Biomedical subjects
Publications and source records attributed to N Gerber.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
I.v. administration of sodium valproate (NaVPA), the sodium salt of 2-n-propylpentanoic acid, VPA, Depakene), to rats and dogs caused an immediate stimulation of bile flow, the magnitude and duration of which was dependent on the dose. In rats given 14C-erythritol, a linear relationship between biliary clearance of erythritol and bile flow indicated that the choleresis was canalicular, rather than ductular, in origin. Increased bile flow was not mediated through an enhanced output of bile acids. Bile produced during choleresis was lower in chloride and bicarbonate concentrations than equivalent bile from control rats given only saline i.v. This anion gap was more than compensated by the amount of VPA-glucuronide (anionic at physiological pH values) in the bile. A close linear relationship existed between the volume of additional bile produced and the amount of conjugated VPA excreted in the bile. The results support the hypothesis that VPA induces choleresis by the osmotic effects of transport of its metabolites across the canalicular membrane.
Explore the source record for details and available documents.
An enzymatic-radioisotopic assay was used to measure free choline in unextracted tissue. The lowest concentration of free choline in any tissue studied was present in human cerebrospinal fluid (mean, 5.7 microM; range, 1.8 + 31.2 microM). A postmortem increase in concentration of free choline occurred in blood (0.2 nmol/min.ml), kidney (13 nmol/min.g) and liver (22 nmol/min.g) of mice. The concentration of free choline in these tissues was estimated by extrapolation to be 5, 77, and 29 nmol/g (or ml), respectively. Several treatments were found to increase the concentration of free choline. For example, intraperitoneal administration of choline or 2-amino-2-methyl-propanol (a choline oxidase inhibitor) induced an increase in the level of choline i blood, kidneys, liver, and brain of mice, and administration of 2-dimethylaminoethanol (deanol) caused an increase in kidney and liver choline. The level of choline in blood was increased when rats were treated orally with either antibiotics or esters of choline such as phosphorylcholine, glycerylphosphorylcholine, laroylcholine, or propionylcholine. The results show that the concentration of free choline may be regulated by intestinal metabolism, availability of esterified precursors, and activity of enzymes that metabolize choline.
This study compared the bronchodilator effect in experimental canine asthma of dyphylline administered by aerosol and intravenous routes in doses producing equivalent concentrations of the drug in the plasma. Pulmonary resistance (RL) was calculated from simultaneous measurements of pressure and flow during fixed-volume controlled ventilation at the same peak flow and corrected for elastic recoil pressure. Dynamic compliance (Cdyn) was calculated by dividing tidal volume by the change in pressure measured between points of zero flow. Concentrations of dyphylline in the plasma were measured using high-performance liquid chromatographic techniques. Rates of infusion of dyphylline were determined from values for clearance observed in preliminary experiments with intravenous injection. Prior to exposure to antigen, RL and Cdyn were not significantly different in control and dyphylline-treated dogs. Following challenge, with antigen RL increased by 8.3 +/- 2.6 times (mean +/- SE) in untreated dogs but only by 2.4 +/- 0.4 times in dyphylline treated dogs. Levels of dyphylline in the plasma averaged 4.2 micrograms/ml +/- 0.6 micrograms/ml at the end of the ten-minute period of aerosol administration and remained at that level for 60 minutes. At equivalent plasma levels (4.3 micrograms/ml +/- 0.3 micrograms/ml), infusion of dyphylline did not significantly after the response to Ascaris antigen, whereas dyphylline administered by the aerosol route markedly attenuated the response.
The pharmacokinetics and urinary excretion of intravenously administered 7-(2,3-dihydroxypropyl) theophylline (dyphylline), were studied in a 37-yr-old asthmatic woman with ethylene diamine sensitivity who manifested intolerance to intravenous aminophylline on three separate occasions. In this subject, intravenously administered dyphylline was tolerated very well and was effective in the subsequent management of acute bronchospastic episodes. Dyphylline was significantly concentrated in the urine. This, coupled with its rapid clearance, suggests potential clinical application in patients with hepatic dysfunction. Though aminophylline sensitivity is rare, ethylene diamine sensitivity should be considered in untoward reactions to this drug.
The protection against bronchospasm afforded by infusions of lignocaine was tested in dogs anaesthetized with thiamylal by challenge with aerosols of citric acid (CAA) or ascaris antigen (AAA). During the infusion of lignocaine, the response to CAA was blocked or markedly attenuated, but AAA still elicited a large increase in pulmonary resistance (RL). In untreated dogs, CAA increased RL from 0.14 +/- 0.05 (mean +/- SEM) kPa litre-1 s to 1.09 +/- 0.18, whereas in dogs treated with lignocaine, RL was 0.19 +/- 0.09 before challenge with CAA and 0.44 +/- 0.13 after challenge. AAA increased RL from 0.14 +/- 0.06 kPa litre-1 s to 3.01 +/- 0.65 in untreated dogs, and from 0.34 +/- 0.10 kPa litre-1 to 1.85 +/- 0.69 in dogs treated with lignocaine. Blood concentrations of lignocaine were 1.5 +/- 0.3 and 2.5 +/- 0.6 microgram ml-1 during challenge with CAA and AAA, respectively. We conclude that lignocaine, at blood concentrations which will reduce the risk of cardiac arrhythmia, markedly reduces reflex bronchonconstriction, but has relatively little effect on that initiated by allergic mediators.
Five adult cynomolgus monkeys (Macaca fascicularis) were each given doses of 15 and 150 mg/kg of sodium valproate on separate occasions through indwelling arterial or venous catheters. Timed samples of blood (0-1440 min) and urine were collected for measurement of free and conjugated valproic acid (VPA). In all animals a brief distribution (alpha) phase, complete by 10 to 15 min, was followed by a biphasic decline in concentration of the drug. The times required for the concentration of VPA in blood at 25 min to decline by 50% were 42.4 +/- 2.6 (S.E.) min and 94 +/- 7.5 (S.E.) min at the 15 and 150 mg/kg doses, respectively. The terminal half-lives (T 1/2) were 345 +/- 46 (S.E.) min and 428 +/- 56 (S.E.) min at the low and high dose, respectively. In contrast to our earlier studies in the rat, surgical exteriorization of the bile did not alter the elimination profile of VPA from the blood of the monkey. Only 3 to 7% of the administered dose of the drug appeared as conjugated VPA in the bile (c.f. 60% in the rat), thereby confirming that enterohepatic circulation of VPA was of minor importance in determining the pattern of elimination of the drug from blood in the monkey. Urinary excretion of conjugated VPA in intact and bile-exteriorized monkeys totaled 56 and 52% of the 15 mg/kg dose and 60 and 63% of the 150 mg/kg dose, respectively. In monkeys, as in rats, sodium valproate caused a dose-dependent, immediate choleretic reponse, the duration of which followed the blood concentration of the drug.
The concentration profile of valproic acid (VPA) in bile-exteriorized rats given an i.v. bolus of 15 mg sodium valproate (NaVPA) per kg has been previously shown to exhibit a limited distribution phase and first-order elimination kinetics (two-compartment open model). At a higher dose of 150 mg NaVPA/kg, the initial elimination was non-linear (capacity-limited). Using an 'iterative modified Euler integration technique,' the results have been fitted to a pharmacokinetic model which allows for both two-compartment redistribution of drug as well as saturable Michaelis-Menten elimination kinetics. A combined pharmacokinetic model of this type has not been previously described.
Methods for obtaining an exact least squares fit of the one and two compartment models have not been previously described. The multi compartment polyexponential pharmacokinetic models have classically been fit to data using nonlinear regression programs such as NonLin (Metzler, 1969). The two compartment open model, for example, can be fit to least squares regression with equation 1 by iteratively varying A, alpha, B, and beta. Y = Ae(-alpha t) + Be(-beta t).
Chronic indwelling catheters in the maternal femoral artery and vein, fetal carotid artery and jugular vein, and amniotic cavity of a pregnant rhesus monkey permitted administration of sodium valproate (NaVPA) and collection of timed samples of maternal and fetal blood and amniotic fluid. After a single IV dose (50 mg/kg) to the mother, a rapid distribution phase (t1/2 alpha = 0.5 minute) was followed by a biphasic decline in concentration in maternal blood (t1/2 beta = 31 minutes, t1/2 gamma = 390 minutes). VPA appeared rapidly in fetal blood, reached a concentration slightly higher than in maternal blood by 15 minutes, and thereafter declined in parallel with the concentration in maternal blood. Terminal fetal/maternal ratios of blood concentration of VPA were about 1.3. Similar patterns of decline were observed after NaVPA was given IV to the fetus. A multicompartment first-order materno-fetal pharmacokinetic model is presented. Tissue distribution studies in the fetus showed that VPA concentration was highest in blood; moderate in heart, liver, spleen, kidney, and skeletal muscle; and low in brain.
The pharmacokinetics, tissue distribution and metabolism of naltrexone were studied in male New Zealand White rabbits. After an i.v. bolus, the plasma half-life of naltrexone between 30 min and 3 hr was 55 +/- 5 min and 53 +/- 3 min for 1 and 5 mg/kg doses of naltrexone . HCl, respectively. The drug concentration in the semen reached a maximum value between 15 and 30 min after the injection. At 120 min, the semen/plasma drug concentration ratio was 14 and 11 for the 1 and 5 mg/kg doses, respectively. Three minutes after injection, 95% of the drug had left the plasma. After 5 min, the conjugate levels exceeded the free drug levels in the plasma suggesting rapid glucuronidation of the drug. The concentrations of naltrexone and 6-beta-naltrexol were measured in different tissues 90 min after injection. Most of the tissues had drug concentrations which exceeded the concurrent plasma concentration. The highest concentrations were observed in the submaxillary gland. Relatively high amounts of 6-beta-naltrexol were found in the brain, fat, spleen, heart, testis, kidney and urine. The principle urinary metabolite was the glucuronide of naltrexone. Minor metabolites identified in urine treated with Glusulase were 6-beta-naltrexol and N-dealkylated naltrexone.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Aortic root blood flow was measured with an electromagnetic (EM) flow meter in unanesthetized horses during rest and exercise. The cardiac output response to exercise, as determined by the EM technique, was compared with the response reported by others who used indicator dilution techniques with good agreement. The EM method will allow making measurement of cardiovascular responses to exercise in the horse, not obtainable with other techniques.
Floctafenin (FFn), 2,3-dihydroxypropyl--N--(8--trifluoromethyl--4--quinolyl) anthranilate, a new nonnarcotic analgesic drug, was studied in man, mice, and the isolated perfused rat liver. In all species the drug is rapidly hydrolyzed to floctafenic acid (FFa). In seven volunteer subjects who each received a single oral dose of 400 mg floctafenin on an empty stomach, the blood concentration of FFa usually reached a maximum between 1 and 2 hours (mean 1.57 +/- 1.28 microgram/ml at 1.5 hours) and declined over the next 6 hours. Eight hours after drug administration the mean concentration of FFa in the blood of the volunteers was 0.1 +/- .05 microgram/ml. Approximately 25 per cent of the administered dose of floctafenin was recovered as FFa and hydroxy-FFa in the urine collected from each subject for 48 hours after drug administration. In mice each having received a single intraperitoneal dose of floctafenin (2 mg), the concentration of floctafenin declined by about 50 per cent in 15 minutes, and this decline was accompanied by a rise in the concentration of FFa that remained constant for 3 hours. The analgesic effect observed after administration of floctafenin to humans is likely to be mediated by its major metabolite, FFa. In these volunteers no free floctafenin was detected in the blood.