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1.
Lancet ; 395(10241): 1938-1948, 2020 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-32563380

RESUMO

The treatment of opioid withdrawal is an important area of clinical concern when treating patients with chronic, non-cancer pain, patients with active opioid use disorder, and patients receiving medication for opioid use disorder. Current standards of care for medically supervised withdrawal include treatment with µ-opioid receptor agonists, (eg, methadone), partial agonists (eg, buprenorphine), and α2-adrenergic receptor agonists (eg, clonidine and lofexidine). Newer agents likewise exploit these pharmacological mechanisms, including tramadol (µ-opioid receptor agonism) and tizanidine (α2 agonism). Areas for future research include managing withdrawal in the context of stabilising patients with opioid use disorder to extended-release naltrexone, transitioning patients with opioid use disorder from methadone to buprenorphine, and tapering opioids in patients with chronic, non-cancer pain.


Assuntos
Tratamento de Substituição de Opiáceos/métodos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Agonistas de Receptores Adrenérgicos alfa 2/efeitos adversos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Esquema de Medicação , Humanos , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/efeitos adversos
2.
PLoS One ; 15(4): e0224720, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348301

RESUMO

Small intestinal strangulation associated with ischaemia-reperfusion injury (IRI) is common in horses. In laboratory animals IRI can be ameliorated by ischaemic preconditioning (IPC) and pharmacological preconditioning (PPC) with dexmedetomidine. The aim of this study was to determine the effect of PPC with dexmedetomidine or IPC in an equine model of small intestinal ischaemia-reperfusion (IR). In a randomized controlled experimental trial, 15 horses were assigned to three groups: control (C), IPC, and PPC with dexmedetomidine (DEX). All horses were placed under general anaesthesia and 90% jejunal ischaemia was induced for 90 minutes, followed 30 minutes of reperfusion. In group IPC, three short bouts of ischaemia and reperfusion were implemented, and group DEX received a continuous rate infusion of dexmedetomidine prior to the main ischaemia. Jejunal biopsies were collected before ischaemia (P), and at the end of ischaemia (I) and reperfusion (R). Mucosal injury was assessed by the Chiu-Score, inflammatory cells were stained by cytosolic calprotectin. The degree of apoptosis and cell necrosis was assessed by cleaved-caspase-3 and TUNEL. Parametric data were analyzed by two-way ANOVA for repeated measurements followed by Dunnetts t-test. Non parametric data were compared between groups at the different time points by a Kruskal-Wallis-Test and a Wilcoxon-2-Sample-test. The mucosal injury score increased during I in all groups. After reperfusion, IRI further progressed in group C, but not in IPC and DEX. In all groups the number of cleaved caspase-3 and TUNEL positive cells increased from P to I. The number of TUNEL positive cells were lower in group DEX compared to group C after I and R. Infiltration with calprotectin positive cells was less pronounced in group DEX compared to group C, whereas in group IPC more calprotectin positive cells were seen. In conclusion, IPC and DEX exert protective effects in experimental small intestinal ischaemia in horses.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Dexmedetomidina/uso terapêutico , Isquemia/terapia , Precondicionamento Isquêmico/métodos , Jejuno/irrigação sanguínea , Traumatismo por Reperfusão/terapia , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Dexmedetomidina/administração & dosagem , Dexmedetomidina/farmacologia , Cavalos , Isquemia/tratamento farmacológico , Jejuno/efeitos dos fármacos , Jejuno/patologia , Distribuição Aleatória , Traumatismo por Reperfusão/tratamento farmacológico
3.
J Clin Psychiatry ; 81(3)2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32297719

RESUMO

OBJECTIVE: To assess guanfacine extended-release (GXR) efficacy and safety in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: This phase 3, double-blind, placebo-controlled study (conducted between October 2016 and July 2017) included Japanese patients aged ≥ 18 years with ADHD (DSM-5). Patients received GXR (n = 101) or placebo (n = 100) titrated from 2 mg/d to 4-6 mg/d (dose-optimization; 5 weeks), followed by 4-6 mg/d (dose-maintenance; 5 weeks), then tapered doses to 2 mg/d (2 weeks). Primary endpoint was change from baseline in total score on the Japanese version of the ADHD-Rating Scale IV with adult prompts (ADHD-RS-IV) at week 10. Other measures were ADHD-RS-IV subscales, Clinical Global Impression-Improvement scale (CGI-I) and Patient Global Impression-Improvement scale (PGI-I) (percentage of patients very much improved/much improved), treatment-emergent adverse event (TEAE) incidences, and TEAEs leading to discontinuation. RESULTS: Compared with placebo, there was statistically significantly greater improvement in ADHD-RS-IV total score reduction with GXR (least squares mean ± SE: GXR vs placebo, -11.55 ± 1.10 vs -7.27 ± 1.07; P = .0005; effect size 0.52). There were significantly greater improvements in GXR for ADHD-RS-IV inattention (-7.39 ± 0.79 vs -4.89 ± 0.76; P = .0032) and hyperactivity-impulsivity (-3.84 ± 0.54 vs -2.10 ± 0.52; P = .0021) subscale scores, CGI-I scores (48.1% vs 22.6%; P = .0007), and PGI-I scores (25.3% vs 11.8%; P = .0283). More patients in the GXR versus the placebo group reported TEAEs (81.2% vs 62.0%) and discontinued due to TEAEs (19.8% vs 3.0%). The main TEAEs in the GXR group were somnolence, thirst, blood pressure decrease, nasopharyngitis, postural dizziness, and constipation; most TEAEs were mild to moderate in severity. CONCLUSIONS: In Japanese adults with ADHD, GXR improved ADHD symptoms without any major safety concerns. Trial Registration: Japan Primary Registries Network (https://rctportal.niph.go.jp/en): JapicCTI-163231


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Guanfacina/administração & dosagem , Administração Oral , Adolescente , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Guanfacina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Resultado do Tratamento , Adulto Jovem
4.
Zoolog Sci ; 37(2): 159-167, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282147

RESUMO

Kawai et al. (2011) recently introduced a mixture of three anesthetic agents (here called MMB) that has an effect similar to ketamine/xylazine in mice, which might allow more effective reaction to changes in the animal condition, as an antagonist is available, and which can be used without license for handling narcotic drugs. Using Kawai's study as a baseline, we tested whether this anesthesia and its antagonist can also be used in avian studies. In the present study, we used two species, the zebra finch and the Bengalese finch, of the avian family Estrildidae. In zebra finches, anesthesia effects similar to the use of ketamine/xylazine and to those obtained in mice can be reached by the use of MMB if a higher dose is applied. MMB leads to more variable anesthesia, but has the advantage of a longer time window of deep anesthesia. An antagonist to one component of MMB reduced the awaking time, but was not as effective as in mice. For Bengalese finches, MMB cannot be generally recommended because of difficult handling and high mortality rate when used without antagonist, but could be used for perfusions instead of pentobarbital.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Anestésicos Combinados/administração & dosagem , Butorfanol/administração & dosagem , Imidazóis/farmacologia , Medetomidina/administração & dosagem , Midazolam/administração & dosagem , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Antagonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Analgésicos Opioides/administração & dosagem , Animais , Feminino , Tentilhões , Hipnóticos e Sedativos/administração & dosagem , Imidazóis/administração & dosagem , Injeções Intramusculares , Ketamina/administração & dosagem , Masculino , Medetomidina/antagonistas & inibidores , Xilazina/administração & dosagem
5.
Pharmacol Rep ; 72(1): 96-103, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32016857

RESUMO

BACKGROUND: Xylazine is an α2 adrenoceptor agonist that is extensively used in veterinary medicine and animal experimentation procedures to produce analgesia, sedation and muscle relaxation without causing general anesthesia. Considering the lack of knowledge of the mechanisms involved in peripheral antinociception induced by xylazine and the potential interactions between the adrenergic and endocannabinoid systems, the present study investigated the contribution of the latter system in the mechanism of xylazine. METHODS: The rat paw pressure test, in which hyperalgesia was induced by the intraplantar injection of prostaglandin E2, was performed. RESULTS: Xylazine administered via an intraplantar injection (25, 50 and 100 µg) induced a peripheral antinociceptive effect against prostaglandin E2 (2 µg)-induced hyperalgesia. This effect was blocked by treatment with the selective CB1 cannabinoid antagonist AM251 (20, 40 and 80 µg) but not by the selective CB2 cannabinoid antagonist AM630 (100 µg). The anandamide reuptake inhibitor VDM11 (2.5 µg) intensified the peripheral antinociceptive effect of a submaximal dose of xylazine (25 µg), and the inhibitor of endocannabinoid enzymatic hydrolysis, MAFP (0.5 µg), showed a tendency towards this same effect. In addition, liquid-chromatography mass spectrometric analysis indicated that xylazine (100 µg) treatment was associated with an increase in anandamide levels in the rat paws treated with PGE2. CONCLUSIONS: The present results provides evidence that the peripheral antinociceptive effect of the α2 adrenoceptor agonist xylazine probably results from anandamide release and subsequent CB1 cannabinoid receptor activation.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Ácidos Araquidônicos/metabolismo , Endocanabinoides/metabolismo , Hiperalgesia/tratamento farmacológico , Alcamidas Poli-Insaturadas/metabolismo , Xilazina/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Animais , Cromatografia Líquida , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Espectrometria de Massas , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptor CB1 de Canabinoide/metabolismo , Xilazina/administração & dosagem
6.
Expert Opin Pharmacother ; 21(4): 417-426, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31971448

RESUMO

Introduction: Attention-deficit/hyperactivity disorder (ADHD) commonly occurs in children, adolescents, and adults. Although symptoms of ADHD often respond robustly to treatment with stimulants (amphetamine or methylphenidate), not all patients are appropriate candidates for treatment with these drugs. Guanfacine extended-release (GXR) is a non-stimulant alternative drug approved for the treatment of ADHD in the United States (U.S.), Canada, and Europe.Areas covered: The chemistry, pharmacokinetics, mechanism of action and dosage of GXR are presented. Efficacy and safety data obtained in clinical trials with subjects aged 6-17 years for both GXR monotherapy and use in combination with stimulants are described. Meta-analyses comparing GXR to other drugs are presented. MedWatch surveillance data collected for GXR since approval in the U.S. are also discussed.Expert opinion: Although GXR is effective for the treatment of ADHD and has a different side effect profile than stimulants, it is not as impressive in reducing symptoms. Despite the availability of multiple pharmacological treatments for ADHD, there remains an unmet need for formulations as potent as stimulants but with fewer adverse effects. Several pharmacological agents for ADHD treatment are in development. It is not clear that any of these compounds will replace currently available formulations as first-line alternatives.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Guanfacina/uso terapêutico , Adolescente , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Agonistas de Receptores Adrenérgicos alfa 2/efeitos adversos , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/efeitos adversos , Criança , Preparações de Ação Retardada , Composição de Medicamentos , Quimioterapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Guanfacina/administração & dosagem , Guanfacina/efeitos adversos , Humanos , Metilfenidato/uso terapêutico , Estados Unidos
8.
Eur J Pharmacol ; 868: 172859, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31843515

RESUMO

The locus coeruleus (LC) adrenergic nuclei constitute a pain-control inhibitory system nucleus implicated in descending modulation of pain through the action on spinal α2-adrenoceptors. Histaminergic innervation from the tuberomammillary nucleus of the LC increases firing of noradrenergic neurons and might contribute to pain control. Here we evaluated the contribution of LC histaminergic innervation in descending modulation of neuropathic hypersensitivity, by investigating the role of the histamine H4 receptor subtype in a mouse model of neuropathic pain. Intra LC administration of the H4 agonist VUF 8430 attenuated mechanical and thermal allodynia of mice that underwent spared nerve injury (SNI). Similarly, histamine in the LC showed mechanical and thermal anti-hypersensitivity. Pretreatment of LC with JNJ 10191584 (H4 antagonist) prevented the beneficial effect of VUF 8430 and histamine on nociceptive behaviour. Comparable results were obtained after intrathecal administration of drugs. The intrathecal administration of the α2-adrenoceptor agonist clonidine ameliorated mechanical and thermal allodynia in SNI mice. The clonidine-induced anti-hypersensitivity effect was prevented by intra LC pretreatment with JNJ 10191584. In addition, clonidine failed to suppress neuropathic pain in H4 deficient mice. LC H4 receptors showed a ubiquitous distribution within LC, a neuronal localization and H4 immunostaining was detected on noradrenergic neurons expressing phosphorylated cAMP response element-binding protein (CREB), a marker of neuronal activation. Under pain pathological conditions H4 stimulation might promote the activation of the coeruleospinal noradrenergic neurons that exert an inhibitory control over spinal dorsal horn neuronal excitability. Thus, histamine H4 receptor stimulation may represent a perspective for neuropathic pain management.


Assuntos
Neurônios Adrenérgicos/efeitos dos fármacos , Guanidinas/administração & dosagem , Locus Cerúleo/efeitos dos fármacos , Neuralgia/tratamento farmacológico , Receptores Histamínicos H4/agonistas , Tioureia/análogos & derivados , Neurônios Adrenérgicos/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Animais , Benzimidazóis/administração & dosagem , Clonidina/administração & dosagem , Modelos Animais de Doenças , Histamina/metabolismo , Humanos , Injeções Espinhais , Locus Cerúleo/patologia , Masculino , Camundongos , Camundongos Knockout , Microinjeções , Neuralgia/patologia , Norepinefrina/metabolismo , Manejo da Dor/métodos , Receptores Histamínicos H4/genética , Receptores Histamínicos H4/metabolismo , Tioureia/administração & dosagem
9.
Anesth Analg ; 130(1): 90-98, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31633505

RESUMO

BACKGROUND: Timing and onset of myocardial ischemia are mostly unpredictable. Therefore, postconditioning could be an effective cardioprotective intervention. Because ischemic postconditioning is an invasive and not practicable treatment, pharmacological postconditioning would be a more suitable alternative cardioprotective measure. For the α2-adrenoreceptor agonist, dexmedetomidine postconditioning has been shown. However, data on a concentration-dependent effect of dexmedetomidine are lacking. Furthermore, it is unclear whether the time point and/or duration of dexmedetomidine administration in the reperfusion period is of relevance. We set out to determine whether infarct size reduction by dexmedetomidine is concentration dependent and whether time point and/or duration of dexmedetomidine application has an impact on the effect size of cardio protection. METHODS: Hearts of male Wistar rats were randomized and placed on a Langendorff system perfused with Krebs-Henseleit buffer at a constant pressure of 80 mm Hg. All hearts were subjected to 33 minutes of global ischemia and 60 minutes of reperfusion. In part I of the study, a concentration-response effect was determined by perfusing hearts with various concentrations of dexmedetomidine (0.3-100 nM) at the onset of reperfusion. Based on these results, part II of the study was conducted with 3 nM dexmedetomidine. Application of dexmedetomidine started directly at the onset of reperfusion (Dex60) and 15 minutes (Dex15), 30 minutes (Dex30), or 45 minutes (Dex45) after the start of reperfusion and lasted always until the end of the reperfusion period. Infarct size was determined by triphenyltetrazolium chloride staining. RESULTS: In part I, infarct size in control (Con) hearts was 62% ± 4%. Three-nanometer dexmedetomidine was the lowest most effective cardioprotective concentration and reduced infarct size to 24% ± 7% (P < .0001 versus Con). Higher concentrations did not confer stronger protection. Infarct size in control hearts from part II was 66% ± 6%. Different starting times and/or durations of application resulted in similar infarct size reduction (all P < .0001 versus Con). CONCLUSIONS: Postconditioning by dexmedetomidine is concentration dependent in ranges between 0.3 and 3 nM. Increased concentrations above 3 nM do not further enhance this cardioprotective effect. This cardioprotective effect is independent of time point and length of application in the reperfusion period.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Dexmedetomidina/administração & dosagem , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Preparação de Coração Isolado , Masculino , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/patologia , Ratos Wistar , Fatores de Tempo , Função Ventricular Esquerda/efeitos dos fármacos
10.
J Dermatolog Treat ; 31(4): 433-434, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30973791

RESUMO

Ulceration is the most common complication of infantile hemangioma (IH). We reported two cases of ulcerated IH treated by new cream formulation of brimonidine 0.2%-timolol 0.5% (a combination of selective α-2-adrenergic agonist and nonselective ß-blocker). In both cases, ulcerations were healed within 7-10 days after twice-daily application. No topical or systemic side effects were reported. In conclusion, brimonidine 0.2%-timolol 0.5% cream is a promising alternative in the topical treatment of ulcerated hemangiomas.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Antagonistas Adrenérgicos beta/administração & dosagem , Tartarato de Brimonidina/administração & dosagem , Hemangioma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Úlcera Cutânea/tratamento farmacológico , Timolol/administração & dosagem , Administração Tópica , Combinação de Medicamentos , Feminino , Hemangioma/complicações , Humanos , Lactente , Pomadas , Neoplasias Cutâneas/complicações , Úlcera Cutânea/etiologia
11.
J Zoo Wildl Med ; 51(3): 490-496, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33480524

RESUMO

A retrospective analysis of 40 extended (>2 hr) anesthetic events in eight lions (Panthera leo) and 32 tigers (Panthera tigris) was performed using a hierarchical linear growth curve model to assess the effects of anesthetic time, α-2 adrenoreceptor agonist dosages, administration of atipamezole, and biochemical parameters on rising plasma K+ concentrations. Hyperkalemia was first noted at a mean time of 187 min (range: 131-226 min), with time under anesthesia as a statistically significant predictor of K+ concentration (P < 0.0001). A significant two-way interaction between time and atipamezole administration (P = 0.0082) for rising K+ concentrations was demonstrated, indicating that administration of atipamezole can mitigate the rise in K+ concentrations. Administration of atipamezole beyond 150 min of anesthetic time was less effective in reducing K+ concentrations than if administered earlier. Electrocardiographic abnormalities were noted in eight animals, including three hyperkalemic individuals. Lions developed significantly greater plasma K+ concentrations than tigers (P = 0.0009) during anesthesia. No biochemical parameter was identified as a significant indicator of which individuals will develop hyperkalemia. Clinicians anesthetizing any large nondomestic felid should monitor electrolytes regularly during anesthetic events; consider early, partial- to full-dose reversal of α-2 agonists; and be prepared to correct potentially life-threatening electrocardiographic abnormalities resulting from hyperkalemia.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Anestesia/veterinária , Hiperpotassemia/veterinária , Imidazóis/administração & dosagem , Leões , Tigres , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Animais , Animais de Zoológico , Feminino , Hiperpotassemia/tratamento farmacológico , Masculino , Estudos Retrospectivos
12.
Trials ; 20(1): 710, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31829274

RESUMO

BACKGROUND: Prolonged treatment with analgesic and sedative drugs in the pediatric intensive care unit (PICU) may lead to undesirable effects such as dependence and tolerance. Moreover, during analgosedation weaning, patients may develop clinical signs of withdrawal, known as withdrawal syndrome (WS). Some studies indicate that dexmedetomidine, a selective α2-adrenoceptor agonist, may be useful to prevent WS, but no clear evidence supports these data. The aims of the present study are to evaluate the efficacy of dexmedetomidine in reducing the occurrence of WS during analgosedation weaning, and to clearly assess its safety. METHODS: We will perform an adaptive, multicenter, randomized, double-blind, placebo-controlled trial. Patients aged < 18 years receiving continuous intravenous analgosedation treatment for at least 5 days and presenting with clinical conditions that allow analgosedation weaning will be randomly assigned to treatment A (dexmedetomidine) or treatment B (placebo). The treatment will be started 24 h before the analgosedation weaning at 0.4 µg/kg/h, increased by 0.2 µg/kg/h per hour up to 0.8 µg/kg/h (neonate: 0.2 µg/kg/h, increased by 0.1 µg/kg/h per hour up to 0.4 µg/kg/h) and continued throughout the whole weaning time. The primary endpoint is the efficacy of the treatment, defined by the reduction in the WS rate among patients treated with dexmedetomidine compared with patients treated with placebo. Safety will be assessed by collecting any potentially related adverse event. The sample size assuring a power of 90% is 77 patients for each group (total N = 154 patients). The study was approved by the Ethics Committee of the University-Hospital S.Orsola-Malpighi of Bologna on 22 March 2017. DISCUSSION: The present trial will allow us to clearly assess the efficacy of dexmedetomidine in reducing the occurrence of WS during weaning from analgosedation drugs. In addition, the study will provide a unique insight into the safety profile of dexmedetomidine. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03645603. Registered on 24 August 2018. EudraCT, 2015-002114-80. Retrospectively registered on 2 January 2019.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Analgésicos Opioides/efeitos adversos , Benzodiazepinas/efeitos adversos , Dexmedetomidina/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Unidades de Terapia Intensiva Pediátrica , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Síndrome de Abstinência a Substâncias/prevenção & controle , Ensaios Clínicos Adaptados como Assunto , Adolescente , Agonistas de Receptores Adrenérgicos alfa 2/efeitos adversos , Fatores Etários , Analgésicos Opioides/administração & dosagem , Benzodiazepinas/administração & dosagem , Criança , Pré-Escolar , Dexmedetomidina/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Tolerância a Medicamentos , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Lactente , Recém-Nascido , Infusões Intravenosas , Itália , Masculino , Estudos Multicêntricos como Assunto , Transtornos Relacionados ao Uso de Opioides/diagnóstico , Transtornos Relacionados ao Uso de Opioides/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome de Abstinência a Substâncias/diagnóstico , Síndrome de Abstinência a Substâncias/etiologia , Fatores de Tempo , Resultado do Tratamento
13.
Best Pract Res Clin Anaesthesiol ; 33(4): 415-423, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31791560

RESUMO

Adjuvants are medications that work synergistically with local anesthetics to help enhance the duration and quality of analgesia in regional techniques. Regional anesthesia has become more prevalent as evidence continues to show efficacy, enhancement of patient care, increased patient satisfaction, and improved patient safety. Practitioners in the perioperative setting need to not only be familiar with regional techniques but also the medications used for them. Some examples of adjuvant medications for regional techniques include dexamethasone, alpha 2 agonists such as clonidine and dexmedetomidine, midazolam, buprenorphine, NMDA antagonists, including ketamine and magnesium, neostigmine, sodium bicarbonate, epinephrine, and non-steroidal anti-inflammatory drugs. The aim of the present investigation, therefore, is to provide a comprehensive review of the most commonly used non-opioid adjuvants in clinical practice today. Regional adjuvants can improve patient safety, increase patient satisfaction, and enhance clinical efficacy. Future studies and best practice techniques can facilitate standardization of regional anesthesia adjuvant dosing when providing nerve blocks in clinical practice.


Assuntos
Anestesia por Condução/métodos , Anestésicos Locais/administração & dosagem , Bloqueio Nervoso/métodos , Dor Pós-Operatória/prevenção & controle , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Analgésicos Opioides/administração & dosagem , Anti-Inflamatórios não Esteroides/administração & dosagem , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Ketamina/administração & dosagem
14.
Acta Cir Bras ; 34(9): e201900905, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31800679

RESUMO

PURPOSE: To investigate efficacy of combined use of parecoxib and dexmedetomidine on postoperative pain and early cognitive dysfunction after laparoscopic cholecystectomy for elderly patients. METHODS: The present prospective randomized controlled study included a total of 80 patients who underwent laparoscopic cholecystectomy surgery during January 2016 to November 2017 in our hospital. All patients were randomly divided into 4 groups, the parecoxib group, the dexmedetomidine group, the parecoxib and dexmedetomidine combined group, and the control group. Demographic data and clinical data were collected. Indexes of heart rate (HR), mean arterial pressure (MAP), levels of jugular venous oxygen saturation (SjvO2) and jugular venous oxygen pressure (PjvO2) were recorded at different time points before and during the surgery. The mini-mental state examination (MMSE) score, Ramsay score and Visual Analogue Score (VAS) were measured. RESULTS: Levels of both SjvO2 and PjvO2 were significantly higher in parecoxib group, dexmedetomidine group and the combined group than the control group. Meanwhile, levels of both SjvO2 and PjvO2 in the combined group were the highest. VAS scores were significantly lower in the combined group than all other groups, and total patient controlled intravenous analgesia (PCIA) pressing times within 48 h after surgery were the lowest in the combined group. Both Ramsay and MMSE scores were the highest in the combined group compared with other groups, while were the lowest in the control group. CONCLUSION: The combined use of parecoxib and dexmedetomidine could reduce the postoperative pain and improve the postoperative sedation and cognitive conditions of patients after laparoscopic cholecystectomy.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Colecistectomia Laparoscópica/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Dexmedetomidina/administração & dosagem , Isoxazóis/administração & dosagem , Dor Pós-Operatória/tratamento farmacológico , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Pressão Arterial/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
15.
Anesth Analg ; 129(6): 1504-1511, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31743169

RESUMO

BACKGROUND: Dexmedetomidine provides smooth and hemodynamically stable emergence at the expense of hypotension, delayed recovery, and sedation. We investigated the optimal dose of dexmedetomidine for prevention of cough, agitation, hypertension, tachycardia, and shivering, with minimal side effects. METHODS: In this prospective, randomized, double-blind trial, 216 adult patients were randomly assigned to dexmedetomidine 1 µg/kg (D 1), 0.5 µg/kg (D 0.5), 0.25 µg/kg (D 0.25), or control (C). During emergence, cough, agitation, hemodynamic parameters, shivering, time to extubation, and sedation scores were recorded. RESULTS: A total of 190 patients were analyzed. The respective incidences for the groups D 1, D 0.5, and D 0.25 versus group C were 48%, 64%, and 64% vs 84% for cough-corrected P < .003 between groups D 1 and C; 33%, 34%, and 33% vs 72% for agitation-corrected P < .003 between group C and each of the study groups; and 4%, 2%, and 7% vs 22% for shivering-corrected P = .03 and corrected P = .009 between groups D 1 and D 0.5 versus group C, respectively. The percent increase from baseline blood pressure on extubation for the 3 treatment groups was significantly lower than group C. Percent increase in heart rate was lower than control in groups D 1 and D 0.5 but not in group D 0.25. Time to extubation and sedation scores were comparable. However, more hypotension was recorded during the emergence phase in the 3 treatment groups versus group C. CONCLUSIONS: D 1 at the end of surgery provides the best quality of emergence from general anesthesia including the control of cough, agitation, hypertension, tachycardia, and shivering. D 0.5 also controls emergence phenomena but is less effective in controlling cough. The 3 doses do not delay extubation. However, they cause dose-dependent hypotension.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Período de Recuperação da Anestesia , Anestesia Geral , Dexmedetomidina/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Adolescente , Agonistas de Receptores Adrenérgicos alfa 2/efeitos adversos , Adulto , Idoso , Anestesia Geral/efeitos adversos , Tosse/prevenção & controle , Dexmedetomidina/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Delírio do Despertar/prevenção & controle , Feminino , Humanos , Hipertensão/prevenção & controle , Hipnóticos e Sedativos/efeitos adversos , Hipotensão/induzido quimicamente , Líbano , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tremor por Sensação de Frio/efeitos dos fármacos , Taquicardia/prevenção & controle , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
16.
Anesth Analg ; 129(6): 1512-1518, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31743170

RESUMO

BACKGROUND: In patients undergoing total knee arthroplasty under spinal anesthesia, we compared the postoperative analgesic effect of intraoperative sedation with dexmedetomidine versus propofol. We hypothesized that sedation with dexmedetomidine would result in lower postoperative opioid analgesic consumption than with propofol. METHODS: Forty-eight patients were enrolled and randomly assigned to either a dexmedetomidine group (n = 24), which received a loading dose of 1 µg/kg dexmedetomidine over 10 minutes, followed by a continuous infusion of 0.1-0.5 µg·kg·hour, or a propofol group (n = 24), which received a continuous infusion of propofol via a target-controlled infusion to maintain the effect-site concentration within a range of 0.5-2.0 µg/mL. The drug infusion rate was determined according to the sedation level, targeting a modified observer's assessment of alertness/sedation score of 3 or 4. The cumulative amounts of fentanyl administered via intravenous patient-controlled analgesia were recorded at 24 and 48 hours postoperatively (primary outcome). The postoperative numerical rating scale for pain was assessed at 6, 12, 24, and 48 hours (secondary outcome). The postoperative use of additional rescue analgesic (ketoprofen) and antiemetic drugs was also compared between the 2 groups at 24 and 48 hours. RESULTS: Dexmedetomidine significantly reduced postoperative fentanyl consumption (median [interquartile range]) during 0-24 hours (45 [30-71] vs 150 [49-248] µg, P = .004; median difference = -105 µg [99.98% CI, 210-7.5]), 24-48 hours (90 [45-143] vs 188 [75-266] µg, P = .005; median difference = -98 µg [99.98% CI, 195-45]), and 0-48 hours (135 [68-195] vs 360 [146-480] µg, P = .003; median difference = -225 µg [99.98% CI, 405-7.5]). The numerical rating scale (median [interquartile range]) was lower at 6 hours (1 [0-2] vs 2 [1-3], P = .003), 12 hours (1 [1-2] vs 3 [2-3], P < .001), 24 hours (1 [1-2] vs 3 [2-3], P < .001), and 48 hours (2 [2-3] vs 3 [3-4], P < .001) after surgery in the dexmedetomidine group compared to the propofol group. No significant intergroup differences were observed in the amount of rescue analgesics and antiemetics at 24 hours (P = .155 and P = .482) and 48 hours (P = .082 and P = .153) after surgery. CONCLUSIONS: Intraoperative dexmedetomidine sedation was associated with a small but clinically important reduction in postoperative opioid use after total knee arthroplasty.


Assuntos
Dor Aguda/prevenção & controle , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Analgésicos não Entorpecentes/administração & dosagem , Raquianestesia , Anestésicos Intravenosos/administração & dosagem , Artroplastia do Joelho/efeitos adversos , Dexmedetomidina/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Dor Pós-Operatória/prevenção & controle , Propofol/administração & dosagem , Dor Aguda/diagnóstico , Dor Aguda/etiologia , Agonistas de Receptores Adrenérgicos alfa 2/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgesia Controlada pelo Paciente , Analgésicos não Entorpecentes/efeitos adversos , Analgésicos Opioides/administração & dosagem , Raquianestesia/efeitos adversos , Anestésicos Intravenosos/efeitos adversos , Dexmedetomidina/efeitos adversos , Feminino , Fentanila/administração & dosagem , Humanos , Hipnóticos e Sedativos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Propofol/efeitos adversos , República da Coreia , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
17.
Anesth Analg ; 129(6): 1519-1528, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31743171

RESUMO

BACKGROUND: Dexmedetomidine is increasingly used off-label in infants and children with cardiac disease during cardiopulmonary bypass (CPB) and in the postoperative period. Despite its frequent use, optimal dosing of dexmedetomidine in the setting of CPB has not been identified but is expected to differ from dosing in those not supported with CPB. This study had the following aims: (1) characterize the effect of CPB on dexmedetomidine clearance (CL) and volume of distribution (V) in infants and young children; (2) characterize tolerance and sedation in patients receiving dexmedetomidine; and (3) identify preliminary dosing recommendations for infants and children undergoing CPB. We hypothesized that CL would decrease, and V would increase during CPB compared to pre- or post-CPB states. METHODS: Open-label, single-center, opportunistic pharmacokinetics (PK) and safety study of dexmedetomidine in patients ≤36 months of age administered dexmedetomidine per standard of care via continuous infusion. We analyzed dexmedetomidine PK data using standard nonlinear mixed effects modeling with NONMEM software. We compared model-estimated PK parameters to those from historical patients receiving dexmedetomidine before anesthesia for urologic, lower abdominal, or plastic surgery; after low-risk cardiac or craniofacial surgery; or during bronchoscopy or nuclear magnetic resonance imaging. We investigated the influence of CPB-related factors on PK estimates and used the final model to simulate dosing recommendations, targeting a plasma concentration previously associated with safety and efficacy (0.6 ng/mL). We used the Wilcoxon rank sum test to evaluate differences in dexmedetomidine exposure between infants with hypotension or bradycardia and those who did not develop these adverse events. RESULTS: We collected 213 dexmedetomidine plasma samples from 18 patients. Patients had a median (range) age of 3.3 months (0.1-34.0 months) and underwent CPB for 161 minutes (63-394 minutes). We estimated a CL of 13.4 L/h/70 kg (95% confidence interval, 2.6-24.2 L/h/70 kg) during CPB, compared to 42.1 L/h/70 kg (95% confidence interval, 38.7-45.8 L/h/70 kg) in the historical patients. No specific CPB-related factor had a statistically significant effect on PK. A loading dose of 0.7 µg/kg over 10 minutes before CPB, followed by maintenance infusions through CPB of 0.2 or 0.25 µg/kg/h in infants with postmenstrual ages of 42 or 92 weeks, respectively, maintained targeted concentrations. We identified no association between dexmedetomidine exposure and selected adverse events (P = .13). CONCLUSIONS: CPB is associated with lower CL during CPB in infants and young children compared to those not undergoing CPB. Further study should more closely investigate CPB-related factors that may influence CL.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacocinética , Ponte Cardiopulmonar , Dexmedetomidina/farmacocinética , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacocinética , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Agonistas de Receptores Adrenérgicos alfa 2/efeitos adversos , Fatores Etários , Ponte Cardiopulmonar/efeitos adversos , Pré-Escolar , Estado de Consciência/efeitos dos fármacos , Dexmedetomidina/administração & dosagem , Dexmedetomidina/efeitos adversos , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Lactente , Recém-Nascido , Masculino , Taxa de Depuração Metabólica , Modelos Biológicos , North Carolina , Uso Off-Label , Projetos Piloto
19.
BMC Anesthesiol ; 19(1): 181, 2019 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604428

RESUMO

BACKGROUND: Intravenous dexmedetomidine is known to attenuate stress response in patients undergoing laparoscopic surgery. We investigated whether the addition of the highly selective alpha-2 adrenergic agonist dexmedetomidine into ropivacaine for ultrasound-guided transversus abdominis plane block could inhibit stress response during laparoscopic surgery, and determined the optimal dose of dexmedetomidine in it. METHODS: One hundred and twenty-five patients undergoing laparoscopic gynecological surgery were included in this prospective and randomized double-blind study. Patients received general anesthesia with or without a total of 60 ml of 0.2% ropivacaine in combination with low (0.25 µg/kg), medium (0.50 µg/kg) or high dose (1.0 µg/kg) of dexmedetomidine for the four-quadrant transversus abdominis plane block (n = 25). The primary outcomes were stress marker levels during the operation. RESULTS: One hundred and twenty patients completed the study protocol. Dexmedetomidine added to ropivacaine for transversus abdominis plane block significantly reduced serum levels of cortisol, norepinephrine, epinephrine, interleukin-6, blood glucose, mean arterial pressure and heart rate in a dose-dependent manner (P < 0.05), accompanied with decreased anesthetic and opioid consumption during the operation (P < 0.05), but the high dose of dexmedetomidine induced higher incidences of bradycardia than low or medium dose of dexmedetomidine (P < 0.05). CONCLUSION: The addition of dexmedetomidine at the dose of 0.5 µg/kg into ropivacaine for ultrasound-guided transversus abdominis plane block is the optimal dose to inhibit stress response with limited impact on blood pressure and heart rate in patients undergoing laparoscopy gynecological surgery. TRIAL REGISTRATION: This study was registered at www.chictr.org.cn on November 6th, 2016 (ChiCTR-IOR-16009753).


Assuntos
Dexmedetomidina/administração & dosagem , Laparoscopia/métodos , Bloqueio Nervoso/métodos , Ropivacaina/administração & dosagem , Estresse Fisiológico/efeitos dos fármacos , Músculos Abdominais , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Adulto , Anestésicos Locais/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Ultrassonografia de Intervenção
20.
J Vet Pharmacol Ther ; 42(6): 738-744, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31584710

RESUMO

The alpha(α)2 -agonist detomidine is used for equine sedation with opioids such as methadone. We retrieved the data from two randomized, crossover studies where detomidine and methadone were given intravenously alone or combined as boli (STUDY 1) (Gozalo-Marcilla et al., 2017, Veterinary Anaesthesia and Analgesia, 2017, 44, 1116) or as 2-hr constant rate infusions (STUDY 2) (Gozalo-Marcilla et al., 2019, Equine Veterinary Journal, 51, 530). Plasma drug concentrations were measured with a validated tandem Mass Spectrometry assay. We used nonlinear mixed effect modelling and took pharmacokinetic (PK) data from both studies to fit simultaneously both drugs and explore their nonlinear kinetics. Two significant improvements over the classical mammillary two-compartment model were identified. First, the inclusion of an effect of detomidine plasma concentration on the elimination clearances (Cls) of both drugs improved the fit of detomidine (Objective Function Value [OFV]: -160) and methadone (OFV: -132) submodels. Second, a detomidine concentration-dependent reduction of distributional Cls of each drug further improved detomidine (OFV: -60) and methadone (OFV: -52) submodel fits. Using the PK data from both studies (a) helped exploring hypotheses on the nonlinearity of the elimination and distributional Cls and (b) allowed inclusion of dynamic effects of detomidine plasma concentration in the model which are compatible with the pharmacology of detomidine (vasoconstriction and reduction in cardiac output).


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacocinética , Analgésicos Opioides/farmacocinética , Cavalos , Imidazóis/farmacocinética , Metadona/farmacocinética , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Animais , Combinação de Medicamentos , Imidazóis/administração & dosagem , Metadona/administração & dosagem , Distribuição Tecidual
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