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Alexander Egle - One of the best experts on this subject based on the ideXlab platform.

  • Liver Toxicity during temozolomide chemotherapy caused by Chinese herbs
    BMC Complementary and Alternative Medicine, 2014
    Co-Authors: Thomas Melchardt, Teresa Magnes, Lukas Weiss, Michael Grundbichler, Michael Strasser, Clemens Hufnagl, Martin Moik, Richard Greil, Alexander Egle
    Abstract:

    Background Complementary and alternative medicine is often used by patients with malignant glioma. Although several interactions of various alternative agents with chemotherapy are known, none has been described for temozolomide so far. Case presentation We report the case of severe Liver Toxicity with jaundice during radiochemotherapy with temozolomide likely due to interaction with a popular Chinese herbal formula after surgery for glioblastoma. After cessation of the herbal formula as well as the chemotherapy Liver enzymes slowly normalized. Due to tumor progression the patient was retreated with temozolomide for 5 cycles without Toxicity. Because of further progression combination treatment of bevacizumab and irinotecan was started and again no Liver Toxicity was observed. Conclusions We conclude that the observed Toxicity with jaundice was probably caused by an interaction of this popular Chinese formula and temozolomide. This is the first report about a relevant interaction of temozolomide and any herbal formula.

  • Liver Toxicity during temozolomide chemotherapy caused by Chinese herbs
    BMC Complementary and Alternative Medicine, 2014
    Co-Authors: Thomas Melchardt, Teresa Magnes, Lukas Weiss, Michael Grundbichler, Michael Strasser, Clemens Hufnagl, Martin Moik, Richard Greil, Alexander Egle
    Abstract:

    Complementary and alternative medicine is often used by patients with malignant glioma. Although several interactions of various alternative agents with chemotherapy are known, none has been described for temozolomide so far. We report the case of severe Liver Toxicity with jaundice during radiochemotherapy with temozolomide likely due to interaction with a popular Chinese herbal formula after surgery for glioblastoma. After cessation of the herbal formula as well as the chemotherapy Liver enzymes slowly normalized. Due to tumor progression the patient was retreated with temozolomide for 5 cycles without Toxicity. Because of further progression combination treatment of bevacizumab and irinotecan was started and again no Liver Toxicity was observed. We conclude that the observed Toxicity with jaundice was probably caused by an interaction of this popular Chinese formula and temozolomide. This is the first report about a relevant interaction of temozolomide and any herbal formula.

Ivonne M. C. M. Rietjens - One of the best experts on this subject based on the ideXlab platform.

  • Monocrotaline-induced Liver Toxicity in rat predicted by a combined in vitro physiologically based kinetic modeling approach
    Archives of Toxicology, 2020
    Co-Authors: Suparmi Suparmi, Sebastiaan Wesseling, Ivonne M. C. M. Rietjens
    Abstract:

    The aim of the present study was to use an in vitro–in silico approach to predict the in vivo acute Liver Toxicity of monocrotaline and to characterize the influence of its metabolism on its relative toxic potency compared to lasiocarpine and riddelliine. In the absence of data on acute Liver Toxicity of monocrotaline upon oral exposure, the predicted dose–response curve for acute Liver Toxicity in rats and the resulting benchmark dose lower and upper confidence limits for 10% effect (BMDL_10 and BMDU_10) were compared to data obtained in studies with intraperitoneal or subcutaneous dosing regimens. This indicated the predicted BMDL_10 value to be in line with the no-observed-adverse-effect levels (NOAELs) derived from availabe in vivo studies. The predicted BMDL_10–BMDU_10 of 1.1–4.9 mg/kg bw/day also matched the oral dose range of 1–3 mg PA/kg bw/day at which adverse effects in human are reported. A comparison to the oral Toxicity of the related pyrrolizidine alkaloids (PAs) lasiocarpine and riddelliine revealed that, although in the rat hepatocytes monocrotaline was less toxic than lasiocarpine and riddelliine, due to its relatively inefficient clearance, its in vivo acute Liver Toxicity was predicted to be comparable. It is concluded that the combined in vitro-PBK modeling approach can provide insight in monocrotaline-induced acute Liver Toxicity in rats, thereby filling existing gaps in the database on PA Toxicity. Furthermore, the results reveal that the kinetic and metabolic properties of PAs can vary substantially and should be taken into account when considering differences in relative potency between different PAs.

  • use of physiologically based kinetic modelling facilitated reverse dosimetry to convert in vitro cytoToxicity data to predicted in vivo Liver Toxicity of lasiocarpine and riddelliine in rat
    Food and Chemical Toxicology, 2018
    Co-Authors: Lu Chen, Sebastiaan Wesseling, Jia Ning, Jochem Louisse, Ivonne M. C. M. Rietjens
    Abstract:

    Lasiocarpine and riddelliine are pyrrolizidine alkaloids (PAs) present in food and able to cause Liver Toxicity. The aim of this study was to investigate whether physiologically based kinetic (PBK) modelling-facilitated reverse dosimetry can adequately translate in vitro concentration-response curves for Toxicity of lasiocarpine and riddelliine to in vivo Liver Toxicity data for the rat. To this purpose, PBK models were developed for lasiocarpine and riddelliine, and predicted blood concentrations were compared to available literature data to evaluate the models. Concentration-response curves obtained from in vitro cytoToxicity assays in primary rat hepatocytes were converted to in vivo dose-response curves from which points of departure (PODs) were derived and that were compared to available literature data on in vivo Liver Toxicity. The results showed that the predicted PODs fall well within the range of PODs derived from available in vivo Toxicity data. To conclude, this study shows the proof-of-principle for a method to predict in vivo Liver Toxicity for PAs by an alternative testing strategy integrating in vitro cytoToxicity assays with in silico PBK modelling-facilitated reverse dosimetry. The approach may facilitate prediction of acute Liver Toxicity for the large number of PAs for which in vivo Toxicity data are lacking.

Thomas Melchardt - One of the best experts on this subject based on the ideXlab platform.

  • Liver Toxicity during temozolomide chemotherapy caused by Chinese herbs
    BMC Complementary and Alternative Medicine, 2014
    Co-Authors: Thomas Melchardt, Teresa Magnes, Lukas Weiss, Michael Grundbichler, Michael Strasser, Clemens Hufnagl, Martin Moik, Richard Greil, Alexander Egle
    Abstract:

    Background Complementary and alternative medicine is often used by patients with malignant glioma. Although several interactions of various alternative agents with chemotherapy are known, none has been described for temozolomide so far. Case presentation We report the case of severe Liver Toxicity with jaundice during radiochemotherapy with temozolomide likely due to interaction with a popular Chinese herbal formula after surgery for glioblastoma. After cessation of the herbal formula as well as the chemotherapy Liver enzymes slowly normalized. Due to tumor progression the patient was retreated with temozolomide for 5 cycles without Toxicity. Because of further progression combination treatment of bevacizumab and irinotecan was started and again no Liver Toxicity was observed. Conclusions We conclude that the observed Toxicity with jaundice was probably caused by an interaction of this popular Chinese formula and temozolomide. This is the first report about a relevant interaction of temozolomide and any herbal formula.

  • Liver Toxicity during temozolomide chemotherapy caused by Chinese herbs
    BMC Complementary and Alternative Medicine, 2014
    Co-Authors: Thomas Melchardt, Teresa Magnes, Lukas Weiss, Michael Grundbichler, Michael Strasser, Clemens Hufnagl, Martin Moik, Richard Greil, Alexander Egle
    Abstract:

    Complementary and alternative medicine is often used by patients with malignant glioma. Although several interactions of various alternative agents with chemotherapy are known, none has been described for temozolomide so far. We report the case of severe Liver Toxicity with jaundice during radiochemotherapy with temozolomide likely due to interaction with a popular Chinese herbal formula after surgery for glioblastoma. After cessation of the herbal formula as well as the chemotherapy Liver enzymes slowly normalized. Due to tumor progression the patient was retreated with temozolomide for 5 cycles without Toxicity. Because of further progression combination treatment of bevacizumab and irinotecan was started and again no Liver Toxicity was observed. We conclude that the observed Toxicity with jaundice was probably caused by an interaction of this popular Chinese formula and temozolomide. This is the first report about a relevant interaction of temozolomide and any herbal formula.

George B. Mcdonald - One of the best experts on this subject based on the ideXlab platform.

  • cyclophosphamide following targeted oral busulfan as conditioning for hematopoietic cell transplantation pharmacokinetics Liver Toxicity and mortality
    Biology of Blood and Marrow Transplantation, 2007
    Co-Authors: Ami Batchelder, Ted Gooley, Jeannine S Mccune, Joachim H Deeg, Scott Cole, Brian Phillips, Gary H Schoch, George B. Mcdonald
    Abstract:

    The pharmacokinetics of cyclophosphamide (CY) and its metabolites hydroxycyclophosphamide and carboxyethylphosphoramide mustard were determined in 75 patients receiving targeted oral busulfan followed by i.v. CY ((T)BU/CY) and in 147 patients receiving i.v. CY followed by total body irradiation (CY/TBI) in preparation for hematopoietic cell transplantation (HCT). In the (T)BU/CY patients only, the association of the pharmacokinetic data with Liver Toxicity, relapse, and survival was evaluated. CY was infused at 60 mg/kg/day over 1 or 2 hours on 2 consecutive days; the majority of patients had BU levels targeted to a steady state plasma concentration (Css) of 800-900 ng/mL. Systemic exposure (i.e., area under the concentration-time curve [AUC]) of CY, hydroxycyclophosphamide, and carboxyethylphosphoramide mustard was measured. Liver Toxicity was assessed as the development of hepatic sinusoidal obstruction syndrome (SOS). CY metabolism was highly variable and age dependent. (T)BU/CY-treated patients had lower AUC(CY) (P .15). In conclusion, CY exhibits conditioning-regimen dependent pharmacokinetics and pharmacodynamics, suggesting that lowering CY doses is unlikely to improve outcomes to (T)BU/CY. Alternative strategies, such as administering i.v. busulfan or CY before BU, should be explored.

  • Cyclophosphamide metabolism, Liver Toxicity, and mortality following hematopoietic stem cell transplantation
    Blood, 2003
    Co-Authors: George B. Mcdonald, John T. Slattery, Michelle E. Bouvier, Song Ren, Ami Batchelder, Thomas F. Kalhorn, H. Gary Schoch, Claudio Anasetti, Ted Gooley
    Abstract:

    Liver Toxicity caused by high-dose myeloablative therapy leads to significant morbidity after hematopoietic cell transplantation. We examined the hypothesis that Liver Toxicity after cyclophosphamide and total body irradiation is related to cyclophosphamide through its metabolism to toxins. Cyclophosphamide was infused at 60 mg/kg over 1 to 2 hours on each of 2 consecutive days, followed by total body irradiation. Plasma was analyzed for cyclophosphamide and its major metabolites. Liver Toxicity was scored by the development of sinusoidal obstruction syndrome (veno-occlusive disease) and by total serum bilirubin levels. The hazards of Liver Toxicity, nonrelapse mortality, tumor relapse, and survival were calculated using regression analysis that included exposure to cyclophosphamide metabolites (as the area under the curve). Of 147 patients, 23 (16%) developed moderate or severe sinusoidal obstruction syndrome. The median peak serum bilirubin level through day 20 was 2.6 mg/dL (range, 0.5-41.1 mg/dL). Metabolism of cyclophosphamide was highly variable, particularly for the metabolite o-carboxyethyl-phosphoramide mustard, whose area under the curve varied 16-fold. Exposure to this metabolite was statistically significantly related to sinusoidal obstruction syndrome, bilirubin elevation, nonrelapse mortality, and survival, after adjusting for age and irradiation dose. Patients in the highest quartile of o-carboxyethyl-phosphoramide mustard exposure had a 5.9-fold higher risk for nonrelapse mortality than did patients in the lowest quartile. Engraftment and tumor relapse were not statistically significantly related to cyclophosphamide metabolite exposure. Increased exposure to toxic metabolites of cyclophosphamide leads to increased Liver Toxicity and nonrelapse mortality and lower overall survival after hematopoietic cell transplantation.

Y. Mouton - One of the best experts on this subject based on the ideXlab platform.

  • Incidence of and risk factors for severe Liver Toxicity in HIV-infected patients on anti-tuberculosis treatment.
    International Journal of Tuberculosis and Lung Disease, 2007
    Co-Authors: E. Pukenyte, F. X. Lescure, D. Rey, C. Rabaud, B. Hoen, P. Chavanet, A. P. Laiskonis, J. L. Schmit, T. May, Y. Mouton
    Abstract:

    OBJECTIVE: To assess the incidence and risk factors for severe Liver Toxicity in human immunodeficiency virus (HIV) infected patients on anti-tuberculosis treatment and the impact of patients' characteristics and concomitant medications instituted during the first week of antituberculosis treatment. METHODS: HIV-infected patients referred to six French hospitals between 1 January 1992 and 31 December 2004, with confirmed or 'presumptive' tuberculosis (TB). Liver Toxicity was studied during the first 2 months of TB treatment. RESULTS: During the 12 years of the study period, 144 patients were enrolled. Severe Liver Toxicity developed in 15 (10.7%). The median time to development of Liver Toxicity was 14 days. In the univariate analysis, high baseline bilirubin levels (P = 0.004), CD4 cell counts between 50 and 100 cells/mm3 (P = 0.022) and the use of fluconazole (P = 0.0005) were associated with Liver Toxicity. In the multivariate analysis, independent risk factors were abnormal baseline alanine aminotransferase (ALT) (P = 0.028) and bilirubin levels (P = 0.033) and the use of fluconazole (P = 0.008). CONCLUSION: Severe Liver Toxicity is frequent, and occurs early in the course of anti-tuberculosis treatment. ALT and bilirubin levels should be closely monitored during the first month of treatment, especially in patients with high baseline ALT or bilirubin levels. We suggest caution when prescribing fluconazole and anti-tuberculosis drugs concomitantly, although this needs to be confirmed and further investigated.