Characterisation of the Role of ETA and ETB Receptors in Regulating Plasma ET-1 and the Vasodilator Response to ET-3 in Man
Endothelin-1 (ET-1) has been linked to a number of conditions including pulmonary arterial hypertension (PAH). ET-1 acts via 2 receptors, ETA and ETB. The ET-1 receptor blockers bosentan and sitaxsentan have been shown to be beneficial in patients with PAH. Bosentan blocks both ETA and ETB receptors. Sitaxsentan selectively blocks ETA receptors. Theoretically, selective ETA blockade may be associated with greater vasodilation and clearance of ET-1 by leaving the ETB receptor unblocked. This has not been directly studied in humans. We aim to investigate the endothelial ETB-mediated vascular responses between bosentan and sitaxsentan by using a ETB selective agonist (ET-3). We hypothesise that at clinically relevant doses: Bosentan will show evidence of ETB receptor blockade compared to sitaxsentan and placebo. These effects will be confirmed by 2 functional markers of ETB receptor antagonism: plasma ET-1 (a very sensitive, but not necessarily clinically relevant marker), and the forearm vasodilator response to ET-3.
The Effect of Sitaxsentan Once Daily Dosing on Proteinuria, 24-Hour Systemic Blood Pressure, and Arterial Stiffness in Subjects With Chronic Kidney Disease
Patients with chronic kidney disease (CKD) have higher blood pressures than the general population. They also tend to have protein leaking into the urine (proteinuria). CKD, high blood pressure and proteinuria independently and together increase the risk of developing atherosclerosis (hardening) of the arteries that leads to diseases such as heart attack and stroke. Although there are a number of drugs available that lower blood pressure, these are not always fully effective. Furthermore, there are even fewer drugs that simultaneously lower blood pressure, reduce proteinuria, and slow down kidney damage in CKD. Recent research has shown that drugs like sitaxsentan not only lower blood pressure but also reduce proteinuria and potentially slow down the progression of CKD [1,2]. Before sitaxsentan can become freely available to individuals with CKD it is important to look at the effects this drug could have on proteinuria and blood pressure. Goddard J, Johnston NR, Hand MF, et al. Endothelin-A receptor antagonism reduces blood pressure and increases renal blood flow in hypertensive patients with chronic renal failure: a comparison of selective and combined endothelin receptor blockade. Circulation 2004;109:1186-1193. Krum H, Viskoper RJ, Lacourciere Y et al. The effect of an endothelin receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. New Engl J Med 1998;338:784-790.
2010-10-01·Biochemical and Biophysical Research Communications3区 · 生物学
Potent in vivo suppression of inflammation by selectively targeting the high affinity conformation of integrin α4β1
3区 · 生物学
作者: Vanderslice, Peter ; Woodside, Darren G. ; Caivano, Amy R. ; Decker, E. Radford ; Munsch, Christy L. ; Sherwood, Sidney J. ; Le Jeune, Wanda S. ; Miyamoto, Yuko J. ; McIntyre, Bradley W. ; Tilton, Ronald G. ; Dixon, Richard A. F.
The development of antagonists to the α4 integrin family of cell adhesion molecules has been an active area of pharmaceutical research to treat inflammatory and autoimmune diseases. Presently being tested in human clinical trials are compounds selective for α4β1 (VLA-4) as well as several dual antagonists that inhibit both α4β1 and α4β7. The value of a dual versus a selective small molecule antagonist as well as the consequences of inhibiting different affinity states of the α4 integrins have been debated in the literature. Here, we characterize TBC3486, a N,N-disubstituted amide, which represents a unique structural class of non-peptidic, small molecule VLA-4 antagonists. Using a variety of adhesion assay formats as well as flow cytometry experiments using mAbs specific for certain activation-dependent integrin epitopes we demonstrate that TBC3486 preferentially targets the high affinity conformation of α4β1 and behaves as a ligand mimetic. The antagonist is capable of blocking integrin-dependent T-cell co-activation in vitro as well as proves to be efficacious in vivo at low doses in two animal models of allergic inflammation. These data suggest that a small molecule α4 integrin antagonist selective for α4β1 over α4β7 and, specifically, selective for the high affinity conformation of α4β1 may prove to be an effective therapy for multiple inflammatory diseases in humans.
2010-01-01·British Journal of Clinical Pharmacology2区 · 医学
The effects of sitaxentan on sildenafil pharmacokinetics and pharmacodynamics in healthy subjects
2区 · 医学
作者: Stavros, Fiona ; Kramer, William G. ; Wilkins, Martin R.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT:
* Endothelin-A receptor antagonists (ETRAs) and phosphodiesterase-type 5 inhibitors are approved monotherapies for the treatment of pulmonary arterial hypertension; combining agents from these two drug classes could be beneficial. * There is a significant pharmacokinetic (PK) interaction between the ETRA bosentan and the phosphodiesterase-type 5 inhibitor sildenafil. * This study assessed whether the ETRA sitaxentan similarly impacts the PK of sildenafil.
WHAT THIS STUDY ADDS:
* This study demonstrates that sitaxentan has little effect on sildenafil PK and pharmacodynamics and that no dose adjustment of either agent is required upon co-administration of sildenafil with sitaxentan.
This study evaluated the effects of sitaxentan on the pharmacodynamic [systemic blood pressure (BP)] and pharmacokinetic (PK) parameters of sildenafil in healthy volunteers.
Healthy subjects (18-60 years, n= 24) were randomized into two sequence groups. Group 1 received sitaxentan sodium 100 mg daily (7 days), followed by placebo (7 days). Group 2 received placebo (7 days), followed by sitaxentan sodium 100 mg (7 days). On day 7 of each treatment period, participants received sildenafil 100 mg. PK parameters and BP were analysed on day 7 in each treatment period.
Sildenafil exposure was slightly higher [AUC(infinity) geometric mean ratio (GMR), 128%] when co-administered with sitaxentan 100 mg vs. placebo, demonstrating a weak, but statistically significant interaction (90% confidence interval 115.5%, 141.2%). The mean maximum positive (E(max)+) and maximum negative (E(max)-) changes from baseline in both systolic and diastolic BP were comparable for sitaxentan and placebo (range 4.8-7.3 mmHg) with three of four geometric mean ratios falling within the equivalence window, suggesting that the drug interaction was not clinically significant. Adverse events were similar between sitaxentan 100 mg (39%) and placebo (30%). No deaths or serious adverse events occurred during the study.
The dose of sildenafil does not need to be adjusted when co-administered with sitaxentan.
2010·Progress in Respiratory Research
Very late activation antigen-4 (VLA-4) antagonists
作者: Vanderslice, Peter ; Woodside, Darren G.
A review. The integrin VLA-4 (very late activation antigen-4) is a cell surface receptor that mediates cellular adhesion events crucial to leukocyte trafficking and activation. Animal studies have demonstrated unequivocally that VLA-4 is critical for leukocyte recruitment to the lung and that inhibition of this integrin results in the improvement of airway function in models of allergic asthma. Although results from human clin. trials using inhaled formulations of small-mol. VLA-4 antagonists have been disappointing to date, a recent trial using an orally available antagonist has proved promising. Natalizumab (Tysabri), a humanized monoclonal antibody directed against the α4 integrin subunit of VLA-4, was successful in clin. trials of multiple sclerosis (MS) and has been approved for this indication. Although natalizumab has provided crucial validation of VLA-4 as a therapeutic target in humans, it has yet to be evaluated in any respiratory indication. Clin. trials with natalizumab also unveiled a potential serious side effect of VLA-4 blockade as three patients were diagnosed with progressive multifocal leukoencephalopathy following treatment. The effectiveness of natalizumab in clin. trials has led many in the pharmaceutical industry to target MS rather than asthma as the primary indication for small-mol. antagonists. As more drugs targeting VLA-4 reach the market, asthma will likely be reconsidered as a potential alternative indication.
RADNOR, Pa., Oct. 10 /PRNewswire/ -- The following statement was issued today by the law firm of Schiffrin & Barroway, LLP:
Notice is hereby given that a class action lawsuit was filed in the United States District Court for the Southern District of Texas on behalf of all securities purchasers of Encysive Pharmaceuticals Inc. ("Encysive" or the "Company") from February 19, 2004 through March 24, 2006, inclusive (the "Class Period").
If you wish to discuss this action or have any questions concerning this notice or your rights or interests with respect to these matters, please contact Schiffrin & Barroway, LLP (Darren J. Check, Esq. or Richard A. Maniskas, Esq.) toll-free at 1-888-299-7706 or 1-610-667-7706, or via e-mail at firstname.lastname@example.org.
The Complaint charges Encysive and certain of its officers and directors with violations of the Securities Exchange Act of 1934. More specifically, the Complaint alleges that the Company failed to disclose and misrepresented the following material adverse facts which were known to defendants or recklessly disregarded by them: (1) that stride tests involving Thelin failed to demonstrate a statistically significant advantage over Bosentan, another drug used to treat pulmonary arterial hypertension ("PAH"); (2) that, in order to portray Thelin's supposed superiority, defendants manipulated the stride tests to achieve statistically significant results; (3) that defendants' claims regarding the potential market for Thelin were based upon overinflated patient numbers; (4) that, as a result of the defendants' manipulations, United States Food and Drug Administration ("FDA") approval for Thelin would not be forthcoming because the FDA would require additional clinical trials before approving the drug; and (5) as a result of the above, the Company's statements concerning Thelin were lacking in any reasonable basis when made.
On March 24, 2006, after the market closed, Encysive stunned investors when the Company announced that, contrary to its previous statements concerning the bright future of Thelin, the Company's new drug for the treatment of PAH, the approvable letter which it received from the FDA requested additional information concerning Thelin, including a request for additional clinical trial work. On this news, shares of Encysive plummeted $4.48, or 49.3 percent, to close, on March 27, 2006, at $4.60 per share, on unusually heavy trading volume. On July 24, 2006, after the market closed, Encysive announced that one issue raised in the FDA's March 2006 approvable letter concerning Thelin remained unresolved. On this news, shares of Encysive sank an additional $2.49, or 40.3 percent, to close, on July 25, 2006, at $3.69 per share, on unusually heavy trading volume.
Plaintiff seeks to recover damages on behalf of class members and is represented by the law firm of Schiffrin & Barroway, which prosecutes class actions in both state and federal courts throughout the country. Schiffrin & Barroway is a driving force behind corporate governance reform, and has recovered billions of dollars on behalf of institutional and individual investors from the United States and around the world. For more information about Schiffrin & Barroway, or to sign up to participate in this action online, please visit .
If you are a member of the class described above, you may, not later than November 27, 2006, move the Court to serve as lead plaintiff of the class, if you so choose. A lead plaintiff is a representative party that acts on behalf of other class members in directing the litigation. In order to be appointed lead plaintiff, the Court must determine that the class member's claim is typical of the claims of other class members, and that the class member will adequately represent the class. Under certain circumstances, one or more class members may together serve as "lead plaintiff." Your ability to share in any recovery is not, however, affected by the decision whether or not to serve as a lead plaintiff. You may retain Schiffrin & Barroway, or other counsel of your choice, to serve as your counsel in this action.
CONTACT: Schiffrin & Barroway, LLP
Darren J. Check, Esq.
Richard A. Maniskas, Esq.
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1-888-299-7706 (toll-free) or 1-610-667-7706
Or by e-mail at email@example.com
Schiffrin & Barroway, LLP
CONTACT: Darren J. Check, Esq. or Richard A. Maniskas, Esq., both ofSchiffrin & Barroway, LLP, +1-888-299-7706, +1-610-667-7706, firstname.lastname@example.org