Bo Siwers

Initial clinical trial based on biochemical methodology of zimelidine (a serotonin uptake inhibitor) in depressed patients.

The bicyclic compound Z‐1‐(4‐bromophenyl)‐1‐(3‐pyridyl)‐3‐dimethylaminopropen (zimelidine) has a pronounced inhibitory effect on neuronal 5‐hydroxytryptamine (5‐HT) uptake in animals. Zimelidine was given to 6 depressed patients in doses ranging between 25 and 150 mg twice dailyfor about 3 wk. To get an objective assessment of its pharmacologic effects, the following variables were monitored: (1) plasma levels of parent compound and its desmethylated metabolite; (2) the 5‐HT and norepinephrine (NE) uptake inhibiting activity in vitro of plasma drawnfrom the patients; and (3) the concentrations of the main metabolites of serotonin (5‐HT), tryptamine, NE, and dopamine in cerebrospinal fluid (CSF), i.e., 5‐hydroxyindoleacetic acid (5‐HIAA), indoleacetic acid (IAA), 4‐hydroxy‐3‐methoxyphenylglycol (HMPG), and homovanillic acid (HVA), respectively. Plasma from the patients markedly inhibited 5‐HT uptake compared to NE uptake. The inhibitory effect on 5‐HT uptake and the plasma concentration of the desmethylated metabolite correlated significantly. The 5‐HIAA levels in CSF decreased markedly in 4 patients while the IAA levels increased. The levels of HMPG also decreased significantly, but less so than the 5‐HIAA levels. The e.fects on HVA were inconsistent. Zimelidine appears to be a selective inhibitor of 5‐HT uptake in central monoamine neurons and is there.fore an interesting pharmacologic tool in future central nervous system (CNS) research.

Polymorphic drug metabolism in schizophrenic patients with tardive dyskinesia.

The metabolism of many neuroleptics cosegregates catalyzed by the polymorphic cytochrome P450 CYP2D6. The population can be phenotyped into extensive metabolizers (EM) and poor metabolizers (PM) with respect to this enzymes activity. PM are likely to achieve higher than average concentrations of neuroleptic drugs in plasma, with an increased risk of extrapyramidal side effects, possibly including tardive dyskinesia. Sixteen white schizophrenic patients who had developed tardive dyskinesia during long-term neuroleptic treatment were phenotyped with debrisoquine and genotyped by CYP2D6-specific DNA amplification and EcoRI restriction fragment length polymorphism analysis. Only 1 (6%) of the 16 patients had a PM genotype, 8 (50%) were homozygous, and 7 (44%) were heterozygous EM. None had a CYP2D6 genotype indicative of ultrarapid debrisoquine hydroxylation capacity. The patients were also phenotyped with mephenytoin, a probe drug for another polymorphic cytochrome P450, CYP2C19. One patient was a PM of S-mephenytoin, which corresponds to the frequency found in healthy white volunteers. In conclusion, there was no overrepresentation of PM of debrisoquine or of S-mephenytoin among the 16 patients with neuroleptic-induced tardive dyskinesia. However, the PM of debrisoquine had the highest score on the Simpson-Angus Rating Scale and the second highest on the Abnormal Involuntary Movement Scale, despite a very low neuroleptic dose. Also, the debrisoquine MR correlated significantly with the SARS score (rs = 0.685, p < 0.05, N = 10), indicating a relationship between the degree of impaired CYP2D5 activity and the severity of extrapyramidal side effects during neuroleptic treatment.

Personality characteristics and platelet MAO activity in women with congenital adrenal hyperplasia (CAH)

Personality traits and platelet monoamine oxidase (MAO) activity were studied in 22 women, 17-34 years old, with prenatal virilization due to congenital adrenal hyperplasia (CAH) (21-hydroxylase deficiency) and 22 healthy controls. The CAH group differed significantly on two of the eight scales of the Karolinska Scales of Personality (KSP), which have earlier shown significant gender differences. Both differences were in the masculine direction, with a high, male level, score for Detachment and a lower score for Indirect Aggression. The Detachment scale reflects distance in social relations, and has earlier been shown to be strongly gender differentiating. There was no significant difference in platelet MAO activity between the CAH group and the controls. Although an influence of psychosocial factors cannot be excluded, the results suggest a possible association between prenatal androgen exposure and the high Detachment score for the CAH group. Gender differences in empathy, affiliation motivation, intimacy and maternal behavior may be relevant parallels.

Bromocriptine treatment of depressive disorders. Clinical and biochemical effects.

Fifteen depressed patients were treated with increasing doses of bromocriptine in an open study. Twelve were treated for 5 weeks (final dose 20–60 mg daily) and nine of these recovered almost completely. As expected from a dopamine agonist, bromocriptine decreased the level of homovanillic acid (HVA) in cerebrospinal fluid (CSF) by 15 % (P < 0.05) and 23% (P < 0.01) after 2 and 5 weeks of treatment, respectively. After 2 but not after 5 weeks of treatment there was also a small but significant decrease (13%; P < 0.001) of the noradrenaline metabolite HMPG in CSF. Although there was no mean effect on 5‐HIAA in CSF, there was a significant relationship between the HVA and 5‐HIAA levels (as % of pretreatment level) both after 2 and 5 weeks of treatment (r = 0.96 and r = 0.62, respectively). This may indicate that the drug has an effect on the serotonin system secondary to the dopamine receptor stimulation. The amelioration of depression was not related to HVA, but did correlate to HMPG in CSF (r = 0.65; P < 0.05) both metabolites measured before treatment These results indicate that bromocriptine may have antidepressant effects possibly mediated through the noradrenergic system rather than the dopaminergic system.

Effects of fluoxetine treatment of platelet 3H-imipramine binding, 5-HT uptake and 5-HT content in major depressive disorder

Platelet 3H-imipramine binding, serotonin (5-HT) uptake and 5-HT concentrations were studied in 14 hospitalized patients with depressive disorder following 6 weeks of treatment with a selective 5-HT uptake blocker, fluoxetine. After 3 weeks of treatment there was a significant decrease in Bmax of 3H-imipramine binding and a significant increase in Kd. A highly significant decrease in Vmax of 5-HT uptake was seen after 3 weeks of treatment which was accompanied by a slight increase in Km. At the same time the platelet 5-HT content was significantly reduced by about 90% of its original level. The platelet 5-HT content continued to decrease with further treatment while there was a tendency for Vmax to return to pretreatment levels. The affinity of the 5-HT uptake carrier continued to decrease significantly. There was no further significant change in Bmax of 3H-imipramine binding during further treatment, although there was an increase in Bmax in the majority of patients. The changes in Bmax and Vmax were closely associated throughout the treatment. In some cases the changes in different platelet parameters correlated with the changes in depression rating scores during treatment, but this correlation did not reach statistical significance.

Normal lateralization for handedness and ear advantage in a verbal dichotic listening task in women with congenital adrenal hyperplasia (CAH)

Functional cerebral asymmetry was studied in 22 women, 17-34 years old, with prenatal virilization due to congenital adrenal hyperplasia (CAH) (21-hydroxylase deficiency) and 22 matched, healthy controls. The theory of an androgen influence on cerebral lateralization has been supported by the observation of sex differences in cognitive performance, anatomical cerebral differences between the sexes and atypical patterns of functional asymmetry in certain anomalous hormonal states. The result of the present study did however not show a significantly different pattern of functional asymmetry for women with CAH and prenatal exposure to high levels of androgens. No significant differences with the controls were found for the Finger Tapping Test (FTT), Edinburgh Handedness Inventory (EHI) or Dichotic Listening (Consonant-Vowel) Test (DL). The CAH group included four non-right-handers (18%) vs two (9%) in the control group. As sex differences generally are small, the present result, may have been influenced by the limited size of the sample.

Clinical and biochemical effects during treatment of depression with nortriptyline: the role of 10-hydroxynortriptyline

Plasma concentrations of nortriptyline (NT) and its major metabolite 10‐hydroxy‐NT (10‐OH‐NT) were measured in 30 patients with depression, treated with NT for 3 weeks. Nine patients who recovered completely had plasma concentrations of NT and 10‐OH‐NT ranging from 358 to 728 nmol/L and from 428 to 688 nmol/L, respectively. Of the 21 patients who did not recover completely, only four had plasma concentrations within the window limited by these two plasma concentration ranges. A correlation was found between the degree of amelioration and the plasma concentration of NT (rs = 0.469; P < 0.01). Lumbar punctures were performed in 26 patients before and after 3 weeks of NT treatment. During treatment there was a 30.9% mean decrease in the noradrenaline metabolite 4‐hydroxy‐3‐methoxyphenylglycol (HMPG) in cerebrospinal fluid (CSF). We could not evaluate the extent to which this decrease was caused by NT or 10‐OH‐NT, respectively, because both are strong inhibitors of noradrenaline uptake. The ratio between the concentration of NT and 10‐OH‐NT in CSF correlated to the reduction of HMPG in CSF (r = 0.397; P < 0.05) and to the amelioration of depression (rs = 0.623; P < 0.001). This might indicate that NT and 10‐OH‐NT interact on the noradrenaline system in a nonadditive way. During treatment there was a 15.2% decrease in CSF concentration of the serotonin metabolite 5‐hydroxyindoleacetic acid. The reduction was significantly correlated to the CSF concentration of NT but not to that of 10‐OH‐NT. This is in accordance with the fact that NT is a more potent inhibitor of serotonin uptake than is 10‐OH‐NT. The dopamine metabolite homovanillic acid in CSF decreased significantly by 10.0%. The biochemical data indicate that noradrenergic, serotoninergic, and dopaminergic systems are affected by NT treatment and that 10‐OH‐NT might be more selective on noradrenergic neurons than the parent drug.

Disposition of single oral doses of E‐10‐hydroxynortriptyline in healthy subjects, with some observations on pharmacodynamic effects

The active and major metabolite of nortriptyline (NT), E‐10‐hydroxynortriptyline (E‐10‐OH‐NT), was taken orally as the hydrogen maleate in single doses by nine healthy subjects. The doses (10 to 100 mg) were completely absorbed, as shown by the high urinary recovery of 86.1% ± 9.9%. Of the given dose, 51.2% ± 8.7% was recovered as conjugated E‐10‐OH‐NT and 23.9% ± 4.3% was recovered as unchanged compound. The plasma t1/2 of E‐10‐OH‐NT was 8.0 ± 1.2 hours and total plasma clearance was 47.5 ± 10.3 L/hr. The rate of elimination varied little between individuals. There was no indication of dose‐dependent elimination. The mean apparent volume of distribution was 7.7 ± 2.1 L/kg. Single oral doses of 50 mg E‐10‐OH‐NT significantly increased the plasma levels of norepinephrine in both the supine and standing positions (P < 0.01). Pulse rate increased in the standing but not the supine position. These effects might result from inhibition of neuronal uptake of norepinephrine by E‐10‐OH‐NT. Coupled with its low affinity for muscarinic receptors, these kinetic and pharmacodynamic features of E‐10‐OH‐NT call for further phase I studies.

Pressor response of oral tyramine in healthy men given amiflamine and placebo

During two baseline challenge tests, oral tyramine (50 to 400 mg) was given to 12 healthy men to find each individuals cardiovascular pressor response. All 12 subjects “tolerated” 200 mg oral tyramine, but three of the 12 developed an increment in systolic blood pressure >30 mm Hg when given a dose of 400 mg. Thereafter, amiflamine, 5 mg bid (n = 8), or placebo, 1 capsule twice a day (n = 4), were given in a double‐blind fashion for 7 days, and oral tyramine challenge tests (12.5 to 400 mg) were given on days 5 to 7. During dosing with amiflamine or placebo, no subject tolerated 400 mg oral tyramine and no difference between the two regimens was found with regard to tyramine response. Plasma concentrations of amiflamine and two of its metabolites were measured on days 4 to 7. Steady‐state concentrations were reached within 4 to 5 days. Plasma concentrations of tyramine after 400 mg tyramine showed a positive correlation with the increase in systolic blood pressure (P < 0.001).

Tolerance and pilot pharmacokinetics of amiflamine after increasing single oral doses in healthy subjects.

Oral doses of 1 to 100 mg amiflamine, a new reversible monoamine oxidase type A—selective inhibitor, were given for the first time in humans to six healthy men. No apparent pharmacologic effects were recorded until the 80 mg dose. After 100 mg, one subject developed symptoms indicative of an overdose. Amiflamine is extensively metabolized by two consecutive N‐demethylations. The biotransformation patterns in plasma and urine were found to correlate with the debrisoquin metabolic ratio.