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Alkaptonuria is a rare disorder of tyrosine catabolism caused by deficiency of homogentisate 1,2-dioxygenase that leads to accumulation of homogentisic acid (HGA). Deposition of HGA-derived polymers in connective tissue causes progressive arthropathy of the spine and large joints, cardiac valvular disease, and genitourinary stones beginning in the fourth decade of life. Nitisinone, a potent inhibitor of the upstream enzyme, 4-hydroxyphenylpyruvate dioxygenase, dramatically reduces HGA production. As such, nitisinone is a proposed treatment for alkaptonuria. A randomized clinical trial of nitisinone in alkaptonuria confirmed the biochemical efficacy and tolerability of nitisinone for patients with alkaptonuria but the selected primary outcome did not demonstrate significant clinical benefit. Given that alkaptonuria is a rare disease with slow progression and variable presentation, identifying outcome parameters that can detect significant change during a time-limited clinical trial is challenging. To gain insight into patient-perceived improvements in quality of life and corresponding changes in physical function associated with nitisinone use, we conducted a post-hoc per protocol analysis of patient-reported outcomes and a functional assessment. Analysis revealed that nitisinone-treated patients showed significant improvements in complementary domains of the 36-Item Short-Form Survey (SF-36) and 6-min walk test (6MWT). Together, these findings suggest that nitisinone improves both quality of life and function of patients with alkaptonuria. The observed trends support nitisinone as a therapy for alkaptonuria.
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Our article "Fingolimod: Assay analysis of US generic capsule products reveals variation in fingolimod content beyond the recommended acceptance criteria" highlighted the variation of active ingredient in generic fingolimod capsule products. This analysis was prompted by reports of clinical adverse events and/or multiple sclerosis relapse in patients following transition from Gilenya® fingolimod capsules (Novartis) to generic fingolimod capsule products. Further assay analysis functioned to both confirm previous out-of-specification findings, and to identify an additional generic product that failed to comply with United States Pharmacopeia (USP) recommendations.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Cloridrato de Fingolimode/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/induzido quimicamente , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/induzido quimicamenteRESUMO
The immunomodulating agent fingolimod is a sphingosine-1-phosphate receptor modulator used in the treatment of multiple sclerosis (MS). We analyzed three FDA approved fingolimod 0.5 mg generic capsule products for fingolimod content. Assay results demonstrated a wide variation in fingolimod content between manufacturers, with one product demonstrating a fingolimod content of 76.8 % of the approved dose. This falls significantly below the FDA acceptance criteria of 90.0-110.0 % of label claim.
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Cloridrato de Fingolimode , Esclerose Múltipla , Humanos , Cloridrato de Fingolimode/uso terapêutico , Imunossupressores/uso terapêutico , Esfingosina , Esclerose Múltipla/tratamento farmacológico , Fatores Imunológicos/uso terapêuticoRESUMO
Use of nicotine-specific monoclonal antibodies (mAbs) to sequester and reduce nicotine distribution to brain has been proposed as a therapeutic approach to treat nicotine addiction (the basis of tobacco use disorder). A series of monoclonal antibodies with high affinity for nicotine (nicâ¢mAbs) was isolated from B-cells of vaccinated smokers. Genes encoding 32 unique nicotine binding antibodies were cloned, and the mAbs expressed and tested by surface plasmon resonance to determine their affinity for S-(-)-nicotine. The highest affinity nicâ¢mAbs had binding affinity constants (KD) between 5 and 67 nM. The 4 highest affinity nicâ¢mAbs were selected to undergo additional secondary screening for antigen-specificity, protein properties (including aggregation and stability), and functional in vivo studies to evaluate their capacity for reducing nicotine distribution to brain in rats. The 2 most potent nicâ¢mAbs in single-dose nicotine pharmacokinetic experiments were further tested in a dose-response in vivo study. The most potent lead, ATI-1013, was selected as the lead candidate based on the results of these studies. Pretreatment with 40 and 80 mg/kg ATI-1013 reduced brain nicotine levels by 56 and 95%, respectively, in a repeated nicotine dosing experiment simulating very heavy smoking. Nicotine self-administration was also significantly reduced in rats treated with ATI-1013. A pilot rat 30-day repeat-dose toxicology study (4x200mg/kg ATI-1013) in the presence of nicotine indicated no drug-related safety concerns. These data provide evidence that ATI-1013 could be a potential therapy for the treatment of nicotine addiction.
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Anticorpos Monoclonais , Afinidade de Anticorpos , Encéfalo/metabolismo , Nicotina , Tabagismo , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Complexo Antígeno-Anticorpo/química , Humanos , Nicotina/química , Nicotina/farmacocinética , Ratos , Ratos Sprague-Dawley , Tabagismo/tratamento farmacológico , Tabagismo/metabolismoRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy with very limited treatment options. Antibody drug conjugates (ADCs) are promising cytotoxic agents capable of highly selective delivery. Aspartate-ß-hydroxylase (ASPH) is a type II transmembrane protein highly expressed in PDACs (97.1%) but not normal pancreas. We investigated anti-tumor effects of an ADC guided by a human monoclonal antibody (SNS-622) against ASPH in human PDAC cell lines and derived subcutaneous (s.c.) xenograft as well as a patient-derived xenograft (PDX) murine model with spontaneous pulmonary metastasis. The cytotoxic effects exhibited by several candidate payloads linked to SNS-622 antibody targeting ASPH+ PDACs were analyzed. After i.v. administration of SNS-622-emtansine (DM1) ADC, the primary PDAC tumor growth and progression (number and size of pulmonary metastases) were determined. The PDAC cell lines, s.c. and PDX tumors treated with ADC were tested for cell proliferation, cytotoxicity and apoptosis by MTS and immunohistochemistry (IHC) assays. SNS-622-DM1 construct has demonstrated optimal anti-tumor effects in vitro. In the PDX model of human PDAC, SNS-622-DM1 ADC exerted substantially inhibitory effects on tumor growth and pulmonary metastasis through attenuating proliferation and promoting apoptosis.
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Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Carcinoma Ductal Pancreático/tratamento farmacológico , Imunoconjugados/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Proteínas de Membrana/antagonistas & inibidores , Oxigenases de Função Mista/antagonistas & inibidores , Proteínas Musculares/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Administração Intravenosa , Animais , Carcinoma Ductal Pancreático/enzimologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoconjugados/farmacologia , Neoplasias Pulmonares/enzimologia , Camundongos , Neoplasias Pancreáticas/enzimologia , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a difficult to treat tumor with a poor prognosis. Aspartate ß-hydroxylase (ASPH) is a highly conserved enzyme overexpressed on the cell surface of both murine and human HCC cells. METHODS: We evaluated therapeutic effects of nanoparticle lambda (λ) phage vaccine constructs against ASPH expressing murine liver tumors. Mice were immunized before and after subcutaneous implantation of a syngeneic BNL HCC cell line. Antitumor actively was assessed by generation of antigen specific cellular immune responses and the identification of tumor infiltrating lymphocytes. RESULTS: Prophylactic and therapeutic immunization significantly delayed HCC growth and progression. ASPH-antigen specific CD4+ and CD8+ lymphocytes were identified in the spleen of tumor bearing mice and cytotoxicity was directed against ASPH expressing BNL HCC cells. Furthermore, vaccination generated antigen specific Th1 and Th2 cytokine secretion by immune cells. There was widespread necrosis with infiltration of CD3+ and CD8+ T cells in HCC tumors of λ phage vaccinated mice compared to controls. Moreover, further confirmation of anti-tumor effects on ASPH expressing tumor cell growth were obtained in another murine syngeneic vaccine model with pulmonary metastases. CONCLUSIONS: These observations suggest that ASPH may serve as a highly antigenic target for immunotherapy.
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Objective. To create a learning environment using Bloom's affective domain as a framework that would reduce third-year pharmacy students' stigmatizing attitudes toward patients with mental illness. Design. Prior to the start of the module, students were asked to complete the 27-question Attribution Questionnaire Short Form (AQ-27). The teaching approach and in-class activities were designed to allow students' to experience the major categories within Bloom's affective domain. The module used patient cases, interactive-learning activities, and reflective discussions to augment pharmacological and therapeutic knowledge with a humanistic understanding of mental illness. Students were asked to retake the AQ-27 after completing the module. Assessment. Paired responses on the AQ-27 were reported for 74 of 104 students, which represents a response rate of 71.2%. Students' scores changed significantly on nine of the 27 questions. Students' attitudes pre- to post-module revealed a significant increase in the help construct, while there was a significant decrease in the dangerousness and fear constructs. Conclusion. Designing and implementing a course along the continuum of Bloom's affective domain resulted in appropriate changes in students' attitudes toward patients with mental illness.
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Atitude do Pessoal de Saúde , Educação em Farmácia/métodos , Transtornos Mentais/psicologia , Estereotipagem , Estudantes de Farmácia/psicologia , Humanos , Inquéritos e QuestionáriosRESUMO
This comment reflects on the recent row over Woodrow Wilson's legacy, which has focussed on his undeniable racism. This was in pursuit of a 'Progressive' agenda which paved the way for the United States to become the geopolitical force that it continues to be today. Without necessarily approving of Wilson's particular judgements, I argue that he operated with a 'world-historic' sense of morality characteristic of Realpolitik, a perspective which might be worth considering by those who believe that modern preoccupations with 'race', 'class' and 'gender' will remain part of the sociological firmament indefinitely.á .
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Methylglyoxal (2-oxopropanal) is a compound known to contribute to the non-peroxide antimicrobial activity of honeys. The feasibility of using infrared spectroscopy as a predictive tool for honey antibacterial activity and methylglyoxal content was assessed. A linear relationship was found between methylglyoxal content (279-1755 mg/kg) in Leptospermum polygalifolium honeys and bacterial inhibition for Escherichiacoli (R(2) = 0.80) and Staphylococcusaureus (R(2) = 0.64). A good prediction of methylglyoxal (R(2) 0.75) content in honey was achieved using spectroscopic data from the mid infrared (MIR) range in combination with partial least squares regression. These results indicate that robust predictive equations could be developed using MIR for commercial application where the prediction of bacterial inhibition is needed to 'value' honeys with methylglyoxal contents in excess of 200mg/kg.
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Antibacterianos/farmacologia , Mel/análise , Aldeído Pirúvico/análise , Austrália , Aldeído Pirúvico/farmacologia , Espectrofotometria InfravermelhoRESUMO
This essay introduces a Focus section on "Neurohistory and History of Science" by distinguishing images of the brain as governor and as transducer: the former treat the brain as the executive control center of the body, the latter as an interface between the organism and reality at large. Most of the consternation expressed in the symposium about the advent of neurohistory derives from the brain-as-governor conception, which is rooted in a "biologistic" understanding of humanity that in recent years has become bound up in various nefarious "neoliberal" political and economic agendas. However, given the sophisticated attitude that neurohistory's leading champion, Daniel Smail, displays toward evolutionary theory's potential impact on historical practice, he is perhaps better understood as part of the brain-as-transducer tradition. This tradition, largely suppressed in current representations of neuroscience, has a strong theological provenance, ultimately concerned with our becoming attuned to the divine frequency, not least by extending the powers of the human nervous system through technology. This essay sympathetically explores the implications of this perspective for historical practice.
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Encéfalo , Neurociências/história , Ciência/história , Evolução Biológica , História do Século XVIII , História do Século XIX , Humanos , Neurociências/métodos , Filosofia , Ciência/métodosAssuntos
Ciência/história , Historiografia , História do Século XXI , Humanos , Ciência/educação , UniversidadesAssuntos
Grupos Raciais , Religião e Ciência , Meio Social , Tabu , Eugenia (Ciência)/tendências , Humanos , PreconceitoRESUMO
An analytical method for the measurement of five naturally occurring bromophenols of sensory relevance in seafood (barramundi and prawns) is presented. The method combines simultaneous distillation-extraction followed by alkaline back extraction of a hexane extract and subsequent acetylation of the bromophenols. Analysis of the bromophenol acetates was accomplished by headspace solid phase microextraction and gas chromatography-mass spectrometry using selected ion monitoring. The addition of (13)C 6 bromophenol stable isotope internal standards for each of the five congeners studied permitted the accurate quantitation of 2-bromophenol, 4-bromophenol, 2,6-dibromophenol, 2,4-dibromophenol, and 2,4,6-tribromophenol down to a limit of quantification of 0.05 ng/g of fish flesh. The method indicated acceptable precision and repeatability and excellent linearity over the typical concentration range of these compounds in seafood (0.5-50 ng/g). The analytical method was applied to determine the concentration of bromophenols in a range of farmed and wild barramundi and prawns and was also used to monitor bromophenol uptake in a pilot feeding trial.
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Fenóis/análise , Alimentos Marinhos/análise , Isótopos de Carbono , Cromatografia Gasosa-Espectrometria de Massas , Técnicas de Diluição do Indicador , PaladarRESUMO
StaphVAX, an unadjuvanted, bivalent vaccine composed of Staphylococcus aureus (S. aureus) capsular polysaccharides (CPS) types 5 and 8 bound to the mutant non-toxic recombinant Pseudomonas aeruginosa exotoxin A (rEPA) conferred approximately 60% protection for 10 months against bacteremia caused by this pathogen in hemodialysis patients. A protective level of 80 microg/ml was estimated based upon geometric mean (GM) antibody levels at the end of the efficacy period. To extend the duration of protection conferred by StaphVAX in hemodialysis patients, recipients of the vaccine were reinjected in a randomized double-blinded, placebo-controlled study. Vaccinees received StaphVAX and a saline placebo injection 14 days apart according to the randomization schedule. The booster dose of StaphVAX was administered an average of 958 days (753-1167 days) after the first injection. There were no serious adverse reactions. Antibody levels at day 14, 28, 92, and 182 post-injection were measured by ELISA. Maximal levels of IgG anti-CPS were observed at the 28-day interval. For type 5, GM antibody levels increased from 73 microg/ml at day 0 to 162 microg/ml (P < 0.001) and for type 8 from 59 microg/ml to 133 microg/ml (P < 0.001). Anti-CPS antibody levels of approximately 80 microg/ml to type 5 and type 8 were achieved in 72.4 and 74.3% of vaccinees, respectively. There was excellent correlation between the level of anti-CPS and opsonic titer (r = 0.93). Moreover, the decline of anti-CPS antibody levels at six months was significantly less rapid than that observed from the first immunization (P < 0.001). We conclude that a booster immunization to maintain protective levels of specific antibodies for an extended period of time is feasible for patients at continuous risk for S. aureus bacteremia.
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Imunização Secundária/efeitos adversos , Diálise Renal , Infecções Estafilocócicas/prevenção & controle , Vacinas Antiestafilocócicas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antibacterianos/sangue , Cápsulas Bacterianas/imunologia , Estudos Cross-Over , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Proteínas Opsonizantes/análise , Placebos , Polissacarídeos Bacterianos/imunologia , Insuficiência Renal/terapia , Vacinas Antiestafilocócicas/efeitos adversos , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/efeitos adversosRESUMO
Staphylococcus aureus is the most common nosocomial pathogen and is responsible for approximately one-third of hospital-acquired bacteremias. The emergence of strains with multidrug resistance, including resistance to vancomycin, the antibiotic of last resort, presents the medical community with a major public health problem. Alternative therapies, including immunotherapy, have been in development for several decades. The discovery of S. aureus capsular polysaccharides from clinical isolates, and their importance to pathogenicity via antiphagocytic activity, opened a new window of opportunity for development of vaccines and immunotherapy against this pathogen. A conjugate vaccine, StaphVAX that includes the two most prevalent capsular polysaccharides, types 5 and 8, coupled to a carrier protein efficient in promoting a Th2 response, was developed. In a recent phase III clinical study in hemodialysis patients, StaphVAX was shown to prevent S. aureus bacteremia for up to 10 months following a single immunization. The history, epidemiology, serology, and development of StaphVAX, including preclinical and clinical studies demonstrating efficacy are described in this review.
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Infecções Estafilocócicas/prevenção & controle , Vacinas Antiestafilocócicas/uso terapêutico , Animais , Ensaios Clínicos Fase III como Assunto , Humanos , Infecções Estafilocócicas/imunologia , Vacinas Antiestafilocócicas/imunologia , Vacinas ConjugadasRESUMO
BACKGROUND: In patients with decreased resistance to infection, Staphylococcus aureus is a major cause of bacteremia and its complications. The capsular polysaccharides are essential for the pathogenesis of and immunity to S. aureus infection and are targets for vaccines. METHODS: In a double-blind trial involving patients with end-stage renal disease who were receiving hemodialysis, we evaluated the safety, immunogenicity, and efficacy of a vaccine with S. aureus type 5 and 8 capsular polysaccharides conjugated to nontoxic recombinant Pseudomonas aeruginosa exotoxin A. Between April 1998 and August 1999, 1804 adult patients at 73 hemodialysis centers were randomly assigned to receive a single intramuscular injection of either vaccine or saline. IgG antibodies to S. aureus type 5 and 8 capsular polysaccharides were measured for up to two years, and episodes of S. aureus bacteremia were recorded. Efficacy was estimated by comparing the incidence of S. aureus bacteremia in the patients who received the vaccine with the incidence in the control patients. RESULTS: Reactions to the vaccine were generally mild to moderate, and most resolved within two days. The capsular polysaccharides elicited an antibody response of at least 80 microg per milliliter (the estimated minimal level conferring protection) in 80 percent of patients for type 5 and in 75 percent of patients for type 8. The efficacy during weeks 3 to 54 was only 26 percent (P=0.23). However, between weeks 3 and 40 after vaccination, S. aureus bacteremia developed in 11 of 892 patients in the vaccine group who could be evaluated for bacteremia, as compared with 26 of 906 patients in the control group (estimate of efficacy, 57 percent; 95 percent confidence interval, 10 to 81 percent; nominal P=0.02). CONCLUSIONS: In patients receiving hemodialysis, a conjugate vaccine can confer partial immunity against S. aureus bacteremia for approximately 40 weeks, after which protection wanes as antibody levels decrease.