RESUMEN
Colors are frequently added to disposable diapers to enhance the diapering experience. The colors in the interior of diapers are composed of nonsensitizing pigments that are bound during the fiber-making process into the fibers of the nonwoven that covers the absorbent core materials. In the past, the use of color in diapers has been called into question based on the presumed use of disperse dyes, known sensitizers in the textile industry, and erroneous reports in literature. In fact, disperse dyes are not used in leading disposable diapers; the colors used in these disposable diapers are nonsensitizing pigments with favorable safety profiles. Numerous safety tests, such as skin patch tests with pigments used on diaper backsheets, have found no evidence of skin irritation or sensitization.
RESUMEN
Tocopheryl Polyethylene Glycol Succinate 1000 (TPGS 1000) can inhibit P-glycoprotein (P-gp); TPGS 1000 was not originally designed to inhibit an efflux pump. Recent work from our laboratories demonstrated that TPGS activity has a rational PEG chain length dependency. In other recent work, inhibition mechanism was investigated and appears to be specific to the ATPase providing P-gp energy. Based on these observations, we commenced rational surface-active design. The current work summarizes new materials tested in a validated Caco-2 cell monolayer model; rhodamine 123 (10microM) was used as the P-gp substrate. These results demonstrate that one may logically construct non-ionic surfactants with enhanced propensity to inhibit in vitro efflux. One new surfactant based inhibitor, Tocopheryl Polypropylene Glycol Succinate 1000 (TPPG 1000), approached cyclosporine (CsA) in its in vitro efflux inhibitory potency. Subsequently, TPPG 1000 was tested for its ability to enhance the bioavailability of raloxifene - an established P-gp substrate -in fasted male rats. Animals dosed with raloxifene and TPPG 1000 experienced an increase in raloxifene oral bioavailability versus a control group which received no inhibitor. These preliminary results demonstrate that one may prepare TPGS analogs that possess enhanced inhibitory potency in vitro and in vivo.
Asunto(s)
Tensoactivos/química , Tensoactivos/farmacología , Vitamina E/análogos & derivados , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Disponibilidad Biológica , Transporte Biológico/efectos de los fármacos , Células CACO-2 , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Portadores de Fármacos , Humanos , Masculino , Espectrometría de Masas , Polietilenglicoles/química , Polietilenglicoles/farmacología , Clorhidrato de Raloxifeno/administración & dosificación , Clorhidrato de Raloxifeno/farmacocinética , Ratas , Ratas Endogámicas , Rodamina 123/farmacocinética , Vitamina E/química , Vitamina E/farmacologíaRESUMEN
BACKGROUND/PURPOSE: Oxybenzone is an active ingredient found in sunscreen products that absorbs a broad spectrum of ultraviolet (UV) light, with absorbance peaking in the UVB region and extending into the UVA region. Although the overall incidence of sensitization and irritation associated with oxybenzone in the general population remains unclear, a few studies have reported on the incidence in specific circumstances. However, the relevance of these studies to the general population is limited, because the sample populations reported in these papers generally have consisted of individuals who sought medical attention for pre-existing skin conditions. Therefore, the reported incidence of allergic reactions to oxybenzone in these studies may be overestimated as related to the general population. The objective of this meta-analysis was to determine the safety of oxybenzone in participants recruited from the general population. METHODS: The data from 64 unpublished exaggerated use human repeat insult patch tests (HRIPT) and photoallergy (PA) studies sponsored by Schering-Plough HealthCare Products Inc. between 1992 and 2006 were aggregated and analyzed to evaluate the irritancy and sensitization potential of sunscreen products containing oxybenzone at concentrations between 1% and 6%. RESULTS: Forty-eight of 19 570 possible dermal responses were considered to be suggestive of irritation or sensitization; the mean rate of responses across all formulations was 0.26%. Sensitization rates did not correlate significantly with oxybenzone concentration. The available re-challenge data indicated that only eight of these responses were contact allergies from oxybenzone, and the mean rate of contact allergy to oxybenzone was 0.07%. The source of the skin responses was not confirmed for 15 subjects who were lost to follow-up. However, all subjects were given the opportunity to participate in follow-up testing. CONCLUSION: Our data indicate that sunscreen products formulated with 1-6% oxybenzone do not possess a significant sensitization or irritation potential for the general public. Furthermore, these data suggest that the incidence rate implied in the published literature overestimates the actual incidence of sensitization/irritation due to oxybenzone-containing sunscreen products in the general population.
Asunto(s)
Benzofenonas/toxicidad , Dermatitis Alérgica por Contacto/etiología , Dermatitis Irritante/etiología , Dermatitis Fotoalérgica/etiología , Protectores Solares/toxicidad , Administración Cutánea , Adulto , Análisis de Varianza , Benzofenonas/administración & dosificación , Dermatitis Alérgica por Contacto/epidemiología , Dermatitis Irritante/epidemiología , Dermatitis Fotoalérgica/epidemiología , Humanos , Incidencia , Masculino , Dosis de Radiación , Pruebas de Irritación de la Piel/métodos , Estadísticas no Paramétricas , Protectores Solares/administración & dosificación , Rayos Ultravioleta/efectos adversosRESUMEN
Raloxifene is a highly insoluble, highly metabolized serum estrogen receptor modulator approved for use in the treatment of osteoporosis. Hydroxybutenyl-beta-cyclodextrin (HBenBCD) is a novel solubility enhancer previously demonstrated to increase the oral bioavailability of tamoxifen, letrozole, and itraconazole. The current study evaluated the pharmacokinetics of raloxifene in oral and intravenous formulations with HBenBCD in male Wistar-Hannover rats. Analytical methodology to measure raloxifene and its metabolites was developed by measuring raloxifene metabolism in vitro. Formulation with HBenBCD significantly increased raloxifene oral bioavailability. Mean+/-S.D. oral bioavailabilities were 2.6+/-0.4% for raloxifene formulated with microcrystalline cellulose, 7.7+/-2.1% for a solid capsule formulation of raloxifene:HBenBCD complex, and 5.7+/-1.3% for a liquid-filled capsule formulation containing raloxifene:HBenBCD/PEG400/H(2)O. Relative to raloxifene/microcrystalline filled capsules, the presence of HBenBCD in the solid capsule formulation afforded: (i) a decrease in raloxifene T(max) (2.5+/-0.5h versus 4.0+/-0.5h); (ii) a two-fold increase in raloxifene C(max) and a three-fold increase in raloxifene AUC; and (iii) a 12-fold increase in raloxifene glucuronide C(max) and a 6.5-fold increase in raloxifene glucuronide AUC. Hence, these studies demonstrate that raloxifene formulations containing HBenBCD significantly increased the oral bioavailability in rats relative to formulations that did not contain HBenBCD.
Asunto(s)
Clorhidrato de Raloxifeno/farmacocinética , Moduladores Selectivos de los Receptores de Estrógeno/farmacocinética , beta-Ciclodextrinas/farmacología , Animales , Disponibilidad Biológica , Perros , Femenino , Humanos , Mucosa Intestinal/metabolismo , Hígado/metabolismo , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos , Microsomas/metabolismo , Microsomas Hepáticos/metabolismo , Clorhidrato de Raloxifeno/administración & dosificación , Clorhidrato de Raloxifeno/sangre , Clorhidrato de Raloxifeno/química , Ratas , Ratas Endogámicas , Moduladores Selectivos de los Receptores de Estrógeno/administración & dosificación , Moduladores Selectivos de los Receptores de Estrógeno/sangre , Moduladores Selectivos de los Receptores de Estrógeno/química , Solubilidad , beta-Ciclodextrinas/administración & dosificaciónRESUMEN
The current research evaluated the ability of hydroxybutenyl-beta-cyclodextrin (HBenBCD) to enhance saquinavir in vitro solubility and in vivo oral bioavailability; both the base and mesylate salt forms of saquinavir were investigated. HBenBCD was effective and significantly improved saquinavir solubility in aqueous media. In the presence of 10 wt % HBenBCD, saquinavir base solubility in water was increased to ca. 5.5 +/- 0.4 mg/mL and represents a 27-fold increase from that observed in water (207 +/- 5 microg/mL) in the absence of HBenBCD. Saquinavir-HBenBCD formulations were found to have rapid dissolution over a wide pH range (1.2-6.8), and saquinavir solubility in these media was maintained throughout the experiments. When saquinavir-HBenBCD formulations were administered to Wistar-Hannover rats, saquinavir was rapidly absorbed and rapidly eliminated. Rapid saquinavir elimination was particularly pronounced when saquinavir-HBenBCD formulations were given as an oral aqueous gavage. Saquinavir oral bioavailability in rats obtained from saquinavir mesylate capsules (2.0% +/- 0.7%) was increased (9 +/- 4)-fold (18.6% +/- 7.3%) when dosed with saquinavir base-HBenBCD capsules. Clearly, HBenBCD can significantly improve the solubility and oral bioavailability of saquinavir; however, further formulation studies are required to optimize saquinavir oral delivery using this technology.
Asunto(s)
Saquinavir/farmacocinética , beta-Ciclodextrinas/administración & dosificación , Administración Oral , Animales , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/farmacocinética , Inyecciones Intravenosas , Ratas , Ratas Wistar , Saquinavir/administración & dosificaciónRESUMEN
BACKGROUND: These studies were conducted to evaluate the potential adverse effects of di-2-ethylhexyl terephthalate (DEHT) exposure on in utero development in mice and rats. In addition, a uterotrophic assay for estrogenic activity was conducted in sexually immature rats. METHODS: In the developmental toxicity studies, diet containing DEHT was fed to four groups of mated female Crl:CD(SD)IGS BR rats (25/group) from gestation day (GD) 0-20 or Crl:CD1(ICR) mice (25/group) from GD 0-18. Concentrations within the feed were 0, 0.3, 0.6, and 1.0% for the rats and 0, 0.1, 0.3, and 0.7% for the mice. Laparohysterectomies were carried out on the last day of exposure and the numbers of fetuses, early and late resorptions, total implantations, and corpora lutea were recorded. The fetuses were weighed, sexed, and examined for external, visceral and skeletal malformations, and developmental variations. The dose rate from dietary DEHT exposure was 0, 226, 458, and 747 mg/kg/day in the rats and 197, 592, and 1382 mg/kg/day in the mice for the control, low, mid, and high-exposure groups, respectively. RESULTS: DEHT exposure did not affect clinical observations. A slight reduction in body weight gain was noted in the high-dose level rat group; the remaining groups were unaffected. At necropsy, increased liver weights were noted in the high-dose rat group and the mid- and high-dose mouse groups. Mean numbers of implantation sites and viable fetuses, mean fetal weights, and mean litter proportions of preimplantation loss, early resorptions, late resorptions, and fetal sex ratios were unaffected by DEHT exposures. No test article-related malformations or variations were observed at any concentration level in the rat and mouse developmental toxicity studies. In the uterotrophic assay for estrogenic activity, sexually immature female rats received oral gavage doses 20, 200, or 2000 mg DEHT/kg bw/day from postnatal day (PND) 19-21. A slight reduction in rate of body weight gain was noted on the first day of dosing in the high dose group, but no other indications of toxicity were evident. DEHT exposure did not affect wet or blotted uterine weight parameters in any of these dose groups. The NOEL for developmental toxicity in rats was 747 mg/kg/day and 1382 mg/kg/day in mice. The NOEL for estrogenic activity was 2000 mg/kg/day. The NOEL for maternal toxicity was 458 mg/kg/day in rats and 197 mg/kg/day in mice. CONCLUSIONS: The lack of adverse developmental effects with DEHT exposure are in contrast to the adverse developmental effects noted after di-2-ethylhexyl phthalate (DEHP) exposure. The difference between the effects noted with the ortho-constituent (DEHP) and the lack of effects reported with the para-constituent (DEHT) is due most likely to differences in metabolism and the formation of the stable monoester, mono-2-ethylhexyl phthalate (MEHP) from the DEHP moiety.
Asunto(s)
Dietilhexil Ftalato/toxicidad , Desarrollo Fetal/efectos de los fármacos , Plastificantes/toxicidad , Útero/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Dietilhexil Ftalato/administración & dosificación , Ingestión de Alimentos/efectos de los fármacos , Femenino , Masculino , Ratones , Ratones Endogámicos ICR , Tamaño de los Órganos/efectos de los fármacos , Plastificantes/administración & dosificación , Embarazo , Ratas , Ratas Sprague-Dawley , Útero/patologíaRESUMEN
The current research evaluated and compared the efficacy of hydroxybutenyl-beta-cyclodextrin (HBenBCD) and hydroxypropyl-beta-cyclodextrin (HPBCD) as enhancers of itraconazole solubility and oral bioavailability. At 10 wt% cyclodextrin, 17-fold and 3.8-fold increases in itraconazole aqueous solubility were observed in the presence of HBenBCD and HPBCD, respectively. Significant differences in the dissolution of itraconazole in the presence of these two cyclodextrins were also observed. Itraconazole pharmacokinetics is known to exhibit a significant food effect. However, testing in biorelevant media indicated that no food effects should be observed after oral administration of itraconazole:HBenBCD complexes. Formulations of itraconazole with HBenBCD were prepared and these complexes, along with the commercial forms of itraconazole with and without HPBCD (Sporanox) were administered to male Sprague-Dawley rats by oral and intravenous routes. Intravenous administration of itraconazole formulated with HBenBCD resulted in a higher AUC relative to Sporanox. When administered as oral solutions, the itraconazole:HBenBCD formulation provided higher oral bioavailability than the Sporanox oral solution. When administered as solid formulations, the itraconazole:HBenBCD solid formulation provided a 2x increase in oral bioavailability relative to the Sporanox solid formulation. No food effects were observed with the itraconazole:HBenBCD solid dosage forms. Drug/metabolite ratios were dependent upon the dosage form.
Asunto(s)
Ciclodextrinas/administración & dosificación , Ciclodextrinas/farmacocinética , Itraconazol/farmacocinética , 2-Hidroxipropil-beta-Ciclodextrina , Administración Oral , Animales , Antifúngicos/administración & dosificación , Antifúngicos/sangre , Antifúngicos/química , Antifúngicos/farmacocinética , Disponibilidad Biológica , Ciclodextrinas/sangre , Ciclodextrinas/química , Interacciones Alimento-Droga , Inyecciones Intravenosas , Itraconazol/administración & dosificación , Itraconazol/sangre , Itraconazol/química , Masculino , Ratas , Ratas Sprague-Dawley , Solubilidad , beta-Ciclodextrinas/administración & dosificación , beta-Ciclodextrinas/sangre , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacocinéticaRESUMEN
BACKGROUND: This study was conducted to evaluate the potential adverse effects of di-2-ethylhexyl terephthalate (DEHT) on reproductive capability from exposure of F(0) and F(1) parental animals. METHODS: Four groups of male and female Crl:CD (SD)IGS BR rats (30/gender/group) were exposed to 0, 0.3%, 0.6%, and 1.0% DEHT in the feed for at least 70 consecutive days before mating for the F(0) and F(1) generations. Exposure for the F(0) and F(1) males continued throughout the mating period until euthanasia. Exposure for the F(0) and F(1) females continued throughout mating, gestation, and lactation. The F(1) and F(2) pups were weaned on postnatal day (PND) 21. Assessments included gonadal function, estrous cyclicity, mating behavior, conception rate, gestation, parturition, lactation, and weaning in the F(0) and F(1) generations, and F(1) generation offspring growth and development. RESULTS: DEHT exposure did not affect clinical observations. However, lethality was observed in F(0) and F(1) dams consuming the 1.0% diet during the post-weaning period. No treatment-related mortality occurred in any of the male groups exposed to DEHT or in the female groups exposed to 0.3% or 0.6% DEHT. Male rats consuming the 1.0% diet in both parental generations gained weight more slowly than the controls. There were no indications of adverse effects on reproductive performance in either the F(0) or F(1) generation. Male and female mating and fertility indices, pre-coital intervals, spermatogenic endpoints, reproductive organ weights, lengths of estrous cycle and gestation, live litter size, developmental landmarks, and postnatal survival were similar in all exposure groups. Additionally, ovarian follicle counts for the F(1) females in the high-exposure group were similar to the control values. No adverse exposure-related macroscopic pathology was noted at any exposure level in the F(0) and F(1) generations. CONCLUSIONS: Increases in liver weights were found in the male and female animals exposed to 0.6% or 1.0% DEHT in the diet. Because there were no accompanying histopathologic changes, this effect was not considered adverse. Significant decreases in feed consumption in the female animals from the groups consuming 1.0% DEHT in the diet during lactation accompanied reduced postnatal pup body weights and rate of weight gain. Reductions in pup body weights later in lactation may also have been due to direct consumption of the treated feed by the pups or taste aversion to the same. Reduced relative spleen weight was found in male weanling pups from the 1.0% group in both generations and reduced relative spleen and thymus weights were found in female pups from the 1.0% group in the F(2) generation at necropsy on PND 21. Therefore, for parental and pup systemic toxicity, 0.3% DEHT in the diet (182 mg/kg/day) was considered no-observed-effect level (NOEL). The 1.0% DEHT (614 mg/kg/day) in the diet exposure concentration was considered a NOEL for F(0) and F(1) reproductive toxicity endpoints.
Asunto(s)
Dietilhexil Ftalato/toxicidad , Preñez , Efectos Tardíos de la Exposición Prenatal , Reproducción/efectos de los fármacos , Animales , Animales Recién Nacidos , Cruzamiento , Femenino , Estudios de Seguimiento , Lactancia/efectos de los fármacos , Masculino , Modelos Biológicos , Embarazo , Ratas , Ratas Endogámicas , Conducta Sexual Animal/efectos de los fármacosRESUMEN
Oral and intravenous administration of tamoxifen base and tamoxifen citrate formulated with hydroxybutenyl-beta-cyclodextrin (HBenBCD) to Sprague-Dawley rats significantly increased the oral bioavailability of tamoxifen relative to that of parent drug (no HBenBCD). When formulated with HBenBCD, the form of tamoxifen (base vs. salt) made no difference in the oral bioavailability of tamoxifen. Liquid formulations (PG:PEG400:H2O) provided higher oral bioavailability than solid formulations dissolved and dosed as aqueous oral solutions. The oral bioavailability of tamoxifen was significantly influenced by both dietary status and time of dosing of the animals. Tamoxifen metabolite plasma concentrations were not affected by complexation of tamoxifen with HBenBCD. Collectively, the data indicated that dosing of fasted animals in the morning with tamoxifen:HBenBCD formulations provided a very significant increase in tamoxifen oral bioavailability (up to 10- to 14-fold).