An Open-Label, Sequential-Group, Dose-Escalation Study To Evaluate The Safety, Pharmacokinetics, and Pharmacodynamics of Intravenous Tecadenoson Alone and in Combination With a Beta-Blocker in Adults With Rapid Atrial Fibrillation (CVT 4129)

Assess the tolerability and safety of a rapid bolus of tecadenoson at different dose levels when given alone and in combination with a beta-blocker (esmolol) in patients with atrial fibrillation to control rapid heart rate. Explore the pharmacokinetic and pharmacodynamic effects when given alone and in combination with beta-blocker (esmolol).

开始日期2008-02-01

申办/合作机构

Gilead Sciences, Inc.

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项与替卡地松相关的文献（医药）

2023-06-01·Computational biology and chemistry

Dual computational and biological assessment of some promising nucleoside analogs against the COVID-19-Omicron variant

Article

作者: Rabie, Amgad M ; Abdalla, Mohnad

Nucleoside analogs/derivatives (NAs/NDs) with potent antiviral activities are now deemed very convenient choices for the treatment of coronavirus disease 2019 (COVID-19) arisen by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. At the same time, the appearance of a new strain of SARS-CoV-2, the Omicron variant, necessitates multiplied efforts in fighting COVID-19. Counteracting the crucial SARS-CoV-2 enzymes RNA-dependent RNA polymerase (RdRp) and 3'-to-5' exoribonuclease (ExoN) jointly altogether using the same inhibitor is a quite successful new plan to demultiplicate SARS-CoV-2 particles and eliminate COVID-19 whatever the SARS-CoV-2 subtype is (due to the significant conservation nature of RdRps and ExoNs in the different SARS-CoV-2 strains). Successive in silico screening of known NAs finally disclosed six different promising NAs, which are riboprine/forodesine/tecadenoson/nelarabine/vidarabine/maribavir, respectively, that predictably can act through the planned dual-action mode. Further in vitro evaluations affirmed the anti-SARS-CoV-2/anti-COVID-19 potentials of these NAs, with riboprine and forodesine being at the top. The two NAs are able to effectively antagonize the replication of the new virulent SARS-CoV-2 strains with considerably minute in vitro anti-RdRp and anti-SARS-CoV-2 EC₅₀ values of 189 and 408 nM for riboprine and 207 and 657 nM for forodesine, respectively, surpassing both remdesivir and the new anti-COVID-19 drug molnupiravir. Furthermore, the favorable structural characteristics of the two molecules qualify them for varied types of isosteric and analogistic chemical derivatization. In one word, the present important outcomes of this comprehensive dual study revealed the anticipating repurposing potentials of some known nucleosides, led by the two NAs riboprine and forodesine, to successfully discontinue the coronaviral-2 polymerase/exoribonuclease interactions with RNA nucleotides in the SARS-CoV-2 Omicron variant (BA.5 sublineage) and accordingly alleviate COVID-19 infections, motivating us to initiate the two drugs' diverse anti-COVID-19 pharmacological evaluations to add both of them betimes in the COVID-19 therapeutic protocols.

2023-02-01·Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents

Evaluation of a series of nucleoside analogs as effective anticoronaviral-2 drugs against the Omicron-B.1.1.529/BA.2 subvariant: A repurposing research study

Article

作者: Abdalla, Mohnad ; Rabie, Amgad M

Abstract:

Mysterious evolution of a new strain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the Omicron variant, led to a new challenge in the persistent coronavirus disease 2019 (COVID-19) battle. Objecting the conserved SARS-CoV-2 enzymes RNA-dependent RNA polymerase (RdRp) and 3′-to-5′ exoribonuclease (ExoN) together using one ligand is a successful new tactic to stop SARS-CoV-2 multiplication and COVID-19 progression. The current comprehensive study investigated most nucleoside analogs (NAs) libraries, searching for the most ideal drug candidates expectedly able to act through this double tactic. Gradual computational filtration afforded six different promising NAs, riboprine/forodesine/tecadenoson/nelarabine/vidarabine/maribavir. Further biological assessment proved that riboprine and forodesine are able to powerfully inhibit the replication of the new virulent strains of SARS-CoV-2 with extremely minute in vitro anti-RdRp and anti-SARS-CoV-2 EC50 values of about 0.21 and 0.45 μM for riboprine and about 0.23 and 0.70 μM for forodesine, respectively, surpassing both remdesivir and the new anti-COVID-19 drug molnupiravir. These biochemical findings were supported by the prior in silico data. Additionally, the ideal pharmacophoric features of riboprine and forodesine molecules render them typical dual-action inhibitors of SARS-CoV-2 replication and proofreading. These findings suggest that riboprine and forodesine could serve as prospective lead compounds against COVID-19.

2022-12-13·ChemistrySelect

A Series of Adenosine Analogs as the First Efficacious Anti‐SARS‐CoV‐2 Drugs against the B.1.1.529.4 Lineage: A Preclinical Repurposing Research Study

Article

作者: Abdalla, Mohnad ; Rabie, Amgad M.

Abstract:

Given the rapid progression of the coronavirus disease 2019 (COVID‐19) pandemic, an ultrafast response was urgently required to handle this major public crisis. To contain the pandemic, investments are required to develop diagnostic tests, prophylactic vaccines, and novel therapies. Lately, nucleoside analog (NA) antivirals topped the scene as top options for the treatment of COVID‐19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infections. Meanwhile, the continuous generation of new lineages of the SARS‐CoV‐2 Omicron variant caused a new challenge in the persistent COVID‐19 battle. Hitting the two crucial SARS‐CoV‐2 enzymes RNA‐dependent RNA polymerase (RdRp) and 3’‐to‐5’ exoribonuclease (ExoN) collectively together using only one single ligand is a very successful new approach to stop SARS‐CoV‐2 multiplication and combat COVID‐19 irrespective of the SARS‐CoV‐2 variant type because RdRps and ExoNs are broadly conserved among all SARS‐CoV‐2 strains. Herein, the current comprehensive study investigated most NAs libraries, searching for the most ideal drug candidates expectedly able to perfectly act through this double tactic. Gradual computational filtration gave rise to six different promising NAs, which are riboprine, forodesine, tecadenoson, nelarabine, vidarabine, and maribavir, respectively. Further biological assessment proved for the first time, using the in vitro anti‐RdRp/ExoN and anti‐SARS‐CoV‐2 bioassays, that riboprine and forodesine, among all the six tested NAs, are able to powerfully inhibit the replication of the new virulent strains of SARS‐CoV‐2 with extremely minute in vitro anti‐RdRp and anti‐SARS‐CoV‐2 EC50 values of about 0.22 and 0.49 μM for riboprine and about 0.25 and 0.73 μM for forodesine, respectively, surpassing both remdesivir and the new anti‐COVID‐19 drug molnupiravir. The prior in silico data supported these biochemical findings, suggesting that riboprine and forodesine molecules strongly hit the key catalytic pockets of the SARS‐CoV‐2 (Omicron variant) RdRp′s and ExoN′s main active sites. Additionally, the ideal pharmacophoric features of riboprine and forodesine molecules render them typical dual‐action inhibitors of SARS‐CoV‐2 replication and proofreading, with their relatively flexible structures open for diverse types of chemical derivatization. In Brief, the current important results of this comprehensive study revealed the interesting repurposing potentials of, mainly, the two nucleosides riboprine and forodesine to effectively shut down the polymerase/exoribonuclease‐RNA nucleotides interactions of the SARS‐CoV‐2 Omicron variant and consequently treat COVID‐19 infections, motivating us to rapidly begin the two drugs′ broad preclinical/clinical anti‐COVID‐19 bioevaluations, hoping to combine both drugs soon in the COVID‐19 treatment protocols.

项与替卡地松相关的新闻（医药）

2007-10-24

·BioSpace

CV Therapeutics, Inc. Announces Presentations at American Heart Association Scientific Sessions 2007

PALO ALTO, Calif., Oct. 23 /PRNewswire-FirstCall/ -- CV Therapeutics, Inc. announced today that multiple abstracts, including data from a prospectively identified analysis of patients with diabetes in the MERLIN TIMI-36 study, have been accepted for presentation at the American Heart Association (AHA) Scientific Sessions 2007, which will be held in Orlando, FL on November 4 - 7, 2007. Ranexa(R) (ranolazine extended-release tablets): Prospective Evaluation of the Prognostic Implications of Low Level Elevation of Cardiac Troponin Using a New Highly-sensitive Assay for Cardiac Troponin I: Results from the MERLIN TIMI-36 Trial; Oral abstract, Monday, November 5, 2007, 9:30 a.m. EST B-type Natriuretic Peptide and the Effect of Ranolazine in Patients with Non- ST Elevation Acute Coronary Syndromes in the MERLIN TIMI-36 Trial; Oral abstract, Monday, November 5, 2007, 10:00 a.m. EST Anti-Ischemic Effects of Ranolazine in Women: Results from the Randomized, Placebo-controlled MERLIN TIMI-36 Trial; Oral abstract, Tuesday, November 6, 2007, 10:00 a.m. EST Effect of Ranolazine on Hemoglobin A1c in the MERLIN TIMI-36 Randomized Controlled Trial; Oral abstract, Tuesday, November 6, 2007, 11:00 a.m. EST Baseline Clinical Risk and Recurrent Ischemia as Detected on Continuous ECG (CECG) Monitoring in Patients with non-ST-Elevation Acute Coronary Syndrome in the MERLIN TIMI-36 Trial; Poster, Wednesday, November 7, 2007, 9:30 - 11:00 a.m. EST Tecadenoson Ventricular Rate Control Using the Adenosine Receptor Agonist CVT 510 in the Goat Model of Atrial Fibrillation: Efficacy During Exercise and Synergistic Effects with Metoprolol; Oral abstract, Tuesday, November 6, 2007, 4:15 p.m. EST Additional information regarding the AHA Scientific Sessions 2007 can be accessed at About CV Therapeutics CV Therapeutics, Inc., headquartered in Palo Alto, California, is a biopharmaceutical company focused on applying molecular cardiology to the discovery, development and commercialization of novel, small molecule drugs for the treatment of cardiovascular diseases. CV Therapeutics' approved product, Ranexa(R) (ranolazine extended-release tablets), is indicated for the treatment of chronic angina in patients who have not achieved an adequate response with other antianginal drugs, and should be used in combination with amlodipine, beta-blockers or nitrates. CV Therapeutics' clinical and preclinical drug development candidates and programs include regadenoson, which is being developed for potential use as a pharmacologic stress agent in myocardial perfusion imaging studies, and CVT- 6883, which is being developed as a potential treatment for cardiopulmonary diseases. Regadenoson and CVT-6883 have not been determined by any regulatory authorities to be safe or effective in humans for any use. Except for the historical information contained herein, the matters set forth in this press release are forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially, including operating losses and fluctuations in operating results; capital requirements; regulatory review and approval of our products; special protocol assessment agreement; the conduct and timing of clinical trials; commercialization of products; market acceptance of products; product labeling; concentrated customer base; and other risks detailed from time to time in CV Therapeutics' SEC reports, including its Quarterly Report on Form 10-Q for the quarter ended June 30, 2007. CV Therapeutics disclaims any intent or obligation to update these forward-looking statements. CONTACT: John Bluth, Executive Director, Corporate Communications & Investor Relations of CV Therapeutics, Inc., +1-650-384-8850 Web site:

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