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The cutting or splitting of pills can be used by patients to create an intermediate dose or to save money in situations where a higher dose is priced at relatively the same cost as a lower dose. A number of studies of selected medications have concluded that pill splitting in general can be done without adverse effects, with the exception of enteric-coated medications and extended-release medications. Individual patients should be assessed for evidence of patient understanding, as well as the physical abilities for pill splitting. Here, we present the case of a patient whose lack of understanding and inability to organize the pill-splitting process led to poor control of her hypertension, resulting in an emergency department (ED) evaluation.
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Objetivo: avaliar a qualidade de vida (QV) de estudantes universitários durante a pandemia da COVID-19 em Santa Catarina, Brasil. Método: estudo observacional transversal com abordagem quantitativa, realizado entre junho e dezembro de 2021 em uma universidade particular de Santa Catarina, Brasil. Foi utilizado um questionário sociodemográfico e WHOQOL-bref. Resultados: dentre os 310 estudantes avaliados, a maioria era do sexo feminino (80,1%), branca (89,7%) e solteira (81,9%). Os domínios físico e psicológico foram afetados significativamente (p < 0,001) quando comparados aos demais domínios. Estudantes do período noturno e vespertino foram mais afetados quando comparados ao período integral nos domínios relações sociais (p = 0,047), meio ambiente (p < 0,001) e geral (p = 0,023). Sofreram maior impacto psicológico, aqueles que residiam com crianças e idosos quando comparados aos que residiam apenas com idosos (p = 0,023). Conclusão: a pandemia da COVID-19 afetou significativamente a QV dos estudantes analisados. Os impactos negativos nos estudantes foram observados conforme o período de estudo e perfil sociodemográfico.
Objective: to assess university students' quality of life (QL) during the COVID-19 pandemic. Method: this is a observational cross-sectional survey with a quantitative approach carried out between June and December 2021 at a private university in Santa Catarina, Brazil, through an online form. A sociodemographic test and WHOQOL-bref were used for QoL analysis. Results: among the 310 evaluated students, 80.1% were female, 89.7% were white and 81.9% were single. The physical and psychological domains were significantly affected (p < 0.001). Night-time and afternoon-time students were more affected when compared to full-time students in the social relationships (p = 0.047), environment (p<0.001) and general (p = 0.023) domains. Moreover, students who lived with children and the elderly suffered a more significant psychological impact when compared to those who lived only with the elderly (p = 0.023). Conclusion: the COVID-19 pandemic significantly affected the QL of academics, mainly in the Physical and Psychological domains. Moreover, negative effects on students were observed according to the period of study and sociodemographic profile.
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Aislamiento Social , Estudiantes , Salud Mental , Educación a Distancia , COVID-19RESUMEN
Melioidosis is an endemic disease in numerous tropical regions. Additionally, the bacterium that causes melioidosis, Burkholderia pseudomallei, has potential to be used as a biological weapon. Therefore, development of effective and affordable medical countermeasures to serve regions affected by the disease and to have medical countermeasures available in the event of a bioterrorism attack remains critical. The current study evaluated the efficacy of eight distinct acute phase ceftazidime treatment regimens administered therapeutically in the murine model. At the conclusion of the treatment period, survival rates were significantly greater in several of the treated groups when compared to the control group. Pharmacokinetics of a single dose of ceftazidime were examined at 150 mg/kg, 300 mg/kg, and 600 mg/kg and were compared to an intravenous clinical dose administered at 2000 mg every eight hours. The clinical dose has an estimated 100% fT > 4*MIC which exceeded the highest murine dose of 300 mg/kg every six hours at 87.2% fT > 4*MIC. Based upon survival at the end of the treatment regimen and supplemented by pharmacokinetic modeling, a daily dose of 1200 mg/kg of ceftazidime, administered every 6 h at 300 mg/kg, provides protection in the acute phase of inhalation melioidosis in the murine model.
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Burkholderia pseudomallei , Melioidosis , Animales , Ratones , Ceftazidima/farmacología , Melioidosis/microbiología , Modelos Animales de Enfermedad , Aerosoles/farmacología , Antibacterianos/farmacologíaRESUMEN
To meet the requirements of the Animal Rule, the efficacy of monotherapy with ANTHRASIL® (Anthrax Immune Globulin Intravenous (Human)) for inhalational anthrax was evaluated in blinded studies using rabbit and nonhuman primate models. Animals in both studies were randomized to treatment groups exposed to ~ 200 LD50 Bacillus anthracis (Ames strain) spores by the aerosol route to induce inhalational anthrax. Rabbits (N = 50/group) were treated with either 15 U/kg ANTHRASIL or a volume-matching dose of IGIV after disease onset as determined by the detection of bacterial toxin in the blood. At the end of the study, survival rates were 2% (1 of 48) in the IGIV control group, and 26% (13 of 50) in the ANTHRASIL-treated group (p = 0.0009). Similarly, ANTHRASIL was effective in cynomolgus monkeys (N = 16/group) when administered therapeutically after the onset of toxemia, with 6% survival in the IGIV control and a dose-related increase in survival of 36%, 43%, and 70% with 7.5, 15 or 30 U/kg doses of ANTHRASIL, respectively. These studies formed the basis for approval of ANTHRASIL by FDA under the Animal Rule.
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Carbunco , Bacillus anthracis , Animales , Humanos , Conejos , Carbunco/microbiología , Inmunoglobulina G/farmacología , Primates , Modelos Animales de Enfermedad , Antígenos BacterianosRESUMEN
Non-human primate (NHP) efficacy data for several Ebola virus (EBOV) vaccine candidates exist, but definitive correlates of protection (CoP) have not been demonstrated, although antibodies to the filovirus glycoprotein (GP) antigen and other immunological endpoints have been proposed as potential CoPs. Accordingly, studies that could elucidate biomarker(s) that statistically correlate, whether mechanistically or not, with protection are warranted. The primary objective of this study was to evaluate potential CoP for Novavax EBOV GP vaccine candidate administered at different doses to cynomolgus macaques using the combined data from two separate, related studies containing a total of 44 cynomolgus macaques. Neutralizing antibodies measured by pseudovirion neutralization assay (PsVNA) and anti-GP IgG binding antibodies were evaluated as potential CoP using logistic regression models. The predictive ability of these models was assessed using the area under the receiver operating characteristic (ROC) curve (AUC). Fitted models indicated a statistically significant relationship between survival and log base 10 (log10) transformed anti-GP IgG antibodies, with good predictive ability of the model. Neither (log10 transformed) PsVNT50 nor PsVNT80 titers were statistically significant predictors of survival, though predictive ability of both models was good. Predictive ability was not statistically different between any pair of models. Models that included immunization dose in addition to anti-GP IgG antibodies failed to detect statistically significant effects of immunization dose. These results support anti-GP IgG antibodies as a correlate of protection. Total assay variabilities and geometric coefficients of variation (GCVs) based on the study data appeared to be greater for both PsVNA readouts, suggesting the increased assay variability may account for non-significant model results for PsVNA despite the good predictive ability of the models. The statistical approach to evaluating CoP for this EBOV vaccine may prove useful for advancing research for Sudan virus (SUDV) and Marburg virus (MARV) candidate vaccines.
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Inhalational anthrax is a fatal infectious disease. Rapid and effective treatment is critically dependent on early and accurate diagnosis. Blood culture followed by identification and confirmation may take days to provide clinically relevant information. In contrast, immunoassay for a shed antigen, the capsular polypeptide gamma-d-polyglutamate (γDPGA), can provide rapid results at the point of care. In this study, a lateral flow immunoassay for γDPGA was evaluated in a robust nonhuman primate model of inhalational anthrax. The results showed that the time to a positive result with the rapid test using either serum or blood as a clinical specimen was similar to the time after infection when a blood culture became positive. In vitro testing showed that the test was equally sensitive with cultures of the three major clades of Bacillus anthracis. Cultures from other Bacillus spp. that are known to produce γDPGA also produced positive results. The test was negative with human sera from 200 normal subjects and 45 subjects with culture-confirmed nonanthrax bacterial or fungal sepsis. Taken together, the results showed that immunoassay for γDPGA is an effective surrogate for blood culture in a relevant cynomolgus monkey model of inhalational anthrax. The test would be a valuable aid in early diagnosis of anthrax, which is critical for rapid intervention and a positive outcome. Use of the test could facilitate triage of patients with signs and symptoms of anthrax in a mass-exposure incident and in low-resource settings where laboratory resources are not readily available. IMPORTANCE Patient outcome in anthrax is critically dependent on early diagnosis followed by effective treatment. We describe a rapid lateral flow immunoassay that detects capsular antigen of Bacillus anthracis that is shed into blood during infection. The test was evaluated in a robust cynomolgus monkey model of inhalational anthrax. Rapid detection of capsular antigen is an effective surrogate for the time-consuming and laboratory-intensive diagnosis by blood culture, direct fluorescent antibody staining, or other molecular testing. The test can be performed at the point of patient contact, is rapid and inexpensive, and can be used by individuals with minimal training.
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Carbunco , Bacillus anthracis , Animales , Carbunco/diagnóstico , Antígenos Bacterianos , Humanos , Inmunoensayo/métodos , Macaca fascicularis , Infecciones del Sistema RespiratorioRESUMEN
Bacillus anthracis and Yersinia pestis, causative pathogens for anthrax and plague, respectively, along with Burkholderia mallei and B. pseudomallei are potential bioterrorism threats. Tebipenem pivoxil hydrobromide (TBP HBr, formerly SPR994), is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) gram-negative pathogens, including quinolone-resistant and extended-spectrum-ß-lactamase-producing Enterobacterales. We evaluated the in vitro activity and in vivo efficacy of tebipenem against biothreat pathogens. Tebipenem was active in vitro against 30-strain diversity sets of B. anthracis, Y. pestis, B. mallei, and B. pseudomallei with minimum inhibitory concentration (MIC) values of 0.001 - 0.008 µg/ml for B. anthracis, ≤0.0005 - 0.03 µg/ml for Y. pestis, 0.25 - 1 µg/ml for B. mallei, and 1 - 4 µg/ml for B. pseudomallei In a B. anthracis murine model, all control animals died within 52 h post challenge. The survival rates in the groups treated with tebipenem were 75% and 73% when dosed at 12 h and 24 h post challenge, respectively. The survival rates in the positive control groups treated with ciprofloxacin were 75% and when dosed 12 h and 25% when dosed 24 h post challenge, respectively. Survival rates were significantly (p=0.0009) greater in tebipenem groups treated at 12 h and 24 h post challenge and in the ciprofloxacin group 12 h post-challenge vs. the vehicle-control group. For Y. pestis, survival rates for all animals in the tebipenem and ciprofloxacin groups were significantly (p<0.0001) greater than the vehicle-control group. These results support further development of tebipenem for treating biothreat pathogens.
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Anthrax lethal factor (LF) is a zinc-dependent endoprotease and a critical virulence factor for Bacillus anthracis, the causative agent of anthrax. The mass spectrometry (MS) method for total-LF quantification includes three steps; 1) LF specific antibody capture/concentration, 2) LF-specific hydrolysis of a peptide substrate, and 3) detection and quantification of LF-cleaved peptides by isotope-dilution MALDI-TOF/MS. Recombinant LF spiked plasma was used for calibration and quality control (QC) materials. Specificity was 100% from analysis of serum and plasma from 383 non-infected humans, 31 rabbits, and 24 rhesus macaques. Sensitivity was 100% from 32 human clinical anthrax cases including infections by inhalation, ingestion, cutaneous and injection exposures and experimental infections for 29 rabbits and 24 rhesus macaques with inhalation anthrax. Robustness evaluation included sample storage, serum and plasma, antimicrobial and antitoxin effects and long-term performance. Data from 100 independent runs gave detection limits 0.01 ng/mL (111 amol/mL) for the 4-h method and 0.0027 ng/mL (30 amol/mL) for an alternate 20-h method. QC precision ranged from 7.7 to 14.8% coefficient of variation and accuracy from 0.2 to 9.8% error. The validated LF MS method provides sensitive quantification of anthrax total-LF using a robust high throughput platform for early diagnosis and evaluation of therapeutics during an anthrax emergency.
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Carbunco/diagnóstico , Carbunco/tratamiento farmacológico , Antígenos Bacterianos/análisis , Bacillus anthracis/química , Toxinas Bacterianas/análisis , Animales , Antibacterianos/farmacología , Bacillus anthracis/efectos de los fármacos , Calibración , Humanos , Macaca mulatta , Control de Calidad , Conejos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
BACKGROUND: Chikungunya virus (CHIKV) is transmitted via mosquito bite and potentially by aerosol, causing chikungunya fever and arthritic disease in humans. There are currently no licensed vaccines or antiviral therapeutics to protect against CHIKV infection in humans. Animal models recapitulating human disease, especially for transmission by aerosol, are needed for licensure of such medical countermeasures. METHODS: Cynomolgus macaques (CMs) were challenged by intradermal (ID) inoculation or exposure to an aerosol containing CHIKV Ross strain at different target infectious doses (103-107 plaque forming units (PFU)). The clinical and virologic courses of disease were monitored up to 14 days post-exposure. RESULTS: ID infection of CMs led to overt clinical disease, detectable viremia, and increased blood markers of liver damage. Animals challenged by aerosol exhibited viremia and increased liver damage biomarkers with minimal observed clinical disease. All animals survived CHIKV challenge. CONCLUSIONS: We have described CHIKV infection in CMs following ID inoculation and, for the first time, infection by aerosol. Based on limited reported cases in the published literature, the aerosol model recapitulates the virologic findings of human infection via this route. The results of this study provide additional evidence for the potential use of CMs as a model for evaluating medical countermeasures against CHIKV.
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Aerosoles , Fiebre Chikungunya/patología , Fiebre Chikungunya/virología , Modelos Animales de Enfermedad , Animales , Femenino , Inyecciones Intradérmicas , Macaca fascicularis , MasculinoRESUMEN
Francisella tularensis is a potential bioterrorism agent that is highly infectious at very low doses. Diagnosis of tularemia by blood culture and nucleic acid-based diagnostic tests is insufficiently sensitive. Here, we demonstrate a highly sensitive F. tularensis assay that incorporates sample processing and detection into a single cartridge suitable for point-of-care detection. The assay limit of detection (LOD) and dynamic range were determined in a filter-based cartridge run on the GeneXpert system. F. tularensis DNA in buffer or CFU of F. tularensis was spiked into human or macaque blood. To simulate detection in human disease, the assay was tested on blood drawn from macaques infected with F. tularensis Schu S4 at daily intervals. Assay detection was compared to that with a conventional quantitative PCR (qPCR) assay and blood culture. The assay LOD was 0.1 genome equivalents (GE) per reaction and 10 CFU/ml F. tularensis in both human and macaque blood. In infected macaques, the assay detected F. tularensis on days 1 to 4 postinfection in 21%, 17%, 60%, and 83% of macaques, respectively, compared to conventional qPCR positivity rates of 0%, 0%, 30%, and 100% and CFU detection of blood culture at 0%, 0%, 0%, and 10% positive, respectively. Assay specificity was 100%. The new cartridge-based assay can rapidly detect F. tularensis in bloodstream infections directly in whole blood at the early stages of infection with a sensitivity that is superior to that of other methods. The simplicity of the automated testing procedures may make this test suitable for rapid point-of-care detection.
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Automatización de Laboratorios/métodos , Técnicas Bacteriológicas/métodos , Sangre/microbiología , Francisella tularensis/aislamiento & purificación , Técnicas de Diagnóstico Molecular/métodos , Tularemia/diagnóstico , Animales , Francisella tularensis/genética , Humanos , Macaca , Sensibilidad y EspecificidadRESUMEN
Although antibiotics treat bacteremia in inhalational anthrax, pathogenesis is mainly driven by bacterial exotoxins. Raxibacumab, an IgG1 monoclonal antibody, binds the protective antigen (PA) of Bacillus anthracis, thus blocking toxin effects and leading to improved survival in the rabbit and monkey models of inhalational anthrax. To assess raxibacumab's added benefit over levofloxacin (LVX) alone, rabbits surviving to 84 h after a challenge with 200 times the median (50%) lethal dose of B. anthracis spores were randomized to receive 3 daily intragastric LVX doses of 50 mg/kg of body weight, with the first LVX dose administered just prior to administration of a single intravenous dose of placebo or 40 mg/kg raxibacumab. The percentages of animals alive at 28 days following the last LVX dose were compared between the 2 treatment groups using a two-sided likelihood-ratio chi-square test. The 82% survival rate for the LVX-raxibacumab combination was higher than the 65% survival rate for LVX alone (P=0.0874). There were nearly 2-fold fewer deaths for the combination (7 deaths; n=39) than for LVX alone (13 deaths; n=37), and the survival time was prolonged for the combination (P=0.1016). Toxin-neutralizing-activity titers were similar for both treatment groups, suggesting that survivors in both groups were able to mount a toxin-neutralizing immune response. Microscopic findings considered consistent with anthrax were present in animals that died or became moribund on study in both treatment groups, and there were no anthrax-related findings in animals that survived. Overall, raxibacumab provided a meaningful benefit over antibiotic alone when administered late in the disease course.
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Carbunco/tratamiento farmacológico , Antibacterianos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Animales , Anticuerpos Monoclonales Humanizados , Femenino , Levofloxacino/uso terapéutico , Masculino , ConejosRESUMEN
BACKGROUND: We have evaluated the therapeutic efficacy of AIGIV when given in combination with levofloxacin and the effective window of treatment to assess the added benefit provided by AIGIV over standard antibiotic treatment alone in a New Zealand white rabbit model of inhalational anthrax. METHODS: Rabbits were exposed to lethal dose of aerosolized spores of Bacillus anthracis (Ames strain) and treated intravenously with either placebo, (normal immune globulin intravenous, IGIV) or 15 U/kg of AIGIV, along with oral levofloxacin treatment at various time points (30-96 hours) after anthrax exposure. RESULTS: The majority of treated animals (>88%) survived in both treatment groups when treatment was initiated within 60 hours of post-exposure. However, reduced survival of 55%, 33% and 25% was observed for placebo + levofloxacin group when the treatment was initiated at 72, 84 and 96 hours post-exposure, respectively. Conversely, a survival rate of 65%, 40% and 71% was observed in the AIGIV + levofloxacin treated groups at these time points. CONCLUSIONS: The combination of AIGIV with antibiotics provided an improvement in survival compared to levofloxacin treatment alone when treatment was delayed up to 96 hours post-anthrax exposure. Additionally, AIGIV treatment when given as an adjunct therapy at any of the time points tested did not interfere with the efficacy of levofloxacin.
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Carbunco/terapia , Antibacterianos/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Infecciones del Sistema Respiratorio/terapia , Animales , Carbunco/inmunología , Carbunco/mortalidad , Antígenos Bacterianos/sangre , Antígenos Bacterianos/inmunología , Bacillus anthracis/inmunología , Bacteriemia/terapia , Modelos Animales de Enfermedad , Quimioterapia Combinada , Femenino , Levofloxacino/uso terapéutico , Masculino , Conejos , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/mortalidad , Toxemia/terapia , Resultado del TratamientoRESUMEN
Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis. Timely administration of antibiotics approved for the treatment of anthrax disease may prevent associated morbidity and mortality. However, any delay in initiating antimicrobial therapy may result in increased mortality, as inhalational anthrax progresses rapidly to the toxemic phase of disease. An anthrax antitoxin, AVP-21D9, also known as Thravixa (fully human anthrax monoclonal antibody), is being developed as a therapeutic agent against anthrax toxemia. The efficacy of AVP-21D9 in B. anthracis-infected New Zealand White rabbits and in cynomolgus macaques was evaluated, and its safety and pharmacokinetics were assessed in healthy human volunteers. The estimated mean elimination half-life values of AVP-21D9 in surviving anthrax-challenged rabbits and nonhuman primates (NHPs) ranged from approximately 2 to 4 days and 6 to 11 days, respectively. In healthy humans, the mean elimination half-life was in the range of 20 to 27 days. Dose proportionality was observed for the maximum serum concentration (Cmax) of AVP-21D9 and the area under the concentration-time curve (AUC). In therapeutic efficacy animal models, treatment with AVP-21D9 resulted in survival of up to 92% of the rabbits and up to 67% of the macaques. Single infusions of AVP-21D9 were well tolerated in healthy adult volunteers across all doses evaluated, and no serious adverse events were reported. (This study has been registered at ClinicalTrials.gov under registration no. NCT01202695.).
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Carbunco/tratamiento farmacológico , Carbunco/inmunología , Antibacterianos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Adolescente , Adulto , Animales , Antibacterianos/efectos adversos , Antibacterianos/farmacología , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Anticuerpos Neutralizantes/efectos adversos , Anticuerpos Neutralizantes/farmacología , Antígenos Bacterianos/sangre , Bacteriemia/sangre , Bacteriemia/tratamiento farmacológico , Anticuerpos ampliamente neutralizantes , Células CHO , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Macaca fascicularis , Masculino , Persona de Mediana Edad , Conejos , Adulto JovenRESUMEN
Bacillus anthracis toxins can be neutralized by antibodies against protective antigen (PA), a component of anthrax toxins. Anthrivig (human anthrax immunoglobulin), also known as AIGIV, derived from plasma of humans immunized with BioThrax (anthrax vaccine adsorbed), is under development for the treatment of toxemia following exposure to anthrax spores. The pharmacokinetics (PK) of AIGIV was assessed in naive animals and healthy human volunteers, and the efficacy of AIGIV was assessed in animals exposed via inhalation to aerosolized B. anthracis spores. In the clinical study, safety, tolerability, and PK were evaluated in three dose cohorts (3.5, 7.1, and 14.2 mg/kg of body weight of anti-PA IgG) with 30 volunteers per cohort. The elimination half-life of AIGIV in rabbits, nonhuman primates (NHPs), and humans following intravenous infusion was estimated to be approximately 4, 12, and 24 days, respectively, and dose proportionality was observed. In a time-based treatment study, AIGIV protected 89 to 100% of animals when administered 12 h postexposure; however, a lower survival rate of 39% was observed when animals were treated 24 h postexposure, underscoring the need for early intervention. In a separate set of studies, animals were treated on an individual basis upon detection of a clinical sign or biomarker of disease, namely, a significant increase in body temperature (SIBT) in rabbits and presence of PA in the serum of NHPs. In these trigger-based intervention studies, AIGIV induced up to 75% survival in rabbits depending on the dose and severity of toxemia at the time of treatment. In NHPs, up to 33% survival was observed in AIGIV-treated animals. (The clinical study has been registered at ClinicalTrials.gov under registration no. NCT00845650.).
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Vacunas contra el Carbunco/administración & dosificación , Carbunco/prevención & control , Anticuerpos Antibacterianos/administración & dosificación , Bacillus anthracis/efectos de los fármacos , Inmunoglobulinas Intravenosas/farmacocinética , Infecciones del Sistema Respiratorio/prevención & control , Esporas Bacterianas/efectos de los fármacos , Animales , Carbunco/inmunología , Carbunco/microbiología , Carbunco/mortalidad , Vacunas contra el Carbunco/inmunología , Anticuerpos Antibacterianos/inmunología , Anticuerpos Antibacterianos/aislamiento & purificación , Antígenos Bacterianos/sangre , Antígenos Bacterianos/inmunología , Bacillus anthracis/inmunología , Bacillus anthracis/patogenicidad , Toxinas Bacterianas/sangre , Toxinas Bacterianas/inmunología , Biomarcadores/análisis , Método Doble Ciego , Femenino , Semivida , Humanos , Inmunoglobulinas Intravenosas/inmunología , Inmunoglobulinas Intravenosas/aislamiento & purificación , Infusiones Intravenosas , Macaca fascicularis , Masculino , Conejos , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/mortalidad , Esporas Bacterianas/inmunología , Esporas Bacterianas/patogenicidad , Análisis de Supervivencia , Factores de Tiempo , VacunaciónRESUMEN
Inhaled Bacillus anthracis spores germinate and the subsequent vegetative growth results in bacteremia and toxin production. Anthrax toxin is tripartite: the lethal factor and edema factor are enzymatic moieties, while the protective antigen (PA) binds to cell receptors and the enzymatic moieties. Antibiotics can control B. anthracis bacteremia, whereas raxibacumab binds PA and blocks lethal toxin effects. This study assessed plasma PA kinetics in rabbits following an inhaled B. anthracis spore challenge. Additionally, at 84 h post-challenge, 42% of challenged rabbits that had survived were treated with either levofloxacin/placebo or levofloxacin/raxibacumab. The profiles were modeled using a modified Gompertz/second exponential growth phase model in untreated rabbits, with added monoexponential PA elimination in treated rabbits. Shorter survival times were related to a higher plateau and a faster increase in PA levels. PA elimination half-lives were 10 and 19 h for the levofloxacin/placebo and levofloxacin/raxibacumab groups, respectively, with the difference attributable to persistent circulating PA-raxibacumab complex. PA kinetics were similar between untreated and treated rabbits, with one exception: treated rabbits had a plateau phase nearly twice as long as that for untreated rabbits. Treated rabbits that succumbed to disease had higher plateau PA levels and shorter plateau duration than surviving treated rabbits.
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Carbunco/prevención & control , Antibacterianos/farmacología , Anticuerpos Monoclonales/farmacología , Antígenos Bacterianos/inmunología , Bacillus anthracis/inmunología , Levofloxacino , Ofloxacino/farmacología , Adyuvantes Inmunológicos/administración & dosificación , Administración por Inhalación , Animales , Carbunco/inmunología , Carbunco/mortalidad , Vacunas contra el Carbunco/administración & dosificación , Vacunas contra el Carbunco/inmunología , Anticuerpos Monoclonales Humanizados , Antígenos Bacterianos/administración & dosificación , Antígenos Bacterianos/metabolismo , Toxinas Bacterianas/inmunología , Modelos Animales de Enfermedad , Femenino , Cinética , Masculino , Conejos , Esporas Bacterianas/inmunología , Análisis de SupervivenciaRESUMEN
Appropriate animal models are required to test medical countermeasures to bioterrorist threats. To that end, we characterized a nonhuman primate (NHP) inhalational anthrax therapeutic model for use in testing anthrax therapeutic medical countermeasures according to the U.S. Food and Drug Administration Animal Rule. A clinical profile was recorded for each NHP exposed to a lethal dose of Bacillus anthracis Ames spores. Specific diagnostic parameters were detected relatively early in disease progression, i.e., by blood culture (â¼37 h postchallenge) and the presence of circulating protective antigen (PA) detected by electrochemiluminescence (ECL) â¼38 h postchallenge, whereas nonspecific clinical signs of disease, i.e., changes in body temperature, hematologic parameters (ca. 52 to 66 h), and clinical observations, were delayed. To determine whether the presentation of antigenemia (PA in the blood) was an appropriate trigger for therapeutic intervention, a monoclonal antibody specific for PA was administered to 12 additional animals after the circulating levels of PA were detected by ECL. Seventy-five percent of the monoclonal antibody-treated animals survived compared to 17% of the untreated controls, suggesting that intervention at the onset of antigenemia is an appropriate treatment trigger for this model. Moreover, the onset of antigenemia correlated with bacteremia, and NHPs were treated in a therapeutic manner. Interestingly, brain lesions were observed by histopathology in the treated nonsurviving animals, whereas this observation was absent from 90% of the nonsurviving untreated animals. Our results support the use of the cynomolgus macaque as an appropriate therapeutic animal model for assessing the efficacy of medical countermeasures developed against anthrax when administered after a confirmation of infection.
Asunto(s)
Carbunco/patología , Carbunco/terapia , Modelos Animales de Enfermedad , Enfermedades de los Primates/patología , Enfermedades de los Primates/terapia , Infecciones del Sistema Respiratorio/patología , Infecciones del Sistema Respiratorio/terapia , Animales , Carbunco/diagnóstico , Anticuerpos Antibacterianos/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Antígenos Bacterianos/sangre , Toxinas Bacterianas/sangre , Biomarcadores/sangre , Encéfalo/patología , Femenino , Adhesión a Directriz , Macaca fascicularis , Masculino , Enfermedades de los Primates/diagnóstico , Infecciones del Sistema Respiratorio/diagnóstico , Análisis de Supervivencia , Factores de Tiempo , Estados Unidos , United States Food and Drug AdministrationRESUMEN
The development of an appropriate animal therapeutic model is essential to assess the potential efficacy of therapeutics for use in the event of a Bacillus anthracis exposure. We conducted a natural history study that showed New Zealand White rabbits exhibited a significant increase in body temperature (SIBT), changes in hematologic parameters, and increases in C-reactive protein and succumbed to disease with an average time to death of approximately 73 h following aerosol challenge with B. anthracis Ames spores. The SIBT was used as a trigger to treat with a fully human monoclonal antibody directed at protective antigen (PA). Ninety percent (9/10) of the treated rabbits survived the lethal inhalational challenge of B. anthracis. Further characterization investigated the protective window of opportunity for anti-PA antibody administration up to 12 h post-onset of SIBT. Eighty-three percent (5/6) of the rabbits treated at SIBT and 100% (6/6) of those treated at 6 h after SIBT survived challenge. Only 67% (4/6) of the rabbits treated at 12 h after SIBT survived. The increase in body temperature corresponded with both bacteremia and antigenemia (PA in the blood), indicating that SIBT is a suitable trigger to initiate treatment in a therapeutic model of inhalational anthrax.
Asunto(s)
Carbunco/patología , Carbunco/terapia , Bacillus anthracis/patogenicidad , Biomarcadores , Fiebre/diagnóstico , Animales , Anticuerpos Antibacterianos/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Antígenos Bacterianos , Toxinas Bacterianas/antagonistas & inhibidores , Células Sanguíneas/fisiología , Proteína C-Reactiva/análisis , Modelos Animales de Enfermedad , Femenino , Inmunoterapia/métodos , Masculino , Conejos , Análisis de Supervivencia , Factores de TiempoRESUMEN
BACKGROUND: Inhalational anthrax caused by Bacillus anthracis is associated with high mortality primarily due to toxin-mediated injury. Raxibacumab is a human IgG1lambda monoclonal antibody directed against protective antigen, a component of the anthrax toxin. METHODS: We evaluated the efficacy of raxibacumab as a prophylactic agent and after disease onset in a total of four randomized, placebo-controlled studies conducted in rabbits and monkeys. Animals were exposed to an aerosolized target exposure of B. anthracis spores that was approximately 100 times (in the prophylactic studies) and 200 times (in the therapeutic-intervention studies) the median lethal dose. In the therapeutic-intervention studies, animals were monitored for the onset of symptoms. Animals with detectable protective antigen in serum, a significant increase in temperature, or both received a single intravenous bolus of placebo or raxibacumab at a dose of either 20 mg per kilogram of body weight or 40 mg per kilogram. The primary end point was survival at day 14 (in rabbits) or at day 28 (in monkeys). Safety studies were conducted with intravenous raxibacumab (40 mg per kilogram) in 333 healthy human volunteers. RESULTS: In both rabbits and monkeys, the time to detection of protective antigen correlated with the time to bacteremia (r=0.9, P<0.001). In the therapeutic-intervention studies, the survival rate was significantly higher among rabbits that received raxibacumab at a dose of 40 mg per kilogram (44% [8 of 18]) than among rabbits that received placebo (0% [0 of 18]; P=0.003). Raxibacumab treatment also significantly increased survival in monkeys (64% [9 of 14], vs. 0% [0 of 12] with placebo; P<0.001). In human subjects, intravenous raxibacumab at a dose of 40 mg per kilogram had a half-life of 20 to 22 days and provided a maximum concentration of the drug in excess of levels that are protective in animals. Concentrations of raxibacumab provide a surrogate end point that should be predictive of clinical benefit. CONCLUSIONS: A single dose of raxibacumab improved survival in rabbits and monkeys with symptomatic inhalational anthrax. (ClinicalTrials.gov number, NCT00639678.)
Asunto(s)
Carbunco/tratamiento farmacológico , Antiinfecciosos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Bacillus anthracis , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Carbunco/inmunología , Antiinfecciosos/efectos adversos , Anticuerpos Antibacterianos/sangre , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales Humanizados , Bacteriemia , Ciprofloxacina/efectos adversos , Ciprofloxacina/uso terapéutico , Evaluación Preclínica de Medicamentos , Quimioterapia Combinada , Femenino , Humanos , Inmunoglobulina G , Macaca fascicularis , Masculino , Persona de Mediana Edad , Conejos , Distribución Aleatoria , Análisis de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: FK778 is a malononitrilamide, a class of immune suppressive compounds with antiviral features and experimental activity in chronic rejection, a potentially interesting combination for organ transplantation. The goal of this project was to study the tolerability, immune suppressive efficacy, and anti-cytomegalovirus (CMV) activity of FK778 and to assess the in vivo relevance of its previously described inhibition of de novo pyrimidine synthesis. METHODS: Heart transplants were performed in rats (Brown Norway [BN] to Lewis) and treated with varying doses of FK778 or leflunomide for 28 days. At 28 days, at the time of rejection or at the death of the animal, the allograft and other vital organs were obtained for study by light microscopy and immunohistochemistry. In separate experiments, Lewis rats were given sublethal irradiation, inoculated with rat CMV (Maastricht strain), and treated with varying doses of FK778 and leflunomide. In both the transplant and CMV studies, IP uridine was given at 250 mg/kg to cohorts or animals receiving FK778 and leflunomide. RESULTS: FK778 controls acute rejection and inhibits CMV replication at 20 mg/kg but is toxic at 25 mg/kg. Toxicity is manifested as anemia, changes in hepatic and intestinal histology, and mortality. The toxicity but not the immune suppressive or antiviral efficacy, is reduced significantly by exogenous uridine administration. CONCLUSION: FK778 has both immune suppressive and antiviral activities, neither of which is entirely dependent on inhibition of pyrimidine synthesis. These, and other published observations, suggest that the antiviral activity and a considerable part of the efficacy of the malononitrilamide family of drugs is attributable to activities other than drug induced pyrimidine deficiency.