A comparison of clinical and research DSM-III-R diagnoses of schizophrenia in a Finnish national birth cohort

As a prerequisite to the use of the Finnish National Hospital Discharge Register in psychiatric epidemiological research, we studied the diagnostic reliability of the register in terms of the psychiatric morbidity experienced by a national birth cohort. We investigated all entries to the register for a sample based upon the Northern Finland 1966 birth cohort at the age of 16 years (n=11017). Until the end of 1993 (age 27 years), a total of 563 subjects had a register diagnosis indicating a psychiatric illness, 37 of them being schizophrenia. When operational criteria (DSM-III-R) were applied to clinical information in the available original hospital records for cases of psychosis, personality disorder and substance abuse (n=249), 71 fulfilled criteria for schizophrenia, including all of the 37 cases in the register and an additional 34 (48% false-negatives), most frequently diagnosed in the register as schizophreniform or other psychosis. Despite the official use of DSM-III-R nomenclature, it appears that the clinical concept of schizophrenia in Finland, manifest within the register, remains very restrictive. The application of operational criteria is a necessary prerequisite for scientific research on schizophrenia.     

Effects of monoamine uptake inhibitors given early postnatally on monoamines in the brain stem,caudate/putamen and cortex,and on dopamine D1 and D2 receptors in the caudate/putamen

Summary Rats were treated with desipramine 5mg/kg, nomifensine 10mg/kg, zimelidine 25 mg/kg or with 0.9% sodium chloride once a day during the second and third weeks after birth, and brain stem, caudate/putamen and cortical monoamines, and caudate/putamen dopamine D₁ (³[H]SCH 23390) and D₂ (³[H]spiroperidol) receptor binding were measured when rats were at two months of age. In the brain stem, the concentration of 3-methoxy-4-hydroxy-phenyl glycol was increased in nomifensine rats and the ratio of 5-hydroxyindoleacetic acid to 5-hydroxytryptamine was increased in zimelidine rats. In the caudate/putamen, the concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid and the ratio of homovanillic acid to dopamine were increased in desipramine rats; neither³[H]SCH 23390 nor³[H]spiroperidol binding were affected by any of the three monoamine uptake inhibiting antidepressants studied. In the cortex, the ratio of 5-hydroxyindoleacetic acid to 5-hydroxytryptamine was increased in desipramine and zimelidine rats. The findings suggest that desipramine but not nomifensine increases the metabolism of dopamine in the caudate/ putamen and nomifensine but not desipramine increases the metabolism of norepinephrine in the brain stem, and furthermore that the metabolism of serotonin is affected by desipramine as well as by zimelidine. It is possible that also treatment of women with these drugs during late pregnancy causes long-lasting changes in the brain of human fetus.     

Factors determining the relationship between renal and hepatic excretion of xenobiotics

Relation between kidney and liver in the excretion of drugs depends on the physicochemical properties of each substance tested. The calculations of this relationship are based on a so-called rank coefficient (0-100) calculated from molecular weight, lipophilicity, degree of dissociation under physiological conditions, and protein binding rate. The results of the correlation between one of these physicochemical values and drug elimination were stochastically. Experiments were performed with 9 test substances which were distinctly different concerning their physicochemical features. Substances with a rank coefficient less than 20 (low molecular weight, low lipophilicity, preferentially ionic at pH 7.4) are eliminated effectively via the kidney. Compounds having an intermediate rank coefficient (40-60) were quantitatively excreted into urine as well. For drugs with high ranks greater than 60 (high values of molecular weight, protein binding, and lipophilicity, almost exclusively nonionic), renal excretion can be neglected. Quite inverse relations between ranks and hepatic excretion have been found: low ranks indicate an ineffective secretion of the respective drug into bile. With increasing ranks (40-60), biliary excretion increases and reaches a maximum (approximately 40% of supply). This maximum is caused by limited hepatic blood flow and by the capacity of hepatic uptake carriers. Blockade of one elimination pathway (bilateral nephrectomy or bile duct ligation) is followed by a sufficient compensation of drug excretion via the alternative elimination route only, if the test substance belongs to the intermediate group (ranks between 40 and 60). For substances with high or low ranks a compensation of drug excretion can be excluded.     

Spinal MRI in vacuolar myelopathy, and correlation with histopathological findings

We correlated MRI features with histopathological findings in an HIV-positive patient with vacuolar myelopathy. On MRI symmetrical nonenhancing high-signal areas in the posterior columns on T2-weighted images result from extensive vacuolation visible on histological sections. Received: 18 November 1997 Accepted: 23 March 1997     

A rat model of monitoring liver allograft rejection

Rat models are often used to study liver allograft rejection. We have established a model for rat liver allograft rejection, monitored by fine needle aspiration biopsy (FNAB), in the strain combination PVG-to-BN with a mean survival time of 37 ± 20 days. In this model, we observed acute rejection with an intense peak of lymphoid blasts and lymphocyte-dominated inflammation in the FNAB [9.1 ± 3.0 corrected increment units (CIU)], and an eventual increase in macrophages (up to 4.2 ± 4.4 CIU), together with fibrosis and parenchymal necrosis in the graft. Markers of immune activation, such as an increase in IL-2-receptor (from 1 % ± 2 % to 21 % ± 13 %) and class II (from 20 % ± 9 % to 43 % ± 13 %) expressing lymphoid cells and induction of ICAM-1 in the graft, were consistent with the overall cellular response. The FNAB correlated well with parallel graft histology. In this rat model, the atraumatic monitoring makes a close follow-up possible without having to sacrifice the experimental animals. This saves work, animals, and costs in the study of liver rejection. Received: 2 July 1996 Accepted: 28 October 1996     

A glutamatergic mechanism for aluminum toxicity in astrocytes

The effect of aluminum on the metabolism of glutamate and glutamine in astrocytes was studied to provide information about a possible biochemical mechanism for aluminum neurotoxicity and its potential contribution to neurodegenerative disease. Exposure of cultured rat brain astrocytes for 3–4 d to 5–7.5 mM aluminum lactate increased glutamine synthetase activity by 100–300% and diminished glutaminase activity by 50–85%. Increased glutamine synthetase enzyme activity was accompanied by an elevated level of glutamine synthetase mRNA. Alterations in glutaminase and glutamine synthetase following aluminum exposure caused increased intracellular glutamine levels, decreased intracellular glutamate levels, and increased conversion of glutamate to glutamine and the release of the latter into the extracellular space. The results of these changes may alter the availability of neurotransmitter glutamate in vivo and may be a mechanism for the aluminum neurotoxicity observed in individuals exposed to the metal during dialysis procedures and other situations.     

Pharmacokinetics of terodiline and a major metabolite in dogs with a correlation to a pharmacodynamic effect

The pharmacokinetics and pharmacodynamics of the anticholinergic and calcium antagonistic drug terodiline, N-tert-butyl-1-methyl-3,3-diphenylpropylamine, have been studied in beagle dogs. The bioavailability was about 25% (0.15 and 0.5 mg/kg), the terminal half-life 3 hr, the systemic clearance 40 ml/min..kg, the volume of distribution (V beta) about 7 l/kg and the unbound fraction in serum 0.14. p-Hydroxyterodiline and p-hydroxy-m-methoxyterodiline were quantitated and constituted 15-40% and 25%, respectively, of the amount excreted in urine (about 60% of the dose) and were the main metabolites, as in man. The dog was used as an experimental model to study the chronotropic effect. An increased heart rate was observed after acute administration of high doses of terodiline as well as after p-hydroxyterodiline. A 20% increase in heart rate was observed at a mean serum concentration of 1086 and 1010 micrograms/l following intravenous injection of terodiline or p-hydroxyterodiline, respectively. The corresponding unbound concentrations were 150 and 474 micrograms/l. The potency ratios of terodiline/p-hydroxyterodiline was 0.9 +/- 0.2 (based on total concentrations) and 3.2 +/- 0.8 (based on unbound concentrations). The estimated potency of parent drug and main metabolite and the fact that p-hydroxyterodiline constitutes 10-20% of the terodiline steady-state level in man, indicate that the contribution of the metabolite to the chronotropic effect observed in clinical studies is minor.     

Pharmacokinetics and haemodynamic effects of ISDN following different dosage forms and routes of administration

The pharmacokinetics and haemodynamic effects of isosorbide dinitrate (ISDN) have been investigated following administration of single doses as a sublingual (SL) spray (2.5 mg), sublingual tablet (5 mg) and peroral tablet (10 mg) in a randomised, placebo-controlled double-blind cross-over trial in 16 healthy volunteers.After the sublingual spray C_max was higher (39.0 ng·ml^-1) and t_max was shorter (3.9 min) than after the sublingual (22.8 ng·ml^-1 and 13.8 min) and peroral (16.9 ng·ml^-1 and 25.6 min) tablets. The AUC of ISDN did not differ following any of the three formulations (1031; 879; 997 ng·ml^-1·min, for the spray, SL tablet and PO-tablet, respectively). Mononitrate metabolites of ISDN (IS-2-MN and IS-5-MN) and total nitrates in plasma increased in proportion to the administered dose. This indicates that the fraction of the dose absorbed was the same for all the formulations but that the extent of first-pass metabolism increased in the order sublingual spray < sublingual tablet < peroral tablet. Thus, compared to the spray, the relative bioavailability of ISDN was 48% and 28% from the sublingual and peroral tablets, respectively.The haemodynamic effects were quantified using the a/b ratio of the finger pulse wave and the systolic blood pressure and heart rate under orthostatic conditions. For the a/b ratio of the finger pulse, the maximal effect was higher (e_max=130%) and the time to e_max (t_emax) shorter (16.6 min) after the spray than the sublingual tablet (84.4% and 25.5 min) or peroral tablet (90.2 and 31.3 min). The onset of effect was within 3, 5 and 7.5 min after the spray, sublingual and peroral tablets, respectively. A larger change in the orthostatically-induced decrease in systolic blood pressure and increase in heart rate was obtained following peroral than sublingual administration despite the similar plasma concentrations of ISDN. This probably reflects the larger amount of pharmacodynamically active mononitrate metabolites formed after oral dosing. The integrated effect following administration of 2.5 mg ISDN as spray was similar to that of a sublingual tablet of 5 mg.     

CYP2D6 genotype determination in the Danish population

CYP2D6 genotyping was carried out by XbaI restriction fragment length polymorphism analysis and polymerase chain reaction in 168 healthy Danish volunteers, 77 extensive metabolizers (EM) and 91 poor metabolizers (PM) of sparteine. All EM were genotyped correctly as heterozygous or homozygous for the functional (wild type) gene, D6-wt. However, the D6-wt gene was apparently also present in 11 (12%) of the PM who accordingly were incorrectly genotyped as EM. The specificity of genotyping PM thus was 100% but the sensitivity was only 88%. The most common allele was the D6-wt with an apparent frequency of 0.741 (0.026) in the Danish population and the second most common allele was the D6-B with an apparent frequency of 0.194 (0.024). The median (range) of the sparteine metabolic ratio (MR) in 47 homozygous D6-wt EM was 0.28 (0.11–4.10) and the corresponding value in heterozygous EM was 0.36 (0.11–9.10). The median difference was 0.09 (95% confidence interval: 0.02–0.16). CYP2D6 phenotyping is a promising tool in tailoring the individual dose of tricyclic antidepressants, some neuroleplics and some antiarrhythmics. However if the genotype test could be improved with regard to both sensitivity in PM and the ability to predict CYP2D6 activity in EM then it would be of even greater clinical value in therapeutic drug monitoring.