Salivary and plasma pharmacokinetics of topotecan in patients with metastatic epithelial ovarian cancer.

The comparative saliva/plasma pharmacokinetics of topotecan were investigated in 13 patients with metastatic epithelial ovarian cancer receiving topotecan (30-min intravenous (i.v.) infusion) on a five consecutive day schedule every 3 weeks. During the first and the second courses of treatment, each patient underwent pharmacokinetic evaluation. Quantitation of the total topotecan (lactone plus carboxylate form) was assessed by a highly specific high-performance liquid chromatographic (HPLC) method. Large patient-to-patient variations in the plasma and saliva concentrations were observed. Plasma and saliva pharmacokinetics could be described using a biexponential pattern. From the saliva data, the half-life of the terminal part of the curve was 2.64 h, it was of the same order of magnitude as the topotecan elimination half-life determined from the plasma data, 3.18 h. Topotecan concentrations were higher in the saliva than in the plasma, the saliva/plasma concentration ratio averaged 2.31 and the ratio area under the parotid saliva (AUC(s)) over plasma (AUC(p)) concentration-time curve (AUC(s)/AUC(p)) averaged 2.11. For each individual, a significant relationship was found between topotecan concentrations in the saliva and in the plasma, the coefficients of correlation ranged from 0.75 to 0.92 according to the patient. Myelosuppression, especially granulocytopenia was the most frequent toxicity encountered during the trial. The percent decrease in the leucocyte count, absolute neutrophil count and platelet count were related to the AUCp/day using sigmoidal E(max) models. The high values of the Hill constant found reflect the very steep AUC-haematoxicity relationship observed. In most cases, abdominal pain occurred in patients presenting high saliva concentrations. One patient with high salivary concentrations (mean S/P ratio=4.60) had grade 1 mucositis. In conclusion, the concentration of topotecan in saliva appeared to be useful as an indirect, non-invasive estimation of the levels of topotecan in the plasma; thus, saliva concentrations could be a good predictor of the behaviour of topotecan in the body.

High-performance liquid chromatographic determination of vinorelbine in human plasma and blood: application to a pharmacokinetic study.

A sensitive and specific high-performance liquid chromatographic method with fluorescence detection (excitation wavelength: 280 nm; emission wavelength: 360 nm) was developed and validated for the determination of vinorelbine in plasma and blood samples. The sample pretreatment procedure involved two liquid-liquid extraction steps. Vinblastine served as the internal standard. The system uses a Spherisorb cyano analytical column (250x4.6 mm I.D.) packed with 5 microm diameter particles as the stationary phase and a mobile phase of acetonitrile-80 mM ammonium acetate (50:50, v/v) adjusted to pH 2.5 with hydrochloric acid. The assay showed linearity from 1 to 100 ng/ml in plasma and from 2.5 to 100 ng/ml in blood. The limits of quantitation were 1 ng/ml and 2.5 ng/ml, respectively. Precision expressed as RSD was in the range 3.9 to 20% (limit of quantitation). Accuracy ranged from 92 to 120%. Extraction recoveries from plasma and blood averaged 101 and 75%, respectively. This method was used to follow the time course of the concentration of vinorelbine in human plasma and blood samples after a 10-min infusion period of 20 mg/m2 of this drug in patients with metastatic cancer.

Profiles of a healthful diet and its relationship to biomarkers in a population sample from Mediterranean southern France.

OBJECTIVES: The failure of single-nutrient supplementation to prevent disease in intervention studies underlines the necessity to develop a holistic view of food intake. The objectives of this study were to devise a diet quality index (DQI) and identify biomarkers of multidimensional dietary behavior. DESIGN: A nutrition survey was conducted in Mediterranean southern France by means of a food frequency questionnaire. The DQI was based on current dietary recommendations for prevention of diet-related diseases such as cardiovascular disease and some cancers. A second DQI included tobacco use. STATISTICAL ANALYSES: performed Spearman rank correlations, cross-classifications and intraclass correlations were computed between the DQI and biomarkers. RESULTS: Of the 146 subjects, 10 had a healthful diet and 18 had a poor diet. Erythrocyte omega-3 fatty acids-eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)-beta carotene, and vitamin E concentrations were lower and cholesterol concentrations were higher in the poor diet; the difference was significant for EPA and DHA and borderline significant for vitamin E. Significant correlation was found between the DQI and vitamin E (-0.12), EPA (-0.30), and DHA (-0.28), and beta carotene (-0.17) when tobacco use was considered, but not between the DQI and cholesterol. The correlation coefficient reached 0.58 (P0.01) for a composite index based on all biomarkers except cholesterol. CONCLUSIONS: Subjects with a beta carotene levels greater thanl micromol/L, vitamin E greater than 30 micromol/L and EPA greater than 0.65% and DHA greater than 4% of fatty acids in erythrocytes were likely to have a healthful diet. Each biomarker indicated the quality of diet, but correlation was higher with a composite index.

[Nitrogen dioxide and ozone exposures in a population sample from Ile-de-France]. / Expositions au dioxyde d'azote et à l'ozone d'une population de l'Ile-de-France.

BACKGROUND: Individual exposure to NO(2)and O(3) has been estimated in an urban population sample in southern France and the determinants identified. The present study was conducted to evaluated individual exposure to NO(2) and O(3) and to identify the environmental determinants of exposure in a larger population living in different environmental conditions. METHODS: Two hundred ninety-four volunteers were recruited from the SUVIMAX sample in Ile-de-France. The study covered 2 periods of 5 consecutive days, one in winter and the other in the fall of 1998. Passive monitors were used to estimate individual exposure and indoor concentration at the participant's dwelling. Background atmosphere concentrations were obtained for the AIRPARIF surveillance network. Single and multiple ANOVA were used for statistical analysis. RESULTS: Individual exposures were low, especially for O(3) in the considered periods of time. Mean NO(2) and O(3)concentrations were 41 microg/m(3)/h and 16 microg/m(3)/h, respectively. The NO(2) individual exposure increased with the time spent in traffic and indoor concentration. The correlation coefficient between indoor and individual levels was r=0.73, and indoor concentration explained 50% of the variance in individual exposure. The site of the dwelling with regard to high traffic street, and most strongly, the presence of a gas stove influenced indoor concentration. However, mechanical air extraction decreased the mean indoor NO(2) level of the dwellings. CONCLUSION: This study allowed identification of the environmental determinants of NO(2) exposure in an urban sample. These data, together with those obtained previously, well be used to establish an exposure matrix for NO(2).

Validation of a food-frequency questionnaire using multiple-day records and biochemical markers: application of the triads method.

BACKGROUND: A food-frequency questionnaire (FFQ) used to assess usual food intake in Southern France has been validated by the classical means of multiple-day food records. To minimise over-estimation of the correlation between the dietary assessments by the FFQ and the reference method, which occurs if the random errors of questionnaire and reference measurement are positively correlated, a triangular comparison, the method of triads, was used. METHODS: We applied the triads model by comparing the FFQ with two multiple-day food records and three biomarkers. Only 87 subjects were included and completed the protocol. One biomarker (beta-carotene) was used for the 87 subjects and two biomarkers (urinary nitrogen and potassium) were measured in only 40 subjects. RESULTS: For beta-carotene intake assessment, the triad model, including the weighed multiple records (PETRA), was the best with estimates of validity coefficient of 0.39 [confidence interval (CI) 0.18-0.60] for the FFQ, 0.52 (CI 0.24-0.86), for PETRA and 0.85 (CI 0.43-1) for plasma levels of the nutrient. For protein and potassium intake assessment, the triad model including the estimated multiple records was the best only for the estimates of FFQ validity coefficient (0.61; CI 0.28-0.96 and 0.31; CI 0.09-0.66 respectively). CONCLUSION: Accuracy of the dietary assessment methods permitted a satisfactory estimation of the validity coefficient for beta-carotene intake by the FFQ, despite a small sample. However, the validity coefficients for protein and potassium showed wide CI values, indicating that a sample size < 50 subjects appears unsatisfactory for validation.

Bayesian estimate of vinorelbine pharmacokinetic parameters in elderly patients with advanced metastatic cancer.

The objective of the present study was to determine the pharmacokinetic profile of vinorelbine in patients 65 years or older with metastatic cancer in progression. Twelve patients were enrolled in this study. Vinorelbine was administered by a 10-min continuous infusion at a dose of 20-30 mg/m2 through a central venous catheter. Chemotherapy was repeated weekly. A total of 46 courses of vinorelbine was studied. Each patient underwent pharmacokinetic evaluation during the first cycle of treatment. Toxicity evaluation was carried out before each course of chemotherapy. Plasma vinorelbine determinations were performed by high-performance liquid chromatography with spectrofluorometric detection. A Bayesian estimation of individual pharmacokinetic parameters was carried out using the nonlinear mixed-effect modeling approach as implemented in the NONMEM computer program. An open three-compartment pharmacokinetic model with a zero order input rate was used to describe the kinetics of vinorelbine. Area under the plasma-concentration time curve (AUC) normalized to a 30 mg/m2 administered dose averaged 0.89 mg/liter x h (coefficient of variation = 23.7%). The total plasma clearance averaged 0.93 liter/h/kg (0.61-1.83 liter/h/kg; coefficient of variation = 38.6%). The elimination half-life was 38.1 +/- 5.8 h. A high correlation was found between patient age and total clearance (r = -0.8; P < 0.001). The main hematological toxicity observed was anemia in 11 patients. Neutropenia occurred in 50% of patients. Significant correlations were found between AUC and the decrease in the hemoglobin level (r = 0.60) and between AUC and the decrease in the neutrophil count (r = 0.66). Thrombocytopenia was observed in only one patient. In conclusion, the age-related decrease in clearance found in this study supports the design of a Phase I study of vinorelbine in patients older than 65 years or perhaps 70 years.

A phase I and pharmacokinetic study of melphalan using a 24-hour continuous infusion in patients with advanced malignancies.

The objectives of the present study were to determine the following: (a) the maximum tolerated dose (MTD) of melphalan using a 24-h continuous infusion; (b) the clinical toxicity; and (c) the pharmacokinetic characteristics of melphalan at each dose level. Twenty-one patients with refractory solid tumors were enrolled in the study. Melphalan, packaged in 3% sodium chloride, was administered i.v. over a 24-h period. Patients were assigned to one of three escalating dose levels of melphalan: (a) 20 mg/m2 (n = 5); (b) 30 mg/m2 (n = 7); and (c) 40 mg/m2 (n = 6). Each patient underwent pharmacokinetic evaluation during the first cycle of treatment. Melphalan concentrations in plasma were determined by high-performance liquid chromatography. Toxicity was evaluated after each course of chemotherapy. All of the patients were assessable for toxicity and pharmacokinetics, and 20 patients were assessable for response analysis. A total of 50 courses of melphalan was studied. The MTD was 30 mg/m2. The dose-limiting toxicity was neutropenia and thrombocytopenia. Hematotoxicity was reversible (nadir, 14-15 days; recovery, 3.5 and 12.5 days for 30 and 40 mg/m2, respectively), cumulative, and related to the administered dose and to the history of previous therapy. There were six episodes of neutropenic sepsis. Individual pharmacokinetic parameters were estimated using a Bayesian approach and linear elimination kinetics. Data were compatible with a one-compartment model. Relationships have been found between the area under the plasma concentration-time curve and doses and between Css and doses. Moreover, clearance, t1/2 elimination, and volume of distribution did not change statistically with dose, which suggests linear kinetics. Two partial responses were observed in patients with ovarian carcinoma or adenocarcinoma of unknown primary origin, and another patient had stabilization disease. In conclusion, melphalan MTD was determined to be 30 mg/m2 when administered as a 24-h infusion. Hematological toxicity was the dose-limiting toxicity. The most important nonhematological toxicity encountered was nausea and vomiting. The recommended dose for Phase II studies was 30 mg/m2.

Plasma and salivary pharmacokinetics of 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer receiving 5-FU bolus plus continuous infusion with high-dose folinic acid.

The comparative saliva/plasma pharmacokinetics of 5-fluorouracil (5-FU) were investigated in 21 patients with metastatic colorectal cancer receiving high-dose folinic acid (LV (leucovorin) 200 mg/m2) followed by 5-FU bolus (400 mg/m2) and continuous infusion (600, 750, 900 or 1200 mg/m2) on days 1 and 2. Quantitation of unchanged drug was assessed by a highly specific high-performance liquid chromatographic method. Large patient-to-patient variations in plasma and saliva 5-FU concentrations were observed. Saliva pharmacokinetics could be described using a bi-exponential pattern. The half-life of the rapid phase averaged 8.0 min, and was of the same order of magnitude as the 5-FU elimination half-life determined from plasma data. The half-life of the terminal part of the curve averaged 8 h; such decrease in salivary concentrations could be due to changes in salivary gland function caused by 5-FU, which results in reduced salivary flow rate. Between individual 5-FU concentrations in parotid saliva and plasma a statistically significant straight line could be fitted with a coefficient of correlation of 0.675. Moreover, the risk of developing 5-FU-related mucositis was significantly linked to 5-FU salivary exposure. Diarrhoea was the most frequent toxicity encountered during the trial.

Circadian rhythm of 5-fluorouracil population pharmacokinetics in patients with metastatic colorectal cancer.

PURPOSE: The purpose of this work was to estimate the population pharmacokinetic parameters of 5-fluorouracil (5-FU) in patients with advanced colorectal cancer using circadian change kinetics. METHODS: Eighty-five patients (32 females, 53 males) were enrolled onto this study. All patients received folinic acid (200 mg/m(2)) by intravenous infusion over 2 h followed by a 5-FU loading dose (400 mg/m(2)) and then continuous infusion (600 mg/m(2)) for 22 h. This whole regimen was repeated on day 2 and was given on a 14-day cycle. Plasma 5-FU determinations were performed by high-performance liquid chromatography with ultraviolet absorbance detection. Pharmacokinetic analyses were performed using the NONMEM computer program through the Visual-NM graphical interface. An open one-compartment pharmacokinetic model with zero-order input rate was used to describe the kinetics of 5-FU; moreover, circadian time-dependent changes in 5-FU concentrations were taken into account in the model. The circadian model was defined as the sum of two cyclic components; the amplitude of the first cyclic component (over 24 h) was about 30% of the average clearance and the amplitude of the second cyclic component (over 12 h) was about 50% of the amplitude of the first component. The acrophase (peak) times of the first and the second periodic component were 04 h 12 m and 00 h 25 m, respectively. The potential sources of variability on the population parameters (65 patients) were investigated using patient's sex, body area, age, body weight, height, liver enzymes and serum creatinine as covariables. RESULTS: Only the estimated clearance circadian changes were different for the two sexes. The population parameter estimates of mean clearance (CL(mean)) and initial volume of distribution (V), were as follows: the male subgroup showed a CL(mean) value twice larger (125 l/h) than the value observed in the female subgroup (65 l/h), and V = 21 l. A validation group of 20 additional patients was used to evaluate the predictive performances of the population parameters. The individual pharmacokinetic parameters were computed by means of a Bayesian fitting procedure. From the resulting individualized parameter values, concentrations of 5-FU in the plasma were calculated. To evaluate the performance of the Bayesian estimation, the experimental concentrations were compared with the predicted ones. CONCLUSION: In conclusion, a chronomodulated delivery schedule of 5-FU should be performed, using a perfusion rate inversely proportional to the circadian variations of clearance in order to maintain stable 5-FU plasma levels. Such a treatment schedule may result in increased effectiveness of the treatment and decreased occurrence of drug-associated side-effects. The present study develops a complete procedure to efficiently estimate 5-FU clearance in order to optimize dosage regimens in individual patients.

Anal sphincter reconstruction by dynamic graciloplasty after abdominoperineal resection for cancer.

PURPOSE: Chronic low-frequency electrical stimulation can safely transform fatiguing muscle into fatigue-resistant muscle. This fundamental discovery was used to reconstruct the anal sphincter. Dynamic graciloplasty was found to be effective in the treatment of fecal incontinence. Our study was undertaken to investigate the oncologic, functional, and quality of life results of dynamic graciloplasty anal reconstruction after an abdominoperineal resection for carcinoma. METHODS: Between April 1993 and April 1996, nine patients (4 males) with a median age of 51.2 (range, 29-69) years underwent an abdominoperineal resection for carcinoma (4 had a rectal adenocarcinoma and 5 had an epidermoidal anal tumor) and an anal sphincter reconstruction with electrically stimulated graciloplasty. Oncologic and functional results were evaluated after a mean follow-up of 32 (range, 14-50) months. A quality of life questionnaire was filled out by seven patients. RESULTS: Sphincter reconstruction required the same hospitalization period as abdominoperineal resection. Two patients died from evolutive disease. Three patients were operated on twice, one for immediate colonic necrosis, two for colonic perforation after enema. One of them refused the graciloplasty and had an abdominoperineal resection. Six patients were dysfunctioned. The mean resting pressure was 24 +/- 10 mmHg, and the mean pressure during stimulation was 95 +/- 25 mmHg. Five patients were continent for solids and liquid; four wore less than three pads per day, and one wore more than three. Four patients used enemas twice a week; one patient had spontaneous evacuation. The quality of life questionnaire showed that the mean scores for social interaction, symptoms, and psychological and physical states were 2.1, 2.2, 2.4, and 2.7, respectively. The mean value was 1.5. CONCLUSIONS: Total anorectal reconstruction with dynamic graciloplasty is an oncologically safe procedure. Functional results improve with time, but careful patient selection guarantees a successful functional outcome. Technical progress is necessary to improve the quality of life.

Ozone exposure and blood antioxidants: a study in a periurban area in Southern France.

Major carotenoids in plasma--especially beta-carotene--are affected by oxidative stress (e.g., tobacco smoking). Environmental ozone induced oxidative stress in experimental in vitro and in vivo studies, and it also increased the incidence of lung cancer in mice. We proposed to measure, after controlling for other determinants, the impact of personal ozone exposure on carotenoids levels in plasma. During the summer, we recruited 58 volunteer subjects who worked in a periurban zone. We asked each subject to wear a passive sample, which measured ozone exposure for 5 consecutive d. At the end of this period, we assessed plasma antioxidants. We observed a negative significant regression coefficient between alpha- or beta-carotene and ozone exposure (r = -.39, p < .01, and r = -.45, p = .02, respectively). In a subsample of 45 nonsmoker subjects, among whom carotene intake was lower than the median intake value (i.e., 6.6 mg/d) of the overall group, we noted that a relatively low exposure to ozone (> or = 50 microg/m3 x h or > or = 23.8 ppb) induced a significant decrease in plasma beta-carotene levels (i.e., 0.7 micromol/l to 0.4 micromol/l). This significant decrease suggested that a high dietary intake of fruit or vegetables can have a beneficial influence on the levels of plasma antioxidants generated in response to ozone exposure.

Effect of mitoxantrone liposomes on multidrug-resistant breast cancer cells.

A major obstacle in efficacy of breast cancer chemotherapy is the emergence of multidrug resistance. We investigated modulation of multidrug resistance by liposome-encapsulated mitoxantrone in a drug resistant human breast MCF7R cell line and the influence of liposome composition. Neutral high phase-transition temperature and anionic low phase-transition temperature phospholipid liposomes, reduced the resistance factor from 142 to 15 and 38, respectively. The higher cytotoxicity obtained with mitoxantrone-encapsulation was not necessarily related to higher intracellular uptake. Our data suggest that liposomes, according to their lipid composition, may alter the P-glycoprotein function by plasma membrane stabilization and modulate multidrug resistance in human cancer.

Influence of the schedule of exposure on the cytotoxic effect of melphalan on human 8226 and A2780 cells.

Melphalan was investigated for antitumoral activity using two schedules of exposure (solid versus sequential exposure) in two human cancer cell lines (8226 and A2780). Sequential exposure of melphalan was more effective than solid exposure at the same total dose. The IC50 values averaged 8.2 (solid exposure) and 0.16 microgram/ml (sequential exposure) for 8226 cells (myeloma), and 7.5 (solid) and 0.53 microgram/ml (sequential) for A2780 cells (ovarian carcinoma). Intracellular melphalan accumulation, determined by high-performance liquid chromatography, showed that the area under the intracellular concentration of melphalan versus time curve (between 0 and 30 h) was significantly higher after sequential doses (9.4 micrograms/ml x h) than after solid dose (6.6 micrograms/ml x h). Moreover, intracellular/extracellular concentration ratios indicated that melphalan uptake followed a passive transport system. The increase of both duration of exposure (11 h after solid exposure versus 20 h after sequential doses) and intracellular concentrations 5-6 h after the beginning of the experiment (approximately 3 times higher after sequential doses) indicate sequential administration of melphalan could be more effective than solid exposure.

Personal exposure to nitrogen dioxide pollution and effect on plasma antioxidants.

We conducted a cross-sectional epidemiological study to evaluate personal exposure to nitrogen dioxide and its effect on blood antioxidants. Personal exposure of 107 volunteers was assessed for 14 d with passive monitors. We excluded heavy smokers (> 10 cigarettes/d) from the study. Sociodemographic and environmental data, as well as beta-carotene intake, were recorded. We mainly attributed the mean nitrogen dioxide personal exposure (31.9 +/- 12.7 microg/m3 [0.017 ppm or 0.70 microM/m3]) (R2 = 0.75) to residence site in the city, time spent in urban traffic, and use of gas stoves. The correlation between nitrogen dioxide exposure and blood antioxidant concentration was weak; in addition, the correlation coefficients for men and women were inconsistent. Nonetheless, we found some evidence of an interaction between carotene intake and nitrogen dioxide exposure: a significantly lower plasma beta-carotene level was evident among subjects who consumed < or = 4.5 mg/jour of carotene and who were exposed to nitrogen dioxide levels that exceeded 40 microg/m3 (0.021 ppm or 0.87 microM/m3) of nitrogen dioxide.

Pharmacokinetics of 5-fluorouracil (5-FUra) in patients with metastatic colorectal cancer receiving 5-FUra bolus plus continuous infusion with high dose folinic acid (LV5FU2).

The pharmacokinetics of 5-fluorouracil (5-FUra) were investigated in 16 patients with metastatic colorectal cancer receiving high-dose folinic acid (LV 200 mg/m2) followed by 5-FUra bolus (400 mg/m2) and continuous infusion (600 mg/m2) on days 1 and 2. Quantitation of unchanged drug was assessed by a highly specific high-performance liquid chromatographic method. The concentrations of 5-FUra at the end of the loading dose averaged 30.7 +/- 13.2 micrograms/ml (i.e., 236 microM). The steady-state plasma concentration averaged 0.31 +/- 0.11 microgram/ml (i.e., 2.4 microM). 5-FUra plasma levels declined rapidly after the end of infusion with an apparent elimination half-life of 7.08 +/- 3.21 minutes. Clearance ranged from 776 to 3023 ml/min/m2. Large patient-to-patient variations in plasma 5-FUra concentrations were observed. No toxicity greater than WHO grade 2 was seen. One patient experienced grade 1 stomatitis and two others experienced grade 1 and 2 myelosuppression. One patient developed diarrhoea and another suffered asthenia. Nausea and vomiting were observed in 5 patients.

High-performance liquid chromatographic assay for methyl-beta-cyclodextrin in plasma and cell lysate.

This paper describes a high-performance liquid chromatographic method with fluorescence detection for the analysis of methyl-beta-cyclodextrin (MEBCD) in plasma and cell lysate, after in situ complexation with 1-naphthol. The size-exclusion HPLC column packed with TSK 3000 SW gel, was equilibrated with an eluent mixture composed of methanol and purified water (2:98, v/v) containing 10(-4) M 1-naphthol as a fluorophore. The detection is based on fluorescence enhancement caused by the formation of inclusion complexes and was performed at 290 and 360 nm for excitation and emission, respectively. The method involved a simple treatment of the samples with chloroform. Daunorubicin was used as internal standard. Limits of quantitation were 0.8 microM in plasma and 0.5 microM in cell lysate. Detection limits of 0.5 microM (50 pmol) and 0.3 microM (30 pmol) were obtained for MEBCD in the two media, respectively. Linear detection response was obtained for concentrations ranging from 1 to 100 microM in plasma and cell lysate. Recovery from plasma proved to be more than 40%. Precision, expressed as C.V. was in the range of 4 to 11%. Accuracy ranged from 89 to 105%.

Determination of 5-fluorouracil and its main metabolites in plasma by high-performance liquid chromatography: application to a pharmacokinetic study.

This paper describes a relatively simple and sensitive high-performance liquid chromatographic assay (HPLC) with ultraviolet absorbance detection for 5-fluorouracil (5-FUra) and its two main metabolites, 5-fluorouridine (5-FUrd) and 5-fluoro-2'-deoxyuridine (5-FdUrd), in plasma. In this study, two plasma clean-up procedures involving addition of internal standard, solid-phase and liquid-liquid extractions have been developed. A reversed-phase Kromasil C18 column was used. The detection was performed at 268 nm for 5-FUra and at 275 nm for the two metabolites. Linear detection responses were obtained for concentrations ranging from 25 to 1000 ng/ml. The average recovery from plasma was 35, 42 and 48% for 5-FUra, 5-FUrd and 5-FdUrd, respectively. Precision, expressed as C.V., ranged from 2.7 to 13% and the mean recovery from 94 to 105%. The limits of quantitation and detection of the three analytes were 20 and 10 ng/ml, respectively. The method was used to monitor the pharmacokinetic profile of 5-FUra and its two metabolites in patients with metastatic colorectal cancer.

Measurement of background urban nitrogen dioxide pollution levels with passive samplers in Montpellier, France.

Background nitrogen dioxide (NO2) pollution levels in Montpellier were measured in the context of an assessment operation carried out by the local monitoring network (AMPADI-LR), using Palmes passive samplers. The equipment was validated by continuous measurement with automatic chemiluminescence analyzers. Measurements from representative background pollution sites and the ensuing cartographic representation provide information about local pollution data, a description of seasonal evolution and an assessment of the influence of various sources. The study may be used to define parameters for establishing an exposure index, taking into account roads with heavy traffic, which affects the distribution of NO2 over Montpellier, and meteorological factors. This is a pilot study which will subsequently be used for a more precise assessment measuring the personal exposure of inhabitants, for the purposes of a study on effects on health.

Tumor progression and oxidant-antioxidant status.

We previously reported on a paradoxical oxidant-antioxidant status in breast cancer patients, more so in pre-menopausal than menopausal women. In this study, measurements were performed on 146 patients with various carcinomas. Vitamin E/total cholesterol increased and plasma malondialdehyde decreased with tumor size and progression. To investigate the difference between young pre-menopausal and aged menopausal breast cancer patients, the same measurements were performed in 365 breast cancer patients according to pathology, tumor size and estrogen receptors. The oxidant-antioxidant status varied with these prognosis factors in the same pattern, and was more pronounced in young than aged women.

Pharmacokinetics of high-dose intravenous melphalan in patients undergoing peripheral blood hematopoietic progenitor-cell transplantation.

The pharmacokinetics of melphalan following high-dose (140 mg/m2) i.v. administration were determined in 20 patients with advanced malignancies undergoing peripheral blood hematopoietic progenitor-cell transplantation. Melphalan was assayed in plasma by a specific HPLC method with UV detection. Plasma levels of melphalan declined in a biexponential fashion with a mean terminal half-life of 83 minutes (range 52-168 minutes). Estimated peak plasma concentrations ranged from 1.65 to 14.5 micrograms/ml. Plasma levels were lower than the limit of quantitation of the method used (20 ng/ml) 24 hours after drug administration. The average volume of distribution and total clearance were 317 ml/min/m2 (range 127-797 ml/min/m2) and 37.9 l/m2 (range 15.4-108 l/m2), respectively. These parameters are similar to those reported in the literature. A weak correlation was found between total clearance of melphalan and creatinine clearance (p < 0.05). No relationship between the pharmacokinetics of melphalan and myelosuppression and non-hematologic toxicities was recovered. This pharmacokinetic study indicates that on the assumption that there is no more circulating melphalan after seven elimination half-lives, it may be possible to reinfuse autologous PBPC 10-20 hours after melphalan administration.