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ABSTRACT: This work presents a short overview on the available data about drugs that are currently used to treat hypertensive emergencies in children with a focus on incidents after stem cell transplantation. It shows that the pediatric use of all hypotensive agents appears to be mainly based on personal experience of the attending physicians rather than on convincing clinical trials.
A literature search was performed in MEDLINE, through PubMed, using the medical subject headings (MeSH) hypertensive emergencies, nifedipine, nicardipine, and children. Further articles were identified by checking cross-references of articles and books.
Hypertensive emergencies in children after stem cell transplantation usually have a renal etiology, because of the treatment with the calcineurin inhibitors cyclosporine and tacrolimus. In these severe cases an immediate action is necessary to avoid possible appearance or exacerbation of endorgan damage. Because of their mechanism of action and a potential nephroprotective effect calcium channel blockers may be particularly suitable in cases of hypertensive emergencies. An intravenous application of nifedipine may compensate the difficulties of accurate dosing, but keeping in mind possible severe side effects and the lack of published experience its use in children is at least questionable. Nicardipine appears to be the hypotensive agent of first choice. In adults, the treatment of hypertensive emergencies with intravenous nicardipine is well-documented, but for an evaluation of safety in pediatric use, the published studies and case reports appear to be barely adequate.
The actual treatment approaches vary widely, demonstrating the lack of hard science on which current treatment of hypertensive emergencies in children is based. The hypotensive agent for the individual situation should be chosen considering the properties, side effects, the limited experiences with its use and the patient's anamnesis.
International journal of clinical pharmacy. 03/2011; 33(2):165-76.
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ABSTRACT: Enoxaparin has been extensively studied in adults on its safety and efficacy during prevention of symptomatic thromboembolism when acute anticoagulation or secondary prevention is required as a result of venous thrombosis or stroke. In children, it is still used off-label and little is known about the pharmacokinetics in children.
The aim of the present study was to evaluate whether a once- or twice-daily dosing regimen would be feasible in children to achieve appropriate plasma levels of enoxaparin.
A population pharmacokinetic model was developed using anti-factor (F)Xa activity data from 126 children (median age: 5.9 years) receiving enoxaparin either as a once- or twice-daily dosing regimen.
A two-compartment model was adequate for describing the enoxaparin kinetics. Body weight proved to be the most predictive covariate for clearance and central volume of distribution: clearance 15 mL h⁻¹ kg⁻¹, central volume of distribution 169 mL kg⁻¹, intercompartmental clearance 58 mL h⁻¹, peripheral volume of distribution 10 L and absorption rate 0.414 h⁻¹. Interindividual variability was found to be 54% for clearance and 42% for volume of distribution.
The model is capable of describing all age groups and dosing levels of our population and predicts 12 h and 24 h enoxaparin activities sufficiently. According to our results, a once-daily enoxaparin dosing regimen with frequent monitoring is feasible. In 53.2% of the patients the median 24 h trough level was above the desired range of 0.1 IU mL⁻¹ anti-FXa activity for prophylaxis therapy.
Journal of Thrombosis and Haemostasis 09/2010; 8(9):1950-8. · 5.73 Impact Factor
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ABSTRACT: In order to monitor CsA serum levels after SCT, trough levels (C0) are widely used. The aim of this study was to estimate the population and individual PK parameters for patients receiving intravenous CsA after SCT. In 27 pediatric patients after SCT receiving CsA (3 mg/kg/day) every 12 h, a total of 289 CsA concentrations was obtained. To describe the PK parameters of CsA, a two-compartment model with first order elimination was used. Covariate analysis identified body weight, age, and the co-administration with itraconazole and tobramycine as factors influencing the Cl. The statistical comparison of AUC, trough level, and C2 indicates a correlation between AUC and C2, but no correlation between the AUC and C0, r = 0.24 (p = 0.146) vs. r = 0.526 (p = 0.000692), respectively. Our results underscore the fact that CsA trough levels do not reflect the drug exposure in patients receiving intravenous CsA after SCT. By contrast, CsA blood levels measured 2-6 h after CsA infusion showed a better correlation with the AUC. Our data provide new information to optimize the balancing act between GvHD-prophylaxis, graft vs. leukemia effect, and CsA side-effects after SCT.
Pediatric Transplantation 06/2008; 13(4):444-50. · 1.48 Impact Factor
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ABSTRACT: Paracetamol (PCM) is frequently used in pediatric patients with neoplastic disease. It is metabolized mainly by conjugation, but at therapeutic concentrations, a small fraction of the drug undergoes oxidative metabolism via cytochrome P450 forming the hepatotoxic intermediate N-acetyl-p-benzo-quinone-imine (NAPQI) which is usually conjugated with glutathione and excreted as paracetamol mercapturate and paracetamol cysteine.
The aim of this monitoring study was to evaluate PCM metabolism with minimal intervention during routine treatment with single and repeated administration in patients undergoing antineoplastic therapy.
A total of 107 urine samples collected 4-12 h after PCM administration from 29 children undergoing antineoplastic treatment, and 10 children without antineoplastic treatment were analyzed for PCM, PCM glucuronide (PCM-G), PCM sulfate (PCM-S), PCM mercapturate (PCM-M) and PCM cysteine (PCM-C).
The median (range) percentages for metabolites in urine were: a) in children with and without chemotherapy after the first administration: PCM: 0 (0-100) and 4 (0-11)%, PCM-G: 55 (0-88) and 51 (18 - 68)%, PCM-S: 30 (0-73) and 32 (22-57)%, PCM-(M+C): 13 (0-52) and 9 (0-24)%, respectively; b) after repeated administration in children with chemotherapy: PCM: 0 (0-51)%, PCM-G: 42 (7-100)%, PCM-S: 28 (0-70)%, PCM-(M+C): 24 (0-66)%.
The pattern of PCM excretion in children undergoing antineoplastic treatment regimens is highly variable. Repeated administration is associated with a significant increase in the products of oxidative metabolism. This might indicate an increase in metabolism via the hepatotoxic NAPQI.
International journal of clinical pharmacology and therapeutics 10/2007; 45(9):496-503. · 1.18 Impact Factor
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ABSTRACT: Plasma samples from 60 transplant patients on mycophenolate mofetil therapy were analysed using validated capillary electrophoresis (CE) method to determine mycophenolic acid (MPA) and its main metabolite mycophenolic acid glucuronide. Enzyme multiplied immunoassay technique (EMIT) values were available for the same samples. The differences between the results from the two methods was clarified by using Bland–Altman analysis and further statistical analysis. More than 90% of the results showed a positive bias, with EMIT giving higher levels than CE.
Chromatographia 09/2006; 64(7):419-421. · 1.20 Impact Factor
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ABSTRACT: In high dose therapy with methotrexate (MTX) the main metabolite 7-hydroxy-methotrexate (7-OH MTX) exceeds the plasma concentration of MTX achieving about tenfold higher levels. To investigate the interaction between 7-OH MTX and MTX ex vivo, the thymidylate synthase inhibition assay was used to quantify antifolate effects in patient blast samples, measuring the inhibition of the key enzyme thymidylate synthase (TS). In 18 leukemic samples (7 ALL, 11 AML) no dose-dependent TS inhibition was observed for 7-OH MTX. However, a statistically significant increase of TS inhibition (p<0.05) was observed for a 1:1 mixture of MTX and 7-OH MTX as compared to the effect of MTX alone. The half-maximal inhibitory concentrations in the short-exposure assay were 0.857 microM for MTX alone versus 0.088 microM for the 1:1 mixture with 7-OH MTX, respectively (p< or =0.05). This interaction was not observed with an excess of 7-OH MTX. Similar results were obtained in long exposure experiments. We conclude that there is a dose-dependent interaction between 7-OHMTX and MTX, despite the lack of TS inhibitory effects of the metabolite alone.
Cancer Chemotherapy and Pharmacology 09/2005; 56(3):322-7. · 2.83 Impact Factor
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ABSTRACT: Times Cited: 0
Meeting Abstract
English
2494
Cited References Count: 0
491WY
1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA
WASHINGTON
Part 1
Blood 11/2001; 98(11):595A. · 9.90 Impact Factor
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ABSTRACT: In clinical transplantation mycophenolate mofetil (MMF) has become an attractive immunosuppressive agent. To quantify mycophenolic
acid (MPA) and its main metabolite mycophenolic acid glucuronide (MPAG) from small plasma volumes, a capillary electrophoresis
method has been developed. Separation of MMF and its metabolites MPA and MPAG was carried out in a 37 cm×50μm-l.D., fused
silica, capillary with an extended light path at the detection window (bubble-cell) and a TRIS buffer, pH 5.37. Detection
was by UV at 214 nm. Sample preparation was by protein precipitation with acetonitrile and concentration of the supernatant.
Naproxen was used as internal standard. Separation of MMF, MPA and MPAG was in less than 6 min. The method is reproducible
and accurate, with lower limits of quantification of 0.5 mgL−1 for MPA and 2 mgL−1 for MPAG.
Chromatographia 10/2001; 54(9):635-637. · 1.20 Impact Factor
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ABSTRACT: A method using capillary electrophoresis with UV laser-induced native fluorescence detection was developed as a sensitive and selective assay for the simultaneous determination of etoposide and etoposide phosphate in human plasma. Laser-induced native fluorescence detection with a frequency-doubled argon ion laser at an excitation wavelength of 257 nm was used for the simultaneous assay of etoposide and etoposide phosphate in plasma to improve the sensitivity compared to that obtained with UV absorption. The detection system consists of an imaging spectrograph and an intensified CCD camera which views an illuminated 1.5-mm section of the capillary. This setup is able to record the whole emission spectra of the analytes to achieve additional wavelength-resolved electropherograms. In the concentration range of 200 microg/L-50 mg/L in plasma for etoposide and 100 microg/L-20 mg/L for etoposide phosphate, coefficients of correlation were better than 0.998. Within-day variation determined with three different concentrations showed accuracies ranging from 91.0 to 109.3% for etoposide and from 91.2 to 109.9% for etoposide phosphate (n = 6) with a precision of about 8%. Day-to-day variation presented accuracies ranging from 91.8 to 107.9% for etoposide and from 94.4 to 109.3% for etoposide phosphate with a relative standard deviation less than 6% (n = 5). To our knowledge, this is the first method for the simultaneous quantification of etoposide and etoposide phosphate in plasma samples.
Analytical Chemistry 06/2001; 73(10):2178-82. · 5.86 Impact Factor
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ABSTRACT: The stability of doxorubicin and idarubicin was studied in spiked human EDTA-, heparin-plasma and whole blood at room temperature
(RT) and at +4°C. The analysis was performed by capillary electrophoresis (CE). Under each sel of conditions, doxorubicin
and idarubicin concentrations decreased rapidly with time; the decrease was insignificantly more rapid with doxorubicin. Neither
doxorubicinol nor idarubicinol were detectable. In order to obtain comparable plasma levels, doxorubicin and idarubicin containing
blood samples should be centrifuged and stored at −20°C immediately.
Chromatographia 06/2000; 52(1):9-13. · 1.20 Impact Factor
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G Hempel
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ABSTRACT: Capillary electrophoresis (CE) is a useful method to quantify drugs in biological fluids. However, especially for blood or plasma samples, the sensitivity is not sufficient to quantify drugs and their metabolites as they often need to be quantified in the lower microg/L range. To overcome this limitation and to increase the sensitivity, two strategies are applied: first, to increase the amount of analyte added to the capillary and, second, to increase the sensitivity on the detector site. To improve the sensitivity on the detector site, alternative detection techniques to UV detection, e.g., laser-induced fluorescence detection (LIF) or mass spectroscopy (MS), can be applied. However, LIF detection can only be used for fluorescent analytes and the current equipment for CE-MS coupling provides only small improvements in sensitivity compared to UV detection. The detection window for UV detection can be enhanced using capillaries with an extended light path (bubble cell) or Z-shaped capillaries. Sensitivity improvements up to a factor of 10 have been reported. Increasing the amount of analyte in the capillary can be done either by chromatographic or by electrokinetic methods. Chromatographic methods such as on-capillary membrane preconcentration have been used for several analytes. However, no validated application has been reported to date. In contrast, several validated examples can be found in which electrokinetic techniques like sample stacking have been applied to achieve limits of quantification in the lower microg/L range. In conclusion, to date, electrokinetic techniques such as field-amplified sample injection offer the most promising results in achieving a sufficient sensitivity to quantify drugs in biological fluids.
Electrophoresis 04/2000; 21(4):691-8. · 3.30 Impact Factor
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ABSTRACT: (E)-5-(2-Bromovinyl)-2'-deoxyuridine is an antiviral drug used for treatment of infections with Herpes simplex virus type 1 as well as Varicella zoster virus. Two fast methods for the determination of the drug and its metabolite in plasma and urine by capillary electrophoresis have been developed. The plasma method can be used for measurement of total as well as unbound drug and metabolite. Plasma and urine samples are prepared for measuring by liquid/liquid extraction resulting in a limit of quantification of 40 ng/ml for total and 10 ng/ml for free BVdU in plasma and 170 ng/ml in urine. Inter- as well as intra-day precision were found to be better than 10% and both methods have been used for drug monitoring of patients.
Journal of chromatography. B, Biomedical sciences and applications 05/1999; 726(1-2):261-8.
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J P Vieira Pinheiro,
E Ahlke,
U Nowak-Göttl, G Hempel,
H J Müller,
K Lümkemann,
M Schrappe,
B Rath,
G Fleischhack,
G Mann,
J Boos
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ABSTRACT: Native forms of asparaginase stem from different biological sources. Previously reported data from children treated with Erwinase showed significantly lower trough levels and pharmacokinetic dose intensity than after E. coli-derived preparations. Hence, schedule optimization was initiated to achieve relevant serum activities. 21 children on reinduction therapy received Erwinase on Mondays, Wednesdays and Fridays for 3 weeks (9 x 20000 IU/m2 i.v.) instead of 4x 10 000IU/m2 of E. coli asparaginase (twice weekly for 2 weeks). Asparaginase trough activities were measured as the primary parameter, targeting 100-200 IU/I after 2 d and >50 IU/l after 3 d. Concurrently, asparagine trough concentrations were monitored. The mean trough activity was 156+/-99 IU/l, with 2/108 samples showing no detectable activity. Regarding trough levels per individual (three or more measurements/patient), means ranged from 52+/-29 to 276+/-114 IU/l (20 patients, 106 samples), with nine, six, and five children inside, below, and above the target range, respectively. The mean 3 d trough activity was 50+/-39 IU/l (20 patients, 51 samples). In 11 of these samples no activity was measurable. Mean trough activities calculated per individual ranged from < 20-84+/-30 IU/l (14 patients, 42 samples) with seven children below the target limit of 50 IU/l and asparagine concentrations <0.2 - 1.5microM. We concluded that an increased dose of 9x20000 IU/m2 of Erwinia asparaginase within 3 weeks resulted in a pharmacokinetic dose intensity comparable to former observations made with 4 x 10 000IU/m2 of the E. coli product Crasnitin which is no longer marketed. High interindividual variability and the phenomenon of 'silent' inactivation necessitate monitoring wherever possible.
British Journal of Haematology 02/1999; 104(2):313-20. · 4.94 Impact Factor
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ABSTRACT: It is generally assumed that drug concentration does not change significantly under cell culture conditions. Nevertheless, most of the therapeutic trials in acute leukemia that were based on in vitro drug sensitivity assays of patient samples have been disappointing. In order to show possible pitfalls of unphysiological alterations in vitro we investigated concentration versus time curves, metabolism and effects on the culture media for some antineoplastic drugs. Oxazaphosphorines and cytarabine were incubated in RPMI and in established cell lines and measured by HPLC. HPLC also served to measure enzyme activity and levels of related amino acids at various concentrations of asparaginase, ammonia release was photometrically determined. Etoposide was monitored by HPLC relative to different contents of FCS in RPMI. All oxazaphosphorines showed a rapid decrease of in vitro activity down to about 10% within 4-6 h, and 2% within 72 h. The level of cytarabine, when incubated in RPMI, was stable over 24h, and no change was seen with K562, while a rapid decrease to below 50% occurred within 6h in the presence of HL 60 and BLIN. 2 U/L of asparaginase led to asparagine depletion of the medium within 4h, while 200 U/L were associated with a preferential increase of glutamic acid and ammonia. Further, there was evidence of instability by rapid adsorption to plastic surfaces (paclitaxel) or isomerisation (etoposide) in RPMI with low FCS content. The instability of drugs in vitro is attributed to a variety of different factors: i.e. physico-chemical instability results in inactivation of oxazaphosphorines, cytarabine disappears by cellular metabolism without saturation depending on the cell-line. Epiphenomena like adsorption and isomerisation in vitro are unphysiological. Results of drug sensitivity assays should be interpreted with great caution.
Advances in experimental medicine and biology 02/1999; 457:397-407. · 1.09 Impact Factor
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ABSTRACT: The successful introduction of 13-cis-retinoic acid (13-cis-RA) and all-trans-retinoic acid (all-trans-RA) in the chemoprevention and treatment of cancer along with the discovery of different retinoic acid receptors transactivated by different retinoic acid isomers resulted in a number of in vitro studies of the antitumor effects of single retinoic acid isomers. Since the formation of retinoic acid isomers with different receptor affinities might modulate retinoic acid response in vitro, we determined retinoic acid disposition in HL-60 cells and cell culture medium during incubation with 13-cis-, 9-cis-, and all-trans-RA. In medium, retinoic acids underwent a thiol-radical mediated isomerization resulting in a mixture of 13-cis-, 9-cis-, 9,13-di-cis-, and all-trans-RA. Except for the 9, 13-di-cis-RA, all isomers generated in medium were also detected in HL-60 cells. Whereas 9-cis-RA and 13-cis-RA showed similar cellular pharmacokinetics, all-trans-RA reached about fourfold higher concentrations in HL-60 cells compared to 9-cis-RA and 13-cis-RA. Due to its better uptake, all-trans-RA became the main isomer within cells as it was formed in the medium when incubated with 13-cis-RA and 9-cis-RA. Thus, due to the simple chemically induced isomerization and its profound influence on cellular retinoic acid concentrations, studies of the efficacy of single retinoic acid isomers in vitro should be interpreted with caution.
The FASEB Journal 01/1999; 12(15):1627-33. · 5.71 Impact Factor
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ABSTRACT: A method for the determination of doxorubicin and its main metabolite doxorubicinol in human plasma is described. Two different sample preparation procedures are applied depending on the expected concentration: To monitor the peak plasma levels, 10 microL of plasma are deproteinated with acetonitrile. After centrifugation, the supernatant is directly applied to the capillary by hydrodynamic injection. For the determination of lower amounts of doxorubicin and its main metabolite doxorubicinol 100 microL of plasma is extracted by liquid-/liquid extraction with chloroform. After evaporation of the organic phase, the sample is reconstituted in acetonitrile/water (95/5 v/v) and injected into the capillary by electrokinetic injection. Idarubicin serves as the internal standard. Laser-induced fluorescence detection with an Ar-ion laser emitting at 488 nm and a 520 nm cut-off filter is used for detection. The accuracy of the method was calculated to be 3.0% at higher concentrations and 15.0% at the limit of quantification. Reproducibility data are in accordance to the generally accepted criteria for bioanalytical methods. The limit of quantification is 2 microg/L, enabling us to monitor doxorubicin plasma levels for several days after application. Noninvasive blood sampling (from the fingertip) using heparinized capillaries was found to be a simple and convenient procedure and provides reproducible data. Initial results show high interindividual variability in doxorubicin peak plasma levels.
Electrophoresis 12/1998; 19(16-17):2939-43. · 3.30 Impact Factor
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ABSTRACT: During the last decade, the oxazaphosphorine trofosfamide was underestimated partly due to its unsuitability for i.v. use. Oral daily doses of 150 mg were tolerated well and showed appreciable response rates in the treatment of lymphoma. Furthermore, activity in sarcoma and cancers sensitive to oxazaphosphorines in general seems probable, because ifosfamide is the main metabolite of trofosfamide. Due to its oral mode of application and good tolerance, trofosfamide will be an important option in view of the increasing demand for treatment regimens suited for an outpatient basis. Results of the major in vitro, in vivo and clinical studies are reported for evaluation of its significance in chemotherapy today.
Anti-Cancer Drugs 07/1997; 8(5):419-31. · 2.41 Impact Factor
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ABSTRACT: To contribute to effective and safe outpatient treatment, we investigated the metabolism of trofosfamide (Trofo) after oral administration. We analyzed Trofo metabolism in 15 patients aged from 3 to 73 years who were treated with 150 or 250 mg/m2 Trofo in combination with etoposide. Serum samples were collected with 13 patients after oral administration, and Trofo and its dechloroethylated metabolites were quantified by gas chromatography. Urine samples were collected from five patients and analyzed by same method. Ifosfamide (Ifo) was the main metabolite in serum and urine (AUCTrofo:AUCIfo 1:13), whereas cyclophosphamide (Cyclo) was formed in smaller amounts (AUC(Ifo):AUC(Cyclo) 18:1). Ifo and Cyclo were further oxidized in the chloroethyl side chains to form 2- and 3-dechlorethylifosfamide in varying quantities. The urinary excretion of Trofo and its dechloroethylated metabolites amounted to about 10% of the total dose. Our results confirm former in vitro observations about the metabolism of Trofo. The main side-chain metabolites Ifo and Cyclo can be further activated by oxidation and formation of their respective phosphoramide mustards. Hence, Trofo is an interesting agent for oral chemotherapy.
Cancer Chemotherapy and Pharmacology 02/1997; 40(1):45-50. · 2.83 Impact Factor
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ABSTRACT: All-trans-retinoic acid (all-trans-RA) and 13-cis-retinoic acid (13-cis-RA), due to their effects on cell differentiation, proliferation and angiogenesis, improved treatment results in some malignancies. Pharmacokinetic studies of all-trans-RA and 13-cis-RA along with monitoring of retinoic acid metabolites may help to optimize retinoic acid therapy and to develop new effective strategies for the use of retinoic acids in cancer treatment. Therefore, we developed a HPLC method for the simultaneous determination in human plasma of the physiologically important retinoic acid isomers, all-trans-, 13-cis- and 9-cis-retinoic acid, their 4-oxo metabolites, 13-cis-4-oxoretinoic acid (13-cis-4-oxo-RA) and all-trans-4-oxoretinoic acid (all-trans-4-oxo-RA), and Vitamin A (all-trans-retinol). Analysis was performed on a silica gel column with UV detection at 350 nm using a binary multistep gradient composed of n-hexane, 2-propanol and glacial acetic acid. For liquid-liquid extraction a mixture of n-hexane, dichloromethane and 2-propanol was used. The limits of detection were 0.5 ng/ml for retinoic acids and 10 ng/ml for all-trans-retinol. The method showed good reproducibility for all components (within-day C.V.: 3.02-11.70%; day-to-day C.V.: 0.01-11.34%). Furthermore, 9-cis-4-oxoretinoic acid (9-cis-4-oxo-RA) is separated from all-trans-4-oxo-RA and 13-cis-4-oxo-RA. In case of clinical use of 9-cis-retinoic acid (9-cis-RA) the pharmacokinetics and metabolism of this retinoic acid isomer can also be examined.
Journal of chromatography. B, Biomedical applications 11/1996; 685(2):233-40.
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ABSTRACT: Zolpidem is a new sleep inducer belonging to the imidazopyridine class. We wish to report a method for the determination of zolpidem and its main metabolites in urine without extraction using capillary electrophoresis with UV laser-induced fluorescence detection with a He-Cd laser. A 10-nl sample of urine can be directly applied to the capillary. The separation is carried out within 10 min, and the limit of detection is 2 ng/ml. This procedure is very simple and fast. No organic solvents are necessary.
Journal of chromatography. B, Biomedical applications 02/1996; 675(1):131-7.
