RESUMO
INTRODUCTION: There is a crucial need to perform clinical trials in pediatrics due to an increased prescription rate of unapproved drugs. Since pediatricians are the gatekeepers of clinical trials, the primary objective of the current study was to evaluate, for the first time in France, pediatricians' views on performing clinical trials. The second objective was to identify the factors that influence their perceptions. MATERIAL AND METHODS: In 2017, pediatricians who were members of the French Pediatric Society completed an online survey comprising 27 questions. Fisher's exact test was performed to evaluate possible correlations between pediatrician characteristics (age, sex, parenthood, professional experience, status, type of practice, previous participation in clinical trials, ethics education) and personal views on clinical trials. A value of P≤0.001 was considered statistically significant. RESULTS: Overall, 207 pediatricians completed the questionnaire. Almost all participants (96.6%) were in favor of performing clinical trials. Pediatricians with teaching experience at university hospitals were more reluctant to propose children's participation in clinical trials for fear of increasing parental stress (P<0.001), or the occurrence of serious adverse reactions (P<0.001). Pediatricians with coordinator or investigator experience considered that one of the ethical drifts in pediatric clinical trials is the risk of child exploitation (P<0.001). CONCLUSION: Our findings suggest a favorable position of pediatricians concerning clinical trials, despite numerous concerns. Another outcome is the need to create an educational system of research in ethics in France dedicated to pediatricians in order to guarantee good clinical practice in research.
Assuntos
Ensaios Clínicos como Assunto/economia , Ensaios Clínicos como Assunto/normas , Conflito de Interesses , Indústria Farmacêutica/ética , Pediatras/psicologia , Adulto , Atitude do Pessoal de Saúde , Ensaios Clínicos como Assunto/ética , Indústria Farmacêutica/normas , Indústria Farmacêutica/tendências , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Pediatras/estatística & dados numéricos , Padrões de Prática Médica/normas , Padrões de Prática Médica/estatística & dados numéricos , Inquéritos e QuestionáriosRESUMO
Basic studies exploring the importance of the cyclic adenosine monophosphate (cAMP) cascade in major depressive disorder (MDD) have noted that the cAMP cascade is downregulated in MDD and upregulated by antidepressant treatment. We investigated cAMP cascade activity by using 11C-(R)-rolipram to image phosphodiesterase-4 (PDE4) in unmedicated MDD patients and after ~8 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI). 11C-(R)-rolipram positron emission tomographic (PET) scans were performed in 44 unmedicated patients during a major depressive episode and 35 healthy controls. Twenty-three of the 44 patients had a follow-up 11C-(R)-rolipram PET scan ~8 weeks after treatment with an SSRI. Patients were moderately depressed (Montgomery-Åsberg Depression Rating Scale=30±6) and about half were treatment naïve. 11C-(R)-rolipram binding was measured using arterial sampling to correct for individual differences in radioligand metabolism. We found in unmedicated MDD patients widespread, ~20% reductions in 11C-(R)-rolipram binding compared with controls (P=0.001). SSRI treatment significantly increased rolipram binding (12%, P<0.001), with significantly greater increases observed in older patients (P<0.001). Rolipram binding did not correlate with severity of baseline symptoms, and increased rolipram binding during treatment did not correlate with symptom improvement. In brief, consistent with the results of basic studies, PDE4 was decreased in unmedicated MDD patients and increased after SSRI treatment. The lack of correlation between PDE4 binding and depressive symptoms could reflect the heterogeneity of the disease and/or the heterogeneity of the target, given that PDE4 has four subtypes. These results suggest that PDE4 inhibitors, which increase cAMP cascade activity, may have antidepressant effects.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , AMP Cíclico/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Adulto , Antidepressivos/uso terapêutico , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono , Estudos de Casos e Controles , Depressão/diagnóstico por imagem , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 4/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Rolipram/farmacocinética , Transdução de Sinais/efeitos dos fármacosRESUMO
Brain cannabinoid CB1 receptors contribute to alcohol-related behaviors in experimental animals, but their potential role in humans with alcohol dependence is poorly understood. We measured CB1 receptors in alcohol dependent patients in early and protracted abstinence, and in comparison with control subjects without alcohol use disorders, using positron emission tomography and [(18)F]FMPEP-d2, a radioligand for CB1 receptors. We scanned 18 male in-patients with alcohol dependence twice, within 3-7 days of admission from ongoing drinking, and after 2-4 weeks of supervised abstinence. Imaging data were compared with those from 19 age-matched healthy male control subjects. Data were also analyzed for potential influence of a common functional variation (rs2023239) in the CB1 receptor gene (CNR1) that may moderate CB1 receptor density. On the first scan, CB1 receptor binding was 20-30% lower in patients with alcohol dependence than in control subjects in all brain regions and was negatively correlated with years of alcohol abuse. After 2-4 weeks of abstinence, CB1 receptor binding remained similarly reduced in these patients. Irrespective of the diagnostic status, C allele carriers at rs2023239 had higher CB1 receptor binding compared with non-carriers. Alcohol dependence is associated with a widespread reduction of cannabinoid CB1 receptor binding in the human brain and this reduction persists at least 2-4 weeks into abstinence. The correlation of reduced binding with years of alcohol abuse suggests an involvement of CB1 receptors in alcohol dependence in humans.
Assuntos
Alcoolismo/metabolismo , Encéfalo/metabolismo , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Adulto , Alcoolismo/diagnóstico por imagem , Alelos , Encéfalo/diagnóstico por imagem , Estudos de Casos e Controles , Neuroimagem Funcional , Humanos , Masculino , CintilografiaRESUMO
Chronic cannabis (marijuana, hashish) smoking can result in dependence. Rodent studies show reversible downregulation of brain cannabinoid CB(1) (cannabinoid receptor type 1) receptors after chronic exposure to cannabis. However, whether downregulation occurs in humans who chronically smoke cannabis is unknown. Here we show, using positron emission tomography imaging, reversible and regionally selective downregulation of brain cannabinoid CB(1) receptors in human subjects who chronically smoke cannabis. Downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After â¼4 weeks of continuously monitored abstinence from cannabis on a secure research unit, CB(1) receptor density returned to normal levels. This is the first direct demonstration of cortical cannabinoid CB(1) receptor downregulation as a neuroadaptation that may promote cannabis dependence in human brain.
Assuntos
Regulação para Baixo/efeitos dos fármacos , Neuroimagem Funcional/psicologia , Fumar Maconha/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Adulto , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Radioisótopos de Flúor , Neuroimagem Funcional/métodos , Humanos , Masculino , Tomografia por Emissão de Pósitrons/métodos , Tomografia por Emissão de Pósitrons/psicologia , Pirrolidinonas , Síndrome de Abstinência a Substâncias/metabolismo , Fatores de TempoRESUMO
P-glycoprotein (P-gp), an efflux transporter, controls the pharmacokinetics of various compounds under physiological conditions. P-gp-mediated drug efflux has been suggested as playing a role in various disorders, including multidrug-resistant cancer and medication-refractory epilepsy. However, P-gp inhibition has had, to date, little or no clinically significant effect in multidrug-resistant cancer. To enhance our understanding of its in vivo function under pathophysiological conditions, substrates of P-gp have been radiolabeled and imaged using single-photon emission computed tomography (SPECT) and positron emission tomography (PET). To accurately quantify P-gp function, a radiolabeled P-gp substrate should be selective for P-gp, produce a large signal after P-gp blockade, and generate few radiometabolites that enter the target tissue. Furthermore, quantification of P-gp function via imaging requires pharmacological inhibition of P-gp, which requires knowledge of P-gp density at the target site. By meeting these criteria, imaging can elucidate the function of P-gp in various disorders and improve the efficacy of treatments.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Compostos Radiofarmacêuticos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Transporte Biológico/fisiologia , Barreira Hematoencefálica/metabolismo , Resistência a Múltiplos Medicamentos , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Humanos , Modelos Biológicos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Farmacocinética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/farmacocinética , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
Nicotine and other constituents of tobacco smoke elevate dopamine (DA) and serotonin (5-HT) levels in brain and may cause homeostatic adaptations in DA and 5-HT transporters. Since sex steroids alter DA and 5-HT transporter expression, the effects of smoking on DA and 5-HT transporter availability may differ between sexes. In the present study, DA and 5-HT transporter availabilities were quantitated using single photon emission computed tomography (SPECT) imaging approximately 22 h after bolus administration of [123I]beta-CIT, an analog of cocaine which labels DA and 5-HT transporters. Forty-two subjects including 21 pairs of age-, race-, and gender-matched healthy smokers and nonsmokers (12 female and 9 male pairs) were imaged. Regional uptake was assessed by the outcome measures, V3", which is the ratio of specific (i.e., ROI-cerebellar activity) to nondisplaceable (cerebellar) activity, and V3, the ratio of specific to free plasma parent. Overall, striatal and diencephalic [123I]beta-CIT uptake was not altered by smoking, whereas brainstem [123I]beta-CIT uptake was modestly higher (10%) in smokers vs. nonsmokers. When subgrouped by sex, regardless of smoking status, [123I]beta-CIT uptake was higher in the striatum (10%), diencephalon (15%), and brainstem (15%) in females vs. males. The sex*smoking interaction was not significant in the striatum, diencephalon, or brainstem, despite the observation of 20% higher brainstem [123I]beta-CIT uptake in male smokers vs. nonsmokers and less than a 5% difference between female smokers and nonsmokers. The results demonstrate higher DA and 5-HT transporter availability in females vs. males and no overall effect of smoking with the exception of a modest elevation in brainstem 5-HT transporters in male smokers. Although these findings are preliminary and need validation with a more selective 5-HT transporter radiotracer, the results suggest that brainstem 5-HT transporters may be regulated by smoking in a sex-specific manner.
Assuntos
Proteínas de Transporte/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Caracteres Sexuais , Fumar , Tomografia Computadorizada de Emissão de Fóton Único , Adulto , Afeto/fisiologia , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/metabolismo , Cocaína/análogos & derivados , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Humanos , Radioisótopos do Iodo , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
The test/retest reproducibility of brain measures of 5-HT2A receptors with positron emission tomography (PET) and [18F]deuteroaltanserin was examined in a group of eight healthy human subjects. PET measures of 5-HT2A receptors were obtained under an equilibrium paradigm, with a 40-min PET acquisition starting approximately at 300 min (308+/-11 min) after bolus plus constant infusion of the radiotracer. Three brain outcome measures were obtained at equilibrium, V(3) (ratio of specific brain uptake to free parent plasma concentration of radiotracer), V(3)' (ratio of specific brain uptake to total parent plasma concentration) and RT (ratio of specific to non-displaceable brain uptakes). V(3)' and RT had high test/retest reproducibility, as measured by mean intra-subject% change for cortical brain areas of 14.1 and 11.0%, respectively. They also had high reliability, as measured by mean intra-class correlation coefficients (ICC) for cortical brain areas of 0.86 and 0.88, respectively. V(3) had low test/retest reproducibility, due to high variability in the measures of free parent tracer in plasma. This study supports the feasibility of equilibrium imaging of 5-HT2A receptors with PET and [18F]deuteroaltanserin. The equilibrium imaging method with [18F]deuteroaltanserin allows a single acquisition and blood measurement to provide an image whose pixel values equal a receptor volume of distribution. Since the single image pixel values are proportional to receptor densities, the images can be used in pixel-by-pixel statistical methods, such as SPM, to assess the distribution and density of 5-HT2A receptors in neuropsychiatric disorders.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de Flúor , Ketanserina/análogos & derivados , Modelos Neurológicos , Receptores de Serotonina/metabolismo , Tomografia Computadorizada de Emissão , Adulto , Idoso , Cromatografia Líquida de Alta Pressão , Estudos de Viabilidade , Feminino , Radioisótopos de Flúor/administração & dosagem , Radioisótopos de Flúor/sangue , Humanos , Infusões Intravenosas , Ketanserina/administração & dosagem , Ketanserina/sangue , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos TestesRESUMO
UNLABELLED: Nicotinic acetylcholine receptors (nAChRs) play an important role in tobacco dependence and a potential therapeutic role in neuropsychiatric disorders such as Alzheimer's disease. [123I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) is a new SPECT tracer that labels alpha4beta2 nAChRs. The purpose of this study was to assess the usefulness of this tracer to measure regional nAChR binding in baboon brain using both a bolus/kinetic paradigm and also a bolus plus constant infusion/equilibrium paradigm. METHODS: A pair of bolus/kinetic and bolus plus constant infusion/equilibrium studies was performed in each of 3 isoflurane-anesthetized baboons. Bolus studies were performed by intravenous injection of 191-226 MBq [123I]5-I-A-85380 and image acquisition for 289-367 min. The data were analyzed with 1- and 2-tissue compartment models. Bolus plus constant infusion/equilibrium studies were performed by a bolus injection (74-132 MBq) followed by a 468- to 495-min infusion with a bolus/infusion ratio (B/I) of 4.8-5.0 h. The distribution volumes in the thalamus were measured in these 2 paradigms. To study whether the cerebellum was appropriate as a receptor-poor region, displacement studies were done in 2 baboons using the B/I paradigm with subcutaneous injection of (-)-cytisine (0.8 and 1.0 mg/kg). RESULTS: The kinetics of this tracer was best described by the 1-tissue compartment model. The 2-compartment model showed poor identifiability of rate constants. The total (specific plus nondisplaceable compartments) distribution volumes (V(T)') agreed between bolus and B/I paradigms (average percentage difference in V(T)', 16.8%). (-)-Cytisine (0.8 and 1.0 mg/kg) displaced 70% and 72% of the radioactivity in the thalamus and 36% and 55% in the cerebellum, respectively, indicating that the latter was not appropriate as a receptor-poor region. CONCLUSION: These results show the feasibility of quantifying alpha4beta2 nAChRs using [123I]5-I-A-85380 and support the use of V(T)' as an appropriate outcome measure.
Assuntos
Azetidinas/farmacocinética , Encéfalo/metabolismo , Radioisótopos do Iodo/farmacocinética , Receptores Nicotínicos/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Alcaloides/farmacologia , Animais , Azetidinas/administração & dosagem , Azocinas , Ligação Competitiva , Encéfalo/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Cerebelo/metabolismo , Processamento de Imagem Assistida por Computador , Infusões Intravenosas , Injeções Intravenosas , Radioisótopos do Iodo/administração & dosagem , Cinética , Análise dos Mínimos Quadrados , Imageamento por Ressonância Magnética , Papio , Quinolizinas , Receptores Nicotínicos/análise , Tálamo/diagnóstico por imagem , Tálamo/metabolismoRESUMO
OBJECTIVE: Evidence of a relationship between genotype and binding availability was assessed for the dopamine and serotonin transporter genes. METHOD: The authors assessed dopamine transporter genotype at the SLC6A3 3' variable number of tandem repeats (VNTR) polymorphism and serotonin transporter genotype at the SLC6A4 promotor VNTR polymorphism in 30 healthy subjects who also underwent single photon emission computed tomography with [(123)I]beta-CIT. RESULTS: Subjects homozygous for the 10-repeat allele at the SLC6A3 locus demonstrated significantly lower dopamine transporter binding than carriers of the nine-repeat allele. There was no effect of SLC6A4 genotype upon serotonin transporter binding. CONCLUSIONS: These findings suggest that genetic variation at the SLC6A3 3' VNTR polymorphism may modify dopamine transporter function.
Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Dopamina/genética , Dopamina/metabolismo , Genótipo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Adulto , Proteínas de Transporte/isolamento & purificação , DNA/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/isolamento & purificação , Repetições Minissatélites/genética , Reação em Cadeia da Polimerase , Polimorfismo Genético/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
UNLABELLED: This study evaluated the test-retest reproducibility of D2 receptor quantification in the thalamus and temporal cortex using [123I]epidepride SPECT. METHODS: Ten healthy volunteers (4 men, 6 women; age range, 19-46 y) underwent 2 SPECT studies (interval, 2-26 d) using a bolus-plus-constant-infusion paradigm (bolus-to-infusion ratio = 6 h; infusion time = 9 h). Plasma clearance (in liters per hour) and free fraction (f1) of the parent tracer were measured. Radioactivity (in becquerels per gram) in the thalamus, temporal cortex, and cerebellum were normalized to the infusion rate (in becquerels per hour). Normalized striatal radioactivity was also measured to assess reproducibility in regions with a high density of receptors and better counting statistics. The outcome measures obtained were V3 (receptor density [Bmax]/equilibrium dissociation constant [KD]), V3' (f1 x Bmax/KD), and RT (specific-to-nondisplaceable tissue ratio). RESULTS: Test-retest variability and reliability (intraclass correlation coefficient) were 10.8% and 0.88, respectively, for plasma clearance and 15.3% and 0.77, respectively, for f1. The test-retest variability of brain-specific (target minus nondisplaceable) radioactivity was higher in the thalamus and temporal cortex than in the striatum, although reliability was comparable. Among the outcome measures, V3' showed better test-retest variability and reliability in the thalamus (13.3% and 0.75, respectively) and temporal cortex (13.4% and 0.86, respectively). CONCLUSION: Brain radioactivity was the main source of variability for quantification of extrastriatal D2 receptors with [123I]epidepride. The reproducibility of outcome measures in extrastriatal regions was good. However, because receptor density was lower in extrastriatal regions than in the striatum, the counting statistics in these regions were low and reproducibility was affected by the higher test-retest variability of brain-specific radioactivity. Compared with V3 and V3', RT showed less test-retest variability in the thalamus and temporal cortex but lower reliability. Moreover, measurement of RT may be affected by the presence of potential lipophilic metabolites entering the brain.
Assuntos
Benzamidas/farmacocinética , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos do Iodo/farmacocinética , Pirrolidinas/farmacocinética , Receptores de Dopamina D2/análise , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Adulto , Cerebelo/diagnóstico por imagem , Cerebelo/metabolismo , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Reprodutibilidade dos Testes , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/metabolismo , Tálamo/diagnóstico por imagem , Tálamo/metabolismoRESUMO
Postmortem studies have provided limited and conflicting data regarding aging effects on the central serotonin transporter (SERT). The present study investigated the effect of age on SERT availability in the human brainstem and diencephalon with single photon emission computed tomography (SPECT) using the ligand [(123)I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([(123)I]beta-CIT). Healthy control subjects (n = 126) who ranged in age from 18 to 88 were injected with 6.0 +/- 0.8 (mean +/- SD) mCi [(123)I]beta-CIT and imaged 23.1 +/- 1.9 h later under equilibrium conditions. A ratio of specific to nondisplaceable brain uptake (i.e. , V(3)" = [brainstem-diencephalon -occipital]/occipital), a measure proportional to the binding potential (B(max)/K(D)), was derived. SERT availability (V(3)") showed a significant inverse correlation with age (r = -0.40, P < 0.0001). Linear regression analysis revealed that V(3)" declined by 29.5% over the age range 18 to 88, or approximately 4.2% per decade. These results demonstrate reductions in the availability of central SERT binding sites with age in living human subjects.
Assuntos
Envelhecimento/metabolismo , Química Encefálica/fisiologia , Proteínas de Transporte/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Tomografia Computadorizada de Emissão de Fóton Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Tronco Encefálico/química , Tronco Encefálico/fisiologia , Cocaína/análogos & derivados , Diencéfalo/química , Diencéfalo/fisiologia , Feminino , Humanos , Radioisótopos do Iodo , Masculino , Pessoa de Meia-Idade , Valores de Referência , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
OBJECTIVE: Increased dopaminergic neurotransmission has been implicated in the pathophysiology of bipolar disorder. However, it remains unclear whether the abnormality is due to increased dopamine release or enhanced postsynaptic receptor sensitivity. In this study, dopamine receptor imaging combined with a pharmacological challenge of amphetamine was used to assess both pre- and postsynaptic aspects of dopamine neurotransmission in euthymic bipolar disorder patients. METHOD: Thirteen patients with bipolar disorder (seven medication free and six receiving mood stabilizer therapy) who had been euthymic for more than 4 weeks and 13 age- and gender-matched healthy comparison subjects were included in the study. Single photon emission computed tomography scans were obtained with the striatal dopamine (D(2)/D(3)) receptor radiotracer iodobenzamide ([(123)I]IBZM) before and after an intravenous amphetamine challenge (0.3 mg/kg). Reduction in striatal [(123)I]IBZM binding potential from the first scan to the second scan was used as an indirect measure of the amount of dopamine released. Behavioral response to amphetamine was measured with the Brief Psychiatric Rating Scale, Young Mania Rating Scale, and visual analogue scales. RESULTS: Bipolar patients and healthy subjects did not differ in terms of mood state or striatal D(2) receptor binding at baseline. Amphetamine challenge led to a significantly greater behavioral response in bipolar patients than in healthy subjects. However, there was no significant difference between the two groups in the amphetamine-induced decrease in striatal [(123)I]IBZM binding. CONCLUSIONS: In a group of euthymic patients with bipolar disorder, this study did not find evidence for increased striatal dopamine release. Instead, these data are consistent with enhanced postsynaptic dopamine responsivity in patients with bipolar disorder.
Assuntos
Anfetamina/farmacologia , Transtorno Bipolar/fisiopatologia , Encéfalo/diagnóstico por imagem , Dopamina/metabolismo , Receptores Dopaminérgicos/efeitos dos fármacos , Tomografia Computadorizada de Emissão de Fóton Único , Adulto , Benzamidas/metabolismo , Transtorno Bipolar/diagnóstico por imagem , Transtorno Bipolar/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Antagonistas de Dopamina/metabolismo , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Radioisótopos do Iodo/metabolismo , Masculino , Pulso Arterial , Pirrolidinas/metabolismo , Receptores Dopaminérgicos/metabolismoRESUMO
OBJECTIVE: Animals exposed to stress exhibit a decrease in benzodiazepine receptor binding in the frontal cortex. No studies have examined central benzodiazepine receptor binding in patients with posttraumatic stress disorder (PTSD). The purpose of this study was to examine measures of benzodiazepine receptor binding in PTSD. METHOD: From 13 patients with Vietnam combat-related PTSD and 13 case-matched healthy comparison subjects, a quantitative measure related to benzodiazepine receptor binding (distribution volume) was obtained with single photon emission computed tomography (SPECT) imaging of [(123)I]iomazenil binding and measurement of radioligand concentration in plasma. Distribution volume image data were analyzed by means of statistical parametric mapping. RESULTS: Lower distribution volumes were found in the prefrontal cortex (Brodmann's area 9) of PTSD patients than in comparison subjects. CONCLUSIONS: These findings of lower values for the benzodiazepine receptor binding measure of distribution volume are consistent with fewer benzodiazepine receptors and/or reduced affinity of receptor binding in the medial prefrontal cortex in patients with PTSD. Alterations in benzodiazepine receptor function in this area may underlie many of the symptoms of PTSD.
Assuntos
Distúrbios de Guerra/diagnóstico , Córtex Pré-Frontal/metabolismo , Receptores de GABA-A/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/estatística & dados numéricos , Adulto , Escalas de Graduação Psiquiátrica Breve/estatística & dados numéricos , Distúrbios de Guerra/metabolismo , Distúrbios de Guerra/fisiopatologia , Flumazenil/análogos & derivados , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Humanos , Radioisótopos do Iodo , Masculino , Mesencéfalo/diagnóstico por imagem , Mesencéfalo/metabolismo , Pessoa de Meia-Idade , Ponte/diagnóstico por imagem , Ponte/metabolismo , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologia , Receptores de GABA-A/fisiologia , Tálamo/diagnóstico por imagem , Tálamo/metabolismo , Veteranos/psicologia , VietnãRESUMO
OBJECTIVE: Recent work has underscored the role of serotonergic neurotransmission in chronic neural adaptations to cocaine dependence. The authors tested for evidence of serotonergic dysfunction during acute abstinence from cocaine, a period of high risk for relapse in cocaine dependence. METHOD: Binding availability of dopamine transporters and serotonin transporters was measured in 15 cocaine-dependent subjects during acute abstinence and in 37 healthy comparison subjects by using [(123)I]beta-CIT and single photon emission computed tomography. RESULTS: Significant increases in diencephalic and brainstem serotonin transporter binding (16.7% and 31.6%, respectively) were observed in cocaine-dependent subjects. Brainstem serotonin transporter binding was significantly inversely correlated with age across diagnostic groups. CONCLUSIONS: These findings provide further evidence of serotonergic dysfunction during acute abstinence from chronic cocaine use. Age-related decline in brainstem serotonin transporter binding may underlie the poor response to selective serotonin reuptake inhibitor antidepressants seen in some elderly depressed patients.
Assuntos
Encéfalo/metabolismo , Proteínas de Transporte/metabolismo , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Serotonina/metabolismo , Adulto , Fatores Etários , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/metabolismo , Tronco Encefálico/fisiopatologia , Proteínas de Transporte/fisiologia , Cocaína/análogos & derivados , Transtornos Relacionados ao Uso de Cocaína/diagnóstico por imagem , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Diencéfalo/diagnóstico por imagem , Diencéfalo/metabolismo , Dopamina/metabolismo , Dopamina/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Humanos , Radioisótopos do Iodo , Masculino , Glicoproteínas de Membrana/fisiologia , Recidiva , Fatores de Risco , Serotonina/fisiologia , Proteínas da Membrana Plasmática de Transporte de Serotonina , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Tomografia Computadorizada de Emissão de Fóton Único/estatística & dados numéricos , Resultado do TratamentoRESUMO
[123I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([123I]-CIT) and its isopropylester analog [123I]PCIT, both of which are phenyltropane derivatives of cocaine with high affinity for the dopamine (DA) transporter, were compared using single photon emission computed tomography in nonhuman primates. Although IPCIT is significantly more selective for the DA transporter than beta-CIT, striatal distribution volumes of specifically bound tracer were similar for both tracers. Compartmental modeling results were compared with a simple peak equilibrium method used previously by this group. The peak equilibrium method is shown to overestimate striatal distribution volumes, primarily due to a difference in the calculated time of peak specific uptake.
Assuntos
Encéfalo/metabolismo , Proteínas de Transporte/metabolismo , Cocaína/análogos & derivados , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Animais , Encéfalo/diagnóstico por imagem , Cromatografia Líquida de Alta Pressão , Cocaína/sangue , Cocaína/metabolismo , Cocaína/farmacocinética , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Meia-Vida , Humanos , Injeções Intravenosas , Radioisótopos do Iodo , Ligantes , Taxa de Depuração Metabólica , Modelos Biológicos , Papio , Especificidade da Espécie , Fatores de Tempo , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
The effect of endogenous dopamine on in vivo measurement of dopamine D(2) receptors in extrastriatal regions (thalamus and temporal cortex) was evaluated with single photon emission computed tomography and the high affinity ligand [123I]epidepride by comparing the binding potential before and after acute dopamine depletion. Dopamine depletion was achieved by per-oral administration of 5.5 g/70 kg body weight alpha-methyl-para-tyrosine given in 37 h. The alpha-methyl-para-tyrosine treatment increased the binding potential significantly in the temporal cortex (13+/-15%, P=0.036) but not in the thalamus (2+/-9%). The increase of the binding potential in the temporal cortex correlated strongly with the increase of dysphoric mood evaluated by the Positive and Negative Symptom Scale (PANSS) (rho=0.88, P=0.004). These results imply that [123I]epidepride, coupled with acute dopamine depletion might provide estimates of synaptic dopamine concentration.
Assuntos
Química Encefálica , Dopamina/metabolismo , Receptores de Dopamina D2/análise , Adulto , Benzamidas/metabolismo , Feminino , Ácido Homovanílico/sangue , Humanos , Radioisótopos do Iodo , Lorazepam/farmacologia , Masculino , Pessoa de Meia-Idade , Pirrolidinas/metabolismo , Receptores de Dopamina D2/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , alfa-Metiltirosina/sangue , alfa-Metiltirosina/farmacologiaRESUMO
UNLABELLED: The purpose of this study was to extend the graphical analysis of reversible tracer binding to account for labeled lipophilic metabolites (metabolites) in quantifying [123I]epidepride binding to striatal and extrastriatal D2 receptors and, additionally, to evaluate the feasibility of simplified analysis to measure the specific volume of distribution (V3') using single-sample blood data because the tissue ratio (RT) may be a less reliable measure of D2 binding in the presence of metabolites. METHODS: Multilinear regression analysis (MLRA) and graphical analysis (GA) using plasma parent (P) plus metabolite (M) activities as input and time activities of receptor-free (RF, cerebellum) and receptor-containing regions (RR, striatum and temporal cortex) derived V3' = (alpha(RR)(P) - alpha(RF)(P)), V3' = (1 + delta) (alpha(RR) - alpha(RF)) and RT = V3'/(V2P' + deltaV2M'), where alpha is a regression coefficient, delta is the equilibrium area ratio of M and P, and (V2P'/V2M') are the corresponding nondisplaceable distribution volumes. V3' by simplified analysis (SA) was calculated from RT determined without blood data and (V2P' + deltaV2M') with single-blood sample data. The accuracy of these three V3' values was assessed relative to the metabolite-accounted kinetic analysis (KA) for [123I]epidepride SPECT studies of 11 healthy volunteers, in which each participant had 27 scans and 30 plasma samples drawn during the 14 h after injection. RESULTS: All three V3' values (mL/g) significantly correlated with those by KA (r > or = 0.90) (striatum/temporal cortex: MLRA, 77.8 +/- 36.6/2.35 +/- 1.16; GA, 98.8 +/- 34.2/4.61 +/- 1.77; SA, 83.9 +/- 24.8/4.26 +/- 1.74; KA, 107.6 +/- 34.4/5.61 +/- 1.84). However, the correlation between RT and V3' was only moderate (r < or = 0.65) because of significant intersubject variability (23%) in (V2P' + deltaV2M'). CONCLUSION: The graphical analysis can be extended to account for metabolites in measuring D2 binding with [123I]epidepride SPECT for both high and low D2 density regions. Additionally, simplified V3' measurements with single blood sampling are feasible and may be a practical alternative to the tissue ratio RT because RT suffers as a measure of D2 binding from significant intersubject variability in the metabolite-contributed distribution volume of the nondisplaceable compartment.
Assuntos
Benzamidas , Encéfalo/diagnóstico por imagem , Radioisótopos do Iodo , Pirrolidinas , Receptores de Dopamina D2/análise , Tomografia Computadorizada de Emissão de Fóton Único , Adulto , Encéfalo/metabolismo , Meios de Contraste , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Receptores de Dopamina D2/metabolismo , Análise de RegressãoRESUMO
PURPOSE: To evaluate effects of vigabatrin (VGB) by using [123I]iomazenil single-photon emission computed tomography (SPECT) to estimate central gamma-aminobutyric acid (GABA(A))/benzodiazepine receptors (BZRs), and magnetic resonance spectroscopy (MRS) to assess tissue GABA levels. METHODS: Six patients with partial seizures had both SPECT and MRS before and 25-84 days after starting VGB (3 g p.o., q.d.). SPECT was acquired by using the constant-infusion method and, after nonuniform attenuation correction, coregistered with T1-weighted MR Imaging (MRI) A volume of interest (VOI) of 3 x 2 x 2 cc over the occipital cortex, used for MRS acquisition, was positioned on both MRI and coregistered SPECT. Occipital activity was divided by either total plasma activity or plasma [123I]iomazenil concentration to estimate BZR distribution volume (V(T)-p and V'(T), respectively). Wilcoxon's test was used for VOI differences in GABA levels, BZR V(T)-p or V'(T). SPM96 (either no global normalization or proportional scaling) was used to compare BZR V(T)-p changes in the patients with and without VGB with test-retest data in eight healthy age-matched controls. RESULTS: Occipital GABA levels were increased threefold (without VGB, 1.1+/-0.1 micromol/g; with VGB, 2.9+/-0.5 micromol/g; p = 0.027). BZR distribution volumes showed no change, when estimated by either V(T)-p (without VGB, 6.00+/-0.91 ml/g; with VGB, 5.86+/-0.44 ml/g; p = 0.92) or V(T) (without VGB, 41.1+/-11.2 ml/g; with VGB, 41.2+/-9.9 ml/g; p = 0.75). No significant changes were detected by SPM96. CONCLUSIONS: A clinically effective dose of VGB caused a threefold increase in tissue GABA levels but was not associated with a substantial BZR downregulation.
Assuntos
Anticonvulsivantes/farmacologia , Flumazenil/análogos & derivados , Espectroscopia de Ressonância Magnética , Lobo Occipital/química , Receptores de GABA/análise , Receptores de GABA/efeitos dos fármacos , Tomografia Computadorizada de Emissão de Fóton Único/estatística & dados numéricos , Vigabatrina/farmacologia , Adulto , Feminino , Humanos , Radioisótopos do Iodo , Masculino , Pessoa de Meia-Idade , Lobo Occipital/efeitos dos fármacos , Lobo Occipital/metabolismoRESUMO
Although positron emission tomography (PET) and single photon emission computed tomography (SPECT) are increasingly used for quantitation of neuroreceptor binding, almost no studies to date have involved a direct comparison of the two. One study found a high level of agreement between the two techniques, although there was a systematic 30% increase in measures of benzodiazepine receptor binding in SPECT compared with PET. The purpose of the current study was to directly compare quantitation of benzodiazepine receptor binding in the same human subjects using PET and SPECT with high specific activity [11C]iomazenil and [123I]iomazenil, respectively. All subjects were administered a single bolus of high specific activity iomazenil labeled with 11C or 123I followed by dynamic PET or SPECT imaging of the brain. Arterial blood samples were obtained for measurement of metabolite-corrected radioligand in plasma. Compartmental modeling was used to fit values for kinetic rate constants of transfer of radioligand between plasma and brain compartments. These values were used for calculation of binding potential (BP = Bmax/Kd) and product of BP and the fraction of free non-protein-bound parent compound (V3'). Mean values for V3' in PET and SPECT were as follows: temporal cortex 23+/-5 and 22+/-3 ml/g, frontal cortex23+/-6 and 22+/-3 ml/g, occipital cortex 28+/-3 and 31+/-5 ml/g, and striatum 4+/-4 and 7+/-4 ml/g. These preliminary findings indicate that PET and SPECT provide comparable results in quantitation of neuroreceptor binding in the human brain.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Flumazenil/análogos & derivados , Compostos Radiofarmacêuticos/farmacocinética , Receptores de GABA-A/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada de Emissão , Adulto , Ligação Competitiva , Bioensaio , Flumazenil/farmacocinética , Nível de Saúde , Humanos , Masculino , Ensaio Radioligante , Fatores de TempoRESUMO
Quantitative SPECT measures of dopamine D(2) like receptors with [(123)I]epidepride is complicated by its high affinity and lipophilic metabolites. The purpose of this study was to use both parent (P) and lipophilic metabolites (M) as input functions in a kinetic paradigm and in comparison to the results of equilibrium studies. Kinetic studies on eleven healthy human subjects, ages 32+/- 10 were performed following i.v. injection of approximately 370 MBq of [(123)I]epidepride. Images were acquired for 13.5+/-1.0 hours. Equilibrium studies were done on seven of eleven subjects with a bolus injection of approximately 140 MBq, bolus/infusion ratio of 10 hours, and infusion for 30-32 hours. High (striatum) and low (temporal cortex) density regions were studied. Two (P and M) and one (P) input function models were applied in the kinetic studies. In receptor-rich regions, the distribution volumes in nondisplaceable compartments were fixed to those in cerebellum. In addition, in the two input function model, K(1)(P)/K(1)(M) was fixed to the values in the cerebellum. The one input function model provided V'(3) values (=f(1)*B'(max)/K(D)) which were consistent with those obtained in equilibrium studies in both receptor-rich regions, while the two input function model provided consistent values only in striatum. Poor identifiability of the rate constants of metabolites seemed to be the source of errors in the two input function model. These results suggest that correct V'(3) values can be obtained with the one input function model both in high- and low-density regions.