Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.073
Filtrar
1.
Zh Nevrol Psikhiatr Im S S Korsakova ; 120(9. Vyp. 2): 46-54, 2020.
Artigo em Russo | MEDLINE | ID: mdl-33076645

RESUMO

Sleep-disordered breathing is one of the most common sleep-associated disorders. At the same time, their prevalence tends to increase with age. One of the most common forms of respiratory failure during sleep is obstructive sleep apnea syndrome (OSA), which is characterized by repeated episodes of cessation of breathing or a significant decrease in respiratory flow while maintaining respiratory effort as a result of obstruction of the upper respiratory tract. Drugs have different effects on OSA. There are drugs that worsen OSA, drugs that do not affect OSA, and drugs that improve OSA. Benzodiazepines, opioids, muscle relaxants, and male hormones adversely affect OSA. Also of clinical interest are drugs that do not affect OSA and can even potentially improve respiratory function during sleep. These include anti-inflammatory drugs, diuretics, bronchodilators, acetylcholinesterase inhibitors, antiparkinsonian, decongestant drugs, drugs for intranasal use, topical soft tissue lubricant, female sex hormones. Finally, the effect of a number of drugs on OSA is not definitively established and requires further study (benzodiazepine receptor agonist hypnotics, angiotensin-converting enzyme inhibitors, opiate receptor antagonists, antidepressants, proton-pump inhibitors, TNF-α antagonists, glutamate receptor antagonists, drugs for the treatment of acromegaly, drugs for the treatment of narcolepsy). Raising awareness of doctors of different specialties about the impact of various drugs on OSA can not only prevent the deterioration of respiratory distress during sleep, but also, with a rational individual approach, makes it possible to even improve the quality of sleep and blood saturation, thereby contributing to a more favorable course of OSA and the underlying disease.


Assuntos
Síndromes da Apneia do Sono , Apneia Obstrutiva do Sono , Feminino , Humanos , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Masculino , Prevalência , Sono , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/tratamento farmacológico
2.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(3): 273-278, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32981285

RESUMO

Objective: To observe the effects of propofol on the activation of hepatic stellate cell line HSC2-T6 induced by transforming growth factor-beta 1 (TGF-ß1) and explore its possible mechanism.Methods: The cells were divided into control group, TGF-ß1 group, propofol group, TGF-ß1 + propofol group, rapamycin group, TGF-ß1 + propofol + rapamycin group. Cells were treated with rapamycin (5 µmol/L) for 1 hour, propofol (100 µmol/L) for 1 hour, then TGF-ß1 (5 ng/ml) was added to co-culture for 24 hours. Cell proliferation was measured by MTT assay. The concentrations of hyaluronic acid (HA), collagen IV (IV-C) and laminin (LN) in the supernatant of cell culture medium were measured by ELISA. The ultrastructure of cells was observed by transmission electron microscopy. The expressions of alpha-smooth muscle actin (α-SMA), mammalian rapamycin target protein (mTOR), phosphorylated mTOR (p-mTOR) and the autophagy related gene Beclin 1, LC3 and p62 were measured by Western blot. Results: Compared with control group, cell proliferation, the expression of α-SMA, the concentrations of HA, IV-C and LN in culture supernatant, the number of autophages, the expressions of Beclin-1 and LC3-II, the ratio of LC3-II/LC3-I in HSC2-T6 cells were increased significantly, while the expression of p-mTOR, the ratio of p-mTOR/mTOR and the expression of p62 protein were decreased significantly in TGF-ß1 group (All P<0.05). Compared with TGF-ß1 group, cell proliferation, the expression of α-SMA, the concentrations of HA, IV-C and LN in culture supernatant, the number of autophages, the expressions of Beclin-1 and LC3-II, the ratio of LC3-II/LC3-I in HSC2-T6 cells in TGF-ß1 group were decreased significantly, and the expression of p-mTOR, the ratio of p-mTOR/mTOR and expression of p62 protein were increased significantly in TGF-ß1 + propofol group (All P<0.05). Conclusion: Propofol inhibits the activation of hepatic stellate cells induced by TGF-beta 1, and its mechanism involves the mTOR-autophagy pathway.


Assuntos
Autofagia , Células Estreladas do Fígado , Propofol , Fator de Crescimento Transformador beta1 , Animais , Autofagia/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Propofol/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Fator de Crescimento Transformador beta1/farmacologia
3.
Medicine (Baltimore) ; 99(36): e21859, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899015

RESUMO

BACKGROUND: The purpose of this study was to evaluate the effects of adding ketamine to propofol on cognitive functions in patients undergoing sedation for colonoscopy. METHODS: In this randomized, double-blinded, and controlled study, 200 patients were randomly allocated to ketamine/propofol admixture group (Group KP, n = 100), and propofol group (Group P, n = 100). Patients in Group KP received 0.25 mg/kg of ketamine and 0.5 mg/kg of propofol. Patients in Group P received 0.5 mg/kg propofol. Cognitive functions were measured using CogState battery before and after the colonoscopy procedure. Ninety five patients in Group KP and 92 patients in Group P had completed the CogStates tests and were included in the data analysis. RESULTS: Compared with before procedure baseline, the performance on detection and identification tasks were significantly impaired after the procedure in both Group KP (P = .004, P = .001) and Group P patients (P = .005, P < .001). However, one-card learning accuracy and One-back memory was only impaired in Group KP patients (P = .006, P = .040) after the endoscopy but left intact in Group P patients. Group KP patients showed more severe impairment in one-card learning accuracy compared with Group P patients (P = .044). Group KP patients have better 5 minutes MAP (P = .005) and were also less likely to suffer from complications such as respiratory depression (P = .023) and hypotension (P = .015). OAA/S scores, BIS, MAP, complications, recovery times, and endoscopist and patient satisfaction were similar between the 2 groups. CONCLUSION: Although adding ketamine to propofol for sedation in colonoscopy provided fewer complications such as respiratory depression and hypotension, it also causes more impairment in cognitive functions.


Assuntos
Colonoscopia/métodos , Sedação Profunda/métodos , Hipnóticos e Sedativos/farmacologia , Ketamina/farmacologia , Complicações Cognitivas Pós-Operatórias/induzido quimicamente , Propofol/farmacologia , Adulto , Sedação Profunda/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Ketamina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Propofol/administração & dosagem , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
Proc Natl Acad Sci U S A ; 117(37): 23106-23112, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32848052

RESUMO

Thalidomide exerts its teratogenic and immunomodulatory effects by binding to cereblon (CRBN) and thereby inhibiting/modifying the CRBN-mediated ubiquitination pathway consisting of the Cullin4-DDB1-ROC1 E3 ligase complex. The mechanism of thalidomide's classical hypnotic effect remains largely unexplored, however. Here we examined whether CRBN is involved in the hypnotic effect of thalidomide by generating mice harboring a thalidomide-resistant mutant allele of Crbn (Crbn YW/AA knock-in mice). Thalidomide increased non-REM sleep time in Crbn YW/AA knock-in homozygotes and heterozygotes to a similar degree as seen in wild-type littermates. Thalidomide similarly depressed excitatory synaptic transmission in the cortical slices obtained from wild-type and Crbn YW/AA homozygous knock-in mice without affecting GABAergic inhibition. Thalidomide induced Fos expression in vasopressin-containing neurons of the supraoptic nucleus and reduced Fos expression in the tuberomammillary nuclei. Thus, thalidomide's hypnotic effect seems to share some downstream mechanisms with general anesthetics and GABAA-activating sedatives but does not involve the teratogenic CRBN-mediated ubiquitin/proteasome pathway.


Assuntos
Hipnóticos e Sedativos/farmacologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Teratogênios/metabolismo , Talidomida/farmacologia , Ubiquitinação/efeitos dos fármacos , Ubiquitinas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
5.
J S Afr Vet Assoc ; 91(0): e1-e8, 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32787423

RESUMO

Potent opioids are known to cause negative alterations to the physiology of immobilised antelope. How these effects differ between species has not been studied. This study aimed to compare time to recumbence and effects of opioid-based immobilisation on the physiology of impala (Aepyceros melampus) and blesbok (Damaliscus pygargus phillipsi). Eight animals of each species were immobilised, with 0.09 mg/kg etorphine and 0.09 mg/kg thiafentanil respectively, in a randomised two-way cross-over study. Variables measured and analysed by means of a linear mixed model included time to recumbence, heart rate, respiratory rate, arterial blood pressure, blood gases, lactate and glucose. In blesbok, mean time to recumbence was not significantly different with either drug (2.5 minutes and 2.2 min, respectively), but in impala thiafentanil achieved a shorter time to recumbence (2.0 min) than etorphine (3.9 min). Mean heart rates of immobilised impala were within reported physiological limits, but lower in immobilised blesbok when both opioids were used (35 beats/min to 44 beats/min vs. 104 ± 1.4 beats/min resting heart rate). Impala developed severe respiratory compromise and hypoxaemia from both opioids (overall mean PaO2 values ranged from 38 mmHg to 59 mmHg over 30 min). In contrast, blesbok developed only moderate compromise. Therefore, significantly different species-specific physiological responses to potent opioid drugs exist in blesbok and impala. Given that these different responses are clinically relevant, extrapolation of immobilising drug effects from one species of African ungulate to another is not recommended.


Assuntos
Analgésicos Opioides/farmacologia , Antílopes/fisiologia , Etorfina/farmacologia , Fentanila/análogos & derivados , Hipnóticos e Sedativos/farmacologia , Imobilização/veterinária , Analgésicos Opioides/administração & dosagem , Animais , Estudos Cross-Over , Etorfina/administração & dosagem , Feminino , Fentanila/administração & dosagem , Fentanila/farmacologia , Hipnóticos e Sedativos/administração & dosagem , Distribuição Aleatória , Especificidade da Espécie
6.
Clin Pharmacokinet ; 59(10): 1195-1216, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32725382

RESUMO

There is an urgent need to identify optimal antiviral therapies for COVID-19 caused by SARS-CoV-2. We have conducted a rapid and comprehensive review of relevant pharmacological evidence, focusing on (1) the pharmacokinetics (PK) of potential antiviral therapies; (2) coronavirus-specific pharmacodynamics (PD); (3) PK and PD interactions between proposed combination therapies; (4) pharmacology of major supportive therapies; and (5) anticipated drug-drug interactions (DDIs). We found promising in vitro evidence for remdesivir, (hydroxy)chloroquine and favipiravir against SARS-CoV-2; potential clinical benefit in SARS-CoV-2 with remdesivir, the combination of lopinavir/ritonavir (LPV/r) plus ribavirin; and strong evidence for LPV/r plus ribavirin against Middle East Respiratory Syndrome (MERS) for post-exposure prophylaxis in healthcare workers. Despite these emerging data, robust controlled clinical trials assessing patient-centred outcomes remain imperative and clinical data have already reduced expectations with regard to some drugs. Any therapy should be used with caution in the light of potential drug interactions and the uncertainty of optimal doses for treating mild versus serious infections.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Analgésicos/farmacologia , Anticoagulantes/farmacologia , Antivirais/farmacocinética , Betacoronavirus , Infecções por Coronavirus/fisiopatologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Oxigenação por Membrana Extracorpórea/métodos , Humanos , Hipnóticos e Sedativos/farmacologia , Pandemias , Pneumonia Viral/fisiopatologia , Terapia de Substituição Renal/métodos , Índice Terapêutico do Medicamento
7.
Br J Anaesth ; 125(3): 267-274, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32660717

RESUMO

BACKGROUND: Anaesthetic agents are likely to alter circulating cytokine concentrations. Because preceding studies have not been able to exclude the contribution of surgical trauma, perioperative stress, or both to circulating cytokine concentrations, the effects of anaesthesia remain unclear. The aim of this study was to quantify serum cytokines in healthy volunteers administered i.v. anaesthetic agents in the absence of surgical trauma and perioperative stress. METHODS: Serum samples obtained during previous standardised studies from healthy volunteers were compared before and 6-8 h after induction of anaesthesia with propofol (n=31), propofol/remifentanil (n=30), dexmedetomidine (n=17) or dexmedetomidine/remifentanil (n=15). Anaesthetic regimens were standardised and volunteers did not undergo any surgical intervention. Serum concentrations of interleukin (IL)2, IL4, IL6, IL10, IL17, IL18, IL21, IL22, IL23, C-X-C motif ligand 8, interferon gamma, E-selectin, L-selectin, major histocompatibility complex class I chain-polypeptide-related sequence (MIC)A, MICB, Granzyme A, and Granzyme B were quantified using a multiplexed antibody-based assay (Luminex). RESULTS: Samples were obtained from volunteers of either sex aged 18-70 yr. After anaesthesia with propofol alone, concentrations of IL4 (P=0.012), IL6 (P=0.027), IL21 (P=0.035), IL22 (P=0.002), C-X-C motif ligand 8 (P=0.004), MICB (P=0.046), and Granzyme A (P=0.045) increased. After anaesthesia with propofol and remifentanil, IL17 (P=0.013), interferon gamma (P=0.003), and MICA (P=0.001) decreased, but IL6 (P=0.006) and L-selectin (P=0.001) increased. After dexmedetomidine alone, IL18 (P=0.002), L-selectin (P=0.017), E-selectin (P=0.002), and Granzyme B (P=0.023) decreased. After dexmedetomidine with remifentanil no changes were observed. CONCLUSIONS: In healthy volunteers not undergoing surgery, different i.v. anaesthesia regimens were associated with differential effects on circulating cytokines.


Assuntos
Citocinas/sangue , Citocinas/efeitos dos fármacos , Dexmedetomidina/farmacologia , Hipnóticos e Sedativos/farmacologia , Propofol/farmacologia , Remifentanil/farmacologia , Adolescente , Adulto , Idoso , Analgésicos Opioides/farmacologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Adulto Jovem
8.
J Clin Psychiatry ; 81(4)2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32609960

RESUMO

OBJECTIVE: INP105 is a drug-device combination of olanzapine and technology that delivers a powder formulation of olanzapine to the vascular-rich upper nasal space. This study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of single ascending doses of INP105, olanzapine intramuscular (OLZ IM), and olanzapine oral disintegrating tablet (OLZ ODT). METHODS: This was a phase 1, active and double-blind placebo comparator-controlled, ascending-dose, 2-period, incomplete-block, 1-way crossover study in 40 healthy subjects, randomized to single doses of OLZ IM (5 or 10 mg) or OLZ ODT (10 mg) in Period 1 and then 1 of 3 doses (5 mg, 10 mg, or 15 mg) of INP105 or placebo in Period 2 between July and October 2018. Sedation and attention were evaluated by visual analog scale (VAS), the Agitation/Calmness Evaluation Scale (ACES), and the Digit Symbol Substitution Test (DSST). RESULTS: At equivalent doses, INP105 provided similar area under the drug concentration-time curve (AUC) from time 0 to the last measurable concentration, AUC from time 0 to infinity, and maximum observed concentration (Cmax) as OLZ IM and greater Cmax than but similar AUCs to OLZ ODT. Median time to maximum concentration was less for INP105 (15, 10, and 9.5 min for 5 mg, 10 mg, and 15 mg, respectively) than for OLZ IM (20 and 15 min for 5 mg and 10 mg, respectively) or OLZ ODT (120 min). Effects as measured with the VAS, ACES, and DSST with INP105 5 mg were comparable to those with OLZ IM 5 mg, with earlier onset for INP105 10 mg and 15 mg and greater effects than placebo and OLZ ODT. The incidence of treatment-emergent adverse events with INP105 5 mg, 10 mg, and 15 mg was 80%, 66.7%, and 75%, respectively, compared to 90% and 100% for OLZ IM 5 mg and 10 mg, respectively, and 83.3% for OLZ ODT; most common were dizziness, hypotension, and orthostatic symptoms. CONCLUSIONS: INP105 has rapid absorption and pharmacodynamic effects and may represent an effective, convenient, noninvasive, and well-tolerated alternative for treating acutely agitated patients by self- or caregiver administration in the home, community, or hospital environments. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03624322.


Assuntos
Olanzapina/efeitos adversos , Olanzapina/farmacocinética , Administração Intranasal , Administração Oral , Adolescente , Adulto , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Atenção/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Hipnóticos e Sedativos/farmacologia , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Olanzapina/administração & dosagem , Olanzapina/farmacologia , Adulto Jovem
9.
Anaesthesia ; 75(11): 1461-1468, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32533791

RESUMO

Children may develop changes in their behaviour following general anaesthesia. Some examples of negative behaviour include temper tantrums and nightmares, as well as sleep and eating disorders. The aim of this study was to determine whether dexmedetomidine reduces the incidence of negative behaviour change after anaesthesia for day case surgery in children aged two to seven years. Children were randomly allocated to one of three groups: a premedication group received 2 mg.kg-1 intranasal dexmedetomidine; an intra-operative group received 1 mg.kg-1 intravenous dexmedetomidine; and a control group. The primary outcome was the incidence of negative behaviour on postoperative day 3 using the Post-Hospitalisation Behaviour Questionnaire for Ambulatory Surgery (PHBQ-AS) and the Strength and Difficulties Questionnaire (SDQ). Secondary outcomes included: the incidence of negative behaviour on postoperative days 14 and 28; anxiety at induction; emergence delirium; pain; length of recovery and hospital stay; and any adverse events. The data for 247 patients were analysed. Negative behaviour change on postoperative day 3 was similar between all three groups when measured with the PHBQ-AS (47%, 44% and 51% respectively; adjusted p=0.99) and the SDQ (median scores 7.5, 6.0 and 8.0 respectively; adjusted p=0.99). The incidence of negative behaviour in the group who received dexmedetomidine intra-operatively was less at postoperative day 28 (15% compared with 36% in the dexmedetomidine premedication group and 41% in the control group, p<0.001). We conclude that dexmedetomidine does not reduce the incidence of negative behaviour on postoperative day 3 in two to seven-year olds having day case procedures.


Assuntos
Comportamento Infantil/efeitos dos fármacos , Dexmedetomidina/farmacologia , Hipnóticos e Sedativos/farmacologia , Cuidados Intraoperatórios/métodos , Complicações Pós-Operatórias/prevenção & controle , Pré-Medicação/métodos , Procedimentos Cirúrgicos Ambulatórios , Criança , Pré-Escolar , Dexmedetomidina/administração & dosagem , Dexmedetomidina/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/uso terapêutico , Masculino , Inquéritos e Questionários
10.
Curr Opin Anaesthesiol ; 33(4): 506-511, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32530890

RESUMO

PURPOSE OF REVIEW: Anaesthesia and sedation are ubiquitous in contemporary medical practice. Developments in anaesthetic pharmacology are targeted on reducing physiological disturbance whilst maintaining or improving titrateability, recovery profile and patient experience. Remimazolam is a new short-acting benzodiazepine in the final stages of clinical development. RECENT FINDINGS: Clinical experience with remimazolam comprises volunteer studies and a limited number of clinical investigations. In addition, laboratory investigations explore the implications of its 'soft drug' pharmacology. SUMMARY: Remimazolam provides effective procedural sedation with superior success rates and recovery profile when compared to midazolam. Comparisons with propofol are required. Preliminary studies suggest potential for using remimazolam as the hypnotic component of general anaesthesia. Definitive studies are awaited. As a benzodiazepine, remimazolam could be evaluated as an anticonvulsant and for intensive care sedation.


Assuntos
Benzodiazepinas/farmacologia , Benzodiazepinas/uso terapêutico , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Sedação Consciente , Humanos , Midazolam , Propofol
11.
Curr Opin Anaesthesiol ; 33(4): 483-489, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32530894

RESUMO

PURPOSE OF REVIEW: Growing concerns about the environmental effects of volatile anaesthetics are likely to lead to increased use of intravenous anaesthetic drugs. Pharmacokinetic/pharmacodynamic (PKPD) models can increase the accuracy of intravenous drug titration, especially in populations that differ from the 'average.' However, with a growing number of PKPD models, and other technology available to date, it can be hard to see the wood for the trees. This review attempts to guide the reader through the PKPD jungle. RECENT FINDINGS: General purpose PKPD models for propofol and remifentanil designed to apply to a broader population, including children, the elderly and the obese, reduce the need for population-specific models. PKPD models for drugs such as dexmedetomidine and antimicrobial agents may be useful for procedural sedation or in the ICU. Technological advances such as Bayesian model adjustment based on point-of-care plasma concentration measurements, closed-loop drug delivery and artificial intelligence may improve the ease of use of the anaesthetic drugs and increase the accuracy of titration. SUMMARY: Newer and more complex modelling techniques and technological advancements can help to deliver anaesthetic drugs, sedatives and other drugs in a more stable and thereby safer way.


Assuntos
Analgésicos Opioides/farmacologia , Analgésicos Opioides/farmacocinética , Anestésicos/farmacologia , Anestésicos/farmacocinética , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/farmacocinética , Propofol/farmacologia , Propofol/farmacocinética , Remifentanil/farmacologia , Remifentanil/farmacocinética , Idoso , Anestesia , Anestésicos Intravenosos , Inteligência Artificial , Teorema de Bayes , Criança , Relação Dose-Resposta a Droga , Humanos , Modelos Biológicos
12.
Artigo em Inglês | MEDLINE | ID: mdl-32549340

RESUMO

To illustrate a new technological advance in the standard drug-induced sleep endoscopy (DISE) model, a new machine was used, the Experimental 5 Video Stream System (5VsEs), which is capable of simultaneously visualizing all the decisional parameters on a single monitor, and recording and storing them in a single uneditable video. The DISE procedure was performed on 48 obstructive sleep apnea (OSA) or snoring patients. The parameters simultaneously recorded on a single monitor are (1) the pharmacokinetics and pharmacodynamics of propofol (through the target controlled infusion (TCI) pump monitor), (2) the endoscopic upper airway view, (3) the polygraphic pattern, and (4) the level of sedation (through the bispectral index (BIS) value). In parallel to the BIS recording, the middle latency auditory evoked potential (MLAEP) was also recorded and provided. Recorded videos from the 5VsEs machine were re-evaluated six months later by the same clinician and a second clinician to evaluate the concordance of the therapeutic indications between the two. After the six-month period, the same operator confirmed all their clinical decisions for 45 out of 48 videos. Three videos were no longer evaluable for technical reasons, so were excluded from further analysis. The comparison between the two operators showed a complete adherence in 98% of cases. The 5VsEs machine provides a multiparametric evaluation setting, defined as an "all in one glance" strategy, which allows a faster and more effective interpretation of all the simultaneous parameters during the DISE procedure, improving the diagnostic accuracy, and providing a more accurate post-analysis, as well as legal and research advantages.


Assuntos
Endoscopia , Hipnóticos e Sedativos , Propofol , Apneia Obstrutiva do Sono , Adulto , Feminino , Humanos , Hipnóticos e Sedativos/farmacocinética , Hipnóticos e Sedativos/farmacologia , Masculino , Propofol/farmacocinética , Propofol/farmacologia , Sono , Apneia Obstrutiva do Sono/diagnóstico , Ronco , Adulto Jovem
13.
Mol Pharmacol ; 98(3): 185-191, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32580996

RESUMO

Several general anesthetics (GAs) produce pain or irritation upon administration, and this occurs predominantly through the activation of the nociceptive ion channel, transient receptor potential ankyrin type 1 (TRPA1). However, the effects of GAs on agonist-mediated TRPA1 activity are unclear. Here we show that a diverse range of noxious and non-noxious volatile anesthetics, at clinically relevant concentrations, inhibit ligand-activated TRPA1 currents. These effects are species-specific; GAs blocks rodent TRPA1 without affecting the Drosophila ortholog. Furthermore, propofol inhibits rodent but not human TRPA1. Analysis of chimeric TRPA1 proteins and mutagenesis combined reveals two amino acid residues located in the S5 domain, Ser876 and Thr877, that are critical for the inhibitory effects of isoflurane and propofol. Introduction of these residues into Drosophila TRPA1 confers anesthetic inhibition. Furthermore, several residues lining the presumptive binding pocket for noxious GAs are not required for the inhibitory effects of GAs. We conclude that anesthetics inhibit TRPA1 by interacting at a site distinct from the activation site. The inhibitory effects of GAs at TRPA1 may contribute to the diverse pharmacological action of these drugs. SIGNIFICANCE STATEMENT: We show that both noxious and non-noxious general anesthetics inhibit agonist-evoked transient receptor potential ankyrin type 1 (TRPA1) activity and identify critical amino acid residues located in the pore domain. Inhibition of TRPA1 may affect pain and vascular signaling during anesthesia.


Assuntos
Hipnóticos e Sedativos/farmacologia , Mutação , Canal de Cátion TRPA1/genética , Canal de Cátion TRPA1/metabolismo , Animais , Drosophila melanogaster , Células HEK293 , Humanos , Isoflurano/farmacologia , Camundongos , Propofol/farmacologia , Domínios Proteicos , Ratos , Especificidade da Espécie , Canal de Cátion TRPA1/química
14.
Anesthesiology ; 133(3): 583-594, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32541553

RESUMO

BACKGROUND: Recent cryo-electron microscopic imaging studies have shown that in addition to binding to the classical extracellular benzodiazepine binding site of the α1ß3γ2L γ-aminobutyric acid type A (GABAA) receptor, diazepam also binds to etomidate binding sites located in the transmembrane receptor domain. Because such binding is characterized by low modulatory efficacy, the authors hypothesized that diazepam would act in vitro and in vivo as a competitive etomidate antagonist. METHODS: The concentration-dependent actions of diazepam on 20 µM etomidate-activated and 6 µM GABA-activated currents were defined (in the absence and presence of flumazenil) in oocyte-expressed α1ß3γ2L GABAA receptors using voltage clamp electrophysiology. The ability of diazepam to inhibit receptor labeling of purified α1ß3γ2L GABAA receptors by [H]azietomidate was assessed in photoaffinity labeling protection studies. The impact of diazepam (in the absence and presence of flumazenil) on the anesthetic potencies of etomidate and ketamine was compared in a zebrafish model. RESULTS: At nanomolar concentrations, diazepam comparably potentiated etomidate-activated and GABA-activated GABAA receptor peak current amplitudes in a flumazenil-reversible manner. The half-maximal potentiating concentrations were 39 nM (95% CI, 27 to 55 nM) and 26 nM (95% CI, 16 to 41 nM), respectively. However, at micromolar concentrations, diazepam reduced etomidate-activated, but not GABA-activated, GABAA receptor peak current amplitudes in a concentration-dependent manner with a half-maximal inhibitory concentration of 9.6 µM (95% CI, 7.6 to 12 µM). Diazepam (12.5 to 50 µM) also right-shifted the etomidate-concentration response curve for direct activation without reducing the maximal response and inhibited receptor photoaffinity labeling by [H]azietomidate. When administered with flumazenil, 50 µM diazepam shifted the etomidate (but not the ketamine) concentration-response curve for anesthesia rightward, increasing the etomidate EC50 by 18-fold. CONCLUSIONS: At micromolar concentrations and in the presence of flumazenil to inhibit allosteric modulation via the classical benzodiazepine binding site of the GABAA receptor, diazepam acts as an in vitro and in vivo competitive etomidate antagonist.


Assuntos
Diazepam/farmacologia , Etomidato/antagonistas & inibidores , Hipnóticos e Sedativos/farmacologia , Receptores de GABA/efeitos dos fármacos , Animais , Antagonismo de Drogas , Hipnóticos e Sedativos/antagonistas & inibidores , Modelos Animais , Peixe-Zebra
15.
Sleep Med Clin ; 15(2): 301-310, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32386703

RESUMO

This article focuses on melatonin and other melatonin receptor agonists, and specifically their circadian phase shifting and sleep-enhancing properties. The circadian system and circadian rhythm sleep-wake disorders are briefly reviewed, followed by a summary of the circadian phase shifting, sleep-enhancing properties, and possible safety concerns associated with melatonin and other melatonin receptor agonists. The recommended use of melatonin, including dose and timing, in the latest American Academy of Sleep Medicine Clinical Practice Guidelines for the treatment of intrinsic circadian rhythm disorders is also reviewed. Lastly, the practical aspects of treatment and consideration of clinical treatment outcomes are discussed.


Assuntos
Ritmo Circadiano/efeitos dos fármacos , Hipnóticos e Sedativos/uso terapêutico , Melatonina/uso terapêutico , Transtornos do Sono do Ritmo Circadiano/tratamento farmacológico , Sono/efeitos dos fármacos , Humanos , Hipnóticos e Sedativos/farmacologia , Melatonina/farmacologia , Resultado do Tratamento
16.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(5): 441-445, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32434638

RESUMO

OBJECTIVE: To compare intranasal midazolam and intramuscular phenobarbital sodium for their sedative effect in neonates undergoing magnetic resonance imaging (MRI). METHODS: A total of 70 neonates who underwent cranial MRI from September 2017 to March 2019 were randomized into an observation group and a control group, with 35 cases in each group. The observation group received intranasal drops of midazolam (0.3 mg/kg), and the control group received intramuscular injection of phenobarbital sodium (10 mg/kg). The sedation status of the neonates was evaluated using the Ramsay Sedation Scale. Meanwhile, the two groups were compared for the success rate of MRI procedure and incidence of adverse reactions. RESULTS: In the observation group, the sedation score was the highest at 20 minutes post administration, then was gradually decreasing, and decreased to the lowest level at 70 minutes post administration. In the control group, the sedation score was the lowest at 10 minutes post administration, then was gradually increasing, and increased to the highest level at 40 minutes and 50 minutes post administration, followed by a gradual decrease. Comparison of the sedation score at each time period suggested that the sedation score was significantly higher in the observation group than in the control group within 40 minutes post administration (P<0.05), while there were no significant differences between the two groups in the sedation score after 40 minutes post administration (P>0.05). The success rate of MRI procedure was significantly higher in the observation group than in the control group (89% vs 69%, P<0.05). There was no significant difference between the two groups in the incidence of adverse reactions (P>0.05). CONCLUSIONS: Intranasal midazolam is superior to intramuscular phenobarbital sodium in the sedative effect in neonates undergoing MRI, with the benefits of being fast, convenient, safe, and effective.


Assuntos
Hipnóticos e Sedativos/farmacologia , Humanos , Recém-Nascido , Espectroscopia de Ressonância Magnética , Midazolam , Estudos Prospectivos , Método Simples-Cego
17.
Anesthesiology ; 133(2): 377-392, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32412932

RESUMO

BACKGROUND: Dexmedetomidine induces a sedative response that is associated with rapid arousal. To elucidate the underlying mechanisms, the authors hypothesized that dexmedetomidine increases the activity of dopaminergic neurons in the ventral tegmental area, and that this action contributes to the unique sedative properties of dexmedetomidine. METHODS: Only male mice were used. The activity of ventral tegmental area dopamine neurons was measured by a genetically encoded Ca indicator and patch-clamp recording. Dopamine neurotransmitter dynamics in the medial prefrontal cortex and nucleus accumbens were measured by a genetically encoded dopamine sensor. Ventral tegmental area dopamine neurons were inhibited or activated by a chemogenetic approach, and the depth of sedation was estimated by electroencephalography. RESULTS: Ca signals in dopamine neurons in the ventral tegmental area increased after intraperitoneal injection of dexmedetomidine (40 µg/kg; dexmedetomidine, 16.917 [14.882; 21.748], median [25%; 75%], vs. saline, -0.745 [-1.547; 0.359], normalized data, P = 0.001; n = 6 mice). Dopamine transmission increased in the medial prefrontal cortex after intraperitoneal injection of dexmedetomidine (40 µg/kg; dexmedetomidine, 10.812 [9.713; 15.104], median [25%; 75%], vs. saline, -0.498 [-0.664; -0.355], normalized data, P = 0.001; n = 6 mice) and in the nucleus accumbens (dexmedetomidine, 8.543 [7.135; 11.828], median [25%; 75%], vs. saline, -0.329 [-1.220; -0.047], normalized data, P = 0.001; n = 6 mice). Chemogenetic inhibition or activation of ventral tegmental area dopamine neurons increased or decreased slow waves, respectively, after intraperitoneal injection of dexmedetomidine (40 µg/kg; delta wave: two-way repeated measures ANOVA, F[2, 33] = 8.016, P = 0.002; n = 12 mice; theta wave: two-way repeated measures ANOVA, F[2, 33] = 22.800, P < 0.0001; n = 12 mice). CONCLUSIONS: Dexmedetomidine activates dopamine neurons in the ventral tegmental area and increases dopamine concentrations in the related forebrain projection areas. This mechanism may explain rapid arousability upon dexmedetomidine sedation.


Assuntos
Dexmedetomidina/farmacologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Hipnóticos e Sedativos/farmacologia , Área Tegmentar Ventral/metabolismo , Animais , Neurônios Dopaminérgicos/química , Neurônios Dopaminérgicos/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Fotometria/métodos , Área Tegmentar Ventral/química , Área Tegmentar Ventral/efeitos dos fármacos
18.
Adv Exp Med Biol ; 1260: 283-296, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32304038

RESUMO

In our society, anxiety and depression are serious health issues that affect a large proportion of the population. Unfortunately, drug therapies are not always effective and can lead to drug abuse, delay of therapeutic effect, dependence, and tolerance. Traditionally, aromatherapy has also been used for anxiety relief and mood improvement. The use of essential oils, in relieving anxiety and depression, does not have the disadvantages associated with currently used drug therapies. In-vivo studies on animal models have verified the anxiolytic effects of these essential oils and the interactions of their major components with central nervous system receptors. Therefore, it seems reasonable to argue that the modulation of glutamate and GABA neurotransmitter systems are likely to be the critical mechanisms responsible for the sedative, anxiolytic, and anticonvulsant proprieties of linalool and essential oils containing linalool in significant proportions. Popular anxiolytic essential oils are generally rich in terpenoid alcohols like linalool, geraniol and citronellol, and the monoterpene limonene (or citral). Therefore, other essential oils or formulations that contain these terpenoids as major components may serve as important aromatherapeutics for relief of anxiety.


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Aromaterapia , Depressão/tratamento farmacológico , Óleos Voláteis/uso terapêutico , Terpenos/uso terapêutico , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Humanos , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Terpenos/química , Terpenos/farmacologia
19.
Am J Vet Res ; 81(4): 299-308, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32228259

RESUMO

OBJECTIVE: To determine whether concurrent vatinoxan administration affects the antinociceptive efficacy of medetomidine in dogs at doses that provide circulating dexmedetomidine concentrations similar to those produced by medetomidine alone. ANIMALS: 8 healthy Beagles. PROCEDURES: Dogs received 3 IV treatments in a randomized crossover-design trial with a 2-week washout period between experiments (medetomidine [20 µg/kg], medetomidine [20 µg/kg] and vatinoxan [400 µg/kg], and medetomidine [40 µg/kg] and vatinoxan [800 µg/kg]; M20, M20V400, and M40V800, respectively). Sedation, visceral and somatic nociception, and plasma drug concentrations were assessed. Somatic and visceral nociception measurements and sedation scores were compared among treatments and over time. Sedation, visceral antinociception, and somatic antinociception effects of M20V400 and M40V800 were analyzed for noninferiority to effects of M20, and plasma drug concentration data were assessed for equivalence between treatments. RESULTS: Plasma dexmedetomidine concentrations after administration of M20 and M40V800 were equivalent. Sedation scores, visceral nociception measurements, and somatic nociception measurements did not differ significantly among treatments within time points. Overall sedative effects of M20V400 and M40V800 and visceral antinociceptive effects of M40V800 were noninferior to those produced by M20. Somatic antinociception effects of M20V400 at 10 minutes and M40V800 at 10 and 55 minutes after injection were noninferior to those produced by M20. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested coadministration with vatinoxan did not substantially diminish visceral antinociceptive effects of medetomidine when plasma dexmedetomidine concentrations were equivalent to those produced by medetomidine alone. For somatic antinociception, noninferiority of treatments was detected at some time points.


Assuntos
Medetomidina/farmacologia , Quinolizinas/farmacologia , Analgésicos/farmacologia , Animais , Estudos Cross-Over , Cães , Frequência Cardíaca/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia
20.
Br J Anaesth ; 124(5): 603-613, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32151384

RESUMO

BACKGROUND: The most currently used general anaesthetics are potent potentiators of γ-aminobutyric acid A (GABAA) receptors and are invariably neurotoxic during the early stages of brain development in preclinical animal models. As causality between GABAA potentiation and anaesthetic-induced developmental neurotoxicity has not been established, the question remains whether GABAergic activity is crucial for promoting/enhancing neurotoxicity. Using the neurosteroid analogue, (3α,5α)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), which potentiates recombinant GABAA receptors, we examined whether this potentiation is the driving force in inducing neurotoxicity during development. METHODS: The neurotoxic potential of CDNC24 was examined vis-à-vis propofol (2,6-diisopropylphenol) and alphaxalone (5α-pregnan-3α-ol-11,20-dione) at the peak of rat synaptogenesis. In addition to the morphological neurotoxicity studies of the subiculum and medial prefrontal cortex (mPFC), we assessed the extra-, pre-, and postsynaptic effects of these agents on GABAergic neurotransmission in acute subicular slices from rat pups. RESULTS: CDNC24, like alphaxalone and propofol, caused dose-dependent hypnosis in vivo, with a higher therapeutic index. CDNC24 and alphaxalone, unlike propofol, did not cause developmental neuroapoptosis in the subiculum and mPFC. Propofol potentiated post- and extrasynaptic GABAA currents as evidenced by increased spontaneous inhibitory postsynaptic current (sIPSC) decay time and prominent tonic currents, respectively. CDNC24 and alphaxalone had a similar postsynaptic effect, but also displayed a strong presynaptic effect as evidenced by decreased frequency of sIPSCs and induced moderate tonic currents. CONCLUSIONS: The lack of neurotoxicity of CDNC24 and alphaxalone may be at least partly related to suppression of presynaptic GABA release in the developing brain.


Assuntos
Encéfalo/efeitos dos fármacos , Hipnóticos e Sedativos/toxicidade , Pregnanodionas/toxicidade , Esteroides/toxicidade , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Relação Dose-Resposta a Droga , Agonistas de Receptores de GABA-A/administração & dosagem , Agonistas de Receptores de GABA-A/farmacologia , Agonistas de Receptores de GABA-A/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Hipocampo/patologia , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/patologia , Pregnanodionas/administração & dosagem , Pregnanodionas/farmacologia , Propofol/administração & dosagem , Propofol/farmacologia , Propofol/toxicidade , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Esteroides/administração & dosagem , Esteroides/farmacologia , Sinapses/efeitos dos fármacos , Sinapses/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA