265 resultados para S ( ) - Ketamine
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Cytochrome P450 (CYP) enzymes catalyze the metabolism of both, the analgesic and anesthetic drug ketamine and the 2 -adrenergic receptor-agonist medetomidine that is used for sedation and analgesia. As racemic medetomidine or its active enantiomer dexmedetomidine are often coadministered with racemic or S-ketamine in animals and dexmedetomidine together with S- or racemic ketamine in humans, drug-drug interactions are likely to occur and have to be characterized. Enantioselective CE with highly sulfated -cyclodextrin as chiral selector was employed for analyzing in vitro (i) the kinetics of the N-demethylation of ketamine mediated by canine CYP3A12 and (ii) interactions occurring with racemic medetomidine and dexmedetomidine during coincubation with ketamine and canine liver microsomes (CLM), canine CYP3A12, human liver microsomes (HLM), and human CYP3A4. For CYP3A12 without an inhibitor, Michaelis-Menten kinetics was determined for the single enantiomers of ketamine and substrate inhibition kinetics for racemic ketamine. Racemic medetomidine and dexmedetomidine showed an inhibition of the N-demethylation reaction in the studied canine enzyme systems. Racemic medetomidine is the stronger inhibitor for CLM, whereas there is no difference for CYP3A12. For CLM and CYP3A12, the inhibition of dexmedetomidine is stronger for the R- compared to the S-enantiomer of ketamine, a stereoselectivity that is not observed for CYP3A4. Induction is observed at a low dexmedetomidine concentration with CYP3A4 but not with CYP3A12, CLM, and HLM. Based on these results, S-ketamine combined with dexmedetomidine should be the best option for canines. The enantioselective CE assay with highly sulfated -cyclodextrin as chiral selector is an effective tool for determining kinetic and inhibition parameters of metabolic pathways.
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Seven captive male African wild dogs (Lycaon pictus) weighing 25-32 kg each, were anesthetized by i.m. injection via hand syringe with a combination of 1.5 mg/kg ketamine, 40 mu g/kg medetomidine, and 0.05 mg/kg atropine. Following endotracheal intubation, each animal was connected to a bain closed-circuit system that delivered 1.5% isoflurane and 2 L/min oxygen. Atipamezole (0.1 mg/kg i.v.; 0.1 mg/kg i.m.) was given at the end of each procedure (60 min following injection of medetomidine/ketamine/atropine). Time to sternal recumbency was 5-8 min. Times to standing after atipamezole administration were 8-20 min. This anesthetic regimen was repeated on three separate occasions (September 2000, February 2002, and October 2002) on all males to perform electroejaculation procedures. Each procedure was < 80 min from injection to standing. Dogs showed excellent muscle relaxation during the procedures. Arterial blood samples were collected at 10-min intervals for blood gases in one procedure (September 2000). Separate venous samples were taken from each dog during each procedure for hematology and biochemistry. These values were within the normal range for this species. Arterial hemoglobin oxygen saturation (SpO2) and heart rate (HR) were monitored continuously in addition to other anesthesia monitoring procedures (body temperature, respiratory rate [RR], capillary refill time, blink response, pupil position, deep pain perception reflex). All dogs maintained relatively stable SpO2 profiles during monitoring, with a mean (+/- SD) SpO2 of 92% +/- 5.4%. All other physiological variables (HR, RR, body temperature, blood pressure) were within normal limits. Following each procedure, normal behavior was noted in all dogs. All the dogs were reunited into the pack at completion of their anesthetic procedures. An injectable medetomidine-ketamine-atropine combination with maintenance by gaseous isoflurane and oxygen provides an inexpensive, reliable anesthetic for captive African wild dogs.
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Recent studies show that higher order oscillatory interactions such as cross-frequency coupling are important for brain functions that are impaired in schizophrenia, including perception, attention and memory. Here we investigated the dynamics of oscillatory coupling in the hippocampus of awake rats upon NMDA receptor blockade by ketamine, a pharmacological model of schizophrenia. Ketamine (25, 50 and 75 mg/kg i.p.) increased gamma and high-frequency oscillations (HFO) in all depths of the CA1-dentate axis, while theta power changes depended on anatomical location and were independent of a transient increase of delta oscillations. Phase coherence of gamma and HFO increased across hippocampal layers. Phase-amplitude coupling between theta and fast oscillations was markedly altered in a dose-dependent manner: ketamine increased hippocampal theta-HFO coupling at all doses, while theta-gamma coupling increased at the lowest dose and was disrupted at the highest dose. Our results demonstrate that ketamine alters network interactions that underlie cognitively relevant theta-gamma coupling.
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Recent studies show that higher order oscillatory interactions such as cross-frequency coupling are important for brain functions that are impaired in schizophrenia, including perception, attention and memory. Here we investigated the dynamics of oscillatory coupling in the hippocampus of awake rats upon NMDA receptor blockade by ketamine, a pharmacological model of schizophrenia. Ketamine (25, 50 and 75 mg/kg i.p.) increased gamma and high-frequency oscillations (HFO) in all depths of the CA1-dentate axis, while theta power changes depended on anatomical location and were independent of a transient increase of delta oscillations. Phase coherence of gamma and HFO increased across hippocampal layers. Phase-amplitude coupling between theta and fast oscillations was markedly altered in a dose-dependent manner: ketamine increased hippocampal theta-HFO coupling at all doses, while theta-gamma coupling increased at the lowest dose and was disrupted at the highest dose. Our results demonstrate that ketamine alters network interactions that underlie cognitively relevant theta-gamma coupling.
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Objective: To critically examine the DSM-IV-TR criteria for Substance-Induced Psychotic Disorder (SIPD). Data sources: Leading electronic databases (such as Medline, Pubmed) were searched for the years 1992 through 2007, using combinations of the following key search terms: substance abuse/dependence, alcohol, marijuana, cannabis, methamphetamine, crack, cocaine, amphetamine, ecstasy, ketamine, phencyclidine, LSD, mental health, drug-induced psychosis, substance-induced psychosis, psychosis, schizophrenia. References identified from bibliographies of pertinent articles and books in the field were also collected and reviewed. Data extraction: Only research studies or case reports series that presented data on populations diagnosed with SIPD using clinical or structured diagnostic interviews published in English were used to assess the validity of the current SIPD criteria. Data synthesis: We identified 49 articles that presented clinical data on SIPD. The majority of these publications were case reports, with only 18 articles specifically focusing on delineating the clinical characteristics or outcomes of individuals diagnosed with SIPD. While several large studies have recently been conducted to assess the stability of SIPD, there is a dearth of research rigorously examining the validity of DSM-IV diagnostic criteria across substances. Conclusions: There remains a striking paucity of information on the outcome, treatment and best practice for substance-associated psychotic episodes. Further work is clearly required before the advent of DSM-V. We propose an alternative, broader classification that better reflects the current evidence base, inferring association rather than causation.
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Migraine is a common genetically linked neurovascular disorder. Approximately ~12% of the Caucasian population are affected including 18% of adult women and 6% of adult men (1, 2). A notable female bias is observed in migraine prevalence studies with females affected ~3 times more than males and is credited to differences in hormone levels arising from reproductive achievements. Migraine is extremely debilitating with wide-ranging socioeconomic impact significantly affecting people's health and quality of life. A number of neurotransmitter systems have been implicated in migraine, the most studied include the serotonergic and dopaminergic systems. Extensive genetic research has been carried out to identify genetic variants that may alter the activity of a number of genes involved in synthesis and transport of neurotransmitters of these systems. The biology of the Glutamatergic system in migraine is the least studied however there is mounting evidence that its constituents could contribute to migraine. The discovery of antagonists that selectively block glutamate receptors has enabled studies on the physiologic role of glutamate, on one hand, and opened new perspectives pertaining to the potential therapeutic applications of glutamate receptor antagonists in diverse neurologic diseases. In this brief review, we discuss the biology of the Glutamatergic system in migraine outlining recent findings that support a role for altered Glutamatergic neurotransmission from biochemical and genetic studies in the manifestation of migraine and the implications of this on migraine treatment.
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This book showcases the development and evaluation of innovative examples of pain management initiatives by advanced practitioners. It considers each service development or community initiative both in terms of advanced practice nursing and pain management. There is a wide range of examples of innovation in pain management included - from the introduction of ketamine use in one trust, to wider issues around meeting the needs of pain management in the community. The book considers issues including use of research, education and interprofessional working in the advanced practitioner role. Each chapter looks at development of the service, challenges of implementation, evaluation of the service's success and justifying the importance of the advanced nurse in the service's achievements.
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Introduction and Aims Wastewater analysis (WWA) is intended to be a direct and objective method of measuring substance use in large urban populations. It has also been used to measure prison substance use in two previous studies. The application of WWA in this context has raised questions as to how best it might be used to measure illicit drug use in prisons, and whether it can also be used to measure prescription misuse. We applied WWA to a small regional prison to measure the use of 12 licit and illicit substances. We attempted to measure the non-medical use of methadone and buprenorphine and to compare our findings with the results of the prison's mandatory drug testing (MDT). Design and Methods Representative daily composite samples were collected for two periods of 12 consecutive days in May to July 2013 and analysed for 18 drug metabolites. Prescription data and MDT results were obtained from the prison and compared with the substance use estimates calculated from WWA data. Results Daily use of methamphetamine, methadone, buprenorphine and codeine was detected, while sporadic detection of ketamine and methylone was also observed. Overall buprenorphine misuse appeared to be greater than methadone misuse. Discussion and Conclusions Compared with MDT, WWA provides a more comprehensive picture of prison substance use. WWA also has the potential to measure the misuse of medically prescribed substances. However, a great deal of care must be exercised in quantifying the usage of any substance in small populations, such as in prisons.
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The measurement of illicit drug metabolites in raw wastewater is increasingly being adopted as an approach to objectively monitor population-level drug use, and is an effective complement to traditional epidemiological methods. As such, it has been widely applied in western countries. In this study, we utilised this approach to assess drug use patterns over nine days during April 2011 in Hong Kong. Raw wastewater samples were collected from the largest wastewater treatment plant serving a community of approximately 3.5 million people and analysed for excreted drug residues including cocaine, ketamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA) and key metabolites using liquid chromatography coupled with tandem mass spectrometry. The overall drug use pattern determined by wastewater analysis was consistent with that have seen amongst people coming into contact with services in relation to substance use; among our target drugs, ketamine (estimated consumption: 14001600 mg/day/1000 people) was the predominant drug followed by methamphetamine (180200 mg/day/1000 people), cocaine (160180 mg/day/1000 people) and MDMA (not detected). The levels of these drugs were relatively steady throughout the monitoring period. Analysing samples at higher temporal resolution provided data on diurnal variations of drug residue loads. Elevated ratios of cocaine to benzoylecgonine were identified unexpectedly in three samples during the evening and night, providing evidence for potential dumping events of cocaine. This study provides the first application of wastewater analysis to quantitatively evaluate daily drug use in an Asian metropolitan community. Our data reinforces the benefit of wastewater monitoring to health and law enforcement authorities for strategic planning and evaluation of drug intervention strategies.
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Opioids are most commonly used for treatment of severe pain. However, the fear of respiratory depression has restricted the use of opioids. Depending on the monitoring system used, different modes of opioid respiratory effects have been noted in previous studies. All opioids also cause alterations in hemodynamics at least to some extent. The main goal of this series of investigations was to elucidate the native ventilatory and hemodynamic effects of different opioids. Studies I-IV each involved 8 healthy male volunteers. Study V involved 13 patients with lower or upper extremity traumas. The opioids studied were morphine, oxycodone, pethidine, fentanyl, alfentanil, tramadol and ketamine. The respiratory parameters used in this study were breathing pattern measured with respiratory inductive plethysmography, gas exchange measured with indirect calorimetry, blood gas analysis and pulse oximetry. Hemodynamics was measured with arterial blood pressure, heart rate and oxygen consumption. Plasma catecholamine and histamine concentrations were also determined. All opioids studied caused an alteration in respiratory function. Respiratory rate, alveolar ventilation and minute ventilation decreased, while tidal volume increased in most situations. Breathing pattern was also significantly affected after opioid administration. The respiratory depression caused by oxycodone was deeper than the one caused by same dose of morphine. An equianalgesic dose of tramadol caused markedly smaller respiratory depression compared to pethidine. The potency ratio for respiratory depression of fentanyl and alfentanil is similar to analgesic potency ratio studied elsewhere. Racemic ketamine attenuated the respiratory depression caused by fentanyl, if measured with minute ventilation. However, this effect was counteracted by increased oxygen consumption. Supplemental oxygen did not offer any benefits, nor did it cause any atelectasis when given to opioid treated trauma patients. Morphine caused a transient hemodynamic stimulation, which was accompanied by an increase in oxygen consumption. Oxycodone, alfentanil, fentanyl, tramadol and pethidine infusions had minimal effects on hemodynamics. Plasma catecholamine concentrations were increased after high dose opioid administration. Plasma histamine concentrations were not elevated after morphine nor oxycodone administration. Respiratory depression is a side effect noted with all opioids. The profile of this phenomenon is quite similar with different opioid-receptor agonists. The hemodynamic effects of opioids may vary depending on the opioid used, morphine causing a slight hemodynamic stimulation. However, all opioids studied could be considered hemodynamically stable.
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Background: Contrary to what is generally thought schizophrenia is a very common mental health issue. For this, several animal models are used to assess the illness in order to develop a definitive. The most widely spread paradigm is the use of pharmacological models. Aim: The aim of this review is to display which are the most used insults for the assessment of social behaviour related negative symptoms in animal models as well as to ascertain which is the most adequate regime. Design: Literature review. Methods: PubMed database was used for this article by the search of the indexed schizophrenia, animal models, social behaviour and negative symptoms descriptors. With the exception of a single article due to it value this review is based on articles from 10 years onwards. Besides, only clinical trials and reviews written in English or Spanish and that had laboratory rodents as target population were accepted. Results: The studies assessed agree that pharmacological models (specially those regarding the NMDA receptor antagonists) are a valuable means for the experimental investigation of negative symptoms in schizophrenia with the necessity to emphasise that only some negative symptoms (anhedonia and social interaction, mainly) can be experimentally assessed. Conclusions: There is not enough evidence regarding the fours aspects of this review. PCP, Ketamine or MK-801 in sub-acute dosage regimes are currently the most indicated insults to mimic schizophrenic symptoms in rodents, although further research in needed, albeit other substances are valuable as well. (In English language exclusively)
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A dor neuroptica uma sndrome dolorosa crnica, que ocorre muito frequentemente em pacientes com hansenase, de difcil tratamento. Objetivou-se avaliar o efeito teraputico da S(+)-cetamina na dor neuroptica e qualidade de vida em portadores de hansenase atendidos em ambulatrios em So Lus - MA. Estudo experimental tipo ensaio clnico, prospectivo, aleatrio, duplamente cego, controlado por placebo, com 34 pacientes distribudos aleatoriamente em um dois grupos, cetamina e placebo por trs meses e randomizados por numerao sequenciada. A dor foi avaliada por meio de escala analgica visual (EAV) nas seis visitas quinzenais (1, 2, 3, 4, 5 e 6), e pelo inventrio DN4, na visita 1 e 6, com distribuio da S(+)-cetamina e o analgsico de resgate e avaliado os efeitos adversos em cada visita. Realizou-se a coleta de 15mL de sangue para exames de segurana na visita 1 e 6 e para quantificao de citocinas plasmticas IL-1, IL-6 e TNFα, nas visitas 1, 2, 4 e 6. Foi tambm, avaliada a qualidade de vida por meio do questionrio WHOQOL-Bref nas visitas 1 e 6. Os resultados demostraram predominncia do sexo feminino, idade de 18 a 29 anos, pardos, solteiros, renda de 2 a 4 salrios mnimos; e mdia de 7,782,21 anos de estudo. Na avaliao da dor pela EAV os dois grupos apresentaram uma reduo dos escores mdios de dor ao longo do tempo, e mostrou significncia estatstica p < 0,05. Entretanto no foi observada diferena estatstica para os escores de dor entre os grupos e tambm, em relao ao uso do medicamento analgsico (codena) de resgate. Houve reduo significante nos escore de DN4 no grupo placebo em relao s avaliaes iniciais e finais comparadas cetamina, ainda os escores iniciais do DN4 foram significativamente menores no grupo placebo, nas avaliaes de antes e depois do uso da S(+)-cetamina. Na avaliao da qualidade de vida nos domnios fsico, psicolgico, relaes sociais e meio ambiente, no se observou diferena estatisticamente significante entre os grupos estudados. Os valores de IL-1, IL-6 e TNF-α, em quatro coletas do soro dos grupos cetamina e placebo no mostraram diferena estatisticamente significante tanto na avaliao intragrupo ao longo das visitas, como entre os grupos. Em relao aos efeitos adversos, houve um predomnio estatisticamente significante no grupo cetamina especialmente para tontura, alterao visual e outros efeitos. Conclui-se que a S(+)-cetamina por via oral na dose utilizada em pacientes com hansenase e dor neuroptica no se mostrou superior ao placebo em relao ao efeito analgsico e no impacto na qualidade de vida.
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O Leito Mvel Simulado (LMS) um processo de separao de compostos por adsoro muito eficiente, por trabalhar em um regime contnuo e tambm possuir fluxo contracorrente da fase slida. Dentre as diversas aplicaes, este processo tem se destacado na resoluo de petroqumicos e principalmente na atualidade na separao de misturas racmicas que so separaes de um grau elevado de dificuldade. Neste trabalho foram propostas duas novas abordagens na modelagem do LMS, a abordagem Stepwise e a abordagem Front Velocity. Na modelagem Stepwise as colunas cromatogrficas do LMS foram modeladas com uma abordagem discreta, onde cada uma delas teve seu domnio dividido em N clulas de mistura interligadas em srie, e as concentraes dos compostos nas fases lquida e slida foram simuladas usando duas cinticas de transferncia de massa distintas. Essa abordagem pressupe que as interaes decorrentes da transferncia de massa entre as molculas do composto nas suas fases lquida e slida ocorram somente na superfcie, de forma que com essa suposio pode-se admitir que o volume ocupado por cada molcula nas fases slida e lquida o mesmo, o que implica que o fator de residncia pode ser considerado igual a constante de equilbrio. Para descrever a transferncia de massa que ocorre no processo cromatogrfico a abordagem Front Velocity estabelece que a conveco a fase dominante no transporte de soluto ao longo da coluna cromatogrfica. O Front Velocity um modelo discreto (etapas) em que a vazo determina o avano da fase lquida ao longo da coluna. As etapas so: avano da fase lquida e posterior transporte de massa entre as fases lquida e slida, este ltimo no mesmo intervalo de tempo. Desta forma, o fluxo volumtrico experimental utilizado para a discretizao dos volumes de controle que se deslocam ao longo da coluna porosa com a mesma velocidade da fase lquida. A transferncia de massa foi representada por dois mecanismos cinticos distintos, sem (tipo linear) e com capacidade mxima de adsoro (tipo Langmuir). Ambas as abordagens propostas foram estudadas e avaliadas mediante a comparao com dados experimentais de separao em LMS do anestsico cetamina e, posteriormente, com o frmaco Verapamil. Tambm foram comparados com as simulaes do modelo de equilbrio dispersivo para o caso da Cetamina, usado por Santos (2004), e para o caso do Verapamil (Perna 2013). Na etapa de caracterizao da coluna cromatogrfica as novas abordagens foram associadas ferramenta inversa R2W de forma a determinar os parmetros globais de transferncia de massa apenas usando os tempos experimentais de residncia de cada enantimero na coluna de cromatografia lquida de alta eficincia (CLAE). Na segunda etapa os modelos cinticos desenvolvidos nas abordagens foram aplicados nas colunas do LMS com os valores determinados na caracterizao da coluna cromatogrfica, para a simulao do processo de separao contnua. Os resultados das simulaes mostram boa concordncia entre as duas abordagens propostas e os experimentos de pulso para a caracterizao da coluna na separao enantiomrica da cetamina ao longo do tempo. As simulaes da separao em LMS, tanto do Verapamil quando da Cetamina apresentam uma discrepncia com os dados experimentais nos primeiros ciclos, entretanto aps esses ciclos iniciais a correlao entre os dados experimentais e as simulaes. Para o caso da separao da cetamina (Santos, 2004), a qual a concentrao da alimentao era relativamente baixa, os modelos foram capazes de predizer o processo de separao com as cinticas Linear e Langmuir. No caso da separao do Verapamil (Perna, 2013), onde a concentrao da alimentao relativamente alta, somente a cintica de Langmuir representou o processo, devido a cintica Linear no representar a saturao das colunas cromatogrficas. De acordo como o estudo conduzido ambas as abordagens propostas mostraram-se ferramentas com potencial na predio do comportamento cromatogrfico de uma amostra em um experimento de pulso, assim como na simulao da separao de um composto no LMS, apesar das pequenas discrepncias apresentadas nos primeiros ciclos de trabalho do LMS. Alm disso, podem ser facilmente implementadas e aplicadas na anlise do processo, pois requer um baixo nmero de parmetros e so constitudas de equaes diferenciais ordinrias.
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A osteoartrite (OA) uma doena degenerativa que afeta grande parte da populao e resulta em significativa morbidade e incapacidade. O presente estudo teve como objetivo investigar os efeitos perifricos da S(+) cetamina na expresso da ciclo-oxigenase 2 (COX-2). Foram utilizados modelos experimentais de osteoartrite em ratos. Inicialmente setenta e dois ratos foram utilizados no estudo. Foram divididos em trs grupos de 24 animais cada. Em dois grupos foi induzida a OA atravs de 2mg de MIA (monoiodo acetato de sdio) por via intra-articular (i.a), em um volume mximo de 50μL e em um dos grupos no foi realizada a induo da OA. No stimo dia aps a induo, dois grupos, incluindo o sem OA, receberam injeo i.a de salina 0,9% em volume mximo de 50μL e o terceiro grupo recebeu injeo de S(+) cetamina na dose de 0,5mg/kg. Nos dias 7, 14, 21 e 28 os animais foram anestesiados e sacrificados para coleta da membrana sinovial e anlise imuno-histoqumica da ciclo-oxigenase-2. Durante o estudo ocorreram 29 perdas do material a ser analisado, totalizando um n = 43. O protocolo adotado para a interpretao imuno-histoqumica foi a imunomarcao citoplasmtica da COX-2 em clulas da membrana sinovial, tecido conjuntivo e adiposo, conforme a intensidade da colorao. A anlise dos resultados foi realizada atravs do teste do quiquadrado. A reatividade da COX-2 foi positiva em 53,8% dos animais do grupo sem OA, em 60% do grupo OA com salina e em 80% dos animais do grupo OA com cetamina, sem diferena estatisticamente significante entre os grupos (p = 0,3069). Esse estudo sugeriu que a S(+) cetamina por via intra-articular no inibiu a expresso da COX-2 em modelos de osteoartrite em ratos.
