RESUMEN
Antepartum depression, general anxiety symptoms, and pregnancy-related anxiety have been recognized to affect pregnancy outcomes. Systematic reviews on these associations lack consistent findings, which is why further research is required. We examined the associations between psychological distress, mode of birth, epidural analgesia, and duration of labor. Data from 3619 women with singleton pregnancies, from the population-based FinnBrain Birth Cohort Study were analyzed. Maternal psychological distress was measured during pregnancy at 24 and 34 weeks, using the Pregnancy-Related Anxiety Questionnaire-Revised 2 (PRAQ-R2) and its subscale "Fear of Giving Birth" (FOC), the anxiety subscale of the Symptom Checklist-90 (SCL-90) and the Edinburgh Postnatal Depression Scale (EPDS). Mode of birth, epidural analgesia, and labor duration were obtained from the Finnish Medical Birth Register. Maternal psychological distress, when captured with PRAQ-R2, FOC, and SCL-90, increased the likelihood of women having an elective cesarean section (OR: 1.04, 95% CI 1.01-1.06, p = .003; OR: 1.13, 95% CI 1.07-1.20, p < .001; OR: 1.06, 95% CI 1.03-1.10, p = .001), but no association was detected for instrumental delivery or emergency cesarean section. A rise in both the PRAQ-R2, and FOC measurements increased the likelihood of an epidural analgesia (OR: 1.02, 95% CI 1.01-1.03, p = .003; OR: 1.09, 95% CI 1.05-1.12, p < .001) and predicted longer second stage of labor (OR: 1.01, 95% CI 1.00-1.01, p = .023; OR: 1.03, 95% CI 1.02-1.05, p < .001). EPDS did not predict any of the analyzed outcomes. The results indicate that maternal anxiety symptoms (measured using PRAQ-R2, FOC, and SCL-90) are associated with elective cesarean section. Psychological distress increases the use of epidural analgesia, but is not associated with complicated vaginal birth.
Asunto(s)
Complicaciones del Trabajo de Parto , Distrés Psicológico , Cohorte de Nacimiento , Cesárea/psicología , Estudios de Cohortes , Femenino , Humanos , Complicaciones del Trabajo de Parto/epidemiología , EmbarazoRESUMEN
A constant rate infusion (CRI) of medetomidine is used to balance equine inhalation anesthesia, but its cardiovascular side effects are a concern. This experimental crossover study aimed to evaluate the effects of vatinoxan (a peripheral α2-adrenoceptor antagonist) on cardiorespiratory and gastrointestinal function in anesthetized healthy horses. Six horses received medetomidine hydrochloride 7µg/kg IV alone (MED) or with vatinoxan hydrochloride 140µg/kg IV (MED+V). Anesthesia was induced with midazolam and ketamine and maintained with isoflurane and medetomidine CRI for 60min. Heart rate, carotid and pulmonary arterial pressures, central venous pressure, cardiac output and arterial and mixed venous blood gases were measured. Selected cardiopulmonary parameters were calculated. Plasma drug concentrations were determined. Fecal output was measured over 24h. For statistical comparisons, repeated measures analysis of covariance and paired t-tests were applied. Heart rate decreased slightly from baseline in the MED group. Arterial blood pressures decreased with both treatments, but significantly more dobutamine was needed to maintain normotension with MED+V (P=0.018). Cardiac index (CI) and oxygen delivery index (DO2I) decreased significantly more with MED, with the largest difference observed at 20min: CI was 39±2 and 73±18 (P=0.009) and DO2I 7.4±1.2 and 15.3±4.8 (P=0.014)mL/min/kg with MED and MED+V, respectively. Fecal output or plasma concentrations of dexmedetomidine did not differ between the treatments. In conclusion, premedication with vatinoxan induced hypotension, thus its use in anesthetized horses warrants further studies. Even though heart rate and arterial blood pressures remained clinically acceptable with MED, cardiac performance and oxygen delivery were lower than with MED+V.
Asunto(s)
Motilidad Gastrointestinal/efectos de los fármacos , Isoflurano/farmacología , Medetomidina/farmacología , Quinolizinas/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2 , Anestesia por Inhalación/veterinaria , Anestésicos por Inhalación/administración & dosificación , Anestésicos por Inhalación/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Estudios Cruzados , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Caballos , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/farmacología , Isoflurano/administración & dosificación , Masculino , Medetomidina/administración & dosificación , Quinolizinas/sangre , Quinolizinas/farmacocinéticaRESUMEN
BACKGROUND: Medetomidine suppresses cardiovascular function and reduces gastrointestinal motility in horses mainly through peripheral α2 -adrenoceptors. Vatinoxan, a peripheral α2 -antagonist, has been shown experimentally to alleviate the adverse effects of some α2 -agonists in horses. However, vatinoxan has not been investigated during constant-rate infusion (CRI) of medetomidine in standing horses. OBJECTIVES: To evaluate effects of vatinoxan on cardiovascular function, gastrointestinal motility and on sedation level during CRI of medetomidine. STUDY DESIGN: Experimental, randomised, blinded, cross-over study. METHODS: Six healthy horses were given medetomidine hydrochloride, 7 µg/kg i.v., without (MED) and with (MED+V) vatinoxan hydrochloride, 140 µg/kg i.v., followed by CRI of medetomidine at 3.5 µg/kg/h for 60 min. Cardiorespiratory variables were recorded and borborygmi and sedation levels were scored for 120 min. Plasma drug concentrations were measured. The data were analysed using repeated measures ANCOVA and paired t-tests as appropriate. RESULTS: Initially heart rate (HR) was significantly lower and mean arterial blood pressure (MAP) significantly higher with MED compared with MED+V. For example at 10 min HR (mean ± s.d.) was 26 ± 2 and 31 ± 5 beats/minute (P = 0.04) and MAP 129 ± 15 and 103 ± 13 mmHg (P<0.001) respectively. At 10 min, cardiac index was lower (P = 0.02) and systemic vascular resistance higher (P = 0.001) with MED than with MED+V. Borborygmi were reduced after MED; this effect was attenuated by vatinoxan (P<0.001). All horses were sedated with medetomidine, but the mean sedation scores were reduced with MED+V until 20 min (6.8 ± 0.8 and 4.5 ± 1.5 with MED and MED+V, respectively, at 10 min, P = 0.001). Plasma concentration of dexmedetomidine was significantly lower in the presence of vatinoxan (P = 0.01). MAIN LIMITATIONS: Experimental study with healthy, unstimulated animals. CONCLUSIONS: Vatinoxan administered i.v. with a loading dose of medetomidine improved cardiovascular function and gastrointestinal motility during medetomidine CRI in healthy horses. Sedation was slightly yet significantly reduced during the first 20 min.. The Summary is available in Portuguese - see Supporting Information.
Asunto(s)
Motilidad Gastrointestinal/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Caballos , Medetomidina/farmacología , Quinolizinas/farmacología , Respiración/efectos de los fármacos , Animales , Área Bajo la Curva , Estudios Cruzados , Femenino , Semivida , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/farmacología , Masculino , Medetomidina/metabolismo , Medetomidina/farmacocinética , Quinolizinas/administración & dosificación , Resistencia Vascular/efectos de los fármacosRESUMEN
The commonly used sedative α2-adrenoceptor agonist dexmedetomidine has adverse cardiovascular effects in dogs that can be prevented by concomitant administration of the peripherally acting α2-adrenoceptor antagonist MK-467. An ancillary effect of dexmedetomidine is to decrease insulin release from the pancreas, whereas MK-467 stimulates insulin release. This study assessed the effects of co-administered dexmedetomidine and MK-467 in a canine glibenclamide-induced hypoglycaemia model. In a randomised, cross-over experiment, eight beagle dogs received five intravenous treatments, comprising two administrations of saline, with dexmedetomidine or dexmedetomidine and MK-467, and three administrations of glibenclamide, with saline, dexmedetomidine or dexmedetomidine and MK-467. Plasma concentrations of glucose, lactate, insulin, glucagon and the test drugs were monitored. Administration of glibenclamide significantly increased insulin secretion and decreased blood glucose concentrations. Dexmedetomidine counteracted glibenclamide-evoked hypoglycaemia. This was opposed by the α2-adrenoceptor antagonist MK-467, but the glibenclamide-evoked hypoglycaemia was not potentiated by co-administration of dexmedetomidine and MK-467. None of the dogs developed uncontrolled hypoglycaemia. Thus, the combination of dexmedetomidine and MK-467 appeared to be safe in this canine hypoglycaemia model. Nevertheless, when MK-467 is used to alleviate the undesired cardiovascular effects of α2-adrenoceptor agonists in dogs, it should be used with caution in animals at risk for hypoglycaemia because of its insulin-releasing and hypoglycaemic effects.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Dexmedetomidina/farmacología , Hipnóticos y Sedantes/farmacología , Hipoglucemia/tratamiento farmacológico , Quinolizinas/farmacología , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Anestesia Intravenosa/veterinaria , Animales , Glucemia/efectos de los fármacos , Estudios Cruzados , Dexmedetomidina/administración & dosificación , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Glucagón/sangre , Glucagón/efectos de los fármacos , Gliburida , Hipnóticos y Sedantes/administración & dosificación , Hipoglucemia/inducido químicamente , Hipoglucemiantes , Insulina/sangre , Insulina/metabolismo , Masculino , Quinolizinas/administración & dosificación , Distribución Aleatoria , Resultado del TratamientoRESUMEN
PURPOSE: Palliative care patients often need sedation to alleviate intractable anxiety, stress, and pain. Dexmedetomidine is used for sedation of intensive care patients, but there is no prior information on its subcutaneous (SC) administration, a route that would be favored in palliative care. We compared the pharmacokinetics and cardiovascular, sympatholytic, and sedative effects of SC and intravenously (IV) administered dexmedetomidine in healthy volunteers. METHODS: An open two-period, cross-over design with balanced randomization was used. Ten male subjects were randomized to receive 1 µg/kg dexmedetomidine both IV and SC. Concentrations of dexmedetomidine and catecholamines in plasma were measured. Pharmacokinetic variables were calculated with non-compartmental methods. In addition, cardiovascular and sedative drug effects were monitored. RESULTS: Eight subjects completed both treatment periods. Peak concentrations of dexmedetomidine were observed 15 min after SC administration (median; range 15-240). The mean bioavailability of SC dexmedetomidine was 81% (AUC0-∞ ratio × 100%, range 49-97%). The mean (SD) peak concentration of dexmedetomidine in plasma was 0.3 (0.1) ng/ml, and plasma concentrations associated with sedative effects (i.e., > 0.2 ng/ml) were maintained for 4 h after SC dosing. Plasma noradrenaline concentrations were significantly lower (P < 0.001) within 3 h after IV than after SC administration. Subjective scores for vigilance and performance were significantly lower 0-60 min after IV than SC dosing (P < 0.001 for both). The onset of the cardiovascular, sympatholytic, and sedative effects of dexmedetomidine was clearly less abrupt after SC than IV administration. CONCLUSIONS: Dexmedetomidine is relatively rapidly and efficiently absorbed after SC administration. Subcutaneous dexmedetomidine may be a feasible alternative in palliative sedation, and causes attenuated cardiovascular effects compared to IV administration. CLINICALTRIALS. GOV IDENTIFIER: NCT02724098 . EUDRA CT number 2015-004698-34 .
Asunto(s)
Dexmedetomidina/farmacología , Dexmedetomidina/farmacocinética , Hemodinámica/efectos de los fármacos , Absorción Subcutánea , Administración Intravenosa , Disponibilidad Biológica , Catecolaminas/sangre , Estudios Cruzados , Dexmedetomidina/administración & dosificación , Dexmedetomidina/sangre , Voluntarios Sanos , Humanos , Hipnóticos y Sedantes/farmacología , Inyecciones Subcutáneas , Masculino , Absorción Subcutánea/efectos de los fármacos , Adulto JovenRESUMEN
The effect of MK-467, a peripheral α2 -adrenoceptor antagonist, on plasma drug concentrations, sedation and cardiopulmonary changes induced by intramuscular (IM) medetomidine was investigated in eight sheep. Additionally, the interactions with atipamezole (ATI) used for reversal were also evaluated. Each animal was treated four times in a randomized prospective crossover design with 2-week washout periods. Medetomidine (MED) 30 µg/kg alone or combined in the same syringe with MK-467 300 µg/kg (MMK) was injected intramuscular, followed by ATI 150 µg/kg (MED + ATI and MMK + ATI) or saline intramuscular 30 min later. Plasma was analysed for drug concentrations, and sedation was subjectively assessed with a visual analogue scale. Systemic haemodynamics and blood gases were measured before treatments and at intervals thereafter. With MK-467, medetomidine plasma concentrations were threefold higher prior to ATI, which was associated with more profound sedation and shorter onset. No significant differences were observed in early cardiopulmonary changes between treatments. Atipamezole reversed the medetomidine-related cardiopulmonary changes after both treatments. Sedation scores decreased more rapidly when MK-467 was included. In this study, MK-467 appeared to have a pronounced effect on the plasma concentration and central effects of medetomidine, with minor cardiopulmonary improvement.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Imidazoles/farmacocinética , Medetomidina/farmacocinética , Quinolizinas/farmacología , Ovinos/sangre , Antagonistas de Receptores Adrenérgicos alfa 2/farmacocinética , Animales , Presión Sanguínea , Temperatura Corporal , Sedación Consciente/veterinaria , Estudios Cruzados , Interacciones Farmacológicas , Femenino , Hemoglobinas , Hipnóticos y Sedantes/farmacocinética , Hipnóticos y Sedantes/farmacología , Imidazoles/sangre , Imidazoles/farmacología , Inyecciones Intramusculares , Medetomidina/sangre , Medetomidina/farmacología , Oxígeno/sangre , Estudios Prospectivos , Quinolizinas/farmacocinética , Respiración , Escala Visual AnalógicaRESUMEN
We investigated the influence of the peripherally acting α2 -adrenoceptor antagonist MK-467 on the sedative and antinociceptive actions and plasma drug concentrations of medetomidine, an α2 -adrenoceptor agonist that is used in veterinary medicine as a sedative and analgesic agent. Eight healthy beagle dogs received intravenous medetomidine (10 µg/kg) or medetomidine with MK-467 (250 µg/kg) in a randomized crossover design. A standardized nociceptive pressure stimulus was applied to a nail bed of a hindlimb. Times for withdrawal of the limb and for head lift were measured, and sedation was scored. EEG data were collected prior to and after stimulation. Plasma drug concentrations were measured. Co-administration of MK-467 significantly attenuated medetomidine analgesia, as assessed with limb withdrawal, and also shortened the duration of sedation. The apparent plasma clearance of both enantiomers of medetomidine, dexmedetomidine and levomedetomidine, was more than doubled in the presence of MK-467. Antagonism by MK-467 of medetomidine-evoked vasoconstriction is seen as the mechanism behind this pharmacokinetic drug interaction. Thus, MK-467 attenuated the antinociceptive and sedative effects of medetomidine. This can probably be explained by increased clearance and decreased concentrations of dexmedetomidine in plasma after co-administration of MK-467 with racemic medetomidine.
Asunto(s)
Analgésicos/farmacocinética , Hipnóticos y Sedantes/antagonistas & inhibidores , Medetomidina/antagonistas & inhibidores , Quinolizinas/farmacología , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Perros , Interacciones Farmacológicas , Electroencefalografía/efectos de los fármacos , Electroencefalografía/veterinaria , Femenino , Hipnóticos y Sedantes/farmacocinética , Hipnóticos y Sedantes/farmacología , Hipnóticos y Sedantes/uso terapéutico , Masculino , Medetomidina/farmacocinética , Medetomidina/farmacología , Medetomidina/uso terapéutico , Dimensión del Dolor/veterinariaRESUMEN
Because of their large population sizes and rapid cell division rates, marine microbes have, or can generate, ample variation to fuel evolution over a few weeks or months, and subsequently have the potential to evolve in response to global change. Here we measure evolution in the marine diatom Skeletonema marinoi evolved in a natural plankton community in CO2-enriched mesocosms deployed in situ. Mesocosm enclosures are typically used to study how the species composition and biogeochemistry of marine communities respond to environmental shifts, but have not been used for experimental evolution to date. Using this approach, we detect a large evolutionary response to CO2 enrichment in a focal marine diatom, where population growth rate increased by 1.3-fold in high CO2-evolved lineages. This study opens an exciting new possibility of carrying out in situ evolution experiments to understand how marine microbial communities evolve in response to environmental change.
Asunto(s)
Evolución Biológica , Dióxido de Carbono/metabolismo , Proliferación Celular/genética , Diatomeas/genética , Diatomeas/metabolismo , Ecosistema , Organismos Acuáticos/genética , Investigación Genética , Variación Genética/genética , Proyectos de Investigación/tendenciasRESUMEN
BACKGROUND: Dexmedetomidine is a highly selective and potent α(2)-adrenoceptor agonist registered for sedation of patients in intensive care units. There is little information on factors possibly affecting its pharmacokinetics during long drug infusions in critically ill patients. We characterized the pharmacokinetics of dexmedetomidine in critically ill patients during long-term sedation using a population pharmacokinetic approach. METHODS: Twenty-one intensive care patients requiring sedation and mechanical ventilation received dexmedetomidine with a loading dose of 3-6 µg kg(-1) h(-1) in 10 min and a maintenance dose of 0.1-2.5 µg kg(-1) h(-1) for a median duration of 96 h (range, 20-571 h). Cardiac output (CO), laboratory and respiratory parameters, and dexmedetomidine concentrations in arterial plasma were measured. The pharmacokinetics was determined by population analysis using linear multicompartment models. RESULTS: The pharmacokinetics of dexmedetomidine was best described by a two-compartment model. The population values (95% confidence interval) for elimination clearance, inter-compartmental clearance, central volume of distribution, and volume of distribution at steady state were 57.0 (42.1, 65.6), 183 (157, 212) litre h(-1), 12.3 (7.6, 17.0), and 132 (96, 189) litre. Dexmedetomidine clearance decreased with decreasing CO and with increasing age, whereas its volume of distribution at steady state was increased in patients with low plasma albumin concentration. CONCLUSIONS: The population pharmacokinetics of dexmedetomidine was generally in line with results from previous studies. In elderly patients and in patients with hypoalbuminaemia, the elimination half-life and the context-sensitive half-time of dexmedetomidine were prolonged.
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Sedación Consciente/métodos , Cuidados Críticos/métodos , Dexmedetomidina/sangre , Hipnóticos y Sedantes/sangre , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/sangre , Dexmedetomidina/administración & dosificación , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Semivida , Hemodinámica/efectos de los fármacos , Humanos , Hipnóticos y Sedantes/administración & dosificación , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Modelos Biológicos , Respiración Artificial , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Some large antagonist ligands (ARC239, chlorpromazine, prazosin, spiperone, spiroxatrine) bind to the human α(2A) -adrenoceptor with 10- to 100-fold lower affinity than to the α(2B)- and α(2C)-adrenoceptor subtypes. Previous mutagenesis studies have not explained this subtype selectivity. EXPERIMENTAL APPROACH: The possible involvement of the extracellular amino terminus and transmembrane domain 1 (TM1) in subtype selectivity was elucidated with eight chimaeric receptors: six where TM1 and the N-terminus were exchanged between the α(2)-adrenoceptor subtypes and two where only TM1 was exchanged. Receptors were expressed in CHO cells and tested for ligand binding with nine chemically diverse antagonist ligands. For purposes of interpretation, molecular models of the three human α(2)-adrenoceptors were constructed based on the ß(2)-adrenoceptor crystal structure. KEY RESULTS: The affinities of three antagonists (spiperone, spiroxatrine and chlorpromazine) were significantly improved by TM1 substitutions of the α(2A)-adrenoceptor, but reciprocal effects were not seen for chimaeric receptors based on α(2B)- and α(2C)-adrenoceptors. Molecular docking of these ligands suggested that binding occurs in the orthosteric ligand binding pocket. CONCLUSIONS AND IMPLICATIONS: TM1 is involved in determining the low affinity of some antagonist ligands at the human α(2A)-adrenoceptor. The exact mechanism is not known, but the position of TM1 at a large distance from the binding pocket indicates that TM1 does not participate in specific side-chain interactions with amino acids within the binding pocket of the receptor or with ligands bound therein. Instead, molecular models suggest that TM1 has indirect conformational effects related to the charge distribution or overall shape of the binding pocket.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Clorpromazina/farmacología , Dioxanos/farmacología , Receptores Adrenérgicos alfa 2/metabolismo , Espiperona/farmacología , Compuestos de Espiro/farmacología , Secuencia de Aminoácidos , Animales , Sitios de Unión , Unión Competitiva , Células CHO , Técnicas de Cultivo de Célula , Cricetinae , Cricetulus , Humanos , Ligandos , Modelos Moleculares , Datos de Secuencia Molecular , Unión Proteica , Estructura Secundaria de Proteína , Receptores Adrenérgicos alfa 2/química , Receptores Adrenérgicos alfa 2/genética , Alineación de Secuencia , TransfecciónRESUMEN
BACKGROUND: Dexmedetomidine is a potent and selective α2-adrenoceptor agonist used for perioperative and intensive care sedation with certain beneficial qualities. However, based on preclinical observations, it might inhibit gastric emptying and gastrointestinal transit, which could result in unwanted effects in intensive care patients. This study evaluated the effects of dexmedetomidine on gastric emptying and oro-caecal transit time in healthy volunteers. METHODS: Twelve healthy male subjects were given 1 µg kg(-1) of dexmedetomidine i.v. over 20 min followed by a continuous i.v. infusion of 0.7 µg kg(-1) h(-1) for 190 min. For comparison, subjects were also given 0.10 mg kg(-1) of morphine hydrochloride i.v. over 20 min and a placebo infusion in a randomized order. Gastric emptying was assessed with the paracetamol absorption test and oro-caecal transit time with the hydrogen breath test. RESULTS: The time to maximum paracetamol concentration in plasma was significantly longer, maximum paracetamol concentration was significantly lower, the area under the plasma paracetamol concentration-time curve was significantly smaller, and oro-caecal transit time was significantly longer during dexmedetomidine infusion compared with morphine or placebo infusion. CONCLUSIONS: Dexmedetomidine markedly inhibits gastric emptying and gastrointestinal transit in healthy volunteers.
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Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Dexmedetomidina/farmacología , Vaciamiento Gástrico/efectos de los fármacos , Tránsito Gastrointestinal/efectos de los fármacos , Hipnóticos y Sedantes/farmacología , Acetaminofén/sangre , Adulto , Analgésicos Opioides/farmacología , Pruebas Respiratorias/métodos , Humanos , Masculino , Morfina/farmacología , Adulto JovenRESUMEN
OBJECTIVE: In Alzheimer disease (AD), the accumulation pattern of beta-amyloid over time and its relationship with dementia severity are unclear. We investigated the brain uptake of the amyloid ligand (11)C-labeled Pittsburgh compound B ([(11)C]PIB) and volumetric brain changes over a 2-year follow-up in patients with AD and in aged healthy controls. METHODS: Fourteen patients with AD (mean age 72 years, SD 6.6) and 13 healthy controls (mean age 68 years, SD 5.4) were examined at baseline and after 2 years (patients with AD: mean 2.0 years, SD 0.2; controls: mean 2.1 years, SD 0.6) with [(11)C]PIB PET, MRI, and neuropsychological assessments. [(11)C]PIB uptake was analyzed with a voxel-based statistical method (SPM), and quantitative data were obtained with automated region-of-interest analysis. MRI data were analyzed with voxel-wise tensor-based morphometry. RESULTS: The [(11)C]PIB uptake of the patients with AD did not increase significantly during follow-up when compared with that of the controls. MRI showed progressive brain volume change in the patients with AD, e.g., in the hippocampal region, temporal cortex, and precuneus (p < 0.05). The mean Mini-Mental State Examination score of the patients with AD declined from 24.3 (SD 3.1) at baseline to 21.6 (SD 3.9) at follow-up (p = 0.009). Cognitive decline was also evident in other neuropsychological test results. Baseline neocortical [(11)C]PIB uptake ratios predicted subsequent volumetric brain changes in the controls (r = 0.725, p = 0.005). CONCLUSIONS: The results suggest no (or only little) increase in (11)C-labeled Pittsburgh compound B ([(11)C]PIB) uptake during 2 years of Alzheimer disease progression, despite advancing brain atrophy and declining cognitive performance. Nevertheless, changes in [(11)C]PIB uptake during a longer follow-up cannot be excluded. High cortical [(11)C]PIB uptake may predict ongoing brain atrophy in cognitively normal individuals.
Asunto(s)
Enfermedad de Alzheimer/patología , Amiloide/metabolismo , Compuestos de Anilina/metabolismo , Encéfalo/patología , Tiazoles/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/psicología , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Radioisótopos de Carbono/metabolismo , Estudios de Casos y Controles , Cognición , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , CintigrafíaRESUMEN
Laboratory rats are commonly fed ad libitum (AL). Moderate dietary restriction (DR) decreases mortality and morbidity when compared with AL feeding, but there are several obstacles to the implementation of DR. Traditional methods of restricted feeding disrupt normal diurnal eating rhythms and are not compatible with group housing. We have designed a novel method, the diet board, to restrict the feeding of group-housed rats. Animals fed from the diet board had 15% lower body weight than the AL-fed animals at the age of 17 weeks. The welfare effects of diet board feeding were assessed by comparing the stress physiology of diet board fed animals with that of AL-fed animals. Diet board feeding was associated with higher serum corticosterone levels and lower faecal secretion of IgA, suggesting the diet board causes a stress reaction. However, the AL-fed group had larger adrenal glands with higher adrenaline and noradrenaline content than the diet board animals. No gastric ulcers were found in any of the animals at necropsy. The diet board thus appears to cause a stress reaction when compared with AL-fed rats, but no apparent pathology was associated with this reaction. The diet board could help to solve the health problems associated with AL feeding, while allowing the rats to be group-housed and to maintain their normal diurnal eating rhythms. The diet board can also be seen as a functional cage furniture item, dividing the cage into compartments and thus increasing the structural complexity of the environment. In conclusion, the diet board appears to possess refinement potential compared with traditional methods of DR.
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Alimentación Animal , Crianza de Animales Domésticos/instrumentación , Bienestar del Animal , Privación de Alimentos/fisiología , Glándulas Suprarrenales/patología , Crianza de Animales Domésticos/métodos , Animales , Corticosterona/sangre , Epinefrina/sangre , Heces/química , Inmunoglobulina A/análisis , Masculino , Norepinefrina/sangre , Tamaño de los Órganos , Ratas , Ratas Wistar , Estrés Fisiológico/fisiologíaRESUMEN
Inhibition of monoamine oxidase type B (MAO-B) activity in the brain is a putative strategy for the treatment of Alzheimer's disease (AD). We performed a dose-selection and validation study of a novel, reversible MAO-B inhibitor, EVT 301. Sixteen healthy volunteers received selegiline (10 mg) or EVT 301 (25, 75, or 150 mg) daily for 7-8 days, and four subjects with AD received 75 mg of EVT 301. MAO-B occupancy in the brain was assessed using positron emission tomography (PET) with [11C]-L-deprenyl-D2. EVT 301 was found to dose-dependently occupy MAO-B in the human brain, with occupancy ranging from 58-78% at a dose of 25 mg to 73-90% at a dose of 150 mg. The corresponding occupancy after selegiline was 77-92%. Determination of MAO-B inhibition in blood platelets underestimated the actual brain occupancy achieved with EVT 301. A daily EVT 301 dose of 75 or 150 mg appears suitable for clinical efficacy studies in patients with AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Malonatos/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/efectos de los fármacos , Anciano , Enfermedad de Alzheimer/enzimología , Plaquetas/efectos de los fármacos , Plaquetas/enzimología , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Radioisótopos de Carbono , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Malonatos/administración & dosificación , Persona de Mediana Edad , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/administración & dosificación , Tomografía de Emisión de Positrones/métodos , Selegilina/farmacologíaRESUMEN
BACKGROUND: This study aimed to assess the contribution of endothelial nitric oxide synthesis to the net responses of human peripheral blood vessels in vivo to the selective alpha(2)-adrenoceptor agonist dexmedetomidine. METHODS: Two groups of healthy young men were studied. In the first experiment, after brachial plexus block, the responses of digital arteries to systemically administered dexmedetomidine (target plasma concentration 1.2 ng ml(-1)) were studied using a photoplethysmograph (n=10) during i.a. infusions of saline and the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA) (8 micromol min(-1)). In a separate experiment, after pre-treatment with acetylsalicylic acid, responses to increasing doses of dexmedetomidine (0.01-164 ng min(-1)) in the presence and absence of L-NMMA were compared in dorsal hand veins (DHV) (n=10) using linear variable differential transformers. RESULTS: L-NMMA significantly augmented dexmedetomidine-induced vasoconstriction of digital arteries as assessed by an increase in light transmission through a finger and by a decrease in finger temperature. The mean (95% confidence interval) extent of the additional effect of L-NMMA over the constrictor effect of dexmedetomidine alone was 19% (14-24) (P<0.0001). In DHV, L-NMMA had variable effects on the dexmedetomidine-constriction dose-response curve. In three subjects, the curve was shifted significantly to the left (with a >10-fold difference in ED(50)), but ED(50) was only marginally affected by L-NMMA in the other subjects (difference in ED(50) Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología
, Dexmedetomidina/farmacología
, Óxido Nítrico Sintasa/antagonistas & inhibidores
, Vasoconstricción/efectos de los fármacos
, Adolescente
, Adulto
, Plexo Braquial
, Dexmedetomidina/antagonistas & inhibidores
, Relación Dosis-Respuesta a Droga
, Inhibidores Enzimáticos/farmacología
, Dedos/irrigación sanguínea
, Humanos
, Hipnóticos y Sedantes/antagonistas & inhibidores
, Hipnóticos y Sedantes/farmacología
, Masculino
, Persona de Mediana Edad
, Bloqueo Nervioso
, Óxido Nítrico/fisiología
, Óxido Nítrico Sintasa/fisiología
, Flujo Sanguíneo Regional/efectos de los fármacos
, Vasoconstricción/fisiología
, Adulto Joven
, omega-N-Metilarginina/farmacología
RESUMEN
An experiment was conducted to investigate the effects of feeding grains naturally contaminated with Fusarium mycotoxins on brain regional neurochemistry of turkeys. The possible preventative effect of a poly-meric glucomannan mycotoxin adsorbent (GMA) was also determined. Forty-five 1-d-old male turkey poults were fed wheat-, corn-, and soybean meal-based diets up to wk 6, formulated with control grains, contaminated grains, or contaminated grains + 0.2% GMA. Deoxynivalenol was the major contaminant, and the concentrations were 2.2 and 3.3 mg/kg of feed during starter and grower phases, respectively. Concentrations of brain monoamine neurotransmitters and metabolites were measured in discrete regions of the brain including the pons, hypothalamus, and cortex by HPLC with electrochemical detection. Neurotransmitters and metabolites analyzed included norepinephrine, dopamine, 3,4-dihydroxyphenylacetic acid, serotonin (5-hydroxytryptamine, 5-HT), and 5-hydroxyindoleacetic acid (5-HIAA). The concentration of 5-HIAA and the 5-HIAA:5-HT-ratio were significantly decreased in pons after feeding contaminated grains. Dietary supplementation with GMA prevented these effects. In the pons, a significant positive correlation (r = 0.52, P < 0.05) was observed between the concentration of 5-HT and BW gain after feeding contaminated diets. The feeding of contaminated diet had no significant effects on the concentrations of neurotransmitters and metabolites in hypothalamus and cortex. It was concluded that consumption of grains naturally contaminated with Fusarium mycotoxins adversely altered the pons serotonergic system of turkeys. Supplementation with GMA partially inhibited these effects.
Asunto(s)
Alimentación Animal/análisis , Encéfalo/efectos de los fármacos , Fusarium/metabolismo , Micotoxinas/toxicidad , Pavos , Animales , Dieta/veterinaria , Masculino , Mananos/uso terapéutico , Micotoxinas/química , Neuroquímica , Aumento de PesoRESUMEN
BACKGROUND AND PURPOSE: The imidazoline-type alpha2-adrenoceptor antagonists (+/-)-efaroxan and phentolamine increase insulin secretion and reduce blood glucose levels. It is not known whether they act by antagonizing pancreatic beta-cell alpha2-adrenoceptors or by alpha2-adrenoceptor-independent mechanisms. Many imidazolines inhibit the pancreatic beta-cell KATP channel, which is the molecular target of sulphonylurea drugs used in the treatment of type II diabetes. To investigate the mechanisms of action of (+/-)-efaroxan and phentolamine, alpha2A-adrenoceptor knockout (alpha2A-KO) mice were used. EXPERIMENTAL APPROACH: Effects of (+/-)-efaroxan, 5 mg kg(-1), and phentolamine, 1 mg kg(-1), on blood glucose and insulin levels were compared with those of the non-imidazoline alpha2-adrenoceptor antagonist [8aR,12aS,13aS]-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]naphthyridine (RS79948-197), 1 mg kg(-1), and the sulphonylurea glibenclamide, in alpha2A-KO and control (wild type (WT)) mice. KEY RESULTS: In fed WT mice, (+/-)-efaroxan, phentolamine and RS79948-197 reduced blood glucose and increased insulin levels. Fasting abolished these effects. In fed alpha2A-KO mice, (+/-)-efaroxan, phentolamine and RS79948-197 did not alter blood glucose or insulin levels, and in fasted alpha2A-KO mice, blood glucose levels were increased. Glibenclamide, at a dose only moderately efficacious in WT mice (5 mg kg(-1)), caused severe hyperinsulinaemia and hypoglycaemia in alpha2A-KO mice. This was mimicked in WT mice by co-administration of RS79948-197 with glibenclamide. CONCLUSIONS AND IMPLICATIONS: These results suggest that (+/-)-efaroxan and phentolamine increase insulin secretion by inhibition of beta-cell alpha2A-adrenoceptors, and demonstrate a critical role for alpha2A-adrenoceptors in limiting sulphonylurea-induced hyperinsulinaemia and hypoglycaemia.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 2 , Antagonistas Adrenérgicos alfa/farmacología , Gliburida/farmacología , Hipoglucemiantes/farmacología , Insulina/metabolismo , Antagonistas Adrenérgicos beta/farmacología , Animales , Derivados de Atropina/farmacología , Benzofuranos/farmacología , Glucemia/metabolismo , Sinergismo Farmacológico , Ayuno/fisiología , Imidazoles/farmacología , Insulina/sangre , Secreción de Insulina , Isoquinolinas/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Antagonistas Muscarínicos/farmacología , Naftiridinas/farmacología , Fentolamina/farmacología , Propranolol/farmacología , Receptores Adrenérgicos alfa 2/genéticaRESUMEN
BACKGROUND: Information has been very limited on the pharmacokinetics of the selective alpha(2)-adrenoceptor agonist dexmedetomidine in children, particularly in children <2 yr of age. METHODS: Eight children aged between 28 days and 23 months and eight children aged between 2 and 11 yr undergoing either elective bronchoscopy or nuclear magnetic resonance imaging were included in the study. Dexmedetomidine 1 microg kg(-1) was infused i.v. over 5 min. Blood samples for the measurement of plasma concentrations of dexmedetomidine were collected for 5 h after starting the infusion. Pharmacokinetic calculations were based on non-compartmental methods. RESULTS: In the two groups of paediatric patients, the median (range) values for total plasma clearance of dexmedetomidine were 17.4 (14.1-27.6) and 17.3 (9.3-22.5) ml kg(-1) min(-1), for volume of distribution at steady state 3.8 (1.9-4.6) and 2.2 (1.3-2.8) litre kg(-1) (P<0.05), and for elimination half-life 139 (90-198) and 96 (69-140) min (P<0.05), respectively. The volume of distribution at steady state was negatively associated with subject age (r=-0.69, P<0.05). CONCLUSIONS: To reach a certain plasma concentration, children younger than 2 yr of age evidently need larger initial doses of dexmedetomidine than the older children, as young children have a larger volume of distribution of the drug than older children and adults. Since the total plasma clearance of dexmedetomidine is independent of age, similar rates of infusion can be used in younger and older children to maintain a steady-state concentration of dexmedetomidine in plasma.
Asunto(s)
Agonistas alfa-Adrenérgicos/sangre , Dexmedetomidina/sangre , Hipnóticos y Sedantes/sangre , Agonistas alfa-Adrenérgicos/administración & dosificación , Envejecimiento/sangre , Broncoscopía , Niño , Preescolar , Sedación Consciente/métodos , Dexmedetomidina/administración & dosificación , Evaluación de Medicamentos , Femenino , Semivida , Humanos , Hipnóticos y Sedantes/administración & dosificación , Lactante , Recién Nacido , Infusiones Intravenosas , Espectroscopía de Resonancia Magnética , MasculinoRESUMEN
BACKGROUND: Dexmedetomidine, a selective alpha(2)-adrenoceptor agonist, induces a unique, sleep-like state of sedation. The objective of the present work was to study human electroencephalogram (EEG) sleep spindles during dexmedetomidine sedation and compare them with spindles during normal physiological sleep, to test the hypothesis that dexmedetomidine exerts its effects via normal sleep-promoting pathways. METHODS: EEG was continuously recorded from a bipolar frontopolar-laterofrontal derivation with Entropy Module (GE Healthcare) during light and deep dexmedetomidine sedation (target-controlled infusions set at 0.5 and 3.2 ng/ml) in 11 healthy subjects, and during physiological sleep in 10 healthy control subjects. Sleep spindles were visually scored and quantitatively analyzed for density, duration, amplitude (band-pass filtering) and frequency content (matching pursuit approach), and compared between the two groups. RESULTS: In visual analysis, EEG activity during dexmedetomidine sedation was similar to physiological stage 2 (S2) sleep with slight to moderate amount of slow-wave activity and abundant sleep spindle activity. In quantitative EEG analyses, sleep spindles were similar during dexmedetomidine sedation and normal sleep. No statistically significant differences were found in spindle density, amplitude or frequency content, but the spindles during dexmedetomidine sedation had longer duration (mean 1.11 s, SD 0.14 s) than spindles in normal sleep (mean 0.88 s, SD 0.14 s; P=0.0014). CONCLUSIONS: Analysis of sleep spindles shows that dexmedetomidine produces a state closely resembling physiological S2 sleep in humans, which gives further support to earlier experimental evidence for activation of normal non-rapid eye movement sleep-promoting pathways by this sedative agent.
Asunto(s)
Dexmedetomidina/farmacología , Electroencefalografía/efectos de los fármacos , Hipnóticos y Sedantes/farmacología , Sueño/fisiología , Adulto , Análisis de Varianza , Electroencefalografía/métodos , Humanos , Masculino , Monitoreo Fisiológico/métodos , Valores de Referencia , Sueño/efectos de los fármacos , Factores de TiempoRESUMEN
BACKGROUND AND PURPOSE: Rodent alpha(2A)-adrenoceptors bind the classical alpha(2)-antagonists yohimbine and rauwolscine with lower affinity than the human alpha(2A)-adrenoceptor. A serine-cysteine difference in the fifth transmembrane helix (TM; position 5.43) partially explains this, but all determinants of the interspecies binding selectivity are not known. Molecular models of alpha(2A)-adrenoceptors suggest that the second extracellular loop (XL2) folds above the binding cavity and may participate in antagonist binding. EXPERIMENTAL APPROACH: Amino acids facing the binding cavity were identified using molecular models: side chains of residues 5.43 in TM5 and xl2.49 and xl2.51 in XL2 differ between the mouse and human receptors. Reciprocal mutations were made in mouse and human alpha(2A)-adrenoceptors at positions 5.43, xl2.49 and xl2.51, and tested with a set of thirteen chemically diverse ligands in competition binding assays. KEY RESULTS: Reciprocal effects on the binding of yohimbine and rauwolscine in human and mouse alpha(2A)-adrenoceptors were observed for mutations at 5.43, xl2.49 and xl2.51. The binding profile of RS-79948-197 was reversed only by the XL2 substitutions. CONCLUSIONS AND IMPLICATIONS: Positions 5.43, xl2.49 and xl2.51 are major determinants of the species preference for yohimbine and rauwolscine of the human versus mouse alpha(2A)-adrenoceptors. Residues at positions xl2.49 and xl2.51 determine the binding preference of RS-79948-197 for the human alpha(2A)-adrenoceptor. Thus, XL2 is involved in determining the species preferences of alpha(2A)-adrenoceptors of human and mouse for some antagonists.