RESUMO
CD4(+)CD25(+) regulatory T cells (Tregs) are potent immunosuppressors that are pivotal in the maintenance of self-tolerance. The involvement of Tregs in therapies for immune-mediated diseases has been proposed, but direct supporting evidence is still lacking. While investigating mechanisms underlying the clinical benefits of glatiramer acetate (GA) in an animal model of multiple sclerosis (MS), i.e., experimental autoimmune encephalomyelitis (EAE), we recently demonstrated that GA can protect mice deficient in the Th(2) cytokines IL-4, IL-10 and IL-4/IL-10 from acquiring EAE, suggesting that mechanisms other than Th(2) cells may be responsible for the therapeutic effects of GA. Here we demonstrate that GA treatment boosts the expression of Foxp3 on Tregs during EAE. Furthermore, adoptive transfer of purified Tregs from GA-treated EAE mice is more effective in preventing EAE development than Tregs from untreated EAE controls. Thus, our current data provide evidence that Tregs may be the major contributor to GA's therapeutic action in EAE and, possibly, MS. Further mechanistic studies to reveal the molecular events linking GA with Tregs may optimize GA treatment and lead to the development of new, even more effective therapies that utilize this mechanism of action.
Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Imunossupressores/uso terapêutico , Peptídeos/uso terapêutico , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Citometria de Fluxo , Fatores de Transcrição Forkhead/efeitos dos fármacos , Fatores de Transcrição Forkhead/metabolismo , Acetato de Glatiramer , CamundongosRESUMO
The synthesis and structural characterization of the sterically congested pyrophosphite 6-[(2,4,8,10-tetrakis(1,1-dimethylethyl)-dibenzo[d,f][1,3,2]dioxaphosphepin-6-yl)oxy]-2,4,8,10-tetrakis(1,1-dimethylethyl)-dibenzo[d,f][1,3,2]dioxaphosphepin, 3, is described. In solution at room temperature, a single species was observed that was consistent with a pyrophosphite structure without any evidence for the tautomeric diphosphine monoxide. Below the coalescence temperature (T(C)), 0 degrees C, three atropisomers were observed with relative absolute configurations of (R,R,R), (R,S,R), and (R,R,S). Ring inversion of the seven-membered rings below the T(C) is slow on the NMR time scale, which leads to observable diastereoisomerism because of the presence of two independent stereoaxes (sp2-sp2 C-C single bond connecting the two aryl rings). Additionally, a rotation about an exocyclic P-O single bond connecting the two seven-membered rings, which constitutes a third stereoaxis, is slowed on the NMR time scale. In the X-ray crystal structure of 3, the solid-state conformation was found to be the same as the major conformation in solution below the T(C), namely, the (R,R,S) atropisomer. The results of a conformational search, performed with a specifically parametrized AMBER force field, were in agreement with the 31P NMR assignment of the major (R,R,S) atropisomer, which was found to be an energy minimum. Additionally, we could independently assign the relative configuration of the minor isomers based on the calculated results.
RESUMO
PURPOSE: We present a validation study of CT and PET lung image registration and fusion based on the chamfer-matching method. METHODS AND MATERIALS: The contours of the lung surfaces from CT and PET transmission images were automatically segmented by the thresholding technique. The chamfer-matching technique was then used to register the extracted lung surfaces. Arithmetic means of distance between the two data sets of the pleural surfaces were used as the cost function. Matching was then achieved by iteratively minimizing the cost function through three-dimensional (3D) translation and rotation with an optimization method. RESULTS: Both anatomic thoracic phantom images and clinical patient images were used to evaluate the performance of our registration system. Quantitative analysis from five patients indicates that the registration error in translation was 2-3 mm in the transverse plane, 3-4 mm in the longitudinal direction, and about 1.5 degree in rotation. Typical computing time for chamfer matching is about 1 min. The total time required to register a set of CT and PET lung images, including contour extraction, was generally less than 30 min. CONCLUSION: We have implemented and validated the chamfer-matching method for CT and PET lung image registration and fusion. Our preliminary results show that the chamfer-matching method for CT and PET images in the lung area is feasible. The described registration system has been used to facilitate target definition and treatment planning in radiotherapy.
Assuntos
Carcinoma de Células Escamosas/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Planejamento da Radioterapia Assistida por Computador/métodos , Tomografia Computadorizada de Emissão , Tomografia Computadorizada por Raios X , Idoso , Carcinoma de Células Escamosas/radioterapia , Fluordesoxiglucose F18 , Humanos , Neoplasias Pulmonares/radioterapia , Masculino , Fenômenos Físicos , Física , Intensificação de Imagem Radiográfica/métodos , Compostos Radiofarmacêuticos , Reprodutibilidade dos TestesRESUMO
The disposition and metabolism of prinomide, the 1:1 triethanolamine salt of 1-methyl-beta-oxo-alpha-(phenylcarbamoyl)-2-pyrrolepropionitrile (CGS 10787B), have been investigated in a number of animal species after single and multiple oral dosing with 14C-labeled and unlabeled drug. After single oral doses of 25 to 50 mg/kg of [14C]prinomide to mice, rats, hamsters, dogs, cynomolgus monkeys, and baboons, radioactivity was excreted primarily in urine, in the form of metabolites. However, in the mouse and monkey, fecal excretion was also significant. In the cynomolgus monkey, a radioactive dose of drug administered after multiple doses of unlabeled drug gave rise to peak plasma concentrations of radioactivity within 1 to 6 hr. Prinomide accounted for approximately 69% of this radioactivity. The terminal plasma half-life of the drug was 24 to 41 hr. Studies in rats with [14C]prinomide indicated that radioactivity was distributed rapidly to all tissues, with the highest levels being observed in blood and well perfused organs and tissues. The lowest levels were detected in fat, eyes, and brain. Tissue levels declined to less than 6% of peak values by 48 hr after dosing, the only exceptions being fat and kidney, which retained 14 and 17% of peak radioactivity, respectively. The metabolism of prinomide was qualitatively similar in all species investigated. Major metabolites identified were the phenyl ring p-hydroxy, M1, and the bicyclic spiro, M2, derivatives of the parent drug. Other common metabolites were M3, the phenyl ring p-hydroxy analog of M2 and a complete rearrangement product in the form of a succinimide derivative, M4.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Pirróis/metabolismo , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Cricetinae , Cães , Fezes/análise , Macaca fascicularis , Espectroscopia de Ressonância Magnética , Mesocricetus , Conformação Molecular , Papio , Pirróis/farmacocinética , Ratos , Ratos Endogâmicos , Especificidade da Espécie , Distribuição TecidualRESUMO
The synthesis of two thiophene-containing analogues of mianserin, i.e., 1,2,3,4,10,13b-hexahydro-2-methylpiperazino[1,2-a]thieno[2, 3-c][1]benzazepine (2), and the corresponding [3,2-c] isomer (12) is described. The key step in the synthesis is the nucleophilic aromatic substitution reaction of the N-lithio derivative of 1-methyl-3-(2-thienyl)piperazine (4) with the oxazoline derivative of o-anisic acid (7) to give the N-phenylpiperazine 8. This substance was converted via ethyl ester 10 to 1-[2-(hydroxymethyl)phenyl]-4-methyl-2-(2-thienyl)piperazine (3), which was cyclized with polyphosphate ester to a 5:1 mixture of 2 and 12. The antidepressant potential of 2 maleate (CGS 11049A) and 12 fumarate (CGS 15413A) were compared with that of mianserin hydrochloride in a variety of biochemical and pharmacological test systems. The three substances exhibited generally similar profiles. However, the results suggest that 2 and 12 bind more strongly to central presynaptic alpha-receptors than does mianserin.
Assuntos
Dibenzazepinas/síntese química , Mianserina/síntese química , Animais , Encéfalo/metabolismo , Liberação de Histamina/efeitos dos fármacos , Mianserina/análogos & derivados , Camundongos , Prazosina/metabolismoRESUMO
The metabolism of aminoglutethimide was studied in the rat by use of the 14C-labeled compound. Following oral doses of 5 and 50 mg/kg, the drug was almost completely eliminated within 48 hr into urine and feces, mostly in the form of metabolites. In bile duct-cannulated rats, biliary excretion of radioactivity amounted to about 52% within 24 hr of an orally administered 50 mg/kg dose, with the remainder of the dose being eliminated into urine. The major urinary metabolites resulted from acetylation of the aniline moiety, hydroxylation of the glutarimide ring at positions 3 and 4, and oxidative elimination of the ethyl sidechain. The polar metabolites are accounted for by aromatic hydroxylation with subsequent sulfate conjugation and by a glutarimide ring-opened compound. In addition, a gamma-butyrolactone derivative was also identified.