Tapentadol Safety and Patient Characteristics Associated with Treatment Discontinuation in Cancer Therapy: A Retrospective Multicentre Study in Japan.

INTRODUCTION: Tapentadol has analgesic effects comparable to those of conventional opioids and is associated with fewer side effects, including gastrointestinal symptoms, drowsiness, and dizziness, than other opioids. However, the safety of tapentadol in the Japanese population remains unclear; the present multicentre study aimed to examine the safety of tapentadol and the characteristics of patients likely to discontinue this treatment owing to adverse events. METHODS: The safety of tapentadol was assessed retrospectively in patients with any type of cancer treated between August 18, 2014 and October 31, 2019 across nine institutions in Japan. Patients were examined at baseline and at the time of opioid discontinuation. Multivariate analysis was performed to identify factors associated with tapentadol discontinuation owing to adverse events. RESULTS: A total of 906 patients were included in this study, and 685 (75.6%) cases were followed up until tapentadol cessation for any reason. Among patients who discontinued treatment, 119 (17.4%) did so because of adverse events. Among adverse events associated with difficulty in taking medication, nausea was the most common cause of treatment discontinuation (4.7%), followed by drowsiness (1.8%). Multivariate analysis showed that those who were prescribed tapentadol by a palliative care physician (odds ratio [OR] 2.60, 95% confidence interval [CI] 1.36-4.99, p = 0.004), patients switching to tapentadol due to side effects from previous opioids (OR 2.19, 95% CI 1.05-4.56, p = 0.037), and patients who did not use naldemedine (OR 5.06, 95% CI 2.47-10.37, p < 0.0001) had an increased risk of treatment discontinuation owing to adverse events. CONCLUSIONS: This study presents the safety profile of tapentadol and the characteristics of patients likely to discontinue this treatment owing to adverse events in the Japanese population. Prospective controlled trials are required to evaluate the safety of tapentadol and validate the present findings. TRIAL REGISTRATION NUMBER: UMIN 000044282 (University Hospital Medical Information Network).

Manganese-catalyzed benzene synthesis by [2+2+2] coupling of 1,3-dicarbonyl compound and terminal acetylene.

Treatment of a mixture of a 1,3-dicarbonyl compound such as a beta-ketoester or 1,3-ketone and a terminal acetylene with a catalytic amount of MnBr(CO)5 in heated toluene produces a benzene derivative by a [2+2+2] coupling reaction incorporating the enol part of the dicarbonyl compound and two moles of the acetylene. When the reaction was carried out using phenylacetylene derivatives, the reaction was completely regioselective, producing p-terphenyl compounds in good to excellent yield. Aliphatic terminal acetylenes also reacted readily but gave a mixture of regioisomers. The reaction features high atom economy, neutral conditions, and functional group tolerance, and will be useful for materials-oriented studies.

Construction of a chiral quaternary carbon center by indium-catalyzed asymmetric alpha-alkenylation of beta-ketoesters.

Construction of a nonracemic all-carbon quaternary stereocenter at the alpha-position of beta-ketoesters was achieved by way of an indium(III)-catalyzed diastereoselective alpha-alkenylation reaction of chiral enamines with 1-alkynes. The enamine bearing a chiral auxiliary derived from l-isoleucine was added to the alkyne to give an alpha-alkenylated product in excellent yield and with a stereoselectivity better than 90% ee. One can ascribe the high selectivity to a chelate intermediate involving the auxiliary and the metal atom and the high yield to efficient interactions between the indium(III) atom and the alkyne. The selectivity increased as the reaction temperature was raised to 120 degrees C and decreased at higher temperatures.

Stereoselective synthesis of trisubstituted E-iodoalkenes by indium-catalyzed syn-addition of 1,3-dicarbonyl compounds to 1-iodoalkynes.

Indium-catalyzed addition of 1,3-dicarbonyl compounds to 1-iodo-1-alkynes takes place exclusively in a syn-fashion to produce E-iodoalkenes. The iodine atom serves both as an activating group and as a group that controls the regioselectivity of the addition. The E-alkenyl iodide product can be further derivatized using either a one-pot or a two-pot procedure into trisubstituted olefins in high overall yield with retention of the stereochemistry.

Stereoselective synthesis of tetra-substituted olefins via addition of zinc enolates to unactivated alkynes.

[reaction: see text] In the presence of a stoichiometric or catalytic amount of diethylzinc, a beta-aminocrotonamide undergoes sequential addition/isomerization reactions with 1-alkyne to produce, upon hydrolysis, an alpha-alkylidene beta-dicarbonyl compound in a highly stereoselective manner. The method complements the conventional Knoevenagel synthesis of this class of compounds as to the choice of the starting material and the scope and stereochemistry of the product.