National Toxicology Program

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Abstract for IMM90010 - Ribavirin (CASRN 36791-04-5)

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 The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by the NTP on March 2009 (see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 Ribavirin (CAS No. 36791-04-5) in Female C57B1/6 Mice

NTP Report Number IMM90010

Introduction

Ribavirin (1-b-ribofuranosyl-1,2,4-triazole-3-carboxamide), a synthetic, non-interferon-inducing, broad-spectrum antiviral agent, has been placed in clinical trials for the treatment of influenza and, more recently, for AIDS. Reports on the immunosuppressive action of ribavirin are conflicting with several studies suggesting that the compound inhibits antibody responses (Potter et al., Nature 259: 496, 1976; Saganuma et al., Toh. J. Exp. Med. 116: 405, 1973) and others reporting no effects or enhancement (Ann. Mtg. Am. Soc. Microbiol., p.227, 1972). This study was performed to determine the potential effects of ribavirin on the immune system of mice.

Design

Ribavirin (greater than 99% pure as determined by HPLC) was a gift from Viratek, ICN Pharmaceuticals, Inc., Costa Mesa, CA. Fresh ribavirin solutions were prepared daily in sterile deionized water. The material was administered to female C57BL/6 mice by oral gavage at dosages of 0, 75, 150, or 300 mg/kg body weight at a volume of 0.1ml/10g body weight. Each animal received the test compound for ten days over a 14 day period. For each of the assays examined, 7-8 mice per group were employed. No positive control groups were included.

Results

There were no drug-related mortalities or overt signs of toxicity from ribavirin exposure. Likewise, there were no consistent treatment-related effects on body weight, measured organ weights, or lymphoid histology except for a decrease in thymus weights at the 150 mg/kg dose level. Serum chemistries examined included SGPT, BUN, glucose, total protein, albumin, globulin and albumin/globulin ratios. There was a dose-related decrease in albumin and albumin/globulin ratios after ribavirin treatment. Hematological values in ribavirin-treated mice were similar to controls, except for a slight decrease in hematocrit at the high dose level (data not shown). The immune and bone marrow studies are summarized in Table 1. The major immunological effect observed from ribavirin treatment was a dose-dependent decrease in the antibody response to sheep erythrocytes and DNP-Ficoll, the latter being a T-independent antigen. Antibody suppression was associated with only a slight decrease in splenic B cell numbers and no (i.e., LPS) or a slight (anti-Ig/IL-4) increase in lymphocyte blastogenesis. There were no effects on T lymphocyte functions as evidenced by normal CTL activity, lymphocyte mitogenesis, mixed leukocyte responsiveness and T cell numbers. Natural killer cell activity was apparently not altered by drug treatment, although the control response was well below historical control values making it difficult to interpret this response.

Bone marrow cellularity and DNA synthesis were unaffected by ribavirin treatment but there was a dose-related increase in CFU- C1 and CFU-C2 progenitor cell formation.

Conclusion

Under these experimental conditions, ribavirin selectively altered immune function. Humoral immune function appears to be the primary immune target. The significance of the increase in bone marrow CFU-C1 and CFU-C2 formation is unknown.

Table 1. Summary of Ribavirin Immune Studies

Parameter Dose (mg/kg)
  0 75 150 300
Body Weight (g) 22.1 21.8 21.8 21.7
Spleen (mg) 8.0 88 77.0 84
Spleen:Body wt. (%) 0.350.400.350.39
Thymus (mg) 85.0 71.062.0**76.0
Thymus:Body wt.% 0.39 0.330.28**0.35
 
Peripheral Leukocyte Count (10E3/mm3) 2.80 2.26 2.07 2.61
Spleen cell no. (x 10E7) 16 17 15 16
Thy 1.2+ (%)41 43 4342
CD4+ (%) 20 212019
CD8+ (%)12 121313
sIg+ (%)5651**51**51**
Cytotoxic T Lymphocytes (% cytotoxicity)25:188 83 8586
 
Natural Killer Cell Activity (% cytotoxicity) 100:1 3.3 1.9 3.1 3.1
sRBC IgM PFC/10E6 cells 648 347**240**145**
sRBC IgM PFC/spleen (x 103) 127 65**45**29**
DNP-Ficoll PFC/10E6 Cells644 563489367*
DNP-Ficoll PFC/Spleen (x10E3)7873 62 43
 
Lymphoproliferation 3H-TdR incorporation (cpm x 10E3):
Concanavalin A 179 175 179 172
Phytohemagglutinin 85 91 96 84
Anti-Ig/IL4 40 48* 48* 47
Lipopolysaccharide 96 95 97 94
Mixed Leukocyte Response 54 50 49 55.4
 
Bone Marrow Cells/Femur (x 10E6) 13.7 14.3 13.3 12.3
DNA Synthesis (cpm x 10E3) 76 75 76 76
CFU-C1/10E5 nucleated cells^ 104 117 120 134**
CFU-C2/10E5 nucleated cells^ 81 95* 101** 118**

note:
^ CFU-C1 and CFU-C2 are defined in Methods- Immunomodulation.
* different from vehicle control at P less than 0.05
** different from vehicle control at P less than 0.01


Report Date: August 1989

NTIS # PB92-140383 [SUMMARY(1-15)]

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