Clazosentan
(Synonyms: Ro 61-1790; VML 588; AXV-034343) 目录号 : GC68435Clazosentan (Ro 61-1790) 是一种选择性的内皮素 A 受体 (ETA receptor) 拮抗剂。Clazosentan 抑制 ET-1 介导的血管收缩。Clazosentan 可预防脑血管痉挛、血管痉挛相关性脑梗死。
Cas No.:180384-56-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
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- SDS (Safety Data Sheet)
- Datasheet
Clazosentan (Ro 61-1790) is a selective endothelin A (ETA) receptor antagonist. Clazosentan inhibits ET-1-mediated vasoconstriction. Clazosentan prevents cerebral vasospasm, vasospasm-related cerebral infarction[1][5].
Clazosentan (0.1 μM) inhibits the ETA receptor in cerebral arteries[3].
Clazosentan is a substrate of the organic anion-transporting polypeptide (OATP) 1B1/1B3[5].
Clazosentan (10 μM, 0.05 mL/kg, intracisternal injection) inhibits the contractile responses to ET-1 in rats[2].
Clazosentan (10 mg/kg, s.c.) inhibits IL-33-induced hypernociception in mice[4].
| Animal Model: | Rats[2] |
| Dosage: | 10 μM, 0.05 mL/kg |
| Administration: | Intracisternal injection |
| Result: | Inhibited the contractile responses to ET-1, without preventing SAH-induced upregulation of ET receptors in cerebral arteries. |
[1]. Juif PE, et al. Clinical Pharmacology of Clazosentan, a Selective Endothelin A Receptor Antagonist for the Prevention and Treatment of aSAH-Related Cerebral Vasospasm. Front Pharmacol. 2021 Feb 4;11:628956.
[2]. Povlsen GK, et al. MEK1/2 inhibitor U0126 but not endothelin receptor antagonist clazosentan reduces upregulation of cerebrovascular contractile receptors and delayed cerebral ischemia, and improves outcome after subarachnoid hemorrhage in rats. J Cereb Blood Flow Metab. 2015 Feb;35(2):329-37.
[3]. Vatter H, et al. Cerebrovascular characterization of clazosentan, the first nonpeptide endothelin receptor antagonist clinically effective for the treatment of cerebral vasospasm. Part I: inhibitory effect on endothelin(A) receptor-mediated contraction. J Neurosurg. 2005 Jun;102(6):1101-7.
[4]. Verri WA Jr, Guerrero AT, Fukada SY, Valerio DA, Cunha TM, Xu D, Ferreira SH, Liew FY, Cunha FQ. IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice. Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2723-8.
[5]. Juif PE, et al. Influence of Rifampin-Mediated Organic Anion-Transporting Polypeptide 1B1/1B3 Inhibition on the Pharmacokinetics of Clazosentan. Clin Transl Sci. 2019 Sep;12(5):440-444.
| Cas No. | 180384-56-9 | SDF | Download SDF |
| 别名 | Ro 61-1790; VML 588; AXV-034343 | ||
| 分子式 | C25H23N9O6S | 分子量 | 577.57 |
| 溶解度 | DMSO : 83.33 mg/mL (144.28 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.7314 mL | 8.657 mL | 17.3139 mL |
| 5 mM | 0.3463 mL | 1.7314 mL | 3.4628 mL |
| 10 mM | 0.1731 mL | 0.8657 mL | 1.7314 mL |
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Clazosentan: First Approval
Drugs 2022 Apr;82(6):697-702.PMID:35362854DOI:10.1007/s40265-022-01708-0.
Clazosentan (PIVLAZ™) is a small molecule, endothelin (ET) A receptor-selective antagonist being developed by Idorsia Pharmaceuticals. ETA receptor inhibition by Clazosentan decreases ET-related cerebral vasospasm, which may occur after an aneurysmal subarachnoid haemorrhage. Clazosentan has been approved in Japan for use in the prevention of cerebral vasospasm, vasospasm-related cerebral infarction and cerebral ischaemic symptoms after aneurysmal subarachnoid haemorrhage, following the results from the JapicCTI163369 and JapicCTI163368 phase III trials. This article summarises the milestones in the development of Clazosentan leading to this first approval in this indication.
Effects of Clazosentan on cerebral vasospasm-related morbidity and all-cause mortality after aneurysmal subarachnoid hemorrhage: two randomized phase 3 trials in Japanese patients
J Neurosurg 2022 Apr 1;137(6):1707-1717.PMID:35364589DOI:10.3171/2022.2.JNS212914.
Objective: Clazosentan has been investigated globally for the prevention of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). The authors evaluated its effects on vasospasm-related morbidity and all-cause mortality following aSAH in Japanese patients. Methods: Two similar double-blind, placebo-controlled phase 3 studies were conducted in 57 Japanese centers in patients with aSAH, after aneurysms were secured by endovascular coiling in one study and surgical clipping in the other. In each study, patients were randomly administered intravenous Clazosentan (10 mg/hr) or placebo (1:1) starting within 48 hours of aSAH and for up to 15 days after aSAH. Stratified randomization based on World Federation of Neurosurgical Societies grade was performed using a centralized interactive web response system. Vasospasm-related morbidity and all-cause mortality within 6 weeks post-aSAH, including new cerebral infarcts and delayed ischemic neurological deficits as well as all-cause mortality, were the first primary endpoint in each study. The second primary endpoint was all-cause morbidity (new cerebral infarct or delayed ischemic neurological deficit from any causes) and all-cause mortality (all-cause morbidity/mortality) within 6 weeks post-aSAH. The incidence of individual components of the primary morbidity/mortality endpoints within 6 weeks and patient outcome at 12 weeks post-aSAH (including the modified Rankin Scale scores) were also evaluated. The above analyses were also performed in the population pooled from both studies. Results: In each study, 221 patients were randomized and 220 were included in the full analysis set of the primary analysis (109 in each Clazosentan group, 111 in each placebo group). Clazosentan significantly reduced the incidence of vasospasm-related morbidity and all-cause mortality after aneurysm coiling (from 28.8% to 13.6%; relative risk reduction 53%; 95% CI 17%-73%) and after clipping (from 39.6% to 16.2%; relative risk reduction 59%; 95% CI 33%-75%). All-cause morbidity/mortality and poor outcome (dichotomized modified Rankin Scale scores) were significantly reduced by Clazosentan after preplanned study pooling. Treatment-emergent adverse events were similar to those reported previously. Conclusions: Clazosentan significantly reduced the combined incidence of vasospasm-related morbidity and all-cause mortality post-aSAH with no unexpected safety findings. Clinical trial registration nos.: JapicCTI-163368 and JapicCTI-163369 (https://www.clinicaltrials.jp).
Clazosentan for Aneurysmal Subarachnoid Hemorrhage: An Updated Meta-Analysis with Trial Sequential Analysis
World Neurosurg 2019 Mar;123:418-424.e3.PMID:30508597DOI:10.1016/j.wneu.2018.10.213.
Objective: Clazosentan, an endothelin receptor antagonist, reduced vasospasm and delayed ischemic neurologic deficit (DIND) but did not improve outcome after subarachnoid hemorrhage (SAH) in clinical trials. However, a lack of dose-dependent analysis and potential overestimation of Clazosentan's effect are concerning. We used stratified analysis and trial sequential analysis (TSA) of existing data to investigate the effects of Clazosentan on SAH outcome. Methods: Studies from PubMed, Embase, and Cochrane were reviewed for eligibility. Primary outcomes were DIND requiring rescue therapy, all-cause mortality, and vasospasm-related morbidity at 6 weeks. Secondary outcomes were moderate-to-severe angiographic vasospasm, new cerebral infarction, and poor clinical outcome at 3 months. TSA was performed to assess the required information size and the α-spending monitoring boundary effect of relative risk (RR) reduction. A stratified analysis of Clazosentan dosage was performed. Results: Five studies (N = 2317) were included. Clazosentan significantly reduced the risk of DIND requiring rescue therapy (RR, 0.625; 95% confidence interval [CI], 0.462-0.846) and vasospasm (RR, 0.543; 95% CI, 0.464-0.635), but did not significantly affect mortality or vasospasm-related morbidity (RR, 0.775; 95% CI, 0.578-1.039), new cerebral infarction (RR, 0.604; 95% CI, 0.383-0.952), or outcome (RR, 1.131; 95% CI, 0.959-1.334). TSA revealed that the studies were underpowered to evaluate the effects of Clazosentan on mortality and vasospasm-associated morbidity. We found 10-15 mg/h of Clazosentan administration was associated with lower rates of vasospasm and new cerebral infarctions compared with 5 mg/h. Conclusions: Clazosentan reduced the risk of DIND requiring rescue therapy and moderate-to-severe vasospasm. Further meta-analyses based on individual patient data with different Clazosentan doses and more refined outcome measures are necessary to clarify Clazosentan's efficacy in improving post-SAH outcome.
Clinical Pharmacology of Clazosentan, a Selective Endothelin A Receptor Antagonist for the Prevention and Treatment of aSAH-Related Cerebral Vasospasm
Front Pharmacol 2021 Feb 4;11:628956.PMID:33613288DOI:10.3389/fphar.2020.628956.
Aneurysmal subarachnoid hemorrhage (aSAH) may lead to cerebral vasospasm and is associated with significant morbidity and mortality. It represents a major unmet medical need due to few treatment options with limited efficacy. The role of endothelin-1 (ET-1) and its receptor ETA in the pathogenesis of aSAH-induced vasospasm suggests antagonism of this receptor as promising asset for pharmacological treatment. Clazosentan is a potent ETA receptor antagonist for intravenous use currently under development for the prevention of aSAH-induced cerebral vasospasm. The pharmacokinetics of Clazosentan are characterized by an intermediate clearance, a volume of distribution similar to that of the extracellular fluid volume, dose-proportional exposure, an elimination independent of drug-metabolizing enzymes, and a disposition mainly dependent on the hepatic uptake transporter organic anion transport polypeptide 1B1/1B3. In healthy subjects, Clazosentan leads to an increase in ET-1 concentration and prevents the cardiac and renal effects mediated by infusion of ET-1. In patients, it significantly reduced the incidence of moderate or severe vasospasm as well as post-aSAH vasospasm-related morbidity and mortality. Clazosentan is well tolerated up to the expected therapeutic dose of 15 mg/h and, in aSAH patients, lung complications, hypotension, and anemia were adverse events more commonly reported following Clazosentan than placebo. In summary, Clazosentan has a pharmacokinetic, pharmacodynamic, and safety profile suitable to become a valuable asset in the armamentarium of therapeutic modalities to prevent aSAH-induced cerebral vasospasm.
Clazosentan for Improvement of Time to Peak Perfusion in Patients with Angiographically Confirmed Severe Vasospasm
Neurocrit Care 2022 Feb;36(1):240-247.PMID:34296399DOI:10.1007/s12028-021-01291-4.
Background: Clazosentan, an endothelin-1 receptor antagonist, has been shown to prevent the development of large vessel angiographic vasospasm after aneurysmal subarachnoid hemorrhage. We hypothesized that Clazosentan can improve cerebral perfusion for territories affected by angiographically confirmed vasospasm. Methods: The REVERSE study (REversal of Vasospasm with Clazosentan post-aneuRysmal Subarachnoid hEmorrhage) was a prospective multicenter open-label pilot study of adult patients with aneurysmal subarachnoid hemorrhage who received intravenous Clazosentan after developing moderate to severe angiographic vasospasm. Using the radiographic data from the REVERSE study and additional retrospective radiographic data from our tertiary medical center, we compared the impact of intravenous Clazosentan with intraarterial vasodilator therapy (medical standard of care) on vasospasm reversal using time to peak perfusion (TTPP; the time interval between the peak opacification of contrast dye in the main artery supplying an anatomically defined territory and the parenchymal phase when the dye is diffusely present in the brain parenchyma). Results: Both intravenous Clazosentan (n = 7 vessels) and intraarterial vasodilator therapy (n = 11 vessels) resulted in a statistically significant improvement in TTPP at 24 h post intervention, when compared with the TTPP just prior to intervention for territories with angiographically confirmed severe vasospasm in the proximal arteries at baseline (linear mixed-effect model, p = 0.02). The Clazosentan and intraarterial vasodilator therapy groups exhibited no statistically significant interaction term [time x treatment group (medical standard of care vs. Clazosentan)] in our model (p = 0.71), suggesting similar temporal course of two therapies. Conclusions: In our small pilot study, intravenous Clazosentan administered for at least 24 h had an effect comparable with that of intraarterial vasodilator therapy in reversing angiographically confirmed severe vasospasm. Our results may indicate that Clazosentan, in an appropriately selected patient cohort, could offer a noninvasive approach for alleviating vasospasm.