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1.
Value Health ; 25(12): 1967-1976, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35760714

RESUMO

OBJECTIVES: The development of accelerated approval programs for high morbidity and unmet need conditions has driven the use of single-arm studies in drug development. Regulatory and health technology assessment (HTA) agencies are recognizing that high-quality external control arms (ECAs), built using real-world data, can reduce uncertainties arising from single-arm studies. This review compared 7 case studies of regulatory and HTA agencies' evaluations of oncology ECAs. METHODS: Food and Drug Administration multidisciplinary reviews for oncology submissions from 2014 to 2021 were screened to identify 7 cases (2 blinatumomab indications, avelumab, and erdafitinib, entrectinib, trastuzumab deruxtecan, and idecabtagene vicleucel) with ECAs to support efficacy claims. Regulatory (Food and Drug Administration, European Medicines Agency, Health Canada) and HTA (pan-Canadian Oncology Drug Review, National Institute for Health and Care Excellence, Federal Joint Committee, Haute Autorité de Santé, and Pharmaceutical Benefits Advisory Committee) submissions for these cases were reviewed. The decision makers' ECA critiques and the level of influence on the decision were analyzed and categorized. RESULTS: Across case studies, selection bias and confounding were the most common ECA critiques. Nevertheless, agreement in critiques between and among regulators and HTA bodies was low. ECA influence on agencies' decisions also varied. CONCLUSIONS: Evaluating the same ECA evidence, agencies focused on methodologic issues (ie, selection bias and confounding), but were often not aligned on their critiques. Further research is needed to fully characterize how agencies evaluate ECAs. This study is a first step in critically evaluating agencies' critiques of ECAs and highlights the need for future guidance development around ECA design and generation.


Assuntos
Oncologia , Avaliação da Tecnologia Biomédica , Humanos , Estados Unidos , Canadá , Pesquisa
2.
Tuberculosis (Edinb) ; 95(6): 689-694, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26547230

RESUMO

We compared phenotypes of five strains of Mycobacterium tuberculosis (Mtb) differing in their expression of rv1248c and its product, 2-hydroxy-3-oxoadipate synthase (HOAS), with a focus on carbon source-dependent growth rates and attenuation in mice. Surprisingly, an rv1248c transposon mutant on a CDC1551 background grew differently than an rv1248c deletion mutant on the same background. Moreover, the same rv1248c deletion in two different yet genetically similar strain backgrounds (CDC1551 and H37Rv) gave different phenotypes, though each could be complemented. Whole genome re-sequencing did not provide an obvious explanation for these discrepancies. These observations offer a cautionary lesson about the strength of inference from complementation and sequence analysis, and commend consideration of more complex phenomena than usually contemplated in Mtb, such as epigenetic control.


Assuntos
Aldeído-Cetona Transferases/genética , Proteínas de Bactérias/genética , Elementos de DNA Transponíveis , Mycobacterium tuberculosis/genética , Deleção de Sequência , Tuberculose Pulmonar/microbiologia , Aldeído-Cetona Transferases/metabolismo , Animais , Carga Bacteriana , Proteínas de Bactérias/metabolismo , Modelos Animais de Doenças , Genótipo , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Fenótipo , Fatores de Tempo
3.
Proc Natl Acad Sci U S A ; 112(43): E5834-43, 2015 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-26430237

RESUMO

Enzymes of central carbon metabolism (CCM) in Mycobacterium tuberculosis (Mtb) make an important contribution to the pathogen's virulence. Evidence is emerging that some of these enzymes are not simply playing the metabolic roles for which they are annotated, but can protect the pathogen via additional functions. Here, we found that deficiency of 2-hydroxy-3-oxoadipate synthase (HOAS), the E1 component of the α-ketoglutarate (α-KG) dehydrogenase complex (KDHC), did not lead to general metabolic perturbation or growth impairment of Mtb, but only to the specific inability to cope with glutamate anaplerosis and nitroxidative stress. In the former role, HOAS acts to prevent accumulation of aldehydes, including growth-inhibitory succinate semialdehyde (SSA). In the latter role, HOAS can participate in an alternative four-component peroxidase system, HOAS/dihydrolipoyl acetyl transferase (DlaT)/alkylhydroperoxide reductase colorless subunit gene (ahpC)-neighboring subunit (AhpD)/AhpC, using α-KG as a previously undescribed source of electrons for reductase action. Thus, instead of a canonical role in CCM, the E1 component of Mtb's KDHC serves key roles in situational defense that contribute to its requirement for virulence in the host. We also show that pyruvate decarboxylase (AceE), the E1 component of pyruvate dehydrogenase (PDHC), can participate in AceE/DlaT/AhpD/AhpC, using pyruvate as a source of electrons for reductase action. Identification of these systems leads us to suggest that Mtb can recruit components of its CCM for reactive nitrogen defense using central carbon metabolites.


Assuntos
Ácido Glutâmico/metabolismo , Complexo Cetoglutarato Desidrogenase/metabolismo , Mycobacterium tuberculosis/metabolismo , Nitrosação , Estresse Oxidativo , Animais , Camundongos , Camundongos Endogâmicos C57BL
4.
Biochemistry ; 52(51): 9375-84, 2013 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-24251446

RESUMO

Tuberculosis remains a global health emergency that calls for treatment regimens directed at new targets. Here we explored lipoamide dehydrogenase (Lpd), a metabolic and detoxifying enzyme in Mycobacterium tuberculosis (Mtb) whose deletion drastically impairs Mtb's ability to establish infection in the mouse. Upon screening more than 1.6 million compounds, we identified N-methylpyridine 3-sulfonamides as potent and species-selective inhibitors of Mtb Lpd affording >1000-fold selectivity versus the human homologue. The sulfonamides demonstrated low nanomolar affinity and bound at the lipoamide channel in an Lpd-inhibitor cocrystal. Their selectivity could be attributed, at least partially, to hydrogen bonding of the sulfonamide amide oxygen with the species variant Arg93 in the lipoamide channel. Although potent and selective, the sulfonamides did not enter mycobacteria, as determined by their inability to accumulate in Mtb to effective levels or to produce changes in intracellular metabolites. This work demonstrates that high potency and selectivity can be achieved at the lipoamide-binding site of Mtb Lpd, a site different from the NAD⁺/NADH pocket targeted by previously reported species-selective triazaspirodimethoxybenzoyl inhibitors.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Di-Hidrolipoamida Desidrogenase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/enzimologia , Sulfonamidas/farmacologia , Ácido Tióctico/análogos & derivados , Antituberculosos/efeitos adversos , Antituberculosos/química , Arginina/química , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Benzenoacetamidas/efeitos adversos , Benzenoacetamidas/química , Benzenoacetamidas/farmacologia , Sítios de Ligação , Transporte Biológico/efeitos dos fármacos , Membrana Celular/metabolismo , Permeabilidade da Membrana Celular , Di-Hidrolipoamida Desidrogenase/química , Di-Hidrolipoamida Desidrogenase/genética , Di-Hidrolipoamida Desidrogenase/metabolismo , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/química , Ensaios de Triagem em Larga Escala , Humanos , Moduladores de Transporte de Membrana/efeitos adversos , Moduladores de Transporte de Membrana/química , Moduladores de Transporte de Membrana/farmacologia , Testes de Sensibilidade Microbiana , Conformação Molecular , Proteínas Mutantes/antagonistas & inibidores , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Sulfonamidas/efeitos adversos , Sulfonamidas/química , Ácido Tióctico/metabolismo
5.
Phys Chem Chem Phys ; 11(36): 7810-8, 2009 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-19727487

RESUMO

Because it is doubly unsaturated, gaseous limonene and ozone reactions exhibit considerable potential for not only a large quantity of secondary organic aerosol (SOA), but also a diverse and complicated product mixture influenced by reactant conditions. We explore the chemistry of limonene ozonolysis and provide evidence that under low-NOx conditions, the endocyclic double bond is oxidized in the gas phase, while under excess ozone conditions, the residual exocyclic double bond in condensed-phase products is heterogeneously oxidized by ozone. We use regular and multinuclear-multidimensional NMR spectroscopy, in particular 1D 1H-NMR, 1H,1H-COSY correlation spectroscopy, and 1H,13C-HSQC (heteronuclear single quantum coherence). For structural assignments we simulate 1H and 13C NMR spectra with ACDLabs online, relying representative products consistent with the postulated reaction mechanism. The 1-D 1H-NMR data allow us to quantify the extent to which the residual unsaturation is oxidized with rising ozone, confirming our hypothesis that the residual unsaturation is oxidized via heterogeneous uptake of ozone to fresh SOA particles.


Assuntos
Aerossóis/química , Atmosfera/química , Cicloexenos/química , Modelos Químicos , Ressonância Magnética Nuclear Biomolecular/métodos , Ozônio/química , Material Particulado/química , Terpenos/química , Atmosfera/análise , Gases/química , Limoneno , Compostos Orgânicos/química , Oxirredução , Transição de Fase
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