Coumarin-Induced Hepatotoxicity: A Narrative Review

Coumarin is an effective treatment for primary lymphoedema, as well as lymphoedema related to breast cancer radiotherapy or surgery. However, its clinical use is limited in several countries due to the possible occurrence of hepatotoxicity, mainly in the form of mild to moderate transaminase elevation. It is worth noting that only a few cases of severe hepatotoxicity have been described in the literature, with no reported cases of liver failure. Data available on coumarin absorption, distribution, metabolism, and excretion have been reviewed, focusing on hepatotoxicity studies carried out in vitro and in vivo. Finally, safety and tolerability data from clinical trials have been thoroughly discussed. Based on these data, coumarin-induced hepatotoxicity is restricted to a small subset of patients, probably due to the activation in these individuals of alternative metabolic pathways involving specific CYP450s isoforms. The aim of this work is to stimulate research to clearly identify patients at risk of developing hepatotoxicity following coumarin treatment. Early identification of this subset of patients could open the possibility of more safely exploiting the therapeutical properties of coumarin, allowing patients suffering from lymphoedema to benefit from the anti-oedematous activity of the treatment.     

Nachweis und Bestimmung des Mangans sowie seine Trennung von anderen Elementen

Ohne Zusammenfassung     

Thermal Conversion of Gels Prepared by the Complex Sol-Gel Process (CSGP) from Li+-Me2+-CH3COO−-Ascorbic Acid (ASC)-NH4 +-OH−-H2O Systems to LiMn2O4 and LiNi x Co1 − x O2

The spinel LiMn₂O₄ and layered oxides LiNi _x Co_{1 – x} O₂ (x = 1; 0.75; 0) have been prepared by Complex Sol-gel Process (CSGP). The appropriate sol compositions were obtained from acetate aqueous solution of metals containing ascorbic acid by alkalizing it with aqueous ammonia. Gels were produced from the systems by evaporation of water and other volatilies at elevated temperatures. A very intense foaming was observed during the heating at the temperatures higher than 140°C. To avoid foaming in the course of the final thermal treatment, a very long (lasting several days) soaking step was found necessary. However pretreated materials exhibit self-ignition at temperature range 320–500°C dependent on socking conditions. The dependence of self-ignition temperature on carbon content in bed as well as on specific surface has not been proved. Final thermal transformation of gel to solid was studied by TG, DTA, XRD, and IR methods. It was observed that final compounds are formed faster from precursors which did not contain Ni (e.g. LiMn₂O₄ and LiCoO₂), while Li carbonate is not formed in these systems. In contrast, in Li-Ni(Co)-O the formation of Li(or Ni)CO₃ was always proved. In addition, during the thermal treatment Ni species are partially reduced even to metallic phase. This effect evidently restrains the formation of pure layered oxides phase. Electrochemical properties of carbonate free compounds are definitely better than of those containing CO₃.     

Analytical resolution of a parallel second‐order reaction mechanism

The competition among the three different elementary second‐order processes involving the radicals A and B, (1) (2) (3) is frequently established in many combustion and atmospheric chemistry systems. The analytical resolution of the above mechanism for k_AB = 2k_AA and k_AB = 2k_BB, that is, for a cross‐combination ratio ? = k_AB/(k_AAk_BB)^1/2 = 2, is well‐known, but it has been claimed not to exist for ? ≠ 2. In the present paper an analytical resolution of the system (1)–(3), performed under the condition k_AB ≠ 2k_AA and k_AB ≠ 2k_BB, leads to The mathematical procedure leading to this equation and the equation itself are valid independently of the nature of the products of the reactions ( 1 ), ( 2 ) and ( 3 ), that is, recombination or disproportionation products, provided that the reactants and the order of the reactions remain the same. The comparison with numerical integration for exemplary cases is performed. The solutions for the particular cases k_AB ≠ 2k_BB or k_AB ≠ 2k_AA are also presented. © 2003 Wiley Periodicals, Inc. Int J Chem Kinet 35: 246–251, 2003     

The Self‐Assembly of Anticancer Camptothecin–Dipeptide Nanotubes: A Minimalistic and High Drug Loading Approach to Increased Efficacy

20‐(S)‐Camptothecin (CPT)‐conjugated dipeptides are reported that preassemble into nanotubes with diameters ranging from 80–120 nm. These nanoassemblies maintain a high (～47 %) drug loading and exhibit greater drug stability (i.e., resistance to lactone hydrolysis), and consequently greater efficacy against several human cancer cells (HT‐29, A549, H460, and H23) in vitro compared with the clinically used prodrug irinotecan. A key and defining feature of this system is the use of the CPT‐conjugated dipeptide as both the drug and precursor to the nanostructured carrier, which simplifies the overall fabrication process.     

Synthesis of arylsulfonyl substituted pyrroles

The cycloaddition reaction of symmetrically and unsymmetrically substituted munchnones with arylsulfonyl alkynes has been studied. The reaction affords pyrrole derivatives whose structures were assigned on the basis of spectroscopic data. The distribution of regioisomers observed in the case of unsymmetrically substituted munchnones is discussed.     

Noncovalent organocatalytic synthesis of enantioenriched terminal aziridines with a quaternary stereogenic center

A high-yielding and enantioselective access to novel N-Boc terminal aziridines, bearing a quaternary stereogenic center, has been developed via an aza-Michael initiated ring-closure (aza-MIRC) reaction of α-acyl acrylates with an N-tosyloxy tert-butyl carbamate catalyzed by a chiral amino thiourea. The feasibility of the aziridine regioselective ring-opening to valuable α,α-disubstituted α-amino acid esters has been demonstrated.     

A Thermal Model for Pulsed EM Field Exposure Effects in Cells at Nonthermal Levels

The thermal response of an isolated cell under pulsed electric field exposure is studied, including a frequency-dependent membrane capacitance model. The possibility of a fast localized membrane heating up to physiologically significant levels is suggested, without sensible increase in the cytoplasmic temperature.      

A matheuristic approach for the two-machine total completion time flow shop problem

This paper deals with the two-machine total completion time flow shop problem. We present a so-called matheuristic post processing procedure that improves the objective function value with respect to the solutions provided by state of the art procedures. The proposed procedure is based on the positional completion times integer programming formulation of the problem with O(n ²) variables and O(n) constraints.     

The Red–Blue transportation problem

This paper considers the Red–Blue Transportation Problem (Red–Blue TP), a generalization of the transportation problem where supply nodes are partitioned into two sets and so-called exclusionary constraints are imposed. We encountered a special case of this problem in a hospital context, where patients need to be assigned to rooms. We establish the problem’s complexity, and we compare two integer programming formulations. Furthermore, a maximization variant of Red–Blue TP is presented, for which we propose a constant-factor approximation algorithm. We conclude with a computational study on the performance of the integer programming formulations and the approximation algorithms, by varying the problem size, the partitioning of the supply nodes, and the density of the problem.