RESUMEN
Following U.S. Food and Drug Administration (FDA) approval for the use of olestra, a noncaloric fat substitute (brand name Olean) in food snacks, the manufacturer agreed to provide safety updates on market experience to the FDA. However, guidelines for food product postmarketing surveillance (PMS) are not available and those typically used with medical products were only partly applicable. In modeling the Olean program, we drew from experience with consumer products and incorporated elements typical of medical product PMS. A cooperative effort was established with Olean snack manufacturers and a two-tiered, multidisciplinary approach enlisting Consumer Relations and Medical Affairs personnel was used to maximize use of specialized skills. The result of this effort was implementation of a reliable PMS system which could handle a high volume of reports from consumers while providing pertinent data required for medical interpretation of these reports. Summaries of data for the Olean snack manufacturers and FDA were generated in timely fashion. In addition to collection of the spontaneous reports from consumers, a clinical studies program was undertaken and an independent medical advisory panel was established. Through these, we gained perspective on the spontaneous reports and additional confirmation of the safety of olestra in savory snacks.
Asunto(s)
Sustitutos de Grasa/efectos adversos , Ácidos Grasos/efectos adversos , Aditivos Alimentarios/efectos adversos , Industria de Alimentos , Vigilancia de Productos Comercializados , Sacarosa/efectos adversos , Ensayos Clínicos como Asunto , Participación de la Comunidad , Recolección de Datos , Toma de Decisiones , Humanos , Relaciones Interinstitucionales , Salud Pública , Control de Calidad , Sacarosa/análogos & derivados , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Weanling Charles River CD rats of both sexes were fed 300 mg/kg/day of Piroctone Olamine, an anti-bacterial agent, and were supplemented with 0, 50, 100 or 200 ppm dietary iron as FeSO4.7H2O for six weeks. However, analytical data indicated that Piroctone was degraded in the diet so that the rats received only 225 mg/kg/day. The rats given Piroctone Olamine without iron gained significantly less body weight and ate significantly less feed than controls, with the effect being more pronounced in the males. They also developed severe microcytic, hypochromic anemia. The rats supplemented with all three levels of dietary iron grew at a rate similar to controls. The rats supplemented with 50 ppm dietary iron had anemia with all of the hematological iron-associated factors being significantly depressed. The 100 ppm supplement restored all hematologic factors to normal in the females, but slight reductions remained in the males. The 200 ppm supplement of iron restored all parameters to values similar to the controls in both sexes. These results suggest that the mechanism of the toxicity of Piroctone Olamine is the prevention of dietary iron absorption by in situ chelation.
Asunto(s)
Etanolaminas/toxicidad , Hierro/farmacología , Piridonas/toxicidad , Animales , Recuento de Células Sanguíneas , Peso Corporal/efectos de los fármacos , Cromatografía de Gases , Dieta , Combinación de Medicamentos/toxicidad , Ingestión de Alimentos/efectos de los fármacos , Femenino , Masculino , RatasRESUMEN
The acute intravenous toxicity of disodium dihydrogen (1-hydroxyethylidene)diphosphonate (etidronate disodium; I) and the mechanism of this toxic response have been investigated in 40 beagle dogs. The intravenous toxicity of I is dependent on the total dose administered and the length of the infusion interval. The toxicity of I is directly related to the ability of the drug to bind or complex with the circulating calcium in the blood. Maximum depressions in ionized calcium coincide in time with peak blood levels of I, and at lethal doses electrocardiographic changes indicative of hypocalcemia are observed. For a 2-min infusion of 2 mg of I/kg, no effect is observed on ionized calcium levels, and the electrocardiogram remains normal. At doses of 16 and 32 mg/kg, coincident with an immediate fall in ionized calcium levels, there is a transient rise in total calcium and a fall in phosphorus levels. The ionized calcium level rises, and total calcium level falls and stabilizes at baseline levels within 30 min after the infusion. However, the phosphorus level rises and exceeds the baseline value, reaching 3-4 times normal by 72 h after the infusion. With proven lethal doses of I (60 mg/kg infused over 2 min) and the simultaneous infusion of an ionized calcium salt such as calcium gluconate (20 mg of Ca2+/kg), electrocardiograms remain normal and death is prevented. Thus, an effective antidote in the event of an overdose or too rapid an infusion of I can be employed to prevent acute toxic effects.
Asunto(s)
Ácido Etidrónico/toxicidad , Anestesia , Animales , Calcio/sangre , Gluconato de Calcio/farmacología , Difosfonatos/sangre , Perros , Electrocardiografía , Ácido Etidrónico/administración & dosificación , Ácido Etidrónico/sangre , Femenino , Infusiones Parenterales , Masculino , Fósforo/sangre , Factores de TiempoRESUMEN
Carbon 13-labeled clodronate disodium was given to healthy adult men by intravenous infusion and orally in a crossover design. Serum and urine levels were determined as a function of time by isotope-ratio mass spectrometry. Clodronate disodium (Cl2/MDP) is primarily excreted unchanged by the kidney; more than 80% of the intravenous dose was recovered within 48 hr. The serum concentrations-time curve over the first 8 hr after intravenous dosing appears biexponential with the disposition phase having a harmonic mean half-life (t 1/2) of 2 hr. The mean serum clearance was found to be 1.4 ml min-1 kg-1 and the apparent volume of distribution was approximately 25% of body weight. Simulations and computer fitting of the cumulative urinary excretion and urinary excretion rates based on the biexponential serum decay curve demonstrated the presence of a slow disposition component with a t 1/2 of 12.8 hr. Thus, the disposition kinetics of Cl2MDP appear to be triexponentials, although the slowest component is not of major significance after a single dose and could not be verified because of a lack of serum data after 8 hr. Cl2MDP is poorly absorbed with an absolute bioavailability of only 1% to 2%.
Asunto(s)
Ácido Clodrónico/metabolismo , Difosfonatos/metabolismo , Hidrocarburos Clorados/metabolismo , Cloruro de Metileno/metabolismo , Administración Oral , Adulto , Disponibilidad Biológica , Isótopos de Carbono , Ácido Clodrónico/administración & dosificación , Difosfonatos/administración & dosificación , Humanos , Infusiones Parenterales , Cinética , Masculino , Espectrometría de Masas/métodos , Cloruro de Metileno/administración & dosificación , Cloruro de Metileno/análogos & derivados , Modelos Biológicos , Distribución AleatoriaRESUMEN
Comparisons of mellitate (MA) and ethane-1-hydroxy-1,1-diphosphonate (EHDP) have been carried out in studies of enamel etching, calcium phosphate crystal growth and animal calculus deposition. In enamel etch studies at pH 5, 6, or 7 and after treatment times of 5 or 170 min, EHDP was less damaging to enamel surfaces than MA as determined by scanning electron microscopy, grazing angle electron diffraction, and quantitative etch solution analyses. Both MA and EHDP inhibited hydroxyapatite crystal growth, although EHDP was more effective than MA. The formation of a tricalcium mellitate surface phase is suggested as the basis of the MA crystal growth effect on apatite. Both MA and EHDP also inhibited rat calculus formation, but EHDP was more effective than MA. The relation between crystal growth inhibition, surface phase solubility, and anti-calculus activity is discussed and a generalized principal for determining an effective inhibitor of calculus is suggested.
Asunto(s)
Benzoatos/farmacología , Fosfatos de Calcio , Cálculos Dentales/tratamiento farmacológico , Esmalte Dental/efectos de los fármacos , Ácido Etidrónico/farmacología , Animales , Benzoatos/uso terapéutico , Calcio , Cristalización , Ácido Etidrónico/uso terapéutico , Concentración de Iones de Hidrógeno , Técnicas In Vitro , Lactatos/farmacología , Ratas , SodioRESUMEN
The bone scanning complex, 99mTc-Sn-EHDP, consisting of the nuclide technetium-99m, stannous ion and ethane-1-hydroxy-1,1-diphosphonate, administered intravenously is retained in soft tissues in proportion to increasing calcium content of the tissues. Within bone tissue, the retention is proportional to vascularity and to surface area of calcium phosphate in bones and not necessarily to calcium and phosphate concentration. The nuclidic agent 99mTcO4-BUT NOT THE 99MTc-diphosphonate is selectively taken up by the thyroid and this uptake can be blocked by administering sodium perchlorate. Among the connective tissues studied, the tracheal cartilage seems to have the greatest potential to calcify with increasing age of the animal and man. Soft tissue does not retain the bone scanning complex 99mTc-Sn-EHDP but does retain 99mTcO4-.
Asunto(s)
Huesos/metabolismo , Tejido Conectivo/metabolismo , Ácido Etidrónico/metabolismo , Compuestos Organofosforados/metabolismo , Tecnecio/metabolismo , Factores de Edad , Animales , Huesos/irrigación sanguínea , Calcio/análisis , Músculos/metabolismo , Percloratos/farmacología , Fósforo/análisis , Conejos , Ratas , Glándula Tiroides/metabolismo , Estaño/metabolismoRESUMEN
Because increased uptake of 99mTc-diphosphonate (ethane-hydroxy-1, 1-diphosphonate) occasionally occurs in the anterior neck region, the possible increased affinity of the diphosphonate bone-scanning agent for cartilage was investigated. In vivo scintigraphic studies and organ analyses from rats and rabbits injected with this bone scintigraphic agent were performed. Trachea-to-muscle uptake ratios were a high 45:1 in adult Sprague-Dawley rats and approached the femur-to-muscle ratio of 93:1. Technetium-99m-diphosphonate uptake was also increased, but to a lesser extent, in xiphoid cartilage, tendon, and ear cartilage; this was proportional to the calcium content of the organ. The thyroid showed a high affinity for free pertechnetate but not 99mTc-diphosphonate, providing further evidence that the increased neck uptake of this 99mTc-diphosphonate is due to tracheal, not thyroid activity. In addition, premedication of three patients with 200 mg of potassium-perchlorate did not block this neck uptake. Interpretation of scintigraphs performed with 99mTc-diphosphonate that show lesions in the cervical spine should take into account the potential for false-positive readings caused by this increased tracheal uptake.