LETTERS to the EDITORPublication bias

The inhibition of the mitogen-activated protein kinases signalling pathway through combined use of BRAF and MEK inhibitors (BRAFi+MEKi) represents an established therapeutic option in patients with BRAF-mutated, advanced melanoma. These efficient therapies are well tolerated with mostly moderate and reversible side effects and a discontinuation rate due to adverse events of 11.5%-15.7%. Median duration of therapy ranges between 8.8 and 11.7 months. Based on data from confirmatory trials, safety profiles of three BRAFi+MEKi combinations were reviewed, that is, dabrafenib plus trametinib, vemurafenib plus cobimetinib and encorafenib plus binimetinib. Many adverse events are class effects, such as cutaneous, gastrointestinal, ocular, cardiac and musculoskeletal events; some adverse events are substance associated. Fever (dabrafenib) and photosensitivity (vemurafenib) are the most common and clinically prominent examples. Other adverse events are less frequent and the association to one substance is less strong such as anaemia, facial paresis (encorafenib), neutropenia (dabrafenib), skin rash, QTc prolongation and increased liver function tests (vemurafenib). This narrative review provides recommendations for monitoring, adverse event evaluation and management focusing on the clinically relevant side effects of the three regimens.

Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management

In this work, we propose a new predictive entropy-scaling approach for Newtonian shear viscosities based on group contributions. The approach is based on Rosenfeld’s original work [Rosenfeld, Y. Phys. Rev. A 1977, 15, 2545−2549]. The entropy scaling is formulated as third order polynomial in terms of the residual entropy as calculated from a group-contribution perturbed-chain polar statistical associating fluid theory (PCP-SAFT) equation of state. In this study, we analyze the course of entropy scaling parameters within homologous series and suggest suitable mixing rules for the parameters of functional groups. The viscosity of nonpolar, of polar, and of self-associating (hydrogen bonding) components are considered. In total, 22 functional groups are parametrized to viscosity data of 110 pure substances, from 12 different chemical families. The mean absolute relative deviations (MADs) to experimental viscosity data are typically around 5%. For three chemical families, namely, branched alkanes, 1-alcohols,...

Group Contribution Method for Viscosities Based on Entropy Scaling Using the Perturbed-Chain Polar Statistical Associating Fluid Theory

Purpose:Mitogen-activates protein kinase (MAPK) inhibitors, particularly MEK inhibitors, have shifted the treatment paradigm for metastatic BRAF-mutant cutaneous melanoma; however, oncologists, ophthalmologists, and patients have noticed different toxicities of variable importance. This review aims

Ocular adverse events associated with mek inhibitors

The viscosities and densities of the ternary mixtures water + ethyl acetate + ethanol and their constituent binaries have been measured at 298.15 and 318.15 K and atmospheric pressure. The excess molar volumes, , and viscosity deviations, Δη, were calculated from density and viscosity, respectively. A rational function due to Myers and Scott was used to describe the composition dependence of these properties. To describe the ternary system, binary pair additivity and the Pando et al. rational functions for the ternary contributions (ΔηT and ) were considered.

/pdf/viscosity-and-density-of-water-ethyl-acetate-ethanol-2s01vsb4cy.pdf

Viscosity and Density of Water + Ethyl Acetate + Ethanol Mixtures at 298.15 and 318.15 K and Atmospheric Pressure

The excess molar volumes, VE, viscosity deviations, Δη, and excess surface tensions were calculated from the measured density, viscosity, and surface tension values, σ, over the whole miscibility composition range for the ternary system water + ethyl butyrate + methanol and their constituent binaries, at 303.15 K and atmospheric pressure. The liquid interfacial tension was measured in the liquid−liquid equilibrium range at the same conditions of temperature and pressure. A Redlich−Kister type equation was used to correlate binary and ternary VE and Δη data. For the correlation of the surface tension of binary and ternary data, the Santos et al. equation was used. The interfacial tension was correlated with the Li and Fu equation.

/pdf/densities-viscosities-and-surface-and-interfacial-tensions-4k3cgdfoc6.pdf

Densities, Viscosities, and Surface and Interfacial Tensions of the Ternary Mixture Water + Ethyl Butyrate + Methanol at 303.15 K

https://www.eq.uc.pt/~fonseca/artigos/008_Water_Esters_Methanol.pdf

Water+esters+methanol: experimental data, correlation and prediction of surface and interfacial tensions at 303.15 K and atmospheric pressure

Objectives: This meta-analysis aims to evaluate the risk of ophthalmic adverse effects associated with MEK inhibitors. Methods: A literature search was conducted in PubMed and the Cochrane Library to identify randomized clinical trials (RCTs) which have been designed to evaluate the efficacy and safety of MEK inhibitors. Overall risk of ophthalmic adverse effects, chorioretinopathy, retinal detachment, blurred vision, uveitis, and eye haemorrhage were the assessed outcomes. Peto odds ratios (ORs) with their 95% confidence intervals (CIs) were pooled. Between-study heterogeneity was assessed using I2 statistics. Results: Thirteen RCTs were included in this meta-analysis. Overall, MEK inhibitors were associated with an increased risk of ophthalmic adverse effects (OR 2.24; 95% CI 1.75-2.87; p 2 = 86.5%). An increased risk was also estimated for chorioretinopathy (OR 5.44; 95% CI 2.89-10.23; p 2 = 0%), retinal detachment (OR 6.54; 95% CI 3.28-13.03; p 2 = 0%), and blurred vision (OR 2.30; 95% CI 1.50-3.54; p 2 = 60.1%), but not for uveitis (OR 0.99; 95% CI 0.14-7.03; p = 0.991; I2 = 2.9%) or eye haemorrhage (OR 0.72; 95% CI 0.04-12.39; p = 0.824; I2 = 29.8%). Conclusions: Treatment with MEK inhibitors seems to increase the risk of ophthalmic adverse effects. A need for monitoring the safety of this class of drugs exists. Regulators, clinicians, and other health care professionals must, together, be involved in this process.

Risk of Ophthalmic Adverse Effects in Patients Treated with MEK Inhibitors: A Systematic Review and Meta-Analysis

To characterize the techniques used to derive health-state utilities (HSU) in the cost-utility studies (CUS) of ophthalmic drugs. A systematic review was conducted in Pubmed/Embase until October 20...

A Systematic Review of Economic Studies Evaluating Ophthalmic Drugs: An Analysis of the Health-state Utilities.

The surface tension of kraft black liquor from eucalyptus has been measured between 20 and 70oC for solids content ranging up to 54 per cent. The dependence of the surface tension on the solids content follows the general pattern observed for black liquors from other woods. An empirical correlation describing the dependence of the surface tension on temperature and on solids content was established. This correlation can be applied to the actual conditions found in the chemicals recovery cycle of the kraft pulping process.

The Surface Tension of Kraft Black Liquor from Eucalyptus

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