Placebo Response to Oral Administration in Osteoarthritis Clinical Trials and Its Associated Factors: A Model-Based Meta-analysis.

Importance: In osteoarthritis (OA) clinical trials, a placebo is often used as control. Therefore, a thorough understanding of the placebo response is important for guiding drug development in OA. Objective: To develop an oral placebo response model for OA. Data Sources: PubMed, EMBASE, and Cochrane Library databases were searched systematically from January 1, 1991, to July 2, 2022. Study Selection: Randomized double-blind placebo-controlled trials of patients with primary OA were included. The interventions and placebo were administered orally. A total of 3032 trials were identified; of these, 130 (4.3%) met the inclusion criteria. Data Extraction and Synthesis: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, dosage form of the placebo, sample size, proportion of patients who previously used nonsteroidal anti-inflammatory drugs, publication year, intervention categories, Kellgren-Lawrence grades, proportion of White patients, duration of pain, funding source, and risk of bias were extracted. A model-based meta-analysis was used to evaluate the time course of the placebo response in OA treatment and estimate the influencing factors. For subgroup analyses, a meta-analysis with a random-effects model was used to summarize the typical values of the model parameters and their SEs. Main Outcomes and Measures: The primary end point was the time course of the oral placebo response on the WOMAC pain, stiffness, and function subscale scores. Results: The 130 trials selected for analysis included 12 673 participants (mean age, 59.9 years; 68.9% women). The baseline scores of WOMAC pain, stiffness, and function subscales were found to be significantly associated with the placebo response. The placebo response reached 90% of its maximum response between 5 and 7 weeks. The placebo responses on the WOMAC subscales were also associated with the sample size, proportion of patients who had previously used nonsteroidal anti-inflammatory drugs, intervention drugs, and publication year. Conclusions and Relevance: In this study, an oral placebo response model of OA was developed that may quantitatively describe the placebo response at different baseline levels of symptoms. The findings may provide valuable references for future clinical trial design and decision-making.

Formation and elimination of pyrraline in the Maillard reaction in a saccharide-lysine model system.

BACKGROUND: Pyrraline, a causative factor for various kinds of disease, is also used as a food contaminant to evaluate the formation of advanced glycation end-products (AGEs) in diet foods. In this study, model systems consisting of lysine and different saccharides were heated at different times, temperatures and initial molar ratios of saccharide to lysine under microwave heating conditions in order to investigate the formation of pyrraline. RESULTS: Increase in initial molar ratio of saccharide to lysine could significantly promote the formation of pyrraline. Specifically, the pyrraline formation rate was influenced by the structure of saccharides involved in the reaction, and decreased in the following order: lactose > fructose > glucose > sucrose; the highest pyrraline was generated in lactose-lysine models. The maximum pyrraline was formed at 140 °C. Moreover, saccharides and lysine had different effects on the stability of pyrraline. Among the reactants, lysine was the major factor for the instability of pyrraline; a dipyrraline and a crosslink by pyrraline reacting with lysine could be formed. CONCLUSION: Pyrraline formation by the saccharide-lysine model system was a dynamic reaction, consisting not only of the pyrraline formation, but also pyrraline elimination with some formation of crosslinks. © 2015 Society of Chemical Industry.

Formation and inhibition of Nε-(carboxymethyl)lysine in saccharide-lysine model systems during microwave heating.

N(ε)-(carboxymethyl) lysine (CML) is the most abundant advanced glycation end product (AGE), and frequently selected as an AGEs marker in laboratory studies. In this paper, the formation and inhibition of N(ε)-(carboxymethyl)lysine in saccharide-lysine model systems during microwave heating have been studied. The microwave heating treatment significantly promoted the formation of CML during Maillard reactions, which was related to the reaction temperature, time and type of saccharide. The order of CML formation for different saccharides was lactose > glucose > sucrose. Then, the inhibition effect on CML by five inhibitors was further examined. According to the results, ascorbic acid and tocopherol did not affect inhibition of CML, in contrast, thiamin, rutin and quercetin inhibited CML formation, and the inhibitory effects were concentration dependent.