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Biomedical subjects

D K Gorecki

Publications and source records attributed to D K Gorecki.

At least 19 recordsLinked to original sources
PubMed2000

Pharmacokinetics and tissue residues of Telazol in free-ranging polar bears.

A pharmacokinetic and tissue residue study was conducted to assess the risks associated with human consumption of polar bears in arctic Canada that have been exposed to the immobilizing drug Telazol, a mixture of tiletamine hydrochloride and zolazepam hydrochloride. Twenty-two bears were remotely injected with about 10 mg/kg of Telazol. Following immobilization, serum samples were collected serially at regular intervals until the bears awakened. Sixteen of the bears were relocated and killed under permit by local hunters at various times from 0.5 to 11 days after dosing. Serum, kidney, muscle and adipose tissue samples were collected immediately after death. All samples were stored at -70 C until analysis by HPLC. The concentration-time data of tiletamine and zolazepam in serum during the immobilization period were fitted to curves by computer and the pharmacokinetic parameters assessed. In addition, the serum and tissue samples collected at the time of death were analyzed for both parent drugs, for one metabolite of tiletamine (CI-398), and for three metabolites of zolazepam (metabolites 1, 2 and 4). A one-compartment model with first-order absorption and elimination best fit the time-series data for the drugs in serum during the immobilization period. This model gave half-lives (mean +/- SE) for tiletamine and zolazepam of 1.8+/-0.2 h and 1.2+/-0.08 h, respectively, clearance values of 2.1+/-0.3 l x h(-1) x kg(-1) and 1.1+/-0.1 l x h(-1) x kg(-1), and volumes of distribution of 5.2+/-0.6 l/kg and 1.8+/-0.2 l/kg. The concentrations of both drugs and their metabolites declined rapidly to trace levels by 24 h post-dosing, although extremely low concentrations of some metabolites were encountered sporadically over the entire sampling period. In particular, zolazepam metabolite 2, remained detectable in fat and muscle tissue at the end of the study, 11 days after dosing. It was concluded that during immobilization, both tiletamine and zolazepam levels decline rapidly in a monoexponential fashion, and their pharmacokinetic parameters in polar bears are similar to those observed in other species. Tissue levels of the drugs and their metabolites declined sufficiently rapidly that individuals eating meat from exposed bears would be unlikely to experience pharmacological effects from the drugs. Nevertheless, slight exposure to the drugs and/or their metabolites might be possible for an indeterminate time after dosing.

Animals↗
PubMed1997

Oscillatory potentials and light microscopic changes demonstrate an interaction between zinc and taurine in the developing rat retina.

Our objective was to investigate whether zinc interacts with taurine to influence the development of retinal structure and function. Virgin female Sprague-Dawley rats were bred overnight and assigned to one of four treatments in a 2 x 2 factorial design with two levels of zinc (50 micrograms/g through gestation and 50 micrograms/g after parturition; 15 micrograms/g through gestation and 7.5 micrograms/g after parturition) and two levels of taurine (2 or 0 mumol/g). The control diet contained 50 micrograms/g zinc and 2 mumol/g taurine. Guanidinoethyl sulfonate (10 g/L), a taurine transport inhibitor, was added to the drinking water of the rats receiving 0 mumol/g taurine. At postnatal d 23, male pups (n = 10) were weaned onto their respective diets. Pup eyes were examined by biomicroscope and indirect ophthalmoscope at 4 and 7 wk; retinal folds and choroidal atrophy were detected in the pups deficient in zinc and taurine. Analysis of plasma zinc and tibial zinc concentrations revealed a significant interaction in these tissues (P < 0.05). Dark-adapted oscillatory potentials (OP) were recorded at 7.5-8.5 wk. Two-way ANOVA showed a significant interaction between zinc and taurine for OP2 and OP3 amplitudes; marginal zinc deficiency decreased the amplitude of the OP only when rats were also deficient in taurine. A significant depressing effect of marginal zinc deficiency was noted for OP1 amplitude. Taurine deficiency significantly depressed the amplitude of OP1 and OP4. Histological examination of the retinas from rats deficient in both zinc and taurine revealed photoreceptor degeneration and confirmed retinal dysplasia. These data provide evidence for an interaction between zinc and taurine in retinal morphology and function.

Animals↗
PubMed1995

Effect of taurine deficiency on tissue taurine concentrations and pregnancy outcome in the rat.

Taurine status and pregnancy outcome were assessed in rats fed low dietary taurine and varying doses of guanidinoethyl sulfonate (GES), a structural analogue of taurine. Female Sprague-Dawley rats (225-270 g) were mated overnight and assigned to one of four groups from day 0 to 20 of gestation. Taurine-deficient animals were fed a basal diet containing < 0.001 mumol taurine/g and 0.5 (n = 7), 1.0 (n = 8), or 2.0% (n = 7) GES in their drinking water, ad libitum. Control animals (n = 8) received similar treatment, with 2 mumol taurine/g added to the diet and no GES in their water. Taurine was analyzed by reverse-phase HPLC, using electrochemical detection after precolumn derivatization with ortho-phthalaldehyde. Treatment of rats with varying doses of GES produced a sharp decline in maternal liver and brain taurine to 15 and 55% of that of control levels, and in fetal liver and brain taurine to 75 and 50% of that of control levels, respectively (p = 0.0001; one-way ANOVA). The 2% group had a smaller mean (+/- SEM) litter weight than the control group (35.8 +/- 6.1 vs. 51.9 +/- 2.8 g; p = 0.042) as a result of a smaller litter size. The decrease in litter size was associated with confinement of implantation sites to either the left or right uterine horn in four of seven dams. Taurine deficiency did not result in intrauterine growth retardation or significant external, visceral, or skeletal malformations. Developmental defects were not found in any of the taurine-deficient groups, but reproductive abnormalities were present at the highest dose of the analogue.

Animals↗
PubMed1992

Sedative/hypnotic effects of chloral hydrate in the neonate: trichloroethanol or parent drug?

Although the metabolism and pharmacokinetics of chloral hydrate (CH) have been reported, there have been no attempts to correlate CH or its metabolite, trichloroethanol (TCE) with the sedative or hypnotic effects. In order to determine whether plasma concentrations of CH or TCE reflect the sedative/hypnotic effects, a sedation/agitation scale was developed. Based on the results of the present study, the sedative/hypnotic effects of TCE cannot be ruled out completely. However, in the neonate, the parent drug CH seems to have a more important role than has been previously suggested from human research.

Chloral Hydrate↗
PubMed1991

In vitro and in vivo assessment of the bioavailability of potassium from a potassium tartrate tablet.

The bioavailability of potassium from orally administered potassium tartrate was evaluated in 20 normal subjects under metabolic balance conditions. Subjects were given 34 mmol potassium (5 tablets of Cal-K) as a divided dose on each of 2 consecutive days. Urinary excretion of potassium, as determined from 24-h urinary collections on the 3 days preceding dosage totalled 192.6 +/- 50.9 mmol (mean +/- S.D., n = 20). It increased significantly (p less than 0.05) to 258.7 +/- 54.2 mmol for the 2 days of dosage and the following day. The difference of 66.1 mmol representing absorbed potassium was close to the 68 mmol potassium given and indicated a bioavailability of potassium in excess of 97 per cent; after correction for creatinine excretion, potassium recovery rose to 99.9 per cent. The dissolution characteristics of the Cal-K tablets were also determined. After dissolution in simulated gastric juice (pH 1.2), 84.4 +/- 10.6 per cent (mean +/- S.D., 6 experiments) was dissolved; after adjustment to pH 7.3, dissolved potassium increased to 91.3 +/- 8.5 per cent. No precipitation or residue formed as a result of the pH change. Both sets of results indicate that potassium from these potassium tartrate tablets is in a highly bioavailable form.

Adult↗
PubMed1991

Intravenous clomipramine and obsessive-compulsive disorder.

A 62 year old woman presented with a long history of obsessive-compulsive disorder, the symptoms of which were not adequately controlled by oral clomipramine. The patient was started on intravenous clomipramine. Drug levels of both clomipramine and its active metabolite desmethylclomipramine were measured. Symptoms were controlled during her hospital stay. A three year follow-up report indicated the patient is doing well with no evidence of obsessive-compulsive or depressive symptoms. A discussion of the blood levels obtained and the caution to be exercised during intravenous administration is presented.

Clomipramine↗
PubMed1991

Chloral hydrate disposition following single-dose administration to critically ill neonates and children.

Although the metabolism and pharmacokinetics of chloral hydrate (CH) have been studied in healthy adults, no comprehensive studies have been done in neonates and young infants. Major physiological differences between these groups could greatly affect drug disposition. In this study the patient population (22 patients) was divided into three groups according to postconceptual age: group 1 = preterm infants (31-37 weeks), group 2 = fullterm infants (38-42 weeks) and group 3 = toddler-child patients (57-708 weeks). After receiving one 50 mg/kg oral dose of CH, the parent drug and its metabolites were determined by gas chromatography utilizing an electron capture detector. CH, contrary to what has been reported in the adult, was detectable for several hours after oral administration to patients in all three groups. A highly significant negative correlation was observed amongst the three groups for the half-life (t1/2) and area-under-the-curve for 0 to infinity values for trichloroethanol (TCE), the active metabolite responsible for the sedation effect. The t1/2 value for TCE in group 3 (9.67 h) was similar to that reported for the adult population, but in the less mature subjects it was approximately three (group 2: 27.8 h) to four times (group 1: 39.8 h) greater. Trichloroacetic acid had a remarkably long residence time in the study population after a single dose of CH. The concentration of this metabolite failed to decline even 6 days after dose. These issues should be carefully considered when CH administration is contemplated for clinical use in neonates, infants and children.

Administration, Oral↗
PubMed1990

Determination of chloral hydrate metabolism in adult and neonate biological fluids after single-dose administration.

A simple, rapid and sensitive electron-capture gas chromatographic method has been developed for the simultaneous determination of chloral hydrate, trichloroethanol and trichloroacetic acid in biological fluids. The described method is applicable to single-dose pharmacokinetic studies of chloral hydrate in the adult. The method also meets the important requirement of using very small sample volumes and is sufficiently sensitive and reliable for disposition studies in the neonate.

Adult↗
PubMed1989

Chloral hydrate sedation in neonates and infants--clinical and pharmacologic considerations.

Chloral hydrate has been used clinically for over 100 years. There is significant paucity of information regarding chloral hydrate metabolism in neonates and infants. Chloral hydrate and its various metabolites were quantitated in 12 neonates and 2 infants at prescribed time intervals. The analysis of the data indicates accumulation of trichloroacetic acid and trichloroethanol in tissue of compromised infants. There is indirect evidence of competition for hepatic glucuronidation for bilirubin with trichloroethanol in ill preterm infants. Multiple dosing of chloral hydrate in preterm infants should be used with caution and frequent monitoring of serum bilirubin concentrations is indicated in such cases. The mechanism of chloral hydrate metabolism is discussed in detail.

Bilirubin↗
PubMed1987

An evaluation of gentamicin dosing according to renal function in neonates with suspected sepsis.

Aminoglycoside antibiotics are frequently used for the treatment of suspected and confirmed sepsis in the newborn patient. In an attempt to evaluate gentamicin dosing based on serum creatinine concentrations, two groups of neonates were studied (infants less than 34 weeks n = 8 and greater than 34 weeks n = 14). The dosing interval was adjusted per protocol depending on the serum creatinine concentrations. Analysis of the results indicate reasonable therapeutic serum gentamicin trough and peak concentrations in most infants.

Bacterial Infections↗
PubMed1984

Establishing a clinical pharmacokinetic service for gentamicin in a community hospital.

To assess the feasibility and acceptability of a pharmacy-based clinical pharmacokinetic service for gentamicin, serum gentamicin levels were measured by radioimmunoassay in 44 patients hospitalized during a three-month period in an acute-care general hospital. Serum levels measured pre- and post-infusion were used to estimate pharmacokinetic parameters and optimum dosage regimens for individual patients. Based on serum level measurements of gentamicin, 30% of patients required no dosage adjustment, 23% an increase in dose and 47% a decrease in dose. Of the 30 changes recommended, 83% were implemented by physicians. Monitoring serum levels and adjusting dosage reduced the number of patients with sub-therapeutic and toxic serum levels. Adjusting dosage with the aid of serum levels appeared to be most useful for the elderly patient or the patient with impaired kidney function. Initial choice of dosage regimens for patients would be improved by appropriate use of the Hull and Sarubbi dosing nomogram (with certain modifications) or method of estimating pharmacokinetic parameters. The Hull and Sarubbi method was considered preferable to the dosing recommendation of 1.1 mg/kg at an interval of eight times the serum creatinine value. Excellent physician acceptance of a gentamicin serum level monitoring service was demonstrated in terms of the physician's usage of the service and implementation of the pharmacist's recommendations. A multidisciplinary approach involving medicine, pharmacy, nursing and laboratory staff was essential for successful operation of the pharmacokinetic service. However, the responsibility for the development and overall coordination of the pharmacokinetic service should remain with the pharmacist.

Gentamicins↗
PubMed1978

Effect of L-cycloserine on brain GABA metabolism.

The administration of L-cycloserine to mice resulted in a dramatic decrease in the activities of 4-aminobutyrate:2-oxoglutarate aminotransferase (GABA-T) and L-alanine:2-oxoglutarate aminotransferase (ALA-T) in both brain and liver. L-Aspartate:2-oxoglutarate aminotransferase was inhibited only slightly, and brain glutamic acid decarboxylase not at all. Liver ALA-T activity returned to near normal levels within 24 h of L-cycloserine administration whereas liver GABA-T and brain ALA-T activities had returned only halfway to normal levels in the same time period. The recovery in the activity of brain GABA-T was even slower. A consequence of the inhibition of brain GABA-T activity was an elevation in the GABA content of the tissue which was maximal 3 h after L-cycloserine administration and which was still noticeable 8 h after the drug treatment. L-Cycloserine was also a potent in vitro inhibitor of brain GABA-T activity. The inhibition was competitive with respect to GABA, the Ki value being 3.1 X 10(-5) M. The prior administration of L-cycloserine to mice significantly delayed the onset of isonicotinic acid hydrazide induced convulsions.

4-Aminobutyrate Transaminase↗
PubMed1977

2,3-Disubstituted 1,8-naphthyridines as potential diuretic agents. 2. 5,7-Dimethyl derivatives.

A variety of 2,3-disubstituted 5,7-dimethyl-1,8-naphthyridines was synthesized and tested in saline-loaded rats for their diuretic properties. The 2-amino-3-carbomethoxy and four 2-amino-3-N-alkylcarbamoyl compounds exhibited significant activity as measured by volume output; however, they were generally less potent than the corresponding 5,7-unsubstituted naphthyridines previously reported. Further screening without saline-loading indicated that the amides lacked kaliuretic properties; while, interestingly, the ester lacked an effect on either urine volume or sodium excretion.

Animals↗