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Reliable neutron star mass measurements are key to determining the equation of state of cold nuclear matter, but such measurements are rare. Black widows and redbacks are compact binaries consisting of millisecond pulsars and semi-degenerate companion stars. Spectroscopy of the optically bright companions can determine their radial velocities, providing inclination-dependent pulsar mass estimates. Although inclinations can be inferred from subtle features in optical light curves, such estimates may be systematically biased due to incomplete heating models and poorly understood variability. Using data from the Fermi Large Area Telescope, we have searched for gamma-ray eclipses from 49 spider systems, discovering significant eclipses in 7 systems, including the prototypical black widow PSR B1957+20. Gamma-ray eclipses require direct occultation of the pulsar by the companion, and so the detection, or significant exclusion, of a gamma-ray eclipse strictly limits the binary inclination angle, providing new robust, model-independent pulsar mass constraints. For PSR B1957+20, the eclipse implies a much lighter pulsar (1.81 ± 0.07 solar masses) than inferred from optical light curve modelling.
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AIM: To evaluate clinical, laboratory, imaging findings, and outcomes of adult patients with bone marrow haemophagocytosis (BMH) who meet the diagnostic criteria for haemophagocytic lymphohistiocytosis (HLH) with those who do not meet the criteria. MATERIALS AND METHODS: A pathology database search was performed from 2009 to 2019 to identify adult patients with BMH. Electronic medical records of 41 patients were reviewed to distinguish those who fulfil the HLH-2004 diagnostic guidelines, which identified 22 patients (11 men; mean age, 53.5 years) who met the criteria (HLH+) and 19 patients (13 men; mean age, 54.7 years) who did not meet the criteria (HLH-). Multi-modality imaging was reviewed to record imaging features. Clinical, laboratory, imaging findings, and outcomes were compared between the two groups using Fisher's exact test and Wilcoxon test. RESULTS: Malignancy (non-Hodgkin's lymphoma) was the major trigger for both groups. 86% of HLH+ and 31% of HLH- patients presented with fever. Compared to the HLH- group, the HLH+ group exhibited higher serum ferritin, triglycerides, and lower fibrinogen levels (p<0.05). Alveolar opacities and hepatosplenomegaly were the most common imaging findings identified in both groups. Median overall survival of HLH+ and HLH- were 123.5 (interquartile range [IQR]: 40.7-681.7 days) and 189 days (IQR: 52-1680 days), respectively. Distribution of imaging features and overall survival did not differ between the groups. CONCLUSION: Malignancy is the major trigger for BMH in both HLH+ and HLH- groups. HLH+ and HLH- groups have similar imaging manifestations or clinical outcomes. Therefore, presence of BMH alone is correlated with high morbidity and mortality.
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Médula Ósea/diagnóstico por imagen , Linfohistiocitosis Hemofagocítica/diagnóstico , Imagen por Resonancia Magnética/métodos , Tomografía de Emisión de Positrones/métodos , Tomografía Computarizada por Rayos X/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Femenino , Humanos , Linfohistiocitosis Hemofagocítica/epidemiología , Masculino , Persona de Mediana Edad , Morbilidad/tendencias , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Treatment options for patients who develop brain metastases secondary to non-small-cell lung cancer have rapidly expanded in recent years. As a key adjunct to surgical and radiation therapy options, systemic therapies are now a critical component of the oncologic management of metastatic CNS disease in many patients with non-small-cell lung cancer. The aim of this review article was to provide a guide for radiologists, outlining the role of systemic therapies in metastatic non-small-cell lung cancer, with a focus on tyrosine kinase inhibitors. The critical role of the blood-brain barrier in the development of systemic therapies will be described. The final sections of this review will provide an overview of current imaging-based guidelines for therapy response. The utility of the Response Assessment in Neuro-Oncology criteria will be discussed, with a focus on how to use the response criteria in the assessment of patients treated with systemic and traditional therapies.
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Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/secundario , Neoplasias Pulmonares/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , RadiólogosRESUMEN
BACKGROUND: This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD) and pharmacokinetics of two dosing schedules of oral topotecan in combination with pazopanib in patients with advanced solid tumours. METHODS: Stage I of this study was to determine whether there was an impact of pazopanib on topotecan exposure. In stage II, the MTD and safety profile of oral topotecan given weekly on days 1, 8 and 15 in a 28-day cycle; or daily-times-five on days 1-5 in a 21-day cycle, both in combination with daily pazopanib, were explored. RESULTS: In total, 67 patients were enroled. Pazopanib co-administration caused a substantial increase in exposure to total topotecan (1.7-fold) compared with topotecan alone, which is considered clinically relevant. Topotecan had no effect on pazopanib concentrations. Safety findings were consistent with the known profile of both agents. There were three drug-related deaths, liver failure, tumour haemorrhage and myelosuppression. Two patients experienced dose-limiting toxicities (DLTs; hand-foot syndrome, myelosuppression and diarrhoea) on the weekly topotecan schedule and four patients experienced DLTs (myelosuppression) on the daily-times-five topotecan schedule. When combined with pazopanib, 800 mg daily, the recommended doses for oral topotecan are: 8 mg weekly and 2.5 mg daily-times-five. Seven of eight patients with partial response had platinum-resistant ovarian cancer. In addition, 54% of patients had stable disease with 22% stable for 6 months. CONCLUSIONS: Total topotecan exposure is 1.7-fold higher when co-administered with pazopanib. Both schedules of administration were tolerated and would permit further evaluation, especially the weekly schedule.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Administración Oral , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Femenino , Humanos , Indazoles , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias Ováricas/patología , Neoplasias Pancreáticas/patología , Pirimidinas/administración & dosificación , Sulfonamidas/administración & dosificación , Topotecan/administración & dosificación , Resultado del Tratamiento , Adulto JovenRESUMEN
Purple sulfur bacteria (PSB) are known to couple the carbon, nitrogen, and sulfur cycling in euxinic environments. This is the first study with multiple strains and species of okenone-producing PSB to examine the carbon (C), nitrogen (N), and sulfur (S) metabolisms and isotopic signatures in controlled laboratory conditions, investigating what isotopic fractionations might be recorded in modern environments and the geologic record. PSB play an integral role in the ecology of euxinic environments and produce the unique molecular fossil okenane, derived from the diagenetic alteration of the carotenoid pigment okenone. Cultures of Marichromatium purpuratum 1591 (Mpurp1591) were observed to have carbon isotope fractionations ((13)ε biomass - CO2), via RuBisCO, ranging from -16.1 to -23.2 during exponential and stationary phases of growth. Cultures of Thiocapsa marina 5653 (Tmar5653) and Mpurp1591 had a nitrogen isotope fractionation ((15)ε biomass - NH 4) of -15, via glutamate dehydrogenase, measured and recorded for the first time in PSB. The δ(34) SVCDT values and amount of stored elemental sulfur for Mpurp1591 cells grown autotrophically and photoheterotrophically were dependent upon their carbon metabolic pathways. We show that PSB may contribute to the isotopic enrichments observed in modern and ancient anoxic basins. In a photoheterotrophic culture of Mpurp1591 that switched to autotrophy once the organic substrate was consumed, there were bulk biomass δ(13)C values that span a broader range than recorded across the Late Devonian, Permian-Triassic, Triassic-Jurassic, and OAE2 mass extinction boundaries. This finding stresses the complexities in interpreting and assigning δ(13)C values to bulk organic matter preserved in the geologic record.
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Isótopos de Carbono/análisis , Carotenoides/biosíntesis , Chromatiaceae/metabolismo , Isótopos de Nitrógeno/análisis , Isótopos de Azufre/análisis , Biomasa , Carotenoides/química , Fósiles , GeologíaRESUMEN
Okenone is a carotenoid pigment unique to certain members of Chromatiaceae, the dominant family of purple sulfur bacteria (PSB) found in euxinic photic zones. Diagenetic alteration of okenone produces okenane, the only recognized molecular fossil unique to PSB. The in vivo concentrations of okenone and bacteriochlorophyll a (Bchl a) on a per cell basis were monitored and quantified as a function of light intensity in continuous cultures of the purple sulfur bacterium Marichromatium purpuratum (Mpurp1591). We show that okenone-producing PSB have constant bacteriochlorophyll to carotenoid ratios in light-harvesting antenna complexes. The in vivo concentrations of Bchl a, 0.151 ± 0.012 fmol cell(-1), and okenone, 0.103 ± 0.012 fmol cell(-1), were not dependent on average light intensity (10-225 Lux) at both steady and non-steady states. This observation revealed that in autotrophic continuous cultures of Mpurp1591, there was a constant ratio for okenone to Bchl a of 1:1.5. Okenone was therefore constitutively produced in planktonic cultures of PSB, regardless of light intensity. This confirms the legitimacy of okenone as a signature for autotrophic planktonic PSB and by extrapolation water column euxinia. We measured the δ(13)C, δ(15)N, and δ(34)S bulk biomass values from cells collected daily and determined the isotopic fractionations of Mpurp1591. There was no statistical relationship in the bulk isotope measurements or stable isotope fractionations to light intensity or cell density under steady and non-steady-state conditions. The carbon isotope fractionation between okenone and Bchl a with respect to overall bulk biomass ((13)ε pigment - biomass) was 2.2 ± 0.4 and -4.1 ± 0.9, respectively. The carbon isotopic fractionation (13ε pigment-CO2) for the production of pigments in PSB is more variable than previously thought with our reported values for okenone at -15.5 ± 1.2 and -21.8 ± 1.7 for Bchl a.
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Bacterioclorofilas/análisis , Isótopos de Carbono/química , Carotenoides/análisis , Chromatiaceae/metabolismo , Carotenoides/biosíntesisRESUMEN
BACKGROUND: The South African Heart Association (SA Heart) is an affiliate of the European Society of Cardiology (ESC). SA Heart endorses ESC treatment guidelines with modification to suit local circumstances. The Heart Failure Society of South Africa (HeFSSA) is a special interest group of SA Heart. This guideline has been compiled on behalf of the HeFSSA and is based on the ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. The focus is on heart failure with reduced ejection fraction (HF-REF) (i.e. ejection fraction <50%). We have recommended interventions in symptomatic patients with HF-REF in general to clarify the 'grey area' between the ESC guidelines definition of REF (<50%) and the predefined ejection fraction used in randomised heart failure trials (<35%). OBJECTIVE: To highlight new changes in the diagnosis and treatment of chronic heart failure with particular emphasis on areas that are relevant to SA. CONCLUSIONS: Randomised clinical trials are a crucial, but not the only, guide in treating HF-REF patients. There always remain questions that are unanswered and groups of patients not studied, so prudent clinical decisions are required.
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Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/terapia , Algoritmos , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Estimulación Cardíaca Artificial , Fármacos Cardiovasculares/uso terapéutico , Árboles de Decisión , Técnicas de Diagnóstico Cardiovascular , Diuréticos/uso terapéutico , Cardioversión Eléctrica , Europa (Continente) , Insuficiencia Cardíaca/etiología , Humanos , Guías de Práctica Clínica como Asunto , Sociedades Médicas , SudáfricaRESUMEN
The stability of the filament lattice in relaxed striated muscle can be viewed as a balance of electrostatic and van der Waals forces. The simplest electrostatic model, where actin and myosin filaments are treated as charged cylinders, generates reasonable lattice spacings for skinned fibers. However, this model predicts excessive radial stiffness under osmotic pressure and cannot account for the initial pressure (â¼1 kPa) required for significant compression. Good agreement with frog compression data is obtained with an extended model, in which S1 heads are weakly attached to actin when the lattice spacing is reduced below a critical value; further compression moves fixed negative charges on the heads closer to the myofilament backbone as they attach at a more acute angle to actin. The model predicts pH data in which the lattice shrinks as pH is lowered and protons bind to filaments. Electrostatic screening implies that the lattice shrinks with increasing ionic strength, but the observed expansion of the frog lattice at ionic strengths above 0.1 M with KCl might be explained if Cl(-) binds to sites on the motor domain of S1. With myosin-myosin and actin-actin interactions, the predicted lattice spacing decreases slightly with sarcomere length, with a more rapid decrease when actin-myosin filament overlap is very small.
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Actinas/metabolismo , Modelos Biológicos , Músculo Esquelético/metabolismo , Miosinas/metabolismo , Electricidad Estática , Animales , Anuros , Concentración de Iones de Hidrógeno , Fibras Musculares Esqueléticas/citología , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/citología , Músculo Esquelético/efectos de los fármacos , Concentración Osmolar , Presión Osmótica , Cloruro de Potasio/farmacología , Unión Proteica , Conejos , Sarcómeros/efectos de los fármacos , Sarcómeros/metabolismoRESUMEN
Electrically charged long-chain macromolecules in an electrolyte can form an ordered lattice whose spacing is greater than their diameter. If entropic effects are neglected, these nematic structures can be predicted from a balance of Coulomb repulsion and van-der-Waals attraction forces. To enhance the utility of such theories, this paper extends existing results for the interaction between charged filaments, and gives approximate formulae for the screened Coulomb and van-der-Waals potentials over the whole range of their centre-to-centre spacing d. The repulsive Coulomb potential is proportional to exp(-λd)/λd for all spacings when the Debye screening length 1/λ is smaller than the sum of the filament radii. The attractive van-der-Waals potential is asymptotic to dâ»5 at large d. For smaller spacings, the potential is calculated by numerical integration and compared with published formulae: the series expansion of Brenner and McQuarrie converges too slowly, whereas the interpolation formula of Moisescu provides reasonable accuracy over the whole range of d. Combining these potentials shows that there is a finite range of charge densities for which a nematic crystal lattice is stable, but this conclusion ignores entropic effects associated with motile filaments. The role of electrostatic forces in aligning filaments and stabilizing a nematic liquid-crystal phase is discussed, in conjunction with other mechanisms such as motor proteins, crosslinkers or scaffolding structures.
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Electrólitos/química , Sustancias Macromoleculares/química , Citoesqueleto de Actina/química , Concentración Osmolar , TermodinámicaRESUMEN
BACKGROUND: A recent study has suggested that abdominal diameter index (ADI), that is, the supine sagittal abdominal diameter divided by thigh circumference, may be a better measure of the increased risk of abdominal adiposity for prevalent ischemic cardiovascular disease (CVD) than body mass index or waist circumference. The risk associated with all of these measures is believed to arise from the link between visceral obesity and insulin resistance. METHODS: Male bridge and tunnel workers in New York City without ischemic CVD in the highest and lowest quartiles of ADI (n=218) in a 1993-1994 cross-sectional study of risk factors and prevalent coronary heart disease were administered telephone follow-up questionnaires after 12 years (2005-2006) to assess incident ischemic CVD (new-onset angina, coronary revascularization, myocardial infarction, stroke, peripheral vascular disease and cardiovascular death). RESULTS: In the univariate analysis of 111 participants able to be contacted, study members in the highest quartile vs the lowest quartile of ADI had a significantly increased cumulative incidence of ischemic CVD (Relative risk (RR)=7.9, P=0.002). In a logistic regression analysis controlling for other cardiovascular risk factors including age, smoking, total cholesterol, high-density lipoprotein cholesterol, triglycerides, blood pressure and glucose, ADI lost statistical significance (RR=4.37, P=0.063), suggesting that ADI may be an anthropometric surrogate for these cardiovascular risk factors. CONCLUSIONS: ADI is a powerful anthropometric index for 12-year cumulative incidence of ischemic CVD in working men in New York City.
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Enfermedades Cardiovasculares/epidemiología , Obesidad/epidemiología , Circunferencia de la Cintura , Análisis de Varianza , Antropometría , Índice de Masa Corporal , Enfermedades Cardiovasculares/etiología , Estudios Transversales , Femenino , Humanos , Incidencia , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Ciudad de Nueva York/epidemiología , Obesidad/complicaciones , Estudios Prospectivos , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
Living cells were used to demonstrate the potential biological applications of the apertureless SNOM when operating under fluid. An oral epithelial squamous cell carcinoma cell line (H357) was imaged under physiological-like conditions using apertureless SNOM following staining with FITC-Phalloidin which preferentially stains intracellular actin filaments of the cytoskeleton. Compared with simultaneously obtained AFM topographic image, the apertureless SNOM data provides greater detail on these cellular structures and the spatial resolution of the apertureless SNOM fluorescence image appears to be about 100 nm.
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Actinas/metabolismo , Microscopía de Fuerza Atómica/métodos , Línea Celular Tumoral , HumanosRESUMEN
The creation of synthetic enzymes with predefined functions represents a major challenge in future synthetic biology applications. Here, we describe six structures of de novo proteins that have been determined using protein crystallography to address how simple enzymes perform catalysis. Three structures are of a protein, DX, selected for its stability and ability to tightly bind ATP. Despite the addition of ATP to the crystallization conditions, the presence of a bound but distorted ATP was found only under excess ATP conditions, with ADP being present under equimolar conditions or when crystallized for a prolonged period of time. A bound ADP cofactor was evident when Asp was substituted for Val at residue 65, but ATP in a linear configuration is present when Phe was substituted for Tyr at residue 43. These new structures complement previously determined structures of DX and the protein with the Phe 43 to Tyr substitution [Simmons, C. R., et al. (2009) ACS Chem. Biol. 4, 649-658] and together demonstrate the multiple ADP/ATP binding modes from which a model emerges in which the DX protein binds ATP in a configuration that represents a transitional state for the catalysis of ATP to ADP through a slow, metal-free reaction capable of multiple turnovers. This unusual observation suggests that design-free methods can be used to generate novel protein scaffolds that are tailor-made for catalysis.
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Adenosina Difosfato/metabolismo , Adenosina Trifosfato/metabolismo , Proteínas/química , Proteínas/metabolismo , Biología Sintética , Cristalografía por Rayos X , Cinética , Modelos Moleculares , Unión Proteica , Conformación ProteicaRESUMEN
Malolactic fermentation (MLF), the conversion of malate to lactate, is an important process leading to the deacidification of hard apple cider. MLF is dependent on the levels of inhibitory factors such as sulfur dioxide and ethanol. To assess the effect of these 2 factors on MLF, hard apple cider was produced from pasteurized, unfiltered apple cider (Malus domestica cvs Red Delicious, Golden Delicious, Braeburn, and Fuji). Apple cider was treated with 2 levels of sulfur dioxide (50 and 80 ppm) and then fermented using Saccharomyces cerevisiae montrachet. After the primary fermentation, 1 set of the samples remained unadjusted and 100% ethyl alcohol was used to adjust other sets of samples to 7%, 9%, or 11% (v/v) ethanol. Following the ethanol adjustment, Oenococcus oeni MCW was used to initiate the MLF in half of the samples. Cider parameters monitored throughout the fermentations included organic acid content, titratable acidity, pH, ethanol production, and sugar content. Since samples containing either sulfur dioxide level had similar sugar utilization rates and ethanol production it was concluded that sulfur dioxide had no effect on the primary fermentation. Sulfur dioxide content was shown to have an impact on MLF. There was no difference in the rate of malic acid consumption, but lactic acid production was faster in the 50-ppm sulfur dioxide samples. MLF was not inhibited by ethanol content.
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Bebidas Alcohólicas/análisis , Fermentación , Malus , Etanol/análisis , Manipulación de Alimentos/métodos , Concentración de Iones de Hidrógeno , Malatos/química , Malus/clasificación , Dióxido de Azufre , Factores de TiempoRESUMEN
Toxicokinetic data have traditionally been presented as maximum observed plasma concentrations (C(max)) and area under the concentration time curve (AUC) values. These values have been used to compare exposures across studies and species to provide valuable interpretation of drug safety data. Increasingly, questions are asked of toxicology studies to more accurately describe the concentration effect relationships in terms of compound affinity for target and off-target receptors. C(max) values can immediately be referenced to known pharmacological activities, particularly when the extent of plasma protein binding is taken into account. This provides a measure of the more pharmacologically relevant free drug exposure. AUC values on the other hand contain the component of time, which means that direct comparison to pharmacological activity values are not immediately possible. Conversion of AUC to average plasma concentration (C(av)) provides a simple and convenient means to allow such a comparison without losing any information imparted by AUC values. In this paper, the benefit and advantage of applying C(av) values is illustrated using examples taken from the literature.
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Seguridad de Productos para el Consumidor , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Farmacocinética , Pruebas de Toxicidad/métodos , Animales , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Humanos , Preparaciones Farmacéuticas/administración & dosificación , Factores de TiempoRESUMEN
OBJECTIVE: Eosinophilic oesophagitis (EoO) is a clinicopathological condition defined by proton pump inhibitor-refractory oesophageal symptoms combined with oesophageal eosinophilia. The pharmacodynamic effect of mepolizumab (a humanised anti-interleukin-5 monoclonal antibody) in EoO was evaluated. METHODS: Eleven adults with active EoO (>20 peak eosinophil number/high power field (hpf) and dysphagia) were randomised to 750 mg of mepolizumab (n = 5) or placebo (n = 6) and received two intravenous infusions, 1 week apart. Those not in complete remission (<5 peak eosinophil number/hpf) after 8 weeks received two further doses 4 weeks apart, 1500 mg of mepolizumab or placebo. The effect of mepolizumab was assessed clinically, endoscopically, histologically, and via blood and tissue biomarkers. RESULTS: As assessed by immunofluorescence, a marked reduction of mean oesophageal eosinophilia (p = 0.03) was seen in the mepolizumab group (-54%) compared with the placebo group (-5%) 4 weeks after initiation of treatment. No further reduction of eosinophil numbers was observed in response to the two additional infusions in either group. Mepolizumab reduced tenascin C (p = 0.033) and transforming growth factor beta1 (p = 0.05) expression in the oesophageal epithelial layer 13 weeks after initiation of treatment. Clinically, limited improvement of symptoms was seen, although a trend was seen between 4 and 13 weeks after initiation of mepolizumab treatment. Mepolizumab was well tolerated. CONCLUSIONS: Mepolizumab significantly reduced eosinophil numbers in oesophageal tissues in adult patients with active EoO, and changes in the expression of molecules associated with oesophageal remodelling were reversed. Minimal clinical improvement was achieved in a subgroup of patients with EoO. Mepolizumab had an acceptable safety profile, even at the high 1500 mg dose level. TRIAL REGISTRATION NUMBER: NCT00274703.
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Anticuerpos Monoclonales/uso terapéutico , Eosinofilia/tratamiento farmacológico , Esofagitis/tratamiento farmacológico , Interleucina-5/inmunología , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Trastornos de Deglución/tratamiento farmacológico , Trastornos de Deglución/etiología , Método Doble Ciego , Esquema de Medicación , Neurotoxina Derivada del Eosinófilo/metabolismo , Eosinofilia/sangre , Eosinofilia/complicaciones , Eosinofilia/inmunología , Eosinófilos/patología , Esofagitis/sangre , Esofagitis/complicaciones , Esofagitis/inmunología , Esofagoscopía , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Recuento de Leucocitos , Masculino , Resultado del TratamientoRESUMEN
Drugs are generally converted to biologically inactive forms and eliminated from the body, principally by hepatic metabolism. However, certain drugs undergo biotransformation to metabolites that can interfere with cellular functions through their intrinsic chemical reactivity towards glutathione, leading to thiol depletion, and functionally critical macromolecules, resulting in reversible modification, irreversible adduct formation, and irreversible loss of activity. There is now a great deal of evidence which shows that reactive metabolites are formed from drugs known to cause hepatotoxicity, such as acetaminophen, tamoxifen, isoniazid, and amodiaquine. The main theme of this article is to review the evidence for chemically reactive metabolites being initiating factors for the multiple downstream biological events culminating in toxicity. The major objectives are to understand those idiosyncratic hepatotoxicities thought to be caused by chemically reactive metabolites and to define the role of toxic metabolites.
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Transformación Celular Neoplásica/inducido químicamente , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Radicales Libres/metabolismo , Neoplasias Hepáticas/inducido químicamente , Hígado/efectos de los fármacos , Animales , Biotransformación , Transformación Celular Neoplásica/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Hígado/metabolismo , Neoplasias Hepáticas/metabolismo , Medición de Riesgo , Transducción de Señal/efectos de los fármacosRESUMEN
Most striated muscles generate steady contractile tension when activated, but some preparations, notably cardiac myocytes and slow-twitch fibers, may show spontaneous oscillatory contractions (SPOC) at low levels of activation. We have provided what we believe is new evidence that SPOC is a property of the contractile system at low actin-myosin affinity, whether caused by a thin-filament regulatory system or by other means. We present a quantitative single-sarcomere model for isotonic SPOC in skeletal muscle with three basic ingredients: i), actin and myosin filaments initially in partial overlap, ii), stretch activation by length-dependent changes in the lattice spacing, and iii), viscoelastic passive tension. Modeling examples are given for slow-twitch and fast-twitch fibers, with periods of 10 s and 4 s respectively. Isotonic SPOC occurs in a narrow domain of parameter values, with small minimum and maximum values for actin-myosin affinity, a minimum amount of passive tension, and a maximum transient response rate that explains why SPOC is favored in slow-twitch fibers. The model also predicts the contractile, relaxed and SPOC phases as a function of phosphate and ADP levels. The single-sarcomere model can also be applied to a whole fiber under auxotonic and fixed-end conditions if the remaining sarcomeres are treated as a viscoelastic load. Here the model predicts an upper limit for the load stiffness that leads to SPOC; this limit lies above the equivalent loads expected from the rest of the fiber.
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Modelos Biológicos , Contracción Muscular , Músculo Esquelético/fisiología , Periodicidad , Actinas/metabolismo , Algoritmos , Animales , Elasticidad , Fibras Musculares de Contracción Rápida/fisiología , Fibras Musculares de Contracción Lenta/fisiología , Miosinas/metabolismo , Ratas , Sarcómeros/fisiología , Factores de Tiempo , Sustancias ViscoelásticasRESUMEN
OBJECTIVE: The aims of this study were to investigate the bioequivalence of a new oral topotecan formulation (i.e., proposed commercial formulation) relative to the current oral formulation (formulation used in previous clinical trials), the effect of food on the absorption and disposition of the new oral topotecan and its safety and tolerability in patients with advanced solid tumors. PATIENTS AND METHODS: This was a multi-center, pharmacological Phase I, multiple-dose, randomized, open-label, cross-over bioequivalence study. In the bioequivalence part, 85 patients were randomized to receive either a 4 mg (4 x 1 mg) dose of the new or current formulation on Days 1 or 8. In the food-effect part, 23 patients received a 4 mg (4 x 1 mg) dose of the new formulation in a fasted and fed state. Total topotecan and topotecan lactone were determined and pharmacokinetic data were analyzed by non-compartmental method. RESULTS: Bioequivalence was demonstrated as the 90% confidence intervals of the ratio of the new to current formulation for both the area under the plasma concentration-time curve (AUC) and the maximal drug concentration (Cmax) for topotecan lactone were contained within the 0.8 - 1.25 boundary. The AUC and Cmax were similar in the fed and fasted state whilst food delayed the tmax for topotecan lactone and total topotecan. Safety data were collected on all subjects enrolled (n = 108) and were consistent with observations from previous studies of oral topotecan. All subjects experienced at least one adverse event, the majority of which were graded as mild to moderate in severity. CONCLUSION: The new oral topotecan formulation demonstrated bioequivalence to the current formulation and demonstrated it can be administered to patients with solid tumors in the fed or fasted state with similar systemic exposure.
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Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Topotecan/farmacocinética , Topotecan/uso terapéutico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Esquema de Medicación , Ayuno , Femenino , Interacciones Alimento-Droga , Humanos , Absorción Intestinal , Masculino , Persona de Mediana Edad , Equivalencia Terapéutica , Topotecan/efectos adversosRESUMEN
The clinical pharmacokinetics and in vitro inhibition of digoxin were examined to predict the P-glycoprotein (P-gp) component of drug-drug interactions. Coadministered drugs (co-meds) in clinical trials (N = 123) resulted in a small,
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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 , Digoxina/metabolismo , Amiodarona/metabolismo , Amiodarona/farmacología , Células CACO-2 , Digoxina/farmacología , Interacciones Farmacológicas , Humanos , Preparaciones Farmacéuticas/metabolismo , Estudios RetrospectivosRESUMEN
Lymphoma is a common tumor in ferrets, but anatomic distribution, histomorphology, immunophenotype, laboratory abnormalities, and response to chemotherapy are incompletely defined. In this study, lymphoma was diagnosed by histopathology of tumor tissue in 29 ferrets ranging in age from 0.8 to 8.5 years, including 12 males and 17 females. Tumors involved the viscera of the abdominal cavity (n = 11), thoracic cavity (n = 1), or abdominal and thoracic cavities (n = 7); the skin (n = 2); or the viscera of both body cavities plus other sites (n = 8). Microscopically, all tumors had diffuse architecture. Assessment by histomorphology and immunophenotype classified tumors as peripheral T-cell lymphoma (n = 17), anaplastic large T-cell lymphoma (n = 5), anaplastic large B-cell lymphoma (n = 4), diffuse large B-cell lymphoma (n = 1), and Hodgkin-like lymphoma (n = 2). Cytologic evaluation of tumor tissue was diagnostic in 11 of 13 cases. Twenty-two of 27 ferrets had anemia, 2 had leukemia, and 5 were neutropenic. Common comorbid disorders were adrenal disease (n = 27) and insulinoma (n = 6). Tumors most frequently involved mesenteric lymph nodes, while enlargement of peripheral lymph nodes was uncommon (n = 3). Ferrets with Hodgkin-like lymphoma had massive enlargement of single lymph nodes. Mean survival of ferrets not immediately euthanized was 5.0 months (T-cell lymphoma) and 8.4 months (B-cell lymphoma). Ferrets treated with chemotherapy survived an average of 4.3 months (T-cell lymphoma, n = 9) or 8.8 months (B-cell lymphoma, n = 4). Results indicate that lymphomas in ferrets most commonly affect abdominal viscera, may be amenable to cytologic diagnosis, are frequently associated with anemia and, in some cases, may be chemosensitive, resulting in relatively long survival times.