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Induction and prevention of shock-like lethal side effects after microfilaricidal treatment in filariae infected
1Institut für Parasitologie, Justus-Liebig-Universität Giessen, Germany.
Abstract:
In contrast to human carriers of microfilariae, filariae infected rodents generally tolerate an effective microfilaricidal treatment without obvious signs of adverse reactions. The study shows, however, that also the filariae (Litomosoides carinii, Brugia malayi) infected rodent Mastomys coucha can be rendered sensitive to side effects of the treatment by the administration of D-galactosamine (D-Gal), due to reduction of liver UTP levels. Independent of the drug (diethylcarbamazine, ivermectin, CGP 20376) and the parasite species, D-Gal-primed infected animals died within 4 days after a microfilaricidal treatment. Lethal effects did also occur in naive animals to which microfilariae had been transfused 18 h prior to the challenge with D-Gal and a microfilaricidal, provided the animals had received at least approximately 10(3) larvae/g body weight. Both infected animals and naive recipients of microfilariae could be protected from death by cyclosporin A, polyclonal antibodies to mouse TNF or suitable amounts of NG-monomethyl-L-arginine. Pentoxifylline was less protective. The results suggest that components play a role in adverse reactions after microfilaricidal treatment, which are released by dying/dead microfilariae and may interact with T lymphocytes independent of a specific state of immunity. In a sequela, TNF released by T cells seems to induce an excess synthesis of N-oxides which appear to be the final morbific agent.
Insights
Filariae-infected rodents can experience severe adverse reactions to microfilaricidal drugs when pre-treated with D-galactosamine (D-Gal). This combination therapy proved lethal, highlighting the role of dying microfilariae components and T-cell responses in drug toxicity.
Area of Science:
- Parasitology
- Immunology
- Pharmacology
Background:
- Rodents infected with microfilariae typically tolerate microfilaricidal treatments well.
- Adverse reactions to these treatments are not commonly observed in rodent models.
Purpose of the Study:
- To investigate if rodents can be sensitized to adverse effects of microfilaricidal treatment.
- To elucidate the mechanisms underlying potential drug-induced toxicity in filariae-infected rodents.
Main Methods:
- Administration of D-galactosamine (D-Gal) to sensitize Mastomys coucha infected with Litomosoides carinii or Brugia malayi.
- Treatment with various microfilaricidal drugs (diethylcarbamazine, ivermectin, CGP 20376).
- Evaluation of protective effects using cyclosporin A, anti-TNF antibodies, and NG-monomethyl-L-arginine.
Main Results:
- D-Gal pre-treatment rendered infected rodents sensitive to lethal side effects of microfilaricidal drugs.
- Lethal effects were observed in both infected and naive animals receiving microfilariae transfusions prior to D-Gal and drug challenge.
- Cyclosporin A, anti-TNF antibodies, and NG-monomethyl-L-arginine provided protection, while pentoxifylline was less effective.
Conclusions:
- Components released from dying microfilariae contribute to adverse reactions, interacting with T lymphocytes.
- Tumor Necrosis Factor (TNF) released by T cells may trigger the synthesis of N-oxides, the ultimate toxic agents.
- This study reveals a mechanism for drug-induced toxicity in filariasis treatment models.
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