Biomedical subjects

F Huguet

Publications and source records attributed to F Huguet.

At least 19 recordsLinked to original sources

PubMed2006

[Epidermoid carcinomas of anal canal treated with radiation therapy and concomitant chemotherapy (5-fluorouracil and cisplatin)].

PURPOSE: To evaluate our results after radiation therapy and concomitant chemotherapy in terms of local control, survival and toxicity in patients with anal cancer. METHODS AND PATIENTS: Between November 1990 and January 2002, 60 patients (pts) were treated with radiation therapy and concomitant chemotherapy. The T-stage according to the 2001 UICC classification were: 2 T1, 26 T2, 25 T3, and 7 T4. There were 20 pts with nodal involvement at presentation. The treatment started with external beam RT (median dose: 45 Gy) and concomitant chemotherapy using 5-fluorouracil and cisplatin during the first week and the fifth week of external beam RT (EBRT). After a rest period of 4 to 6 weeks, a boost of 20 Gy was delivered by EBRT in 58 pts and by interstitial (192)Ir brachytherapy in 2 pts. Mean follow-up were 78.5 months. RESULTS: At the end of RT with concomitant chemotherapy local tumor clinical complete response rate was 83%. Out of 10 non responders or local progression, 5 (50%) were salvaged with abdominoperineal resection (APR). Out of 5 local tumor relapses, 3 were salvaged with APR. The overall local tumor control (LC) rate with or without salvage local treatment were 88%. LC rate with a good anal function scoring (score 0 and 1) was 70%. Among 43 pts who preserved their anus, 98% had a good anal function scoring. The 5-year disease-free survival was 75%. After multivariate analysis, 2 independent predicting factors significantly influenced the disease-free survival: HIV-positive pts (negative vs positive, P=0.032) and clinical tumor response after the first course of radiotherapy (<50% vs >or=50%, P=0.00032). Acute grade 2 or 3 toxicities were low: haematological toxicity in 4 pts and intestinal complication corresponding to diarrhea in 10 pts. Late severe complication was observed in 3 pts: 2 pts with painful necrosis of the anus requiring colostomy and 1 pt with grade 3 rectal bleeding. CONCLUSION: We confirm the good results with RT and concomitant chemotherapy. The clinical tumor response after the first course of RT and concomitant chemotherapy is probably the most important predictive factor on the disease-free survival. For patients with T3 or T4 lesion and tumor regression <or=50% after the first course of radiation therapy, surgical non conservative treatment should be discussed.

Adult↗

PubMed2006

Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study.

Adult patients with acute lymphoblastic leukemia (ALL) and t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4 have a poor outcome. We have evaluated the impact of an intensified post-remission therapy using a high-dose chemotherapy course followed by allogeneic or autologous SCT on the outcome of 58 patients with t(1;19)/E2A-PBX1 (E2A group, n=24) or t(4;11)/MLL-AF4 (MLL group, n=34) treated in the LALA-94 multicenter prospective study. Patients in the MLL group had higher WBC counts and more frequent DIC. CR rates achieved by MLL and E2A groups were similar to other B-cell ALL (87, 82 and 86% respectively). While in CR, patients with a donor were assigned to alloSCT (n=22), the remaining patients with were randomized between autoSCT (n=15) or chemotherapy (n=8). Five-year overall survival was 31 and 45% for E2A and MLL groups, respectively. In both groups, DFS was higher in the alloSCT arm as compared to autoSCT and chemotherapy arms. The results of this study show that chemotherapy intensification did not overcome the poor prognosis of adults with t(1;19)/E2A-PBX1. Allogeneic SCT should thus be offered in first CR to patients with t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4. New therapeutic approaches are needed for patients without donor.

Adolescent↗

PubMed2006

High-dose imatinib mesylate combined with vincristine and dexamethasone (DIV regimen) as induction therapy in patients with resistant Philadelphia-positive acute lymphoblastic leukemia and lymphoid blast crisis of chronic myeloid leukemia.

Imatinib combined with high-dose chemotherapy is now becoming the gold standard for treatment of Philadelphia chromosome-positive acute leukemias. However, in all studies imatinib dosage was tapered to 400-600 mg per day. We decided to initiate a clinical trial to evaluate an opposite strategy based on high-dose imatinib (800 mg per day) combined with a less intensive chemotherapeutic regimen (vincristine and dexamethasone), which we called the DIV induction regimen. Thirty-one patients (18 relapsing or refractory Ph+ acute lymphoblastic leukemias and 13 lymphoid blast crisis chronic myelogenous leukemias) were enrolled. Complete remission (CR) was obtained in 28 out of 30 assessable patients. The median bcr-abl/abl ratio after the induction course was 0.1%. Median time to neutrophil recovery was 21 days. Fungus infections were observed in six patients out of 31 and possibly related to dexamethasone. Neuropathy due to vincristine was noted in 14 cases. Nine out of 19 patients under 55 years received allogenic stem cell transplantation after a median time of 78 days post-CR. Patients older than 55 years experienced a 90% CR rate without additional toxicities, suggesting the DIV regimen may also be proposed as a front line therapy in older patients.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

[Radiation oncology training in France: demography, analysis of motivations of the young specialists, evaluation of the training].

During the 5 past national courses organised by the French society of radiation oncology (SFRO), three different types of survey were performed to analyse demography, motivations and quality of training of the young specialists. During the 5 past years, 50 radiation oncologists were training for the whole country (about 15 per year were graduated). A recent increase the number of young specialists is observed with a total number of 50 in 2000 to 75 in 2005. Nevertheless, the number of young specialists is dramatically insufficient and exposes for the future to an important demographic crisis. Analysis of motivations of choice for radiation oncology confirms the influence of a practical stage of oncology during the second cycle of the medical studies for 60% of the young specialists. Analysis of practical and theoretical training was performed according to the point of view and living experiences of the students. On the other hand, informations from teachers were less complete. Some needs are emphased as: 1) the quality of the follow during the training (importance of the recent implementation of a logbook); 2) importance of theoretical and practical training at the radiotherapy department; 3) help and incentive for research and scientific publication.

Demography↗

PubMed2005

A new recurrent inversion, inv(7)(p15q34), leads to transcriptional activation of HOXA10 and HOXA11 in a subset of T-cell acute lymphoblastic leukemias.

Chromosomal translocations with breakpoints in T-cell receptor (TCR) genes are recurrent in T-cell malignancies. These translocations involve the TCRalphadelta gene (14q11), the TCRbeta gene (7q34) and to a lesser extent the TCRgamma gene at chromosomal band 7p14 and juxtapose T-cell oncogenes next to TCR regulatory sequences leading to deregulated expression of those oncogenes. Here, we describe a new recurrent chromosomal inversion of chromosome 7, inv(7)(p15q34), in a subset of patients with T-cell acute lymphoblastic leukemia characterized by CD2 negative and CD4 positive, CD8 negative blasts. This rearrangement juxtaposes the distal part of the HOXA gene cluster on 7p15 to the TCRbeta locus on 7q34. Real time quantitative PCR analysis for all HOXA genes revealed high levels of HOXA10 and HOXA11 expression in all inv(7) positive cases. This is the first report of a recurrent chromosome rearrangement targeting the HOXA gene cluster in T-cell malignancies resulting in deregulated HOXA gene expression (particularly HOXA10 and HOXA11) and is in keeping with a previous report suggesting HOXA deregulation in MLL-rearranged T- and B cell lymphoblastic leukemia as the key factor in leukaemic transformation. Finally, our observation also supports the previous suggested role of HOXA10 and HOXA11 in normal thymocyte development.

Adolescent↗

PubMed2003

Therapy-related acute promyelocytic leukemia.

PURPOSE: To analyze patient cases of therapy-related acute promyelocytic leukemia (tAPL), occurring after chemotherapy (CT), radiotherapy (RT) or both for a prior disorder, diagnosed during the last 20 years in three European countries. PATIENTS AND METHODS: The primary disorder and its treatment, interval from primary disorder to tAPL, characteristics of tAPL, and its outcome were analyzed in 106 patients. RESULTS: Eighty of the 106 cases of tAPL were diagnosed during the last 10 years, indicating an increasing incidence of tAPL. Primary disorders were predominantly breast carcinoma (60 patients), non-Hodgkin's lymphoma (15 patients), and other solid tumors (25 patients). Thirty patients had received CT alone, 27 patients had received RT alone, and 49 patients had received both. CT included at least one alkylating agent in 68 patients and at least one topoisomerase II inhibitor in 61 patients, including anthracyclines (30 patients), mitoxantrone (28 patients), and epipodophyllotoxins (19 patients). Median interval from primary disorder to tAPL diagnosis was 25 months (range, 4 to 276 months). Characteristics of tAPL were generally similar to those of de novo APL. With treatment using anthracycline-cytarabine-based CT or all-trans-retinoic acid combined with CT, actuarial survival was 59% at 8 years. CONCLUSION: tAPL is not exceptional, and develops usually less than 3 years after a primary neoplasm (especially breast carcinoma) treated in particular with topoisomerase II-targeted drugs (anthracyclines or mitoxantrone and less often etoposide). Characteristics and outcome of tAPL seem similar to those of de novo APL.

Adult↗

PubMed2002

Treatment of acute lymphoblastic leukemia in the elderly: an evaluation of interferon alpha given as a single agent after complete remission.

Although interferon (IFN) has been used in elderly patients with acute lymphoblastic leukemia (ALL), the benefits from IFN therapy have not been properly assessed, especially as it was given combined with other cytotoxic drugs, which obscured the role of IFN if any. In 1997, we started a study aimed at improving our previous results in elderly patients with ALL and at assessing the therapeutic role of IFN in this disease. Fifty-eight patients with ALL, aged 55-81 years (median: 64.9 years), were randomly allocated to treatment with vindesine or vincristine during induction. After a first consolidation course, IFN was administered as a single agent for three months together with cranial radiotherapy. Chemotherapy was then resumed with a second consolidation course and maintenance. A complete remission (CR) was obtained in 58% of patients (CI: 45-71%), significantly less than in our previous study which included IFN combined with chemotherapy during maintenance (CR: 85%, CI:70-94%, p = 0.007). Overall survival (median: 289 vs 434 days in the previous study, p = 0.01) and disease-free survival (median: 146 vs 427 days, p = 0.009) were also inferior in the present study. In particular, the pattern of relapses over time suggested that the 3 month IFN treatment phase with no additional chemotherapy might have contributed to the comparatively poor outcome of this cohort. In addition, vindesine given during induction did not prove less neurotoxic than vincristine, did not improve the CR rate, and had no impact on survival. In conclusion, although similar to published studies in elderly patients with ALL, this study is inferior to our previous one. INF, given as a single drug, has a modest role if any in the treatment of older persons with ALL.

Aged↗

PubMed2001

A new in vitro approach for investigating the MPTP effect on DA uptake.

Previous studies have shown that dopamine (DA) uptake was decreased after preincubation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP(+)) in in vitro slice and synaptosome models. The present study, conducted with and without preincubation, attempted to determine whether inhibition results from a direct effect of neurotoxins on neuronal DA transporter or from an alteration of the transporter secondary to other toxic events. DA uptake was inhibited about 50% in the presence of MPTP+O(2) or MPP(+) (0.1, 1 and 5 mM) in rat striatal slices and synaptosomes. Such inhibition was obtained in synaptosomes preincubated for 150 min with MPP(+) and then washed. Inhibition of DA uptake was lower in slices preincubated with MPTP (5 mM)+O(2) and then washed (30%). Experiments in synaptosomes prepared from slices preincubated with MPTP or MPP(+) showed greater inhibition of DA uptake with MPTP. The results suggest that the inhibition of DA uptake in vitro by MPTP or MPP(+) results initially from a direct effect on the transporter during its penetration in nerve endings and subsequently from a transporter alteration related to toxic events. Thus, the preincubation of striatal slices followed by DA uptake measurement in synaptosomes would appear to be a good in vitro model for studying the dopaminergic toxicity of MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2001

Ultrastructural study of rat hippocampus after chronic administration of aluminum L-glutamate: an acceleration of the aging process.

An ultrastructural study of rat hippocampus was performed on young (group 1) and old (group 4) rats receiving daily subcutaneous injections of aluminum L-glutamate and on old untreated rats (group 5). Young controls were treated with sodium L-glutamate (group 2) and physiological saline (group 3). Group 1 showed vacuolated astrocytes with numerous lipofuscin deposits, mitochondrial swelling, a thinning of the myelin sheath, and many multivesicular bodies invading the cytoplasm. Cellular structure did not appear to be affected in groups 2 and 3. Group 4 showed swollen mitochondria, a demyelination process in axonal regions, sizable perivascular oedema with vessel retraction and gliofilament bundles. In this group, lipofuscin deposits in astrocytes were associated with multivesicular bodies that thinned the myelin sheath to the breaking point; however, no excitotoxic glutamate-induced effects were observed. In group 5, extreme cytoplasmic vacuolation was observed, with massive mitochondrial swelling, considerable thinning of the myelin sheath (at times to the breaking point), sizable vacuolar degeneration and gliofilament bundles. These results indicate that ultrastructural alterations in the hippocampus, such as cell vacuolization, massive mitochondrial swelling and the demyelination process, occur with aging and independently of aluminum intoxication. Similar alterations were observed in aluminum L-glutamate-intoxicated young rats, but not in controls. These results are consistent with aluminum-induced acceleration of the aging process.

Aging↗

PubMed2000

Treatment of relapsing acute promyelocytic leukemia by all-trans retinoic acid therapy followed by timed sequential chemotherapy and stem cell transplantation. APL Study Group. Acute promyelocytic leukemia.

The purpose of this study was to assess the safety and efficacy of stem cell transplantation (SCT) mainly autologous SCT as consolidation therapy in APL patients who relapsed and achieved a second complete remission (CR2). Fifty adult patients with a first relapsed APL, of whom 39 had been previously treated with ATRA, entered a multicenter trial of oral ATRA until complete remission (CR) achievement followed by timed sequential chemotherapy (EMA combining etoposide 200 mg/m2/day for 3 days, mitoxantrone 12 mg/m2/day for 3 days, and cytarabine 500 mg/m2/day for two sequences of 3 days). EMA was started either after CR achievement, or on day 1 of ATRA because of initial white blood cell (WBC) counts >5 x 10(9)/l, or rapidly added to ATRA in order to prevent ATRA syndrome because WBC count increased under ATRA. Forty-five patients (90%, 95% CI 78%-97%) were in CR after induction therapy. Five patients died from infection during aplasia following EMA chemotherapy. Eleven patients who achieved CR had a familial HLA-identical donor and were allografted. The median disease-free survival (DFS) of allografted patients was 8.2 months. The 34 other CR patients were scheduled for autologous peripheral blood (PB) SCT (intent-to-treat group). Actually, autologous transplantation was only carried out in 22 patients (65%) (17 PBSCT and five autologous bone marrow transplantation (BMT)). Reasons for not autografting were early relapse (three patients), severe toxicity of EMA chemotherapy (six patients), and refusal or failure of stem cell harvest (three patients). The 3-year DFS rate of patients actually autografted was 77%. Among the 17 autografted patients still in CR2, nine patients have already reached a longer CR2 than first CR (CR1). Results of detection of PML/RARalpha by RT-PCR after autologous transplantation show negative findings in eight of the nine patients tested. We conclude that (1) ATRA combined to EMA chemotherapy is effective in the treatment of relapsed APL; (2) allogeneic BMT may be too toxic after salvage treatment including EMA intensive chemotherapy; (3) clinical outcome of autografted patients and preliminary molecular results regarding detection of PML/RARalpha after autologous PBSCT are encouraging.

Adult↗

PubMed2000

Additional chromosomal abnormalities in patients with acute promyelocytic leukaemia (APL) do not confer poor prognosis: results of APL 93 trial.

In spite of the recent improvement in the outcome of acute promyelocytic leukaemia (APL) with treatment combining all trans retinoic acid (ATRA) and chemotherapy (CT), some patients with this disease still have a poor outcome. The prognostic significance of chromosomal abnormalities in addition to t(15;17) in APL is uncertain. We examined the prognostic significance of secondary chromosomal changes in 292 patients included in a European trial who were treated with ATRA and CT. The incidence of chromosomal abnormalities in addition to t(15;17) was 26% and trisomy 8 was the most frequent secondary change (46% of the cases with secondary changes). No significant differences were seen with regard to age, sex, initial white blood cell count, % of circulating blasts, platelet count, fibrinogen level and incidence of microgranular variants between patients with or without additional rearrangements. Outcome was also similar between patients with t(15;17) alone and patients with t(15;17) and other clonal abnormalities for complete remission (92% vs. 93% respectively), event-free survival at 2 years (76.1% vs. 78.1% respectively), relapse at 2 years (16.7% vs. 11.6% respectively) and overall survival at 2 years (79.9% vs. 79.5% respectively). Analysis according to the type of induction treatment (ATRA followed by CT or ATRA plus CT) or the type of maintenance treatment (with ATRA, low-dose CT or both) also failed to show any difference between the two groups. Thus, in a large cohort of APL patients treated with ATRA and CT, additional chromosomal abnormalities had no impact on prognosis.

Adult↗

PubMed1999

Origin of 4-hydroxynonenal incubation-induced inhibition of dopamine transporter and Na+/K+ adenosine triphosphate in rat striatal synaptosomes.

Previous experiments reported that an incubation of striatal synaptosomes with 4-hydroxynonenal (4-HNE) resulted in an inhibition of dopamine (DA) uptake and Na+/K+ adenosine triphosphate (ATPase) activity. The present work investigated whether theses inhibitions are related to a 4-HNE binding to the DA transporter (DAT) and the Na+/K+ ATPase. The number of specific [125I]-PE21 binding sites on the DAT was significantly reduced after incubation with 4-HNE. The Na+/K+ ATPase activity decrease induced by 4-HNE was partially reversed, in a dose-dependent manner, by veratridine, a pump stimulator agent. Our previous data (Morel, P., Tallineau, C., Pontcharraud, R., Piriou, A. and Huguet, F., Effects of 4-hydroxynonenal, a lipid peroxidation product, on dopamine transport and Na+/K+ ATPase in rat striatal synaptosomes. Neurochem. Int., 33 (1999) 531-540) combining with the data observed in this study suggest that changes in DA uptake in striatal synaptosomes are directly related to 4-HNE binding to the DAT, whereas the decrease in Na+/K+ ATPase activity resulted only partially from 4-HNE binding to the pump and is mainly secondary to membrane lipid disruption.

Adenosine Triphosphatases↗

PubMed1999

A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group.

All transretinoic acid (ATRA) followed by daunorubicin (DNR)-AraC chemotherapy (CT) has improved the outcome of acute promyelocytic leukemia (APL) by comparison to CT alone. In a randomized trial, (1) we compared 2 induction schedules (ATRA followed by CT [ATRA-->CT] and ATRA plus CT [ATRA+CT, with CT added on day 3 of ATRA treatment]) and (2) we assessed the role of maintenance treatment. Four hundred thirteen patients </=75 years of age and with newly diagnosed APL were included. Induction treatment was stratified on white blood cell (WBC) count and age: patients </=65 years of age and with an initial WBC count of </=5,000/microL (n = 208) were randomized between ATRA-->CT and ATRA+CT (initially randomized patients); patients with a WBC count greater than (high WBC count group, n = 163) and patients 66 to 75 years of age with a WBC count greater than 5,000/microL (elderly group, n = 42) were not initially randomized and received ATRA+CT from day 1 and ATRA -->CT, respectively. All patients achieving CR received 2 additional DNR-AraC courses (only 1 in patients 66 to 75 years of age) and were then randomized for maintenance between no treatment, intermittent ATRA (15 days every 3 months) for 2 years, continuous low-dose CT (6 mercaptopurine + methotrexate) for 2 years, or both, using a 2-by-2 factorial design. Overall, 381 (92%) of the patients achieved complete remission (CR), 31 (7%) suffered an early death, and only 1 patient had leukemic resistance. ATRA syndrome occurred in 64 patients (15%) and was fatal in 5 cases. The CR rate was similar in all induction treatment groups. Event-free survival (EFS) was significantly lower in the high WBC group (P =.0002) and close to significance in the elderly group (P =.086) as compared with initially randomized patients. Relapse at 2 years was estimated at 6% in the ATRA+CT group, versus 16% in the ATRA-->CT group (P =.04, relative risk [RR] =.41). EFS at 2 years was estimated at 84% in the ATRA+CT group, versus 77% in the ATRA-->CT group (P =.1, RR =.62). Two hundred eighty-nine patients were randomized for maintenance. The 2-year relapse rate was 11% in patients randomized to continuous maintenance CT and 27% in patients randomized to no CT (P =.0002) and 13% in patients randomized to intermittent ATRA and 25% in patients randomized to no ATRA (P =.02). An additive effect of continuous maintenance CT and intermittent ATRA was seen, and only 6 of the 74 patients who received both maintenance treatments had relapsed. Overall survival was improved in patients who received maintenance CT (P =.01), and there was a trend for better survival in patients who received maintenance ATRA (P =.22). Our findings strongly suggest that early addition of chemotherapy to ATRA and maintenance therapy combining continuous CT and intermittent ATRA can reduce the incidence of relapse in APL. This effect already translates into significantly better survival for maintenance treatment with continuous CT.

Adolescent↗

PubMed1999

Lactic acid-induced increase of extracellular dopamine measured by microdialysis in rat striatum: evidence for glutamatergic and oxidative mechanisms.

Striatal lactacidosis was induced by direct lactic acid perfusion to obtain a local pH as close as possible to that observed in ischemia. In a previous study we showed that such lactacidosis produces a diphasic increase in extracellular dopamine (DA). The present work investigated whether DA accumulation is related to a glutamatergic mechanism and/or production of reactive oxygen species (ROS) in the striatum. Concentrations of extracellular DA, glutamate and hydroxyl radicals ((.)OH) were measured in the presence or absence of an N-methyl-D-aspartate (NMDA) receptor blocker (dizocilpine, MK-801) or an antioxidant (Trolox). Measurements were performed using high-performance liquid chromatography (HPLC) with electrochemical and fluorimetric detection on samples obtained by an in vivo microdialysis perfusion technique and stored at -80 degrees C. The increase in lactic acid-induced DA was entirely suppressed by MK-801 and Trolox. Lactacidosis also induced an increase in extracellular glutamate and (.)OH concentrations at the same time as the first DA accumulation, as well as another (.)OH accumulation which preceded and accompanied the second DA concentration peak. Glutamate release was totally inhibited by MK-801 or Trolox. The first peak of (.)OH production was completely suppressed by MK-801 and Trolox, but the second one was only suppressed by Trolox. These data showed that the increase in DA induced by lactic acid was related to glutamatergic excitotoxicity and ROS production, suggested that the kinetic of events was different for the two DA accumulations.

Acidosis, Lactic↗

PubMed1999

Origin of extracellular dopamine increase induced by lactic acid striatal perfusion monitored by microdialysis in the awake rat.

In previous studies we showed that a striatal lactic acid perfusion-induced lactacidosis produces a diphasic increase in extracellular dopamine (DA). In the present study, different pharmacological reagents were used to determine the origin of accumulated DA. Our data show that both DA accumulations were totally suppressed by tetrodotoxin and nicardipine, indicating a relationship with membrane depolarization and a Ca(2+)-dependent effect. The first DA peak was largely reduced by a specific inhibitor of DA uptake such as GBR-12935, and the second was totally suppressed by tyramine and reserpine and lowered and delayed by GBR-12935. These results compared to data in the literature suggest that the first increase in extracellular DA resulted mainly from a release of cytosolic DA by reversal of the DA transporter, while the second was mainly due to a release of vesicular DA by exocytosis. These data indicate that lactic acid perfusion helps clarify the mechanisms involved in this process and could be useful for the study of new treatments against the hyperactive dopaminergic reaction occuring during ischemia.

Adrenergic Uptake Inhibitors↗

PubMed1999

Chronic administration of aluminium L-glutamate in young mature rats: effects on iron levels and lipid peroxidation in selected brain areas.

Clinical and experimental studies have demonstrated the neurotoxicity of aluminium (Al), notably as a result of lipid peroxidation in vitro. We previously showed that Al is able to cross the blood-brain barrier as an L-glutamate complex and be deposited in rat brain. The present work in young mature rats investigated the in vivo effects of chronic Al-L-glutamate treatment on Al and iron movement in plasma and selected brain regions. Brain lipid peroxidation was determined by evaluating the production of thiobarbituric acid reactive substances (TBARS) and analysing polyunsaturated fatty acids (PUFAs) such as C20:4n-6 and C22:6n-3. Our results indicate that iron concentration was decreased in plasma and that Al accumulated especially in striatum where iron levels were decreased and in the hippocampus where TBARS were increased without PUFA modifications. These data show that Al administered chronically as an L-glutamate complex is neurotoxic in vivo and thus provides a good model for studying Al toxic mechanisms.

Aluminum↗

PubMed1999

Pharmacokinetic-pharmacodynamic contributions to the convulsant activity of fluoroquinolones in rats.

The in vivo convulsant activities in rats of five representative fluoroquinolones (FQs), norfloxacin, enoxacin, sparfloxacin, fleroxacin, and pefloxacin, were compared. The experimental approach allowed distinction between the drugs' ability to reach the pharmacological receptors at the level of the central nervous system (pharmacokinetic contribution) and their ability to interact with these receptors (pharmacodynamic contribution). The presence of a methyl group on the piperazine moiety decreased the pharmacodynamic contribution to the convulsant activity by severalfold, and the ratios of concentrations of the FQs in cerebrospinal fluid (CSF) to concentrations of unbound FQs in plasma varied from about 5 to 75% as a function of lipophilicity. Interestingly, FQs with the highest intrinsic convulsant activities had the lowest levels of diffusion in CSF and vice versa. This in vivo approach provides information complementary to that of in vitro experiments and should be recommended for early preclinical assessment of a new FQ's epileptogenic risk.

Animals↗

PubMed1999

[Tox-Didact:CD-ROM for toxicology education. Value in hospital toxicology].

New teaching techniques should allow students more independence in their training, particularly in learning from problems and using clinical reasoning. We designed Tox-Didact, a modular multimedia educational software program, which is suitable for both students and professionals, regardless of their orientation (pharmacy or medicine) or level. Each module concerns four domains: diagnosis, biological monitoring, curative treatment and prevention. Tox-Didact is multidisciplinary, interactive, simple to use and reliable. Nineteen modules are now being prepared. In final form, Tox-Didact will cover all the acute and chronic pathologies of toxicology.

CD-ROM↗