Efficacy and Safety of Long-Term Imatinib Therapy for Pulmonary Arterial Hypertension

Speich, Rudolf; Ulrich, Silvia; Domenighetti, Guido; Huber, Lars C; Fischler, Manuel; Treder, Ursula; Berndt, Alexander

doi:10.1159/000381923

Cited by 24 publications

(17 citation statements)

References 32 publications

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“…; Speich et al. ). Previous studies have focused on single pathways, and cross‐talk between different pathways needs more attention.…”

Section: Discussionmentioning

confidence: 97%

“…increased in both PAH animal models and patients (Benisty et al 2004;Izikki et al 2009). Inhibition of both PDGF and FGF signaling have been shown to ameliorate PAH, however, treatment of patients with their inhibitors was accompanied by severe adverse events and drug discontinuation was common (Frost et al 2015;Speich et al 2015). Previous studies have focused on single pathways, and cross-talk between different pathways needs more attention.…”

Section: Discussionmentioning

confidence: 99%

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MiR-339 inhibits proliferation of pulmonary artery smooth muscle cell by targeting FGF signaling

Chen

Cui

et al. 2017

Physiol Rep

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Pulmonary artery hypertension (PAH) is a fatal disorder. Recent studies suggest that microRNA (miRNA) plays an important role in regulating proliferation of pulmonary artery smooth muscle cells (PASMC), which underlies the pathology of PAH. However, the exact mechanism of action of miRNAs remains elusive. In this study, we found that miR‐339 was highly expressed in the cardiovascular system and was downregulated by a group of cytokines and growth factors, especially PDGF‐BB and FGF2. Functional analyses revealed that miR‐339 can inhibit proliferation of PASMC. Also, miR‐339 inhibited FGF2‐induced proliferation, but had no effect on proliferation induced by PDGF‐BB. The fibroblast growth factor receptor substrate 2 (FRS2) was identified as a potential direct target of miR‐339. Consistent with the actions of miR‐339, knockdown of FRS2 only inhibited FGF2‐ but not PDGF‐BB‐induced proliferation of PASMC. In addition, our results showed that inhibition of ERK and PI3K abrogated the downregulation of miR‐339 induced by PDGF‐BB. Finally, miR‐339 expression was found to be decreased in the pulmonary arteries of rats with MCT‐induced PAH. Our study is the first report on the biological role of miR‐339 in regulating proliferation of PASMC by targeting FGF signaling, providing new mechanistic insights into PASMC proliferation and pathogenesis of PAH.

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“…; Speich et al. ). Previous studies have focused on single pathways, and cross‐talk between different pathways needs more attention.…”

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

MiR-339 inhibits proliferation of pulmonary artery smooth muscle cell by targeting FGF signaling

Chen

Cui

et al. 2017

Physiol Rep

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“…Why does the right ventricle dilate in one PAH patient and not in the other? Although this question cannot be answered yet, it became clear from another recent study that the contractile reserve of the right ventricle in advanced stages of PAH is absent [28]. For this reason dilatation might be the only option for the right ventricle to preserve stroke volume.…”

Section: Novel Insights Into Treatment Strategy In Pahmentioning

confidence: 99%

Pulmonary hypertension

2016

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In 2015, more than 800 papers were published in the field of pulmonary hypertension. A Clinical Year in Review article cannot possibly incorporate all this work and needs to be selective. The recently published European guidelines for the diagnosis and treatment of pulmonary hypertension contain an inclusive summary of all published clinical studies conducted until very recently. Here, we provide an overview of papers published after the finalisation of the guideline. In addition, we summarise recent advances in pulmonary vasculature science. The selection we made from the enormous amount of published work undoubtedly reflects our personal views and may not include all papers with a significant impact in the near or more distant future. The focus of this paper is on the diagnosis of pulmonary arterial hypertension, understanding the success of combination therapy on the right ventricle and scientific breakthroughs. @ERSpublicationsThe review summarises advances in pulmonary hypertension since the publication of the recent ESC/ERS guidelines http://ow.ly/WUwoeThe global picture of pulmonary arterial hypertension Table 1 summarises the recent classification of pulmonary hypertension [1,2]. Based on data from the large European and North American registries, the most common types of pulmonary arterial hypertension (PAH) are idiopathic PAH and PAH associated with connective tissue disease. Less is known of the epidemiology of PAH in other parts of the world. Using the data from a large reference centre in Brazil, ALVES et al. [3] showed that schistosomiasis is among the top three of causes of PAH in that country. These global epidemiological data emphasise the importance of accounting for such differences in future clinical trials. Pulmonary veno-occlusive diseaseAn important change from the previous classification is that significant progress has been made in the field of pulmonary veno-occlusive disease (PVOD). Several causes of PVOD have been identified in recent years, including genetics, drugs and radiation therapy. The finding of the EIF2AK4 (eukaryotic translation initiation factor 2α kinase 4) mutation in familial PVOD and pulmonary capillary haemangiomatosis (PCH) might boost further research [4,5]. By the discovery of this gene, it is possible to confirm the diagnosis of PVOD or PCH by demonstrating the presence of the mutation instead of a histological diagnosis [5]. Of interest is the recent study by PERROS et al. [6] showing not only that mitomycin is a risk factor for the development of PVOD, but also that mitomycin induces pulmonary vascular disease in rats that resembles the pathological features of PVOD. This finding not only offers a representative animal model to study the disease but also sheds new light on the possible role of alkylating chemotherapy on the development of pulmonary hypertension [7]. New associations between drugs and disease were not only made in PVOD; in PAH, a possible relationship between a drug and the disease also was found. A recent

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“…As this agent also shows inhibitory effects on the plateletderived growth factor and c-KIT signaling, it was suggested that it may be efficacious in PAH, but it was not approved due to side effects and serious adverse events [18] . Patients who participated in the phase III trial often continued treatment with imatinib due to good clinical response and positive effects on quality of life [19] . 28 cation plasma concentrations in the Center for Pulmonary Hypertension, Thorax Clinic at the University Hospital Heidelberg.…”

Section: Introductionmentioning

confidence: 99%

Plasma Drug Concentrations in Patients with Pulmonary Arterial Hypertension on Combination Treatment

Grünig

Ohnesorge²,

Benjamin³

et al. 2017

Respiration

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Background: Combination therapy with the phosphodiesterase type 5 inhibitors (PDE-5i) sildenafil or tadalafil and the endothelin receptor antagonists (ERA) bosentan, ambrisentan, or macitentan may cause mutual pharmacokinetic interactions in patients with pulmonary arterial hypertension (PAH). Objective: The objective of this study was to analyze plasma drug concentrations in PAH patients receiving different combination treatments. Methods: PAH patients receiving a stable combination treatment with ERA and PDE-5i with targeted dosage for at least 1 month were routinely assessed, including clinical parameters and plasma drug concentrations. Concentrations were normalized considering dose and time from last medication intake and presented as multiples of the expected mean (MoM) of the respective monotherapies. Results: A total of 125 PAH patients (84 female, 41 male, 57% idiopathic/heritable) were included. Sildenafil and tadalafil concentrations were lowest in combination with bosentan (MoM 0.44 ± 0.42, 95% confidence interval [CI] 0.30-0.57, and MoM 0.89 ± 0.53, 95% CI 0.50-1.28, respectively) compared to the combination with ambrisentan (MoM 1.3 ± 0.97, 95% CI 0.86-1.73, and MoM 1.67 ± 0.63, 95% CI 1.40-1.94, respectively) and macitentan (MoM 1.16 ± 0.87, 95% CI 0.86-1.46, and MoM 1.59 ± 0.99, 95% CI 0.80-2.38, respectively). The combination of sildenafil and bosentan led to more than twice the expected bosentan concentrations in 53.8%. Patients switching from sildenafil-bosentan to macitentan showed a significant increase in sildenafil concentrations (p < 0.001). Conclusions: Only the combination with macitentan or ambrisentan led to targeted mean PDE-5i plasma concentrations and should therefore be preferred to combination with bosentan. Sildenafil-bosentan showed the strongest interaction, with low sildenafil and high bosentan concentrations. The study was not powered to analyze whether lower PDE-5i concentrations cause unsatisfying clinical response. However, plasma concentrations within a targeted range are desirable and may become of increasing importance.

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Efficacy and Safety of Long-Term Imatinib Therapy for Pulmonary Arterial Hypertension

Cited by 24 publications

References 32 publications

MiR-339 inhibits proliferation of pulmonary artery smooth muscle cell by targeting FGF signaling

MiR-339 inhibits proliferation of pulmonary artery smooth muscle cell by targeting FGF signaling

Pulmonary hypertension

Plasma Drug Concentrations in Patients with Pulmonary Arterial Hypertension on Combination Treatment

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