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Biomedical subjects

K Linnet

Publications and source records attributed to K Linnet.

At least 19 recordsLinked to original sources
PubMed2001

Fully automated on-line determination of olanzapine in serum for routine therapeutic drug monitoring.

A method is presented for unattended fully automated extraction and on-line determination of the atypical antipsychotic drug olanzapine in serum. An ASPEC automatic sample-preparing apparatus with Isolute cyanopropyl-bonded silicagel cartridges was used for solid-phase extraction of the drugs from serum. The adsorbed drugs were eluted with methanol and an aliquot injected into a high-performance liquid chromatograph (HPLC) apparatus. Trifluoperazine was used as internal standard, and the analytes were separated on an unmodified silicagel column using methanol-ammonium acetate buffer pH 9.9 (85:15) as mobile phase. Ultraviolet detection at 257 nm was used for quantitation. Within the therapeutic range for the serum concentration of olanzapine, the interday variations for the quantitative determinations were <8%. Comparisons between concentrations measured using liquid-liquid extraction and the present on-line extraction method showed good agreement. Other drugs often used in combination with olanzapine did not interfere with the quantitative determinations. The method has been in routine use for more than 1 year for therapeutic drug monitoring.

Antipsychotic Agents↗
PubMed2000

Determination of nortriptyline in human serum by fully automated solid-phase extraction and on-line high-performance liquid chromatography in the presence of antipsychotic drugs.

A fully automated on-line method for determination of nortriptyline in human serum was developed using an ASPEC XL (Gilson) solid-phase extraction apparatus in combination with high-performance liquid chromatography. Solid phase extraction was performed on cyanopropyl cartridges. HPLC was carried out using a C18 column with a mobile phase of acetonitrile-0.01 M triethylamine (34:66 v/v) buffer, pH 3.0. UV detection was at 242 nm. The Inter-day CV% was <5%. Comparison with liquid-liquid extraction of serum from patients treated with nortriptyline showed good agreement. Studies of analytical interference from coadministered psychoactive drugs revealed that only imipramine and a methotrimeprazine metabolite interfered.

Antidepressive Agents, Tricyclic↗
PubMed2000

[Monitoring of serum olanzapine during antipsychotic treatment].

Olanzapine steady-state serum concentrations of 334 patients were measured by high pressure liquid chromatography. The patients were subjected to routine therapeutic drug monitoring of antipsychotic treatment. In cases with more than one serum determination per patient, only the first measurement was included. Eighty-four percent of the patients received daily doses in the recommended range from 5 to 20 mg. The interval 25-140 nmol/l covered about 80% of the concentrations observed for the daily dose range 5-20 mg. This interval may be used as a reference for therapeutic drug monitoring of olanzapine, indicating whether a patient has a typical or an atypical concentration level at a given dose. Such a judgment may be helpful in situations characterized by side effects, insufficient effect, doubts about compliance or possible pharmacokinetic interactions.

Antipsychotic Agents↗
PubMed2000

The effect of acute citalopram on extracellular 5-HT levels is not augmented by lithium: an in vivo microdialysis study.

A substantial number of patients do not respond sufficiently to antidepressant drugs and are therefore often co-medicated with lithium as an augmentative strategy. Since lithium has been demonstrated to affect 5-HT neurotransmission, we examined the effect of acute and subchronic lithium on 5-HT levels after a challenge with citalopram. We found that subchronic administration of lithium increases extracellular 5-HT baseline level and decreases the extracellular 5-HIAA baseline. However, we found no evidence that the effect of acute citalopram on extracellular 5-HT levels is augmented by acute or subchronic lithium.

Animals↗
PubMed2000

Opposing changes in serotonin and norepinephrine transporter mRNA levels after serotonin depletion.

We and others have earlier shown that severe serotonin depletion leads to a compensatory down-regulation in the expression of the serotonin transporter (5HTT) gene. We have now investigated the expression of both the 5HTT and the norepinephrine transporter (NET) gene to assess the possible interaction between the noradrenergic and the serotonergic neurotransmitter systems. Acute severe serotonin depletion induced by p-chlorophenylalanine (PCPA) treatment leads to enhanced NET(Long) mRNA levels and reduced 5HTT mRNA level. This change in transporter mRNA expression was paralleled by a non-significant change in protein expression. Chronic severe serotonin depletion combined with treatment with the antidepressant imipramine leads to enhanced NET(Long) mRNA levels. Acute treatment with the monoamine oxidase A inhibitor clorgyline, acute moderate NE reduction (alpha-methyl-p-tyrosine treatment) or less severe depletion for 3 weeks have no effect on the gene expression of the transporters. Taken together, the present data demonstrate that the NET gene expression is enhanced in case of severe serotonin depletion.

Adrenergic Uptake Inhibitors↗
PubMed2000

Identification of the human cytochrome P450 isoforms mediating in vitro N-dealkylation of perphenazine.

AIMS: To identify the human cytochrome P450 (CYP) isoforms mediating the N-dealkylation of the antipsychotic drug perphenazine in vitro and estimate the relative contributions of the CYP isoforms involved. METHODS: cDNA-expressed CYP isoforms were used to identify the isoforms that are able to mediate the N-dealkylation of perphenazine, which is considered a major metabolic pathway for the drug. Using human liver microsomal preparations (HLM), inhibition studies were carried out to establish the relative contributions of the CYP isoforms involved in the N-dealkylation reaction. RESULTS: CYP isoforms 1A2, 3A4, 2C8, 2C9, 2C18, 2C19 and 2D6 were able to mediate the N-dealkylation of perphenazine. Reaction velocities and their relative abundance in HLM suggested that CYP1A2, 3A4, 2C19 and 2D6 were the most important contributors to N-dealkylation. Apparent Km values of CYP1A2 and CYP2D6 were in the range 1-2 microM, and Km values of CYP2C19 and CYP3A4 were 14 microM and 7.9 microM, respectively. Ketoconazole inhibition of N-dealkylation mediated by a mixed HLM indicated that CYP3A4 accounted for about 40% of perphenazine N-dealkylation at therapeutically relevant concentrations. The contribution of the CYP isoforms 1A2, 2C19 and 2D6 amounted to 20-25% each as measured by the percentage inhibition obtained by addition of furafylline, fluvoxamine or quinidine, respectively. HLM-mediated N-dealkylation of perphenazine accounted for 57% of the total amount of substrate consumed during incubation. CONCLUSIONS: The present in vitro study suggests that CYP isoforms 1A2, 3A4, 2C19 and 2CD6 are primarily involved in the N-dealkylation of perphenazine. The relatively modest role of CYP2D6 is at variance with in vivo studies, which indicate a greater contribution of this isoform. Alternative metabolic pathways, corresponding to 43% of the HLM-mediated metabolism of the drug, may depend more strongly on CYP2D6.

Alkylation↗
PubMed2000

Fluvoxamine-Clozapine drug interaction: inhibition in vitro of five cytochrome P450 isoforms involved in clozapine metabolism.

Administration of fluvoxamine to patients receiving clozapine therapy may increase the steady-state serum concentrations of clozapine by a factor of 5 to 10. The authors undertook in vitro studies to disclose the mechanism behind this clinically important interaction. In a human liver microsome preparation, fluvoxamine showed a concentration-dependent inhibition of clozapine N-demethylation. Fluvoxamine was much less effective as an inhibitor of clozapine N-oxidation. Fluvoxamine also inhibited in a concentration-dependent manner the activity of all five cytochrome P450 (CYP) isoforms previously determined to be capable of catalyzing the demethylation of clozapine. Fluvoxamine inhibited CYP1A2 and 2C19 with the highest affinities (Ki values of 0.041 and 0.087 microM, respectively). The Ki values for CYP2C9 and 2D6 were 2.2 and 4.9 microM, respectively, whereas the Ki for CY3A4 was 24 microM. Assuming a hepatic tissue concentration of fluvoxamine in the range of 4 to 7 microM under therapeutic conditions, a clinically significant inhibition of all but CYP3A4 is expected in relation to clozapine N-demethylation. No significant effect of fluvoxamine on clozapine N-oxidation is to be expected under therapeutic conditions. Because of the large interindividual variability of the quantity of the various CYP isoforms in liver tissue, it is not possible to predict the fluvoxamine-induced increase in the plasma concentration of clozapine of an individual patient.

Clozapine↗
PubMed1999

Olanzapine serum concentrations in psychiatric patients given standard doses: the influence of comedication.

We recorded steady state serum concentrations of olanzapine in 56 psychiatric patients under routine conditions. Twenty-two patients (39%) underwent monotherapy; the rest received additional psychotropic drugs. Doses were given once daily in the evening, and serum olanzapine levels were measured 12 hours later. For the whole group, the concentration-to-dose ratio (C/D) varied 26-fold, with a median value of 4.8 (nmol/L)/(mg/24 hours), but 80% of the patients had C/D values within the range 2 to 10 (nmol/L)/(mg/24 hours). All but three patients received standard doses (5-20 mg/24 hours), of whom 80% had serum concentrations of olanzapine within the range 22 to 146 nmol/L. Patients comedicated with potential inhibitors of CYP2D6 and other drugs displayed a median C/D approximately 40% higher than the group undergoing monotherapy. Patients comedicated with carbamazepine had a median C/D 36% lower than that of the monotherapy group. Therefore, the serum concentration range (12-hour values) of 25 to 150 nmol/L can be expected for patients receiving a standard daily dose.

Adolescent↗
PubMed1999

Studies on the stereoselective metabolism of citalopram by human liver microsomes and cDNA-expressed cytochrome P450 enzymes.

The involvement of CYP enzymes in the metabolism of citalopram was studied, inclusive the conversion of demethylcitalopram to didemethylcitalopram and the formation of citalopram N-oxide, which both have not been considered previously. Using human mixed liver microsomes and cDNA-expressed CYP enzymes, we confirmed that CYP3A4, 2C19 and 2D6 are involved in the first demethylation step of citalopram, all favouring conversion of the biologically active S-enantiomer. Inhibitor studies indicated that at therapeutic citalopram concentrations CYP3A4 was responsible for 40-50% of demethylcitalopram formation, while the contribution of CYP2C19 increased and that of CYP2D6 tended to decrease with increasing drug concentration. CYP2D6 exclusively mediated the second demethylation step, and citalopram N-oxide was also exclusively formed by CYP2D6. None of the studied CYP enzymes mediated deamination to the propionic acid derivative.

Citalopram↗
PubMed1999

Necessary sample size for method comparison studies based on regression analysis.

BACKGROUND: In method comparison studies, it is of importance to assure that the presence of a difference of medical importance is detected. For a given difference, the necessary number of samples depends on the range of values and the analytical standard deviations of the methods involved. For typical examples, the present study evaluates the statistical power of least-squares and Deming regression analyses applied to the method comparison data. METHODS: Theoretical calculations and simulations were used to consider the statistical power for detection of slope deviations from unity and intercept deviations from zero. For situations with proportional analytical standard deviations, weighted forms of regression analysis were evaluated. RESULTS: In general, sample sizes of 40-100 samples conventionally used in method comparison studies often must be reconsidered. A main factor is the range of values, which should be as wide as possible for the given analyte. For a range ratio (maximum value divided by minimum value) of 2, 544 samples are required to detect one standardized slope deviation; the number of required samples decreases to 64 at a range ratio of 10 (proportional analytical error). For electrolytes having very narrow ranges of values, very large sample sizes usually are necessary. In case of proportional analytical error, application of a weighted approach is important to assure an efficient analysis; e.g., for a range ratio of 10, the weighted approach reduces the requirement of samples by >50%. CONCLUSIONS: Estimation of the necessary sample size for a method comparison study assures a valid result; either no difference is found or the existence of a relevant difference is confirmed.

Clinical Laboratory Techniques↗
PubMed1998

Determination of olanzapine in serum by high-performance liquid chromatography using ultraviolet detection considering the easy oxidability of the compound and the presence of other psychotropic drugs.

A method for determination of the atypical neuroleptic drug olanzapine in serum was developed. After a single-step liquid-liquid extraction, the compound was separated from other constituents on a normal-phase silica gel column using a buffer-methanol mobile phase and measured by UV absorption at 270 nm. Addition of 0.25% ascorbic acid to serum protects olanzapine against oxidation during extraction and stabilizes the easily oxidised compound during storage. Inter-day variation was <8% at serum levels found in olanzapine treated patients. Analytical interference from coadministered psychoactive drugs and their metabolites were studied. Only risperidone, also a relatively newly developed antipsychotic drug, interfered, but the most commonly used antidepressants and traditional antipsychotics and their metabolites did not interfere.

Antipsychotic Agents↗
PubMed1998

Serum concentrations and side effects in psychiatric patients during risperidone therapy.

Steady state serum concentrations of risperidone and 9-hydroxyrisperidone (9-OH-risperidone), the active moiety, were measured in 42 patients. The concentration-to-dose ratios (C/D) varied by a factor of 20, from 1.8 to 36.8 (nmol/l)/(mg/24 hours), and 90% of the active moiety was constituted of 9-OH-risperidone. No correlation between the serum concentration of the active moiety and the side effects evaluated by the UKU Side Effect Scale was found. The absence of CYP2D6 (poor metabolizers) or the coadministration of drugs other than benzodiazepines increased the ratio between parent compound and metabolite but did not significantly influence the C/D of the total active moiety. A therapeutic range for serum risperidone has not been established, but 6 mg/day is considered the optimum dose for most patients. The authors found that in 90% of 22 patients administered 6 mg/day risperidone, the serum levels were within 50 to 150 nmol/l.

Adult↗
PubMed1998

Performance of Deming regression analysis in case of misspecified analytical error ratio in method comparison studies.

Application of Deming regression analysis to interpret method comparison data presupposes specification of the squared analytical error ratio (lambda), but in cases involving only single measurements by each method, this ratio may be unknown and is often assigned a default value of one. On the basis of simulations, this practice was evaluated in situations with real error ratios deviating from one. Comparisons of two electrolyte methods and two glucose methods were simulated. In the first case, misspecification of lambda produced a bias that amounted to two-thirds of the maximum bias of the ordinary least-squares regression method. Standard errors and the results of hypothesis-testing also became misleading. In the second situation, a misspecified error ratio resulted only in a negligible bias. Thus, given a short range of values in relation to the measurement errors, it is important that lambda is correctly estimated either from duplicate sets of measurements or, in the case of single measurement sets, specified from quality-control data. However, even with a misspecified error ratio, Deming regression analysis is likely to perform better than least-squares regression analysis.

Bias↗
PubMed1997

Simplified high-performance liquid chromatographic method for determination of risperidone and 9-hydroxyrisperidone in serum from patients comedicated with other psychotropic drugs.

A HPLC method was developed for determination of risperidone and its therapeutically active main metabolite 9-hydroxyrisperidone in serum. After a single-step liquid-liquid extraction the analytes were separated on a C18 column and measured by UV detection at 280 nm. Inter-day coefficient of variation was <7% for both compounds at serum levels occurring in patients treated with ordinary doses. Studies of analytical interference showed that the most commonly coadministered antidepressants and benzodiazepines did not interfere. Some conventional low dose neuroleptics and clozapine did interfere, but this is of minor importance, because risperidone is intended as an alternative to these drugs.

Antipsychotic Agents↗
PubMed1997

Citalopram and desmethylcitalopram concentrations in breast milk and in serum of mother and infant.

A case is presented with measurements of the selective serotonin reuptake inhibitor (SSRI)-antidepressant citalopram in serum of mother and breast-fed infant and in breast milk. We found a milk-to-serum concentration ratio of approximately 3 for both citalopram and the main metabolite desmethylcitalopram. Peak milk concentrations of citalopram occurred 3-9 h after drug intake by the mother. The infant received approximately 5% of the mother's dose, adjusted for weight. Accordingly, the serum level in the infant of approximately 7 nM corresponded to approximately 1/15 of the trough serum concentration of the mother (104 nM). No signs of drug effects in the infant were observed.

Adult↗