| 1. |
- Bengtsson, Finn
(författare)
-
Therapeutic drug monitoring of psychotropic drugs - TDM "Nouveau"
- 2004
-
Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 26:2, s. 145-151
-
Tidskriftsartikel (refereegranskat)abstract
- TDM applied in psychiatry dates back several decades. The reason for this is that, after the advent of modem clinical psychopharmacology around the middle of the past century, an insight came to common knowledge about the existence of (1) a large inter-individual pharmacokinetic (PK) variability for virtually all psychoactive drugs and (2) a worse clinical efficacy not only in inadequate drug concentrations but also in excessively high concentrations. From this concept, the definition of a therapeutic concentration "window" was evidenced for a substantial number of, primarily, antidepressant drugs. However, with the further extensive development of the clinically available pharmacopoeia of psychoactive drugs from the later 1980s until today, the concept of less toxic compounds than before has commonly been launched in the marketing strategies for these newer drugs. This concept also led to the idea that TDM was no longer necessary for the newer types of psychoactive drugs, a position backed up by difficulties in unraveling concentration-effect relationships generally for these drugs in clinical trials. The present survey summarizes the background history for TDM in psychiatry and makes a critical appraisal of why a "lack" of definition of concentration-effect relationships for newer psychoactive drugs is now common. This survey also provides the reader with a novel concept challenging ambient TDM strategies (referred to as TDM "traditionelle") in psychiatry by forwarding a theoretical model called TDM "nouveau." In this model both inter- and intraindividual (over time) PK variation is suggested to be used for dose optimization by TDM in a naturalistic clinical setting. The previous concept of a simple, common concentration "window" existing for all such drugs is questioned by promotion of the use of available PK data merely as "guiding principles" rather than as "reference values" when interpreting the TDM outcome in individual cases.
|
|
| 2. |
- Blessborn, Daniel, et al.
(författare)
-
Determination of pyronaridine in whole blood by automated solid-phase extraction and high-performance liquid chromatography
- 2003
-
Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 25:3, s. 264-270
-
Tidskriftsartikel (refereegranskat)abstract
- A new extraction procedure for the analysis of pyronaridine in whole blood is presented. A weak cation exchanger with a carboxylic acid (CBA) sorbent was found to be a suitable solid phase sorbent for the extraction of pyronaridine. High-performance liquid chromatography with UV detection at 278 nm and an electrochemical detector at +0.75 V is used. The electrochemical detector gives higher selectivity than the UV detector. The separation was performed using a C18 reversed phase column with mobile phase of acetonitrile-phosphate buffer (0.01 mol/L, pH 2.5)- sodium perchlorate (1.0 mol/L; 22:77:1, v/v/v). The within-day RSDs were below 5% at all concentration levels between 75 nmol/L and 1500 nmol/L, and the between-day RSDs were below 14% at all concentration levels. The limit of quantification was about 50 nmol/L in 1000 microL whole blood with an RSD of 20% or less on a day-to-day basis. The stability of pyronaridine is increased if the pH is less than 3 in water solutions. In whole blood, the concentration decreases by about 10% for each freeze-thaw cycle performed. At room temperature (about 22 degrees C), pyronaridine concentration in whole blood decreases by about 10% within 12 to 24 hours.
|
|
| 3. |
- Hindorf, U., et al.
(författare)
-
Assessment of thiopurine methyltransferase and metabolite formation during thiopurine therapy : Results from a large swedish patient population
- 2004
-
Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 26:6, s. 673-678
-
Tidskriftsartikel (refereegranskat)abstract
- This study examined thiopurine methyltransferase (TPMT) and the relationship to thioguanine nucleotides (TGN) and methylthioinosine monophosphate (meTIMP) in a large Swedish patient population. The current hypothesis is that the cytotoxic effects of thiopurine drugs are mediated by the incorporation of TGN into DNA. The authors assayed the TPMT activity in red blood cells from 1151 subjects and the concentrations of TGN (n = 602) and meTIMP (n = 593) from patients treated with thiopurine drugs. The TPMT frequency distribution in both adults and children showed some differences from what had been found in unselected general populations. Children had lower median TPMT activity than adults (12.0 versus 12.9 U/mL RBC, P < 0.001). Relative differences in both TGN formation [medians: normal TPMT, 1.3, intermediate TPMT, 3.3, low TPMT, 47.9 pmol/8 × 108 RBC per mg azathioprine (AZA), P < 0.001] and meTIMP formation (medians: normal TPMT, 13, intermediate TPMT, 7.3, low TPMT, 0 pmol/8 × 108 RBC per mg AZA, P = 0.001) per 1 mg administered drug were noted among the 3 TPMT activity groups. Women formed higher concentrations of both TGN (1.5 versus 1.3 pmol/8 × 108 RBC per mg AZA, P = 0.01) and meTIMP (14.4 versus 10.7 pmol/8 × 108 RBC per mg AZA, P = 0.01) than men did. There was a significant correlation between the AZA dose and the meTIMP concentrations (r = 0.45, P < 0.001). Furthermore, dose alterations made in subjects with normal TPMT (n = 84) and intermediate TPMT (n = 22) activity resulted in more pronounced increases in TGN concentrations (170 versus 30 pmol/8 × 10 8 RBC, P < 0.001) in intermediate TPMT activity, whereas in normal TPMT activity changes in meTIMP concentrations were more pronounced (1.3 versus 0 nmol/8 × 108 RBC, P < 0.001). In normal TPMT activity both metabolites increased in a dose-dependent fashion, whereas in intermediate TPMT activity only TGN concentrations increased. The results of this study demonstrate the dynamic nature of thiopurine metabolism and its importance for thiopurine dosing.
|
|
| 4. |
- Jones, A Wayne, 1945-, et al.
(författare)
-
Distribution of diazepam and nordiazepam between plasma and whole blood and the influence of hematocrit
- 2004
-
Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 26:4, s. 380-385
-
Tidskriftsartikel (refereegranskat)abstract
- The binding of drugs to plasma proteins is important to consider when concentrations in whole blood (eg, in forensic toxicology) are compared with therapeutic and toxic concentrations based on the analysis of plasma or serum. The plasma to whole blood distribution of diazepam (D) and its major metabolite nordiazepam (ND) was investigated under in vitro and ex vivo conditions. Studies in vitro were done by spiking whole blood with D and ND to give concentrations ranging from 0.1 to 1.0 μg/g. Venous blood was also obtained from hospital blood donors (n = 66) after informed consent. The hematocrit, hemoglobin, and water content of blood specimens were determined by routine procedures before D and ND were added to produce target concentrations of ∼0.5 μg/g for each substance. The ex vivo work was done with blood specimens from hospital outpatients who were being medicated with D. Concentrations of D and ND were determined in body fluids by capillary column gas chromatography after adding prazepam as internal standard and solvent extraction with butyl acetate. The method limit of quantitation was 0.03 μg/g for both D and ND. The concentrations of D and ND were highest in plasma and lowest in erythrocytes. The plasma/blood (P/B) distribution ratios did not depend on drug concentration between 0.1 and 1.0 μg/g. The mean P/B ratios were 1.79:1 for D and 1.69:1 for ND when hematocrit was 45%. Furthermore, the P/B ratio for D (y) was positively correlated with blood hematocrit (x) and the regression equation was y = 0.636 + 0.025x (r = 0.86, P < 0.001). A similar strong association was found between the P/B ratio and hematocrit for ND (r = 0.79). P/B ratios of D and ND, blood hematocrit, hemoglobin, and the water content differed between sexes (P < 0.001). The overall mean P/B ratios for D and ND were 1.69 ± 0.097 (± SD) and 1.62 ± 0.08 (P < 0.001, n = 66) respectively when the mean hematocrit was 42.9 ± 3.4 (± SD). For forensic purposes, it would be better to forgo making any conversion of a drug concentration measured in whole blood to that expected in plasma or serum, instead, therapeutic and toxic concentrations should be established for the actual specimens received.
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
- Lindegårdh, N, et al.
(författare)
-
Automated solid-phase extraction method for the determination of piperaquine in whole blood by rapid liquid chromatography.
- 2003
-
Ingår i: Therapeutic drug monitoring. - 0163-4356 .- 1536-3694. ; 25:5, s. 544-51
-
Tidskriftsartikel (refereegranskat)abstract
- A bioanalytic method for the determination of piperaquine in whole blood by solid-phase extraction and rapid liquid chromatography has been developed and validated. Whole blood was hemolyzed with deionized water, and an internal standard was added to the samples before they were loaded onto a PRS cation-exchange solid-phase extraction column. Piperaquine and internal standard were analyzed by liquid chromatography on a Chromolith Performance (100 x 4.6 mm) column with mobile phase acetonitrile:phosphate buffer, I = 0.1, pH 2.5 (8:92, vol/vol), flow rate 4 mL x min-1, and UV detection at 345 nm. The intraassay precision for whole blood was 3.2% at 3.00 microM and 12.3% at 0.100 microM. The interassay precision for whole blood was 1.8% at 3.00 microM and 5.2% at 0.100 microM. The lower limit of quantification and the limit of detection were 0.050 microM and 0.010 microM, respectively.
|
|
| 8. |
- Lundmark, Jöns, 1953-, et al.
(författare)
-
Serum concentrations of fluoxetine in the clinical treatment setting
- 2001
-
Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 23:2, s. 139-147
-
Tidskriftsartikel (refereegranskat)abstract
- This article discusses fluoxetine serum concentrations as displayed in a clinical setting. A racemic serum fluoxetine and norfluoxetine high-performance liquid chromatography method, including ultraviolet light detection, was used for routine therapeutic drug monitoring (TDM) purposes. In all, 508 samples were analyzed. For the scientific investigation, predefined inclusion and exclusion criteria were applied and 150 samples representative of trough values in steady-state conditions with essential clinical information provided on the assay request forms were evaluated. Fluoxetine plus norfluoxetine concentration-to-dose (C/D) ratio showed Gaussian distribution. Interindividual coefficients of variation of fluoxetine and norfluoxetine serum concentrations after different doses were found to be 40-63%. Intraindividual fluoxetine TDM variability was low. The Spearman rank correlation coefficient for fluoxetine and norfluoxetine C/D ratios in first and second samples was 0.68. Minor increases in norfluoxetine C/D and fluoxetine plus norfluoxetine C/D ratios were found in elderly patients compared with younger adult patients. A higher body-mass index was associated with minor decreases in fluoxetine and fluoxetine plus norfluoxetine C/D ratios. New fluoxetine pharmacokinetic data are added to the results from earlier phases of drug development. Moreover, the results of this study support the usefulness of a fluoxetine TDM procedure for individual dose optimization, detection of drug interactions, and assessments of patient compliance.
|
|
| 9. |
- Lundmark, Jöns, 1953-, et al.
(författare)
-
Therapeutic drug monitoring of sertraline : Variability factors as displayed in a clinical setting
- 2000
-
Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 22:4, s. 446-454
-
Tidskriftsartikel (refereegranskat)abstract
- This report describes sertraline pharmacokinetics derived from routine therapeutic drug monitoring (TDM) data. A high-performance liquid chromatographic method with ultraviolet detection was established for routine sertraline TDM, and 924 analyses were performed from April 1995 to May 1997. Extensive predefined inclusion/exclusion criteria were applied to increase the validity of scientifically evaluated data. Subsequently, 605 samples (65.5%) were excluded. The remaining 319 samples from 319 patients, representative of steady state through specimens and accompanied by essential clinical information provided on request forms, were scrutinized. A pronounced interindividual variability was observed. Smokers had significantly lower concentration-to-dose (C/D) mean ratios of serum sertraline (s-sert) and its main metabolite desmethylsertraline (s-dsert) than nonsmokers. Higher s-sert and s-dsert C/D mean ratios were found in elderly patients than in adults aged less than 65 years. In a subset of 20 patients in whom repeated TDM analyses were performed, observed intraindividual sertraline TDM outcome variability was low. The results highlight sertraline TDM as a tool for individual dose optimization and evaluation of patient drug compliance as well as drug-drug interactions.
|
|
| 10. |
- Pettersson, B, et al.
(författare)
-
Differences between children and adults in thiopurine methyltransferase activity and metabolite formation during thiopurine therapy : Possible role of concomitant methotrexate
- 2002
-
Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 24:3, s. 351-358
-
Tidskriftsartikel (refereegranskat)abstract
- This study examined the role of thiopurine methyltransferase (TPMT) polymorphism in the metabolism and clinical effects of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease and childhood leukemia. The current hypothesis is that the cytotoxic effects of thiopurines are caused by the incorporation of thioguanine nucleotides into DNA. In this context, S-methylation catalyzed by TPMT can be regarded as a competing metabolic pathway. The authors assayed the TPMT activity in red blood cells from 122 patients treated with azathioprine or 6-mercaptopurine (83 adults with inflammatory bowel disease and 39 children with acute lymphoblastic leukemia) and in 290 untreated controls (219 adult blood donors and 71 children). The concentrations of thioguanine nucleotides and methylthioinosine monophosphate were also assayed in red blood cells from the patients. The TPMT activity and the concentrations of methylthioinosine monophosphate and thioguanine nucleotides were higher in children than in adults. All children but no adult patient received concomitant methotrexate. Interaction between methotrexate and 6-mercaptopurine has been described, and may explain the results. Low TPMT activity in adult patients with inflammatory bowel disease correlated to an increased incidence of adverse drug reactions. However, there was no correlation between TPMT activity and the red blood cell concentrations of methylthioinosine monophosphate or thioguanine nucleotides, or between the concentrations of these metabolites and the occurrence of adverse effects. The results show that the role of thiopurine metabolism for drug effects is complex.
|
|
