| 1. |
- Bogason, Alex, et al.
(författare)
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Inverse relationship between leukaemic cell burden and plasma concentrations of daunorubicin in patients with acute myeloidleukaemia
- 2011
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 71:4, s. 514-521
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Tidskriftsartikel (refereegranskat)abstract
- center dot In vitro studies show that daunorubicin (DNR) cytotoxicity decreases with increasing cell density because of a high cellular uptake and depletion of drug in the medium. center dot It is not known whether such an effect also occurs in vivo. WHAT THIS STUDY ADDS center dot We have shown that a large leukaemic cell burden lowers the plasma concentration of DNR in patients with acute myeloid leukaemia. center dot Our analysis supports that a large leukaemic cell burden increases the central volume of distribution for DNR. center dot Our study indicates that a dose adjustment of DNR may be of importance in acute myeloid leukaemia patients with high white blood cell counts. AIMS It has been shown that the cellular uptake and cytotoxicity of anthracyclines decrease with increasing cell density in vitro, an event termed 'the inocculum effect'. It is not known whether such an effect occurs in vivo. In this study the relationships between white blood cell (WBC) count, plasma and cellular concentrations of daunorubicin (DNR) in patients with acute myeloid leukaemia were investigated. METHODS Plasma and mononuclear blood cells were isolated from peripheral blood from 40 patients with acute myeloid leukaemia at end of infusion (time 1 h), 5 and 24 h following the first DNR infusion. DNR concentrations were determined by high-pressure liquid chromatography and related to the WBC count at diagnosis. A population pharmacokinetic model was used to estimate the correlations between baseline WBC count, volume of distribution and clearance of DNR. RESULTS A clear but weak inverse relationship between the baseline WBC count and plasma concentrations of DNR (r2 = 0.11, P < 0.05) at time 1 was found. Furthermore, a clear relationship between baseline WBC count and DNR central volume of distribution using population pharmacokinetic modelling (dOFV 4.77, P < 0.05) was also noted. Analysis of plasma DNR and the metabolite daunorubicinol (DOL) concentrations in patients with a high WBC count support that the low DNR/DOL concentrations are due a distribution effect. CONCLUSION This study shows that the leukaemic cell burden influences the plasma concentrations of anthracyclines. Further studies are needed to explore if patients with high a WBC count may require higher doses of anthracyclines.
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| 2. |
- Elmongy, Hatem, et al.
(författare)
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Development and validation of a UHPLC-HRMS method for the simultaneous determination of the endogenous anabolic androgenic steroids in human serum
- 2020
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Ingår i: Journal of Chromatography A. - : Elsevier BV. - 0021-9673 .- 1873-3778. ; 1613
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Tidskriftsartikel (refereegranskat)abstract
- Being performance enhancing hormones, endogenous anabolic androgenic steroids (EAAS) are banned from most competitive sports by the World Anti-doping Agency (WADA). In anti-doping control laboratories, routine assays are mainly performed on urine samples of athletes in and out of competitions. Serum constitutes a promising alternative to urine as it is less subjected to manipulation or contamination that may influence the method sensitivity. The simultaneous determination of EAAS including conjugated metabolites using LC-MS is very challenging due to their contradicting chemical behaviors at the ionization interface of the mass spectrometer. This may prejudice their detection or limit the method sensitivity. Herein, we have addressed these challenges and developed a new method for the simultaneous determination of unconjugated, sulphate- and glucuronide-conjugated EAAS (Androsterone, Etiocholanolone, testosterone, epitestosterone, dihydrotestosterone, dehydroepiandrosterone, androstenedione and 17a-hydroxyprogesterone) in human serum using ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS). The use of mass spectrometric detection in full scan mode facilitated the study of the most versatile adducts for detection and quantitation. A solid phase extraction method was developed for the sample preparation prior to analysis. The method limits of quantitation ranged from 0.006 to 7.904 ng/mL and the recoveries ranged from 70.2% to 96.5%. The method calibration was performed in untreated serum representing realistic matrix composition with correlation coeffecients ranged from 0.9859 to 0.9988. Finally, the serum-levels of the investigated steroids were determined in 4 male and 1 female human subjects to provide estimates of baseline levels based on individual values.
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| 3. |
- Helldén, Anders, et al.
(författare)
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Fluconazole-induced intoxication with phenytoin in a patient with ultra-high activity of CYP2C9
- 2010
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 66:8, s. 791-5
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The cytochrome P450 enzyme CYP2C9 metabolizes several important drugs, such as warfarin and oral antidiabetic drugs. The enzyme is polymorphic, and all known alleles, for example, CYP2C9*2 and*3, give decreased activity. Ultra-high activity of the enzyme has not yet been reported.METHODS: We present a patient with Behçet's disease who required treatment with high doses of phenytoin. When fluconazole, a potent inhibitor of CYP2C9, was added to the treatment regimen, the patient developed ataxia, tremor, fatigue, slurred speech and somnolence, indicating phenytoin intoxication. On suspicion of ultra-high activity of CYP2C9, a phenotyping test for CYP2C9 with losartan was performed.RESULTS: The patient was shown to have a higher activity of CYP2C9 than any of the 190 healthy Swedish Caucasians used as controls.CONCLUSIONS: Our finding of an ultrarapid metabolism of losartan and phenytoin may apply to other CYP2C9 substrates, where inhibition of CYP2C9 may cause severe adverse drug reactions.
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| 4. |
- Masquelier, Michéle, et al.
(författare)
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Cytotoxic effect of a lipophilic alkylating agent after incorporation into low density lipoprotein or emulsions : Studies in human leukemic cells
- 2006
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Ingår i: Leukemia Research. - : Elsevier BV. - 0145-2126 .- 1873-5835. ; 30:2, s. 136-144
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Tidskriftsartikel (refereegranskat)abstract
- The use of low density lipoprotein (LDL) as drug carrier in acute myeloblastic leukemia chemotherapy is attractive due to high LDL uptake by leukemic cells. Lipid-based formulations, such as liposomes or microemulsions are promising alternatives. In the current study, we incorporated N-trifluoroacetyl-adriamycin-14-valerate (AD32), a lipophilic derivative of daunorubicin (DNR), and WB4291, a lipophilic alkylating agent, into LDL or lipid microemulsions and evaluated their cytotoxic activities towards leukemic cell lines using as references DNR and melphalan. The incorporation of AD32 into LDL or emulsion resulted in complexes with poor cytotoxicity. WB4291-LDL and WB4291-emulsion exerted, on the other hand, promising cytotoxic effects towards parental and resistant K562 and HL60 cell lines. © 2005 Elsevier Ltd. All rights reserved.
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| 5. |
- Masquelier, Michèle
(författare)
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Leukemia chemotherapy : experimental studies on pharmacological optimisation
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Our main goal has been to identify new means to improve chemotherapy of acute leukaemia: 1. By using low-density lipoprotein (LDL) as a drug carrier to increase the selectivity of antileukemic drugs, based on high LDL uptake in acute myeloid leukemia (AML) cells. Our first concern was to investigate the importance of chemical structures to obtain a stable anchorage of the drug into LDL. The only stable complex was obtained when incorporating cholesteryl-linoleat in LDL as shown by dialysis and autoradiography data. With N-trifluoroacetyl-adriamycin-14-valerat-LDL (AD32-LDL) the drug leaked slowly into the plasma. In AML patients a rapid plasma dissociation of AD-32-LDL was observed, illustrating a much higher in vivo instability of this complex. We thereafter synthesised five lipophilic derivatives of daunorubicin (DNR) for incorporation into LDL. Three incorporated successfully into LDL: 2 benzyloxy and the isonicotinoyl derivatives. In vitro these complexes were more cytotoxic towards a LDL receptor positive cell line than to LDL receptor negative cells, but non-specific cytotoxicity was quite high and was explained by slow dissociation of the drug-LDL complexes in plasma. These results underline the difficulty in obtaining a stable LDL complex. Finally we studied the cytotoxicity of WB4291, a lipophilic alkylating agent, after incorporation in LDL or lipid microemulsions towards sensitive and resistant myeloid cell lines. The complexes exerted a better activity than melphalan and DNR towards all the resistant sublines expressing Pgp, K562/Vcr and/Dnr. 2. By studying the relation between DNR concentration and apoptosis induction in leukemic cells. We studied the time course of induction of apoptosis by DNR in HL60 and K562 cells and in isolated leukemic cells from patients with AML, after a pulse incubation with increasing drug concentrations. Caspase-3-like activity correlated positively with DNR concentrations, appearing faster at high DNR concentrations in all the cells. DNA fragmentation occured in two steps, an intranucleosomal cleavage producing high MW DNA fragments, followed by an internucleosomal cleavage and the apparition of small fragments observed in a typical DNA ladder. The high MW fragments were observed in all the cells with the exception of K562 cells. DNA fragmentation was faster at high DNR concentrations in all the cells except K562 cells. In leukemic cells from patients with AML, the time course of DNA fragmentation at 0.25?g/ml showed large interindividual variations in in vitro chemosensitivity that could reflect variations in in vivo sensitivity. The results support the concept of dose intensification in induction therapy with DNR. 3. By studying of the impact of cell density on drug cytotoxicity in order to optimise individual treatment. White blood cell count (WBC) is generally accepted as a significant prognostic risk factor in acute leukemia outcome and shows a marked variation at diagnosis. Actually the dose regimen currently used ignores the size of the tumor burden and the standardization of the dose is generally based only on body surface area. In this study we investigated the effect of cell density on the cytotoxic activity of DNR and Ara-C in HL60 cells and in leukemic cells isolated from patients with AML. We showed that their cytotoxicity decreased with cell density and that apoptosis induction in isolated leukemic cells by DNR was reduced at higher cell density. This correlated with the marked reduction of DNR and AraC uptake in HL60 cells at high cell density. We hypothesised that a high WBC will lower the plasma concentration through a high uptake in the tumor cells and in this way decrease the drug concentration in leukemic blasts. In patients with high WBC, a dose increase and an optimal administration schedule should be evaluated for treatment with DNR and/or AraC.
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