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M Debray

Publications and source records attributed to M Debray.

At least 37 records · Page 2Linked to original sources
PubMed1999

Age-induced cognitive alterations in OF1 mice.

Female OF1 mice aged 17-18 months were compared with female OF1 mice aged 7-11 weeks for locomotor activity, pain sensitivity, and cognitive performance using the Morris water maze, passive and active avoidance, and the elevated plus-maze learning protocol. Performance of old mice was impaired compared to those of young mice for both locomotor activity, pain sensitivity, and the four cognitive tests including the elevated plus-maze not previously used in studies on aging. Using complementary experiments and a detailed analysis of the results, we have shown that the reduction of learning and memory do not result from a decline of sensory and motor capacities. We conclude that female OF1 mice aged 17-18 months show true cognitive deficits.

Aging↗
PubMed1999

Diet deficient in alpha-linolenic acid alters fatty acid composition and enzymatic properties of Na+, K+-ATPase isoenzymes of brain membranes in the adult rat.

The effects of dietary (n-6)/(n-3) polyunsaturated fatty acid balance on fatty acid composition, ouabain inhibition, and Na(+) dependence of Na(+), K(+)-ATPase isoenzymes of whole brain membranes were studied in 60-day-old rats fed over two generations a diet either devoid of alpha-linolenic acid [18:3(n-3)] (sunflower oil diet) or rich in 18:3(n-3) (soybean oil diet). In the brain membranes, the sunflower oil diet led to a dramatic decrease in docosahexaenoic acid [22:6(n-3)] membrane content. The activities of Na(+), K(+)-ATPase isoenzymes were discriminated on the basis of their differential affinities for ouabain and their sensitivity to sodium concentration. The ouabain titration curve of Na(+), K(+)-ATPase activity displayed three inhibitory processes with markedly different affinity [i.e., low (alpha1), high (alpha2), and very high (alpha3)] for brain membranes of rats fed the sunflower oil diet, whereas the brain membranes of rats fed the soybean oil diet exhibited only two inhibitory processes, low (alpha1) and high (alpha2' = alpha2 + alpha3). Regardless of the diet, on the basis of the Na(+) dependence of Na(+), K(+)-ATPase activity, three isoenzymes were found: alpha1 form displaying an affinity 1.5- to 2-fold higher that of than alpha2 and 3-fold higher that of alpha3. In rats fed the sunflower oil diet, alpha2 isoenzyme exhibited higher affinity for sodium (Ka = 8.8 mmol/L) than that of rats fed the soybean oil diet (Ka = 11.7 mmol/L). These results suggest that the membrane lipid environment modulates the functional properties of Na(+), K(+)-ATPase isoenzymes of high ouabain affinity (alpha2).

Journal Article↗
PubMed1999

Single- and repeated-dose pharmacokinetics of intramuscular thiocolchicoside in healthy volunteers.

OBJECTIVE: The aim of this study was to investigate the pharmacokinetics and the accumulation and stationarity of thiocolchicoside after repeated intramuscular administration. METHOD: The pharmacokinetics of thiocolchicoside were studied in 6 healthy male volunteers after one single dose and repeated intramuscular doses of 4 mg twice a day for seven days. Plasma and urine samples were assayed for thiocolchicoside levels by a radioimmunoassay (RIA) using a cross-reacting colchicine-specific polyclonal antibody. The pharmacokinetic parameters between the first and the last days were compared using Student's t-test. RESULTS: Thiocolchicoside pharmacokinetic parameters, calculated after the single dose using non-compartmental analysis, were in good agreement with those obtained in previous studies. Following the repeated-dose regimen, the terminal half-life was not significantly different (2.7 (0.3) h) from that predicted from a single-dose (2.8 (0.2) h). The accumulation ratio, based on the repeated-dose/single-dose ratio of AUCtau was approximately 1.25. A decrease of CLT/f was found between day 1 (24.1 (5.2) l/h) and day 7 (19.9 (3.4) l/h), suggesting that moderate time-related alterations occur in the pharmacokinetics of thiocolchicoside, which may be due to a change in its CL(NR) (CL(R) was constant) or to the extent of bioavailability, explained by enterohepatic recirculation. CONCLUSION: Serum thiocolchicoside concentrations accumulated to steady-state when the drug was given twice a day for seven days and the pharmacokinetics were modified. But no adjustments of dose or dosing interval were necessary because the accumulation did not lead to marked change in the plasma levels.

Absorption↗
PubMed1999

Central nervous system involvement in Sjögren's syndrome: evidence from neuropsychological testing and HMPAO-SPECT.

OBJECTIVE: To investigate the clinical, neuropsychological and imaging manifestations of Sjögren's syndrome (SS), a chronic auto-immune disease with peripheral and central nervous system (CNS) involvement. DESIGN/METHODS: Fourteen female patients suffering from confirmed SS underwent within 2 weeks: neurological examination, immunological staging, brain MRI, brain 99m Tc-HMPAO SPECT, psychological evaluation and in-depth neuropsychological testing. RESULTS: All patients showed neuropsychological abnormalities. The cognitive symptoms were of the same type in all patients, mostly frontal lobe syndrome and memory problems. The neuropsychological involvement was not associated with other kinds of CNS involvement or MRI abnormalities, but accurately reflected HMPAO imaging results. CONCLUSIONS: The results of this study indicate that cognitive evaluation is the most sensitive clinical test to diagnose CNS involvement in patients with SS, and that CNS involvement in SS seems to be more frequent when systematically assessed by neuropsychological tests.

Adult↗
PubMed1998

Interspecies scaling of clearance and volume of distribution for horse antivenom F(ab')2.

F(ab')2 fragments are sometimes preferred to whole IgG for therapeutic or diagnostic uses. Preclinical pharmaceutical development studies are necessary before their use in humans. Here we propose an allometric approach among three mammalian species to predict F(ab')2 pharmacokinetic parameters in humans. Plasma disposition of horse antivenom F(ab')2 fragments labeled with iodine 125 was studied at a dose of 10 mg/kg i.v. in mice, rats, and rabbits. Using the allometric method, we demonstrate that the pharmacokinetic parameters that correlated with body weight were distribution volume (Vdc (ml) = 0.125 W0.87; Vdss (ml) = 0.251 W0.87; Vd beta (ml) = 0.290 W0.87, r2 = 1), total clearance (Cltot (ml/h) = 0.049 W0.53, r2 = 0.99), and terminal half-life (t1/2 beta (h) = 4.35 W0.33). The F(ab')2 plasma concentration-time data plotted as a complex Dedrick relationship were superimposable. Using these allometric techniques, Vdss, Vd beta, Cltot, and t1/2 beta were calculated as 4.12 liter, 4.78 liter, 19.07 ml/h, and 7.2 days, respectively, for a human subject of 70 kg body wt. Predicted human pharmacokinetic parameters were comparable for volume of distribution with the value reported by Hnatowich et al. (Cancer Res. 47, 6111-6117, 1987): 3.5 liter. However, the clearance was six-fold lower than values given by Hnatowich et al. (130 ml/h) and Ho et al.

Animals↗
PubMed1998

Absorption and elimination of viper venom after antivenom administration.

The mechanisms by which antivenom neutralizes the venom are still poorly understood. In the present work, we studied the effects of antivenom, constituted with either F(ab')2 or Fab, on the processes of absorption and elimination of Vipera aspis venom in experimentally envenomed rabbits. We first concluded from this study that during the few hours after intramuscular injection, the venom rapidly disappeared from the site of injection but did not immediately reach the vascular system, suggesting that it is partly absorbed via the lymphatic circulation. Concerning the elimination process of the venom in the presence of antivenom, we observed that the elimination of F(ab')2/venom complexes is slower than that of free venom in the absence of antivenom but faster than that of free F(ab')2, suggesting that F(ab')2/venom complexes are eliminated by phagocytosis. The Fab/venom complexes, on the other hand, are eliminated more slowly than free Fab. These complexes are not eliminated through the renal route in agreement with their high molecular weight. In addition, we observed that the treatment of envenomed rabbits with antivenom made of Fab, but not F(ab')2, is responsible for an oliguria that could be responsible for clinical problems.

Animals↗
PubMed1998

A cross-over pharmacokinetic study of a double viral inactivated factor IX concentrate (15 nm filtration and SD) compared to a SD factor IX concentrate.

A double blind randomized cross-over multi-center study has been conducted to compare the pharmacokinetic and coagulation activation markers of high-purity factor IX concentrate subjected to both solvent/ detergent (SD) treatment and 15 nm-filtration (FIX-SD-15) with the licensed product subjected only to solvent-detergent (FIX-SD). This filtration process allows the elimination of small particles, such as non-enveloped viruses (i.e., hepatitis A and parvovirus B19). Eleven severe hemophilia B patients (FIX coagulant activity <2 IU/dl) received one infusion of 60 IU/kg of FIX-SD and one infusion of 60 IU/kg of FIX-SD-15 at least at 10 days interval. Blood samples were obtained before and at various time up to 72 h after infusion. The decay curves of factor IX (FIX:C and FIX:Ag) were evaluated by a model independent method. Bioequivalence was found between the two concentrates using the Schuirmann test. The mean FIX:C and FIX:Ag recovery of FIX-SD-15 was 1.08 and 0.89 IU/dl/IU/kg respectively with a mean half-life of 33.3 h for FIX:C and 25.6 h for FIX:Ag. Six months after initial enrollment, pharmacokinetic parameters were similar in the 7 patients tested. There was no significant variation of prothrombin fragment 1+2 and thrombin-antithrombin complexes measured up to 6 h after infusion, indicating that there was no activation process after administration of FIX. In conclusion, these data demonstrate that the introduction of a 15 nm filtration does not alter the pharmacokinetic profile of a well characterized SD FIX concentrate while providing additional viral safety.

Adolescent↗
PubMed1997

Modulation of P-glycoprotein activity by glial factors and retinoic acid in an immortalized rat brain microvessel endothelial cell line.

P-glycoprotein (P-gp), a product of the multidrug-resistant (mdr) genes, is expressed in the endothelial cells of the blood-brain barrier (BBB). Effects of glial factors and retinoic acid (RA) on P-gp activity and level were investigated in the immortalized rat brain endothelial cell line RBE4, which expressed immunodetectable P-gp associated with a decrease in accumulation of the P-gp substrates, vinblastine and colchicine. When RBE4 cells were cultured either in the presence of C6-conditioned medium or on C6- or astrocyte-extracellular matrix, intracellular vinblastine and colchicine concentrations were decreased. When the cells were treated with RA, increases in P-gp activities were correlated with increases in P-gp levels. Effects of simultaneous treatments with glial factors and RA were studied in RBE4 cells cultured on astrocyte-extracellular matrix and were shown to be additive on P-gp activity and level. RBE4 cells may serve as a useful in vitro model for basic research on P-gp regulation at the level of the BBB.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Isolation impairs place preference conditioning to morphine but not aversive learning in mice.

Morphine (8-100 mg/kg IP) induces place preference conditioning in mice. The effect of two different periods of isolation (15 and 30 days) was examined. Mice isolated for 15 days but not 30 days exhibited place preference conditioning to morphine (8 mg/kg). After 30 days of isolation morphine could not induce place preference conditioning with the following doses (8, 16, 64, 100 mg/kg). Social regrouping of male mice previously isolated for 30 days with naive female mice for 15 or 30 days resulted in a reappearance of the conditioned place preference to morphine (16 mg/kg). The specificity of this associative deficit was examined by testing learning in isolated compared to non-isolated mice in two distinct settings: escape learning in the Morris water maze and passive avoidance acquisition and retention. On the Morris water maze isolated mice did not differ from non-isolated mice regarding place learning, the probe trial or extinction. Isolated mice were unimpaired in passive avoidance acquisition and retention. It was concluded that the deficits in place preference conditioning were not the result of a global learning impairment in isolated mice.

Analgesics, Opioid↗
PubMed1997

Effect of antivenom on venom pharmacokinetics in experimentally envenomed rabbits: toward an optimization of antivenom therapy.

Antivenomous immunotherapy is still used empirically. To improve the efficacy and safety of immunotherapy, we studied the effects of administering antivenom antibodies (F(ab')2) on the pharmacokinetics of the Vipera aspis venom in rabbits. Free venom levels were measured by enzyme-linked immunosorbent assay and total concentrations were quantified by measuring the radioactivity of trichloroacetic acid-precipitable radioiodinated venom. The intravenous infusion of 125 mg of antivenom 7 h after intramuscular injection with 700 microg x kg(-1) of V. aspis venom produced a redistribution of the venom antigens from the extravascular to the vascular space. Moreover, anti-venom antibodies were able to neutralize the totality of venom antigens in the vascular space, because no free plasma venom was detectable by enzyme-linked immunosorbent assay within 15 min after antivenom injection. Similar effects were obtained after injection of 25 mg of antivenom; however, the venom was only partially neutralized with lower doses (5 and 2.5 mg). We further established that intravenous injection is the most efficient route for antivenom administration, and we examined the effects of early and late immunotherapy. Finally, the efficacy of Fab antibodies was compared with that of F(ab')2; the plasma redistribution and the immunoneutralization of the venom were lower than those induced after injection of the same dose of F(ab')2. The difference between the effects of F(ab')2 and Fab could be explained by the differential pharmacokinetics of the two fragments.

Animals↗
PubMed1996

Interspecies scaling of clearance and volume of distribution for digoxin-specific Fab.

Digoxin-specific Fab are recognized to be effective in the treatment of acute cardiac glycoside poisoning but no pharmacokinetic studies have been performed in human volunteers. We thus propose an allometric approach among three mammalian species to predict Fab pharmacokinetic parameters in humans. Plasma disposition of digoxin-specific Fab was studied at a 20 mg/kg i.v. dose in mice, rats, and rabbits. Fab plasma concentration was determined by a sensitive and specific radioimmunoassay. Allometric equations showed that the pharmacokinetic parameters (distribution volumes (Vc (ml) = 0.084 W0.96; Vdss (ml) = 0.24 W0.96; Vd beta (ml) = 0.55 W0.96, r2 = 1), total body clearance (Cltot (ml/hr) = 0.61 W0.67, r2 = 0.999), and terminal half-life (t 1/2 beta (hr) = 0.63 W0.29) correlated with body weight. The Fab plasma concentration-time data plotted as a complex Dedrick relationship were superimposable. Using these allometric techniques, Vdss, Vd beta, Cltot and t 1/2 beta were calculated as 10.75 liter, 24.64 liter, 17.9 ml/min, and 16 hr, respectively, for a human subject of 70 kg body weight. These values are in accordance with those previously described in digoxin-Fab-treated patients (body weight = 61 +/- 3 kg, Vd beta = 24.9 +/- 3. 7 liter; Cltot = 20.8 +/- 2.1 ml/min; t 1/2 beta = 14.3 +/- 1.8 hr). Results indicate that the primary Fab pharmacokinetic parameters can be reasonably estimated in man using pharmacokinetic data from three animal species.

Animals↗
PubMed1996

Effect of dietary alpha-linolenic acid deficiency on habituation.

Three weeks before mating, two groups of SWISS OF1 mice were fed a diet that was similar but contained either peanut oil poor in alpha-linolenic acid [18:3(n-3)] (n-3 deficient = deficient mice = (n-3)-) or peanut + rapeseed oil rich in alpha-linolenic acid (n-3 nondeficient = controls = (n-3)+). Pups, fed the same diet as their dams, aged 45 to 62 days were used for brain lipid analysis and for behavioral experiments, aimed at determining whether there is a relation between the dietary intake of alpha-linolenate and a simple form of learning: habituation. The behavior of mice was compared using four models: exploration recorded in a photocell actimeter, activity in an open-field, duration of immobility in the forced swimming test and number of escape attempts from a small closed space. Habituation was measured by testing the mice in the same situation after some time had elapsed since the first test. Exploration in the photocell actimeter was significantly reduced between day 1 and 4 in nondeficient mice, but, not in deficient mice. The number of square crossings in the open-field was significantly reduced on the second test neither in the control nor in the deficient mice. In the forced swimming test, the habituation (increase in duration of immobility) was significantly greater (255%) in nondeficient than in deficient mice (163%). In the escape attempt experiment, the habituation showed a trend to be greater in controls than in deficient mice (p = 0.061) and was significantly greater in females than in males (p = 0.028). These results suggest that a simple form of learning, habituation, occurs more slowly in mice fed a diet deficient in alpha-linolenic acid.

Animals↗
PubMed1996

Effect of isolation on morphine-induced running and changes in body temperature.

1. The influence of isolation of three durations 8, 15 and 30 days has been examined in mice on the effects of morphine on rectal temperature and on locomotor activity. Isolated mice were compared to non isolated mice with the same age. 2. Morphine (20 mg/kg ip) induced in mice an early hypothermia followed by a late hyperthermia. The hypothermic effect was significantly reduced following isolation, but the duration of isolation (8, 15, 30 days) had no influence. Isolation did not modify the hyperthermic effect of morphine. 3. Morphine (40 mg/kg ip) induced in mice an increase in locomotor activity called "running". The running activity was significantly increased following isolation. The duration of isolation (8, 15, 30 days) did not seem to influence this effect. 4. These results show that isolation does not modify in the same way every effects of morphine, they suggest that isolation alters the mechanism involved in the running activity and in the hypothermic effect. The nature of these mechanisms is discussed.

Analysis of Variance↗
PubMed1996

Dose-dependent reversal of digoxin-inhibited activity of an in vitro Na+K+ATPase model by digoxin-specific antibody.

We investigated the potency of digoxin-specific Fab fragments to reverse digoxin-induced Na+K+ATPase inhibition in rat brain microsomes according to (a) the extent of initial inhibition of Na+K+ATPase and (b) the neutralizing dose of antibody. Mathematical analysis of the digoxin concentration-Na+K+ATPase inhibition curve supports the existence of 2 digoxin sensitive Na+K+ATPase isoforms. The IC50 was 1.3 x 10(-4) M and 2.5 x 10(-8) M for the low (alpha 1) and high (alpha 2) digoxin affinity isoenzyme, respectively. The reversal of digoxin-induced Na+K+ATPase inhibition was dependent on the digoxin-specific Fab concentration. The maximal effect was observed when the Fab:digoxin ratio was stoichiometrical and addition of an excess of antibodies did not result in a complete reversal of inhibition at the 4 digoxin concentrations studied. This simple and rapid in vitro model will be a useful tool to predict the efficacy of a new generation of antibodies.

Animals↗
PubMed1996

Changes in the execution of a complex manual task after ipsilateral ischemic cerebral hemispheric stroke.

OBJECTIVE: To analyze behavioral adaptation of hemiplegic patients performing a complex manual task without time constraint. It was postulated that ipsilateral motor disturbance could not be observed after a hemispheric stroke. DESIGN: Two manual tasks were used: (1) a new one, "Pig-Tail," required the patients to run a 3-cm-diameter copper ring in a wooden handle along a wavy copper wire without any time constraint; (2) the second task was the Nine-Hole Peg Test (NHPT). SETTING: A hospital department of rehabilitation. PATIENTS: A consecutive sample of 36 patients, who had all suffered an ischemic stroke in the middle cerebral artery territory, 18 with left hemisphere damage (LHD) and 18 with right (RHD), and who had similar ages (mean 54 +/- 13), stroke severity, time since stroke (mean 60 days), and functional independence according to the FIM. MAIN OUTCOME MEASURE: Main data were number of faults, time in seconds, and difference of time for two trials. Analysis compared the results with the same hand for patients and 86 healthy subjects. RESULTS: Patients scores for NHPT were worse than controls, whatever the side of the lesion (p < .05). For Pig-Tail, the number of faults by patients was greater than by controls (p < .05); time was higher for LHD, but not significantly, and was similar to controls for RHD. All patients and controls speeded up between the two trials. Although the RHD were clumsy, they were always faster than LHD patients. CONCLUSION: There are ipsilateral motor disturbances in a complex manual task after hemispheric stoke, even without a speed constraint, and regardless of the hemisphere damaged. Further studies are needed to examine speed control that seemed impaired by right hemisphere damage and could explain clumsiness in these patients.

Adaptation, Physiological↗
PubMed1996

Colonic ischemia reveals thromboangiitis obliterans (Buerger's disease).

Two years before the appearance of distal peripheral manifestations of thromboangiitis obliterans (Buerger's disease), a young man had acute peritonitis attributable to an ischemic perforation of the sigmoid colon. Only the histological examination of excised tissue was able to differentially diagnose this entity unambiguously.

Adult↗
PubMed1996

A dose-searching trial of an anti-LFA1 monoclonal antibody in first kidney transplant recipients.

25.3, a mouse IgG1 monoclonal antibody (MoAb), directed at the alpha chain of the LFA1 molecule (CD11a) has been used in prophylaxis of rejection in recipients of cadaveric kidney graft. Promising clinical results have been obtained for both tolerance and efficacy [1]. The aim of this trial was to determine the optimal dosage, base on a pharmacokinetic-pharmacodynamic analysis of the data obtained from the 15 patients included in this dose-searching study. Biological parameters, such as circulating levels and functional inhibition (as detected in an adhesion assay of patient lymphocytes), were measured during and after treatment. A Hill relation was calculated between the effect and the concentration measured and led us to select a 15 mg/day dose for further clinical trials, with a loading dose of 30 mg. An additional group receiving this protocol was submitted to the same calculation, and the results from this last group were in agreement with this previous analysis.

Adolescent↗