Unmasking Adenosine: The Purinergic Signalling Molecule Critical to Arrhythmia Pathophysiology and Management

Matthews, Gareth Dk; Grace, Andrew A.

doi:10.15420/aer.2019.05

Cited by 6 publications

(5 citation statements)

References 172 publications

(230 reference statements)

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“…Traditionally, caution has been exercised when administering adenosine to patients with asthma, patients with chronic obstructive pulmonary disease, or patients regularly taking methylxanthine, owing to adenosine's propensity to cause bronchospasm. 15 However, in individuals with normal airway function adenosine-induced bronchoconstriction is infrequent and is often misinterpreted as dyspnea. 15 It is advisable to exercise caution when administering adenosine in this cohort of patients.…”

Section: When Adenosine Does Not Workmentioning

confidence: 99%

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Management of acute supraventricular tachycardia in children

Abbasi,

Vijayashankar,

Goldman

2023

Can Fam Physician

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Question Recently, a 3-year-old patient in my practice urgently needed to go to the emergency department. The patient was found to have supraventricular tachycardia (SVT) and needed immediate treatment with adenosine. What evidence is currently available for management of SVT in children?Answer Supraventricular tachycardia is a common cardiac condition in the pediatric population that manifests as a narrow QRS complex tachycardia on electrocardiography. Symptoms may range from palpitations, poor feeding, and irritability to more substantial hemodynamic instability. Patients who are hemodynamically stable can benefit from interventions such as vagal maneuvers, which can be done in the office. Such maneuvers include the Valsalva maneuver, stimulation of the diving reflex (for infants), and unilateral carotid sinus massage. Other children may need pharmacologic therapies to restore normal heart rhythm, which usually consists of a rapid intravenous injection of adenosine under monitoring. For patients who are hemodynamically unstable, emergency cardioversion may be needed. Supraventricular tachycardia (SVT) is a relatively common cardiac condition in the pediatric population, with an incidence of 1:250 to 1:1000 in otherwise healthy children. 1 Supraventricular tachycardia is a group of rhythmic disturbances in which electrical impulses originating from any point proximal to the atrioventricular (AV) bundle result in a narrow QRS complex tachycardia (normal QRS duration is variable during childhood and can be <80 milliseconds in the neonatal period to <120 milliseconds in adolescents) as observed on electrocardiography. 2 The presentation of SVT can vary based on the age of the patient. Signs and symptoms in infants include poor feeding, vomiting, irritability, increased sleepiness, fainting, and perspiration, as well as pallor, cough, and respiratory distress if congestive heart failure is present. 3 Toddlers and school-aged children will present with palpitations, chest pain, dizziness, shortness of breath, or fainting. Adolescents frequently present with all of these symptoms and may also have perspiration, fatigue, and anxiety. 3 Supraventricular tachycardia is considered an emergency when the patient is hemodynamically unstable, requiring immediate intervention. These patients present with low systolic blood pressure for their age, acute altered mental status, signs of shock, chest pain, or acute severe heart failure symptoms, and they will typically require immediate cardioversion. 4 Patients with SVT who are hemodynamically stable experience an excessively fast heart rate that needs to be addressed, as it can cause uncomfortable symptoms, lead to hemodynamic decompensation, and can recur without intervention. Various interventions can be used to restore normal heart rhythm including vagal maneuvers, pharmacologic intervention, and, in some cases, electrical cardioversion. 4

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Section: When Adenosine Does Not Workmentioning

confidence: 99%

“…15 However, in individuals with normal airway function adenosine-induced bronchoconstriction is infrequent and is often misinterpreted as dyspnea. 15 It is advisable to exercise caution when administering adenosine in this cohort of patients.…”

Section: When Adenosine Does Not Workmentioning

confidence: 99%

Management of acute supraventricular tachycardia in children

Abbasi,

Vijayashankar,

Goldman

2023

Can Fam Physician

View full text Add to dashboard Cite

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“…On fait généralement preuve de prudence dans l'administration d'adénosine aux patients souffrant d'asthme ou d'une maladie pulmonaire obstructive chronique, ou qui prennent régulièrement de la méthylxanthine, parce que l'adénosine tend à causer un bronchospasme 15 . Toutefois, chez les personnes dont la fonction respiratoire est normale, la bronchoconstriction induite par l'adénosine n'est pas fréquente et est souvent confondue avec la dyspnée 15 . Il est indiqué de faire preuve de prudence lorsqu'on administre de l'adénosine à cette cohorte de patients.…”

Section: Lorsque L'adénosine Ne Donne Pas De Résultatsunclassified

Prise en charge de la tachycardie supraventriculaire aiguë chez les enfants

Abbasi,

Vijayashankar,

Goldman

2023

Can Fam Physician

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“…We first sought to establish the quantitative relationship between adenosine concentration and its biological effect. As adenosine is not stable in human blood, with a biological half-life less than 10 s [34,35], its stable analogue 5′-N-ethylcarboxamide adenosine (NECA) was used instead [36,37]. Briefly, human whole blood samples from 3 donors were collected and mixed with different concentrations of NECA.…”

Section: Adenosine Stimulates Creb Phosphorylation and Inhibits Ifn-γ...mentioning

confidence: 99%

Overcoming high level adenosine-mediated immunosuppression by DZD2269, a potent and selective A2aR antagonist

Bai

Zhang²,

Jiao³

et al. 2022

J Exp Clin Cancer Res

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Background Adenosine is a potent immunosuppressant whose levels in the tumor microenvironment (TME) are often much higher than those in normal tissues. Binding of adenosine to its receptor A2aR activates a cascade of genes and leads to immunosuppression. In addition, immune checkpoint blockage markedly increases A2aR expression in T cells, which could dampen their anti-tumor response. Several A2aR antagonists are under clinical development, but with limited clinical benefit reported so far. These A2aR antagonists showed much diminished activity at high adenosine levels found in TME, which may explain their clinical underperformance. We report the discovery and early clinical development of DZD2269, a novel A2aR antagonist which can fully block A2aR mediated immunosuppression commonly found in TME. Adenosine stimulates phosphorylation of cyclic AMP response element binding protein (CREB) in T cells and inhibits anti-tumor cytokine secretion in PBMCs in a dose-dependent manner. DZD2269 was able to reverse the immunosuppression induced by high concentrations of adenosine, as demonstrated by inhibiting CREB phosphorylation in T cells, restoring Th1 cytokine secretion in PBMCs, and stimulating dendritic cells (DCs) maturation. As a single agent, DZD2269 showed anti-tumor growth in multiple syngeneic mouse tumor models, and more profound anti-tumor effects were observed when DZD2269 was in combination with immune checkpoint inhibitors, radiotherapy, or chemotherapy. A good PK/PD relationship was observed in these animal models. In the phase 1 clinical study, downregulation of pCREB was detected in human T cells, consistent with preclinical prediction. Our data support further clinical development of DZD2269 in patients with cancer. Methods The selectivity of DZD2269 for adenosine receptors was tested in engineered cell lines, and its efficacy in blocking A2aR signaling and reversing adenosine-mediated immunosuppression was assessed in human T cells and peripheral blood mononuclear cells (PBMCs). The anti-tumor effects of DZD2269 were evaluated in multiple syngeneic mouse models as a single agent as well as in combination with chemotherapy, radiotherapy, or immune checkpoint inhibitors. A phase 1 study in healthy volunteers (NCT04932005) has been initiated to assess safety, pharmacokinetics (PK) and pharmacodynamics (PD) of DZD2269. Results Adenosine stimulates phosphorylation of cyclic AMP response element binding protein (CREB) in T cells and inhibits anti-tumor cytokine secretion in PBMCs in a dose-dependent manner. DZD2269 was able to reverse the immunosuppression induced by high concentrations of adenosine, as demonstrated by inhibiting CREB phosphorylation in T cells, restoring Th1 cytokine secretion in PBMCs, and stimulating dendritic cells (DCs) maturation. As a single agent, DZD2269 showed anti-tumor growth in multiple syngeneic mouse tumor models, and more profound anti-tumor effects were observed when DZD2269 was in combination with immune checkpoint inhibitors, radiotherapy, or chemotherapy. A good PK/PD relationship was observed in these animal models. In the phase 1 clinical study, downregulation of pCREB was detected in human T cells, consistent with preclinical prediction. Conclusion DZD2269 is a novel A2aR antagonist which can fully block A2aR mediated immunosuppression commonly found in TME. Clinical development of DZD2269 in patients with cancer is warranted (NCT04634344).

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Unmasking Adenosine: The Purinergic Signalling Molecule Critical to Arrhythmia Pathophysiology and Management

Cited by 6 publications

References 172 publications

Management of acute supraventricular tachycardia in children

Management of acute supraventricular tachycardia in children

Prise en charge de la tachycardie supraventriculaire aiguë chez les enfants

Overcoming high level adenosine-mediated immunosuppression by DZD2269, a potent and selective A2aR antagonist

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