farmacológico
19.
Pediatr Surg Int ; 38(9): 1241-1247, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35841395

RESUMO

PURPOSE: Off-label use of prostacyclins to manage congenital diaphragmatic hernia-associated pulmonary hypertension (CDH-PHTN) has been described over recent years, but use is not standardized across institutions. This study aims to describe trends in use of these medications in the CDH Study Group (CDHSG) patients. METHODS: The CDHSG was queried for all patients born from 2007 to 2019. Records were reviewed to describe the number of patients receiving prostacyclins, the day of life on which the agent was started, start time relative to ECLS, the duration of medication use, and continuation of the medication at the time of discharge. Finally, trends in use by year of birth were evaluated to assess for changes in use over time. RESULTS: There were 6439 patients identified from the registry who were born during the study period. 4372 (68%) patients received medications to treat pulmonary hypertension. Of these, 604 (14%) received a prostacyclin at some point during their care. The median start time for prostacyclins was 7.5 days of life (mean 16.9 days, SD 32.5 days), and the median duration was 12.5 days (mean 25.1 days, SD 49.1 days). Among patients who received prostacyclins, 340 patients required ECLS during care, 53 (15.5%) of whom started the prostacyclin prior to ECLS, and 159 (46.8%) of whom started prostacyclin therapy during their ECLS run. Only a small cohort (26/604, 4.3%) required continuation of the prostacyclin at the time of discharge. The proportion of patients receiving a prostacyclin remained relatively stable over the study period. CONCLUSIONS: While the proportion of patients receiving a prostacyclin for management of CDH-PHTN has remained relatively stable over the last 13 years, there is significant variation in timing of initiation and duration of use especially in the pre-ECLS period that warrants further investigation to describe optimal use in these patients.


Assuntos
Hérnias Diafragmáticas Congênitas , Hipertensão Pulmonar , Epoprostenol/uso terapêutico , Hérnias Diafragmáticas Congênitas/terapia , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Sistema de Registros , Estudos Retrospectivos
20.
PLoS One ; 17(6): e0270646, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35759496

RESUMO

OBJECTIVE: To compare the efficacy and outcomes with inhaled nitric oxide (iNO) and inhaled epoprostenol (iEPO) in patients with refractory hypoxemia due to COVID-19. DESIGN: Retrospective Cohort Study. SETTING: Single health system multicenter academic teaching hospitals. PATIENTS OR SUBJECTS: Age group of 18-80 years admitted to the medical ICU. INTERVENTIONS: Mechanically ventilated patients with COVID-19 infection, who received either iNO or iEPO between March 1st, 2020, and June 30th, 2020. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the change in the PaO2/FiO2 (P/F) ratio 1 hour after initiation of pulmonary vasodilator therapy. Secondary outcomes include P/F ratios on days 1-3 after initiation, positive response in P/F ratio (increase of at least 20% in PaO2), total days of treatment, rebound hypoxemia (if there was a drop in oxygen saturation after treatment was stopped), ventilator free days (if any patient was extubated), days in ICU, days to extubation, days to tracheostomy, mortality days after intubation, 30-day survival and mortality. 183 patients were excluded, as they received both iNO and iEPO. Of the remaining 103 patients, 62 received iEPO and 41 received iNO. The severity of ARDS was similar in both groups. Change in P/F ratio at one hour was 116 (70.3) with iNO and 107 (57.6) with iEPO (Mean/SD). Twenty-two (53.7%) patients in the iNO group and 25 (40.3%) in the iEPO group were responders to pulmonary vasodilators n(%)(p = 0.152) (more than 20% increase in partial pressure of oxygen, Pao2), and 18 (43.9%) and 31 (50%) patients in the iNO and iEPO group (p = 0.685), respectively, had rebound hypoxemia. Only 7 patients in the cohort achieved ventilator free days (3 in the iEPO group and 4 in iNO group). CONCLUSIONS: We found no significant difference between iNO and iEPO in terms of change in P/F ratio, duration of mechanical ventilation, ICU, in-hospital mortality in this cohort of mechanically ventilated patients with COVID-19. Larger, prospective studies are necessary to validate these results.


Assuntos
COVID-19 , Epoprostenol , Administração por Inalação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/complicações , Epoprostenol/uso terapêutico , Humanos , Hipóxia/tratamento farmacológico , Pessoa de Meia-Idade , Óxido Nítrico/uso terapêutico , Oxigênio/uso terapêutico , Estudos Prospectivos , Estudos Retrospectivos , Vasodilatadores/uso terapêutico , Adulto Jovem
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