Sven J. Dencker

Imipramine: clinical effects and pharmacokinetic variability.

Sixty-six hospitalized depressed patients were treated for 4 weeks with imipramine (Tofranil®) 225 mg/day. Blood samples were drawn twice weekly 15 h after the last drug intake, and IP and DMI concentrations in plasma were assayed by quantitative in situ thin-layer chromatography. Clinical rating was carried out once weekly by Hamiltons Rating Scale (HRS), Becks Depression Inventory, WHO Depression Scale (Quantitative Part), and a side-effect scale. The patients were classified on the basis of the WHO Depression Scale (Qualitative Part) as ‘endogenous’ (N=37) or ‘non-endogenous’ depressions (N=29). Antidepressive effect was evaluated on the basis of the posttreatment rating scores.In patients classified as ‘endogenous’ depressions all 12 responding patients (HRS≦7) had plasma levels of IP>45 μg/l and DMI>75 μg/l, whereas 11 out of 14 nonresponding patients (HRS≧16) had plasma levels of one or both compounds below these limits. Ten out of 12 responders had levels of IP+DMI above 240 μg/l, and all nonresponders had levels of IP+DMI below this limit. Patients with partial response (HRS: 8–15) formed an overlapping group. There was no sign of an upper plasma level limit for the antidepressive effect of imipramine.The plasma level/effect relationship was less clear in patients with ‘non-endogenous’ depressions, since several of them responded at low plasma levels.Some relationship between effect on blood pressure (orthostatic effect) and high plasma levels of IP and DMI was found.Using a plasma level limit of IP≷45 μg/l and DMI≷75 μg/l, it was possible to predict the response of the ‘endogenous’ depression group for 10 out of 12 responders and 10 out of 14 nonresponders on the basis of plasma level measurements obtained after 1 week of treatment.

Steady-state kinetics of imipramine in patients.

Steady-state plasma level kinetics were studied in 76 patients given imipramine (IP) 150 to 225 mg/day for 2–5 weeks. IP was given in three divided doses at 8.00 a.m., 1.00 p.m. and 5.00 p.m. Plasma concentrations of IP and its active metabolite desipramine (DMI) were determined by quantitative in situ thin-layer chromatography. The plasma levels of IP and DMI showed pronounced flucutations throughout the day with a ratio of about 2 between highest and lowest level. Patients with steady-state levels of IP and/or DMI below 50 μg/l reached this within 1 week of treatment. Patients with higher steady-state levels reached steady-state concentrations within 2–3 weeks. There were some intraindividual fluctuations in plasma levels from week to week after steady state had been reached (coefficient of variation: 10–20%). Interindividually, the steady-state levels corrected to a dose of 3.5 mg/kg per day varied considerably: IP: 6–356 μg/l, DMI: 24–659 μg/l and IP+DMI: 58–809 μg/l. The steady-state plasma levels showed a skew distribution that became normal by logarithmic transformation. The IP/DMI ratio ranged from 0.07 to 5.5 with a median value of 0.47. Compared to data from amitriptyline treated patients the IP/DMI ratios had significantly lower median value and larger variation than the corresponding plasma level ratios of amitriptyline/nortriptyline. Several statistically significant differences in steady-state levels between age groups were found. For IP: Women aged 30–39 had lower levels than women aged 20–29, 40–49, and 50–59, and men aged 50–59 and 60–65; men aged 30–39 had lower levels than men aged 60–65. For DMI: Women aged 30–39 had lower levels than women aged 50–59.

High doses of fluphenazine enanthate in schizophrenia: A CONTROLLED STUDY

The results from this controlled study of 12 schizophrenics refractory to ordinary doses of neuroleptics indicate that treatment with fluphenazine enanthate in higher doses than normal (10–20 times higher) might give reduction in psychopathology beyond what can be obtained with normal doses. In four patients the symptom reduction on high doses was pronounced. Moreover, we found that the high fluphenazine plasma levels demonstrated did not increase extrapyramidal and general side effects. The results presented also speak in favour of certain “non‐responding” patients needing a higher plasma level of a neuroleptic drug than the average patient.

Serum concentrations of cis(Z)-flupentixol and prolactin in chronic schizophrenic patients treated with flupentixol and cis(Z)-flupentixol decanoate.

Nine chronic schizophrenic patients selected from three hospital departments were treated with flupentixol (orally and IV) and cis(Z)-flupentixol decanoate in Viscoleo (IM) in a three-phase pharmacokinetic study. Oral administration (single and repeated dosage) showed a relatively slow absorption with maximum serum concentration around 4 h after administration. Intravenous injection indicated multicompartment kinetics for cis(Z)-flupentixol. The biological half-lives calculated after the different doses were the same, indicating that the pharmacokinetics of cis(Z)-flupentixol does not differ between single and repeated administration and does not change when moderately higher doses are given. The bioavailability of orally administered cis(Z)-flupentixol was calculated to be about 40% with IV injection as reference. After IM administration maximum serum concentration was seen between 4 and 10 days in most patients. Calculation of a disappearance half-life gave very variable results, indicating that the release of the drug from the oil depot is not a monoexponential process. The intramuscular depot had a much lower bioavailability than IV injection, which means that steady state has not been obtained after 8 weeks of depot treatment. Serum prolactin concentrations were elevated during neuroleptic treatment, but no correlation was found between prolactin concentrations and the serum concentrations of cis(Z)-flupentixol. A correlation between the changes in clinical ratings and concentrations of cis(Z)-flupentixol or prolactin was not found.

Intestinal absorption, demethylation, and enterohepatic circulation of imipramine.

The intestinal absorption and metabolism of single oral doses of imipramine (ip) have been studied in man by portal catheterization. The concentration of ip and the formed desipramine (dmi) was followed in blood‐plasma obtained from the portal and cubital veins. The absorption of ip seemed to be completed 80 min after the administration of the drug. There was no sign of demethylation of ip during the passage across the intestinal wall. Evidence was found of an enterohepatic circulation of both ip and dmi.

Plasma fluphenazine and prolactin levels in schizophrenic patients during treatment with low and high doses of fluphenazine enanthate

The relationship between plasma prolactin (PRL) and drug levels in patients receiving neuroleptic drugs is of special interest in view of evidence that the PRL elevation induced by these durgs reaches its maximum at sub-therapeutic doses.Plasma PRL and fluphenazine (FPZ) levels were measured by radioimmunoassay (RIA) in each of 11 chronic schizophrenics (nine men, two women) during two 4-week periods of treatment with FPZ enanthate at a ‘High Dose’ (250 mg per week) and a ‘Low Dose’ (12.5 mg per week) given in random order.Plasma PRL levels were above normal in 9 of 11 subjects during the last week of Low Dosage. High Dosage resulted in PRL levels significantly greater than found during Low Dose treatment in 9 of 11 patients. Thus the PRL response had not reached its “ceiling” during Low Dosage in most patients.A significant correlation between PRL and FPZ levels was found in seven subjects; evidence that immunoreactive FPZ levels relate to an effect caused by blockade of dopamine receptors. The plasma FPZ pattern between injections during week 1 of Low Dosage was remarkably stable; High Doses produced an initial drug peak at 1–2 h and a secondary peak occurring on days 2–3 followed by a return to preinjection levels by day 7.

Quantification of naturally occurring benzodiazepine-like substances in human breast milk

The possible occurrence of benzodiazepine-like substances in human breast milk was investigated in 35 healthy, newly delivered women who were known not to be taking benzodiazepines. Maternal blood samples and a sample of breast milk were obtained on the fifth post partum day. A radioreceptor technique (lower limit of detection 1.5 ng/ml; difference between duplicates at various concentrations <7%) was used for measuring benzodiazepine-like substances in blood and breast milk (with and without prior extraction). No benzodiazepine-like substances could be demonstrated in any of the blood samples taken from the 35 women. Measurable concentrations of benzodiazepine-like substances were demonstrated in all but 1 of the 35 breast milk samples. The mean concentration of benzodiazepine-like substances for all 35 women was 4.3±2.3 ng/ml (range 0–9.3 ng/ml) expressed as lorazepam. The corresponding value for extracted breast milk was 2.6±1.5 ng/ml (range 0–7.0 ng/ml). There was no association between concentrations of benzodiazepine-like substances in breast milk and maternal age, weight, height and body mass or parity, or the sex of the infant and infant birth weight. We suggest that non-detectable amounts of benzodiazepine-like substances in serum are concentrated in the mammillary glands and excreted in a higher concentration in breast milk. It is less likely that the relevant benzodiazepines are produced in the mammillary glands.

Demonstration of large blood protieus in cerebrospinal fluid

THE ORIGIN of the proteins in the cerebrospinal fluid is still conjectural. The electrophoretic mobility of these proteins when studied with paper electrophoresis does not differ from that of serum proteins. In addition, the cerebrospinal fluid proteins are usually precipitated by antihuman serum, which also suggests that they are identical with the serum proteins. On the other hand, in some respects, the proteins in cerebrospinal fluid differ from those in blood. The normal fluid protein pattern will thus show 1 or 2 prealbumin fractions and a &-fraction, which are not found in the serum by usual paper electrophoresis. The p,-globulin fraction is rather large and the 7-globulin fraction relatively low in the cerebrospinal fluid in comparison with serum. Furthermore, by immunoelectrophoresis, the transfenin is found to have a different appearance in the cerebrospinal fluid.l.2 The protein pattern of pathologic cerebrospinal fluid sometimes resembles that of serum very much, and increased diffusion of blood proteins into the cerebrospinal spaces then may be assumed. This resemblance of the electrophoretic curve for fluid proteins with serum proteins may not entirely be due to diffusion of proteins into the central nervous system. Thus, Frick and Scheid-Seydel,a who used labeled proteins, showed that proteins may be synthetized within the central nervous system. Therefore, the possibility of demonstrating or excluding the presence of large molecules of normal blood proteins-which because of their size and molecular complexity per se can be excluded as being of central nervous originin the cerebrospinal fluid may be valuable. Microimrnunoelectrophoresis, which requires only very small amounts of protein sample, permits serial analysis of a given specimen with special antisera and staining methods. This paper is concerned with the Occurrence and diagnostic value of diffusion of large normal blood proteins into the cerebrospinal fluid. The fluid was studied for the presence of the following 4 blood proteins: 1. al-Epoprotein is an ellipsoid-spherical molecule with a molecular weight of 200,000. Its appearance in the cerebrospinal fluid has been discussed in a previous paper.* 2. a2-macroglobulin was isolated by Schultze and associatess in 1955. It appears that the cerebrospinal fluid has hitherto not been studied for this protein. It is a spherical glycoprotein with a molecular weight of 846,000. On paper electrophoresis, this protein migrates as an a2-globulin. 3. /+lipoprotein is a spherical molecule with a molecular weight of 1,300,000. The occurrence in the cerebrospinal fluid of this component has been discussed in the above-mentioned paper. 4 4. Fibrinogen has a cross-sectional diameter of 38 A and a length of 700 A. It is thus a very long ellipsoid molecule. Its molecular weight is 330,000. Fibrinogen has been demonstrated also in cerebrospinal fluid samples without any clotting web. 6

CIRCULATORY STUDIES DURING PHYSICAL EXERCISE IN MENTALLY DISORDERED PATIENTS. II: Effects of Physical Training in Patients with and without Administration of Chlorpromazine

1. Nine patients who were not given chlorpromazine (mean age 29 years), and eight patients (mean age 30 years) who received large doses of chlorpromazine (1500–3600 mg/day) were studied, with determination of oxygen uptake, ventilation, cardiac output, arterial blood pressure and arterial blood lactate, pyruvate and noradrenaline concentrations at rest supine, and when cycling in the sitting position on a bicycle ergometer with successively increasing work loads. The heart volume was measured roentgenologically with the patient prone. 2. Four patients were studied before, and 1.5–5 months after, the beginning of chlorpromazine treatment. They maintained their physical performance during that period. 3. All patients had a low physical working capacity on the bicycle ergometer; and most of them had a reduced stroke volume in relation to the heart volume. 4. The patients treated with chlorpromazine tended to show further reduction in stroke volume and lower cardiac output during exercise than those who did not receive such treatment. 5. The arterial blood pressure at rest was largely the same in the two groups of patients, but was reduced during exercise in those treated with chlorpromazine. Chlorpromazine did not cause a significant change in peripheral vascular resistance. 6. A high blood noradrenaline level was recorded during exercise after treatment with chlorpromazine. 7. A small stroke volume, especially in patients treated with chlorpromazine, and the fall in arterial blood pressure in this group, are factors that limit physical performance. The importance is stressed of exercise tests in clinical routine in the activation of patients receiving phenothiazines, at least for those receiving large doses.

THE CEREBROSPINAL FLUID γ‐GLOBULIN PROFILE IN SUBACUTE SCLEROSING LEUCOENCEPHALITIS

The diagnosis of subacute sclerosing leucoencephalitis (SSLE) is now widely regarded as including such cases as those described by Dawson, by van Bogaert and by Pette & Doring. The disease is more common in childhood and adolescence than in adult age. The onset is usually insidious and mental symptoms are often predominant. Eventually deterioration and various rather characteristic neurologic symptoms appear and the outcome is usually fatal within 2-5 years. The diagnosis is supported by histo-pathologic findings (van Boguert 1957), fairly characteristic electroencephalographic abnormalities (Radermecker & Poser 1960), and excessively large amounts of total y-globulin in the cerebrospinal fluid (CSF) without any corresponding increase in serum. The high total y-globulin value in the CSF suggests involvement of the immunologic apparatus, and the discrepancy between the findings in the CSF and those in the serum in respect of the y-globulin amount argues for an isolated process within the central nervous system. This aspect will be further elucidated with the immuno-electrophoretic technique in the relevant study. Lowenthal, Kurcher & van Sunde using agargel-electrophoresis, however, found an increase of y-globulin fractions of slow mobility in the CSF as well as in the serum in SSLE, a finding indicating a systemic disease.