The Application of Half-Life in Clinical Decision Making: Comparison of the Pharmacokinetics of Extended-Release Topiramate (USL255) and Immediate-Release Topiramate

Objective: For extended-release drugs with multi-compartment kinetics, such as topiramate, effective half-life (t1/2eff) may be a more clinically relevant parameter than elimination half-life (t1/2z). Using topiramate as a real-life example, the objective was to compare these half-life values for immediate- and extended-release topiramate (TPM-IR and USL255, respectively) to understand how drug pharmacokinetics may impact drug dosing recommendations. Methods: The t1/2z and t1/2eff for USL255 and TPM-IR were compared using data from a phase I study (N = 36) of 200 mg USL255 administered once daily (QD) or TPM-IR twice daily (BID); effect of sampling duration on t1/2z was investigated. To further explore the relationship between half-life and dosing, steady-state PK was simulated for USL255 and TPM-IR. Results: As previously reported, mean t1/2z was similar between USL255 (80.2 h) and TPM-IR (82.8 h); TPM-IR t1/2z was ∼4 times longer than reported in the Topamax label (21 h). In contrast, USL255 displayed a 1.5 fold longer t1/2eff (55.7 vs 37.1 h for TPM-IR). When t1/2z was calculated from 48 to 336 h, values ranged from 28.8 to 82.8 h. Simulated steady-state PK profiles of USL255 QD exhibited reduced plasma fluctuations during a dosing interval vs TPM-IR QD or BID. Significance: As expected for the same moiety, t1/2z of USL255 and TPM-IR were similar; however, the longer t1/2eff for USL255 better approximates differences in recommend dosing (QD USL255 vs BID TPM-IR). Further, sampling duration impacted t1/2z, diminishing its predictive value for determining dose regimens; sampling-time differences may also explain t1/2z discrepancy between TPM-IR here versus Topamax label. As expected, steady-state simulations confirm that although TPM-IR has a long t1/2z, taking TPM-IR QD would lead to large plasma fluctuations. These data demonstrate that t1/2z may be less clinically meaningful than t1/2eff, and using t1/2z for some drugs may lead to erroneous conclusions regarding dosing regimens

Multipole Amplitudes of Pion Photoproduction on Nucleons up to 2GeV within Dispersion Relations and Unitary Isobar Model

Two approaches for analysis of pion photo- and electroproduction on nucleons in the resonance energy region are checked at $Q^2=0$ using the results of GWU(VPI) partial-wave analysis of photoproduction data. The approaches are based on dispersion relations and unitary isobar model. Within dispersion relations good description of photoproduction multipoles is obtained up to $W=1.8 GeV$. Within unitary isobar model, modified with increasing energy by incorporation of Regge poles, and with unified Breit-Wigner parametrization of resonance contributions, good description of photoproduction multipoles is obtained up to $W=2 GeV$.Comment: 23 pages, LaTe

Measurement of the Alpha Asymmetry Parameter for the Omega- to Lambda K- Decay

We have measured the alpha parameter of the Omega- to Lambda K- decay using data collected with the HyperCP spectrometer during the 1997 fixed-target run at Fermilab. Analyzing a sample of 0.96 million Omega- to Lambda K^-, Lambda to p pi- decays, we obtain alpha_Omega*alpha_Lambda = [1.33+/-0.33(stat)+/-0.52(syst)] x 10^{-2}. With the accepted value of alpha_Lambda, alpha_Omega is found to be [2.07+/-0.51(stat)+/-0.81(syst)] x 10^{-2}.Comment: 5 pages, 4 figures, to be appeared as a Rapid Communication in Phys. Rev.

Evidence for the Decay Sigma+ -> p mu+ mu-

We report the first evidence for the decay Sigma+ -> p mu+ mu- from data taken by the HyperCP experiment(E871) at Fermilab. Based on three observed events, the branching ratio is B(Sigma+ -> p,mu+,mu-) = [8.6 +6.6,-5.4(stat) +/-5.5(syst)] x 10**-8. The narrow range of dimuon masses may indicate that the decay proceeds via a neutral intermediate state, Sigma+ -> p P0, P0 -> mu+ mu-, with a P0 mass of 214.3 +/- 0.5 MeV/c**2 and branching ratio B(Sigma+ -> p P0; P0 -> mu+ mu-) = [3.1 +2.4,-1.(stat) +/-1.5(syst)] x 10**-8.Comment: As published in PR

Search for the Lepton-Number-Violating Decay Ξ−→pμ−μ−\Xi^- \to p \mu^- \mu^-

A sensitive search for the lepton-number-violating decay $\Xi^-\to p \mu^-\mu^-$ has been performed using a sample of $\sim10^9$ $\Xi^-$ hyperons produced in 800 GeV/$c$ $p$-Cu collisions. We obtain $\mathcal{B}(\Xi^-\to p \mu^-\mu^-)< 4.0\times 10^{-8}$ at 90% confidence, improving on the best previous limit by four orders of magnitude.Comment: 9 pages, 5 figures, to be published in Phys. Rev. Let

Observation of Parity Violation in the Omega-minus -> Lambda + K-minus Decay

The alpha decay parameter in the process Omega-minus -> Lambda + K-minus has been measured from a sample of 4.50 million unpolarized Omega-minus decays recorded by the HyperCP (E871) experiment at Fermilab and found to be [1.78 +/- 0.19(stat) +/- 0.16(syst)]{\times}10^{-2}. This is the first unambiguous evidence for a nonzero alpha decay parameter, and hence parity violation, in the Omega-minus -> Lambda + K-minus decay.Comment: 10 pages, 7 figure

Search for flavor-changing neutral currents and lepton-family-number violation in two-body D0 decays

Results of a search for the three neutral charm decays, D0 -> mu e, D0 -> mu mu, and D0 -> e e, are presented. This study was based on data collected in Experiment 789 at the Fermi National Accelerator Laboratory using 800 GeV/c proton-Au and proton-Be interactions. No evidence is found for any of the decays. Upper limits on the branching ratios, at the 90% confidence level, are obtained.Comment: 28 pages, 18 figures. Submitted to Physical Review

HyperCP: A high-rate spectrometer for the study of charged hyperon and kaon decays

The HyperCP experiment (Fermilab E871) was designed to search for rare phenomena in the decays of charged strange particles, in particular CP violation in $\Xi$ and $\Lambda$ hyperon decays with a sensitivity of $10^{-4}$. Intense charged secondary beams were produced by 800 GeV/c protons and momentum-selected by a magnetic channel. Decay products were detected in a large-acceptance, high-rate magnetic spectrometer using multiwire proportional chambers, trigger hodoscopes, a hadronic calorimeter, and a muon-detection system. Nearly identical acceptances and efficiencies for hyperons and antihyperons decaying within an evacuated volume were achieved by reversing the polarities of the channel and spectrometer magnets. A high-rate data-acquisition system enabled 231 billion events to be recorded in twelve months of data-taking.Comment: 107 pages, 45 Postscript figures, 14 tables, Elsevier LaTeX, submitted to Nucl. Instrum. Meth.