Assuntos
Butanóis/efeitos adversos , Pigmentação da Pele/efeitos dos fármacos , Pele/patologia , Vitiligo/induzido quimicamente , Administração Cutânea , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/análise , Antígenos CD/metabolismo , Butanóis/administração & dosagem , Caderinas/análise , Caderinas/metabolismo , Estudos de Casos e Controles , Feminino , Glutamato-Cisteína Ligase/análise , Glutamato-Cisteína Ligase/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Melanócitos/efeitos dos fármacos , Melanócitos/metabolismo , Pessoa de Meia-Idade , Monofenol Mono-Oxigenase/análise , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Pele/citologia , Pele/efeitos dos fármacos , Vitiligo/patologia , Adulto JovemRESUMO
Saccharomyces cerevisiae genetically engineered to enhance butanol production will be used in a manufacturing process similar to that of fuel ethanol production, including co-production of distillers products for animal feed. A poultry feeding trial was conducted with simulated isobutanol-derived dried distillers grains with solubles (bDDGS), comprising non-fermentable corn solids and heat-inactivated Butamax modified yeast (BMY), to determine potential health effects. Simulated dried distillers grains were produced in 2 variants: bDDGS containing 10% (B10) or 50% (B50) BMY. The BMY concentrations were selected based on a conservative estimate from ethanol-derived distillers grains (eDDGS) approximating 2.5 and 12-fold margins of exposure. The B10 and B50 DDGS were evaluated in a 42-day feeding trial using male Ross 708 broiler chickens fed diets containing eDDGS, B50 DDGS, or B10 DDGS without or with isobutanol, 2,3-butanediol, and isobutyric acid metabolites each at target concentrations of 2 (B10-2), 5 (B10-5), or 10 (B10-10) times the anticipated specification limit in the commercial product. Diets were fed (n = 50 broilers/treatment) in 3 phases: starter phase with 8% DDGS and grower and finisher phases each with 15% DDGS. No statistically significant differences or diet-related effects on mortality, clinical pathology, or organ weights, and no microscopic observations associated with consumption of diets containing B10, B50, or B10 supplemented with metabolites at any targeted exposure level were observed. A lower (P < 0.05) mean absolute bursa of Fabricius weight in the B10-10 group compared to the B10 group was considered to be within the range of biological variability. A non-significant trend toward lower weight, gains, and feed intake, and higher feed:gain ratio was observed in the B10-10 group, and was considered a non-adverse palatability effect of consuming high concentrations of metabolites. These results demonstrate that consumption of phase diets containing simulated DDGS from a novel isobutanol production process was well-tolerated.
Assuntos
Ração Animal/análise , Butanóis/administração & dosagem , Ração Animal/efeitos adversos , Fenômenos Fisiológicos da Nutrição Animal , Animais , Biocombustíveis , Butanóis/efeitos adversos , Butanóis/metabolismo , Galinhas/crescimento & desenvolvimento , Destilação/métodos , Grão Comestível/química , Fermentação , Engenharia Genética , Masculino , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , SegurançaRESUMO
Cosmetics containing rhododendrol (RD) were voluntarily recalled after incidents of leukoderma related to their use. Users reported using up to five different RD-containing products by layered application. In this study, we investigated the effects of layered application, formulations, and their components on the skin permeation of cosmetics containing RD. Experiments were designed to simulate actual in-use conditions, such as varying application volumes, physical mixing of formulations, sequence of cosmetics application and time interval between applications, to establish their effect on the skin permeation of RD. Milk and lotion RD-containing cosmetics (2%), 1% aqueous RD, and preparations of formulation components were applied as the first or second layers as finite doses of 10 or 20 µL/cm2. Permeation experiments were performed through excised porcine ear skin using Franz diffusion cells with an effective diffusion area of 1.77 cm2. Cosmetics applied by layered application exhibited lower skin permeation of RD compared with a single application despite having the same application dose. High initial volume (20 µL at 0 or 5 sec) did not exhibit any significant reduction in the permeation of RD. Formulations and their components caused varying reductions in RD permeation, probably due to changes in thermodynamic activity of the active component. Layered application, formulation components, application volume, time interval and sequence of application had significant influences on the skin permeation of the active component. Moreover, this study established a method of investigating the influence of formulations and their components on the skin permeation of actives after layered application.
Assuntos
Butanóis/administração & dosagem , Cosméticos/administração & dosagem , Absorção Cutânea , Administração Cutânea , Animais , Butanóis/química , Composição de Medicamentos , Técnicas In Vitro , Pele/metabolismo , SuínosRESUMO
BACKGROUND: Rhododendrol (rhododenol), an inhibitor of tyrosinase activity, is used as a skin-whitening component. Many cases of leukoderma after the application have been reported, termed rhododenol-induced leukoderma (RIL). The aim of this study was to clarify the pathogenesis of RIL morphologically through comparison with vitiligo. METHODS: We examined 14 cases of RIL and 15 cases of vitiligo using routine histopathology and immunohistochemistry. Thirteen cases of RIL, six cases of vitiligo and specimens of the RIL mouse model were evaluated by electron microscopy. RESULTS: There were common findings in RIL and vitiligo at the light-microscopic level: (a) vacuolar changes in the dermo-epidermal junction, (b) melanophages in the papillary dermis, (c) perifollicular lymphocyte infiltration, (d) loss or decrease of basal melanin pigment and (e) decrease of melanocytes in the lesions. The ultrastructural observations showed specific findings of RIL: (a) remaining melanocytes in depigmented lesions, (b) inhomogeneous melanization in melanocytes and (c) degenerated melanosomes in melanocytes. Some of the findings were observed in a RIL mouse model. Furthermore, it is notable that cell organelles of melanocytes were intact in our RIL cases. CONCLUSION: Morphological changes of RIL targeting melanosomes in melanocytes without degeneration of organelles reflect the reversible clinical course of most cases.
Assuntos
Butanóis/efeitos adversos , Melanócitos , Nevo , Neoplasias Cutâneas , Vitiligo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Butanóis/administração & dosagem , Feminino , Humanos , Melanócitos/metabolismo , Melanócitos/patologia , Camundongos , Pessoa de Meia-Idade , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Nevo/induzido quimicamente , Nevo/metabolismo , Nevo/patologia , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Vitiligo/metabolismo , Vitiligo/patologiaRESUMO
The genus Passiflora is popularly used to treat anxiety. Recent studies showed antidepressant-like effects of two varieties of P. edulis (edulis and flavicarpa) in mice. However, the mechanisms of antidepressant actions are still unknown. Here, the effects of P. edulis fo. edulis aqueous extract (AE, 100-300mg/kg, po), and ethyl acetate (AcOEt, 25-50mg/kg, po), butanol (BuOH, 25-50mg/kg, po) and residual aqueous (25-100mg/kg, po) fractions were investigated in the mouse forced swimming test. In addition, the involvement of monoamines in the P. edulis fractions-induced antidepressant actions was approached. HPLC analyses showed that AcOEt and BuOH, but not residual, fractions shared with AE the main peaks between 25 and 70min (UV 340nm), which are suggestive of flavonoids. Nortriptyline and fluoxetine reduced the immobility time and similar results were observed for AE, AcOEt and BuOH but not residual fractions. PCPA (inhibitor of 5-HT synthesis), AMPT (inhibitor of catecholamine synthesis) and sulpiride (selective D2 receptor antagonist), but not DSP-4 (noradrenergic neurotoxin), blocked the antidepressant actions of AcOEt and BuOH. In conclusion, AcOEt and BuOH fractions shared with AE similar phytochemical composition and antidepressant actions. Preserved 5-HT and dopamine transmissions were required for the antidepressant effects of P. edulis fractions.
Assuntos
Antidepressivos/administração & dosagem , Monoaminas Biogênicas/metabolismo , Depressão/metabolismo , Passiflora/química , Extratos Vegetais/administração & dosagem , Transmissão Sináptica , Acetatos/administração & dosagem , Animais , Antidepressivos/isolamento & purificação , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos Tricíclicos/administração & dosagem , Comportamento Animal , Benzilaminas/administração & dosagem , Butanóis/administração & dosagem , Catecolaminas/antagonistas & inibidores , Catecolaminas/metabolismo , Depressão/tratamento farmacológico , Antagonistas de Dopamina/administração & dosagem , Fluoxetina/administração & dosagem , Masculino , Camundongos , Nortriptilina/administração & dosagem , Extratos Vegetais/isolamento & purificação , Sulpirida/administração & dosagemRESUMO
The studies evaluating the effect of smoking on olfaction reveals opposite results. In vitro and animal studies and epidemiological evidence from volunteers and patients, demonstrated the association between olfaction and erectile functions. In smoking man the reduction of olfactory acuity could adversely affect sexuality. The aim of the present study was to investigate the relationship between erectile dysfunction (ED) and olfactory dysfunction (OD) by comparing a group of healthy adult men with a group of smoking adult men. This prospective study involved 62 volunteers, who were recruited and divided into two groups; one consisted of 35 smoking adult men, and the other included 27 healthy non-smoking men. All participants in both groups were examined in detail for any condition with the potential to cause OD. They all had a normal genitourinary system suffered from no circulatory diseases, diabetes mellitus, hypertension, coronary artery disease nor hyperlipidemia; they had no history of medication affecting genitourinary system. Butanol threshold test and sniffin' stick® (Burghart, Wedel; Germany) screening test was used to asses olfactory functions in both groups. Participants' sexual desire was assessed using an International Index of Erectile Function (IIEF-5) scale. The means of sniffin' sticks scores, butanol threshold scores and IIEF-5 scores were statistically higher in non-smoking group. Butanol threshold scores and sniffin' sticks scores are correlated statistically with IIEF-5 in non-smoking and smoking groups. This study found an association between olfaction and erectile function in smoking and non-smoking men. As far as we know this study is the third published study to show the relationship olfactory and erectile function. In the future studies electrophysiological olfactory methods could be used to confirm in large cohorts the results obtained by the psychophysical approach.
Assuntos
Disfunção Erétil/etiologia , Transtornos do Olfato/etiologia , Fumar/fisiopatologia , Adulto , Butanóis/administração & dosagem , Humanos , Masculino , Odorantes , Limiar Sensorial/fisiologia , Índice de Gravidade de Doença , Fumar/psicologia , Estatísticas não Paramétricas , Adulto JovemRESUMO
Miracle fruit (Synsepalum dulcificum) belongs to the Sapotaceae family. It can change flavors on taste buds, transforming acidic tastes to sweet. We evaluated various miracle fruit extracts, including water, butanol, ethyl acetate (EA), and hexane fractions, to determine its antioxidant effects. These extracts isolated from miracle fruit exerted potential for reduction of uric acid and inhibited xanthine oxidase activity in vitro and in monosodiumurate (MSU)-treated RAW264.7 macrophages. Moreover, we also found that the butanol extracts of miracle fruit attenuated oxonic acid potassium salt-induced hyperuricaemia in ICR mice by lowering serum uric acid levels and activating hepatic xanthine oxidase. These effects were equal to those of allopurinol, suggesting that the butanol extract of miracle fruit could be developed as a novel anti-hyperuricaemia agent or health food.
Assuntos
Antioxidantes/administração & dosagem , Butanóis/administração & dosagem , Hiperuricemia/tratamento farmacológico , Extratos Vegetais/análise , Synsepalum/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Butanóis/química , Butanóis/farmacologia , Modelos Animais de Doenças , Hiperuricemia/sangue , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Camundongos , Camundongos Endogâmicos ICR , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Células RAW 264.7 , Ácido Úrico/sangue , Xantina Oxidase/metabolismoRESUMO
BACKGROUND: Rhododendrol, 4-(4-hydroxyphenyl)-2-butanol, Rhododenol(®) (RD), a naturally occurring phenolic compound, was developed as a tyrosinase inhibitor for skin-lightening/whitening cosmetics. In 2013, skin depigmentation was reported in consumers using RD-containing skin-brightening cosmetics; this condition is called RD-induced leukoderma. OBJECTIVE: The etiology of RD-induced leukoderma is still largely unknown. Here, to assess the depigmentation potential of RD, we developed a new mouse model of leukoderma by topically applying RD. METHODS: Hairless hk14-SCF Tg mice with melanocytes distributed in the epidermis were used for this study. RD was applied on the dorsal skin of the mice daily for 28 days. Then, immunohistological, biochemical, and electron microscopic analyses were performed on biopsy samples taken from these mice. RESULTS: The depigmentation in the RD-treated sites appeared on Day 14. Histological examination indicated a loss of epidermal melanocytes at Day 7. On the other hand, the melanocyte number did not decrease in the albino mice having the same background as the hairless hk14-SCF Tg, but without tyrosinase activity. Biochemical analyses showed that the eumelanin content decreased in the RD-treated sites and metabolites of RD-quinone, i.e., non-protein thiol adducts and protein-SH adducts, were produced. Electron microscopic analyses revealed double-membrane-walled structures containing electron-dense material, which might be typical for melanin-containing autophagosomes and a dilated endoplasmic reticulum (ER), which would indicate ER stress. CONCLUSIONS: These data suggested that RD exerted tyrosinase-dependent melanocyte cytotoxicity and that tyrosinase-dependent accumulation of ER stress from activation of the autophagy pathway contributed to melanocyte cytotoxicity.
Assuntos
Butanóis/farmacologia , Preparações Clareadoras de Pele/farmacologia , Pigmentação da Pele/efeitos dos fármacos , Administração Tópica , Animais , Povo Asiático , Autofagia/efeitos dos fármacos , Butanóis/administração & dosagem , Contagem de Células , Modelos Animais de Doenças , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Células Epidérmicas , Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Antígeno MART-1/metabolismo , Melaninas/metabolismo , Melanócitos/citologia , Melanócitos/efeitos dos fármacos , Melanócitos/metabolismo , Camundongos , Camundongos Pelados , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Animais , Monofenol Mono-Oxigenase/antagonistas & inibidores , Preparações Clareadoras de Pele/administração & dosagem , Pigmentação da Pele/fisiologia , Vitiligo/etiologiaRESUMO
The aim of this study was to investigate whether there are differences between women and men in how chemosensory stimuli are processed. Event-related potentials from 36 participants (18 men) showed that women had larger P3 amplitudes when attending, but not when ignoring CO(2) and amyl acetate stimuli compared with men. Conversely, auditory P3 was reduced by the same degree in women and men. No gender differences were found in magnitude estimations over time. Women had lower detection thresholds for CO(2), but not for n-butanol, compared with men. The main finding was that women and men differ in cognitive measures of chemosensory processing.
Assuntos
Atenção/fisiologia , Potenciais Evocados/fisiologia , Habituação Psicofisiológica , Limiar Sensorial/fisiologia , Caracteres Sexuais , Estimulação Acústica , Adolescente , Adulto , Vias Aferentes/fisiologia , Análise de Variância , Butanóis/administração & dosagem , Dióxido de Carbono/administração & dosagem , Eletroencefalografia , Feminino , Humanos , Masculino , Odorantes , Tempo de Reação/fisiologia , Estatísticas não Paramétricas , Estimulação Química , Adulto JovemRESUMO
PURPOSE: NK1 receptors have been implicated in various neuropsychiatric and other disorders. R116301 is a selective NK1 receptor antagonist. In this pilot study, [(11)C]R116301 was evaluated as a potential positron emission tomography (PET) ligand for the NK1 receptor. PROCEDURES: Two dynamic PET studies were performed in three normal volunteers before and after a blocking dose of aprepitant. Data were analyzed using striatum to cerebellum standardized uptake value (SUV) ratios. RESULTS: Baseline SUV ratios at 60-90 min after injection ranged from 1.22 to 1.70. Following aprepitant administration, this specific signal was completely blocked. Aprepitant administration did not significantly affect uptake in cerebellum, confirming the absence of NK1 receptors in cerebellum. CONCLUSION: These preliminary results indicate that [(11)C]R116301 has potential as a radioligand for in vivo assessment of NK1 receptors in the human brain.
Assuntos
Encéfalo/metabolismo , Butanóis/farmacocinética , Isótopos de Carbono/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Receptores da Neurocinina-1/metabolismo , Adulto , Aprepitanto , Encéfalo/diagnóstico por imagem , Butanóis/administração & dosagem , Isótopos de Carbono/administração & dosagem , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Ligantes , Malatos , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Projetos Piloto , Piperidinas , Compostos Radiofarmacêuticos/administração & dosagemRESUMO
Indigofera tinctoria is a perennial shrub, which belongs to the family Papilionaceae. As a part of our drug discovery program we have investigated the antidyslipidemic activity of the alcoholic extract from Indigofera tinctoria as well as its three other components, that is, chloroform, butanol and aqueous fractions in dyslipidemic hamsters that were fed a high fat diet. The chloroform fraction showed a significant decrease in the plasma triglycerides (TG, 52%) (P < 0.001), total cholesterol (TC, 29%) (P < 0.05), glycerol (Gly, 24%) and free fatty acids (FFA, 14%). This decrease was also accompanied by an increase in high density lipoproteins (HDL) by 9% and an increased HDL-C/TC ratio of 52% at the dose of 250 mg/kg of body weight.
Assuntos
Butanóis/administração & dosagem , Clorofórmio/administração & dosagem , Hipolipemiantes/administração & dosagem , Indigofera/química , Administração Oral , Animais , Butanóis/química , Clorofórmio/química , Colesterol/metabolismo , Ésteres do Colesterol/metabolismo , LDL-Colesterol/metabolismo , Cricetinae , Gorduras na Dieta , Relação Dose-Resposta a Droga , Glicerol/metabolismo , Hipolipemiantes/química , Hipolipemiantes/isolamento & purificação , Lipoproteínas HDL/metabolismo , Masculino , Extratos Vegetais/administração & dosagem , Plantas Medicinais/química , Triglicerídeos/metabolismoRESUMO
The butanolic fraction of dried leaves of Acacia pennata (Mimosaceae) was tested for analgesic and anti-inflammatory activities in animal models. It showed significant protective effects against chemical stimuli (acetic acid and formalin) in the mouse. It also produced a significant increase of the threshold of sensitivity to pressure-induced pain in the rats. The extract revealed an inhibitory effect in carrageenin-induced rat paw oedema in the late phase. The results suggested that a peripheral mechanism is involved in the analgesic, associated to anti-inflammatory effect (NSAIDs-like). Among the class of compounds characterized in this fraction, flavonoids may be mainly responsible for the pharmacological activities.
Assuntos
Analgésicos não Narcóticos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Mimosa/química , Ácido Acético/administração & dosagem , Ácido Acético/efeitos adversos , Administração Oral , Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/isolamento & purificação , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Butanóis/administração & dosagem , Butanóis/química , Butanóis/uso terapêutico , Carragenina/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Edema/induzido quimicamente , Edema/prevenção & controle , Feminino , Flavonoides/química , Flavonoides/isolamento & purificação , Formaldeído/administração & dosagem , Formaldeído/efeitos adversos , Formaldeído/antagonistas & inibidores , Membro Posterior/fisiopatologia , Masculino , Camundongos , Dor/tratamento farmacológico , Dor/etiologia , Dor/prevenção & controle , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Folhas de Planta/química , Pressão/efeitos adversos , Ratos , Ratos Wistar , Estimulação Química , Tramadol/farmacologiaRESUMO
The antioxidant activities of Acanthopanax senticosus stems were evaluated in CCl4-intoxicated rats. The n-butanol fraction from the water extract of the stems, when pretreated orally at 200 mg/kg/day for 7 consecutive days in rats, was demonstrated to exhibit significant increases in antioxidant enzyme activities such as hepatic cytosolic superoxide dismutase, catalase and glutathione peroxidase by 30.31, 19.82 and 155%, respectively. The n-butanol fraction whereas showed a significant inhibition of serum GPT activity (65.79% inhibition) elevated with hepatic damage induced by CCl4-intoxication. Eleutheroside B, a lignan component, isolated from the n-butanol fraction was found to cause a moderate free radical scavenging effect on DPPH, its scavenging potency as indicated in IC50 value, being 58.5 microM. These results suggested that the stems of A. senticosus possess not only antioxidant but also hepatoprotective activities.
Assuntos
Antioxidantes/farmacologia , Eleutherococcus/química , Lignanas/farmacologia , Caules de Planta/química , Administração Oral , Alanina Transaminase/sangue , Alanina Transaminase/efeitos dos fármacos , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Aspartato Aminotransferases/sangue , Aspartato Aminotransferases/efeitos dos fármacos , Compostos de Bifenilo , Butanóis/administração & dosagem , Butanóis/química , Butanóis/farmacocinética , Intoxicação por Tetracloreto de Carbono/tratamento farmacológico , Intoxicação por Tetracloreto de Carbono/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Sequestradores de Radicais Livres/metabolismo , Sequestradores de Radicais Livres/farmacologia , Glucosídeos/administração & dosagem , Glucosídeos/química , Glucosídeos/farmacocinética , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Indicadores e Reagentes , Lignanas/química , Lignanas/isolamento & purificação , Masculino , Fenilpropionatos/administração & dosagem , Fenilpropionatos/química , Fenilpropionatos/farmacocinética , Picratos/antagonistas & inibidores , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Silimarina/administração & dosagem , Silimarina/farmacocinética , Silimarina/uso terapêutico , Solubilidade , Água/químicaRESUMO
The recent development of selective NK(1) receptor antagonists that are active in vivo provides an important research tool to examine the role of substance P in the regulation of circadian rhythmicity. First, we tested whether R116301 [(2R-trans)-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S) hydroxybutanedioate], a new selective NK(1) antagonist, alters the phase-shifting effects of light. Hamsters housed in constant darkness were injected with different doses of R116301, just before being exposed to a light pulse during the subjective night. The results were compared with those obtained with the NK(1) antagonist L-760,735 [2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylaminomethyl)-1,2,3-trioazol-4-yl)methyl-3-(5)-phenyl)morpholine]. Second, the effects of the NK(1) antagonists R116301 or L-760,735 injected immediately after exposure to a light pulse were similarly determined. Third, we investigated whether R116301 or L-760,735 injected during the mid-subjective day or the late subjective night can phase-shift the circadian rhythm of locomotor activity in hamsters housed in constant light. Both compounds reduced, by more than 30%, the phase-advancing effects of a light pulse in hamsters otherwise maintained in constant darkness, only when the drugs were administered before the light pulse. Under constant light conditions, both NK(1) receptor antagonists induced significant phase-advances when injected during the subjective day, but not during the subjective night. The present results indicate that tachykinergic neurotransmission modulates the photic responses of the circadian system upstream of phase resetting mechanisms and suggest that an inhibition of the NK(1) receptor signals "darkness" to the circadian clock.
Assuntos
Butanóis/administração & dosagem , Ritmo Circadiano/fisiologia , Antagonistas dos Receptores de Neurocinina-1 , Receptores da Neurocinina-1/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Ritmo Circadiano/efeitos dos fármacos , Cricetinae , Escuridão , Relação Dose-Resposta a Droga , Esquema de Medicação , Injeções Intraperitoneais , Luz , Malatos , Masculino , Mesocricetus , Morfolinas/administração & dosagem , Atividade Motora/efeitos dos fármacos , Fotoperíodo , PiperidinasRESUMO
OBJECTIVE: To test the effect of the neurokinin-1 receptor antagonist hydroxybutanedioate (R116301) in human hand veins in vivo. METHODS: In a randomized, double-blind, placebo-controlled crossover study we used the hand vein compliance method to evaluate the inhibition of the response to substance P by R116301. RESULTS: In hand veins preconstricted with phenylephrine to 21% +/- 2.6% (mean +/- SEM, placebo) and 25% +/- 3.0% (R116301) of the initial diameter, substance P resulted in a mean venodilation of 84% +/- 7% and 87% +/- 13% (P = .8) before administration of placebo and R116301, respectively. Oral administration of 300 mg R116301 resulted in peak plasma concentrations of 1.16 +/- 0.1 microg/mL within 128 +/- 14 minutes. With increasing R116301 plasma concentrations, substance P-induced venodilation decreased significantly (P < .001), whereas placebo had no effect. Mean substance P-induced venodilation was markedly reduced to 8% +/- 7%. CONCLUSION: This study confirms the presence of neurokinin-1 receptors in human veins and the effectiveness of the neurokinin-1 receptor antagonist R116301 in human hand veins.
Assuntos
Butanóis/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Substância P/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Administração Oral , Adulto , Área Sob a Curva , Butanóis/administração & dosagem , Butanóis/sangue , Estudos Cross-Over , Método Duplo-Cego , Mãos/irrigação sanguínea , Humanos , Malatos , Masculino , Piperidinas , Valores de Referência , Substância P/administração & dosagem , Vasoconstritores/administração & dosagem , Vasoconstritores/sangue , Vasodilatadores/administração & dosagem , Veias/efeitos dos fármacosRESUMO
Lifibrol (4-(4'-tert-butylphenyl)-1-(4'carboxyphenoxy)-2-butanol), a new hypocholesterolemic drug, effectively reduces total cholesterol (CH), low density lipoprotein (LDL)-CH, and apolipoprotein (apo) B in experimental animals and in humans. The impact of Lifibrol on the metabolism of apoB-100 containing lipoproteins in patients with hyperlipoproteinemia using endogenous labeling with stable isotopes is examined. Kinetic studies were performed in four male hypercholesterolemic individuals (type IIa) before and on treatment with 450 mg of Lifibrol daily for 4 weeks, and in five male individuals suffering from mixed hyperlipidemia (type IIb) before and on therapy for 12 weeks. Kinetic parameters were estimated by multicompartmental modeling. Lifibrol therapy reduced total CH by 16% (P = 0.012) in all patients, increased triglycerides (TG) by 11% (not significant) in type IIa patients and decreased TG by 34% (P = 0.059) in type IIb patients. During Lifibrol therapy, LDL apoB-100 concentrations decreased by 19% (P = 0.011) in all patients. The decrease in LDL apoB concentrations with Lifibrol therapy was due to an overall increase (75%, P = 0.006) of the fractional catabolic rates (FCR) of LDL apoB. This increase was partially attenuated by a 33% increase in LDL apoB production rate (PR) (P = 0.041). The overall production of apoB increased only slightly. Our data suggest that the major mechanism by which Lifibrol lowers LDL-CH is an increase in receptor-mediated catabolism of LDL rather than a decrease in hepatic apoB production.
Assuntos
Anticolesterolemiantes/administração & dosagem , Apolipoproteínas B/efeitos dos fármacos , Butanóis/administração & dosagem , Hidroxibenzoatos/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Lipoproteínas LDL/efeitos dos fármacos , Adulto , Apolipoproteínas B/metabolismo , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/metabolismo , Hiperlipidemias/complicações , Hiperlipidemias/diagnóstico , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Lipoproteínas LDL/metabolismo , Masculino , Pessoa de Meia-Idade , Estatísticas não Paramétricas , Resultado do TratamentoRESUMO
OBJECTIVES: To investigate the possibility of applying diffusive air sampling and urinalysis (for mother compound and metabolites) to the monitoring of exposure of factory workers to 1-butanol. METHODS: The performance of carbon cloth in adsorbing 1-butanol vapor in air was studied by experimental exposure of the cloth to 1-butanol at 50, 100, 200 or 400 ppm for up to 10 h. 1-Butanol in the exposed cloth was extracted with carbon disulfide and this was followed by gas-chromatographic (GC) analysis. Urine samples were collected from factory workers occupationally exposed to 1-butanol and from rats exposed experimentally to 1-butanol vapour (up to 200 ppm). The urine samples were analyzed by GC without any pretreatment, or after treatment with hydrochloric acid or hydrolase preparation. RESULTS: The performance of the carbon cloth was such that it adsorbed 1-butanol in proportion to the concentration (up to 400 ppm) and the duration (up to 10 h) of exposure, and responded quantitatively to a 15-min exposure up to 400 ppm. The amount of 1-butanol (after enzymic or acid hydrolysis) in post-exposure urine samples from rats was proportional to the exposure intensity. The proportion of free 1-butanol in total 1-butanol (i.e., free+conjugated) in urine was higher after 100 or 200 ppm exposure (35-40%) than after 50 ppm exposure (about 8%). There was a significant increase in total 1-butanol concentration (but not in free 1-butanol) in shift-end urine samples of workers exposed to 1-butanol at concentrations up to 3 ppm. CONCLUSIONS: Diffusive sampling with carbon cloth as an adsorbent can be applied to ambient air monitoring of exposure to 1-butanol. Urinalysis for 1-butanol after hydrolysis is sensitive enough to detect occupational 1-butanol vapour exposure at 3 ppm.
Assuntos
Butanóis/urina , Monitoramento Ambiental/métodos , Doenças Profissionais/urina , Exposição Ocupacional/análise , 1-Butanol , Administração por Inalação , Adsorção , Animais , Butanóis/administração & dosagem , Carbono/química , Cromatografia Gasosa , Feminino , Humanos , Masculino , Ratos , Ratos WistarRESUMO
Olfactory threshold was investigated in patients with verified allergic rhinitis to birch pollen. In 20 patients the olfactory threshold was measured before and after challenge with topically applied birch pollen allergen during a non-symptomatic period. After provocation a statistically significant impaired detection sensitivity was found. The change in olfactory threshold was correlated with the measured amount of nasal secretions but not with subjectively or objectively registered nasal obstruction. A pronounced allergic reaction after allergen challenge is accompanied by an elevated olfactory threshold.
Assuntos
Alérgenos , Pólen , Rinite Alérgica Sazonal/fisiopatologia , Limiar Sensorial/fisiologia , Olfato/fisiologia , 1-Butanol , Administração Intranasal , Adolescente , Adulto , Butanóis/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/metabolismo , Obstrução Nasal/fisiopatologia , Testes de Provocação Nasal , Nariz/patologia , Nariz/fisiopatologia , Odorantes , Rinite Alérgica Sazonal/patologia , ÁrvoresRESUMO
Post mortem diffusion of paint thinner (toluene/ethyl acetate/isobutanol 8:1:1 v/v) from gastric residue (25 ml or 100 ml) and airways contamination (25 ml) was assessed in a human cadaver model, with sampling after 24 h at room temperature. Four torso blood samples showed less toluene diffusion after gastric instillation (0.5-3.8 micrograms/ml) than after tracheal instillation (10.5-421 micrograms/ml). Isobutanol diffused more readily than toluene with four torso blood samples 1.8-256 micrograms/ml after gastric instillation and 26-576 micrograms/ml after tracheal instillation. Following 25 ml gastric instillation, toluene concentrations (microgram/ml or microgram/mg) were: pericardial fluid 0.7-4.0; bile 0.5-0.6; urine 0-0.6; brainstem 1.1; lung 0.4-4.4; liver 0-162; spleen 0.6-0.7; kidneys 0.4-0.6; peri-renal fat 0.3-30.3; psoas muscle 0.3-0.8; concentrations of toluene and isobutanol were markedly higher in the left lobe of the liver than the right. Ethyl acetate was mostly undetectable in tissue samples but variably present in five blood samples: 0-21.2 micrograms/ml following 25 ml or 100 ml gastric instillation and 0-198 micrograms/ml following 25 ml tracheal instillation. Ethyl acetate was always detectable in pericardial fluid but not always detectable in gastric contents. We conclude that post mortem diffusion of toluene from gastric residue or airways contamination is unlikely to compromise the analytical validity of femoral venous blood samples, brain, or liver from deep within the right lobe. Analysis of pericardial fluid and gastric contents allows identification of ethyl acetate and isobutanol thus implicating thinner solution.
Assuntos
Acetatos/farmacocinética , Butanóis/farmacocinética , Solventes/farmacocinética , Tolueno/farmacocinética , Acetatos/administração & dosagem , Administração por Inalação , Administração Oral , Butanóis/administração & dosagem , Difusão , Medicina Legal , Humanos , Solventes/administração & dosagem , Fatores de Tempo , Tolueno/administração & dosagemRESUMO
Tertiary butyl alcohol and trichloroacetic acid (TCA) are known to be contaminants in drinking water. In order to evaluate the interactive toxicity of t-butyl alcohol (TBA) with TCA, young male Wistar rats were dosed through water at a dose level of TBA (0.5% v/v), 25 ppm TCA and a combined dose of TBA+TCA (0.5% v/v TBA, 25 ppm TCA) for a period of 10 weeks ad libitum and were maintained on normal diet. The control animals received plain water and normal diet. There was remarkable loss of body weight and significantly decreased liver triglycerides in the treatment groups in the order of TBA+TCA, TCA, TBA and increased liver weights were observed. Serum succinate dehydrogenase (SDH) levels were significantly increased in TCA- and TBA+TCA-treated groups. There was no significant change in serum alanine (GPT), aspartate (GOT) aminotransferase, serum alkaline (ALP) and acid (ACP) phosphatase levels as well as liver glutathione (GSH) and liver and serum cholesterol levels in the treated groups. But serum triglycerides, liver glycogen, serum glucose (only in TBA- and TCA-treated animals) were significantly high in the treated groups. Lipid peroxidation measured by diene conjugation was significant in TBA+TCA-treated group and kidney GSH levels were significantly low in the treated groups. These results show that interaction of TBA+TCA does bring about alteration in biochemical parameters which may play a pivotal role in toxic responses on long-term exposure.