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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleArticle

ACTIONS OF S,2-AMINOETHYLISOTHIURONIUM BR. HBR (AET). TOXICITY AND PROTECTIVE EFFECT AGAINST NITROGEN MUSTARD TOXICITY

Margaret G. Kelly, David P. Rall, Glenn E. Trivers, Roger W. O'Gara and Charles G. Zubrod
Journal of Pharmacology and Experimental Therapeutics June 1960, 129 (2) 218-230;
Margaret G. Kelly
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David P. Rall
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Glenn E. Trivers
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Roger W. O'Gara
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Charles G. Zubrod
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Abstract

The acute toxicity of AET was determined in mice by intravenous, intraperitoneal, subcutaneous and oral routes, and in rats, guinea pigs and dogs by intraperitoneal route. In rodents, the majority of deaths occurred within the first few hours, and were generally preceded by convulsions. In dogs, death occurred in 18 to 96 hours, and was preceded by emesis, ataxia and prostration. The lethality of AET in mice was significantly increased by atropine and glucose and possibly also by SY-28 and ethanol; it was not modified by chlorpromazine, pentobarbital sodium or phenobarbital. Subcutaneous injection of AET produced a severe ulcerative inflammatory reaction in mice at the site of injection.

The subacute toxicity of AET was determined by intraperitoneal route in mice, rats and dogs. AET had a cumulative toxicity on daily administration and was tolerated at intervals of 48 hours or longer. In dogs, objective signs of toxicity (tremors, emesis) were produced at levels of AET substantially lower (ca. one-fifth) than the dose which caused death.

Injection of AET (oral, subcutaneous, intraperitoneal) 15 to 30 minutes before administration of HN2 effectively protected mice and rats against supralethal dose levels of nitrogen mustard given intraperitoneally This action was obtained at nonlethal and relatively nontoxic dose levels of AET. Administration of AET 15 minutes or longer after HN2 had no protective effect against nitrogen mustard toxicity.

In addition to its action with HN2, pretreatment with AET also protected against the lethality of uracil mustard. It was ineffective, however, in reducing the lethality of thioTEPA, and increased the lethality of cyclophosphamide, colchicine, trimethylcolchicinic acid methyl ether-d-tartrate and possibly also of Myleran.

AET did not prevent either the initial loss of body weight or the decrease in spleen weight caused by nitrogen mustard, but did shorten the lag period before initiation of the recovery phase.

AET decreased the severity of the damage to bone marrow, intestine and spleen produced by HN2, and accelerated the rate of recovery of these tissues.

Footnotes

    • Received October 28, 1959.

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Journal of Pharmacology and Experimental Therapeutics
Vol. 129, Issue 2
1 Jun 1960
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Research ArticleArticle

ACTIONS OF S,2-AMINOETHYLISOTHIURONIUM BR. HBR (AET). TOXICITY AND PROTECTIVE EFFECT AGAINST NITROGEN MUSTARD TOXICITY

Margaret G. Kelly, David P. Rall, Glenn E. Trivers, Roger W. O'Gara and Charles G. Zubrod
Journal of Pharmacology and Experimental Therapeutics June 1, 1960, 129 (2) 218-230;

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Research ArticleArticle

ACTIONS OF S,2-AMINOETHYLISOTHIURONIUM BR. HBR (AET). TOXICITY AND PROTECTIVE EFFECT AGAINST NITROGEN MUSTARD TOXICITY

Margaret G. Kelly, David P. Rall, Glenn E. Trivers, Roger W. O'Gara and Charles G. Zubrod
Journal of Pharmacology and Experimental Therapeutics June 1, 1960, 129 (2) 218-230;
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