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1.
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
2.
J Am Vet Med Assoc ; 256(5): 573-579, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32068510

RESUMO

OBJECTIVE: To evaluate SC administration of alfaxalone-midazolam and dexmedetomidine-midazolam for sedation of ball pythons (Python regius). ANIMALS: 12 healthy juvenile ball pythons. PROCEDURES: In a randomized crossover study, each snake was administered a combination of alfaxalone (5 mg/kg [2.3 mg/lb]) and midazolam (0.5 mg/kg [0.23 mg/lb]) and a combination of dexmedetomidine (0.05 mg/kg [0.023 mg/lb]) and midazolam (0.5 mg/kg), SC, with a washout period of at least 7 days between protocols. Respiratory and heart rates and various reflexes and behaviors were assessed and compared between protocols. Forty-five minutes after protocol administration, sedation was reversed by SC administration of flumazenil (0.05 mg/kg) alone or in combination with atipamezole (0.5 mg/kg; dexmedetomidine-midazolam protocol only). Because of difficulties with visual assessment of respiratory effort after sedative administration, the experiment was repeated for a subset of 3 ball pythons, with plethysmography used to assess respiration. RESULTS: Both protocols induced a similar level of moderate sedation with no adverse effects aside from transient apnea. Cardiopulmonary depression was more profound, but time to recovery after reversal was significantly shorter, for the dexmedetomidine-midazolam protocol than for the alfaxalone-midazolam protocol. Plethysmographic findings were consistent with visual observations and suggested that snakes compensated for a decrease in respiratory rate by increasing tidal volume amplitude. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that both protocols induced clinically relevant sedation in ball pythons and should be useful for minor procedures such as venipuncture and diagnostic imaging. However, caution should be used when sedating snakes with compromised cardiopulmonary function. (J Am Vet Med Assoc 2020;256:573-579.


Assuntos
Boidae , Sedação Consciente/veterinária , Hipnóticos e Sedativos/administração & dosagem , Animais , Boidae/fisiologia , Sedação Consciente/métodos , Estudos Cross-Over , Dexmedetomidina , Midazolam , Pregnanodionas
3.
Res Vet Sci ; 129: 6-12, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31901533

RESUMO

This study aimed to investigate the specific pharmacokinetic profile and effects of alfaxalone after intravenous (IV) and intramuscular (IM) administration to rabbits and evaluate the potential interaction with dexmedetomidine. The study design was a blinded, randomized crossover with a washout period of 2 weeks. Five New Zealand white rabbits were used. Each animal received single IV and IM injections of alfaxalone at a single dose of 5 mg/kg, and single IV and IM injections of alfaxalone (5 mg/kg) combined with dexmedetomidine (100 µg/kg) administered intramuscularly. Blood samples were collected at predetermined times and analysed by high-performance liquid chromatography. The plasma concentration-time curves were analysed by non-compartmental analysis. Sedation/anaesthesia scores were evaluated by a modified numerical rating scale. At pre-determined time points heart and respiratory rates were measured. Times to sternal recumbency and standing position during the recovery were recorded. Concentrations of alfaxalone alone were very similar (slighty smaller) to concentrations when alfaxalone was combined with dexmedetomidine, after both routes of administration. Dexmedetomidine enhanced and increase the duration of the sedative effects of alfaxalone. In conclusion, alfaxalone administered in rabbits provides rapid and smooth onset of sedation. After IV and IM injections of alfaxalone combined with dexmedetomidine, a longer MRT and a deeper and extended sedation have been obtained compared to alfaxalone alone. Consequently, alfaxalone alone or in combination with dexmedetomidine could be useful to achieve respectively moderate to deep sedation in rabbits.


Assuntos
Anestésicos/farmacocinética , Dexmedetomidina/farmacocinética , Hipnóticos e Sedativos/farmacocinética , Pregnanodionas/farmacocinética , Anestésicos/farmacologia , Animais , Estudos Cross-Over , Dexmedetomidina/farmacologia , Hipnóticos e Sedativos/farmacologia , Injeções Intramusculares/veterinária , Injeções Intravenosas/veterinária , Pregnanodionas/farmacologia , Coelhos , Distribuição Aleatória
4.
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
5.
Anesth Analg ; 130(3): 704-714, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31124836

RESUMO

BACKGROUND: Previous formulations of alfaxalone have shown it to be a fast-acting intravenous anesthetic with high therapeutic index. Alfaxalone has been reformulated for human use as Phaxan, an aqueous solution of 10 mg/mL of alfaxalone and 13% betadex. This study assessed the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of alfaxalone given as a bolus intravenous injection of this formulation to human male volunteers. METHODS: A dose of 0.5 mg/kg (0.42-0.55 mg/kg) of alfaxalone [mean (range)] was given by single intravenous bolus injection to 12 healthy subjects. Plasma alfaxalone concentrations and bispectral index (BIS) values were analyzed using an integrated pharmacokinetic-pharmacodynamic (PKPD) model using nonlinear mixed-effects models. Effect (BIS) was described using a sigmoidal fractional maximum effect (EMAX) model. All parameters were scaled using allometry and standardized to a 70-kg person using exponents of 0.75 for clearance parameters (CL, Q2, and Q3), 1.0 for volumes (V1, V2, and V3), and 0.25 for time-related parameters half-time keo (t1/2keo). RESULTS: A 3-compartment model used to fit PK data with an additional compartment, linked by t1/2keo to describe the effect compartment, yielded alfaxalone PK parameter estimates: CL: 1.08 L/min; 0.87-1.34 L/min (median; 95% confidence interval [CI]); central volume of distribution (V1): 0.99 L; 0.53-2.05 L (median; 95% CI); intercompartment CLs (Q2): 0.87 L/min; 0.32-1.71 L/min (median; 95% CI) and Q3: 0.46 L/min; 0.19-1.03 L/min (median; 95% CI); and peripheral volumes of distribution (V2): 6.36 L; 2.79-10.7 L (median; 95% CI) and V3: 19.1 L; 8.61-37.4 L (median; 95% CI). PD interrogation assumed a baseline BIS of 96, with an estimated EMAX: 0.94; 0.71-0.99 (median; 95% CI), a plasma concentration (Cp) for 50% effect (C50): 0.98 mg/L; 0.83-1.09 mg/L (median; 95% CI), and a Hill coefficient (γ): 12.1; 6.7-15 (median; 95% CI). The t1/2keo was 8 minutes; 4.70-12.8 minutes (median; 95% CI). The mean time to a BIS 50 was 0.94 minutes (standard deviation [SD] = 0.2 minutes). CONCLUSIONS: After a single bolus intravenous injection, alfaxalone has a high plasma CL equal to hepatic blood flow as reported for earlier studies of bolus injections of a previous formulation of alfaxalone. The plasma levels associated with BIS values of <60 are comparable to those previously reported in patients anesthetized with alfaxalone. The t1/2keo is relatively high, but the large Hill coefficient contributes to rapid onset and offset of action. This information can inform future studies of this formulation.


Assuntos
Anestésicos/administração & dosagem , Anestésicos/farmacocinética , Estado de Consciência/efeitos dos fármacos , Pregnanodionas/administração & dosagem , Pregnanodionas/farmacocinética , Adolescente , Adulto , Anestésicos/sangue , Monitores de Consciência , Composição de Medicamentos , Meia-Vida , Voluntários Saudáveis , Humanos , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica , Modelos Biológicos , Nova Zelândia , Pregnanodionas/sangue , Adulto Jovem
6.
Am J Vet Res ; 81(1): 65-76, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31887090

RESUMO

OBJECTIVE: To evaluate the sedative and cardiorespiratory effects of IM administration of alfaxalone and butorphanol combined with acepromazine, midazolam, or dexmedetomidine in dogs. ANIMALS: 6 young healthy mixed-breed hounds. PROCEDURES: Dogs received each of 3 treatments (alfaxalone [2 mg/kg] and butorphanol [0.4 mg/kg] combined with acepromazine [0.02 mg/kg; AB-ace], midazolam [0.2 mg/kg; AB-mid], or dexmedetomidine [0.005 mg/kg; AB-dex], IM) in a blinded, randomized crossover-design study with a 1-week washout period between treatments. Sedation scores and cardiorespiratory variables were recorded at predetermined time points. Data were analyzed by use of mixed-model ANOVA and linear generalized estimating equations with post hoc adjustments. RESULTS: All treatments resulted in moderate to deep sedation (median score, ≥ 15/21) ≤ 5 minutes after injection. Sedation scores did not differ among treatments until the 40-minute time point, when the score was higher for AB-dex than for other treatments. Administration of AB-dex resulted in median scores reflecting deep sedation until 130 minutes, versus 80 and 60 minutes for AB-ace and AB-mid, respectively, after injection. Heart rate, cardiac output, and oxygen delivery decreased significantly after AB-dex, but not AB-ace or AB-mid administration. Respiratory variables remained within clinically acceptable ranges after all treatments. Undesirable recovery characteristics were observed in 4 dogs after AB-mid treatment. Four dogs required atipamezole administration 180 minutes after AB-dex injection. CONCLUSIONS AND CLINICAL RELEVANCE: All protocols produced reliable sedation. The results indicated that in young, healthy dogs, AB-mid may produce undesirable recovery characteristics; AB-dex treatment caused cardiovascular depression and should be used with caution.


Assuntos
Anestesia/veterinária , Anestésicos/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Sedação Profunda/veterinária , Injeções Intramusculares/veterinária , Acepromazina/administração & dosagem , Anestesia/efeitos adversos , Anestesia/normas , Anestésicos/administração & dosagem , Animais , Butorfanol/administração & dosagem , Estudos Cross-Over , Dexmedetomidina/administração & dosagem , Cães , Feminino , Frequência Cardíaca/efeitos dos fármacos , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/farmacologia , Masculino , Midazolam/administração & dosagem , Pregnanodionas/administração & dosagem
7.
Am J Vet Res ; 80(12): 1089-1098, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31763939

RESUMO

OBJECTIVE: To compare anesthetic effects of alfaxalone-ketamine-dexmedetomidine (AKD) and alfaxalone-butorphanol-midazolam (ABM) in naked mole-rats (Heterocephalus glaber). ANIMALS: 20 naked mole-rats. PROCEDURES: Naked mole-rats received AKD (alfaxalone, 2 mg/kg; ketamine, 20 mg/kg; and dexmedetomidine, 0.02 mg/kg; n = 10) or ABM (alfaxalone, 2 mg/kg; butorphanol, 2 mg/kg; and midazolam, 1 mg/kg; 9) IM; 1 animal was removed from the study. Atipamezole (I mg/kg) and flumazenil (0.1 mg/kg) were administered 40 minutes after anesthetic induction (defined as loss of the righting reflex) with AKD and ABM, respectively. Heart rate, respiratory rate, oxygen saturation, and reflexes were recorded every 5 minutes. RESULTS: The ABM group had significantly longer median times for induction and recovery than the AKD group. Administration of ABM resulted in significantly lower respiratory rates than administration of AKD from time of anesthetic induction to 10 minutes after induction. Respiratory rate significantly decreased in the AKD group from I0 minutes after induction through the end of the anesthetic period but did not change over time in the ABM group. Males had higher respiratory rates in both groups. Loss of the righting reflex was still evident 40 minutes after induction in both groups. In the AKD group, all tested reflexes were absent from I0 to 40 minutes after induction; the ABM group had variable reflexes that recovered within individual animals over time. CONCLUSIONS AND CLINICAL RELEVANCE: Both AKD and ABM provided effective immobilization in naked mole-rats, but AKD appeared to provide more consistent and deeper anesthesia, compared with administration of ABM.


Assuntos
Anestésicos/administração & dosagem , Anestésicos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Injeções Intramusculares , Ratos-Toupeira , Taxa Respiratória/efeitos dos fármacos , Animais , Butorfanol/administração & dosagem , Butorfanol/farmacologia , Dexmedetomidina/administração & dosagem , Dexmedetomidina/farmacologia , Feminino , Ketamina/administração & dosagem , Ketamina/farmacologia , Masculino , Midazolam/administração & dosagem , Midazolam/farmacologia , Pregnanodionas/administração & dosagem , Pregnanodionas/farmacologia
8.
J Vet Pharmacol Ther ; 42(6): 713-721, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31435964

RESUMO

Pharmacokinetics and pharmacodynamics of alfaxalone was performed in mallard ducks (Anas platyrhynchos) after single bolus injections of 10 mg/kg administered intramuscularly (IM; n = 10) or intravenously (IV; n = 10), in a randomized cross-over design with a washout period between doses. Mean (±SD) Cmax following IM injection was 1.6 (±0.8) µg/ml with Tmax at 15.0 (±10.5) min. Area under the curve (AUC) was 84.66 and 104.58 min*mg/ml following IV and IM administration, respectively. Volume of distribution (VD ) after IV dose was 3.0 L/kg. The mean plasma clearance after 10 mg/kg IV was 139.5 (±67.9) ml min-1  kg-1 . Elimination half-lives (mean [±SD]) were 15.0 and 16.1 (±3.0) min following IV and IM administration, respectively. Mean bioavailability at 10 mg/kg IM was 108.6%. None of the ducks achieved a sufficient anesthetic depth for invasive procedures, such as surgery, to be performed. Heart and respiratory rates measured after administration remained stable, but many ducks were hyperexcitable during recovery. Based on sedation levels and duration, alfaxalone administered at dosages of 10 mg/kg IV or IM in mallard ducks does not induce clinically acceptable anesthesia.


Assuntos
Anestésicos/farmacocinética , Patos/sangue , Pregnanodionas/farmacocinética , Anestésicos/administração & dosagem , Anestésicos/sangue , Animais , Área Sob a Curva , Feminino , Meia-Vida , Injeções Intramusculares , Injeções Intravenosas , Masculino , Pregnanodionas/administração & dosagem , Pregnanodionas/sangue
9.
Am J Vet Res ; 80(9): 819-824, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31449447

RESUMO

OBJECTIVE: To compare IV doses of alfaxalone and ketamine needed to facilitate orotracheal intubation and assess effects of each treatment on selected physiologic variables in goats undergoing orthopedic surgery with isoflurane anesthesia. ANIMALS: 18 healthy adult goats. PROCEDURES: Behavior was assessed before and after sedation with midazolam (0.1 mg/kg, IV) for IV catheter placement. Anesthesia was induced with additional midazolam (0.1 mg/kg, IV) and alfaxalone (n = 9) or ketamine (9) at 2 mg/kg, IV, over 30 seconds. An additional dose of alfaxalone or ketamine (1 mg/kg) was given IV if needed for intubation; anesthesia was maintained with isoflurane in oxygen and IV fluids with ketamine (0.5 to 1 mg/kg/h). Direct systolic (SAP), diastolic (DAP), and mean (MAP) arterial blood pressures; heart rate; and respiratory rate were recorded before induction, immediately after intubation, and during surgery. Qualitative anesthetic induction and recovery characteristics were assessed. Variables were compared within and between groups by statistical methods. RESULTS: No preinduction variables differed significantly between groups. Postintubation and 30-minute intraoperative SAP, DAP, and MAP were higher for the ketamine group than for the alfaxalone group; within the alfaxalone group, postintubation SAP, MAP, and respiratory rate prior to mechanical ventilation were lower than respective preinduction values. All alfaxalone-group goats were intubated after 1 dose of the induction agent; 5 of 9 ketamine-group goats required an additional (1-mg/kg) dose. Postoperative recovery was good to excellent for all animals. CONCLUSIONS AND CLINICAL RELEVANCE: Both drugs were suitable for induction of anesthesia after sedation with midazolam, but most goats required higher doses of ketamine to allow intubation. For situations in which alfaxalone administration is appropriate, the potential for decreased arterial blood pressures and respiratory rate should be considered.


Assuntos
Anestesia Intravenosa/veterinária , Anestesia/veterinária , Anestésicos Intravenosos/administração & dosagem , Cabras/cirurgia , Isoflurano/administração & dosagem , Ketamina/administração & dosagem , Pregnanodionas/administração & dosagem , Animais , Feminino , Frequência Cardíaca/efeitos dos fármacos , Midazolam/administração & dosagem , Estudos Prospectivos , Distribuição Aleatória , Taxa Respiratória/efeitos dos fármacos , Método Simples-Cego
10.
Vet Anaesth Analg ; 46(5): 605-612, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31395484

RESUMO

OBJECTIVE: To evaluate the cardiovascular effects, pharmacokinetic (PK) data and recovery characteristics of an alfaxalone constant rate infusion (CRI) of different duration in dogs at manufacturer's recommended dose rate. STUDY DESIGN: Experimental, prospective, randomized, crossover study. ANIMALS: Six intact female Beagles. METHODS: Following an intravenous alfaxalone bolus (3 mg kg-1), anaesthesia was maintained using an alfaxalone CRI at 0.15 mg kg-1 minute-1 for 90 (short CRI) or 180 minutes (long CRI). Venous blood samples were collected to determine the PK profile. Cardiovascular variables and recovery characteristics were evaluated. Recovery was scored on a scale ranging from 0, excellent to 4, bad. A mixed-model statistical approach was used to compare the cardiovascular parameters (global α = 0.05). An analysis of variance was performed to compare PK parameters and recovery times between treatments. RESULTS: No significant difference was noted between protocols for any PK parameter. Volume of distribution at steady state (935.74 ± 170.25 versus 1119.15 ± 190.65 mL kg-1), elimination half-life (12 ± 2 versus 13 ± 3 minutes), clearance from the central compartment (26.02 ± 4.41 versus 27.74 ± 5.65 mL kg-1 minute-1) and intercompartmental clearance (8.47 ± 4.06 versus 12.58 ± 7.03 mL kg-1 minute-1) were comparable for short CRI and long CRI. Cardiovascular variables remained within physiological limits. Mechanical ventilation was necessary (short CRI: n = 1, long CRI: n = 4). The manufacturer's recommended dose rate resulted in a light plane of anaesthesia. No significant differences in recovery times and scores were observed between treatments. The quality of recovery was scored as very poor with both protocols. CONCLUSIONS AND CLINICAL RELEVANCE: PK data were similar between long and short infusions of alfaxalone at the manufacturer's recommended dose, with acceptable cardiovascular conditions. Nevertheless, both protocols resulted in a superficial plane of general anaesthesia with poor recovery characteristics.


Assuntos
Anestesia Intravenosa/veterinária , Anestésicos Intravenosos/farmacocinética , Cães/fisiologia , Pregnanodionas/farmacocinética , Período de Recuperação da Anestesia , Anestésicos Intravenosos/administração & dosagem , Anestésicos Intravenosos/sangue , Anestésicos Intravenosos/farmacologia , Animais , Estudos Cross-Over , Cães/metabolismo , Feminino , Frequência Cardíaca/efeitos dos fármacos , Pregnanodionas/administração & dosagem , Pregnanodionas/sangue , Pregnanodionas/farmacologia , Estudos Prospectivos
11.
Vet Anaesth Analg ; 46(5): 597-604, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31303447

RESUMO

OBJECTIVE: To characterize the hemodynamic effects of subclinical, clinical and supraclinical plasma alfaxalone concentrations in cats. STUDY DESIGN: Experimental study. ANIMALS: A group of six adult healthy male neutered cats. METHODS: Cats were anesthetized with desflurane in oxygen for instrumentation. Catheters were placed in a medial saphenous vein for drug administration and in a carotid artery for arterial blood pressure measurement and blood collection. A thermodilution catheter was placed in the pulmonary artery via an introducer placed in a jugular vein for measurement of central venous pressure, pulmonary artery pressure, pulmonary artery occlusion pressure, cardiac output and core body temperature, and for sampling mixed venous blood. A lead II electrocardiogram was connected. Desflurane administration was discontinued and a target-controlled infusion system was used to administer alfaxalone to reach six plasma alfaxalone concentrations ranging from 1.0 to 30.4 mg L-1, with 7.6 mg L-1 considered a clinical concentration for anesthesia. Cardiovascular measurements were recorded, and arterial and mixed-venous blood samples were collected for blood-gas analysis and plasma alfaxalone concentration measurement at each target concentration. Data were analyzed using a repeated-measures analysis of variance and Dunnett's test for comparisons to the lowest target concentration. Significance was set at p < 0.05. RESULTS: Mean ± standard deviation plasma alfaxalone concentrations were 0.73 ± 0.32, 1.42 ± 0.41, 3.44 ± 0.40, 6.56 ± 0.43, 18.88 ± 6.81 and 49.47 ± 5.50 mg L-1 for the 1, 1.9, 3.8, 7.6, 15.2, and 30.4 mg L-1 target concentrations, respectively. PaCO2 increased with increasing target plasma alfaxalone concentrations and was 69.4 ± 14.2 mmHg (9.3 ± 1.9 kPa) at the 30.4 mg L-1 target. Some cardiovascular variables were statistically significantly affected by increasing target plasma alfaxalone concentrations. CONCLUSION AND CLINICAL RELEVANCE: Within the plasma concentration range studied, alfaxalone caused hypoventilation, but the cardiovascular effects were of small clinical significance.


Assuntos
Anestesia Intravenosa/veterinária , Anestésicos Intravenosos/farmacocinética , Gatos/fisiologia , Pregnanodionas/farmacocinética , Anestésicos Intravenosos/administração & dosagem , Anestésicos Intravenosos/sangue , Anestésicos Intravenosos/farmacologia , Animais , Determinação da Pressão Arterial/veterinária , Gatos/metabolismo , Hemodinâmica/efeitos dos fármacos , Masculino , Pregnanodionas/administração & dosagem , Pregnanodionas/sangue , Pregnanodionas/farmacologia
12.
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
13.
Gen Comp Endocrinol ; 282: 113221, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301283

RESUMO

Progesterone has received substantial attention for the essential role it plays in establishing and maintaining pregnancy in placental vertebrates. Despite the prevalence of progesterone during development, relatively little is known about how embryos respond to progesterone. This is true of placental vertebrates as well as egg-laying vertebrates where levels of progesterone in the yolk tend to be higher than most other steroids in the yolk. Bird eggs provide an opportunity to investigate the effects of progesterone on embryonic development because progesterone can be easily manipulated without any confounding effects on maternal physiology. To understand how progesterone might influence embryonic development, it is important to characterize the metabolic fate of progesterone given its potential to be converted to a wide range of steroids. We investigated the metabolic fate of tritiated progesterone over the first four days of development using chicken eggs (Gallus gallus) and identified 5ß-pregnanedione as the primary metabolite during this period. After only one day of development, 5ß-pregnanedione could be detected within the yolk. Levels of 5ß-pregnanedione in both the yolk and albumen tended to rise early in development but conjugated metabolites began to accumulate towards the end of our sampling period. Additionally, in vitro assays using embryo homogenates collected after 72 h of development demonstrated that embryos were capable of carrying out the conversion of progesterone to 5ß-pregnanedione. Overall these results have important implications for deciphering the mechanisms through which yolk progesterone might influence embryonic development. Effects could arise via progesterone receptors or receptors capable of binding 5ß-pregnanedione but we found no evidence that progesterone is serving as a precursor for androgen or estrogen production.


Assuntos
Galinhas/metabolismo , Desenvolvimento Embrionário , Pregnanodionas/metabolismo , Progesterona/metabolismo , Animais , Embrião de Galinha , Gema de Ovo/metabolismo , Feminino , Metaboloma , Gravidez , Fatores de Tempo
14.
J Avian Med Surg ; 33(2): 115-122, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31251498

RESUMO

This study was conducted to compare the effects of 3 different sedative agents on electroretinography (ERG) in domestic pigeons (Columba livia). Six pigeons were sedated with alfaxalone, xylazine, and medetomidine at separate times with a 1-week washout period between sedative administration. After sedation with each agent, pigeons underwent the modified ERG protocol adapted from the standardized protocol for dogs. The scotopic mixed rod and cone response was recorded after 20 minutes of dark adaptation, and the photopic cone response and photopic flicker response were recorded after 10 minutes of light adaptation. Either a 1-way analysis of variance or a Kruskall-Wallis test was used to compare the a-wave and b-wave implicit time and amplitude. No significant differences were observed in the scotopic mixed rod and cone response among all 3 sedatives used. Compared with alfaxalone, medetomidine significantly prolonged the a-wave implicit time, depressed the b-wave amplitude of photopic cone response, and prolonged the peak implicit time of the photopic flicker response (P < .05). These results show that medetomidine has a depressant effect on photopic ERG in pigeons at a dosage that produces light sedation.


Assuntos
Columbidae , Eletrorretinografia/veterinária , Medetomidina/farmacologia , Pregnanodionas/farmacologia , Xilazina/farmacologia , Anestésicos/farmacologia , Animais , Estudos Cross-Over , Hipnóticos e Sedativos/farmacologia
15.
Vet Anaesth Analg ; 46(4): 435-442, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31202619

RESUMO

OBJECTIVE: To compare the effect of chemical and mechanical stimulation on arytenoid cartilage motion during anaesthetic induction with alfaxalone, thiopentone or propofol. STUDY DESIGN: Masked, randomized, crossover study. ANIMALS: A group of eight adult Beagle dogs. METHODS: Anaesthesia was induced with thiopentone (7.5 mg kg-1), propofol (3 mg kg-1) or alfaxalone (1.5 mg kg-1) intravenously (IV), which were concurrently paired with either chemical (doxapram at 2.5 mg kg-1 IV) or mechanical (gentle pressure to the corniculate process of the right arytenoid cartilage using a cotton bud) stimulation for enhanced assessment of laryngeal motion, in random order, with a 1 week wash-out period between treatments. If deemed inadequately anaesthetized, supplemental boli of thiopentone (1.8 mg kg-1), propofol (0.75 mg kg-1) or alfaxalone (0.4 mg kg-1) were administered. Assessment of number of arytenoid motions and vital breaths, among others, was initiated immediately after induction. Chemical (doxapram) and mechanical stimulation were begun 2 minutes after anaesthetic induction. Data were collected at 2, 3 and 5 minutes after anaesthetic induction and the Friedman rank-sum or repeated-measures analysis of variance tests were used when applicable for statistical analysis. RESULTS: The duration of examination time was shorter among treatments combined with chemical stimulation (p=0.001). Examination time during induction was longer for alfaxalone-chemical (8.9 minutes) and -mechanical (10.9 minutes) compared to both induction with thiopentone-chemical (3.8 minutes) and propofol-chemical (4.0 minutes). The median number of arytenoid motions for both thiopentone (67) and propofol (59) induction combined with chemical stimulation was significantly higher in comparison to that of alfaxalone (1), thiopentone (2) and propofol (2), when combined with mechanical stimulation at 3 minutes after induction. CONCLUSION AND CLINICAL RELEVANCE: Among the regimens for assessing laryngeal motion assessed in the present study, combinations of thiopentone or propofol with doxapram are the most effective means of stimulating arytenoid motion and could improve the accuracy of diagnosis of laryngeal paralysis in dogs.


Assuntos
Doenças do Cão/diagnóstico , Cães , Pregnanodionas/farmacologia , Propofol/farmacologia , Tiopental/farmacologia , Paralisia das Pregas Vocais/veterinária , Anestesia/veterinária , Anestésicos/administração & dosagem , Anestésicos/farmacologia , Anestésicos Intravenosos/farmacologia , Animais , Estudos Cross-Over , Laringe/efeitos dos fármacos , Laringe/patologia , Pregnanodionas/administração & dosagem , Propofol/administração & dosagem , Distribuição Aleatória , Tiopental/administração & dosagem , Paralisia das Pregas Vocais/diagnóstico
16.
Vet Anaesth Analg ; 46(4): 483-487, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31178411

RESUMO

OBJECTIVE: To describe clinically relevant, physiological measurements collected during a 3 hour duration of alfaxalone total intravenous anaesthesia. STUDY DESIGN: Case series. ANIMALS: A total of 112 client-owned middle-aged or older dogs. METHODS: Dogs were premedicated with intramuscular acepromazine (0.03 mg kg-1). Anaesthesia was induced and subsequently maintained for up to 3 hours with alfaxalone administered intravenously. Dogs breathed 100% oxygen via an endotracheal tube. Heart rate, respiratory rate and blood pressure were evaluated 30 minutes after administration of acepromazine and used as baseline values for comparisons of intra-anaesthetic data. Blood glucose was measured 1 week prior to anaesthesia and every hour during alfaxalone anaesthesia. Quality and duration of recovery were recorded. Mean data for physiological variables were compared over three time points-before induction of anaesthesia, for the first hour of anaesthesia and from 60 minutes to discontinuation of anaesthesia. RESULTS: Mean induction dose of alfaxalone was 1.4 mg kg-1 [95% confidence interval (CI) 1.3-1.5). Post induction apnoea for >60 seconds occurred in 13 (11.6%) dogs. Mean alfaxalone infusion rate during the first 60 minutes of anaesthesia was 0.099 mg kg-1 minute-1; mean infusion rate was 0.092 mg kg-1 minute-1 from 60 minutes until discontinuation of anaesthesia. Heart rate was well maintained; hypotension (mean arterial blood pressure < 60 mmHg) was encountered in 23 (21%) dogs. Blood glucose levels did not alter during anaesthesia. Median time between discontinuation of alfaxalone infusion and extubation was 17 (7-35 minutes), time to assuming sternal recumbency was 75 (58-110 minutes), and time to standing was 109 (88-140 minutes). CONCLUSIONS AND CLINICAL RELEVANCE: Alfaxalone infusion provided effective anaesthesia in this population. In a minority of cases, respiratory and haemodynamic support of the patient was required.


Assuntos
Anestesia Intravenosa/veterinária , Anestésicos/farmacologia , Doenças do Cão/diagnóstico por imagem , Osteoartrite/veterinária , Pregnanodionas/farmacologia , Radiografia/veterinária , Anestésicos/administração & dosagem , Anestésicos/efeitos adversos , Animais , Apneia/induzido quimicamente , Apneia/veterinária , Glicemia , Pressão Sanguínea/efeitos dos fármacos , Dióxido de Carbono/sangue , Estudos de Casos e Controles , Cães , Feminino , Frequência Cardíaca/efeitos dos fármacos , Masculino , Osteoartrite/diagnóstico por imagem , Oxigênio/sangue , Pregnanodionas/administração & dosagem , Pregnanodionas/efeitos adversos , Respiração/efeitos dos fármacos
17.
Vet Anaesth Analg ; 46(4): 421-428, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31178412

RESUMO

OBJECTIVE: To investigate alfaxalone total intravenous anaesthesia (TIVA) following premedication with methadone combined with acepromazine (ACP) or dexmedetomidine in bitches undergoing ovariohysterectomy. STUDY DESIGN: Prospective, blinded, randomized, experimental study. ANIMALS: A group of 12 female Beagles. METHODS: Dogs were premedicated intravenously with methadone (0.2 mg kg-1) combined with ACP (20 µg kg-1, group AM) or dexmedetomidine (5 µg kg-1, group DM). Anaesthesia was induced with alfaxalone (2 mg kg-1). Anaesthetic maintenance was obtained with an alfaxalone variable rate infusion (VRI) started at 0.15 mg kg-1 minute-1 and adjusted every 5 minutes based on clinical assessment. Mechanical ventilation was initiated when necessary to maintain normocapnia. Anaesthetic monitoring included electrocardiogram, heart rate (HR), invasive diastolic (DAP), systolic (SAP) and mean arterial blood pressure, arterial haemoglobin oxygen saturation, respiratory variables and oesophageal temperature. Data were recorded every 5 minutes. A mixed model statistical approach was used to compare cardiovascular variables within and between groups (α = 0.05). A Wilcoxon rank-sum test was used to compare body temperature, VRI alfaxalone rate, administered rescue analgesia, sedation, induction, intubation, recovery scores and recovery times between treatments. RESULTS: Overall HR, SAP and DAP differed between groups (p = 0.001, 0.016, 0.019, respectively). The mean VRI dose rate of alfaxalone differed between groups DM [0.13 (0.11-0.14) mg kg-1 minute-1] and AM [0.18 (0.13-0.19) mg kg-1 minute-1; p = 0.030]. Rescue analgesia was administered more in group AM (p = 0.019). No significant difference in recovery times and scores was observed between protocols. CONCLUSIONS AND CLINICAL RELEVANCE: Alfaxalone TIVA following dexmedetomidine/methadone premedication produced a more stable plane of anaesthesia to perform ovariohysterectomy than ACP/methadone. A dose reduction of alfaxalone of 27.7% was obtained in group DM compared with group AM. Recovery quality and recovery times were comparable between both groups.


Assuntos
Acepromazina/farmacologia , Dexmedetomidina/farmacologia , Cães , Pregnanodionas/farmacologia , Pré-Medicação , Acepromazina/administração & dosagem , Anestésicos/administração & dosagem , Anestésicos/farmacologia , Animais , Dexmedetomidina/administração & dosagem , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/farmacologia , Feminino , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacologia , Histerectomia/veterinária , Metadona , Ovariectomia/veterinária , Pregnanodionas/administração & dosagem , Distribuição Aleatória
18.
Aust Vet J ; 97(6): 197-201, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31136692

RESUMO

CASE REPORT: We describe the clinical signs and management of a case of anaphylaxis in a dog after intravenous administration of alphaxalone (Alfaxan®, Jurox, NSW, Aust), which has not been previously published. A female spayed cattle dog undergoing routine imaging for forelimb lameness was induced with Alfaxan after receiving sedation with acepromazine and methadone 70 min prior. Immediately after intravenous administration of Alfaxan, the dog exhibited vomiting and diarrhoea associated with acute hypotension. Gallbladder wall oedema was visualised consistent with anaphylaxis. The dog responded to rapid volume expansion. Adrenaline was not required. The dog made a full recovery within 6 h of the reaction and was re-anaesthetised 3 days later without incident, using propofol as the induction agent. CONCLUSION: To our knowledge, this is the first published case of anaphylaxis associated with intravenous Alfaxan in the dog. The APVMA reporting of reactions in small animals from 2003 to 2013 of Alfaxan is consistent with this case report's finding involving the respiratory, circulatory and gastrointestinal systems.


Assuntos
Anafilaxia/veterinária , Anestésicos/efeitos adversos , Doenças do Cão/induzido quimicamente , Pregnanodionas/efeitos adversos , Anafilaxia/induzido quimicamente , Anestésicos/uso terapêutico , Animais , Cães , Feminino , Pregnanodionas/uso terapêutico
20.
Vet Anaesth Analg ; 46(4): 496-500, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31076335

RESUMO

OBJECTIVE: To evaluate if intramuscular (IM) lidocaine potentiates the sedative effects of alfaxalone and results in cardiopulmonary changes in sedated bearded dragons. STUDY DESIGN: Prospective experimental crossover study. ANIMALS: A group of eight adult bearded dragons (Pogona vitticeps) weighing 334 ± 46 g. METHODS: Animals were administered alfaxalone (10 mg kg-1 subcutaneously) and 15 minutes later either lidocaine 2% (4 mg kg-1) or 0.9% sodium chloride (0.2 mL kg-1) was administered IM in the thoracic limb. The treatments were randomized and separated by 7 days. Sedation was scored based on body position, eye closure, jaw tone, swallowing, pick up response, righting reflex and pelvic limb withdrawal reflex. Heart rate (HR) and respiratory rate (fR) were recorded every 5 minutes until recovery from sedation. RESULTS: Lidocaine had no significant effect on duration or depth of alfaxalone sedation. HR increased significantly for <10 minutes following lidocaine administration by a median (interquartile range) of 33% (28-37%; p = 0.024). No clinically significant effects on fR occurred following lidocaine injection. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of lidocaine 2% (4 mg kg-1) IM did not potentiate alfaxalone sedation but resulted in a transient clinically relevant increase in HR.


Assuntos
Anestésicos Locais/farmacologia , Anestésicos/farmacologia , Lidocaína/farmacologia , Lagartos , Pregnanodionas/farmacologia , Anestésicos/administração & dosagem , Anestésicos Locais/administração & dosagem , Animais , Estudos Cross-Over , Feminino , Injeções Intramusculares , Lidocaína/administração & dosagem , Masculino , Pregnanodionas/administração & dosagem , Distribuição Aleatória
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