ABSTRACT
We present a clinical proof-of-concept (PoC) study in chronic obstructive pulmonary disease with the objective of assessing the bronchodilatory effect of an experimental drug as compared with an active control treatment. In such an exploratory Phase II setting, we discuss the formal inclusion of relevant historical information and tailored PoC criteria for the purpose of a more efficient use of the available evidence to support clinical decision making. We provide guidance with regard to practical and methodological aspects for assessing the relevance of the historical data, synthesizing the evidence via a meta-analytic-predictive approach, and defining transparent statistical PoC decision criteria that are aligned with the clinical context. The case study was implemented using the Bayesian approach, which offers an ideal framework for the early phases of drug development.
Subject(s)
Bronchodilator Agents/therapeutic use , Drug Discovery/statistics & numerical data , Pulmonary Disease, Chronic Obstructive/drug therapy , Bayes Theorem , Biostatistics , Clinical Trials, Phase II as Topic/statistics & numerical data , Decision Making , Evidence-Based Medicine , Forced Expiratory Volume/drug effects , Humans , Meta-Analysis as Topic , Models, Statistical , Pulmonary Disease, Chronic Obstructive/physiopathologySubject(s)
Anemia, Sickle Cell/microbiology , Penicillin Resistance , Pharynx/microbiology , Streptococcus pneumoniae/isolation & purification , Adolescent , Case-Control Studies , Child , Child, Preschool , Female , Humans , Infant , Male , Ohio , Penicillins/therapeutic use , Pneumococcal Infections/prevention & control , Prospective StudiesABSTRACT
Ornithine-oxo-acid aminotransferase (EC 2.6.1.13) from rat kidney was prepared as a single homogeneous protein as judged by polyacrylamide gel electrophoresis, ultracentrifuge analysis and double diffusion precipitin test. Content of pyridoxal phosphate, light absorption spectra, circular dicroism spectra, Km values, inhibitors, and electrophoretic mobilities of the proteins after reactions with group modifying reagents were similar for the ornithine-oxo-acid aminotransferases of rat kidney and liver. Rates of reaction with group modifying reagents, stabilities to storage at -15 degrees C, and stabilities to temperatures above 55 degrees C differed significantly for the two enzymes. The liver enzyme contained two more cysteine residues than the kidney enzyme as determined by three different methods. Heating the liver enzyme at 66-67 degrees C at pH 5.9 for 1 h decreased the thiol groups titratable by 5,5'-dithio-bis(2-nitrobenzoic acid) (Nbs2). Uncer the same conditions titratable thiol groups of the kidney enzyme were not decreased. Amino acid analysis revealed probably significant differences in tyrosine and isoleucine content in addition to cysteine. It was concluded that the primary structures of ornithine-oxo-acid aminotransferases of rat liver and kidney are not fully identical.
