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Abstract for IMM97007 - Clarithromycin (CASRN 81103-11-9)

Abstract

The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program (NTP). The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by the NTP on March 2009 (see http://ntp.niehs.nih.gov/ntp/htdocs/levels/09-3566%20NTP-ITOX-R1.pdf). The findings and conclusions for this study should not be construed to represent the views of the NTP or the US Government.

The Immunotoxicity of Clarithromycin
(CAS No. 81103-11-9)

in Female B6C3F1 Mice
NTP Report Number IMM97007

Summary

Clarithromycin (CRTM) is a semi-synthetic macrolide antibiotic used in the treatment of disseminated mycobacterial infections which occur in late stage AIDS patients with histories of multiple opportunistic infections1. CRTM is also being used with increasing frequency to treat upper and lower respiratory tract infections, steroid-dependent asthma2, gastric H. pylori infections, and may also be used in combination therapy to treat M. leprae infections1. In addition to its' antimicrobial properties, clinical trials have reported that CRTM has both antiinflammatory and immunomodulatory properties, both of which have contributed to the increasing popularity of this antibiotic2.

Clarithromycin was nominated to the NTP for toxicological evaluation and was selected for immunotoxicity studies by the project officer. The purpose of these studies is to determine the potential effects of CRTM on the immune system.

The study reported here is an immunotoxicological study conducted in female B6C3F1 mice, treated daily for 28 days by oral gavage. The in-life phase of the study was conducted between September 30, 1997 and October 8, 1998. CRTM was prepared weekly as a solution in the vehicle 0.5% methyl cellulose.

The baseline toxicology studies are summarized in Table ES-1. In this study, in which CRTM was administered orally at 125, 250 and 500 mg/kg/day for 28 days, there were no effects on body weight or weight gain. There were no notable changes among the standard toxicological parameters that were assessed.

The immunological studies are summarized in Table ES-2. Minimal immunotoxicological effects were observed in mice treated with CRTM, and they were clearly not dose-dependent. There was a 14% increase in the antibody-forming cell response to sRBCs observed in the 250 mg/kg CRTM treatment group. However, this response was not considered to be biologically meaningful in that the response was not dose-dependent. A 27% increase in the number of spleen macrophages was observed in mice treated with 125 mg/kg CRTM; however, this increase was also not dose-dependent. In addition to its lack of effect on humoral immunity, CRTM did not affect either cell-mediated immunity nor innate immunity, as indicated by no significant immunotoxicological effect on the mixed leukocyte response, NK activity, and cytotoxic T lymphocyte activity, or change spleen NK cell, B cell, and T cell numbers.

In conclusion, CRTM treatment, ranging from 125 mg/kg to 500 mg/kg, produced no significant toxicological effects as indicated by weight change, pathology, and hematological parameters. Minimal immunotoxicological effects were observed in mice treated with CRTM, and they were clearly not dose-dependent. CRTM did not significantly affect total spleen cell o r leukocyte sub-population numbers, and no significant changes in humoral immunity, cellmediated immunity, or innate immunity were observed. Based on these results, 28 days of treatment with CRTM does not appear to be immunotoxic to the murine immune system within the tested dose range.


1 American Foundation for AIDS Research, Vol 8, No. 1, February 1996.
2 Frost, D.A., Leung, D.M., Matrin, R.J., Brown, E.E., Szefler, S.J., and Spahn, J.D. (1999). Inhibition of methylperdnisolone elimination in the presence of clarithromycin therapy. J. Allergy Clin. Immunol. 103:1031-5.



Table ES-1
SUMMARY TABLE FOR TOXICOLOGY STUDIES
CRTM-28-1 M-PO
Parameter Result Maximum Effect Dose Comment
Body Weight
   Day 8 No Effect      
   Day 15 No Effect      
   Day 22 No Effect      
   Day 29 No Effect      
Weight Changes
   Day 8-1 No Effect      
   Day 15-1 No Effect      
   Day 22-1 No Effect      
   Day 29-1 No Effect      
Pathology
Gross Pathology No Effect      
Histopathology Not Processed      
Organ Weights
   Liver No Effect      
   Spleen No Effect      
   Lungs No Effect      
   Thymus No Effect      
   Kidney No Effect      
Hematology
RBCs No Effect      
   Hemoglobin No Effect      
   Hematocrit No Effect      
   MCV No Effect      
   MCH No Effect      
   MCHC No Effect      
   Reticulocytes No Effect      
Leukocytes No Effect      
    Leukocyte Diff No Effect      


Table ES-2
SUMMARY TABLE FOR IMMUNOLOGY STUDIES
DEA-14-1-PO
Parameter Results Maximum Effect Dose Comment
Surface Markers (Absolute Values)
   Ig+

No Effect

     
   CD3+

No Effect

     
   CD4+CD8-

No Effect

     
   CD4-CD8-

No Effect

     
   CD4+CD8+

No Effect

     
   NK1.1+CD3-

No Effect

     
   MAC-3+

Increase

27% 125 mg/kg  
IgM Humoral Immune Response to Sheep Erythrocytes
   IgM AFC/106 Cells

No Effect

     
   IgM AFC/Spleen

Increase

14% 250 mg/kg NBRa
   Serum Titer

No Effect

     
Mixed Leukocyte Response
   MLR Responders+
   Stimulators

No Effect

     
CTL Activity
   CTL

No Effect

     
NK Cell Activity
   LU/107

No Effect

     
   LU/Spleen

No Effect

     
aNot Biologically Relevant


Report Date: August 2000

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