Inhibiting cholesterol absorption with CP-88,818 (beta-tigogenin cellobioside; tiqueside): studies in normal and hyperlipidemic subjects.

CP-88,818 (beta-tigogenin cellobioside; tiqueside) is a synthetic saponin developed to treat hypercholesterolemia by inhibiting the absorption of biliary and dietary cholesterol. Two studies are reported here: one in patients to assess safety and efficacy, and one in normal volunteers to explore the mechanism of action. The former included 15 hypercholesterolemic outpatients [low-density lipoprotein cholesterol (LDL-C) > or = 160 mg/dl] treated with 1, 2, and 3 g of tiqueside daily (b.i.d.) in a crossover design for three 2-week treatment periods, each separated by a 3-week placebo period. The mechanistic study was conducted with 24 healthy male subjects who were randomized in a parallel group design to either placebo (n = 6) or tiqueside (2 or 4 g/day; n = 9 each) once daily for 3 weeks. All subjects in this study were fed a low-fat, low-cholesterol diet [National Cholesterol Education Program (NCEP) Step 1]. Fecal steroid excretion rates and plasma lipid levels were determined at baseline and after 3 weeks of treatment. Fractional cholesterol absorption was measured before and after treatment by the continuous feeding, dual-isotope method. Tiqueside produced a dose-dependent reduction in plasma LDL cholesterol levels in the hypercholesterolemic patients. In the mechanistic study, it decreased fractional cholesterol absorption rates and increased fecal neutral sterol excretion rates, changes associated with trends toward lower LDL cholesterol levels. Other lipoprotein levels were unaffected, as were fecal fat and bile acid excretion and fat-soluble vitamin absorption. Thus tiqueside dose-dependently inhibits cholesterol absorption in humans, resulting in a reduction in serum LDL cholesterol levels.

Inhibition of cholesterol absorption with CP-148,623 lowers serum cholesterol in humans.

OBJECTIVE: To determine the effects of the reduction of intestinal cholesterol absorption with CP-148,623 on serum cholesterol levels in men with mild hyperlipidemia. METHODS: In an outpatient study in a university medical center, healthy male volunteers (n = 25) with borderline-high serum cholesterol levels participated in a double-blind, placebo-controlled parallel-group study. A 3-week dietary run-in period was followed by 2 weeks of treatment with either CP-148,623 (300 mg twice a day; n = 12) or placebo (n = 13). RESULTS: Fractional cholesterol absorption (by the dual-isotope, continuous-feeding technique), fecal neutral sterol excretion, and serum lipids were measured after the diet run-in and after the treatment periods. CP-148,623 caused a marked inhibition (by 38%) of fractional cholesterol absorption (50% +/- 2% [baseline] to 31% +/- 1%) and a 71% increase in fecal neutral sterol excretion (481 +/- 39 mg/day [baseline] to 804 +/- 55 mg/day), compared with negligible changes in the placebo group (p < 0.0001 for both). Mean percent reductions from baseline in serum low-density lipoprotein (LDL) cholesterol levels were 11.6% with CP-148,623 (119 +/- 17 mg/dl to 104 +/- 13 mg/dl) versus a nonsignificant 1.8% reduction with placebo (change with CP-148,623 versus placebo, p < 0.0002). CONCLUSIONS: In healthy male volunteers with mild hypercholesterolemia, treatment for 2 weeks with 600 mg/day CP-148,623 inhibited fractional cholesterol absorption by 35% to 40%, increased fecal neutral sterol excretion by 60% to 70%, and reduced serum LDL cholesterol by 10% to 12%.

Spiked! A cross-country injury.

In this new series, GPs with a special interest in a particular sport describe the practical management of a typical injury. Frank Newton begins with the spiking injury seen in cross-country running.

Maintenance and generalization of 40-Hz EEG biofeedback effects.

Maintenance of conditioning of 40-Hz EEG activity was investigated in six adults 1 to 3 years after they had experienced biofeedback training to increase 40-Hz EEG. Subjects were first retrained to alternately increase and suppress 40-Hz EEG. All six subjects achieved a preset performance criterion in 16-20 minutes. Five of these subjects also subsequently demonstrated significant control of 40-Hz EEG without feedback. The sixth subject did not demonstrate control after 76 minutes and four sessions of attempted retraining with feedback. Transfer of 40-Hz EEG control to a problem-solving task was tested in all subjects in a final session. Cognitive test items were presented and subjects were instructed to alternately increase and suppress 40-Hz EEG while solving the problems. Rates of 40-Hz EEG in suppression periods during problem solving wer significantly greater than during suppression periods without problems. No significant differences in problem-solving performance were found comparing 40-Hz increase and suppression periods. This study supports previous research suggesting an association between 40-Hz EEG and mental activity, and suggests methods for further study of transfer of EEG biofeedback effects.

Biofeedback training of 40-Hz EEG in humans.

This study was a preliminary evaluation of biofeedback training of human subjects to control high-frequency EEG responses in the 35- to 45-Hz (40-Hz) and 21- to 31-Hz ranges. A total of 22 adult males divided into three groups were successfully trained for increases or suppression of 40-Hz EEG, or increases of 21- to 31-Hz EEG. Dissociation of rates of 40-Hz EEG recorded from scalp leads and 40-Hz EMG responses from prominent muscle contaminators, and partial dissociation of 40-Hz and 21- to 31-Hz EEG responses were noted. After biofeedback training, 8 subjects demonstrated increase and suppression of 40-Hz EEG without feedback. No consistent descriptors of subjective experiences accompanying EEG changes were reported by subjects in any of the groups. The study suggests the utility of biofeedback procedures in research on high-frequency EEG activity.

Behavioral and electroencephalographic correlates of 40-Hz EEG biofeedback training in humans.

Two groups of eight adults successfully trained with biofeedback for increases in 40-Hz EEG responses in left or right hemispheres also demonstrated significant 40-Hz EEG increases during baseline periods, and increases in the contralateral hemisphere during training periods. No changes in heart rate, 40-Hz EMG, or 21- or 31-Hz beta, alpha, or theta EEG occurred over training days. Three subjects returning for additional training demonstrated suppression of 40-Hz EEG. A group of four subjects experiencing daily bidirectional training produced substantial within-session control of 40-Hz EEG but no changes over days. Data from posttraining tests without feedback for successful subjects in both groups indicated significant control of 40-Hz EEG responses in the initial parts of these sessions, and some correlated changes in other EEG responses. Measures of successful subjects' experiences during training and control tests indicated awareness of changes in subjective concomitants of EEG responses. This study suggests further strategies for research on behavioral correlates of EEG activity.