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The longitudinal dynamics of a stored proton beam bunch, acted upon by a nonlinear damping force, was studied experimentally at the Indiana University Cyclotron Facility Cooler Ring. The effect of the nonlinear damping force on synchrotron motion was explored by varying the relative velocity between the cooling electron and the stored proton beams, Maintained longitudinal oscillations were observed, whose amplitude grew rapidly once a critical threshold in the relative velocity between the proton and electron beams was exceeded. We attribute this phenomenon to a negative resistance instability occurring after a Hopf bifurcation.

Objectives To evaluate the effect of CYP3A5 genotype on the extent of CYP3A inhibition by verapamil (VER) and to examine the effect of VER on intestinal and hepatic CYP3A activity in vivo. Methods Healthy subjects were prescreened for the CYP3A5 genotypes and participated the study at the GCRC. MDZ was given i.v. (0.05 mg/kg over 30 min) and orally (4 mg) on consecutive days before and after a 7‐day regimen of VER (SR, 240 mg qd). CYP3A5 genotypes were determined by the real‐time PCR. Blood MDZ concentrations were determined by LC/MS. Results 18 subjects (4 CYP3A*1*1, 6 CYP3A*1*3 and 8 CYP3A**3) completed the study. The oral clearance (CLpo) of MDZ was decreased from 93.6±67.7 L/hr to 26.7±17.1 L/hr (p=0.03) and the systemic clearance (CLiv) was decreased from 24.4±9.1 L/hr to 16.8±10.3 L/hr (p=0.02) after VER treatment. The oral availability (F) (0.3±0.1 to 0.7±0.3, p=0.0002), hepatic F (0.7±0.1 to 0.8±0.1, p=0.02) and intestinal F (0.4±0.1 to 0.8±0.3, p=0.0002) were also significantly increased. There was a significant correlation between intestinal and oral F. Fold decreases in CLiv (1.9±0.5 vs 1.4±0.2, p=0.04) and CLpo (4.2±0.9 vs 3.1±1.1, p=0.049) were significantly greater in CYP3A*3 homozygous compared to CYP3A*1 carriers. No genotype‐phenotype associations were found in basal and inhibited CLiv and CLpo. Conclusions These data indicate that the intestine is the major site of the interaction between MDZ and VER. The extent of interaction was less in individuals with at least one CYP3A*1 allele. Clinical Pharmacology & Therapeutics (2005) 77, P3–P3; doi:

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