A novel chitosan antioxidant bearing sulfhydryl group: Synthesis, characterization and activity assessment.

To improve the antioxidant activity, sulfhydryl groups (-SH) were introduced into chitosan. Acylated chitosan derivatives, chitosan cationic salt derivatives, hydroxypropyl trimethylammonium chloride chitosan quaternary ammonium salt (HACC) derivatives and N,N,N-trimethyl chitosan iodine (TMC) derivatives were obtained. The chitosan derivatives were characterized by FTIR and 1H NMR to confirm the successful synthesis. Ellman's reagent was used to determine that the compound contained free sulfhydryl groups. The water solubility and thermal stability of chitosan and derivatives were evaluated. The antioxidant activities of the derivatives were verified, including DPPH radical scavenging activity, superoxide anion radical scavenging activity and reducing power activity. The novel chitosan derivatives showed excellent antioxidant activities. Toxicity assay used L929 cells proved that the derivatives had no significant toxic. The results showed that the chitosan derivatives bearing sulfhydryl groups described in this paper has a certain antioxidant effect, which provides a practical approach for further study of chitosan.

Three-Dimensional Assessment of Radiographic Changes after Indirect Pulp Capping Using Silver Diamine Fluoride with or without Potassium Iodide in Young Permanent Teeth (12-Month RCT).

The aim of this study was to conduct a three-dimensional (3D) evaluation of radiographic changes after indirect pulp capping (IPC) with silver diamine fluoride (SDF) with or without potassium iodide (KI) and resin-modified glass ionomer cement (RMGIC) in deep carious young permanent molars using cone-beam computed tomography (CBCT). 108 first permanent molars with deep occlusal cavitated caries lesions, in forty-nine 6- to 9-year-old children, were randomly allocated to one of 3 groups (n = 36) and treated with SDF+KI, SDF, and RMGIC as IPC materials. CBCT scans were taken at 0 and 12 months to assess tertiary dentin formation (volume and grey level intensity), increase in root length, and pathological changes such as secondary caries, periapical radiolucency, internal resorption, and obliteration of the pulp. The 3D image analysis procedures were performed using ITK-SNAP and 3D Slicer CMF. Comparisons were made using analysis of variance with a fixed effect for treatment and random effects for patient and patient-by-treatment to account for within-patient correlations. A two-sided 5% significance level was used. There were no significant differences among the three groups regarding tertiary dentin volume (p = 0.712) and grey level intensity (p = 0.660), increase in root length (p = 0.365), prevention of secondary caries (p = 0.63), and periapical radiolucency (p = 0.80) in the analysed 69 CBCT scans. The study did not find differences among the groups regarding quality and quantity of tertiary dentin formed, increase in root length, absence of secondary caries, and other signs of failure as shown by CBCT. Clinical Significance: The results show no significant differences in radiographic outcomes (quality and quantity of tertiary dentin formed, increase in root length, absence of secondary caries, and other signs of failure) when using SDF+KI, SDF, and RMGIC in IPC. The results of this study can help guide treatment decision-making regarding use of SDF and SDF+KI as IPC materials in deep cavitated lesions.

Atom Economical QPCs: Phenyl-Free Biscationic Quaternary Phosphonium Compounds as Potent Disinfectants.

Quaternary ammonium compounds (QACs) are vital disinfectants for the neutralization of pathogenic bacteria in clinical, domestic, and commercial settings. After decades of dependence on QACs, the emergence of antimicrobial resistance to this class of compounds threatens the ability of existing QAC products to effectively manage rising bacterial threats. The need for new disinfectants is therefore urgent, with quaternary phosphonium compounds (QPCs) emerging as a new class of promising antimicrobials that boast significant activity against highly resistant bacteria. Reported here is a series of twenty-one novel QPCs that replace phenyl substituents on the phosphorus center with alkyl groups yet allow for rapid synthetic routes in high yields. Within this series are structures containing methyl, ethyl, or cyclohexyl phosphonium substituents on bisphosphane scaffolds bearing ethyl linkers, affording atom economical structures and ones that represent exact analogs to nitrogenous amphiphiles. The resultant bisQPC structures display high antibacterial efficacy enjoyed by comparably constructed QACs, with three structures in the single-digit micromolar activity range despite structural simplification.

Solvent-Free Strategy for Direct Access to Versatile Quaternary Ammonium Salts with Complete Atom Economy.

A solvent-free method for the synthesis of quaternary ammonium salts (QAS) by iodoquaternization of alkenes with N-heteroarenes was reported. Its advantages lie in energy-saving and clean production by using iodine as the oxidant and manual grinding the starting materials, together with the complete atom economy and low process mass intensity (PMI) value. Demonstrated by 50 examples, the generated QAS was proved to be able to produce valuable chemicals, such as biological protease inhibitors, anti-cancer agents, and organic fluorescent materials.

Assessment of ecological hazards and environmental fate of disinfectant quaternary ammonium compounds.

Disinfectant quaternary ammonium compounds (Quats) have diverse uses in a variety of consumer and commercial products, particularly cleaning products. With the emergence of the COVID-19 pandemic, they have become a primary tool to inactivate the SARS-CoV-2 virus on surfaces. Disinfectant Quats have very low vapor pressure, and following the use phase of the products in which they are found, disposal is typically "down-the-drain" to wastewater treatment systems. Consequently, the potential for the greatest environmental effect is to the aquatic environment, from treated effluent, and potentially to soils, which might be amended with wastewater biosolids. Among the earliest used and still common disinfectant Quats are the alkyl dimethyl benzyl ammonium chloride (ADBAC) compounds and the dialkyl dimethyl ammonium chloride (DDAC) compounds. They are cationic surfactants often found in consumer and commercial surface cleaners. Because of their biocidal properties, disinfectant Quats are heavily regulated for human and environmental safety around the world. Consequently, there is a robust database of information regarding the ecological hazards and environmental fate of ADBAC and DDAC; however, some of the data presented are from unpublished studies that have been submitted to and reviewed by regulatory agencies (i.e., EPA and European Chemicals Agency) to support antimicrobial product registration. We summarize the available environmental fate data and the acute and chronic aquatic ecotoxicity data for freshwater species, including algae, invertebrates, fish, and plants using peer-reviewed literature and unpublished data submitted to and summarized by regulatory agencies. The lower limit of the range of the ecotoxicity data for disinfectant Quats tends to be lower than that for other surface active agents, such as nonionic or anionic surfactants. However, ecotoxicity is mitigated by environmental fate characteristics, the data for which we also summarize, including high biodegradability and a strong tendency to sorb to wastewater biosolids, sediment, and soil. As a result, disinfectant Quats are largely removed during wastewater treatment, and those residues discharged in treated effluent are likely to rapidly bind to suspended solids or sediments, thus mitigating their toxicity.

Assessment of early onset surface damage from accelerated disinfection protocol.

Background: The objective of this study was to evaluate the extent and potential mechanisms of early onset surface damage from simulated wiping typical of six-months of routine disinfection and to assess the subsequent microbial risk of surfaces damaged by disinfectants. Methods: Eight common material surfaces were exposed to three disinfectants and a neutral cleaner (neutral cleaner, quaternary ammonium, hydrogen peroxide, sodium hypochlorite) in accelerated aging tests to simulate a long-term disinfection routine. Materials were also immersed in dilute and concentrated chemical solutions to induce surface damage. Surfaces were chemically and physically characterized to determine extent of surface damage. Bactericidal efficacy testing was performed on the Quat-based disinfectant using a modified version of EPA standard operating procedure MB-25-02. Results: The wiping protocol increased surface roughness for some material surfaces due to mechanical abrasion of the wiping cloth. The increased roughness did not correlate with changes in bactericidal efficacy. Chemical damage was observed for some surface-disinfectant combinations. The greatest observed effects from disinfectant exposure was in changes in wettability or water contact angle. Conclusions: Early onset surface damage was observed in chemical and physical characterization methods. These high-throughput material measurement methods were effective at assessing nanoscale disinfectant-surface compatibility which may go undetected though routine macroscale testing.

Assessment of the bacterial viability of chlorine- and quaternary ammonium compounds-treated Lactobacillus cells via a multi-method approach.

AIMS: The assessment of the bacterial viability of chlorine- and quaternary ammonium compounds (QACs)-treated Lactobacillus cells by culture-dependent and -independent methods. METHODS AND RESULTS: Lactobacillus isolates (Lactobacillus plantarum G1, Lactobacillus plantarum B1, Lactobacillus brevis S1 and Lactobacillus paracasei W1) in biofilm and planktonic cell suspensions were treated with chlorine-based (0·018 and 0·18%) and QACs-based (0·2 and 2·0%) disinfectants for 5 min and then analysed by plate counting, flow cytometry (FCM) and fluorescence activated cell sorting (FACS). The reaction of sessile cells to disinfectants was assessed with the confocal laser scanning microscopy (CLSM). Plate counts revealed L. paracasei W1 to be substantially inactivated by both disinfectants, while counts of the other isolates to be significantly reduced only by QACs, with L. plantarum B1 and L. brevis S1 showing a greater difference between QACs concentrations and cell types. In several cases, the disinfectants caused slightly higher inactivation of planktonic than biofilm cells, with L. plantarum B1 being significantly less sensitive to QACs in biofilm cells (P < 0·05). Following FCM with a Syto® 9/PI assay, which addresses cell membrane integrity, the emergence of damaged (Syto® 9- PI+ ) and injured (Syto® 9+ PI+ ) subpopulations was often observed in cells when they were treated with QACs, whereas intact (Syto® 9+ PI- ) and unstained (Syto® 9- PI- ) subpopulations were mostly encountered in chlorine-treated cells. Except Syto® 9- PI+ , all subpopulations were recovered on agar plates following FACS, with biofilm cells showing higher culturability irrespective of conditions, probably because of the residues of the biofilm matrix which serve as a protective cover for the bacteria. The CLSM revealed a substantial cell membrane damage within the QACs-treated biofilms, however, some cells deep in the biofilm were still intact and thus remained protected against this disinfectant. CONCLUSION: We found that FCM/FACS proved useful in the analysis of lactobacilli membrane integrity in disinfection experiments as well as in recovery evaluation of planktonic-biofilm cell subpopulations. In turn, CLSM was particularly useful in investigating the resistance mechanism when Lactobacillus cells were embedded in biofilms. SIGNIFICANCE AND IMPACT OF THE STUDY: This study highlights the need for treatment optimization on a case-by-case basis to avoid the emergence of cells in intermediate states with recovery potential and to reach and, thus, kill all bacteria in already developed lactobacilli biofilms.

Preparation and Characterization of Novel Cationic Chitosan Derivatives Bearing Quaternary Ammonium and Phosphonium Salts and Assessment of Their Antifungal Properties.

Chitosan is an abundant and renewable polysaccharide, its derivatives exhibit attractive bioactivities and the wide applications in various biomedical fields. In this paper, two novel cationic chitosan derivatives modified with quaternary phosphonium salts were successfully synthesized via trimethylation, chloride acetylation, and quaternization with tricyclohexylphosphine and triphenylphosphine. The structures and properties of synthesized products in the reactions were characterized by FTIR spectroscopy, ¹H-NMR, 31P-NMR, elemental and thermogravimetric analysis. The antifungal activities of chitosan derivatives against four kinds of phytopathogens, including Phomopsis asparagi, Watermelon fusarium, Colletotrichum lagenarium, and Fusarium oxysporum were tested using the radial growth assay in vitro. The results revealed that the synthesized cationic chitosan derivatives showed significantly improved antifungal efficiency compared to chitosan. It was reasonably suggested that quaternary phosphonium groups enabled the obviously stronger antifungal activity of the synthesized chitosans. Especially, the triphenylphosphonium-functionalized chitosan derivative inhibited the growth of Phomopsis asparagi most effectively, with inhibitory indices of about 80% at 0.5 mg/mL. Moreover, the data demonstrated that the substituted groups with stronger electron-withdrawing ability relatively possessed greater antifungal activity. The results suggest the possibility that cationic chitosan derivatives bearing quaternary phosphonium salts could be effectively employed as novel antifungal biomaterials for application in the field of agriculture.

6-methoxyflavanones as bitter taste receptor blockers for hTAS2R39.

Many (dietary) bitter compounds, e.g. flavonoids, activate bitter receptor hTAS2R39 in cell-based assays. Several flavonoids, amongst which some flavanones, are known not to activate this receptor. As certain flavanones are known to mask bitter taste sensorially, flavanones might act as bitter receptor antagonists. Fourteen flavanones were investigated for their potential to reduce activation of hTAS2R39 by epicatechin gallate (ECG), one of the main bitter compounds occurring in green tea. Three flavanones showed inhibitory behavior towards the activation of hTAS2R39 by ECG: 4'-fluoro-6-methoxyflavanone, 6,3'-dimethoxyflavanone, and 6-methoxyflavanone (in order of decreasing potency). The 6-methoxyflavanones also inhibited activation of hTAS2R14 (another bitter receptor activated by ECG), though to a lesser extent. Dose-response curves of ECG at various concentrations of the full antagonist 4'-fluoro-6-methoxyflavanone and wash-out experiments indicated reversible insurmountable antagonism. The same effect was observed for the structurally different agonist denatonium benzoate.

Assessment of bactericidal effects of quaternary ammonium-based antibacterial monomers in combination with colloidal platinum nanoparticles.

Pretreatment of dentin using colloidal platinum nanoparticles (CPtN) can enhance the bond strength of dentin adhesives. However, the combination of CPtN, which is negatively charged, with cationic monomer-containing adhesive may reduce the antibacterial activity of the original material. Thus, the purpose of this study was to assess the effect of CPtN on the bactericidal activity of two cationic antibacterial monomers, 12-methacryloyloxydodecylpyridinium bromide (MDPB) and methacryloxylethyl cetyl dimethyl ammonium chloride (DMAE-CB). The rapid killing effects of the two monomers against planktonic or attached Streptococcus mutans in the presence or absence of CPtN were examined by viable cell counts. The measurement of minimum inhibitory and bactericidal concentrations demonstrated that CPtN up to 2.5 mM has no antibacterial activity. In the absence of CPtN, rapid killing of both planktonic and attached Streptococcus mutans were achieved by the two cationic monomers. Combination with 0.1 mM CPtN did not reduce the bactericidal effects of the two monomers, indicating that CPtN may be used as a pretreatment with antibacterial adhesives.

Methylnaltrexone: a subcutaneous treatment for opioid-induced constipation in palliative care patients.

Opioid-induced constipation is common in palliative care and causes considerable distress to patients taking opioids. Opioid-induced constipation can be difficult to manage with conventional laxatives, often requiring invasive rectal interventions. A unique bowel intervention linked specifically to opioid-induced constipation in the form of a subcutaneous injection is now available for the management of opioid-induced constipation. This article will examine all aspects of opioid-induced constipation with particular reference to this new management option, methylnaltrexone bromide (Relistor).

Broad tuning of the human bitter taste receptor hTAS2R46 to various sesquiterpene lactones, clerodane and labdane diterpenoids, strychnine, and denatonium.

Sesquiterpene lactones are a major class of natural bitter compounds occurring in vegetables and culinary herbs as well as in aromatic and medicinal plants, where they often represent the main gustatory and pharmacologically active component. Investigations on sesquiterpene lactones have mainly focused on their bioactive potential rather than on their sensory properties. In the present study, we report about the stimulation of heterologously expressed human bitter taste receptors, hTAS2Rs, by the bitter sesquiterpene lactone herbolide D. A specific response to herbolide D was observed i.a. for hTAS2R46, a so far orphan bitter taste receptor without any known ligand. By further investigation of its agonist pattern, we characterized hTAS2R46 as a bitter receptor broadly tuned to sesquiterpene lactones and to clerodane and labdane diterpenoids as well as to the unrelated bitter substances strychnine and denatonium.

Control of single channel conductance in the outer vestibule of the Kv2.1 potassium channel.

Current magnitude in Kv2.1 potassium channels is modulated by external [K+]. In contrast to behavior expected from the change in electrochemical driving force, outward current through Kv2.1 channels becomes larger when extracellular [K+] is increased within the physiological range. The mechanism that underlies this unusual property involves the opening of Kv2.1 channels into one of two different outer vestibule conformations, which are defined by their sensitivity to TEA. Channels that open into a TEA-sensitive conformation generate larger macroscopic currents, whereas channels that open into a TEA-insensitive conformation generate smaller macroscopic currents. At higher [K+], more channels open into the TEA-sensitive conformation. In this manuscript, we examined the mechanism by which the conformational change produced a change in current magnitude. We started by testing the simplest hypothesis: that each pharmacologically defined channel conformation produces a different single channel conductance, one smaller and one larger, and that the [K+]-dependent change in current magnitude reflects the [K+]-dependent change in the percentage of channels that open into each of the two conformations. Using single channel and macroscopic recordings, as well as hidden Markov modeling, we were able to quantitatively account for [K+]-dependent regulation of macroscopic current with this model. Combined with previously published work, these results support a model whereby an outer vestibule lysine interferes with K+ flux through the channel, and that the [K+]-dependent change in orientation of this lysine alters single channel conductance by changing the level of this interference. Moreover, these results provide an experimental example of single channel conductance being modulated at the outer end of the conduction pathway by a mechanism that involves channel activation into open states with different outer vestibule conformations.

[Investigation of neuromuscular blocking agents at Richter Ltd]. / Szteroid izomrelaxánsok kutatása a Richterben.

Investigation of new neuromuscular blocking agents was started 30 years ago in Richter Ltd. This paper presents the results obtained by Richter's scientists. 2 compounds out of 100 bisquaternary ammonio steroid having androstane skeleton were selected for further pharmacological study. One of these agents, pipecuronium bromide (Arduan) elicited long-lasting block of neuromuscular transmission without cardiovascular side effects in both animal experiments and clinical studies. Arduan is a powerful competitive antagonist of acetylcholine, since it can bind pre- and postsynaptic (N1) receptors of the transmitters. It has no remarkable cumulative effect. Neostigmine rapidly and completely antagonized the neuromuscular blockade caused by pipecuronium. Arduan was introduced into clinical practice. The second compound, RGH-4201 (Duador) evoked a neuromuscular block of short duration. It showed slight atropin-like cardio-vagolytic effect in animal experiments. In the clinical studies, however, the cardiovascular side effects were found to be too strong. Therefore, it was not introduced in clinical practice.

Comparative assessment of ibutilide, D-sotalol, clofilium, E-4031, and UK-68,798 in a rabbit model of proarrhythmia.

Class III agents have been associated with development of a polymorphic ventricular tachycardia (PVT) known as torsades de pointes. We compared the class III agent ibutilide, which prolongs repolarization through enhancement of an inward sodium current, with the potassium channel blockers E-4031, UK-68,798, clofilium, and D-sotalol for proarrhythmic effects in an anesthetized rabbit model. In these animals, prolongation of repolarization during alpha 1 stimulation with methoxamine produces early after depolarizations (EADs) and a pause-dependent torsades de pointes-like PVT. Agents were compared over dosage ranges that produced maximal increases in QTc interval and monophasic action potential duration (MAPD). PVT typically developed after atrioventricular (A-V) conduction block and slowing of heart rate (HR), and was preceded by development of repolarization arrhythmias characterized by EADs and triggered activity producing extrasystolic beats. Ibutilide administration resulted in significantly lower EAD amplitudes and a lower incidence of repolarization arrhythmias and PVT as compared with administration of other class III agents. The percentage of rabbits developing PVT for each agent was ibutilide 12%, D-sotalol 70%, E-4031 56%, UK-68,798 69%, and clofilium 80%. Rabbits receiving saline vehicle instead of a class III agent never developed conduction or repolarization abnormalities or PVT. Under the conditions of this study at doses that generate maximal class III effects, ibutilide produces lesser increases in QTc interval and MAPD, and EADs of lower amplitude, resulting in a lower incidence of repolarization arrhythmias and PVT as compared with other class III agents.

Assessment of potential selectivity of antispasmodics for the various sections of the gastrointestinal tract of the rat as a guideline for their clinical use.

Two spasmolytic drugs, N-butylscopolammonium bromide and octylonium bromide have been challenged against topical carbachol-induced contracture of gastric antrum, duodenum, jejunum, ileum, caecum, colon and rectum of the rat. Experimental data indicate that N-butylscopolammonium bromide, a competitive anticholinergic agent, is more effective on the upper than on the lower sections of the rat gastrointestinal tract. On the other hand octylonium bromide, which has been reported to have little if any competitive antimuscarinic properties at effective spasmolytic doses, showed a more composite spectrum of activity. Hexamethonium, a nicotinic cholinoceptor antagonist, was about equally effective in inhibiting carbachol-induced contractions of all the GIT sections under study. Data in the literature and our own findings do not support the use of competitive antimuscarinic drugs for the treatment of colonic hypermotility. In fact, at effective spasmolytic doses they are expected to produce a greater inhibition of motility of the upper sections of the GIT than at the colonic level.