Studies were conducted in healthy male volunteers (n = 171; age range, 19-49 years; 22-27 subjects per study) to examine the following: pharmacokinetics and dose proportionality of the antihistamine clemastine; the effect of coadministration of phenylpropanolamine and clemastine on the pharmacokinetics of the two drugs; and the bioavailability of clemastine tablets and combination tablets of clemastine and sustained-release phenyl-propanolamine under fasted and fed conditions after single-dose administration and at steady state. All studies used crossover designs, with randomized drug treatments separated by a 7-day washout period for the single-dose studies, and with administration every 6 or 12 hours for 7 days per treatment for the steady-state studies. After single oral doses of clemastine solution (1,2, and 4 mg), the area under the concentration-time curve (AUC) and maximum concentration (Cmax) were dose proportional. Clemastine showed a first-pass reduction in the extent of absorption, with oral bioavailability calculated as 39.2 +/- 12.4%. Extravascular distribution of drug was suggested by the high volume of distribution (799 +/- 315 L) and low Cmax (0.577 +/- 0.252 ng/mL/mg) observed at 4.77 +/- 2.26 hours after administration, and by the biphasic decline in plasma concentration. The terminal elimination half-life (t1/2) of clemastine was 21.3 +/- 11.6 hours. Steady-state concentrations of clemastine were consistent with linear pharmacokinetic processes, and clearance was unaffected by age in the range studied, or by race. Clemastine solution and tablets were bioequivalent, and food had no significant effect on rate and extent of absorption of clemastine. The 1- and 2-mg clemastine tablets showed proportional bioavailability. Coadministration of clemastine with phenylpropanolamine did not significantly influence the pharmacokinetics of clemastine or the AUC and elimination t1/2 of phenylpropanolamine, but reduced the rate of absorption of phenylpropanolamine. Combination tablets containing 1 mg or 2 mg of immediate-release clemastine plus 75 mg of sustained-release phenylpropanolamine for twice daily administration were bioequivalent to the separate components and showed no significant interaction with food.
M.B.G. wishes to express his thanks for support in the form of a Stauffer Fellowship awarded by the chemistry department. Work was also supported by a grant from the Graduate School, University of
An instrument, which incorporates a lock-in amplifier based on a digital phase sensitive detector, has been designed and constructed for ac electrochemical measurements of solutions containing low concentrations of analyte. The performance of the lock-in amplifier was characterized experimentally. Phase angle resolution is better than 0.01", and signal capture ratios up to about 80,000 can be attained. An up/down counter replaces the multiplier of the typical analog phase-sensitive detector. Provision was made to sum the net count over a preselected number of cycles of the reference signal to improve the sensitivity and signal-to-noise ratio of the phase-sensitive detector. The lock-in amplifier output can be read on a recorder via a digital-to-analog converter or sent to a computer. Overall instrument performance is demonstrated using ac amperometry at a carbon paste electrode and flow injection techniques to determine o-dianisidine. Peak currents corresponding to a solution concentration of 6 nM in the detector were successfully measured.
MRODUCTIONThe advantages of phase-sensitive detection in the determination of the faradaic current by alternating current electrochemical techniques are well known. The lock-in amplifier discriminates against charging current because the output of its phase-sensitive detector (PSD) is proportional to the cosine of the phase angle between the measured current and the applied signal. In the case of charging current, the phase angle is 90" and the cosine function is zero. The ability to reject the quadrature component is often of little interest in spectroscopic applications of the lock-in amplifier, but it is critical in electroanalytical applications. The importance of quadrature signal rejection places unusual demands on some features of the lock-in amplifier, particularly when measurements are made on very dilute solutions of the sought constituent. For example, since the charging current is not usually dependent on the concentration of analyte while the faradaic current is, the ratio of faradaic current to charging current can be on the order of 0.00001 as nanomolar concentrations are approached. If considers this as the signal-to-noise ratio, it is indeed small.Under these circumstances, two key features of the lock-in amplifier are the phase angle resolution and the signal capture ratio. The former is important because the faradaic component of the current vector is so small relative to the charging current component, and the latter is a measure of the ability of the device to extract signal from noise. Both of these characteristics relate to the quality of the PSD. The major operations carried out by the PSD are multiplication followed by low-pass filtering. A choice of analog or digital implementation is available.In this work, we have elected to use digital implementation of the PSD because of the better resolution this offers over analog circuits. A choice then has to be made between software or hardware approaches. Software implementation has been demonstrat...
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