Low expression of ANT1 confers oncogenic properties to rhabdomyosarcoma tumor cells by modulating metabolism and death pathways.

Rhabdomyosarcoma (RMS) is the most frequent form of pediatric soft-tissue sarcoma. It is divided into two main subtypes: ERMS (embryonal) and ARMS (alveolar). Current treatments are based on chemotherapy, surgery, and radiotherapy. The 5-year survival rate has plateaued at 70% since 2000, despite several clinical trials. RMS cells are thought to derive from the muscle lineage. During development, myogenesis includes the expansion of muscle precursors, the elimination of those in excess by cell death and the differentiation of the remaining ones into myofibers. The notion that these processes may be hijacked by tumor cells to sustain their oncogenic transformation has emerged, with RMS being considered as the dark side of myogenesis. Thus, dissecting myogenic developmental programs could improve our understanding of RMS molecular etiology. We focused herein on ANT1, which is involved in myogenesis and is responsible for genetic disorders associated with muscle degeneration. ANT1 is a mitochondrial protein, which has a dual functionality, as it is involved both in metabolism via the regulation of ATP/ADP release from mitochondria and in regulated cell death as part of the mitochondrial permeability transition pore. Bioinformatics analyses of transcriptomic datasets revealed that ANT1 is expressed at low levels in RMS. Using the CRISPR-Cas9 technology, we showed that reduced ANT1 expression confers selective advantages to RMS cells in terms of proliferation and resistance to stress-induced death. These effects arise notably from an abnormal metabolic switch induced by ANT1 downregulation. Restoration of ANT1 expression using a Tet-On system is sufficient to prime tumor cells to death and to increase their sensitivity to chemotherapy. Based on our results, modulation of ANT1 expression and/or activity appears as an appealing therapeutic approach in RMS management.

Differences in prefrontal cortex GABA/glutamate ratio after acute restraint stress in rats are associated with specific behavioral and neurobiological patterns.

In patients suffering from stress-related pathologies and depression, frontal cortex GABA and glutamate contents are reported to decrease and increase, respectively. This suggests that the GABA and/or glutamate content may participate in pathological phenotype expression. Whether differences in frontal cortex GABA and glutamate contents would be associated with specific behavioral and neurobiological patterns remains unclear, especially in the event of exposure to moderate stress. We hypothesized that an increase in prefrontal cortex GABA/glutamate ratio would be associated with a blunted prefrontal cortex activation, an enhanced hypothalamo-pituitary-adrenocortical (HPA) axis activation and changes in behavior. Rats being restrained for 1-h were then tested in an open-field test in order to assess their behavior while under stress, and were sacrificed immediately afterward. The GABA/glutamate ratio was assessed by (1)H high-resolution magic angle spinning magnetic resonance spectroscopy ((1)H-HRMAS-MRS). The neurobiological response was evaluated through prefrontal cortex mRNA expression and plasma corticosterone levels. The stressed rats were distributed into two subgroups according to their high (H-G/g) or low (L-G/g) GABA/glutamate ratio. Compared to the L-G/g rats, the H-G/g rats exhibited a decrease in c-fos, Arc, Npas4, Nr4a2 mRNA expression suggesting blunted prefrontal cortex activation. They also showed a more pronounced stress with an enhanced rise in corticosterone, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), creatine kinase (CK) and lactate dehydrogenase (LDH) levels, as well as behavioral disturbances with decreased locomotion speed. These changes were independent from prefrontal cortex energetic status as mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK) pathway activities were similar in both subpopulations. The differences in GABA/glutamate ratio in the frontal cortex observed in the stressed animals may participate in shaping individual differences in psychophysiological reactions.

Interaction of the malonyldialdehyde molecule with membranes. A differential scanning calorimetry, 1H-, 31P-NMR and ESR study.

The membrane interactions of malonyldialdehyde (MDA), natural product of polyunsaturated fatty acids peroxidation were investigated by differential scanning calorimetry, and ESR or NMR spectroscopy. This component is located in the superficial part of the bilayer, where it increases the local fluidity. High concentrations of MDA induce major membrane damage. Similar consequences of MDA-membrane interactions were observed on erythrocyte ghosts.

Association between hospital-acquired infections and patients' transfers.

OBJECTIVE: To assess the risk of nosocomial infection in transferred patients and to determine whether transfer is only a risk marker or is independently associated with nosocomial infection. DESIGN: Retrospective analysis. SETTING: A 400-bed general hospital in the Paris area. PATIENTS: All the patients hospitalized on the days of the surveys were included. METHODS: Epidemiological analysis of data collected in four annual nosocomial infection prevalence surveys conducted between 1993 and 1996. RESULTS: Of the 1,326 patients included in the four surveys, 70 (5.3%) had been transferred from another hospital and 199 (15.0%) from another ward of our hospital. Transferred patients more frequently had known risk factors of nosocomial infection: age >65 years (P<10(-5)), a length of hospital stay >7 days on the day of the survey (P<10(-6)), at least one invasive procedure (34.2% vs 27.2%; P<.05), a recent surgical intervention (P<.05), and an immunosuppression (P<.01). The prevalence rate of infected patients was 6.7% (95% confidence interval, 5.3-8.1). The risk of being infected on a given day was more than 4 times higher in transferred patients (P<10(-6)); however, the risk was similar between patients transferred from another hospital (20.0%) and patients transferred within the hospital (17.1%). The multivariate analysis performed by logistic regression showed that intrahospital transfer, a length of hospital stay >7 days, and having had at least one invasive procedure were independent risk factors of infection. CONCLUSION: According to this study, patient transfer is both a risk marker (associated with several known risk factors) and independently associated with nosocomial infection. The origin of a transferred patient is readily known at admission. It would be useful to adopt specific measures for such patients, particularly if they have other risk factors of nosocomial infection, both to protect them and to prevent transmission of the infection to other hospitalized patients.

Pharmacokinetics of cyclophosphamide (CP) and 4-OH-CP/aldophosphamide in systemic vasculitis.

Cyclophosphamide given in association with corticosteroids has markedly improved the prognosis of systemic vasculitis. Little information has been reported on cyclophosphamide pharmacokinetics in these diseases and data evaluating its metabolite, 4-hydroxycyclophosphamide/aldophosphamide, pharmacokinetics and concentrations are lacking. Cyclophosphamide was administered as a 1-h intravenous infusion every 3 weeks for six cycles to ten vasculitis patients. Serum cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide concentrations were assayed on the first cycle of the treatment by reversed-phase high-pressure liquid chromatography with ultraviolet detection. The mean (+/- SD) 4-hydroxycyclophosphamide/aldophosphamide and cyclophosphamide areas under the serum concentration-time curves were, respectively, 1.86 +/- 1.12 and 154.1 +/- 62.7 mg/L x h with a ratio of 1.30 +/- 0.76%. The mean maximum serum 4-hydroxycyclophosphamide/aldophosphamide was reached 2.3 h after cyclophosphamide administration. The mean (+/- SD) cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide half-lives were, respectively, 5.5 +/- 3.1 and 7.6 +/- 2.3 h. The results are consistent with those obtained for cancer patients, in spite of a wide interpatient variability of concentrations and pharmacokinetic parameters.

Comparison of two methods to obtain a desired first isepamicin peak in intensive care patients.

A randomized multicenter study in intensive care unit (ICU) patients, evaluated the capacity of a Bayesian method to obtain an optimal first isepamicin (ISP) peak of 80 mg/L in comparison to a fixed loading dose (LD). Patients (n=236) over 18 years of age were enrolled from 6 September 1997 to 17 July 1999 and randomly assigned to received ISP in a calculated dose (CD) or a loading dose (LD) of 25 mg/kg body weight. The CD was estimated using a specific population model with Bayesian methodology implemented in the PKS program (Abbott PKS, Abbott Diagnostics, Rungis, France). The data required included age, body weight, height, gender and serum creatinine. ISP disposition is described by a one-compartment model. Blood samples were drawn 1 and 24 h after the start of infusion for fluorescence polarization immunoassay measurement of serum ISP concentrations. The predictive performance was assessed by computing bias and precision. Peak concentrations were significantly higher in CD group than the LD group (84.2 +/- 28.6 vs. 74.7 +/- 24.1 mg/L, respectively; P=0.008), but trough levels were comparable. The optimal ISP peak was attained by a significantly higher percentage of CD patients (P=0.018), and by significantly more CD patients on mechanical ventilation (P=0.025), and with simplified acute physiological scores (SAPS) > 35 (P=0.002). Pharmacokinetic parameters were similar for the two groups with large interindividual variations. Mean (+/- SD) volume of distribution of ventilated patients (72%) was significantly higher than of nonventilated patients (23.31 +/- 7.35 vs. 20.60 +/- 6.30 L, respectively; P=0.001). No relationship was found between the volume of distribution and SAPS. Total clearance was significantly correlated with estimated CLCR (creatinine clearance) (P=0.0001). Precision (RMSE) is better for CD than for LD strategy, respectively 27.96 and 28.66 mg/L. The Bayesian method was significantly more accurate and performed particularly well in ventilated patients and patients with high SAPS, compare to an LD of 25 mg/kg to obtain a first ISP peak of 80 mg/L in ICU patients. Therefore, a fixed dose of 28.5 mg/kg would be also adequate to reach a peak of 80 mg/L.

Pharmacokinetics of glafenine and glafenic acid in patients with cirrhosis, compared to healthy volunteers.

Pharmacokinetic parameters were evaluated in 12 patients with alcoholic cirrhosis and 12 healthy volunteers after a single 400 mg oral dose of glafenine. Glafenine (G) and its major active metabolite glafenic acid (GA) were measured at regular intervals using a specific high performance liquid chromatographic method. Glafenine absorption was significantly delayed in cirrhotic patients (CP) (Tmax = 2.8 +/- 1.3 hvs 1.5 +/- 0.4 h, p less than 0.01) and was dramatically reduced in 3 patients. The large hepatic 'first pass' effect observed in healthy volunteers was markedly reduced in CP (ratio Cmax GA/Cmax G = 3.6 +/- 2.9 vs 18.9 +/- 9.8, p less than 0.001; ratio areas under the curves AUC GA/AUC G = 2.3 +/- 2.3 vs 18.2 +/- 11.2, p less than 0.001). The elimination half-life of G was prolonged in the CP (13.0 +/- 13.1 h vs 1.5 +/- 0.5 h, p less than 0.01). In CP, GA elimination half-life was increased (12.0 +/- 13.4 h vs 4.3 +/- 1.3 h, NS) but the difference did not reach statistical significance because of large variability. The significant rise of G plasma concentrations (Cmax = 2.2 +/- 2.1 mg/L vs 0.7 +/- 0.2 mg/L, p less than 0.05) and its longer half-life would lead to an accumulation if the usual dosage regimen was prescribed for CP and could result in nephrotoxicity. On the other hand, lower dosage would be ineffective because only GA is active and nephrotoxic. Hence, G should be given with great caution to CP.

Pharmacokinetics of vidarabine in the treatment of polyarteritis nodosa.

The pharmacokinetics of vidarabine were studied in 8 patients with polyarteritis nodosa related to hepatitis B virus infection. The drug was administered by continuous infusion for three weeks at doses of 15 (1 week) and 7.5 (2 weeks) mg/kg per day, during which time 15 plasma exchanges were performed. Plasma was assayed for vidarabine and its principal metabolite, hypoxanthine arabinoside by high pressure liquid chromatography. Vidarabine was not detected in the plasma of any patients. Hypoxanthine arabinoside levels were used to evaluate vidarabine kinetics. The serum levels of hypoxanthine arabinoside ranged from 3.6 to 21.5 mg/l. The mean elimination half-life (+/- SD) was 3.0 +/- 1.7 h. The plasma clearance (mean +/- SD) was 195 +/- 270 ml/min when the dose was 7.5 mg/kg per day and 66.3 +/- 47 ml/min for a 15 mg/kg per day/dose (NS). Except for the elimination half-life, these results were not fully consistent with those observed in other studies. The influence of multiple plasma exchanges on vidarabine kinetics is limited and dosage adjustment is not required based on the continuous infusion of vidarabine.

Pharmacokinetics of cyclophosphamide in patients with systemic necrotizing angiitis.

Cyclophosphamide pharmacokinetics were investigated following administration to patients with systemic necrotizing angiitis. Ten patients (eight women and two men) received cyclophosphamide as a 1-h-rate-constant intravenous infusion at doses ranging from 600 to 1200 mg. All patients received concomitant oral prednisone (1 mg/kg/d). Blood samples were collected at the end of drug infusion and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h later. Serum cyclophosphamide concentrations were assayed by high pressure liquid chromatography. The peak serum cyclophosphamide levels ranged from 15.7 to 29.4 mg/L. The mean cyclophosphamide elimination half-life was 6.2 +/- 1.3 h (mean +/- SD). The mean apparent volume of distribution and mean total plasma clearance were, respectively, 0.75 +/- 0.22 L/kg (mean +/- SD) and 83 +/- 22 mL/min (mean +/- SD). These results obtained in systemic vasculitic diseases were consistent with those observed in other studies with cancer patients receiving comparable doses of cyclophosphamide.

Mechanism of alpha-cyclodextrin-induced hemolysis. 1. The two-step extraction of phosphatidylinositol from the membrane.

It has been suggested that the interaction of cyclodextrins with the lipid components of the erythrocyte membranes is the determining factor in the hemolysis induced by these cyclic oligosaccharides. In the case of alpha-cyclodextrin (cyclomaltohexose), phospholipids have been identified as the cell target. In our study, evidence for the interaction between alpha-cyclodextrin and different phospholipids has been obtained using synthetic membranes. Since phosphatidylinositol (PI) showed the strongest affinity for alpha-cyclodextrin, it has been selected to investigate the respective contributions of the polar head group and the aliphatic chains to the association process using 31P, 2H, and 1H NMR spectroscopy. In this work, we describe the two-step extraction of PI from the membrane following its association with alphaCD: a cyclodextrin molecule is first attracted to the membrane surface by electrostatic remote interactions and associates with the lipid head group. Then the whole PI molecule is extracted, and inclusion of its unsaturated sn-2 acyl chain into another alphaCD molecule occurs in the bulk.

Mechanism of alpha-cyclodextrin induced hemolysis. 2. A study of the factors controlling the association with serine-, ethanolamine-, and choline-phospholipids.

A nuclear magnetic resonance (NMR) spectroscopy and molecular modeling study of the interaction between alpha-cyclodextrin (alpha-CD) and phospholipids with serine, ethanolamine, or choline headgroups is presented. The experimental approach is based on 31P and 1H NMR measurements on small unilamellar vesicles (SUV), multilamellar systems (MLV), and aqueous suspensions of lipids using a direct complex preparation with alpha-CD. Molecular dynamics computer simulations are used to investigate the trajectory of alpha-CD in the vicinity of a membrane surface and the influence of the charge and dipole moment of the phospholipid headgroups. These factors of charge and orientation of dipole moment seem to play a key role in the interaction of phospholipids with alpha-CD and reflect very well the experimentally observed selectivity of the phospholipid -alpha-CD approach. However, with this approach, there is no evidence for the formation of a complex with the phospholipid headgroup (except for phosphatidylinositol) that results from electrostatic forces. Rather, after a possible extraction of the lipid from the membrane, a classical inclusion of the sn-2 chain in the cavity of alpha-CD occurs. This step depends on the alkyl chain length and saturation state of the lipids as well as on their organization (i.e., as vesicles or dispersions). Based on our results, chemical modifications of the alpha-CD molecule to control the hemolytic properties of alpha-CD are discussed.

Synthetic pyridopurines derived from food pyrolysis products: intercalation, interactions with membranes, cyclodextrin complexation, and biological mitogenic properties.

Crucial conditions for the pharmacological use of active compounds are their ability to cross the biological barriers and reach their intracellular target. In the case of two antiviral pyridopurine derivatives, 1 and 2, this included essentially the membranes and the nucleic acids. Thus the interactions of 1 and 2 with model membranes and oligonucleotides were studied using NMR spectroscopy. It was found that these hydrophobic molecules can be incorporated into the model membranes at the terminal methyl group level, inducing dynamic perturbations in the bilayer. In the presence of the synthetic oligonucleotide ACATGT, both molecules can intercalate aspecifically in AT and GC systems. Inclusion complexes of 1 and 2 beta-cyclodextrins with a 1:1 stoichiometry, were also prepared. This led to to propose two galenic forms 1 and 2, i.e. included in phospholipid vesicles in the form of a beta-cyclodextrin complex

Pharmacokinetics of paracetamol, diclofenac and vidarabine during plasma exchange.

In order to establish guidelines for prescribing drugs in patients treated with plasma exchange (PE), we studied the pharmacokinetics of paracetamol (5 patients), diclofenac (4 patients) and vidarabine (3 patients) during one or several PE. Results were compared with those obtained without PE. Diclofenac and paracetamol were chosen because they presented different volume distribution and protein binding characteristics. Vidarabine was studied because we use it for the treatment of patients with polyarteritis nodosa related to hepatitis B virus. Diclofenac (100 mg) and paracetamol (1000 mg) were given 1 hour before PE. Samples were obtained 60 and 30 min before PE, every 15 min during PE and hourly for 2 hours after the end of PE. Vidarabine was given in continuous infusion, 15 mg/kg/d during the first week of treatment and 7.5 mg/kg/d during subsequent weeks. Samples were obtained before PE, 3 times during PE and every 30 min for 4 hours after the end of PE. Paracetamol, diclofenac, vidarabine and hypoxanthine arabinoside were assayed by high performance liquid chromatography. During each PE 60 ml/kg were removed and replaced by albumin. We found that 17% of diclofenac, 4.3% of paracetamol and 4.9% of vidarabine were removed during each session. Plasmapheresis clearance was 51% of plasma clearance for diclofenac, 15% for paracetamol and 10% for vidarabine. Drugs which are mainly removed during PE are those which are bound to proteins with a small distribution volume. Those drugs, such as diclofenac, must be administered after the end of each PE session. Drugs which present a large distribution volume and low protein binding can be given before the session. Vidarabine can be administered during PE without loss of effectiveness due to drug removal.

Digoxin Toxicity : Evaluation in Clinical Practice with Pharmacokinetic Correlations.

OBJECTIVE: To evaluate digoxin pharmacokinetic parameters using Bayesian estimation in 60 patients, and to identify factors that appeared to affect the risk of digoxin toxicity. PATIENTS AND METHODS: 60 patients with serum digoxin concentrations were evaluated retrospectively. We collected demographic, clinical and laboratory data, and information on concurrent medications and clinical and electrocardiographic features of digoxin toxicity. The incidence of digoxin toxicity was evaluated in 50 patients. Serum digoxin concentrations were measured with fluorescence polarisation immunoassay Individual pharmacokinetic parameters were estimated by Bayesian method using Abbottbase Pharmacokinetic Systems. RESULTS: Signs of digoxin toxicity were present in 23 patients (46%). Patients without signs of digoxin toxicity had a significantly lower mean serum digoxin concentration than patients with signs, 1.99 ± 0.9 µg/L vs 2.7 ± 1.5 µ.g/L, respectively (p = 0.047). Patients with serum digoxin concentrations >2.2 µg/L differed significantly from those with values ≤2.2 µg/L, respectively, for the following parameters: age (82.0 ± 8.0 vs 72.0 ± 16.0 years; p = 0.005), serum creatinine levels (133.0 ± 55.0 vs 106.0 ± 26.0 µmo1/L; p = 0.012), bodyweight (57.4 ± 12.8 vs 69.2 ± 17.8kg; p = 0.01), volume of distribution (208.5 ± 89.5 vs 315.7 ± 91.2L; p = 0.0001), total clearance (1.60 ± 0.65 vs 3.4 ± 1.5 L/h; p = 0.0001), and elimination half-life (94.2 ± 28.6 vs 72.4 ± 16.7h; p = 0.001). Estimation of optimal dose showed that the doses recommended in intoxicated patients should be 3.5 times lower to reach the therapeutic range. CONCLUSION: Digoxin concentrations were higher in patients with toxicity. Older age enhanced the risk of digoxin toxicity. Monitoring digoxin concentrations may help to confirm suspected digitalis toxicity.

Clinical pharmacokinetics during plasma exchange.

Drug removal during plasma exchange (PE) is a complex phenomenon that is defined by the molecule pharmacokinetic characteristics. Plasma-protein binding and the volume of distribution (Vd) are two kinetic parameters that strongly affect the efficiency of drug removal by PE. The effect of PE on drug kinetics has been specifically studied with antivirals, cardiotonic agents, antibiotics, corticosteroids, antalgics, anti-epileptic agents and non-steroidal anti-inflammatory drugs. This effect can be evaluated using different parameters: extracorporeal clearance, half-life, amount eliminated, and fraction of the drug removed. The estimated fraction eliminated (Fe) from the body by PE is the best parameter to evaluate the effectiveness of the exchange procedure; it can account for 0.5-30 per cent. Results reported in the literature showed that PE most influences drugs with a low Vd, regardless of the extent of protein binding. We established that, during PE, there is a linear relationship between Fe and the fraction of the drug in extracellular fluids. The fraction eliminated during PE is approximately one-seventh of the fraction of the drug in extracellular fluids. We propose to use this extracellular fraction as a predictive index: when < 20, extraction is low; the amount eliminated becomes consequential only when the index > 20. Dosage supplementation may be needed to maintain an adequate drug concentration in the body. Practically, for drugs with a low Vd (< 0.3 l/kg), it seems necessary to adjust the dosage.

[Extraction of drugs in plasma exchange]. / Extraction des médicaments au cours des échanges plasmatiques.

Plasma exchange has been proposed for treating diseases mediated by circulating immune complexes. Removal of drugs during plasma exchange is a complex function of pharmacokinetic characteristics and specifications of the plasma exchange procedure: the time of plasma exchange, the filtered volume of plasma, the number of procedure. The effect of plasma exchange on the kinetics of drugs can be evaluated by different parameters: amount eliminated, extracorporeal clearance, fractional drug removal, extracorporeal elimination rate constant. Knowledge of the impact of plasma on the elimination of drugs is essential to the design of the dosage regimen in patients treated with plasma exchange. The fraction of the estimated amount in body removed by plasma exchange is the best parameter to evaluate the effectiveness of the exchange procedure, but it is necessary to know the proportion of body pool of drug at the start of the plasma exchange. Drug recovery by each exchange may account for 0.5%-30% of the dose. Controlled studies are needed to quantify the effects of plasma exchange on drug therapy. Dosage adjustment is sometimes required.

[Impact of medical prescription computerisation on the incidence of adverse drug effects]. / Impact d'une prescription médicale informatisée sur la réduction du mésusage thérapeutique.

INTRODUCTION: Adverse drug effects are a significant public health problem. Prescription errors are responsible for a significant proportion of these adverse effects. METHODS: We have aimed to improve the link between generation of and interpretation of a prescription through computerisation. The prescription sheet, which is generated daily, was organised to allow care planning without the need to re-copy out treatments on the sheet. A prescription aid was available which was based on a core group of drugs commonly used in our respiratory service. The aim of the study was to compare the various types of errors observed during 6 weeks of computerized prescriptions (229 files) to a retrospective series of handwritten prescriptions of the service at an identical time (184 files) the previous year. The case-mix was identical for both analysed periods. RESULTS: The total number of technical prescribing errors in the 1,599 handwritten lines (49.27% error) was significantly higher (p<0.001) than the 1,805 computerized prescriptions lines (42.88% error). The errors of copying (p<0.001), eligibility (p<0.001) and incorrect spelling (p<0.05) were the main sources of error which were significantly reduced by computerisation. CONCLUSION: Computerised prescription is likely to reduce the incidence of prescribing errors and adverse drug effects.

[Demonstration of molecular combinations of alpha cyclodextrin (ACD) with dioctanoyl glycerol]. / Mise en évidence des associations moléculaires des alpha cyclodextrines (ACD) avec le dioctanoyl glycérol.

The molecular association of dioctanoyl glycerol (DOG) with the natural alpha cyclodextrin molecule (ACD) was studied using small unilamellar vesicles (SUV) by proton and 13C NMR. While no classic inclusion complex was found, a molecular association exists, leading to the formation of an insoluble precipitate. The possibility of a polar head group implication is discussed about the dimyristoyl phosphatidyl choline model.

[Interaction between 4-hydroxynonenane with membrane system. 1H, 31P, 2H NMR study]. / Interaction du 4-hydroxynonénane avec les systèmes membranaires. Etude RMN du 1H, 31P et 2H.

The interactions between membranes and 4-hydroxynonenane (HNE)-a natural product of polyinsatured fatty acids peroxidation-were investigated by NMR spectroscopies. This molecule is located in the intermediate part of the bilayer. The presence of the HNE induces an increase of the fluidity in the deep part of the membrane, while a rigidification of the superficial part is found.

[Substituted cyclodextrins as chelating reagents for ethers, thioethers and yperite]. / Etude des cyclodextrines substituées comme agents cryptants des éthers, thioéthers et de l'ypérite.

The complexation of mustard gas Cl(CH(2))(2)S(CH(2))(2) Cl, HD, yperite) and of ethers and thioethers derivatives by cyclodextrins: natural alpha-cyclodextrin (ACD) and substituted B-cyclodextrins was studied by NMR. A 1/1 stoechiometry was found in all cases, while affinity constants were found relatively weak (from 5 M(-1) to 100 M(-1)). However, these results show that chelation of HD by cyclodextrins can be reasonably expected, especially if chemical modifications provide stronger affinity constants.