Study of the Ability of Clarithromycin to Induce Oxidative Stress - Full Text View

Sponsored by:	Rigshospitalet, Denmark
Information provided by:	Rigshospitalet, Denmark
ClinicalTrials.gov Identifier:	NCT00707330

Purpose

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.

Condition	Intervention	Phase
Oxidative Stress	Drug: Clarithromycin	Phase I

MedlinePlus related topics: Urine and Urination

Drug Information available for: Vitamin E alpha-Tocopherol alpha-Tocopheryl acetate Tocopherols Clarithromycin Ascorbic acid

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Screening, Randomized, Open Label, Crossover Assignment, Pharmacodynamics Study
Official Title:	A Randomized, Single Blinded, Open-Label Crossover-Study of the Possible Induction of Oxidative Stress by Clarithromycin in Healthy Subjects

Further study details as provided by Rigshospitalet, Denmark:

Primary Outcome Measures:

Amount of 8-oxo-deoxyguanine in 24 hour-urine measured in nmol/mmol creatinine [ Time Frame: End of study (July-August 2008) ] [ Designated as safety issue: No ]
Amount of Malondialdehyde in plasma [ Time Frame: End of study (July-August 2008) ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Amount of Total Vitamin C (Ascorbic acid) in plasma [ Time Frame: End of study (July-August 2008) ] [ Designated as safety issue: No ]
Caffeine-metabolite ratio in 24 hour-urine [ Time Frame: End of Study (July-August 2008) ] [ Designated as safety issue: No ]

Enrollment:	26
Study Start Date:	May 2008
Study Completion Date:	July 2008
Primary Completion Date:	July 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental 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 Prolonged release tablet, 500 mg, 1 tablet a day for a week
2: Active Comparator 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 Prolonged release tablet, 500 mg, 1 tablet a day for a week

Detailed Description:

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.

Eligibility

Ages Eligible for Study:	18 Years to 35 Years
Genders Eligible for Study:	Male
Accepts Healthy Volunteers:	Yes

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00707330

Locations

Denmark
Department of Clinical Pharmacology Q, Rigshospitalet, Blegdamsvej 9
Kopenhagen O, Denmark, 2100

Sponsors and Collaborators

Rigshospitalet, Denmark

Investigators

Principal Investigator:

Henrik E Poulsen, dr. med.

Head of Department, Department of Clinical Pharmacology, Rigshospitalet

More Information

Publications:

Muhlestein JB, Anderson JL. Infectious serology and atherosclerosis: how burdensome is the risk? Circulation. 2003 Jan 21;107(2):220-2. No abstract available.

Gupta S, Leatham EW, Carrington D, Mendall MA, Kaski JC, Camm AJ. Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction. Circulation. 1997 Jul 15;96(2):404-7.

Gurfinkel E, Bozovich G, Daroca A, Beck E, Mautner B. Randomised trial of roxithromycin in non-Q-wave coronary syndromes: ROXIS Pilot Study. ROXIS Study Group. Lancet. 1997 Aug 9;350(9075):404-7.

Jespersen CM, Als-Nielsen B, Damgaard M, Hansen JF, Hansen S, Helo OH, Hildebrandt P, Hilden J, Jensen GB, Kastrup J, Kolmos HJ, Kjoller E, Lind I, Nielsen H, Petersen L, Gluud C; CLARICOR Trial Group. Randomised placebo controlled multicentre trial to assess short term clarithromycin for patients with stable coronary heart disease: CLARICOR trial. BMJ. 2006 Jan 7;332(7532):22-7. Epub 2005 Dec 8. Erratum in: BMJ. 2006 Jan 21;332(7534):151.

Dhalla NS, Temsah RM, Netticadan T. Role of oxidative stress in cardiovascular diseases. J Hypertens. 2000 Jun;18(6):655-73. Review.

Kohanski MA, Dwyer DJ, Hayete B, Lawrence CA, Collins JJ. A common mechanism of cellular death induced by bactericidal antibiotics. Cell. 2007 Sep 7;130(5):797-810.

Responsible Party:	Head of Department of Clinical Parmacology ( Henrik Enghusen Poulsen, professor, dr. med., overlæge )
Study ID Numbers:	3-12-1-18-15-23, EudraCT 2008-001299-61, VEK H-D-2008-026, DKMA 2612-3720, Datatilsynet 2008-41-2030
Study First Received:	June 26, 2008
Last Updated:	August 8, 2008
ClinicalTrials.gov Identifier:	NCT00707330
Health Authority:	Denmark: Danish Medicines Agency; Denmark: Ethics Committee; Denmark: Danish Dataprotection Agency

Keywords provided by Rigshospitalet, Denmark:

oxidative stress
8-oxo-deoxyguanine
8-oxodG
clarithromycin

malondialdehyde
mda
vitamine C
ascorbic acid

Study placed in the following topic categories:

Tocopherols
Clarithromycin
Tocopherol acetate
Vitamin E

Stress
Healthy
Ascorbic Acid
Alpha-Tocopherol

Additional relevant MeSH terms:

Anti-Infective Agents
Anti-Bacterial Agents
Protein Synthesis Inhibitors
Pathologic Processes

Molecular Mechanisms of Pharmacological Action
Therapeutic Uses
Enzyme Inhibitors
Pharmacologic Actions

ClinicalTrials.gov processed this record on January 16, 2009