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Biomedical subjects

K D Haegele

Publications and source records attributed to K D Haegele.

At least 55 records · Page 3Linked to original sources
PubMed1986

Quantitative analysis of the dihydropyridines, 3-(2-furoyl)-5-methoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl)- 1,4-dihydropyridine and nifedipine, by high-performance liquid chromatography with electrochemical detection.

An analytical method based on solvent extraction and reversed-phase high-performance liquid chromatographic separation with electrochemical detection has been developed for the dihydropyridines, 3-(2-furoyl)-5-methoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl) -1,4-dihydropyridine (MDL 72.567) and nifedipine. The analysis includes an internal standard of similar light sensitivity to correct for possible photodegradation during the procedure. The specificity of electrochemical detection precludes interference from oxidized metabolites. Total analysis time was 35 min per sample, and the detection limit for quantification was 1-2 ng/ml. Linear regression analysis gave calibration curves with coefficients or correlation of 0.9992 for MDL 72.567 (1-100 ng) and 0.997 for nifedipine (1-50 ng). Assays for within-run and day-to-day reproducibility gave coefficients of variation of 3.9% and 6.0%, respectively, at concentrations of 50 ng/ml. The method has been applied to the analysis of plasma levels of nifedipine and MDL 72.567 in dogs.

Animals↗
PubMed1986

Pharmacokinetics of piroximone (MDL 19.205) in healthy volunteers.

Six healthy, male subjects received single intravenous and oral doses of piroximone. Plasma piroximone concentrations were assayed up to 8 h after each dose by HPLC. Urinary excretion of the parent compound was also determined. Following the oral dose, piroximone reached peak plasma concentrations within 30 to 90 min. The t1/2 of the terminal decay phase was 2.8 h, the mean apparent volume of distribution was 2.5 l/kg, and the mean total body clearance was 755 ml/min. Mean urinary recovery of parent drug within 24 h was 50% after the intravenous dose and 41% after the oral dose. Renal clearance accounted for approximately 50% of total body clearance. Oral bioavailability, estimated from AUC or urinary recovery, was 80%.

Administration, Oral↗
PubMed1986

Electrophysiological effects of intravenous MDL 17.043.

MDL 17.043, a nonglycoside, noncatecholamine imidazolone derivative with phosphodiesterase inhibiting activity, has been shown to possess both positive inotropic and vasodilator properties. In the present study, the electrophysiological effects of intravenous MDL 17.043 were assessed in 10 patients undergoing programmed right atrial stimulation for diagnostic purposes. MDL 17.043 was administered as a single intravenous bolus injection of 1.5 mg/kg body weight over 4 min followed by an intravenous infusion of 0.75 mg/kg body weight over 20 min. With the dosage schedule used, the MDL 17.043 plasma levels achieved were similar to those previously reported to be associated with significant hemodynamic improvement of congestive heart failure. Electrophysiological measurements were performed before and during MDL 17.043 administration. MDL 17.043 consistently shortened basic sinus cycle length, sinus node recovery time and sinuatrial conduction time and decreased Wenckebach cycle length, atrioventricular and atrial refractoriness leading to positive chronotropic and dromotropic effects.

Adult↗
PubMed1986

Psychophysiological and psychometric studies after manipulating the GABA system by vigabatrin, a GABA-transaminase inhibitor.

This study is concerned with the alterations in central and peripheral psychophysiological measures and psychometric variables after experimental manipulation of the most important inhibitory transmitter system of the CNS, the gamma-aminobutyric acid (GABA) system. Vigabatrin (GVG), a new enzyme-activated, irreversible inhibitor of GABA transaminase, which increases cerebrospinal fluid concentrations of GABA and other substrates of GABA transaminase, was given in single oral doses of 1 g, 2 g and 3 g to 10 normal healthy volunteers. In this double-blind, placebo-controlled crossover study, 3 mg lorazepam was given as reference compound. Blood sampling for vigabatrin kinetics, EEG recordings and evaluation of pulse, blood pressure and side effects were carried out at the hours 0, 1, 2, 4, 6, 8 and 24, and psychometric tests at the same times (except the first hour). Pharmacokinetic analyses demonstrated good absorption of GVG with peak plasma concentrations found within the first two hours, dose-dependent areas under the plasma concentration-time curves and about 65% recovery in the 24-h urine. Computer-assisted spectral analysis of the EEG suggested that GVG produces only small changes in the normal CNS, characterized by an augmentation of total power, absolute and relative power of the beta activity and acceleration of the centroid of the total activity. There was also a trend towards an increase of alpha activity and of the absolute and relative power of the dominant frequency, decrease in the alpha centroid and increase of the centroid of the combined delta and theta activity. Lorazepam 3 mg, in contrast, produced highly significant changes characterized by a decrease of total power, alpha activity, absolute and relative power of the dominant frequency and centroid of the combined delta and theta activity, while beta activity as well as the centroid of the alpha, beta and total activity increased. In the resting condition an additional augmentation of slow activity suggested hypnotic properties of 3 mg lorazepam. The latter changes are typical for anxiolytic sedatives and were also reflected at the behavioral level where psychometric data demonstrated a deterioration in the noo- and thymopsychic parameters and sedative effects in psychophysiological variables. GVG, on the other hand, produced only subtle changes characterized by an improvement of noo- and thymopsychic variables and vegetative activation.

4-Aminobutyrate Transaminase↗
PubMed1986

Kinetics of the enantiomers of vigabatrin after an oral dose of the racemate or the active S-enantiomer.

Six healthy men received single oral doses of 1500 mg of vigabatrin [(R,S)-gamma-vinyl-GABA] and 750 mg of S(+)-gamma-vinyl-GABA on two occasions. Concentrations of the individual enantiomers were assayed by a stereoselective procedure based on combined GC/MS. At peak, concentrations of the R(-)-enantiomer exceeded concentrations of the S(+)-enantiomer, with an approximate ratio of 2:1. The mean terminal t1/2 ranged from 6 to 8 hours for both enantiomers. Mean urinary recovery of the S(+)-enantiomer was 49% after both doses and was 65% for the R(-)-enantiomer. Plasma concentration values obtained for the S(+)-enantiomer after a dose of the pure S(+)-enantiomer and an equivalent dose of the racemate showed good agreement for both the concentrations observed at any time point and the elimination characteristics, demonstrating bioequivalence. Renal clearance values for the S(+)-enantiomer are not affected by concomitant dosing with the pharmacologically inactive R(-)-enantiomer. No chiral inversion was detected after dosing with the pure S(+)-enantiomer.

4-Aminobutyrate Transaminase↗
PubMed1985

Evidence against putrescine and polyamines as endogenous mediators of fever.

Endogenous concentrations of putrescine, spermidine, spermine and related biosynthetic enzymes were not affected by the administration of bacterial endotoxin and the subsequent development of fever in rabbits. In addition, the febrile response to endotoxin was unaffected either by the ornithine decarboxylase inhibitor, DL-alpha-difluoromethylornithine or by putrescine. These data indicate polyamines are not involved in the development of fever.

Animals↗
PubMed1984

Kinetics of fenoximone, a new cardiotonic, in healthy subjects.

Fenoximone, a new cardiotonic, was given to six healthy men as a single intravenous dose of 1 mg/kg and a single oral dose of 3 mg/kg as solution in a crossover study. Plasma concentrations were monitored for 8 hr and urine was collected for 24 hr. Peak plasma concentrations (Cmax) were reached 30 min after the oral dose. Decay of plasma concentrations was fitted to a mean (+/- SD) elimination t1/2 (t1/2 beta) of 60 +/- 14 min after intravenous injection and 78 +/- 26 min after oral dosing. Mean total body clearance for intravenous dosing was 2062 +/- 846 ml/min, renal clearance (ClR) was 5.3 +/- 2.4 ml/min, and extrapolated volume of distribution was 0.37 +/- 0.26 l/kg. The sulfoxide derivative was detected as the main metabolite. Cmax of the sulfoxide metabolite occurred 10 min after the end of the intravenous infusion and 20 to 60 min after oral dosing. From the decay of the plasma concentrations of the sulfoxide, the t1/2 beta s were calculated as 132 +/- 15 min after intravenous injection and 140 +/- 27 min after oral dosing of fenoximone. ClR of the sulfoxide was 499 +/- 106 ml/min after intravenous injection; 24-hr urinary recovery of the sulfoxide was 75.7% +/- 5.7% after intravenous injection and 64.3% +/- 10.4% after oral dosing. Mean oral bioavailability of fenoximone was 53% (range 44% to 69%).

Administration, Oral↗
PubMed1983

Determination of the R(-)- and S(+)-enantiomers of gamma-vinyl-gamma-aminobutyric acid in human body fluids by gas chromatography--mass spectrometry.

An analytical procedure, which allows the determination and quantitation of the R(-)- and S(+)-enantiomers of gamma-vinyl-gamma-aminobutyric acid (gamma-vinyl-GABA; MDL 71.754) in body fluids was developed. The method is based on a combined gas chromatographic--mass spectrometric technique. A glass capillary column coated with a chiral phase enabled the separation of the enantiomers of gamma-vinyl-GABA as their N-trifluoroacetyl-O-methyl ester derivatives. This was followed by quantitation using a selected ion monitoring technique in the electron-impact mode of ionization. The internal standard, gamma-acetylenic GABA, was included throughout the work-up of the samples. The assay was shown to be reproducible, specific and sensitive. No interferences were encountered from plasma, urine or cerebrospinal fluid constituents. The method was applied to the analysis of plasma samples obtained from a human volunteer who had received racemic gamma-vinyl-GABA. Significant differences in the plasma concentrations and plasma half-lives of the two enantiomers were seen, clearly illustrating the need for a specific assay technique capable of distinguishing between the enantiomers of this drug.

Alkynes↗
PubMed1983

Kinetics of medroxalol, a beta- and alpha-adrenoceptor antagonist.

Eight healthy men received single oral doses of 400, 800, and 1200 mg medroxalol and a single intravenous dose of 1 mg per kg body weight on four occasions separated by at least 2 wk. Plasma medroxalol concentrations were assayed up to 24 hr after each dose by a specific high-pressure liquid chromatographic assay. Urinary excretion of parent compound was determined as well. Following oral doses medroxalol reached peak plasma concentrations within 2.5 to 3 hr. The t 1/2 of the terminal decay phase was 11.1 hr. Mean apparent volume of distribution (aVD) was between 11.2 and 16.4 l/kg, and mean total body clearance (ClT) was between 0.73 and 0.99 l hr-1 kg-1. Mean urinary recovery of parent drug within 48 hr was 2.3%, 3.9%, and 3.6% after the oral doses compared to 8.2% after the intravenous dose. Bioavailability estimated from AUC was 27.2% after 400 mg, 31.3% after 800 mg, and 37.4% after 1200 mg by mouth. Since aVD, t 1/2, ClT, and urinary excretion did not differ significantly after the three oral doses, medroxalol kinetics appear to follow a dose-linear model.

Administration, Oral↗
PubMed1982

Endogenous generation of hydralazine from labile hydralazine hydrazones.

The hypothesis that the pharmacologically active hydralazine hydrazones (HH) are endogenously hydrolyzed to parent hydralazine (H) was tested in a series of in vitro and in vivo systems. The stable hydrazones H alpha-ketoglutaric acid hydrazone and H pyruvic acid hydrazone did not hydrolyze to H in vitro (buffer or plasma), were inactive in vivo and did not generate urinary metabolites of parent H. By contrast, the labile HH, H acetaldehyde hydrazone and acetone hydrazone (HAH) generated H in vitro. H acetaldehyde hydrazone produced in vitro effects that were equipotent to the H concentration measured in the dose solutions. When administered to conscious rats and rabbits, the labile hydrazones reduced blood pressure. This effect was more gradual in onset than that of H. The hypotensive effects of HH were significantly greater than predicted by the amount of H contained in the dose solutions. Metabolic studies were conducted with the labile HH, HAH. After administration of HAH to rabbits, the proportional excretion of the urinary H metabolite, H pyruric acid hydrazone, was equal to that observed after the administration of H. We conclude that HH are inactive, except when hydrolyzed to H. The hydrolysis of certain HH, including HAH and H acetaldehyde hydrazone, in vivo may be nearly complete. Differences in the pharmacodynamic properties between labile HH and H may be related to the time course of generation of H, sequestration of hydrolysis in physiologically inactive sites or other unrecognized mechanisms.

Animals↗
PubMed1981

Kinetics of alpha-difluoromethylornithine: an irreversible inhibitor of ornithine decarboxylase.

We gave alpha-difluoromethylornithine (DFMO), a selective, irreversible inhibitor of ornithine decarboxylase, to six health men in single intravenous doses of 5 and 10 mg/kg body weight and oral doses of 10 and 20 mg/kg. Plasma concentrations were monitored during the 24 hr after each dose. Urine was collected from 0 to 24 hr after drug and amount of unchanged drug excreted was determined. Peak plasma concentrations were reached within 6 hr after oral doses. The decay of the plasma concentrations followed first-order kinetics with a mean half-life (t 1/2) for all four doses studied of 199 +/- 6 min (+/- SD). Mean total body clearance (ClT) for the four doses was 1.20 +/- 0.06 ml . min-1 . kg-1. Mean renal clearance was determined as 0.99 +/- 0.03 ml . min-1 . kg-1, accounting for 83% of drug elimination. Mean apparent volume of distribution (aVD) was 0.337 +/- 0.031 l/kg-1, corresponding to 24 l for 70 kg of body weight. The amount of unchanged drug in 24-hr urine samples was 47 +/- 7% and 40 +/- 11% after 10 and 20 mg/kg orally, and 78% and 81 +/- 8% after 5 and 10 mg/kg intravenously. Bioavailability of the 10 mg/kg dose was estimated as 58% from the urinary recoveries and as 54% from the areas under the plasma concentration curves (AUC 0 leads to infinity). Since doubling of the dose resulted in a doubling of the mean AUC 0 leads to infinity and since other kinetic parameters, such as aVD, t 1/2, ClT, and the urinary recovery of unchanged drug, were essentially the same at all doses, DFMO kinetics follow a dose-linear model.

Administration, Oral↗
PubMed1980

Quantitative analysis of hydralazine pyruvic acid hydrazone, the major plasma metabolite of hydralazine.

A specific, high-performance liquid chromatographic technique for the measurement of hydralazine pyruvic acid hydrazone is described. This method utilized reversed-phase chromatography for the separation of this hydrophilic metabolite of hydralazine from other fluid constituents present in serum, plasma, or urine of human volunteers and rabbits receiving hydralazine. Detection of the compound of interest is accomplished spectrophotometrically at 250 nm.

Animals↗
PubMed1979

High-pressure liquid chromatographic assay for hydralazine in human plasma.

A specific high-performance liquid chromatographic assay for hydralazine in human plasma was developed. Plasma hydralazine is reacted with 10 microliter of p-anisaldehyde for 7 min at room temperature to form hydralazine p-anisaldehyde hydrazone. This derivative is extracted into ethyl acetate, and the solvent is removed by evaporation. The residue is reconstituted in 100 microliter of methanol, and 90 microliter is injected onto a reversed-phase column. The mobile phase is 32% acetonitrile in 0.75 M acetate buffer, pH 3.4, at a flow rate of 2 ml/min. The retention time of hydralazine p-anisaldehyde hydrazone is 6.5 min. The average coefficient of variation over 10-200 ng/ml is 5.5%, and the sensitivity limit is 5 ng/ml. Under the assay conditions, hydralazine pyruvic acid hydrazone, a known plasma metabolite of hydralazine, yields less than 0.1% hydralazine. Detectable plasma hydralazine levels of 5-20 ng/ml were found 10-30 min after a 0.5-mg/kg oral dose of hydralazine hydrochloride was given to a male volunteer.

Adult↗
PubMed1979

Pharmacokinetics and cardiovascular effects in rabbits of a major hydralazine metabolite, the hydralazine pyruvic-acid hydrazone.

The hydrazone of hydralazine and pyruvic acid (HPH) has been recognized as a quantitatively important metabolite of hydralazine in human plasma. We evaluated the disposition of [14C] HPH after its i.v. administration to normal, anephric and probenecid-pretreated rabbits. Renal clearance of HPH in normal rabbits exceeded the glomerular filtration rate by a factor of 3 to 4 and accounted for 80 to 90% of the total body clearance. Active tubular secretion was established by the effect of probenecid pretreatment to reduce the renal clearance of HPH by 80%. Total body clearance of HPH in anephric rabbits was 10% of that of normal animals, emphasizing the minor importance of metabolic conversion for the overall disposition of HPH. HPH in a maximum dose of 50 mumol/kg i.v. had no hypotensive effect in renal hypertensive rabbits and did not interfere with the subsequent hypotensive response to hydralazine. This HPH dose produced plasma levels at least 50 times in excess of those reported in humans after administration of therapeutic doses of parent hydralazine. HPH is consequently of negligible clinical significance, despite the relatively high plasma concentration of this metabolite which occurs after administration of parent hydralazine.

Animals↗
PubMed1979

Pharmacokinetics of hydralazine, apparent hydralazine and hydralazine pyruvic acid hydrazone in humans.

Hydralazine is an antihypertensive vasodilator agent. Lack of specific assay techniques for its measurement have delayed elucidation of its pharmacokinetic profile. This study compares the plasma profiles of hydralazine, measured both by a specific and by a previously published nonspecific assay and of a major plasma metabolite, hydralazine pyruvic acid hydrazone. After po and iv administration of hydralazine, peak hydralazine levels were lower (7-33%) and plasma half lives were shorter (15-31%) when measured by the specific technique. The mean plasma half life of the pyruvic acid hydrazone was 156 min and mean urinary clearance, 28 ml/min. The plasma profile of hydralazine and of the major metabolite, the pyruvic acid hydrazone, do not appear to correspond to the duration of antihypertensive effect of administered hydralazine.

Acetylation↗
PubMed1978

Microdetermination of procainamide in human serum.

An electron-capture GLC method to measure procainamide (0.1-1 microgram/sample) in human serum was developed. An internal standard, p-amino-N-[2-(dipropylamino)ethyl]benzamide, is added to the serum before the sample is alkalinized with pH 10.5 phosphate buffer and extracted with ethyl acetate. The ethyl acetate phase is evaporated to dryness, and the residue is reacted with pentafluoropropionic anhydride. N-Pentafluoropropionyl derivatives of the drug and the internal standard had retention times of 5 and 8 min, respectively, when chromatographed at 235 degrees on a 1-m (4-mm i.d.) glass column packed with 5% OV-17 (carrier gas flow of 40 ml/min). The coefficient of variation was less than 5% for spiked standards. Furthermore, N-acetylprocainamide added to samples did not interfere. One hundred and eighty-six samples from 16 patients receiving procainamide intravenously were assayed by this GLC procedure and by a standard colorimetric method. Linear regression analysis yielded a correlation coefficient of 0.985 (slope, 1.040; intercept, 0.015).

Chromatography, Gas↗
PubMed1978

Identification of hydrallazine and hydrallazine hydrazone metabolites in human body fluids and quantitative in vitro comparisons of their smooth muscle relaxant activity.

1 Serum and urine from hypertensive subjects on chronic oral hydrallazine therapy were studied using gas chromatographic/mass spectrometry techniques. 2 Metabolites resulting from acetylation, hydrolysis and conjugation reactions were detected. The acetone, pyruvate and alpha-ketoglutarate hydrazone were identified. 3 The activity of the pyruvate and alpha-ketoglutarate hydrazones were compared with that of hydrallazine using isolated rabbit aortic strips. 4 Both hydrazones were active under in vitro conditions, producing smooth muscle relaxant effects equal to those of hydrallazine. 5 It is concluded that hydrazone metabolites will contribute to the hypotensive effects of hydrallazine therapy in proportion to their relative abundance, persistence in vascular tissues and intrinsic activity.

Animals↗