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Pulmonary Circulation 2020This manuscript on drug repurposing incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative as... (Review)
Review
This manuscript on drug repurposing incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. Drug repurposing, use of a drug in a disease for which it was not originally developed, in pulmonary arterial hypertension has been a remarkable success story, as highlighted by positive large phase 3 clinical trials using epoprostenol, bosentan, iloprost, and sildenafil. Despite the availability of multiple therapies for pulmonary arterial hypertension, mortality rates have modestly changed. Moreover, pulmonary arterial hypertension patients are highly symptomatic and frequently end up on parental therapy and lung transplant waiting lists. Therefore, an unmet need for new treatments exists and drug repurposing may be an important avenue to address this problem.
PubMed: 33282182
DOI: 10.1177/2045894020941494 -
Pharmaceuticals (Basel, Switzerland) Sep 2023Pulmonary hypertension (PH) is a severe vascular complication of connective tissue diseases (CTD). Patients with CTD may develop PH belonging to diverse groups: (1)... (Review)
Review
Pulmonary hypertension (PH) is a severe vascular complication of connective tissue diseases (CTD). Patients with CTD may develop PH belonging to diverse groups: (1) pulmonary arterial hypertension (PAH), (2) PH due to left heart disease, (3) secondary PH due to lung disease and/or hypoxia and (4) chronic thromboembolic pulmonary hypertension (CTEPH). PAH most often develops in systemic scleroderma (SSc), mostly in its limited variant. PAH-CTD is a progressive disease characterized by poor prognosis. Therefore, early diagnosis should be established. A specific treatment for PAH-CTD is currently available and recommended: prostacyclin derivative (treprostinil, epoprostenol, iloprost, selexipag), nitric oxide and natriuretic pathway: stimulators of soluble guanylate cyclase (sGC: riociguat) and phosphodiesterase-five inhibitors (PDE5i: sildenafil, tadalafil), endothelin receptor antagonists (ERA: bosentan, macitentan, ambrisentan). Moreover, novel drugs, e.g., sotatercept, have been intensively investigated in clinical trials. We aim to review the literature on recent advances in the treatment strategy and prognosis of patients with PAH-CTD. In this manuscript, we discuss the mechanism of action of PAH-specific drugs and new agents and the latest research conducted on PAH-CTD patients.
PubMed: 37765060
DOI: 10.3390/ph16091252 -
Polish Archives of Internal Medicine Jun 2022Large vessel vasculitis (LVV), including Takayasu arteritis (TAK) and giant cell arteritis (GCA), causes granulomatous vascular inflammation mainly in large vessels, and...
Large vessel vasculitis (LVV), including Takayasu arteritis (TAK) and giant cell arteritis (GCA), causes granulomatous vascular inflammation mainly in large vessels, and is the most common primary vasculitis in adults. Vascular inflammation may evoke many clinical features including vision impairment, stroke, limb ischemia, and aortic aneurysms. The best way to diagnose LVV is to combine medical history, physical examination, various laboratory tests, and imaging modalities. Progress in imaging modalities facilitated early diagnosis and follow‑up of the disease activity. Conventional angiography is no longer the gold standard for the diagnosis of TAK. Similarly, temporal artery biopsy is no longer the only tool for diagnosing cranial GCA. In selected cases, color Doppler ultrasound may be used for this purpose. Despite some similarities, TAK and GCA differ in many aspects and they are different diseases. They also have different clinical subtypes. The presence of aortitis does not always implicate the diagnosis of TAK or GCA; infectious aortitis, as well as noninfectious aortitis associated with other autoimmune rheumatic diseases should be excluded. Treatment of LVV includes glucocorticoids (GCs), conventional immunosuppressive agents, and biological drugs. Tumor necrosis factor inhibitors are ineffective in GCA but effective in TAK. On the other hand, tocilizumab may be used to treat both diseases. Promising targeted therapies evaluated in ongoing clinical trials include, for example, anti‑IL‑12/23 (ustekinumab), anti‑IL‑17 (secukinumab), anti‑IL‑1 (anakinra), anti‑IL‑23 (guselkumab), anti‑cytotoxic T‑lymphocyte antigen 4 (abatacept), Janus kinase inhibitors (tofacitinib and upadacitinib), anti‑granulocyte / macrophage colony‑stimulating factor (mavrilimumab), and endothelin receptor (bosentan) therapies.
Topics: Adult; Aortitis; Giant Cell Arteritis; Glucocorticoids; Humans; Inflammation; Takayasu Arteritis
PubMed: 35699647
DOI: 10.20452/pamw.16272 -
Frontiers in Cardiovascular Medicine 2022There is little evidence of the effectiveness of switching from the endothelin receptor antagonists (ERAs) bosentan and ambrisentan to a novel ERA, macitentan, in...
BACKGROUND
There is little evidence of the effectiveness of switching from the endothelin receptor antagonists (ERAs) bosentan and ambrisentan to a novel ERA, macitentan, in patients with pulmonary arterial hypertension (PAH). Therefore, a systematic review and meta-analysis was performed to evaluate the efficacy and safety of patients with PAH switching from other ERAs to macitentan.
METHODS
We retrieved the relevant literature published before January 2022 for the meta-analysis from the PubMed, EMBASE, and Cochrane Library databases. Efficacy included changes in the 6-min walk distance (6MWD), World Health Organization functional class (WHO-FC), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, hemodynamics, echocardiography and survival.
RESULTS
Nine studies, consisting of 408 PAH patients, that met the inclusion criteria were included. The switch from bosentan or ambrisentan to macitentan effectively increased the 6MWD by 20.71 m (95% CI: 10.35-31.07, < 0.00001, = 0%). Six months after conversion, the tricuspid annular plane systolic excursion was found to improve from 19.0 ± 4.0 to 21.0 ± 5.0 mm in adults and from 16.00 ± 5.0 to 18.25 ± 4.8 mm in children. Ordinal logistic regression showed that the WHO-FC significantly improved by 0.412 (95% CI: 0.187-0.908, = 0.028). The switch did not show significant improvement in NT-proBNP levels. In addition, the switch was well tolerated.
CONCLUSION
The switch from bosentan or ambrisentan to macitentan significantly increased the 6MWD in PAH patients, improved the WHO-FC, and exerted safety benefits. The effects of the switch on NT-proBNP levels, hemodynamics, and echocardiography still need to be further confirmed.
SYSTEMATIC REVIEW REGISTRATION
[https://www.crd.york.ac.uk/prospero/], identifier [CRD42021292554].
PubMed: 36568539
DOI: 10.3389/fcvm.2022.977110 -
Frontiers in Pediatrics 2019Idiopathic pulmonary arterial hypertension (IPAH) is a complex disease associated with progressive deterioration. Targeted therapy for IPAH has improved in the last... (Review)
Review
Idiopathic pulmonary arterial hypertension (IPAH) is a complex disease associated with progressive deterioration. Targeted therapy for IPAH has improved in the last several decades. However, there remain many challenges to current treatment of children with IPAH, including poor prognosis and a median survival of 0.8 years. Endothelin-1 (ET-1) appears to be a key mediator in the pathogenesis of IPAH, with elevated concentrations in the plasma. Bosentan, an endothelin receptor antagonist, has been confirmed in Food and Drug Administration (FDA) to effectively treat IPAH when administered in recent studies. This review focuses on related studies and advance of bosentan in the treatment of IPAH in children.
PubMed: 31396496
DOI: 10.3389/fped.2019.00302 -
Pharmacogenomics and Personalized... 2023Pulmonary arterial hypertension (PAH) is a rare disease with heterogeneous causes that can lead to right ventricular (RV) failure and death if left untreated. There are... (Review)
Review
Pulmonary arterial hypertension (PAH) is a rare disease with heterogeneous causes that can lead to right ventricular (RV) failure and death if left untreated. There are currently 10 medications representative of five unique pharmacologic classes that are approved for treatment. These have led to significant improvements in overall clinical outcome. However, substantial variability in dosing requirements and treatment response is evident, leading to suboptimal outcome for many patients. Furthermore, dosing is empiric and iterative and can lead to delays in meeting treatment goals and burdensome adverse effects. Pharmacogenomic (PGx) associations have been reported with certain PAH medications, such as treprostinil and bosentan, and can explain some of the variability in response. Relevant genes associated with treprostinil include , and and are the genes encoding the major metabolizing liver enzymes for treprostinil, and reduced function variants (*2, *3) with were associated with lower treatment persistence. Additionally, a higher activity score was associated with a significantly less risk of treatment discontinuation. Other genes of interest that have been explored with treprostinil include , which is associated with right ventricular dysfunction and significantly higher dose requirements. Similarly, is associated with lower concentrations of cyclic adenosine monophosphate and significantly higher dose requirements. Genes of interest with the endothelin receptor antagonist (ERA) class include and . A genetic variant in (rs11157866) was linked to a significantly increased rate of clinical improvement with ERAs. The *2 variant with (encoding for the major metabolizing enzyme for bosentan) was significantly associated with a higher risk for elevations in hepatic aminotransferases and liver injury. In summary, this article reviews the relevant pharmacogenes that have been associated to date with dosing and outcome among patients who received PAH medications.
PubMed: 37457231
DOI: 10.2147/PGPM.S361222 -
Biomedicine & Pharmacotherapy =... Feb 2022The most grievous complication of the COVID-19 is the acute respiratory distress syndrome. A specific, rescue treatment for rapidly deteriorating patients should emerge... (Review)
Review
INTRODUCTION
The most grievous complication of the COVID-19 is the acute respiratory distress syndrome. A specific, rescue treatment for rapidly deteriorating patients should emerge to improve respiratory function and help patients to survive the most challenging period. Drugs used in targeted therapy of pulmonary arterial hypertension (PAH) appears to be suitable for this task and this article describes their potential for treatment of severe cases of COVID-19.
METHODS
The authors reviewed the following databases for randomized controlled trials, reviews and meta-analyses published up to July 2020: Pubmed, Scopus, Google Scholar, Cochrane Database and ClinicalKey. The authors included every study contributory to the assessment of the potential of drugs used in targeted PAH therapy in treatment of COVID-19.
RESULTS
Endothelin receptor antagonists, phosphodiesterase 5 inhibitors, riociguat and prostacyclin have proven ani-inflammatory effect and reduce pulmonary artery blood pressure, lung oedema and remodelling. Bosentan shows antiviral properties and sildenafil, as well as epoprostenol, inhibits apoptosis of lung epithelial cells. Among patients with lung lesions the decrease of pulmonary blood pressure can lead to increase of ventilation/perfusion mismatch and decrease of blood oxygenation.
CONCLUSIONS
Among all assessed drugs bosentan, sildenafil and epoprostenol appear to be most promising and a combination of these drugs should be considered due to synergism. The targeted PAH therapy in treatment of COVID-19 associated ARDS could be a useful tool saving lives of patients with severe SARS-CoV-2 infection, however, its introduction should be investigated and monitored very carefully as it can lead to transient deterioration of patient condition.
Topics: Animals; COVID-19; Endothelin Receptor Antagonists; Humans; Phosphodiesterase Inhibitors; Prostaglandins; Pulmonary Artery; Pyrazoles; Pyrimidines; Respiratory Distress Syndrome; COVID-19 Drug Treatment
PubMed: 35062063
DOI: 10.1016/j.biopha.2021.112592 -
Cancer Letters Sep 2022Delivery of therapeutic agents in pancreatic cancer (PC) is impaired due to its hypovascular and desmoplastic tumor microenvironment. The Endothelin (ET)-axis is the...
Delivery of therapeutic agents in pancreatic cancer (PC) is impaired due to its hypovascular and desmoplastic tumor microenvironment. The Endothelin (ET)-axis is the major regulator of vasomotor tone under physiological conditions and is highly upregulated in multiple cancers. We investigated the effect of dual endothelin receptor antagonist bosentan on perfusion and macromolecular transport in a PC cell-fibroblast co-implantation tumor model using Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI). Following bosentan treatment, the contrast enhancement ratio and wash-in rates in tumors were two- and nine times higher, respectively, compared to the controls, whereas the time to peak was significantly shorter (7.29 ± 1.29 min v/s 22.08 ± 5.88 min; p = 0.04). Importantly, these effects were tumor selective as the magnitudes of change for these parameters were much lower in muscles. Bosentan treatment also reduced desmoplasia and improved intratumoral distribution of high molecular weight FITC-dextran. Overall, these findings support that targeting the ET-axis can serve as a potential strategy to selectively enhance tumor perfusion and improve the delivery of therapeutic agents in pancreatic tumors.
Topics: Bosentan; Endothelin Receptor Antagonists; Endothelins; Humans; Pancreatic Neoplasms; Perfusion; Sulfonamides; Tumor Microenvironment
PubMed: 35732216
DOI: 10.1016/j.canlet.2022.215801 -
Interventional Medicine & Applied... Aug 2021Pulmonary Arterial Hypertension (PAH) carries a poor prognosis in both adult and pediatric patients. It is a life-threatening condition in newborns. Current...
BACKGROUND
Pulmonary Arterial Hypertension (PAH) carries a poor prognosis in both adult and pediatric patients. It is a life-threatening condition in newborns. Current recommendations advocate the use of targeted monotherapy as a first-line approach for the treatment of Persistent Pulmonary Hypertension of the Newborn (PPHN). In case of an inadequate clinical response to treatment, an addition of a second or third agent is considered. PAH is usually managed with a phosphodiesterase 5 inhibitor or an endothelin receptor blocker. There are limited pediatric studies that address questions like which class of therapy should be initiated first or if a combination should be initiated together. With this background, the present study was initiated to compare the efficacy, safety, and tolerability of bosentan as an adjuvant to sildenafil and sildenafil alone in PPHN.
RESULTS
A total of 40 patients were enrolled in the study. Out of them, 26 were males (65%) and 14 were females (35%). PPHN was most commonly seen in the 29 (72.5%) of participants with a history of first order birth. Mean duration of symptoms was 14.05 ± 2.06 days. The participants were randomized to two groups. Group A consisted of total 25 participants that received both bosentan and sildenafil and group B had 15 participants that received sildenafil alone. Both groups were comparable in terms of birth weight and present weight, consanguinity, and mode of delivery. Efficacy was determined by the reduction in mean baseline Pulmonary Artery Systolic Pressure (PASP). PASP in group A was 75.56 ± 10.62 mm Hg and in group B was 64.86 ± 12.25 mm Hg which was not statistically significant ( > 0.05). PASP on the third and seventh day in group A were 43.72 ± 8.63 and 24.47 ± 3.52 mm Hg compared to 42.28 ± 9.43 and 27.276 ± 8.38 respectively in group B which was statistically significant ( < 0.05).There were two deaths each in both groups. Two participants in Group A developed liver function abnormalities. None of the participants in Group B had adverse effects.
CONCLUSION
Most common clinical manifestations were nonspecific. Cardiovocal syndrome was common in PPHN. We conclude that oral sildenafil treatment is a safe, simple and effective treatment for persistent pulmonary hypertension in newborn. Combination of bosentan with sildenafil is more effective and safe in reducing pulmonary artery (PA) pressures in high-risk patients with PPHN.
PubMed: 36343291
DOI: 10.1556/1646.2020.00004 -
Zhongguo Dang Dai Er Ke Za Zhi =... Mar 2022To systematically evaluate the efficacy and safety of bosentan in the treatment of persistent pulmonary hypertension of the newborn (PPHN). (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To systematically evaluate the efficacy and safety of bosentan in the treatment of persistent pulmonary hypertension of the newborn (PPHN).
METHODS
Chinese Journal Full-text Database, Weipu Database, Wanfang Data, China Biology Medicine disc, PubMed, Web of Science, Embase, and Cochrane Library were searched for literature on bosentan in the treatment of PPHN published up to August 31, 2021.
RESULTS
A total of 8 randomized controlled trials were included for Meta analysis. The results of the Meta analysis showed that compared with the control group, the bosentan treatment group had a significantly lower treatment failure rate (=0.23, <0.001), a significantly greater reduction in pulmonary artery pressure [mean difference ()=-11.79, <0.001)], significantly greater increases in oxygen partial pressure (=10.21, =0.006) and blood oxygen saturation (=8.30, <0.001), and a significantly shorter length of hospital stay (=-1.35, <0.001). The descriptive analysis showed that the bosentan treatment group had a lower degree of tricuspid regurgitation than the control group after treatment. The main adverse reactions of bosentan treatment included abnormal liver function, anemia and edema. The results of subgroup analysis based on treatment regimen, research area, and drug dose were consistent with those before stratification.
CONCLUSIONS
Bosentan is effective in the treatment of PPHN. However, when using bosentan, attention should be paid to adverse reactions such as abnormal liver function.
Topics: Bosentan; China; Humans; Hypertension, Pulmonary; Infant, Newborn; Treatment Failure
PubMed: 35351265
DOI: 10.7499/j.issn.1008-8830.2109151