e16152 Background: Androgen suppression is the standard palliative treatment for metastatic, loca... more e16152 Background: Androgen suppression is the standard palliative treatment for metastatic, localized or locally advanced prostate cancer. This phase III, open-label, international multicenter clinical study was conducted to investigate the efficacy and safety profile of a new formulation of leuprolide acetate (Lutrate 3.75mg Depot) in suppressing testosterone levels in prostate cancer patients. Methods: 160 patients with prostate cancer who could benefit from androgen deprivation therapy received single intramuscular injections of Lutrate 3.75 mg Depot every 28 days for a total of six doses. Plasma testosterone was determined at specific times throughout the study. The primary endpoint was the proportion of successful patients over the total number of evaluable patients. Patients’ success was defined as testosterone suppression (<0.5 ng/ml) at day 28 and continuance of castration until day 168, with no missing data at the monthly assessments. An exact two-sided binomial test (5% significance level) with two-sided 95% confidence interval (CI) estimated with exact method was performed to test the null hypothesis of 86% successful patients versus the alternative hypothesis of 94% . Results: The proportion of successful patients over the total number of evaluable patients was 96.8% (152/157); the exact binomial test was satisfied (p=0.000094, 90% CI: 92.7–99.0 %). The 78.7% (122/157) of evaluable patients achieved testosterone suppression by day 21. At day 28, 96.8% of the patients achieved castrate levels and 73.1% achieved testosterone levels ≤0.2 ng/ml. At conclusion of the trial, all patients (100%)maintained castration and 92.8% had testosterone levels ≤0.2 ng/ml. The most common treatment-related adverse event were hot flashes (45%), associated with testosterone suppression. Fatigue, hyperhydrosis, night sweats and headache occurred in ≤6.3% of patients. The most frequently reported local adverse reaction was pain at the injection site, experienced by 8.1% of patients. Conclusions: The results of this study demonstrate that Lutrate 3.75 mg Depot is as effective as presently marketed one-month leuprolide acetate formulations in establishing and maintaining testosterone concentration below castration levels in prostate cancer patients. [Table: see text]
Safinamide is an orally administered α-aminoamide derivative with both dopaminergic and non-dopam... more Safinamide is an orally administered α-aminoamide derivative with both dopaminergic and non-dopaminergic properties. Nonlinear mixed effects models for population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PKPD) analyses were developed using records from, respectively, 623 and 668 patients belonging to two Phase 3, randomized, placebo-controlled, double-blind efficacy studies. The aim was to estimate safinamide population PK parameters in patients with Parkinson's disease (PD) on stable levodopa therapy, and to develop a model of safinamide effect on the PD phase of normal functioning (ON-time). The final models were internally evaluated using visual predictive checks (VPCs), prediction corrected-VPC, and nonparametric bootstrap analysis. Safinamide profiles were adequately described by a linear one-compartmental model with first-order absorption and elimination. CL/F, Vd/F, and KA (95% confidence interval [CI]) were 4.96 (4.73-5.21) L/h, 166 (158-174) L, and 0.58...
Cancer Epidemiology Biomarkers Prevention a Publication of the American Association For Cancer Research Cosponsored By the American Society of Preventive Oncology, Mar 1, 2002
As part of a large programme on food risk assessment, we have become Interested in the endogenous... more As part of a large programme on food risk assessment, we have become Interested in the endogenous production of genotoxic agents from dietary precursors. Malondialdehyde (MDA), a product of lipid peroxidation and prostaglandin biosynthesis, is mutagenic in bacterial and mammalian systems. MDA reacts with DNA, and the major adduct (M1-dG) has been detected in healthy human liver and leukocyte DNA. Analytical methods used so far for the detection of M1-dG have not been applied to large numbers of individuals or a large variety of samples. Often, only a few micrograms of DNA from human tissues are available for analysis, and a very sensitive assay is needed to detect background levels of M1-dG in very small amounts of DNA. In this paper, we describe the development of an immunoslot-blot (ISB) assay for the measurement of M1-dG in 1 microgram of DNA. The limit of detection of the assay is about 5 adducts per 10(8) bases. The advantages of ISB over other assays for DNA adduct detection, such as the possibility of analysing 1 microgram DNA per sample and the fact that it is less time-consuming and laborious, mean that it can be more easily used for routine analysis of large numbers of samples in biomonitoring. A series of human samples was analysed, and levels of 0.3-6.43 M1-dG per 10(7) normal bases were detected in 42 gastric biopsy samples and 0.7-16.65 M1-dG per 10(7) normal bases in 28 samples of leukocyte DNA. In an initial study in five human volunteers on standardized diets, the levels of M1-dG in leukocyte DNA changed in relation to meat, vegetable and tea intake.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2001
Curcumin prevents colon cancer in rodent models. It inhibits lipid peroxidation and cyclooxygenas... more Curcumin prevents colon cancer in rodent models. It inhibits lipid peroxidation and cyclooxygenase-2 (COX-2) expression and induces glutathione S-transferase (GST) enzymes. We tested the hypothesis that 14 days of dietary curcumin (2%) affects biomarkers relevant to cancer chemoprevention in the rat. Levels of inducible COX-2, as reflected by prostaglandin E(2) production by blood leukocytes, were measured ex vivo. Total GST activity and adducts of malondialdehyde with DNA (M(1)G), which reflect endogenous lipid peroxidation, were measured in colon mucosa, liver, and blood leukocytes. Curcumin and its metabolites were analyzed by high-performance liquid chromatography in plasma, and its pharmacokinetics were compared following a diet containing 2% curcumin versus intragastric (i.g.) administration of curcumin suspended in an amphiphilic solvent. The curcumin diet did not alter any of the markers in the blood but increased hepatic GST by 16% and decreased colon M(1)G levels by 36% wh...
International journal of clinical pharmacology and therapeutics, 2014
Finasteride, a selective inhibitor of type 2 5-alpha reductase isoenzyme, inhibits the conversion... more Finasteride, a selective inhibitor of type 2 5-alpha reductase isoenzyme, inhibits the conversion of testosterone to dihydrotestosterone (DHT) and is indicated in the treatment of male androgenetic alopecia. The study objective was to evaluate a newly developed finasteride 0.25% topical solution in comparison to the marketed finasteride 1 mg tablet, with respect to finasteride pharmacokinetics and suppressive effects on plasma DHT. 24 healthy men with androgenetic alopecia were randomized in a single center, open-label, parallel-group, exploratory study, and received either multiple scalp applications of the topical solution b.i.d. or oral doses of the reference tablet o.d. for 7 days. Plasma finasteride, testosterone and DHT concentrations were determined. After multiple doses, mean (± SD) finasteride Cmax and AUC0-t corresponded to 0.46 ± 0.28 ng/mL and 6.64 ± 7.50 ng/mL x h for the topical solution and to 6.86 ± 1.78 ng/mL and 57.93 ± 29.38 ng/mL x h for the tablet. Plasma DHT wa...
We have developed an HPLC-32P-postlabelling procedure to detect DNA adducts formed by epoxybutene... more We have developed an HPLC-32P-postlabelling procedure to detect DNA adducts formed by epoxybutene and diepoxybutane. The method exploits the interaction of the two epoxides with deoxynucleotides and polydeoxynucleotides to optimize the HPLC enrichment of adducted nucleotides before 32P-postlabelling. Using this approach, a number of guanine adducts were identified after the exposure of dGMP, poly(dG-dC) or calf thymus DNA to epoxybutene and diepoxybutane, and a major adenine adduct was identified in poly(dA-dT) and calf thymus DNA exposed to diepoxybutane.
1,2-Epoxy-3-butene and 1,2:3,4-diepoxybutane, the two oxidative metabolites of 1,3-butadiene, are... more 1,2-Epoxy-3-butene and 1,2:3,4-diepoxybutane, the two oxidative metabolites of 1,3-butadiene, are considered to be involved in some of the carcinogenicity of the parent compound. Diepoxybutane is a bifunctional alkylating agent and reacts with DNA to form monoadducts and cross-links. We investigated DNA alkylation after exposure to diepoxybutane in order to develop a method for human biomonitoring. After reacting dAMP and then poly(dA-dT) (dA-dT) with diepoxybutane, we identified a major adenine adduct. Preliminary mass spectrometry indicated an adenine adducted by diepoxybutane at the N6 position. A high-performance liquid chromatography/32P-postlabelling method was developed, and the adduct was detected in calf thymus DNA and in DNA from Chinese hamster cells after exposure to diepoxybutane. The labelling efficiency, the amount of the adduct and its stability suggest that it could be a suitable indicator of exposure to butadiene.
The identification and quantitation of DNA adducts formed by reaction of genotoxic chemicals with... more The identification and quantitation of DNA adducts formed by reaction of genotoxic chemicals with DNA may provide direct evidence of exposure t o mutagens and carcinogens and may make possible a beginning of risk estimation based on Molecular Dosimetry approach.
e16152 Background: Androgen suppression is the standard palliative treatment for metastatic, loca... more e16152 Background: Androgen suppression is the standard palliative treatment for metastatic, localized or locally advanced prostate cancer. This phase III, open-label, international multicenter clinical study was conducted to investigate the efficacy and safety profile of a new formulation of leuprolide acetate (Lutrate 3.75mg Depot) in suppressing testosterone levels in prostate cancer patients. Methods: 160 patients with prostate cancer who could benefit from androgen deprivation therapy received single intramuscular injections of Lutrate 3.75 mg Depot every 28 days for a total of six doses. Plasma testosterone was determined at specific times throughout the study. The primary endpoint was the proportion of successful patients over the total number of evaluable patients. Patients’ success was defined as testosterone suppression (<0.5 ng/ml) at day 28 and continuance of castration until day 168, with no missing data at the monthly assessments. An exact two-sided binomial test (5% significance level) with two-sided 95% confidence interval (CI) estimated with exact method was performed to test the null hypothesis of 86% successful patients versus the alternative hypothesis of 94% . Results: The proportion of successful patients over the total number of evaluable patients was 96.8% (152/157); the exact binomial test was satisfied (p=0.000094, 90% CI: 92.7–99.0 %). The 78.7% (122/157) of evaluable patients achieved testosterone suppression by day 21. At day 28, 96.8% of the patients achieved castrate levels and 73.1% achieved testosterone levels ≤0.2 ng/ml. At conclusion of the trial, all patients (100%)maintained castration and 92.8% had testosterone levels ≤0.2 ng/ml. The most common treatment-related adverse event were hot flashes (45%), associated with testosterone suppression. Fatigue, hyperhydrosis, night sweats and headache occurred in ≤6.3% of patients. The most frequently reported local adverse reaction was pain at the injection site, experienced by 8.1% of patients. Conclusions: The results of this study demonstrate that Lutrate 3.75 mg Depot is as effective as presently marketed one-month leuprolide acetate formulations in establishing and maintaining testosterone concentration below castration levels in prostate cancer patients. [Table: see text]
Safinamide is an orally administered α-aminoamide derivative with both dopaminergic and non-dopam... more Safinamide is an orally administered α-aminoamide derivative with both dopaminergic and non-dopaminergic properties. Nonlinear mixed effects models for population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PKPD) analyses were developed using records from, respectively, 623 and 668 patients belonging to two Phase 3, randomized, placebo-controlled, double-blind efficacy studies. The aim was to estimate safinamide population PK parameters in patients with Parkinson's disease (PD) on stable levodopa therapy, and to develop a model of safinamide effect on the PD phase of normal functioning (ON-time). The final models were internally evaluated using visual predictive checks (VPCs), prediction corrected-VPC, and nonparametric bootstrap analysis. Safinamide profiles were adequately described by a linear one-compartmental model with first-order absorption and elimination. CL/F, Vd/F, and KA (95% confidence interval [CI]) were 4.96 (4.73-5.21) L/h, 166 (158-174) L, and 0.58...
Cancer Epidemiology Biomarkers Prevention a Publication of the American Association For Cancer Research Cosponsored By the American Society of Preventive Oncology, Mar 1, 2002
As part of a large programme on food risk assessment, we have become Interested in the endogenous... more As part of a large programme on food risk assessment, we have become Interested in the endogenous production of genotoxic agents from dietary precursors. Malondialdehyde (MDA), a product of lipid peroxidation and prostaglandin biosynthesis, is mutagenic in bacterial and mammalian systems. MDA reacts with DNA, and the major adduct (M1-dG) has been detected in healthy human liver and leukocyte DNA. Analytical methods used so far for the detection of M1-dG have not been applied to large numbers of individuals or a large variety of samples. Often, only a few micrograms of DNA from human tissues are available for analysis, and a very sensitive assay is needed to detect background levels of M1-dG in very small amounts of DNA. In this paper, we describe the development of an immunoslot-blot (ISB) assay for the measurement of M1-dG in 1 microgram of DNA. The limit of detection of the assay is about 5 adducts per 10(8) bases. The advantages of ISB over other assays for DNA adduct detection, such as the possibility of analysing 1 microgram DNA per sample and the fact that it is less time-consuming and laborious, mean that it can be more easily used for routine analysis of large numbers of samples in biomonitoring. A series of human samples was analysed, and levels of 0.3-6.43 M1-dG per 10(7) normal bases were detected in 42 gastric biopsy samples and 0.7-16.65 M1-dG per 10(7) normal bases in 28 samples of leukocyte DNA. In an initial study in five human volunteers on standardized diets, the levels of M1-dG in leukocyte DNA changed in relation to meat, vegetable and tea intake.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2001
Curcumin prevents colon cancer in rodent models. It inhibits lipid peroxidation and cyclooxygenas... more Curcumin prevents colon cancer in rodent models. It inhibits lipid peroxidation and cyclooxygenase-2 (COX-2) expression and induces glutathione S-transferase (GST) enzymes. We tested the hypothesis that 14 days of dietary curcumin (2%) affects biomarkers relevant to cancer chemoprevention in the rat. Levels of inducible COX-2, as reflected by prostaglandin E(2) production by blood leukocytes, were measured ex vivo. Total GST activity and adducts of malondialdehyde with DNA (M(1)G), which reflect endogenous lipid peroxidation, were measured in colon mucosa, liver, and blood leukocytes. Curcumin and its metabolites were analyzed by high-performance liquid chromatography in plasma, and its pharmacokinetics were compared following a diet containing 2% curcumin versus intragastric (i.g.) administration of curcumin suspended in an amphiphilic solvent. The curcumin diet did not alter any of the markers in the blood but increased hepatic GST by 16% and decreased colon M(1)G levels by 36% wh...
International journal of clinical pharmacology and therapeutics, 2014
Finasteride, a selective inhibitor of type 2 5-alpha reductase isoenzyme, inhibits the conversion... more Finasteride, a selective inhibitor of type 2 5-alpha reductase isoenzyme, inhibits the conversion of testosterone to dihydrotestosterone (DHT) and is indicated in the treatment of male androgenetic alopecia. The study objective was to evaluate a newly developed finasteride 0.25% topical solution in comparison to the marketed finasteride 1 mg tablet, with respect to finasteride pharmacokinetics and suppressive effects on plasma DHT. 24 healthy men with androgenetic alopecia were randomized in a single center, open-label, parallel-group, exploratory study, and received either multiple scalp applications of the topical solution b.i.d. or oral doses of the reference tablet o.d. for 7 days. Plasma finasteride, testosterone and DHT concentrations were determined. After multiple doses, mean (± SD) finasteride Cmax and AUC0-t corresponded to 0.46 ± 0.28 ng/mL and 6.64 ± 7.50 ng/mL x h for the topical solution and to 6.86 ± 1.78 ng/mL and 57.93 ± 29.38 ng/mL x h for the tablet. Plasma DHT wa...
We have developed an HPLC-32P-postlabelling procedure to detect DNA adducts formed by epoxybutene... more We have developed an HPLC-32P-postlabelling procedure to detect DNA adducts formed by epoxybutene and diepoxybutane. The method exploits the interaction of the two epoxides with deoxynucleotides and polydeoxynucleotides to optimize the HPLC enrichment of adducted nucleotides before 32P-postlabelling. Using this approach, a number of guanine adducts were identified after the exposure of dGMP, poly(dG-dC) or calf thymus DNA to epoxybutene and diepoxybutane, and a major adenine adduct was identified in poly(dA-dT) and calf thymus DNA exposed to diepoxybutane.
1,2-Epoxy-3-butene and 1,2:3,4-diepoxybutane, the two oxidative metabolites of 1,3-butadiene, are... more 1,2-Epoxy-3-butene and 1,2:3,4-diepoxybutane, the two oxidative metabolites of 1,3-butadiene, are considered to be involved in some of the carcinogenicity of the parent compound. Diepoxybutane is a bifunctional alkylating agent and reacts with DNA to form monoadducts and cross-links. We investigated DNA alkylation after exposure to diepoxybutane in order to develop a method for human biomonitoring. After reacting dAMP and then poly(dA-dT) (dA-dT) with diepoxybutane, we identified a major adenine adduct. Preliminary mass spectrometry indicated an adenine adducted by diepoxybutane at the N6 position. A high-performance liquid chromatography/32P-postlabelling method was developed, and the adduct was detected in calf thymus DNA and in DNA from Chinese hamster cells after exposure to diepoxybutane. The labelling efficiency, the amount of the adduct and its stability suggest that it could be a suitable indicator of exposure to butadiene.
The identification and quantitation of DNA adducts formed by reaction of genotoxic chemicals with... more The identification and quantitation of DNA adducts formed by reaction of genotoxic chemicals with DNA may provide direct evidence of exposure t o mutagens and carcinogens and may make possible a beginning of risk estimation based on Molecular Dosimetry approach.
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Papers by Chiara Leuratti