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1.
J Zoo Wildl Med ; 50(4): 868-873, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31926517

RESUMO

Blue poison dart frogs (Dendrobates tinctorius azureus) are commonly maintained in zoological institutions and are becoming popular in the pet trade industry. Sedation or light anesthesia is required for safe and effective handling of this species. In this study, the sedative effects of subcutaneously administered alfaxalone-midazolam-dexmedetomidine (AMD) (20, 40, 5 mg/kg, respectively) and ketamine-midazolam-dexmedetomidine (KMD) (100, 40, 5 mg/kg, respectively) were compared in a prospective, randomized, blinded, crossover study in juvenile blue poison dart frogs (n = 10). Both protocols were partially reversed 45 min after administration of either protocol with subcutaneously administered flumazenil (0.05 mg/kg) and atipamezole (50 mg/kg). Heart rate, pulmonic respiratory rate, various reflexes, and behavioral parameters were monitored after drug administration. Both protocols resulted in rapid loss of righting reflex [median (range): AMD, 5 min (5-5 min); KMD, 5 min (5-10 min)]. Time to complete recovery was similar with both protocols (mean ± SD: AMD, 97.5 ± 11.4 min; KMD, 96.5 ± 25.4 min). The AMD protocol resulted in pulmonic respiratory depression, whereas no significant difference in heart rate was found between the two protocols. All frogs were observed eating within 24 hr of chemical restraint. Gastric prolapses occurred in four frogs (AMD 3, KMD 1) that were easily reduced with a cotton-tip application. No other adverse reactions were observed. The results of this study provide two different subcutaneous chemical restraint protocols in juvenile blue poison dart frogs.


Assuntos
Dexmedetomidina/farmacologia , Midazolam/farmacologia , Pregnanodionas/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Envelhecimento , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Anestésicos/administração & dosagem , Anestésicos/farmacologia , Animais , Antídotos/administração & dosagem , Antídotos/farmacologia , Anuros , Sedação Consciente , Estudos Cross-Over , Dexmedetomidina/administração & dosagem , Quimioterapia Combinada , Flumazenil/administração & dosagem , Flumazenil/farmacologia , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacologia , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Ketamina/administração & dosagem , Ketamina/farmacologia , Midazolam/administração & dosagem , Pregnanodionas/administração & dosagem
2.
Am J Vet Res ; 80(9): 878-884, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31449443

RESUMO

OBJECTIVE: To evaluate the effects of injectable dexmedetomidine-ketamine-midazolam (DKM) and isoflurane inhalation (ISO) anesthetic protocols on selected ocular variables in captive black-tailed prairie dogs (Cynomys ludovicianus; BTPDs). ANIMALS: 9 zoo-kept BTPDs. PROCEDURES: The BTPDs received dexmedetomidine hydrochloride (0.25 mg/kg, IM), ketamine hydrochloride (40 mg/kg, IM), and midazolam hydrochloride (1.5 mg/kg, IM) or inhalation of isoflurane and oxygen in a randomized complete crossover design (2-day interval between anesthetic episodes). Pupil size, globe position, tear production, and intraocular pressure measurements were recorded at 5, 30, and 45 minutes after induction of anesthesia. For each BTPD, a phenol red thread test was performed in one randomly selected eye and a modified Schirmer tear test I was performed in the other eye. Intraocular pressure was measured by rebound tonometry. RESULTS: Compared with findings for the DKM protocol, pupil size was smaller at all time points when the BTPDs underwent the ISO protocol. Globe position remained central during anesthesia with the DKM protocol, whereas it varied among central, ventromedial, and ventrolateral positions during anesthesia with the ISO protocol. Tear production and intraocular pressure decreased significantly over time when the BTPDs underwent either protocol. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that ophthalmic examination findings for anesthetized BTPDs can be influenced by the anesthetic protocol used. The DKM protocol may result in more consistent pupil size and globe position, compared with that achieved by use of the ISO protocol. Tear production and intraocular pressure measurements should be conducted promptly after induction of anesthesia to avoid the effect of anesthetic episode duration on these variables.


Assuntos
Anestesia/veterinária , Anestésicos Inalatórios/farmacologia , Olho/efeitos dos fármacos , Sciuridae , Anestésicos Inalatórios/administração & dosagem , Anestésicos Intravenosos/farmacologia , Animais , Animais de Zoológico , Dexmedetomidina/farmacologia , Pressão Intraocular/efeitos dos fármacos , Isoflurano/farmacologia , Ketamina/farmacologia , Masculino , Midazolam/farmacologia , Lágrimas/efeitos dos fármacos
3.
Neurochem Res ; 44(9): 2147-2155, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31385137

RESUMO

Inhibitors of acetylcholinesterase (AChE), which have an important role in the prevention of excessive AChE activity and ß-amyloid (Aß) formation are widely used in the symptomatic treatment of Alzheimer's disease (AD). The inhibitory effect of anesthetic agents on AChE was determined by several approaches, including binding mechanisms, molecular docking and kinetic analysis. Inhibitory effect of intravenous anesthetics on AChE as in vitro and in vivo have been discovered. The midazolam, propofol and thiopental have shown competitive inhibition type (midazolam > propofol > thiopental) and Ki values were found to be 3.96.0 ± 0.1, 5.75 ± 0.12 and 29.65 ± 2.04 µM, respectively. The thiopental and midazolam showed inhibition effect on AChE in vitro, whereas they showed activation effect in vivo when they are combined together. The order of binding of the drugs to the active site of the 4M0E receptor was found to be midazolam > propofol > thiopental. This study on anesthetic agents that are now widely used in surgical applications, have provided a molecular basis for investigating the drug-enzyme interactions mechanism. In addition, the study is important in understanding the molecular mechanism of inhibitors that are effective in the treatment of AD.


Assuntos
Acetilcolinesterase/metabolismo , Anestésicos Intravenosos/farmacologia , Inibidores da Colinesterase/farmacologia , Midazolam/farmacologia , Propofol/farmacologia , Tiopental/farmacologia , Acetilcolinesterase/química , Adulto , Anestésicos Intravenosos/metabolismo , Domínio Catalítico , Inibidores da Colinesterase/metabolismo , Humanos , Cinética , Masculino , Midazolam/metabolismo , Simulação de Acoplamento Molecular , Propofol/metabolismo , Ligação Proteica , Tiopental/metabolismo , Adulto Jovem
4.
Vet Anaesth Analg ; 46(5): 662-666, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31371196

RESUMO

OBJECTIVE: To establish and compare the effectiveness of two medetomidine-based immobilization protocols in Persian fallow deer (Dama dama mesopotamica). STUDY DESIGN: Prospective, randomized, blinded clinical study. ANIMALS: A group of 31 captive Persian fallow deer. METHODS: Deer scheduled for translocation were immobilized with a combination of medetomidine (76 ± 11 µg kg-1) and ketamine (1.0 ± 0.2 mg kg-1) (MK; n = 15) or medetomidine (77 ± 11 µg kg-1) and midazolam (0.10 ± 0.01 mg kg-1) (MM; n = 16) administered intramuscularly. An observer unaware of group assignments recorded times to immobilization and recovery, monitored physiologic variables and scored the quality of induction, immobilization and recovery (scale 1-5: 1, poor; 5, excellent). Atipamezole was administered for reversal. Data analysis was performed using the t test, the Mann-Whitney U test, the chi-square test and the Fisher's exact test. Significance was set at p < 0.05. RESULTS: Data are presented as mean ± standard deviation or median (range). Time to induce immobilization was 9 ± 4 and 10 ± 4 minutes in the MK and MM groups, respectively. Immobilization quality score was 5 (1-5) following both combinations. Hemoglobin oxygen saturation (SpO2) was significantly lower in the MK (80 ± 8%) than in the MM group (87 ± 8%) although respiratory frequency did not differ between MK and MM (11 ± 5 and 10 ± 2 breaths minute-1, respectively). Recovery times were 13 ± 6 (MK) and 14 ± 7 minutes (MM) and did not differ between groups. No morbidities or mortalities were recorded during 1 month after immobilization. CONCLUSIONS AND CLINICAL RELEVANCE: The MK and MM combinations produced sufficient immobilization in captive Persian fallow deer for short nonpainful procedures. Based on the SpO2 values, the MM combination may be associated with less respiratory depression; nevertheless, both combinations may result in a decrease in SpO2.


Assuntos
Anestésicos Dissociativos/farmacologia , Cervos/fisiologia , Imobilização/veterinária , Ketamina/farmacologia , Medetomidina/farmacologia , Midazolam/farmacologia , Anestésicos Dissociativos/administração & dosagem , Animais , Animais Selvagens , Comportamento Animal/efeitos dos fármacos , Método Duplo-Cego , Quimioterapia Combinada/veterinária , Feminino , Ketamina/administração & dosagem , Masculino , Medetomidina/administração & dosagem , Midazolam/administração & dosagem , Estudos Prospectivos
5.
Vet Anaesth Analg ; 46(5): 613-619, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31285156

RESUMO

OBJECTIVE: To qualitatively assess the co-induction of anaesthesia with midazolam and alfaxalone and to determine cardiovascular or respiratory alterations compared with alfaxalone alone. STUDY DESIGN: A randomized, blinded, clinical trial. ANIMALS: A total of 29 American Society of Anesthesiologists grade I or II, client-owned dogs undergoing elective orthopaedic or soft tissue surgery. METHODS: All dogs received 0.02 mg kg-1 acepromazine and 0.3 mg kg-1 methadone intramuscularly 30 minutes prior to anaesthesia. Measurements of heart rate (HR), respiratory frequency and blood pressure (BP) were assessed pre-induction and at 0, 2 and 5 minutes post-induction. Anaesthesia was induced with 0.5 mg kg-1 alfaxalone followed by either 0.4 mg kg-1 midazolam intravenously (group M) or an equal volume of saline (group S). Conditions were assessed for intubation and further boluses of 0.25 mg kg-1 alfaxalone were given as required. Response to co-induction, ease of intubation and quality of induction were scored, and total dose of alfaxalone required for intubation was recorded. Repeated measures one-way analysis of variance with post hoc Tukey's test was used to assess within group changes over time and Student t tests were used to compare between groups. Incidence of apnoea was assessed using a Fisher's exact test. Data are shown as mean ± standard deviation. RESULTS: Group M included 14 dogs and group S 15 dogs. There was a significant difference in the total dose of alfaxalone required for intubation, 0.65 ± 0.20 mg kg-1 group M and 0.94 ± 0.26 mg kg-1 group S (p = 0.002). Apnoea occurred significantly more frequently in group M (p = 0.007). There were no clinically significant differences in HR or BP at the measured time points between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Co-induction with midazolam had significant alfaxalone-sparing effects with no clinically detectable cardiovascular changes. Apnoea is common after co-induction.


Assuntos
Anestesia Intravenosa/veterinária , Anestésicos Intravenosos/farmacologia , Cães/fisiologia , Midazolam/farmacologia , Pregnanodionas/farmacologia , Anestésicos Intravenosos/administração & dosagem , Animais , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Quimioterapia Combinada/veterinária , Feminino , Frequência Cardíaca/efeitos dos fármacos , Masculino , Midazolam/administração & dosagem , Pregnanodionas/administração & dosagem
6.
Cardiovasc Intervent Radiol ; 42(11): 1597-1608, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31243542

RESUMO

PURPOSE: In percutaneous ablation procedures, periprocedural pain, unrest and respiratory concerns can be detrimental to achieve a safe and efficacious ablation and impair treatment outcome. This study aimed to compare the association between anesthetic technique and local disease control in patients undergoing percutaneous microwave ablation (MWA) of colorectal liver metastases (CRLM) and hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This IRB-exempted single-center comparative, retrospective analysis of three cohorts analyzed 90 patients treated for hepatic malignancies from January 2013 until September 2018. The local tumor progression-free survival (LTPFS), safety and periprocedural pain perception were assessed using univariate and multivariate Cox proportional hazard regression analyses to correct for potential confounders. RESULTS: In 114 procedures (22 general anesthesia; 32 midazolam; 60 propofol), 171 liver tumors (136 CRLM; 35 HCC) were treated with percutaneous MWA. Propofol and general anesthesia were superior to midazolam/fentanyl sedation regarding LTPFS (4/94 [4.3%] vs. 19/42 [45.2%] vs. 2/35 [5.7%]; P < 0.001, respectively). Local tumor progression rate was 14.6% (25/171). Eighteen tumors (72.0%) were retreated by ablation. Of them, 14 (78%) were previously treated with midazolam. Propofol versus midazolam (P < 0.001), general anesthesia versus midazolam (P = 0.016), direct postprocedural visual analog pain score above 5 (P = 0.050) and more than one tumor per procedure (P = 0.045) were predictors for LTPFS. Multivariate analysis revealed that propofol versus midazolam (HR 7.94 [95% CI 0.04-0.39; P < 0.001]) and general anesthesia versus midazolam (HR 6.33 [95% CI 0.04-0.69; P = 0.014]) were associated with LTPFS. Pain during and directly after treatment was significantly worse in patients who received midazolam sedation (P < 0.001). CONCLUSIONS: Compared to propofol and general anesthesia, midazolam/fentanyl sedation was associated with an increased periprocedural perception of pain and lower local tumor progression-free survival. To reduce the number of repeat procedures required to eradicate hepatic malignancies, general anesthesia and propofol sedation should be favored over midazolam.


Assuntos
Técnicas de Ablação/métodos , Anestesia Geral/métodos , Neoplasias Hepáticas/cirurgia , Midazolam/farmacologia , Dor/tratamento farmacológico , Propofol/farmacologia , Idoso , Estudos de Coortes , Feminino , Humanos , Hipnóticos e Sedativos/farmacologia , Masculino , Micro-Ondas , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
7.
Drug Des Devel Ther ; 13: 1729-1737, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190751

RESUMO

Background: Sevoflurane is generally the preferred anesthetic agent for general anesthesia in pediatric patients, due to its rapid induction and recovery characteristics. However, it has been recognized that a major complication is emergence agitation when awakening from general anesthesia. The aim of this study was to evaluate the occurrence rate of emergence agitation in the operating room and postoperative recovery area following intraoperative administration of midazolam to pediatric patients under general anesthesia. Patients and methods: One hundred and twenty pediatric patients undergoing dental treatment under sevoflurane anesthesia were enrolled in this study. The patients were divided into three groups (n=40 each in the 0.1 mg/kg midazolam, 0.05 mg/kg midazolam, and control with saline groups). Midazolam or saline was injected intravenously approximately 30 minutes before the end of the dental treatment. We used the Richmond Agitation and Sedation Scale (RASS) to assess the level of sedation and drowsiness at emergence phase in the operating room. We also used the Pediatric Anesthesia Emergence Delirium Scale (PAED) to assess the level of agitation and delirium at the full recovery phase from anesthesia in the recovery area. Results: At the emergence phase, the incidence of emergence agitation in the 0.1 mg/kg midazolam group was significantly lower than in the other groups (p=0.0010). At the recovery phase, there was no significant difference among the three groups. The odds ratio between PAED score and RASS score was 4.0 using logistic regression analysis. The odds ratio between PAED score and Disability was 2.5. Conclusion: Administration of a single dose of 0.1 mg/kg midazolam dose significantly decreases the incidence of severe emergence agitation at the emergence after sevoflurane anesthesia, but not at the recovery phase. Furthermore, the evaluation of sedative and agitation condition using RASS score at emergence from anesthesia is useful to predict occurrence of agitation in the recovery phase.


Assuntos
Anestesia Dentária/efeitos adversos , Anestesia Geral/efeitos adversos , Delírio do Despertar/prevenção & controle , Delírio do Despertar/psicologia , Hipnóticos e Sedativos/farmacologia , Midazolam/farmacologia , Sevoflurano/efeitos adversos , Período de Recuperação da Anestesia , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Delírio do Despertar/tratamento farmacológico , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/uso terapêutico , Injeções Intravenosas , Masculino , Midazolam/administração & dosagem , Midazolam/uso terapêutico , Análise de Regressão
8.
Drug Metab Pharmacokinet ; 34(4): 247-252, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31088714

RESUMO

Accurate prediction of cytochrome P450 (CYP) 3A activity in the early stage of drug development and in clinical practice is important. This study aimed to evaluate the previously constructed CYP3A activity prediction model after administration of CYP3A inhibitors and inducers and to modify the model for better prediction of CYP3A activity. Healthy male subjects received the following study drugs during three study periods: midazolam alone (control phase); midazolam with 200 mg of itraconazole (CYP3A inhibition phase); and midazolam with 150 mg of rifampicin (CYP3A induction phase). We quantified the concentrations of several endogenous CYP3A markers in both urine and plasma using gas chromatography-mass spectrometry. The urinary markers, including 6ß-hydroxy (OH)-cortisol/cortisol, 6ß-OH-cortisone/cortisone, 16α-OH-dehydroepiandrosterone (DHEA)/DHEA, 16α-OH-androstenedione (A-dione)/A-dione and 7ß-OH-DHEA/DHEA, were significantly correlated with midazolam clearance in both the CYP3A inhibition and induction phases. We constructed a statistical prediction model after integrating data from a previous study to predict midazolam clearance as follows: Ln(midazolam clearance) = 2.5545 + 0.3988 × ln(7ß-OH-DHEA/DHEA) + 0.1984 × ln(16α-OH-DHEA/DHEA) + 0.5031 × ln(6ß-OH-cortisol/cortisol) - 0.1261 [ln(7ß-OH-DHEA/DHEA) × ln(6ß-OH-cortisol/cortisol)] (r2 = 0.75). We suggest that quantitating endogenous markers in vivo coupled with the statistical prediction model may be useful for predicting CYP3A parameters.


Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/metabolismo , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Relação Dose-Resposta a Droga , Voluntários Saudáveis , Humanos , Itraconazol/administração & dosagem , Itraconazol/farmacologia , Cetoconazol/administração & dosagem , Cetoconazol/farmacologia , Masculino , Midazolam/administração & dosagem , Midazolam/farmacologia , Rifampina/administração & dosagem , Rifampina/farmacologia , Adulto Jovem
9.
Tissue Cell ; 58: 1-7, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31133236

RESUMO

Sevoflurane is a widely used anesthetics in surgery and considered as a safe reagent for clinical use. However, recent studies demonstrated that sevoflurane has a neurotoxic effect in central nervous system. Thus, finding ways to alleviate the side effect of sevoflurane is of importance. In this study, we identified the neuroprotective role of midazolam in hippocampal neurons. Midazolam treatment could alleviate the neuronal death and promote the neuronal maturation in hippocampal neurons in vitro. In vivo studies demonstrated that midazolam injection could improve behavioral deficit in sevoflurane-exposed animals. The anti-apoptotic function of midazolam in sevoflurane-exposed neurons was mediated by ERK signaling. Collectively, we elucidated a new role of midazolam in preventing hippocampal neuronal death from sevoflurane exposure, potentially providing a new strategy to resist the neurotoxicity in the clinical application of sevoflurane.


Assuntos
Hipocampo/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Midazolam/farmacologia , Neurônios/metabolismo , Sevoflurano/efeitos adversos , Animais , Morte Celular/efeitos dos fármacos , Hipocampo/patologia , Camundongos , Neurônios/patologia , Sevoflurano/farmacologia
10.
Anesthesiology ; 131(1): 36-45, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31094751

RESUMO

BACKGROUND: Midazolam has been found to exacerbate or unmask limb motor dysfunction in patients with brain tumors. This study aimed to determine whether the exacerbated upper limb motor-sensory deficits are mediated through benzodiazepine sites by demonstrating reversibility by flumazenil in patients with gliomas in eloquent areas. METHODS: This was an interventional, parallel assignment, nonrandomized trial. Study subjects were admitted in the operating room. Patients with supratentorial eloquent area gliomas and volunteers of similar age without neurologic disease were sedated with midazolam, but still responsive and cooperative. Motor and sensory functions for upper extremities were evaluated by the Nine-Hole Peg Test before and after midazolam, as well as after flumazenil reversal. RESULTS: Thirty-two cases were included: 15 in the glioma group and 17 in the control group. The total dose of midazolam and flumazenil were comparable between the groups. In the glioma group, the times to task completion after midazolam in the contralateral hand (P = 0.001) and ipsilateral hand (P = 0.002) were 26.5 (95% CI, 11.3 to 41.7) and 13.7 (95% CI, 5.0 to 22.4) seconds slower than baseline, respectively. After flumazenil reversal, the contralateral hand (P = 0.99) and ipsilateral hand (P = 0.187) performed 1.2 (95% CI, -3.3 to 5.8) and 1.5 (95% CI, -0.5 to 3.5) seconds slower than baseline, respectively. In the control group, the dominant (P < 0.001) and nondominant hand (P = 0.006) were 2.9 (95% CI, 1.4 to 4.3) and 1.7 (95% CI, 0.5 to 2.9) seconds slower than baseline, respectively. After flumazenil, the dominant hand (P = 0.99) and nondominant hand (P = 0.019) performed 0.2 (95% CI, -0.7 to 1.0) and 1.3 (95% CI, -0.2 to 2.4) seconds faster than baseline, respectively. CONCLUSIONS: In patients with eloquent area gliomas, mild sedation with midazolam induced motor coordination deficits in upper limbs. This deficit was almost completely reversed by the benzodiazepine antagonist flumazenil, suggesting that this is a reversible abnormality linked to occupation of the receptor by midazolam.


Assuntos
Neoplasias Encefálicas/fisiopatologia , Flumazenil/farmacologia , Glioma/fisiopatologia , Midazolam/farmacologia , Transtornos Motores/tratamento farmacológico , Extremidade Superior/fisiopatologia , Adulto , Neoplasias Encefálicas/complicações , Feminino , Moduladores GABAérgicos/farmacologia , Glioma/complicações , Humanos , Hipnóticos e Sedativos/farmacologia , Masculino , Pessoa de Meia-Idade , Transtornos Motores/induzido quimicamente , Transtornos Motores/fisiopatologia
11.
Int J Neurosci ; 129(10): 986-994, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30957600

RESUMO

Background: Numerous experimental studies show that anesthetics are potentially toxic to the immature brain. Even though benzodiazepines are widely used in pediatric anesthesia and intensive care medicine, only a few studies examine the effects of these drugs on immature neurons. Methods: Hippocampal neuronal cell cultures of embryonic Wistar rats (15 days in culture) were incubated with midazolam 100 or 300 nM for either 30 min or 4 h. The time course of the mRNA expression of the glutamate receptors subunits NR1, NR2A and NR2B of the NMDA receptor, the GluA-1 and A-2 subunits of the AMPA receptor as well as the alpha 1 subunit of the GABAA receptor were examined by PCR. Apoptosis was detected using Western blot analysis for BAX, Bcl-2 and Caspase-3. Results: Midazolam at 100 and 300 nM applied for 30 min and 100 nM for 4 h affected glutamate receptor and GABAA receptor subunit expression. However, these effects were reversible within 72 h following washout. When 300 nM midazolam was applied for 4 h a significant increase in the NR 1 and NR 2A mRNA subunit expression could be detected. The increase in NR 2B receptor subunit expression as well as the GluA1 subunit expression was not reversible within 72 h following washout. This increase in mRNA glutamate receptor subunit expression was associated with a significant increase in neuronal apoptosis. Conclusion: In immature neurons midazolam altered GABA and glutamate mRNA receptor subunit expression. Prolonged increase in midazolam-induced glutamate receptor expression was associated with apoptosis.


Assuntos
Moduladores GABAérgicos/farmacologia , Hipocampo/metabolismo , Midazolam/farmacologia , Neurônios/metabolismo , RNA Mensageiro/biossíntese , Receptores de GABA-A/biossíntese , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/embriologia , Neurônios/efeitos dos fármacos , RNA Mensageiro/genética , Ratos , Ratos Wistar , Receptores de GABA-A/genética
12.
Kaohsiung J Med Sci ; 35(3): 160-167, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30887720

RESUMO

To find the right sedation technique for different types of treatment methods and the right amount of sedatives so the chances of side effects happening can be reduced. This was a retrospective cohort analysis conducted on prospectively collected data. Patients who underwent esophagogastroduodenoscopy only (E group) were sub-divided into two subgroups: (a) Those who received 0.5 mg/kg of propofol (E-a), (b) Those who received 0.025 mg/kg of midazolam and 0.5 mg/kg of propofol (E-b). Patients who underwent esophagogastroduodenoscopy with colonoscopy (EC group) were also sub-divided into three subgroups: (a) Those who received 0.5 mg/kg of propofol (EC-a), (b) Those who received 0.025 mg/kg of midazolam and 0.5 mg/kg of propofol (EC-b), (c) Those who received 25 mg (12.5 mg if body weight < 50 kg or age > 70) of meperidine and 0.025 mg/kg of midazolam along with 0.5 mg/kg of propofol (EC-c). When the level of target was not reached, 10-20 mg of propofol was additionally injected. Sedation efficacy and safety were then compared among groups. E-b and EC-b decreased the overall amount of propofol and reduced side effect of temporary hypoxemia compared to E-a and EC-a. EC-b shortened patient recovery time compared to EC-c and reduced paradoxical reaction. In terms of the patient satisfaction and patient cooperation by endoscopists, there were no significant differences between EC-b and EC-c. Concomitant use of low dosages of both propofol and midazolam is found to be useful and safe when endoscopy needs to be performed.


Assuntos
Sedação Consciente , Endoscopia do Sistema Digestório , Midazolam/farmacologia , Propofol/farmacologia , Colonoscopia , Relação Dose-Resposta a Droga , Endoscopia do Sistema Digestório/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
13.
Life Sci ; 221: 178-186, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30771312

RESUMO

Neutrophil extracellular traps (NETs) are net-like chromatin fibers that can trap and kill microorganisms. Although several anti-inflammatory effects of intravenous anesthetics have been reported, it has not been investigated whether intravenous anesthetics influence NET formation. AIMS: To compare the effects of four intravenous anesthetics (propofol, thiamylal sodium, midazolam, and ketamine) on phorbol myristate acetate (PMA)-induced NET formation and analyze the associated signaling pathways. MATERIALS AND METHODS: PMA-stimulated NETs formed in the absence or presence of intravenous anesthetics were stained with SYTOX Green and then quantified. Inhibitors were applied to investigate the related mechanism, which was confirmed by western blotting, and ROS were detected. KEY FINDINGS: The neutrophils incubated with propofol showed the lowest degree of NET formation compared with those incubated with the other intravenous anesthetics. Propofol significantly reduced the level of myeloperoxidase (MPO)-derived HOCl but not that of superoxide. Aminopyrine, an MPO inhibitor, markedly decreased the number of PMA-induced NETs, indicating the involvement of HOCl in the inhibitory effect of propofol on NET formation. According to western blotting results, the level of p-ERK was reduced by propofol during PMA-induced NET formation. The ERK inhibitor PD98059 decreased NET formation but did not inhibit PMA-induced HOCl generation, and aminopyrine did not reduce ERK phosphorylation. SIGNIFICANCE: Through this study, we define a new anti-inflammatory effect of intravenous anesthetics. Of the four intravenous anesthetics tested, propofol was the most potent inhibitor of NET formation. Moreover, propofol resulted in a decrease in PMA-induced NET formation by two independent mechanisms: inhibition of HOCl and p-ERK.


Assuntos
Armadilhas Extracelulares/efeitos dos fármacos , Propofol/farmacologia , Anestésicos Intravenosos/metabolismo , Anestésicos Intravenosos/farmacologia , Cromatina/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Ácido Hipocloroso/metabolismo , Ketamina/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Midazolam/farmacologia , Neutrófilos/fisiologia , Propofol/metabolismo , Espécies Reativas de Oxigênio , Transdução de Sinais , Acetato de Tetradecanoilforbol/metabolismo , Acetato de Tetradecanoilforbol/farmacologia , Tiamilal/farmacologia
14.
Biopharm Drug Dispos ; 40(2): 81-93, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30724384

RESUMO

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


Assuntos
Alprazolam/farmacologia , Indutores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/biossíntese , Midazolam/farmacologia , Rifampina/farmacologia , Triazolam/farmacologia , Alprazolam/sangue , Animais , Área Sob a Curva , Biomarcadores/sangue , Biomarcadores/urina , Indutores do Citocromo P-450 CYP3A/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Hidrocortisona/análogos & derivados , Hidrocortisona/urina , Hidroxicolesteróis/sangue , Macaca fascicularis , Masculino , Midazolam/sangue , Rifampina/sangue , Triazolam/sangue
15.
Int J Mol Sci ; 20(3)2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30720745

RESUMO

Drug repositioning promises the advantages of reducing costs and expediting approvalschedules. An induction of the anesthetic and sedative drug; midazolam (MDZ), regulatesinhibitory neurotransmitters in the vertebrate nervous system. In this study we show the potentialfor drug repositioning of MDZ for dentin regeneration. A porcine dental pulp-derived cell line(PPU-7) that we established was cultured in MDZ-only, the combination of MDZ with bonemorphogenetic protein 2, and the combination of MDZ with transforming growth factor-beta 1. Thedifferentiation of PPU-7 into odontoblasts was investigated at the cell biological and genetic level.Mineralized nodules formed in PPU-7 were characterized at the protein and crystal engineeringlevels. The MDZ-only treatment enhanced the alkaline phosphatase activity and mRNA levels ofodontoblast differentiation marker genes, and precipitated nodule formation containing a dentinspecificprotein (dentin phosphoprotein). The nodules consisted of randomly orientedhydroxyapatite nanorods and nanoparticles. The morphology, orientation, and chemicalcomposition of the hydroxyapatite crystals were similar to those of hydroxyapatite that hadtransformed from amorphous calcium phosphate nanoparticles, as well as the hydroxyapatite inhuman molar dentin. Our investigation showed that a combination of MDZ and PPU-7 cellspossesses high potential of drug repositioning for dentin regeneration.


Assuntos
Dentina/efeitos dos fármacos , Reposicionamento de Medicamentos , Midazolam/farmacologia , Regeneração , Animais , Proteína Morfogenética Óssea 2/farmacologia , Proteína Morfogenética Óssea 2/uso terapêutico , Linhagem Celular , Dentina/fisiologia , Midazolam/uso terapêutico , Odontoblastos , Suínos , Fator de Crescimento Transformador beta1/farmacologia , Fator de Crescimento Transformador beta1/uso terapêutico
16.
Chin Med J (Engl) ; 132(4): 437-445, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30707179

RESUMO

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a serious complication after surgery, especially in elderly patients. The anesthesia technique is a potentially modifiable risk factor for POCD. This study assessed the effects of dexmedetomidine, propofol or midazolam sedation on POCD in elderly patients who underwent hip or knee replacement under spinal anesthesia. METHODS: The present study was a prospective randomized controlled preliminary trial. From July 2013 and December 2014, a total of 164 patients aged 65 years or older who underwent hip or knee arthroplasty at China-Japan Friendship Hospital and 41 non-surgical controls were included in this study. Patients were randomized in a 1:1:1 ratio to 3 sedative groups. All the patients received combined spinal-epidural anesthesia (CSEA) with midazolam, dexmedetomidine or propofol sedation. The sedative dose was adjusted to achieve light sedation (bispectral index[BIS] score between 70 and 85). All study participants and controls completed a battery of 5 neuropsychological tests before and 7 days after surgery. One year postoperatively, the patients and controls were interviewed over the telephone using the Montreal cognitive assessment 5-minute protocol. RESULTS: In all, 60 of 164 patients (36.6%) were diagnosed with POCD 7 days postoperatively, POCD incidence in propofol group was significantly lower than that in dexmedetomidine and midazolam groups (18.2% vs. 40.0%, 51.9%, χ = 6.342 and 13.603, P = 0.012 and < 0.001). When the patients were re-tested 1 year postoperatively, the incidence of POCD was not significantly different among the 3 groups (14.0%, 10.6% vs. 14.9%, χ = 0.016 and 0.382, P = 0.899 and 0.536). CONCLUSION: Among dexmedetomidine, propofol and midazolam sedation in elderly patients, propofol sedation shows a significant advantage in term of short-term POCD incidence.


Assuntos
Disfunção Cognitiva/epidemiologia , Dexmedetomidina/farmacologia , Hipnóticos e Sedativos/farmacologia , Midazolam/farmacologia , Complicações Pós-Operatórias/epidemiologia , Propofol/farmacologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos Prospectivos
17.
Artigo em Inglês | MEDLINE | ID: mdl-30790623

RESUMO

INTRODUCTION: Organophosphorus nerve agents (OPNAs) irreversibly block acetylcholinesterase activity, resulting in accumulation of excess acetylcholine at neural synapses, which can lead to a state of prolonged seizures known as status epilepticus (SE). Benzodiazepines, the current standard of care for SE, become less effective as latency to treatment increases. In a mass civilian OPNA exposure, concurrent trauma and limited resources would likely cause a delay in first response time. To address this issue, we have developed a rat model to test novel anticonvulsant/ neuroprotectant adjuncts at delayed time points. METHODS: For model development, adult male rats with cortical electroencephalographic (EEG) electrodes were exposed to soman and administered saline along with atropine, 2-PAM, and midazolam 5, 20, or 40 min after SE onset. We validated our model using three drugs: scopolamine, memantine, and phenobarbital. Using the same procedure outlined above, rats were given atropine, 2-PAM, midazolam and test treatment 20 min after SE onset. RESULTS: Using gamma power, delta power, and spike rate to quantify EEG activity, we found that scopolamine was effective, memantine was minimally effective, and phenobarbital had a delayed effect on terminating SE. Fluoro-Jade B staining was used to assess neuroprotection in five brain regions. Each treatment provided significant protection compared to saline + midazolam in at least two brain regions. DISCUSSION: Because our data agree with previously published studies on the efficacy of these compounds, we conclude that this model is a valid way to test novel anticonvulsants/ neuroprotectants for controlling benzodiazepine-resistant OPNA-induced SE and subsequent neuropathology.


Assuntos
Anticonvulsivantes/farmacologia , Benzodiazepinas/farmacologia , Memantina/farmacologia , Agentes Neurotóxicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Fenobarbital/farmacologia , Escopolamina/farmacologia , Estado Epiléptico/tratamento farmacológico , Animais , Atropina/farmacologia , Encéfalo/efeitos dos fármacos , Eletroencefalografia/métodos , Masculino , Midazolam/farmacologia , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Soman/farmacologia , Estado Epiléptico/induzido quimicamente
18.
Med Hypotheses ; 124: 42-52, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30798915

RESUMO

The neural correlates of consciousness and the mechanisms by which general anesthesia (GA) modulate such correlates to induce loss of consciousness (LOC) has been described as one of the biggest mysteries of modern medicine. Several cellular targets and neural circuits have been identified that play a critical role in LOC induced by GA, including the GABAA receptor and ascending arousal nuclei located in the basal forebrain, hypothalamus, and brain stem. General anesthetics (GAs) including propofol and inhalational agents induce LOC in part by potentiating chloride influx through the GABAA receptor, leading to neural inhibition and LOC. Interestingly, nearly all GAs used clinically may also induce paradoxical excitation, a phenomenon in which GAs promote neuronal excitation at low doses before inducing unconsciousness. Additionally, emergence from GA, a passive process that occurs after anesthetic removal, is associated with lower anesthetic concentrations in the brain compared to doses associated with induction of GA. AMPK, an evolutionarily conserved kinase activated by cellular stress (e.g. increases in calcium [Ca2+] and/or reactive oxygen species [ROS], etc.) increases lifespan and healthspan in several model organisms. AMPK is located throughout the mammalian brain, including in neurons of the thalamus, hypothalamus, and striatum as well as in pyramidal neurons in the hippocampus and cortex. Increases in ROS and Ca2+ play critical roles in neuronal excitation and glutamate, the primary excitatory neurotransmitter in the human brain, activates AMPK in cortical neurons. Nearly every neurotransmitter released from ascending arousal circuits that promote wakefulness, arousal, and consciousness activates AMPK, including acetylcholine, histamine, orexin-A, dopamine, and norepinephrine. Several GAs that are commonly used to induce LOC in human patients also activate AMPK (e.g. propofol, sevoflurane, isoflurane, dexmedetomidine, ketamine, midazolam). Various compounds that accelerate emergence from anesthesia, thus mitigating problematic effects associated with delayed emergence such as delirium, also activate AMPK (e.g. nicotine, caffeine, forskolin, carbachol). GAs and neurotransmitters also act as preconditioning agents and the GABAA receptor inhibitor bicuculline, which reverses propofol anesthesia, also activates AMPK in cortical neurons. We propose the novel hypothesis that cellular stress-induced AMPK activation links wakefulness, arousal, and consciousness with paradoxical excitation and accelerated emergence from anesthesia. Because AMPK activators including metformin and nicotine promote proliferation and differentiation of neural stem cells located in the subventricular zone and the dentate gyrus, AMPK activation may also enhance brain repair and promote potential recovery from disorders of consciousness (i.e. minimally conscious state, vegetative state, coma).


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Anestesia/métodos , Transtornos da Consciência/metabolismo , Metformina/farmacologia , Período de Recuperação da Anestesia , Anestésicos/farmacologia , Animais , Mapeamento Encefálico , Cálcio/metabolismo , Linhagem da Célula , Proliferação de Células , Estado de Consciência , Transtornos da Consciência/induzido quimicamente , Dexmedetomidina/farmacologia , Humanos , Isoflurano/farmacologia , Ketamina/química , Ketamina/farmacologia , Aprendizagem , Potenciação de Longa Duração , Memória , Midazolam/farmacologia , Modelos Neurológicos , Nicotina/farmacologia , Propofol/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sevoflurano/farmacologia , Inconsciência
19.
Bioorg Med Chem ; 27(5): 790-799, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30704835

RESUMO

Protein kinase C theta (PKCθ) plays a critical role in T cell signaling and has therapeutic potential for T cell-mediated diseases such as transplant rejection and rheumatoid arthritis. PKCθ inhibitors have emerged as effective immunomodulative agents for the prevention of transplant rejection. We previously reported that the 2,4-diamino-5-cyanopyrimidine derivative 2 was a potent PKCθ inhibitor; however, it exhibited CYP3A4 time-dependent inhibition (TDI). Here, we report the structural modification of compound 2 into 34 focusing on mitigating CYP3A4 TDI. Compound 34 exhibited potent in vitro activity with mitigated CYP3A4 TDI and efficacy in vivo transplant model.


Assuntos
Diaminas/farmacologia , Proteína Quinase C-theta/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Inibidores do Citocromo P-450 CYP3A/síntese química , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Diaminas/síntese química , Diaminas/farmacocinética , Descoberta de Drogas , Interações Medicamentosas , Feminino , Rejeição de Enxerto/prevenção & controle , Haplorrinos , Humanos , Células Jurkat , Microssomos Hepáticos/metabolismo , Midazolam/farmacologia , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos Endogâmicos ACI , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Relação Estrutura-Atividade
20.
Biochem Pharmacol ; 163: 215-224, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30796914

RESUMO

Human CYP3A4 (Cyp3a11 in mice) is one of the most important enzymes for drug metabolism and detoxification. Here, we aimed to investigate a potential role for E4bp4 in regulation of Cyp3a11 expression and activity. The regulatory effects of E4bp4 on Cyp3a11 enzyme were assessed using E4bp4-/- mice and Hepa-1c1c7 cells. The mRNA and protein levels were quantified using qPCR and Western blotting, respectively. In vitro microsomal Cyp3a11 activity was probed using its specific substrates midazolam and testosterone. Pharmacokinetic studies were performed with wild-type and E4bp4-/- mice after midazolam administration. Global deletion of E4bp4 led to significant upregulation of Cyp3a11 mRNA and protein in major metabolic organs (i.e., the liver, kidney and small intestine). E4bp4 ablation also caused an increased microsomal Cyp3a11 activity consistent with the enzyme's expression change. Overexpression of E4bp4 in Hepa-1c1c7 cells resulted in reduced levels of Cyp3a11 mRNA and protein, whereas E4bp4 knockdown caused upregulation of Cyp3a11 expression. In addition, the systemic exposure of midazolam was lowered in E4bp4-/- mice compared with wild-type mice. This was accompanied by enhanced formation of its metabolite 1'-hydroxymidazolam. Furthermore, luciferase reporter and mobility shift assays revealed that E4bp4 repressed Cyp3a11 transcription via direct binding to C-site (-1539/-1529 bp) in the promoter region. In conclusion, E4bp4 negatively regulates Cyp3a11 expression, thereby impacting drug metabolism and pharmacokinetics.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Citocromo P-450 CYP3A/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Midazolam/farmacologia , Testosterona/farmacologia , Androgênios/química , Androgênios/metabolismo , Androgênios/farmacologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Linhagem Celular , Citocromo P-450 CYP3A/genética , Moduladores GABAérgicos/metabolismo , Moduladores GABAérgicos/farmacologia , Regulação da Expressão Gênica/fisiologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Midazolam/química , Midazolam/metabolismo , Estrutura Molecular , Testosterona/química , Testosterona/metabolismo , Regulação para Cima
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