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Biomedical subjects

J Hendel

Publications and source records attributed to J Hendel.

At least 37 records · Page 2Linked to original sources
PubMed1984

Entero-hepatic cycling of methotrexate estimated by use of the D-isomer as a reference marker.

The absorption and elimination kinetics of 4-amino-N10-methylpteroyl-D-glutamic acid (D-MTX), the optical isomer of methotrexate (L-MTX), were examined. Test doses of 10 mg D-MTX were administered i.v. and orally to nine patients and its plasma concentration and urinary excretion were followed. The plasma curves after an i.v. bolus injection of D-MTX declined strictly biexponentially and reached zero after about 16 h. The elimination rate constants were estimated as the terminal first order rate constants. The absorption of orally administered D-MTX, estimated by its 24 h urinary recovery, in all cases was less than 3% of the dose administered. The insignificant intestinal absorption made it possible to estimate the renal and biliary secretion rates of D-MTX from the overall elimination rate constant and from the fraction of the dose excreted in urine. In three of the patients, elimination rate constants both for D-MTX and L-MTX were obtained. The renal elimination rates of the two compounds were found to be nearly identical. The median ratio of biliary/renal excretion of D-MTX was 0.94 (range 0.41-1.50), which indicates extensive entero-hepatic cycling and active absorption of L-MTX at the therapeutic dose levels used in psoriasis.

Administration, Oral↗
PubMed1984

Nonlinear renal elimination kinetics of methotrexate due to saturation of renal tubular reabsorption.

The plasma concentration and urinary excretion of methotrexate were followed in twelve psoriatic patients after intravenous and oral doses of methotrexate ranging from 7.5 to 30 mg. In six of the patients, a nonlinear relation was found between the fractional amount of methotrexate excreted in the urine and the corresponding area under the plasma concentration-time curve. The methotrexate clearance was found to be increased during the initial high plasma concentration, probably due to saturation of the tubular reabsorption of methotrexate. Considerable interindividual variation was found in the apparent saturation point of the active reabsorption, but up to 500-800 ng/ml first order kinetics still applied. At plasma concentrations below saturation, the renal clearance of methotrexate ranged from 52-102 ml/min (mean +/- SD, 83 +/- 19.4 ml/min).

Absorption↗
PubMed1984

Pharmacokinetics of methotrexate in erythrocytes in psoriasis.

The intraerythrocytic levels of folate and methotrexate were measured in 25 patients on long-term methotrexate therapy for recalcitrant psoriasis. The mean steady state concentration of methotrexate in erythrocytes was 85 nmol/l and the mean erythrocyte folate concentration was 729 nmol/l. A linear correlation was not observed between these parameters, but the greatest methotrexate accumulation was found in cells at the lower end of the erythrocyte folate concentration range. In 5 patients started on methotrexate therapy the erythrocyte concentrations of methotrexate and folate were followed over 6 months. 3-4 days after the first dose, methotrexate had been accumulated against a concentration gradient in the erythrocytes. The methotrexate concentration increased steadily until the steady state level was reached after 4-6 weeks. The steady state level was maintained during the 6 month observation period. The erythrocyte folate concentration did not change during this period. The data suggest that methotrexate polyglutamate synthesis within the circulating erythrocyte is a major cause of methotrexate accumulation in these cells.

Adult↗
PubMed1984

The effects of carbamazepine and valproate on folate metabolism in man.

The effect of carbamazepine and valproate treatment on folate metabolism was studied in 11 epileptic patients. The absorption of folic acid and of Pteroyl-gamma-L-glutamyl-gamma-L-glutamyl-L-glutamic acid, a synthetic substrate for intestinal folate deconjugase , was measured prior to and after 2 months of antiepileptic therapy with either carbamazepine (5 cases) or valproate (6 cases). After 2 months' treatment, the area under plasma concentration versus time curve was significantly decreased and t-max (time when maximal plasma concentration is obtained) was significantly prolonged. No inhibition of intestinal folate deconjugation was observed and the liver metabolism of folic acid was found to be unaffected by the treatment. These findings are interpreted as an inhibition of intestinal folic acid absorption caused by the antiepileptic therapy.

Adolescent↗
PubMed1981

Methotrexate in the plasma and cerebrospinal fluid of children treated with intermediate dose methotrexate.

Serious complications can follow treatment with intermediate dose methotrexate of acute lymphoblastic leukemia in childhood. Toxicity has been shown to be correlated to plasma methotrexate concentrations. During intravenous infusions of methotrexate (500 mg/m2) the mean concentrations achieved 1 to 41/2 hours after the start of infusion were 1.3 X 10(-7) mol/l in cerebrospinal fluid and 1.7 X 10(-5) mol/l in plasma. At 72 hours after start of methotrexate infusion, plasma methotrexate concentrations were significantly higher in cases with symptoms of toxicity. In all the children who developed toxic symptoms 72-hour plasma methotrexate concentration was above 1 X 10(-7) mol/l. Assuming that leucovorin is given 48 hours after the start of methotrexate infusion, 72-hour plasma methotrexate is suitable for detection of patients at risk for toxicity. In children treated with intermediate dose methotrexate we therefore recommend estimating plasma methotrexate concentration 72 hours after the start of infusion, and instituting supplementary leucovorin when plasma methotrexate concentration exceeds 1 X 10(-7) mol/l.

Brain Neoplasms↗
PubMed1981

Radioimmunoassay for pteroylglutamic acid.

I describe a radioimmunoassay for specific determination of pteroylglutamate in plasma, erythrocytes, and urine. Antiserum was raised in rabbits immunized with a conjugate of pteroylglutamic acid and methylated bovine serum albumin. The lowest detection limit of the assay was 0.1 microgram/L; the coefficient of variation ranged from 4.01 to 14.63%. No significant interference was demonstrated from tetrahydrofolic acid, 5-methyl-tetrahydrofolic acid, or methotrexate. Under normal sampling and storing conditions dihydrofolic acid was oxidized to pteroylglutamic acid and estimated as such in the assay. The clinical applicability of the assay is demonstrated by measurements of pteroylglutamate absorption rates after oral doses of pteroylglutamic acid or pteroyltriglutamic acid and by the estimation of the accumulation of pteroylglutamate and dihydrofolate in plasma during therapy with methotrexate.

Erythrocytes↗
PubMed1980

Anxiety and sedation during a stressful situation after single dose of diazepam versus N-desmethyldiazepam--a controlled trial.

Twenty milligram diazepam (DZ) was compared with 20 mg of its main metabolite N-desmethyldiazepam (NDDZ) as single dose, oral premedication in a genuine stressful situation. Fifty patients participated in the randomized, double-blind controlled study. Anxiety and sedation were measured the day before an operation and one hour after premedication, just before the operation. NDDZ was significantly less sedative while the degree of anxiety was rated equal in the two groups. The results may support the hypothesis that a competition between DZ and NDDZ can explain the shift in the effect profile of DZ during long term treatment.

Adult↗
PubMed1980

Kinetics and neuropsychologic effects of IV diazepam in the presence and absence of its active N-desmethyl metabolite in humans.

In 12 healthy volunteers the kinetics and neuropsychological actions of IV diazepam (DZ) (single dose) were studied with and without the presence of its main metabolite N-desmethyldiazepam (NDDZ). Both the maximal plasma concentration and the steepness of the alpha-slope were correlated with variations in the corresponding continuous reaction time (CRT). EEG profiles, CRT and clinical ratings for anxiety and sedation all showed significant changes between the situations with the metabolite present or absent, but no significant correlation could be found with the kinetic pattern of DZ in the two situations. Tolerance to NDDZ did not develop. The results indicate that the presence of the active metabolite changes the pharmacodynamic profile of the parent compound probably by an interaction at the receptor site between DZ and NDDZ. Changes in the spectrum of effects during long-term therapy with DZ may, therefore, partly be explained in this way.

Adolescent↗
PubMed1979

Noninvasive assessment of cardiac motion: comparison of the apexcardiogram and cardiokymorgram.

The apexcardiogram (ACG) and cardiokymogram (CKG) (displacement cardiogram) tracings were compared in 45 patients with a variety of cardiac diseases and in 16 normal subjects. The ACG and CKG were generally comparable in waveform and timing of standard tracing intervals; however, on a case by case comparison frequent discrepancies between the ACG and CKG were observed. In 13 patients where no ACG could be recorded, an interpretable CKG tracing was obtained. However, the CKG produced frequent artifacts, mirror images, was very sensitive to probe position, and was judged to be of limited advantage over the ACG.

Adult↗
PubMed1977

Production of Methotrexate antiserum in rabbits: the significance of immunogen solubility, hapten content, and mode of administration of the antibody response.

A method for raising specific antibodies of high avidity against Methotrexate in rabbits is described. The antibody response was tested after intramuscular and after multi-site intradermal adminstration of three different immunogens. Antisera of high specificity and avidity were obtained by multi-site intradermal administration of a water-soluble immunogen with high hapten content (40 mol hapten/mol protein). A water-soluble immunogen with low hapten content (15-18 mol hapten/mol protein) resulted in antisera of high specificity but low avidity. No antibody response was obtained with a water-insoluble immunogen with high hapten content (40 mol hapten/mol protein).

Animals↗
PubMed1976

Neuropsychologic effects of diazepam related to single dose kinetics and liver function.

The neurophysiologic and neuropsychologic effects and their relation to the kinetics of diazepam (DZ) were studied in 10 patients with impaired liver function of various degrees and in three normal subjects after 10 mg DZ i.v. The plasma concentration data were treated according to a two-compartment open model. Neurophysiologic effect measurements were obtained from galvanic skin response, continuous reaction times (CRT), heart rate, and averaged evoked potentials; neuropsychologic measurements were obtained from trail making A + B, hidden pattern, word fluency, and subtraction tests; in addition, clinical effects were rated by Beechers Mood Scale and Spielbergers Anxiety Scale. Except for trail making A and word fluency all tests discriminated well between the experimental conditions with or without diazepam. No difference from normal in the response to acute diazepam administration could be detected in patients with reduced liver function. A linear correlation between prolongation in CRT and DZ log plasma concentration was demonstrated in the entire, heterogenous patient material. In the clinical ratings only items of a predominantly sedative and autonomic significance responded to the diazepam injection, while predominantly anxiolytic items did not.

Diazepam↗
PubMed1976

Pharmacokinetics of diazepam in disordered liver function.

The plasma elimination curves of diazepam following intravenous administration of 10 mg were studied in nine patients with cirrhosis of the liver and four patients without liver disease. The data were analyzed according to a two compartment model. The mean biological half-life (T/2) of diazepam was increased five-fold in patients with cirrhosis compared to the controls (164 hours vs. 32.1 hours). The plasma clearance of diazepam could be correlated neither with a quantitative measure of liver function, as estimated by galactose elimination capacity, nor to semiquantitative measures of liver function, such as serum albumin and prothrombin. It is suggested that the plasma clearance of diazepam is an inaccurate index of its rate of hepatic metabolism due to the complex kinetics of the drug.

Adult↗
PubMed1976

Kinetics and dose calculations of amikacin in the newborn.

The pharmacokinetics of a new aminoglycoside, amikacin, was evaluated in 37 infants between 1 and 34 days old. Fifteen were below 2,500 gm in weight. Initial studies, including intravenous infusion in some of the infants, indicated that the disposition of amikacin was best described by a 2 compartment model. The absorption was evaluated in 8 of the infants after intramuscular injection of 7.5 mg amikacin per kilogram of body weight. The absorption rate, estimated by the tmax, was significantly faster than reported in adults. The total body clearance and apparent volume of distribution were studied in 22 infants after the same dose of amikacin intramuscularly. The body clearance expressed in relation to body surface or body weight was significantly less than in adults and correlated with the postnatal age. No correlation could be demonstrated between clearance and gestational age or birth weight. The volume of distribution per kilogram was significantly greater than in adults. On the basis of the derived kinetic parameters, a dose schedule is presented. In 5 children there was a reasonable agreement between the measured and predicted serum levels.

Absorption↗
PubMed1976

Clinical and psychological effects of intravenous diazepam related to plasma levels. A controlled, double-blind, cross-over study in oral surgery involving local analgesia.

In a controlled, double-blind, cross-over study with diazepam (DZ) and placebo (PL) various clinical, psychological, and pharmacological parameters were studied in 33 patients having identical impacted third molars removed. The patients were admitted to the study consecutively and nonparametric statistics were used throughout the study for the evaluation (Wilcoxon's matched-pairs signed test). The following aspects were examined: Continous reaction times (CRT), rating scales (a.m. Beecher), blood pressure, pulse, plasma concentration of DZ and of N-desmethyldiazepam, visual changes, amnesia, adverse reactions, recalling of duration of surgery, orientation in time, phlebitis, and final evaluation performed by the patient. The operative conditions were found to be excellent, and only a few adverse effects were noticed. The patients expressed an overall enthusiasm about the sedation. In the rating scales only the predominantly sedative items were affected and not the anxiolytic ones. Neither the heart rate nor the systolic blood pressure were significantly changed; on the contrary, the DZ-group was less affected than the PL-group when maximum increases in the systolic blood pressure were compared in the two groups. The continuous reaction times were significantly correlated to the plasma concentrations of diazepam, especially 1 hour after sedation. The reported recurrence of initial clinical symptoms 6 hours after sedation due to the N-desmethyldiazepam could not be demonstrated in this study. The CRT has proved itself to be of great value in discriminating between different kinds of cerebral affections; the patients with DZ-intoxication showed significantly faster CRT 1 hour after injection than did patients suffering from well-documented cerebral disorders such as organic brain damage or hepatic encephalopathia.

Adolescent↗