A Challenge to the Medical and Pharmaceutical Communities THE ANTI-INFECTIVE Advisory Committee to the Food and Drug Administration (FDA) recently recommended the approval of zidovudine (azidothymidine [AZT]) for use as a treatment of selected patients with acquired immunodeficiency syndrome (AIDS), but only for those with advanced illness characterized by Pneumocystis carinii pneumonia and depressed immunity and for symptomatic cases of AIDS\x=req-\ related complex (ARC). It did not, however, recommend approval of zidovudine for treatment of pre-AIDS or nonadvanced AIDS cases with other opportunistic infections.Within two months of that recommendation, the FDA released the drug for use for the above indications.The committee, which I chaired, was made up of 11 medical
Exposure to radiation damages the immune, hematopoietic, and gastrointestinal components of the host defense system. This may lead to serious endogenous or exogenous infections. When radiation injury is combined with other physical trauma, e.g., burn or wound, the resulting damage to these systems is synergistic, and treatment for infection requires multiple approaches. This paper reviews successful single and combined therapeutic modalities for infections in irradiated mice and irradiated mice inflicted with trauma that are currently conducted at the Armed Forces Radiobiology Research Institute. The models of endogenous and exogenous infection and combined injury are described. The management of wounds infected with bacteria, exogenous systemic infection due to gram-negative enteric bacteria, and the chemoprophylaxis of enteric-derived systemic infection with quinolones is described. Infections can be treated successfully with proper antimicrobial therapy. In gamma- and neutron-irradiated mice, the immunomodulator trehalose dimycolate (TDM) was effective in treating endogenous infection. TDM with the antimicrobial ceftriaxone was effective in treating exogenous infection due to Klebsiella pneumoniae. Improvement in managing infection in irradiated and injured hosts will require further research using these diagnostic and therapeutic modalities. Accurate biological dosimetry is critical in determining if victims are at risk of developing infection. We found that radiation induced changes in plasma diamine oxidase activity; monitoring these changes was a useful indicator of the severity of radiation injury.
Unprimed mouse spleen cells cultured in vitro on syngeneic tumor cell monolayers have been previously shown to become specifically sensitized and to mediate cytotoxicity against the same type of tumor cells. This complete in vitro system of cell-mediated response has been presently used to test the effect of a thymic humoral factor (THF) upon the differentiation process leading to the generation of specifically committed lymphocytes. Culture media were supplemented with 2% THF during either the sensitization or effector phase, or both phases of the reaction. Whereas the addition of THF during both phases or during sensitization only resulted in a significant increase in the cytotoxicity index, THF added during the effector phase was ineffective. The behavior of unsensitized spleen cells and of spleen cells sensitized against nonrelated transplantation antigens remained unmodified by THF. After showing that the entire reaction is mediated by lymphocytes of thymic origin, THF was directly tested on T or B spleen cells. It was found that only T cells reacted to THF by an increased cytotoxic capacity, while B cells remained inactive after addition of THF. It was therefore concluded that THF activates a postthymic population of lymphoid cells, transforming them into fully competent lymphocytes.
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