Study of the Ability of Clarithromycin to Induce Oxidative Stress

Oxidative Stress Clinical Trial

— CLAROX  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00707330
• Other study ID #: 3-12-1-18-15-23
• Secondary ID: EudraCT 2008-001
• Status: Completed
• Phase: Phase 1
• First received: June 26, 2008
• Last updated: August 8, 2008
• Start date: May 2008
• Est. completion date: July 2008

Study information

• Verified date: August 2008
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Health authority: Denmark: Danish Medicines AgencyDenmark: Ethics CommitteeDenmark: Danish Dataprotection Agency
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 26
• Est. completion date: July 2008
• Est. primary completion date: July 2008
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 35 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Screening

Related Conditions & MeSH terms

• Oxidative Stress

Intervention

Drug:
• Clarithromycin
Prolonged release tablet, 500 mg, 1 tablet a day for a week

Locations

Country	Name	City	State
Denmark	Department of Clinical Pharmacology Q, Rigshospitalet, Blegdamsvej 9	Kopenhagen O

Sponsors (1)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark

Country where clinical trial is conducted

Denmark, 

References & Publications (6)

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

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. — View Citation

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. — View Citation

Jespersen CM, Als-Nielsen B, Damgaard M, Hansen JF, Hansen S, Helø OH, Hildebrandt P, Hilden J, Jensen GB, Kastrup J, Kolmos HJ, Kjøller 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. — View Citation

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. — View Citation

Muhlestein JB, Anderson JL. Infectious serology and atherosclerosis: how burdensome is the risk? Circulation. 2003 Jan 21;107(2):220-2. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Amount of 8-oxo-deoxyguanine in 24 hour-urine measured in nmol/mmol creatinine		End of study (July-August 2008)	No
Primary	Amount of Malondialdehyde in plasma		End of study (July-August 2008)	No
Secondary	Amount of Total Vitamin C (Ascorbic acid) in plasma		End of study (July-August 2008)	No
Secondary	Caffeine-metabolite ratio in 24 hour-urine		End of Study (July-August 2008)	No