Combined Antioxidant Therapy Against Myocardial Reperfusion Injury. Phase I Study.
Study Details
Study Description
Brief Summary
Background: Acute myocardial infarction (AMI) has remained a leading cause of mortality and disability worldwide. Although percutaneous coronary angioplasty (PCA) is the best treatment for these patients, paradoxically this procedure causes reperfusion injury. Considerable efforts aimed to reduce this damage have been made, but the results are disappointing and there is still no effective therapy for preventing the damage. Previously, our team has achieved a reduction of infarct size in an acute myocardial infarction model of isolated rat heart through a synergistic effect of three compounds in a combined antioxidant therapy (CAT).
In this study, we aim to describe the pharmacokinetics and safety of CAT intravenously administered to healthy subjects. This is the first step to a later clinical application of CAT in AMI patients.
Methodology: The safety and pharmacokinetics of the CAT (deferoxamine, N-acetylcysteine, and ascorbate) will be assessed in healthy volunteers in a "phase I clinical trial". Subjects (18-30 years old, n=18) will be randomized 2:1 to receive CAT or placebo over 60 minutes. Blood concentrations of each CAT component will be measured in plasma at 0, 15, 30, 60, 90, 120, and 180 minutes after the infusion onset. Adverse reactions will be registered from the onset of infusion until day 7.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
Healthy subjects from 18-30 years old will be allocated to a placebo or an intravenous combined antioxidant therapy (CAT) following a fixed-dose scalation approach in a single-blind trial. Before the study onset, blood samples will be drawn from eligible subjects to measure a general health profile, and also a physician evaluation and medical exams will be scheduled to further confirm the healthy status two weeks after the CAT/placebo infusion.
The infusions (CAT or placebo) will be administered at the "CREA" - Hospital Clínico Universidad de Chile. The first nine subjects will be randomized 1:2 to placebo (dextrose 5%) or CAT (deferoxamine, ascorbate, and N-acetylcysteine) to be infused I.V over 90 min at a constant rate. If the stopping rules are not observed (see below), then the next nine subjects will be randomized 1:2 to placebo or CAT with two different rates (one in the first 30 min, and another one in the following 60 minutes). The protocol will be stopped at any time if more than 33% of the subjects in a group (2 volunteers) suffer a severe adverse event, following the international definitions (death, disability, life-threatening, medical admission).
Vital signs will be continuously assessed along with the I.Vinfusion, as well as any adverse reaction. Blood samples will be collected at 0, 15, 30, 60, 90, 120, and 180 minutes. Subjects will be daily contacted by phone asking for adverse reactions until day 7. Concentrations of ascorbate, deferoxamine and N-acetylcysteine will be measured by HPLC.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Combined antioxidant therapy (CAT) Intravenous administration of deferoxamine, n-acetylcysteine, and ascorbate over 90 minutes. |
Drug: Antioxidant formula
Active therapy
Other Names:
|
| Placebo Comparator: Placebo Intravenous administration of dextrose 5% over 90 minutes |
Drug: Dextrose 5% in water
Placebo
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Pharmacokinetic of the combined antioxidant therapy administered by intravenous route during 90 minutes [0 (just before infusion onset) and 30, 60, 90 120 and 180 minutes after infusion onset.]
Pharmacokinetic profile of each antioxidant component (deferoxamine, n-acetylcysteine, and ascorbate) assessed by plasma concentrations during and up to 90 minutes after the I.V infusion onset
- Frequency of severe adverse events during combined antioxidant therapy infusion [180 minutes (from infusion onset up to 90 minutes after infusion ending)]
Frequency of events that resulted in death, disability, life-threatening, or medical admission of a patient
Secondary Outcome Measures
- Frequency of any adverse event up to seven days after infusion ending [From day 0 to day 7 after the intervention]
Frequency of severe and non-severe adverse events from day 0 to day 7 after the intervention Frequency of severe and non-severe adverse events
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Healthy subjects from 18 to 35 years old
-
Normal BMI (19-24.9 kg/m2)
Exclusion Criteria:
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Impaired renal function (creatinine > 1.5 mg/dL)
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Liver impairment (liver enzymes over normal values)
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Glucosa 6-phosphate deshidrogenase deficency
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Any chronic disease
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Any acute disease in the last two weeks
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To be enrolled in other clinical study
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Chile | Santiago de Chile | Chile |
Sponsors and Collaborators
- University of Chile
- Fondo Nacional de Desarrollo Científico y Tecnológico, Chile
Investigators
- Study Director: Ramón Rodrigo, Prof., Program of Pharmacology, ICBM, Faculty of Medicine, University of Chile
- Study Chair: Abraham IJ Gajardo, MD, PhD, Intensive Care Unit, Hospital Clínico Universidad de Chile
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- FONDECYT 1211850