Quimioterápicos y cardiotoxicidad: un enfoque actual y práctico para el clínico de una disciplina en pleno desarrollo / Chemotherapy agents and cardiotoxicity: a current and user-friendly approach for the clinician, a developing discipline

La cardiotoxicidad por fármacos quimioterápicos es un efecto adverso frecuente y esperado. En este sentido se ha creado una especialización, la cardiooncología, que tiene como principal objetivo la prevención de estos efectos. La forma de expresión de este fenómeno es muy variada, pudiendo manifestarse como: insuficiencia cardíaca, hipertensión arterial, eventos coronarios agudos y/o trastornos del ritmo. La clave en la prevención está en la idividualización del riesgo cardiotóxico de cada paciente (en base a factores reconocidos como edad, sexo, irradiación mediastinal previa, tipo de fármaco, dosis acumulada, cardiopatía asociada previamente) y el riesgo potencial cardiotóxico de cada quimioterápico. En este sentido se han creado algoritmos de actuación fundamentados en la monitorización y el inicio de tratamiento precoz y oportuno de cada efecto, previniendo el mal mayor en cada paciente.

Synthesis and molecular-cellular mechanistic study of pyridine derivative of dacarbazine

Dacarbazine is an antitumor prodrug which is used for the treatment of malignant metastatic melanoma and Hodgkin's disease. It requires initial activation in liver through an N-demethylationreaction. The active metabolite prevents the progress of disease via alkylation of guanine bases in DNA strands. In order to investigate the importance of imidazole ring and its dynamictautomerization in anticancer activity of dacarbazine, a pyridine analog of this drug was synthesized and the cytotoxic activity and cellular-molecular mechanisms of action for this compound were compared with those of dacarbazine. EC50 values for dacarbazine and the pyridine analog were found to be 56 micro M and 33 micro M respectively. Both dacarbazine and the pyridine analog resulted in formation of reactive oxygen species [ROS] upon their addition to the isolated rat hepatocytes. They also decreased the mitochondrial membrane potential and caused lysosomal membrane rupture. Cytotoxicity was prevented by ROS scavengers and antioxidants. Cytotoxicity was also prevented by CYP[450] inhibitors, lysosomalinactivators and MPT [Mitochondrial Permeability Transition Pore] blockers

[Effects of vitamin E and ginseng extract on fertility changes induced by cyclophosphamide in rats]

Cyclophosphamide [CP] is a mustard alkylating agent used in the treatment of some neoplastic diseases such as leukemia, breast and pulmonary cancers. CP administration induces oxidative stress and has cytotoxic effects on normal cells, especially in the reproductive organs. A major side-effect of CP is the alteration of male reproductive function which may result in oligospermia or azoospermia. The aim of the present study was to evaluate the protective effects of vitamin E and ginseng extract on the reproductive system of male rats during cyclophosphamide administration. Fifty-six adult male Wistar rats [220 +/- 30 g] were randomly divided into seven groups of eight. To eliminate the stress induced by gavage, the animals in the first group were considered as the control group and only received water and food. The second group received the placebo for CP via gavage. The third group received CP, 6.1 mg/kg/day, through intraperitoneal administration. The fourth and fifth groups, respectively, received Ginseng, 500 mg/kg/day, and vitamin E 100 mg/kg/day via gavage. The eighth group received both antioxidants by intubation 1 h prior to CP administration for 50 days. The animals were sacrificed one day after the last injection. The testes, body weight, sperm parameters and fertility status of animals were evaluated at the end of the experiments. For the evaluation of fertility index, the male rats were mated with untreated female rats on the 40[th] day of the treatment period. Cyclophosphamide decreased sperm count, lowered fertility rate and decreased testis weight while it increased the number of dead and abnormal sperms [p < 0.01]. In addition, the number of pregnant animals and viable offspring were reduced too; while antioxidant use diminished the adverse effects of CP. The results of the study showed that antioxidative agents vitamin E and Ginseng could diminish the adverse effects of cyclophosphamide in the reproductive system of male rats during cyclophosphamide administration

Fetal Central Nervous System and Thymic Alterations Following Cyclophosphamide Treatment of Pregnant Mice / Alteraciones del Sistema Nervioso Central Fetal y Tunicas Posterior al Tratamiento con Ciclofosfamida en Ratas Preñadas

The present study assessed central nervous system (CNS) and immune system changes in murine fetuses after cyclophosphamide (CP) exposure during intrauterine life. A single CP dose of 0, 10, or 20mg/kg body weight was administered by intraperitoneal inj ection to pregnant mice (20/group) on day 11 of gestation (GD 11) and fetuses were evaluated on day 19 of gestation (GD 19). Fetuses were examined for external changes, and then the brains and thymuses were removed for further evaluations of histological changes, protein content, apoptotic cell count, DNA fragmentation, and in vitro cell proliferation using 1 fetus/litter for each assessment. Brains and thymuses from CP-exposed fetuses were smaller in size and distorted in overall shape compared to those from the control group. Estimated mean protein content (mg/mL) of brains was decreased in the CP-exposed groups. In both brain cells and thymocytes there was an increase in mean apoptotic cell counts and in mean percent DNA fragmentation in the exposed groups. The in vitro cell proliferation assays conducted with cells from exposed fetuses exhibited a mean decrease in the number of both brain cells and thymocytes generated. These findings indicate that maternal CP treatment on GD 11 in mice results in marked fetal toxicity characterized by reduced live litter size, fetal body weights as well as brain and thymic weights and malformations which are accompanied by changes in brain protein content, brain and thymic apoptosis, DNA fragmentation and in vitro cell proliferation at term.

El presente estudio evaluó los cambios en el sistema nervioso e inmunológico en fetos de roedores, luego de exposición a ciclofosfamida (CF) durante la vida intrauterina. Una dosis única de CF de 0, 10, y 20 mg/kg de peso se administró por medio de inyección intraperitoneal en ratas preñadas (grupo de 20) en el día 11 de gestación (DG11) y luego los fetos se evaluaron en el día 19 de gestación (DG19). Fueron examinados los cambios externos de los fetos, y los cerebros y timos se extrajeron para evaluar los cambios histológicos, contenido de proteínas, conteo de células apoptóticas, fragmentación de DNA y proliferación de células in vitro, usando 1 feto por carnada para cada evaluación. Los cerebros y timos de fetos expuestos a CF eran pequeños y completamente deformados , comparado con los del grupo control. La estimación del contenido proteico (mg/mL) de los cerebros estuvo disminuida en los grupos expuestos a CF. En las células del cerebro y timocitos hubo un incremento en el promedio del conteo de células apoptóticas y el porcentaje promedio de la fragmentación de DNA en los grupos expuestos. Los ensayos de proliferación celular in vitro realizados en células de fetos expuestos, mostraron una disminución en el promedio de células cerebrales y timocitos generados. Estos hallazgos indican que el tratamiento materno en el DG11 con CF en ratones significa una marcada toxicidad fetal caracterizada por un reducido tamaño de los nacidos vivos de la carnada, reducidos pesos fetal, cerebral y del timo y malformaciones, las cuales son acompañadas por cambios en el contenido proteico cerebral, apoptosis de células cerebrales y del timo, fragmentación del DNA y proliferación celular in vitro al término.

Antimutagenic effects of piperine on cyclophosphamide-induced chromosome aberrations in rat bone marrow cells.

Piperine is a major pungent substance and active component of black pepper (Piper nigrum Linn.) and long pepper (Piper longum Linn.). Both plants are used worldwide as household spices and condiments. They are also used as important ingredients in folklore medicine in many Asian countries. Therefore, it is of interest to study antimutagenic effects of piperine. In this study, its influence on chromosomes was investigated in rat bone marrow cells. Male Wistar rats were orally administered piperine at the doses of 100, 400 and 800 mg/kg body weight for 24 hours then challenged with cyclophosphamide at a dose of 50 mg/kg body weight by intraperitoneal injection. Twenty-four hours thereafter, all animals were sacrificed and bone marrow samples were collected for chromosomal analysis. The results demonstrated that piperine at a dose of 100 mg/kg body weight gave a statistically significant reduction in cyclophosphamide-induced chromosomal aberrations. In conclusion, piperine may have antimutagenic potential. The underlying molecular mechanisms now require attention.

Effect of pinacidil on the contractile response of cyclophosphamide-treated rat vas deferens.

Effect of pinacidil, a K+ channel opener, was studied on contractility of cyclophosphamide-treated rat vas deferens. The mean IC50 value of pinacidil against 1 mmol barium chloride induced rhythmic contractions and 40 mmol potassium chloride induced tonic contractions was significantly (P < 0.01 and P < 0.001, respectively) increased in the cyclophosphamide treated group as compared to the control. The mean EC50 value of norepinephrine (NE) in the presence of pinacidil (10(-6) mol) was significantly (P < 0.001) increased in the cyclophosphamide treated group. These findings indicate that the responsiveness of rat vas deferens smooth muscle to pinacidil is reduced following cyclophosphamide treatment.