RESUMO
Hormones have not been found in concentrations of orders of magnitude higher than nanograms per milliliter. Here, we report urine concentrations of a catecholamine (norepinephrine) ranging from 0.05 to 0.5 g/l, and concentrations of its metabolite DL-3,4-dihydroxyphenyl glycol (DOPEG) ranging from 1.0 to 44.5 g/l, in wild male red deer Cervus elaphus hispanicus after LC-MS analyses. The dark ventral patch of male red deer, a recently described sexually selected signal, contains high amounts of DOPEG (0.9-266.9 mg/l) stuck in the hairs, while DOPEG is not present in non-darkened hair. The formation of this dark patch is explained by the chemical structure of DOPEG, which is a catecholamine-derived o-diphenol susceptible to be oxidized by air and form allomelanins, nitrogen-free pigments similar to cutaneous melanins; by its high concentration in urine; and by the urine spraying behavior of red deer by which urine is spread through the ventral body area. Accordingly, the size of the dark ventral patch was positively correlated with the concentration of DOPEG in urine, which was in turn correlated with DOPEG absorbed in ventral hair. These findings represent catecholamine concentrations about one million higher than those previously reported for any hormone in an organism. This may have favored the evolution of the dark ventral patch of red deer by transferring information on the fighting capacity to rivals and mates. Physiological limits for hormone production in animals are thus considerably higher than previously thought. These results also unveil a novel mechanism of pigmentation based on the self-application of urine over the fur.
Assuntos
Catecolaminas/metabolismo , Cabelo/metabolismo , Pigmentação/fisiologia , Animais , Catecolaminas/urina , Cromatografia Líquida de Alta Pressão , Cervos , Cabelo/química , Masculino , Espectrometria de Massas , Melaninas/metabolismo , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/urinaRESUMO
The purpose of this study was to evaluate functional measures of diminished sympathetic activity after postganglionic neuronal loss in the conscious rat. To produce variable degrees of sympathetic postganglionic neuronal loss, adult rats were treated daily with toxic doses of guanethidine (100mg/kg) for either 5days or 11days, followed by a recovery period of at least 18days. Heart rate, blood pressure, cardiac baroreflex responsiveness, urinalysis (for catecholamine metabolite, 3-methoxy-4-hydroxyphenylethylenglycol; MHPG), and pupillometry were performed during the recovery period. At the end of the recovery period stereology of superior cervical ganglia (SCG) was performed to determine the degree of neuronal loss. Total number of SCG neurons was correlated to physiological outcomes using regression analysis. Whereas guanethidine treatment for 11days caused significant reduction in the number of neurons (15,646±1460 vs. 31,958±1588), guanethidine treatment for 5days caused variable levels of neuronal depletion (26,009±3518). Regression analysis showed that only changes in urinary MHPG levels and systolic blood pressure significantly correlated with reduction of SCG neurons (r2=0.45 and 0.19, both p<0.05). Although cardiac baroreflex-induced reflex tachycardia (345.7±19.6 vs. 449.7±20.3) and pupil/iris ratio (0.50±0.03% vs. 0.61±0.02%) were significantly attenuated in the 11-day guanethidine treated rats there was no significant relationship between these measurements and the number of remaining SCG neurons after treatment (p>0.05). These data suggest that basal systolic blood pressure and urinary MHPG levels predict drug-induced depletion of sympathetic activity in vivo.
Assuntos
Guanetidina/toxicidade , Neurônios/efeitos dos fármacos , Gânglio Cervical Superior/efeitos dos fármacos , Simpatolíticos/toxicidade , Testes de Toxicidade Aguda/métodos , Animais , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Catecolaminas/metabolismo , Estado de Consciência , Frequência Cardíaca/efeitos dos fármacos , Masculino , Metoxi-Hidroxifenilglicol/urina , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVES: Research has found that spirituality/religiosity has a salutary association with mental/physical health. However, the association of belief in life after death with well-being has rarely been studied, and the same is true of its association with biological indices, such as monoamine transmitters. Therefore, we examined the associations between well-being and religiosity, salivary 3-methoxy-4-hydroxyphenylglycol (sMHPG), and demographic characteristics. METHODS: The participants were 346 community-dwelling people, aged 65 years or older, without cognitive or mental deficits, in rural Japan. Measures of religiosity consisted of belief in life after death, attachment to life, and experiences related to death and religion. The measures were assessed by scales specifically suited for Japanese religious orientations. Participants' well-being was assessed by a life satisfaction scale containing two subscales. We also measured sMHPG, a major metabolite of noradrenaline that is thought to reflect certain psychological states, such as psychomotor retardation and effortful attention. RESULTS: One subscale of life satisfaction was positively associated with belief in life after death and sMHPG, and the other life satisfaction subscale was positively associated with education and death/religion-related experiences (e.g., visiting family graves or loss of a friend). Gender differences were found in afterlife beliefs and each life satisfaction subscale. CONCLUSIONS: These results suggest that religiosity, including belief in life after death and death/religion-related experiences, is salubriously associated with mental health among older people, especially women, living in rural Japan. The basal level of sMHPG was positively associated with life satisfaction, but not with belief in life after death.
Assuntos
Atitude Frente a Morte , Transtornos Cognitivos/psicologia , Metoxi-Hidroxifenilglicol/urina , Satisfação Pessoal , Religião , Espiritualidade , Idoso , Idoso de 80 Anos ou mais , Transtornos Cognitivos/urina , Etilenoglicóis , Feminino , Humanos , Japão , Masculino , Metoxi-Hidroxifenilglicol/análogos & derivados , Fenóis , População RuralRESUMO
Calcitonin gene-related peptide (CGRP) is reported to play important roles in cardiovascular regulation in human and animal models. In spite of this, its role remains controversial. We aim to clarify this by studying the autonomic cardiovascular function and vascular structure in CGRP knockout (CGRP(-/-)) mice. Blood pressure (BP) and heart rate (HR) were assessed by telemeters. Urine (24-hour) and blood were collected for catecholamines measurements. Baroreflex sensitivity was assessed using phenylephrine and sodium nitroprusside administered in an acute study. Daytime mean arterial pressure (MAP; 12-hour period) was significantly higher in the CGRP(-/-) mice than in the wild type (WT) mice (114.5 vs. 104.5 mm Hg; P = .04). Norepinephrine was elevated in plasma and 24-hour urine in the knockouts (Urine, 956 vs. 618 pg/mL; P = .004; Plasma, 2505 vs. 1168 pg/mL; P = .04). Paradoxically, cardiovagal baroreflex sensitivity was higher in CGRP(-/-) mice (3.2 vs. 1.4 ms/mm Hg; P = .03). To increase insight, we studied aortic stiffness in CGRP(-/-) mice and found it increased compared with age-matched WT mice, as evidenced by the depression of the compliance curve (P < .05). CGRP(-/-) mice have higher BP due to elevated sympathetic signals and abnormalities in blood vessel structure. Moreover, our data also showed that CGRP plays an important role in the regulation of the cardio-vagal tone.
Assuntos
Barorreflexo/fisiologia , Pressão Sanguínea/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/genética , Frequência Cardíaca/fisiologia , Rigidez Vascular/fisiologia , Animais , Epinefrina/sangue , Deleção de Genes , Masculino , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/urina , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/fisiologia , Norepinefrina/sangue , Norepinefrina/urinaRESUMO
Duloxetine selectively inhibits the serotonin (5-HT) and norepinephrine (NE) transporters (5-HTT and NET, respectively), as demonstrated in vitro and in preclinical studies; however, transporter inhibition has not been fully assessed in vivo at the approved dose of 60 mg/d. Here, the in vivo effects of dosing with duloxetine 60 mg once daily for 11 days in healthy subjects were assessed in 2 studies: (1) centrally (n = 11), by measuring concentrations of 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylglycol (DHPG), and NE in cerebrospinal fluid, and (2) versus escitalopram 20 mg/d (n = 32) in a 2-period crossover study by assessing the ΔDHPG/ΔNE ratio in plasma during orthostatic testing and by pharmacokinetic/pharmacodynamic modeling of reuptake inhibition using subjects' serum in cell lines expressing cloned human 5-HTT or NET. At steady state, duloxetine significantly reduced concentrations of DHPG and 5-hydroxyindoleacetic acid (P < 0.05), but not NE, in cerebrospinal fluid; DHPG was also decreased in plasma and urine. The ΔDHPG/ΔNE ratio in plasma decreased significantly more with duloxetine than escitalopram (65% and 21%, respectively; P < 0.0001). Ex vivo reuptake inhibition of 5-HTT was comparable (EC50 = 44.5 nM) for duloxetine and escitalopram, but duloxetine inhibited NET more potently (EC50 = 116 nM and 1044 nM, respectively). Maximal predicted reuptake inhibition for 5-HTT was 84% for duloxetine and 80% for escitalopram, and that for NET was 67% and 14%, respectively. In summary, duloxetine significantly affected 5-HT and NE turnover in the central nervous system and periphery; these effects presumably occurred via inhibition of reuptake by the 5-HTT and NET, as indicated by effects on functional reuptake inhibition ex vivo.
Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Tiofenos/farmacologia , Inibidores da Captação Adrenérgica/efeitos adversos , Inibidores da Captação Adrenérgica/sangue , Inibidores da Captação Adrenérgica/farmacocinética , Adulto , Idoso , California , Sistema Nervoso Central/metabolismo , Citalopram/farmacologia , Estudos Cross-Over , Cloridrato de Duloxetina , Feminino , Voluntários Saudáveis , Humanos , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Masculino , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/sangue , Metoxi-Hidroxifenilglicol/líquido cefalorraquidiano , Metoxi-Hidroxifenilglicol/urina , Pessoa de Meia-Idade , Norepinefrina/sangue , Norepinefrina/líquido cefalorraquidiano , Norepinefrina/urina , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/sangue , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Texas , Tiofenos/efeitos adversos , Tiofenos/sangue , Tiofenos/farmacocinética , Adulto JovemRESUMO
A sensitive and easy analytical method for catecholamine metabolites including 4-hydroxy-3-methoxyphenylglycol sulfate (HMPG sulfate), vanillylmandelic acid (VMA) and homovanillic acid (HVA) determination was developed based on liquid chromatography-tandem mass spectrometry in a negative multiple reaction monitoring mode. The analytes were rapidly separated on a reversed-phase Waters Xbridge C18 column (150 × 2.1 mm i.d.) with the mobile phase of 15% (v/v) acetonitrile containing 2 mM ammonium formate and 85% (v/v) formic acid solution (0.05%, v/v). Mass spectrometric conditions, such as characteristic fragmentations and quantification ion transitions, both with chromatographic conditions including separation column type and mobile phase composition, were systematically investigated to get optimal sensitivity and specificity. The limits of detection were in the range of 0.03-0.7 ng/mL for the targets. Recovery rates of spiked urine samples with three different concentration levels (low, middle and high) were above 86% with precisions less than 5.7%. For serum analysis, acetonitrile chosen both as protein precipitation reagent and extraction solvent facilitates to reduce matrix effects. Recovery rates of spiked serum sample were in the range of 90.6% to 111.1% for three targets. The intra-day and inter-day precisions were satisfactory less than 8.7%. This proposed method was successfully applied to determine HMPG sulfate, HVA and VMA present in human urine and serum.
Assuntos
Catecolaminas/sangue , Catecolaminas/urina , Espectrometria de Massas em Tandem/métodos , Catecolaminas/metabolismo , Cromatografia Líquida/economia , Cromatografia Líquida/métodos , Ácido Homovanílico/sangue , Ácido Homovanílico/metabolismo , Ácido Homovanílico/urina , Humanos , Limite de Detecção , Modelos Lineares , Metoxi-Hidroxifenilglicol/sangue , Metoxi-Hidroxifenilglicol/metabolismo , Metoxi-Hidroxifenilglicol/urina , Espectrometria de Massas em Tandem/economia , Ácido Vanilmandélico/sangue , Ácido Vanilmandélico/metabolismo , Ácido Vanilmandélico/urinaRESUMO
Milk products contaminated with melamine caused renal disease in young children in mainland China in 2008. The present study was designed to identify potential markers and assess the underlying metabolomic mechanisms of melamine-induced nephrolithiasis in young children. Urine samples were collected from healthy children (n=74) and from children diagnosed with nephrolithiasis (n=73) with either a positive (n=40) or a negative (n=33) history of melamine exposure. Ultra high-performance liquid chromatography coupled to time of flight mass spectrometry (U-HPLC-MS/MS) was applied to profile the abundances of metabolites. Partial least squares-discriminant analysis (PLS-DA) was used to discriminate between the samples. Seven compounds were found to highly discriminate between healthy controls and nephrolithiasis patients with a history of melamine exposure. The critical markers such as proline and 5C-aglycone were the predominant markers in the control group and detected only rarely in nephrolithiasis patients with a history of melamine exposure. In contrast, hypoxanthine at was the most significant compound that distinguished nephrolithiasis patients with a history of melamine exposure. It was increased to 116.12±23.34 µg/L (mean±S.D.) in the melamine-induced nephrolithiasis group, whereas the non-melamine group was at the level of 67.47±9.33 µg/L (p<0.001). The biomarkers for melamine-induced nephrolithiasis identified by this study may have clinical application in determining the aetiology of renal disease in young children.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Nefrolitíase/induzido quimicamente , Nefrolitíase/urina , Espectrometria de Massas em Tandem/métodos , Triazinas/intoxicação , Biomarcadores/análise , Biomarcadores/urina , Estudos de Casos e Controles , Pré-Escolar , Dipeptídeos/urina , Análise Discriminante , Feminino , Homocisteína/análogos & derivados , Humanos , Hipoxantina/urina , Lactente , Cálculos Renais , Análise dos Mínimos Quadrados , Masculino , Metoxi-Hidroxifenilglicol/urina , Prolina/urina , Reprodutibilidade dos Testes , Triazinas/metabolismo , Vitamina K/análogos & derivadosRESUMO
Children with Asperger and Kanner syndromes in the stable state demonstrate similar decrease in plasma norepinephrine. In the aggravated state, these changes become more expressed and are characterized by a decrease in plasma tyrosine, norepinephrine, normetanephrine and by an increase in dopamine and homovanylic acid and a decrease in excretion of norepinephrine and an increase in excretion of homovanylic acid, epinephrine and MHPG. Only in children with Kanner syndrome in the aggravated state plasma MHPG increases, excretion of tyrosine decreases and excretion of normetanephrine increases. The observed imbalance in dopamine and epinephrine/norepinephrine systems justifies combined analysis of changes in catecholamines and their metabolites levels as the most informative approach in the study of the effect of autistic disorders.
Assuntos
Síndrome de Asperger/metabolismo , Transtorno Autístico/metabolismo , Catecolaminas/sangue , Catecolaminas/urina , Síndrome de Asperger/sangue , Síndrome de Asperger/urina , Transtorno Autístico/sangue , Transtorno Autístico/urina , Catecolaminas/metabolismo , Criança , Pré-Escolar , Dopamina/sangue , Dopamina/metabolismo , Dopamina/urina , Epinefrina/sangue , Epinefrina/metabolismo , Epinefrina/urina , Ácido Homovanílico/sangue , Ácido Homovanílico/metabolismo , Ácido Homovanílico/urina , Humanos , Metoxi-Hidroxifenilglicol/sangue , Metoxi-Hidroxifenilglicol/metabolismo , Metoxi-Hidroxifenilglicol/urina , Norepinefrina/sangue , Norepinefrina/metabolismo , Norepinefrina/urina , Tirosina/sangue , Tirosina/metabolismo , Tirosina/urinaRESUMO
This study investigated changes in the urine dihydroxyphenylglycol to norepinephrine ratio in patients with attention-deficit hyperactivity disorder (ADHD) treated with atomoxetine. The possible relationship with clinical response was also explored. Newly ADHD diagnosed, treatment-naïve children or adolescents were double-blindly randomized (2:1) to atomoxetine (n = 28) or placebo (n = 13). The dihydroxyphenylglycol to norepinephrine ratio decreased in both groups, showing significantly greater changes with atomoxetine than with placebo at week 6 (-42% versus -14%; P = .001), when dosed at 1.2 mg/kg/day, than at week 2 (-20% versus -2%; P = .118) with a dose of 0.5 mg/kg/day. Although the significant dihydroxyphenylglycol to norepinephrine ratio decrease with atomoxetine indicated norepinephrine transporter blockade, no association with ADHD clinical response (ADHD Rating Scale-IV-Parent:Investigator) was found. Therefore, dihydroxyphenylglycol to norepinephrine ratio might be a useful pharmacodynamic/pharmacokinetic biomarker, although not sufficiently sensitive to predict clinical efficacy. It remains a possibility that this ratio might have value to facilitate personalized atomoxetine pharmacotherapy in ADHD patients.
Assuntos
Inibidores da Captação Adrenérgica/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/urina , Metoxi-Hidroxifenilglicol/análogos & derivados , Norepinefrina/urina , Propilaminas/uso terapêutico , Adolescente , Cloridrato de Atomoxetina , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Metoxi-Hidroxifenilglicol/urina , Projetos Piloto , Resultado do TratamentoRESUMO
In the human body, the catecholamine norepinephrine is mainly metabolized to 3,4-dihydroxyphenylglycol (DHPG) which therefore serves as an important biomarker for norepinephrine's metabolism. Most data on DHPG concentrations in human plasma and urine has been generated by using HPLC-ECD or GC-MS technologies. Here, we describe a stable-isotope dilution GC-MS/MS method for the quantitative determination of DHPG in human urine using trideutero-DHPG (d(3)-DHPG) as internal standard and a two-step derivatization process with pentafluorobenzyl bromide (PFB-Br) and N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA). Two pentafluorobenzyl (PFB) trimethylsilyl (TMS) derivatives were obtained and identified, i.e., two isomeric DHPG-PFB-(TMS)(3) derivatives and the later eluting DHPG-tetrafluorobenzyl-(TMS)(2) derivative, i.e., DHPG-TFB-(TMS)(2). To our knowledge the DHPG-TFB-(TMS)(2) derivative and the underlying reaction have not been reported previously. In this reaction both vicinal aromatic hydroxyl groups of DHPG react with PFB-Br to form a heterocyclic seven-membered [1,4]dioxepin compound. The DHPG-TFB-(TMS)(2) derivative was used for quantitative GC-MS/MS analysis in the electron-capturing negative-ion chemical ionization mode by selected-reaction monitoring of m/z 351 from m/z 401 for DHPG and of m/z 352 from m/z 404 for d(3)-DHPG. Validation experiments on human urine samples spiked with DHPG in a narrow (0-33 nM) and a wide range (0-901 nM) revealed high recovery (86-104%) and low imprecision (RSD; 0.01-2.8%). LOD and relative LLOQ (rLLOQ) values of the method for DHPG were determined to be 76 amol and 9.4%, respectively. In urine of 28 patients suffering from chronic inflammatory rheumatic diseases, DHPG was measured at a mean concentration of 238 nM (38.3 µg/g creatinine). The DHPG concentration in the respective control group of 40 healthy subjects was measured to be 328 nM (39.2 µg/g creatinine). Given the unique derivatization reaction and collision-induced dissociation, and the straightforwardness the present method is highly specific, accurate, precise, and should be useful in clinical settings.
Assuntos
Catecóis/urina , Fluorbenzenos/química , Cromatografia Gasosa-Espectrometria de Massas/métodos , Metoxi-Hidroxifenilglicol/análogos & derivados , Febre Reumática/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Modelos Lineares , Masculino , Metoxi-Hidroxifenilglicol/urina , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem/métodos , Adulto JovemRESUMO
BACKGROUND: The selective MAO-B inhibitor selegiline has been evaluated in clinical trials as a potential medication for the treatment of cocaine dependence. This study evaluated the safety of and pharmacologic interactions between 7 days of transdermal selegiline dosed with patches (Selegiline Transdermal System, STS) that deliver 6 mg/24 hours and 2.5 mg/kg of cocaine administered over 4 hours. METHODS: Twelve nondependent cocaine-experienced subjects received deuterium-labeled cocaine-d5 intravenously (IV) 0.5 mg/kg over 10 minutes followed by 2 mg/kg over 4 hours before and after one week of transdermal selegiline 6 mg/24 hours. Plasma and urine were collected for analysis of selegiline, cocaine, catecholamine and metabolite concentrations. Pharmacodynamic measures were obtained. RESULTS: Selegiline did not change cocaine pharmacokinetic parameters. Selegiline administration increased phenylethylamine (PEA) urinary excretion and decreased urinary MHPG-sulfate concentration after cocaine when compared to cocaine alone. No serious adverse effects occurred with the combination of selegiline and cocaine, and cocaine-induced physiological effects were unchanged after selegiline. Only 1 peak subjective cocaine effects rating changed, and only a few subjective ratings decreased across time after selegiline. CONCLUSION: No pharmacological interaction occurred between selegiline and a substantial dose of intravenous cocaine, suggesting the combination will be safe in pharmacotherapy trials. Selegiline produced few changes in subjective response to the cocaine challenge perhaps because of some psychoactive neurotransmitters changing in opposite directions.
Assuntos
Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Selegilina/farmacologia , Administração Cutânea , Adulto , Afeto/efeitos dos fármacos , Anfetamina/metabolismo , Anfetaminas/metabolismo , Análise de Variância , Cocaína/administração & dosagem , Cocaína/análogos & derivados , Cocaína/metabolismo , Cocaína/farmacocinética , Cocaína/toxicidade , Inibidores da Captação de Dopamina/farmacocinética , Inibidores da Captação de Dopamina/toxicidade , Interações Medicamentosas/fisiologia , Feminino , Ácido Homovanílico/sangue , Ácido Homovanílico/metabolismo , Humanos , Infusões Intravenosas , Masculino , Metanfetamina/metabolismo , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/metabolismo , Metoxi-Hidroxifenilglicol/urina , Monitorização Fisiológica , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/administração & dosagem , Inibidores da Monoaminoxidase/farmacocinética , Fenetilaminas/metabolismo , Fenetilaminas/urina , Prolactina/sangue , Prolactina/metabolismo , Selegilina/administração & dosagem , Selegilina/farmacocinética , Estatísticas não Paramétricas , Síndrome de Abstinência a Substâncias/psicologia , Adulto JovemRESUMO
Relationships between Cloninger's temperament and character dimensions and plasma sex hormone levels and biogenic amine turnover were studied in male prison inmates convicted of rape (n=61) or child molestation (n=24) and normal male controls (n=25). The participants completed the Temperament and Character Inventory (TCI), which includes the temperament dimensions Novelty Seeking, Harm Avoidance, Reward Dependence and Persistence as well as the character dimensions Self-Directedness, Cooperativeness and Self-Transcendence. Plasma levels of testosterone, dihydrotestosterone, sex hormone binding globulin, luteinizing hormone (LH) and follicle-stimulating hormone were estimated in plasma samples and 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in urine samples. Both sex offender groups had higher Novelty, Seeking and lower Reward Dependence, Self-Directedness and Cooperativeness scores compared with the controls. Plasma levels of testosterone and dihydrotestosterone were significantly higher in rapists than in controls. Novelty Seeking scores were positively correlated with LH levels in rapists, and with testosterone levels in child molesters. Harm Avoidance scores were negatively correlated with 5-HIAA levels in rapists and with HVA levels in child molesters. In rapists, the calculated free androgen index showed a negative correlation with 5-HIAA. For the sex offender sample as a whole, the subgroup with high testosterone levels had higher Harm Avoidance scores, the subgroup with low HVA levels had lower Cooperativeness scores, and the subgroups with high 5HIAA or MHPG levels had lower Persistence scores. The results indicate that Novelty Seeking behavior in the group of rapists is associated with a hyperactive hypothalamic-pituitary-gonadal axis. In addition, low serotonin turnover and low dopamine turnover seem to be associated with a passive-avoidant behavioral style in rapists and child molesters, respectively.
Assuntos
Aminas Biogênicas/sangue , Caráter , Hormônios Esteroides Gonadais/sangue , Transtornos da Personalidade/epidemiologia , Delitos Sexuais/estatística & dados numéricos , Temperamento , Adulto , Di-Hidrotestosterona/sangue , Comportamento Exploratório , Hormônio Foliculoestimulante/sangue , Ácido Homovanílico/urina , Humanos , Hormônio Luteinizante/sangue , Masculino , Metoxi-Hidroxifenilglicol/urina , Estupro , Serotonina/urina , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangueRESUMO
BACKGROUND: To assess the sensitivity of biochemical, physiological, and pharmacological markers of peripheral norepinephrine (NE) transporter (NET) function, we chronically antagonized NET by a range of doses of duloxetine [(+)-N-methyl-3-(1-naphthalenyloxy)-2 thiophenepropanamine], which blocks the NE reuptake process. METHODS AND RESULTS: Duloxetine was administered in a randomized, placebo-controlled study in 15 healthy volunteers. Plasma from duloxetine-treated subjects (ex vivo effect) dose-dependently decreased radioligand binding to human NET (maximum inhibition was 60%) (P=0.02). The dose of intravenous tyramine required to raise systolic blood pressure by 30 mm Hg (PD30) increased dose-dependently with duloxetine and was significant at the end of the 120-mg/d dosage (P<0.001). The plasma dihydoxyphenylglycol to NE (DHPG/NE) ratio was reduced significantly at 2 weeks of treatment with 80 mg/d duloxetine (11.3 at baseline, 3.4 at 240 mg/d, P<0.001). Plasma NE was significantly increased starting at 120 mg/d duloxetine. Urine results (corrected for 24-hour creatinine excretion) showed a dose-dependent change from the baseline urinary excretion for NE, DHPG, and the DHPG/NE ratio. The most sensitive measure, the DHPG/NE ratio, was significant at the 80-mg dose. Urinary NE excretion was significantly raised after 2 weeks of treatment with 80 mg/d duloxetine (P<0.001), the lowest dose used in the study. CONCLUSIONS: These findings suggest that the degree of NET blockade can be assessed with the plasma or urine DHPG/NE ratio and the pressor effect of tyramine. Also, the DHPG/NE ratio is more sensitive at the lower end of NET inhibition, whereas tyramine exhibits a linear relation, with NET inhibition commencing at a higher dose.
Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Metoxi-Hidroxifenilglicol/análogos & derivados , Simportadores/antagonistas & inibidores , Tiofenos/farmacologia , Adolescente , Inibidores da Captação Adrenérgica/administração & dosagem , Adulto , Relação Dose-Resposta a Droga , Cloridrato de Duloxetina , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Metoxi-Hidroxifenilglicol/urina , Norepinefrina/sangue , Norepinefrina/urina , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Postura , Ensaio Radioligante , Sensibilidade e Especificidade , Sístole/efeitos dos fármacos , Tiofenos/administração & dosagem , Tiramina/administração & dosagem , Tiramina/farmacologiaRESUMO
OBJECTIVE: To determine whether there are consistent neurobiological differences between patients with bipolar I disorder (BD I) and those with bipolar II disorder (BD II). METHOD: We reviewed the literature in areas where the most consistent neurobiological findings have been reported for bipolar disorder, specifically, neuroimaging and brain metabolism. The imaging studies reviewed examined structure, using magnetic resonance imaging (MRI), and function, using functional MRI, positron emission tomography, and single photon emission computed tomography. We used magnetic resonance spectroscopy to examine brain chemistry. We reviewed those metabolic studies that examined cell calcium, 3-methoxy-4-hydroxyphenylglycol, and protein kinase C. RESULTS: Some genetic studies suggest that there may be differences between BD II and BD I patients. However, our review of the imaging and metabolic studies identified few studies directly comparing these 2 groups. In those studies, there were few differences, if any, and these were not consistent. CONCLUSIONS: While genetic data suggest there may be differences between BD II patients and BD I patients, the neurobiological findings to date do not provide support. However, this may be owing to the small number of studies directly comparing the 2 groups and also to the fact that those carried out have not been adequately powered to detect possible small true differences. This is an important issue because, if there are no neurobiological differences, it would be anticipated that similar treatments would be similarly effective in both groups. Given the importance of understanding whether there are neurochemical differences between these groups, further research in this area is clearly needed.
Assuntos
Transtorno Bipolar/classificação , Transtorno Bipolar/diagnóstico , Encéfalo , Transtorno Bipolar/metabolismo , Encéfalo/anatomia & histologia , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Cálcio/sangue , Circulação Cerebrovascular/fisiologia , Diagnóstico Diferencial , Humanos , Imageamento por Ressonância Magnética , Metoxi-Hidroxifenilglicol/sangue , Metoxi-Hidroxifenilglicol/urina , Tomografia por Emissão de Pósitrons , Proteína Quinase C/metabolismo , Tomografia Computadorizada de Emissão de Fóton ÚnicoAssuntos
Afeto , Cognição , Torcicolo/complicações , Tremor/etiologia , Nível de Alerta/efeitos dos fármacos , Antagonistas Colinérgicos/uso terapêutico , Transtornos Cognitivos/etiologia , Humanos , Deficiências da Aprendizagem/etiologia , Transtornos Mentais/etiologia , Metoxi-Hidroxifenilglicol/urina , Testes Neuropsicológicos , Desempenho Psicomotor , Torcicolo/tratamento farmacológico , Torcicolo/psicologia , Torcicolo/urinaRESUMO
Prior to 1970, childhood depression was not considered a valid clinical entity by American psychiatrists. One of the early clues was provided in the 1950s by the author's observation of depressive symptoms in children and young adolescents with undescended testicles. This finding was extended to children with several chronic diseases, many of whom exhibited depressive symptoms as well. Eventually, depressive symptomatology was found in children without any physical disorders. This was followed by the introduction of a diagnostic instrument, called the Children's Affective Rating Scale (CARS), later converted into a more formal system called the Child Assessment Schedule (CAS). A provisional classification of childhood depression was published in 1972. Our examination of children with depressive disorders has revealed several modes of family interaction, of which the most important were: separation from important love objects; depreciation and rejection; and affective disorders in parents. Several children with bipolar disorder stimulated our interest in this disorder and led to a pilot study of children of bipolar, lithium-responding parents. Some of these children with bipolar illness had a clear-cut response to lithium and were strong augmenters of the average evoked potentials (EPs). Next, our group investigated the urinary excretion of norepinephrine and its metabolites in chronically depressed children who differed from a normal control group. The foregoing studies, along with major contributions by other child psychiatrists, eventually led to the acceptance of childhood depression as a clinical entity in US psychiatry. The acceptance of juvenile bipolar disorder had to await further research by a new generation of child and adult psychiatrists.
Assuntos
Transtorno Depressivo/história , Transtorno Depressivo/psicologia , Nível de Saúde , Psicologia da Criança/história , Ansiedade de Separação/psicologia , Transtorno Bipolar/psicologia , Catecolaminas/urina , Criança , Pré-Escolar , Transtorno Depressivo/urina , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , História do Século XX , Humanos , Masculino , Metoxi-Hidroxifenilglicol/urina , Norepinefrina/metabolismo , Índice de Gravidade de DoençaRESUMO
Evidence suggests that compounds that increase the synaptic availability of more than one neurotransmitter have greater efficacy in the treatment of depression than single-acting drugs. Preclinical studies indicate that duloxetine acts to inhibit serotonin (5-HT) and norepinephrine (NE) transporters. The ability of duloxetine to alter 5-HT and NE reuptake was tested in 12 healthy male subjects. Placebo, desipramine 50 mg b.i.d., and duloxetine (80 mg q.d. or 60 mg b.i.d.) were compared in a randomized, double-blind, three-period crossover study in 12 healthy male subjects. Whole-blood 5-HT, urinary excretion of NE and major metabolites, and TYR PD30 (IV tyramine pressor dose needed to increase systolic blood pressure by 30 mmHg) were measured at steady state. Vital signs were measured periodically. Duloxetine affected 5-HT reuptake, with whole-blood 5-HT depletion vs placebo (80 mg q.d.: p=0.07; 60 mg b.i.d.: p=0.02; combined regimens: p=0.01). Cardiovascular changes reflecting increased sympathetic tone were observed with both duloxetine and desipramine, and both treatments significantly decreased whole body NE turnover (p<0.01). Duloxetine and desipramine were associated with similar mean increases in fractional extraneuronal NE concentration, although these changes did not reach statistical significance. TYR PD30 increased significantly with desipramine dosing (p<0.01). In conclusion, whole-blood measurements confirm that duloxetine inhibits platelet 5-HT uptake in vivo. Urinary and cardiovascular measurements suggest that duloxetine has an effect on NE synthesis and turnover, indicative of NE reuptake inhibition. The lack of a detectable impact of duloxetine on TYR PD30 suggests that this may not be the most sensitive indirect measure of NE reuptake when assessing dual reuptake inhibitors.
Assuntos
Antidepressivos/farmacologia , Norepinefrina/urina , Serotonina/sangue , Tiofenos/farmacologia , Adulto , Pressão Sanguínea/efeitos dos fármacos , Estudos Cross-Over , Desipramina/administração & dosagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Cloridrato de Duloxetina , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Ácidos Mandélicos/urina , Metoxi-Hidroxifenilglicol/urina , Normetanefrina/urina , Simpatomiméticos/administração & dosagem , Fatores de Tempo , Tiramina/administração & dosagem , Tiramina/efeitos adversos , Tiramina/farmacocinéticaRESUMO
The psychobiologic status of cyclists after 4 days of training and the kinetics of recovery were assessed by measuring the sympatho-adrenal level, the central noradrenergic activity and the cortisol/testosterone status by non-invasive methods. For this purpose, urinary excretion of methoxyamines (metanephrine [MN], normetanephrine [NMN]), which are metabolites of circulating catecholamines, 3-methoxy-4-hydroxyphenyl glycol sulfate (MHPG-S), a metabolite of brain norepinephrine, and salivary output of cortisol and testosterone were measured in twelve national cyclists (aged 19.5 +/- 4.5 years), just before (T 1 ) and at the end of the training (T 2 ), and during the three following recovery days (R 1, R 2, R 3 ). Urinary and salivary samples were also collected during a period of relative rest, in order to get reference values (T 0 ). At T 0, T 1 and T 2, mood states, as measured by the Profile of Mood States, and rating of perceived muscle soreness were assessed. The overall mood and muscle soreness levels were not affected by the training. The load increased by 187 % as an average between the first and the fourth day of training. A significant increase in NMN levels and a decrease in T:F ratio were observed at T 2, while MHPG-S excretion remained unchanged. Persistent high urinary output of NMN and MN were observed during the post-training recovery period for 24 h (R 1 ) and 48 h (R 2 ), respectively. After 72 h of recovery (R 3 ), MN levels had returned to baseline while NMN output was lower than the control level. T:F values returned to their control levels within 48 h of recovery. The strenuous training seems to induce an alteration in peripheral neuro-endocrine parameters without modifications of central factors. The hormonal status remained altered for at least 1 day of post-training recovery and seemed to be achieved within 3 days.
Assuntos
Ciclismo/fisiologia , Ciclismo/psicologia , Exercício Físico/fisiologia , Músculo Esquelético/fisiologia , Educação Física e Treinamento/métodos , Adaptação Fisiológica/fisiologia , Adolescente , Adulto , Afeto/fisiologia , Exercício Físico/psicologia , Humanos , Hidrocortisona/análise , Metanefrina/urina , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/urina , Normetanefrina/urina , Saliva/química , Testosterona/análiseRESUMO
A major metabolite of norepinephrine (NE) in brain is 4-hydroxy-3-methoxyphenylethylene glycol (MHPG). In many species, a large fraction of MHPG formed in brain is converted to the sulfate conjugate. Consequently, MHPG sulfate has been proposed as a biomarker for NE metabolism in the central nervous system. As part of the clinical trials of the monoamine oxidase inhibitor selegiline for treating cocaine addiction, we required a method for measuring urine concentrations of MHPG sulfate. Using a deuterium-labeled analogue as an internal standard, we developed a liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/ MS) method for determination of MHPG sulfate in human urine. Sample preparation involves simply diluting 50 microL of urine with 1 mL of ammonium formate buffer and adding the internal standard. The sample is centrifuged, the supernate is transferred to an autosampler vial, and 10 microL is injected into the LC-MS/MS system. Standard curves from 50 to 10,000 ng/mL are generated. Only one sample of 277 clinical samples analyzed had a concentration outside of this range. Precision (coefficient of variation) ranged from 1.9 to 9.7%, and accuracy ranged from 97 to 103% of expected values for controls prepared by spiking sulfatase-treated urine with MHPG sulfate.
Assuntos
Metoxi-Hidroxifenilglicol/urina , Arilsulfatases/urina , Cromatografia Líquida de Alta Pressão , Humanos , Indicadores e Reagentes , Marcação por Isótopo , Metoxi-Hidroxifenilglicol/análogos & derivados , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
The investigation of biological correlates of suicidal behavior is important in searching for possible changes in neuronal systems activity related to that behavior, so that pharmacological interventions may be proposed, especially in high-risk subjects. In a sample of 111 subjects admitted in a general hospital after suicide attempt, we studied the turnover of neurotransmitters by measuring the urinary output of the main metabolites of serotonin, dopamine and noradrenaline (5-HIAA, HVA, MHPG respectively), as well as serum cholesterol, and compared them to those of a group of 62 healthy controls. Venous blood samples and urine samples were collected within 24 hours of admission. Psychiatric diagnosis was made according to DSM-IIIR criteria and assessment of suicide intent with Beck's Suicidal Intent Scale (SIS). Fifty-four (54) subjects received the diagnosis of adjustment disorder, 25 of depression, 16 of schizophrenia and 16 of personality disorder. Fourteen subjects (14) had employed a violent mode of attempt. Urinary MHPG was found significantly higher in all diagnostic groups compared to controls. No difference was found concerning the excretion of HVA and 5-HIAA. Serum total cholesterol was found significantly lower both in violent and non-violent attempters compared to controls after correcting for age. No difference in serum cholesterol or MHPG was found between violent and non-violent attempts. Serum cholesterol and MHPG correlated negatively, while the correlations between cholesterol and 5-HIAA or HVA were not significant. Our results confirm previous reports of lower serum cholesterol in attempted suicide. They are also indicative of an increased noradrenaline turnover in subjects who attempt suicide, at least within 24 hours after the attempt. Whether this activation precedes or follows the attempt because of the specific stress, can not be answered at present.