No description available.

No description available.

This paper studies the the synthesis of certain alkoxy compounds of 2,3-dichloro-1,4-naphthoquinone that can be considered chemotherapeutic agents.

No description available.

No description available.

No description available.

O câncer é umas das principais causas de morte no mundo. Com a falta de critério individual para o tratamento de câncer metastático, a quimioterapia ainda é realizada com fármacos de toxicidade significativa como antraciclinas e taxanos. Portanto, a busca por novos fármacos é de suma importância. Os alquilfosfolipídios constituem uma nova classe de fármacos antineoplásicos, tendo como protótipo a miltefosina, empregada para o tratamento tópico de metástases cutâneas de câncer de mama. No entanto, este fármaco apresenta toxicidade gastrointestinal e ação hemolítica. Neste trabalho, investigou-se a rota sintética da miltefosina, bem como a síntese de novos análogos cicloalquílicos possivelmente menos hemolíticos e menos tóxicos. Para a síntese da miltefosina, 4 etapas foram realizadas: a) obtenção do Dicloreto de fosforoexadecila; b) obtenção de 2-(hexadeciloxi)-3-metil-oxa-1,3,2- oxazofosfolano; c) obtenção do fosfato de 2-(metilamino) etil hexadecila; d) obtenção da miltefosina (hexadecilfosfocolina); sendo o fármaco obtido com sucesso. Em seguida, metodologias de monossubstituição em dióis simétricos foram investigadas para obtenção de ω-hidroxidecil-cicloalquilmetil éteres a serem empregados na rota da miltefosina visando análogos alcoxicicloalquilicos. Diversas tentativas foram empregadas sem sucesso, impedindo-nos de dar continuidade à síntese destes análogos. Partindo-se do reagente cicloexanoetanol e empregando-se a rota de síntese aprimorada da miltefosina, obtivemos o intermediário fosfato de 2-(metilamino)etil cicloexila puro. A última etapa, referente à metilação da amina, resultou em composto dimetilado ao invés do trimetilado esperado. Um ajuste dos parâmetros reacionais como, por exemplo, aumento da concentração dos reagentes de partida, deve resultar no composto planejado. Tanto o intermediário obtido quanto o análogo desejado poderão ser futuramente ensaiados quanto à atividade antitumoral e potencial hemolítico. / Cancer is one of the major causes of death worldwide. Due to the lack of individual standard treatment for metastatic cancer, chemotherapy is still based in the use of significantly toxic drugs like anthracyclines and taxanes. Hence, there is a need to search for new anticancer agents. Alkylphospholipids recently emerged as a new antitumor class and its lead compound, miltefosine, has been used for the topical treatment of cutaneous metastasis in breast cancer. However, this drug exhibits gastrointestinal toxicity and hemolytic activity. We investigated miltefosine synthetic route as well as the synthesis of cycloalkyl analogues possibly less toxic and hemolytic. We started from miltefosine synthesis, which included four steps: a) generation of hexadecyl phosphorodichloridate; b) generation of 2-(hexadecyloxy)-3-methyl-oxo-1,3,2-oxazaphospholane; c) generation of hexadecyl 2-(methylamino) ethyl phosphate; d) production of the final product miltefosine (hexadecylphosphocholine). The route was optimized, resulting in the desired drug. After that, several methods for symmetrical diols monoprotection were investigated aiming at the generation of ω-hydroxydecyl cycloalkylmethyl ethers to be further employed in miltefosine synthetic route aiming at alkoxycycloalkyl analogues. Several attempts were realized however unsuccessfully, preventing us to move on in these analogues synthesis. In a different approach, we started from cyclohexylethanol and, employing the synthetic route of miltefosine, obtained the third intermediate, 2-cyclohexylethyl 2- (methylamino)ethyl phosphate pure. The methylation step, last one to obtain the cycloalkyl analogue, resulted in a dimethyl analogue instead of a trymethyl one. We believe that adjusting the reaction parameters, such as increasing reagents concentrations, should result in a successful methylation step. The intermediate obtained as well as the analogue planned might be future evaluated in terms of hemolytic potential and antitumor activity.

Os pacientes submetidos ao tratamento antineoplásico necessitam de um acesso venoso que permita a infusão segura das drogas quimioterápicas, evitando assim o risco do extravasamento. O extravasamento quimioterápico é definido como o escape de drogas do vaso sanguíneo para os tecidos circunjacentes, e seus efeitos tóxicos locais variam podendo causar dor, necrose tissular ou descamação do tecido. A morbidade depende do tipo da droga, da quantidade extravasada, da sua concentração, da localização do extravasamento, das condições do paciente e do intervalo entre o fato, seu reconhecimento e o tratamento. A prática baseada em evidências é uma abordagem que capacita os profissionais buscarem a melhor evidência para o cuidado, respeitando a opinião dos pacientes e seus familiares. O presente estudo é uma revisão integrativa da literatura, que teve como objetivo buscar e avaliar as evidências disponíveis na literatura sobre as intervenções eficazes frente ao extravasamento de drogas quimioterápicas vesicantes, em cateteres periféricos, prevenindo e minimizando lesões no paciente adulto oncológico. Para a seleção dos artigos utilizamos a base de dados Medline, e a amostra constituiui-se de 16 artigos. As medidas de prevenção do extravasamento são consideradas mais eficazes e recomendadas. Para o manejo do extravasamento das drogas doxorrubicina e epirrubicina é recomendado aplicação de gelo local, os antídotos dimetilsulfoxide tópico e dexrazoxane intravenoso, intervenção cirúrgica se houver persistência dos sintomas ou para grande quantidade de droga extravasada. Para o extravasamento de mitomicina C, gelo local e intervenção cirúrgica em lesões detectadas após 48 horas; para mecloretamina é indicado gelo e o antídoto tiossulfato de sódio. Para o manejo da vinorelbine é recomendado calor local e o antídoto hialuronidase por via subcutânea. As evidências extraídas dos estudos analisados podem auxiliar a implementação de cuidados de enfermagem eficazes relacionados ao extravasamento das drogas vesicantes contribuindo assim com a melhoria da assistência à saúde. / Patients submitted to antineoplastic chemotherapy need a venous access that allows for the safe infusion of chemotherapeutic drugs, thus avoiding the risk of chemotherapeutic extravasation. Chemotherapeutic extravasation is defined as the escape of drugs from the blood vessel to surrounding tissues. Its local toxic effects vary and can cause pain, tissue necrosis or flaking. Morbidity depends on the type of drug, the extravasated quantity, its concentration, the location of the extravasation, the patient s conditions and the interval between the fact and its recognition and treatment. Evidence-based practice is an approach that trains professionals to look for the best evidence for care, respecting the opinions of patients and their relatives. This study is an integrative literature review that aimed to look for and assess available evidence in literature about effective interventions in case of extravasation of vesicant chemotherapeutic drugs, in peripheral catheters, minimizing skin injuries of adult cancer patients. To select the articles, we used the database Medline, and the sample consisted of 16 articles. Extravasation prevention measures are considered as the most effective and recommended measures. To handle the extravasation of doxorubicin and epirubicin, the local application of ice is recommended, the antidotes topic dimethyl sulphoxide and intravenous dexrazoxane, and surgical intervention if the symptoms persist or if a large quantity of the drug has extravasated. For the extravasation of mitomycin C, local ice and surgical intervention in injuries detected after 48 hours; for mecloretamine, ice is indicated, as well as the antidote sodium thiosulphate. To handle vinorelbine, local heat is recommended, as well as the subcutaneous application of the antidote hyaluronidase. The evidence extracted from the analyzed studies can support the implementation of effective nursing care related to the extravasation of vesicant drugs, thus contributing to the improvement of nursing care.

INTRODUCTION: The blood brain barrier (BBB), formed by the brain capillary endothelial cells separating the blood from the brain. Furthermore, the brain endothelial cells also express numerous transporter systems which help regulate and maintain the brain microenvironment. The protective function of the BBB and their transporter systems under pathological disease states, including brain tumor, can be an obstacle for the entry of therapeutic agents to the brain. OBJECTIVES: The current study set out to characterize brain tumor-induced alterations of the BBB of a mouse brain tumor model. Studies were performed to address changes in BBB permeability to P-gp dependent solutes using Rhodamine (R800). Furthermore, the use of lysophosphatidic acid (LPA) to modulate BBB permeability was also examined in healthy mice and tumor-bearing mice. METHODS: Tumors were induced by injecting Lewis Lung carcinoma (3LL) cells into the right hemisphere of female Balb/c mice. Changes in BBB permeability were assessed at various stages of tumor development, using both gadolinium contrast-enhanced agent (Gad) and 3H-mannitol. Functional activity of P-gp in the BBB was examined in adult mice following i.v. injection of R800 in the presence and absence of GF120918 (a P-gp inhibitor). Alterations in BBB permeability were characterized in healthy and tumor-bearing mice using a small (Gad) and large (IRdye800cw PEG) vascular permeability agent as well as R800 (changes in P-gp mediated permeability). RESULTS: Median mouse survival following 3LL injection was 17 days. The BBB was largely intact during tumor development with disruptions observed at the later stages of tumor development as indicated by Gad permeability. By inhibiting the function of P-gp with GF120918, the distribution of R800 in the brain increased by 4-fold. The enhancement effect of LPA on BBB permeability occurs within 3-6 minutes of injection with the barrier being restored back to its normal function within 20 minutes. Furthermore, an increased in brain penetration of IRdye800ce PEG and R800 were observed following LPA injection in both healthy and tumo-bearing mice. CONCLUSION: These studies provide the initial proof of concept for the use of BBB modulators including LPA and GF120918 to enhance drug delivery to the brain and the tumor sites.

INTRODUCTION: The blood brain barrier (BBB), formed by the brain capillary endothelial cells separating the blood from the brain. Furthermore, the brain endothelial cells also express numerous transporter systems which help regulate and maintain the brain microenvironment. The protective function of the BBB and their transporter systems under pathological disease states, including brain tumor, can be an obstacle for the entry of therapeutic agents to the brain. OBJECTIVES: The current study set out to characterize brain tumor-induced alterations of the BBB of a mouse brain tumor model. Studies were performed to address changes in BBB permeability to P-gp dependent solutes using Rhodamine (R800). Furthermore, the use of lysophosphatidic acid (LPA) to modulate BBB permeability was also examined in healthy mice and tumor-bearing mice. METHODS: Tumors were induced by injecting Lewis Lung carcinoma (3LL) cells into the right hemisphere of female Balb/c mice. Changes in BBB permeability were assessed at various stages of tumor development, using both gadolinium contrast-enhanced agent (Gad) and 3H-mannitol. Functional activity of P-gp in the BBB was examined in adult mice following i.v. injection of R800 in the presence and absence of GF120918 (a P-gp inhibitor). Alterations in BBB permeability were characterized in healthy and tumor-bearing mice using a small (Gad) and large (IRdye800cw PEG) vascular permeability agent as well as R800 (changes in P-gp mediated permeability). RESULTS: Median mouse survival following 3LL injection was 17 days. The BBB was largely intact during tumor development with disruptions observed at the later stages of tumor development as indicated by Gad permeability. By inhibiting the function of P-gp with GF120918, the distribution of R800 in the brain increased by 4-fold. The enhancement effect of LPA on BBB permeability occurs within 3-6 minutes of injection with the barrier being restored back to its normal function within 20 minutes. Furthermore, an increased in brain penetration of IRdye800ce PEG and R800 were observed following LPA injection in both healthy and tumo-bearing mice. CONCLUSION: These studies provide the initial proof of concept for the use of BBB modulators including LPA and GF120918 to enhance drug delivery to the brain and the tumor sites.