We conducted a double-blind, placebo-controlled trial of oral azidothymidine (AZT) in 282 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex. Although significant clinical benefit was documented (N Engl J Med 1987; 317:185-91), serious adverse reactions, particularly bone marrow suppression, were observed. Nausea, myalgia, insomnia, and severe headaches were reported more frequently by recipients of AZT; macrocytosis developed within weeks in most of the AZT group. Anemia with hemoglobin levels below 7.5 g per deciliter developed in 24 percent of AZT recipients and 4 percent of placebo recipients (P less than 0.001). Twenty-one percent of AZT recipients and 4 percent of placebo recipients required multiple red-cell transfusions (P less than 0.001). Neutropenia (less than 500 cells per cubic millimeter) occurred in 16 percent of AZT recipients, as compared with 2 percent of placebo recipients (P less than 0.001). Subjects who entered the study with low CD4 lymphocyte counts, low serum vitamin B12 levels, anemia, or low neutrophil counts were more likely to have hematologic toxic effects. Concurrent use of acetaminophen was also associated with a higher frequency of hematologic toxicity. Although a subset of patients tolerated AZT for an extended period with few toxic effects, the drug should be administered with caution because of its toxicity and the limited experience with it to date.

The common cold is one of the most fre¬ quent and universal infections of man.Nevertheless, little is known regarding its specific etiology, and the diagnosis must be a clinical one. Until the infectious agent can be propagated, characterized by microbiologic and pathologic methods and consist¬ ently transmitted to experimental animals or in tissue cultures, transmission to humans appears to be the best method for study.In this manner, information can be obtained about the nature of the infection, factors that influence the susceptibility or resistance of the human host, and conditions that favor spread of the illness.During the past five years we have made observations upon more than 1000 volun¬ teers who were challenged with infectious nasal secretions obtained from persons with a common cold or with a blank solution used as a control. The clinical findings were re-Dr. Spiesman died Sept. 11, 1954. corded daily. Examination of the nose and throat was of no value in detecting the presence of a cold, and it was necessary to develop an objective and consistent method of scoring symptoms. Upon this basis, cri¬ teria were developed for the diagnosis of a cold following challenge with an infectious secretion which permitted the uniform eval¬ uation of serial experiments. The present report describes the clinical features of the common cold among volunteers and the criteria that were used to diagnose an ex¬ perimental cold. MethodsNasal secretions were obtained from a donor with a typical common cold and filtered through a bactériologie porcelain filter. The specimen was diluted 1:10 with an isotonic salt solution buffered to pH 7.4 to which 0.5% yeast extract or 5% human Type O hemoglobin was added as a stabilizing protein. Multiple aliquote were stored in screw cap vials at -70 C in a mechanical re¬ frigerator. Samples of the nasal secretion were routinely inoculated into embryonated hen eggs by both the allantoic and the amniotic routes, for the identification of influenza, mumps, and psittacosis viruses. Suckling mice were given intraperitoneal injections, and adult mice, both intraperitoneal and intracranial, for the identification of Coxsackie, herpes, and encephalitis agents. Human epithelial cells, strain HeLa, and monkey-kidney cells in tissue cultures were used to identify adenovirus and poliomyelitis viruses. Suckling hamsters were given inoculations of some of the secretions. Serial passages, animal fatality, hemagglutination, cytotoxicity, histocytology, and sero¬ logie methods were used to identify, insofar as possible, strains of known viruses. Secretions that were found to be free of disease-producing agents were tested for infectivity in from 6 to 12 volunteers.

Adaptive resistance to the bactericidal effect of an aminoglycoside antibiotic was induced in Pseudomonas aeruginosa and other aerobic gram-negative bacilli by initial exposure to the drug. Both subinhibitory and inhibitory concentrations produced resistance in bacterial cells surviving the effects of the initial ionic binding. Development of drug refractoriness required an adaptive period of growth, was enhanced by the continued presence of drug, and reversed after several hours of growth in drug-free medium. Unstable resistance was not explained by selection of mutants. The mechanism of adaptive resistance was down-regulation of aminoglycoside uptake during the period of accelerated energy dependent drug transport (EDP II). Down-regulation induced by gentamicin or tobramycin produced cross-resistance to other aminoglycosides. The kinetics of unstable first-exposure resistance suggests that a continuous drug level might not provide the most effective therapy with aminoglycosides and gives rationale to larger initial and longer interval bolus dosing.

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