Nine years of patch testing with isocyanates in a clinic of occupational dermatology.

BACKGROUND: Isocyanates are used as starting materials of polyurethane (PU) products. They are relatively important occupational skin sensitizers. OBJECTIVES: To analyse results of a large isocyanate patch test series of 19 isocyanate test substances and 4,4'-diaminodiphenylmethane (MDA), a marker of 4,4'-diphenylmethane diisocyanate (MDI) hypersensitivity. METHODS: Test files were screened for positive reactions in the isocyanate series. Patients with positive reactions were analysed for occupation, exposure and diagnosis. RESULTS: In 2010-2019, 53 patients had positive reactions in the series (16% of 338 patients tested). MDA, the well-established screening substance for MDI allergy, was positive in 30 patients, an in-house monomeric MDI test substance in 23 patients and 3 different polymeric MDI test substances in 19-21 patients. We diagnosed 16 cases of occupational allergic contact dermatitis (OACD) from MDI including 3 pipe reliners. Hexamethylene-1,6-diisocyanate (HDI) oligomers in paint hardeners caused 5 cases of OACD, more cases than 2,4-toluene diisocyanate (TDI; n = 3) and isophorone diisocyanate (IPDI; n = 1) put together. CONCLUSIONS: In contrast to previous studies, polymeric MDI test substances were not superior to a monomeric MDI. Pipe reliners may get sensitised not only by epoxy products and acrylates but also by MDI in hardeners of PU pipe coatings. HDI oligomers were the second most important causes of OACD after MDI.

Review article: do stimulant laxatives damage the gut? A critical analysis of current knowledge.

Stimulant laxatives are well established as first- or second-line treatments for constipation and although they have a reliable therapeutic effect, alleged safety concerns still exist, particularly with long-term use. The potential harmful effects on the gastrointestinal system (including carcinogenicity) of the long-term use of diphenylmethane [bisacodyl, sodium picosulfate (SPS)] and senna stimulant laxatives were assessed in a comprehensive review of the publications identified in literature searches performed in PubMed and Embase up to and including June 2023. We identified and reviewed 43 publications of interest. While stimulant laxatives at supratherapeutic doses have been shown to cause structural alterations to surface absorptive cells in animals and humans, these effects are reversible and not considered clinically relevant. No formal long-term studies have demonstrated morphological changes in enteric neural elements or intestinal smooth muscle with bisacodyl or SPS in humans. Furthermore, there is no convincing evidence that stimulant laxatives are associated with the development of colon cancer, and in fact, chronic constipation itself has been reported to potentially increase the risk of colon cancer, therefore, the use of stimulant laxatives might reduce this risk. Many studies suggesting a possible harmful effect from laxatives were limited by their failure to consider confounding factors such as concomitant neurological disease, metabolic disorders, and age. These findings highlight the lack of evidence for the harmful effects of laxatives on the colon, and thus, the benefits of treatment with stimulant laxatives, even in the long-term, should be reconsidered for the management of patients with constipation.

Do stimulant laxatives damage the gut? Stimulant laxatives are widely used treatments for constipation that work by causing the muscles in the gut to contract and so move stool more effectively. Examples of these treatments include senna, bisacodyl and sodium picosulfate. Treatments such as these are typically available without a doctor's prescription and have a long history of helping people relieve their constipation. However, some concerns have been expressed about the safety of these treatments, particularly when they are used for a long time. We did a critical review of published studies of the safety of stimulant laxatives to try to find out whether there is any strong evidence for harm being caused by these treatments. We found 43 papers with information on the gut safety of stimulant laxatives. These studies looked at whether the treatments are associated with changes to gut structure or function and at whether there might be a link between these treatments and bowel cancer. Unfortunately, many of the studies were of poor quality. For instance, they did not look for things, in addition to the laxatives, that could have affected the results, such as the age of the patients, other medications they were taking or whether they had other health conditions that might have affected the bowel. Also, the populations in which the studies were done differed a lot, so they were hard to compare with one another. However, we did not find any strong evidence suggesting that stimulant laxatives damage the gut or cause cancer. We therefore concluded that the harms associated with stimulant laxatives are likely to have been overstated, and that patients should not be denied the benefits of stimulant laxatives for constipation, especially as they have been on the market for a very long time with no serious problems emerging.

Curing Kinetics of Methylene Diphenyl Diisocyanate-Based Polyurethane Elastomers.

The curing kinetics of MDI-based polyurethane elastomers were studied by non-isothermal differential scanning calorimetry (DSC). The kinetic parameters of the reaction system were calculated by the Kissinger method. The changing activation energy was observed by the Flynn−Wall−Ozawa method and the Friedman method. The results of model free fitting showed that the curing reaction could be divided into two stages, showing a change in reaction order when α > 0.45 and a piecewise curing mechanism function of the MDI-based polyurethane elastomers reaction system was deduced by autocatalytic model. The extrapolation method was used to determine the optimum curing conditions for the system, which can accurately describe the curing process. In addition, the optimal curing conditions are when: the constant temperature curing temperature of the system is 81 °C, the curing time is 29 min, and the post-curing temperature is 203 °C.

Identified Seaweed Compound Diphenylmethane Serves as an Efflux Pump Inhibitor in Drug-Resistant Escherichia coli.

Drug efflux pumps are one of the major elements used by antibiotic-resistant bacteria. Efflux pump inhibitors (EPIs) are potential therapeutic agents for adjunctive therapy, which can restore the activity of antibiotics that are no longer effective against pathogens. This study evaluated the seaweed compound diphenylmethane (DPM) for its EPI activity. The IC50 and modulation results showed that DPM has no antibacterial activity but can potentiate the activity of antibiotics against drug-resistant E. coli. Time-kill studies reported that a combination of DPM and erythromycin exhibited greater inhibitory activity against drug-resistant Escherichia coli. Dye accumulation and dye efflux studies using Hoechst 33342 and ethidium bromide showed that the addition of DPM significantly increased dye accumulation and reduced dye efflux in drug-resistant E. coli, suggesting its interference with dye translocation by an efflux pump. Using MALDI-TOF, it was observed that the addition of DPM could continuously reduce antibiotic efflux in drug-resistant E. coli. Additionally, DPM did not seem to damage the E. coli membranes, and the cell toxicity test showed that it features mild human-cell toxicity. In conclusion, these findings showed that DPM could serve as a potential EPI for drug-resistant E. coli.

Animal models of cathartic colon.

The incidence of cathartic colon has been increasing, but satisfactory treatments are still lacking. In order to study the pathological mechanisms of the disorder and identify effective treatment methods, researchers have established different animal models of cathartic colon. This minireview briefly summarizes several common cathartic colon animal models, induced with anthraquinone laxatives such as rhubarb, total anthraquinone, rhein, and emodin, or induced with diphenylmethane laxatives such as phenolphthalein. The advantages and limitations of these models are evaluated and analyzed. We hope that this review will facilitate the selection of suitable models and improve relevant modeling methods. We anticipate the development of more convenient and stable models that can reflect the characteristics of cathartic colon in humans, and serve as useful tools for further studies.

[Determination of N-[4- (4-aminobenzyl) -phenyl] acetamide hemoglobin adduct in blood by ultra performance liquid chromatography-tandem mass spectrometry].

Objective: To establish the method for the determination of N-Acetyl-4, 4'-diaminodiphenylmethane (AcMDA) adduct in the hemoglobin by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) . Methods: The 20 mg hemoglobin sample was weighed into a 15 ml centrifuge tube, adding 20 µg/L internal standard solution AcMDA-D8 10 µl, then hydrolyzed with 1 ml 0.1 mol/L sodium hydroxide solution at 37°C for 0.5 hours, extracted with dichloromethane and concentrated by vacuum concentrator. The residue was dissolved in acetonitrile and detected by UPLC-MS/MS, then quantitative by internal standard method. Results: The linearity of the method was good at the range of 0.05-25.00 µg/L with a correlation coefficient of 0.9996, the detection limit (LOD) and limit of quantitation (LOQ) were 0.07 and 0.2 ng/g Hb, respectively. The recovery rate was ranged from 91.0%-95.4%; the relative standard deviation (RSD) of intra-and inter-batch precision were 4.5%-6.3% and 3.7%-4.4%, respectively. Conclusion: The determination method meet the requirement of GBZ/T 210.5-2008.

Effect of Diisocyanates as Compatibilizer on the Properties of BF/PBAT Composites by In Situ Reactive Compatibilization, Crosslinking and Chain Extension.

Due to the hydrophobic nature of poly (butylene terephthalate) (PBAT), and the hydrophilic nature of bamboo flour (BF), a BF/PBAT (50/50) blend shows low mechanical properties, and especially shows poor impact strength. In order to increase the interfacial adhesion between BF and PBAT, diisocyanate was used as a reactive compatibilizer to modify bamboo powder. A series of BF/PBAT composites were prepared by the method of mixing and melting in an internal mixer. After adding reactive compatibilizer 4,4'-methylenebis(phenyl isocyanate) (MDI), BF/PBAT (50/50) composites with high mechanical properties were successfully prepared. The tensile strength, elongation at break, and impact strength of the BF/MDI-2/PBAT composite with 2 wt % MDI content were increased by 1.9, 6.8, and 4.3 times respectively over the BF/PBAT blend without the added MDI. The higher toughening effect of MDI in BF/PBAT composites can be mainly ascribed to the improved interface bonding between BF and PBAT. The isocyanate group of MDI can react with the hydroxyl group on the BF surface and in situ formation of the carbamate group on the BF surface. The residual isocyanate can then react with the hydroxyl group of PBAT and form carbamate groups. The rheological behaviors demonstrate that addition of appropriate amounts of MDI, 1 wt % and 2 wt %, can promote the flowability of the molten BF/PBAT composites due to the decrease in interparticle interaction between bamboo powder and the increase in the thermal motion of the molecules.

[Determination of diphenylmethane diisocyanate in workplace air by HPLC with impregnated filter membrane].

Objective: To develop a method for determining diphenylmethane diisocyanate in workplace air by HPLC with impregnated filter membrane. Methods: MDI in workplace air reacted with 1- (2-pyridyl) piperazine on impregnated filter membrane to form MDI-urea derivatives, after elution and filtration, it was detected by HPLC-UV. Results: Limit of detection was 0.003 8 µg/ml and limit of quantification was 0.013 µg/ml. Good linearity was obtained in the range of 0.013~2.000 µg/ml (r=0.999 7) . The precision was 3.10%~8.03% (n=6) , while the recovery was 96.3%~101.9%. Asorption capacity of the membrane was 40.8 µg MDI, and could be stored for 14 days in the light-proof environment of 2~8 ℃. Conclusion: The method optimized testing steps for MDI's standard curve, and provided good guidance for determination of MDI in workplace air with impregnated fiter membrane.

Characterization of Aerosol Release during Spraying of Isocyanate Products.

The aerosol release during the professional application of two different isocyanate based two component spray systems was identified and the physicochemical properties of the released airborne aerosols were characterized. For this purpose, aerosol release fractions were measured using a mass balance method described by Schwarz and Koch. Besides the release of total aerosol mass special emphasis was directed to the content of free monomeric MDI (4,4'- and 2,4'-diphenylmethane diisocyanate) in three particle size fractions relevant for inhalation uptake: inhalable, thoracic, and respirable size fraction. Two products were investigated: a two component PUR (polyurethane) spray foam (Elastopor) and a polyurea spray coating (Elastocoat). The mass fraction of the applied products released with the overspray as inhalable aerosol is 6.3 × 10-4 (Elastopor) and 4.0 × 10-4 (Elastocoat). Of the released total overspray aerosol 75 or 80% were in the thoracic size range, and 26 or 47% in the respirable regime for the PUR spray foam or the polyurea spray coating, respectively. At the time point of release the content of monomeric MDI in the aerosol corresponds to the composition of the bulk product. However, analysis of air samples indicates that <1% of the spray foam aerosol mass release fraction is attributed to free monomeric 4,4'- and 2,4'-MDI. For the Spray Coating the monomeric MDI fraction is <0.1%. Higher oligomers of MDI and prereacted oligomeric reaction products make up a few percent of the aerosol. This results in a total fraction of 0.0023% (spray foam) and 0.00015% (spray coating), respectively, of the sprayed monomeric MDI that is transferred into an inhalable aged aerosol. This data demonstrates, that during professional spraying only a small fraction of the total applied mass is released as airborne aerosol. The potential distribution of the theoretically inhalable aerosol in the respiratory tract and a low residual monomer content is described, significantly contributing to a refined safety assessment of the spray applications at the workplaces.

Structure-based drug design and in vitro testing reveal new inhibitors of enoyl-acyl carrier protein reductases.

The need for new antibacterial agents is increasingly becoming of great importance as bacterial resistance to current drugs is quickly spreading. Enoyl-acyl carrier protein reductases (FabI) are important enzymes for fatty acid biosynthesis in bacteria and other micro-organisms. In this project, we conducted structure-based virtual screening against the FabI enzyme, and accordingly, 37 compounds were selected for experimental testing. Interestingly, five compounds were able to demonstrate antimicrobial effect with variable inhibition activity against various strains of bacteria and fungi. Minimum inhibitory concentrations of the active compounds were determined and showed to be in low to medium micromolar range. Subsequently, enzyme inhibition assay was carried out for our five antimicrobial hits to confirm their biological target and determine their IC50 values. Three of these tested compounds exhibited inhibition activity for the FabI enzyme where our best hit MN02 had an IC50 value of 7.8 µM. Furthermore, MN02 is a small bisphenolic compound that is predicted to have all required features to firmly bind with the target enzyme. To sum up, hits discovered in this work can act as a good starting point for the future development of new and potent antimicrobial agents.

Derivatives of Natural Product Agrimophol as Disruptors of Intrabacterial pH Homeostasis in Mycobacterium tuberculosis.

This article reports the rational medicinal chemistry of a natural product, agrimophol (1), as a new disruptor of intrabacterial pH (pHIB) homeostasis in Mycobacterium tuberculosis (Mtb). Through the systematic investigation of the structure-activity relationship of 1, scaffold-hopping of the diphenylmethane scaffold, pharmacophore displacement strategies, and studies of the structure-metabolism relationship, a new derivative 5a was achieved. Compound 5a showed 100-fold increased potency in the ability to reduce pHIB to pH 6.0 and similarly improved mycobactericidal activity compared with 1 against both Mycobacterium bovis-BCG and Mtb. Compound 5a possessed improved metabolic stability in human liver microsomes and hepatocytes, lower cytotoxicity, higher selectivity index, and similar pKa value to natural 1. This study introduces a novel scaffold to an old drug, resulting in improved mycobactericidal activity through decreasing pHIB, and may contribute to the critical search for new agents to overcome drug resistance and persistence in the treatment of tuberculosis.

Determination of diphenylmethane diisocyanate in workplace air by HPLC with impregnated filter membrane / 中华劳动卫生职业病杂志

Objective@#To develop a method for determining diphenylmethane diisocyanate in workplace air by HPLC with impregnated filter membrane.@*Methods@#MDI in workplace air reacted with 1- (2-pyridyl) piperazine on impregnated filter membrane to form MDI-urea derivatives, after elution and filtration, it was detected by HPLC-UV.@*Results@#Limit of detection was 0.003 8 μg/ml and limit of quantification was 0.013 μg/ml. Good linearity was obtained in the range of 0.013~2.000 μg/ml (r=0.999 7) . The precision was 3.10%~8.03% (n=6) , while the recovery was 96.3%~101.9%. Asorption capacity of the membrane was 40.8 μg MDI, and could be stored for 14 days in the light-proof environment of 2~8 ℃.@*Conclusion@#The method optimized testing steps for MDI's standard curve, and provided good guidance for determination of MDI in workplace air with impregnated fiter membrane.

[Determination of methylenedianiline in urine by high performance liquid chromatography-tandemmass spectrometry].

Objective: To develop a method for determination of metabolites of diphenylmethane diisocyanate (MDI) in urine, i.e. methylenedianiline (MDA) by high performance liquid chromatography-tandem mass (LC-MS-MS) . Methods: Urine samples were prepared by hydrolyzation with sulfuric acid and extraction by acetonitrile, and then separated on a Shim-pack XR-ODS column, analyzed with high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) . The external solvent standard calibration were tested. Results: The linearity ranges were 0.05~20.00 µg/L, The related coefficients were 0.999 5. The limit of detection was 0.02 µg/L. The rats of recovery were 91.0%~103.4%. The relative standard deviations were between 2.7%~7.3%. Conclusion: The method was sensitive, accurate and suitable for the MDA determination in urine of MDI exposed population.

Assessment of dermal uptake of diphenylmethane-4,4'-diisocyanate using tape stripping and biological monitoring.

Very little is known about the dermal uptake of isocyanates, and dermal exposure to isocyanates has been discussed as a factor involved in the induction of respiratory diseases. To investigate the dermal uptake of diphenylmethane-4,4'-diisocyanate (4,4'-MDI). Four volunteers were dermally exposed to 10, 25, 49 and 50 mg 4,4'-MDI, respectively, for eight hours. The exposed areas were tape stripped. Urine and blood were biologically monitored for 48 hours. Tape strips, plasma, and urine were analysed by liquid chromatography-mass spectrometry. In total, 35-70% of the applied dose of 4,4'-MDI was absorbed by the skin. Very low fractions of applied dose were found in the tape strips. The 4,4'-MDA concentration in plasma and urine was low, but peaked in urine at 10-14 hours and plasma at 8-32 hours after exposure. 4,4'-MDI is readily absorbed by human skin. Only small fractions of 4,4'-MDI remain as such in the superficial skin layers. The amounts found in blood and urine were only small fractions of the total applied doses which indicates that very small amounts of 4,4'-MDI penetrate the skin and reach the blood stream. The dermal uptake and distribution of 4,4'-MDI is much slower compared to that associated with airway uptake. Our data strongly indicate that formation of 4,4'-MDA from 4,4'-MDI upon reacting with water in the skin can only occur to a very limited extent.

Determination of methylenedianiline in urine by high performance liquid chromatography-tandemmass spectrometry / 中华劳动卫生职业病杂志

Objective@#To develop a method for determination of metabolites of diphenylmethane diisocyanate (MDI) in urine, i.e. methylenedianiline (MDA) by high performance liquid chromatography-tandem mass (LC-MS-MS) . @*Methods@#Urine samples were prepared by hydrolyzation with sulfuric acid and extraction by acetonitrile, and then separated on a Shim-pack XR-ODS column, analyzed with high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) . The external solvent standard calibration were tested. @*Results@#The linearity ranges were 0.05~20.00 μg/L, The related coefficients were 0.999 5. The limit of detection was 0.02 μg/L. The rats of recovery were 91.0%~103.4%. The relative standard deviations were between 2.7%~7.3%. @*Conclusion@#The method was sensitive, accurate and suitable for the MDA determination in urine of MDI exposed population.

Efficient synthesis of a multi-substituted diphenylmethane skeleton as a steroid mimetic.

Steroids are important components of cell membranes and are involved in several physiological functions. A diphenylmethane (DPM) skeleton has recently been suggested to act as a mimetic of the steroid skeleton. However, difficulties are associated with efficiently introducing different substituents between two phenyl rings of the DPM skeleton, and, thus, further structural development based on the DPM skeleton has been limited. We herein developed an efficient synthetic method for introducing different substituents into two phenyl rings of the DPM skeleton. We also synthesized DPM-based estrogen receptor (ER) modulators using our synthetic method and evaluated their ER transcriptional activities.

The C-terminal tails of 4,4'-diphenylmethane-bis(methyl) carbamate are essential for binding to receptor for advanced glycation end products to attenuate advanced glycation end products-induced inflammation and apoptosis responses in human umbilical vein endothelial cells.

OBJECTIVES: A novel compound 4,4'-diphenylmethane-bis(methyl) carbamate (CM1) was shown to possess preventive activity on AGEs-induced human umbilical vein endothelial cells (HUVECs) damage via binding to RAGE. However, the underlying structural basis of CM1 on binding to RAGE was not fully understood. METHODS: In the present study, CM1 analogues were designed and synthesized to compare the activity differences on inhibiting AGEs-induced inflammatory response including TGF-ß1, RAGE protein expression in HUVECs, and macrophages migration and adhesion to HUVECs. In addition, the cell viability and anti-apoptosis activities of CM1 analogues were also examined. KEY FINDINGS: These results indicated that CM1 had higher activities on preventing AGEs-induced HUVECs damage (inflammation, cell viability and apoptosis) than other analogues. The bioaffinity assay was conducted by CMC and demonstrated that the IC50 and dissociation equilibrium constants (Kd) of CM1 were lower whereas the Bmax was higher than other analogues. The incubation of RAGE protein with CM1 analogues by equilibrium dialysis method showed CM1 had a stronger binding rate than other CM1 analogues. CONCLUSION: Our findings suggested that the C-terminal tails (methoxycarbonyl groups) of CM1 were the active groups for binding to RAGE and then led to the attenuation on RAGE-mediated endothelial dysfunction.