We studied 58 recipients of bone-marrow transplants to evaluate immune responses to cytomegalovirus infection. Such infection developed in 43 patients; it was fatal in 12, nonfatal in 23, and present at death from other causes in eight. All patients had low or absent cytomegalovirus-specific cytotoxic lymphocyte activity before the onset of infection. Cytomegalovirus-specific cytotoxic responses developed in all survivors, whereas only two patients with fatal infection had even low-level cytomegalovirus-specific cytotoxic responses. Natural and antibody-dependent killer-cell activities were depressed both before and during infection in patients with fatal infections, but not in those who survived. The outcome of the infection did not correlate with the nature of the underlying disease, the type of transplant received, the pretransplantation cytomegalovirus-antibody status, or lymphocyte-proliferation responses to cytomegalovirus antigens or concanavalin A. The correlation between effective virus-specific cytotoxic response and recovery from infection indicates that these effector cells probably mediate recovery from cytomegalovirus infection.

The 6-Minute Walk Distance (6-MWD) has been the most utilized endpoint for judging the efficacy of pulmonary arterial hypertension (PAH) therapy in clinical trials conducted over the past two decades. Despite its simplicity, widespread use in recent trials and overall prognostic value, the 6-MWD has often been criticized over the past several years and pleas from several PAH experts have emerged from the literature to find alternative endpoints that would be more reliable in reflecting the pulmonary vascular resistance as well as cardiac status in PAH and their response to therapy. A meeting of PAH experts and representatives from regulatory agencies and pharmaceutical companies was convened in early 2012 to discuss the validity of current as well as emerging valuable endpoints. The current work represents the proceedings of the conference.

Thirteen male subjects received 1 mg of either gentamicin or netilmicin per kg, first intramuscularly and then intravenously. After the intramuscular dose, concentrations of gentamicin in the serum were more variable than those of netilmicin. After the intravenous dose, the distribution phase of netilmicin was twice as rapid as gentamicin. The average half-times of the elimination phase were similar, but there was marked variability among the subjects receiving gentamicin. Serum clearance of netilmicin was more rapid than that of gentamicin and could not be attributed to renal elimination. The data indicate that, after intramuscular administration, netilmicin may produce more predictable blood levels than gentamicin and suggest that the body distribution of netilmicin may differ from that of gentamicin.Netilmicin is a new semisynthetic aminoglycoside (32). Netilmicin is N-ethyl sisomicin, with the substituent attached to 2-deoxystreptamine. Another aminoglycoside in clinical use with a substitution on 2-deoxystreptamine is amikacin, a hydroxyaminobutyric acid derivative of kanamycin A. In vitro testing in our laboratory and others (8-10, 20, 23, 27, 31) indicates that the activity of netilmicin against Enterobacteriaceae, Pseudomonas, and Staphylococcus, in general, approximates that of gentamicin. Serum concentrations in animals and humans are comparable to those of gentamicin (27).Netilmicin appears to have two advantages. First, like amikacin, it is effective against some organisms resistant to gentamicin, including indole-negative proteus and strains that produce aminoglycoside-adenylating enzymes (16,23). Second, animal studies indicate that netilmicin has significantly less oto-and nephrotoxicity than does gentamicin (19, 27; R. E. Brummett and K. E. Fox, Fed. Proc. 35:621, 1976). If reduced toxicity is also found in humans, it will strongly influence the relative usefulness of this agent.Netilmicin is now in the early stages of therapeutic evaluation, and expanded information concerning its pharmacology will be of benefit to physician investigators and their patients. For this reason, we have investigated the disposition of netilmicin in humans. MATERIALS AND METHODSThirteen adult male graduate students were used in our study. The subjects underwent a complete medical history and psychological evaluation; physical examination; determination of base line blood chemistries (chloride, carbon dioxide, potassium, sodium, blood urea nitrogen and glucose, total protein, serum albumin, calcium, inorganic phosphorus, cholesterol, uric acid, creatinine, total bilirubin, alkaline phosphatase, creatine phosphokinase, lactic dehydrogenase, serum glutamic oxaloacetic transferase); complete blood count; urinalysis, including microscopic urinalysis and determination of creatinine clearance. All subjects were judged free from any recognizable illness by the above parameters. The experimental design of the project and the drugs used were explained, and informed consent was obtained from each individual. The study was appr...