Impact of breast cancer on prospective memory functioning assessed by virtual reality and influence of sleep quality and hormonal therapy: PROSOM-K study.

BACKGROUND: Breast cancer (BC) is the most frequent cancer in women with more than 70% of BC patients being treated with hormonal therapy (HT). Among these patients, some report difficulties in remembering what they are supposed to do at the right moment, referring to prospective memory (PM). PM is essential for autonomy and medical adherence of patients, and requires an ecological assessment. Virtual reality, that recreates naturalistic environment, seems to be a promising method to evaluate PM. Several BC patients also report sleep disturbances. Given the role of sleep on memory consolidation, it is imperative to explore the influence of sleep quality on PM in BC patients treated with HT. The purpose of PROSOM-K study is to assess PM functioning using virtual reality and sleep quality in BC treated or not with HT. METHODS: PROSOM-K is a prospective study including post-menopausal BC patients ≤70 years old treated with radiotherapy (n = 25) or with radiotherapy and HT (n = 25), and healthy post-menopausal women (n = 25) matched for age and education. PM will be assessed using a virtual reality based task. Other cognitive functions and psychosocial factors will be assessed with validated questionnaires and neuropsychological tests. The study is divided in 3 sessions: a session of familiarisation with the virtual environment and the PM task: a day-time session during which participants learn intentions during the morning and recall them in the evening; and a night-time session during which participants learn intentions in the evening and recall them the following morning. Women will be monitored by wrist actigraphy; during the night-time session, objective sleep quality and quantity will be measured by polysomnography. DISCUSSION: This is a novel study aiming to assess PM using virtual reality, coupled with the evaluation of other cognitive functions. Polysomnographic study of sleep will provide further information about architectural sleep disturbances in BC. Association between sleep architecture parameters and PM mechanism in BC women treated with HT will be described in detail. We expect our results will provide knowledge for patients and clinicians and further help to improve patient care and cognitive therapy. TRIAL REGISTRATION: NCT03420105 , registered: January 10, 2018.

[Senile insomnia treated with integrated acupuncture and medication therapy: a randomized controlled trial].

OBJECTIVE: To compare the efficacy difference in the treatment of senile insomnia among western, medication, acupuncture and the integrated therapy of acupuncture and western medication. METHODS: Ninety-eight patients of senile insomnia were randomized into a western medication group (30 cases), an acupuncture group (35 cases) and an integrated acupuncture and medication group (35 cases). In the western medication group, estazolam 1mg was prescribed, taken 30 min before going to bed, oryzanol 20 mg, oral administration, three times a day, for 4 weeks totally. In the acupuncture group, the simple acupuncture therapy was applied at Shenmen (HT 7), Sanyinjiao (SP 6), Anmian (Extra), Baihui (GV 20) and Sishencong (EX-HN 1), as well as the supplementary points selected according to the differentiation. The acupuncture treatment was given once a day, 5 treatments a week, for 4 weeks totally. In the integrated acupuncture and medication group, the western medication was combined with acupuncture. The dosage and usage of western medication were same as those in the western medication group; and acupoints in acupuncture treatment were same as those in the acupuncture group. The treatment lasted for 4 weeks in the three groups. Pittsburgh sleep quality index (PSQI) and clinical efficacy were observed before treatment, after 4 weeks' treatment and in 4 weeks after discontinuity of treatment in the three groups. RESULTS: Four weeks after treatment, the clinical curative rates were 3. 3% (1/30), 21. 2% (7/33) and 25. 7% (9/35) in the western medication group, the acupuncture group and the integrated acupuncture and medicines group separately. The total effective rates were 70. 0%(21/30), 93. 9%(31/33) and 97. 1%(34/35) in the three groups separately. The curative rates and the total effective rates in the integrated acupuncture and medication group and the acupuncture group were higher than those in the western medication group separately (all, P<0. 01). PSQI scores after 4 Weeks' treatment were all improved as compared with those before treatment in the three groups (all P<0. 05). PSQI score in either the integrated acupuncture and medication group or the acupuncture group was lower than that in the western medication group, indicating the significant difference (both P< 0. 05). Four weeks after discontinuity of treatment, the efficacy was stable in the acupuncture group and the integrated acupuncture and medication group. PSQI score did not change as compared with that in the 4th week of treatment. The score in the western medication group ran back, close to that before treatment (P>0. 05). During the treatment, a few patients had dry mouth in the western medication group. The adverse reactions were not discovered in the other two groups. CONCLUSION: The integrated therapy of acupuncture and medication achieves the quick efficacy on senile insomnia and rapidly relieves the symptoms, with quite high clinical curative rate and total effective rate obtained. The long-term efficacy is better than that of western medication. The integrated therapy is the first option among the three therapeutic programs.

[Antipsychotics-induced acute necrotizing enterocolitis: a case report]. / À propos d'un cas d'entérocolite nécrosante aiguë sous antipsychotiques.

The acute necrotizing enterocolitis (ANE) is a partial or total necrosis of the small and large intestine. This is a case report of an antipsychotic induced ANE.

Comparative bioavailability of two estazolam tablet formulations in Indonesian healthy volunteers.

AIM: To compare the bioavailability of two estazolam (CAS 29975-16-4) tablet formulations (Estalin 2 mg tablets as test formulation and 2 mg tablets of the originator product as reference formulation). METHODS: The study was conducted according to an open label, randomized two-way cross-over design with a two-week washout period. Twenty-four subjects received each of the two estazolam formulations. Blood samples for pharmacokinetic profiling were taken up to 72 h after drug administration in fasting condition. Plasma concentrations of estazolam were determined with a validated HPLC method with ultraviolet detection. Pharmacokinetic parameters were calculated from observed plasma concentration-time profiles. RESULTS: The mean AUC(0-t), AUC(0-infinity) and Cmax were 2581.38 ng x h/mL, 2934.37 ng x h/mL and 95.25 ng/mL, respectively for the test formulation and 2835.75 ng x h/ mL, 3207.73 ng x h/mL and 99.32 ng/mL, respectively, for the reference formulation. The median Tmax for both formulations was 1 h. The point estimates and 90% confidence Intervals for AUC(0-t), AUC(0-infinity) and Cmax were 91.03% (87.48-94.72%), 91.48% (86.67-96.55%) and 95.90% (92.60-99.31%) respectively, satisfying the bloequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration guidelines. CONCLUSION: These results indicate that two formulations of estazolam are bioequivalent and, thus, may be prescribed interchangeably.

Effects of the CYP2C19 genotype and cigarette smoking on the single oral dose pharmacokinetics and pharmacodynamics of estazolam.

The effects of the cytochrome P450 (CYP)2C19 genotype and cigarette smoking on the single oral dose pharmacokinetics and pharmacodynamics of estazolam were studied in 16 healthy male volunteers. The two mutated alleles (CYP2C19*2 and CYP2C19*3) causing absent CYP2C19 activity were identified by PCR-based restriction enzyme analysis. Five subjects had no mutated allele, five had one mutated allele, and six had two mutated alleles. Seven subjects were smokers, and nine were nonsmokers. The subjects received a single oral 4-mg dose of estazolam, and blood samplings and evaluation of psychomotor function were conducted up to 72 h after dosing. There was no significant difference among the groups with no, one, and two mutated alleles for the peak plasma concentration (145.2+/-36.5 vs. 142.1+/-33.6 vs. 113.2+/-29.7 ng/ml), area under the plasma concentration-time curve (0- infinity ) (4916.0+/-1276.4 vs. 4389.6+/-736.1 vs. 4047.3+/-613.8 ng x h/ml), apparent oral clearance (0.22+/-0.05 vs. 0.25+/-0.03 vs. 0.25+/-0.03 ml/min/kg), and elimination half-life (24.4+/-4.6 vs. 29.6+/-8.5 vs. 30.7+/-3.9 h). Similarly, none of the pharmacokinetic parameters was significantly different between the nonsmoker and smoker groups. Neither the number of mutated allele nor cigarette smoking affected the psychomotor function parameters significantly. The present study suggests that neither the CYP2C19 genotype nor cigarette smoking affects the single oral dose pharmacokinetics and pharmacodynamics of estazolam.

No effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of estazolam.

To examine the involvement of cytochrome P450 3A4 in the metabolism of estazolam, the effect of itraconazole, a potent inhibitor of this enzyme, on the single oral dose pharmacokinetics and pharmacodynamics of estazolam was studied in a double-blind randomized crossover manner. Ten healthy male volunteers received itraconazole 100 mg/day or placebo orally for 7 days, and on the 4th day they received a single oral 4-mg dose of estazolam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test, Visual Analog Scale, and Stanford Sleepiness Scale were conducted up to 72 hours after estazolam dosing. There was no significant difference between the placebo and itraconazole phases for the peak plasma concentration, apparent oral clearance, and elimination half-life. Similarly, none of the psychomotor function parameters was significantly different between the two phases. The current study showed no significant effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of estazolam, suggesting that cytochrome P450 3A4 is not involved in the metabolism of estazolam to a major extent.

Central serotonergic mechanisms on head twitch response induced by benzodiazepine receptor agonists.

Intraperitoneal injection of benzodiazepine receptor agonists (estazolam, zopiclone, triazolam: 0.03-0.24 mmol/kg) induces the head twitch response (HTR). The present study was undertaken to examine the possible participation of the serotonergic system in the mechanism of head twitches induced by benzodiazepine receptor agonists (BZ-RAs). The HTR induced by BZ-RAs was suppressed by pretreatment with ketanserine (1 mg/kg, i.p.), a selective 5-HT(2) receptor antagonist. Pretreatment with fluoxetine (10 mg/kg, i.p.), a 5-HT reuptake inhibitor, and 8-hydroxy-2-(di-n-propylamino)tetralin, a 5-HT(1A) receptor agonist, also suppressed the HTR induced by BZ-RAs. These results suggest that the HTR induced by BZ-RAs may be the result of an activation of postsynaptic 5-HT(2) receptors, probably due to direct action.

Relationship between clinical symptoms and EEG findings in borderline personality disorder.

Borderline personality disorder (BPD) was diagnosed in female patients (N = 41) between the ages of 18 and 30 using the Diagnostic Interview for Borderline Patients (DIB) and DSM-III. Comparing the EEG findings of BPD (N = 18) and non-BPD (N = 21) groups, there were no EEG findings characteristic of BPD. We also assessed the relationship between the EEG findings and DIB items. Positive spikes appeared in patients with high scores for Impulse Action Patterns, while wave and spike phantoms were observed in patients with high scores for Interpersonal Relations. Dividing the patients into BPD and non-BPD groups, a similar tendency to that observed from an analysis of all patients was observed in the non-BPD group, but no such tendency was observed in the BPD group. The results suggest that BPD patients include those in whom vulnerability of cerebral function plays an important role in the development of these two clinical symptoms as well as those in whom vulnerability of cerebral function plays almost no pathogenic role.

[Cervical ripening and drug dilatation for birth control operations].

Cervical ripening in induced labor at second trimester of pregnancy was studied in 81 cases. The method consisted of injecting diazepam gel through Foley's catheter, into the extra-amniotic space, and at the level of cervical internal os. The cervix was found to be softened, the time interval between induction and onset of labor shortened and there was no cervical laceration. A comparison between the experimental and control groups showed significant difference. The use of suppositories for cervical dilatation in 719 cases of induced abortion and 34 cases of insertion and/or removal of IUD was also studied. The results were satisfactory. The mechanism of cervical dilatation and ripening with drug had been investigated at different periods of pregnancy and in non-pregnant women as well.

Hypnotic efficacy of estazolam compared with flurazepam in outpatients with insomnia.

Estazolam is a new benzodiazepine hypnotic agent with an intermediate half-life of 12 to 15 hours. The authors designed an investigation to compare its hypnotic efficacy to that of flurazepam, generally considered the reference standard. The hypnotic efficacy of estazolam at two doses (1 mg and 2 mg) was compared with that of flurazepam (30 mg) in a double-blind, placebo-controlled, multicenter, 7-night study that involved 223 outpatients with insomnia. On subjective assessments of the patients, no differences were noted between estazolam 2 mg and flurazepam 30 mg on any of six sleep parameters. Patients who were receiving estazolam 1 mg rated their sleep significantly better than did patients who were receiving placebo on all parameters except sleep latency. Global evaluation of the physicians indicated significant improvement in quality of sleep, sleep depth, sleep duration, and nocturnal awakenings in all three active treatment groups; estazolam 2 mg and flurazepam also decreased sleep latency significantly. The percentage of patients who reported any adverse experience was 68% for flurazepam, 58% for estazolam 2 mg, and 54% for estazolam 1 mg; the incidence of adverse events in the placebo group was 43%. In conclusion, estazolam 2 mg was found to be as effective a hypnotic as flurazepam 30 mg. Estazolam 1 mg is also effective in the treatment of outpatients with insomnia, but to a lesser degree.

Ventilatory response to single, high dose estazolam in healthy humans.

The purpose of this study was to determine the effect of oral estazolam at two and three times the usually recommended dosage (2 mg) on ventilation and respiratory drive during wakefulness. Sixty healthy subjects were randomized to receive a single oral dose of either: 1) estazolam 4 mg; 2) estazolam 6 mg; 3) placebo; or 4) morphine 0.15 mg/kg. Predrug and postdrug measurements were obtained for ventilation, respiratory cycle timing, metabolic rate, temperature, and ventilatory and mouth occlusion pressure (P0.1) responses to exogenous CO2. No difference between placebo and the study drugs was noted during eupneic breathing. During administration of exogenous CO2, morphine caused a decrease in the slope of the ventilatory (-0.4 +/- 0.1 L/min/mm Hg, P = .008) and P0.1 (-0.22 +/- 0.06 cm H2O/mm Hg, P = .015) responses. Estazolam (4 and 6 mg) had no effect on the ventilatory response to exogenous CO2. However, estazolam (6 mg) caused the P0.1 at a PCO2 of 57 mm Hg to decrease (-0.67 +/- 0.30 cm H2O, P = .005). The preservation of ventilation with the highest dose of estazolam, despite the decrease in P0.1, indicates that a compensatory strategy independent of respiratory center drive may have been activated. Sedation was a common side effect of estazolam reported in 13% and 53% of subjects at the 4 mg and 6 mg doses, respectively. We conclude that a single, high dose of estazolam does not cause ventilatory depression during wakefulness in healthy subjects.

Safety of estazolam. The United States clinical experience.

The safety profile of estazolam, a new triazolobenzodiazepine hypnotic medication, has been developed in 1,320 normal volunteers and patients with insomnia. No clinically significant effects of estazolam on vital signs or laboratory values were detected. Drug-specific adverse effects such as somnolence, dizziness, hypokinesia, and abnormal coordination occurred, but these are expected extensions of benzodiazepine pharmacologic activity. No consistent effects on psychomotor performance, including memory, were seen at the recommended hypnotic doses in insomniac subjects. These data, combined with the evidence for hypnotic activity, indicate that estazolam is a safe and effective treatment for insomnia.

The clinical pharmacokinetics of single doses of estazolam.

The pharmacokinetics of estazolam were examined in 17 healthy male subjects. Plasma concentration-time profiles were compared following the oral administration of one 1-mg tablet, two 1-mg tablets, and one 2-mg tablet. No statistically significant differences were detected among the mean time of maximal plasma concentration (Tmax), maximal plasma concentration (Cmax), area under the plasma concentration-time curve from zero to 72 hours (AUC), or half-life values for the 2-mg doses. Mean Cmax was 97.7 and 98.6 ng/ml and mean Tmax was 1.9 and 1.6 hours for two 1-mg tablets and one 2-mg tablet, respectively. Proportionately decreased Cmax and AUC were observed following the 1-mg dose. Mean Cmax was 54.7 ng/ml for the 1-mg dose. Mean Tmax and elimination half-life values were similar to those observed after the 2-mg doses. The overall harmonic mean half-life was 14.4 hours.

Efficacy of estazolam. The United States clinical experience.

The hypnotic efficacy of estazolam, a triazolobenzodiazepine, has been established in well-controlled sleep laboratory and outpatient clinical trials. Estazolam 1.0 mg and 2.0 mg significantly improves sleep latency, total sleep time, number of nocturnal awakenings, depth of sleep, and sleep quality in adults with chronic insomnia. Long-term studies indicate that estazolam 2.0 mg remains an effective hypnotic for at least six weeks of continuous nightly administration with no evidence of clinically significant tolerance. Estazolam is an effective treatment for situational insomnia and significantly improves sleep in patients with insomnia associated with moderately severe anxiety or depression.

Benzodiazepine self-administration in rhesus monkeys: estazolam, flurazepam and lorazepam.

The ability of three benzodiazepines to maintain self-administration behavior was studied in rhesus monkeys using a substitution procedure. Lever-press responding was maintained in six monkeys under a fixed-ratio schedule of IV pentobarbital delivery in daily sessions of 3 hr duration. Each of several doses of flurazepam, lorazepam and estazolam as well as saline and vehicle was periodically substituted for 4-13 consecutive sessions. Between dose or vehicle substitutions, responding was maintained by pentobarbital. All six monkeys self-administered flurazepam above vehicle or saline levels. In addition four of five monkeys tested with lorazepam and four of six tested with estazolam self-administered at least one dose of drug above control levels. These results indicate that self-administration performance can be reliably maintained in rhesus monkeys by certain benzodiazepines under appropriate experimental conditions.

Comparative efficacy of estazolam, flurazepam, and placebo in outpatients with insomnia.

The efficacy and safety of estazolam, an investigational triazolobenzodiazepine, and flurazepam were compared in 65 insomniac outpatients. Patients completed sleep questionnaires each morning. Global evaluations demonstrated that both treatments were significantly superior to placebo. However, estazolam was preferred over flurazepam in a global rating that reflected how well rested and refreshed the subjects felt on arising. Improvement in complaints of difficulty in going to sleep showed only a trend toward significance favoring estazolam and flurazepam over placebo. Residual daytime drowsiness and fatigue accounted for approximately 70% of all side effects with both active treatments. Significantly more side effects occurred with flurazepam than with estazolam. Flurazepam-treated patients had a significantly more severe rating of adverse reactions than did placebo-treated patients.

Kinetic and pharmacological studies on estazolam in mice and man.

After i.v. and oral doses of estazolam (5 mg/kg) to mice, the drug was rapidly cleared with a beta half-life (t1/2 beta) of 0.7 h. The active metabolite, 1-oxo-estazolam, was present in traces in mouse plasma and brain. Its elimination t1/2 (beta), determined after i.v. injection of 1-oxo-estazolam (5 mg/kg) to mice, was similar to that of the parent drug in both plasma and brain. After a single oral dose of estazolam (4 mg) to four human volunteers the drug was rapidly absorbed and reached maximum plasma concentrations in one to three hours. Elimination t1/2 of estazolam in humans was 19 h. The metabolite was undetectable in human plasma after either single or multiple doses of estazolam. These results, together with the finding that 1-oxo-estazolam was less effective than estazolam, in terms of ED50 and brain concentrations necessary to antagonize leptazol convulsions and disrupt rota-rod performance in mice, indicate that the metabolite does not contribute significantly to the pharmacological effects of its parent drug.

Nuevas Benzodiazepinas / New Benzodiazepines

En el último decenio han aparecido en nuestro mercado cuatro benzodiazepinas, ellas podrían representar avances sutiles pero importantes en el tratamiento de los desórdenes de ansiedad y del insomnio. En este trabajo se revisa brevemente la farmacología, la farmacocinética y las características clínicas de este grupo para facilitar su mejor manejo por el médico. Además, se presenta someramente algunas perspectivas futuras.