Nonlinear kinetics and pharmacologic response to mibefradil.

BACKGROUND: Increasing oral doses of mibefradil (10 to 320 mg) decrease its apparent oral clearance; however, intravenous doses up to 80 mg do not reduce its systemic clearance. This study aimed to understand the mechanisms underlying the zero-order kinetics of mibefradil. METHODS: A group of 10 normotensive volunteers received 50 mg/day oral mibefradil for 8 days and, on days 1 and 8, 5 mg deuterated mibefradil by infusion. Ten additional volunteers observed the same protocol with a daily oral dose of 100 mg mibefradil. Serial blood samples were withdrawn, and mibefradil plasma concentrations were assayed by liquid chromatography-mass spectrometry. Blood pressure and heart rate were measured for 4 hours, and an ECG was performed 2 hours after drug administration. RESULTS: Repeated oral administration of 50 mg mibefradil generated zero-order kinetics secondary to a decrease in mibefradil systemic clearance. Compared with the 50-mg dose, single and repeated oral doses of 100 mg further decreased mibefradil clearance. Mibefradil bioavailability was not affected by increasing mibefradil doses. Mean diastolic blood pressure was decreased by single and repeated doses of 100 mg to the same extent. Repeated doses of 100 mg reduced heart rate and prolonged the PR and QTc, changes that were associated with mibefradil plasma concentrations. CONCLUSIONS: Repeated doses of 50 mg or doses of 100 mg mibefradil generated zero-order kinetics secondary to a decrease in hepatic extraction of the drug. Zero-order kinetics did not affect the response-concentration relationship of mibefradil.

Input rate as a major determinant of furosemide pharmacodynamics: influence of fluid replacement and hypoalbuminemia.

To investigate how the response to a bolus and an infusion of furosemide is modulated by the rate of fluid replacement and by hypoalbuminemia, rabbits received 5 mg/kg of furosemide as a bolus or infused over 60 min, whereas diuresis was replaced with 13, 121, or 238 ml/h NaCl 0.9%/glucose 5% (50:50). Natriuretic and diuretic efficiencies were greater with the infusion than with the bolus of furosemide. Fluid replacement increased natriuretic and diuretic efficiency of furosemide bolus but only diuretic efficiency of furosemide infusion. Furosemide net fluid depletion reached a plateau when fluid replacement increased beyond 121 ml/h. Repeated plasmapheresis decreased plasma albumin by 30% (P <.05) and increased furosemide unbound fraction (P <.05). Compared with control rabbits, hypoalbuminemia decreased the natriuresis of the bolus (22.7 +/- 1.5-16.6 +/- 1.3 mmol, P <.05) but not that elicited by furosemide infusion (26.2 +/- 1.8 mmol). Given as a bolus, furosemide natriuretic and diuretic response as a function of its urinary rate of excretion exhibited an hyperbolic relationship, and after its infusion a clockwise hysteresis, denoting tolerance. Plasma renin activity was increased by the bolus and the infusion of furosemide, even in the presence of 121 ml/h of fluid replacement. It is concluded that: 1) the increase in natriuretic/diuretic efficiency of the bolus induced by fluid replacement is greater than when furosemide is infused, 2) furosemide net effect does not increase proportionally to fluid replacement, and 3) the infusion of furosemide prevents the hypoalbuminemia-induced decrease in response of furosemide given as a bolus.

Acute and chronic role of 5-HT3 neuronal system on behavioral and neuroendocrine changes induced by intravenous cholecystokinin tetrapeptide administration in humans.

The influence of single and multiple oral doses of ondansetron, a selective 5-HT3 receptor antagonist, was evaluated against placebo on cholecystokinin tetrapeptide (CCK-4)-induced behavioral and neuroendocrine changes in humans. As compared to placebo, subjects receiving acute ondansetron treatment showed a significant decrease in the sum intensity of CCK-4-induced-panic symptoms (iPSS). Pre-CCK-4 neuropeptide Y (NPY) plasma levels were significantly higher and maximal changes in cortisol, growth hormone, and prolactin secretion from baseline (delta max) were significantly lower in the ondansetron group. After ondansetron and placebo chronic administration, there were no statistical differences in the iPSS between groups. Pre-CCK-4 NPY plasma levels were significantly higher; whereas, delta max for NPY significantly lower in the ondansetron group as compared to placebo. These results suggest a role for the 5-HT3 receptor in the neurobiology of panic disorder through a possible interaction with CCK and NPY systems. Ondansetron chronic effect on CCK-4-induced behavioral changes needs further exploration.

Effect of oral ondansetron on total cholecystokinin plasma levels following CCK-4 panic challenge procedure in healthy men.

OBJECTIVE: To gain insight into whether ondansetron treatment induces changes in total cholecystokinin (CCKT) plasma levels before and after administration of the cholecystokinin tetrapeptide (CCK-4) panic challenge procedure in healthy men. METHODS: Thirty-eight volunteers received a 50-microgram bolus of CCK-4 60 minutes after a single oral dose (acute treatment) and multiple oral doses (chronic treatment) of ondansetron or placebo. RESULTS: Results showed no difference in CCKT plasma levels of CCKT elimination rate constant between the ondansetron and the placebo groups after either acute or chronic treatment. CONCLUSION: Results from this study suggest that total CCK plasma levels are not influenced by either acute or chronic treatment with ondansetron. However, the effect of ondansetron on the different CCK component fractions still needs exploration.

[A metastatic neuroendocrine tumor with exceptional outcome!]. / Une tumeur neuroendocrine métastatique d'évolution exceptionnelle!

INTRODUCTION: Neuroendocrine tumors are rare, with poor prognosis when not or poorly differentiated. EXEGESIS: The authors report the case of a patient who presented with a metastatic poorly differentiated neuroendocrine tumor that was resistant to chemotherapy. The different sites of the carcinoma were lung, pancreas, kidney and lymph nodes. The patient received no treatment and complete spontaneous remission appeared after 21 months. This remission has been lasting for five years. CONCLUSION: It is the first case of spontaneous remission of a metastatic poorly differentiated neuroendocrine tumor. The evolution and classical sites of neuroendocrine tumors are reviewed. Renal metastasis is also unusual. This report illustrates the fact that neuroendocrine tumors are heterogeneous.

Effect of Maalox on the oral absorption of sparfloxacin.

Sparfloxacin is a broad-spectrum oral fluoroquinolone antimicrobial agent with a long elimination half-life (t(1/2)). Concurrent treatment with antacids has demonstrated a reduction in the oral absorption of many quinolones. This study was undertaken to determine an optimal time for dosing antacids in relation to sparfloxacin administration to minimize antacid-induced reduction in sparfloxacin bioavailability. This open-label, single-dose, randomized, four-way crossover study was conducted in 20 healthy male volunteers between the ages of 18 and 38 years. Treatments consisted of single 400-mg oral doses of sparfloxacin alone and with Maalox 30 mL given 2 hours before, 2 hours after, and 4 hours after oral administration of sparfloxacin. All 20 subjects completed the study. A 400-mg single oral dose of sparfloxacin was well tolerated both given alone and with Maalox. Maalox given 4 hours after sparfloxacin administration was the only regimen that did not cause a statistically significant reduction in the rate and extent of sparfloxacin absorption. The 90% confidence intervals comparing sparfloxacin alone with the preceding regimen in terms of area under the concentration-time curve from zero to infinity (AUC(0-infinity)) and maximum plasma concentration (Cmax) were within the range 80% to 125%. Administration of Maalox 2 hours before, 2 hours after, and 4 hours after sparfloxacin caused mean decreases in AUC(0-infinity) of 23%, 17%, and 5%, respectively. Corresponding decreases in mean Cmax values were 29% with Maalox administered 2 hours before sparfloxacin and 13% with Maalox administered 2 hours after sparfloxacin. The mean Cmax value was un affected when Maalox was administered 4 hours after sparfloxacin administration. The 90% confidence intervals for these comparisons with sparfloxacin alone were outside the 80% to 125% range and did not include 100%. Time to Cmax and t(1/2) were similar for all four regimens. The elimination rate of sparfloxacin was unaffected by concomitant administration with Maalox in healthy male volunteers.

Plasma levels of nicotine and safety of smokers wearing transdermal delivery systems during multiple simultaneous intake of nicotine and during exercise.

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.

High-resolution liquid chromatographic method using ultraviolet detection for determination of ondansetron in human plasma.

This paper describes a simple technique for extraction and a sensitive high-performance liquid chromatographic method for separation and quantitation of ondansetron in human plasma. The procedure involved liquid-liquid extraction of ondansetron from plasma, reversed-phase HPLC separation and ultraviolet detection at 305 nm. The internal standard method was applied for quantitation. The recovery of ondansetron was >85%. Linearity was good throughout the concentration range anticipated in human plasma from investigations in panic disorder (0.5-15 ng/ml, r2 ranging from 0.9953 to 0.9988). This method was applied to the determination of plasma concentrations of ondansetron in humans.

Quantification of ketoprofen enantiomers in human plasma based on solid-phase extraction and enantioselective column chromatography.

An HPLC method for the quantification of ketoprofen enantiomers in human plasma is described. Following extraction with a disposable C18 solid-phase extraction column, separation of ketoprofen enantiomers and I.S. (3,4-dimethoxy benzoic acid) was achieved using a chiral column [Chirex 3005; (R)-1-naphthylglycine 3,5-dinitrobenzoic acid] with the mobile phase, 0.02 M ammonium acetate in methanol, set at a flow-rate of 1.2 ml/min. Baseline separation of ketoprofen enantiomers and I.S., free from interferences, was achieved in less than 20 min. The calibration curves (n = 14) were linear over the concentration range of 0.16 to 5.00 micrograms/ml per enantiomer [mean r2 of 0.999 for both enantiomers, root mean square error were 0.015 for R(-) and 0.013 for S(+)]. The inter-day coefficient of variation for duplicate analysis of spiked samples was less than 7% and the accuracy was more than 93% over the over the concentration range of 0.2 to 4.0 micrograms/ml for individual enantiomer using 1 ml of plasma sample. This method has been applied to a pharmacokinetic study from healthy human volunteers following the administration of a ketoprofen extended release product (200 mg). This method is simple, fast and should find wide application in monitoring pharmacokinetic studies of ketoprofen.

Organ-specific pattern of inhibition of diltiazem metabolism at steady state in rabbits.

Plasma levels of diltiazem, after its chronic administration, are usually higher than predicted. Because several organs contribute to diltiazem metabolism, this study aimed to determine the effect of an infusion of diltiazem to steady state on the ability of the intestine, liver and lungs to metabolize diltiazem and its metabolites N-desmethyldiltiazem (MA) and desacetyldiltiazem (M1). The kinetics of diltiazem were assessed after a single i.v. injection (2 mg/kg) and after an infusion (1.4 mg/kg/hr over 15 hr) of diltiazem. After serial blood sampling, the rabbits were sacrificed, and diltiazem, MA and M1 constant rates of metabolism (Kmet) were estimated in the 10,000 x g supernatants of the intestinal mucosa, liver and lungs. In vivo, the systemic clearance of infused diltiazem was lower than that estimated after i.v. injection of diltiazem, i.e., 54.4 +/- 2.4 vs. 70.3 +/- 5.8 ml/min/kg (P < .05). In vitro, diltiazem Kmet was reduced in liver homogenates from rabbits that had received the infusion of diltiazem, but not in the intestine or lungs. Moreover, the production of MA was reduced in liver homogenates and that of M1 in intestinal and lung homogenates. The Kmet of MA was not affected by the infusion of diltiazem in any tissue studied; however, the Kmet of M1 was reduced by the infusion in the three tissues tested. It is concluded that, in rabbits, long-term administration of diltiazem leads to an accumulation of diltiazem primarily because its N-demethylation is decreased in the liver, in addition, the demethylation of M1 is reduced in the small intestine, liver and lungs.

The influence of time of administration on the pharmacokinetics of a once-a-day diltiazem formulation: morning against bedtime.

Twenty-three young, healthy, male volunteers received, in a randomized crossover design, 240 mg of a once-a-day diltiazem formulation at 08:00 (AM) or 22:00 (HS) for 6 days. A 7 day washout period was observed between the two modes of administration. Diltiazem plasma concentrations were monitored every hour for 24 h and at 30, 36, and 48 h after the last dose. Differences were found between AM and HS dosing for Cmin (mean (SD) = 47 center dot 2 (25 center dot 8) against 39 center dot 6 (21 center dot 1) ng mL-1, p = 0 center dot 038), AUC0-24 (2008 (814) against 1754 (714) ng h mL-1, p = 0 center dot 024), and AUC0-48 (2662 (1244) against 2395 (238) ng h mL-1, p = 0 center dot 034). Overall the two modes of administration did not produce bioequivalent pharmacokinetic profiles. Also HS dosing gave significantly higher plasma concentrations of diltiazem in the early morning hours when the incidence of cardiovascular events is higher. If one assumes a strong correlation between plasma concentrations and myocardial protection then HS dosing should be recommended for QD formulation of diltiazem. Clinical studies should be performed to confirm this theoretical pharmacokinetic advantage.

First-pass metabolism of diltiazem in anesthetized rabbits: role of extrahepatic organs.

PURPOSE: The aim of this study was to assess in vivo which organs contribute to the first-pass metabolism of diltiazem. METHODS: Anaesthetized rabbits received diltiazem into the thoracic aorta (TA) ( 1mg/kg), jugular vein (JV) (2 mg/kg), portal vein (PV) (4 mg/kg) or small intestine (SI) (5 mg/kg). Serial blood samples were withdrawn from the abnormal aorta to assay diltiazem, N-demethyl-diltiazem (MA) and deacetyldiltiazem (M1). RESULTS: The area under diltiazem plasma concentration curve/time (AUC0-infinity) normalized by the dose was AUCTA approximately equal to AUCJV > AUCPV > AUCSI: Intestinal and hepatic diltiazem availability was 43 and 33%, respectively. The systemic availability of oral diltiazem was 12%. Diltiazem given into the SI and PV generated primarily MA, and injected into the JV and TA produced mainly M1. CONCLUSIONS: 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.

[X-ray computed tomographic diagnosis of primary cardiac malignant lymphoma in AIDS]. / Diagnostic tomodensitométrique d'un lymphome malin cardiaque primitif au cours du SIDA.

Primary lymphomas rarely affect the heart. The myocardial disease is usually latent and the diagnosis is based on post mortem observations. The cardiac symptoms do not reveal the disease and symptomatology is not specific. Our observation shows the complementarity of non invasive techniques, for a better screening of cardiac tumoral forms. Although echocardiography is the main examination, CT scan provides a detection of infiltrative forms and of extracardiac extension. Concurrently, MRI remains the method of choice to display beginning infiltrative forms, revealed by pericardial effusion in AIDS disease.

Lack of presystemic metabolism of nifedipine in the rabbit.

In humans, oral bioavailability of nifedipine has been reported to be around 60%, although the organ(s) contributing to its first-pass metabolism have not been determined. The aim of this study was to determine in vivo, in anesthetized and conscious rabbits the role of the intestine, liver, and lungs in the first-pass metabolism of nifedipine. To assess the extraction of nifedipine by the intestine, liver, and lungs, nifedipine was administered before and after each organ, and serial blood samples were withdrawn from an artery. In conscious rabbits, the systemic clearance of nifedipine injected into a lateral vein of an ear was 14.6 +/- 1.6 ml/min per kg, a value that was slightly decreased by anesthesia. In anesthetized rabbits, compared to the clearance estimated when nifedipine was administered into the thoracic aorta, the administration of nifedipine into a jugular vein, into the portal vein, or into the portal vein, or into the duodenum did not increase the value of the systemic clearance. In conscious rabbits, the clearance of nifedipine estimated when the drug was administered into the duodenum, the peritoneum, the portal vein, or into the jugular vein was identical to the clearance calculated when the drug was injected into the thoracic aorta. In vitro, nifedipine was metabolized in liver and intestinal epithelial cells homogenates but not in lungs or kidneys. We concluded that in the rabbit, oral nifedipine is not subjected to a first-pass metabolism, even though the intestine and the liver may contribute to nifedipine systemic clearance.

Safety, tolerability, and pharmacokinetic actions of diltiazem in pediatric liver transplant recipients on cyclosporine.

Thirty-two children who had undergone liver transplantation were paired according to their posttransplantation duration, renal function, and diagnoses when possible and randomized either to continue nifedipine (NIF group) or switch to diltiazem (DIL group), in addition to continuing their usual immunosuppressive medications. The cases were followed prospectively regarding diltiazem tolerance, cyclosporine dose requirements, effect on cyclosporine kinetics, diltiazem kinetics, as well as effect on renal function. Diltiazem was well tolerated at a dose of 3 mg to 6.4 mg/kg/day (max 180 mg/day) with infrequent self-limited mild side effects. Cyclosporine daily dose was reduced by a mean of 36.7% and 38.3% at 3 and 6 months, respectively, in the DIL group to achieve target trough cyclosporine levels without modifying liver function. No significant difference in renal function was observed after 3 to 6 months in either group based on blood urea nitrogen and creatinine levels and glomerular filtration rate by the DTPA method. Diltiazem appears to be well tolerated in children and allows for substantial dose reductions of CSA without apparent effects on liver graft function.

The site of absorption in the small intestine determines diltiazem bioavailability in the rabbit.

PURPOSE: Since the ability of the small intestine to biotransform a drug may decrease in distal segments of the intestine, this study aimed to assess whether the site of administration in the small intestine could affect the systemic bioavailability of diltiazem and its two active metabolites, N-desmethyldiltiazem (MA) and desacetyl-diltiazem (M1). METHODS: Five mg/kg of diltiazem were administered into the lumen of the proximal (0-30 cm, n = 9) or the distal (150-180 cm) small intestine (n = 7) of anesthetized New Zealand rabbits. Blood samples were drawn from the femoral artery for 6 hours, and diltiazem, MA and M1 were assayed by HPLC. RESULTS: The area under the curve (AUC0-->infinity) of diltiazem administered into the distal small intestine was larger than that estimated when diltiazem was given in the proximal segment (14.20 +/- 2.82 vs 8.14 +/- 0.88 micrograms.min/ml, p < 0.05), due to a lower diltiazem oral clearance (440 +/- 78 vs 660 +/- 55 ml/min/kg, p < 0.05). The AUC0-->360 of MA was not affected by the site of diltiazem administration, but the AUC0-->360 of M1 was increased when diltiazem was administered in the distal segment of the small intestine. When administered into the distal segment of the intestine, the molar sum of diltiazem and its active metabolites was 48% greater than when delivered into the 0-30 cm segment of the small intestine; as a consequence, absorption of diltiazem in distal segments of the small intestine may enhance its pharmacological response. CONCLUSIONS: The site of absorption into the intestine modulates the bioavailability of diltiazem and its two active metabolites.

Stereospecific high-performance liquid chromatographic assay of ketoprofen in human plasma and urine.

A high-performance liquid chromatographic (HPLC) assay suitable for the analysis of the enantiomers of ketoprofen (KT), a 2-arylpropionic acid (2-APA) non-steroidal antiinflammatory drug (NSAID), in plasma and urine was developed. Following the addition of racemic fenoprofen as internal standard (I.S.), plasma containing the KT enantiomers and I.S. was extracted by liquid-liquid extraction at an acidic pH. After evaporation of the organic layer, the drug and I.S. were reconstituted in mobile phase and injected into the HPLC system. The enantiomers were separated at ambient temperature on a commercially available 250 x 4.6 mm amylose carbamate-packed chiral column (Chiralpak AD) column with hexane-isopropyl alcohol-trifluoroacetic acid (80:19.9:0.1, v/v/v) as the mobile phase pumped at 1.0 ml/min. The enantiomers of KT were quantified by ultraviolet detection with the wavelength set at 254 nm. The assay described allows for the direct quantitation of KT enantiomers without pre-column derivatization, and is suitable for clinical studies of KT enantiomers in human plasma and urine after administration of therapeutic doses.

Metabolism of diltiazem in hepatic and extrahepatic tissues of rabbits: in vitro studies.

Diltiazem (DTZ) is a calcium channel blocker widely used in the treatment of angina and hypertension. DTZ undergoes extensive metabolism yielding several metabolites, some of which are active like N-desmethyldiltiazem (MA), desacetyldiltiazem (M1) and N-desmethyl,desacetyldiltiazem (M2). Due to the nature of its biotransformation, several organs should have the ability to metabolize DTZ, however it is still assumed that the liver is the only organ implicated in its elimination. In this study, the fate of DTZ, MA and M1 was assessed in several organs that could contribute to their biotransformation. To this purpose, DTZ (48.2 microM) was incubated in the 10,000 x g supernatant of homogenates of rabbit tissues for 60 min at 37 degrees C. Multiple samples were withdrawn, and DTZ and its metabolites were assayed by HPLC. The elimination rate constant of DTZ in 10,000 x g supernatants varied between the organs: liver 334 +/- 45, proximal small intestine 69 +/- 11, distal small intestine 25 +/- 3, lungs 15 +/- 6 and kidneys 8 +/- 6 (10(-4) min-1). The metabolism of DTZ in the liver generated large amounts of MA but no M1, and in the small intestine, modest amounts of both metabolites. When MA (50.0 microM) or M1 (53.7 microM) were incubated in liver homogenates, the estimated elimination rate constant were 166 +/- 23 and 468 +/- 53 (10(-4) min-1), respectively. The rate of degradation of the metabolites in the small intestine was much slower.(ABSTRACT TRUNCATED AT 250 WORDS)