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Although there have been two-dimensional electrophoretic studies on fetal brain tissue (for instance, Yoshida and Takahashi, 1980), the emphasis in most of this work has been on developmental changes in protein expression, and not on the effects that drugs have on fetal brain protein complement. Klose and co-workers (1977) did an early study using two-dimensional gel electrophoresis to determine the effects of various teratogens on whole embryos. No protein changes were found and that line of research was not continued. In this study two-dimensional gel electrophoresis is extensively used, in the belief that the usefulness of this technique to experimental teratology has not been fully evaluated. It is reasonable to suppose that a central nervous system teratogen administered during critical periods of susceptibility will led to perturbations of orderly brain development, and that these perturbations will be reflected as changes to the protein complement. The total brain protein complement of mice that have been exposed to drugs in utero will therefore be analysed, in the hope that any inductions or deletions of proteins as a result of drug exposure may provide a clue to the molecular events underlying drug injury to the fetus.

The trace elements zinc and copper are essential components of many enzymes, some of which are of importance for the development and function of the central nervous system. Deficiency of the metals has been shown to lead to malformations and to the loss of myelin in animals. Earlier reports of zinc concentrations in the cerebrospinal fluid are few and the results variable. In multiple sclerosis and in epilepsy therapy with phenytoin there are varying reports of changes in serum concentrations of zinc and copper. A method was developed for the determination of zinc in cerebrospinal fluid by flame atomic absorption spectrophotometry utilizing a pulse nebulizer technique. Zinc and copper in serum were determined by flame atomic absorption spectrophotometry with conti nous aspiration. The normal concentrations of zinc in cerebrospi nal fluid was 0.16_+0.03 micromoles per litre (mean +_ S.D.). The zinc concentrations were correlated with protein and albumin concentrations in the cerebrospinal fluid but not with the serum zinc levels. In the patients with increased protein concentrations in the cerebrospinal fluid or with subarachnoid haemorrhage increased zinc levels were found. In 50 patients with multiple sclerosis lower serum concentrations of zinc were found compared to age and sex matched controls. In younger patients low serum levels of copper were also observed. There was no correlation between zinc and protein parameters in the cerebrospinal fluid of multiple sclerosis patients. In untreated epileptic males low serum zinc concentrations were observed. During the first 72 hours of phenytoin therapy increased serum concentrations of zinc and copper were found. during long-term therapy with phenytoin alone or in combination with other antiepileptic drugs there was an increased serum concentration of copper and ceruloplasmin but no change in zinc concentration compared with controls. / <p>Diss. Umeå, Umeå universitet, 1982, härtill 4 uppsatser</p> / digitalisering@umu

The effect of triacetin in combination with common cosolvents on the solubility of phenytoin and diazepam was studied. The cosolvents were PEG 400 and propylene glycol. In addition, the data were used to test the following model: UNFORMATTED EQUATION FOLLOWS: log Sᵈ(c,p,w) = log Sᵈ(w) + f(c)σᵈ(c) + [Sᵖ(w)10(f(c)σᵖ(c))/D(p)] σᵈ(p). UNFORMATTED EQUATION ENDS. The term on the left side of the equation is the solubility of a drug in the ternary system. This is related to the aqueous solubility of the drug, the solubility of the drug in a completely miscible organic solvent (CMOS), and the solubility of the partially miscible organic solvent (PMOS). This model was proposed by Gupta et al. (1989) and predicts the solubility of a ternary system composed of a CMOS and PMOS. The results indicate the triacetin does increase the solubility of the two poorly water-soluble drugs. There is good correlation between the observed and predicted increase in the solubility of the drugs.

Dilantin (diphenylhydantoin or DPH) has been given to epileptic mothers to control seizures during pregnancy. Previous research has demonstrated that exposure of human embryos to Dilantin in vivo results in an increased probability of abnormal development and early fetal loss. Preliminary results with cultured 1-cell and 2-cell mouse embryos demonstrated that Dilantin causes mouse embryonic cleavage events to slow during preimplantation development (Chatot et al., unpublished). Dilantin may be responsible for this by inhibiting the rate of DNA synthesis during cleavage or by affecting the expression of proteins that control cell cycle progression. The standard expression pattern of these cell cycle regulatory proteins (cyclins) has not previously been determined in the mouse preimplantation embryo model. In this study, immunolabellingtechniques have been used to determine the expression pattern of cyclins D, A, and B 1 in the first three cell cycles of preimplantation mouse embryo development.This study reveals a unique expression pattern of cyclins D, A, and B1 in the first three cell cycles of preimplantation embryo development. Examination of the beginning of the first cell cycle, or G1, indicated a moderate expression of cyclin B1 and A but no cyclin D expression. During DNA synthesis (S-phase) all cyclin expression was virtually nonexistent. Toward the end of the cell cycle at G2/M, cyclin D expression appeared to be at moderate levels while cyclins A and B 1 exhibited minimal degrees of expression.In G 1 of the second cell cycle, cyclins D and A were minimally to moderately expressed and cyclin B 1 expression was minimal. At S-phase, cyclin D expression dropped to minimal levels whereas cyclins A and B 1 were at minimal to moderate levels of expression. At G2/M of the second cell cycle, cyclin B1 was expressed at minimal to moderate levels and cyclins A and D were both expressed at minimal levels.The third cell cycle began at G 1 with cyclin B 1 being expressed at moderate levels followed by minimal to moderate levels of cyclin D expression and minimal expression for cyclin A. Cyclin D expression increased to moderate levels at S-phase and cyclin A exhibited minimal to moderate levels of expression. Cyclin B 1 was observed at moderate levels of expression at S-phase of the third cell cycle. G2 of the third cell cycle included a drop to minimal levels of expression of cyclin D, while cyclin A expression remained at minimal to moderate levels and cyclin B remained at moderate levels of expression.The cyclin expression pattern for the first three cell cycles in preimplantation mouse embryos is unique compared to known cyclin expression patterns in other species. Cyclin D is expressed in G1 and is known to be necessary for advancement to S-phase in human glioblastoma cell lines (Xiong et al., 1991). Cyclin A is active at S-phase through Win human fibroblasts and xenopus oocytes (Giordino et al., 1991; Minshul et al., 1990). Cyclin B is present at G2 through mitosis in human fibroblasts and xenopus oocytes (Pines and Hunter, 1990; Minshul et al, 1990). / Department of Biology

The anticonvulsant drug, Dilantin, in many cases must be taken by epileptic mothers to control seizures during pregnancy, but unfortunately, it has been characterized as a human teratogen. It has also been demonstrated that many of the teratogenic effects of Dilantin occur during postimplantation, but some studies implicate a detrimental role for Dilantin during the preimplantation stages of development. Some of the postimplantation effects include congenital malformations and the potential'loss of the fetus. Our lab has proposed that in preimplantation mouse embryos the drug may be altering the timing of expression of cell cycle regulatory proteins and therefore, we have begun to examine the expression of these proteins. Thus, it was the goal of this study to characterize and localize various cell cycle proteins at specific time points in normal in vivo preimplantation mouse embryos, as this will provide important baseline information for studies on how anticonvulsant drugs may alter cell cycle regulation in embryos.Western blotting has confirmed the presence of cyclin BI in G1 of the first cell cycle. Both cyclin E and CDK2 were not detected in GI or G2/M of the first cell cycle or GI of the second cell cycle.From the immunogold TEM experiments, the density of cyclin B1 staining was observed to be the highest at G1 of the first cell cycle and declined at S and G2/M. Cyclin B 1 was detected in all regions of the embryo including the microvilli, cortical cytoplasm, interior cytoplasm, and was observed to be associated with vesicles and some filaments. The gold particles at GI, S, and G2/N4 of the first cell cycle and G1 of the second cell cycle appear to be associated with filamentous and membraneous structures and not free in the cytoplasmic spaces. Cyclin B 1 expression was more concentrated around vesicles at G1 of the first cell cycle and in general, was more concentrated around vesicles than in microvilli and cortical cytoplasm, interior cytoplasm, or around filaments at each cell cycle stage tested. / Department of Biology

published_or_final_version / Medicine / Master / Master of Philosophy

Access to abstract restricted until 12/14/2014. / Access to thesis restricted until 12/14/2014. / Department of Biology

Thesis (Ph. D.)--University of Washington, 2008. / Vita. Includes bibliographical references (leaves 186-207).

Made available in DSpace on 2015-07-22T20:49:34Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-05-25 / Este trabalho tem como objetivo avaliar o efeito do uso tópico da fenitoína na cicatrização de feridas cutâneas. A fenitoína como terapia sistêmica tem ação anticonvulsivante, e com o uso tópico tem ação de acelerar a cicatrização de feridas cutâneas. Neste estudo foram avaliados 100 pacientes cada um com 2 feridas cutâneas resultantes da excisão de lesões de nevos melanocíticos, sendo 50 pacientes com lesões na face e 50 pacientes com lesões em dorso do tórax, totalizando 200 lesões excisadas com punch modificado. Durante o tratamento o mesmo paciente recebia a fenitoína a 0,5% em creme e o creme base (controle), para fazer os curativos diariamente. O seguimento dos pacientes foi realizado no periodo de 7, 14, 21 e 60 dias, sendo avaliados os seguintes parâmetros: sangramento, exsudato, eritema na borda da ferida, infecção, presença de tecido de granulação hipertrófico, tempo de cicatrização, intensidade da epitelização, área da ferida cutânea, o formato e área da cicatriz, as possíveis reações adversas e o resultado cosmético. Os pacientes foram comparados quanto a idade, peso, altura, fototipo, tipo histológico da lesão. A fenitoína apresentou melhor resultado terapêutico e cosmético comparado com o creme base (controle). A fenitoína é uma droga de baixo custo, que acelera a cicatrização de feridas cutâneas. / This study aims to evaluate the effect of topical use of phenytoin in healing of skin wounds. A systemic therapy with phenytoin have anticonvulsant activity, and the topical use action is to accelerate the healing of skin wounds. This study evaluated 100 patients each with 2 wounds resulting from excision of lesions of melanocytic nevi, 50 patients with lesions on the face and 50 whith back injuries in the chest, total of 200 lesions excised with punch modified. During treatment the patient received phenytoin to 0.5% in the cream and cream base (control), to make the dressing daily. The follow up of patients was carried out from 7, 14, 21 and 60 days, where the following parameters were evaluated: bleeding, exudate, erythema at the edge of the wound, infection, presence of hypertrophic granulation tissue, healing time, intensity of epithelialization, the wound area, the shape and area of the scar, possible adverse reactions and cosmetic outcome. The patients were compared in age, weight, height, phototype, histological type of lesion. The phenytoin showed better therapeutic and cosmetic results compared with the cream base (control). The phenytoin is a drug of low cost, which accelerates the healing of skin wounds. / TEDE / BV UNIFESP: Teses e dissertações