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1
Corrales, Roberta Cristina Novaes Reis. "Síntese e avaliação biológica de derivados de 6-mercaptopurina, carboidratos e aminoálcoois." Universidade Federal de Juiz de Fora (UFJF), 2011. https://repositorio.ufjf.br/jspui/handle/ufjf/4290.
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A tese de doutorado intitulada Síntese e Avaliação Biológica de Derivados de 6-Mercaptopurina, Carboidratos e Aminoálcoois está apresentada em três capítulos que descrevem a síntese e caracterização de compostos com potencial atividade antiparasitária (Leishmania, Plasmodium berghei), antibacteriana (bactérias Gram positiva e negativa, Mycobacterium tuberculosis) e em macrófagos peritoneais de mamíferos. Foram obtidos 53 compostos neste trabalho, sendo 30 inéditos, a saber: no capitulo 1 foi descrita a síntese de 27 compostos, sendo 14 derivados inéditos de 6mercaptopurina (6-MP); no capítulo 2 foi descrita a síntese de 14 compostos, sendo 6 derivados inéditos da D-glicose e 1 derivado inédito da D-ribonolactona; no capítulo 3 foi descrita a síntese de 14 compostos, sendo 9 aminoálcoois inéditos. O primeiro capítulo mostra a síntese de derivados de 6-MP contendo 1,2,3-triazol e derivados de esteróides. Os derivados triazólicos de 6-MP foram obtidos através de uma reação de cicloadição 1,3-dipolar tipo “click” usando um alcino terminal e um grupo azido. Os derivados de 6-MP contendo esteróides, sem o espaçador triazólico, foram obtidos através de uma reação de substituição nucleofílica entre o sal de 6-MP e mesilatos do ácido cólico e do ácido desoxicólico. Dentre os compostos submetidos à avaliação biológica, os derivados de 6-MP conjugados com esteróides apresentaram melhor atividade em Leishmania e a maioria apresentou importante atividade em P. berghei. Nenhum composto testado apresentou citotoxicidade in vitro para macrófagos peritoneais de camundongos até a máxima concentração de 48 µg/mL. O segundo capítulo mostra a síntese e caracterização de derivados da D-glicose contendo 1,2,3-triazol, obtidos através de reação tipo “click” e de derivados da D-gliconolactona e D-ribonolactona. Apesar dos compostos testados não terem apresentado atividade antiparasitária e antibacteriana efetiva, nenhum apresentou toxidez para os macrófagos de mamíferos. O terceiro capítulo descreve a síntese e caracterização de derivados aminoálcoois aromáticos com variada extensão de cadeia e de função química e apresentaram importante atividade biológica, principalmente em L. major. As estruturas dos produtos obtidos foram elucidadas pelos seus espectros na região do infravermelho, Ressonância Magnética Nuclear de 1H e 13C, Mapa de contornos homonuclear COSY, faixa de fusão e espectros de massas de alta resolução.
The doctoral thesis entitled Synthesis and Biological Evaluation of Derivatives of 6-Mercaptopurine, Carbohydrates and Aminoalcohol is presented in three chapters that describe the synthesis and characterization of compounds with potential antiparasitic activity (Leishmania, Plasmodium berghei), antibacterial (bacteria Gram positive and negative, Mycobacterium tuberculosis) and peritoneal macrophages of mammals. 53 compounds were obtained in this work, with 30 firsts, namely: Chapter 1 was described in the synthesis of compounds 27, 14 novel derivatives of 6-mercaptopurine (6MP), was described in Chapter 2 the synthesis of compounds 14, 6 being derived from unpublished 1 D-glucose and derived novel D-ribonolactona, was described in Chapter 3 the synthesis of compounds 14, 9 amino unpublished. The first chapter shows the synthesis of derivatives of 6-MP containing 1,2,3triazole derivatives and steroids. The triazole derivatives of 6-MP were obtained by a reaction of type 1,3-dipolar cycloaddition "click" using a terminal alkyne and an azide group. Derivatives of 6-MP containing steroids, without the spacer triazole, was obtained through a nucleophilic substitution reaction between the salt of 6-MP and mesylates cholic acid and deoxycholic acid. Among the compounds subjected to biological evaluation, derivatives of 6-MP in conjunction with steroids showed better activity in Leishmania and most showed a significant activity in P. berghei. No compound tested showed cytotoxicity in vitro for mouse peritoneal macrophages to g / mL.µthe maximum concentration of 48 µg/mL. The second chapter shows the synthesis and characterization of D-glucose derivatives containing 1,2,3-triazole, obtained by reaction type "click" derivatives of Dgliconolactona and D-ribonolactona. Although the compounds tested did not show effective antibacterial and antiparasitic activity, showed no toxicity to mammalian macrophages. The third chapter describes the synthesis and characterization of aromatic amino derivatives with varied chain length and chemical function and had significant biological activity, especially in L. Major. The structures of the products obtained were elucidated by their spectra in the infrared, 1H NMR and 13C, homonuclear COSY contour map, melting point and mass spectra with high resolution.
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LIMA, Carlos Henrique Vasconcelos de. "Farmacogenética do Gene TPMT na resposta A 6-Mercaptopurina, em pacientes com Leucemia Linfoblástica Aguda." Universidade Federal do Pará, 2016. http://repositorio.ufpa.br/jspui/handle/2011/7252.
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Leucemia Linfoblástica Aguda (LLA) é o tipo de câncer mais frequente em crianças menores de 15 anos de idade. O 6-mercaptopurina (6-MP) é um dos agentes quimioterápicos mais amplamente utilizado no tratamento da LLA infantil. Polimorfismos no gene Tiopurina s-metiltransferase (TPMT) podem estar associados a variações individuais na resposta ao tratamento da LLA infantil, como aumento de toxicidade grave (grau 3 e 4). O objetivo deste trabalho foi associar polimorfismos do gene TPMT: TPMT*2 (238G>C), TPMT*3A (460G>A e 719A>G), TPMT*3B (460G>A), TPMT*3C (719A>G), TPMT*8 (644G>A) e a variante intrônica rs12201199 (94T>A) com a ocorrência de toxicidades graves em pacientes com LLA tratados com 6-MP, na Região Norte do Brasil. Foram investigados 137 pacientes infantis com LLA tratados no Hospital Ophir Loyola, no estado do Pará. O polimorfismo rs12201199 foi genotipado pela técnica de PCR em tempo Real (equipamento 7500 Real-Time PCR System) e os demais polimorfismos foram genotipados por sequenciamento direto, utilizando o sequenciador automático ABI PRISM 3130 Genetic Analyzer (Applied Biosytems, CA, USA). Os haplótipos entre os polimorfismos investigados foram derivados através de estimativas de máxima verossimilhança utilizando o programa PHASE. Foi empregado um painel de 48 Marcadores Informativos de Ancestralidade, como controle genômico na amostra e as análises estatísticas foram realizadas no programa SPSS v.20.0 (SPSS, Chicago, IL, EUA). Todos os testes estatísticos consideraram a probabilidade (p-valor) significativa quando ≤0,05. Em relação à ascendência genômica, observou-se que a composição étnica dos pacientes com LLA foi de 44% Europeu, 22% Africano e 34% Ameríndio. Entre as toxicidades relatadas, a infecciosa foi a mais prevalente (86%), seguida da hematológica (65%), da gastrointestinal (64,8%) e toxicidade no sistema nervoso central (29,9%). A frequência alélica do polimorfismo rs12201199 foi de 0,482 entre os indivíduos estudados. As variantes haplotípicas mais prevalentes foram TPMT*3A (7,6%), seguido pelo TPMT*3C e TPMT*8, ambos com 7,3%. Não foi observada uma associação significativa entre o perfil de metabolização deficiente da TPMT com nenhuma das toxicidades graves relatadas nos pacientes com LLA estudados. No entanto, os dados encontrados mostram que há uma significativa relação entre o polimorfismo do gene TPMT (rs12201199) e a ocorrência de toxicidade infecciosa grave durante o tratamento da LLA infantil. Foi observado que os pacientes que possuem o genótipo homozigoto mutante AA para o polimorfismo no gene TPMT têm um risco de 4,098 vezes maior de apresentar toxicidade grave infecciosa durante o tratamento para LLA infantil em relação aos que apresentam os outros genótipos. Este resultado pode ser importante para ajudar a predizer riscos de toxicidade durante o tratamento, contribuindo para um melhor prognóstico individual dos pacientes com LLA infantil.
Acute Lymphoblastic Leukemia (ALL) is the most common type of cancer in children under 15 years of age. 6-mercaptopurine (6-MP) is one of the most widely used chemotherapeutic agents in the treatment of childhood ALL. Polymorphisms in thiopurine S-methyltransferase gene (TPMT) may be associated with individual variation in the response to treatment of childhood ALL, such as increased severe toxicity (grade 3 and 4). The aim of this study was to associate polymorphisms of TPMT gene: TPMT*2 (238G>C), TPMT*3A (460G>A and 719A>G), TPMT*3B (460G>A), TPMT*3C (719A>G), TPMT* 8 (644G>A) and intronic variant rs12201199 (94T>A) with the occurrence of serious toxicities in patients with ALL treated with 6-MP, in Northern Brazil. One hundred thirty-seven pediatric patients with ALL and treated at the Ophir Loyola Hospital in the state of Pará were investigated. The rs12201199 polymorphism was genotyped by real-time PCR (equipment 7500 Real-Time PCR System) and other polymorphisms were genotyped by direct sequencing using the automated sequencer ABI PRISM 3130 Genetic Analyzer (Applied Biosytems, CA, USA). The haplotypes among the studied polymorphisms were derived via maximum likelihood estimates using the program PHASE. A panel of 48 markers Ancestry Informative was used as genomic control in the sample and statistical analyses were performed using SPSS v.20.0 software (SPSS, Chicago, IL, USA). All statistical tests considered the probability (p) significant when ≤0, 05. In relation to the genomic ancestry, it was noted that the ethnic composition of ALL patients was 44% Caucasian, 22% African and 34% Amerindian. Among the reported toxicities, infectious was most prevalent (86%), followed by hematological (65%), gastrointestinal (64.8%) and central nervous system toxicity (29.9%). Allele frequency of polymorphism rs12201199 was 0.482 among the studied subjects. The most prevalent haplotype variants were TPMT*3A (7.6%), followed by TPMT*3C and TPMT*8, both 7.3%. There was no significant association between poor metabolism profiles of TPMT with none of the serious toxicities reported in the studied patients with LLA. However, our data show that there is a significant relationship between the polymorphism of TPMT gene (rs12201199) and the occurrence of severe infectious toxicity during treatment of childhood ALL. It has been observed that patients who have mutant homozygous AA genotype for this polymorphism in TPMT gene have 4.098 times higher risk of presenting severe infectious toxicity during the treatment for childhood ALL compared to those with the other genotypes. This result may be important to help predict risk of toxicity during treatment, contributing to a better individual prognosis of patients with childhood ALL.
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Canales, López Cristina. "Asociación de efectos adversos al tratamiento de mercaptopurinas con polimorfismos genéticos de la enzima TPTM en niños con leucemia linfoblástica aguda tratados en el Hospital Dr. Luis Calvo Mackenna." Tesis, Universidad de Chile, 2012. http://www.repositorio.uchile.cl/handle/2250/111229.
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Memoria para optar al título de Química FarmacéuticaLa Leucemia Linfoblástica Aguda (LLA) es la neoplasia más común en niños, siendo la 6-mercaptopurina (6-MP) una droga que cumple un rol fundamental para el tratamiento de esta neoplasia. Sin embargo, se han asociado al uso de esta droga una serie de efectos adversos. La presencia de polimorfismos presentes en genes que codifican enzimas involucradas en su metabolización, aparece como una de las principales causantes de los efectos adversos a 6-MP. Uno de los polimorfismos involucrados en el metabolismo de la 6-MP, corresponde a aquellos presentes en el gen TPMT*1 que codifica la enzima Tiopuril S-metiltransferasa (TPMT). Se han asociado a diversos polimorfismos en este gen, la presencia de concentraciones plasmáticas tóxicas de nucleótidos de tioguanina (TGNs), un metabolito de la 6-MP, aumentando el riesgo de desarrollar eventos adversos durante la terapia, lo que conduce al abandono o suspensión de la terapia, obligando a controlar o reducir las dosis recibidas de 6-MP en pacientes que presentan algún polimorfismo en el gen TPMT*1. El conocimiento de la prevalencia de este polimorfismo y su efecto en el tratamiento de la LLA ha permitido el desarrollo de una farmacogenética efectiva, mejorando sustancialmente la calidad de vida de los pacientes durante el tratamiento. Estudios previos de nuestro grupo permitieron encontrar la presencia de polimorfismos en el gen TPMT en un 8% de una población de 103 niños chilenos con LLA. En este trabajo se analizó la relación existente entre la presencia de polimorfismo en el gen TPMT*1 con los efectos adversos y la disminución de la dosis de 6-MP durante el periodo de mantención en el tratamiento de la LLA. El análisis de 35 pacientes con LLA atendidos en el Hospital Dr. Luis Calvo Mackenna muestra que se administra una dosis significativamente menor de 6-MP durante el periodo de mantención en los niños con LLA que presentan un alelo polimórfico del gen TPMT*1. Los resultados obtenidos apoyan el uso de una farmacogenética efectiva para el tratamiento de la LLA en nuestro país.
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. The drug 6-mercaptopurine (6-MP) plays a fundamental role in the treatment of this malignancy. However, a number of side effects have been associated with the use of this drug. The presence of polymorphisms in genes encoding enzymes involved in its metabolism, appears as a major cause of adverse effects of 6-MP. Several of the polymorphisms involved in the metabolism of 6-MP corresponds to those present in the gene encoding the TPMT*1 enzyme, Tiopuril S-methyltransferase (TPMT). Some of these have been associated with the presence of toxic plasma concentrations of thioguanine nucleotides (TGNs), metabolites of 6-MP. These metabolites increase the risk of adverse events during therapy, leading to the abandonment or suspension of therapy, and demand an increased control of 6-MP doses in patients with a polymorphism of this gene. Knowledge of the prevalence of this polymorphism and its effect on the treatment of ALL has allowed the development of an effective pharmacogenetic approach, substantially improving the quality of life of patients during treatment. Previous studies from our group found polymorphisms in the TPMT gene in 8% of a population of 103 Chilean children with ALL. In this work we analyzed the relationship between the presence of one polymorphism of the TPMT*1gene with the side effects and the decrease of the 6-MP dose during the treatment of ALL and the decrease of the 6-MP dose during maintenance treatment of ALL. The analysis of 35 patients with ALL treated at the Hospital Dr. Luis Calvo Mackenna shows that there is a significant decrease in the dose of 6-MP during maintenance in children with ALL with a polymorphic allele of the TPMT*1gene. The results support the use of an effective pharmacogenetics strategy for the treatment of ALL in our country.
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Souza, Nicolli Bellotti de. "Avaliação da atividade antiplasmodial de análogos da cloroquina." Universidade Federal de Juiz de Fora (UFJF), 2011. https://repositorio.ufjf.br/jspui/handle/ufjf/2495.
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A malária é causada por protozoários do gênero Plasmodium e é responsável por 250 milhões de casos e 1 milhão de mortes anualmente. Um dos principais empecilhos para o controle da doença é o desenvolvimento de resistência do parasito aos fármacos comumente usados, o que torna urgente a pesquisa por novos antimaláricos. Nesse contexto, análogos de cloroquina acoplados a 6-mercaptopurina e a alquil aminas e complexos de platina foram avaliados quanto a atividade antimalárica utilizando o teste supressivo descrito por Peters em modelo murino de infecção por Plasmodium berghei NK65. Tais análogos exibiram altos valores de supressão da parasitemia, entre 60% e 94% em comparação com o controle não tradado. Considerando o papel imunossupressor de derivados de purina, o análogo de cloroquina acoplado a 6-mercaptopurina MPQUI foi avaliado quanto a aspectos imunológicos (contagem de leucócitos específicos, dosagem de TNF-α e IL-10), não interferindo na resposta imune tendo como base os parâmetros analisados. Portanto, esses análogos devem ser objetos de futuras pesquisas, podendo fornecer novos antimaláricos, já que apresentaram-se promissores e não influenciaram a resposta imune nos parâmetros analisados.
Malaria is caused by protozoan parasites of the genus Plasmodium and is responsible for 250 million cases and 1 million deaths annually. One of the main obstacles for the disease control is the development of resistance by the parasite to the commonly used antimalarials, what makes the research for new ones urgent. In this context, chloroquine analogs attached to 6-mercaptopurine and to alkyl-amines and platinum complexes were evaluated for their antimalarial activity using the 4-day suppressive test described by Peters which was carried out in mice infected with Plasmodium berghei NK65. These analogs exhibited high values of parasitemia suppression, which ranged from 60% to 94% in comparison to untreated control. Considering the immune suppressor role of purine derivates, the chloroquine analog attached to 6-mercaptopurine MPQUI was evaluated for immunological aspects (specific leukocytes count, TNF-α and IL-10 measurements in sera of mice), revealing no interference in the immune response considering these parameters. Therefore, these analogs may be objects of further research, aiming at new antimalarials, since they were shown to be promising and did not influence the immune response in the parameters analyzed.
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Vashist, Usha. "Aspectos biológicos da inoculação experimental e atividade malaricida da 4-(6-mercaptopurina)-7-cloroquinolina em Gallus gallus Linnaeus, 1758 experimentalmente infectados por Plasmodium (Novyella) juxtanucleare Versiani & Gomes, 1941 (Apicomplexa, Plasmodiidae)." Universidade Federal de Juiz de Fora (UFJF), 2007. https://repositorio.ufjf.br/jspui/handle/ufjf/2915.
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Plasmodium juxtanucleare é o agente causador da malária aviária que ocorre em alguns estados do Brasil. Esta malária está relacionada a diversos sinais clínicos e pode causar danos em criações rústicas de aves. O modelo aviário já foi utilizado para a investigação de drogas no combate à malária e hoje em dia o modelo mais utilizado é o Plasmodium berghei em roedores. A busca por anti-maláricos e malaricidas é de extrema relevância. O objetivo deste trabalho foi verificar o efeito da 4-(6-MERCAPTOPURINA)-7-CLOROQUINOLINA, uma substância recém sintetizada a partir da cloroquina, sobre a malária aviária em Gallus gallus e aprimorar o modelo aviário para testes de potenciais malaricidas. Para o encontro de uma ave doadora, foram visitadas no município de Juiz de Fora duas granjas e feitos esfregaços sangüíneos de 30 aves. A prevalência foi de 100%. Dentre as 30 aves examinadas, as seis com os maiores valores de parasitemia foram adquiridas e levadas para o laboratório. Para verificar qual o melhor dia para a retirada de sangue de aves infectadas e imunossuprimidas pelo acetato de metilprednisolona, cinco das seis aves receberam em dose única este imunossupressor e uma serviu como controle. A parasitemia das aves foi acompanhada por 26 dias após o dia da imunossupressão, por meio de esfregaços sangüíneos preparados a cada dois dias. Também foram aferidos o peso e temperatura corporal e feitos microhematócritos sangüíneos. Verificou-se que ao 10º dia pós-imunossupressão ocorreu pico de parasitemia. Houve queda de peso corporal e correlação com a parasitemia. Ocorreu pouca variação na temperatura corporal e hematócrito e não houve correlação destes com a parasitemia. Em outras oito aves adquiridas em casa comercial com 15 dias de idade, foram realizadas infecções experimentais com sangue inoculado via intramuscular e via intraperitonial nas doses de 0,3mL e 0,5mL para as duas vias. Durante um mês as aves tiveram o valor médio de parasitos acompanhado para comparar qual a via mais efetiva e se havia diferença entre as doses testadas no estabelecimento da infecção. Não foi observada diferença entre as xv dosagens, mas foi possível verificar que a infecção via intraperitonial atinge mais rapidamente o pico de parasitemia, com médias de parasitos mais altas, entretanto ao fim do experimento o número total de parasitos quase não diferiu entre as doses e vias. Para testar o efeito malaricida da 4-(6-MERCAPTOPURINA)-7-CLOROQUINOLINA, uma droga derivada da cloroquina, recém sintetizada, foram infectados 45 pintos, Leghorn branco, via intramuscular. As aves foram separadas em quatro grupos experimentais com 15 aves por grupo (Grupo1- não infectado, Grupo 2- infectado e sem tratamento, Grupo 3- infectado e tratado com a cloroquina e grupo 4- infectado e tratado com o derivado da cloroquina). A droga foi administrada via gavagem por 4 dias consecutivos na dose de 100mg/Kg de peso vivo. Para a avaliação do efeito malaricida da droga, as aves tiveram o número médio de parasitos encontrados acompanhados por esfregaços sangüíneos feitos a cada dois dias após o décimo dia da inoculação. Também foram aferidos o peso e temperatura corporal a cada dois dias e hematócrito a cada quatro dias. O derivado da cloroquina teve atividade malaricida, mantendo a parasitemia mais baixa em relação ao grupo controle não tratado e ao grupo controle tratado com a cloroquina. Entretanto em todos os grupos a parasitemia se manteve baixa. Sugere-se a investigação da ação malaricida desta droga em modelos com P. berghei ou culturas com P. falciparum.
Plasmodium juxtanucleare is the agent of the avian malaria that occurs in some states of Brazil. This malaria is related to several clinical signs and it can cause damages in the poultry section. The aviary model was already used for the investigation of drugs in the combat to the malaria and nowadays the model more used is the Plasmodium berghei in rodents. The search for anti-malarial drugs is of extreme importance. The aim of this study was to accomplish experimental infections of Plasmodium juxtanucleare in Gallus gallus and to test a substance recently synthesized, the 4-(9H-purin-6-ylthio)-7-cloroquinoline, derived of the cloroquine, to verify their effects on the avian malaria and to improve the aviary model for these types of tests. For a bird donor's encounter, two chicken farms were visited in the Juiz de Fora city and blood smears made in 30 hens. The prevalence was 100%. Among the 30 examined hens, six with the largest parasitemia values had been acquired and taken to the laboratory. To verify which the best day to retreat the blood to infected hens, five of the six hens received only dose of the imunossupressor substance (metilprednisolon acetate) and one served as control. The parasitaemia of the hens was accompanied by 26 days after the day of the imunossupression, through blood smears prepared each two days. The weight and corporal temperature were checked and made blood hematocrits. It was verified that to the 10th day powder-imunossupression it happened parasitaemia pick. There were fall of body weight and correlation with the parasitaemia. There was a little variation in the body temperature and hematocrite and there was not correlation of these with the parasitaemia. In other eight acquired hens in commercial house with 15 days old, experimental infections were accomplished with blood inoculated through intramuscle and intraperitoneally in the 0,3mL and 0,5mL for the two routes. During one month the hens had the value of parasites accompanied to compare which the most effective route and difference among the doses tested in the establishment of the infection. Significant difference was not observed among the xvii doses but it was possible to verify that the infection through intraperitonial reaches the parasitemia pick more quickly, with higher averages of parasites, however to the end of the experiment the total number of parasites differed hardly between the doses and routes. To test the effect a derived drug of the cloroquine, 45 chicks were infected, white Leghorn, through intramuscle route . The hens were separate in four experimental groups, 15 chicks for group (Group1 - no infected, Group 2 - infected and without treatment, Group 3 - infected and treated with the cloroquine and Group 4 - infected and treated with derived of the cloroquine) The drug was administered four consecutive days in the 100mg/Kg of alive weight dose. For the evaluation of the antimalarial effect of the drug, the hens had the number of parasites accompanied by blood smears done each two days after the tenth day of the inoculation. Also the weight and corporal temperature were checked each two days and hematocrit four days. Derived of the cloroquine had antimalarial activity, reducing the number of parasites and maintaining the lowest parasitaemia in relation to the group not treated and to the group treated with cloroquine.
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Londero, Margherita. "Sviluppo di strategie farmacologiche per la personalizzazione della terapia della leucemia linfoblastica acuta nel bambino." Doctoral thesis, Università degli studi di Trieste, 2015. http://hdl.handle.net/10077/10852.
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2012/2013L'attività dell'enzima tiopurina-S-metil transferasi (TPMT) è un determinante importante di eventi avversi severi durante il trattamento della leucemia linfoblastica acuta (LLA) con l'antimetabolita mercaptopurina. Recentemente è stato dimostrato che la proteina PACSIN2 modula l'attività di TPMT e la tossicità indotta da mercaptopurina, mediante un meccanismo molecolare che si ipotizza riguardi la regolazione dell'autofagia. Nell’ambito del protocollo italiano per il trattamento della LLA AIEOP 2009, si vogliono sviluppare strategie farmacologiche (farmacogenetiche, farmacocinetiche e farmacodinamiche) in vitro da integrare agli attuali parametri di risposta del paziente per personalizzare la terapia. Queste strategie comprendono la valutazione dell’attività e di polimorfismi genetici di enzimi importanti per la biotrasformazione della mercaptopurina, ovvero TPMT ed inosina trifosfato-pirofosfatasi (ITPA), della concentrazione dei metaboliti attivi della mercaptopurina e della sensibilità in vitro dei blasti dei pazienti raccolti alla diagnosi e trattati con diversi farmaci antitumorali. Si vuole poi validare l’effetto dei polimorfismi di PACSIN2 sull’attività dell’enzima TPMT. I dati preliminari ottenuti sostengono il ruolo dei polimorfismi d’interesse sulla farmacocinetica della mercaptopurina. In particolare, la casistica considerata finora valida un contributo dello SNP di PACSIN2 rs2413739 sull’attività enzimatica di TPMT. Lo studio è in continuo aggiornamento. Il suo ampliamento e l’integrazione dei dati farmacologici con i dati clinici dei pazienti contribuiranno a comprendere l’impatto di queste variabili farmacocinetiche/farmacogenomiche sull’efficacia e la tossicità del trattamento con tiopurine. Per determinare se PACSIN2 e l'autofagia contribuiscono alla variabilità interindividuale nell'attività di TPMT e nella suscettibilità alla tossicità da mercaptopurina abbiamo eseguito degli esperimenti in cellule con meccanismo di autofagia alterato (ovvero fibroblasti murini embrionali, MEF, da topi con ATG7 disattivato) e alterazione di PACSIN2 (cellule NALM6 con silenziamento di PACSIN2). Le cellule con meccanismo di autofagia alterato esprimono costitutivamente livelli più alti di PACSIN2 endogeno; questo avviene anche per altre proteine correlate all'autofagia come p62. Il trattamento con rapamicina induce la degradazione di PACSIN2 nelle cellule con autofagia funzionante, ma non in quelle con meccanismo di autofagia alterato. Il silenziamento dell'espressione di PACSIN2 ha indotto un aumento nel livello basale di autofagia, come documentato dall'accumulo di LC3-II e autofagosomi. La sequenza proteica di PACSIN2 contiene due siti di legame per LC3 e la co-immunoprecipitazione di PACSIN2 e LC3 dimostra l'interazione delle due proteine nelle linee cellulari NALM6. La stabilità di TPMT è diminuita quando l'espressione di PACSIN2 è alterata, in confronto a cellule con livelli normali di PACSIN2. Qui dimostriamo che PACSIN2 è bona fide una proteina dell'autofagia e che il suo ruolo come modulatore dell'autofagia influenza la variabilità interindividuale nell'attività di TPMT.
XXVI Ciclo
1980
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Monteil-Ganiere, Catherine. "Mercaptopurine et polymorphisme génétique." Nantes, 2003. https://archive.bu.univ-nantes.fr/pollux/show/show?id=6d743aea-4878-4f8f-a5a1-0dbe73f78509.
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Le polymorphisme génétique de l'activité thiopurine-méthyltransférase (TPMT), enzyme qui catabolise les thiopurines, a des répercussions importantes en clinique. Le génotype et l'activité TPMT ont été déterminés chez 304 adultes donneurs de sang, 147 enfants et 18 nouveaux-nés (sang de cordon) tous Caucasiens. L'activité TPMT varie de 0,43 à 30,38 U/mL PRBC chez l'adulte, de 8,25 à 30,0 U/mL PRBC chez l'enfant et 9,24 à 22,79 U/mL PRBC pour les sangs de cordons. Il n'y a pas de différence significative entre les activités TPMT des sangs de cordon et des adultes (p = 0,424). Mais on retrouve une activité légèrement plus faible chez l'enfant que chez l'adulte (p = 0,016). Dans le groupe constitué d'enfants et nouveaux-nés, nous n'avons pas mis en évidence de corrélation significative entre l'activité TPMT et l'âge (p = 0,127), ce qui indique que l'activité TPMT est déjà mature à la naissance. Dans l'ensemble de la population, 91,9% sont homozygotes sauvages, 7,9% hétérozygotes et 0,2% homozygote muté. La fréquence des allèles mutés est 3,0% pour TPMT*3A, 0,7% pour TPMT*2 et 0,4% pour TPMT* 3C. Pour les valeurs d'activité TPMT proches de l'antimode, il existe un chevauchement entre les sujets homozygotes et hétérozygotes concernant 4,5% de la population. Les conséquences du polymorphisme de la TPMT ont été étudiées chez 54 enfants leucémiques traités par 6-mercaptopurine (6-MP) au cours de la phase de maintenance. 39 (90,7%) génotypes TPMT sont homozygotes *1/*1 et 4 (9,3%) hétérozygotes *1/*3A. L'activité TPMT au diagnostic est 20,4% plus faible que celle de la population d'enfants de référence. Pendant la maintenance, l'activité TPMT est 27,4% plus élevée que pour la population de référence. Nos résultats montrent une corrélation inverse entre l'activité TPMT et les TGNs intraérythrocytaires, métabolites actifs de la 6-MP, responsables, au moins en partie, de l'effet antileucémique. L'enzyme TPMT joue donc un rôle majeur au niveau de la métabolisation de 6-MP et de la réussite du traitementTPMT genotype and activity were determined in 304 adult blood donors, 147 children and 18 newborns (cord bloods), all Caucasian. TPMT activity ranged from 0. 43 to 30. 38 U/mL PRBC in adults, from 8. 25 to 30. 0 U/mL PRBC in children and from 9. 24 to 22. 79 U/mL PRBC in cord bloods. There was no significant difference between cord bloods and adults (p = 0. 424). But we found a slightly lower TPMT activity in children than in adults (p = 0. 016). In the children and cord bloods group, no significant correlation was evidenced between TPMT and age (p = 0. 127): TPMT is already mature at birth. In the whole population, 91. 9% was homozygous wild-type, 7. 9% heterozygous and 0. 2% homozygous and 0. 2% homozygous mutant. The frequency of mutant allele was 3. 0% for TPMT/*3A, 0. 7% for TPMT*2 and 0. 4% for TPMT*3C. For TPMT activities close to the antimode value, there was an overlap between homozygous and heterozygous subjects concerning 4. 5% of subjects. Consequences of TPMT polymorphism were studied in 54 leukemic children treated with 6-MP during maintenance phase. 39 (90. 7%) TPMT genotypes were homozygous *1/*1 and 4 (9. 3%) heterozygous *1/*3A. Diagnosis TPMT activity is 20. 4% lower than in the reference children population. During maintenance, TPMT activity was 27. 4% higher than the reference population. Our results showed an inverse correlation between TPMT activity and red blood cells TGNs, which are 6-MP active metabolites, responsible, at least in part, for the anti-leukemic effect. TPMT enzyme plays a major role for 6-MP metabolisation and treatment success
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Monteil-Ganiere, Catherine Bourin Michel Pineau Alain. "Mercaptopurine et polymorphisme génétique." [S.l.] : [s.n.], 2003. http://theses.univ-nantes.fr/thesemed/DOCmonteil.pdf.
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Rabello, Celia Maria de Almeida. "An investigation of the effects of variation in drug metabolism in children with acute lymphoblastic leukaemia undergoing continuing therapy." Thesis, University of Newcastle Upon Tyne, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308017.
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TAI, ROYA. "Devenir au long cours des patients atteints de maladie de crohn mis en remission complete par l'azathioprine ou la 6-mercaptopurine." Reims, 1993. http://www.theses.fr/1993REIMM076.
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Soares, Roberta Reis. "Avaliação da atividade antimalárica de análogos de 4-aminoquinolinas e 6-mercaptopurinas em modelo murino." Universidade Federal de Juiz de Fora (UFJF), 2013. https://repositorio.ufjf.br/jspui/handle/ufjf/4279.
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CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico
FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais
A malária permanece ao longo dos anos como emergência global em saúde pública. São aproximadamente 87 milhões de casos e 106.820 mortes ocorridas anualmente no mundo. As principais estratégias atuais no controle da doença se baseiam no diagnóstico precoce e tratamento oportuno dos casos, devendo ser considerada a resistência dos parasitos a praticamente todos os fármacos atualmente em uso, o que torna urgente a busca por novos antimaláricos. Neste contexto, análogos de 4-aminoquinolinas e 6-mercaptopurinas contendo 1,2,3-triazol ou esteroide foram sintetizados e tiveram sua atividade antimalárica investigada utilizando o teste supressivo de Peters em modelo murino de infecção por Plasmodium berghei NK65. Dentre os 11 análogos avaliados, 5 exibiram atividade antimalárica significativa, alcançando percentuais de supressão de até 81% em relação ao controle não tratado. Além da atividade antimalárica, um composto promissor não pode apresentar efeitos indesejáveis às células do hospedeiro, sendo assim foram avaliadas a citotoxicidade e atividade hemolítica dos análogos. A maioria dos compostos foram considerados seguros às células do hospedeiro mesmo nas maiores concentrações avaliadas. Portanto, estes análogos merecem ser objeto de futuras investigações visando compor novos antimaláricos.
Malaria remains over the years as a global public health emergency. There are approximately 87 million cases and 106.820 deaths worldwide each year. The main current strategies to control the disease are based on early diagnosis and appropriate treatment cases and should be considered the resistance of parasites to almost all drugs currently in use, which makes urgent the search for new antimalarials. In this context, analogs of 4-aminoquinolines and 6-mercaptopurines containing 1,2,3-triazole or steroid were synthesized and investigated for their antimalarial activity using the 4-day suppressive test described by Peters in a murine model of infection by Plasmodium berghei NK65. Among the 11 analogues evaluated, 5 exhibited significant antimalarial activity, reaching percentages of suppression up to 81% compared to untreated control. Besides antimalarial activity, a promising compound cannot have undesirable effects on host cells, thus was evaluated the cytotoxicity and hemolytic activity of analogs. Most compounds were considered safe to host cells even at the highest concentrations evaluated. So, this analogs deserve to be object of future investigations aiming compose new antimalarials.
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Burdett, David Norman. "6-mercaptopurine induced cleft palate in the hamster : morphological and cellular aspects." Thesis, University of British Columbia, 1985. http://hdl.handle.net/2429/24490.
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A study on the pathogenesis of 6-mercaptopurine induced cleft palate was undertaken using light and electron microscopic, and enzyme acid phosphatase cytochemical techniques.
Palatal development in control fetuses was observed in six stages at the gross level and five stages at the histological level. Between days 9:18 (9 days:18 hours) and 10:00 of gestation palatal primordia appeared from the roof of the oronasal cavity, and developed in the vertical direction until day 12:00 of gestation. Between days 12:00 and 13:00 of gestation the palatal shelves became horizontal and fused with one another. During closure the timely appearance of lysosomes was responsible for elimination of the intervening epithelia of the opposing palatal shelves through an intracellular process of autolysis.
Gross observations showed that 6-mercaptopurine affected the vertical development of palatal shelves. In contrast to normal development, vertically developing palatal shelves on day 10:00 of gestation showed sublethal injury of the mesenchymal cells characterized by swelling of the perinuclear space and lysosomal development. Subsequently the epithelial cells were damaged, and the basal lamina fragmented and disappeared. The epithelial and mesenchymal cells communicated with one another. Eventually, however, the epithelial and mesenchymal cells recovered and the basal lamina re-established its continuity. It was concluded that sublethal injury of the mesenchymal and epithelial cells following 6-mercaptopurine treatment disturbed the controlled process of cytodifferentiation, and thus affected vertical development of the palatal shelves to develop a cleft palate.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate
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Rohan, Jennifer M. "The Relationship of 6-Mercaptopurine Medication Adherence to Clinical Outcomes in Pediatric Cancer." University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1416570460.
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Rey, Frédéric. "Pharmacocinetique de la 6-mercaptopurine plasmatique apres administration orale d'imurel (azathioprine) chez l'enfant transplante renal." Toulouse 3, 1992. http://www.theses.fr/1992TOU31116.
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Vikingsson, Svante. "Development of new methodology for therapeutic drug monitoringof thiopurine treatment." Doctoral thesis, Linköpings universitet, Klinisk farmakologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-84626.
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The three thiopurine drugs azathioprine (AZA), 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are used to treat several diseases, including inflammatory bowel disease (IBD). They are pro-drugs and are believed to act through the formation of thioguanine nucleotides (TGNs). Other important metabolites are the methylthioinosine nucleotides (meTINs). These metabolites are active in the white blood cells (WBCs).Most patients respond well to the thiopurine drugs but up to a third have to modify or discontinue their treatment due to adverse events or a lack of therapeutic effects. This could be caused by inter-patient variability in the metabolism of the drugs. Therapeutic drug monitoring (TDM) of thiopurine nucleotides in red blood cells (RBCs) is used to guide treatment. Current routine assays measure the nucleotides after hydrolysation to nucleic bases and are therefore unable to distinguish between mono-, di-, and triphosphates. Recently it was shown that these assays failed to predict the clinical outcome in about 40% of the patients. It has been suggested that measuring thioguanosine triphosphate (TGTP) (believed to be the most active of the TGNs) separately might increase the clinical value.An assay suitable for measuring thioguanosine mono- (TGMP) and diphosphate (TGDP) and TGTP, as well as methylthioinosine mono- (meTIMP), di- (meTIDP) and triphosphate (meTITP) separately in RBCs in clinical samples has been developed. In clinical studies of 82 IBD patients, we found no correlation between the thiopurine dose and metabolite levels in RBCs, thus illustrating the importance of metabolite measurements in the TDM of thiopurines.The TGN peak measured by the routine assay during TDM of patients treated with thiopurines consisted of TGTP and TGDP with a small contribution from TGMP. The meTIN also consisted of mono-, di- and triphosphates, but in different proportions, indicating differences in the formation. The inter-individual differences in nucleotide distribution were very small and a strong correlation between the different nucleotides and their respective sums was observed. As a consequence, measuring the mono-, di- and triphosphates separately was not beneficial in predicting remission, which was confirmed by the results from the clinical study.Further research into the metabolism and mode of action of thiopurine drugs is needed to understand the inter-patient variability in response and metabolite formation. An assay suitable for such studies, measuring TGNs and meTINs in cultured cells, has also been developed.
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Patrel, Bruno. "Production de 5'IMP et d'hypoxanthine par fermentation : application à Brevibacterium ammoniagenes." Compiègne, 1988. http://www.theses.fr/1988COMPD108.
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Afin d'obtenir des souches de Brevibacterium ammoniagenes, productrices de 5'IMP et/ou d'hypoxanthine, des mutants auxotrophes pour l'adénine, dérivés de la souche sauvage BS 1, ont été isolés par mutagénèse U. V. Et mutagénèse à l'éthyle méthane sulfonate (EMS). La mise au point d'un crible de sélection sur milieu gélosé a permis de sélectionner les mutants producteurs d'hypoxanthine. L'étude de l'activité PRPP amidotransférasique chez 5 d'entre eux a montré qu'un seul (mutant BA 6) n'était plus régulé par l'adénine au niveau de cette enzyme. A cause d'un catabolisme du 5'IMP déficient, ce mutant produit cependant moins d'hypoxanthine+ 5'IMP que les autres mutants. Un mutant adénine- et résistant à la 6-mercaptoguanosine (mutant BA 10) produit deux fois plus d'hypoxanthine+ 5'IMP que son parent adénine- (souche BA 5). Chez BA 10, la production reste partiellement régulée par l'adénineIn order to obtain strains of Brevibacterium ammoniagenes able to produce 5'IMP and/or hypoxanthine, adenine-less mutants have been isolated by mutagenesis U. V. Or mutangenesis by ethyl methane sulfonate (EMS), from the wild strain BS 1. By the mean of a screening on solid medium, strains producing hypoxanthine have been selected from these mutants. The study of PRPP amidotransferase activity for five mutants has proved that one of them is not anymore regulated by adenine as far this enzyme is concerned. Because of a deficient catabolism of 5'IMP, this mutant produces half less than the others. The mutant BA 10, adenine- -6-mercaptoguanosine-resistant, produces twice more hypoxanthine+5' IMP than its adenine-less parent (stain BA 5). Production, by this strain, is only partially regulated by adenine
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Setshedi, Mashiko. "Risk of malignancy in patients with inflammatory bowel disease treated with Azathioprine or 6-mercaptopurine : the Cape Town experience." Master's thesis, University of Cape Town, 2008. http://hdl.handle.net/11427/9317.
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Includes bibliographical references (leaves 55-63).The benefits of the use of Azathioprine (AZA) and its metabolite 6-mercaptopurine (6-MP) in the treatment of Inflammatory Bowel Disease (IBD) are well established. However, concern regarding the long-term use of these agents in the induction of certain malignancies particularlty lymphoma and skin cancer has been reported in renal transplant and rheumatoid arthritis patients. In IBD patients hoever, several retropsective and prospective studies have been conducted (including two meta-analyses) with divergent results. The primary objective of this study was to compare the incidence of cancer in IBD patients treated with AZA/6BMP with those not treated. Secondary objectives were to assess if skin cancer had a higher incidence of occurrence than other cancers, and to determine the independent risk factors associated with cleveloping any malignancy.
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Vayron, de la Moureyre-Spire Catherine. "Polymorphisme génétique de la thiopurine S-méthyltranférase (TPMT)." Lille 2, 2004. http://www.theses.fr/2004LIL2S007.
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Fotoohi, Alan Kambiz. "Pharmacological and molecular investigations on the mechanisms underlying resistance of human leukaemia cells to the antimetabolites methotrexate, 6-mercaptopurine and 6-thioguanine /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-087-9/.
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Krieger, Anna-Saskia [Verfasser]. "Azathioprin und 6-Mercaptopurin in der Therapie chronisch entzündlicher Darmerkrankungen : retrospektive Analyse einer Korrelation von Metabolitenspiegeln, entzündlicher Aktivität und hämatologischen Nebenwirkungen / Anna-Saskia Krieger." Lübeck : Zentrale Hochschulbibliothek Lübeck, 2012. http://d-nb.info/1020428597/34.
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Garat, Anne. "PHARMACOGENETIQUE DES MEDICAMENTS THIOPURINIQUES Implication des enzymes TPMT et IMPDH2 et de la RhoGTPase RAC1." Phd thesis, Université du Droit et de la Santé - Lille II, 2009. http://tel.archives-ouvertes.fr/tel-00439266.
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Les médicaments thiopuriniques que sont l'azathioprine, la 6-mercaptopurine et la 6-thioguanine sont utilisés depuis des décennies pour leurs propriétés cytotoxiques et immunosuppressives dans le traitement de certaines leucémies, de maladies inflammatoires chroniques ou auto-immunes ainsi que dans la prévention du rejet de greffe. Certains patients, traités par des doses conventionnelles de ces molécules, développent cependant des effets indésirables parfois très sévères. Le déficit d'activité, d'origine génétique, de la thiopurine S-méthyltransférase (TPMT), enzyme impliquée dans le métabolisme des thiopurines, constitue l'un des facteurs majeurs de la myélotoxicité de ces médicaments. La détermination du phénotype TPMT par génotypage, qui est une mesure préventive avant l'introduction d'un traitement thiopurinique, repose sur l'identification des mutations inactivatrices les plus fréquentes du gène TPMT. Une partie de ce travail a consisté en l'analyse fonctionnelle de quatre variants alléliques rares du gène TPMT dans un système d'expression hétérologue, la levure S. cerevisiae. Le caractère non-fonctionnel de deux d'entre eux a ainsi été démontré. Cependant, le déficit d'activité de la TPMT ne permet d'expliquer qu'environ 30 % des cas de myélotoxicité sous thiopurines, ce qui laisse supposer l'existence d'autres anomalies génétiques affectant d'autres gènes impliqués dans la réponse de l'organisme à ces molécules. Ainsi, nous avons étudié le polymorphisme génétique de deux autres protéines candidates, celui de l'inosine monophosphate déshydrogénase de type 2 (IMPDH2), enzyme-clé de la formation des métabolites actifs des thiopurines, et celui de la RhoGTPase RAC1, qui est l'une des cibles pharmacologiques de ces molécules. Certains des polymorphismes que nous avons identifiés dans ces deux gènes semblent affecter in vitro l'expression et/ou l'activité de ces protéines et pourraient, par conséquent, contribuer aux variations inter-individuelles de réponse aux thiopurines
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Tafazzoli-Lari, Julia Frederike [Verfasser]. "Zusammenhang zwischen der klinischen Symptomatik der Multiplen Sklerose und ausgewählten Parametern des Thiopurinstoffwechsels (Thiopurin-S-Methyltransferase-Aktivität, 6-Thioguanin, 6 Methyl-Thioguanin und 6-Methyl-Mercaptopurin) / Julia Frederike Tafazzoli-Lari." Lübeck : Zentrale Hochschulbibliothek Lübeck, 2011. http://d-nb.info/1011801132/34.
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Perez-Ruiz, Edgar. "Analyse vibrationnelle et structurale comparée de biomolécules à visée thérapeutique : 1,7 dihydro-6h-purine-6-thione (6-mercaptopurine), 1,5-dihydro-4h-pyrazolo(3,4-d)pyrimidine-4-thione (tisopurine) et leurs chlorures." Montpellier 1, 1997. http://www.theses.fr/1997MON13521.
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Garat, Anne. "Pharmacogénétique des médicaments thiopuriniques : implication des enzymes TPMT et IMPDH2 et de la RhoGTPase RAC1." Lille 2, 2009. http://www.theses.fr/2009LIL2S029.
Full textAbstract:
Les médicaments thiopuriniques que sont l'azathioprine, la 6-mercaptopurine et la 6-thioguanine sont utilisés depuis des décennies pour leurs propriétés cytotoxiques et immunosuppressives dans le traitement de certaines leucémies, de maladies inflammatoires chroniques ou auto-immunes ainsi que dans la prévention du rejet de greffe. Certains patients, traités par des doses conventionnelles de ces molécules, développent cependant des effets indésirables parfois très sévères. Le déficit d'activité, d'origine génétique, de la thiopurine S-méthyltransférase (TPMT), enzyme impliquée dans le métabolisme des thiopurines, constitue l'un des facteurs majeurs de la myélotoxicité de ces médicaments. La détermination du phénotype TPMT par génotypage, qui est une mesure préventive avant l'introduction d'un traitement thiopurinique, repose sur l'identification des mutations inactivatrices les plus fréquentes du gène TPMT. Une partie de ce travail a consisté en l'analyse fonctionnelle de quatre variants alléliques rares du gène TPMT dans un système d'expression hétérologue, la levure S. Cerevisiae. Le caractère non-fonctionnel de deux d'entre eux a ainsi été démontré. Cependant, le déficit d'activité de la TPMT ne permet d'expliquer qu'environ 30 % des cas de myélotoxicité sous thiopurines, ce qui laisse supposer l'existence d'autres anomalies génétiques affectant d'autres gènes impliqués dans la réponse de l'organisme à ces molécules. Ainsi, nous avons étudié le polymorphisme génétique de deux autres protéines candidates, celui de l'inosine monophosphate déshydrogénase de type 2 (IMPDH2), enzyme-clé de la formation des métabolites actifs des thiopurines, et celui de la RhoGTPase RAC1, qui est l'une des cibles pharmacologiques de ces molécules. Certains des polymorphismes que nous avons identifiés dans ces deux gènes semblent affecter in vitro l'expression et/ou l'activité de ces protéines et pourraient, par conséquent, contribuer aux variations inter-individuelles de réponse aux thiopurinesThe thiopurine drugs, azathioprine, 6-mercaptopurine and 6-thioguanine, have been used for decades for their cytotoxic and immunosuppressive properties in the treatment of leukemias, chronic inflammatory or autoimmune diseases and in the prevention of allograft rejection. However, some patients treated with conventional doses of these molecules develop very severe side effects. The deficient activity of the thiopurine S-methyltransferase (TPMT), an enzyme involved in thiopurine inactivation, is one of the key factors in the myelotoxicity of these drugs. The determination of the TPMT phenotype by genotyping test is a preventive measure before the initiation of thiopurine therapy and is based on the identification of the most common inactivating mutations of the TPMT gene. First, our study consisted in the functional analysis of four new allelic variants of TPMT, using an heterologous expression system, the yeast S. Cerevisiae. The non-functional character of two of those variants was demonstrated. However, TPMT deficiency explain only about 30 % of cases of thiopurine myelotoxicity, suggesting the existence of other genetic abnormalities affecting other genes involved in the response toward thiopurines. Accordingly, we studied the genetic polymorphism of two other proteins, the inosine monophosphate dehydrogenase type 2 (IMPDH2), a key enzyme in the production of the active metabolites of thiopurine, and the RhoGTPase RAC1, which is one of the pharmacological targets of these molecules. Some of the polymorphisms that we identified in those two genes seem to affect in vitro the expression and / or activity of these proteins and, therefore, could contribute to inter-individual variations of the response to thiopurine
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Szkandera, Roman. "Testování modifikovaných sorbetů Iontosorb pro užití v technice difúzního gradientu v tenkém filmu (DGT)." Master's thesis, Vysoké učení technické v Brně. Fakulta chemická, 2008. http://www.nusl.cz/ntk/nusl-216360.
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6-mercaptopurine was joined by diazotation and copulation reactions on Iontosorb AV. Presence of thiol groups in modified resin was showed by infrared spectrometry. Amount of thiol groups was determined by iodometric titration. Resin gel was preparated from modified resin and agarose and both of them were tested for mercury determination by DGT technique.
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Barbosa, Daniella Reis. "Impacto do tratamento com os imunomoduladores azatioprina e 6-mercaptopurina sobre o estado nutricional de pacientes com doença inflamatória intestinal." Master's thesis, 2009. http://hdl.handle.net/10316/14811.
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Dissertação de mestrado em Nutrição Clínica, apresentada à Faculdade de Medicina da Universidade de CoimbraDoença inflamatória intestinal (DII) é o termo genérico dado a um grupo heterogêneo de desordens idiopáticas do intestino, caracterizadas por inflamação crônica, com períodos de atividade e remissão. As duas principais formas da DII são a Doença de Crohn (DC) e Colite Ulcerativa (CU). Embora, ainda, não haja cura, o tratamento médico destas enfermidades inclui terapia farmacológica de longo prazo, que pode ser eficaz em induzir e manter a remissão da doença. Azatioprina (AZA) e seu metabólito 6-mercaptopurina (6-MP) têm sido os agentes imunomoduladores mais utilizados, apesar da preocupação com seus efeitos colaterais. Estes agentes são geralmente adequados a pacientes aos quais a dose de corticosteroide não pode ser reduzida ou interrompida, permitindo uma diminuição gradual do corticoide e prolongando a remissão. Inúmeros estudos relatam a eficácia dos imunomoduladores na manutenção da remissão da doença, viabilizando, assim, a melhora nutricional do doente. Objetivos: analisar e descrever, retrospectivamente, o estado nutricional dos pacientes com CU e DC tratados com os imunomoduladores AZA e 6-MP, segundo análise de variáveis bioquímica e antropométrica. Pacientes e método: foram avaliados, retrospectivamente, dados clínicos de Janeiro de 1993 a Maio de 2007, de doentes com DII, em acompanhamento ambulatorial, tratados com AZA e 6-MP, por dependência ou refratariedade a corticoides. As fontes dos dados resultaram das histórias disponíveis na Unidade de DII e no arquivo central do hospital Clínico San Carlos de Madri. A coleta das informações priorizou a obtenção dos dados em dois momentos, 1º) ao início do tratamento com os imunomoduladores e 2º) ao final de 18 meses de tratamento com os mesmos. Os parâmetros avaliados foram: IMC, albumina, linfócitos, hemoglobina, proteína C reativa, ferro e colesterol. Na seleção dos doentes, foram levantados dados com relação à história clínica (cirurgia), sexo, diagnóstico, idade ao início do tratamento imunomodulador, idade no momento do diagnóstico, tipo de imunomodulador, dose no início e ao final de 18 meses de tratamento, fenótipo localização da DC, fenótipo extensão da CU, data do diagnóstico. Para fins comparativos, os doentes foram divididos em grupos por diagnóstico e sexo, momento inicial e final do tratamento. Resultados: Em ambas as doenças, todos os parâmetros apresentaram variações positivas significantes (p˂0,05) após 18 meses de tratamento imunomodulador, com exceção do colesterol, que apresentou um aumento, não-significativo. Os parâmetros IMC, albumina, hemoglobina e ferro apresentaram aumento significativo, indicando valores médios normais após 18 meses. Estratificando por diagnóstico, na CU, a PCR não apresentou redução significativa. Na DC, o IMC, apesar de ter apresentado um incremento no seu valor médio, esse não foi significativo. O restante dos parâmetros, exceto o colesterol, em ambas as enfermidades, obteve variações significativas. Menos que 10% dos doentes apresentavam baixo peso, segundo critérios da OMS, ao iniciar o tratamento imunomodulador; e menos que 5%, ao final dos 18 meses. Os níveis de linfócitos apresentaram uma redução significativa, conduzindo à linfopenia, tanto na CU como na DC. Em nenhum parâmetro, verificou-se variação estatística significativa em função do diagnóstico. Apenas na hemoglobina encontrou-se diferença significativa na sua variação média entre homens e mulheres. Conclusão: Os resultados demonstraram, após 18 meses, uma melhora nos parâmetros IMC, albumina, PCR, ferro e hemoglobina dos doentes com DII, submetidos a tratamento com os imunomoduladores AZA e 6-MP. No entanto, faz-se necessária a realização de uma avaliação nutricional completa para afirmações mais conclusivas.
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Chang, Chih-Zen, and 張志任. "Anti-inflammatory study of 6-mercaptopurine and Atorvastatin in vasospasm after experimental subarachnoid hemorrhage." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/27649313179459744785.
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博士高雄醫學大學
醫學研究所
98
According to the statistic report of the Department of Health, the Exective Yuan, R.O.C. in 2005, stroke ranks as the second leading cause of death. Among stroke patients, there are seventy percentages with ischemic stroke, and 20% intracerebral hemorrhage. Aneurysmal subarachnoid hemorrhage (SAH) accounts for a critic part of hemorrhagic stroke. The incidence of ruptured cerebral aneurysm is estimated approximately 2-3 among one hundred thousand people per year19,29,42,58. Despite studies in the past fifty years, the pathognesis of aneurysmal vasospasm remained unclear. Those studies accumulated lots of knowledge support that cerebral vasospasm is induced by multifactors, which persist to stimulate more preclinical and clinical studies. However, cerebral vasospasm subject to SAH remains to be a catastrophic mobidity amend to be solved by now. Over the past decades, the neurosurgery team in Kaohsiung Medical University is devoted to the researches dealing with SAH induced vasospasm. Professor Howng and Professor Kwan had been dwelled in the studies of prostaglandin, endothelin-converting enzyme inhibitor, such as CGS26303, CGS26393, CGS35066, in the experimental SAH and endothelin-related cerebral vasospasm. 16,50-51,70-72,81 The study of Professor Lin is set on the preventive and therapeutic effects of female hormone (estrogen) in the pathogenesis of cerebral vasospasm.75-82 The further study of Shi et al is to investigate the effect of 17β-estrodiol on SAH induced cerebral vasospasm through the Nuclear factor-kB (NFκB) path.117 In these studies, the role of inflammatory response cannot be omitted in the whole pathogenesis of SAH induced vasospasm and the relationship has not been well clarified. Therefore, an inflammation-related study is carried out. 2,22,31 The study of 6-mercaptopurine indicates that this compound can be effective in the triscription of deoxyribose nucleotides(DNA) to ribose nucleotides(RNA), direct propriate protein synthesis in the cellular proliferation , as well as white blood cell activation. According to above unsolved pitfalls, it is interested to perform the following studies: 1. 6-mercaptopurine, a nucleotide anti-metabolite, in pro-inflammatory cytokines (IL-1α, IL-1β, IL-6, TNF-α) generation and perivascular common leukocyte antigen, CD45(+) leukocytes infiltration in experimental SAH. Cytokines, derived from marcrophages, play a critic role in the organization and regulation of immune response in many mammalian diseases. Several varieties of cytokines, such as IL-1, IL-6, IL-12, and Tumor necrosis factor-α(TNF-α), deem to empower the bursting immune response. In the contrary, IL-8 is known to be one of the important factors which counteract the immune response. 31,39,46,83 The increased serum TNF-α would promote vascular endothelial cells and polymorphologic neutrophils (PMN) to produce excessive amount of endothelin-1, thereby increasing the tendency of cerebral vasospasm. Therefore, regarding to the immune study of SAH, the utility of purine nucleotide antagonist, 6-mercaptopurine, may be by reducing the bioactivity of Nerve Growth Factor-Induced-B (NGFI-B), while further reduce the levels of IL-1, IL-6 and TNF-α in serum and cerebrospinal fluid. Likewise, 6-mercaptopurine can prohibit the chemoattractant CD45 (+) monocytes migrating to the adventia, and protect vascular endothelial cells as well as decrease the aggregation of white blood cells. Owing to reduce TNF-α levels, the serum level of endothelin and circulating endothelin in the cerebrospinal fluid was decreases. Through this mechanism, 6-mercaptopurine achieves its preventive effect as well as reversal of experimental SAH-induced vasospasm. The interest of current research is that the reduced serum TNF-α level will activate the negative feedback of the Neuron factor-κB (NF-κB) 6,11,44,49,102, hence inhibit the expression of nitric oxide synthase (NOS) in endothelial cells. Thus 6–mercaptopurine is shown to reduce the production of endothelin through the NO-independent mechanism. The conditions of an ideal medication for treatment of cerebral vasospasm subject to SAH should include the lower price, lowest effective dose devoid of side effects. 6-mercaptopurine is a widely used medication for the treatment of leukemia. In our studies, this compound is proved to be able to reduce the white blood production, while reducing the endothelial cells of adhesion molecules inter-cellular adhesion molecule 1(ICAM-1), E-selectin, to achieve the antivasospastic effect within a short duration of therapy. Talking about the side effect of 6-mercaptopurine, long-term administration of 6-mercaptopurine has the potential to destroy the function of bone marrow, also cause damage to the hepatic and renal function. Under the indication of safety, it is not recommended long-term therapy of 6-mercaptopurine, and the patients must undergo regular liver and renal function and hematological examination. Fortunately, in the clinical cases of vascular spasm caused by SAH, the peak of vascular constriction often occur between the fourth day and the 14th day after SAH occurred, and therefore the treatment of such agents will not last for a long period. 6-mercaptopurine is believed to be used as one of the adjuvant treatment in the therapy of aneurysmal vasospasm. 2. The antioxidant and anti-inflammatory effect of Statins in the treatment of SAH-induced vasospasm. Statins have now been used to treat the modern metabolic diseases: three high (high blood lipids, hypertension, high cholesterol). Statins have also been found to treating diseases other than dyslipidemia. Statins are known to have a pleotropic effects such as: anti-oxidation, anti-immune protection of endothelial cells, protecting the apotposis of nerve cells. 3,10,23,33-34,52,65 In our experiment, we found Atorvastain have effectively activated endothelial cell nitric oxide enzymes, while in the pre-conditional status, Atorvastatin will reduce the production of endothelin-1. Atorvastatin can effectively prevent SAH-induced vascular spasm, not only by increasing bioactivation of nitric oxide synthase. It also reduces the infiltration of pSTAT (+) macrophage and 12 lipooxygenase (12LO) white blood cell proliferation. Statins have shown in the diversity of characteristics of treatment of dyslipidemia. In the research of myocardial cell, Statins were found by controlling NO-related Ras homolog gene, member A (RhoA) / Rho kinase (ROCK) path to achieve the vasodilation73-74,101 and therefore it can be regarded that Statins could be included in the treatment of SAH related vasospasm in the future. In conclusion, when considering the mechanism of SAH related vasospasm, it is unclear that inflammation may enhance the vascular spasm caused by SAH immediately or lead to chronic vascular spasm. Lots of experiments show that inhibition of inflammation subsequent to SAH helps to alleviate the nerve damagein the episode of SAH. Presently, we will continue to explore the immunosupressant in bio-medicine, molecular biology and other fields and aim to clarify the mechanism of post-SAH vasospasm. By the way, to grasp the effective treatment of vasospasm subject to SAH.The final target of our studies look forward to find an early solution in clinical practice, in the bitter-free recipe for the treatment of aneurismal vasospasm .
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Hwang, In Young. "Synthesis and evaluation of S-conjugates as kidney-selective prodrugs of 6-mercaptopurine and 6-thioguanine." 1992. http://catalog.hathitrust.org/api/volumes/oclc/28706593.html.
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Donnan, Jennifer. "Health Technology Assessment of Thiopurine Methyltransferase Testing for Guiding 6-Mercaptopurine Doses in Pediatric Patients with Acute Lymphoblastic Leukemia." Thesis, 2009. http://hdl.handle.net/1807/18282.
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This study determined whether phenotype or genotype tests for thiopurine methyltransferase (TPMT) are cost effective interventions for guiding doses of 6-mercaptopurine in children with acute lymphoblastic leukemia (ALL) compared to standard weight-based dosing. A systematic review of the literature was conducted to assess the accuracy of the TPMT technologies, followed by a cost effectiveness analysis which compared genotype, phenotype and weight-based dosing strategies over a three month time horizon. Both TPMT phenotype and genotype technologies were considered accurate though there is no gold standard. Additionally, included studies were of low methodological quality. Neither of the interventions showed a benefit in survival and both were more costly compared to standard weight-based dosing. At this time there is insufficient evidence to recommend the use of phenotype or genotype testing prior to 6-mercaptopurine therapy to guide initial doses in pediatric ALL patients.
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Wang, Chun-Chi, and 王俊棋. "Determination of mercaptopurine and its four metabolites in plasma by large volume sample stacking with polarity switching in capillary electrophoresis." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/33437804888012225134.
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碩士高雄醫學大學
藥學研究所碩士班
93
This study describes approaches for stacking and analyzing mercaptopurine, 6-methyl-mercaptopurine, thioguanine, thioguanosine, and thioxanthine by large volume sample stacking (LVSS) and polarity switching (PS) in capillary electrophoresis (CE). After filling run buffer (60 mM borate buffer, pH 8.5), large sample volume was loaded by hydrodynamic injection (2.5 psi, 99.9 sec), followed by the removal of sample matrix from capillary using PS (-15 kV). Monitoring the current and normalizing the polarity when 95% of current recovered, the separation of anionic analytes was performed in a run buffer under 20 kV. Around 44-90 fold improvement of sensitivity in peak height for those analytes was achieved by LVSSPS when compared with CE without stacking. This method was feasible for determining analytes spiked in plasma. Removing most of electrolytes from plasma is a key step for performing LVSS. Solid-phase extraction was used for pretreatment of biological samples. To our knowledge, this study is one of very few applications which could analyze biological samples by LVSSPS in CE.
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Li, Chung-Ta, and 李宗達. "Analysis of thiopurine drugs in tablets, and mercaptopurine and its metabolites in whole blood by liquid chromatography and capillary electrophoresis." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/46694934996368425421.
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碩士高雄醫學大學
藥學研究所碩士班
92
This study describes the establishment of (1) high performance liquid chromatography, and (2) capillary electrophoresis methods for the determination of thiopurines in available commercial formulations, and the analysis of mercaptopurine and its metabolites in whole blood. (1) High performance liquid chromatography--- The liquid chromatograph consisted of a module 501 pump connected with UV detector (200 nm). Mercaptopurine (MP) and thioguanine (TG) were eluted using a mobile phase consisting of monobasic phosphate buffer (10 mM, pH 3.5) and acetonitrile (93:7, v/v). A LiChroCART® RP-18 column (250 × 4.0 mm; 5 μm) was used. Thiouracil was used as an internal standard. Based on the optimized LC conditions, the method validation was evaluated over the range of 2-100 μM. The correlation coefficients of linear regression lines (n=3) were all greater than 0.999. The method was validated and applied to the analysis of MP and TG in tablets. The RE and RSD were all less than 5％ in intra- and inter-day assay. All of the recoveries were greater than 97 %. The limits of detection were 25 nM for MP or TG (S/N=3). This method was feasible for the application of commercial tablets (Purinethol®, Lanvis®). All of the analytical values fell within labeled amount required by the USP XXV (TG, AZA: 93-107%; MP: 93-110%). In order to increase the sensitivity, electrochemical detector (ECD) was used for detection of MP and its metabolites, TG and thioxanthine (TX), in whole blood (100 μL). Effects of parameters on the separation were investigated. The analytes were eluted using a mobile phase consisting of borate buffer (50 mM, pH 8.00) in LC RP-18 column (150 mm × 3.9 mm; 5 μm), and detected by ECD. The method validation was evaluated over the range of 0.2 – 3 μM for MP and 0.5 – 3 μM for TG or TX. The correlation coefficients of calibration curves(n=3) were all greater than 0.99. The RE and RSD were all less than 11％ in intra- and inter-day assay. The limits of detection were 50 nM for MP or TG (S/N=3). This method was applied for monitoring blood MP in a patient with acute lymphoblastic leukemia. (2) Capillary electrophoresis--- A simple CZE method was established for simultaneous determination of MP、AZA and TG. The untreated fused-silica capillary was used (40 cm, effective length 30 cm, 50 μm I.D.) for the analysis. The analysis was optimized using glycine buffer (200 mM, pH 9.00) at 25 kV and detected under 214 nm. On the method validation, the calibration curves were linear (r≧0.999) over 20.0- 400.0 μM for TG or AZA, and 50.0-400.0 μM for MP. The RSD and RE were all less than 5% for the intra- and inter-day assay. All of the recoveries were greater than 95 %. The limits of detection were 5 μM for TG or AZA and 15 μM for MP (S/N=3, hydrodynamic injection 5 sec). This method was feasible for the application of commercial tablets (Lanvis®, Azapress® and Purinethol®). All of the analytical values fell within labeled amount required by the USP XXV.（TG, AZA: 93-107 %; MP: 93-110 %）. For monitoring drug levels, capillary zone electrophoresis method was also developed for the determination of MP and its four metabolites, including thioguanosine (rTG), thioguanine (TG), methyl–mercaptopurine (MMP) and methyl-mercaptopurine riboside (rMMP) in whole blood. The untreated fused-silica capillary was used (40 cm, effective length 30 cm, 50 μm I.D.). The analysis was optimized using borate buffer (50 mM, pH 8.50) at 25 kV and detected under 214 nm. The limits of detection were 20 μM for MMP, rMMP and MP, and 100 μM for TG and rTG (S/N=3, hydrodynamic injection 5 sec). This sensitivity can not afford for drug monitoring in whole blood. On-line concentration - CE method is still under investigation.
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Kotalczyk-Zepke, Adam [Verfasser]. "Neue HPLC-Methode zur parallelen Bestimmung und Quantifizierung der Nukleotide von 6-Thioguanin, 6-Mercaptopurin und ihrer Metabolite : Evaluation der Methode durch Untersuchung der Metabolite und Stoffwechselwege in vitro und bei Patienten / vorgelegt von Adam Kotalczyk-Zepke." 2006. http://d-nb.info/981724841/34.
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