Biomedical subjects
Publications and source records attributed to P Schulz.
Prescribing patterns were studied in a psychiatric outpatient clinic. Psychiatrists tended to prescribe large quantities of antidepressants or other drugs. In contrast, the daily doses for antidepressants and neuroleptics were often too low. Significant variations were noted between three outpatient clinics in the choices among a various psychotropic drugs from a given therapeutic group.
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The amount of ATP, ADP and AMP and also the adenylate energy charge and the ATP/ADP ratio were determined in preimplantation mouse embryos (strain NMRI) in vivo. The ATP content decreased from 0.64 pmol at fertilization to 0.21 pmol in late blastocysts. ADP decreased from 0.1 pmol in the zygote to 0.06 pmol in 4-8-cell embryos and increased again to 0.15 pmol in late blastocysts. AMP changed considerably at the 1-cell and the 2-cell stage and increased from 0.04 to 0.2 pmol between the 4-cell and the late blastocyst stage. These developmental changes between fertilization and implantation result in a continuous decline of the total amount of adenine ribonucleotides (from 0.79 to 0.64 pmol), of the adenylate energy charge (from 0.87 to 0.45) and of the ATP/ADP ratio (from 6.4 to 1.4). In C57BL embryos developing to the 2-cell stage in vivo or in vitro there was a decrease in ATP content, as in NMRI embryos in vivo whereas the ATP content remained unchanged in NMRI embryos during culture to the 2-cell stage (no further development in vitro). In blastocysts cultured for 24 h in media supporting differentiation during implantation (MEM and NCTC-109) the content of ATP and ADP increased but AMP remained constant. The total adenine ribonucleotide content rose to 1 pmol and the ATP/ADP ratio and adenylate energy charge remained unchanged. After 48 h of culture in the two media to late blastocysts there was a decrease in ATP, an increase in AMP and a decline in adenylate energy charge and ATP/ADP ratio, as occurs in vivo.
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Three mucopolysaccharides (MPS) used in the treatment of degenerative joint disease were compared to heparin to establish their relative potencies on 3 coagulation tests, the aPTT, the antifactor Xa activity and the dilute thrombin time. One of the compounds, Arteparon, was one fourth as potent as heparin on the aPTT, but had little or no influence on the 2 other tests. Further in vitro studies suggested that Arteparon acted at a higher level than factor Xa generation in the intrinsic amplification system and that its effect was independent of antithrombin III. In vivo administration of Arteparon confirmed its anticoagulant properties, which raises the question of the clinical use of this MPS.
In a companion paper we described the disposition of a 75 mg single dose of amitriptyline in normal volunteers who were phenotyped as extensive or poor metabolizers of debrisoquine and bufuralol, and had a four-fold range in the oral clearance of the antidepressant, 50 mg of amitriptyline was also administered to the same volunteers. This paper compares the results after both doses and suggests that the disposition of amitriptyline is linear even in subjects with a low oral clearance. There was no relation between the pharmacokinetic data and the intensity of sedation or of psychomotor impairment.
The effect of low doses of heparin on the binding of phenytoin and prazosin to plasma proteins was evaluated in four normal subjects. Heparin activates the hydrolysis of triglycerides in plasma. The ensuing increase in non-esterified fatty acids (NEFA) was more marked in vitro than in vivo and increased the free fraction (FF) of phenytoin and prazosin in plasma. The higher FF caused a change in the plasma to whole blood ratio (P/B ratio) of both drugs. The changes in FF and P/B ratio after heparin were small, but could be of significance in pharmacokinetic studies.
The disposition of a single parenteral or single oral dose of amitriptyline was followed in seven young (mean age 22 yr, range 21 to 23) and five elderly (mean age 71 yr, range 62 to 81) healthy men. The mean systemic clearance did not change with age (10.8 +/- 2.1 ml/min/kg in elderly and 12.5 +/- 2.3 ml/min/kg in young subjects). Mean t 1/2 was longer in the older (21.7 +/- 2.9 hr) than in the younger group (16.2 +/- 6.1 hr) as a result of an increase in the volume of distribution (17.1 +/- 2.4 and 14.1 +/- 2.0 l/kg). The bioavailability and the fraction of the drug bound to plasma proteins did not change with age. Single doses of amitriptyline were not well tolerated clinically by either elderly or young subjects, which confirms the need for a gradual buildup in the therapeutic regimen and for close clinical surveillance of elderly depressed patients treated with amitriptyline.
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Using the Schedule for Interviewing Borderlines and the MMPI, 20 subjects diagnosed as borderline and/or schizotypal personality disorder were examined to determine 1) whether having one diagnosis affected the likelihood of having the other, 2) the amount of diagnostic overlap between the two diagnoses, and 3) whether different MMPI profiles could be found. The results indicated some overlap but also some differentiation between the borderline and schizotypal disorders. The modest overlap in diagnostic criteria was consistent with other studies and justifies the continued separation of the two diagnoses. The MMPI may be used as an initial screen to identify persons who warrant further evaluation for a borderline personality disorder but would not be appropriate as a screen for a schizotypal personality disorder.
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A sensitive, specific, high-pressure liquid chromatographic method using an internal standard was developed for the determination of amitriptyline and its major metabolites in whole blood. Analysis was carried out on a microparticulate silica column with a mobile phase consisting of acetonitrile-methanol-aqueous ammonium hydroxide (93:7:0.4). Linear calibration curves ranging to 250 ng/ml were obtained for all compounds using UV absorbance detection at 220 nm. The lower limit of detection was 2 ng/ml for amitriptyline and 10-hydroxyamitriptyline, and 6 and 16 ng/ml for nortriptyline and its 10-hydroxylated metabolite, respectively. Human whole blood samples collected after single intravenous and single oral doses can be analyzed using this procedure.
Single doses of the antidepressant amitriptyline were given to 12 normal males. After parenteral or oral dose of the drug, the concentration of growth hormone in plasma rose in one third of the subjects. Amitriptyline could have multiple and potentially opposite pharmacological actions on growth hormone. Antidepressants appear to be poor pharmacological tools for assessing the regulation of growth hormone release.
We have measured the metabolites (demethylated and hydroxylated) of amitriptyline in a group of seven normal volunteers. They were phenotyped as extensive or poor metabolizers using debrisoquine and bufuralol. The results demonstrate that the oxidative metabolism (aliphatic hydroxylation) of amitriptyline is under the same genetic control as that of debrisoquine and bufuralol. However, phenotypic polymorphism cannot be used to predict amitriptyline blood concentration after a single oral dose, since the principal metabolic pathway of amitriptyline is demethylation and not aliphatic hydroxylation.
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