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Biomedical subjects

M Breda

Publications and source records attributed to M Breda.

At least 19 recordsLinked to original sources
PubMed2005

An optimized experimental protocol based on neuro-evolutionary algorithms application to the classification of dyspeptic patients and to the prediction of the effectiveness of their treatment.

OBJECTIVE: This paper aims to present a specific optimized experimental protocol (EP) for classification and/or prediction problems. The neuro-evolutionary algorithms on which it is based and its application with two selected real cases are described in detail. The first application addresses the problem of classifying the functional (FD) or organic (OD) forms of dyspepsia; the second relates to the problem of predicting the 6-month follow-up outcome of dyspeptic patients treated by helicobacter pylori (HP) eradication therapy. METHODS AND MATERIAL: The database built by the multicentre observational study, performed in Italy by the NUD-look Study Group, provided the material studied: a collection of data from 861 patients with previously uninvestigated dyspepsia, being referred for upper gastrointestinal endoscopy to 42 Italian Endoscopic Services. The proposed EP makes use of techniques based on advanced neuro-evolutionary systems (NESs) and is structured in phases and steps. The use of specific input selection (IS) and training and testing (T and T) techniques together with genetic doping (GenD) algorithm is described in detail, as well as the steps taken in the two benchmark and optimization protocol phases. RESULTS: In terms of accuracy results, a value of 79.64% was achieved during optimization, with mean benchmark values of 64.90% for the linear discriminant analysis (LDA) and 68.15% for the multi layer perceptron (MLP), for the classification task. A value of 88.61% was achieved during optimization for the prediction task, with mean benchmark values of 49.32% for the LDA and 70.05% for the MLP. CONCLUSIONS: The proposed EP has led to the construction of inductors that are viable and usable on medical data which is representative but highly not linear. In particular, for the classification problem, these new inductors may be effectively used on the basal examination data to support doctors in deciding whether to avoid endoscopic examinations; whereas, in the prediction problem, they may support doctors' decisions about the advisability of eradication therapy. In both cases the variables selected indicate the possibility of reducing the data collection effort and also of providing information that can be used for general investigations on symptom relevance.

Algorithms↗
PubMed2004

Bioanalytical method validation: a risk-based approach?

Bioanalysis frequently involves the measurement of very low analyte concentrations in complex and potentially variable matrices. It is not possible to test in validation every possible circumstance that may be encountered when analyzing study samples; logically, therefore, some risk of obtaining erroneous results exists when validated methods are applied to study samples. An initial attempt has been made to apply a risk management tool to the bioanalytical situation, with the hope that this will stimulate further discussion on the idea of more formally addressing "risk" with regards to bioanalytical method validation.

Biological Assay↗
PubMed2004

Simultaneous determination of estramustine phosphate and its four metabolites in human plasma by liquid chromatography-ionspray mass spectrometry.

A sensitive and selective method, using liquid chromatography-ionspray mass spectrometry, was developed and validated for the simultaneous determination of Estracyt (estramustine phosphate) and its four metabolites, estramustine, estromustine, estrone and estradiol, in human plasma. Deuterated internal standards were available for all analytes. The five compounds were extracted from plasma by protein precipitation with acetonitrile. The chromatographic separation was performed using a Zorbax SB C18, (150 x 4.6 mm i.d., 5 microm) reversed-phase column under gradient conditions with a mobile phase containing 2 mm ammonium acetate buffer (pH 6.8) and acetonitrile. MS detection was by electrospray ionization with multiple reaction monitoring in the positive ion mode for estramustine phosphate, estromustine and estramustine, and in the negative ion mode for estrone and estradiol. The limit of quantitation was 10 ng/mL for estramustine phosphate, 3 ng/mL for estromustine, estramustine and estrone and 30 ng/mL for estradiol. Linearity was verified from these LLOQs up to about 4000 ng/mL for the parent drug and 2000 ng/mL for the metabolites. Inter-day precision and accuracy values were all less than 15%. This assay was applied successfully to the routine analysis of human plasma samples collected in cancer patients administered estramustine phosphate intravenously.

Antineoplastic Agents, Alkylating↗
PubMed2003

Simultaneous determination of JTT-501 and its main metabolite in human plasma by liquid chromatography-ionspray mass spectrometry.

An LC-MS-MS analytical method was developed for the determination of a new antidiabetic agent, JTT-501 and its main metabolite (JTP-20604) in human plasma. The compounds were isolated from plasma by protein precipitation before analysis by HPLC with atmospheric pressure positive ionisation MS-MS detection. An isotopically labelled analog of JTT-501 was used as the internal standard. Linearity was demonstrated over the calibration range of about 5-10000 ng/ml for both compounds. The assay was validated with respect to accuracy, precision and analyte stability. This method was used for the determination of plasma concentrations for the two compounds in a clinical tolerability study. A cross-validation exercise between two different mass spectrometers, used for the determination of clinical samples, is also reported.

Chromatography, High Pressure Liquid↗
PubMed2002

A phase I and pharmacokinetic study of MAG-CPT, a water-soluble polymer conjugate of camptothecin.

Polymeric drug conjugates are a new and experimental class of drug delivery systems with pharmacokinetic promises. The antineoplastic drug camptothecin was linked to a water-soluble polymeric backbone (MAG-CPT) and administrated as a 30 min infusion over 3 consecutive days every 4 weeks to patients with malignant solid tumours. The objectives of our study were to determine the maximal tolerated dose, the dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document anti-tumour activity. The starting dose was 17 mg m(-2) day(-1). Sixteen patients received 39 courses at seven dose levels. Maximal tolerated dose was at 68 mg m(-2) day(-1) and dose-limiting toxicities consisted of cumulative bladder toxicity. MAG-CPT and free camptothecin were accumulated during days 1-3 and considerable amounts of MAG-CPT could still be retrieved in plasma and urine after 4-5 weeks. The half-lives of bound and free camptothecin were equal indicating that the kinetics of free camptothecin were release rate dependent. In summary, the pharmacokinetics of camptothecin were dramatically changed, showing controlled prolonged exposure of camptothecin. Haematological toxicity was relatively mild, but serious bladder toxicity was encountered which is typical for camptothecin and was found dose limiting.

Acrylamides↗
PubMed2000

Species-differences in disposition and reductive metabolism of methoxymorpholinodoxorubicin (PNU 152243), a new potential anticancer agent.

Plasma pharmacokinetics, excretion balance and urinary metabolites of methoxymorpholino doxorubicin (MMDX) were investigated in male and female rats and in female dogs after i.v. administration of the(14)C-labelled drug. The mean total recovery of radioactivity in 96 h (urine plus faeces) was approximately 74 and 60% dose in male and female rats, respectively, while in female dogs approximately 72% dose was recovered in 336 h. Most of the radioactivity was present in faeces, with the urinary elimination accounting for only 3-4% dose in rats and dogs. These data suggest that biliary excretion is an important route of elimination of MMDX and/or its metabolites in both species. No differences were observed in the urinary metabolic profile of male and female rats. Two main peaks were present in radiochromatograms of urine from rats and dogs, i.e. MMDX and its 13-dihydro metabolite (MMDX-ol), accounting for approximately 25 and 20% of total radioactivity in 0-24-h urine in rats and 30 and 36% in dogs. The MMDX-ol/MMDX ratio in dog urine was higher than that observed in rat urine. No aglycones were detected in the urine samples from either species. In the rat, the plasma concentration-time profile suggested that the disposition of MMDX, MMDX-ol and total radioactivity is not sex-dependent. MMDX was the major species present in the systemic circulation; its AUC (0-96 h) accounted for 70% of total plasma radioactivity with the sum of AUC (MMDX) plus AUC (MMDX-ol) accounting for 77% of total radioactivity. In the dog, the sum of AUC (MMDX) plus AUC (MMDX-ol) amounted to 8% of radioactivity AUC(0-t(z) indicating that an important proportion of other(s) unknown metabolite(s) is present in dog plasma. Plasma levels of MMDX-ol in the rat were approximately 10-fold lower than those of the parent compound, whereas they were three times higher than those of MMDX in the dog. These data show that the reduction of the 13-keto group of MMDX is species-dependent, and occurs preferentially in the dog compared to the rat.

Animals↗
PubMed1999

Determination of 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyldaunorubicin+ ++ and its 13-hydroxy metabolite by direct injection of human plasma into a column-switching liquid chromatography system with mass spectrometric detection.

A selective, sensitive and fully automated column-switching LC system using direct injection of human plasma followed by mass spectrometry (MS) detection was developed and validated to determine the concentrations of 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyldaunorubicin++ + (PNU-159548) and its 13-hydroxy metabolite (PNU-169884). A 50-microl human plasma sample was directly introduced into a C4-alkyl-diol silica clean-up column separating analytes from proteins and polar endogenous compounds using water and methanol as the mobile phase. The fraction containing PNU-159548 and its metabolite was back-flushed and transferred to the analytical column. The compounds were separated using a Zorbax SB C8 column (150x4.6 mm, 5 microm) under gradient conditions with the mobile phase containing acetonitrile and 2 mM ammonium formate, pH 3.5. MS detection was by atmospheric pressure ionisation with multiple reaction monitoring in positive ion mode. Linearity was demonstrated over the calibration range of 0.051-10.291 ng/ml for PNU-159548 and 0.104-10.434 ng/ml for PNU-169884. The assay was validated with respect to accuracy, precision and analyte stability. On the basis of the validation data, the developed analytical method was found to be suitable for use in Phase I clinical studies.

Antibiotics, Antineoplastic↗
PubMed1999

Effect of rifabutin on ethambutol pharmacokinetics in healthy volunteers.

The effect of repeated administration of rifabutin on the pharmacokinetics and metabolism of ethambutol was evaluated in ten healthy volunteers. The subjects received a single oral administration of 1200 mg ethambutol on days 1 and 10 and a single daily oral dose of 300 mg rifabutin from days 3 to 9. No statistically significant difference was found in plasma pharmacokinetics (C(max), t(max), AUC, half-life and MRT) and in the renal clearance, whereas a significant decrease in the amount of unchanged ethambutol excreted in urine was observed. The decrease observed in ethambutol urinary excretion may be accounted for by taking into consideration the variability of the urinary excretion of ethambutol reported in the literature. However, a slight, likely not clinically relevant, induction or activation of kidney alcohol and/or aldehyde dehydrogenase isoenzymes by rifabutin cannot be ruled out at present. Evidence exists in the present study for autoinduction of rifabutin metabolism; this is shown by the lower plasma concentrations obtained 24 h after the seventh dose as compared to the theoretical concentrations.

Adult↗
PubMed1998

Determination of PNU 157706, a new dual inhibitor of 5alpha-reductase, in rat plasma by high-performance liquid chromatography with ultraviolet detection.

A HPLC procedure was developed and validated for determining nanogram per milliliter concentrations of the dual 5alpha-reductase inhibitor PNU 157706 in rat plasma. The compound was extracted from plasma with diethyl ether followed by purification using a CN cartridge. The chromatographic separation was performed with a C18 column using a water-acetonitrile-methanol mixture as eluent. UV detection at 210 nm was used for the quantification of the compound over the concentration range 5-500 ng/ml plasma. The method has a lower limit of quantification of 5 ng/ml and good precision and accuracy. This method has performed well during analysis of several toxicokinetic and pharmacokinetic studies in the rat.

Androstenes↗
PubMed1997

Enantioselective determination of FCE 28833, a new potential antiischemic agent, in gerbil plasma using column switching HPLC with UV detection.

A sensitive and selective high performance liquid chromatographic method using an automated column switching technique for the determination of FCE 28833 enantiomers in gerbil plasma was developed. After solid-liquid extraction using a Supelcosil C18 cartridge, FCE 28833 was eluted on a clean-up column (Spherisorb CN) and the enantiomers were separated using an analytical chiral column (Crownpack CR(+)). The mobile phase (15% methanol in HClO4 1 mM) was directed through the columns at a flow rate of 1 ml/min and the fraction eluted between 13 and 40 min was transferred from the clean-up column into the analytical column. FCE 28833 enantiomers were monitored at 257 nm. The limit of quantitation of the method was 20 ng/ml plasma for both enantiomers and proved to be linear, precise, and accurate for the assay of both enantiomers in the 20-6,000 ng/ml concentration range. No interference from the blank gerbil plasma sample was observed. The suitability of the method was assessed using plasma samples obtained from male gerbils treated with a single oral dose (400 mg/kg) of FCE 28833.

Animals↗
PubMed1996

Determination of ethambutol in human plasma and urine by high-performance liquid chromatography with fluorescence detection.

A sensitive and selective HPLC method for the determination of ethambutol in human plasma and urine was developed. Ethambutol was extracted from basified plasma samples (0.2 ml) with diethyl ether, back-extracted into 0.01 M phosphoric acid and derivatized with 4-fluoro-7-nitrobenzo-2-oxa-1, 3-diazole. After 30 min at 80 degrees C and elimination of the reactive excess, the compound was determined by reversed-phase liquid chromatography. urine was analysed for ethambutol after dilution 1:200 with distilled water and derivatization as described for plasma. Quantification in plasma and urine was achieved by fluorescence detection of the eluate. The linearity, precision and accuracy of the method were evaluated. No interference from the constituents of human plasma and urine was observed. The limit of quantification was 10 ng/ml in plasma and 10 micrograms/ml in urine. The suitability of the method for in vivo samples was checked by analysis of plasma and urine samples drawn from healthy volunteers who had received a 1200-mg oral dose of the test compound.

Antitubercular Agents↗
PubMed1995

The use of a pig liver xenograft for temporary support of a patient with fulminant hepatic failure.

A 26-year-old female patient with fulminant hepatic failure and a history of autoimmune hepatitis was heterotopically transplanted with a pig hepatic xenograft to provide temporary metabolic support prior to transplantation with a human donor organ. Circulating natural antipig antibodies were removed prior to transplantation by plasmapheresis and ex vivo en bloc perfusion of the donor pig kidneys. The liver xenograft functioned after transplantation as measured by active bile production, stabilization of prothrombin levels, and reduction in the circulating levels of lactic acid and the enzymes AST and ALT. Despite the removal of greater than 90% of the recipient's natural xenoantibodies prior to transplantation, the levels of antibody rapidly returned and were associated with antibody and complement-mediated rejection of the donor graft. Immunohistochemical evidence of graft rejection could be detected by the deposition of antibody, complement components including properdin, and endothelial swelling as early as 3 hr posttransplantation. These lesions progressed in severity and were accompanied by evidence of thrombosis and ischemic necrosis of the liver xenograft by 34 hrs posttransplantation. The main portal vein, hepatic artery, and vena cava were patent. The placement of the liver graft did not result in any improvement in the neurological status of the patient and she died 34 hr after xenografting due to irreversible brain damage. The information derived from this case has renewed interest in the clinical use of bioartificial devices and whole organ perfusion using xenogeneic tissue for temporary bridging of patients prior to allografting.

Adult↗
PubMed1995

Phase I clinical and pharmacokinetic study of 3'-deamino-3'-(2-methoxy-4-morpholinyl)doxorubicin (FCE 23762).

Methoxymorpholinyldoxorubicin (FCE 23762) is a novel, highly lipophilic doxorubicin analogue. It possesses potent in vitro and in vivo antitumor activity including efficacy in multidrug-resistant tumor cell lines. It is also metabolically activated in vivo resulting in an 80-fold increase in potency over the parent drug. In this phase I study the drug was administered by i.v. bolus injection at 3-week intervals. Fifty-three patients with refractory solid tumors were treated; 133 courses of FCE 23762 were administered at doses ranging from 30 to 2250 micrograms/m2. The dose limiting toxicity was reversible myelo-suppression (granulocytopenia and thrombocytopenia), demonstrating a delayed nadir and recovery in comparison to doxorubicin. Other toxicities included transient elevation of hepatic transaminases, delayed and prolonged nausea and vomiting, mucositis, anorexia, fatigue, and diarrhea. Heavily pretreated patients demonstrated more myelosuppression than previously untreated patients at 1250 micrograms/m2. No cardiotoxicity was observed. Four objective tumor responses were seen: one complete response in a patient with pelvic recurrence of cervical cancer; one partial response in a patient with cutaneous and lymph gland metastases from head and neck cancer; and two minor responses in patients with liver metastases from colorectal cancer. Plasma concentrations of FCE 23762 and its 13-dihydro metabolite, FCE 26176, were measured in 20 patients at doses > or = 675 micrograms/m2, using HPLC with fluorescence detection. The area under the plasma concentration-time curve ranged from 30 to 80 ng/h/ml; plasma data suggested linear kinetics in the range of tested doses (although there was considerable interpatient variability). The maximum tolerated dose defined in this study using this schedule is 1500 micrograms/m2. A safe phase II dose for previously untreated patients using this schedule is 1250 micrograms/m2; however, this may actually be below the optimal dose for this patient population.

Adult↗
PubMed1993

Determination of exemestane, a new aromatase inhibitor, in plasma by high-performance liquid chromatography with ultraviolet detection.

A sensitive and selective high-performance liquid chromatographic method for the determination of 6-methylen-androsta-1,4-diene-3,17-dione (exemestane) and its 17-dihydro metabolite in human plasma has been developed. The analytes and internal standard (Norgestrel) were extracted from plasma samples with a methylene chloride-iso-octane mixture; the organic phase was dried and the residue was reconstituted with an acetonitrile-water mixture, then analyzed by reversed-phase liquid chromatography. Quantification was achieved by ultraviolet detection of the eluate. The linearity, precision and accuracy of the method were evaluated. No interference from the constituents of human blank plasma was observed. The lower limit of quantification was 10 ng/ml plasma. The suitability of the method for in vivo samples was checked by analysis of plasma samples drawn from healthy male volunteers who had received a 200-mg single oral dose of the test compound.

Androstadienes↗
PubMed1992

Determination of 3'-deamino-3'-[2(S)-methoxy-4-morpholinyl]doxorubicin, a new morpholinyl anthracycline, in plasma by high-performance liquid chromatography with fluorescence detection.

A sensitive and selective high-performance liquid chromatographic method for the determination of 3'-deamino-3'-[2(S)-methoxy-4-morpholinyl]doxorubicin and its possible 13-dihydro metabolite in human plasma has been developed. The plasma samples were buffered and the drugs and internal standard (doxorubicin) were extracted with diethyl ether-n-butanol, back-extracted into 0.3 M phosphoric acid, then analysed by reversed-phase liquid chromatography. Quantitation was achieved by fluorescence detection of the eluate. The linearity, precision and accuracy of the method were evaluated. No interference from blank plasma sample was observed. The suitability of the method for in vivo samples was checked by analysis of plasma samples drawn from female rats that had received repeated intravenous doses of the test compound.

Animals↗