RESUMEN
The aim of the study was to evaluate the association between in utero exposure to drugs that potentially exhibit immunosuppressive activity and occurrence of infections during the first year of life. We conducted a cohort study on the prescription data of pregnant women and their children registered in EFEMERIS cohort (France), during a one-year period. We classified in utero child exposure according to the number of reimbursements for immunosuppressive drugs during pregnancy. The number of infectious episodes during the first year of life was estimated through the number of anti-infective drugs dispensed. The association was estimated by a quasi-Poisson regression with adjustment for confounders. The study population consisted of 9614 children, 3141 of whom had been exposed to immunosuppressive drugs during pregnancy. The most frequently immunosuppressive drugs prescribed were corticosteroids. The mean number of infectious episodes during the first year after birth gradually increased with the number of immunosuppressive drugs dispensed during pregnancy (from 2.38 in controls to 3.88 in the most exposed group). After adjustment for potential confounders, in utero exposure to immunosuppressive drugs was significantly associated with the number of infectious episodes during the first year of life (RR 3ormoreexposuresVS0=1.35, 95% CI 1.24-1.46). Intrauterine exposure to potentially immunosuppressive drugs could be associated with an increased susceptibility to infections in early childhood.
Asunto(s)
Enfermedades Transmisibles/etiología , Enfermedades Transmisibles/inmunología , Inmunosupresores/efectos adversos , Inmunosupresores/inmunología , Útero/efectos de los fármacos , Útero/inmunología , Adulto , Estudios de Cohortes , Femenino , Francia , Humanos , Lactante , Recién Nacido , Masculino , Embarazo , RiesgoRESUMEN
Glucocorticoids are widely used for the management of inflammatory bowel disease, albeit with known limitations for long-term use and relevant adverse effects. In turn, they have harmful effects in experimental colitis. We aimed to explore the mechanism and possible implications of this phenomenon. Regular and microbiota depleted C57BL/6 mice were exposed to dextran sulfate sodium (DSS) to induce colitis and treated with budesonide. Colonic inflammation and animal status were compared. In vitro epithelial models of wound healing were used to confirm the effects of glucocorticoids. Budesonide was also tested in lymphocyte transfer colitis. Budesonide (1-60µg/day) exerted substantial colonic antiinflammatory effects in DSS colitis. At the same time, it aggravated body weight loss, increased rectal bleeding, and induced general deterioration of animal status, bacterial translocation and endotoxemia. As a result, there was an associated increase in parameters of sepsis, such as plasma NOx, IL-1ß, IL-6, lung myeloperoxidase and iNOS, as well as significant hypothermia. Budesonide also enhanced DSS induced colonic damage in microbiota depleted mice. These effects were correlated with antiproliferative effects at the epithelial level, which are expected to impair wound healing. In contrast, budesonide had significant but greatly diminished deleterious effects in noncolitic mice or in mice with lymphocyte transfer colitis. We conclude that budesonide weakens mucosal barrier function by interfering with epithelial dynamics and dampening the immune response in the context of significant mucosal injury, causing sepsis. This may be a contributing factor, at least in part, limiting clinical usefulness of corticoids in inflammatory bowel disease.
Asunto(s)
Antiinflamatorios/uso terapéutico , Budesonida/uso terapéutico , Modelos Animales de Enfermedad , Fármacos Gastrointestinales/uso terapéutico , Glucocorticoides/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Mucosa Intestinal/efectos de los fármacos , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/efectos adversos , Traslocación Bacteriana/efectos de los fármacos , Biomarcadores/sangre , Budesonida/administración & dosificación , Budesonida/efectos adversos , Colon/efectos de los fármacos , Colon/inmunología , Colon/microbiología , Colon/patología , Sulfato de Dextran , Relación Dosis-Respuesta a Droga , Disbiosis/inducido químicamente , Disbiosis/etiología , Disbiosis/prevención & control , Endotoxemia/inducido químicamente , Endotoxemia/etiología , Endotoxemia/prevención & control , Femenino , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/efectos adversos , Hemorragia Gastrointestinal/inducido químicamente , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/prevención & control , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/fisiopatología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Organismos Libres de Patógenos Específicos , Pérdida de Peso/efectos de los fármacosRESUMEN
Low methyl-esterified pectins obtained from the cell walls of the campion (SV, SV>300), tansy (TV, TV>300) and duckweed (LM, LM>300) callus cultures and apple pectin (AP, Classic AU 701) were used as the carriers for colon delivery of prednisolone. The pectins with molecular weight more than 300kDa (SV>300, TV>300, LM>300) formed gels which exhibited the higher gel strength. The higher gel strength of these gels appeared to be related to the higher Mw and the lower degree of methylesterification (DE) of these pectins. Release aspects of prednisolone in the simulated gastric (pH 1.25), intestinal (pH 7.0) and colonic (pH 7.0+pectinase) media were investigated. The LM-5%, AP-3% and AP-5% beads destroyed in simulated intestinal medium probably due to the higher DE of the LM and AP pectins. The SV>300-3% and TV>300-3% prednisolone loaded bead systems showed a high stability at pH 1.25 and pH 7.0. Prednisolone release occurred in a larger extent in colonic medium due to the enzymatic erosion of the beads. The SV>300-3% and TV>300-3% particles showed a more controlled release that appeared to be related to the lower DE, rhamnogalacturonan content, rhamnogalacturonan I branching and the higher linearity and Mw of the TV>300 and SV>300 pectins, as well as to the higher gel strength. This in vitro study suggests that calcium pectinate gel beads obtained from callus cultures pectins can be proposed as potential systems for colon-targeted drug delivery.
Asunto(s)
Sistemas de Liberación de Medicamentos , Pectinas/química , Colon , Medios de Cultivo , Preparaciones de Acción Retardada , Geles/química , Prednisolona/administración & dosificaciónRESUMEN
Meclizine is an agonist of human pregnane X receptor (PXR). It increases CYP3A4 mRNA expression, but decreases CYP3A-catalyzed testosterone 6ß-hydroxylation in primary cultures of human hepatocytes, as assessed at 24h after the last dose of meclizine. Therefore, the hypothesis to be tested is that meclizine inactivates human CYP3A enzymes. Our findings indicated that meclizine directly inhibited testosterone 6ß-hydroxylation catalyzed by human liver microsomes, recombinant CYP3A4, and recombinant CYP3A5. The inhibition of human liver microsomal testosterone 6ß-hydroxylation by meclizine occurred by a mixed mode and with an apparent Ki of 31±6µM. Preincubation of meclizine with human liver microsomes and NADPH resulted in a time- and concentration-dependent decrease in testosterone 6ß-hydroxylation. The extent of inactivation required the presence of NADPH, was unaffected by nucleophilic trapping agents or reactive oxygen species scavengers, attenuated by a CYP3A substrate, and not reversed by dialysis. Meclizine selectively inactivated CYP3A4, but not CYP3A5. In contrast to meclizine, which has a di-substituted piperazine ring, norchlorcyclizine, which is a N-debenzylated meclizine metabolite with a mono-substituted piperazine ring, did not inactivate but directly inhibited hepatic microsomal CYP3A activity. In conclusion, meclizine inhibited human CYP3A enzymes by both direct inhibition and mechanism-based inactivation. In contrast, norchlorcyclizine is a direct inhibitor but not a mechanism-based inactivator. Furthermore, a PXR agonist may also be an inhibitor of a PXR-regulated enzyme, thereby giving rise to opposing effects on the functional activity of the enzyme and indicating the importance of measuring the catalytic activity of nuclear receptor-regulated enzymes.
Asunto(s)
Inhibidores del Citocromo P-450 CYP3A/farmacología , Citocromo P-450 CYP3A/metabolismo , Meclizina/farmacología , Receptores de Esteroides/agonistas , Inhibidores del Citocromo P-450 CYP3A/química , Relación Dosis-Respuesta a Droga , Humanos , Técnicas In Vitro , Cinética , Meclizina/química , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Modelos Biológicos , Estructura Molecular , Piperazinas/química , Piperazinas/farmacología , Receptor X de Pregnano , Proteínas RecombinantesRESUMEN
The administration of boldenone and androstadienedione to cattle is forbidden in the European Union, while prednisolone is permitted for therapeutic purposes. They are pseudoendogenous substances (endogenously produced under certain circumstances). The commonly used matrices in control analyses are urine or liver. With the aim of improving the residue controls, we previously validated a method for steroid analysis in bile. We now compare urine (a 'classic' matrix) to bile, both collected at the slaughterhouse, to understand whether the detection of steroids in the latter is easier. With the aim of having clearer results, we tested the presence of the synthetic corticosteroid dexamethasone. The results show that bile does not substantially improve the detection of boldenone, or its conjugates, prednisolone and prednisone. Dexamethasone, instead, was found in 10 out of 53 bovine bile samples, but only in one urine sample from the same animals. Bile could constitute a novel matrix for the analysis of residues in food-producing animals, and possibly not only of synthetic corticosteroids.
Asunto(s)
Androstadienos/orina , Bilis/química , Glucocorticoides/orina , Testosterona/análogos & derivados , Androstadienos/análisis , Animales , Bovinos , Cromatografía Liquida/métodos , Cortisona/análisis , Cortisona/orina , Dexametasona/análisis , Dexametasona/orina , Glucocorticoides/análisis , Glucuronatos/análisis , Glucuronatos/orina , Hidrocortisona/análisis , Hidrocortisona/orina , Masculino , Prednisolona/análisis , Prednisolona/orina , Prednisona/análisis , Prednisona/orina , Reproducibilidad de los Resultados , Sulfatos/análisis , Sulfatos/orina , Espectrometría de Masas en Tándem/métodos , Testosterona/análisis , Testosterona/orinaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Stahlianthus involucratus (Zingiberaceae) has long been used in traditional medicine to treat inflammation, pain, and fever. However, no pharmacological study of this plant has been reported to confirm these activities. The aim of this study was to investigate the anti-inflammatory, antinociceptive and antipyretic activities of Stahlianthus involucratus rhizome ethanol extract (SiE) in animal models. MATERIALS AND METHODS: Anti-inflammatory activity of SiE was investigated in rats using ethyl phenylpropiolate (EPP)-induced ear edema, carrageenan- and arachidonic acid (AA)-induced hind paw edema, and cotton pellet-induced granuloma formation models. Acetic acid-induced writhing response in mice and tail-flick test in rats as well as yeast-induced hyperthermia in rats were used to investigate the antinociceptive and antipyretic activities, respectively. RESULTS: SiE significantly inhibited EPP-induced ear edema, carrageenan- and AA-induced hind paw edema. Its inhibitory effect in carrageenan-induced hind paw edema seemed to be in a dose-dependent manner. In cotton pellet-induced granuloma formation, SiE showed suppressive effects on granuloma formation but not on body weight gain and dry thymus weight. It could normalize serum alkaline phosphatase activity to nearly normal level. SiE also possessed a significant inhibitory effect, which seemed to be dose-dependent, on acetic acid-induced writhing response, whereas only at the highest dose of SiE could significantly increase test reaction time at all time-points in tail-flick test. However, no antipyretic activity was observed. CONCLUSIONS: These results suggest that SiE possesses anti-inflammatory and antinociceptive, but not antipyretic, activities. This study therefore rationalizes the traditional use of SiE for the treatment of inflammation and pain.
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios/farmacología , Antipiréticos/farmacología , Extractos Vegetales/farmacología , Zingiberaceae/química , Ácido Acético/toxicidad , Analgésicos/química , Animales , Antiinflamatorios/química , Antipiréticos/química , Ácido Araquidónico/toxicidad , Carragenina/toxicidad , Diclofenaco/farmacología , Edema/inducido químicamente , Edema/tratamiento farmacológico , Etanol/química , Granuloma/tratamiento farmacológico , Granuloma/etiología , Masculino , Ratones , Fenilpropionatos/toxicidad , Extractos Vegetales/química , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
The establishment of physiologically relevant in vitro-in vivo correlations (IV-IVCs) is key for any biorelevant dissolution test. Historically, bicarbonate buffers have produced better correlations than compendial phosphate buffered media, though such tests are usually performed at a constant pH experiment, overlooking the notion that the pH of the luminal fluids is variable and fluctuating. In this work, we have devised a dynamic dissolution test method employing a physiological bicarbonate buffer under pH conditions of the proximal gut in order to assess the dissolution behaviour of various enteric polymer-coated (gastro-resistant) prednisolone tablets. The pH of the media is modulated and controlled by an Auto pH System™ which exploits the physiological equilibria between [H2CO3] and [HCO3(-)], to match it to the aboral change in pH with transit of the dosage form through the proximal small intestine (from pH 5.6 up to 6.8). The lag time values for an accelerated release and standard EUDRAGIT(®) L30D-55 coated formulation (25 min and 60 min, respectively) were close to the previously reported initial tablet disintegration time data obtained in-vivo by γ-scintigraphy (28 min and 66 min, respectively). Dissolution of alternative delayed release coated products was also better discriminated in the dynamic buffer system. These data confirm the dynamic dissolution system provides a robust and reliable platform to predict the in vivo fate of oral products in a laboratory setting.
Asunto(s)
Química Farmacéutica/métodos , Modelos Biológicos , Prednisolona/química , Celulosa/análogos & derivados , Celulosa/química , Preparaciones de Acción Retardada , Liberación de Fármacos , Concentración de Iones de Hidrógeno , Metilcelulosa/análogos & derivados , Metilcelulosa/química , Ácidos Polimetacrílicos/química , Polivinilos/química , Prednisolona/administración & dosificación , SolubilidadRESUMEN
Age-mediated changes in gut physiology are considerations central to the elucidation of drug performance from oral formulations. Using rats of different age groups we measured the pH, buffer capacity, fluid volume, osmolality, and surface tension of gastrointestinal (GI) fluids, and therein explored the impact of these variables on prednisolone and mesalazine solubility in luminal fluids. We also studied the distribution of gut associated lymphoid tissue (GALT) and mucus layer thickness across the GI tract in rats of different age groups. At a mucosal level, there was an increase in GALT from young to adult rat. Gastrointestinal pH and buffer capacity remained mostly unchanged with age, except some pH differences in stomach and distal small intestine and a higher buffer capacity in the large intestinal fluids of young rats. Osmolality and surface tension also remained unaffected with the exception of a lower osmolality in elderly stomach and a lower surface tension in the small intestine of young rats. The difference in luminal environment on ageing influenced the solubility of studied drugs, for instance prednisolone solubility was shown to be higher in adult rats (mid small intestine and caecum) and solubility of mesalazine was significantly higher in the elderly distal small intestine.
Asunto(s)
Envejecimiento , Jugo Gástrico/química , Tracto Gastrointestinal/química , Secreciones Intestinales/química , Animales , Tracto Gastrointestinal/anatomía & histología , Concentración de Iones de Hidrógeno , Tejido Linfoide , Masculino , Mesalamina/química , Moco/química , Concentración Osmolar , Prednisolona/química , Ratas Wistar , Solubilidad , Tensión Superficial , Agua/análisisRESUMEN
The aim of this study was to investigate the stability of four corticosteroids in the presence of human colonic bacteria to understand better their luminal behaviour when delivered orally in the treatment of inflammatory bowel disease. The stability of prednisolone, budesonide, beclometasone (17, 21) dipropionate (BDP) and its active metabolite, beclometasone-17-monopropionate (17-BMP), were investigated at three different concentrations following incubation in a mixed faecal inoculum (simulated human colonic fluid) under anaerobic conditions. Prednisolone, at all three concentrations, was completely degraded within 3 h. The degradation of budesonide progressed at a slower rate, with complete degradation occurring within 7h; the degradation of the S epimer of budesonide was faster than the R epimer. BDP degraded completely within 2 h while its active metabolite 17-BMP was comparatively stable. In contrast to the results in the faecal inoculum, all molecules were stable in the simulated colonic fluid in the absence of human faeces (control). This study demonstrates that prednisolone, BDP and budesonide are completely metabolized in simulated human colonic fluid and confirms the role of colonic bacteria in the metabolism of corticosteroids.