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P Labarre

Publications and source records attributed to P Labarre.

At least 19 recordsLinked to original sources
PubMed2002

Pharmacokinetic study of cystemustine, administered on a weekly schedule in cancer patients.

BACKGROUND: Cystemustine is a chloroethylnitrosourea mostly active in humans against glioma and melanoma. The present report describes the results of a new phase I trial with cystemustine administered on a weekly schedule. The pharmacokinetic and pharmacodynamic properties of cystemustine were investigated. PATIENTS AND METHODS: Forty-three patients entered this study. Cystemustine was administered at dose levels ranging from 30 to 60 mg/m2. The drug was given on days 1, 8, 15 and 22, followed by a 4-week rest period. RESULTS: Thrombocytopenia was the dose-limiting toxicity and appeared to be reversible, but probably cumulative. This toxicity appeared dose-related, both in frequency and severity. The maximum tolerated dose was 60 mg/m2. Nonhematological toxicity was generally mild. Three partial responses were observed at dose levels of 50 and 60 mg/m2. Pharmacokinetics analysis showed mono- or biphasic cystemustine blood disposition with a mean a half-life of 4 min and mean terminal half-life of 49 min. CONCLUSIONS: There was a clear linear relationship between the area under the blood drug concentration-time curve (AUC) and the dose of cystemustine (P < 0.001). There was also a significant relationship between the AUC and the toxic effects of cystemustine on platelets, granulocytes and leukocytes (P < 0.001). A reasonable starting dose for phase II studies is 40 mg/m2, with dose escalation based on blood cell counts.

Adolescent↗
PubMed2002

Melanin affinity of N-(2-diethylaminoethyl)-4-iodobenzamide, an effective melanoma imaging agent.

The cellular uptake and incorporation in macromolecules of iodine-125 labelled N-(2-diethylaminoethyl)-4-iodobenzamide ([125I]BZA), a melanoma imaging agent, was studied using human melanoma cells M3Dau (amelanotic) and M4Beu (melanotic). The interaction between [125I]BZA and synthetic melanin was examined in various conditions of incubation. The results showed that uptake was high only for M4Beu, whereas the incorporation in trichloroacetic acid-precipitable proteins was very low for both model cell lines, with no correlation with melanin content. Experiments with synthetic melanin showed that BZA binding to melanin was saturable and reversible, and involved several types of interaction. The influence of the ionic environment indicated that electrostatic forces play a role in the affinity, and the decrease in binding produced by the presence of an alcohol in the medium suggested that hydrophobic interactions may be involved in the binding mechanism. This was supported by the Scatchard analysis, which revealed two classes of binding sites, and the determination of two association constants (K1 = 3.9 +/- 1.9 x 106/M and K2 = 2.9 +/- 0.9 x 104/M). The affinity of BZA for melanin might explain the good results obtained in a phase II clinical trial for the diagnosis of malignant melanoma metastases, in which the specificity was 100%.

Benzamides↗
PubMed2001

Synthesis, characterization and comparative biodistribution study of a new series of p-iodine-125 benzamides as potential melanoma imaging agents.

Iodobenzamides are reported to possess some affinity for melanoma. In order to identify the compound having the most appropriate pharmacokinetic properties as a potential melanoma imaging agent, thirteen new [125I]radioiodobenzamides with a butylene amide-amine spacer and various substituents on the terminal amino group were investigated. Their synthesis, radioiodination and biodistribution in B16 melanoma bearing C57BL6 mice are described and compared to [125I] labeled N-(2-diethylaminoethyl)-4-iodobenzamide ([125I]BZA), our reference compound. Changes in the terminal amino constituents induced modifications of lipophilicity, tumor uptake and organ distribution. The dimethylaminobutyl iodobenzamide appeared to be the most promising radiopharmaceutical imaging agent for the detection of melanoma and its metastases.

Animals↗
PubMed1999

Study of implanted biomaterial functionality by diphosphonate molecules labeled with radioactive 99mTc.

An implanted biomaterial can be transformed into young bone after some months, but it has not necessary reached full biofunctionality. Mineral concentration kinetics and crystal-structure studies, still being carried out in our group, are completed here by biofunctionality determinations. A natural coral is implanted in vivo at the cortical level of the femoral diaphyoff++ in rabbits. Diphosphonates molecules labeled with radioactive 99mTc are then injected in rabbits and the fixation of the radioactivity is analyzed in several sites for 8 mo after the implantation. Nuclear instruments and methods are used for the measurements. Four successive cycles of osseous remodeling are determined before reaching a biofunctional phase.

Animals↗
PubMed1999

Evaluation in mice of some iodinated melanoma imaging agents using cryosectioning and multi-wire proportional counting.

AMBIS 4000, a multi-wire proportional counter, was calibrated for iodine-125 measurements. The detector displayed a linear response over a wide dynamic range. Using whole-body mice cryosections, a linear relationship could be established between count rate per area (cpm/mm2) measured with the AMBIS 4000 detector and the count rate per gram (dpm/g) determined with an NaI(Tl) scintillation detector. A calibration curve could, thus be constructed. This new method allowed direct visual and quantitative evaluation of the biodistribution of a short series of 125I-labelled benzamides in melanoma-bearing mice. All the compounds studied showed good tumoral targeting ability. For one of them, ortho-N-(2-diethylaminoethyl)-4-iodobenzamide, liver and lung uptake decreased rapidly after dosing, making it a suitable tracer for scintigraphic detection of malignant melanoma.

Animals↗
PubMed1998

A new quantitative method to evaluate the biodistribution of a radiolabelled tracer for melanoma using whole-body cryosectioning and a gaseous detector: comparison with conventional tissue combustion technology.

Whole-body autoradiography (WBA) and multi-wire proportional counting allow for spatial imaging of the radioactive material present in the tissues and organs of dehydrated animal sections. AMBIS 4000 counting of whole-body cryosections offers a sensitive, accurate and reproducible novel method for the quantitative measurement of the tissue distribution of a [14C] radiopharmaceutical. Intensity of AMBIS 4000 counting (net cpm/mm2) and concentration of radioactivity (nCi/g) were linearly related, yielding a standard curve. Evaluating biodistribution (a) provides pharmacokinetic data for predicting the potential tissue deposition of an absorbed dose of radioactivity in man, and (b) allows visual and quantitative evaluation of radioactivity in small anatomical structures that otherwise could not be detected by conventional tissue combustion technology. This new method of WBA, coupled with AMBIS 4000 counting, should prove a valuable method for pharmacodynamic studies, and afford a predictive tool for nuclear medicine by assessing specific targeting of selected tissues.

Animals↗
PubMed1997

Tissue distribution and metabolism in rat of an ethynesulphonamide with filaricidal activity.

1. The tissue distribution and metabolism of a new filaricidal agent P903 (N-[(2-phenylethynyl)sulfonyl]morpholine) were studied in rat. 2. After s.c. administration of 14C and 13C P903, the Tmax in the blood was observed on day 2. Elimination was slow and > 95% was bound to protein. Radioactivity was distributed in the whole organism but particularly in erythrocytes and the lymphatic channel. Four days later, > 60% of the radioactivity was excreted in urine and faeces at equal amounts and 15% remained at the injection point. 3. In all biological fluids tested no P903 was found but only its metabolites. 4. One principal metabolite, the N-[(2-phenyloxo-2-ethane) sulphonyl] morpholine or oxosulphonamide was identified in blood, urine and faeces as compared with the reference compound by GC/MS and NMR. This latter molecule was detected following hydrolysis by hydrochloric acid but not with beta glucuronidase/sulphatase. 5. Unconjugated and conjugated oxosulphonamide represented > 85% of the radioactivity at all times tested in blood but only 38 and 35% respectively of urinary and faecal radioactivity on day 1 after the administration of the labelled drug. 6. Thus, P903 is rapidly converted to a reactive metabolite, probably an oxirene, which is then conjugated with endogenous components to form conjugated oxosulphonamide and an unknown metabolite. The role of this reactive metabolite in antifilarial activity seems to be very important in understanding the mechanism of action of P903.

Animals↗
PubMed1995

Synthesis, radiolabeling, and preliminary evaluation in mice of some (N-diethylaminoethyl)-4-iodobenzamide derivatives as melanoma imaging agents.

N-(2-Diethylaminoethyl)-4-iodobenzamide (BZA) is a radiopharmaceutical recently developed in our laboratory for the scintigraphic detection of melanoma and metastases. Optimal time for imaging was between 18-24 h p.i. of [123I] BZA. With a view to selecting compounds able to provide quality images shortly after the injection, synthesis of an initial series of BZA derivatives and their evaluation in B16 melanoma bearing mice have been carried out. The [125I] radiolabeled products were obtained by a simple isotopic exchange procedure with high radiochemical yields (85-95%). After i.v. administration of the compounds we observed a good tumoral targeting ability. Tumoral activity peaked at 2.6 to 7.70% injected dose per g within 1 h post-injection. One of the benzamides with a blood clearance faster than that of BZA--0.06 vs. 0.2% I D/g--6 h p.i. gave the same tumor to blood and to organ ratios as BZA at 12-18 h p.i. Based on these preclinical data we hope to obtain good tumoral images 6 h p.i. in scintigraphic studies in man.

Animals↗
PubMed1993

Disposition of stiripentol in the pregnant and non-pregnant female rat.

1. The disposition of stiripentol labelled with 14C and 3H on two positions has been studied in the pregnant and non-pregnant female rat after p.o. administration of a 200 mg/kg dose. 2. For both labelled species radioactivity was eliminated mainly in the faeces (69% within 72 h). Urinary excretion was rather low (22% within 72 h). No significant difference was found between the disposition of the two labelled species. 3. For both labelled species concentrations of radioactivity reached a plateau in the plasma and tissues between 1 and 6 h after administration. The liver, fat, mammary gland and adrenal gland were the most extensively-labelled organs. The affinity for the mammary gland was significantly greater in pregnant rats and for the adrenal gland was significantly greater in the non-pregnant rats. The fact that the concentration in the placenta was higher than in the foetus demonstrated that this membrane acts as a barrier for the penetration of the drug in the amniotic fluid. 4. Chromatographic analysis of the faeces and urine showed that an important portion of the dose remained unabsorbed through the gastrointestinal tract. The absorbed fraction undergoes an extensive first-pass metabolism involving mainly the oxidative cleavage of the methylenedioxy ring. Comparison with the results of other work conducted on the non-pregnant rat demonstrated that pregnancy did not affect the disposition and metabolic process.

Adrenal Glands↗
PubMed1991

An evaluation of four methods of root canal preparation using 14C urea.

One-hundred twenty single-rooted teeth were used in vitro in order to compare the four following methods of endodontic preparation: manual, Giromatic, MM 3000 Sonic Air with, and sonic air without the contact shaping technique. Each endodontic preparation was filled according to the McSpadden technique. Teeth were immersed in 14C urea. Radioactivity was evaluated qualitatively by autoradiography and quantitatively by scintigraphy. Data were statistically analyzed with a nonparametric test. The results show that the highest degree of leakage occurs with the manual method and that for the three other methods, maximum leakage takes place near the apices.

Dental Leakage↗
PubMed1987

Disposition of new sulphur-containing 2-(chloroethyl)nitrosoureas in rats.

N'-(2-Chloroethyl)-N-[2-(methylsulphinyl) ethyl] and N'-(2-chloroethyl)-N-[2-(methylsulphonyl) ethyl]-N and N'-nitrosoureas (CMSOEN1, CMSO2EN1, CMSOEN2 and CMSO2EN2) are new nitrosoureas derived from cysteamine. Two of them (CMSOEN2 and CMSO2EN2) have shown excellent efficacy against several murine tumours. The inactive agents (CMSOEN1 and CMSO2EN1) display low alkylating activity but high carbamoylating activity. In contrast, the active agents (CMSOEN2 and CMSO2EN2) are strong alkylating agents but relatively weak carbamoylators. The disposition of CMSOEN2 and CMSO2EN2 was studied in rat, using two differently labelled species of each compound, administered i.v. (60 mumol/kg). Plasma disappearance, tissue distribution (with the exception of the brain) and elimination of radioactivity are similar for the two compounds similarly labelled. In contrast, these parameters are strongly influenced by the label position used. Plasma disappearance of unchanged CMSOEN2 and CMSO2EN2 follows a first-order kinetic process with the same half-life for both compounds (30-31 min). More unchanged CMSO2EN2 is found in brain compared to its congener (55 nmol/g and 37 nmol/g respectively at five minutes). This is most likely the consequence of the higher lipophilic character of the former compound. The breakdown product 2-chloroethanol was identified in plasma.

Alkylation↗
PubMed1982

Metabolism of adiphenine. II. Identification of major excretion metabolites in rats.

1. Major metabolites isolated from rat urine after administration of a single dose of [14C]adiphenine or [3H]adiphenine were identified by chromatography and n.m.r. spectrometry, and by comparison with authentic reference compounds chemically synthesized. 2. Adiphenine was extensively metabolized by hydrolysis of the ester bond into diethylaminoethanol, diphenylacetic acid, diphenylacetic acid glucuronide and, in small quantities, the corresponding glycine and glutamine conjugates.

Animals↗
PubMedDate not supplied

Brain uptake of labelled adiphenine in rats.

This study describes the behaviour of a dual labelled drug, adiphenine, in the rat brain. Macroautoradiographies show images of the brain at different times after injection. Some of the tissue metabolites are identified at the brain level and the passage of the blood brain barrier is compared with tritiated water. The obtained data give very interesting indications on the blood brain distribution and on the metabolism at the brain level. Different techniques of high pressure liquid chromatography, macro- and histoautoradiographies allowed us to visualize how the drug is fixed on cerebral structures, giving indications on its mechanism of action. This fat soluble compound freely crosses the normal blood brain barrier and if labelled with the appropriate emittor could be very useful in nuclear medicine to obtain imaging of the brain.

Animals↗
PubMedDate not supplied

Adiphenine plasma levels and blood-brain barrier crossing in the rat.

Adiphenine was administered in 3H-labelled form in doses of 15 mumole/kg intravenously to male Wistar rats. Plasma and brain levels of the unchanged drug were measured. The elimination of the 3H-labelled compound from the plasma was monophasic with a half-life of 13 minutes. The unchanged drug was detectable in the plasma for 30 minutes after the injection. The time course of brain levels of unchanged drug paralleled that found in the plasma with a half-life of 9 to 12 minutes. In all experiments, brain and plasma levels of unchanged adiphenine correlate highly.

Animals↗
PubMedDate not supplied

Disposition and metabolism of O6-alkylguanine-DNA alkyltransferase inhibitor in nude mice bearing human melanoma.

Tumor resistances to chloroethylnitrosourea (CENU) are mainly due to O6-alkylguanine-DNA alkyltransferase (AGT). Our laboratory has synthesized a new water-soluble AGT inhibitor. O6-benzyl-N-acetylguanosine (BNAG). We have shown that this compound is able to deplete AGT activity on M4Beu human melanoma cells and to enhance the antitumor power of CENU N'-[2-chloroethyl]-N-[2-(methylsulfonyl)ethyl]-N'-nitrosourea (cystemustine) towards the M4Beu melanoma grafted on nude mice. With a view to determining the best combination BNAG/CENUs conditions, we have studied the distribution and metabolism of BNAG in nude mice bearing M4Beu human melanoma. BNAG, labelled with carbon-14 on the benzyl group, was administered by single i.v. dose of 40 mg/kg. Blood analysis showed that the main radioactive compound was unchanged molecule, and only a small part was found as hippuric acid resulting from the metabolic cleavage of the benzyl group. BNAG and hippuric acid were mainly eliminated in the urine. Unchanged BNAG blood kinetics showed three phases: blood epuration (t1/2 (1) = 13 min), reabsorption and elimination (t1/2 (2) = 1.7 hr). This kinetic profile is probably due to an enterohepatic cycle. BNAG is distributed in several tissues (kidney, liver, skin, duodenum, colon, tumor) but not in the central nervous system, suggesting a poor blood-brain crossing. Because an important part of the administered dose is not metabolized, high unchanged BNAG level remains in most tissues, including M4Beu tumor, and AGT depletion can occur several hours after dosing.

Animals↗
PubMedDate not supplied

Main urinary metabolites of two cysteamine-containing 2-(chloroethyl) nitrosoureas in rats.

Urine is the major route of excretion of N'-(2-chloroethyl)-N-[2-(methylsulfinyl)ethyl]-N'-nitrosourea (CMSOEN2), N'-(2-chloroethyl)-N-[2-(methylsulfonyl)ethyl]-N'-nitrosourea (CMSO2EN2), and their metabolites in the rat. Labeling the two compounds with 14C in three different positions facilitated their metabolic study in animals. The 14C-ethyl species were chosen in order to investigate the presence of unchanged compounds and that of the denitrosated forms. With the same 14C label position, we showed that isolated metabolites derived from this part of the molecule were degradation products of alkylated glutathione and/or cysteine. They are common to both CMSOEN2 and CMSO2EN2, namely thiodiacetic acid and its sulfoxide, the sum of which represents about half of urinary radioactivity. N-acetyl carboxymethylcysteine and N-acetyl hydroxyethylcysteine, accounting for approximately 6% to 7% of the eliminated 14C radioactivity, were also characterized. However, four minor metabolites corresponding to less than 10% of the excreted radioactivity remained unidentified. With the [14C]cysteamine and [14C]carbonyl labels related to the isocyanate moiety behavior, we indirectly showed that more than 60% to 70% of the excreted metabolites were carbamoylation products of endogenous substrates. A small amount of free amines, 2-methylsulfinylethylamine and/or 2-methylsulfonylethylamine, representing 15%-16% of the eliminated radioactivity, was also detected. The total data confirm the predominant function of glutathione and/or cysteine in the detoxifying system of the chloroethyl moieties and reveal the unexpected but important role played by carbamoylation reactions in the metabolic fate of the drug isocyanate moieties.

Animals↗