RESUMEN
Risedronate reduces the risk of vertebral fractures by up to 70% within the first year of treatment. Increases in bone mineral density or decreases in bone turnover markers explain only a portion of the anti-fracture effect, suggesting that other factors, such as changes in trabecular bone architecture, also play a role. Our objective was to determine the effects of risedronate on bone architecture by analyzing iliac crest bone biopsy specimens using three-dimensional microcomputed tomography (3-D micro CT). Biopsy specimens were obtained at baseline and after 1 year of treatment from women enrolled in a double-blind, placebo-controlled study of risedronate 5 mg daily for the prevention of early postmenopausal bone loss. Trabecular architecture deteriorated in the placebo group (n = 12), as indicated by a 20.3% decrease in bone volume (25.1% vs. 20.0%, P = 0.034), a 13.5% decrease in trabecular number (1.649 vs. 1.426 mm(-1), P = 0.052), a 13.1% increase in trabecular separation (605 vs. 684 microm, P = 0.056), and an 86.2% increase in marrow star volume (3.251 vs. 6.053 mm(3), P = 0.040) compared with baseline values. These changes in architectural parameters occurred in the presence of a concomitant decrease from baseline in lumbar spine bone mineral density (-3.3%, P = 0.002), as measured by dual energy x-ray absorptiometry. There was no statistically significant ( P < 0.05) deterioration in the risedronate-treated group (n = 14) over the 1-year treatment period. Comparing the actual changes between the two groups, the placebo group experienced decreases in bone volume (placebo, -5.1%; risedronate, +3.5%; P = 0.011), trabecular thickness (placebo, -20 microm; risedronate, +23 microm; P = 0.032), and trabecular number (placebo, -0.223 mm(-1); risedronate, +0.099 mm(-1); P = 0.010), and increases in percent plate (placebo, +2.79%; risedronate, -3.23%; P = 0.018), trabecular separation (placebo, +79 microm; risedronate, -46 microm; P = 0.010) and marrow star volume (placebo, +2.80 mm(3); risedronate, -2.08mm(3); P = 0.036), compared with the risedronate group. These data demonstrate that trabecular architecture deteriorated significantly in this cohort of early postmenopausal women, and that this deterioration was prevented by risedronate. Although there is no direct link in this study between fracture and preservation of architecture, it is reasonable to infer that the preservation of bone architecture may play a role in risedronate's anti-fracture efficacy.
Asunto(s)
Densidad Ósea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/uso terapéutico , Ácido Etidrónico/análogos & derivados , Ácido Etidrónico/uso terapéutico , Ilion/efectos de los fármacos , Imagenología Tridimensional/métodos , Osteoporosis Posmenopáusica/prevención & control , Tomógrafos Computarizados por Rayos X , Absorciometría de Fotón , Método Doble Ciego , Femenino , Humanos , Ilion/diagnóstico por imagen , Ilion/metabolismo , Persona de Mediana Edad , Osteoporosis Posmenopáusica/metabolismo , Ácido RisedrónicoRESUMEN
Bismuth subsalicylate (BSS) and placebo were evaluated in a double-blind, placebo-controlled study as adjunct to rehydration therapy in 123 children, aged 4 to 28 months, hospitalized with acute diarrhea. The dosing regimen was 20 mg/kg five times daily for 5 days. Significant benefits were noted in the BSS group compared with placebo as manifested by decreases in stool frequency and stool weights and an improvement in stool consistency, significant improvement in clinical well-being, and shortening of the disease duration. Patients treated with BSS had a significant reduction in duration of hospital stay (6.9 days) compared with placebo-treated patients (8.5 days). Also, intravenous fluid requirements decreased significantly more rapidly and to a greater degree in the BSS-treated group. Bismuth subsalicylate was associated with clearance of pathogenic Escherichia coli from the stools in 100% of cases but was not different from placebo in rotavirus elimination. Bismuth subsalicylate was well tolerated with no reported adverse effects. Blood bismuth and serum salicylate levels were well below levels considered toxic. In this study, BSS provided effective adjunctive therapy for acute diarrhea, allowing children to get well sooner with less demand on the nursing and hospital staff.
Asunto(s)
Bismuto/uso terapéutico , Diarrea Infantil/tratamiento farmacológico , Compuestos Organometálicos/uso terapéutico , Salicilatos/uso terapéutico , Enfermedad Aguda , Bismuto/sangre , Preescolar , Método Doble Ciego , Infecciones por Escherichia coli/tratamiento farmacológico , Heces/citología , Heces/microbiología , Fluidoterapia , Humanos , Lactante , Tiempo de Internación , Compuestos Organometálicos/sangre , Infecciones por Rotavirus/tratamiento farmacológico , Salicilatos/sangreRESUMEN
This report demonstrates that bismuth subsalicylate (BSS) effectively inhibits growth of a number of bacterial strains known to cause diarrhea, including Escherichia coli, Salmonella, Shigella, and Campylobacter. Other bismuth salts and sodium salicylate, a hydrolysis product of BSS in the gut, also were examined and were shown to have various degrees of activity. Growth of the organisms was monitored in vitro by inoculating culture fluid that contained one of the compounds to be tested and determining the concentration of viable organisms over a 24-hour period. Control cultures of each organism were grown in the absence of bismuth subsalicylate. BSS inhibited growth of all organisms examined in a dose-dependent fashion. Reductions of 2-6 logs, as compared with controls, were observed in cultures grown in the presence of 10-50 mM BSS. Other bismuth salts displayed various degrees of inhibition. These results suggest that the efficacy of BSS as an antidiarrheal agent may be related to an antimicrobial mechanism of action.
Asunto(s)
Bacterias/efectos de los fármacos , Bismuto/farmacología , Diarrea/microbiología , Compuestos Organometálicos/farmacología , Salicilatos/farmacología , Bacterias/crecimiento & desarrollo , Campylobacter fetus/efectos de los fármacos , Campylobacter fetus/crecimiento & desarrollo , Relación Dosis-Respuesta a Droga , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Humanos , Salmonella/efectos de los fármacos , Salmonella/crecimiento & desarrollo , Shigella/efectos de los fármacos , Shigella/crecimiento & desarrollo , Vibrio cholerae/efectos de los fármacos , Vibrio cholerae/crecimiento & desarrollo , Yersinia enterocolitica/efectos de los fármacos , Yersinia enterocolitica/crecimiento & desarrolloRESUMEN
This study compared the clinical efficacy of three mouthrinses containing either 0.12% chlorhexidine, phenolic compounds, or sanguinarine, which were used unsupervised, in a placebo-controlled, double-blind study of 6 months' duration. The study was conducted according to ADA clinical guidelines for evaluation of antigingivitis agents and was completed by 481 adults. Following baseline exams and a prophylaxis, subjects were randomly divided into treatment groups matched for age, gender, and gingivitis severity, and were instructed to use the rinses in accordance with manufacturer's directions. Followup examinations evaluated supragingival plaque, gingivitis, and gingival bleeding. Compared to placebo at 6 months, the group rinsing with 0.12% chlorhexidine had significantly less gingivitis (31% reduction), gingival bleeding (39% reduction), and plaque (49% reduction) and was significantly better than any of the other treatment groups (P less than 0.05). Both the phenolic and sanguinarine groups showed moderate, yet significant, reductions in plaque compared to placebo (24% and 12% respectively) yet were significantly less effective than the 0.12% chlorhexidine rinse (P less than 0.05). However, neither the phenolic nor sanguinarine rinses were significantly different than placebo in their effects on gingivitis or gingival bleeding. These results support previous published results on the superiority of 0.12% chlorhexidine when used in conjunction with professional care and as an adjunct to routine oral hygiene practices.
Asunto(s)
Alcaloides/uso terapéutico , Antiinfecciosos/uso terapéutico , Clorhexidina/uso terapéutico , Placa Dental/prevención & control , Gingivitis/prevención & control , Antisépticos Bucales , Fenoles/uso terapéutico , Adulto , Alcaloides/administración & dosificación , Antiinfecciosos/administración & dosificación , Benzofenantridinas , Clorhexidina/administración & dosificación , Ensayos Clínicos como Asunto , Método Doble Ciego , Femenino , Hemorragia Gingival/prevención & control , Humanos , Isoquinolinas , Masculino , Fenol , Fenoles/administración & dosificación , Placebos , Distribución Aleatoria , Decoloración de Dientes/inducido químicamenteRESUMEN
In a randomized double-blind study, Swiss adults traveling to tropical countries for 12 to 28 days took a solid formulation of bismuth subsalicylate (1.05 or 2.1 g/day on a twice-daily regimen) or placebo. Efficacy was evaluated in 231 volunteers. Diarrheal incidence was reduced by 41% in persons taking the high dose (P = 0.007) and by 35% in those taking the low dose (P = 0.03) with excellent compliance. No serious adverse reactions occurred, but objectionable taste, constipation, and nausea were seen more frequently with active medication (P = 0.04). Twenty patients provided stool samples: no bacteria were detected in the 8 volunteers who were on active medication, but various bacteria were found in 5 of the 12 patients who had taken placebo (P = 0.04).
Asunto(s)
Bismuto/administración & dosificación , Diarrea/prevención & control , Compuestos Organometálicos , Salicilatos/administración & dosificación , Viaje , Diarrea/microbiología , Humanos , Cooperación del Paciente , Salmonella enteritidis/aislamiento & purificación , Shigella dysenteriae/aislamiento & purificación , ComprimidosRESUMEN
Pseudomonas exotoxin A enters mouse LM fibroblasts by receptor-mediated endocytosis and ultimately causes cell death. Here we present evidence for the existence of a specific receptor for the toxin. Toxin association with LM cells at 18 and 37 degrees C, but not at 4 degrees C, was highly specific. At 37 degrees C, the association increased with time, reaching a steady state by 5 h. Binding to paraformaldehyde-fixed cells at 37 degrees C was saturable (Kd = 5.4 nM), was reversible, and indicated ca. 100,000 binding sites per cell. It is believed that receptor-bound toxin is responsible for cell death. Once the kinetics of toxin entry were described, we examined the effect of reduced temperatures on the intracellular processing of toxin and thus its expression. Toxin-induced inhibition of protein synthesis was minimal at temperatures below 20 degrees C. This was seen even though at 20 degrees C sufficient toxin was internalized to kill cells, and toxin enzyme activity was maximal. Internalization of 125I-labeled toxin, but not of 125I-labeled horseradish peroxidase (marker of fluid-phase endocytosis), became rate limiting at 20 degrees C or below. These data suggest that reduced temperatures block a step in the receptor-mediated endocytic pathway essential for the expression of Pseudomonas toxin activity.
Asunto(s)
Toxinas Bacterianas/metabolismo , Proteínas Portadoras , Receptores de Superficie Celular , Receptores Colinérgicos/metabolismo , Animales , Toxinas Bacterianas/toxicidad , Membrana Celular/metabolismo , Células Cultivadas , Endocitosis , Cinética , Ratones , Temperatura , Toxinas BiológicasRESUMEN
Clustering of ligands into coated regions of the plasma membrane is an early step in receptor-mediated endocytosis. The association of Pseudomonas exotoxin A (PE) with mouse LM fibroblasts was visualized by using biotinyl-PE and avidingold. Movement of PE into coated regions occurred within 30 s of warming monolayers to 37 degrees C. This clustering was stopped by the primary amines methylamine and ammonium chloride but was not altered by the tertiary amine chloroquine. Toxin internalization was rapid, with a half-time of approximately 5 min. Although primary amines stopped clustering, they did not alter the rate of toxin internalization; they did alter the route followed after entry. We have shown previously that methylamine protects cells from the lethal action of PE. Here we suggest that methylamine protects, at least in part, by blocking clustering, and that receptor-mediated endocytosis is required for efficient expression of PE toxicity.
Asunto(s)
ADP Ribosa Transferasas , Toxinas Bacterianas , Proteínas Portadoras , Endocitosis/efectos de los fármacos , Exotoxinas/metabolismo , Metilaminas/farmacología , Receptores de Superficie Celular , Receptores Colinérgicos/efectos de los fármacos , Factores de Virulencia , Animales , Células Cultivadas , Invaginaciones Cubiertas de la Membrana Celular/efectos de los fármacos , Exotoxinas/fisiología , Fluidez de la Membrana/efectos de los fármacos , Ratones , Exotoxina A de Pseudomonas aeruginosaRESUMEN
The nature of the interaction between the Ib tumor-associated surface antigen (Ib-TASA) and the Dk and Kk (Dk/Kk) regions of the major histocompatibility complex on the surface of line Ib lymphocytes was evaluated by immuno-electron microscopy using a double-label bridging technique. Quantitation of antigenic sites by direct counts showed 44% of the Ib-TASA sites coincident with Dk/Kk antigens. This is greater than the predicted random interaction of two independent cell surface determinants suggesting an associative interaction, i.e. 'altered-self' antigen. The remaining 56% of the Ib-TASA sites were in a non-associative mode. On the basis of data presented here, we postulate that the interaction between 'self'- and 'non-self' antigens is not an 'all or none' phenomenon.