RESUMEN
BACKGROUND: The use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment for survivors of out of hospital cardiac arrest. However, this type of therapy is cumbersome and associated with several side-effects. We investigated the feasibility of using a transient receptor potential vanilloid type 1 (TRPV1) agonist for obtaining drug-induced sustainable mild hypothermia. METHODS: First, we screened a heterogeneous group of TRPV1 agonists and secondly we tested the hypothermic properties of a selected candidate by dose-response studies. Finally we tested the hypothermic properties in a large animal. The screening was in conscious rats, the dose-response experiments in conscious rats and in cynomologus monkeys, and the finally we tested the hypothermic properties in conscious young cattle (calves with a body weight as an adult human). The investigated TRPV1 agonists were administered by continuous intravenous infusion. RESULTS: Screening: Dihydrocapsaicin (DHC), a component of chili pepper, displayed a desirable hypothermic profile with regards to the duration, depth and control in conscious rats. Dose-response experiments: In both rats and cynomologus monkeys DHC caused a dose-dependent and immediate decrease in body temperature. Thus in rats, infusion of DHC at doses of 0.125, 0.25, 0.50, and 0.75 mg/kg/h caused a maximal ΔT (°C) as compared to vehicle control of -0.9, -1.5, -2.0, and -4.2 within approximately 1 hour until the 6 hour infusion was stopped. Finally, in calves the intravenous infusion of DHC was able to maintain mild hypothermia with ΔT > -3°C for more than 12 hours. CONCLUSIONS: Our data support the hypothesis that infusion of dihydrocapsaicin is a candidate for testing as a primary or adjunct method of inducing and maintaining therapeutic hypothermia.
Asunto(s)
Capsaicina/análogos & derivados , Hipotermia Inducida , Paro Cardíaco Extrahospitalario/terapia , Animales , Capsaicina/administración & dosificación , Capsaicina/farmacología , Bovinos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Infusiones Intravenosas , Macaca fascicularis , Paro Cardíaco Extrahospitalario/fisiopatología , Ratas , Ratas Sprague-Dawley , Resucitación/métodos , Canales Catiónicos TRPV/agonistas , Canales de Potencial de Receptor Transitorio/agonistasRESUMEN
BACKGROUND: Survivors of a cardiac arrest often have persistent cardiovascular derangements following cardiopulmonary resuscitation including decreased cardiac output, arrhythmias and morphological myocardial damage. These cardiovascular derangements may lead to an increased susceptibility towards the external and internal environment of the cardiovascular system as compared to the healthy situation. METHODS: Here we tested the hypothesis that the cardiovascular system in healthy rats and rats resuscitated from a cardiac arrest may be differentially affected by a transient receptor potential vanilloid type 1 agonist, by continuous intravenous infusion of dihydrocapsaicin (DHC). RESULTS: Compared to baseline, infusion of DHC caused an initial increase in mean arterial blood pressure in both healthy and resuscitated rats of 25% and 10%, respectively. Also, we observed an initial response of tachycardia in both healthy and resuscitated rats of 30% and 20%, respectively. Then, at high levels of DHC infusion (> 2.0 mg/kg/hr) we observed two single episodes of transient bradycardia and hypotension in 33% of the healthy rats, which was consistent with a TRPV1 agonist induced Bezold-Jarisch reflex. In contrast, in resuscitated rats we observed multiple episodes of bradycardia/hypotension in 100% of the rats and at a dose of DHC of 0.65 mg/kg/hr. Notably, this DHC effect could be completely blocked in the resuscitated rats by pre-treatment with atropine, a muscarinic acetylcholine antagonist. CONCLUSIONS: Our results indicate that the susceptibility of the rats towards TRPV1 agonist induced Bezold-Jarisch reflex is increased in those resuscitated from cardiac arrest compared to the healthy situation.
Asunto(s)
Capsaicina/análogos & derivados , Paro Cardíaco/tratamiento farmacológico , Resucitación , Animales , Arritmias Cardíacas , Capsaicina/administración & dosificación , Capsaicina/efectos adversos , Capsaicina/farmacología , Gasto Cardíaco Bajo , Modelos Animales de Enfermedad , Cardioversión Eléctrica , Paro Cardíaco/fisiopatología , Humanos , Infusiones Intravenosas , Masculino , Ratas , Ratas Sprague-Dawley , Canales Catiónicos TRPV/agonistas , Canales de Potencial de Receptor Transitorio/agonistasRESUMEN
The low density of cerebellar dopamine D(2)/D(3) receptors provides the basis for using the cerebellum as a representation of free- and non-specifically bound radioligand in positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies. With the development of ultra high-affinity dopamine D(2)/D(3) ligands like [(123)I]epidepride, [(18)F]fallypride, and [(11)C]FLB-457, quantification of extrastriatal low density receptor populations including the cerebellum is possible with important implications for calculation of binding parameters. [(123)I]epidepride-SPECT was performed in 23 patients with schizophrenia before and after 3 months of antipsychotic treatment with either risperidone (n=14) or zuclopenthixol (n=9). In the unblocked situation and partially blocked situation, the average distribution volumes were 5.2+/-1.3 mL/mL and 4.0+/-0.8 mL/mL, respectively. The paired distribution volumes were reduced by 22+/-15% (mean+/-SD) after antipsychotic treatment (p<0.0001, paired Student's t-test). From the paired distribution volumes in cerebellum and extrastriatal regions, the average distribution volume representing free and non-specifically bound [(123)I]epidepride was calculated to be 3.3+/-0.8 mL/mL. Both the % [(123)I]epidepride fraction of plasma radioactivity (p>0.76) and the plasma [(123)I]epidepride concentration (p>0.45) were unchanged after antipsychotic treatment (paired Student's t-test). These results strongly suggest the presence of "non-negligible" specific [(123)I]epidepride binding to dopamine D(2)/D(3) receptors in the cerebellum. Using the cerebellum as a representation of free and non-specifically bound radioligand and neglecting the specifically bound component may lead to results that erroneously imply that antipsychotic drugs bind to extrastriatal dopamine D(2)/D(3) receptors with a higher affinity than to striatal dopamine D(2)/D(3) receptors.
Asunto(s)
Benzamidas/farmacocinética , Cerebelo/metabolismo , Radioisótopos de Yodo , Pirrolidinas/farmacocinética , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Adulto , Unión Competitiva , Cerebelo/diagnóstico por imagen , Humanos , Cinética , Radiografía , Ensayo de Unión Radioligante/métodos , Valores de Referencia , Tomografía Computarizada de Emisión de Fotón Único/métodosRESUMEN
BACKGROUND: The aim of the study was to examine extrastriatal dopamine D(2/3) receptor binding and psychopathology in schizophrenic patients, and to relate binding potential (BP) values to psychopathology. METHODS: Twenty-five drug-naive schizophrenic patients and 20 healthy controls were examined with single-photon emission computerized tomography (SPECT) using the D(2/3)-receptor ligand [123I]epidepride. RESULTS: In the hitherto largest study on extrastriatal D(2/3) receptors we detected a significant correlation between frontal D(2/3) BP values and positive schizophrenic symptoms in the larger group of male schizophrenic patients, higher frontal BP values in male (n = 17) compared to female (n = 8) patients, and - in accordance with this - significantly fewer positive schizophrenic symptoms in the female patients. No significant differences in BP values were observed between patients and controls; the patients, however, had significantly higher BP in the right compared to the left thalamus, whereas no significant hemispheric imbalances were observed in the healthy subjects. CONCLUSIONS: The present data are the first to confirm a significant correlation between frontal D(2/3) receptor BP values and positive symptoms in male schizophrenic patients. They are in agreement with the hypothesis that frontal D(2/3) receptor activity is significant for positive psychotic symptoms. Additionally, the data support a thalamic hemispheric imbalance in schizophrenia.
Asunto(s)
Lóbulo Frontal/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Esquizofrenia/metabolismo , Psicología del Esquizofrénico , Caracteres Sexuales , Adulto , Benzamidas/farmacocinética , Mapeo Encefálico , Escalas de Valoración Psiquiátrica Breve/estadística & datos numéricos , Estudios de Casos y Controles , Medios de Contraste/farmacocinética , Femenino , Lóbulo Frontal/diagnóstico por imagen , Lóbulo Frontal/efectos de los fármacos , Humanos , Isótopos de Yodo/farmacocinética , Masculino , Pirrolidinas/farmacocinética , Esquizofrenia/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único/métodosRESUMEN
The iodinated cocaine derivative [(123)I]PE2I is a new selective ligand for in vivo studies of the dopamine transporter (DAT) with single-photon emission tomography (SPET). The aim of the present study was to describe a method for accurate quantification of binding data following a bolus injection of [(123)I]PE2I. Six healthy subjects (age 51+/-24 years) underwent xenon-133 SPET for quantification of regional CBF and [(123)I]PE2I SPET for quantification of DAT binding. rCBFs were within normal limits in all subjects. Fitting data to a two-tissue compartment model resulted in striatal K(1) values of 0.39+/-0.08 ml ml(-1) min(-1), equal to a first-pass extraction fraction of 0.72+/-0.13. Distribution volumes (DVs) were calculated using compartment analysis, area under the curve analysis and Logan analysis. Logan analysis is preferred since stable DV values were already obtained 120 min after [(123)I]PE2I injection. Mean striatal DV was 37.9+/-9.6 ml ml(-1) and mean occipital cortex DV was 5.5+/-0.7 ml ml(-1). In the absence of local pathology in a reference tissue, Logan analysis without blood sampling is an attractive method for accurate quantification of striatal [(123)I]PE2I binding. The distribution volume ratio (DVR) (6.6+/-1.4) was in good agreement with the DVR calculated with blood (6.7+/-1.4).