On the basis of clinical studies, some researchers have advocated that the neurohormone and antioxidant melatonin, shown to possess intrinsic anticancer properties, be used as co-therapy in cancer patients being treated with the antineoplastic agent 5-fluorouracil, as increased patient survival times and enhanced quality of life have been observed. The focus of this research was thus to investigate the mechanisms of this seemingly beneficial drug interaction between 5-fluorouracil and melatonin. Metabolism studies were undertaken, in which it was established that there is no hepatic metabolic drug interaction between these agents by cytochrome P450, and that neither agent alters the activity of this enzyme system. Co-therapy with melatonin is thus unlikely to alter plasma levels of 5-fluorouracil by this mechanism. Novel mechanisms by which 5-fluorouracil is toxic were elucidated, such as the induction of lipid peroxidation, due to the formation of reactive oxygen species; decreases in brain serotonin, dopamine and norepinephrine levels, possibly leading to depression; hippocampal shrinkage and morphological alterations and lysis of hippocampal cells, which may underlie cognitive impairment; and a reduction in the nociceptive threshold when administered acutely. All these deleterious effects are attenuated by the co-administration of melatonin, suggesting that the agent exhibits antidepressive and analgesic properties, in addition to its known antioxidative and free radical-scavenging abilities. This suggests that melatonin cotherapy can significantly decrease 5-fluorouracil-induced toxicity, but this may also exert a protective effect on cancer cells and thus compromise the anticancer efficacy of 5-fluorouracil. It was, furthermore, found that stimulation of indoleamine 2,3-dioxygenase activity, mediated by increases in superoxide anion and interferon-γ levels, may underlie resistance to 5-fluorouracil therapy. Melatonin was shown to increase superoxide anion levels in vivo, and this is believed to be by conversion to the metabolite and known oxidant 6- hydroxymelatonin. This highlights that the possible deleterious effects of melatonin metabolites should be studied further. Serum corticosterone levels and cytokine profiles are unaltered by both 5-FU and melatonin, suggesting that these agents may be used by HIV infected individuals without promoting the progression to AIDS. It can thus be concluded that melatonin co-therapy is potentially useful in countering 5-fluorouracil toxicity.

Orientadores: Alan Roger dos Santos Silva, Ana Lúcia Carrinho Ayroza Rangel / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-26T10:30:04Z (GMT). No. of bitstreams: 1 Iachinski_TatianaSantosAssumpcao_D.pdf: 1245874 bytes, checksum: 0e426f4d5b6b5c707e92933df790258a (MD5) Previous issue date: 2014 / Resumo: O tratamento do câncer pode provocar efeitos colaterais que limitam a efetividade da terapia e ter grande impacto na qualidade de vida do paciente. A dor orofacial em pacientes oncológicos é comum e pode estar relacionada à quimioterapia. A neurotoxicidade periférica e a dor neuropática são complicações de diversos agentes quimioterápicos, como a Oxaliplatina, que apresenta alta incidência de efeitos colaterais por toxicidade aguda e crônica. O objetivo deste estudo foi pesquisar as manifestações sensitivas e motoras orofaciais causadas pela neurotoxicidade do esquema quimioterápico FOLFOX 4. Na avaliação clínica prospectiva, foram avaliados 23 pacientes com câncer de cólon e reto, submetidos ao esquema quimioterápico FOLFOX 4 - FOL: Ácido Folínico (Leucovorina), F: Fluorouracil (5-FU), OX: Oxaliplatina. Os pacientes foram avaliados em quatro momentos da quimioterapia: no ciclo 1, entre o ciclo 2 e 3, entre o ciclo 6 e 8 e no último ciclo (12). Exame clínico e questionário foram aplicados para pesquisar ocorrência e as características clínicas da neuropatia periférica, incluindo: dor orofacial, parestesia perioral, disgeusia, disfagia, disartria, câimbra nos músculos mastigatórios, perda de sensibilidade tátil, disestesia, e a ocorrência de odontalgia neuropática. O acompanhamento durante os ciclos da quimioterapia buscou avaliar fatores desencadeantes, de piora e melhora, para intervenções dirigidas à dor. A manifestação da neurotoxicidade orofacial ocorreu no sintoma de parestesia em lábio, língua ou perioral, em 13% dos pacientes, e disgeusia, em 57% dos pacientes. Dor neuropática em face, boca ou dentes não foram detectadas na pesquisa. Os sintomas foram transitórios, caracterizando uma toxicidade aguda. Pode-se concluir que o esquema quimioterápico FOLFOX 4 está associado a neurotoxicidades orofaciais transitórias como parestesia e disgeusia, sugerindo neuropatia aguda. Contudo, o protocolo de tratamento em questão não desencadeou dor orofacial / Abstract: The treatment of cancer can produce side effects, which are dose-limiting and provoke a great impact on patient's quality of life. Orofacial pain often affects cancer patients, and it may be related to chemotherapy. The peripheral neurotoxicity and the neuropathic pain are complications of chemotherapeutic agents, such as oxaliplatin, which leads to a high incidence of acute and chronic side effects. The aim of this study was to investigate the orofacial sensory and motor manifestations of neurotoxicity induced by FOLFOX 4 chemotherapy in the treatment of colon cancer. Twenty-three patients were enrolled in this clinical prospective study, treated by FOLFOX 4 - FOL: Folic Acid (Leucovorin), F: Fluorouracil (5-FU), OX: Oxaliplatin (Eloxatin). The assessment was conducted in four stages of chemotherapy: cycle 1, between cycle 2 and 3, between cycle 6 and 8, and in the last cycle (12). The symptoms of the peripheral neuropathy manifestation were investigated using a questionnaire and clinical examination, in order to determine the occurrence and the clinical characteristics of the following symptoms: orofacial pain, perioral paresthesia, dysgeusia, dysphagia, dysarthria, cramps, loss of tactile sensitivity, dysesthesia, and the neuropathic dental pain. The monitoring during cycles of chemotherapy aimed to identify trigger points, worsening and improvement factors for interventions oriented toward the pain. The manifestation of neurotoxicity occurred as paresthesia in lips, tongue or perioral region, in 13% of patients, while dysgeusia affected 57% of the patients during the treatment. In this research, neuropathic pain in the face, oral region or teeth was not detected. The manifested symptoms were transient, remaining about three days, suggesting an acute toxicity. This study demonstrated that FOLFOX 4 is related to oral symptoms, such as paresthesia and dysgeusia, which decreased at the end of treatment, charactering acute neuropathy. Conversely, this protocol did not triggered orofacial pain / Doutorado / Estomatologia / Doutora em Estomatopatologia

A própolis vermelha é uma resina natural produzida por abelhas do gênero Apis a partir de exsudados vegetais e tem atraído a atenção dos pesquisadores de todo o mundo devido à sua potente atividade em diversos modelos biológicos. Essa resina natural é rica em polifenóis e compostos voláteis, sendo que mais 300 compostos químicos já foram identificados em amostras de diferentes regiões. Técnicas de identificação química de alta precisão são imprescindíveis para a correta elucidação dos compostos químicos presentes nas amostras e para o entendimento dos efeitos biológicos. Neste estudo, buscou-se utilizar técnicas de fracionamento como uma metodologia capaz de ser explorada em estudos envolvendo amostras de própolis vermelha, buscando-se a identificação e caracterização de frações ativas, bem como o uso de modelos celulares de câncer de cólon para o screening de moléculas bioativas. As frações ativas foram identificadas por meio HPLC-MS e ESI-MS/MS, evidenciando uma composição química complexa baseada em compostos fenólicos e flavonoides. Entre os resultados obtidos, destacam-se as frações 05 e 06, as quais foram capazes de produzir inibição significativa sobre as linhagens tumorais HT-29 e HCT-116, respectivamente, com menores efeitos sobre as células não-tumorais. As frações obtidas no estudo apresentaram menor diversidade química do que a encontrada no extrato total da própolis, favorecendo a sua bioatividade in vitro, e, como resultado, esta técnica pode favorecer a descoberta e o desenvolvimento de novos fármacos utilizando a própolis como fonte de potencial de moléculas contra o câncer. / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, CAPES. / Red propolis is a natural resin produced by bees of the genus Apis from plant exudates and has attracted the attention of researchers worldwide due to its potent activity in several biological models. This natural resin is rich in polyphenols and volatile compounds and more than 300 chemical compounds have been identified in samples from different regions. High precision chemical identification techniques are essential for the correct elucidation of the chemical compounds present in the samples and for the understanding of the biological effects. In this study, we sought to use fractionation techniques as a methodology able to be explored in studies involving samples of red propolis, seeking the identification and characterization of active fractions, as well as the use of cellular models of colon cancer for screening of bioactive molecules. The active fractions were identified by techniques of HPLC-MS and ESI-MS/MS, evidencing a complex chemical composition based on phenolic compounds an flavonoids. Among the obtained results, we highlight the fractions 05 and 06, which are able to produce significant inhibition on the HT-29 and HCT-116 tumor lines.The fractions obtained in this study showed lower chemical diversity than that found in the total extract of propolis, favoring its bioactivity, and as a result, this technique may favor the discovery and development of new drugs using propolis as a potential source of molecules against cancer.

No description available.

This dissertation reports the preparation of several types of anthraquinones structurally related to adriamycin. It describes the synthesis of two types of 2-aminoquinizarin compounds. It also presents two new syntheses of a heterocyclic tetracyclic ring system, similar to the aglicone ring system of adriamycin. A series of 2-aminoquinizarins was prepared by adding several primary amines to quinizarin. Quinizarin was shown to be essentially inert toward secondary amines. Several secondary amine adducts with quinizarin have been prepared, however, by treating the bis-boroacetate ester of quinizarin with the amines. Both types of 2-aminoquinizarin compounds exhibit outstanding potential for possessing antineoplastic activity, and several have been submitted to the National Cancer Institute for testing in their screening program for antineoplastic agents.

During the several years in which this therapy has been developed and evaluated, as standard dermatological preparation has not been available. The objective of the present work was to study the release of 5-FU from various ointment bases and to attempt to determine the type of base which would release the compound most satisfactorily. The methods chosen were designed to determine the release and penetration of 5-FU both by in vitro and in vivo methods. A modified agar plate method was chosen as the in vitro test for measuring release and subsequent diffusion into the agar. The penetration of the compound from various bases was determined by applying the medicated bases to the skin of guinea pigs and subsequently analyzing a biopsy of the inuncted skin, using quantitative spectrophotometry.

The benefits of intravenous therapy have become more and more apparent over the years. Medications can be given rapidly with an expectant rapid onset of action. The response to the drugs or fluids can often be closely controlled by regulating the dose or rate of administration. Frequently, adequate blood and tissue levels needed to eradicate many serious infections can be reached only by this route. Intravenous therapy is an especially appropriate method when the use of the oral tract, for one reason or another, cannot be used. The development of intravenous therapy, however, did not proceed without its difficulties. Problems of allergic reactions, incompatible blood groups, bacterial contamination, particulate matter, thrombophlebitic syndromes, stability of solutions, and incompatibilities of admixtures soon became apparent. The purpose of this paper is to explore certain aspects of the latter problem, i.e., intravenous incompatibilities.

Additional Hydroxyl group on CT6 (3,4-dihydroxy-5,7-dimethoxyflavone), a flavone extracted from Chromolaena Tacotana potentially confers additional activity against pancreatic cancer as compared to CT7 (4-hydroxy-5,7-dimethoxyflavone) Parker Wade1, Miranda Green1, April Weaver1, Omri Coke1, Ruben D. Torrenegra2, and Victoria Palau1 1Department of Pharmaceutical Sciences, College of Pharmacy, East Tennessee State University, Johnson City, TN. 2Department of Chemistry, Universidad de Ciencias Aplicadas y Ambientales, Bogota, Colombia and Pancreatic cancer is one of the deadliest types of cancers, with a mortality rate of about 95%. This high mortality rate signifies there is a need for further research into finding treatment options for those affected by pancreatic cancer. Recent studies have found cytotoxic effects on cancerous cells elicited from compounds, such as flavones, in plants indigenous to Western South America, specifically Colombia. The flavones 3,4-dihydroxy-5,7-dimethoxyflavone (CT6) and 4-hydroxy-5,7-dimethoxyflavone (CT7) were isolated from Chromolaena Tacotana, member of the asteraceae family. The molecular structures of the flavones differ only by an additional hydroxyl group on CT6. Both of these compounds were tested on MIA PaCa2 and Panc28 pancreatic cancer cells at concentrations ranging from 5μM to 80μM. Cell viability after dosing of CT6 and CT7 was determined using MTT and spectrophotometry analysis. MIA PaCa2 is more poorly differentiated than Panc28. CT6 conferred greater activity on both cell lines compared to CT7. Percent cell viability of the Panc28 cell line reached a low of 35.55% (p=0.0001) with CT6, compared to 84.25% (p=0.0275) with CT7. Percent cell viability of the MIA PaCa2 cell line reached a low of 46.72% (p=0.000001)with CT6. However, CT7 showed no significant difference, with percent cell viability reaching 103.73% (p=0.5605) when compared to the control for this cell line. While CT6 exerted cytotoxic activity on both Panc28 and MIA PaCa2, CT6 had significantly more cytotoxic activity on Panc28, which could be related to the greater differentiation status of this cell line. More in depth studies will need to be conducted to determine the exact reasons for greater activity of CT6 on Panc28 cells. This could be due to the compound’s target, mitochondrial activity of the cell lines, and the minor structural differences between the two compounds.

No description available.

No description available.