This is a randomized, double-blind, crossover study in healthy adult subjects. Each subject will receive a single dose of bisoprolol 5 mg p.o. and nebivolol 5 mg p.o. with 1 week washout period. All subjects will undergo a physical examination, 12-lead electrocardiography and a comprehensive echocardiographic study before the administration of the study drug and 5 hours thereafter.

Start Date01 Jan 2030

Sponsor / Collaborator-

NCT06473116 / Not yet recruitingPhase 4IIT

Epinephrine Versus Isoprenaline During Out-of-Hospital Cardiac Arrest With Asystole: A Randomized Clinical Trial

Background: During out-of-hospital cardiac arrest (OHCA), the patient presents with either a shockable or a non-shockable rhythm. Early cardiopulmonary resuscitation (CPR) and defibrillation of the shockable rhythm may increase chance of survival to more than 50%, however, if untreated, the heart rhythm will deteriorate to a non-shockable rhythm with dismal survival outcomes of 1-5%. Isoprenaline is a pro-arrhythmic drug used to treat bradycardia, and has a structural resemblance to epinephrine, which is the drug of choice during cardiac arrest with non-shockable rhythms.
Aims: To evaluate whether intravebous (IV) administration of isoprenaline increases the chance of return of spontaneous circulation (ROSC) to hospital arrival (main outcome) compared with IV epinephrine.
Study design: A randomized-controlled trial.
Setting: The study will be conducted in the Region of Southern Denmark, which has about 1.2 million inhabitants and an annual incidence of 1,200 OHCAs. The study will include bystander-witnessed patients with asystole at the arrival of the emergency medical services (EMS). Randomization will take place on arrival of the EMS, where the OHCA patients randomly will be assigned to receive an intravenous injection of isoprenaline (600 µg) or an intravenous injection of adrenaline (1 mg) in a 1:1 ratio. The study will include 1,178 OHCAs over a time period of about 3.5 years.

Start Date01 Mar 2025

Sponsor / Collaborator

University of Southern Denmark

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100 Clinical Results associated with β2-adrenergic receptor x β1-adrenergic receptor

100 Translational Medicine associated with β2-adrenergic receptor x β1-adrenergic receptor

0 Patents (Medical) associated with β2-adrenergic receptor x β1-adrenergic receptor

776

Literatures (Medical) associated with β2-adrenergic receptor x β1-adrenergic receptor

01 Oct 2024·Clinical Pharmacology & Therapeutics

Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4, and GRK5 Genotypes and Beta‐Blocker Therapy

Review

Author: Stein, C. Michael ; Huddart, Rachel ; Lee, Craig R. ; van Schaik, Ron H. N. ; Klein, Teri E. ; Schwab, Matthias ; Nagy, Mohamed ; Uppugunduri, Chakradhara Rao S. ; Agundez, Jose A. G. ; Thomas, Cameron D. ; Caudle, Kelly E. ; Donnelly, Roseann S. ; Lanfear, David E. ; Baye, Jordan F. ; Duarte, Julio D. ; Monte, Andrew A. ; Luzum, Jasmine A. ; Gaedigk, Andrea

Beta‐blockers are widely used medications for a variety of indications, including heart failure, myocardial infarction, cardiac arrhythmias, and hypertension. Genetic variability in pharmacokinetic (e.g., CYP2D6) and pharmacodynamic (e.g., ADRB1, ADRB2, ADRA2C, GRK4, GRK5) genes have been studied in relation to beta‐blocker exposure and response. We searched and summarized the strength of the evidence linking beta‐blocker exposure and response with the six genes listed above. The level of evidence was high for associations between CYP2D6 genetic variation and both metoprolol exposure and heart rate response. Evidence indicates that CYP2D6 poor metabolizers experience clinically significant greater exposure and lower heart rate in response to metoprolol compared with those who are not poor metabolizers. Therefore, we provide therapeutic recommendations regarding genetically predicted CYP2D6 metabolizer status and metoprolol therapy. However, there was insufficient evidence to make therapeutic recommendations for CYP2D6 and other beta‐blockers or for any beta‐blocker and the other five genes evaluated (updates at www.cpicpgx.org).

01 Aug 2024·International Journal of Obesity

Genetic evidence for involvement of β2-adrenergic receptor in brown adipose tissue thermogenesis in humans

Article

Author: Kuroiwa, Miyuki ; Tanaka, Riki ; Yoneshiro, Takeshi ; Fuse, Sayuri ; Kurosawa, Yuko ; Nishimura, Takayuki ; Motoi, Midori ; Ishida, Yuka ; Hamaoka, Takafumi ; Matsushita, Mami ; Saito, Masayuki ; Maeda, Takafumi ; Nakayama, Kazuhiro

AbstractBackgroundSympathetic activation of brown adipose tissue (BAT) thermogenesis can ameliorate obesity and related metabolic abnormalities. However, crucial subtypes of the β-adrenergic receptor (AR), as well as effects of its genetic variants on functions of BAT, remains unclear in humans. We conducted association analyses of genes encoding β-ARs and BAT activity in human adults.MethodsSingle nucleotide polymorphisms (SNPs) in β1-, β2-, and β3-AR genes (ADRB1, ADRB2, and ADRB3) were tested for the association with BAT activity under mild cold exposure (19 °C, 2 h) in 399 healthy Japanese adults. BAT activity was measured using fluorodeoxyglucose-positron emission tomography and computed tomography (FDG-PET/CT). To validate the results, we assessed the effects of SNPs in the two independent populations comprising 277 healthy East Asian adults using near-infrared time-resolved spectroscopy (NIRTRS) or infrared thermography (IRT). Effects of SNPs on physiological responses to intensive cold exposure were tested in 42 healthy Japanese adult males using an artificial climate chamber.ResultsWe found a significant association between a functional SNP (rs1042718) in ADRB2 and BAT activity assessed with FDG-PET/CT (p < 0.001). This SNP also showed an association with cold-induced thermogenesis in the population subset. Furthermore, the association was replicated in the two other independent populations; BAT activity was evaluated by NIRTRS or IRT (p < 0.05). This SNP did not show associations with oxygen consumption and cold-induced thermogenesis under intensive cold exposure, suggesting the irrelevance of shivering thermogenesis. The SNPs of ADRB1 and ADRB3 were not associated with these BAT-related traits.ConclusionsThe present study supports the importance of β2-AR in the sympathetic regulation of BAT thermogenesis in humans. The present collection of DNA samples is the largest to which information on the donor’s BAT activity has been assigned and can serve as a reference for further in-depth understanding of human BAT function.

05 Jul 2024·Circulation Research

Internalized β2-Adrenergic Receptors Oppose PLC-Dependent Hypertrophic Signaling

Article

Author: Smrcka, Alan V ; Wei, Wenhui

BACKGROUND:Chronically elevated neurohumoral drive, and particularly elevated adrenergic tone leading to β-adrenergic receptor (β-AR) overstimulation in cardiac myocytes, is a key mechanism involved in the progression of heart failure. β1-AR (β1-adrenergic receptor) and β2-ARs (β2-adrenergic receptor) are the 2 major subtypes of β-ARs present in the human heart; however, they elicit different or even opposite effects on cardiac function and hypertrophy. For example, chronic activation of β1-ARs drives detrimental cardiac remodeling while β2-AR signaling is protective. The underlying molecular mechanisms for cardiac protection through β2-ARs remain unclear.METHODS:β2-AR signaling mechanisms were studied in isolated neonatal rat ventricular myocytes and adult mouse ventricular myocytes using live cell imaging and Western blotting methods. Isolated myocytes and mice were used to examine the roles of β2-AR signaling mechanisms in the regulation of cardiac hypertrophy.RESULTS:Here, we show that β2-AR activation protects against hypertrophy through inhibition of phospholipaseCε signaling at the Golgi apparatus. The mechanism for β2-AR–mediated phospholipase C inhibition requires internalization of β2-AR, activation of Gi and Gβγ subunit signaling at endosome and ERK (extracellular regulated kinase) activation. This pathway inhibits both angiotensin II and Golgi-β1-AR–mediated stimulation of phosphoinositide hydrolysis at the Golgi apparatus ultimately resulting in decreased PKD (protein kinase D) and histone deacetylase 5 phosphorylation and protection against cardiac hypertrophy.CONCLUSIONS:This reveals a mechanism for β2-AR antagonism of the phospholipase Cε pathway that may contribute to the known protective effects of β2-AR signaling on the development of heart failure.

News (Medical) associated with β2-adrenergic receptor x β1-adrenergic receptor

31 Aug 2023

·www.pharmaceutical-technology.com

Zerva acquires Acer Therapeutics to bolster rare disease portfolio

Phalguni Deswal @Phalguni_GD The news caused Acer’s stock to skyrocket by 140% when the markets opened on 31 August. Image Credit: 3rdtimeluckystudio / Shutterstock. Zerva Therapeutics, formerly KemPharm, has announced a strategic acquisition of Acer Therapeutics to expand its rare therapies portfolio. The biggest Acer assets include the marketed rare therapy Olpruva (sodium phenylbutyrate formulation), and late-stage drug celiprolol. Recommended Reports Reports LOA and PTSR Model - Rozanolixizumab in Demyelinating Diseases GlobalData Reports LOA and PTSR Model - Satralizumab in Demyelinating Diseases GlobalData View all Companies Intelligence Zevra Therapeutics Inc Acer Therapeutics Inc View all The acquisition is expected to be worth up to $91m in stock and cash payments, of which $76m is contingent upon milestone-based payments for Olpruva and celiprolol. Additionally, Zerva purchased Acer’s secured debt at a discounted value of $35.3m from its creditor, Nantahala Capital. The news caused Acer’s stock to skyrocket by 140% when the markets opened on 31 August. Zerva has a market cap of $165.25m, with a reported Q1 2023 revenue of $2.9m, as per the company’s financial report . Whilst Acer reported a loss of $8.1m in Q2 2023, as per the company’s Q2 financials . Olpruva is an oral suspension approved for the treatment of urea cycle disorders by the US Food and Drug Administration (FDA) in 2022. Urea cycle disorders are a type of rare genetic metabolic disorder that causes a build-up of toxic levels of ammonia. Celiprolol is a beta-1 selective adrenoceptor antagonist with partial beta-2 agonist activity currently in Phase III (NCT05432466) clinical development for the rare connective tissue disorder, vascular Ehlers-Danlos syndrome. Another Acer pipeline drug is the menopausal therapy, ACER-801 (osanetant), which was licensed from Sanofi. However, the drug development was paused after a Phase IIa trial failed to meet its primary endpoint. Zerva’s marketed portfolio consists of Azstarys (serdexmethylphenidate and dexmethylphenidate), an attention-deficit/hyperactivity disorder (ADHD) drug for children aged six years or older. Zerva has a licensing agreement with Corin for marketing Azstarys in the US. The pipeline portfolio of Zerva includes arimoclomol for treating Niemann-Pick Disease Type C , and KP1077 for rare sleep disorders such as idiopathic hypersomnia and narcolepsy.

Drug ApprovalAcquisitionLicense out/inPhase 3Phase 2

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