Phytol exerts sedative-like effects and modulates the diazepam and flumazenil's action, possibly through the GABAA receptor interaction pathway.

This study aimed at the evaluation of the sedative effect of phytol (PHY) with possible molecular mechanisms through in vivo and in silico studies. For this, adult male mice were randomly divided into six individual groups, namely control (vehicle), two standards (DZP: diazepam at 2 m/kg, FLU: flumazenil at 0.1 mg/kg), three test groups (PHY at 25, 50, and 75 mg/kg), and three combined groups with the DZP-2 and/or FLU-0.1 with PHY-75 mg/kg. After thirty minutes, each animal was treated with thiopental sodium (TS) at 40 mg/kg to produce sedation and observed for latency and duration of sleep up to 4 h. In silico studies were performed with the 6X3X protein of the GABAA receptor α1 and ß2 subunits. The results demonstrate that PHY dose-dependently enhanced sleep duration in animals. However, it produced an insignificant sleep duration compared to the control and standard groups. It also significantly (p < 0.05) decreased the latency and increased the duration of sleep with DZP-2, while reducing these parameters with FLU-0.1. In in silico studies, DZP and FLU exhibited binding affinities with 6X3X by -6.8 and -6.9 kcal/mol, respectively, while PHY exhibited -6.9 kcal/mol. Taken together, PHY may exert a sedative-like effect in TS-induced sleeping mice and modulate the effects of DZP and FLU, possibly through interacting with the 6X3X protein of the GABAA receptor. PHY may be one of the good candidates for the management of sleep disturbances, such as insomnia.

Effective Dose of Dexmedetomidine with Nalbuphine Hydrochloride or Butorphanol Tartrate for Sedation in Buff Orpington Hens (Gallus gallus domesticus).

Chickens (Gallus gallus domesticus) are commonly used for research, food production, show, and companionship. Sedation is often necessary for sample collection, imaging, or treatment. Dexmedetomidine has been previously used to sedate birds, often with other sedatives. Butorphanol tartrate, a Schedule IV controlled substance, is commonly used but presents regulatory challenges. Nalbuphine hydrochloride, an opioid with similar receptor affinity to butorphanol, has potential as a noncontrolled alternative. Although information regarding nalbuphine use in birds is limited, its noncontrolled status makes it more accessible. The purpose of this study was to determine the effective dose to produce sedation in 50% (ED50) of patients and to estimate the calculated effective dose of dexmedetomidine in combination with either butorphanol (DexBut) or nalbuphine (DexNal) in domestic hens to sedate 99% of patients (ED99). Eighteen 33-week-old laying Buff Orpington hens were divided into 2 groups: one receiving DexBut (n = 9) and the second receiving DexNal (n = 9). Each hen was sedated with varying doses of intramuscular dexmedetomidine with a constant dose of either 2 mg/kg IM butorphanol or 12.5 mg/kg IM nalbuphine by an up-and-down design. Sedation was determined using a clinically applicable scoring system. The ED50 values of dexmedetomidine with 2 mg/kg IM of butorphanol, calculated by both the up-and-down method and logistic regression, were 38 and 49 µg/kg, respectively, while the ED50 values of dexmedetomidine in combination with 12.5 mg/kg IM of nalbuphine were 19 and 18 µg/kg, respectively. The estimated dexmedetomidine ED99 values with butorphanol or nalbuphine were 51 and 19 µg/kg, respectively. Multiple chickens in both groups exhibited open-mouth breathing and comb pallor but no lasting morbidity or mortality occurred. Combinations of DexBut or DexNal should be considered for sedation of domestic chickens.

Locomotor-Reducing, Sedative, and Antidepressant-Like Effects of Confectionery Flavours Coumarin and Vanillin.

Coumarin and vanillin are compounds with comforting scents and are often used for flavouring confectionery. The locomotor-reducing, sedative, and antidepressant-like effects of coumarin and vanillin vapours administered via inhalation were investigated. Coumarin and vanillin showed all these effects. In particular, antidepressant-like effects were observed over a wide range of doses and were stronger than the positive control, fluoxetine (10 mg/kg). These results suggest that coumarin and vanillin may be suitable as antidepressant-like agents without strict dose control.

Evaluation of the sedative properties of oral trazodone, gabapentin or their combination in healthy cats.

OBJECTIVES: Sedation before veterinary visits is advocated to help reduce fear and anxiety in cats and facilitate safe handling. The aim of this study was to evaluate the effectiveness of trazodone, gabapentin and a trazodone/gabapentin combination for oral sedation in healthy feline patients before blood donation. METHODS: A total of 21 cats were included in the study. Baseline sedation scores were obtained, and cats were randomly assigned to receive oral trazodone at 5 mg/kg (T), oral gabapentin at 10 mg/kg (G), their combination (TG) or placebo (control group). A sedation score was obtained 1 h after drug administration. A blood sample was obtained at the time of blood collection for quantification of drug plasma concentrations. Agreement between observers was tested with a Cohen's Kappa test. Sign tests to compare change within treatment and a Skilling-Mack rank ANOVA to test for differences between groups were performed to compare pre- and post-sedation scores as well as a magnitude of differences over time between the groups. A Spearman's rank correlation coefficient test was used to correlate sedation scores with drug plasma concentrations. RESULTS: Post-sedation final scores were significantly higher only in the T (P = 0.022) and TG groups (P <0.001). The magnitude of change between pre- and post-sedation scores was larger in the TG (P <0.0032) and T groups (P <0.038) compared with the control group. There were no other significant differences between the groups. There was no correlation between drug plasma concentrations and sedation scores in any of the groups. CONCLUSIONS AND RELEVANCE: Administration of oral trazodone alone at 5 mg/kg or in combination with gabapentin at 10 mg/kg resulted in significant sedation in healthy cats with no evident side effects. The degree of sedation was more profound when both drugs were combined, but a gabapentin dose of 10 mg/kg alone failed to provide significant sedation in this population.

Sedation and general anaesthesia of crocodilians: a systematic review.

Sedation and general anaesthesia of crocodilians pose unique challenges due to their aggressive nature, poikilothermic physiology, and specific anatomical and physiological characteristics, all factors that complicate crocodilian anaesthesia. This review aimed to systematically review the literature regarding sedation and general anaesthesia of crocodilians with focus on efficacy and impact on vital parameters. A systematic literature search was performed according to PRISMA guidelines on May 2, 2023 in the databases Embase, PubMed, Scopus and Web of Science. Publications were excluded based on predefined exclusion criteria, which encompassed non-standard publications and publications unrelated to crocodilians, with fewer than five animals and/or with insufficient data on sedation and general anaesthesia. Five key factors were used to evaluate the strength of evidence: number of included animals, study design, definition of recovery time, blinded assessment of recovery and conflict of interest. Ten publications were included in this systematic review. Drugs used included alpha-2-adrenoceptor agonists, dissociative anaesthetics, benzodiazepines, neuromuscular blocking agents, propofol, alfaxalone, and inhalant gasses. The studies included in total 55 Alligator mississippiensis, 110 Crocodylus porosus, 15 Crocodylus johnstoni, and 15 Crocodylus niloticus. Factors such as temperature, administration route, dose, species, and age influenced protocols for sedation and general anaesthesia of crocodilians. The studies included used five different study designs. Only one study included a control group, done on retrospectively collected data. Blinded recovery assessments and declarations of no conflict of interest were noted in some studies. The use of four distinct recovery definitions posed challenges to comparability in this systematic review. The studies reported that medetomidine provided stable and reversible sedation, although it depressed heart rate. Alfaxalone was less stable outside the optimal temperature range. Intubation and inhalation anaesthesia were effective, and adrenaline reduced the length of the recovery period. Overall, the review provides valuable insights for veterinarians, researchers, and wildlife professionals involved in sedation and general anaesthesia of the crocodilian species, however, the literature is limited, and further research is needed to improve evidence-based medical management.

Evaluation of the sedative-motor effects of novel GABAkine imidazodiazepines using quantitative observation techniques in rhesus monkeys.

BACKGROUND: Benzodiazepines bind to γ-aminobutyric acid type A (GABAA) receptor subtypes identified by different α subunits (i.e., α1GABAA, α2GABAA, α3GABAA, and α5GABAA). Sedative-motor effects of benzodiazepines are thought to involve α1GABAA and α3GABAA subtypes. AIMS: We evaluated observable measures of sedative-motor effects and species-typical behaviors in monkeys following acute administration of novel GABAkines (positive allosteric modulators of GABAA receptors), with varying degrees of selective efficacy at different GABAA receptor subtypes. We predicted that the induction of sedative-motor effects would depend on the degree of α1GABAA and α3GABAA efficacy. METHODS: Adult female rhesus monkeys (N = 4) were implanted with chronic indwelling i.v. catheters. Quantitative behavioral observation was conducted by trained observers following administration of multiple doses of the conventional benzodiazepine alprazolam and the GABAkines MP-III-80 (preferential efficacy at α2/α3/α5GABAA subtypes), KRM-II-81, MP-III-24 (both with preferential efficacy for α2/α3GABAA subtypes), and MP-III-22 (preferential potency and efficacy for α5GABAA subtypes). RESULTS: As with alprazolam, all GABAkines induced significant levels of mild sedation ("rest/sleep posture"). Deep sedation was observed with alprazolam, MP-III-80, and MP-III-22; motoric effects (observable ataxia) were obtained with alprazolam, KRM-II-81, and MP-III-22 only. Surprisingly, the order of potency for rest/sleep posture was significantly associated only with potency at α5GABAA subtypes. CONCLUSIONS: GABAkines with preferential efficacy at α2/α3GABAA and/or α5GABAA subtypes engendered sedative-motor effects in monkeys, although only compounds with α5GABAA activity engendered deep sedation. Moreover, the significant relationship between potency obtained with in vitro electrophysiology data and the rest/sleep posture measure suggests a role for the α5GABAA subtype in this milder form of sedation.

Neonatal anesthesia with remimazolam Reduces the expression of synaptic proteins and increases depressive behavior in adult mice.

The demand for pediatric anesthesia has risen in decades, raising concerns about the neurotoxic potential of anesthetics like remimazolam, which may impact neurodevelopment and later cognitive function. This study utilized a neonatal mouse model to assess remimazolam's neurodevelopmental effects. Results indicate that remimazolam-exposed mice displayed cognitive impairment and depressive behaviors in adulthood. Acute reductions in synaptic protein expression post-anesthesia were observed, along with long-term decreases in hippocampal choline acetyltransferase levels, reduced dendritic spine density in the CA1 region, and microglial proliferation. Collectively, these findings suggest that remimazolam can induce neurotoxicity and neuroinflammation, leading to synaptic dysfunction and associated cognitive and behavioral deficits.

Oral trazodone results in quantifiable sedation but does not result in a xylazine-sparing effect in healthy adult horses.

OBJECTIVE: To evaluate sedation and IV xylazine requirements to achieve 45% of baseline head height above ground measurements following oral (PO) administration of 2 trazodone dosages. METHODS: 8 healthy, adult mares of various weights and breeds belonging to a university teaching herd were utilized in a blinded, crossover study design. Horses were randomly assigned to 1 of 3 PO treatments: control (no trazodone), trazodone at 3 mg/kg (low dose [LD]), or trazodone at 6 mg/kg (high dose [HD]). Before treatment, cardiac auscultation, EquiSed sedation score, and head height above ground (HHAG; cm) measurements were performed (baseline) followed by feeding of the treatment mixture. After 120 minutes, sedation score and HHAG were recorded. Xylazine was administered IV (0.25 mg/kg bolus followed by 0.1 mg/kg/min) until HHAG reached 45% of baseline or a total dose of 1 mg/kg was reached. Individual data for xylazine dosage, sedation scores, and HHAG were analyzed using mixed linear models with repeated measures. RESULTS: Sedation scores were significantly improved (LD, P = .045; HD, P = .01) and HHAG was lowered (LD, P = .045; HD, P = .09) by trazodone administration. Xylazine dose requirements were increased by LD trazodone administration (increase of 0.26 ± 0.26 mg/kg; P = .03) and unchanged by HD (increase of 0.13 ± 0.25 mg/kg; P = .38). CONCLUSIONS: Oral trazodone administration increases quantifiable sedation in horses. Xylazine requirements are significantly increased by LD trazodone administration. CLINICAL RELEVANCE: Oral administration of LD trazodone may increase xylazine requirements. Further clinical studies are required to fully assess the clinical relevance of this finding on other parameters such as cardiovascular physiology.

Influence of gabapentin on the degree of sedation, physiological variables and propofol dosage in cats premedicated with acepromazine and methadone: a randomized, prospective, blinded, clinical study.

This study evaluated the influence of gabapentin on sedation, propofol dosage, and physiological variables in cats premedicated with acepromazine and methadone. Thirty-four cats were randomly assigned to receive 100 mg of oral gabapentin (Gabapentin group) or placebo (Control group) 100 min before intramuscular premedication with acepromazine (0.05 mg/kg) plus methadone (0.3 mg/kg). Variables recorded included sedation, using the Dynamic Interactive Visual Analog Scale (DIVAS, range 0-100 mm) and a Numeric Descriptive Scale (NDS, range 0-14), heart rate, respiratory rate and Doppler systolic arterial pressure (SAP). All variables were measured before (T0), 100 min after administration of gabapentin or placebo (T1), and 30 min after premedication (T2). Physiological variables were also recorded after anesthetic induction with propofol (T3). At T2, NDS scores were higher in Gabapentin than the Control group [median (interquartile range): 4 (2-5) versus 2 (1-4), p = 0.028], whereas DIVAS scores were not significantly different [Control: 9 (4-13); Gabapentin: 12 (5-32)]. Despite the significant difference between groups in NDS scores, overall sedation scores were mild at T1 and T2 regardless of gabapentin administration. The propofol dosage did not differ between groups. The most concerning adverse effect was arterial hypotension (SAP < 90 mmHg), recorded only at T3 in 71% of cats in the Control group and 100% in the Gabapentin group, without significant difference between groups. Administration of gabapentin before premedication with acepromazine and methadone in healthy cats did not result in a clinically significant influence on sedation levels, physiological variables, or propofol dosage required for anesthesia induction.

Effects of acepromazine, xylazine and propofol on spinal reflexes in healthy dogs.

BACKGROUND: In the neurological examination, it is crucial to identify the possible location of the lesion in order to determine the appropriate treatment process. In aggressive animals, chemical restraint may be necessary due to their non-cooperative behaviour. However, sedatives may distort the results of examinations. Therefore, a drug should be found that has minimal impact on the examination results. OBJECTIVES: To investigate the effects of acepromazine, xylazine, and propofol on spinal reflexes in healthy dogs. METHODS: In a randomized, blinded study, ten native adult mixed-breed dogs were participated in three groups with a 1-week washout period between each group. Before performing each step, the spinal reflexes were evaluated. Then, in the first group, acepromazine (0.05 mg/kg, IM), in the second group, xylazine (1 mg/kg, IM), and in the third group, propofol (3 mg/kg, IV for initial bolus and 0.1 mg/kg/min for maintenance) were injected for sedation. The spinal reflexes were reevaluated at maximum sedation and at 15, 30, and 45 min thereafter. RESULTS: Acepromazine increased the patellar reflex and decreased the panniculus reflex. Xylazine increased the cranial tibial reflex and decreased the panniculus reflex, while propofol decreased the withdrawal, and extensor carpi radialis reflexes, and suppressed the palpebral and gag reflexes. CONCLUSIONS: The drugs used in the present study did not have a significant impact on the most important reflexes evaluated in neurological examinations. Among the drugs, acepromazine has the least effects compared to other drugs, making it a suitable choice for sedation.

CARDIORESPIRATORY EFFECTS OF VATINOXAN IN BLESBOK (DAMALISCUS PYGARGUS PHILLIPSI) IMMOBILIZED WITH THIAFENTANIL-MEDETOMIDINE.

Combinations of a low dose of opioid, such as thiafentanil, and a high dose of medetomidine, are increasingly being used for immobilization of African ungulates. Both drugs can have undesirable cardiorespiratory effects. In this study we assessed whether vatinoxan, a peripherally acting alpha2-adrenergic receptor antagonist, can be used to alleviate some of these effects without affecting the immobilization quality. Eight healthy, female, boma-confined blesbok (Damaliscus pygargus phillipsi), weighing a mean (SDtion) of 56.8 (4.4) kg, were immobilized twice in a randomized cross-over study with a 2-wk washout period using (1) 0.5 mg thiafentanil + 1.5 mg medetomidine (TM), (2) TM + vatinoxan: 0.5 mg thiafentanil + 1.5 mg medetomidine + 15 mg vatinoxan per milligram medetomidine (total of 22.5 mg, administered intramuscularly at 10 min post recumbency). Heart rate, respiratory rate, rectal temperature, oxygen saturation (SpO2), arterial blood pressure, and sedation scores from 1 to 5 (1 = limited effect; 5 = excessively deep) were measured every 5 min. Arterial blood gases (PaO2 and PaCO2) were measured at 10, 15, 25, and 35 min postrecumbency and the alveolar--arterial oxygen gradient (P[A-a]O2) was calculated. Induction times and immobilization quality did not differ between groups. The heart rate was significantly higher and the mean arterial pressure significantly lower in blesbok after receiving vatinoxan. All animals were hypoxemic and there were no significant differences in the respiratory rates, PaO2, PaCO2, SpO2, or P(A-a)O2 gradients at any time point. Although vatinoxan did not improve respiratory variables and blood oxygenation in these animals, the change in cardiovascular variables may suggest that it improves tissue perfusion, a positive outcome that requires further investigation.

EVALUATION OF A BUTORPHANOL-MIDAZOLAM-MEDETOMIDINE PROTOCOL FOR SHORT PROCEDURES IN LESSER CHEVROTAINS (TRAGULUS SP.).

Twenty lesser chevrotains (Tragulus sp.), 10 males and 10 females, were anesthetized with a combination of butorphanol-midazolam-medetomidine (BMidM), to assess the efficacy of this protocol for short procedures in this genus. The animals received BMidM (0.32, 0.06, 0.15 mg/kg, respectively) intramuscularly via hand injection. Physiological variables were recorded once the animals reached a working depth of anesthesia that lasted 30 min (range 12-60 min). At the end of the procedure, medetomidine and butorphanol were antagonized with atipamezole (0.75 mg/kg) and naltrexone (0.3 mg/kg) intramuscularly, respectively. Induction and recovery were 9.4 ± 4.0 min and 10.2 ± 4.1 min, respectively. Supplementation with isoflurane via face mask was required in five animals to reach light anesthesia. Times to reach the various stages of anesthesia were compared between sexes. There was no difference between males and females reaching the different stages of anesthesia, except for the time required to reach the ambulatory stage, in which females took a significantly longer time (11.8 min vs 7.8 min for the males) to stand after the injection of the antagonists (P = 0.02). Heart rate, respiratory rate, rectal temperature, and peripheral hemoglobin oxygen saturation were similar between sexes and stable throughout the procedure. At the dosage tested BMidM was a reliable and safe protocol for short, minimally invasive procedures in lesser chevrotains with a fast induction and smooth recovery without complications.

IMMOBILIZATION OF BLACK HOWLER MONKEYS (ALOUATTA PIGRA) USING BUTORPHANOL, AZAPERONE, MEDETOMIDINE IS SAFE AND EFFECTIVE FOR NONINVASIVE PROCEDURES.

Administration of butorphanol, azaperone, and medetomidine (BAM) for immobilization of black howler monkeys (Alouatta pigra) has not been previously reported. In this observational study, 0.02 ml/kg of compounded BAM (butorphanol 27.3 mg/ml, azaperone 9.1 mg/ml, medetomidine 10.9 mg/ml) was administered IM in 10 captive black howler monkeys. Time to immobilization was recorded, an arterial blood gas performed, and at 5-min intervals, HR, RR, oscillometric arterial blood pressure, SPO2, and rectal temperature were measured. Naltrexone and atipamezole were administered IM at procedure completion and recovery times were recorded. If invasive procedures such as surgery were necessary and additional drugs needed, further data from that individual was removed from data analysis. Final BAM dosages were 0.55 ± 0.12 mg/kg butorphanol, 0.19 ± 0.04 mg/kg azaperone, and 0.22 ± 0.05 mg/kg medetomidine. Nine of 10 monkeys achieved sedation allowing for physical exam, venipuncture, and tuberculin skin testing within 4 ± 2 min. No monkeys reached a plane of immobilization allowing for intubation. Physiologic variables were acceptable for this species. Hypoxemia (SPO2 < 95%) was observed in three monkeys via pulse oximetry, and normoxemia was observed on arterial blood gas. Recovery was smooth and rapid. Therefore, BAM is a viable option for noninvasive procedures or as a premedication prior to induction of anesthesia in black howler monkeys.

Discovery, synthesis and SAR of 2-acyl-1-biarylmethyl pyrazolidines, dual orexin receptor antagonists designed as fast and short-acting sleeping drugs.

Dual orexin receptor antagonists (DORAs) are approved for the treatment of sleep onset and/or sleep maintenance insomnia. In the present disclosure, we report the discovery of a new class of DORAs designed to treat sleep disorders requiring a fast onset and a short duration of action (<4 h). We used early human pharmacokinetic-pharmacodynamic (PK-PD) predictions and in vivo experiments to identify DORAs eliciting this specific hypnotic profile. A high-throughput screening campaign revealed hits based on a rarely precedented tricyclic pyrazolidine scaffold. After unsuccessful structure-activity-relationship (SAR) studies on this hit series, a scaffold hopping exercise, aimed at reducing the molecular complexity of the tricyclic scaffold, resulted in the discovery of the 2-acyl-1-biarylmethylpyrazolidine series. SAR studies on this achiral series gave rise to the lead compound DORA 42. In vitro and in vivo parameters of DORA 42, and its PK-PD simulation for human use are detailed.

Comparison of Remimazolam and Dexmedetomidine for Sedation in Awake Endotracheal Intubation in Scoliosis Surgery: A Retrospective Analysis.

BACKGROUND Awake endotracheal intubation (AEI) involves the placement of an endotracheal tube in patients who can maintain spontaneous respirations. This retrospective study aimed to compare sedation with remimazolam during AEI with that of dexmedetomidine in patients who underwent scoliosis correction surgery. MATERIAL AND METHODS This is a retrospective study based on data from 98 patients who had AEI procedures between January and December 2023. The remimazolam group included 55 patients, and the dexmedetomidine group included 43 patients. Remimazolam 0.05 mg/kg was injected 1 min before intubation, while dexmedetomidine 1 ug/kg was pumped 10 min before intubation. Evaluations of AEI, hemodynamics, and respiratory adverse events were then compared between the 2 groups. RESULTS There was no significant difference in demographic data between the groups. After administrating sedation, dexmedetomidine led to a larger reduction of mean arterial pressure (MAP) and heart rate (HR) than did remimazolam (11.30±1.86 vs 8.33±2.28 mmHg, P<0.001; 12.28±2.50 vs 2.85±1.82 beats/min, P<0.001). When conducting intubation, the increase of MAP in the remimazolam group was lower than that in the dexmedetomidine group (7.40±2.81 vs 9.26±5.08 mmHg, P=0.024), while the difference in HR change was not significant (7.53±5.41 vs 8.37±5.31 beats/min, P=0.441). When combined with local anesthesia, the success rate of AEI, time of AEI procedure, attempt times, increase of MAP during intubation, depth of sedation, and respiratory adverse events were comparable between the groups (P>0.05). CONCLUSIONS With local anesthesia, remimazolam and dexmedetomidine sedation can facilitate AEI for patients with scoliosis. However, remimazolam is associated with more stable hemodynamics.

Sedative-Hypnotic Effect and Mechanism of Carbon Nanofiber Loaded with Essential Oils of Ligusticum chuanxiong (Ligusticum chuanxiong Hort.) and Finger Citron (Citrus medica L. var. sarcodactylis) on Mice Models of Insomnia.

(1) Background: Insomnia is a neurological illness that poses a significant threat to both physical and mental health. It results in the activation of neuroglial cells, heightened neuroinflammation, oxidative stress, and disruptions in the Hypothalamic-Pituitary-Adrenal (HPA) axis. Ligusticum Chuanxiong (CX) and Finger citron (FC) are frequently utilized botanicals for addressing sleeplessness. Both herbs possess notable anti-inflammatory properties in their volatile oils. However, their effectiveness is hindered by the nasal mucosal irritation and instability they exhibit. (2) Methods: This study involved the preparation of a nanofiber composite system using carbon nanofiber (CNF) suspensions containing essential oils of Ligusticum chuanxiong-Finger citron (CXEO-FCEO-CNF). The effects and mechanisms of these essential oils in improving insomnia were investigated using an insomnia mouse model after encapsulation. (3) Results: The CXEO-FCEO-CNF had an average particle size of 103.19 ± 1.64 nm. The encapsulation rates of essential oils of Ligusticum chuanxiong (CXEO) and essential oils of Finger citron (FCEO) were 44.50% and 46.15%, respectively. This resulted in a considerable improvement in the stability of the essential oils over a period of 30 days. The essential oils effectively decreased the irritation of the nasal mucosa following encapsulation. Furthermore, CXEO-FCEO-CNF enhanced voluntary activity and sleep in mice with insomnia, notably boosted the activity of superoxide dismutase (SOD), reduced the concentration of lipoxidized malondialdehyde (MDA), decreased the levels of hormones associated with the HPA axis, and regulated the levels of neurotransmitters, resulting in a beneficial therapeutic outcome. CXEO-FCEO-CNF contains a total of 23 active ingredients, such as alpha-Asarone, (E)-methyl isoeugenol, and Senkyunolide. These ingredients primarily work by modulating the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling system to decrease oxidative stress and inflammatory reactions. (4) Conclusions: This study presented initial evidence that the combination of CXEO and FCEO in nanofiber formulations effectively reduces the nasal mucosal irritation and instability of essential oils. Furthermore, it demonstrated the potential anti-neuroinflammatory and therapeutic effects of these formulations in treating insomnia. Overall, this study provides a theoretical foundation for developing new essential oil formulations derived from herbs.

γ-Aminobutyric acid type A receptor ß1 subunit gene polymorphisms are associated with the sedative and amnesic effects of midazolam.

Midazolam is widely used for intravenous sedation. However, wide interindividual variability is seen in the sensitivity to midazolam. The association between genetic factors and interindividual differences in midazolam sensitivity remains unclear. The present study explored the association between common genetic variants and sedative and amnesic effects of midazolam. This prospective study included patients who were scheduled to undergo dental procedures under intravenous sedation. The sedative effect was evaluated using the Ramsay sedation scale 5 min after midazolam (0.05 mg/kg) administration. We employed two parallel approaches in this study: genome-wide approach and candidate gene approach. The γ-aminobutyric acid type A receptor subunit genes were selected as candidate genes. Multivariate linear regression analyses were performed to investigate the association between the Ramsay sedation scale and genetic variants. We also analyzed the association between the presence of anterograde amnesia and genetic variants using multivariate binominal logistic regression analyses. The analyses were adjusted for potential confounding factors. A total of 191 patients were included in the analyses. In the genome-wide association analyses, no significant association was found between the genetic variants and Ramsay scores. In the candidate gene analyses, the rs73247636 (dominant model: ß = 0.72 [95% confidence interval, 0.34 to 1.10], P < 0.001) and rs56278524 (dominant model: ß = 0.73 [0.37 to 1.10], P < 0.001) polymorphisms of the GABRB1 gene were significantly associated with Ramsay scores. Additionally, the rs73247636 (dominant model: odds ratio [OR] = 8.39 [2.36 to 29.85], P = 0.001) and rs56278524 (dominant model: OR = 15.26 [3.42 to 68.07], P < 0.001) polymorphisms were also significantly associated with the presence of anterograde amnesia. The rs73247636 and rs56278524 single-nucleotide polymorphisms of GABRB1 were associated with the sedative and amnesic effects of midazolam.

Sedative Effects of Daidzin, Possibly Through the GABAA Receptor Interaction Pathway: In Vivo Approach with Molecular Dynamic Simulations.

The soy isoflavone daidzin (DZN) has been considered a hopeful bioactive compound having diverse biological activities, including anxiolytic, memory-enhancing, and antiepileptic effects, in experimental animals. However, its sedative and hypnotic effects are yet to be discovered. This study aimed to evaluate its sedative/hypnotic effect on Swiss mice. Additionally, in silico studies were also performed to see the possible molecular mechanisms behind the tested neurological effect. For this, male Swiss albino mice were treated with DZN (5, 10, or 20 mg/kg) intraperitoneally (i.p.) with or without the standard GABAergic medication diazepam (DZP) and/or flumazenil (FLU) and checked for the onset and duration of sleeping time using thiopental sodium-induced as well as DZP-induced sleeping tests. A molecular docking study was also performed to check its interaction capacity with the α1 and ß2 subunits of the GABAA receptor. Findings suggest that DZN dose-dependently and significantly reduced the latency while increasing the duration of sleep in animals. In combination therapy, DZN shows synergistic effects with the DZP-2 and DZP-2 + FLU-0.01 groups, resulting in significantly (p < 0.05) reduced latency and increased sleep duration. Further, molecular docking studies demonstrate that DZN has a strong binding affinity of - 7.2 kcal/mol, which is closer to the standard ligand DZP (- 8.3 kcal/mol) against the GABAA (6X3X) receptor. Molecular dynamic simulations indicated stability and similar binding locations for DZP and DZN with 6X3X. In conclusion, DZN shows sedative effects on Swiss mice, possibly through the GABAA receptor interaction pathway.

Novel neuropharmacological activity of citrus lime (Citrus aurantifolia): A standardized lime peel supplement enhances non-rapid eye movement sleep by activating the GABA type A receptor.

Polyphenols have been well-established to exert sedative-hypnotic effects in psychopharmacology. Lime (Citrus aurantifolia) peel is rich in biologically active polyphenols; however, the effects of lime peel extract on sleep have not yet been demonstrated. A comparison was conducted in mice, between the sleep-promoting effects of a standardized lime peel supplement (SLPS) and a well-known hypnotic drug, zolpidem, and its hypnotic mechanism was investigated using in vivo and in vitro assays. The effects of SLPS on sleep were assessed using a pentobarbital-induced sleep test and sleep architecture analysis based on recording electroencephalograms and electromyograms. Additionally, a GABAA receptor binding assay, electrophysiological measurements, and in vivo animal models were used to elucidate the hypnotic mechanism. SLPS (200 and 400 mg/kg) was found to significantly decrease sleep latency and increase the amount of non-rapid eye movement sleep without altering delta activity. The hypnotic effects of SLPS were attributed to its flavonoid-rich ethyl acetate fraction. SLPS had a binding affinity to the GABA-binding site of the GABAA receptor and directly activated the GABAA receptors. The hypnotic effects and GABAA receptor activity of SLPS were completely blocked by bicuculline, a competitive antagonist of the GABAA receptor, in both in vitro and in vivo assays. To the best of our knowledge, this study is the first to demonstrate the hypnotic effects of SLPS, which acts via the GABA-binding site of the GABAA receptor. Our results suggest that lime peel, a by-product abundantly generated during juice processing, can potentially be used as a novel sedative-hypnotic.

Chemical Immobilization Effects on Cougar (Felis concolor) Movement.

Capturing and handling wildlife is a common practice for both management and research. As telemetry use has become common, the need to capture and chemically immobilize wildlife has increased. Understanding how long the effects of immobilizing agents last after releasing the animal is often poorly understood but needed to ensure that analyses use data that reflect natural behavior. Between 2016 and 2021, 60 cougars (Puma concolor) were chemically immobilized with medetomidine, zolazepam, and tiletamine (MZT) and collared across west-central Alberta, Canada, 27 of which were individuals being recollared. We examined the distance an individual traveled per day and compared equivalent periods before and after the recollaring event to determine whether postcapture movement rates were significantly different from precapture rates. Within 1 d of the recollaring, daily movement rates had returned to precapture rates (t20=2.09, P=0.18). Our results provide insight on how MZT used in cougars affects their postcapture movement and thus may be helpful in interpreting movement data after release.