. It is as active as chlorpheniramine and about 40 times as potent as diphenhydramine in protecting guinea pigs against lethal doses of histamine. At intravenous doses of 10 mg. per kilogram, it had no effect on electroencephalogram measurements in cats and was not sedative. Ro 5-9110/1 has a low toxicity in various species: Rats given 200 mg. per kilogram and dogs given 40 mg. per kilogram for 13 weeks as dietary admixture showed no toxic manifestations. Sedation also was not observed in these species."' The present study was designed to evaluate the efficacy of this agent in reducing the size of the wheal and the flare produced by several intradermal injections of
250histamine and to compare the usefulness of paper transcripts and measurements of wheal and flare diameters as discriminative parameters of drug action.
Material and methodsTwelve healthy Caucasian volunteers ( 2 women and 10 men) participated in the study. Their ages ranged from 21 to 37 years (mean, 26). The following laboratory tests were performed before and after the study: complete blood count, urinalysis, fasting blood sugar, alkaline phosphatase, blood urea nitrogen, and serum glutamic pyruvic transaminase determinations. In some instances serum bilirubin concentrations were also determined. Individuals with previous skin diseases and allergies (hay fever, asthma, urticaria, food and drug allergies) were excluded from the study.The dose levels studied were 0 (placebo), 4, 8, and 16 mg. of Ro 5-9110/1. The double-blind technique was followed. Each subject served as his own control,
Thirty-three patients with advanced malignancy were treated with oral spirogermanium in a Phase I study to determine a maximum tolerated dose. Patients were entered in the study at doses of 100, 200, and 300 milligrams daily. The dose-limiting toxicity was gastrointestinal with moderate nausea and vomiting occurring with the 300 milligram dose. No myelosuppression or renal dysfunction was noted. Elevations of serum transaminase were seen in 41 percent of the patients at study entry. While abnormalities in hepatic function were recorded during the study, the relationship to spirogermanium could not be determined. No patient exhibited clinical hepatic dysfunction or elevation of serum bilirubin. It is recommended that future studies of oral spirogermanium incorporate careful monitoring of these parameters. Two patients with lymphoproliferative disorders had objective responses to therapy. A dose of 200 milligrams is recommended for further Phase II trials.
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