Developmental toxicity study of tetramethylurea (TMU) in rats.

The developmental toxicity of tetramethylurea (TMU) was assessed in rats by inhalation exposure of the test material over days 6-20 of gestation. Groups of 25 mated female Crl:CD BR rats were exposed whole-body for 6 hours/day to concentrations of either 0, 2, 20 or 100 ppm TMU. The dams were euthanized on day 21 and the offspring were weighted, sexed, and examined for external, visceral, and skeletal alterations. Maternal toxicity was demonstrated at both 20 and 100 ppm. Maternal body weights, weight changes, and food consumption were statistically significantly reduced at these concentrations; effects were more pronounced at 100 ppm. There was evidence of developmental toxicity only at 100 ppm. The only finding was a decrease in mean fetal weight. No fetal malformations or variations occurred in fetuses derived from rats exposed to all 3 test concentrations (up to 100 ppm). The maternal no-observed-effect-level (NOEL) was 2 ppm, the fetal NOEL was 20 ppm. Thus, TMU was not considered to be uniquely toxic to the rat conceptus.

Coadministration of zidovudine and interleukin-2 increases absolute CD4 cells in subjects with Walter Reed stage 2 human immunodeficiency virus infection: results of ACTG protocol 042.

Interleukin-2 (IL-2) can increase numbers of absolute CD4 cells in persons infected with the human immunodeficiency virus who are receiving antiretroviral therapy. Twenty-five subjects with > 400/mm3 absolute CD4 cells received zidovudine and low-dose intravenous or subcutaneous IL-2 (< or = 10(6) U/m2). Absolute CD4 cells increased significantly during IL-2 treatment, and 56% of the subjects achieved a maximal increase of > or = 500 cells/mm3. A dose-response relationship favored increasing IL-2 doses, and subcutaneous delivery offered greater increases than intravenous administration. Fifteen subjects had persistent increases of > or = 100 cells/mm3 6 weeks after IL-2 was discontinued. No changes occurred in delayed-type hypersensitivity or helper T cell responses to recall antigens. Cell-mediated cytotoxicities increased against Daudi cells. IL-2 was well tolerated and only 1 subject required dose reduction. Relatively low-dose IL-2 delivered by subcutaneous or intravenous routes may provide an important complement to antiretroviral therapy to increase absolute CD4 cells with the potential for less toxicity than with higher IL-2 doses.

Adverse consequences of fluoxetine-MAOI combination therapy.

The authors describe two series of patients: 12 treated simultaneously with fluoxetine and a monoamine oxidase inhibitor and 6 patients started on treatment with an MAOI 10 days or more after stopping fluoxetine treatment. All patients had extremely refractory depression and were treated in open fashion before general knowledge was obtained of the side effects that may accompany the fluoxetine-MAOI combination. During the fluoxetine-MAOI trial, most patients continued to receive other psychotropic combinations that had been partially helpful. The use of fluoxetine and an MAOI, either together or in close succession, was accompanied by a very high incidence of adverse effects, especially the "serotonergic syndrome." This syndrome was characterized by mental status changes, such as hypomania and confusion, and physical symptoms, such as myoclonus, hypertension, tremor, and diarrhea. Because of the high incidence of side effects and the lack of definite efficacy, the concurrent use of fluoxetine and MAOIs should generally be avoided. The long half-lives of fluoxetine and norfluoxetine, as well as the prolonged metabolic effects of MAOIs, may also dispose patients to an interaction if one of the drugs is started soon after stopping the other.