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Purpose: The impact of the UGT1A4, CYP1A2, and MDR1 genetic variants on olanzapine plasma levels, in relation to those of other individual factors, such as gender, smoking status, body weight, and age, was investigated in patients with schizophrenia. Methods: A total of 121 patients were recruited from psychosis-specialized outpatient departments in Stockholm County. Olanzapine plasma concentrations were determined by high-performance liquid chromatography. Genotyping was carried out by PCR-restriction fragment length polymorphism or minisequencing, and haplotypes were analyzed using specialized computer software on population genetics. Multiple regression analysis was performed to investigate the combined effect of patient characteristics and genotypes/haplotypes on daily dose-corrected plasma concentrations of olanzapine. Results: In addition to , the results indicate that inter-patient differences in olanzapine exposure were explained by the known factor of time of sampling from last dose intake and by the following individual factors in order of relative impact: (1) male gender, (2) carrier of the UGT1A4 142T>G single nucleotide polymorphism (SNP), and (3) smoking. Each of these three factors predicted a decrease in daily dosecorrected plasma concentrations of 35, 25, and 21%, respectively. In contrast, age, body weight, and MDR1 or CYP1A2 haplotype did not have a significant impact. Conclusions: At 12 h after dose intake, the regression model predicted a 5.1-fold higher olanzapine plasma level in a non-smoking female patient who did not carry the UGT1A4 142T>G SNP compared to a smoking man treated with the same dose but heterozygous for UGT1A4 142T>G SNP. Whether these combined genetic and environmental factors influence the risk of therapeutic failure remains to be established. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the influence of paroxetine on metoprolol concentrations and its effect in patients treated for acute myocardial infarction (AMI) who are routinely given paroxetine as a co-treatment of depression. METHODS: We recruited 17 depressed AMI patients who received metoprolol as a routine part of their therapy (mean dose 75 +/- 39 mg/day). Patients were genotyped for CYP2D6 *3, *4 and gene duplication. Metoprolol and alpha-hydroxy-metoprolol were analyzed in plasma 0, 2, 6 and 12 h post-dose. Heart rates (HR) at rest were registered after each sampling. Paroxetine 20 mg daily was then administered, and all measurements were repeated on day 8. RESULTS: All patients were genotypically extensive metabolizers (EMs) (nine with *1/*1 and eight with *1/*3 or *4). Following the administration of paroxetine, mean metoprolol areas under the concentration-time curve (AUC) increased (1064 +/- 1213 to 4476 +/- 2821 nM x h/mg per kg, P = 0.0001), while metabolite AUCs decreased (1492 +/- 872 to 348 +/- 279 n M x h/mg per kg, P < 0.0001), with an increase of metabolic ratios (MR) (0.9 +/- 1.3 to 26 +/- 29; P < 0.0001). Mean HRs were significantly lower after the study week at each time point. Mean area under the HR versus time curve (AUEC) decreased (835 +/- 88 to 728 +/- 84 beats x h/min; P = 0.0007). Metoprolol AUCs correlated with patients' AUECs at the baseline (Spearman r = -0.64, P < 0.01), but not on the eighth day of the study. A reduction of metoprolol dose was required in two patients due to excessive bradycardia and severe orthostatic hypotension. No other adverse effects of the drugs were identified. CONCLUSION: A pronounced inhibition of metoprolol metabolism by paroxetine was observed in AMI patients, but without serious adverse effects. We suggest, however, that the metoprolol dose is controlled upon initiation and withdrawal of paroxetine. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Because treatment with tumor necrosis factor (TNF) antagonists may increase the risk of tuberculosis (TB), and because knowledge of the risk of TB in rheumatoid arthritis (RA) not treated with biologics is scarce and of uncertain generalizability to low-risk populations, this study sought to determine the risk of TB among Swedish patients with RA. METHODS: Using data from Swedish nationwide and population-based registers and data from an ongoing monitoring program of TNF antagonists, the relative risks of TB in patients with RA (versus the general population) and of TB associated with TNF antagonists (versus RA patients not treated with biologics) were determined by comparing the incidence of hospitalization for TB in 3 RA cohorts and 2 general population cohorts from 1999 to 2001. We also reviewed the characteristics of all reported cases of TB in RA patients treated with TNF antagonists in Sweden and calculated the incidence of TB per type of TNF antagonist between 1999 and 2004. RESULTS: During 1999-2001, RA patients who were not treated with TNF antagonists were at increased risk of TB versus the general population (relative risk 2.0, 95% confidence interval [95% CI] 1.2-3.4). RA patients treated with TNF antagonists had a 4-fold increased risk of TB (relative risk 4.0, 95% CI 1.3-12) versus RA patients not treated with TNF antagonists. The reported TB cases during 1999-2004 in RA patients exposed to TNF antagonists (9 infliximab, 4 etanercept, 2 both) were predominantly pulmonary. TB occurred up to 3 years following the start of treatment. CONCLUSION: Irrespective of whether TNF antagonists are administered, Swedish patients with RA are at increased risk of TB. During 1999-2001, TNF antagonists were associated with an increased risk of TB, up to 4-fold in magnitude. This increased risk may persist over time during treatment and is related to both infliximab and etanercept. [ABSTRACT FROM AUTHOR]

Objective: The nocturnal serum melatonin (MT) level increases after ingestion of fluvoxamine (FLU) – a selective serotonin re-uptake inhibitor (SSRI) with antidepressive properties. The mechanism behind the MT increase is unknown. Citalopram (CIT) is another SSRI. It is not known whether CIT affects the serum MT level. It may well be that these two compounds affect serum MT levels differently, inasmuch as the ways they inhibit cytochrome P450 (CYP) enzymes in the liver differ markedly. FLU inhibits CYP1A2 potently, and to some extent also CYP2C19, whereas CIT is without such an effect. CYP enzymes are probably involved in the hepatic metabolism of MT. If FLU, but not CIT, inhibits liver enzymes involved in the metabolism of MT, different serum MT concentrations should probably ensue. The objective of this investigation was to test this hypothesis. Methods: Seven healthy subjects participated in three different experiments, which were performed in random order 6–8 days apart. In experiment A, placebo was given, in experiment B 40 mg CIT and in experiment C 50 mg FLU. All doses were given orally at 1600 hours. Serum MT concentrations were determined at regular intervals between 1600 hours and noon next day (20 h). Plasma concentrations of CIT were measured repeatedly in experiment B, and plasma FLU concentrations in experiment C. MT areas under the curve representing the 20-h period (MT-AUC0–20) were compared in the three experiments, and differences were statistically evaluated. Results: FLU augmented the MT-AUC0–20 by a factor of 2.8 compared with the effect of placebo (P < 0.01), whereas CIT was without significant effect. More MT was excreted in the urine after ingestion of FLU than after placebo. In contrast, CIT did not influence the MT excretion. A clear relationship was found between serum levels of MT and plasma concentrations of FLU. Conclusion: The serum MT level increased markedly after ingestion of FLU but not after CIT. The exact mechanism behind this finding is unknown, but decreased hepatic metabolism of MT by either CYP1A2 or CYP2C19, or both, is probable. Although exogenous MT, causing high MT concentration in plasma, has sleep-promoting properties in man, it is at this stage unknown whether serum MT concentrations in the range found in this study have similar effects. This has to be given further attention in additional studies. [ABSTRACT FROM AUTHOR]

A single injection of fenfluramine or p-chloroamphetamine (PCA) (100 μmol/kg intraperitoneally) decreases the serotonin (5HT) content and the tryptophan hydroxylase activity in various areas of the rat brain. Other reports have shown that a single injection of fenfluramine or PCA causes cytopathological changes in a serotonergic midbrain nucleus which was termed B9 by Dahlstrom and Fuxe (1). Despite this cytopathological change, fenfluramine fails to reduce the tryptophan hydroxylase activity in B9. In hippocampus the decrease of tryptophan hydroxylase elicited by fenfluramine persists for less than 21 days; in contrast PCA reduces the tryptophan hydroxylase activity in hippocampus, striatum, septal nuclei and B9 for longer than 21 days. Probably the decrease of tryptophan hydroxylase elicited by PCA in B9 is due to retrograde degeneration; the intensity and duration of the biochemical lesion elicited by fenfluramine and PCA in serotonergic terminals are a factor in determining the extent of the biochemical lesion in serotonergic cell bodies. [ABSTRACT FROM AUTHOR]

Debrisoquine (DQ) has no chiral centre, but hydroxylation in position 4 leads to formation of an asymmetric carbon centre with two possible enantiomers, their absolute configuration being R(-) and S(+)-4- hydroxydebrisoquine (4-OHDQ). Since the absolute stereochemistry of the 4-hydroxylation of DQ in man is unknown, the enantioselectivity of this process was studied in panels of extensive (EM) and poor metabolizers (PM) of DQ. In EM subjects 4-hydroxylation of DQ leads almost exclusively to the formation of S(+)-4-OHDQ. In contrast, PM subjects were not only characterized by a decreased total 4-OHDQ formation but also a marked loss of enantioselectivity in product formation. Between 5 to 36% of total 4-OHDQ was excreted as R(-)-4-OHDQ. [ABSTRACT FROM AUTHOR]

In 20 depressed patients treated with nortriptyline (NT) there was a significant relationship between the plasma concentration of NT and the debrisoquine metabolic ratio (rs = 0.77; P less than 0.01). (The debrisoquine test was performed after stopping NT treatment). This is in agreement with the hypothesis that the hydroxylations of NT and debrisoquine are mediated by similar enzymatic mechanisms. In contrast there was no significant relationship between the debrisoquine metabolic ratio and the plasma concentrations of the active metabolite 10-hydroxy-nortriptyline. In 11 of the patients the debrisoquine metabolic ratio was significantly higher during than after NT treatment. This may be due to an inhibition of the debrisoquine hydroxylation by NT. [ABSTRACT FROM AUTHOR]

Thirty-five healthy subjects who had been classified as extensive or poor metabolizers of both sparteine and debrisoquine were given a single oral dose of antipyrine. Saliva concentration of antipyrine and urinary excretion of its three major oxidation metabolites were measured. All the parameters of antipyrine metabolism which were estimated had similar distributions in both the 28 EM and 7 PM genetic phenotypes defined by the metabolism of sparteine and debrisoquine. The clearance of antipyrine by the formation of 4-hydroxy-antipyrine and 3- hydroxy-antipyrine respectively were closely correlated (r = 0.83, P less than 0.001) and both were significantly higher in smokers than in non-smokers. Demethylation of antipyrine also seemed to be influenced by smoking, but not to a statistically significant extent. These findings confirm the influence of the environmental factor of smoking in antipyrine oxidative biotransformations. [ABSTRACT FROM AUTHOR]