Ticagrelor and Adenosine

The Effect of Ticagrelor on the Adenosine System

Preclinical studies have shown that the P2Y12 receptor antagonist ticagrelor can increase the extracellular concentration of the endogenous nucleoside adenosine by inhibiting the cellular uptake of adenosine via the equilibrative nucleoside transporter (ENT). This mechanism can contribute to the beneficial effects and to the side effects (dyspnea) of ticagrelor in patients with an acute myocardial infarction. In the current research proposal, we aim to investigate whether ticagrelor increases adenosine receptor stimulation in humans in vivo by ENT inhibition.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Placebo; Drug: Ticagrelor 180 mg single dose

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6500 HB
      • Radboud University Nijmegen Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Male sex
• Age 18-40 years
• Healthy
• Written informed consent

Exclusion Criteria:

• Smoking
• Hypertension (Blood pressure >140 mmHg and/or >90 mmHg - SBP/DBP-)
• Diabetes Mellitus (fasting glucose > 7.0 mmol/L or random > 11.0 mmol/L)
• History of any cardiovascular disease
• History of chronic obstructive pulmonary disease (COPD) or asthma
• Bleeding tendency
• Concomitant use of medication
• Renal dysfunction (MDRD < 60 ml/min)
• Liver enzyme abnormalities (ALAT > twice upper limit of normality)
• Thrombocytopenia (<150*109/ml)
• Second/third degree AV-block on electrocardiography

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo single dose	Drug: Placebo
Active Comparator: Ticagrelor 180 mg single dose	Drug: Ticagrelor 180 mg single dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forearm blood flow response	Forearm blood flow response to the intrabrachial administration of incremental dosages of adenosine, after treatment with ticagrelor compared to placebo. The forearm blood flow will be measured by plethysmography.	2 hours after intake of ticagrelor/placebo
Forearm blood flow response	Directly after 2 and 5 minutes of forearm ischemia.The forearm blood flow will be measured by plethysmography.	Directly after 2 and 5 minutes of forearm ischemia

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forearm blood flow respons	Forearm blood flow response to the intrabrachial administration of incremental dosages of dipyridamole, after treatment with ticagrelor compared to placebo. The forearm blood flow will be measured by plethysmography	Directly after administration of dipyridamole
ex-vivo adenosine uptake in isolated erythrocytes	To study whether ticagrelor inhibits the ex-vivo adenosine uptake in isolated erythrocytes	2 hours after intake of studymedication

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: G. Rongen, MD, PhD, Radboud University Medical Center; Principal Investigator: M. Gomes, MD, PhD, Dept Cardiology, Canisius Wilhelmina Hospital Nijmegen; Principal Investigator: S. El Messaoudi, MD, Radboud University Medical Center

Publications and helpful links

General Publications

• van den Berg TN, El Messaoudi S, Rongen GA, van den Broek PH, Bilos A, Donders AR, Gomes ME, Riksen NP. Ticagrelor Does Not Inhibit Adenosine Transport at Relevant Concentrations: A Randomized Cross-Over Study in Healthy Subjects In Vivo. PLoS One. 2015 Oct 28;10(10):e0137560. doi: 10.1371/journal.pone.0137560. eCollection 2015.

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: April 26, 2013
• First Submitted That Met QC Criteria: November 21, 2013
• First Posted (Estimate): November 27, 2013

Study Record Updates

• Last Update Posted (Estimate): January 10, 2014
• Last Update Submitted That Met QC Criteria: January 9, 2014
• Last Verified: February 1, 2013

More Information

Terms related to this study

• Keywords: Endothelial function; Adenosine receptor stimulation
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Ticagrelor
• Other Study ID Numbers: NL43379.091.13