Enfermedad de Pompe de inicio infantil en siete niños mexicanos / Infantile-onset Pompe disease in seven Mexican children

Resumen Introducción: La enfermedad de Pompe (EP) es una forma rara de miopatía metabólica; la presentación infantil clásica es severa y el fallecimiento acontece antes del año de vida, y la forma no clásica es de progresión más lenta y la sobrevivencia puede superar el año. Objetivo: Describir genotipo y características de pacientes mexicanos con EP de inicio infantil. Métodos: Se incluyeron siete pacientes con enfermedad confirmada mediante actividad enzimática y estudio molecular del gen GAA. Se revisaron las mutaciones en bases de datos genómicas. Resultados: La mediana de la edad de inicio de los síntomas fue de cuatro meses (1-12 meses) y la edad de diagnóstico fue de ocho meses (4-16 meses). Todos los pacientes tenían cardiomiopatía: cuatro que fallecieron antes del año presentaron mutaciones que predicen enfermedad severa (c.2431dup, c.2560C>T, c.655G>A, c.1987delC) y CRIM (cross-reactive immunologic material) negativo; tres sobrevivieron después del año de edad con terapia de reemplazo enzimático, uno casi cinco años, otro 18 meses y una niña tenía casi tres años al momento de este informe; sus variantes patogénicas predecían enfermedad potencialmente menos severa (c.1979G>A, c.655G>A, c.1447G>A) y CRIM positivo. Conclusión: Existió buena correlación entre genotipo y fenotipo en niños con enfermedad de Pompe.

Abstract Introduction: Pompe disease (PD) is a rare form of metabolic myopathy; the classic infantile presentation is severe, with death occurring before reaching one year of life, and the non-classical form is of slower progression and survival can exceed one year. Objective: To describe the genotype and characteristics of Mexican patients with infantile-onset PD. Methods: Seven patients with PD confirmed by enzymatic activity determination and GAA gene molecular analysis were included. Mutations were reviewed in genomic databases. Results: Median age at symptom onset was four months (1-12 months) and age at diagnosis was eight months (4-16 months). All patients had cardiomyopathy: four who died before one year of age had mutations that predicted severe disease (c.2431dup, c.2560C>T, c.655G>A, c.1987delC) and were negative for cross-reactive immunologic material (CRIM). Three patients survived after one year of age with enzyme replacement therapy; one survived almost five years, another 18 months, and one girl was almost three years of age at the time of this report; their pathogenic variants predicted potentially less severe disease (c.1979G>A, c.655G>A, c.1447G>A) and they were positive for CRIM. Conclusion: There was a good correlation between genotype and phenotype in children with Pompe disease.

Ergosterol biosynthesis and drug development for Chagas disease

This article presents an overview of the currently available drugs nifurtimox (NFX) and benznidazole (BZN) used against Trypanosoma cruzi, the aetiological agent of Chagas disease; herein we discuss their limitations along with potential alternatives with a focus on ergosterol biosynthesis inhibitors (EBI). These compounds are currently the most advanced candidates for new anti-T. cruzi agents given that they block de novo production of 24-alkyl-sterols, which are essential for parasite survival and cannot be replaced by a host's own cholesterol. Among these compounds, new triazole derivatives that inhibit the parasite's C14± sterol demethylase are the most promising, as they have been shown to have curative activity in murine models of acute and chronic Chagas disease and are active against NFX and BZN-resistant T. cruzi strains; among this class of compounds, posaconazole (Schering-Plough Research Institute) and ravuconazole (Eisai Company) are poised for clinical trials in Chagas disease patients in the short term. Other T. cruzi-specific EBI, with in vitro and in vivo potency, include squalene synthase, lanosterol synthase and squalene epoxidase-inhibitors as well as compounds with dual mechanisms of action (ergosterol biosynthesis inhibition and free radical generation), but they are less advanced in their development process. The main putative advantages of EBI over currently available therapies include their higher potency and selectivity in both acute and chronic infections, activity against NFX and BZN-resistant T. cruzi strains, and much better tolerability and safety profiles. Limitations may include complexity and cost of manufacture of the new compounds. As for any new drug, such compounds will require extensive clinical testing before being introduced for clinical use, and the complexity of such studies, particularly in chronic patients, will be compounded by the current limitations in the verification of true parasitological...

La quimiosensibilidad de Plasmodium falciparum de Venezuela / The drug-resistance of plasmodium falciparum of Venezuela

En este trabajo se presentan algunas estrategias que pudieran mejorar el grave problema creado por la quimioresistencia de Plasmodium falciparum a algunos medicamentos en los países con áreas endémicas para la malaria, entre los cuales Venezuela. Nuestros resultados muestran en las estirpes de P.falciparum que circulan en el país, la presencia de resistencia a la cloroquina, a la amodiaquina y a la combinación primetamina/sulfadoxina, así como la sensibilidad de los parásitos a la quinina y a la mefloquina. Una alternativa fue también evaluar la posibilidad de vertir o modular la resistencia a la cloroquina en los parásitos resistentes. Demostrar que P.falciparum que circula en el meridional endémico de Venezuela, también es susceptible al efecto revertidor de la desipramina, reportado para parásitos de otros países endémicos, mientras que el verapamil, postulado igualmente como revertidor de la respuesta a la cloroquina, no presenta esta propiedad en P.falciparum de Venezuela. La evaluación de una actividad inhibidora antimalárica de compuestos no convencionales, indicó un efecto importante para las drogas azoles como el ketoconazol y el derivado bis-triazol ICI 195,739, sobre los parámetros de P.falcparum resitente a la cloroquina directamente de pacientes infectados en las áreas maláricas. Igualmente, la evaluación de compuestos con una estructura química completamente novedosa, mostró un gran potencial antimalárico de los mismos sobre los parásitos resistentes que circulan en Venezuela. Tales resultados promisorios estimulan la continuación de los otros estudios que se requieran para la futura utilización de estos compuestos en la quimioterapia de esta enfermedad. En base a los resultados se plantean algunas recomendaciones para las autoridades sanitarias en relación a la problematica de la resistencia a drogas que manifiesta P.falciparum de Venezuela

Sinergismo en la acción antiproliferativa de inhibidores de la sintesis de esteroles sobre el trypanosoma cruzi in vitro e in vivo implicaciones terapéuticas / Sinergistic in the antiproliferative action of sterol synthesis inhibitors on in vitro and in vivo thypanosoma cruzi: therapeutic aspects

Los estudios realizados desde el punto de vista molecular, celular y organismico revelan que el Trypanosoma cruzi en su proliferación depende de la producción de esteroles endógenos. Cualquier intervención farmacológica que modifique esta ruta biosintética previene la proliferación del parásito, in vivo e in vitro. Además cuando se combinan estos agentes, ellos pueden tener acción sinergética sobre la proliferación del parásito, lo que permite pensar, que podría ser útil en el tratamiento de la Enfermedad de Chagas, sin efectos secundarios. Las combinaciones hasta ahora conocidas son el ketoconazol (Janssen) Lamisil (Sandoz) y el ketoconazol-Mevacor (Merk Sharp & Dohme). Otras combinaciones han sido evaluadas por nuestro grupo y la OMS, como el itraconazol (Janssen) que posee mayor actividad y menor toxicidad que el anterior, usándolo en combinación con la sinvastatina (Merk Sharp & Dohne) y la fluvastatina (Sandoz). Finalmente, las terapéuticas propuestas pueden ser útiles en el tratamiento de otras enfermedades parasitarias y algunas micosis sistémicas

The limitations of paradigms: studies on the intermediary metabolism of Trypanosoma cruzi

We review the development of our knowledge and interpretations of the intermediary metabolism of Trypanosoma (Schizotrypanum) cruzi. Already in the 1950's it was clearly established that when this organism was exposed to large external concentrations of carbohydrates it was unable to catabolize them completely, even in the presence of oxygen, producing a mixture of CO2, dicarboxylic acids (succinic, malic) and alanine as end products. However, subsequent work tended to emphasize such paradigmatic features as a full complement of glycolytic enzymes in all stages of the life cycle of the parasite, a functional Kreb's cycle, a cytochrome-dependent electron transport chain and phosphorylative oxidation which suggested that T. cruzi had the basic metabolic properties of classical glucose-utilizing cells, in contrast with the degenerate glycolytic metabolism of bloodstream African trypanosomes. Only in the 1980's interest revived on the how and why of the incomplete carbohydrate catabolism by this parasite. The primary reason for this anomaly was found to be the presence of a constitutive phospho-enol-pyruvate carboxykinase (PEPCK, ATP-dependent, E.C.4.1.1.49), present in all stages of the parasite's life cycle, and the lack of regulation of the glycolytic route at its classical control points, hexokinase and phosphofructokinase. On the other hand, the presence of two distinct glutamate dehydrogenases (NAD+ and NADP(+)-dependent), the former being strictly regulated by the energy charge of the cell and the Krebs' cycle activity, indicated that amino acids can be a primary source of energy for this organism.(ABSTRACT TRUNCATED AT 250 WORDS)

Concentration and time dependence of the effects of Ketoconazole on growth and sterol synthesis by Trypanosoma (Schizotrypanum) cruzi Epimastigotes / Dependencia del tiempo y la concentración en los efectos del etoconazol sobre la proliferación y síntesis de esteroles de epimastigotes del Trypanosoma (Schizotrypanum) cruzi

Ketoconazole, a dioxolane imidazole, affects growth and sterol synthesis by Trypanosoma (Schizotryparum) cruzi epimastigotes in a time - and concentration - dependent manner. Starting with a cell density of 10 7 cells/ml, a 10 -4M concentration of the drug blocks instantaneously growth, but with 10 -5M and 10 -6M growth arrest takes place at 48 and 96 hours, respectively. A study of the sterol content of the parasites and their de novo synthesis reveals that the drug induces the accumulation of trimethyl- and, to a much lesser extent, dimethyl-sterols with a progressive decrease of ergosterol-like desmethyl-sterol pool. Sterols added to the growth medium can partially reverse the growth inhibitory effects of ketoconazole, ergosterol being much more effective that cholesterol in this action. These facts suggest an essential function performed in T cruzi by ergosterol, which cannot be replaced by cholesterol, a compound which is passively absorbed from the growth medium and remains in the drug-treated cells. At 10 -6M ketoconazole blocks completely the incorporation of 14C-acetate in desmethyl-sterols and >97% of the radioactivity appears in the trimethyl-sterol fraction at 24 hours; further incubation leads to the appearance of a slight amount of radioactivity in the dimethyl-sterol fraction (10% at 96 hours)..