Neurophysiological studies of L-acetylcarnitine administration in man

Systemic administration of L-acetylcarnitine HCl (LAC) increases in human subjects the amplitude of visual evoked potentials (VEPs) obtained with patterned elements of 7.5 min of visual angle, of steady-state VEPs obtained with intermittent luminous stimulation, of EEG theta, alpha and beta bands. The latency of the "cognitive" P300 potential obtained with an auditory "oddball" paradigm was also reduced by LAC injection, while the amplitude of this potential was increased. These results were obtained in control volunteers and in patients affected by different forms of dementias. The modifications induced by LAC appear 10-15 min after the i.v. injection and last for 50-90 min. These results parallel previously described findings of animal experiments and suggest an effect of LAC on cholinergic neurotransmission.     

Naltrexone disposition in man after subcutaneous administration

The metabolism, excretion, and pharmacokinetics of [15,16-3H2]naltrexone were studied in six human males after sc administration of the hydrochloride salt. Biological fluids were analyzed by a combination of high performance liquid chromatography with liquid scintillation measurement of radioactivity. After administration, naltrexone was rapidly absorbed into the systemic circulation. The mean absorption rate constant was 0.091 +/- 0.008 min-1 (half-life of 7.6 min). In general the metabolic, excretory, and pharmacokinetic patterns for naltrexone were similar to those observed after iv administration of naltrexone to man. The terminal phase plasma rate constant was 0.413 +/- 0.035 hr-1 (half-life of 1.68 hr) for parent drug and 0.0786 +/- 0.0090 hr-1 (half-life of 8.8 hr) for the major metabolite, 6 beta-naltrexone. An average of 76 +/- 6% (+/- SD) of the total radioactivity was recovered in the urine within 72 hr after administration. Naltrexone was found in the urine in both the free (3.4 +/- 0.8% of dose) and conjugated (6.8 +/- 2.1% of dose) form. 6 beta-Naltrexol was present in urine largely in the unconjugated form (28 +/- 7% of dose) but the conjugated form was also found (12 +/- 3% of dose).     

Chronopharmacokinetic and bioequivalence studies of two formulations of trimipramine after oral administration in man

The bioavailability of two oral formulations of trimipramine, tablets and solution, was performed in twelve healthy volunteers, in a cross-over study. Each formulation was administered in the morning after a fasted period, and in the evening after a meal, in order to evaluate the role of both administration time and food consumption on the plasma kinetic parameters, under usual therapeutic conditions. A high interindividual variability of data was found. First, the extent of bioavailability was identical for the two formulations but the rate of bioavailability seemed to be different, with the p.o. solution, being more rapidly absorbed (tmax = 1.50 h). The effect of administration time was more obvious for the solution as shown by a lower quantitative absorption as well as a delay in time to reach the maximal concentration. Regardless of formulation and administration time, the t1/2 beta was about 10 hours and the mean MRT value was 11 hours.     

Pharmacokinetics of morphine after epidural administration in man

The concentration of morphine and morphine glucuronide in serum after epidural injection of 9 patients with aortic abdominal surgery was measured using gas chromatography-mass fragmentography. The decline of morphine serum concentration after epidural administration of 0.1 mg/kg was described by a bi- or triexponential decay equation with a mean terminal half-life (t1/2) of 134.7 +/- 107.9 min. Pharmacokinetic parameters were calculated from the fit parameters mean values for clearance and apparent volume of distribution were 1.16 +/- 0.65 l/min, and 156.6 +/- 107.3 l, respectively, for free morphine and 0.19 +/- 0.09 l/min and 37.2 +/- 17.7 l, respectively, for morphine glucuronide. Peak concentration of morphine 79 +/- 19 ng/ml was reached within 10 min after administration. Haemodynamic values, ECG, end-expiratory CO2 concentration, temperature, acid-base status, hemoglobin, Na+, K+, total Ca++, lactate, glucose concentration in the blood and the urine were registered before, during and after the operation.     

Pharmacokinetics of bretylium in man after intravenous administration

The pharmacokinetic profile of bretylium was studied in four normal male volunteers using a new sensitive EC-GC procedure for its quantitation in biological fluids. The plasma concentrations and urinary excretion rates following the constant i.v. infusion of a single 4mg/kg dose of bretylium tosylate declined biexponentially and the data were fitted to a two-compartment model with a renal and a nonrenal route of elimination. The drug had a mean half-life (t_1/2)of 7.8 hr and apparent volume of distribution (V_d,)of 8.18 liters/kg. The renal clearance, which was 6 times that of the glomerular filtration rate, accounted for almost 84% of the total body clearance and correlated linearly with the subjects' creatinine clearance. The observed side effects of bretylium were mild and similar to those of other adrenergic blocking agents.This work was supported in part by a grant from Arnar-Stone Laboratories, Inc., McGaw Park, Illinois.     

Pharmacokinetics of teicoplanin in man after intravenous administration

The pharmacokinetics of teicoplanin, a new glycopeptide antibiotic active against gram-positive aerobic and anaerobic bacteria, was studied in adult male volunteers given 2- and 3- mg/ kg doses by a constant-rate 0.5-hr infusion. Serum and urine samples were collected up to 96 hr. Mean peak serum levels after the two doses were 15.7 and 22.4 g/ml. Postinfusion serum teicoplanin levels showed triexponential decay. A three-compartment body model gave close values for pharmacokinetic parameters after the two doses. The mean half-life of the ₁ phase was 20.3 min, that of the ₂ phase was 2.9 hr, and the half-life of the estimated ₃ phase was 40.5 hr, in good agreement with that of the _Z phase (45.9 hr) calculated from the last urine data. The mean volume of distribution of the central compartment was 0.09 liter/kg and the steady-state volume of distribution using noncompartmental analysis was 0.84 liter/kg. Total clearance averaged 16.05 ml/hr/kg, with renal clearance arbout half this (9.51 ml/hr/kg), calculated by two different methods. The average total recovery of active teicoplanin in urine over 4 days was 52%, suggesting that both renal and nonrenal mechanisms are involved in elimination of the drug. The concentrations of teicoplanin in serum and urine exceeded the MIC (ranging from 0.02 to 2 g/ml) on many pathogenic organisms for at least 1 day after administration.This work was supported in part by a grant from Gruppo Lepetit, Milan, Italy, and by a CNR (National Research Council, Rome, Italy) grant on Clinical Pharmacology and Rare Diseases.This work was presented in part at the 13th International Congress of Chemotherapy, Vienna, August 28 to September 2, 1983.     

Metabolism of phenazone in man after hydrocortisone administration

Summary The influence of a high plasma concentration of hydrocortisone on the metabolism of phenazone in humans has been studied. Two series of experiments were carried out, Group A to demonstrate any enzyme-inducing effect of hydrocortisone, and Group B to study the immediate effect of hydrocortisone on the metabolism of phenazone. 9 subjects (Group A) received a total 250–400 mg hydrocortisone i.m. twice daily for three days and the 24-hour elimination of phenazone was studied before and afterwards. In a further 5 subjects (Group B) the elimination of phenazone was examined during administration of hydrocortisone or placebo. The elimination rate and the apparent volume of distribution of phenazone remained unchanged under both experimental conditions.     

Pharmacokinetics of teicoplanin in man after intravenous administration

The pharmacokinetics of teicoplanin, a new glycopeptide antibiotic active against gram-positive aerobic and anaerobic bacteria, was studied in adult male volunteers given 2- and 3-mg/kg doses by a constant-rate 0.5-hr infusion. Serum and urine samples were collected up to 96 hr. Mean peak serum levels after the two doses were 15.7 and 22.4 micrograms/ml. Postinfusion serum teicoplanin levels showed triexponential decay. A three-compartment body model gave close values for pharmacokinetic parameters after the two doses. The mean half-life of the lambda 1 phase was 20.3 min, that of the lambda 2 phase was 2.9 hr, and the half-life of the estimated lambda 3 phase was 40.5 hr, in good agreement with that of the lambda z phase (45.9 hr) calculated from the last urine data. The mean volume of distribution of the central compartment was 0.09 liter/kg and the steady-state volume of distribution using noncompartmental analysis was 0.84 liter/kg. Total clearance averaged 16.05 ml/hr/kg, with renal clearance arbout half this (9.51 ml/hr/kg), calculated by two different methods. The average total recovery of active teicoplanin in urine over 4 days was 52%, suggesting that both renal and nonrenal mechanisms are involved in elimination of the drug. The concentrations of teicoplanin in serum and urine exceeded the MIC (ranging from 0.02 to 2 micrograms/ml) on many pathogenic organisms for at least 1 day after administration.     

Pharmacokinetics of ketoprofen in man after repeated percutaneous administration

A topical formulation of ketoprofen, a widely used nonsteroidal antiinflammatory drug, has recently been developed. Ten healthy young subjects (mean age 23.5 +/- 2.5 years) received daily 15 g of 2.5% ketoprofen gel, corresponding to 375 mg on the skin of the back over an area of 750 cm2. Plasma samples were collected after the first dose and after 10 days of chronic treatment. Urine was also collected. Ketoprofen was assayed by HPLC. The peak plasma concentration was 144 +/- 91 ng/ml after the first administration with apparent absorption and elimination half-lives of 3.2 +/- 2.4 h and 27.7 +/- 18.0 h, respectively. The total quantities of ketoprofen eliminated in the urine represented about 2.6% of the first dose applied. At the end of the study, the apparent half-life of unchanged ketoprofen was 17.1 +/- 9.1 h, and there was no accumulation. In this study, no sign of local intolerance was seen.     

Methaqualone pharmacokinetics after single- and multiple-dose administration in man

Serum levels of methaqualone (MTQ) were determined in eight unfasted subjects following single- and multiple-dose administration of 1×300 mgtablet over a 28-day period. Data were analyzed by a two-compartment open model. Following a fairly rapid absorptive phase (K _a =0.82±0.32 hr^–1),the serum elimination curve was biexponential, consisting of a phase predominantly due to distribution (=0.97±0.55 hr^–1)and a phase predominantly due to elimination (=0.036±0.004 hr^–1).A steady-state MTQ serum concentration profile was observed within the first week. There were no significant changes in the kinetics of absorption, distribution, or elimination over the 28-day period of drug administration. Urinary D-glucaric acid excretion, which increased two-to threefold after the first week of MTQ dosing, returned to normal levels when the drug was discontinued. The significance of the pharmacokinetic parameters in relation to bioavailability and biological disposition of single and multiple dose MTQ administration is discussed.     

Changes in GABA content and turnover in discrete regions of rat brain after systemic administration of caerulein

The effects of systemically injected caerulein, a cholecystokinin octapeptide analogue, on GABA content and turnover have been studied in various regions of rat brain. Caerulein decreased GABA levels in the nucleus accumbens, tuberculum olfactorium and substantia nigra and diminished GABA turnover rates in the striatum, nucleus accumbens and substantia nigra, as estimated from the rate of GABA accumulation after inhibition of GABA transaminase by aminooxyacetic acid (AOAA). These results indicate the effect of caerulein on the utilization of GABA in specific cerebral regions and suggest that the GABAergic system is involved in the mechanism of action of peripherally administered caerulein.     

Malathion percutaneous absorption after repeated administration to man

Prediction of exposure and toxic potential of pesticides such as malathion are routinely based upon acute exposure and single-dose percutaneous absorption determination. What has become obvious with pesticide exposure such as the malathion spraying for the medfly is that chronic daily exposure is the more relevant situation. Our objective was to determine the percutaneous absorption of chronically applied malathion in man and to compare chronic absorption to single-dose absorption. The experimental design was to first topically apply [14C]malathion to human male volunteers. This procedure was followed by repeated administration of nonradioactive malathion to the same site of application (ventral forearm). [14C]Malathion was reapplied (Day 8) when urinary excretion of radioactivity from the first application reached minimum detectable levels. The first [14C]malathion absorption was compared to the second [14C]malathion application. The percutaneous absorption from the first [14C]malathion application was 4.48 +/- 1.3% (SD) of the applied dose. The absorption from the second [14C]malathion administration was 3.53 +/- 1.0%, a value not significantly (p greater than 0.05) different from the first application. Therefore, for malathion the single-dose application data are relevant for predicting the toxic potential for longer-term exposure.     

The disposition of amodiaquine in man after oral administration.

A method is described for the simultaneous determination of amodiaquine (AQ) and desethylamodiaquine (AQm) in plasma, urine, whole blood and packed red cells. After oral administration of AQ (600 mg) to seven healthy subjects, absorption of AQ was rapid, reaching peak concentrations in plasma, whole blood, and packed cells at 0.5 +/- 0.03, 0.5 +/- 0.1 and 0.5 +/- 0.1 h respectively (mean +/- s.e. mean). The apparent terminal half-life of AQ was 5.2 +/- 1.7 h. AQ was detectable for no longer than 8 h. AQ underwent rapid conversion to AQm, which reached peak concentrations in plasma, whole blood and packed cells at 3.4 +/- 0.8, 2.3 +/- 0.5 and 3.6 +/- 1.1 h respectively. AQm was still detectable at the end of the sampling period (96 h) when the plasma concentration was 29 +/- 8 ng ml-1. The area under the plasma concentration vs time curve (AUC(0, infinity] for AQ was 154 +/- 38 ng ml-1 h; the corresponding value for AQm was 8037 +/- 1383 ng ml-1 h. There were no significant differences in the values for AUC of AQ between plasma, whole blood, or packed cells. The whole blood to plasma concentration ratio for AQm was 3.1 +/- 0.2, and the AUC (0.24) for AQm in whole blood (6811 +/- 752 ng ml-1 h) was significantly greater than that in plasma (2304 +/- 371 ng ml-1 h), P less than 0.001. The recovery of AQm from urine collected 0-24 h was 6.8 +/- 0.8 mg (n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic fate of delmopinol in man after mouth rinsing and after oral administration

1. The metabolism of delmopinol, an inhibitor of plaque formation and gingivitis. has been studied after mouth rinsing or an oral dose of 14C-delmopinol to healthy male volunteers. The metabolite pattern was studied in urine and plasma samples (unhydrolysed or hydrolysed with conjugate cleaving enzymes) by liquid chromatography (LC) with radio detection. Metabolite identifications were carried out by gas chromatography-electron-impact mass spectrometry (GC-MS) and by liquid chromatography-thermospray mass spectrometry (LC-MS). 2. The metabolic clearance of delmopinol was high, and < 0.2% of the dose was excreted as intact delmopinol in the urine. The main metabolites were, for both administration routes, glucuronide conjugates of delmopinol and of (omega-1-hydroxy) delmopinol. These metabolites were predominant and accounted for nearly the entire urinary radioactivity and most of the plasma radioactivity. After mouth rinsing, parent delmopinol was also one of the main compounds in plasma. 3. Several other products of oxidation of the aliphatic side-chain were present in minor amounts in urine. These metabolites also appeared to be excreted as glucuronic acid conjugates. 4. Glucuronidated (omega-1-hydroxy) delmopinol separated into three peaks by the LC system used. This could be due to different chromatographic properties of conjugate isomers, positional or optical.     

Metabolic fate of delmopinol in man after mouth rinsing and after oral administration

1. The metabolism of delmopinol, an inhibitor of plaque formation and gingivitis, has been studied after mouth rinsing or an oral dose of ¹⁴C-delmopinol to healthy male volunteers. The metabolite pattern was studied in urine and plasma samples (unhydrolysed or hydrolysed with conjugate cleaving enzymes) by liquid chromatography (LC) with radio detection. Metabolite identifications were carried out by gas chromatography-electron-impact mass spectrometry (GC-MS) and by liquid chromatography-thermospray mass spectrometry (LC-MS). 2. The metabolic clearance of delmopinol was high, and &lt; 0.2% of the dose was excreted as intact delmopinol in the urine. The main metabolites were, for both administration routes, glucuronide conjugates of delmopinol and of (ω-1-hydroxy) delmopinol. These metabolites were predominant and accounted for nearly the entire urinary radioactivity and most of the plasma radioactivity. After mouth rinsing, parent delmopinol was also one of the main compounds in plasma. 3. Several other products of oxidation of the aliphatic side-chain were present in minor amounts in urine. These metabolites also appeared to be excreted as glucuronic acid conjugates. 4. Glucuronidated (ω-1-hydroxy) delmopinol separated into three peaks by the LC system used. This could be due to different chromatographic properties of conjugate isomers, positional or optical.