Anesthetic effects of the ketamine and midazolam association by intranasal or intramuscular route in domestic chickens: prospective, blinded, randomized and crossover study.

This prospective, blinded, randomized crossover study aimed to assess the anesthetic effects of the combination of 30 mg/kg ketamine and 2 mg/kg midazolam via intranasal (IN) or intramuscular (IM) routes in twelve domestic chickens. Physiological parameters (respiratory rate - RR, heart rate - HR, and cloacal temperature -Tºcloacal) were monitored throughout the experiment, along with recovery time and sedation level (S0: awake, no recumbency, responsive to stimuli; S1: blinking eyes, recumbency, relaxed, response to stimulus, mild movement; S2: open eyes, recumbency, relaxed, mild response to stimuli; S3: closed eyes, recumbency, relaxed, no movement). In the IM group, all birds reached S3, while in IN 5/12 reached S3, 4/12 reached at most S1, and 1/12 at most S2. IM administration showed higher sedation at 5, 10, 15, 20, 30, 35, 40, and 45 minutes (p<0.05). IN administration exhibited a shorter total recovery time (26.3±21.4 min vs. 92.9±33.4 min; p<0.001). No time, group, or time-group interaction effects were observed in HR and cloacal Tº, with a trend to a decrease in RR both groups (p<0.001). Increased incidences of vocalization and agitation was observed via IM (4/12 vs. 0/12; p=0.028), with no difference in salivation. Despite faster recovery with less agitation and vocalization, the ketamine and midazolam combination via IN provided less consistent sedation compared to the IM route in chickens.

Este estudo crossover randomizado objetivou avaliar os efeitos anestésicos da associação de 30 mg/kg de cetamina e 2 mg/kg de midazolam via intranasal (IN) ou intramuscular (IM) em doze galinhas. Além dos parâmetros fisiológicos (frequência respiratória ­ FR e cardíaca ­ FC e temperatura cloacal ­ Tºcloacal), registrou-se o tempo de recuperação e o grau de sedação ao longo do experimento (S0: acordada, sem decúbito, responsiva a estímulos; S1: olhos piscando, decúbito, relaxada, resposta a estímulo, movimentação leve; S2: olhos abertos, decúbito, relaxada, resposta leve a estímulos; S3: olhos fechados, decúbito, relaxada, sem movimentação. Pela via IM, todas as aves atingiram o grau S3, enquanto pela via IN 5/12 alcançaram S3, 4/12 atingiram no máximo S1 e 1/12 no máximo S2. A via IM apresentou maior sedação em 5, 10, 15, 20, 30, 35, 40 e 45 min (p<0,05). A via IN apresentou menor tempo total até recuperação (26,3±21,4 min vs. 92,9±33,4 min; p<0,001). Não foram observados efeitos de tempo, grupo e interação tempo-grupo na FC e na Tºcloacal com uma tendência de queda da FR nos dois grupos (p<0,001). Observou-se maior incidência de vocalização e agitação pela via IM (4/12 vs. 0/12; p=0,028), não havendo diferença para sialorreia. Apesar da recuperação mais rápida e com menos agitação e vocalização, a associação cetamina e midazolam via IN levou a uma sedação menos consistente que a via IM em galinhas.

Remimazolam versus propofol for sedation in gastrointestinal endoscopic procedures: a systematic review and meta-analysis.

BACKGROUND: Propofol has a favourable efficacy profile in gastrointestinal endoscopic procedures, however adverse events remain frequent. Emerging evidence supports remimazolam use in gastrointestinal endoscopy. This systematic review and meta-analysis compares remimazolam and propofol, both combined with a short-acting opioid, for sedation of adults in gastrointestinal endoscopy. METHODS: We searched MEDLINE, Embase, and Cochrane databases for randomised controlled trials comparing efficacy-, safety-, and satisfaction-related outcomes between remimazolam and propofol, both combined with short-acting opioids, for sedation of adults undergoing gastrointestinal endoscopy. We performed sensitivity analyses, subgroup assessments by type of short-acting opioid used and age range, and meta-regression analysis using mean patient age as a covariate. We used R statistical software for statistical analyses. RESULTS: We included 15 trials (4516 subjects). Remimazolam was associated with a significantly lower sedation success rate (risk ratio [RR] 0.991; 95% confidence interval [CI] 0.984-0.998; high-quality evidence) and a slightly longer induction time (mean difference [MD] 9 s; 95% CI 4-13; moderate-quality evidence), whereas there was no significant difference between the sedatives in other time-related outcomes. Remimazolam was associated with significantly lower rates of respiratory depression (RR 0.41; 95% CI 0.30-0.56; high-quality evidence), hypotension (RR 0.43; 95% CI 0.35-0.51; moderate-quality evidence), hypotension requiring treatment (RR 0.25; 95% CI 0.12-0.52; high-quality evidence), and bradycardia (RR 0.42; 95% CI 0.30-0.58; high-quality evidence). There was no difference in patient (MD 0.41; 95% CI -0.07 to 0.89; moderate-quality evidence) and endoscopist satisfaction (MD -0.31; 95% CI -0.65 to 0.04; high-quality evidence) between both drugs. CONCLUSIONS: Remimazolam has clinically similar efficacy and greater safety when compared with propofol for sedation in gastrointestinal endoscopies.

Benzodiazepine Consumption, Functionality, Cognition, and Somnolence in Older Adults at a Tertiary Care Psychiatric Hospital in Mexico City.

BACKGROUND: The aging population in Mexico, particularly those aged 60 and above, faces challenges in healthcare, including potentially inappropriate prescriptions of benzodiazepines. Physiological changes in older adults make precise drug prescriptions crucial. OBJECTIVE: This study aims to evaluate and compare functionality, cognition, and daytime somnolence in older adults using benzodiazepines versus non-users. Additionally, it outlines the demographic and clinical characteristics of both groups. METHODS: A cross-sectional study enrolled 162 participants aged 60 and above, categorized as benzodiazepine consumers or non-consumers. Assessment tools included Lawton's Index, Montreal Cognitive Assessment, Epworth Sleepiness Scale, and Benzodiazepine Dependence Questionnaire. Statistical analysis employed t-tests and chi-square tests. RESULTS: Benzodiazepine users (n=81) exhibited lower cognitive scores, increased sleepiness, and reduced daily living activities compared to non-users (n=81). Demographically, BZD users had lower education levels. CONCLUSION: Benzodiazepine use in older adults is associated with cognitive decline, daytime somnolence, and functional limitations, emphasizing the need for cautious prescription practices and continual monitoring. This study contributes insights into the impact of benzodiazepines on the cognitive health of older adults in Mexico.

Pharmacists' contribution to benzodiazepine deprescribing in older outpatients: a systematic review and meta-analysis.

BACKGROUND: Consolidated and reliable evidence regarding the effectiveness of pharmacist interventions for deprescribing benzodiazepines in older outpatients is lacking. AIM: This study evaluated and summarized the impact of pharmacist interventions on benzodiazepine deprescribing among older outpatients. METHOD: A literature search was conducted until August 2022 in PubMed, PsycINFO, and the Cochrane Central Register of Controlled Trials databases. The review included randomized controlled trials that assessed the impact of pharmacist interventions on deprescribing benzodiazepine in older outpatients. Two independent investigators conducted the study selection, data extraction, and risk of bias assessment. Meta-analyses were conducted using random-effect models in the RStudio software. RESULTS: A total of 893 records were identified. Five studies, including 3,879 patients, met the inclusion criteria and were included in the systematic review. All five studies used health education as an intervention strategy, and three also conducted medication reviews. There was no evidence of the pharmacist's authority to modify prescriptions during benzodiazepine deprescribing. One study was classified as having a low risk of bias, whereas the other had some concerns or a high risk of bias. Three studies were included in the meta-analysis and a significant impact of pharmacist interventions on benzodiazepines deprescribing rates in older outpatients was observed (RR = 2.75 [95%CI 1.29; 5.89]; p = 0.04; I2 = 69%; low certainty of evidence). CONCLUSION: Pharmacists may contribute to deprescribing benzodiazepines in older outpatients. Further studies are needed to increase the reliability of these findings. PROSPERO registration number: CRD42022358563.

Heteroaromatic salvinorin A analogue (P-3 l) elicits antinociceptive and anxiolytic-like effects.

Previous studies have attributed the prominent analgesic, hallucinogenic, sedative, and anxiolytic properties of Salvia divinorum to Salvinorin A. However, the overall pharmacological profile of this isolate limits its clinical applications. To address these limitations, our study evaluates the C(22)-fused-heteroaromatic analogue of salvinorin A [2-O-salvinorin B benzofuran-2-carboxylate] (P-3l) in mice nociception and anxiety models while assessing possible mechanism of action. In comparison with the control group, orally administered P-3l (1, 3, 10, and 30 mg/kg) attenuates acetic acid-induced abdominal writhing, formalin-induced hind paw licking, the thermal reaction to the hotplate, and/or aversive response in the elevated plus-maze, open field, and light-dark box; and potentiates the effect of morphine and diazepam at sub-effective doses (1.25 and 0.25 mg/kg, respectively) without eliciting significant alterations in relative organ weight, or haematological or biochemical parameters. The in vivo blockade of P-3 l effects by naloxone (non-selective opioid receptor antagonist), naloxonazine (antagonist of specific subtypes mu1 of µ-OR), and nor-binaltorphimine (selective ĸ-OR antagonist) supports initial results from binding assays and the interpretations made possible from computational modeling of the interactions of P-3 l with the opioid receptor subtypes. In addition to the opioidergic mechanism, the blockade of the P-3 l effect by flumazenil suggests benzodiazepine binding site involvement in its biological activities. These results support P-3 l potentially possessing clinical utility and substantiate the need for additional pharmacological characterization.

Individual differences in the effects of midazolam on anxiety-like behavior, learning, reward, and choice behavior in male mice.

Introduction: The aim of the present study was to investigate the behavioral effects of the benzodiazepine midazolam in male mice, in models of anxiolysis, learning, and abuse-related effects. Methods: In a first set of experiments, male Swiss mice were submitted to the training session of a discriminative avoidance (DA) task on the elevated plus maze to evaluate anxiety-like behavior and learning after vehicle or midazolam (1, 2 or 5 mg/kg, i.g.) administration. The same animals were submitted to a conditioned place preference (CPP) protocol with midazolam (1, 2 or 5 mg/kg, i.g.). In a second experiment, outbred (Swiss) and inbred (C57BL/6) male mice were submitted to a two-bottle choice (TBC) oral midazolam drinking procedure. Animals were exposed to one sucrose bottle and one midazolam (0.008, 0.016 or 0.032 mg/ml) plus sucrose bottle. Results: Midazolam (1 and 2 mg/kg) induced anxiolytic-like effects, and all doses of midazolam prevented animals from learning to avoid the aversive closed arm during the DA training session. Assessment of midazolam reward via the CPP procedure and choice via the TBC procedure showed notable variability. A 2-step cluster analysis for the CPP data showed that midazolam data were well-fitted to 2 separate clusters (preference vs. aversion), albeit with the majority of mice showing preference (75%). Correlational and regression analyses showed no relationship between midazolam reward and anxiolytic-like effects (time spent in the open arms in the DA test) or learning/memory. Two-step cluster analysis of the TBC data also demonstrated that, regardless of strain, mice overall fell into two clusters identified as midazolam-preferring or midazolam-avoiding groups. Both midazolam preference and avoidance were concentration-dependent in a subset of mice. Discussion: Our findings show that midazolam preference is a multifactorial behavior, and is not dependent solely on the emergence of therapeutic (anxiolytic-like) effects, learning impairments, or on genetic factors (inbred vs. outbred animals).

Behavioral Despair Is Blocked by the Flavonoid Chrysin (5,7-Dihydroxyflavone) in a Rat Model of Surgical Menopause.

Women have a high susceptibility to the negative effects of stress. Hormonal changes experienced throughout their reproductive life partially contribute to a higher incidence of anxiety and depression symptoms, particularly, during natural or surgical menopause. In preclinical research, the flavonoid chrysin (5,7-dihydroxyflavone) exerts anxiolytic- and anti-despair-like effects; however, it is unknown whether chrysin exerts a protective effect against the behavioral changes produced by acute stress on locomotor activity and behavioral despair in rats at 12-weeks post-ovariectomy. Ovariectomized female Wistar rats were assigned to eight groups: vehicle group (10% DMSO), three groups with chrysin and three groups with the same dose of allopregnanolone (0.5, 1, and 2 mg/kg), and one group with diazepam (2 mg/kg). The treatments were administered for seven consecutive days and the effects were evaluated in the locomotor activity and swimming tests. Chrysin (2 mg/kg) increased the latency to first immobility and decreased the total immobility time in the swimming test as the reference drugs allopregnanolone and diazepam (2 mg/kg); while locomotor activity prevented the behavioral changes produced by swimming. In conclusion, chrysin exerts a protective effect against the behavioral changes induced by acute stress, similarly to the neurosteroid allopregnanolone and the benzodiazepine diazepam in rats subjected to a surgical menopause model.

Intra-uterine diazepam exposure decreases the number of catecholaminergic and serotoninergic neurons of neonate rats.

Benzodiazepines, such as diazepam (DZP), are used to treat anxiety disorders, and are prescribed to pregnant woman for therapeutic purposes. Concerns regarding their consequences on postnatal development rise as they cross the placenta and interact with the embryo. Occurrence of malformation and behavioral syndromes have been reported for different ages, but little is known about their effects on the brain after exposure during intrauterine life. Thus, we sought to evaluate the effects of intrauterine exposure to DZP on the number of brainstem's catecholaminergic and serotonergic neurons, implicated in respiratory control, in male and female rats on postnatal (P) day 12-13, using immunofluorescence labeling for tyrosine-hydroxylase (TH) and serotonin (5-HT). We observed a reduction in the number of catecholaminergic neurons for males and females. Special attention is given to the reduction in the density of neurons in the A6 region, involved in ventilatory responses to CO2. Interestingly, only males showed a reduction in the number of serotonergic neurons, while females were not affected. These findings suggest that in utero exposure to DZP results in deleterious neuroanatomical effects on P12-13 rats and raises a note of concern for women clinicians to make more informed choices about the use of anxiolytic treatments during gestation.

Treatment of zolpidem poisoning with flumazenil in a cat / Tratamento da intoxicação por zolpidem com flumazenil em um gato

This report aims to describe the case of a cat intoxicated with zolpidem that was treated with flumazenil. Flumazenil is an imidazodiazepine that effectively reverses the central effects of benzodiazepines. In humans, it is used to treat zolpidem poisoning. Zolpidem is a sedative hypnotic agent, non-benzodiazepine, that is used to treat patients with insomnia. A 2-year-old Bengal cat weighing 2.5 kg showed signs of ataxia, incoordination and diarrhea after accidental ingestion of 10 mg zolpidem (Stilnox®). The cat was administered with 0.1 mg/kg of flumazenil intravenously, and after 20 minutes all clinical signs disappeared. To our knowledge, this is the first report of the use of flumazenil for the treatment of zolpidem poisoning in cats. Discussion regarding the treatment of zolpidem poisoning is necessary owing to the increased prescription of this drug in humans and, consequently, to a greater possibility of accidental poisoning in domestic animals

Este relato tem como objetivo descrever o caso de um gato intoxicado por zolpidem que foi tratado com flumazenil. O flumazenil é uma imidazodiazepina eficaz na reversão dos efeitos centrais dos benzodiazepínicos. Em humanos, é usado para tratar a intoxicação por zolpidem. Zolpidem é um agente hipnótico sedativo, não benzodiazepínico, utilizado para pacientes com insônia. Um gato Bengal de 2 anos, pesando 2.5 kg, apresentou sinais de ataxia, incoordenação e diarreia após ingerir 10 mg de zolpidem (Stilnox®) de forma acidental. O gato recebeu 0.1 mg/kg de flumazenil por via intravenosa, e após 20 minutos todos os sinais clínicos desapareceram. Esta é a primeira publicação relatando o uso de flumazenil no tratamento de intoxicação por zolpidem em gatos. A discussão sobre o tratamento da intoxicação por zolpidem se faz necessária devido ao aumento da prescrição desse medicamento em humanos e, consequentemente, à maior possibilidade de intoxicação acidental de animais domésticos

First evaluation of the anxiolytic-like effects of a bromazepam­palladium complex in mice.

A significant fraction of patients are affected by persistent fear and anxiety. Currently, there are several anxiolytic drug options, however their clinical outcomes do not fully manage the symptoms. Here, we evaluated the effects of a bromazepam­palladium derivative [2-{(7-bromo-2-oxo-1,3-dihydro-2H-1,4-benzodiazepin-5-il)pyridinyl-κ2-N,N}chloropalladium(II)], [(BMZ)PdCl2], on fear/anxiety and memory-related behavior in mice. For this, female Swiss mice were treated intraperitoneally (i.p.) with saline (NaCl 0.9%) or [(BMZ)PdCl2] (0.5, 5.0, or 50 µg/kg). After 30 min, different tests were performed to evaluate anxiety, locomotion, and memory. We also evaluated the acute toxicity of [(BMZ)PdCl2] using a cell viability assay (neutral red uptake assay), and whether the drugs mechanism of action involves the γ-aminobutyric acid type A (GABAA) receptor complex by pre-treating animals with flumazenil (1.0 mg/kg, i.p., a competitive antagonist of GABAA-binding site). Our results demonstrate that [(BMZ)PdCl2] induces an anxiolytic-like phenotype in the elevated plus-maze test and that this effect can be blocked by flumazenil. Furthermore, there were no behavioral alterations induced by [(BMZ)PdCl2], as evaluated in the light-dark box, open field, and step-down passive avoidance tests. In the acute toxicity assay, [(BMZ)PdCl2] presented IC50 and LD50 values of 218 ± 60 µg/mL and 780 ± 80 mg/kg, respectively, and GSH category 4. Taken together, our results show that the anxiolytic-like effect of acute treatment with [(BMZ)PdCl2] occurs through the modulation of the benzodiazepine site in the GABAA receptor complex. Moreover, we show indications that [(BMZ)PdCl2] does not promote sedation and amnesia and presents the same toxicity as the bromazepam prototype.

Sexually dimorphic effects of prenatal diazepam exposure on respiratory control and the monoaminergic system of neonate and young rats.

Pregnancy is highly affected by anxiety disorders, which may be treated with benzodiazepines, especially diazepam (DZP), that can cross the placental barrier and interact with the fetal GABAergic system. We tested whether prenatal exposure to DZP promotes sex-specific postnatal changes in the respiratory control of rats. We evaluated ventilation ([Formula: see text]) and oxygen consumption ([Formula: see text] O2) in resting conditions and under hypercapnia (7% CO2) and hypoxia (10% O2) in newborn [postnatal day (P) 0-1 and P12-13)] and young (P21-22) rats from mothers treated with DZP during pregnancy. We also analyzed brainstem monoamines at the same ages. DZP exposure had minimal effects on room air-breathing variables in females, but caused hypoventilation (drop in [Formula: see text]/[Formula: see text] O2) in P12-13 males, lasting until P21-22. The hypercapnic ventilatory response was attenuated in P0-1 and P12-13 DZP-treated females mainly by a decrease in tidal volume (VT), whereas males had a reduction in respiratory frequency (fR) at P12-13. Minor changes were observed in hypoxia, but an attenuation in [Formula: see text] was seen in P12-13 males. In the female brainstem, DZP increased dopamine concentration and decreased 5-hydroxyindole-3-acetic acid (5-HIAA) and the 3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine ratio at P0-1, and reduced DOPAC concentration at P12-13. In males, DZP decreased brainstem noradrenaline at P0-1. Our results demonstrate that prenatal DZP exposure reduces CO2 chemoreflex only in postnatal females and does not affect hypoxia-induced hyperventilation in both sexes. In addition, prenatal DZP alters brainstem monoamine concentrations throughout development differently in male and female rats.

Mechanism of action involved in the anxiolytic-like effects of Hibalactone isolated from Hydrocotyle umbellata L.

Background and aim: Hibalactone (HB) is a lignan related to the anxiolytic-like effects of Hydrocotyle umbellata L. However, there is a need to understand better the mechanism of action of this lignan to support the ethnopharmacological uses of the species. This work aimed to evaluate by in vivo and in silico analysis the mechanism of action of HB involved in its anxiolytic-like effects. Experimental procedure: The effects of HB in mice were evaluated on light-dark box (LDB) and elevated plus maze (EPM) tests. The participation of 5-HT1A receptor and the benzodiazepine site of GABAA receptor was evaluated to investigate the possible mechanism of action. In silico tools were used to better elucidate the anxiolytic-like effects of HB. Results: Oral treatment with HB at a dose of 33 mg/kg showed an anxiolytic-like effect in the LDB and EPM tests. Besides that, the treatment altered the ethological parameters, frequency of head dips, and stretched-attend postures (SAP), important to better describe the anxiolytic profile of HB. Pretreatment with flumazenil (2 mg/kg) reverted the anxiolytic-like effect of HB on LDB and EPM tests. On the other hand, pretreatment with NAN-190 (0.5 mg/kg) not reverted the activity observed. In silico predictions revealed the potential of HB to increase GABAergic neurotransmission. Pharmacophore modelling and docking simulations showed that HB might interact with the α1ß2γ2 GABAA receptor. Conclusion: Together, the results presented herein suggest that activation of the benzodiazepine site of the GABAA receptor contributes to the anxiolytic-like effect of HB.

To BDZ or not to BDZ? That is the question! Is there reliable scientific evidence for or against using benzodiazepines in the aftermath of potentially traumatic events for the prevention of PTSD? A systematic review and meta-analysis.

BACKGROUND: Most international guidelines suggest that benzodiazepines (BDZs) may be inefficient or iatrogenic in the aftermath of a potentially traumatic event (PTE). The goal of this study was to assess the strength of the evidence on whether the use of BDZs in the aftermath of a PTE negatively affects the incidence and severity of post-traumatic stress disorder (PTSD). METHODS: We systematically scrutinized the ISI Web of Knowledge, MEDLINE, SCOPUS, and PTSDpubs electronic databases in addition to citation searching. We included original studies providing data about the development of PTSD in adults after BDZ administration in the aftermath of a PTE. We screened 387 abstracts and selected eight studies for the qualitative synthesis and seven for the meta-analysis. We performed two separate meta-analyses, one for randomized clinical trials (RCTs) and the other for cohort studies. Heterogeneity between studies was evaluated with Higgins I² statistic and tested using the χ². This study was registered at PROSPERO (number 127170). RESULTS: The meta-analysis of the cohort studies showed an increased risk of PTSD in patients who received BDZs compared to those who did not (risk ratio (RR) = 1.53; 95% confidence interval (CI): 1.05-2.23) with a modest heterogeneity among studies (I2 = 41.8, p = 0.143). Regarding the RCTs, the combined measure revealed a tendency toward an increased severity of the PTSD symptoms (standardized mean difference (SMD): 0.24; 95% CI: 0.32-0.79). CONCLUSION: The studies reviewed showed a possible harmful effect of BDZs when used immediately after a PTE. However, these conclusions were based on a small number of studies of poor to moderate methodological quality.

Comparative study between ketamine-S-dexmedetomidine and ketamine-S-midazolam-methadone in the anesthesia of capuchin monkeys (Sapajus apella) / Estudo comparativo entre quetamina-S-dexmedetomidina e quetamina-S-midazolam- metadona na anestesia de macacos-prego (Sapajus apella)

Anesthetic protocols have been developed to obtain the most effective and safe association in wildlife. This study compared the anesthetic effects and cardiorespiratory parameters of ketamine-S (+) (10 mg/kg)/dexmedetomidine (0.020 mg/kg) (KD ) and ketamine-S (+) (10 mg/kg)/midazolam (0.5 mg/kg)/methadone (1.0 mg/kg) (KMM ) in capuchin monkeys (Sapajus apella). Eight capuchin monkeys were randomly assigned to KD (n = 4) or KMM (n = 4) to evaluate induction, immobilization, and recovery scores, heart and respiratory rate parameters, besides systolic, mean, diastolic arterial pressure and arterial blood gas. There was no difference (P = 0.56) in the quality of induction, immobilization, and anesthetic recovery between the protocols. The time for anesthetic induction was 4 ± 1 min in the KD group and 5 ± 1 min in the KMM group, and these values were statistically equal (P = 0.28). The mean immobilization time in the KD and KMM groups were 35 ± 13 and 33 ± 15 min, respectively. Heart rate was lower in animals in the KD group (P < 0.001), while respiratory rate (P = 0.03), and mean blood pressure (P = 0.046) were higher than that of the animals in the KMM group. Respiratory acidosis occurred in the KMM group, with lower pH (7.25±0.047; P = 0.0055) and higher pCO2 (51 ± 6;mmHg; P = 0.008). Both protocols exhibited good induction quality, immobilization, and anesthetic recovery, despite cardiorespiratory and blood gas alterations observed, which warrants monitoring of cardiorespiratory variables during KD or KMM chemical restraint.

Protocolos anestésicos foram desenvolvidos para obter a associação mais eficaz e segura em animais selvagens. O objetivo deste estudo foi comparar os efeitos anestésicos e os parâmetros cardiorrespiratórios de cetamina-S (+) (10 mg / kg) / dexmedetomidina (0,020 mg / kg) (KD) e cetamina-S (+) (10 mg / kg) / midazolam (0,5 mg / kg) / metadona (1,0 mg / kg) (KMM) em macacos-prego (Sapajus apella). Oito macacos-prego foram distribuídos aleatoriamente em KD (n = 4) ou KMM (n = 4) para avaliar os escores de indução, imobilização e recuperação, parâmetros de frequência cardíaca e respiratória, além da pressão arterial sistólica, média, diastólica e gasometria arterial. Não houve diferença (P = 0,56) na qualidade da indução, imobilização e recuperação anestésica entre os protocolos. O tempo de indução anestésica foi de 4 ± 1 min no grupo KD e 5 ± 1 min no grupo KMM, sendo esses valores estatisticamente iguais (P = 0,28). O tempo médio de imobilização nos grupos KD e KMM foram 35 ± 13min e 33 ± 15 min, respectivamente. A frequência cardíaca foi menor nos animais do grupo KD (P < 0,001), enquanto a frequência respiratória (P = 0,03) e a pressão arterial média (P = 0,046) foram maiores do que nos animais do grupo KMM. Acidose respiratória ocorreu no grupo KMM, com menor pH (7,25 ± 0,047; P = 0,0055) e maior pCO2 (51 ± 6; mmHg; P = 0,008). Ambos os protocolos apresentaram boa qualidade de indução, imobilização e recuperação anestésica, apesar das alterações cardiorrespiratórias e gasométricas observadas, o que justifica o monitoramento das variáveis cardiorrespiratórias durante a contenção química com KD ou KMM.

Anticonvulsant, Anxiolytic and Antidepressant Properties of the ß-caryophyllene in Swiss Mice: Involvement of Benzodiazepine-GABAAergic, Serotonergic and Nitrergic Systems.

BACKGROUND: Central nervous system disorders such as anxiety, depression and epilepsy are characterized by sharing several molecular mechanisms in common and the involvement of the L-arginine/NO pathway in neurobehavioral studies with ß-caryophyllene is still little discussed. OBJECTIVES: One of the objectives of the present study was to demonstrate the anxiolytic behavioral effect of ß-caryophyllene (ß-CBP) in female Swiss mice, as well as to investigate the molecular mechanisms underlying the results obtained. METHODS: This study evaluated the neurobehavioral effects of ß-CBP using the open field test, rota- rod test, elevated plus maze test, novelty suppressed feeding test, tail suspension test and forced swim test, as well as pilocarpine, pentylenetetrazole and isoniazid-induced epileptic seizure models. RESULTS: The results demonstrated that the neuropharmacological activities of ß-CBP may involve benzodiazepine/GABAergic receptors, since the pre-treatment of ß-CBP (200 mg/kg) associated with flumazenil (5 mg/kg, benzodiazepine receptor antagonist) and bicuculline (1 mg/kg, selective GABAA receptor antagonist) reestablished the anxiety parameters in the elevated plus-maze test, as well as the results of reduced latency to consume food in the novelty suppressed feeding test. In addition to benzodiazepine/GABAergic receptors, the neuropharmacological properties of ß-CBP may be related to inhibition of nitric oxide synthesis, since pre-treatment with L-arginine (500-750 mg/kg) reversed significantly the anxiolytic, antidepressant and anticonvulsant activities of ß-CBP. CONCLUSION: The results obtained provide additional support in understanding the neuromolecular mechanisms underlying the anxiolytic, antidepressant and anticonvulsive properties of ß-CBP in female Swiss mice.

Anestesia de cutias (Dasyprocta prymnolopha) com dextrocetamina e midazolam / Anesthesia of agoutis (Dasyprocta prymnolopha) with dextroketamine and midazolam

Research has increasingly focused on wild animals, and this requires the use of chemical restraints that are safe for both the species and the team involved. Dextroketamine is the levorotatory ketamine isomer that has been used on domestic species as an alternative that is more potent and safer than the racemic form. Midazolam is a benzodiazepine that induces muscle relaxation and minimal cardiorespiratory changes. The purpose of this study was to determine whether a combination of dextroketamine and midazolam can be safely used for the chemical restraint of agoutis (Dasyprocta prymnolopha), and the effects of this protocol on physiological and anesthetic parameters. This study was carried out under conditions similar to those found for wild animals in captivity or in zoos. A pre-evaluation was also made to compare the baseline values of this study with those of other studies on the same species. Nine healthy adult agoutis were used, weighing between 1.5 kg and 2 kg. All the parameters were evaluated and recorded before the drugs were applied, and this was considered the baseline moment (M0). The dextroketamine and midazolam combination was then administered intramuscularly, in the same syringe, in dosages of 15 mg/kg and 0.5 mg/kg, respectively. Successive evaluations were made every 10 min over a period of 40 min (M10, M20, M30 and M40). The latency stage of anesthesia, effective stage and recovery stage were observed. Heart rate (HR) and breathing frequency (f), body temperature (BT), systolic blood pressure (SBP), peripheral oxygen saturation (SpO2 ) and electrocardiogram were recorded. HR and SBP showed no significant difference between moments. Breathing frequency (f) showed a significant decline at M10 and M20 when compared to baseline values (P < 0.05). BT decreased from the moment the drugs were administered until the end of the experimental period, with a significant difference between M0 and M40, and M10 and M40 (P < 0.05). SpO2 decreased significantly at M10 and M20 when compared to baseline values (P < 0.01). There was no significant difference in the duration and amplitude of the P wave or in the duration of the QRS complex, QT interval and amplitude of the R wave. Regarding the PR interval, there was a significant difference only at M40 when compared to baseline values (P < 0.05). No arrhythmia was observed. An evaluation of the effects of anesthesia indicated that the animals had an average latency stage of 2 min, an effective stage of 87 min, and an average recovery stage of 111 min. Adverse effects observed during the anesthetic recovery period consisted of tearing, salivation, tongue protrusion, vocalization and chewing reflex. The results indicated that the association of anesthetic drugs under study caused minimal changes in the animals' physiological parameters, except for the breathing frequency (f), which declined considerably, resulting in a reduction in SpO2 , which was compensated during the study. In addition, there was a rapid onset of restraint and a satisfactory duration. Thus, from the cardiorespiratory standpoint, the combination of dextroketamine and midazolam in the doses used provides a safe anesthetic protocol for agoutis (Dasyprocta prymnolopha) and can be used for the chemical restraint of these animals for the performance of non-invasive and short-term procedures.(AU)

Deprescribing benzodiazepines: Do Brazilian package inserts address this issue? / Desprescrição de benzodiazepínicos: As bulas brasileiras abordam essa temática?

OBJECTIVE: To analyze the presence and quality of content on drug deprescribing in Brazilian package inserts for benzodiazepine drugs. METHODS: Documentary study where we analyzed data on deprescribing extracted from electronic package inserts of drugs containing benzodiazepines; these documents were available at the Brazilian Health Surveillance Agency website. Our search was performed independently by 2 researchers who used the following keywords: "deprescription," "withdrawal," and "tapering." The deprescribing plan, when presented by the package insert, was compared to deprescribing protocols for benzodiazepines found in the literature. Moreover, we assessed the presence of guidance on the maximum length of treatment and risks of long-term use. RESULTS: We found 12 package inserts for benzodiazepines and 100% of them suggested gradual withdrawal; only 1 (8.33%) suggested a systematized deprescribing plan. One document (8.33%) did not offer guidance on maximum treatment duration. Eleven (91.67%) had the information on long-term use possibly causing dependence or tolerance, and 1 (8.33%) did not describe the risks of continuous use. CONCLUSIONS: It is known that benzodiazepines should be withdrawn in a gradual and schematized manner, but package inserts do not currently bring this information in detail. It is of utmost importance that health professionals be educated on their conduct, hence the necessity for updating medication package inserts.

OBJETIVO: Analisar a presença e a qualidade do conteúdo sobre desprescrição em bulas brasileiras de benzodiazepínicos. METODOLOGIA:Estudo do tipo documental, em que foram analisados dados sobre a desprescrição extraídos de bulas eletrônicas de medicamentos que contêm benzodiazepínicos disponibilizadas na página eletrônica da Agência Nacional de Vigilância Sanitária. A busca foi realizada de forma independente por dois pesquisadores que utilizaram as palavras-chave "desprescrição", "retirada" e "redução". Para fins de comparação, quando a bula apresentou esquema de desprescrição, este foi comparado com protocolos de desprescrição de benzodiazepínicos encontrados na literatura. Além disso, foi analisada nas bulas a existência de orientações quanto ao tempo máximo de uso e os riscos do uso prolongado. RESULTADOS: Foram encontradas 12 bulas de benzodiazepínicos e 100% delas sugeriram a redução gradual do medicamento; apenas uma (8,33%) sugeria o esquema sistematizado de desprescrição. Uma (8,33%) não apresentou orientações quanto ao tempo máximo de uso. Onze (91,67%) continham a informação de que o uso prolongado pode causar dependência ou tolerância e uma (8,33%) não descrevia os riscos do uso contínuo. CONCLUSÕES: Sabe-se que os benzodiazepínicos devem ser retirados de forma gradual e esquematizada, porém, atualmente, as bulas não trazem essas informações de forma detalhada. É de suma importância que os profissionais de saúde sejam orientados quanto a sua conduta e, por isso, há grande necessidade de atualização das bulas.

Barriers and enablers to deprescribing benzodiazepines in older adults: elaborating an instrument and validating its content / Facilitadores e dificultadores do processo de desprescrição de benzodiazepínicos em idosos: elaboração de um instrumento e validação de seu conteúdo

OBJECTIVE: To elaborate and validate an instrument on barriers and enablers to deprescribing benzodiazepines in the patient's perspective. METHODS: This study was conducted in 3 stages: (1) a methodological stage, (2) a semi-structured pilot interview with 25 older adults undergoing clonazepam deprescribing, and (3) content validation with the Delphi technique. Content validation was performed by 50 specialists with degrees and/or experience with primary health care and/or health care of older adults, such as physicians, pharmacists, and nurses. For evaluating the obtained results, we analyzed the concordance of evaluations with the coefficient of content validity (CCV). We considered values equal to or higher than 0.8 as acceptable levels of concordance. RESULTS: The instrument was considered validated in the first round of evaluation, where all items obtained a CCV of more than 0.8 in the specialists' assessment. Nevertheless, they proposed improvements that were incorporated to the final version of the questionnaire. CONCLUSION: The instrument represents an important tool to be used by health care professionals for optimizing benzodiazepine deprescribing, with suitable levels of clarity and validity.

OBJETIVO: Elaborar e validar um instrumento sobre facilitadores e dificultadores do processo de desprescrição de benzodiazepínicos na perspectiva do paciente. METODOLOGIA: Estudo desenvolvido em três etapas, quais sejam: (1) metodológica, (2) entrevista piloto semiestruturada com 25 idosos em desprescrição de clonazepam e (3) validação de conteúdo por meio da técnica de Delphi. A validação deu-se por 50 especialistas com formação e/ou experiência na área da Atenção Primária à Saúde e/ou Saúde do Idoso, entre eles médicos, farmacêuticos e enfermeiros. Como medidas para avaliar os resultados obtidos, foi analisada a concordância da avaliação por meio do coeficiente de validade de conteúdo (CVC). Considerou-se como nível aceitável de concordância o valor maior ou igual a 0,8. RESULTADOS: O instrumento foi considerado validado na primeira rodada de avaliação, em que todos os itens avaliados obtiveram CVC superior a 0,8 na avaliação dos especialistas. Entretanto, estes propuseram sugestões de melhorias que foram incorporadas na versão final do questionário. CONCLUSÃO: O instrumento apresenta-se como uma importante ferramenta a ser utilizada pelos profissionais de saúde para a otimização do processo de desprescrição de benzodiazepínicos, possuindo índice de clareza e de validade adequados.

Flubromazolam: Detection in five post-mortem cases.

Flubromazolam is a potent triazole benzodiazepine with moderately long-lasting central nervous system-depressant effects relative to other benzodiazepines such as commonly prescribed diazepam. Flubromazolam has been studied in the living. However, there are no published reports including measured drug concentrations in post-mortem cases. We report five cases in which flubromazolam was detected in a systematic screen using high-resolution mass spectrometry and then quantified in femoral blood. In none of the five cases was the cause of death directly attributed to flubromazolam toxicity, as there was a variety of both sedative and stimulant drugs also present. However, it is important that the drug concentrations that were measured are made available for future post-mortem forensic interpretation.