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1.
J Thromb Haemost ; 16(9): 1732-1742, 2018 09.
Article in English | MEDLINE | ID: mdl-29935043

ABSTRACT

Essentials A pediatric pharmacogenetic dosing algorithm for acenocoumarol has not yet been developed. We conducted a multicenter retrospective follow-up study in children in the Netherlands. Body surface area and indication explained 45.0% of the variability in dose requirement. Adding the genotypes of VKORC1, CYP2C9 and CYP2C18 to the algorithm increased this to 61.8%. SUMMARY: Background The large variability in dose requirement of vitamin K antagonists is well known. For warfarin, pediatric dosing algorithms have been developed to predict the correct dose for a patient; however, this is not the case for acenocoumarol. Objectives To develop dosing algorithms for pediatric patients receiving acenocoumarol with and without genetic information. Methods The Children Anticoagulation and Pharmacogenetics Study was designed as a multicenter retrospective follow-up study in Dutch anticoagulation clinics and children's hospitals. Pediatric patients who used acenocoumarol between 1995 and 2014 were selected for inclusion. Clinical information and saliva samples for genotyping of the genes encoding cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), CYP4F2, CYP2C18 and CYP3A4 were collected. Linear regression was used to analyze their association with the log mean stable dose. A stable period was defined as three or more consecutive International Normalized Ratio measurements within the therapeutic range over a period of ≥ 3 weeks. Results In total, 175 patients were included in the study, of whom 86 had a stable period and no missing clinical information (clinical cohort; median age 8.9 years, and 49% female). For 80 of these 86 patients, genetic information was also available (genetic cohort). The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. After addition of the VKORC1, CYP2C9, and CYP2C18 genotypes to the algorithm, this increased to 61.8%. Conclusions These findings show that clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Nevertheless, genetic factors, and especially VKORC1, also explained a significant part of the variability.


Subject(s)
Acenocoumarol/administration & dosage , Anticoagulants/administration & dosage , Acenocoumarol/analysis , Acenocoumarol/pharmacokinetics , Adolescent , Age Factors , Algorithms , Anticoagulants/analysis , Anticoagulants/pharmacokinetics , Biological Variation, Individual , Biotransformation/genetics , Body Surface Area , Child , Child, Preschool , Cytochrome P-450 Enzyme System/genetics , Cytochrome P-450 Enzyme System/metabolism , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Genetic Association Studies , Humans , Infant , Male , Models, Biological , Polymorphism, Single Nucleotide , Practice Guidelines as Topic , Retrospective Studies , Saliva/chemistry , Thrombophilia/drug therapy , Vitamin K/antagonists & inhibitors
2.
Talanta ; 178: 308-314, 2018 Feb 01.
Article in English | MEDLINE | ID: mdl-29136827

ABSTRACT

A novel approach for therapeutic drug monitoring of oral anticoagulants (OA) in clinical samples is reported, based on a NP-based biobarcode assay. The proposed strategy uses specific antibodies for acenocumarol (ACL) covalently bound to magnetic particles (pAb236-MP) and a bioconjugate competitor (hACL-BSA) linked to encoded polystyrene probes (hACL-BSA-ePSP) on a classical competitive immunochemical format. By using this scheme ACL can be detected in low nM range (LOD, 0.96 ± 0.26, N = 3, in buffer) even in complex samples such as serum or plasma (LOD 4 ± 1). The assay shows a high reproducibility (%CV 1.1 day-to-day) and is robust, as it is demonstrated by the fact that ACL can be quantified in complex biological samples with a very good accuracy (slope = 0.97 and R2 = 0.91, of the linear regression obtained when analyzing spiked vs measured values). Moreover, we have demonstrated that the biobarcode approach has the potential to overcome one of the main challenges of the multiplexed diagnostic, which is the possibility to measure in a single run biomarker targets present at different concentration ranges. Thus, it has been proven that the signal and the detectability can be modulated by just modifying the oligonucleotide load of the encoded probes. This fact opens the door for combining in the same assay encoded probes with the necessary oligonucleotide load to achieve the detectability required for each biomarker target.


Subject(s)
Acenocoumarol/analysis , Anticoagulants/analysis , Drug Monitoring/methods , Acenocoumarol/administration & dosage , Administration, Oral , Anticoagulants/administration & dosage , Humans , Limit of Detection , Magnets/chemistry , Polystyrenes/chemistry
3.
J Chromatogr Sci ; 55(10): 989-991, 2017 Nov 01.
Article in English | MEDLINE | ID: mdl-28985280

ABSTRACT

Acenocoumarol, an anticoagulant drug, was separated successfully using polysaccharide-based chiral stationary phases columns namely Cellulose Chiralpak® IB and Chiralcel® OD, using various normal mobile phases by high-performance liquid chromatography. However, the appearance of four well separated peaks confirmed the presence of the hemiketal form of 4-hydroxy-3-[1-(4-nitrophenyl)-3-oxobutyl]-2H-chromen-2-one.


Subject(s)
Acenocoumarol , Anticoagulants , Chromatography, High Pressure Liquid/methods , Acenocoumarol/analysis , Acenocoumarol/chemistry , Acenocoumarol/isolation & purification , Anticoagulants/analysis , Anticoagulants/chemistry , Anticoagulants/isolation & purification , Cellulose/analogs & derivatives , Stereoisomerism
4.
Chemosphere ; 169: 181-187, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27883912

ABSTRACT

Regular use of a reference material and participation in a proficiency testing program can improve the reliability of analytical data. This paper presents the preparation of candidate reference materials for the drugs metoprolol, propranolol, carbamazepine, naproxen, and acenocoumarol in freshwater bottom sediment and cod and herring tissues. These reference materials are not available commercially. Drugs (between 7 ng/g and 32 ng/g) were added to the samples, and the spiked samples were freeze-dried, pulverized, sieved, homogenized, bottled, and sterilized by γ-irradiation to prepare the candidate materials. Procedures for extraction and liquid chromatography coupled with tandem mass spectrometry were developed to determine the drugs of interest in the studied material. Each target drug was quantified using two analytical procedures, and the results obtained from these two procedures were in good agreement with each other. Stability and homogeneity assessments were performed, and the relative uncertainties due to instability (for an expiration date of 12 months) and inhomogeneity were 10-25% and 4.0-6.8%, respectively. These procedures will be useful in the future production of reference materials.


Subject(s)
Environmental Monitoring/methods , Fishes/metabolism , Water Pollutants, Chemical/analysis , Acenocoumarol/analysis , Acenocoumarol/metabolism , Animals , Carbamazepine/analysis , Carbamazepine/metabolism , Chromatography, Liquid/methods , Environmental Monitoring/standards , Metoprolol/analysis , Metoprolol/metabolism , Naproxen/analysis , Naproxen/metabolism , Propranolol/analysis , Propranolol/metabolism , Reference Standards , Reproducibility of Results , Seafood , Tandem Mass Spectrometry/methods , Water Pollutants, Chemical/metabolism , Water Pollutants, Chemical/standards
5.
J Chromatogr B Analyt Technol Biomed Life Sci ; 850(1-2): 507-14, 2007 May 01.
Article in English | MEDLINE | ID: mdl-17293173

ABSTRACT

We describe a new fully validated enantioselective LC-MS/MS method for stereospecific quantification of both the racemic forms of Warfarin (WF), Phenprocoumon and Acenocoumarol in human plasma. Measurement specificity was assessed by using different blank donor plasma samples, where no interfering reagent peak appeared at the retention time (RT) of the targeted analytes. Response was linear for all analytes. Typical linear regression coefficients have >0.99. The recoveries ranged from 98% to 118%. Determinations in 10 normal healthy individuals revealed a high reproducibility of RTs. These findings confer to the method suitability for large population studies.


Subject(s)
Acenocoumarol/analysis , Chromatography, Liquid/methods , Phenprocoumon/analysis , Spectrometry, Mass, Electrospray Ionization/methods , Tandem Mass Spectrometry/methods , Warfarin/analysis , Acenocoumarol/chemistry , Phenprocoumon/chemistry , Reproducibility of Results , Sensitivity and Specificity , Stereoisomerism , Warfarin/chemistry
6.
Acta Pharm ; 54(2): 119-31, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15274755

ABSTRACT

A complex of neodymium(III) with 4-hydroxy-3[1-(4-nitrophenyl)-3-oxobutyl]-2H-1-benzopyran-2-one (acenocoumarol) was synthesized by mixing water solutions of neodymium(III) nitrate and the ligand (metal to ligand molar ratio of 1:3). The complex was characterized and identified by elemental analysis, conductivity, IR, 1H NMR and mass spectral data. DTA and TGA were applied to study the composition of the compound. Elemental and mass spectral analysis of the complex indicated the formation of a compound of the composition NdR3 x 6H2O, where R = C19H14NO6-) The reaction of neodymium(III) with acenocoumarol was studied in detail by the spectrophotometric method. The stepwise formation of three complexes, vis., NdR2+, NdR2+ and NdR3 was established in the pH region studied (pH 3.0-7.5). The equilibrium constants for 1:1, 1:2 and 1:3 complexes were determined to be log K1 = 6.20 +/- 0.06; log K2 = 3.46 +/- 0.07 and log K2) = 2.58 +/- 0.05, respectively.


Subject(s)
Acenocoumarol/chemistry , Lanthanoid Series Elements/chemistry , Neodymium/chemistry , Acenocoumarol/analysis , Coumarins/analysis , Coumarins/chemistry , Drug Stability , Lanthanoid Series Elements/analysis , Neodymium/analysis
8.
Tijdschr Kindergeneeskd ; 61(5): 175-7, 1993 Oct.
Article in Dutch | MEDLINE | ID: mdl-8266311

ABSTRACT

Oral anticoagulants are frequently prescribed during lactation. Because these drugs could affect the hemostasis of the newborn, we did a literature search to find out whether precautions should be taken. It appeared that acenocoumarol and warfarin are not detectable in human milk. Besides the usual daily supplementation of 25 micrograms vitamin K for every breast-fed infant, precautions are not necessary. Phenprocoumon, ethylbiscoumacetate and phenindione are excreted in human milk and could affect neonatal hemostasis.


Subject(s)
Anticoagulants/analysis , Breast Feeding , Hemorrhage/chemically induced , Milk, Human/chemistry , Acenocoumarol/analysis , Anticoagulants/adverse effects , Ethyl Biscoumacetate/analysis , Female , Humans , Infant , Infant, Newborn , Phenprocoumon/analysis , Warfarin/analysis
9.
Br J Clin Pharmacol ; 25(5): 591-8, 1988 May.
Article in English | MEDLINE | ID: mdl-3408639

ABSTRACT

1. A stereospecific h.p.l.c. assay of nicoumalone in plasma has been developed. 2. The assay was applied to a study in which 20 mg racemic nicoumalone was given orally to three volunteers and blood samples taken for 168 h. 3. The mean pharmacokinetic parameters of the individual enantiomers were: clearance/bioavailability 1.28 1 h-1, R-enantiomer; 17.5 1 h-1, S-enantiomer: volume of distribution/bioavailability 12.5 1, R-enantiomer; 22.6 1, S-enantiomer: terminal half-life 6.8 h, R-enantiomer; 0.91 h, S-enantiomer. 4. The data are consistent with a substantial first-pass hepatic loss of S-nicoumalone.


Subject(s)
Acenocoumarol/analysis , Acenocoumarol/blood , Acenocoumarol/pharmacokinetics , Adult , Chromatography, High Pressure Liquid , Humans , Male , Protein Binding , Stereoisomerism
10.
J Chromatogr ; 274: 231-8, 1983 May 13.
Article in English | MEDLINE | ID: mdl-6874824

ABSTRACT

Acenocoumarin and its acetamido metabolite, after extraction at pH 4.4, were analysed by isocratic reversed-phase high-performance liquid chromatography using aqueous acetonitrile (pH 4.90) as eluent. Warfarin was used as internal standard. The amino metabolite, after back-extraction into 0.5 N HCl, was derivatized by diazotization and heat treatment. The resulting product was analysed by the same reversed-phase system. The sensitivity of the method for acenocoumarin and its amino metabolite was in the range of 20 ng/ml. To achieve this sensitivity for the analysis of the acetamido compound, the acetonitrile content of the eluent had to be lowered. The assay was applied to the analysis of plasma samples of patients under acenocoumarin therapy. The disposition of the amino compound in rats was investigated.


Subject(s)
Acenocoumarol/analogs & derivatives , Acenocoumarol/analysis , Body Fluids/analysis , Warfarin/analogs & derivatives , Acenocoumarol/blood , Acenocoumarol/isolation & purification , Acenocoumarol/metabolism , Acetonitriles , Animals , Chromatography, High Pressure Liquid , Humans , Hydrogen-Ion Concentration , Rats
12.
J Pharm Sci ; 66(7): 997-1000, 1977 Jul.
Article in English | MEDLINE | ID: mdl-18595

ABSTRACT

Acenocoumarol, to which a 14C-labeled internal standard has been added, is extracted at pH 4 into ethyl acetate-heptane (20:80 v/v), back-extracted into aqueous sodium hydroxide solution after solvent washing with a pH 7 buffer, and reextracted after acidification in the solvent mixture. It is then acetylated with 3H-acetic anhydride. The acenocoumarol acetyl derivative is separated from the metabolite derivatives by TLC, and its radioactivity is measured. The method is specific and sensitive to a concentration of 8 ng/ml.


Subject(s)
Acenocoumarol/analysis , Acenocoumarol/blood , Acenocoumarol/urine , Acetylation , Carbon Radioisotopes , Chromatography, Thin Layer , Hydrogen-Ion Concentration , Isotope Labeling , Kinetics , Methods , Tritium
13.
J Assoc Off Anal Chem ; 58(1): 80-4, 1975 Jan.
Article in English | MEDLINE | ID: mdl-49348

ABSTRACT

This collaborative study was undertaken to determine if the anticoagulants acenocoumarol, phenprocoumon, and potassium warfarin could be analyzed by the automated analysis system described in the collaborative study for the analysis of sodium warfarin and dicumarol. Collaborators were supplied with a composited tablet sample of each anticoagulant. Results agreed well with the National Formulary methods for phenprocoumon and potassium warfarin, and an unpublished method for acenocoumarol. For acenocoumarol, coefficients of variation on individual sets of data ranged from 0.30 to 1.94% For phenprocoumon, coefficients of variation ranged from 0.52 to 1.20%. For potassium warfarin, coefficients of variation ranged from 0.54 to 1.79%. The results of this study show that acenocoumarol, phenprocoumon, and potassium warfarin can be analyzed by the official AOAC method for the analysis of sodium warfarin and dicumarol tablets.


Subject(s)
Acenocoumarol/analysis , Coumarins/analysis , Phenprocoumon/analysis , Warfarin/analysis , Autoanalysis/methods , Dicumarol/analysis , Potassium/analysis , Tablets
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