Pharmacokinetic characterisation of a valproate Autism Spectrum Disorder rat model in a context of co-exposure to α-Hexabromocyclododecane.

Assessing the role of α-hexabromocyclododecane α-HBCDD as a factor of susceptibility for Autism Spectrum disorders by using valproic acid-exposed rat model (VPA) required characterizing VPA pharmacokinetic in the context of α-HBCDD-co-exposure in non-pregnant and pregnant rats. The animals were exposed to α-HBCDD by gavage (100 ng/kg/day) for 12 days. This was followed by a single intraperitoneal dose of VPA (500 mg/kg) or a daily oral dose of VPA (500 mg/kg) for 3 days. Exposure to α-HBCDD did not affect the pharmacokinetics of VPA in pregnant or non-pregnant rats. Surprisingly, VPA administration altered the pharmacokinetics of α-HBCDD. VPA also triggered higher foetal toxicity and lethality with the PO than IP route. α-HBCDD did not aggravate the embryotoxicity observed with VPA, regardless of the route of exposure. Based on this evidence, a single administration of 500 mg/kg IP is the most suitable VPA model to investigate α-HBCDD co-exposure.

[Intervention focused on resources to reduce anxiety and depression disorders in cancer patients: A pilot study]. / Intervention centrée sur les ressources pour réduire les troubles anxieux et dépressifs chez les patients atteints de cancer : une étude pilote.

INTRODUCTION: Cancer, a widespread chronic disease, represented 400,000 diagnoses in France in 2017. The diagnoses as well as the treatments are a major source of stress for most patients concerned. Secondary effects may be painful and disturbing (pain, nausea, fatigue, loss of social and/or professional status, anxiety of death), and may lead to maladaptive coping strategies (avoidant coping), psychological inflexibility, anxiety, depression, and suicide risks which are twice as important as in the general population. Research in the field of psychotherapy for cancer patients represents an important international target, in particular in what concerns enhanced patient quality of life during and after treatment. Cognitive Behavioral Therapy, Mindfulness-Based Stress Reduction, as well as adapted physical activity have shown promising results to enhance patients' quality of life at different stages of the process. However, results mainly show significant short-term effects and usually only for patients with high levels of anxiety and depression symptoms. With the development of third wave Cognitive Behavioral Therapy, more global interventions (not just aimed at anxiety and depression symptoms) have emerged. Research has underlined their efficacy on both symptom reduction (anxiety and depression) and quality of life enhancement through the development of more varied and adaptive responses to stressful situations. Positive psychology interventions, mindfulness, and Acceptance and Commitment Therapy have inspired third wave Cognitive Behavioral Therapy. Emotional acceptance, mindful awareness of thoughts and emotions, and engaging in actions that are coherent with one's values all form part of the means by which these interventions may help patients to find ways to better adjust to their stressful situation. The results of the efficacy trials carried out using these approaches were mixed, and effects were mainly modest. Furthermore, most of the studies only tested one approach at a time, while each approach activated mechanisms, which can be useful for these patients. Hence, the aim of the current study was to test an integrative program based on classical second wave Cognitive Behavioral Therapy as well as on practices from the third wave of Cognitive Behavioral Therapy. We aimed at carrying out a preliminary study assessing the potential effects of the program on cancer patients' anxiety, depression symptoms, well-being and psychological flexibility. METHOD: Sixteen cancer patients were enrolled in a second and third wave Cognitive Behavioral Therapy workshop composed of six sessions. In-session practices were based on validated practices. Participants completed the following questionnaires before the first workshop (T1) and at the end of the sessions (T2) in order to assess anxiety, depression symptoms, well-being and psychological flexibility: HAD, WEMWBS, MPFI, AAQ-2. Qualitative data regarding acceptability were also collected at the end of the last session. RESULTS: Among the sixteen participants, nine women (mean age=56.1years old) completed the questionnaires seven of whom had breast cancer. The results of this preliminary study showed a significant pre-to-post reduction in anxiety and depression symptoms (P=0.017) as well as on certain dimensions of psychological flexibility: reduced "self as content" (P=0.011), and enhanced cognitive diffusion (P=0.018). Only marginal differences were found on other dimensions: reduced inaction (P=0.074) and experiential avoidance (P=0.089), and enhanced "self as context" (P=0.062). Content analysis showed (1) increased positive perceptions about experiences with more serenity, (2) positive attitudes towards self (self-compassion), (3) enhanced positive relationships, and (4) ability to accept negative affect. CONCLUSION: Patients' qualitative feedback highlighted the potential feasibility and adaptability of the program for this population. The results of this preliminary study show promising avenues for research in the field of cancer patients' adaptive coping enhancement as well as reduce anxiety and depression symptoms. This type of workshop can be considered as complementary to individual psychotherapies as they may tap into different mechanisms that help foster psychological flexibility as the group format enhances decentering processes. Further research avenues are proposed in order to assess the efficacy of such interventions in cancer patients compared to other types of interventions. Further research should also look into individual differences in order to orient patients towards practices that fit them best.

[Human rabies in France in 2004: update and management]. / La rage humaine en France en 2004: état des lieux et prise en charge.

Twenty people died of rabies in France between 1970 and 2003 (compared to 55,000 yearly worldwide), 80% on returning from Africa. Dogs were the contaminating animals in 90% of the cases and children were the most common victims. The last instance of rabies in a native French animal was reported in 1998. However the illegal importation of animals still poses a risk. The disease is transmitted by saliva, even before the appearance of clinical symptoms, through a bite, scratch, or licks of mucous membranes or broken skin. Person-to-person transmission has only been observed in cases of grafts (cornea). The mean incubation time of 1 to 3 months is long enough to allow passive immunization and vaccination. After its onset, the disease presents as encephalitis or a paralytic syndrome the outcome of which is always fatal. Clinical diagnosis may be difficult in the early stages of the disease. If rabies is suspected, the National Reference Centre is responsible for the sampling and proper transportation of these samples so as to ensure assessment results within 5 days. If stringent hygiene rules are complied to, there is no risk of contamination for those in close contact. Vaccination, which is performed in official rabies centers, is only performed after a diagnosis based on laboratory evidence, and solely for exposed persons or those for whom a reliable history cannot be established (children under 6 years). Prevention is based on information. People traveling abroad, particularly to Africa, are warned not to approach unknown animals (especially dogs) nor to try to import them, and are advised to comply with vaccinal recommendations for travelers, particularly for toddlers.

Introduction: the need for a multidimensional and multidisciplinary approach.

This special issue combines contributions from several disciplines within the social sciences on how to understand long-term use or dependency on various kinds of psychotropics. It emphasizes the need for a multidisciplinary approach in order to understand the complexity of such long-term use. The papers in this issue will base their arguments on psychological, sociological, anthropological, clinical, and social pharmacy perspectives. Different disciplines focus specially on certain topics. For example, psychology can help us to understand what kind of mental processes that are involved in the development of long-term tranquillizer use. Sociology, anthropology and social pharmacy have a particular contribution to make in helping us, in different ways, to understand the social meanings of psychotropic drug use.

Mass media representations as drug information for patients: the prozac phenomenon.

Results of a 20-year study of mass media representations of antidepressant medications and their use are presented. The recent Prozac phenomenon stands out as a primary example of media-generated drug information for patients. Various forms of mass media are important in providing perceptions of the effects, benefits, and safety of these new antidepressant drugs. Clinical research, however, suggests that the latest generation of antidepressant medications is no more effective in treating depressive symptoms than the first generation, tricyclic antidepressants. Yet, these new antidepressants have become the model drug not only for treating depression, but also for cosmetic psychopharmacology.

Characterization of the catalytic activities of the PhoQ histidine protein kinase of Salmonella enterica serovar Typhimurium.

Studies of Escherichia coli membranes that were highly enriched in the Salmonella enterica serovar Typhimurium PhoQ protein showed that the presence of ATP and divalent cations such as Mg2+, Mn2+, Ca2+, or Ba2+ resulted in PhoQ autophosphorylation. However, when Mg2) or Mn2+ was present at concentrations higher than 0.1 mM, the kinetics of PhoQ autophosphorylation were strongly biphasic, with a rapid autophosphorylation phase followed by a slower dephosphorylation phase. A fusion protein lacking the sensory and transmembrane domains retained the autokinase activity but could not be dephosphosphorylated when Mg2+ or Mn2+ was present at high concentrations. The instability of purified [32P]phospho-PhoP in the presence of PhoQ-containing membranes indicated that PhoQ also possesses a phosphatase activity. The PhoQ phosphatase activity was stimulated by increasing the Mg2+ concentration. These data are consistent with a model in which Mg2+ binding to the sensory domain of PhoQ coordinately regulates autokinase and phosphatase activities.

Characterization of non-peptide bradykinin B2 receptor agonist (FR 190997) and antagonist (FR 173657).

Pharmacologic parameters for a novel non-peptide bradykinin (BK)-B2 receptor agonist, 8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoylcinnamidoacetyl]-N-+ ++methylano] benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (FR 190997) (pEC50, ED50 values) and for the antagonist (E)-3-(6-acetamido-3-pyridyl)-[N-[2,4-dichloro-3-[(2-methyl-8-quinolinyl ) oxymethyl] phenyl]-N-methylaminocarbonylmethyl] acrylamide (FR 173657) (pIC50, ID50 values) were measured using conventional contractile B2 receptor bioassays from rabbit, guinea pig and rat tissues and by mean of animal blood pressure models performed on anesthetized animals in the same species. In vitro assays (on the rabbit jugular vein and the guinea pig ileum) demonstrated that both the onset and duration of action of FR 190997 are prolonged compared to BK. These in vitro effects of FR 190997 strongly desensitized upon repeated tissue applications. Similar pEC50 values (7.7) were measured on the rabbit and the guinea pig tissues. In vivo, when injected intraarterially, FR 190997 produced hypotensive responses in rabbits and guinea pigs with ED50 values of 3.7 +/- 0.5 and 8.9 +/- 3.6 nmol/kg, respectively. Both the contractile and the hypotensive effects of FR 190997 were abolished by pretreating tissues (1 microM) or animals (0.1-0.5 micromol/kg) with D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]BK (HOE 140) or FR 173657. FR 173657 (pIC550 approximately 8.40), as well as other known antagonists (e.g., HOE 140, D-Arg-[Hyp3,D-Phe7,Leu8]BK), inhibited the in vitro myotropic effects of BK on the rabbit, guinea pig and rat tissues. FR 173657 also abrogated the in vivo hypotensive responses elicited by BK in the rabbit (ID50 57 +/- 9 nmol/kg), the guinea pig (ID50 215 +/- 56 nmol/kg) and the rat (ID50 187 +/- 50 nmol/kg). The in vivo duration of action of FR 173657 was significantly lower in the rabbit (= 20 min) than in the guinea pig and the rat (> 90 min). It is concluded that the non-peptides FR 190997 and FR 173657 enable efficient activation and antagonism of rabbit and guinea pig B2 receptors. These non-peptide molecules represent a marked progress in medicinal chemistry and may be useful to define the role played by the kallikrein/kinin system in vivo.

Sodium butyrate induces G2 arrest in the human breast cancer cells MDA-MB-231 and renders them competent for DNA rereplication.

When exposed to sodium butyrate (NaBut), exponentially growing cells accumulate in G1 and G2 phases of the cell cycle. In the human breast cancer cell line MDA-MB-231, an arrest in G2 phase was observed when the cells were released from hydroxyurea block (G1/S interface) in the presence of NaBut. The inhibition of G2 progression was correlated with increased contents both of total p21(Waf1) and of p21(Waf1) associated with cyclin A and with an inhibition of cyclin A- and B1-associated histone H1 kinase activities measured in cell lysates, as well as with dephosphorylation of the RB protein. A decrease in the cell contents of cyclins A and B1 was also observed but this decrease was preceded by p21(Waf1) accumulation. When NaBut was removed from the culture medium of cells blocked in G2 phase, p21(Waf1) level decreased and, instead of proceeding to mitosis, these cells resumed a progression toward DNA rereplication. These results suggest that the induction of p21(Waf1) by NaBut leads to the inhibition of the sequential activation of cyclin A- and B1-dependent kinases in this cell line, resulting in the inhibition of G2 progression and rendering the cells competent for a new cell division cycle.

[Cutaneous sarcoidosis secondary to inhalation of wall insulating material particles]. / Sarcoïdose cutanée secondaire à l'inhalation de particules de flocage d'isolation.

BACKGROUND: Sarcoidosis is a systemic disease defined by multiple granulomas. We report a case of sarcoidosis which occur concomitantly or secondary to foreign body granuloma of the lung. CASE REPORT: A 50-year-old women presented with Lofgren syndrome, subcutaneous granulomatous nodular lesions on the arms and legs. Computed tomography revealed a foreign body granuloma of the lung centered on particles of mural isolation material that the patient had inhaled accidentally. Analysis of the foreign body particles showed non crystalline silica, calcite monohydrate and phenol resin. DISCUSSION: Recent studies support the hypothesis that sarcoidosis is an antigen-driven disease involving pulmonary T-cell activation. The antigen-mediated reaction may be caused by infectious agents, particularly mycobacteria, occupational and environmental agents (beryllium) or as in our observation following inhalation of mural isolation material particles.

Effects of olomoucine, a selective inhibitor of cyclin-dependent kinases, on cell cycle progression in human cancer cell lines.

We have studied the effects of olomoucine, a selective inhibitor of cdk2, cdc2 and MAP kinase, on the rate of proliferation and the cell cycle progression in human cancer cells in culture. Olomoucine inhibited the growth of the KB 3-1, MDA-MB-231 and Evsa-T cell lines in a concentration-dependent manner, with EC50 values of 45, 75 and 85 microM, respectively. Incubation of exponentially growing KB 3-1 cells in the presence of olomoucine led to an increased proportion of cells in G1 phase after 24 h or more of incubation. Olomoucine failed to rapidly affect the phosphorylation of the Rb tumor-supressor gene product. However, [3H]thymidine incorporation into the cell DNA was rapidly inhibited. We show that this inhibition is due, at least in part, to the diminution of thymidine entry into the cells. Surprisingly, all these cell lines, when synchronized at the G1/S interface and relaxed in the presence of olomoucine, progressed unhindered through the S phase. Under these conditions, the G2 phase transit was markedly retarded but not prevented. Insufficient permeability of the cell membrane to olomoucine may explain the low activity of the drug.

[From the pharmacology of drugs to their use: formation of knowledge about psychotropic drugs]. / De l'activité pharmacologique à l'usage des drogues: la construction des connaissances sur les psychotropes.

Drug effects are complex events in drug users' lives. What do we know about the effects of major psychotropic drugs, and how have we arrived at this knowledge? An exercise is presented herein that assists the reader in assessing the state of her or his knowledge about the effects of certain psychotropic drugs. The exercise format allows the reader to explore how their and others' knowledge about psychotropic drugs are constructed, by examining cellular, organal, behavioral, and social levels of experience for specific drugs. Examples of effects for five specific drugs, identified from a variety of sources, are presented and described in the context of these different levels of experience.

Barriers to compliance with OBRA'90 regulations in community pharmacies.

OBJECTIVE: To identify which barriers have been most significant to community pharmacists in their ability to comply with the Omnibus Budget Reconciliation Act of 1990 (OBRA'90) regulations during its first year of implementation. METHODS: Mailing of a two-page survey in April 1994. SETTING: Four hundred randomly selected community pharmacies in the Commonwealth of Massachusetts. PARTICIPANTS: Of 400 pharmacies surveyed, 156 surveys were completed and returned for analysis. RESULTS: Barriers that were considered most significant to pharmacies surveyed in their ability to implement OBRA'90 regulations were excessive workload, lack of financial compensation, and patients' attitudes. Of least significance were inadequate knowledge about drugs, inadequate references, and store layout. Almost half the responding pharmacists indicated that OBRA'90 regulations had not affected or changed their practice, one-quarter of the pharmacists believed their practice was less rewarding after OBRA'90, and about one-fifth believed it was more rewarding. CONCLUSIONS: Community pharmacists in Massachusetts are making an attempt to comply with OBRA'90, but there are specific barriers that are affecting their ability to do so. The OBRA'90 regulations appear to have had little impact on the practice of most community pharmacies. Community pharmacy management needs to examine (1) expanded roles of supportive personnel to give pharmacists more time to spend counseling patients, (2) reimbursement mechanisms for cognitive service, and (3) approaches to educating patients about these changes in the pharmacy profession.

Estradiol induces vasoactive intestinal peptide and prolactin gene expression in the rat anterior pituitary independently of plasma prolactin levels.

It is well established that estrogens are potent stimulators of prolactin (PRL) secretion. It has also been demonstrated that estradiol (E2) can increase the expression and the anterior pituitary levels of the vasoactive intestinal peptide (VIP), a peptide which also acts as a potent PRL-releasing factor. It thus remained unknown whether the effects on pituitary VIP were due to E2 itself or to E2-induced hyperprolactinemia (HPRL). In order to test this hypothesis, various plasma PRL levels were induced in rats either with ectopic pituitary grafts, PRL secreting tumours or E2 implants, and VIP mRNA expression in the anterior pituitary was measured by in situ hybridization and Northern blot analyses. Whereas decreases in VIP mRNA can be observed in pituitaries of rats with pure HPRL, a 6-fold increase in VIP mRNA can be seen in E2-treated rats. E2 increased both 1.0 and 1.7 Kb VIP mRNA species. The presence of the graft in E2-treated rats significantly reduced the increase in VIPmRNA observed following E2. The direct stimulation by E2 of VIP mRNA expression was further demonstrated by the fact that statistical analysis of the data indicated that both E2 and graft were acting independently of each other, and that a new selective antiestrogen, RU 58668, almost totally blocked the effect of E2. Moreover, under similar experimental conditions, pituitary PRL mRNA levels were reduced in the graft group and a marked up-regulation was observed similarly in both E2 and in E2 rats bearing ectopic grafts.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of substance use problems: models, factors, and processes.

The use of substances for medical or nonmedical reasons occurs in most cultures. Regardless of the reason for use, however, most types of substance use (or drug-taking behaviors) have their associated problem states. The prevention of substance use problems is an important issue and need in every society. In this review we present and discuss various models and factors that purport to describe and predict patterns of drug use, and we discuss various strategies to prevent the occurrence of substance use problems.

Drugs, music, and ideology: a social pharmacological interpretation of the Acid House Movement.

During the summer of 1988, a musical concert experience called Acid House arrived on the cultural scene in many British cities. The media created a frenzy of misinformation in reporting about the latest drug craze. Acid House music was then banned from the pop music charts, radio and television, and retail outlets. Some psychoactive substances have been bought, sold, and consumed at Acid House events, but drug use does not appear to be extensive. At the physiological level, the nature of Acid House music, especially the drumming aspect, seems instrumental in providing altered states of consciousness. At the interpersonal and social level, the set and setting of Acid House events further enhances and reinforces the specific physiological and psychological responses. The degree of acceptance by various subcultural groups may depend greatly on the amount of media and societal exposure given to it, particularly if authoritarian attempts to suppress it enhance its political or ideological aspects.

Changes in vasoactive intestinal Peptide binding site densities in the female rat central nervous system and pituitary during lactation.

Using quantitative autoradiography, vasoactive intestinal peptide (VIP) binding site densities were investigated in the female rat during lactation. Plasma prolactin levels were significantly (P<0.01) elevated on days 3 and 10 of lactation. In the brain, there was a significant (P<0.05) increase in VIP binding sites during lactation in the striatum, thalamus, anterior portion of the paraventricular nucleus of the hypothalamus, and several cortical areas compared to virgin female diestrous rats. VIP binding density in the anterior pituitary was significantly higher (P<0.01) when measured on day 3 of lactation, and decreased to diestrous levels by day 10. Pup removal resulted in a significant reversal of the lactation-induced increase in VIP binding density in the thalamus, parietal and insular cortices, and the anterior portion of the paraventricular nucleus. Taken together, modifications in VIP binding site density in the pituitary and in several central areas are associated with changes in the level of prolactin secretion. Moreover, the pattern of VIP receptor induction during lactation suggests a role for VIP in the brain that extends beyond the regulation of prolactin secretion.