The conjugated enol, 2-hydroxymuconate (1), is an unusually stable dienol that is reportedly generated in the course of bacterial catabolism of catechol by the enzymes of the meta-fission pathway. The dienol ketonizes chemically in aqueous solution and enzymatically by the action of 4-oxalocrotonate tautomerase (EC 5.3.2) to either the /3,7-unsaturated ketone 2 or its ,/S-conjugated isomer 3. Mechanistic studies for both processes remain largely unexplored. An examination of the behavior of 1 in phosphate buffer has been completed using UV,

Our objective was to develop a beta regression (BR) model to describe the longitudinal progression of the 11 item Alzheimer's disease (AD) assessment scale cognitive subscale (ADAS-cog) in AD patients in both natural history and randomized clinical trial settings, utilizing both individual patient and summary level literature data. Patient data from the coalition against major diseases database (3,223 patients), the Alzheimer's disease neruroimaging initiative study database (186 patients), and summary data from 73 literature references (representing 17,235 patients) were fit to a BR drug-disease-trial model. Treatment effects for currently available acetyl cholinesterase inhibitors, longitudinal changes in disease severity, dropout rate, placebo effect, and factors influencing these parameters were estimated in the model. Based on predictive checks and external validation, an adequate BR meta-analysis model for ADAS-cog using both summary-level and patient-level data was developed. Baseline ADAS-cog was estimated from baseline MMSE score. Disease progression was dependent on time, ApoE4 status, age, and gender. Study drop out was a function of time, baseline age, and baseline MMSE. The use of the BR constrained simulations to the 0-70 range of the ADAS-cog, even when residuals were incorporated. The model allows for simultaneous fitting of summary and patient level data, allowing for integration of all information available. A further advantage of the BR model is that it constrains values to the range of the original instrument for simulation purposes, in contrast to methodologies that provide appropriate constraints only for conditional expectations.

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Polatuzumab vedotin, an antibody‐drug conjugate containing monomethyl auristatin E, was associated with an incidence of grade ≥2 peripheral neuropathy (PN) of 55–72% in patients with indolent non‐Hodgkin lymphoma in a phase II study, when dosed 1.8–2.4 mg/kg every 3 weeks until progression or for a maximum of 17 cycles. To quantify the correlation of conjugate exposure and treatment duration with PN risk, a time‐to‐event model was developed using data from phase I and II studies. The model suggested that PN risk increased with conjugate exposure and treatment cycles, and a trend for increased risk with body weight and albumin concentration. When capping the treatment duration to six to eight cycles, the risk ratio of a dose of 2.4 mg/kg vs. 1.8 mg/kg was ≥1.29; the predicted incidence of grade ≥2 PN at 1.8–2.4 mg/kg dose levels was 17.8–37.2%, which is comparable with other antimicrotubule agents for lymphoma treatment.

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