Determinación de la actividad estabilizadora de microtúbulos de fracciones ricas en diterpenoides obtenidas mediante HPLC de extractos de hojas, tallos y corteza de Taxus globosa.

Tesis (Maestría en Ciencias con Especialidad en Química de Productos Naturales) UANL

Inhibition of cancer cell proliferation and apoptosis-inducing activity of fungal taxol and its precursor baccatin III purified from endophytic Fusarium solani

Background: Taxol (generic name paclitaxel), a plant-derived antineoplastic agent, used widely against breast, ovarian and lung cancer, was originally isolated from the bark of the Pacific yew, Taxus brevifolia. The limited supply of the drug has prompted efforts to find alternative sources, such as chemical synthesis, tissue and cell cultures of the Taxus species both of which are expensive and yield low levels. Fermentation processes with microorganisms would be the methods of choice to lower the costs and increase yields. Previously we have reported that F. solani isolated from T. celebica produced taxol and its precursor baccatin III in liquid grown cultures J Biosci 33: 259-67, 2008. This study was performed to evaluate the inhibition of proliferation and induction of apoptosis of cancer cell lines by the fungal taxol and fungal baccatin III of F. solani isolated from T. celebica. Methods: Cell lines such as HeLa, HepG2, Jurkat, Ovcar3 and T47D were cultured individually and treated with fungal taxol, baccatin III with or without caspase inhibitors according to experimental requirements. Their efficacy on apoptotic induction was examined. Results: Both fungal taxol and baccatin III inhibited cell proliferation of a number of cancer cell lines with IC50 ranging from 0.005 to 0.2 mu M for fungal taxol and 2 to 5 mu M for fungal baccatin III. They also induced apoptosis in JR4-Jurkat cells with a possible involvement of anti-apoptotic Bcl2 and loss in mitochondrial membrane potential, and was unaffected by inhibitors of caspase-9,-2 or -3 but was prevented in presence of caspase-10 inhibitor. DNA fragmentation was also observed in cells treated with fungal taxol and baccatin III. Conclusions: The cytotoxic activity exhibited by fungal taxol and baccatin III involves the same mechanism, dependent on caspase-10 and membrane potential loss of mitochondria, with taxol having far greater cytotoxic potential.

Rethinking production of Taxol (R) (paclitaxel) using endophyte biotechnology

Taxol (R) (generic name paclitaxel) represents one of the most clinically valuable natural products known to mankind in the recent past. More than two decades have elapsed since the notable discovery of the first Taxol (R) producing endophytic fungus, which was followed by a plethora of reports on other endophytes possessing similar biosynthetic potential. However, industrial-scale Taxol (R) production using fungal endophytes, although seemingly promising, has not seen the light of the day. In this opinion article, we embark on the current state of knowledge on Taxol (R) biosynthesis focusing on the chemical ecology of its producers, and ask whether it is actually possible to produce Taxol (R) using endophyte biotechnology. The key problems that have prevented the exploitation of potent endophytic fungi by industrial bioprocesses for sustained production of Taxol (R) are discussed.

Farmacología Veterinaria I

El presente Compendio de Farmacología Veterinaria I fue elaborado con el espíritu de colaborar con la preparación de los estudiantes de la carrera de Medicina Veterinaria que cursan el III año de esta noble profesión. Se presentan de manera resumida los temas que conciernen a la Farmacología General, dando al estudiante las bases de los procesos farmacodinámicos de los medicamentos, sus vías de administración, las diferentes presentaciones farmacéuticas, la manera de calcular las dosis de los medicamentos y la escritura de la receta médica. Así también se presentan los temas relacionados a la Farmacología del Sistema Nervioso donde el estudiante obtendrá la información concerniente a anestésicos, analgésicos, antiinflamatorios y relajantes musculares. La Farmacología como toda ciencia está en constante cambio y actualización y es por esto que cito textualmente a los Doctores. Sumano y Ocampo: “Las palabras que se eligen para establecer un hecho farmacológico como cierto, son válidas en el mejor de nuestro entendimiento, pero sólo por un tiempo limitado, hasta que surge nueva información que matice estas “verdades” o incluso las contradiga”

Farmacología veterinaria II

La Universidad Nacional Agraria (UNA), pone en manos de la comunidad educativa superior nicaragüense y en manos de la sociedad en general, el libro de texto Farmacología Veterinaria II cuya autoría corresponde a la médico veterinaria Varinia Paredes V. MSc., miembro del claustro de profesores de la Facultad de Ciencia Animal. El documento está en correspondencia con las temáticas que se abordan en el Curso de Farmacología Veterinaria y fue elaborado con el propósito de colaborar con la preparación de los estudiantes de la Carrera de Medicina Veterinaria de la Universidad Nacional Agraria. En el texto se enuncian fármacos de reciente incorporación y temas que conciernen a la terapéutica antimicrobiana, como los antibióticos, antisépticos y desinfectantes. También se nombra la farmacología de los sistemas digestivo, cardiovascular, tegumentario así como lo concerniente al equilibrio de líquidos, corticosteroides suprarrenales sintéticos, antihistamínicos y vitaminas. La profesora Paredes ha sido una estudiosa de la farmacología veterinaria, la cual como toda ciencia, está en constante cambio y actualización. Es por eso que el contenido del presente texto es un material de consulta útil para los profesionales veterinarios, a quienes en su labor, les permitirá hacer uso racional de los fármacos.

Farmacología Veterinaria I

Prólogo 1; Principios Generales de Farmacología 5; Definiciones 5; Farmacognosia 7; Farmacocinética 9; Farmacodinamia 20; Factores Que Afectan La Respuesta de los Fármacos 27; Formas Farmacéuticas se los medicamentos 31; La Receta 33; Medicamentos Que Actúan sobre el Sistema Nervioso Central 37; Neurolépticos, Tranquilizantes Y Anestesia Local 51; Medicamentos Anticonvulsivos Y Analgésicos 63; Estimulantes del Sistema Nervioso Central 74; Medicamentos Que Actúan sobre El Sistema Nervioso Autónomo 79; Agentes Parasimpaticomimeticos y Parasimpaticoliticos 88; Relajantes Musculares 96; Bibliografía

Selection with melphalan or paclitaxel (Taxol) yields variants with different patterns of multidrug resistance, integrin expression and in vitro invasiveness

A melphalan-resistant variant (Roswell Park Memorial Institute (RPMI)-2650M1) and a paclitaxel-resistant variant (RPMI-1650Tx) of the drug-sensitive human nasal carcinoma cell line, RPMI-2650. were established. The multidrug resistance (MDR) phenotype in the RPMI-2650Tx appeared to be P-glycoprotein (PgP)-mediated. Overexpression of multidrug resistant protein (MRP) family members was observed in the RPMI-2650M1 cells, which were also much more invasive in vitro than the parental cell line or the paclitaxel-resistant variant. Increased expression of alpha (2), alpha (5), alpha (6), beta (1) and beta (4) integrin subunits, decreased expression of alpha (4) integrin subunit, stronger adhesion to collagen type IV, laminin, fibronectin and matrigel, increased expression of MMP-2 and MMP-9 and significant motility compared with the parental cells were observed, along with a high invasiveness in the RPMI-7650M1 cells. Decreased expression of the alpha (2) integrin subunit, decreased attachment to collagen type IV, absence of cytokeratin 18 expression, no detectable expression of gelatin-degrading proteases and poor motility may be associated with the non-invasiveness of the RPMI-2650Tx variant. These results suggest that melphalan exposure can result in not only a MDR phenotype. but could also make cancer cells more invasive, whereas paclitaxel exposure resulted in MDR without increasing the in vitro invasiveness in the RPMI-2650 cells. (C) 2001 Elsevier Science Ltd. All rights reserved.

Synthesis of a tetraoxy-bis-nortaxadiene, en route to taxol, using a cascade radical cyclisation sequence

Concise syntheses of the substituted enynediones 28a, 33b and 36 starting from the cyclohexenealdehyde 18, corresponding to ring A in the taxanes, and the vinylstannane 24, are described. Treatment of 36 with Bu3SnH–AIBN did not lead to the oxy-substituted taxadiene 37 expected from a tandem radical macrocyclisation–radical transannulation sequence; instead, a mixture of unidentified products resulted. When the PMB ether 33b corresponding to the alcohol 36 was treated with Bu3SnH–AIBN under similar conditions, p-anisaldehyde was isolated, as a major by-product, but no evidence for the formation of a taxadiene could be observed. In contrast, the iododienynedione 41, i.e., deoxy 36, underwent a tandem radical macrocyclisation–transannulation sequence, when treated with Bu3SnH–AIBN, leading to the tetraoxy-bis-nortaxadiene 42 in 44% yield. Attempts to synthesise the alcohol 28b from the silyl ether 28a en route to the iodide 28c instead gave the substituted tetrahydrofuran 29 via an intramolecular oxy-Michael reaction.

Subcutaneous study on the controlled release of Etanidazole and Taxol for the treatment of Glioma

BALB/c nude mice 6 weeks old were inoculated with glioma C6 cell-line and the efficacy of the different amount of Etanidazole-discs and Taxol-microspheres was investigated. Poly (D,L-lactic-co-glycolic acid) (PLGA) was used as the main encapsulating polymer and polyethylene glycol was added to increase the porosity. The 1% drug loading microspheres of each drug were produced by spray drying and the discs were obtained by compressing the Etanidazole-microspheres. Intra-tumoral injection followed by irradiation resulted in high systemic dosage and thus systemic toxicity. Tumors grown for 6 days, 9 days and 16 days were implanted with 0.5 mg or 1.0 mg or 1.5 mg of the drug. A radiation dosage of 2 Gy each time for a number of times was given for animals implanted with Etanidazole and no irradiation was given for animals implanted with Taxol. Increasing the number of doses clearly decreased the rate of tumor growth. The increase in the amount of drug on smaller sized tumors controlled the tumor better and there was agglomeration of the microspheres resulting in deviation of release profile of the drug as compared to the in vitro studies. It was observed that 1.0 mg of Taxol given to a tumor grown for 6 days was able to suppress the tumor for a total period of approximately two months and no tumor resurrection was observed during the second month.

Investigación sobre la evaluación en la enseñanza de Farmacología durante el período 1986-1989.

Analizar las distintas técnicas de evaluación a que son sometidos los estudiantes de Farmacología. Se hace un seguimiento en la evaluación a alumnos del primer ciclo de Farmacología durante el período 1986-1989. Se valoran los distintos métodos de evaluación detallando sus ventajas e inconvenientes: preguntas en seminario, exámenes tipo ensayo, examen final ante tribunal, régimen tutorial especial para los alumnos de 5, 6, 7 y 8 convocatoria, exámenes programados, etc. Se calculan en las preguntas los índices de dificultad y de discriminación. Para el contraste estadístico se emplea estadística paramétrica y no paramétrica y se establece la correlación entre las distintas modalidades de evaluación. Los métodos de evaluación continuada proporcionan mejores resultados que el método tradicional de uno o ningún examen parcial no liberatorio y que el examen ante tribunal. La perturbación de la normalidad académica influye muy negativamente sobre el rendimiento académico de los alumnos. En el examen de licenciatura se observa correlación positiva entre la calificación del expediente académico y la del examen teórico, no ocurriendo lo mismo con el examen práctico.. Se sugiere la conveniencia de la utilización de varias técnicas de evaluación para conocer mejor a los alumnos y para una mejor valoración de los mismos, ya que por el momento ninguno de los métodos de evaluación empleados aisladamente proporciona información completa. El examen práctico individual en el laboratorio y la resolución de casos programados manejando bibliografía serán las nuevas modalidades de examen a las que recurrimos para evaluar en el futuro, aunque no se puede prescindir de una prueba objetiva ni de una tipo ensayo, oral o escrita.