[RÉALITÉ LT, a pharmacoepidemiological study of semiology and therapeutic strategy of patients with schizophrenia treated by antipsychotic loxapine in routine clinical practice]. / RÉALITÉ LT : Recherche Épidémiologique sur l'Activité de la Loxapine et ses Indications en Thérapeutique quotidiennE lors d'une utilisation à Long Terme. Étude pharmacoépidémiologique : sémiologie et stratégie thérapeutique d'une population de patients présentant des troubles schizophréniques traités par loxapine.

INTRODUCTION: Data concerning the clinical and therapeutic characteristics of patients with schizophrenia treated by antipsychotic in naturalistic conditions are useful. Two national pharmacoepidemiological studies were conducted in France, a retrospective survey RÉALITÉ and a prospective study RÉALITÉ LT, to examine the use of loxapine, first in acute and chronic psychotic states and second in long-term treatment prescribed for patients with schizophrenia. AIM OF STUDY: The aim of RÉALITÉ LT is to specify the clinical characteristics of schizophrenic patients treated by loxapine for at least 4 months and the description of the methods of use of this antipsychotic medication during a 6-month follow-up in "real life" conditions. DESIGN OF STUDY: RÉALITÉ LT is an epidemiologic, observational, longitudinal, prospective (during a half-year period), multicenter and national study of the prescription of loxapine in routine clinical practice. For this study, 645 patients with schizophrenia treated by loxapine were recruited, assessed by PANSS, CGI, GAF, MeDra-SOC-PT for side effects and Girerd questionnaire for compliance; statistical analysis used SAS 9.2. RESULTS: Six hundred and forty-five adult patients were included and assessed at inclusion, month 3 and 6. These patients were mostly male (69%), with an average age of 41, inactive (68%), lonely with no child (79%), under psychiatric care for more than 5 years (81%), less than one third were inpatients. The subtypes of schizophrenia were paranoid (59%), disorganised (21%), undifferentiated or residual (10%), the outcome of psychotic illness was episodic (50%) or continuous (33%). The daily mean dosage of loxapine was 168,4 mg/d, in antipsychotic loxapine monotherapy (27%) or in combination with other antipsychotics (63%); it was often associated with psychotropic medications (anxiolytic [72%], antidepressant [21%], normothymic [19%]). The stability of the dosage of loxapine during the 6 months follow-up (60%) was associated with strict loxapine monotherapy or antipsychotic monotherapy (loxapine associated with other psychotropic medication). Safety, side effects and compliance were compared with previous studies. DISCUSSION AND CONCLUSION: These results are discussed, comparing the two pharmacoepidemiological studies RÉALITÉ and RÉALITÉ LT, loxapine is used in compliance with the two indications (smpc) and French guidelines (HAS, Haute Autorité de santé).

Real-time near-field acoustic holography for continuously visualizing nonstationary acoustic fields.

Near-field acoustic holography (NAH) is an effective tool for visualizing acoustic sources from pressure measurements made in the near-field of sources using a microphone array. The method involving the Fourier transform and some processing in the frequency-wavenumber domain is suitable for the study of stationary acoustic sources, providing an image of the spatial acoustic field for one frequency. When the behavior of acoustic sources fluctuates in time, NAH may not be used. Unlike time domain holography or transient method, the method proposed in the paper needs no transformation in the frequency domain or any assumption about local stationary properties. It is based on a time formulation of forward sound prediction or backward sound radiation in the time-wavenumber domain. The propagation is described by an analytic impulse response used to define a digital filter. The implementation of one filter in forward propagation and its inverse to recover the acoustic field on the source plane implies by simulations that real-time NAH is viable. Since a numerical filter is used rather than a Fourier transform of the time-signal, the emission on a point of the source may be rebuilt continuously and used for other post-processing applications.

[Therapeutics approach of adult patients with acute and chronic psychotic states: REALITE survey]. / Approche thérapeutique d'une population de patients présentant des troubles psychotiques aigus ou chroniques: enquête REALITE (Recherche Epidémiologique sur l'activité de la Loxapine et ses Indications en Thérapeutique quotidiennE).

A retrospective observational pharmaco-epidemiological survey was conducted during 24 weeks between October 2004 and March 2005 in metropolitan France (384 investigators) to more clearly define the use of loxapine in acute and chronic psychotic states. The objective of this national survey was to specify the clinical and therapeutic profile of patients managed by this antipsychotic in two cohorts of adult patients: one in "acute phase" (prescription of loxapine during the previous 4 weeks), the other in "maintenance phase" (prescription of loxapine for more than 8 weeks). The two groups of the recruited population (1,511 patients) presented identical sociodemographic data. Selection criteria were adapted to the data collected to ensure statistically relevant analysis: 696 patients in acute phase and 633 patients in maintenance phase. The acute phase group was predominantly composed of known patients (82% of patients had a psychotic history) with schizophrenia (47%) or mood disorders (57%) who had already presented acute episodes (an average of 5.4). The current episode consisted of a state of agitation (88%) lasting an average of two weeks, requiring hospitalization (87%), scheduled admission [HDT (admission at the request of another person) in 47.5% of cases and HO (statutory admission) in 40.8% of cases] and prescription of loxapine monotherapy (56%) at a mean daily dose of 177,3 mg. The maintenance phase group comprised a population of known patients (87.5%), schizophrenics (63%), presenting psychotic symptoms (dissociation 82%, delusions 74%) or mood disorders (71%) requiring voluntary hospitalization (78%) for a mean duration of 180 days and a prescription of loxapine monotherapy in 28% of cases at a mean daily dose of 131.6 mg. The loxapine-haloperidol combination (21%) was prescribed more frequently in the second group in the case of chronic disorders; in the other cases, loxapine was coprescribed with the main second generation antipsychotics: risperidone (16%), olanzapine (16%), amisulpride (11%). CGI assessment of the overall study population revealed a marked or very marked clinical improvement with no significant adverse effects in more than 80% of cases.

In vitro and in vivo models for the evaluation of potent inhibitors of male rat 17alpha-hydroxylase/C17,20-lyase.

The C(17,20)-lyase is a key enzyme in the biosynthesis of androgens by both the testes and adrenals. A complete inhibition of this enzyme would provide an alternative means of androgen suppression for the treatment of prostatic cancers. In the present study, the inhibitory effects of new non-steroidal compounds were tested in vitro on rat C(17,20)-lyase versus abiraterone, a reference steroidal inhibitor. Their activities were also evaluated in vivo on plasma testosterone (T) and luteinizing hormone (LH) levels and on testes, adrenals, seminal vesicles (SV) and ventral prostate (VP) weights after 3 days of oral treatment to adult male rats (50mg/kg per day p.o.). Inhibition in the nanomolar range was obtained with TX 977, the lead racemate product in this series, and optimization is ongoing based on a slight dissociation observed between its two diastereoisomers, TX 1196-11 (S) and TX 1197-11 (R). These non-steroidal compounds (including YM 55208, a reference competitor) proved to be more active in vivo than abiraterone acetate in this model, but the observed impact on adrenal weight suggests that the specificity of lyase inhibition versus corticosteroid biosynthesis deserves further investigations with this new class of potentially useful agents for the treatment of androgen-dependent prostate cancer.

In vitro and in vivo models for the evaluation of new inhibitors of human steroid sulfatase, devoid of residual estrogenic activity.

The goal of our research project is to develop a new class of orally active drugs, estrone sulfatase inhibitors, for the treatment of estrogen-dependent (receptor positive) breast cancer. Several compounds were synthesized and their pharmacological potencies explored. Based on encouraging preliminary results, three of them, TX 1299, TX 1492 and TX 1506 were further studied in vitro as well as in vivo. They proved to be strong inhibitors of estrone sulfatase when measured on the whole human JEG-3 choriocarcinoma and MCF-7 breast cancer cells and their IC(50)s found to be in the range of known standard inhibitors. Their residual estrogenic activity was checked as negative in the test of induction of alkaline phosphatase (APase) activity in whole human endometrial adenocarcinoma Ishikawa cells. In addition, their effect on aromatase activity in JEG-3 cells was also examined, since the goal of inhibiting both sulfatase and aromatase activities appears very attractive. However, it has been unsuccessful so far. Then, in vivo potencies of TX 1299, the lead compound in our chemical series, were evaluated in comparison with 6,6,7-COUMATE, a non-steroidal standard, in two different rat models and by oral route. First, the absence of any residual estrogenic activity for these compounds was checked in the uterotrophic model in prepubescent female rats. Second, antiuterotrophic activity in adult ovariectomized rat supplemented with estrone sulfate (E(1)S), showed that both compounds were potent inhibitors, the power of TX 1299 relative to 6,6,7-COUMATE being around 80%. This assay was combined with uterine sulfatase level determination and confirmed the complete inhibition of this enzyme within the target organ. Preliminary studies indicated that other non-steroid compounds in the Théramex series were potent in vitro and in vivo inhibitors of estrone sulfatase in rats and further studies are in progress.

Systematic errors of phase-shifting speckle interferometry.

A theoretical and numerical investigation of the systematic phase errors in phase-shifting speckle interferometry is presented. The theoretical investigation analyzes the behavior of some systematic error induced by intensity variations in two cases of data-computing techniques. The first case deals with the technique in which the phase change is computed, unwrapped, and then linearly filtered; the second case deals with the technique in which the data are linearly filtered before the arctangent calculation and then unwrapped. With the first filtering technique it is shown that it is preferable when the phase change is of relatively low spatial frequency, leading to a particularly accurate method. With the second case it is demonstrated that an important parameter of speckle interferometry is the modulation factor of the interference frame that induces phase errors when the data are filtered before the arctangent calculation. We show that this technique is better than the first when the phase change is composed of high-spatial-frequency variations. The theoretical investigation of the two techniques is compared with numerical simulations, considering the frequency characteristics of the phase change, and this shows a good match between theory and simulations.

[Survey on the announcement of schizophrenia diagnosis in France]. / Enquête sur l'annonce du diagnostic de schizophrénie en France.

Medical information for the general public, patients and their families is a current Public Health priority. What information can be given to a patient suffering from schizophrenia, whose understanding and judgement capacities are supposedly affected by this mental disease? In the United States, 70% of psychiatrists inform patients of schizophrenia and diagnosis of schizophreniform disorder, while in Japan less than 30% do this. The lack of information given to the general public on the disease may contribute to reinforcing the difficulty in announcing the diagnosis. Indeed, the beliefs and attitudes of the patient, his/her family, the general population and health carers concerning the disease do not match up. However, the first two years seem to be a main issue for the subsequent evolution of the disease. No specific data on the attitude of French clinicians with respect to the announcement of the diagnosis is available. In the current legal context and in view of the advances in treatment, we have carried out a survey among French psychiatrists. It is an auto-questionnaire, transversal epidemiological, descriptive and analytical. The questionnaire was sent to a population of 12,958 psychiatrists. It comprised 48 questions: 7 referred to the socio-demographic and professional characteristics of the subjects, 22 to the attitude with respect to the announcement of the diagnosis to the patients, and the last 18 concerned the attitude with respect to the announcement of the diagnosis to the families. 1,691 questionnaires were returned by free post and analysed. The socio-demographic characteristics of the sample are close to those of French psychiatrists as a whole. The number of patients suffering from schizophrenia in the active files of the psychiatrists is 24% (+/- 21.4) on the entire sample. Approximately a third (37.8%) of psychiatrists deem it necessary to announce the schizophrenia diagnosis and approximately two thirds (69.5%) declare that they sometimes announce it. Among the patients suffering from schizophrenia in the active files of the psychiatrists who responded, approximately a third (34%) were informed of their diagnosis. The main reasons for not announcing the diagnosis are firstly the "reticence to give a diagnosis label" and secondly "the functional incapacity of the patient to understand the concept". The alternative diagnosis term most commonly used is "psychosis" (46.5%). However, 48.1% of practitioners state that the announcement of a specific diagnosis allows a better therapeutic combination. Depending on the proportion of patients suffering from schizophrenia in their active file presented in two categories (< 10% and > 10%), psychiatrists significantly most frequently announce the specific diagnosis (17.3% vs 25.3%, p < 10(-3). A statistically significant proportion of younger psychiatrists (44.4 vs 46.3, p < 10(-3) with fewer years of practice (14.1 vs 15.8), more often believe that it is necessary to announce the diagnosis. The rate of response (13.5%) for this type of survey seems high, which could indicate a high interest among psychiatrists with respect to this question. Our data showed the existence of a correlation between age, number of years in practice, type of practice and the proportion of patients suffering from schizophrenia in the active file on the one hand and the attitude of the psychiatrists with respect to the announcement of the diagnosis on the other hand. It is possible that the multi-disciplinary team work of public practice psychiatrists and the fact that they are more often confronted with schizophrenic disease facilitate the announcement of this diagnosis. In the survey population, the inability to give a diagnosis may be related to the questions of the practitioners about the capacity of the subjects to understand, the lack of precision of this diagnosis, the fear of disheartening the patients and the absence of curative treatment. The risk of suicide does not seem to be one

[What is the meaning of "stabilization" in schizophrenic patients?]. / Que recouvre le terme "stabilisation" des patients schizophrènes?

UNLABELLED: The notion of stabilization in schizophrenia has been investigated, in France, through a survey of 875 psychiatrists. This survey, which has been conducted on the 9th, 10th and 11th of December 1997, looked into the clinical, therapeutic and socio-demographic variables, and the means of patient management, which are used by psychiatrists to ascertain that their patients are stabilized. The data was collected by each psychiatrist by way of a questionnaire administered to his or her next three patients, either at the hospital or in private practice (2,464 questionnaires were completed). RESULTS: 65% of the patients seen during this survey were considered stabilized by their psychiatrist (n = 1,597). The most common clinical presentation was of the paranoïd type. An insiduous onset of disease seems to be correlated with an absence of stabilization. Stabilization appears to be estimated at a given time rather than over a time period, since over half the patients who were considered stabilized had suffered at least one relapse over the last 2 years, and had been rehospitalized an average of 2.4 times over that period. In terms of drug therapy, they received 1.4 neuroleptic drugs, which does not differ markedly from the 1.5 neuroleptics administered to patients who were considered non stabilized. Co-prescriptions of anticholinergic medications, benzodiazepines and antidepressants were very common in these patients considered stabilized (49.9%, 39.8% and 24.8% respectively), which is similar to that observed in their non-stabilized counterparts (47.6%, 45%, 8% and 26.4%, respectively). Patient follow-up remained above an average of 1 patient visit per month (an average of 8.9 visit over the last 6 months), despite the fact that patients were considered stabilized. Two primary criteria were used by psychiatrists to determine that a patient was stabilized: treatment compliance and the absence of positive symptoms. However, 43% of the patients which were considered stabilized still presented with positive symptoms. Negative symptoms were also very prevalent in these patients (65%), as well as concomitant depressive signs (36%) and anxiety (64%). CONCLUSION: Even though the concept of stabilization remains difficult to define, it appears that schizophrenic patients are considered by their psychiatrist as stabilized on the grounds of good treatment compliance and decreased positive symptoms. Therefore, even in these so-called stabilized patients, enhancements are still possible, as symptoms remain present.

Fuzzy Petri net-based programmable logic controller.

Programmable logic controllers (PLCs) are able to directly implement control sequences specified by means of standard languages such as Grafcet or formal models such as Petri nets. In the case of simple regulation problems between two steps it could be of great interest to introduce a notion of "fuzzy events" in order to denote a continuous evolution from one state to another. This could result from a linear interpolation between the commands attached to two control steps represented by two Petri net (PN) places. This paper is an attempt to develop fuzzy PN-based PLCs in a similar way as fuzzy controllers (regulators). Our approach is based on a combination of Petri nets with possibility theory (Petri nets with fuzzy markings).

[Complaints of depression and therapeutic perspectives]. / A propos de la plainte dépressive et des perspectives thérapeutiques.

Having reviewed the place of depressive complaint within contemporary nosography, the authors study the psychopathological aspect of clinical pictures called "dysthymias". The rapport of patients with their internal or external objects is deeply ambivalent and characterized by a link that Michael Balint calls "ocnophilic". Those patients also appear peculiar regarding their relationship with temporality, with what can be called: a "dictatorship of the present" reflecting their inability to be located in a "narrative" development. Some principles stem from these considerations, concerning therapeutic strategies as does a reminder of the difficulties in bringing about a genuine evolution.

New antihistaminic theophylline or theobromine derivatives.

A series of 3,4-dihydro-1,3-dimethyl-7-[3-(4-substituted-piperazin-1-yl)- substituted-alkyl]-1H-purine-2,6-diones and 3,7-dihydro-3,7-dimethyl-1-[3-(4-substituted-piperazin-1-yl)- substituted-alkyl]-1H-purine-2,6-diones was synthesized and evaluated for antihistaminic activity. Some of them displayed good inhibition of both histamine-induced bronchospasm in the anesthetized guinea pig at 10 micrograms/kg by the intravenous route and of passive cutaneous anaphylaxis in the rat at 10 mg/kg by the oral route. Comparison of the two most active compounds revealed a higher antihistaminic activity with the compounds containing a (phenylthio)propyl group (1 and 2) as compared with that containing a phenoxy group. Compound 2 [RS-49014, 3,4-dihydro-1,3-dimethyl-7-[3-[4-[3-(phenylthio)propyl]piperazin-1 -yl]- 2-hydroxypropyl]-1H-purine-2,6-dione] was selected for clinical trials on the basis of a comparative pharmacological study with chlorpheniramine, ketotifen, promethazine, and theophylline.

Occurrence of 7-methyl-7-hexadecenoic acid, the corresponding alcohol, 7-methyl-6-hexadecenoic acid, and 5-methyl-4hexadecenoic acid in sperm whale oils.

Two sperm whale oils from the northern hemisphere and two from the southern hemisphere were fractionated. Triglyceride and wax esters were examined for fatty acids and alcohols with monoethylenic unsaturation bearing a methyl branch on an ethylenic carbon. The 7-methyl-7-hexadecenoic acid (0.37-1.37%) was accompanied by the corresponding alcohol (0.28-0.72%), but these materials were not accompanied by shorter chain homologues. The 7-methyl-6-hexadecenoic acid was relatively less important (0.23-0.68%), but was accompanied by 5-methyl-4-hexadecenoic acid (0.10-0.39%), and a partially identified C13 compound. Chromatographic properties on silver nitrate impregnated silicic acid TLC and on three GLC liquid phases are reported.