Although transdermal nicotine patches have been studied extensively under recommended conditions, the present studies were designed to assess the nicotine plasma levels and the safety of transdermal nicotine patches in smokers undergoing situations suspected to result in increased nicotine plasma levels. The first study examined the effects of increasing nicotine intake through sequential administration of a nicotine patch (day 2), a patch followed by consumption of nicotine gum (day 3), and a patch followed by gum consumption and cigarette smoking (day 4). In this study, nicotine plasma levels increased transiently after the addition of each nicotine source. Mean areas under the concentration-time curves from 0 to 24 hours (AUC0-24) for nicotine were 453 +/- 120 ng.hr/mL (day 2), 489 +/- 143 ng.hr/mL (day 3), and 485 +/- 143 ng.hr/mL (day 4). The second study evaluated the effects of physical exercise on the kinetics and the safety of two different types of nicotine transdermal devices: Nicoderm and Habitrol. The mean delivered dose of nicotine was higher with Nicoderm compared with Habitrol, and the two products were not considered to be bioequivalent. During a 20-minute exercise period, nicotine plasma levels increased by 13 +/- 9% for Nicoderm and 30 +/- 20% for Habitrol. This increase in nicotine plasma levels was probably related to the exercise-induced increase in peripheral circulation at the patch site. Results from both studies indicate a clinically nonsignificant increase in blood pressure and heart rate after the administration of nicotine. After exercise, subjects taking Habitrol tended to have a higher incidence of adverse events compared with baseline values. Safety profiles remained acceptable in both studies despite the increases in nicotine plasma levels. It was concluded that both superimposed nicotine sources and physical exertion result in short-lived plasma nicotine elevations and temporarily increase nicotine pharmacodynamic parameters without increased risk to the volunteers.

In the present study we investigated the relationship between pharmacodynamic and pharmacokinetic properties of the benzothiazepine-like calcium antagonists, clentiazem and diltiazem. Experiments were carried out in closed-chest anesthetized dogs, instrumented for hemodynamic recording and blood sampling. Clentiazem and diltiazem bolus injections (400 micrograms/kg) were administered intravenously, and subgroups of animals were sacrificed at 15, 30, 60, or 120 minutes Clentiazem and diltiazem plasma and myocardial levels were determined by high performance liquid chromatography (HPLC). Clentiazem elicited a more marked reduction in mean arterial pressure (-17% for clentiazem vs. -12% for diltiazem), along with an attenuation of the expected positive reflex chronotropic response. Pharmacokinetic analysis revealed that clentiazem had a greater volume of distribution (33 +/- 16 l vs. 15 +/- 9 l for diltiazem), while the half-life of elimination (t1/2 beta) was similar (55 +/- 21 minutes vs. 59 +/- 23 minutes). The kinetic disposition profile of both drugs was analyzed through myocardial/plasma concentration ratios. In the distribution phase (0-15 minutes), this ratio was similar (26 +/- 2 for clentiazem vs. 18 +/- 5 diltiazem), suggesting that the myocardium was not a preferential site of distribution for either drugs. Data collected within the elimination phase indicate significant myocardial retention for clentiazem; at the end of the study period, the myocardial/plasma concentration ratio was twofold higher for clentiazem. The observed retention of clentiazem in the myocardium may be responsible for attenuation of the baroreflex. Clentiazem increased potency was confirmed by the fact that its hypotensive and cardioinhibitory effects were observed at lower plasma concentrations.

The aim of this study was to investigate the effects of an infusion of angiotensin II (50 ng/kg/min) on furosemide pharmacodynamics and kinetics in the conscious rabbit. The protocol included a 90-minute phase to estimate the glomerular filtration rate and the renal plasma flow, followed by a 60-minute phase where 5 mg/kg (n = 12) or 10 mg/kg (n = 9) of furosemide were administered. During the pre-furosemide phase, compared to control rabbits, angiotensin II increased natriuresis and diuresis. In the presence of angiotensin II, the furosemide-induced natriuresis decreased, that is, it was 174 +/- 14 versus 95 +/- 25 mumol/min (p < 0.05) and 187 +/- 17 versus 89 +/- 21 mumol/min (p < 0.05) for the 5 and the 10 mg/kg doses, respectively. The infusion of angiotensin II decreased renal plasma flow without modifying the glomerular filtration rate, thus the filtration fraction was increased. Angiotensin II increased the area under the furosemide plasma concentrations as a function of time since it decreased its systemic clearance. However, furosemide urinary excretion rate was not altered and its renal clearance decreased slightly without reaching statistical significance. It is concluded that angiotensin II decreases the response to furosemide and the mechanism underlying this effect is related to the pharmacodynamics rather than the kinetics of the diuretic.

The site of absorption into the intestine modulates the bioavailability of diltiazem and its two active metabolites.

In rabbits, the intestine and the liver contribute to the first-pass metabolism of diltiazem, and the amount and species of metabolites generated depend upon the route of administration of diltiazem.