RESUMO
The majority of therapeutic strategies for mycosis require the protracted administration of antifungals, which can result in significant toxicities and have unacceptable failure rates. Hence, there is an urgent need for the development of improved therapeutic approaches, and monoclonal antibody-based drugs are potentially a powerful alternative to standard antifungals. To develop a broad antibody-like reagent against mycosis, wheat germ agglutinin (WGA) was linked to the effector Fc region of murine IgG2a. The resultant WGA-Fc displayed high affinity to purified chitin and bound efficiently to fungal cell walls, co-localizing with chitin, in patterns ranging from circular (Histoplasma capsulatum) to punctate (Cryptococcus neoformans) to labeling at the bud sites (Candida albicans and Saccharomyces cerevisiae). WGA-Fc directly inhibited fungal growth in standard cultures. WGA-Fc opsonization increased fungal phagocytosis, as well augmented the antifungal functions by macrophages. Prophylactic administration of WGA-Fc fully protected mice against H. capsulatum, correlating with a reduction in lung, spleen and liver fungal burdens. Administration of WGA-Fc also dramatically diminished pulmonary inflammation. Hence, the opsonic activity of WGA-Fc effectively modulates fungal cell recognition and promotes the elimination of fungal pathogens. Therefore, we propose WGA-Fc as a potential "pan-fungal" therapeutic that should be further developed for use against invasive mycoses.
Assuntos
Antifúngicos/farmacologia , Fungos/efeitos dos fármacos , Imunoconjugados/farmacologia , Infecções Fúngicas Invasivas/tratamento farmacológico , Proteínas Recombinantes de Fusão/farmacologia , Animais , Antifúngicos/uso terapêutico , Células CHO , Parede Celular/efeitos dos fármacos , Parede Celular/metabolismo , Quitina/metabolismo , Cricetulus , Modelos Animais de Doenças , Fungos/metabolismo , Humanos , Hibridomas , Imunoconjugados/genética , Imunoconjugados/uso terapêutico , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/farmacologia , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Imunoglobulina G/genética , Imunoglobulina G/farmacologia , Imunoglobulina G/uso terapêutico , Infecções Fúngicas Invasivas/microbiologia , Camundongos Endogâmicos C57BL , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/uso terapêutico , Aglutininas do Germe de Trigo/genética , Aglutininas do Germe de Trigo/farmacologia , Aglutininas do Germe de Trigo/uso terapêuticoRESUMO
The protozoan parasite Giardia lamblia is a major cause of waterborne enteric disease worldwide. Lectins are proteins that bind to carbohydrate (sugar) moieties. Potential targets for lectins are found on the surface of most single-celled organisms. Modest concentrations of wheat germ agglutinin (WGA) have been shown to inhibit G. lamblia excystation and trophozoite growth in vitro and can reduce cyst passage in mice infected with the closely related protozoan parasite, G. muris. Commercial preparations of wheat germ (WG) contain 13-53 microg of WGA per gram. We performed a double-masked, placebo-controlled study of dietary supplementation with WG in 63 subjects with giardiasis in Montreal and Lima (25 asymptomatic patients passing cysts; 38 patients with symptoms). Asymptomatic subjects received WG (2 g, 3 times a day) or placebo (cornstarch, 2 g, 3 times a day) for 10 days, followed by metronidazole (250 mg 3 times a day) for 7 days. Symptomatic subjects received metronidazole (250 mg 3 times a day) plus either WG or placebo for 7 days. Stool specimens were collected every day (Montreal) or every other day (Lima) for 10 days and on Day 35 for microscopic examination and coproantigen determination. Subjects kept a diary of symptoms for 10 days after recruitment. In asymptomatic subjects, both cyst passage and coproantigen levels were reduced by approximately 50% in those taking WG compared with the placebo group (P < 0.01 and P = 0.06, respectively). In symptomatic subjects, cyst passage and coproantigen levels fell precipitously in response to metronidazole therapy, and there were no clinically important differences between those receiving supplemental WG or placebo. However, symptoms appear to have resolved more rapidly in the subjects taking WG in addition to metronidazole. The WG supplement was well tolerated in both symptomatic and asymptomatic subjects. These data suggest that components of WG, possibly WGA, either alone or in combination with antiprotozoal agents, can influence the course of human giardiasis.
Assuntos
Antitricômonas/uso terapêutico , Suplementos Nutricionais , Giardíase/tratamento farmacológico , Fitoterapia , Triticum , Aglutininas do Germe de Trigo/uso terapêutico , Adulto , Animais , Antitricômonas/administração & dosagem , Método Duplo-Cego , Fezes/parasitologia , Feminino , Giardia lamblia/isolamento & purificação , Humanos , Masculino , Metronidazol/administração & dosagem , Metronidazol/uso terapêutico , Peru , Lectinas de Plantas , Quebeque , Resultado do Tratamento , Aglutininas do Germe de Trigo/administração & dosagemRESUMO
El ectropión del cérvix es un trastorno común en la práctica ginecológica. El tratamiento más satisfactorio es la destrucción del tejido afectado mediante electrocauterización, criocirugía o vaporización con rayo láser, que obtienen la cicatrización con la posterior reparación mediante la proliferación de fibroblastos y reepitelización. La reepitelización completa puede llevar más de ocho semanas. Con el objeto de acortar el tiempo requerido para la reepitelización, se evaluó la eficacia del extracto acuoso de Triticum vulgare en un estudio doble ciego comparativo con placebo. Se estudiaron 40 pacientes con ectropión tratadas con vaporización mediante rayo láser. Posteriormente las pacientes del primer grupo fueron tratadas con óvulos de Triticum vulgare, dos veces al día durante dos semanas consecutivas; las pacientes del grupo control recibieron placebo. El extracto acuoso de Triticum vulgare fue capaz de acortar el tiempo para la reepitelización. Al día 40, el 40 por ciento de las pacientes tratadas con Triticum vulgare presentaron una reepitelización completa, comparado con 5 por ciento de las que recibieron placebo; 75 por ciento vs 35 por ciento al día 48, y 85 por ciento vs 55 por ciento al día 56, respectivamente. No se observaron eventos adversos. Se concluye que el extracto acuoso de Triticum vulgare acelera la reepitelización postratamiento del ectropión con rayo láser y tiene buena tolerabilidad vaginal.