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Find video protocols related to scientific articles indexed in Pubmed.
Cardiac Safety Research Consortium: can the thorough QT/QTc study be replaced by early QT assessment in routine clinical pharmacology studies? Scientific update and a research proposal for a path forward.
Am. Heart J.
PUBLISHED: 06-06-2014
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The International Conference on Harmonization E14 guidance for the clinical evaluation of QT/QTc interval prolongation requires almost all new drugs to undergo a dedicated clinical study, primarily in healthy volunteers, the so-called TQT study. Since 2005, when the E14 guidance was implemented in United States and Europe, close to 400 TQT studies have been conducted. In February 2012, the Cardiac Safety Research Consortium held a think tank meeting at Food and Drug Administration's White Oak campus to discuss whether "QT assessment" can be performed as part of routine phase 1 studies. Based on these discussions, a group of experts convened to discuss how to improve the confidence in QT data from early clinical studies, for example, the First-Time-in-Human trial, through collection of serial electrocardiograms and pharmacokinetic samples and the use of exposure response analysis. Recommendations are given on how to design such "early electrocardiogram assessment," and the limitation of not having a pharmacologic-positive control in these studies is discussed. A research path is identified toward collecting evidence to replace or provide an alternative to the dedicated TQT study.
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Population pharmacokinetic/pharmacodynamic analysis of the bactericidal activities of sutezolid (PNU-100480) and its major metabolite against intracellular Mycobacterium tuberculosis in ex vivo whole-blood cultures of patients with pulmonary tuberculosis.
Antimicrob. Agents Chemother.
PUBLISHED: 03-31-2014
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Sutezolid (PNU-100480 [U-480]) is an oxazolidinone antimicrobial being developed for the treatment of tuberculosis. An active sulfoxide metabolite (PNU-101603 [U-603]), which reaches concentrations in plasma several times those of the parent, has been reported to drive the killing of extracellular Mycobacterium tuberculosis by sutezolid in hollow-fiber culture. However, the relative contributions of the parent and metabolite against intracellular M. tuberculosis in vivo are not fully understood. The relationships between the plasma concentrations of U-480 and U-603 and intracellular whole-blood bactericidal activity (WBA) in ex vivo cultures were examined using a direct competitive population pharmacokinetic (PK)/pharmacodynamic 4-parameter sigmoid model. The data set included 690 PK determinations and 345 WBA determinations from 50 tuberculosis patients enrolled in a phase 2a sutezolid trial. The model parameters were solved iteratively. The median U-603/U-480 concentration ratio was 7.1 (range, 1 to 28). The apparent 50% inhibitory concentration of U-603 for intracellular M. tuberculosis was 17-fold greater than that of U-480 (90% confidence interval [CI], 9.9- to 53-fold). Model parameters were used to simulate in vivo activity after oral dosing with sutezolid at 600 mg twice a day (BID) and 1,200 mg once a day (QD). Divided dosing resulted in greater cumulative activity (-0.269 log10 per day; 90% CI, -0.237 to -0.293 log10 per day) than single daily dosing (-0.186 log10 per day; 90% CI, -0.160 to -0.208 log10 per day). U-480 accounted for 84% and 78% of the activity for BID and QD dosing, respectively, despite the higher concentrations of U-603. Killing of intracellular M. tuberculosis by orally administered sutezolid is mainly due to the activity of the parent compound. Taken together with the findings of other studies in the hollow-fiber model, these findings suggest that sutezolid and its metabolite act on different mycobacterial subpopulations.
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Iddm30 controls pancreatic expression of Ccl11 (Eotaxin) and the Th1/Th2 balance within the insulitic lesions.
J. Immunol.
PUBLISHED: 03-19-2014
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The autoimmune diabetic syndrome of the BioBreeding diabetes-prone (BBDP) rat is a polygenic disease that resembles in many aspects human type 1 diabetes (T1D). A successful approach to gain insight into the mechanisms underlying genetic associations in autoimmune diseases has been to identify and map disease-related subphenotypes that are under simpler genetic control than the full-blown disease. In this study, we focused on the ? cell overexpression of Ccl11 (Eotaxin), previously postulated to be diabetogenic in BBDR rats, a BBDP-related strain. We tested the hypothesis that this trait is genetically determined and contributes to the regulation of diabetes in BBDP rats. Similar to the BBDR strain, we observed a time-dependent, insulitis-independent pancreatic upregulation of Ccl11 in BBDP rats when compared with T1D-resistant ACI.1u.lyp animals. Through linkage analysis of a cross-intercross of these two parental strains, this trait was mapped to a region on chromosome 12 that overlaps Iddm30. Linkage results were confirmed by phenotypic assessment of a novel inbred BBDP.ACI-Iddm30 congenic line. As expected, the Iddm30 BBDP allele is associated with a significantly higher pancreatic expression of Ccl11; however, the same allele confers resistance to T1D. Analysis of islet-infiltrating T cells in Iddm30 congenic BBDP animals revealed that overexpression of pancreatic Ccl11, a prototypical Th2 chemokine, is associated with an enrichment in Th2 CD4+ T cells within the insulitic lesions. These results indicate that, in the BBDP rat, Iddm30 controls T1D susceptibility through both the regulation of Ccl11 expression in ? cells and the subsequent Th1/Th2 balance within islet-infiltrating T lymphocytes.
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Mycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis.
PLoS ONE
PUBLISHED: 01-01-2014
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Sutezolid (PNU-100480) is a linezolid analog with superior bactericidal activity against Mycobacterium tuberculosis in the hollow fiber, whole blood and mouse models. Like linezolid, it is unaffected by mutations conferring resistance to standard TB drugs. This study of sutezolid is its first in tuberculosis patients.
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Inhibition of mycobacterial growth in vitro following primary but not secondary vaccination with Mycobacterium bovis BCG.
Clin. Vaccine Immunol.
PUBLISHED: 08-28-2013
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Despite the widespread use of the Mycobacterium bovis BCG vaccine, there are more than 9 million new cases of tuberculosis (TB) every year, and there is an urgent need for better TB vaccines. TB vaccine candidates are selected for evaluation based in part on the detection of an antigen-specific gamma interferon (IFN-?) response. The measurement of mycobacterial growth in blood specimens obtained from subjects immunized with investigational TB vaccines may be a better in vitro correlate of in vivo vaccine efficacy. We performed a clinical study with 30 United Kingdom adults who were followed for 6 months to evaluate the abilities of both a whole-blood- and a novel peripheral blood mononuclear cell (PBMC)-based mycobacterial growth inhibition assay to measure a response to primary vaccination and revaccination with BCG. Using cryopreserved PBMCs, we observed a significant improvement in mycobacterial growth inhibition following primary vaccination but no improvement in growth inhibition following revaccination with BCG (P < 0.05). Mycobacterial growth inhibition following primary BCG vaccination was not correlated with purified protein derivative (PPD) antigen-specific IFN-? enzyme-linked immunospot (ELISPOT) responses. We demonstrate that a mycobacterial growth inhibition assay can detect improved capacity to control growth following primary immunization, but not revaccination, with BCG. This is the first study to demonstrate that an in vitro growth inhibition assay can identify a difference in vaccine responses by comparing both primary and secondary BCG vaccinations, suggesting that in vitro growth inhibition assays may serve as better surrogates of clinical efficacy than the assays currently used for the assessment of candidate TB vaccines.
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Tuberculosis biomarkers discovery: developments, needs, and challenges.
Lancet Infect Dis
PUBLISHED: 03-24-2013
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Biomarkers are indispensable to the development of new tuberculosis therapeutics and vaccines. The most robust biomarkers measure factors that are essential to the underlying pathological process of the disease being treated, and thus can capture the full effects of many types of interventions on clinical outcomes in multiple prospective, randomised clinical trials. Many Mycobacterium tuberculosis and human biomarkers have been studied over the past decade. Present research focuses on three areas: biomarkers predicting treatment efficacy and cure of active tuberculosis, the reactivation of latent tuberculosis infection, and the induction of protective immune responses by vaccination. Many older, non-specific markers of inflammation, when considered in isolation, do not have sufficient predictive values for clinical use in tuberculosis. Although no new accurate, tuberculosis-specific biomarkers have yet been discovered, substantial progress has been made in some areas. However, the qualification of biomarkers as a surrogate for a clinical endpoint in tuberculosis is very challenging, and, for biomarkers that are non-culture-based, impossible to pursue without the availability of well characterised biobanks containing biospecimens from patients who have had adequate follow-up to establish long-term treatment outcome. We review progress in tuberculosis biomarker development and efforts being made to harness resources to meet future challenges.
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Application of a stochastic modeling to assess the evolution of tuberculous and non-tuberculous mycobacterial infection in patients treated with tumor necrosis factor inhibitors.
PLoS ONE
PUBLISHED: 01-28-2013
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In this manuscript we apply stochastic modeling to investigate the risk of reactivation of latent mycobacterial infections in patients undergoing treatment with tumor necrosis factor inhibitors. First, we review the perspective proposed by one of the authors in a previous work and which consists in predicting the occurrence of reactivation of latent tuberculosis infection or newly acquired tuberculosis during treatment; this is based on variational procedures on a simple set of parameters (e.g. rate of reactivation of a latent infection). Then, we develop a full analytical study of this approach through a Markov chain analysis and we find an exact solution for the temporal evolution of the number of cases of tuberculosis infection (re)activation. The analytical solution is compared with Monte Carlo simulations and with experimental data, showing overall excellent agreement. The generality of this theoretical framework allows to investigate also the case of non-tuberculous mycobacteria infections; in particular, we show that reactivation in that context plays a minor role. This may suggest that, while the screening for tuberculous is necessary prior to initiating biologics, when considering non-tuberculous mycobacteria only a watchful monitoring during the treatment is recommended. The framework outlined in this paper is quite general and could be extremely promising in further researches on drug-related adverse events.
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Month 2 culture status and treatment duration as predictors of tuberculosis relapse risk in a meta-regression model.
PLoS ONE
PUBLISHED: 01-01-2013
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New drugs and regimens with the potential to transform tuberculosis treatment are presently in early stage clinical trials.
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Biologics and infections: lessons from tumor necrosis factor blocking agents.
Infect. Dis. Clin. North Am.
PUBLISHED: 11-08-2011
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In the decade since tumor necrosis factor ? (TNF-?) antagonists were first approved for clinical use, they have proven invaluable for the treatment of specific types of chronic inflammation. Currently licensed TNF blockers fall into two classes, monoclonal antibody (or antibody fragments) and soluble receptor. Although they are equally effective in rheumatoid arthritis and psoriasis, important differences have emerged with regard to efficacy in granulomatous inflammation and risks of granulomatous infections, particularly tuberculosis. This article focuses on recent studies that inform prevention and management of infections in this susceptible patient population.
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Biomarker-assisted dose selection for safety and efficacy in early development of PNU-100480 for tuberculosis.
Antimicrob. Agents Chemother.
PUBLISHED: 11-15-2010
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Tuberculosis is a serious global health threat for which new treatments are urgently needed. This study examined the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of the oxazolidinone PNU-100480 in healthy volunteers, using biomarkers for safety and efficacy. Subjects were randomly assigned to PNU-100480 or placebo (4:1) at schedules of 100, 300, or 600 mg twice daily or 1,200 mg daily for 14 days or a schedule of 600 mg twice daily for 28 days to which pyrazinamide was added on days 27 and 28. A sixth cohort was given linezolid at 300 mg daily for 4 days. Signs, symptoms, and routine safety tests were monitored. Bactericidal activity against Mycobacterium tuberculosis was measured in ex vivo whole-blood culture. Plasma drug and metabolite concentrations were compared to the levels required for inhibition of M. tuberculosis growth and 50% inhibition of mitochondrial protein synthesis. All doses were safe and well tolerated. There were no hematologic or other safety signals during 28 days of dosing at 600 mg twice daily. Plasma concentrations of PNU-100480 and metabolites at this dose remained below those required for 50% inhibition of mitochondrial protein synthesis. Cumulative whole-blood bactericidal activity of PNU-100480 at this dose (-0.316 ± 0.04 log) was superior to the activities of all other doses tested (P < 0.001) and was significantly augmented by pyrazinamide (-0.420 ± 0.06 log) (P = 0.002). In conclusion, PNU-100480 was safe and well tolerated at all tested doses. Further studies in patients with tuberculosis are warranted. Biomarkers can accelerate early development of new tuberculosis treatments.
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Pulmonary infectious complications of tumor necrosis factor blockade.
Infect. Dis. Clin. North Am.
PUBLISHED: 08-03-2010
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The understanding of the infection risks posed by tumor necrosis factor (TNF) antagonists has continued to evolve in the 10 years since these drugs first were introduced. Recent prospective studies have confirmed the risk of tuberculosis (TB) reactivation posed by TNF antibodies to be several fold greater than soluble TNF receptor. Certolizumab pegol, a monovalent anti-TNF Fab fragment, appears to share this risk, despite its lack of Fc and its inability to cross-link transmembrane TNF or activate complement. Two-step (boosted) tuberculin skin test screening and initiation of treatment for latent TB infection can greatly reduce the TB risk of anti-TNF treatment in western countries. Current recommendations for withdrawal of anti-TNF therapy when TB is diagnosed place patients at risk for paradoxical worsening due to recovery of TNF-dependent inflammation. Further research is needed to determine how best to prevent and manage their infectious complications and to determine their potential adjunctive therapeutic role in chronic infectious diseases.
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Pharmacokinetics and whole-blood bactericidal activity against Mycobacterium tuberculosis of single doses of PNU-100480 in healthy volunteers.
J. Infect. Dis.
PUBLISHED: 07-16-2010
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The oxazolidinone PNU-100480 is superior to linezolid against experimental murine tuberculosis. Two metabolites contribute to but do not fully account for its superiority. This study examined the safety, tolerability, pharmacokinetics, and mycobactericidal activity of single ascending doses of PNU-100480.
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A metabolomic approach to identifying chemical mediators of mammal-plant interactions.
J. Chem. Ecol.
PUBLISHED: 05-19-2010
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Different folivorous marsupials select their food from different subgenera of Eucalyptus, but the choices cannot be explained by known antifeedants, such as formylated phloroglucinol compounds or tannins, or by nutritional quality. Eucalypts contain a wide variety of plant secondary metabolites so it is difficult to use traditional methods to identify the chemicals that determine food selection. Therefore, we used a metabolomic approach in which we employed (1)H nuclear magnetic resonance spectroscopy to compare chemical structures of representatives from the two subgenera and to identify chemicals that consistently differ between them. We found that dichloromethane extracts of leaves from most species in the subgenus Eucalyptus differ from those in Symphyomyrtus by the presence of free flavanones, having no substitution in Ring B. Although flavanoids are known to deter feeding by certain insects, their effects on marsupials have not been established and must be tested with controlled feeding studies.
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Biomarkers and diagnostics for tuberculosis: progress, needs, and translation into practice.
Lancet
PUBLISHED: 05-18-2010
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Human infection with Mycobacterium tuberculosis can progress to active disease, be contained as latent infection, or be eradicated by the host response. Tuberculosis diagnostics classify a patient into one of these categories. These are not fixed distinct states, but rather are continua along which patients can move, and are affected by HIV infection, immunosuppressive therapies, antituberculosis treatments, and other poorly understood factors. Tuberculosis biomarkers-host or pathogen-specific-provide prognostic information, either for individual patients or study cohorts, about these outcomes. Tuberculosis case detection remains difficult, partly because of inaccurate diagnostic methods. Investments have yielded some progress in development of new diagnostics, although the existing pipeline is limited for tests for sputum-smear-negative cases, childhood tuberculosis, and accurate prediction of reactivation of latent tuberculosis. Despite new, sensitive, automated molecular platforms for detection of tuberculosis and drug resistance, a simple, inexpensive point-of-care test is still not available. The effect of any new tests will depend on the method and extent of their introduction, the strength of the laboratories, and the degree to which access to appropriate therapy follows access to diagnosis. Translation of scientific progress in biomarkers and diagnostics into clinical and public health programmes is possible-with political commitment, increased funding, and engagement of all stakeholders.
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Biomarkers of disease activity, cure, and relapse in tuberculosis.
Clin. Chest Med.
PUBLISHED: 11-21-2009
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The changing face of tuberculosis, with epidemics fueled by HIV and urbanization in much of the world and a relative increase in the importance of latent tuberculosis as a source of cases in the more economically developed countries, has led to a demand for more robust, clinically applicable diagnostic tools. As a result, research aiming to identify biomarkers of Mycobacterium tuberculosis infection and disease has flourished. This article discusses the most recent findings of that work.
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Advances in immunotherapy for tuberculosis treatment.
Clin. Chest Med.
PUBLISHED: 11-21-2009
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Immunotherapies have the potential to improve the outcome in all patients with tuberculosis (TB) including those with multidrug-resistant (MDR)-TB and extensively drug-resistant (XDR)-TB. Immunotherapy for TB may shorten duration of treatment and reduce pathology in individuals cured by chemotherapy, potentially preventing recurrence. Currently none of the available candidate agents have proof of efficacy for use in MDR-TB or XDR-TB. Further development and evaluation of existing immunotherapeutic agents is required to identify an effective agent that can be used adjunctively with chemotherapy to improve treatment outcomes for drug-susceptible TB, MDR-TB, and XDR-TB. With a range of potential immunotherapeutics, some of which have been produced to good manufacturing practice (GMP) standards and are registered for other indications in humans, the immunotherapy option should no longer be ignored.
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Integrated risk assessment and predictive value to humans of non-clinical repolarization assays.
Br. J. Pharmacol.
PUBLISHED: 09-25-2009
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The potential for drugs to be associated with the life-threatening arrhythmia, Torsades de Pointes (TdeP), continues to be a topic of regulatory, academic and industrial concern. Despite being an imperfect biomarker, prolongation of the QT interval of the surface ECG is used to assess the risk of a drug being associated with TdeP such that a thorough examination of drug effects on the QT interval is required for all new chemical entities. Numerous studies have investigated the relationship between non-clinical findings and the risk of TdeP and QT prolongation in the general population. There are many literature references supporting the strong correlation between the clinical safety margin over human ether-a-go-go (hERG) inhibitory potency and the risk of drug-induced arrhythmia and sudden death. A quantitative analysis of the relationship between non-clinical studies and the outcome of a human Thorough QT study has also been reported. In the current manuscript, based on the outcome of the non-clinical assays the sensitivity and specificity of each assay and an integrated risk assessment for predicting the outcome of the human Thorough QT study has been conducted. The data suggest that for QT prolongation mediated through inhibition of the hERG current the non-clinical assays are highly predictive of drug effects on the QT interval. Based on the literature review and specific quantitative analysis reported above it is concluded that non-clinical assays predict the risk of compounds to prolong the QT interval and cause TdeP in humans if the mechanism is through inhibition of the hERG current.
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Infectious complications of tumor necrosis factor blockade.
Curr. Opin. Infect. Dis.
PUBLISHED: 06-04-2009
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Our understanding of the infection risks posed by tumor necrosis factor (TNF) antagonists has continued to evolve in the 10 years since these drugs were first introduced. This review summarizes recent data regarding infection risk, examines potential structure-function relationships that may account for the differences, and discusses their implications with regard to tuberculosis prevention and management.
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Biomarkers for tuberculosis disease status and diagnosis.
Curr Opin Pulm Med
PUBLISHED: 04-28-2009
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Every year, over 8 million people develop tuberculosis and nearly 1.8 million die from it, despite extensive vaccination and drug treatment programmes. It is increasingly recognized that the diagnosis of tuberculosis, which relies heavily on century-old techniques, is one of the weakest links in the chain of tuberculosis control, hampering not just treatment but also the development of new drugs and vaccines. As a result, recent years have seen the initiation of large-scale studies aiming to identify biomarkers of Mycobacterium tuberculosis infection and disease. This review discusses initial results and future prospects for that work.
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Adalimumab treatment of life-threatening tuberculosis.
Clin. Infect. Dis.
PUBLISHED: 04-15-2009
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Most guidelines call for the discontinuation of treatment with tumor necrosis factor blockers in patients who develop tuberculosis. We report a case of life-threatening tuberculosis paradoxical reaction involving the lungs caused by withdrawal of the anti-tumor necrosis factor antibody adalimumab. Clinical improvement occurred only after resumption of adalimumab treatment.
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Biomarkers for tuberculosis disease activity, cure, and relapse.
Lancet Infect Dis
PUBLISHED: 02-28-2009
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New drugs, vaccines, and other therapies will be required to realise the goal of global tuberculosis elimination or control. This Review covers the important role biomarkers can have in accelerating drug development by providing validated surrogate endpoints that can bring enhanced statistical power to small short studies. Candidate biomarkers should differentiate people with active tuberculosis from healthy individuals, normalise with therapy, and reproducibly predict clinical outcomes in diverse patient populations. Although a large number of promising candidate biomarkers have been examined to date, few patients in these studies have reached clinically meaningful outcomes, and few of the studies have been conducted to international research standards. These markers must be further studied in tuberculosis treatment trials to evaluate the kinetics of the responses and their relation to long-term clinical outcomes. These studies will benefit from multidisciplinary collaborations including microbiologists, immunologists, clinicians, tuberculosis control personnel, and the pharmaceutical and biotechnology industry.
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Strain specificity of antimycobacterial immunity in whole blood culture after cure of tuberculosis.
Tuberculosis (Edinb)
PUBLISHED: 02-18-2009
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Bactericidal assays have facilitated development of most modern vaccines, and have been proposed as indicators of protection after vaccination against tuberculosis. We examined control of intracellular growth of Mycobacterium tuberculosis in whole blood cultures of cured TB patients and tuberculin-negative healthy volunteers. Cured patients showed superior restriction of growth of the strain with which they had been infected. They similarly showed superior control of growth of a clinical strain (MP-28) that had become attenuated during passage. However, patients and healthy volunteers did not differ with regard to control of M. tuberculosis H37Ra. The ability of cured patients to control growth of the strain with which they had been infected correlated with MP-28, but not with H37Ra. These findings indicate M. tuberculosis MP-28 may be suitable to assess mycobacterial immunity as growth inhibition in whole blood culture, whereas H37Ra is not. However, additional studies will be required to confirm these observations in additional patient and microbial populations that are distinct according to geography and microbial and host genetics.
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Type 1 diabetes in the BB rat: a polygenic disease.
Diabetes
PUBLISHED: 01-23-2009
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Two type 1 diabetes susceptibility genes have been identified in the spontaneously diabetic biobreeding diabetes-prone (BBDP) rat, the major histocompatibility complex (MHC) (RT1) class II u haplotype (Iddm1) and Gimap5 (Iddm2). The strong effects of these have impeded previous efforts to map additional loci. We tested the hypothesis that type 1 diabetes is a polygenic disease in the BBDP rat.
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Sustainable tuberculosis drug development.
Clin. Infect. Dis.
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Six new antituberculosis compounds in 4 classes are presently in clinical trials. Although these show substantial promise for drug-resistant (DR) tuberculosis, the presently planned studies of these compounds will not inform their optimal use, as each will be tested singly vs placebo with existing drugs, rather than in new regimens. Each successive regulatory approval will increase the size, cost, and complexity of trials for those that follow, causing delays during which suboptimal use will occur and resistance will emerge. This paper proposes the development of a novel regimen with the potential for use in both drug-sensitive (DS) and DR tuberculosis. Adaptive licensing for DR tuberculosis based on 2-month sputum culture would shorten time to initial approval by several years. A global outcomes registry would confirm safety and effectiveness in both DS and DR tuberculosis, making possible the second transformation of tuberculosis treatment. We should do our utmost to see it succeed.
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Sterilizing activities of novel combinations lacking first- and second-line drugs in a murine model of tuberculosis.
Antimicrob. Agents Chemother.
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Novel oral regimens composed of new drugs with potent activity against Mycobacterium tuberculosis and no cross-resistance with existing agents are needed to shorten and simplify treatment for both drug-susceptible and drug-resistant tuberculosis. As part of a continuing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, several 3- and 4-drug combinations containing new agents currently in phase 2/3 trials (TMC207 [bedaquiline], PA-824 and PNU-100480 [sutezolid], and/or clofazimine) proved superior to the first-line regimen of rifampin, pyrazinamide, and isoniazid. TMC207 plus PNU-100480 was the most effective drug pair. In the second experiment, in which 3- and 4-drug combinations composed of TMC207 and pyrazinamide plus rifapentine, clofazimine, PNU-100480, or both rifapentine and clofazimine were evaluated, the rank order of drugs improving the sterilizing activity of TMC207 and pyrazinamide was as follows: rifapentine plus clofazimine ? clofazimine ? rifapentine > PNU-100480. The results revealed potential new building blocks for universally active short-course regimens for drug-resistant tuberculosis. The inclusion of pyrazinamide against susceptible isolates may shorten the duration of treatment further.
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Rapid evaluation in whole blood culture of regimens for XDR-TB containing PNU-100480 (sutezolid), TMC207, PA-824, SQ109, and pyrazinamide.
PLoS ONE
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There presently is no rapid method to assess the bactericidal activity of new regimens for tuberculosis. This study examined PNU-100480, TMC207, PA-824, SQ109, and pyrazinamide, singly and in various combinations, against intracellular M. tuberculosis, using whole blood culture (WBA). The addition of 1,25-dihydroxy vitamin D facilitated detection of the activity of TMC207 in the 3-day cultures. Pyrazinamide failed to show significant activity against a PZA-resistant strain (M. bovis BCG), and was not further considered. Low, mid, and high therapeutic concentrations of each remaining drug were tested individually and in a paired checkerboard fashion. Observed bactericidal activity was compared to that predicted by the sum of the effects of individual drugs. Combinations of PNU-100480, TMC207, and SQ109 were fully additive, whereas those including PA-824 were less than additive or antagonistic. The cumulative activities of 2, 3, and 4 drug combinations were predicted based on the observed concentration-activity relationship, published pharmacokinetic data, and, for PNU-100480, published WBA data after oral dosing. The most active regimens, including PNU-100480, TMC207, and SQ109, were predicted to have cumulative activity comparable to standard TB therapy. Further testing of regimens including these compounds is warranted. Measurement of whole blood bactericidal activity can accelerate the development of novel TB regimens.
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SQ109 and PNU-100480 interact to kill Mycobacterium tuberculosis in vitro.
J. Antimicrob. Chemother.
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To investigate in vitro interaction between two compounds, SQ109 and PNU-100480, currently in development for the treatment of Mycobacterium tuberculosis (MTB).
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.