Complexation study of the anticancer agent EO-9 with 2-hydroxypropyl-beta-cyclodextrin.

For the development of a bladder instillation of the indoloquinone agent EO-9, use of the complexing agent 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) was considered. Therefore, a complexation study of EO-9 with HPbetaCD was performed. Complexation was studied in aqueous solution and in solid freeze-dried products. A phase solubility study, UV-visible spectroscopy (UV/VIS), and analysis of the effect of HPbetaD on the stability of EO-9 were performed. With the phase solubility study, a complexation constant (K1:1) of 32.9, a complexation efficiency (CE) of 0.0457, and a utility number (UCD) of 38.3 were calculated. These K1:1 and CE values indicate a weak complex, but the UCD shows that HPbetaCD can be very useful as solubilizer in the desired formulation. Furthermore, a positive effect of HPbetaCD on the chemical stability of EO-9 in solution was seen. Subsequently, complexation in the freeze-dried products was studied more thoroughly using Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and scanning electron microscopy (SEM) analyses. HPbetaCD was found to be an excellent pharmaceutical complexing agent for application in formulations for EO-9 bladder instillations. Reconstitution before use of the developed freeze-dried products can be simply accomplished with water for injection.

[The Incidence of occupational asthma in Alsace from 2001 to 2002. Results of intensification of the ONAP project in Alsace (2001-2002). Regional specificities]. / L'asthme professionnel en Alsace: quelques particularités régionales. Résultats de l'intensification locale de l'ONAP en 2001-2002.

INTRODUCTION: A national surveillance programme (ONAP project) was created in France in 1996 by two professional societies to estimate the incidence and identity the characteristics of occupational asthma. MATERIALS AND METHODS: In 2001 and 2002 chest physicians and occupational physicians in Alsace were intensively solicited for better voluntary reporting of cases of occupational asthma. The objective of this study was to evaluate the consequences of such a procedure on the number of cases reported, with a view to collecting comprehensive data. RESULTS: The mean annual incidence of occupational asthma was estimated at 126 cases per million workers with a female predominance (52.4%). Flours and isocyanates represented 40% of the suspected agents. Isocyanate asthma (21% of the total) was reported mainly in workers in the car supply industry, and seems to be a specific feature of the region. Persulfates represented 5.3% of the cases; latex and aldehydes 2.6%. The study also points to emergent aetiologies and work risks, i.e. quaternary ammonium compounds in disinfecting detergent products used by cleaners and healthcare workers. CONCLUSION: This study, which allowed better assessment of the real incidence of OA in Alsace and better detection of substances and occupations at risk, is an incentive to continue our Surveillance programme.

Dynamics of the mammalian sperm plasma membrane in the process of fertilization.

Sexual reproduction requires the fusion of sperm cell and oocyte during fertilization to produce the diploid zygote. In mammals complex changes in the plasma membrane of the sperm cell are involved in this process. Sperm cells have unusual membranes compared to those of somatic cells. After leaving the testes, sperm cells cease plasma membrane lipid and protein synthesis, and vesicle mediated transport. Biophysical studies reveal that lipids and proteins are organized into lateral regions of the sperm head surface. A delicate reorientation and modification of plasma membrane molecules take place in the female tract when sperm cells are activated by so-called capacitation factors. These surface changes enable the sperm cell to bind to the extra cellular matrix of the egg (zona pellucida, ZP). The ZP primes the sperm cell to initiate the acrosome reaction, which is an exocytotic process that makes available the enzymatic machinery required for sperm penetration through the ZP. After complete penetration the sperm cell meets the plasma membrane of the egg cell (oolemma). A specific set of molecules is involved in a disintegrin-integrin type of anchoring of the two gametes which is completed by fusion of the two gamete plasma membranes. The fertilized egg is activated and zygote formation preludes the development of a new living organism. In this review we focus on the involvement of processes that occur at the sperm plasma membrane in the sequence of events that lead to successful fertilization. For this purpose, dynamics in adhesive and fusion properties, molecular composition and architecture of the sperm plasma membrane, as well as membrane derived signalling are reviewed.

Nuclear fragmentation cross-sections of 400 A MeV 36Ar and 40Ar in collisions with light and heavy target nuclei.

We have measured fragmentation cross-sections of Ar projectile nuclei at beam energy of 400 A MeV using experimental set-ups with plastic nuclear track detectors and different targets. In this paper total charge changing cross-sections and elemental fragmentation cross-sections for the production of fragments with charges ZF > or = 7 in interactions with H, C, Al, Cu, Ag and Pb target nuclei are presented. The dependence of the cross-sections on the fragment charge number and target charge number are discussed. The experimental results are compared to predictions of semi empirical cross-section models.

Rhodoquinone is synthesized de novo by Fasciola hepatica.

Most adult parasitic helminths have an anaerobic energy metabolism in which fumarate is reduced to succinate by fumarate reductase. Rhodoquinone (RQ) is an essential component of the electron transport associated with this fumarate reduction, whereas ubiquinone (UQ) is used in the aerobic energy metabolism of parasites. Not known yet, however, is the RQ and UQ composition during the entire life cycle nor the origin of RQ in parasitic helminths. This report demonstrates the essential function of RQ in anaerobic energy metabolism during the entire life cycle of Fasciola hepatica, as the amount of RQ present reflected the importance of fumarate reduction in various stages. We also studied the origin of RQ, as earlier studies on the protozoan Euglena gracilis suggested that RQ is synthesized from UQ. Therefore, in parasitic helminths RQ might be synthesized by modification of UQ obtained from the host. However, we demonstrated that in F. hepatica adults RQ was not produced by modification of UQ obtained from the host but that RQ was synthesized de novo, as (i) the chain-length of the quinones of F. hepatica adults was not related to the chain length of the quinone of the host, (ii) despite many attempts we could never detect any in vitro conversion of UQ9 into RQ9 or into UQ10, neither by intact adult flukes nor by homogenates of F. hepatica adults and (iii) F. hepatica adults used mevalonate as precursor for the synthesis of RQ. We also showed that the rate of quinone synthesis in F. hepatica adults was comparable to that in the free-living nematode Caenorhabditis elegans. These results prompted the suggestion that RQ is synthesized via a pathway nearly identical to that of UQ biosynthesis: possibly only the last reaction differs.

GC-MS procedure for the analysis of zipeprol.

A sensitive and specific quantitative method for the determination of zipeprol, a newly abused antitussive, in human fluids is described. Zipeprol and an internal standard, levallorphan, are isolated by a basic extraction and back-extraction process. The final extract is derivatizated with BSTFA + 1% TMCS and separated on a 12-m HP-1 capillary column. Drugs are detected by selected ion monitoring at m/z 335 and m/z 355 for zipeprol and the internal standard, respectively. The minimum detectable quantities are 0.6 and 0.4 ng ml-1, for zipeprol in plasma and urine, respectively. Relative standard deviations for within-run data are less than 6%.

Repeated measurements of aldicarb in blood and urine in a case of nonfatal poisoning.

A nonfatal case of poisoning involving aldicarb, an extremely toxic carbamate pesticide, is presented. A 39-year-old female ingested an unknown amount of aldicarb, together with alprazolam and sertraline. On admission to ICU (T0), she displayed marked cholinergic symptoms and a deep coma. The patient was given pralidoxime and atropine. Her condition gradually improved on days 2 and 3 and she was discharged at T0+80 h. Aldicarb was assayed by high-performance liquid chromatography on 21 blood and 8 urine samples successively taken during hospitalization. At the same time, serum pseudocholinesterase activity was followed on 21 successive samples. Blood aldicarb level was 3.11 microg/mL at T0 and peaked at T0+3.5 h (3.22 microg/mL), then followed a two-slope decay with a terminal half-life of ca. 20 h. Aldicarb was detected in all urine samples (peak level: 6.95 microg/mL at T0+31.5 h) and was still present at the time of discharge. Serum pseudo-cholinesterase activity remained low (< or = 10% of normal) until the 30th hour then rapidly increased and returned to normal after the 60th hour. The patient's clinical picture closely followed blood aldicarb levels and serum pseudo-cholinesterase activities. To our knowledge, this is the first report of an aldicarb poisoning documented by repeated measurements of the drug in the intoxicated person.

Dynamics in the membrane organization of the mammalian sperm cell and functionality in fertilization.

The capacitation process of sperm cells involves complex changes in the composition and orientation of molecules at the surface of the sperm cell. Here we focus on the lipid architecture in the sperm plasma membrane and demonstrate that the sperm plasma membrane is not static but is an extremely dynamic structure. Advanced fluoroscopic techniques enabled continuous monitoring of lipid organization in living cells and extremely rapid lipid movements were observed. The orientation of lipids in the sperm plasma membrane changed under capacitative treatments, was found to be sensitive for temperature and also changed upon binding of sperm cells to the zona pellucida. The changes in membrane properties coincided with an activation of protein kinases resulting in tyrosine phosphorylation of specific plasma membrane proteins. The detected membrane changes relate to intrinsic membrane properties such as fluidity, permeability, adhesiveness and fusibility. We think that these results may provide a physiological basis for new assays, able to discriminate between functional and non-physiological sperm cells.

Energy spectra of HZE-particles inside the International Space Station.

To measure the energy spectra of low energy ions inside the International Space Station (ISS) we will expose three stacks of CR-39 plastic nuclear track detectors aligned to the three coordinate axes of the space station. The energies of cosmic ray nuclei at the stack surfaces can be determined by reconstructing the trajectories of ions stopping inside the detector material and by measuring their ranges. To measure only HZE (high charge Z and energy E) ions with charges of Z6 stopping in our experiment a special batch of CR-39 detectors with low sensitivity will be used. This detector material has been already tested by an exposure to carbon ions at the GSI accelerator in Darmstadt, Germany.

Energy spectrum of iron nuclei measured inside the MIR space craft using CR-39 track detectors.

We have exposed stacks of CR-39 plastic nuclear track detectors inside the MIR space craft during the EUROMIR95 space mission for almost 6 months. Over this long period a large number of tracks of high LET events was accumulated in the detector foils. The etching and measuring conditions for this experiment were optimized to detect tracks of stopping iron nuclei. We found 185 stopping iron nuclei inside the stack and identified their trajectories through the material of the experiment. Based on the energy-range relation the energy at the surface of the stack was determined. These particles allow the determination of the low energy part of the spectrum of iron nuclei behind shielding material inside the MIR station.

[Accidental ingestion of a battery]. / Ingestion accidentelle d'une pile électrique.

A case of accidental battery ingestion by a three-year old boy is reported. The possible complications are local (i.e. necrosis of tissues by leakage of the alkaline electrolyte, by electrical injury or by impaction of the battery) and general (mercury poisoning). Large diameter batteries impacted in the oesophagus need prompt removal. When the battery is located in the stomach, two attitudes are discussed: some authors allow it to progress through the gastrointestinal tract spontaneously under radiological control, others recommend rapid removal by endoscopy or surgery in order to avoid the complications above described.

[Acute poisoning during substitution therapy based on high-dosage buprenorphine. 29 clinical cases--20 fatal cases]. / Intoxications aiguës par traitement substitutif à base de buprénorphine haut dosage. 29 observations cliniques--20 cas mortels.

OBJECTIVES: Buprenorphine has been an important advance in care for drug abusers, but the toxic risk may be fatal. We report here two original series of buprenorphine poisoning in opiate abusers on substitution therapy. PATIENTS: The first series included 20 males and 9 females, aged 20-35 years (mean = 27.5) with non-fatal poisoning. The second series included 20 subjects (19 males, 1 female) aged 14-48 years (mean = 26.6) with a fatal outcome. All subjects were opiate addicts taking high-dosage sublingual buprenorphine formulation as substitution therapy. RESULTS: Blood concentrations of buprenorphine were found in all cases to remain at a low level (1.0-2.3 ng/ml, m = 1.4 ng/ml, and 1.1-29.0 ng/ml, m = 8.4 ng/ml in non-fatal and fatal cases respectively). Almost all cases involved concomitant intake of psychotropic medications, especially benzodiazepines (18 non-fatal and 17 fatal cases). DISCUSSION: These observations confirm previously reported data on the danger of buprenorphine-benzodiazepine combinations. Intravenous injection of crushed tablets also appears to be a risk factor (8 deaths and 10 non-fatal poisonings). This series highlights the need for improvement in the recently developed French program for substitution therapy with high-dosage buprenorphine in heroin addicts.