A B S T R A C T Five patients received cholesterol7a-3H intravenously during control periods. Specific activity of total serum cholesterol was determined serially during the 1st wk and weekly thereafter. 28-59 wk after the injection of the tracer, when no further radioactivity could be detected in serum cholesterol, 2 g of oral neomycin was given daily to four patients for the remainder of the experiment. Average total serum cholesterol concentrations were reduced by 20, 21, 26, and 29%, respectively, in these subjects. The fifth patient, given placebo, had no change in serum cholesterol. After a period of 12-26 wk of medication the intravenous injection of cholesterol7a-3H was repeated, and while neomycin or placebo administration was continued, serum cholesterol specific activity was again determined serially during the 1st wk and weekly thereafter for 23-42 wk. The data were subjected to a twocompartment analysis. During the administration of neomycin, half-times of the cholesterol radioactivity decay curves were decreased in two patients and remained unchanged in two subjects.

Fresh feces from 25 patients were homogenized and incubated with labeled cholic or chenodeoxycholic acid. After 24 hours of incubation, the percent change to the 7a-dehydroxylated form was measured. In 11 patients, the oral administration of 2g of neomycin daily significantly reduced the levels of serum cholesterol (from an average of 316 mg/100 ml plasma to 237 mg/100 ml plasma) and markedly inhibited the extent of 7a-dehydroxylation of cholic acid (from 89% to 9%); in 2 patients whose serum cholesterol levels were not lowered, the degradation of cholic acid remained unchanged (control 93%, neomycin 91%). In 5 patients the administration of kanamycin reduced serum cholesterol levels (from 280 mg/100 ml plasma to 252 mg/100 ml plasma) and also inhibited 7a-dehydroxylation of cholic acid (from 92% to 21%); in 3 additional patients this drug failed to lower serum cholesterol concentrations and had no effect on bile acid degradation (control 91%, kanamycin 92%). Similar results were obtained with chloramphenicol in 3 patients, and equivocal results were obtained with chlortetracyeline in 3 patients. The correlation coefficient between undegraded cholic acid and percent decrease in serum cholesterol concentrations (r = 0.732) was statistically significant ( P < 0.001). It is proposed that serum cholesterol levels might be controlled in part by the prevalence of bile acid-degrading bacteria within the gastrointestinal tract.

A B S T R A C T In four patients with hypercholesterolemia (type II hyperlipoproteinemia) and xanthomatosis the decay of serum cholesterol specific activity was followed for 53-63 wk after pulse labeling. Specific activity of biopsied xanthoma cholesterol was measured four times in the course of the study. The xanthoma specific activity curve crossed and thereafter remained above the serum specific activity curve. The average ratio of xanthoma to serum specific activity was 4.7 at the end of the study. The final half-time of the xanthoma decay curves was significantly greater (average: 200 days) than the slowest half-time of serum specific activity decay (average: 93 days). The data were analyzed by input-output analysis and yielded the following results. The average value for the total input rate of body cholesterol (IT) (sum of dietary and biosynthesized cholesterol) was 1.29 g/day. The average size of the rapidly miscible pool of cholesterol (Ma) was 55.7 g, and of the total exchangeable body mass of cholesterol (M) 116.5 g. The average value of M -Ma (remaining exchangeable mass of cholesterol) was 60.8 g. The derived values for exchangeable masses of cholesterol, in the present patients with marked hypercholesterolemia, were significantly larger than in a group of patients with normal serum lipids in previous studies. One of the four patients died of a sudden acute myocardial infarction 53 wk after pulse labeling. Specific activity of aortic wall and atheroma cholesterol was 3.12 times that of serum. The ratio was close to 2 for adipose tissue and spleen, and was slightly above 1 or was close to unity in most other organs studied, with the exception of brain which showed a ratio of 0.19.

The effect and tolerance of long-term oral administration of small doses of neomycin as a serum cholesterol reducing agent has been investigated. Sixteen patients were given neomycin sulfate orally for periods varying from 12 to 40.1 months, following control periods of 2.6 to 14.6 months. After an initial daily dose of 2 g of neomycin, the daily dose was varied between 0.5 and 2 g according to response. Average total serum cholesterol concentrations decreased in each of the 16 patients by 15 to 32%; the average decrease for the group was 22%. The difference was statistically significant in each patient at the 0.1% level. Serum cholesterol concentrations were maintained at the lower plateau as long as the drug was given. In an additional patient, after administration of neomycin for 2 months there was no change in serum cholesterol concentrations and the study was discontinued. Another developed severe diarrhea, nausea, and abdominal cramps during the first week of the study, so that medication was interrupted. No other serious side effects occurred. During the first 2 weeks of medication eight of the 16 patients experienced mild diarrhea or abdominal cramps or both which subsided spontaneously during continued medication. Physical examinations were carried out, kidney and liver functions remained normal, and pathogens were not grown from stool cultures.