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Poisoning of benzodiazepines, particularly triazolam, estazolam and alprazolam usually is caused by consumption of the drug in bigger doses than prescribed. So, for the fast determination of material caused poisoning, selective and effective methods of analysis are requested. Methods. Benzodiazepines triazolam, estazolam and alprazolam, were chosen for investigation. Analysis was performed using chromatograph „Waters 2695” with a photodiode array detector (Waters 996, at wavelength 200-400 nm range), ACE C18 (2,1 mm x 5,0 cm, 5 μm) chromatographic column, gradient eluent flow (sulfuric acid buffer 0,1% and ACN), eluent flow rate 0,1 ml/min and injection volume of 10 µl. Results.Methodics for identification and quantification of triazolam, estazolam, alprazolam and their mixture was developed using reference solutions. Validated methodic was adapted for identification and quantification of triazolam, estazolam, alprazolam in medicinal products. Conclusions.Selected methodic is suitable for qualification and quantification of the medicinal preparations: ACE C18 (2,1 mm x 5,0 cm, 5 μm) chromatographic column, gradient eluent flow (sulfuric acid buffer 0,1% and ACN), eluent flow rate 0,1 ml/min, injection volume of 10 µl and diode array detector. Mixture of components has been examined and retention times have been stated as follows: alprazolam (13,216 min), estazolam (13,407 min) and triazolam (14,340 min). Retention time upon repetition of analysis have not exceeded the relative error of p Limits of detection of alprazolam is 0,01 µg/ml, estazolam 0,012 µg/ml, triazolam 0,020 µg/ml. Limit of quantification of alprazolam is 0, 022 µg/ml, estazolam 0, 025 µg/ml, triazolam 0, 045 µg/ml

CYP3A probe drugs such as midazolam and endogenous markers, and plasma 4β-hydroxycholesterol (4β-OHC) and urinary 6β-hydroxycortisol-to-cortisol ratios (6β-OHC/C) have been used as markers of CYP3A induction in cynomolgus monkeys, as with humans. However, there is limited information on their sensitivity and ability to detect CYP3A induction, as most studies were evaluated only at a high dose of the inducer, rifampicin (RIF; 20 mg/kg). In the present study, the CYP3A induction by RIF over a range doses of 0.2, 2 and 20 mg/kg (n = 4) was examined using CYP3A probe drugs (midazolam, triazolam and alprazolam) and the plasma and urinary endogenous CYP3A markers (4β-OHC and 6β-OHC/C). The sensitivity and relationship for detecting CYP3A induction was compared among the markers. Four days repeated oral administration of rifampicin to cynomolgus monkeys reduced the area under the plasma concentration-time curve of all CYP3A probe drugs in a rifampicin dose-dependent manner. Although the endogenous CYP3A markers (4β-OHC and 6β-OHC/C) were also changed for the middle (2 mg/kg) and high (20 mg/kg) doses of rifampicin, the fold-changes were relatively small, and CYP3A induction could not be detected at the lowest dose of rifampicin (0.2 mg/kg). In conclusion, CYP3A probe drugs are more sensitive for detecting CYP3A induction than endogenous CYP3A markers in cynomolgus monkeys, even for a short experimental period.

Background: Anecdotal evidence suggests that there may be sex differences in Drug-drug Interactions (DDI) involving specific drugs. Regulators have provided general guidance for the inclusion of females in clinical studies. Some clinical studies have reported sex differences in the Pharmacokinetics (PK) of CYP3A4 substrates, suggesting that DDI involving CYP3A4 substrates could potentially show sex differences. Objective: The aim of this review was to investigate whether recent prospective DDI studies have included both sexes and whether there was evidence for the presence or absence of sex differences with the DDIs. Methods: The relevant details from 156 drug interaction studies within 124 papers were extracted and evaluated. Results: Only eight studies (five papers) compared the outcome of the DDI between males and females. The majority of the studies had only male volunteers. Five studies had females only while 60 had males only, with 7.7% of the studies having an equal proportion of both sexes. Surprisingly, four studies did not specify the sex of the subjects. : Based on the limited number of studies comparing males and females, no specific trends or conclusions were evident. Sex differences in the interaction were reported between ketoconazole and midazolam as well as clarithromycin and midazolam. However, no sex difference was observed with the interaction between clarithromycin and triazolam or erythromycin and triazolam. No sex-related PK differences were observed with the interaction between ketoconazole and domperidone, although sex-related differences in QT prolongation were observed. Conclusion: This review has shown that only limited progress had been made with the inclusion of both sexes in DDI studies.

psychotropic medicines: bromazepam, nitrazepam, and triazolam. analysis using thin layer chromatography and high performance liquid chromatography methods aim: To optimize thin-layer chromatography and high-performance liquid chromatography methods for bromazepam, nitrazepam, triazolam and their mixture qualitative analysis. results: - This mobile phase is suitable for examined substances separation, the qualitative analysis in mixture and determination in pharmaceutical products. -HPLC methodic is suitable for examined substances separation, the qualitative analysis in mixture and determination in pharmaceutical products. methodics: - High performance liquid chromatography(HPLC) : HPLC method bromazepam, nitrazepam, triazolam and their mixture solutions of 0, 1 mg/ml in methanol were analyzed. Chromatograph with a photodiode array detector at wavelength 240 nm range and chromatographic column ACE C18 (5.0 cm x 2.1 mm) with sorbent particle size 5 μm were used for qualitative determination. The analysis was performed by using 0, 1 mol/L sulfuric acid-methanol – acetonitrile (7:8:9) mixture as eluent. Optimized methodic was applied in the analysis of pharmaceutical products “Bromazepam Lannacher” (G.L. Pharma GmbH), “Eunoctin” (Gedeon Richter Plc,), “Halcion” (Pfizer H.C.P) (authorized in LT medicines) test solutions in 0.1% sulphuric acid: ACN solvents. HPLC method was performed using ACE C18 (5.0 cm x 2.1 mm) chromatographic column. Gradient elution mode was used (a mixture of 0, 1% sulfuric acid buffer solvent and ACN solvent – as eluent). Flow rate 1 ml/min. Injection volume 10 μl. Photodiode array detector (200- 600 nm wavelength). Bromazepam, nitrazepam, triazolam absorption of UV light was similar as in scientific literature - Thin layer chromatography (TLC) : For optimization of TLC method bromazepam, nitrazepam, triazolam and their mixture solutions in methanol were analyzed. For mobile phase were used: cyclohexane, methanol, diethylamine, sulfuric acid, acetonitrile (solvents). For spots visualization was used: UV light lamp (254 nm; 365nm). Optimized methodic was applied for pharmaceutical products “Bromazepam Lannacher” (G.L. Pharma GmbH), “Eunoctin” (Gedeon Richter Plc,), “Halcion” (Pfizer H.C.P) (authorized in LT medicines) test solutions in cyclohexane-methanol-diethylamine (75:15:10) solvent system. The best mobile phases for bromazepam, nitrazepam and triazolam mixture qualitative analysis using TLC was: “Cyclohexane-methanol-diethylamine (75:15:10) solvents system with an appropriate ratio

Outdoor artificial nighttime light is increasingly recognized as a form of environmental pollution. Excessive nighttime light exposure, whether from indoor or outdoor sources, has been associated with a number of deleterious effects on human health. We performed a population-based cohort study in South Korea to assess the possible association between outdoor nocturnal lighting and insomnia in older adults, as measured by prescriptions for hypnotic drugs.This study used data from the 2002-2013 National Health Insurance Service-National Sample Cohort (NHIS-NSC), and a total of 52,027 adults who were age 60 years or older were included in the study. Light data were based on satellite mapping of artificial light. The usage data of two hypnotic drugs, zolpidem (N05CF02) and triazolam (N05CD05), were extracted from the NHIS-NSC records.Of the 52,027 patients in this cohort, 11,738 (22%) had prescriptions for hypnotic drugs. Increasing outdoor artificial nighttime light exposure (stratified by quartile) was associated with an increased prevalence of hypnotic prescriptions and daily dose intake. Compared with individuals in the lowest quartile 1, the regression coefficients for prescription days and daily defined doses of all hypnotic drugs and certain hypotonic drugs were significantly higher among those living in areas with higher outdoor artificial nighttime light (quartiles 2 through 4).Outdoor artificial nighttime light exposure was significantly associated with prescription of hypnotic drugs in older adults. These findings are consistent with the hypothesis that outdoor artificial nighttime light may cause sleep disturbances.

Objective To assess the effects of hypnotics on prefrontal cortex activity in healthy subjects using near-infrared spectroscopy (NIRS) in a double-blind, placebo-controlled crossover trial. Methods Eighteen healthy males received acute doses of ramelteon (8 mg), triazolam (0.125 mg), or placebo in a predetermined randomization schedule, with a washout period of more than 1 week. All subjects performed a verbal fluency task during NIRS assessments at baseline and at 1 and 4 hr post-dose. The number of words correctly generated during the task (behavioral performance) and scores on the Stanford Sleepiness Scale (SSS) were also recorded at each test time. Results Compared with the placebo, triazolam (0.125 mg) significantly decreased oxyhemoglobin (oxy-Hb) concentration change in NIRS during the posttask period and significantly increased behavioral performance, whereas triazolam (0.125 mg) and ramelteon (8 mg) significantly increased SSS scores. Conclusions The differential effects of two types of hypnotics on oxy-Hb change measured by NIRS were observed in acute dosing, suggesting that when assessing brain activity of patients with psychiatric disorders, researchers should consider how certain types of hypnotics can influence brain function. This would also provide useful information to clinicians when prescribing hypnotics suitable for their patients' conditions.

To investigate the relationship between benzodiazepine and risk of developing pneumonia in patients with schizophrenia, whose benzodiazepine dosage and usage frequency was higher than that of the general population. We conducted a nested case–control study to assess the association between benzodiazepine use and pneumonia among patients with schizophrenia. By using the Taiwan National Health Insurance Research Database, we identified a schizophrenia cohort comprising 34,929 patients during 2000–2010. Within the schizophrenia cohort, 2501 cases of pneumonia and 9961 matched control patients (1:4 ratio) were identified. Benzodiazepine exposure was categorized by drug, treatment duration, and daily dose. Conditional logistic regression models were used to examine the association between benzodiazepine exposure and the risk of pneumonia. The current use (within 30 days) of midazolam led to the highest pneumonia risk (adjusted risk ratio = 6.56, P

Stupor is a diagnostic challenge at emergency department. Differential diagnosis includes idiopathic recurrent stupor, formerly attributed to “endozepine-4” accumulation. This condition has been recently questioned because many suspected cases resulted in exogenous benzodiazepine intake that eludes the conventional toxicological assay. In case of unexplained recurrent stupor, to extend the benzodiazepine search in nonconventional matrices can allow unmasking of hidden toxic behavior.

We have studied whether the phase II metabolism of 19-norandrosterone, the most representative metabolite of 19-nortestosterone (nandrolone), can be altered in the presence of other drugs that are not presently included on the Prohibited List of the World Anti-Doping Agency. In detail, we have evaluated the effect of non-prohibited drugs belonging to the classes of anti-fungals, benzodiazepines, and non-steroidal anti-inflammatory drugs on the glucuronidation of 19-norandrosterone. In vitro assays based on the use of either pooled human liver microsomes or specific recombinant isoforms of uridine diphosphoglucuronosyl-transferase were designed and performed to monitor the formation of 19-norandrosterone glucuronide from 19-norandrosterone. Determination of 19-norandrosterone (free and conjugated fraction) was performed by gas chromatography - mass spectrometry after sample pretreatment consisting of an enzymatic hydrolysis (performed only for the conjugated fraction), liquid/liquid extraction with tert-butylmethyl ether, and derivatization to form the trimethylsilyl derivative. In parallel, a method based on reversed-phase liquid chromatography coupled to tandem mass spectrometry in positive electrospray ionization with acquisition in selected reaction monitoring mode was also developed to identify the non-prohibited drugs considered in this study. Incubation experiments have preliminarily shown that the glucuronidation of 19-norandrosterone is principally carried out by UGT2B7 (39%) and UGT2B17 (31%). Inhibition studies have shown that the yield of the glucuronidation reaction is reduced in the presence of the anti-fungals itraconazole, ketoconazole, and miconazole, of the benzodiazepine triazolam and of the non-steroidal anti-inflammatory drugs diclofenac and ibuprofen, while no alteration was recorded in the presence of all other compounds considered in this study. Copyright © 2015 John Wiley & Sons, Ltd.

Benzodiazepines are positive allosteric modulators of the GABAA receptor and are prescribed as anxiolytics, hypnotics, and anticonvulsants. While these drugs clearly have clinical value, their use is associated with unwanted side effects such as sedation and motor impairment. Neuroactive steroids are endogenous modulators of GABAA receptors and recent evidence has shown that combinations of the triazolo-benzodiazepine triazolam and the endogenous neuroactive steroid pregnanolone can produce both supra-additive anxiolytic effects and infra-additive reinforcing effects. In the present study, we investigated these same combinations as well as combinations of two clinically-relevant drugs from different chemical classes, the 1, 4 substituted (7-nitro) benzodiazepine clonazepam and the synthetic neuroactive steroid ganaxolone, in rats trained under a 10-response, fixed ratio (FR) schedule of food reinforcement. All four drugs induced a significant and dose-dependent suppression of food-maintained responding. From the dose-response functions, ED50s (i.e., the doses that engendered 50% of the maximum rate-decreasing effect) were generated for each drug. Dose-response functions for combinations of triazolam/pregnanolone, clonazepam/ganaxolone, triazolam/ganaxolone, and clonazepam/pregnanolone were then determined. Isobolographic analysis of the rate-decreasing effects of these combinations revealed that the potencies of the triazolam/pregnanolone combinations were supra-additive while the clonazepam/ganaxolone combinations were additive or infra-additive in relation to predicted values based on dose-additive effects. Furthermore, mixtures of clonazepam/pregnanolone were supra-additive while triazolam/ganaxolone combinations were additive, infra-additive and supra-additive. These results suggest that the ability of benzodiazepine and neuroactive steroid combinations to attenuate rates of food-maintained responding depends critically on both the constituent drugs and the dose of drug in the mixtures.

BACKGROUND: Triazolam has similar pharmacological properties as other benzodiazepines and is generally used as a sedative to treat insomnia. Alprazolam represents a possible alternative to midazolam for the premedication of surgical patients. The purpose of this study was to evaluate the anxiolytic, sedative, and amnestic properties of triazolam and alprazolam as pre-anesthetic medications. METHODS: Sixty adult patients were randomly allocated to receive oral triazolam 0.25 mg or alprazolam 0.5 mg one hour prior to surgery. A structured assessment interview was performed in the operating room (OR), the recovery room, and the ward. The levels of anxiety and sedation were assessed on a 7-point scale (0 = relaxation to 6 = very severe anxiety) and a 5-point scale (0 = alert to 4 = lack of responsiveness), respectively. The psychomotor performance was estimated using a digit symbol substitution test. As a memory test, we asked the patients the day after the surgery if they remembered being moved from the ward to the OR, and what object we had shown them in the OR. RESULTS: There were no significant differences between the groups with respect to anxiety and sedation. The postoperative interviews showed that 22.2% of the triazolam-treated patients experienced a loss of memory in the OR, against a 0% memory loss in the alprazolam-treated patients. In comparison with alprazolam 0.5 mg, triazolam 0.25 mg produced a higher incidence of amnesia without causing respiratory depression. CONCLUSIONS: Oral triazolam 0.25 mg can be an effective preanesthetic medication for psychomotor performance.

Objective Older people are more likely to have insomnia. One of the most prescribed hypnotics in Japan is triazolam. Although some studies showed the possibility of adverse effects of triazolam in older people, there have been few studies investigating these effects in a clinical setting. The aim of this study was to determine whether patients who used triazolam regularly had increased risks of pneumonia, trauma, and pressure ulcers. Methods The research design was a retrospective cohort study using claim data. The subjects of the study were patients who were insured by Fukuoka Late Stage Elderly Healthcare Insurance. We defined patients who had received triazolam for 180 days or longer during fiscal year 2011 as the triazolam group, and those who had not received any hypnotics during the period as the non-triazolam group. Each patient in the triazolam group was then matched with a unique control from the non-triazolam group according to propensity score. Multivariate conditional logistic regression analyses were used to obtain adjusted odds ratios for pneumonia, trauma, and pressure ulcer in the triazolam group compared with the non-triazolam group. Results The number of patients in the triazolam and non-triazolam groups in the unmatched cohort was 13,015 and 411,610, respectively. Adjusted odds ratios show that the risks for pneumonia, trauma, and pressure ulcer in the matched cohort increased by approximately 40%, 30%, and slightly less than 30%, respectively (all statistically significant). Conclusions Regular use of triazolam is a risk factor for pneumonia, trauma, and pressure ulcer in older people. Copyright © 2015 John Wiley & Sons, Ltd.

The search for new anticonvulsant agent with more selectivity and lower toxicity continues to be an area of rigorous investigation in medicinal chemistry. Epilepsy is a chronic disorder of brain whose treatment consists of controlling seizures with antiepileptic drugs that very often related with side-effects which in rare circumstances can be potentially life-threatening. Triazolam and Alprazolam are established drugs used in epilepsy which have triazole moiety. The potency and broad spectrum of the pharmacological response of triazole moiety as anticonvulsant agent have attracted the attention of medicinal chemists to explore this framework for its potential. The literature shows that different substitution on triazole ring exhibit potent antiepileptic activity with no or lesser neurotoxicity. The present review is a sincere attempt to compile the reported potent triazole derivatives with significant anticonvulsant action.

We have previously shown that menthol attenuates the anticoagulant effect of warfarin by increasing the expression levels of CYP3A and CYP2C in the liver. This study evaluated the effects of menthol on the pharmacokinetics of the CYP3A substrate triazolam and the CYP2C substrate phenytoin. Menthol was orally administered to mice for 7 d. Twenty-four hours after the administration of menthol, triazolam was orally administered, and the plasma concentration was measured. In addition, the CYP3A metabolic activity for triazolam and the CYP3A expression level in the liver were determined. The effects of menthol on the pharmacokinetics of phenytoin were assessed in the same manner. In the menthol-treated group, the area under the blood concentration-time curve (AUC) of triazolam was lower and its clearance was higher compared with the control group. The CYP3A metabolic activity and CYP3A expression level in the liver were significantly increased in the menthol-treated group compared with the control group. Similarly, the AUC of phenytoin was lower and the hepatic CYP2C expression level was higher in the menthol-treated group. Thus, menthol lowered the plasma concentrations of triazolam and phenytoin when concurrently administered. These effects may be attributed to an increased metabolic activity for these drugs due to the increased expression of CYP3A and CYP2C in the liver.

It has been reported that insomnia characterized by difficulty returning to sleep following a nocturnal awakening, otherwise defined as the middle-of-the-night (MOTN) insomnia, is a common form of insomnia in adults with growing prevalence by increasing age. The aim of this study is to evaluate the efficacy and safety of different dosages of triazolam in insomnia patients when taken after a MOTN awakening with difficulty returning to sleep. In this double-blind, randomized, parallel group study, 24 patients (mean age 41.00±Â10.40, 10 female and 14 male) affected by MOTN insomnia were enrolled and randomized into three groups according to different dosages of triazolam: group A (0.0625Âmg), group B (0.125Âmg), and group C (0.250Âmg). A significant increment of total sleep time, sleep efficiency and a reduction of wake after sleep onset, number of awakening and non-REM sleep stage 1 was observed in T1 (triazolam) in comparison to T0 (placebo) by means of polysomnographic recording, irrespective of dosage. After 2Âweeks of the treatment, insomnia severity significantly improved in all three groups in comparison to baseline without diurnal residual effects. This study demonstrates that low dose of triazolam objectively and subjectively improves the sleep of patients having MOTN insomnia.

The induction of cytochrome P450 enzymes (CYPs) is an important source of drug-drug interaction (DDI) and can result in pronounced changes in pharmacokinetics (PK). Rifampicin (RIF) is a potent inducer of CYP3A4 and also acts as a competitive inhibitor which can partially mask the induction. The objective of this study was to determine a clinical DDI study design for RIF resulting in maximum CYP3A4 induction. A physiologically based pharmacokinetic (PBPK) model was developed to project the dynamics and magnitude of CYP3A4 induction in vivo from in vitro data generated with primary human hepatocytes. The interaction model included both inductive and inhibitory effects of RIF on CYP3A4 in gut and liver and accounting for the observed RIF auto-induction. The model has been verified for 4 CYP3A4 substrates: midazolam, triazolam, alfentanil and nifedipine using plasma concentration data from 20 clinical study designs with intravenous (n=7) and oral (n=13) administrations. Finally, the influence of the time between RIF and substrate administration was explored for the interaction between midazolam and RIF. The model integrating in vitro induction parameters correctly predicted intravenous induction but underestimated oral induction with 30% of simulated concentrations more than 2-fold higher than of observed data. The use of a 1.6-fold higher value for the maximum induction effect (Emax) improved significantly the accuracy and precision of oral induction with 82% of simulated concentrations and all predicted PK parameters within 2-fold of observed data. Our simulations suggested that a concomitant administration of RIF and midazolam resulted in significant competitive inhibition limited to intestinal enzyme. Accordingly, a maximum induction effect could be achieved with a RIF pretreatment of 600 mg/day during 5 days and a substrate administration at least 2 h after the last RIF dose. A period of 2 weeks after RIF removal was found sufficient to allow return to baseline levels of enzyme.

AIM: Short term administration of benzodiazepines (BZD) was found to prolong reaction time (RT) in experimental studies. However, studies on long term BZD use did not always adjust for important confounders and showed inconsistent results. We aimed to identify a possible relationship between long term BZD use and RT in BZD users in this large cross-sectional, observational study. METHODS: The RTs of non-users (n = 2404) were compared with low (n = 288), intermediate (n = 74), and high dose BZD users (n = 57) in the Netherlands Study of Depression and Anxiety (NESDA). RTs were obtained from the Implicit Association Test. Analyses were adjusted for sociodemographic characteristics, health indicators, severity of psychopathology and antidepressant use. RESULTS: Of the NESDA participants, 419 subjects (14.8%) used BZDs. A higher dose of BZDs was associated with prolonged RTs (P = 0.01). When comparing the different dose groups, the high dose group, but not the low and medium dose groups, had significantly longer RTs than the non-users. CONCLUSIONS: Tolerance for the RT prolonging effect of relatively high doses of BZDs does not seem to develop. As prolonged RTs can have adverse consequences in daily life, BZDs should be prescribed conservatively at the lowest possible dose.

Aim Short term administration of benzodiazepines (BZD) was found to prolong reaction time (RT) in experimental studies. However, studies on long term BZD use did not always adjust for important confounders and showed inconsistent results. We aimed to identify a possible relationship between long term BZD use and RT in BZD users in this large cross-sectional, observational study. Methods The RTs of non-users (n = 2404) were compared with low (n = 288), intermediate (n = 74), and high dose BZD users (n = 57) in the Netherlands Study of Depression and Anxiety (NESDA). RTs were obtained from the Implicit Association Test. Analyses were adjusted for sociodemographic characteristics, health indicators, severity of psychopathology and antidepressant use. Results Of the NESDA participants, 419 subjects (14.8%) used BZDs. A higher dose of BZDs was associated with prolonged RTs (P = 0.01). When comparing the different dose groups, the high dose group, but not the low and medium dose groups, had significantly longer RTs than the non-users. Conclusions Tolerance for the RT prolonging effect of relatively high doses of BZDs does not seem to develop. As prolonged RTs can have adverse consequences in daily life, BZDs should be prescribed conservatively at the lowest possible dose.

Continuing our studies for the analyses of drugs of abuse in municipal wastewater, a method was developed for the analysis of benzodiazepines in wastewater samples using liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS). Ten benzodiazepines and metabolites were analyzed (structures were found), including alprazolam, α-OH-alprazolam (the primary urinary metabolite of alprazolam), chlordiazepoxide, flurazepam, 2-OH-ethylflurazepam (the primary urinary metabolite of flurazepam), 7-NH2-flunitrazepam, nordiazepam, oxazepam, temazepam and α-OH-triazolam (the primary urinary metabolite of triazolam) (representative chromatograms were found). These drugs were chosen because of their widespread abuse. Wastewater samples were collected at both the Oxford Wastewater Treatment Plant (WWTP) in Oxford, Mississippi (MS) and the University WWTP in University, MS. These wastewater samples were collected on weekends in which the Ole Miss Rebel football team held home games at the Vaught-Hemingway Stadium, University, and one weekend on which there was no game. The collected samples were analyzed using a validated method and found to contain alprazolam, α-OH-alprazolam, nordiazepam, oxazepam and temazepam. None of the samples contained chlordiazepoxide, flurazepam, 2-hydroxyethyl-flurazepam, 7-NH2-flunitrazepam and α-OH-triazolam.

Objective The most common mental diseases in pregnant women are depression and anxiety disorders (estimated prevalence 6.5–12.9% and 15.6%, respectively [1] , [2] ). The drugs used in their treatment (antidepressants and benzodiazepines) can produce serious obstetric complications, as well as deleterious effects in fetal development and later in life [1] . The aim of this study was to compare maternal hair and meconium for detecting in utero drug exposure to benzodiazepines and antidepressants. Methods Maternal hair and meconium samples were collected after delivery from 145 mother–newborn dyads. Samples were analyzed for the determination of benzodiazepines (alprazolam, clonazepam, bromazepam, diazepam, nordiazepam, lorazepam, lormetazepam, oxazepam, flunitrazepam, 7-aminoflunitrazepam, triazolam, and zolpidem), antidepressants (amitriptyline, clomipramine, fluoxetine, paroxetine, venlafaxine, citalopram), and 6 metabolites by LC-MS/MS. Hair samples were segmented in 3 segments corresponding with the 3 trimesters (n = 99), but if the amount of hair was not enough a 8-cm segment was employed (n = 46). Maternal hair results (LOQ = 5–20 pg/mg) and meconium Results (LOQ = 5–20 ng/g) were compared. Results Forty-nine hair samples (33.8%) tested positive, 23 (15.9%) for benzodiazepines (19 segmented and 4 non-segmented) and 33 (22.8%) for antidepressants (23 segmented and 10 non-segmented). Specifically, the most frequently detected compounds in hair were nordiazepam (n = 13, > LOD-224.6 pg/mg), citalopram (n = 11, 30.2–7166.1 pg/mg), diazepam (n = 10, 6.6–879.5 pg/mg), amitriptyline (n = 8, 11.3–556.5 pg/mg), and venlafaxine (n = 8, 14.4–659.1 pg/mg). Twenty-eight meconium samples (19.3%) tested positive, 24 (16.6%) for benzodiazepines and 8 (5.5%) for antidepressants. The most frequently detect compounds in meconium were nordiazepam (n = 16, > LOD-125.1 ng/g), diazepam (n = 12, > LOD-68.6 ng/g), citalopram (n = 5, > LOD-2729.5 ng/g) and its metabolite desmethylcitalopram (n = 4, > LOD-1286.1 ng/g), and alprazolam (n = 3, 5.7–42.2 ng/g). The overall agreement between maternal hair and meconium results was 66.9%, but this value increased to 70.2% when only the hair results corresponding with the third trimester were compared with meconium. This good agreement was due to the high percentage of negative results (n = 84), but if only positive results were analyzed the percentage decreased to 19.7% and 42.6%, respectively. A better correlation was found between positive results in both specimens for benzodiazepines (39.1%) than antidepressants (18.2%). Moreover, when hair samples were positive in the three trimesters (n = 15), meconium was positive in 7 cases, and in the remaining cases the concentration in hair was decreasing along pregnancy, except in one case. Surprisingly, when benzodiazepines were administrated during delivery (n = 15), in 6 cases meconium tested positive at low concentrations (1.1–8.6 ng/g). Conclusion Maternal hair was more sensitive than meconium to detect consumption during pregnancy, while meconium was able to detect consumption during the third trimester and also during delivery.

Objective: To assess the effects of hypnotics on prefrontal cortex activity in healthy subjects using near‐infrared spectroscopy (NIRS) in a double‐blind, placebo‐controlled crossover trial. Methods: Eighteen healthy males received acute doses of ramelteon (8 mg), triazolam (0.125 mg), or placebo in a predetermined randomization schedule, with a washout period of more than 1 week. All subjects performed a verbal fluency task during NIRS assessments at baseline and at 1 and 4 hr post‐dose. The number of words correctly generated during the task (behavioral performance) and scores on the Stanford Sleepiness Scale (SSS) were also recorded at each test time. Results: Compared with the placebo, triazolam (0.125 mg) significantly decreased oxyhemoglobin (oxy‐Hb) concentration change in NIRS during the posttask period and significantly increased behavioral performance, whereas triazolam (0.125 mg) and ramelteon (8 mg) significantly increased SSS scores. Conclusions: The differential effects of two types of hypnotics on oxy‐Hb change measured by NIRS were observed in acute dosing, suggesting that when assessing brain activity of patients with psychiatric disorders, researchers should consider how certain types of hypnotics can influence brain function. This would also provide useful information to clinicians when prescribing hypnotics suitable for their patients' conditions., ファイル公開：2019-11-01