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STUDY QUESTION: Is preconception vitamin D level associated with the risk of miscarriage? SUMMARY ANSWER: Preconception vitamin D levels are not associated with the risk of miscarriage in a population of women conceiving naturally. WHAT IS KNOWN ALREADY: In humans, low vitamin D has been associated with prolonged menstrual cycles, delayed ovulation and a lower probability of conception. Animal and in vitro data indicate that vitamin D may affect implantation. STUDY DESIGN, SIZE, DURATION: This prospective time-to-pregnancy study included 362 women who were trying to conceive naturally between 2008 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included participants who had been trying to conceive naturally for 3 months or less at enrollment and aged 30-44 years. A preconception blood sample was collected and 25-hydroxyvitamin D [25(OH)D] was measured. Women who conceived (N = 362) were at risk of a miscarriage from the day of a reported positive pregnancy test until either a participant-reported pregnancy loss or 20 weeks post day of last menstrual period, whichever came first. Gestational age was defined by ovulation. Time to miscarriage (days) or censoring was modeled using a multivariate Cox proportional hazards model. Multiple imputation was performed for missing covariates and missing day of ovulation. MAIN RESULTS AND THE ROLE OF CHANCE: The mean age was 33 years (SD: 3.0 years). Mean 25(OH)D was lower among those who reported their race as African-American and those with a higher BMI. After adjustment for age, race, BMI, education, exercise, alcohol and caffeine intake, compared to the referent group (30-<40 ng/ml), the hazard ratio (HR) and 95% CI for those with a low 25(OH)D level (<30 ng/ml) was 1.10 (CI: 0.62, 1.91). Among participants with a higher 25(OH)D level (≥40 ng/ml), the HR was 1.07 (CI: 0.62, 1.84). LIMITATIONS, REASONS FOR CAUTION: This study was limited by a 25(OH)D measurement at only a single time point. A large percentage of women in this study had sufficient vitamin D levels, which may have limited our power to detect an effect of deficiency. Women in this study were older (30-44 years), and predominantly reported their race as White which may limit generalizability. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study do not suggest an association between preconception vitamin D and miscarriage. Future research should focus on women at greater risk for miscarriage or in populations at risk for vitamin D deficiency or on supplementation. STUDY FUNDING/COMPETING INTEREST(S): This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01ES103333). This research was also supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH) under award numbers R00HD079659 and R01HD067683. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.
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Aborto Espontáneo , Aborto Espontáneo/epidemiología , Aborto Espontáneo/etiología , Adulto , Cafeína , Niño , Femenino , Humanos , Embarazo , Estudios Prospectivos , Tiempo para Quedar Embarazada , Vitamina DRESUMEN
Metopograpsus messor, a brachyuran crab inhabiting the estuaries of North Kerala (India), is a prolific breeder releasing approximately 14-16 broods a year. The present paper reports the sequence information on the DNA binding domain (C domain, DBD), linker (D domain) and ligand binding domain (E domain, LBD) of M. messor ecdysteroid receptor (MmEcR) gene, the first grapsid brachyuran crab EcR examined. We have also measured MmEcR transcript levels in the ovary and the hepatopancreas throughout the annual cycle, with special reference to seasons of molt and reproduction. MmEcR expression in both the tissues is found to be at its peak (P<0.05) in late premolt crabs (January/May, molt/reproduction season); the expression levels are lowest (P<0.05) during June/July, when the females would neither molt nor reproduce (season for molt/reproduction repose). Intermediate levels of expression were found during the breeding season (August/December). Interestingly, this pattern of gene expression is in concordance with the fluctuating ecdysteroid levels of the hemolymph and Y organ secretory activity. The significant levels of fluctuation in the ovarian expression of MmEcR strongly suggest the ovary as a potential target for ecdysteroid action. A season-wise comparison of the gene expression reveals that ovarian MmEcR transcript levels are higher in breeding crabs (August/December) than the non-breeding animals (June/July), implicating a possible ecdysteroid role in reproduction in M. messor.
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Braquiuros/genética , Braquiuros/fisiología , Regulación del Desarrollo de la Expresión Génica , Muda/genética , Receptores de Esteroides/genética , Estaciones del Año , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular , Ecdisteroides/metabolismo , Femenino , Humanos , Ligandos , Modelos Moleculares , Datos de Secuencia Molecular , Filogenia , Estructura Terciaria de Proteína , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Esteroides/química , Receptores de Esteroides/metabolismo , Reproducción/genética , Alineación de SecuenciaRESUMEN
AIMS: Immune checkpoint inhibitors (ICIs) are used in incurable urothelial cancers, both in chemo-naïve and platinum-refractory patients. Efficacy and toxicity data published outside controlled clinical trials are limited. We report overall survival, progression-free survival and toxicities of ICIs in locally advanced (LABC) or metastatic bladder cancer (MBC). We aimed to develop and validate a prognostic model for these patients. MATERIALS AND METHODS: A multicentre real-world individual patient-level data study (n = 272) evaluating ICIs in the first-line platinum-ineligible or platinum-refractory setting for LABC/MBC between March 2017 and February 2020 was undertaken. Cox regression analyses evaluated the association of prognostic factors with overall survival. Data were split to create a training (n = 208) and validation (n = 64) cohort. The backward elimination method with a P-value cut-off of 0.05 was used to develop a reduced prognostic model using the training data set. The concordance index and assessment of observed versus predicted survival probabilities were used to evaluate the final model. RESULTS: The median follow-up was 18.9 (15.8-21.5) months. The median overall survival and progression-free survival in the training cohort were 9.2 (95% confidence interval 7.4-10.5) and 4.5 months (3.5-5.7), respectively. The most common grade 1/2 adverse events recorded were fatigue (47.8%) and infection (19.9%). Five key prognostic factors found in the training set were low haemoglobin, high neutrophil count, choice of immunotherapy favouring pembrolizumab, presence of liver metastasis and steroid use within 30 days of treatment. The concordance index for the training and validation cohorts was 0.66 (standard error = 0.05) and 0.64 (standard error = 0.04), respectively, for the final model. A nomogram was developed to calculate the expected survival probabilities based on risk factors. CONCLUSIONS: Real-world data were used to produce a validated prognostic model for overall survival in LABC/MBC treated with ICIs. This model could assist in patient stratification, interpreting and framing future trials incorporating PD-1/PD-L1 inhibitors in LABC/MBC.
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Inmunoterapia , Neoplasias de la Vejiga Urinaria , Hemoglobinas , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Nomogramas , Platino (Metal)/uso terapéutico , Receptor de Muerte Celular Programada 1 , Esteroides/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
OBJECTIVES: To evaluate and describe brainstem auditory-evoked response measurements in healthy African pygmy hedgehogs (Atelerix albiventris). MATERIALS AND METHODS: Brainstem auditory-evoked response measurements were performed in 12 adult African pygmy hedgehogs (seven males, five females) under general anaesthesia. Waveform morphology was assessed and wave latencies, amplitudes and interpeak latencies calculated. RESULTS: Brainstem auditory-evoked response measurements were successfully performed in both ears from all hedgehogs. Three distinct waves were reproducible in all patients in both ears using a stimulus with an intensity of 90 dB nHL (decibel above normal hearing level). Amplitudes of waves I and V, latencies of waves I, II-III and V and interpeak latencies of waves I-V were calculated at 90 dB for both ears of each animal. CLINICAL SIGNIFICANCE: This study describes normal brainstem auditory-evoked response morphology and latencies for African pygmy hedgehogs. General anaesthesia is required to perform this neurodiagnostic, given the unique behaviour and anatomy of hedgehogs. This baseline data may be useful for investigating hearing abnormalities and central nervous system disorders in hedgehogs.
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Potenciales Evocados Auditivos del Tronco Encefálico , Erizos , Animales , Tronco Encefálico , Femenino , MasculinoRESUMEN
The objective of this study was to assess the efficacy of knotless barbed sutures in intraoral wound closure for maxillofacial trauma in comparison with conventional (vicryl) sutures. This was a randomised controlled clinical trial involving 40 patients with isolated mandibular angle fractures who required intraoral incisions for open reduction and internal fixation (ORIF). The sample was randomised into the study group (20 patients) and control group (20 patients). Following fracture fixation by a standardised surgical protocol, the wound closure was done with bidirectional knotless barbed suture and vicryl for the study and control groups, respectively. The wounds were closed in layers (periosteum and mucosa). All operations were performed by a single surgeon. Outcome parameters measured were intraoperative wound closure time and wound healing using 'Landry's wound healing index' on the first, third, and seventh postoperative days. Statistically significant difference in suturing time was noted between the study and control group (p value <0.001). The study group demonstrated a mean (SD) suturing time of 9.46 (2.01) minutes, compared with the 17.61 (2.57) minutes in the control group. Wound healing was found to be better and statistically significant in the study group than the control group (p value<0.001). Knotless barbed suture is a promising alternative to vicryl for intraoral wound closure.
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Fracturas Mandibulares , Técnicas de Sutura , Humanos , Fracturas Mandibulares/cirugía , Suturas , Cicatrización de HeridasRESUMEN
The metabolism and excretion of taranabant (MK-0364, N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2{[5-(trifluoromethyl)pyridine-2-yl]oxy}propanamide), a potent cannabinoid-1 receptor inverse agonist, were evaluated in rats and rhesus monkeys. Following administration of [¹4C]taranabant, the majority of the radioactivity was excreted within 72 h. In both rats and rhesus monkeys, taranabant was eliminated primarily via oxidative metabolism, followed by excretion of metabolites into bile. Major pathways of metabolism that were common to rats and rhesus monkeys included hydroxylation at the benzylic carbon adjacent to the cyanophenyl ring to form a biologically active circulating metabolite M1, and oxidation of one of the two geminal methyl groups of taranabant or M1 to the corresponding diastereomeric carboxylic acids. Oxidation of the cyanophenyl ring, followed by conjugation with glutathione or glucuronic acid, was a major pathway of metabolism only in the rat and was not detected in the rhesus monkey. Metabolism profiles of taranabant in liver microsomes in vitro were qualitatively similar in rats, rhesus monkeys and humans and included formation of M1 and oxidation of taranabant or M1 to the corresponding carboxylic acids via oxidation of a geminal methyl group. In human liver microsomes, metabolism of taranabant was mediated primarily by CYP3A4.
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Amidas/metabolismo , Agonismo Inverso de Drogas , Piridinas/metabolismo , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Amidas/sangre , Amidas/química , Amidas/farmacocinética , Animales , Anticuerpos Monoclonales/farmacología , Líquidos Corporales/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Femenino , Haplorrinos , Humanos , Cetoconazol/farmacología , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Piridinas/sangre , Piridinas/química , Piridinas/farmacocinética , Radiactividad , RatasRESUMEN
OBJECTIVES: To evaluate the sedative and cardiorespiratory effects of alfaxalone in ball pythons following subcutaneous administration in the cranial versus caudal third of the body. MATERIALS AND METHODS: In a prospective, randomised, blinded, complete crossover study, eight ball pythons ( Python regius ) received alfaxalone in the cranial or caudal third of the body. Sedative and cardiorespiratory parameters were recorded. RESULTS: Administration of alfaxalone in the cranial third of the body resulted in significantly deeper and longer sedation compared with administration in the caudal third of the body. Righting reflex was lost in five of eight snakes following cranial injection compared with one of eight snakes after caudal injection. Jaw tone was lost in all snakes following cranial injection and intubation was successfully performed in seven. In contrast, snakes did not lose jaw tone and intubation was not possible following caudal injection. Heart rate and respiratory rate were significantly decreased following administration of alfaxalone in the cranial third of the body. CLINICAL SIGNIFICANCE: Administration of drugs that undergo hepatic metabolism or excretion should not be performed in the caudal third of the body in snakes, because it can result in significantly reduced drug efficacy. A hepatic first-pass effect is assumed to be the most likely underlying cause for the observed effect because part of the venous return from the caudal body flows directly to the liver.
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Anestesia/veterinaria , Anestésicos/administración & dosificación , Boidae/fisiología , Pregnanodionas/administración & dosificación , Anestesia/métodos , Anestésicos/farmacología , Animales , Estudios Cruzados , Femenino , Inyecciones Subcutáneas/métodos , Inyecciones Subcutáneas/veterinaria , Masculino , Pregnanodionas/farmacología , Estudios Prospectivos , Distribución AleatoriaRESUMEN
A total of 19 methicillin-resistant Staphylococcus aureus (MRSA) isolates were investigated for Panton-Valentine leukocidin (PVL) toxin, PVL gene sequence variation and PVL-encoding phages. Whole genome sequencing was performed for all isolates. Analysis of MRSA isolates (n = 19) confirmed that most MRSA (n = 11) were positive for the PVL gene and were multidrug resistant. ST772-MRSA-V was the predominant PVL-positive MRSA clone, although all of them were found to carry the ΦIND772PVL phage in the genome. This study provides insights into the evolution of a new lineage of PVL-MRSA and highlights the potential risk of the emergence of multidrug-resistant community-acquired MRSA with high virulence.
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OBJECTIVE: To determine the vertebral heart size in chinchillas using right and left lateral radiographic views and CT images. To evaluate the agreement between radiographic and CT modalities. METHODS: Twenty-one clinically healthy chinchillas and seven chinchillas with cardiovascular abnormalities underwent cardiovascular examination before thoracic radiographs and thoracic CT obtained under dexmedetomidine-ketamine anaesthesia. Two observers calculated vertebral heart size for radiographic and CT studies. Reference intervals were calculated with the robust method. Agreement between radiographic and CT-derived vertebral heart size was evaluated with Bland-Altman plots and Deming regression. RESULTS: Mean ±sd vertebral heart size for lateral radiographs was 8·9 ±0·62 (reference interval: 7·5 to 10·2) and for CT-derived vertebral heart size was 8·2 ±0·55 (reference interval: 7·1 to 9·4). CT significantly underestimated the radiographic vertebral heart size by 0·66 vertebrae. There was no significant difference between vertebral heart size for right and left lateral radiographic views, or between female and male chinchillas. CLINICAL SIGNIFICANCE: Radiographic vertebral heart size for chinchillas is larger than that reported for similar rodents. Vertebral heart size can be calculated using radiography or CT in chinchillas, but these techniques are not interchangeable.
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Chinchilla/anatomía & histología , Corazón/anatomía & histología , Corazón/diagnóstico por imagen , Radiografía Torácica/veterinaria , Tomografía Computarizada por Rayos X/veterinaria , Animales , Enfermedades Cardiovasculares/veterinaria , Femenino , Masculino , Tamaño de los Órganos , Vértebras Torácicas/anatomía & histología , Vértebras Torácicas/diagnóstico por imagenRESUMEN
Human angiofibromas are rare and arise typically in the nasopharynx. In veterinary medicine they have only been described in the dog. Microscopically, angiofibromas consist of irregular groups of blood vessels within a stroma of connective tissue, with oedema and secondary inflammation often present. A cockatiel (Nymphicus hollandicus) was presented with an oral mass that consisted of aggregates of blood vessels surrounded by a connective tissue stroma, with the presence of oedema and secondary inflammation. Tumours of the oral cavity are uncommon in birds and to the authors' knowledge this is the first case of avian angiofibroma.
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Angiofibroma/veterinaria , Enfermedades de las Aves/patología , Cacatúas , Neoplasias de la Boca/veterinaria , Angiofibroma/patología , Animales , Femenino , Neoplasias de la Boca/patologíaRESUMEN
Two series of potential angiotensin II antagonists derived from carboxyl-functionalized "diazole" heterocycles have been prepared and evaluated. Initially, a limited investigation of 4-arylimidazole-5-carboxylates led to 2-n-butyl-4-(2-chlorophenyl)-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-y l] methyl]-1H-imidazole-5-carboxylic acid (12b), which was found to be a highly potent antagonist of the rabbit aorta AT1 receptor (IC50 0.55 nM). In conscious, normotensive rats, 12b at 0.1 mg/kg iv inhibited the pressor response to AII by 88%, with a duration of > 6 h. More extensively studied was an isosteric series of 3-alkyl-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazole -5- carboxylates bearing aryl, alkyl, or aralkyl substituents at N1. These compounds were available in highly regioselective fashion via condensation of a substituted hydrazine hydrochloride with a 2-(methoxyimino)-4-oxoalkanoate intermediate. In vitro, the most potent pyrazolecarboxylic acids had n-butyl at C3 and were substituted at N1 by such groups as 2,6-dichlorophenyl (19h), 2-(trifluoromethyl)phenyl (19k), benzyl (19t), and phenethyl (19u), all with IC50 values of 0.18-0.24 nM. Although less potent in the receptor assay, 3-n-propylpyrazolecarboxylic acids were at least as effective as their butyl counterparts in vivo. Several of the pyrazolecarboxylic acid derivatives demonstrated potent, long-lasting oral activity in rats. At 1 mg/kg po, the 1-benzyl-3-butyl (19t), 1-(2,6-dichlorophenyl)-3-propyl (19v), 3-propyl-1-(2,2,2-trifluoroethyl) (19y), and 1-benzyl-3-propyl (19z) analogues all gave > or = 75% inhibition of the AII pressor response in the rat model, with duration of action > 23 h.
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Angiotensina II/antagonistas & inhibidores , Ácidos Carboxílicos/síntesis química , Imidazoles/síntesis química , Pirazoles/síntesis química , Angiotensina II/farmacología , Antagonistas de Receptores de Angiotensina , Animales , Aorta/metabolismo , Presión Sanguínea/efectos de los fármacos , Ácidos Carboxílicos/farmacología , Fenómenos Químicos , Química Física , Imidazoles/farmacología , Masculino , Estructura Molecular , Pirazoles/farmacología , Conejos , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Apicidin's indole was efficiently converted into a series of N-substituted quinolone derivatives by indole N-alkylation followed by a two-step, one-pot, ozonolysis/aldol condensation protocol. The new quinolones exhibited good parasite selectivity and potency both at the level of their molecular target, histone deacetylase, and in their whole cell antiproliferative activity in vitro.
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Antiprotozoarios/síntesis química , Inhibidores Enzimáticos/síntesis química , Inhibidores de Histona Desacetilasas , Indoles/síntesis química , Péptidos Cíclicos/química , Quinolonas/síntesis química , Animales , Antimaláricos/síntesis química , Antimaláricos/química , Antimaláricos/farmacología , Antiprotozoarios/química , Antiprotozoarios/farmacología , Unión Competitiva , División Celular/efectos de los fármacos , Extractos Celulares , Pollos , Eimeria tenella/citología , Eimeria tenella/efectos de los fármacos , Eimeria tenella/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Células HeLa , Histona Desacetilasas/metabolismo , Humanos , Técnicas In Vitro , Indoles/química , Indoles/farmacología , Hígado/metabolismo , Plasmodium falciparum/efectos de los fármacos , Quinolonas/química , Quinolonas/farmacología , Relación Estructura-ActividadRESUMEN
[reaction: see text]. Radical cyclization of 6 affords the bicyclic vinyl ether 9 with the appropriate stereochemistry for elaboration (seven steps) to griseolic acid B (1).
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Adenosina/análogos & derivados , Adenosina/síntesis química , Inhibidores de Fosfodiesterasa/síntesis química , 3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Ciclización , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Oxidación-Reducción , Estereoisomerismo , Streptomyces/químicaRESUMEN
Methods for the quantitative determination of efavirenz in human plasma and the qualitative assessment of the stereochemical integrity of efavirenz in post-dose human plasma samples are described. After the addition of an internal standard, plasma samples were extracted with hexane-methylene chloride (65/35, v/v%). The extracts were evaporated to dryness and reconstituted in mobile phase. Upon exposure to UV light, the analyte was found to form fluorescent products; the major fluorescent product was isolated and identified as a substituted quinoline. Thus, the plasma extracts were analyzed via HPLC with post-column photochemical derivatization and fluorescence detection. Reverse phase chromatography was used for the quantitative assay, whereas chromatography with a column containing a chiral stationary phase (dinitrobenzoyl leucine) was used for the stereochemical assessment. The quantitative assay has been validated in the concentration range of 50-1000 ng/ml using 0.5 ml samples. Analyte recovery was better than 89% at all points on the standard curve. Intra-day precision was better than 5% C.V., while accuracy was between 95 and 104% of nominal over the range of the assay. The selective detection method reduces the likelihood of interference by co-administered medications or endogenous species. The stereochemical configuration of efavirenz was confirmed to remain intact in post-dose human plasma samples. The quantitative method has been successfully utilized to support a study in which a possible drug interaction between co-administered HIV protease inhibitors and efavirenz was evaluated.
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Oxazinas/sangre , Inhibidores de la Transcriptasa Inversa/sangre , Alquinos , Benzoxazinas , Cromatografía Líquida de Alta Presión , Ciclopropanos , Humanos , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Oxazinas/farmacocinética , Fotoquímica , Fotólisis , Control de Calidad , Inhibidores de la Transcriptasa Inversa/farmacocinética , Espectrometría de Fluorescencia , Espectrofotometría Ultravioleta , EstereoisomerismoRESUMEN
The aim was to investigate the metabolic activation potential of a pentafluorophenylethylamine derivative (compound I) in vitro in the rat and to identify the cytochrome P450 (CYP) enzymes that catalyse these metabolic activation processes. Reduced glutathione (GSH) was fortified in rat hepatocytes and liver microsomes to trap possible reactive intermediates. Four glutathione conjugates (M1-4) were identified by LC-MS(n) following incubation of compound I in GSH-enriched rat hepatocytes and liver microsomes. Three of these conjugates (M2-4) have not been reported previously for pentafluorophenyl derivatives. Elemental composition analysis of these conjugates was obtained using high-resolution quadrupole time-of-flight mass spectrometry. The formation of GSH conjugate M1 was rationalized as a direct nucleophilic replacement of fluoride by glutathione, whereas the formation of the GSH conjugates M2-4 was proposed to occur by NADPH-dependent metabolic activation of the pentafluorophenyl ring via arene oxide, quinone and/or quinoneimine reactive intermediates. Formation of these conjugates was enhanced three- to five-fold in liver microsomes obtained from phenobarbital- and dexamethasone-treated rats. In incubations with pooled rat liver microsomes and recombinant rat CYP3A1 and CYP3A2, troleandomycin (TAO) reduced the formation of GSH conjugates M2-4 by 80-90%, but it had no effect on the formation of M1. Incubation of compound I with rat supersomes indicated that only CYP3A1 and CYP3A2 were capable of mediating these metabolic activation processes.
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Sistema Enzimático del Citocromo P-450/metabolismo , Glutatión/metabolismo , Hepatocitos/enzimología , Microsomas Hepáticos/enzimología , Fenetilaminas/farmacocinética , Animales , Antibacterianos/metabolismo , Antibacterianos/farmacología , Biotransformación , Técnicas In Vitro , Masculino , Fenetilaminas/administración & dosificación , Fenetilaminas/metabolismo , Ratas , Ratas Sprague-Dawley , Troleandomicina/metabolismo , Troleandomicina/farmacologíaRESUMEN
Cigarettes were prepared from tobaccos grown in the greenhouse on a soil to which a low rate of a municipal sewage sludge was applied. The cigarettes were smoked by machine and the mainstream particulate fraction was analyzed for total cadmium and nickel content. Sludge-grown and control (soil-grown) tobaccos contained, respectively, 5.33 and 1.87 ppm of cadmium and 1.15 and 0.64 ppm of nickel. The average quantities of cadmium and nickel (ng/cigarette) found in the mainstream particulate fractions were, respectively, 220.5 and 78.5 for the sludge-grown and 147.4 and 72.6 for the control treatments. The difference between treatments was highly significant (p less than 0.001) for cadmium but not significant for nickel.
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Cadmio/análisis , Níquel/análisis , Nicotiana/análisis , Plantas Tóxicas , Aguas del Alcantarillado/análisis , Humo/análisis , Contaminantes del Suelo/análisis , Mutágenos/análisisRESUMEN
The disposition and metabolism of [3H]pioglitazone was determined in male rats after oral administration. The peak plasma concentration of 10 micrograms/ml occurred 1 hr after dosing at 10 mg/kg p.o.; the apparent plasma terminal half-life was 7.5 hr. Most of the radioactivity in plasma up to 8 hr after dosing was due to the parent drug. Pioglitazone was highly protein-bound in plasma; only 1-2% was free at concentrations of 0.1-10 micrograms/ml. Within 3 days after oral administration to bile duct-cannulated rats, 36% and 15% of the oral dose was recovered in the bile and urine, respectively. The pattern of biliary and urinary metabolites was similar. A total of eight metabolites were isolated and identified on the basis of NMR spectroscopy and MS. Metabolites resulting from hydroxylation of either carbon adjacent to the pyridine ring were conjugated with glucuronic acid (M7) or sulfuric acid (M6). The metabolite hydroxylated on the terminal carbon of the ethyl side chain was further oxidized to the carboxylic acid derivative (M3). Oxidative loss of the terminal carbon led to a nicotinic acid derivative (M2) and loss of both carbon atoms to the corresponding 3-hydroxypyridine (M9) derivative that was excreted as the sulfate conjugate (M8). The two carboxylic acid metabolites were also conjugated with taurine (M4 and M5).