Abstract:
AIMS:SAR247799 is a selective G-protein-biased sphingosine-1 phosphate receptor-1 (S1P1 ) agonist with potential to restore endothelial function in vascular pathologies. SAR247799, a first-in-class molecule differentiated from previous S1P1 -desensitizing molecules developed for multiple sclerosis, can activate S1P1 without desensitization and consequent lymphopenia. The aim was to characterize SAR247799 for its safety, tolerability, pharmacokinetics and pharmacodynamics (activation and desensitization). METHODS:SAR247799 was administered orally to healthy subjects in a double-blind, randomized, placebo-controlled study with single (2.5-37.5 mg) or 2-week once-daily (0.5-15 mg) doses. An open-label single dose pilot food-interaction arm with 10 mg SAR247799 in cross-over design was also performed. RESULTS:SAR247799 was well tolerated and, at the higher end of the dose ranges, caused the expected dose-dependent pharmacodynamics associated with S1P1 activation (heart rate reduction) and S1P1 desensitization (lymphocyte count reduction). SAR247799 demonstrated dose-proportional increases in exposure and was eliminated with an apparent terminal half-life of 31.2-33.1 hours. Food had a small effect on the pharmacokinetics of SAR247799. SAR247799 had a low volume of distribution (7-23 L), indicating a potential to achieve dose separation for endothelial vs cardiac S1P1 activation pharmacology. A supratherapeutic dose (10 mg) of SAR247799 produced sustained heart rate reduction over 14 days, demonstrating cardiac S1P1 activation without tachyphylaxis. Sub-lymphocyte-reducing doses (≤5 mg) of SAR247799, which, based on preclinical data, are projected to activate S1P1 and exhibit endothelial-protective properties, had minimal-to-no heart rate reduction and displayed no marked safety findings. CONCLUSION:SAR247799 is suitable for exploring the biological role of endothelial S1P1 activation without causing receptor desensitization.
journal_name
Br J Clin Pharmacoljournal_title
British journal of clinical pharmacologyauthors
Bergougnan L,Armani S,Golor G,Tardat A,Vitse O,Hurbin F,Scemama M,Poitiers F,Radzik D,Gaudin C,Hovsepian L,Muslin AJ,Kirkesseli S,Deutsch P,Parkar AAdoi
10.1111/bcp.14422subject
Has Abstractpub_date
2020-06-10 00:00:00eissn
0306-5251issn
1365-2125pub_type
杂志文章abstract:AIMS:The purposes of this work were to: (1) compare pharmacokinetic (PK) parameters for hydroxycarbamide in children receiving their first dose (HCnew ) vs. those receiving chronic therapy (HCchronic ), (2) assess the external validity of a published PK dosing strategy, and (3) explore the accuracy of dosing strategies...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1111/bcp.13426
更新日期:2018-07-01 00:00:00
abstract::The pharmacokinetics of single and co-administered didanosine and stavudine were evaluated in 10 HIV-seropositive subjects in an open, within subject design in which each subject received each of three treatments. Single doses of didanosine 100 mg were alternated randomly with single doses of stavudine 40 mg on days 1...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1111/j.1365-2125.1994.tb04374.x
更新日期:1994-11-01 00:00:00
abstract:AIMS:Inhaled corticosteroids alone or in combination with long acting beta2-agonists are indicated for use in mild persistent asthmatics. We set out to evaluate effects on airway hyperresponsiveness (AHR) and airway calibre using hydrofluoroalkane fluticasone/salmeterol (FP/SM) vs. double the dose of fluticasone alone ...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1046/j.1365-2125.2003.01831.x
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abstract:AIMS:To evaluate if rivaroxaban, an oral factor Xa (FXa) inhibitor, could modify the expression in vitro of inflammatory and oxidative stress biomarkers in abdominal aortic aneurysmal (AAA) sites showing intraluminal thrombus. METHODS:AAA sites with intraluminal mural thrombus were obtained from six patients undergoin...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.13383
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abstract::The deployment of artesunate for severe malaria and the artemisinin combination therapies (ACTs) for uncomplicated malaria has been a major advance in antimalarial therapeutics. These drugs have reduced treated mortality, accelerated recovery and reduced treatment failure rates and transmission from the treated infect...
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journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1984.tb02341.x
更新日期:1984-03-01 00:00:00
abstract:AIMS:To examine the potency of ticlopidine (TCL) as an inhibitor of cytochrome P450s (CYP450s) in vitro using human liver microsomes (HLMs) and recombinant human CYP450s. METHODS:Isoform-specific substrate probes of CYP1A2, 2C19, 2C9, 2D6, 2E1 and 3A4 were incubated in HLMs or recombinant CYPs with or without TCL. Pre...
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pub_type: 杂志文章
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journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:2004-05-01 00:00:00
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pub_type: 临床试验,杂志文章
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更新日期:1997-04-01 00:00:00
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pub_type: 杂志文章
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journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1986.tb02901.x
更新日期:1986-09-01 00:00:00
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pub_type: 杂志文章,随机对照试验
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更新日期:2012-07-01 00:00:00
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pub_type: 杂志文章
doi:10.1111/bcp.12565
更新日期:2015-06-01 00:00:00
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journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:1989-01-01 00:00:00
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journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
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journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
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pub_type: 杂志文章,评审
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pub_type: 杂志文章
doi:10.1111/j.1365-2125.1984.tb02484.x
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pub_type: 临床试验,杂志文章
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更新日期:2019-12-01 00:00:00
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pub_type: 杂志文章
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doi:10.1111/j.1365-2125.1987.tb03037.x
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pub_type: 杂志文章
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journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,评审
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更新日期:2015-10-01 00:00:00
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pub_type: 临床试验,杂志文章
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journal_title:British journal of clinical pharmacology
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更新日期:1999-04-01 00:00:00
abstract:AIMS:Angiotensin II is a putative mediator in bronchial asthma. There have been very few studies investigating the involvement of angiotensin II receptors in bronchial hyper-responsiveness in asthmatic patients. We examined the effect of candesartan cilexetil, a specific angiotensin II type 1 (AT1) receptor antagonist,...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:2002-12-01 00:00:00
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journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1988.tb03362.x
更新日期:1988-07-01 00:00:00