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Encysive Pharmaceuticals

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Stavros F.,Encysive Pharmaceuticals | Kramer W.G.,Kramer Consulting LLC | Wilkins M.R.,Imperial College London
British Journal of Clinical Pharmacology | Year: 2010

Aims This study evaluated the effects of sitaxentan on the pharmacodynamic [systemic blood pressure (BP)] and pharmacokinetic (PK) parameters of sildenafil in healthy volunteers. Methods 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. Results Sildenafil exposure was slightly higher [AUC ∞ 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. Conclusion The dose of sildenafil does not need to be adjusted when co-administered with sitaxentan. © 2010 The British Pharmacological Society.


Vanderslice P.,Encysive Pharmaceuticals | Woodside D.G.,Encysive Pharmaceuticals
Progress in Respiratory Research | Year: 2010

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 clinical trials using inhaled formulations of small-molecule 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 clinical 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. Clinical 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 clinical trials has led many in the pharmaceutical industry to target MS rather than asthma as the primary indication for small-molecule antagonists. As more drugs targeting VLA-4 reach the market, asthma will likely be reconsidered as a potential alternative indication. © 2010 S. Karger AG, Basel.


Vanderslice P.,Encysive Pharmaceuticals | Woodside D.G.,Encysive Pharmaceuticals | Caivano A.R.,Encysive Pharmaceuticals | Decker E.R.,Encysive Pharmaceuticals | And 7 more authors.
Biochemical and Biophysical Research Communications | Year: 2010

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 Elsevier Inc.


Patent
Encysive Pharmaceuticals | Date: 2012-02-08

The present invention relates to CCR-9 antagonists, pharmaceutical compositions containing them and their use.


Encysive Pharmaceuticals | Entity website

Pfizer increases its global presence through the acquisitions of Warner-Lambert and Pharmacia. Additionally, through strategic partnerships and acquisitions of diversified businesses, such as Wyeth, Pfizer solidifies its place as one of the most diversified companies in the global health care industry ...


PubMed | Encysive Pharmaceuticals
Type: Journal Article | Journal: Biochemical and biophysical research communications | Year: 2010

The development of antagonists to the 4 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 41 (VLA-4) as well as several dual antagonists that inhibit both 41 and 47. The value of a dual versus a selective small molecule antagonist as well as the consequences of inhibiting different affinity states of the 4 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 41 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 4 integrin antagonist selective for 41 over 47 and, specifically, selective for the high affinity conformation of 41 may prove to be an effective therapy for multiple inflammatory diseases in humans.


Encysive Pharmaceuticals | Entity website

Welcome to Pfizers news section designed to give you access to timely and relevant information about our company. In this section you will find information and resources for journalists, including current and archived Pfizer press releases, a full company press kit, and a comprehensive collection of images and videos in our multimedia library


Encysive Pharmaceuticals | Entity website

Principles The Pfizer Board understands and acts on the fundamental principle that good corporate governance is critical to organizational success and the protection of shareholder value. In 1994, the Pfizer Board took the unprecedented step of creating a corporate governance committee of the Board ...


PubMed | Encysive Pharmaceuticals
Type: Journal Article | Journal: British journal of clinical pharmacology | Year: 2010

* 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.* 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.

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