Study of the Ability of Clarithromycin to Induce Oxidative Stress

Study Overview
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Brief Summary
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The purpose of the study is to examine whether Klacid® (Clarithromycin) will induce oxidative stress (stress from oxygen) in healthy subjects. This is done by measuring the content of a particular substance in the urine sample, which is released when the body is exposed to oxidative stress. In addition, there will also be taken blood samples, which is analysed for another substance that is indicative of oxidative stress.

Detailed Description
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The purpose of the study is to examine whether Klacid® induce oxidative stress in healthy subjects. Many studies have shown that atherosclerosis can cause acute myocardial infarction (AMI). The development of atherosclerosis is exacerbated by simultaneous infection with Chlamydophila pneumoniae, and its accompanying inflammation. There has been shown a positive association between Chlamydophila pneumoniae antibodies and the incidence of cardiovascular complications, suggesting that Chlamydophila pneumoniae could exacerbate the development of atherosclerosis [1]. It has therefore been tried to treat atherosclerotic AMI- patients prophylactically with macrolide antibiotics (which is used to treat Chlamydia infections), to halt development of the atherosclerosis and the accompanying risk of a new acute myocardial infarction. Two minor studies have demonstrated a positive effect of macrolide-treatment, why a major Danish study of Clarithromycin was implemented [2-4]. Clarithromycin treatment was tested against placebo in 4373 atherosclerotic patients who had had an AMI. It appeared that the use of clarithromycin led to an increased cardiovascular mortality, which could not be explained [4]. The finding of the study suggests that clarithromycin cannot be used for secondary prophylaxis of cardiovascular complications, but whether clarithromycin can be used for primary prophylaxis is not known. It has been shown that oxidative stress can participate in the development of cardiovascular complications [5], and it could be such an oxidative stress that had led to the increased mortality in the above study. Especially because a recent american study found evidence that bactericidal antibiotics induce oxidative stress in bacteria, leading to cell death [6]. This oxidative stress contributes significantly to the impact of the bactericidal antibiotics, which was thought to be primarily attributed to their specific drug/target interactions. The same study also examined erythromycin, from which clarithromycin is a derivate. Erythromycin showed no induction of oxidative stress, but clarithromycin is twice as effective as erythromycin, which could be due to oxidative stress caused by clarithromycin. This study seeks to clarify a possible mechanism for clarithromycin, by an examination on healthy volunteers without atherosclerosis.

Official Title
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A Randomized, Single Blinded, Open-Label Crossover-Study of the Possible Induction of Oxidative Stress by Clarithromycin in Healthy Subjects

Conditions
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Oxidative Stress

Intervention / Treatment
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* Drug: Clarithromycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Caucasian Non-smoker Body mass index (BMI) must be ≥18 and ≤ 30 Blood pressure must be within the following limits: Systolic blood pressure (110 mmHg > X < 140 mmHg) Diastolic blood pressure (60 mmHg > Y < 90 mmHg) Normal lipid plasma levels: Total cholesterol (≤ 6,0 mmol/l) HDL-cholesterol (≥ 0,9 mmol/l) LDL-cholesterol (≤ 4,5 mmol/l) Triglycerides (0,5-2,2 mmol/l) Exclusion Criteria: Smokers CRP: > 10 mg/l Prolonged QT interval (defined as QTc > 450 msec.) Severe renal insufficiency (Cpl (creatinine) > 0100 mmol/l) Hereditary galactose intolerance A special form of hereditary lactase deficiency (Lapp Lactase deficiency) Glucose/galactose malabsorption Use of medicines and herbal remedies that affect/is affected by Clarithromycin, or lead to QT prolongation, for example, cisapride, pimozide, terfenadine, ergotamine, dihydroergotamine, fluconazole, ritonavir, carbamazepine, kinidin, disopyramide, lovastatin, simvastatin, warfarin, acenocoumarol, sildenafil, Tadalafil, vardenafil, theophylline, tolterodine, triazolo benzodiazepins, omeprazole, colchinine, digoxin, zidovudine, phenytoin, valproat, atazanavir, itraconazole, saquinavir Inborn condition with prolonged QT interval The following disorders: Coronary artery disease Former cardiac arrhythmias Severe heart insufficiency Non-compensated hypokalemia (defined as Cpl (K) < 3.2 mmol/ l) and/or hypomagnesemia (defined as Cpl (Mg) < 0.67 mmol/l) Bradycardia ( < 50 bpm) Known allergy to clarithromycin or other macrolides Narcotic Eating food supplements

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Screening
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Subjects randomised to this arm will first be treated with Clarithromycin for a week, then have a 2-week washout, and finally one week of no treatment | Drug: Clarithromycin<br>* Prolonged release tablet, 500 mg, 1 tablet a day for a week<br>* Other names: ATC: J01FA09;|
| Active Comparator: 2<br>Subjects randomised to this arm will first receive one week of no treatment, then have a 2-week washout, and finally be treated with Clarithromycin for a week | Drug: Clarithromycin<br>* Prolonged release tablet, 500 mg, 1 tablet a day for a week<br>* Other names: ATC: J01FA09;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amount of 8-oxo-deoxyguanine in 24 hour-urine measured in nmol/mmol creatinine |  | End of study (July-August 2008) | 
| Amount of Malondialdehyde in plasma |  | End of study (July-August 2008) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amount of Total Vitamin C (Ascorbic acid) in plasma |  | End of study (July-August 2008) | 
| Caffeine-metabolite ratio in 24 hour-urine |  | End of Study (July-August 2008) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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oxidative stress, 8-oxo-deoxyguanine, 8-oxodG, clarithromycin, malondialdehyde, mda, vitamine C, ascorbic acid