RESUMEN
BACKGROUND: There is controversy regarding the influence of ketamine and its enantiomers on cerebral haemodynamics at increased intracranial pressure (ICP). This study was designed to compare cerebrovascular responses, with particular respect to ICP, to bolus injections of racemic, S(+)- and R(-)-ketamine in an experimental model of intracranial hypertension. METHODS: Nine pigs were anaesthetised with fentanyl and vecuronium during mechanical normoventilation. The ICP was raised with extradural balloon catheters to 23 mmHg. The intra-arterial xenon clearance technique was used to determine cerebral blood flow (CBF). Three 60-s bolus injections of racemic ketamine (10 mg/kg), S-ketamine (5 mg/kg) and R-ketamine (20 mg/kg) were given in a randomised sequence. Cerebral and systemic haemodynamic responses were evaluated before and at 1, 5, 10, 15, 30 and 45 min after each injection. RESULTS: Racemic ketamine decreased ICP (P=0.026) by maximally 10.8%, whereas there was no effect on ICP of S- (P=0.178) or R-ketamine (P=0.15). All study drugs had similar biphasic effects on CBF, with maximal initial decreases by 25-29%, followed by transient increases by 7-15%, and a reduction of mean arterial pressure by maximally 22-37%. CONCLUSIONS: A decrease or a lack of an increase in ICP in response to intravenous bolus injections of racemic, S- or R-ketamine suggests that the administration of racemic or S-ketamine might be safe in patients with intracranial hypertension due to a space-occupying lesion. The ICP-lowering effect indicates that racemic ketamine might offer a therapeutic advantage over S-ketamine.
Asunto(s)
Ketamina/química , Ketamina/farmacología , Animales , Presión Intracraneal/efectos de los fármacos , Flujo Sanguíneo Regional/efectos de los fármacos , Estereoisomerismo , PorcinosRESUMEN
BACKGROUND: Little is known about the influence of ketamine and its enantiomers on cerebral haemodynamics, and there are no direct comparison reports. This study was designed to evaluate cerebrovascular responses to bolus injections of racemic, S(+)- and R(-)-ketamine in an established experimental model. METHODS: Anaesthesia was induced with propofol in 14 pigs and maintained with fentanyl and vecuronium. The intra-arterial xenon clearance technique was used to calculate the cerebral blood flow (CBF). Eight pigs (part I) were given three consecutive 60-s intravenous (i.v.) bolus injections of 10 mg/kg of racemic ketamine (Ketalar, Pfizer), and cerebral and systemic physiological responses were studied for 30 min after each injection. Following the determination of equipotent doses of the racemate and its enantiomers by recumbency tests, bolus injections of racemic ketamine (10 mg/kg), S-ketamine (5 mg/kg) and R-ketamine (20 mg/kg) were given in randomized sequence to another six pigs (part II) and evaluated at 1, 5, 10, 15, 25 and 40 min. RESULTS: No statistically significant acute tolerance in the CBF response to racemic ketamine was found in part I of the study. In part II, the decreases in the mean arterial pressure (MAP) and CBF by S-ketamine were significantly smaller than those by racemic and R-ketamine (both P < 0.001). No study drug had any significant effect on the cerebral arteriovenous oxygen content difference (C(av)O(2)) over time, but S-ketamine was associated with lower C(av)O(2) than racemic ketamine (P = 0.008) and R-ketamine (P = 0.016). CONCLUSIONS: Bolus injection of S-ketamine was associated with less cerebral and systemic haemodynamic depression than racemic or R-ketamine in equipotent doses in this experimental model. These findings indicate possible advantages of S-ketamine over racemic ketamine.
Asunto(s)
Anestésicos Disociativos/farmacología , Circulación Cerebrovascular/efectos de los fármacos , Ketamina/farmacología , Anestésicos Disociativos/administración & dosificación , Anestésicos Disociativos/química , Animales , Biotransformación , Presión Sanguínea/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Inyecciones Intravenosas , Ketamina/administración & dosificación , Ketamina/química , Oxígeno/sangre , Estereoisomerismo , Porcinos , Resistencia Vascular/efectos de los fármacosRESUMEN
OBJECTIVE: There is a growing interest in low-dose ketamine as an analgesic agent in different intractable pain conditions. Due to its narrow therapeutic window, well-defined pharmacokinetic parameters are essential for its successful use in these situations. Arterial data for ketamine or its enantiomers have not been reported before. The metabolic pathways involved in the metabolism of S- and R-ketamines are not known. METHODS: Ten healthy male volunteers received 7 mg infusions of R- and S-ketamine-hydrochloride in a randomised order over 30 min on 2 separate days. Six were extensive metabolisers, two were poor metabolisers of debrisoquine (CYP2D6) and two were poor metabolisers of mephenytoin (CYP2C19). Arterial and venous concentrations and non-analgesic side effects were measured. RESULTS: Subjective side effects were mild but more pronounced for S- than for R-ketamine. There were no salient differences between the subjects with reduced and normal metabolic capacity in pharmacokinetic parameters or in side effects. Volumes of distribution and mean residence times were 40% smaller for arterial than for venous data. The mean clearance of R-ketamine, 0.020 l min(-1) kg(-1), was slightly but significantly lower than of S-ketamine, 0.024 l min(-1) kg(-1). CONCLUSIONS: There are large differences between arterial and venous data in the pharmacokinetic parameters that are heavily dependent on distribution processes. Parameters mainly reflecting elimination, such as clearance and area under the concentration time curve, are unchanged. The choice of sampling site could be important when computer-controlled infusions are used.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas , Ketamina/farmacocinética , Adulto , Área Bajo la Curva , Cognición/efectos de los fármacos , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6/fisiología , Sistema Enzimático del Citocromo P-450/fisiología , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Oxigenasas de Función Mixta/fisiología , EstereoisomerismoRESUMEN
The analgesic effect of the N-methyl-D-aspartate (NMDA) receptor blocker ketamine in 17 patients (13 females and four males, age 32-88 years) who had suffered neuropathic orofacial pain for time periods ranging from 6 months to 28 years was examined. The patients were given an i.m. test-dose of 0.4 mg/kg ketamine combined with 0.05 mg/kg midazolam. Four patients did not experience any analgesic effect of the i.m. test dose. The remaining 13 patients experienced an analgesic effect which lasted for less than 1 h (transient effect) in seven and for several hours (long-term effect) in six. One week later they were given 4 mg/kg ketamine to be taken orally in combination with a hypnotic drug for three consecutive nights. All patients who reported a long-term analgesic effect after i.m. ketamine also reported reduced pain intensity on days after taking ketamine at night. The findings of this open study are in accord with the results from a previous double-blind randomized investigation. In order to evaluate the role of age and pain duration for the analgesic effect of ketamine, we pooled the data from the two studies and performed a correlation analysis of 43 patients. We found a positive correlation between a long pain-history and lack of analgesic effect and also between a short pain-history and a long-term analgesic effect of low-dose ketamine. The apparent relationship between patient age and ketamine response was, however, not statistically significant. Further, patients with pain following a nerve lesion and patients without a known lesion of peripheral nerves were equally distributed between the three response groups. These results indicate that pain mechanisms are subject to alterations with time and that these alterations involve transition from NMDA to non-NMDA receptor mediated transmission in central pain pathways.
Asunto(s)
Analgésicos/administración & dosificación , Sistema Nervioso Central/efectos de los fármacos , Dolor Facial/tratamiento farmacológico , Ketamina/administración & dosificación , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Adyuvantes Anestésicos/administración & dosificación , Adyuvantes Anestésicos/efectos adversos , Administración Oral , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Analgésicos/efectos adversos , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/fisiopatología , Enfermedad Crónica , Vías de Administración de Medicamentos , Esquema de Medicación , Quimioterapia Combinada , Dolor Facial/metabolismo , Dolor Facial/fisiopatología , Femenino , Humanos , Hipnóticos y Sedantes/uso terapéutico , Inyecciones Intramusculares , Ketamina/efectos adversos , Masculino , Midazolam/administración & dosificación , Midazolam/efectos adversos , Persona de Mediana Edad , Dimensión del Dolor/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Pain and other phantom limb (PL) sensations have been proposed to be generated in the brain and to be reflected in activation of specific neural circuits. To test this hypothesis, hypnosis was used as a cognitive tool to alternate between the sensation of PL movement and pain in 8 amputees. Brain activity was measured using positron emission tomography. PL movement and pain were represented by a propagation of neuronal activity within the corresponding sensorimotor and pain-processing networks. The sensation of movement was significantly (corrected for multiple comparisons) related to activity in the supplementary motor area and the primary sensorimotor cortex. The sensation of a painful PL posture activated the same brain areas but was weaker and less extended in the supplementary motor area. In contrast to the sensation of movement, pain was significantly related to activity in the thalamus, anterior cingulate, and lateral prefrontal cortex. Subjectively rated PL pain sensation correlated positively to activations in the anterior and posterior cingulate. These findings provide evidence that PL sensations are produced by the same central nervous processes that underlie the experience of the body when it is intact and that the corporeal awareness of PL pain is encoded in a thalamocortical network.
Asunto(s)
Encéfalo/diagnóstico por imagen , Circulación Cerebrovascular/fisiología , Dolor/diagnóstico por imagen , Miembro Fantasma/diagnóstico por imagen , Sensación/fisiología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor/fisiopatología , Miembro Fantasma/fisiopatología , Tomografía Computarizada de EmisiónRESUMEN
UNLABELLED: 6-O(2-[18F]fluoroethyl)-6- -desmethyldiprenorphine ([18F]DPN) was developed and biologically evaluated. Results of animal experiments, binding studies in vivo, and a human PET study are reported and compared with those of [11C]DPN. METHODS: [18F]DPN was obtained by 18F-fluoroethylation of 3-O-trityl-6-O-desmethyldiprenorphine and subsequent deprotection in good radiochemical yields (23% +/- 7%; 100 min; 37 TBq/mmol). Binding of [18F]DPN to mu, kappa, and delta opioid receptors was shown by autoradiography studies on rat brain slices. Quantification of cerebral opioid receptor binding in men was performed by spectral analysis of a dynamic PET scan (25 frames, 90 min) after intravenous application of 63 MBq [18F]DPN (36 GBq/micromol) and correction for metabolites. RESULTS: [18F]DPN shows high affinity to opioid receptors. Parametric images (impulse response function at 60 min) of this human study showed a binding pattern of [18F]DPN equal to that of a control group (n = 9 healthy volunteers) after administration of [11C]DPN. CONCLUSION: The advantage of the longer half-life of 18F will allow extended scanning periods, more flexible interventions (e.g., displacement studies), and DPN to be available to PET centers without an on-site cyclotron.
Asunto(s)
Diprenorfina/análogos & derivados , Tomografía Computarizada de Emisión , Adulto , Anciano , Animales , Autorradiografía , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Diprenorfina/síntesis química , Diprenorfina/farmacocinética , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores Opioides/metabolismo , Distribución TisularAsunto(s)
Analgésicos/administración & dosificación , Alucinógenos/administración & dosificación , Ketamina/administración & dosificación , Analgésicos/efectos adversos , Alucinógenos/efectos adversos , Humanos , Ketamina/efectos adversos , Medios de Comunicación de Masas , Trastornos Relacionados con Sustancias/etiología , Trastornos Relacionados con Sustancias/psicologíaRESUMEN
Administration of the N-methyl-D-aspartate (NMDA) antagonist S-ketamine in normals produces a psychosis-like syndrome including several positive and negative symptoms of schizophrenic disorders (Abi-Saab WM, D'Souza DC, Moghaddam B, Krystal JH. The NMDA antagonist model for schizophrenia: promise and pitfalls. Pharmacopsychiatry 1998;31:104-109). Given the clinical efficacy of dopamine (DA) D2 receptor antagonists in the treatment of positive symptoms, it is conceivable that S-ketamine-induced psychotic symptoms are partially due to a secondary activation of dopaminergic systems. To date, animal and human studies of the effects of NMDA antagonists on striatal DA levels have been inconsistent. The present study used positron emission tomography (PET) to determine whether a psychotomimetic dose of S-ketamine decreases the in vivo binding of [11C]raclopride to striatal DA D2 receptors in humans (n = 8). S-ketamine elicited a psychosis-like syndrome, including alterations in mood, cognitive disturbances, hallucinations and ego-disorders. S-ketamine decreased [11C]raclopride binding potential (BP) significantly in the ventral striatum (-17.5%) followed by the caudate nucleus (-14.3%) and putamen (-13.6%), indicating an increase in striatal DA concentration. The change in raclopride BP in the ventral striatum correlated with heightened mood ranging from euphoria to grandiosity. These results provide evidence that the glutamatergic NMDA receptor may contribute to psychotic symptom formation via modulation of the DA system.
Asunto(s)
Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Antagonistas de Dopamina/efectos adversos , Antagonistas de Dopamina/farmacocinética , Antagonistas de Aminoácidos Excitadores/efectos adversos , Antagonistas de Aminoácidos Excitadores/farmacocinética , Ketamina/efectos adversos , Ketamina/farmacocinética , Psicosis Inducidas por Sustancias/diagnóstico por imagen , Racloprida/efectos adversos , Racloprida/farmacocinética , Receptores de Dopamina D2/efectos de los fármacos , Tomografía Computarizada de Emisión , Adulto , Unión Competitiva/fisiología , Núcleo Caudado/diagnóstico por imagen , Núcleo Caudado/metabolismo , Método Doble Ciego , Humanos , Masculino , Putamen/diagnóstico por imagen , Putamen/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresAsunto(s)
Dependencia de Heroína/tratamiento farmacológico , Inactivación Metabólica , Antagonistas de Narcóticos/administración & dosificación , Dependencia de Heroína/metabolismo , Dependencia de Heroína/rehabilitación , Humanos , Metadona/administración & dosificación , Antagonistas de Narcóticos/metabolismo , Antagonistas de Narcóticos/farmacocinética , Receptores Opioides/efectos de los fármacos , Receptores Opioides/metabolismoRESUMEN
We examined the role of N-methyl-D-aspartate (NMDA) receptors in chronic (pathological) pain in humans by using the NMDA receptor antagonist ketamine as a probe. Thirty patients with neuropathic pain in the trigeminal area were given an i.m. injection of ketamine 0.4 mg/kg combined with midazolam 0.05 mg/kg. Pethidine 1.0 mg/kg served as a control. Three different response patterns were observed. Ketamine caused a long-term (6-24 h) analgesic effect partly dissociated from the mental side effects in 8 of the 26 patients who completed the study; these patients also had a slight analgesic effect of pethidine. In nine patients, ketamine caused a short-lasting (<2 h) analgesic effect closely associated with the mental side effects, whereas pethidine caused little or no analgesia. The remaining nine patients did not experience any reduction of pain after either drug in spite of characteristic side effects. One week after the i.m. challenge the patients received either 4.0 mg/kg ketamine hydrochloride or placebo capsules to be taken orally as a nightly dose for three consecutive nights. Five of the eight patients who had a long-term analgesic effect of the i.m. challenge reported decreased pain on days after ketamine. None of the others reported an analgesic effect. The phenomenon of long-term depression of pain in a subgroup of patients was thus confirmed when ketamine was given p.o. These findings indicate that NMDA receptors are involved in the perception and maintenance of pathological pain in some patients. In others, pain appears to be mediated by NMDA receptor-independent mechanisms. We suggest that NMDA receptor-independent transmission in central pain pathways may contribute to the reduced efficiency of analgesic drugs often seen in chronic pain states.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/uso terapéutico , Ketamina/uso terapéutico , Dolor/tratamiento farmacológico , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Estudios Cruzados , Método Doble Ciego , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Femenino , Humanos , Inyecciones Intramusculares , Ketamina/administración & dosificación , Masculino , Persona de Mediana Edad , Dimensión del DolorRESUMEN
PURPOSE: To determine whether neurochemical activation of the N-methyl-D-aspartate (NMDA) receptor-gated ion channel shows quantitative changes, measured as binding of 11C-labeled (S)-[N-methyl]ketamine, in patients with medial temporal lobe epilepsy (MTLE). METHODS: Eight patients with MTLE who were evaluated regarding epilepsy surgery underwent positron emission tomography (PET) with (S)-[N-methyl-11C]ketamine. The presurgical investigations included magnetic resonance imaging (MRI), PET with 18F-fluoro-deoxyglucose (18FDG), and seizure monitoring by using video-EEG. The uptake of (S)-[N-methyl-11C]ketamine in the temporal lobe of ictal onset was compared with the contralateral side and correlated to changes in regional glucose metabolism measured by PET with 18FDG. RESULTS: (S)-[N-methyl-11C]ketamine rapidly reached the brain, and high radioactivities were measured in the striatum, thalamic nuclei, and cortical regions. Overall the brain uptake and regional binding potentials of (S)-[N-methyl-11C]ketamine were similar to measurements observed previously in healthy controls. However, 20 min after administration, when blood flow influence was negligible, a side-to-side comparison revealed a 9-34% reduction of tracer radioactivity in the temporal lobes of ictal onset. At earlier times, the differences in binding potentials were less pronounced, 9-21%. The magnitude and distribution of the reduction were similar to the metabolic pattern seen on PET scans with 18FDG. CONCLUSIONS: Radioactivity uptake of intravenously administered (S)-[N-methyl-11C]ketamine was reduced in temporal lobes of ictal in patients with TLE. This may reflect reduced NMDA-receptor density, reduced perfusion, focal atrophy, or other factors.
Asunto(s)
Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Epilepsia del Lóbulo Temporal/metabolismo , Ketamina , Receptores de N-Metil-D-Aspartato/metabolismo , Lóbulo Temporal/diagnóstico por imagen , Tomografía Computarizada de Emisión , Adulto , Radioisótopos de Carbono/metabolismo , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Electroencefalografía/estadística & datos numéricos , Epilepsia del Lóbulo Temporal/diagnóstico , Femenino , Fluorodesoxiglucosa F18 , Lateralidad Funcional , Glucosa/metabolismo , Humanos , Ketamina/química , Ketamina/metabolismo , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Lóbulo Temporal/metabolismo , Núcleos Talámicos/diagnóstico por imagen , Núcleos Talámicos/metabolismo , Grabación de Cinta de VideoAsunto(s)
Analgésicos/uso terapéutico , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Ketamina/uso terapéutico , Percepción/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Analgésicos/metabolismo , Arteriosclerosis/fisiopatología , Enfermedad Crónica , Antagonistas de Aminoácidos Excitadores/metabolismo , Humanos , Activación del Canal Iónico/efectos de los fármacos , Isquemia/fisiopatología , Ketamina/metabolismo , Pierna/irrigación sanguínea , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Fenciclidina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/fisiología , Sensación/efectos de los fármacosRESUMEN
Until recently, racemic ketamine (S-ketamine/R-ketamine = 50:50) has been used to study NMDA receptor hypofunction in relation to pathophysiological models of schizophrenia. Ketamine given to normal humans in subanesthetic doses produces a model psychosis including both positive and negative symptoms of schizophrenia. More recently it has been shown that at subanesthetic doses the pure (S)- and (R)-ketamine enantiomeres interact differently with the NMDA and sigma receptor sites in human brain. It was found that (S)-ketamine binds with a 3-4 time higher affinity to the PCP binding site of the NMDA receptor than (R)-ketamine, and that at these concentrations (R)-ketamine interacts also weakly with the sigma receptor sites, where (S)-ketamine binds only negligibly. To further investigate the role of NMDA-receptor mediated neurotransmission in schizophrenic psychosis, the effects of pure (S)- and (R)-ketamine enantiomeres on brain energy metabolism in normal humans using positron emission tomography and [18F]fluorodeoxyglucose (FDG) are reported here. Psychotomimetic doses of (S)-ketamine increased cerebral metabolic rates of glucose (CMRglu) markedly in the frontal cortex including the anterior cingulate, parietal and left sensorimotor cortex, and in the thalamus. The metabolic changes in the frontal and left temporal cortex correlated with ego-disintegration and hallucinatory phenomena. Equimolar doses of (R)-ketamine tended to decrease CMRglu across brain regions and significantly suppressed CMRglu in the temporomedial cortex and left insula. (R)-ketamine did not produce psychotic symptoms, but a state of relaxation. The (S)-ketamine-induced metabolic hyperfrontality appears to parallel similar metabolic findings in acute psychotic schizophrenic patients and encourages further investigations of glutamatergic disturbances in schizophrenia.
Asunto(s)
Química Encefálica/fisiología , Glucosa/metabolismo , Ketamina , Psicosis Inducidas por Sustancias/metabolismo , Psicosis Inducidas por Sustancias/psicología , Adulto , Química Encefálica/efectos de los fármacos , Corteza Cerebral/metabolismo , Femenino , Lateralidad Funcional/fisiología , Humanos , Ketamina/sangre , Cinética , Masculino , Escalas de Valoración Psiquiátrica , Psicometría , Estereoisomerismo , Tomografía Computarizada de EmisiónRESUMEN
We report the effect of a single daily dose of ketamine in a 54 year old woman with fibromyalgia and severe post-traumatic neuropathic pain. A number of different approaches for pain relief had been tried with little effect. An intramuscular test dose of 0.4 mg/kg ketamine combined with 0.05 mg/kg midazolam lead to analgesia which lasted for almost two days. Long-term analgesia was also obtained by 250 mg/kg ketamine hydrochloride taken orally in the form of capsules every night at bedtime. The patient has now used this dose for nine months. Ketamine is an NMDA receptor antagonist. A single sub-anaesthetic dose of ketamine causes a long-term depression of pain intensity in some, but not in all, patients suffering chronic pain. This effect is distinctly different from the short-lasting (10-30 min) analgesic effect in cases of acute nociceptive pain. The long-term depression of the intensity of chronic pain states may be due to a reversal of NMDA receptor-dependent long-term potentiation of synapses in central pain pathways. By giving ketamine as a single dose at night the mental side-effects are reduced or avoided.
Asunto(s)
Anestésicos Disociativos/administración & dosificación , Fibromialgia/tratamiento farmacológico , Ketamina/administración & dosificación , Dolor/tratamiento farmacológico , Administración Oral , Femenino , Humanos , Persona de Mediana Edad , Neuralgia/tratamiento farmacológico , Nociceptores/efectos de los fármacosRESUMEN
In order to elucidate the mechanisms of action of ketamine, we have investigated the binding of the chiral forms of ketamine to opioid (mu, delta and kappa), phencyclidine, sigma and muscarinic receptors and we have performed detailed concentration-response experiments in the guinea-pig ileum preparation. The affinity ratios for the chiral forms at phencyclidine, mu and kappa receptors correlated with the potency ratio of the chiral forms in the ischaemic pain test found previously. The affinities were highest for phencyclidine receptors. The affinities for muscarinic receptors were lower than for phencyclidine receptors by a factor of about 10-20. The concentration-response experiments revealed one opioid (naloxone sensitive) and one non-opioid component. The two component are very close, which explains why other authors have reported that naloxone antagonizes the ketamine effect only partly. The concentrations of naloxone necessary to shift the opioid part of the curves indicate that ketamine is a kappa agonist in the guinea-pig ileum preparation. We conclude that the analgesic effect of ketamine in humans is most probably mediated via phencyclidine receptors, although a kappa effect can not be excluded. Binding to kappa and muscarinic receptors may contribute to the psychotomimetic side effects seen during recovery from ketamine anaesthesia.
Asunto(s)
Anestésicos Disociativos/farmacología , Anestésicos Intravenosos/farmacología , Ketamina/farmacología , Receptores Muscarínicos/metabolismo , Receptores Opioides/metabolismo , Receptores de Fenciclidina/metabolismo , Anestésicos Disociativos/administración & dosificación , Anestésicos Disociativos/farmacocinética , Anestésicos Intravenosos/farmacocinética , Animales , Sitios de Unión , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Cobayas , Íleon/efectos de los fármacos , Íleon/fisiología , Técnicas In Vitro , Ketamina/administración & dosificación , Ketamina/farmacocinética , Masculino , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Ensayo de Unión Radioligante , EstereoisomerismoRESUMEN
Plasma concentrations, maximum regional brain concentrations, and specific regional binding in the brain after administration of 0, 0.1, and 0.2 mg/kg doses of (S)-ketamine were measured in a randomized, double-blind, crossover study in five volunteers and were related to induced effects such as analgesia, amnesia, and mood changes. Specific binding in the brain was assessed by simultaneous administration of (S)-[N-methyl-11C]ketamine quantified by positron emission tomography. High radioactivities in the brain corresponded to regional distribution of N-methyl-D-aspartate receptor complexes. A significant and dose-dependent reduction of binding was measured as a result of displacement of (S)-[N-methyl-11C]ketamine. Memory impairment and psychotomimetic effects were related to dose, plasma concentration 4 minutes after administration, and decreased regional binding of (S)-ketamine in the brain and were consistently seen at plasma and maximum regional brain (S)-ketamine concentrations higher than 70 and 500 ng/ml, respectively. The magnitude of specific binding of (S)-ketamine, measured with positron emission tomography, can be related directly to drug effects.
Asunto(s)
Encéfalo/metabolismo , Ketamina/administración & dosificación , Ketamina/farmacología , Tomografía Computarizada de Emisión , Adulto , Afecto/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Ketamina/sangre , Ketamina/farmacocinética , Masculino , Memoria/efectos de los fármacos , Persona de Mediana Edad , Dolor/prevención & control , Valores de Referencia , Distribución TisularRESUMEN
The regional brain kinetics of the two enantiomers of the NMDA channel blocker ketamine radiolabelled with 11C was studied in the Rhesus monkey by means of positron emission tomography (PET). The uptake in brain areas which showed high radioactivities was blocked in a dose-dependent manner for both 11C-labelled enantiomers with simultaneous doses of the respective unlabelled (S)- or (R)-ketamine, indicating specific binding. The binding in the striatum and cortical areas of (S)-[N-methyl-11C]ketamine was selective and displaceable by the (R)-enantiomer and by MK-801.