Dual Endothelin Receptor Antagonist Research Articles

A dual blocker of endothelin A/B receptors mitigates hypertension but not renal dysfunction in a rat model of chronic kidney disease and sleep apnea.

Obstructive sleep apnea is characterized by recurrent episodes of pharyngeal collapse during sleep, resulting in intermittent hypoxia (IH), and is associated with a high incidence of hypertension and accelerated renal failure. In rodents, endothelin (ET)-1 contributes to IH-induced hypertension, and ET-1 levels inversely correlate with glomerular filtration rate in patients with end-stage chronic kidney disease (CKD). Therefore, we hypothesized that a dual ET receptor antagonist, macitentan (Actelion Pharmaceuticals), will attenuate and reverse hypertension and renal dysfunction in a rat model of combined IH and CKD. Male Sprague-Dawley rats received one of three diets (control, 0.2% adenine, and 0.2% adenine + 30 mg·kg-1·day-1 macitentan) for 2 wk followed by 2 wk of recovery diet. Rats were then exposed for 4 wk to air or IH (20 short exposures/h to 5% O2-5% CO2 7 h/day during sleep). Macitentan prevented the increases in mean arterial blood pressure caused by CKD, IH, and the combination of CKD + IH. However, macitentan did not improve kidney function, fibrosis, and inflammation. After CKD was established, rats were exposed to air or IH for 2 wk, and macitentan feeding continued for 2 more wk. Macitentan reversed the hypertension in IH, CKD, and CKD + IH groups without improving renal function. Our data suggest that macitentan could be an effective antihypertensive in patients with CKD and irreversible kidney damage as a way to protect the heart, brain, and eyes from elevated arterial pressure, but it does not reverse toxin-induced tubule atrophy.

Pharmacological Characterization of Aprocitentan, a Dual Endothelin Receptor Antagonist, Alone and in Combination with Blockers of the Renin Angiotensin System, in Two Models of Experimental Hypertension.

The endothelin (ET) system has emerged as a novel target for hypertension treatment where a medical need persists despite availability of several pharmacological classes, including renin angiotensin system (RAS) blockers. ET receptor antagonism has demonstrated efficacy in preclinical models of hypertension, especially under low-renin conditions and in hypertensive patients. We investigated the pharmacology of aprocitentan (N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-sulfamide), a potent dual ETA/ETB receptor antagonist, on blood pressure (BP) in two models of experimental hypertension: deoxycorticosterone acetate (DOCA)-salt rats (low-renin model) and spontaneously hypertensive rats [(SHR), normal renin model]. We also compared the effect of its combination with RAS blockers (valsartan and enalapril) with that of the combination of the mineraloreceptor antagonist spironolactone with the same RAS blockers on BP and renal function in hypertensive rats. Aprocitentan was more potent and efficacious in lowering BP in conscious DOCA-salt rats than in SHRs. In DOCA-salt rats, single oral doses of aprocitentan induced a dose-dependent and long-lasting BP decrease and 4-week administration of aprocitentan dose dependently decreased BP (statistically significant) and renal vascular resistance, and reduced left ventricle hypertrophy (nonsignificant). Aprocitentan was synergistic with valsartan and enalapril in decreasing BP in DOCA-salt rats and SHRs while spironolactone demonstrated additive effects with these RAS blockers. In hypertensive rats under sodium restriction and enalapril, addition of aprocitentan further decreased BP without causing renal impairment, in contrast to spironolactone. In conclusion, ETA/ETB receptor antagonism represents a promising therapeutic approach to hypertension, especially with low-renin characteristics, and could be used in combination with RAS blockers, without increasing the risk of renal impairment.

The protective effect of endothelin receptor antagonists against surgically induced impairment of gastrointestinal motility in rats.

Endothelin (ET) receptor antagonists: BQ-123 (ETA), BQ-788 (ETB), tezosentan (dual ET receptor antagonist) protect against the development of postoperative ileus (POI) evoked by ischemia-reperfusion (I/R). The current experiments explored whether ET antagonists prevent the occurrence of POI evoked by surgical gut manipulation. Intestinal transit was assessed by measuring the rate of dye migration subsequent to skin incision (SI), laparotomy (L), or laparotomy and surgical gut handling (L+M) in diethyl ether anaesthesized rats (E). Experimental animals were randomly sub-divided into two groups depending on the time of recovery following surgery: viz. either 2 or 24 h (early or late phase POI). E and SI did not affect the gastrointestinal (GI) transit. In contrast, L and L+M significantly reduced GI motility in comparison to untreated group (UN). Tezosentan (10 mg/kg), BQ-123 and BQ-788 (1 mg/kg) protected against development of L+M evoked inhibition of intestinal motility in the course of late phase, but not early phase POI. Furthermore, tezosentan alleviated the decrease in the contractile response of the longitudinal jejunal smooth muscle strips to carbachol in vitro induced by L+M. The serum ET(1–21) concentration was not increased in either the early or the late phase POI groups after surgery compared to control animals. This study indicates that delay in the intestinal transit in late phase of surgically induced POI involves an ET-dependent mechanism.

Topical Administration of Bosentan Prevents Retinal Neurodegeneration in Experimental Diabetes.

Experimental evidence suggests that endothelin 1 (ET-1) is involved in the development of retinal microvascular abnormalities induced by diabetes. The effects of ET-1 are mediated by endothelin A- and B-receptors (ETA and ETB). Endothelin B-receptors activation mediates retinal neurodegeneration but there are no data regarding the effectiveness of ETB receptor blockage in arresting retinal neurodegeneration induced by diabetes. The main aim of the present study was to assess the usefulness of topical administration of bosentan (a dual endothelin receptor antagonist) in preventing retinal neurodegeneration in diabetic (db/db) mice. For this purpose, db/db mice aged 10 weeks were treated with one drop of bosentan (5 mg/mL, n = 6) or vehicle (n = 6) administered twice daily for 14 days. Six non-diabetic (db/+) mice matched by age were included as the control group. Glial activation was evaluated by immunofluorescence using specific antibodies against glial fibrillary acidic protein (GFAP). Apoptosis was assessed by TUNEL method. A pharmacokinetic study was performed in rabbits. We found that topical administration of bosentan resulted in a significant decrease of reactive gliosis and apoptosis. The results of the pharmacokinetic study suggested that bosentan reached the retina through the trans-scleral route. We conclude that topical administration of bosentan was effective in preventing neurodegeneration in the diabetic retina and, therefore, could be a good candidate to be tested in clinical trials.

BOSENTAN - endothelin receptor antagonist

Activation of the endothelin system has been demonstrated in the plasma and lung tissue of PAH (Pulmonary Artery Hypertension) patients. Although it is not clear if the increases in endothelin plasma levels are a cause or a consequence of PH (Pulmonary Hypertension), the data supports a prominent role for the endothelin system in the pathogenesis of PAH. Bosentan is an endothelin receptor antagonist used in the treatment of Primary pulmonary hypertension (PPH) which is a progressive disease with high mortality and administration of the orally active, dual endothelin receptor antagonist bosentan improves exercise endurance, haemodynamics, and functional class over the short term. First-line bosentan therapy was found to improve survival in patients with advanced primary pulmonary hypertension.International Journal of Human and Health Sciences Vol. 03 No. 01 January’19. Page : 10-13

Macitentan reduces progression of TGF-β1-induced pulmonary fibrosis andpulmonary hypertension.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with an unknown cause. Two drugs, nintedanib and pirfenidone, have been shown to slow, but not stop, disease progression. Pulmonary hypertension (PH) is a frequent complication in IPF patients and is associated with poor prognosis. Macitentan is a dual endothelin receptor antagonist that is approved for pulmonary arterial hypertension treatment. We hypothesised that using macitentan to treat animals with pulmonary fibrosis induced by adenoviral vector encoding biologically active transforming growth factor-β1 (AdTGF-β1) would improve the PH caused by chronic lung disease and would limit the progression of fibrosis.Rats (Sprague Dawley) which received AdTGF-β1 were treated by daily gavage of macitentan (100 mg·kg-1·day-1), pirfenidone (0.5% food admix) or a combination from day 14 to day 28. Pulmonary artery pressure (PAP) was measured before the rats were killed, and fibrosis was subsequently evaluated by morphometric measurements and hydroxyproline analysis.AdTGF-β1 induced pulmonary fibrosis associated with significant PH. Macitentan reduced the increase in PAP and both macitentan and pirfenidone stopped fibrosis progression from day14 to day 28. Macitentan protected endothelial cells from myofibroblast differentiation and apoptosis whereas pirfenidone only protected against fibroblast-to-myofibroblast differentiation. Both drugs induced apoptosis of differentiated myofibroblasts in vitro and in vivoOur results demonstrate that dual endothelin receptor antagonism was effective in both PH and lung fibrosis whereas pirfenidone only affected fibrosis.

Pulmonary hypertension: reasonable selection of specific therapy

Pulmonary hypertension is characterized with persistent increase in pulmonary vascular resistance leading to progressive worsening of right ventricular failure and death. The basis for pulmonary arterial hypertension is structural changes in pulmonary arteries and arterioles caused by endothelial dysfunction. Endothelin-1 is the main pathogenic trigger of pulmonary hypertension and potential target for therapeutic exposure. The efficacy of endothelin receptor antagonists is proved in various preclinical and clinical studies. In patients with pulmonary arterial hypertension, the efficacy of dual and selective endothelin receptor antagonists is comparable despite the varied activity against various receptors. Bosentan is the most widely used pulmonary vasodilator which improves exercise tolerance and decelerates disease progression.

Macitentan in daily clinical practice: A single centre, 1-year experience

The effectiveness and safety of macitentan, a dual endothelin-receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH), were shown in an extensive clinical trial oriented towards morbidity and mortality events. Our aim was to describe a single centre's experience of the utilization of macitentan in patients with PAH in clinical practice settings. Thirteen patients with different aetiologies and previous PAH treatments were studied. After 12 months of macitentan treatment, 11 patients improved their functional class (FC), all patients improved their 6-minute walk distance (6MWD) test, and 10 patients lowered their NT-proBNP plasma levels. Additionally, cardiac imaging parameters were also improved. No cases resulted in hospitalization, septostomy, transplant or death.

Separation and Characterization of New Forced Degradation Products of Macitentan: A Dual Endothelin Receptor Antagonist

Macitentan (MCT) is an endothelin receptor antagonist used for the treatment of pulmonary arterial hypertension. In the present study, MCT was subjected to forced degradation as per ICH guidelines. The drug degraded extensively in acidic, basic as well as neutral hydrolytic conditions and seven degradation products (DPs) were formed. All these DPs were selectively separated using high-performance liquid chromatography (HPLC) with a stationary phase of Inertsil C18 column (150 × 4.6 mm, 5 μm) and a mobile phase consisting of gradient mixture of 0.02% trifluoroacetic acid (TFA) and acetonitrile (ACN). The developed HPLC method was transferred to LC–ESI–QTOF–MS/MS for identification of DPs. The final mass spectrometric conditions were optimized for better ionization of drug and DPs with optimum mass signal sensitivity. All the formed DPs were new and well separated with sufficient resolution. The developed HPLC method was validated as per ICH-guidelines and can be used in drug testing labs for determination of quality of MCT in bulk and finished formulations.

The Endothelin Receptor Antagonist Macitentan Improves Isosorbide-5-Mononitrate (ISMN) and Isosorbide Dinitrate (ISDN) Induced Endothelial Dysfunction, Oxidative Stress, and Vascular Inflammation.

Objective Organic nitrates such as isosorbide-5-mononitrate (ISMN) and isosorbide dinitrate (ISDN) are used for the treatment of patients with chronic symptomatic stable coronary artery disease and chronic congestive heart failure. Limiting side effects of these nitrovasodilators include nitrate tolerance and/or endothelial dysfunction mediated by oxidative stress. Here, we tested the therapeutic effects of the dual endothelin (ET) receptor antagonist macitentan in ISMN- and ISDN-treated animals. Methods and Results Organic nitrates (ISMN, ISDN, and nitroglycerin (GTN)) augmented the oxidative burst and interleukin-6 release in cultured macrophages, whereas macitentan decreased the oxidative burst in isolated human leukocytes. Male C57BL/6j mice were treated with ISMN (75 mg/kg/d) or ISDN (25 mg/kg/d) via s.c. infusion for 7 days and some mice in addition with 30 mg/kg/d of macitentan (gavage, once daily). ISMN and ISDN in vivo therapy caused endothelial dysfunction but no nitrate (or cross-)tolerance to the organic nitrates, respectively. ISMN/ISDN increased blood nitrosative stress, vascular/cardiac oxidative stress via NOX-2 (fluorescence and chemiluminescence methods), ET1 expression, ET receptor signaling, and markers of inflammation (protein and mRNA level). ET receptor signaling blockade by macitentan normalized endothelial function, vascular/cardiac oxidative stress, and inflammatory phenotype in both nitrate therapy groups. Conclusion ISMN/ISDN treatment caused activation of the NOX-2/ET receptor signaling axis leading to increased vascular oxidative stress and inflammation as well as endothelial dysfunction. Our study demonstrates for the first time that blockade of ET receptor signaling by the dual endothelin receptor blocker macitentan improves adverse side effects of the organic nitrates ISMN and ISDN.

Clinical efficacy and safety of switch from bosentan to macitentan in children and young adults with pulmonary arterial hypertension.

Macitentan is an orally active, potent, dual endothelin receptor antagonist and is the only registered treatment for pulmonary arterial hypertension that significantly reduced morbidity and mortality in a long-term event-driven study. Aim Few studies compared the clinical efficacy and safety of switch from bosentan to macitentan only in adult patients with pulmonary arterial hypertension. We aimed to evaluate the clinical efficacy and safety of switch from bosentan to macitentan in children and young adults. This is a single-institution, 24-week prospective study. Patients ⩾12 years of age with idiopathic/heritable pulmonary arterial hypertension or related to CHD or residual pulmonary arterial hypertension due to repaired congenital systemic-to-pulmonary shunts and on bosentan therapy were included. Concomitant treatment with oral phosphodiesterase type 5 inhibitors and inhaled prostanoids was allowed. Outcome measures included change from baseline to week 24, in the 6-minute walk distance, functional class, oxygen saturation at rest/after 6-minute walk distance test, systolic pulmonary artery pressure estimated by echocardiography, and brain natriuretic peptide levels. Safety end points included adverse events laboratory abnormalities. A total of 13 patients - 5 male and 8 female - completed the study. The mean age was 20.3±6.5 years (12-35) and weight was 54.0±14.5 kg (27-75). Five patients were ⩽18 years of age. Macitentan improved 6-minute walk distance from baseline (mean: 466±35 m (300-590)), at 12 weeks (mean: 494±78 m (325-590), +28 m) (p0.05). None of the patients had anaemia, hepatotoxicity, and peripheral oedema. Our study is the first study that showed that switch from bosentan to macitentan significantly improved exercise capacity in children and young adults with pulmonary arterial hypertension and is well tolerated without any adverse events.

The Discovery of Macitentan - A Standard Medicinal Chemistry Program?

A plethora of properties are typically studied during a medicinal chemistry program and many of these parameters may shape the cascade of compound selection. Given the task to discover a molecule with a profile superior to that of the dual endothelin receptor antagonist bosentan, we tailored our compound profiling cascade to the specific properties that were not optimal in bosentan, namely in vivo efficacy and safety. Contrary to conventional thinking, we therefore focused on corresponding in vivo experiments. In the following, we highlight and illustrate some key learnings of our approach that led to the discovery of macitentan (1), an orally available potent dual endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension.

CLINICAL CASE OF COMBINATION THERAPY INCLUDING AMBRIZENTAN IN THE PATIENT WITH SEVERE IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION

Idiopathic pulmonary hypertension (IPAH) is a rare cardiovascular disease of unknown etiology, but the most common form of pulmonary arterial hypertension, defined as mean pulmonary arterial pressure >25 mmHg and pulmonary vascular resistance >3 Wood Units. Endothelial dysfunction seems to play an integral role in the pathogenesis of IPAH: the activation of endothelin-1 causes the hypertrophy of smooth muscle cells and endothelial cells, fibrotic changes, immune inflammation and vasoconstriction which leads to small pulmonary arteries and arterioles remodeling. The endothelial system activation is the reason for using endothelin receptor antagonists (ERA) to block the endothelin receptors type A (ETA) or both types (ETA, ETB). ERA, as the main class of PAH-specific therapy, is presented by bosentan and macitentan, dual endothelin receptor antagonists, and ambrisentan, non-sulfonamide, ETA-selective ERA. This clinical case demonstrates the successful treatment with ambrisentan as the part of combination therapy in the patient with severe IPAH.

Effect of amphiphilic graft co-polymer-carrier on physical stability of bosentan nanocomposite: Assessment of solubility, dissolution and bioavailability

Bosentan is a dual endothelin receptor antagonist used in the treatment of pulmonary arterial hypertension (PAH). But the solubility and bioavailability of this drug are poor, which has restricted the design and development of dosage forms for efficient and successful therapy. The present study was carried out to develop nanocomposites using an amphiphilic graft co-polymer (Soluplus®) as a carrier to enhance the solubility and bioavailability of bosentan. The graft co-polymer-based nanocomposite formulation was prepared using the single-emulsion technique. The nanocomposite was characterised in terms of particle size analysis, solubility, percentage entrapment efficiency, drug-loading capacity, surface morphology, drug content, in vitro dissolution, stability and bioavailability. FT-IR study revealed that there was no interaction between the drug and Soluplus®. DSC analysis of the nanocomposite formulation confirmed that the bosentan was completely encapsulated within a Soluplus®. XRD analysis showed that the drug was converted to an amorphous form irreversibly. SEM images showed that the particles were of size 96–129μm and had slightly smooth to rough textured surface. TEM analysis indicated that the diameters of the prepared bosentan nanocomposite after dispersion in distilled water were 13.69–96.78nm. Statistically significant increases in the solubility, dissolution and bioavailability of the drug were observed. It was confirmed that the use of a graft co-polymer carrier-based nanocomposite formulation is a good approach for efficient delivery of bosentan, the solubility and bioavailability being increased manifold.

Improvement in Dissolution of Bosentan Monohydrate by Solid Dispersions Using Spray Drying Technique

Background: Bosentan monohydrate (BM), a dual endothelin receptor antagonist, is indicated for the treatment of patients with pulmonary arterial hypertension (PAH). It is poorly soluble in water, and having absolute bioavailability of 50%. Objective: The aim of the present work is to develop and evaluate the solid dispersions (SD) of a poorly water soluble drug bosentan monohydrate (BM). Method: Solid dispersions (SDs) systems of BM were prepared with Hydroxy propyle β-cyclodextrin (HPβ-CD) and Polyethylene glycol (PEG-4000) polymers using a spray drying technique. Result: The significant rise in a saturation solubility 174.23±1.36 mg/mL; and drug dissolution 95.11±1.22%; was observed with optimized formulation (SD 6). The solid state characterization of optimized formulation (SD 6) by SEM, DSC, and XRPD revealed the absence of crystalline nature of BM in solid dispersion. High dissolution rate of solid dispersion (SD 6) compared with pure drug indicated the increase in dissolution characteristics. Conclusion: In conclusion, our studies illustrated that spray drying technique could be useful large scale producing method to prepare the solid dispersion of bosentan with HP β-CD, which can improve the solubility as well as stability of the formulation.

Possible role of endothelin receptor against hyperhomocysteinemia and β-amyloid induced AD type of vascular dementia in rats.

Vascular dementia (VaD) is considered as the second commonest form of dementia after Alzheimer's disease (AD). The study was designed to investigate the effect of endothelin receptor against β-amyloid induced AD type of vascular dementia. This disease was induced by combine administration of single ICV (intracerebroventricle) infusion of β-amyloid (Aβ) once and chronic oral administration of l-Methionine for 21 days. Bosentan (dual endothelin receptor antagonist) was administered for 21 days. Behavioral alterations were observed during different time interval of the study. Animals were killed immediately following the last behavior session. Oxidative parameters, acetylcholinesterase activity, neuro-inflammatory markers, amyloid beta levels were determined in hippocampus and cortex while serum homocysteine, serum nitrite carotid artery superoxide anion level were also determined. Endothelial function was measured on isolated carotid artery using myograph instrument. Aβ+l-Methionine showed more significant development of cognitive and vascular endothelial deficits, manifested in terms of increase in serum homocysteine level, endothelial dysfunction, impairment of learning and memory, enhanced brain acetylcholinesterase activity, marked mito-oxidative damage in rats. We have observed that l-Methionine and combination of Aβ+l-Methionine significantly enhanced Aβ level both in cortex as well as hippocampus. Treatment of bosentan attenuated Aβ+l-Methionine induced impairment of learning and memory, enhanced Aβ level, mitochondrial and endothelial dysfunction. The results of present study concluded that bosentan offers protection against β-amyloid-induced vascular dementia in rats. Endothelin receptor may be considered as a potential pharmacological target for the management of AD type of vascular dementia.

SERAPHIN haemodynamic substudy: the effect of the dual endothelin receptor antagonist macitentan on haemodynamic parameters and NT-proBNP levels and their association with disease progression in patients with pulmonary arterial hypertension.

AimsThe effect of macitentan on haemodynamic parameters and NT-proBNP levels was evaluated in pulmonary arterial hypertension (PAH) patients in the SERAPHIN study. Association between these parameters and disease progression, assessed by the primary endpoint (time to first morbidity/mortality event), was explored.Methods and resultsOf the 742 randomized patients, 187 with right heart catheterization at baseline and month 6 participated in a haemodynamic sub-study. Prespecified endpoints included change from baseline to month 6 in cardiac index (CI), right atrial pressure (RAP), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), mixed-venous oxygen saturation, and NT-proBNP. Exploratory analyses examined associations between CI, RAP, and NT-proBNP and disease progression using the Kaplan-Meier method and Cox regression models. Macitentan improved CI, RAP, mPAP, PVR and NT-proBNP vs. placebo at month 6. Absolute levels of CI, RAP and NT-proBNP at baseline and month 6, but not their changes, were associated with morbidity/mortality events. Patients with CI > 2.5 L/min/m2, RAP < 8 mmHg, or NT-proBNP < 750 fmol/ml at month 6 had a lower risk of morbidity/mortality than those not meeting these thresholds (HR 0.49, 95% CL 0.28–0.86; HR 0.72, 95% CL 0.42–1.22; and HR 0.22, 95% CL 0.15–0.33, respectively).ConclusionsFor all treatment groups, baseline and month 6 values of CI, RAP, and NT-proBNP, but not their changes, were associated with morbidity/mortality events, confirming their relevance in predicting disease progression in patients with PAH. By improving those parameters, macitentan increased the likelihood of reaching threshold values associated with lower risk of morbidity/mortality.

The role of endothelin-1 and endothelin receptor antagonists in allergic rhinitis inflammation: ovalbumin-induced rat model

Desloratadine is a biologically active metabolite of loratadine which is indicated for the treatment of allergic rhinitis. Bosentan is a dual endothelin receptor antagonist used to treatment of pulmonary artery hypertension (PAH). In this study, we aimed to determine the role of endothelins in allergic rhinitis (AR) and the effects of endothelin receptor antagonists in AR rat models through comparison with desloratadine. In total, 20 adult Sprague-Dawley rats were used in this study. An ovalbumin-induced allergic rhinitis model was formed in three study groups except for the control group. Bosentan (100 mg/kg/day) was given to the bosentan-treated group for 7 days and desloratadine (10 mg/kg/day) was administered to the antihistaminic-treated group for 7 days. Nasal symptom scorings and histopathological examinations of the nasal tissues were carried out. Serum IgE levels and ET-1 and TNF-alpha mRNA expression levels were analysed. Between group comparisons for nasal symptoms, histopathological analysis, and molecular analyses were performed with a one-way ANOVA and Duncans multiple comparison tests. Significance was accepted at p smaller than 0.05. Bosentan inhibited nasal symptom more significantly than desloratadine. The IgE level, ET-1 and TNF-alpha mRNA expression levels statistically increased in the allergic rhinitis group when compared to other groups. Conversely, the bosentan-treatment group showed a significant recovery from the same parameters. The deterioration in histopathological parameters reached the highest levels in the allergic rhinitis group. The histopathological findings were close to those of the control group in the bosentan and antihistaminic-treated group. ET-1 is one of the mediators that impact AR development and ET-1 antagonists can be useful for symptom control and for decreasing allergic inflammation in AR patients.

新規デュアルエンドセリン受容体拮抗薬マシテンタン（オプスミット&lt;sup&gt;®&lt;/sup&gt;錠）の薬理学的特性及び臨床試験成績

マシテンタン（製品名：オプスミット®錠）はActelion Pharmaceuticals Ltd.において創製された新規エンドセリン受容体拮抗薬（ERA：endothelin receptor antagonist）であり，肺動脈性肺高血圧症（PAH：pulmonary arterial hypertension）を効能・効果として，米国において2013年10月，欧州において2013年12月，本邦においては2015年3月に製造販売承認を取得した新規ERAである．マシテンタンはエンドセリン（ET：endothelin）A及びB受容体の両方に対して親和性を有し，競合的な阻害作用を示すデュアル拮抗薬である．マシテンタンは肺高血圧症（PH：pulmonary hypertension）の動物病態モデルにおいて，肺動脈圧，肺動脈肥厚，右室肥大，線維化の抑制及び生存期間の延長効果等を示し，その効力は既存治療薬であるボセンタン（製品名：トラクリア®錠）に比べて強いことが確認されている．安全性面においては，既存治療薬の課題である肝障害，末梢性浮腫等の懸念が少なく，また薬物代謝酵素に対する影響も臨床上考えられないことから，多剤併用治療の機会が多いPAH治療において非常に使用しやすい薬剤である．マシテンタンの臨床試験成績として，PAH患者742例を対象にした第Ⅲ相プラセボ対照二重盲検比較試験（SERAPHIN試験：Study with Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome）において，マシテンタンは主要評価項目として設定した「最初のmorbidity/mortalityイベントの発現までの時間」を有意に延長した．これまでPAH治療薬の主要評価項目として用いられてきた6分間歩行距離（6MWD：6-minute walk distance）は副次的評価項目としたが，マシテンタンは主要評価項目及び副次的評価項目ともにプラセボ群に比べて有意な改善効果を示し，加えて忍容性も良好であった．本邦においてはPAH患者30例を対象にした第Ⅱ/Ⅲ相オープンラベル試験を実施し，マシテンタンは主要評価項目である肺血管抵抗（PVR：pulmonary vascular resistance）をベースラインに比べて有意に改善した．以上，マシテンタンは非臨床試験において強力な効力を示し，臨床試験においてはPAH治療の真のエンドポイントであるmorbidity/mortalityイベントの発現リスクの低下を初めて立証した薬剤である．忍容性も良好であり，今後のPAH治療における新たな選択肢として極めて有用性の高い薬剤となることが期待される．

A Novel Beneficial Role for Macitentan in Patients at High Thrombosis Risk: Attenuation of Platelet-Mediated Derangements of Blood Coagulation in Eisenmenger Syndrome

IntroductionEisenmenger syndrome is a rare manifestation of congenital cardiac disease with pulmonary hypertension. Potentially dangerous thrombotic and haemorrhagic complications frequently occur in patients with ES and raise significant clinical dilemmas. Underlying mechanisms are unknown but are thought to be linked to the underlying pulmonary vascular disease. Endothelin-1 (ET-1) signalling in the pulmonary vasculature is implicated in the pathogenesis of ES and Macitentan (a novel dual ET-1 receptor antagonist) has been shown to improve clinical outcomes. However the effect of Macitentan on reversing abnormal blood coagulation is unknown.We aimed to characterise derangements in physiological procoagulant and anticoagulant pathways in ES and to assess the effect of Macitentan therapy in modulating haemostasis in this disorder. We hypothesized that an enhanced understanding of pro-and anticoagulant mechanisms in these patients has the potential to improve risk stratification and targeting of antithrombotic therapy to patients at high risk of thrombosis.MethodsBlood was collected from subjects with ES and age/gender-matched healthy controls into citrated tubes, some containing corn trypsin inhibitor (CTI, a contact pathway inhibitor; final concentration 50µg/mL).Parameters of plasma thrombin generation in platelet-rich and platelet-poor plasma were assessed by calibrated automated thrombography (CAT) in the presence or absence of exogenous tissue factor (TF), anionic phospholipid (PL) and activated protein C (APC).ResultsPlatelet-dependent blood coagulation measured by CAT was enhanced in ES platelet-rich plasma (PRP) relative to healthy volunteers despite lower platelet counts: peak thrombin generation (TG) was significantly higher in ES subjects v controls in PRP (230.6±10.9 vs 188.3±13.1 nM; p=0.025) and lagtime to TG (6.1±0.3 vs 7.8±0.5 mins, p=0.005), time to peak TG (11.5±0.5 vs 15.2±0.6 mins, p=0.0003) and TG velocity index (43.9±3.7 vs 26.3±2.4 nM/min, p=0.001) were significantly accelerated. No significant differences in TG parameters in PPP were observed between groups suggesting a critical mechanistic role for platelet activity in supporting hypercoagulability in ES. TG in PRP was also found to be significantly enhanced in ES in the presence of CTI, suggesting that in vitro or in vivocontact pathway activation does not contribute to the enhanced coagulation activation observed in this disorder.The anticoagulant activity of APC is PL dependent and in healthy PPP incubated with exogenous PL (as a substitute for platelet PL), TG was potently inhibited. Conversely, in healthy PRP (in the absence of exogenous PL), APC activity was attenuated. Remarkably, this effect was not observed among the ES subjects, where APC anticoagulant activity was significantly increased in PRP, with significantly lower residual peak plasma thrombin generation and endogenous thrombin potential relative to that observed in healthy volunteer PRP. APC anticoagulant activity in PPP (both in the presence and absence of exogenous PL) was similar between groups. These findings suggest that platelets also modulate the activity of the APC pathway in ES, but in a manner which could promote bleeding.Among the 7 subjects who commenced macitentan therapy, at 6 months peak TG in PRP was significantly lower (234.5±9.8 vs 204.6±14.1 nM, p=0.002) and the enhanced sensitivity to APC in PRP was also attenuated. No significant difference in any parameter of TG was observed in PPP following macitentan therapy.ConclusionPlatelet activity appears to contribute significantly to hypercoagulability in ES but also appears to modulate the activity of endogenous anticoagulant pathways reflecting the clinical phenotype where bleeding and thrombotic risks frequently co-exist. Our findings suggest that targeted pharmacological agents such as the dual endothelin-1 antagonists (which crucially do not confer a bleeding risk) may attenuate platelet-mediated derangements in blood coagulation. Given the significant clinical dilemmas posed by the presence of competing thrombotic and haemorrhagic tendencies in ES, these finding are likely to be of significant translational relevance. DisclosuresWalsh:Actelion UK: Research Funding. Maguire:Actelion UK: Research Funding. Ní Áinle:Actelion UK: Research Funding.