The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Halvard Bonig - One of the best experts on this subject based on the ideXlab platform.
-
safety and efficacy of Healthy Volunteer stem cell mobilization with filgrastim g csf and mobilized stem cell apheresis results of a prospective longitudinal 5 year follow up study
Vox Sanguinis, 2013Co-Authors: M M Mueller, H Bialleck, B Bomke, Susanne Brauninger, C Varga, C Seidl, Erhard Seifried, Torsten Tonn, Halvard BonigAbstract:Background and Objectives G-CSF-mobilized peripheral blood stem cells have long replaced marrow as the major source for allogeneic transplants. Conclusive evidence questioning the long-term safety of G-CSF for donors has not been provided, but the cumulative number of followed donors remains insufficient to rule out rare adverse events. A long-term active follow-up study of G-CSF-mobilized Healthy Volunteer donors was therefore performed. Patients and Methods Two hundred and three successive donors were evaluated pre-apheresis, subjected to G-CSF-mobilization/apheresis, and actively followed for 5 years by the same physicians and laboratories. Follow-up laboratory work included standard biochemical/haematological tests and T-cell phenotyping. Results Donor epidemiology was typical for reported stem cell donor cohorts. Acute adverse effects of G-CSF and apheresis were mild and transient, consistent with the previous reports. Mean circulating CD34+ cells after nine doses of G-CSF were 124 per μl. Other biochemical/haematological parameters were also altered, consistent with G-CSF treatment. Spleen enlargement was modest. At first follow-up, all clinical and laboratory parameters had normalized. Leucocyte/lymphocyte counts and CD4/CD8 ratios were the same as during premobilization work-up and remained unchanged throughout. A single severe but likely unrelated adverse event, a case of papillary thyroid carcinoma, was reported. Conclusion The studies add an observation time of almost 500 donor years to the growing body of evidence of the long-term safety of G-CSF for allogeneic donor stem cell mobilization.
David S Alberts - One of the best experts on this subject based on the ideXlab platform.
-
resveratrol modulates drug and carcinogen metabolizing enzymes in a Healthy Volunteer study
Cancer Prevention Research, 2010Co-Authors: Hh Sherry Chow, Linda L Garland, Chiu Hsieh Hsu, Donna R Vining, Wade M Chew, Jessica A Miller, Marjorie Perloff, James A Crowell, David S AlbertsAbstract:Resveratrol has been shown to exhibit cancer-preventive activities in preclinical studies. We conducted a clinical study to determine the effect of pharmacologic doses of resveratrol on drug- and carcinogen-metabolizing enzymes. Forty-two Healthy Volunteers underwent baseline assessment of cytochrome P450 (CYP) and phase II detoxification enzymes. CYP1A2, CYP2D6, CYP2C9, and CYP3A4 enzyme activities were measured by the metabolism of caffeine, dextromethorphan, losartan, and buspirone, respectively. Blood lymphocyte glutathione S-transferase (GST) activity and GST-pi level and serum total and direct bilirubin, a surrogate for UDP-glucuronosyl transferase (UGT) 1A1 activity, were measured to assess phase II enzymes. After the baseline evaluation, study participants took 1 g of resveratrol once daily for 4 weeks. Enzyme assessment was repeated upon intervention completion. Resveratrol intervention was found to inhibit the phenotypic indices of CYP3A4, CYP2D6, and CYP2C9 and to induce the phenotypic index of 1A2. Overall, GST and UGT1A1 activities were minimally affected by the intervention, although an induction of GST-pi level and UGT1A1 activity was observed in individuals with low baseline enzyme level/activity. We conclude that resveratrol can modulate enzyme systems involved in carcinogen activation and detoxification, which may be one mechanism by which resveratrol inhibits carcinogenesis. However, pharmacologic doses of resveratrol could potentially lead to increased adverse drug reactions or altered drug efficacy due to inhibition or induction of certain CYPs. Further clinical development of resveratrol for cancer prevention should consider evaluation of lower doses of resveratrol to minimize adverse metabolic drug interactions.
-
abstract a57 high dose resveratrol modulates drug and carcinogen metabolizing enzymes in a Healthy Volunteer study
Cancer Prevention Research, 2010Co-Authors: Hh Sherry Chow, Linda L Garland, Chiu Hsieh Hsu, Donna R Vining, Jessica A Miller, Marjorie Perloff, James A Crowell, Wade Chew, David S AlbertsAbstract:Purpose: Resveratrol (RES) or 3, 4′, 5‐trihydroxystilbene has been shown to inhibit carcinogenesis by affecting various molecular events in the initiation, promotion and progression stages. The cancer chemopreventive activity of RES has been demonstrated in vivo in a wide variety of tumors including skin, mammary, gastrointestinal, and liver cancer models. Modulation of Phase I and Phase II enzymes has been suggested to be one of the mechanisms responsible for the cancer preventive effect of RES. We conducted a clinical study to determine the effect of pharmacological doses of RES on drug and carcinogen metabolizing enzymes. Methods: Forty‐two Healthy Volunteers underwent baseline assessment of Phase I and Phase II enzymes. A cocktail of cytochrome P450 (CYP) metabolic probe drugs, including caffeine, dextromethorphan, losartan, and buspirone, were administered to assess the activity of CYP1A2, 2D6, 2C9, and 3A4, respectively. Blood and urine samples were collected for 8 hours after probe drug administration to determine parent probe drug and metabolite concentrations for measurements of CYP enzyme activities. Blood lymphocyte glutathione S‐transferase (GST) activity and GST‐π level, and serum total and direct bilirubin, a surrogate for UDP‐glucuronosyl transferase (UGT) 1A1 activity, were measured to assess Phase II enzymes. After the baseline evaluation, study participants took 1 gm of RES once daily for 4 wks. Enzyme assessment was repeated upon intervention completion. Results: RES intervention was found to suppress the activity of CYP3A4, 2D6, and 2C9. The geometric mean change of the activity index of CPY3A4, 2D6, and 2C9 was 33% (p = 0.01), 70% (p = 0.01), and 171% (p Conclusion: We conclude that high doses of RES administration may modulate enzyme systems involved in carcinogen activation and detoxification, which may be one mechanism by which RES inhibits carcinogenesis. However, high doses of RES administration may lead to clinically relevant metabolic drug interactions. Further clinical studies are needed to determine whether lower doses of RES could be used to achieve cancer preventive activities. (Supported by N01CN35158 from the National Cancer Institute, Division of Cancer Prevention) Citation Information: Cancer Prev Res 2010;3(1 Suppl):A57.
Nicholas J White - One of the best experts on this subject based on the ideXlab platform.
-
population pharmacokinetics of halofantrine in Healthy Volunteers and patients with symptomatic falciparum malaria
Journal of Pharmacy and Pharmacology, 2012Co-Authors: Kerenaftali Klein, Nicholas J White, Leon Aarons, Feiko O Ter Kuile, Francois Nosten, Michael D Edstein, Paktiya TejaisavadharmAbstract:Aims To investigate the population pharmacokinetics of the antimalarial halofantrine (HF) in Healthy Volunteers and patients with symptomatic falciparum malaria. Methods Healthy Volunteer data were obtained from six Volunteers who received three different doses of HF (250, 500 and 1000 mg) after an overnight fast with a washout period of at least 6 weeks between doses. Patient data (n = 188) were obtained from randomised controlled trials conducted on the Thai–Burmese border in the early 1990s. They were either assigned to receive a total HF dose of 24 mg/kg (8 mg/kg every 6 h for 24 h) or 72 mg/kg (8 mg/kg every 6 to 10 h for 3 days). The population pharmacokinetics of HF were evaluated using non-linear mixed effects modelling with a two-compartment model with first-order absorption. Key findings The population estimates of apparent clearance (CL), volume of compartment one (V1), distributional clearance (CLD) and volume of compartment two (V2) of HF in Healthy Volunteers were 2453 l/day (102 l/h), 2386 l, 716 l/day (29.8 l/h) and 2641 l, respectively. The population estimates of the PK parameters in patients were 429 l/day (17.9 l/h), 729 l, 178 l/day (7.42 l/h) and 1351 l, respectively. All PK parameters were significantly related to body weight and some were related to sex, sampling method, pre-treatment parasite density and whether patients vomited or not. When the two datasets were analysed jointly using a maximum likelihood method, the population estimates in patients were 196 l/day (8.17 l/h), 161 l, 65 l/day (2.71 l/h) and 89 l, respectively, and the parameters were significantly related to body weight and sex. Bayesian analysis of the patient data, with a diffuse prior based on the Healthy Volunteer data analysis results, yielded the population estimates 354 l/day (14.8 l/h), 728 l, 162 l/day (6.75 l/h) and 1939 l, respectively. Conclusions The pharmacokinetic properties of HF in patients with malaria are affected by several demographic variables as well as other relevant covariates. Apparent differences between the Healthy Volunteer and the patient data analysis results are not entirely due to differences in bioavailability. For the patient data analysis, the Bayesian method was preferred, as the fitting procedure was more stable, allowing random effects to be estimated for all four dispositional parameters.
-
pitfalls in estimating piperaquine elimination
Antimicrobial Agents and Chemotherapy, 2005Co-Authors: Joel Tarning, Niklas Lindegardh, Anna Annerberg, T Singtoroj, Michael Ashton, Nicholas J WhiteAbstract:By using a sensitive new assay, the terminal elimination half-life of the antimalarial piperaquine in a Healthy Volunteer was estimated to be 33 days, which is longer than estimated previously. This result illustrates the importance of extended sampling duration and sensitive assay methodologies in characterizing the disposition of slowly eliminated antimalarial drugs.
Hh Sherry Chow - One of the best experts on this subject based on the ideXlab platform.
-
resveratrol modulates drug and carcinogen metabolizing enzymes in a Healthy Volunteer study
Cancer Prevention Research, 2010Co-Authors: Hh Sherry Chow, Linda L Garland, Chiu Hsieh Hsu, Donna R Vining, Wade M Chew, Jessica A Miller, Marjorie Perloff, James A Crowell, David S AlbertsAbstract:Resveratrol has been shown to exhibit cancer-preventive activities in preclinical studies. We conducted a clinical study to determine the effect of pharmacologic doses of resveratrol on drug- and carcinogen-metabolizing enzymes. Forty-two Healthy Volunteers underwent baseline assessment of cytochrome P450 (CYP) and phase II detoxification enzymes. CYP1A2, CYP2D6, CYP2C9, and CYP3A4 enzyme activities were measured by the metabolism of caffeine, dextromethorphan, losartan, and buspirone, respectively. Blood lymphocyte glutathione S-transferase (GST) activity and GST-pi level and serum total and direct bilirubin, a surrogate for UDP-glucuronosyl transferase (UGT) 1A1 activity, were measured to assess phase II enzymes. After the baseline evaluation, study participants took 1 g of resveratrol once daily for 4 weeks. Enzyme assessment was repeated upon intervention completion. Resveratrol intervention was found to inhibit the phenotypic indices of CYP3A4, CYP2D6, and CYP2C9 and to induce the phenotypic index of 1A2. Overall, GST and UGT1A1 activities were minimally affected by the intervention, although an induction of GST-pi level and UGT1A1 activity was observed in individuals with low baseline enzyme level/activity. We conclude that resveratrol can modulate enzyme systems involved in carcinogen activation and detoxification, which may be one mechanism by which resveratrol inhibits carcinogenesis. However, pharmacologic doses of resveratrol could potentially lead to increased adverse drug reactions or altered drug efficacy due to inhibition or induction of certain CYPs. Further clinical development of resveratrol for cancer prevention should consider evaluation of lower doses of resveratrol to minimize adverse metabolic drug interactions.
-
abstract a57 high dose resveratrol modulates drug and carcinogen metabolizing enzymes in a Healthy Volunteer study
Cancer Prevention Research, 2010Co-Authors: Hh Sherry Chow, Linda L Garland, Chiu Hsieh Hsu, Donna R Vining, Jessica A Miller, Marjorie Perloff, James A Crowell, Wade Chew, David S AlbertsAbstract:Purpose: Resveratrol (RES) or 3, 4′, 5‐trihydroxystilbene has been shown to inhibit carcinogenesis by affecting various molecular events in the initiation, promotion and progression stages. The cancer chemopreventive activity of RES has been demonstrated in vivo in a wide variety of tumors including skin, mammary, gastrointestinal, and liver cancer models. Modulation of Phase I and Phase II enzymes has been suggested to be one of the mechanisms responsible for the cancer preventive effect of RES. We conducted a clinical study to determine the effect of pharmacological doses of RES on drug and carcinogen metabolizing enzymes. Methods: Forty‐two Healthy Volunteers underwent baseline assessment of Phase I and Phase II enzymes. A cocktail of cytochrome P450 (CYP) metabolic probe drugs, including caffeine, dextromethorphan, losartan, and buspirone, were administered to assess the activity of CYP1A2, 2D6, 2C9, and 3A4, respectively. Blood and urine samples were collected for 8 hours after probe drug administration to determine parent probe drug and metabolite concentrations for measurements of CYP enzyme activities. Blood lymphocyte glutathione S‐transferase (GST) activity and GST‐π level, and serum total and direct bilirubin, a surrogate for UDP‐glucuronosyl transferase (UGT) 1A1 activity, were measured to assess Phase II enzymes. After the baseline evaluation, study participants took 1 gm of RES once daily for 4 wks. Enzyme assessment was repeated upon intervention completion. Results: RES intervention was found to suppress the activity of CYP3A4, 2D6, and 2C9. The geometric mean change of the activity index of CPY3A4, 2D6, and 2C9 was 33% (p = 0.01), 70% (p = 0.01), and 171% (p Conclusion: We conclude that high doses of RES administration may modulate enzyme systems involved in carcinogen activation and detoxification, which may be one mechanism by which RES inhibits carcinogenesis. However, high doses of RES administration may lead to clinically relevant metabolic drug interactions. Further clinical studies are needed to determine whether lower doses of RES could be used to achieve cancer preventive activities. (Supported by N01CN35158 from the National Cancer Institute, Division of Cancer Prevention) Citation Information: Cancer Prev Res 2010;3(1 Suppl):A57.
Paktiya Tejaisavadharm - One of the best experts on this subject based on the ideXlab platform.
-
population pharmacokinetics of halofantrine in Healthy Volunteers and patients with symptomatic falciparum malaria
Journal of Pharmacy and Pharmacology, 2012Co-Authors: Kerenaftali Klein, Nicholas J White, Leon Aarons, Feiko O Ter Kuile, Francois Nosten, Michael D Edstein, Paktiya TejaisavadharmAbstract:Aims To investigate the population pharmacokinetics of the antimalarial halofantrine (HF) in Healthy Volunteers and patients with symptomatic falciparum malaria. Methods Healthy Volunteer data were obtained from six Volunteers who received three different doses of HF (250, 500 and 1000 mg) after an overnight fast with a washout period of at least 6 weeks between doses. Patient data (n = 188) were obtained from randomised controlled trials conducted on the Thai–Burmese border in the early 1990s. They were either assigned to receive a total HF dose of 24 mg/kg (8 mg/kg every 6 h for 24 h) or 72 mg/kg (8 mg/kg every 6 to 10 h for 3 days). The population pharmacokinetics of HF were evaluated using non-linear mixed effects modelling with a two-compartment model with first-order absorption. Key findings The population estimates of apparent clearance (CL), volume of compartment one (V1), distributional clearance (CLD) and volume of compartment two (V2) of HF in Healthy Volunteers were 2453 l/day (102 l/h), 2386 l, 716 l/day (29.8 l/h) and 2641 l, respectively. The population estimates of the PK parameters in patients were 429 l/day (17.9 l/h), 729 l, 178 l/day (7.42 l/h) and 1351 l, respectively. All PK parameters were significantly related to body weight and some were related to sex, sampling method, pre-treatment parasite density and whether patients vomited or not. When the two datasets were analysed jointly using a maximum likelihood method, the population estimates in patients were 196 l/day (8.17 l/h), 161 l, 65 l/day (2.71 l/h) and 89 l, respectively, and the parameters were significantly related to body weight and sex. Bayesian analysis of the patient data, with a diffuse prior based on the Healthy Volunteer data analysis results, yielded the population estimates 354 l/day (14.8 l/h), 728 l, 162 l/day (6.75 l/h) and 1939 l, respectively. Conclusions The pharmacokinetic properties of HF in patients with malaria are affected by several demographic variables as well as other relevant covariates. Apparent differences between the Healthy Volunteer and the patient data analysis results are not entirely due to differences in bioavailability. For the patient data analysis, the Bayesian method was preferred, as the fitting procedure was more stable, allowing random effects to be estimated for all four dispositional parameters.
