Irritant Effects Research Articles

Utility of silver birch and house dust mite extracts derived from licensed sublingual tablets for nasal allergen challenge.

Nasal allergen challenge (NAC) is used to investigate the effects of allergen exposure and assess treatment efficacy in allergic rhinitis (AR). This study aims to establish dose-responses to NAC using licensed silver birch (SB) pollen and house dust mite (HDM) sublingual tablets as sources of the allergen extracts in participants with AR. Sixteen volunteers with HDM-induced perennial AR and 15 volunteers with SB pollen-induced seasonal rhinitis underwent a graded up-dosing NAC with extracts derived from HDM allergen (Acarizax®) and SB (Itulazax®) tablets, respectively. Total nasal symptom score (TNSS, range 0-12) and peak nasal inspiratory flow (PNIF) were recorded before, at 10min and at the end of the NAC. The dose of each allergen that provoked a TNSS of at least 7 ("provoking dose 7") in most allergic participants was identified. NACs using the "provoking dose 7" were performed on 5 non-allergic individuals to test for irritant effects. The "provoking dose 7" of HDM extract was used in a subgroup of two SB allergic, non-HDM allergic, volunteers, and vice versa for SB extract, to test for allergen specificity of the responses. Most patients experienced a TNSS of at least 7/12 at a median concentration of 1500AU/mL for both SB pollen and HDM. The average decline in PNIF at this dose was 63.15% for SB and 63.99% for HDM. NACs using the 1500AU/mL concentrations were performed on 5 non-allergic individuals with no symptomatic or PNIF response. 1500AU/mL of HDM extract produced no symptoms in SB allergics nor 1500AU/mL SB extract in HDM allergics. For both SB and HDM extracts, the optimal allergen dose for NAC to cause a moderate-severity response ("provoking dose 7/12") was 1500AU/mL. Licensed sublingual allergen tablets provide a readily available and inexpensive source of SB and HDM extracts for use in future interventional studies in AR.

Valorisation of Raspberry Seeds in Cosmetic Industry-Green Solutions.

The fruit processing industry generates large quantities of by-products well known to be rich in bioactive compounds with numerous nutritional properties and beneficial effects for human health. We developed a strategy to valorise raspberry seeds and obtain valuable ingredients with potential application in cosmetic skincare formulas. Cold press extraction technology was applied to extract oil, and the remaining defatted raspberry seed cake was treated with three proline based deep eutectic solvents (DES) to extract polyphenols. The most potent was proline/citric acid extract, with free and total ellagic acid content (52.4 mg/L and 86.4 mg/L), total phenolic content (TPC, 550.1 mg GAE/L) and radical scavenging activity (RSA, 4742.7 mmol TE/L). After the direct mixing of the extract and after encapsulation with starch as a carrier, the skincare emulsion and microemulsion were characterised by irritation potential (Zein test), transepidermal water loss (TEWL), red blood cell (RBC), and DPPH antioxidant test. The resulting preparations were of improved quality in comparison to the control hand cream, with a low skin irritation effect, lower TEWL, and higher antioxidant potential. This work complies with circular economy principles and green technology standards, and represents the efficient model on how to reuse natural resources through waste minimization.

Therapeutic Effects of 30 nm Cyclosporin A-Loaded Nanoparticles Using PLGA-PEG-PLGA Triblock Copolymer for Transdermal Delivery in Mouse Models of Psoriasis

This study aimed to evaluate the effectiveness of poly(DL-lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(DL-lactide-co-glycolide) triblock copolymers (PLGA-PEG-PLGA) as a drug carrier in the treatment of psoriasis. Nanoparticles containing cyclosporin A (CsA) were prepared, and their cytotoxicity and skin irritation properties were investigated. These results revealed that the nanoparticles themselves had no obvious cytotoxicity or skin irritation effects. Furthermore, it was shown that loading CsA into nanoparticles promoted its cellular uptake. The therapeutic effect of CsA-loaded PLGA-PEG-PLGA nanoparticles on psoriasis was evaluated using a mouse model of psoriasis induced by imiquimod. In psoriatic skin, we confirmed that nanoparticles penetrate deep into the skin. Furthermore, it was suggested that by using PLGA-PEG-PLGA, drug carriers could reach the dermal layer, which is the target site for psoriasis treatment. The observation of skin sections after the treatment experiment showed that excessively proliferated keratinocytes were restored to an almost normal state by using PLGA-PEG-PLGA nanoparticles as drug carriers. Additionally, the quantitative measurement results for cytokines revealed that the levels of TNF-α, IL-17A, and IL-22 were significantly decreased compared with those of the group to which CsA suspended in a 20% ethanol solution was administered. These results indicate that PLGA-PEG-PLGA nanoparticles are promising drug carriers for the transdermal administration of CsA.

Toxicity of vapor-gas flows from technogenic substance

The relevance. Vapor-gas flows from technogenic substances (storage wastes of the mining industry), carrying a high amount of potentially toxic elements, are a big problem for the environment and the population, because metals and metalloids in the composition of emanations are in an easily digestible bioavailable forms and are able to easily penetrate into living organisms. The main aim of this study is an assessment of toxicity for living organisms of air mixtures containing gaseous products emitted by a surfaces of mine tailings freely located near settlements and under the influence of climatic factors and microorganisms. Methods. Carrying out experiments with white rats male Wistar, analysis of organs for the content of a wide range of elements by ICP-MS on a NexION 300D mass spectrometer (PerkinElmer, USA) (PNL GGC IShPR TPU). In the experiment, a pooled sample of the waste substance was used. The sample was analyzed for the content of oxides of the silicate group by XRF using X-ray fluorescence spectrometer ARL-9900-XP (Thermo Electron Corporation, Switzerland) at the Laboratory of X-ray Spectral Analysis Methods of the IGM SB RAS; elemental analysis was carried out by ICP-MS using an ELAN-9000 DRC-e instrument Perkin Elmer, USA (HAC Plasma). Results. Under the influence of vapor-gas emanations from the substance of arsenide tailings of the Tuvacobalt plant on a group of rats male Wistar, pathological changes occurred in the experimental group. Small foci of hemorrhages formed in the lungs, the tissues became edematous and inflamed. The liver of all animals increased, the share structure became sharply expressed, the color became light beige. Single hemorrhages were found in the kidneys. The vessels of the meninges are dilated, petechial hemorrhages are observed. The synthetic function of cells and the stability of cellular and intracellular membranes were disrupted, first of all, the endothelium of blood vessels was affected, the physiological functioning of organs and tissues was disrupted with the accumulation of intermediate products of biochemical reactions, determined macroscopically. Also, dystrophy of internal organs was determined, in particular, the liver, lungs, kidneys, and brain. Elemental analysis of animal organs showed the accumulation of toxic elements in comparison with the control group. The most characteristic elements, the excess of which was recorded in most cases, are mercury and arsenic. They were unevenly distributed throughout the organs. Mercury accumulated mainly in the lungs, kidneys and liver, while arsenic accumulated mainly in the liver and brain. This may indicate the entry of mercury and arsenic ions in a biologically available form into the bloodstream by inhalation, and local irritating and toxic effects on the lungs were not prevailing, and the liver was the most damaged organ according to the results of toxicochemical and morphological studies. The homeostasis of micro and macro elements is finely regulated, and any concentration imbalance in the form of a deficiency leads to a progressive decrease and disruption of normal biological function, to severe physiological and clinical outcomes, which we observed from the results of the experiment. The data obtained proved the acute toxic effect of vapor-gas flows on living organisms, and also confirmed the possibility of the removal of many chemical elements in easily accessible and assimilable forms.

Rosacea in Older Adults and Pharmacologic Treatments.

Rosacea is a chronic inflammatory skin condition that is often more severe in older patients. The main clinical features are erythema, telangiectasia, and inflammatory lesions of the face. The pathogenesis of this condition is not fully understood but certainly multifaceted. Immune and inflammatory dysregulation, genetics, neurogenic dysregulation, microbiome dysbiosis, and systemic disease have all been implicated in rosacea pathogenesis. As we better understand the various pathways that lead to rosacea, we acknowledge that the different symptoms may have unique underlying triggers and mechanisms. Aging also impacts rosacea diagnosis and treatment. Older adults have more severe rosacea symptoms while also having more sensitive and fragile skin than younger patients; therefore, rosacea treatments for older patients require a balance between delivering adequate potency while also minimizing skin irritation and other adverse effects. Until recently, rosacea diagnoses were based on concrete subtypes that did not necessarily capture each patient's manifestation of rosacea. There is now an emphasis on more personalized phenotype-based diagnoses and treatments, which allows for more emphasis on treating individual symptoms and accounting for the unique characteristics of older patients. Centrofacial erythema is best treated with brimonidine and oxymetazoline, while phymatous change and telangiectasia are best treated with surgery and laser ablation. Treatment for rosacea papules and pustules ranges from topicals, such as azelaic acid, ivermectin, metronidazole, minocycline, and encapsulated benzoyl peroxide, to systemics, such as doxycycline and isotretinoin. It is important to understand these treatments in relation to adverse effects and drug interactions that may specifically arise in older populations to provide optimal care. As we advance in understanding rosacea's pathogenesis and adopt personalized phenotype-based approaches, optimizing care for older patients becomes crucial. Continued research into novel treatments is essential to address their unique needs.

Impacts of o-cresol spill on composition and function of river sediment and soil microbial communities.

o-Cresol is a toxic substance with strong irritating and corrosive effects on skin and mucous membranes. To date, information on the effects of o-cresol on microbial communities in the natural environment is very limited. In the present study, 16S rRNA sequencing and metagenomic technique were carried out to elucidate the effects of the o-cresol spill on microbial communities in river sediments and nearby soils. o-Cresol spill induced the increase in the relative abundance of phyla Planctomycetes and Gemmatimonadetes, suggesting their resilience to o-cresol-induced stress. Uncultured Gemmatimonadetes genera and the MND1 genus exhibited enrichment, while the Pseudomonas genus dominated across all samples, indicating their potential pivotal roles in adapting to the o-cresol spill. Moreover, o-cresol spill impaired the metabolic functions of microbes but triggered their defense mechanisms. Under o-cresol pressure, microbial functions related to carbon fixation were upregulated and functions associated with sulfur metabolism were downregulated. In addition, the o-cresol spill led to an increase in functional genes related to the conversion of o-cresol to 3-methylcatechol. Several genes involved in the degradation of aromatic compounds were also identified, potentially contributing to the biodegradation of o-cresol. This study provides fresh insights into the repercussions of an abrupt o-cresol spill on microbial communities in natural environments, shedding light on their adaptability, defense mechanisms, and biodegradation potential.

Laboratory evaluation of the contact irritancy of a clothianidin solo formulation vs. clothianidin-deltamethrin mixture formulations for indoor residual spraying against pyrethroid-resistant Anopheles gambiae sensu lato

BackgroundClothianidin-based indoor residual spraying (IRS) formulations have become available for malaria control as either solo formulations of clothianidin or a mixture of clothianidin with the pyrethroid deltamethrin. While both formulations have been successfully used for malaria control, studies investigating the effect of the pyrethroid in IRS mixtures may help improve our understanding for development of future IRS products. It has been speculated that the irritant effect of the pyrethroid in the mixture formulation may result in shorter mosquito contact times with the treated walls potentially leading to a lower impact.MethodsWe compared contact irritancy expressed as the number of mosquito take-offs from cement surfaces treated with an IRS formulation containing clothianidin alone (SumiShield® 50WG) to clothianidin-deltamethrin mixture IRS formulations against pyrethroid-resistant Anopheles gambiae sensu lato under controlled laboratory conditions using a modified version of the World Health Organisation cone bioassay. To control for the pyrethroid, comparison was made with a deltamethrin-only formulation. Both commercial and generic non-commercial mixture formulations of clothianidin and deltamethrin were tested.ResultsThe clothianidin solo formulation did not show significant contact irritancy relative to the untreated control (3.5 take-offs vs. 3.1 take-offs, p = 0.614) while all deltamethrin-containing IRS induced significant irritant effects. The number of take-offs compared to the clothianidin solo formulation (3.5) was significantly higher with the commercial clothianidin-deltamethrin mixture (6.1, p = 0.001), generic clothianidin-deltamethrin mixture (7.0, p < 0.001), and deltamethrin-only (8.2, p < 0.001) formulations. The commercial clothianidin-deltamethrin mixture induced similar contact irritancy as the generic clothianidin-deltamethrin mixture (6.1 take-offs vs. 7.0 take-offs, p = 0.263) and deltamethrin-only IRS (6.1 take-offs vs. 8.2, p = 0.071), showing that the irritant effect in the mixture was attributable to its deltamethrin component.ConclusionsThis study provides evidence that the enhanced contact irritancy of the pyrethroid in clothianidin-deltamethrin IRS mixtures can shorten mosquito contact times with treated walls compared to the clothianidin solo formulation. Further trials are needed to directly compare the efficacy of these formulation types under field conditions and establish the impact of this enhanced contact irritancy on the performance of IRS mixture formulations containing pyrethroids.Graphical

Efecto de las emociones sobre la empatía en adolescentes vulnerables

This study analyzes the effect of emotional self-efficacy, irritability and aggressiveness on empathy in vulnerable adolescents. Quantitative, non-experimental- cross-sectional study and correlational scope. We worked with 69 adolescents to whom the Interpersonal Reactivity Index and the Self-Efficacy Scales for Emotional Regulation, Irritability and Physical and Verbal Aggressiveness were applied. Empathy correlated directly with emotional self-efficacy and inversely with irritability and physical and verbal aggressiveness. Path analysis showed that emotional self-efficacy, irritability, physical and verbal aggressiveness provided a predictive effect on perspective taking, concern, empathy, and emotional distress.

The association between family socioeconomic status and suicide ideation among adolescent: A conditional process model

Traditionally, most researchers believe that low family socioeconomic status (SES) is closely related to high suicide ideation, but this view remains controversial in empirical studies. Meanwhile, less is known about the mechanisms underlying this association. Moreover, previous studies on the relationship between family SES and suicide ideation have mostly focused on adults rather than adolescents and relatively lacked support from Chinese samples. Therefore, this study is based on the integrated motivational–volitional model of suicide behaviour and the context-process-outcomes model, aiming to determine whether and how family SES is associated with adolescents’ suicide ideation and to evaluate the chain-mediating effect of effortful control and irritability, as well as the moderating effect of future orientation on this association. Data were extracted from 1058 girls and 855 boys, aged 11 to 19 years (14.86 ± 1.61 years), who completed a self-reported online survey. Descriptive statistics, t-test, chi-square test, bivariate correlations, and regression analysis were performed using IBM SPSS version 25. The conditional process model (CPM) was examined using SPSS PROCESS Macro 4.0. The results showed that there were differences in some demographic factors and the main study variables between adolescents with and without suicide ideation. In addition, the results suggested that family SES was not directly related to suicide ideation in adolescents, but it could indirectly effect suicide ideation through the chain-mediating effect of effortful control and irritability. Furthermore, future orientation moderated the relationship between irritability and suicide ideation. These findings provide evidence for current debates and conflicting conclusions, reveal the effect mechanism of family SES on suicide ideation, and add to empirical support for the prevention and intervention of adolescent suicide ideation.

Functional human skin explants as tools for assessing mast cell activation and inhibition.

Mast cells are activated through a variety of different receptors to release preformed granules and mediators synthesized de novo. However, the physiology and function of mast cells are not fully understood. Traditional studies of mast cell activation in humans have utilized cultures of tissue-derived mast cells including CD34+ progenitor cells or well-characterized commercially available cell lines. One limitation of these methods is that mast cells are no longer in a natural state. Therefore, their applicability to human skin disorders may be limited. Human skin explant models have been utilized to investigate the short-term effects of cell mediators, drugs, and irritants on skin while avoiding the ethical concerns surrounding in vivo stimulation studies with non-approved agents. Nonetheless, few studies have utilized intact human tissue to study mast cell degranulation. This "Methods" paper describes the development and application of an intact skin explant model to study human mast cell activation. In this manuscript, we share our protocol for setting up ex vivo human skin explants and describe the results of stimulation experiments and techniques to minimize trauma-induced histamine release. Skin explants were generated using de-identified, full-thickness, non-diseased skin specimens from plastic and reconstructive surgeries. Results were reproducible and demonstrated FcɛRI- and MRGPRX2-induced mediator release which was inhibited with the use of a BTK inhibitor and QWF, respectively. Thus, this explant model provides a quick and accessible method of assessing human skin mast cell activation and inhibition.

Synthesis and Bioactive Properties of the Novel Coloured Compound Obtained via the Laccase-Mediated Transformation of 5-Aminosalicylic Acid.

Biocatalysis processes based on oxidoreductases, such as fungal laccase, are important for discovering new organic compounds with broad structures and potential applications. They include bioactive compounds, which can be obtained through laccase-mediated oxidation of organic substrates having hydroxyl and/or amino groups especially, e.g., 5-aminosalicylic acid (5-ASA) is characterised for its potential for oxidation by a fungal laccase obtained from a Cerrena unicolor strain. The biotransformation process was optimised in terms of the buffer and co-solvent concentration, buffer pH value, and laccase activity. Selected crude dyes were analysed for their bioactive properties, toxicity, and suitability for the dyeing of wool fibres. The data obtained clearly indicated that a low concentration of the reaction buffer in the pH range from 5 to 6 and in the presence of 10% acetonitrile increased the rate of substrate oxidation and the amount of the product formed. The red-brown compound obtained via laccase-mediated oxidation of 5-aminosalicylic acid showed antioxidant properties and unique antimicrobial activity against Staphylococcus aureus and Staphylococcus epidermidis strains with the MIC value of 0.125 mg/mL detected for the purest dye. In addition, it was reported to have good wool fibre dyeing properties and no irritant effect after patch tests on a selected group with increased skin sensitivity.

The results of an experimental toxicological assessment of the pharmaceutical substance ambroxol hydrochloride, justification of the maximum permissible content in the air of the working area

Introduction. Ambroxol hydrochloride is a biologically active substance used as a pharmaceutical substance in the manufacture of medicines for secretolytic therapy in the case of acute and chronic bronchopulmonary diseases. To date, there is no hygienic standard for the safe content of substances in the air of the working area in the republic.&#x0D; The study aims to substantiate and develop the maximum permissible concentrations and hazard class of the pharmaceutical substance ambroxol hydrochloride in the air of the working area.&#x0D; Materials and methods. The authors have conducted experimental toxicological studies of the pharmaceutical substance on animals (rats, mice, rabbits) in accordance with the requirements of technical regulatory legal acts and recommendations of methodological documents regulating the justification of hygienic standards.&#x0D; Results. Scientists have found that the pharmaceutical substance ambroxol hydrochloride, when injected into the stomach and inhaled, is classified as a low-hazard substance at an average lethal dose/concentration (according to GOST 12.1.007-76), has a mild irritant effect on the skin and moderate on the mucous membranes of the eyes, does not exhibit a skin-resorptive effect, is characterized by a weak cumulative effect and does not it has sensitizing activity. Under the conditions of inhalation of the substance into the body of laboratory animals (rats), the threshold values of acute and chronic harmful effects of this pharmaceutical substance were at the level of 90 mg/m3 (in terms of the effect on the functional state of the nervous activity of rats) and 30 mg/m3, respectively (in terms of changes in behavioral indicators, weight and mass coefficient spleen, blood glucose, alanine aminotransferases and urea) accordingly.&#x0D; Conclusion. Based on the experimental results of the toxicological assessment, the authors have justified the standard of permissible content of the pharmaceutical substance ambroxol hydrochloride in the air of the working area at the level of 4.0 mg/m3, they also have established the hazard class of the substance according to GOST 12.1.007-76 (class 3, medium-hazard substances).&#x0D; Ethics. The Bioethics Commission of the State Enterprise "SPCH” has approved the use of laboratory animals for experimental purposes (Protocol No. 1 dated 03/04/2020). The treatment of animals was in accordance with the provisions of Directive 2010/63/EU of the European Parliament and of the Council of the European Union of September 22, 2010 on the protection of animals used for scientific purposes.

Social anxiety moderates the association between adolescent irritability and bully perpetration.

Preliminary work suggests anxiety moderates the relationship between irritability and bullying. As anxiety increases, the link between irritability and perpetration decreases. We hypothesize that any moderation effect of anxiety is driven by social anxiety symptoms. We sought to explicate the moderating effect of anxiety, while clarifying relations to other aggressive behaviors. A sample of adolescents (n = 169, mean = 12.42 years of age) were assessed using clinician rated assessments of anxiety, parent reports of irritability and bullying behaviors (perpetration, generalized aggression, and victimization). Correlations assessed zero-order relations between variables, and regression-based moderation analyses were used to test interactions. Johnson-Neyman methods were used to represent significant interactions. Irritability was significantly related to bullying (r = .403, p < .001). Social, but not generalized, anxiety symptoms significantly moderated the effect of irritability on bully perpetration (t(160) = -2.94, b = -.01, p = .0038, ΔR2 = .0229, F(1, 160) = 8.635). As social anxiety symptoms increase, the link between irritability and perpetration decreases. Understanding how psychopathology interacts with social behaviors is of great importance. Higher social anxiety is linked to reduced relations between irritability and bullying; however, the link between irritability and other aggression remains positive. Comprehensively assessing how treatment of psychopathology impacts social behaviors may improve future intervention.

Anti-UV Microgel Based on Interfacial Polymerization to Decrease Skin Irritation of High Permeability UV Absorber Ethylhexyl Methoxycinnamate.

Ethylhexyl methoxycinnamate (EHMC) is frequently employed as a photoprotective agent in sunscreen formulations. EHMC has been found to potentially contribute to health complications as a result of its propensity to produce irritation and permeate the skin. A microgel carrier, consisting of poly(ethylene glycol dimethacrylate) (pEDGMA), was synthesized using interfacial polymerization with the aim of reducing the irritation and penetration of EHMC. The thermogravimetric analysis (TGA) indicated that the EHMC content accounted for 75.72% of the total composition. Additionally, the scanning electron microscopy (SEM) images depicted the microgel as exhibiting a spherical morphology. In this study, the loading of EHMC was demonstrated through FTIR and contact angle tests. The UV resistance, penetration, and skin irritation of the EHMC-pEDGMA microgel were additionally assessed. The investigation revealed that the novel sunscreen compound, characterized by limited dermal absorption, had no irritant effects and offered sufficient protection against ultraviolet radiation.

Comprehensive in vitro and in ovo assessment of cytotoxicity: Unraveling the impact of sodium fluoride, xylitol, and their synergistic associations in dental products.

Over the past several decades, dental health products containing fluoride have been widely employed to mitigate tooth decay and promote oral hygiene. However, concerns regarding the potential toxicological repercussions of fluoride exposure have incited continuous scientific inquiry. The current study investigated the cytotoxicity of sodium fluoride (NaF) and xylitol (Xyl), both individually and in combination, utilizing human keratinocyte (HaCaT) and osteosarcoma (SAOS-2) cell lines. In HaCaT cells, NaF decreased proliferation in a concentration-dependent manner and induced apoptosis-related morphological changes at low concentrations, whereas Xyl exhibited dose-dependent cytotoxic effects. The combination of NaF and Xyl reduced cell viability, particularly at higher concentrations, accompanied by apoptosis-like morphological alterations. Sub-cytotoxic NaF concentrations (0.2%) significantly affected caspase activity and the expression of pro-apoptotic genes. Conversely, Xyl demonstrated no discernible effect on these biological parameters. In SAOS-2 cells, NaF increased proliferation at high concentrations, contrasting with Xyl's concentration-dependent cytotoxic effects. The combination of NaF and Xyl had a minimal impact on cell viability. Sub-cytotoxic NaF concentrations did not influence caspase activity or gene expression, while Xyl induced dose-dependent morphological alterations, increased caspase activity, and upregulated pro-apoptotic gene expression. In ovo experiments on the chorioallantoic membrane (CAM) revealed that only NaF induced irritant effects, suggesting potential vascular adverse outcomes. This study advocates for the combined use of NaF and Xyl, highlighting their cytotoxicity benefits in healthy cells while maintaining safety considerations for tumor cells.

Safety testing of Ovaprene: An investigational nonhormonal monthly vaginal contraceptive

ObjectiveEvaluate safety of Ovaprene, an investigational non-hormonal vaginal contraceptive designed for monthly use. Study designOpen-label, multicenter study enrolling heterosexually-active women with previous permanent contraception who underwent assessments during five menstrual cycles: baseline postcoital test cycle, diaphragm postcoital test cycle, Ovaprene safety cycle, and two Ovaprene postcoital test cycles. Safety outcomes included treatment emergent adverse events (TEAEs), systemic laboratory findings, pelvic examinations, colposcopies, Nugent scores, determination of community state types of vaginal microbiota, and anti-Escherichia coli activity and inflammatory markers in cervicovaginal fluids. ResultsWe enrolled 38 participants. Of these, 33 used Ovaprene and completed 77 Ovaprene cycles. The most common product-related urogenital TEAEs were bacterial vaginosis (BV) and vaginal odor. The frequency of transitioning from Lactobacillus-dominated community state type to community state type IV (not Lactobacillus-dominated) was similar before Ovaprene use and afterwards. Mean Nugent scores were <4 at each visit without a discernable upward trend. Inflammatory markers showed wide variation but no upward trend, and E. coli inhibitory activity of cervical secretions did not change. We found no Staphylococcus aureus, the causative agent in Toxic Shock Syndrome, on used Ovaprenes or in vaginal samples. No clinically important changes in systemic laboratory findings, pelvic examinations, or colposcopies occurred during Ovaprene use. ConclusionOvaprene use did not result in cervicovaginal irritation or adverse effects on resident vaginal microbiota, and did not impact transitions from a Lactobacillus-dominated community state type to community state type IV. ImplicationsThe finding that use of Ovaprene, an investigational monthly user-controlled nonhormonal vaginal contraceptive, does not appear to result in adverse changes in vaginal health during short term use supports further evaluation of the contraceptive potential of the device.

PHYSICOCHEMICAL AND PHARMACOKINETIC ANALYSIS AND DOCKING OF DRUG REPOSITIONING AGAINST SARS-COV-2: AN IN SILICO STUDY

Studies on the development of effective and cost-effective oral drugs are the new priority of the pharmaceutical industry for the prevention and treatment of COVID-19. This work was based on the computational analysis of physicochemical parameters, pharmacokinetic and toxicological measurements, molecular docking and in silico measurement of the antiviral activity of 12 repositionable drugs. The Molinspiration platform (physical-chemical parameters), pkCSM® (absorption, distribution, metabolism and excretion), OSIRIS Property Explorer® (toxicological measurements), Seam® (Docking with the RdRp protein) and AVCpred server® (antiviral activity) were used. Considering the 12 selected repositionable drugs, molecular anchoring data with the RdRp protein, only the drug tilorone had lower binding energy than the control used in this study (Molnupiravir). Ledipasvir, daclatasvir and piperaquine showed the best percentage of antiviral inhibition considering the control pattern. ADMETox data showed that piperaquine has a high toxicological potential for mutagenesis, tumorigenesis and irritant effects. The findings of this study indicate that ledipasvir and daclatasvir showed greatest potential for inhibition RdRp and action against COVID-19.

Synergistic treatment of androgenetic alopecia with follicular co-delivery of minoxidil and cedrol in metal–organic frameworks stabilized by covalently cross-linked cyclodextrins

Androgenetic alopecia seriously affects the physical and mental health of patients. The main clinical therapeutic agent, minoxidil tincture, is challenged by solvent irritation and dose-dependent side effects. Our recent work has identified a biosafety natural product, cedrol, that is synergistic in combination with minoxidil, thereby improving medication safety by substantially reducing the clinical dose of minoxidil. In addition, ccross-linked CD-MOF were designed as carriers for hair follicle delivery, and γ-CD in the carriers was cross-linked by diphenyl carbonate with covalent bonds to protect the CD-MOF from rapid disintegration in an aqueous environment. This improved nanocarrier has a drug loading of 25%, whereas nanocarriers increased drug delivery to the hair follicles through ratchet effect, and increased human dermal papilla cells uptake of drugs via endocytosis pathways mainly mediated by lattice proteins, energy-dependent active transport, and lipid raft-dependent, thus improved cell viability, proliferation, and migration, followed by significantly enhancing the anti-androgenetic alopecia effect, with cedrol focusing on inhibiting 5α-reductase and activating Shh/Gli pathway, and minoxidil, which up-regulated VEGF, down-regulated TGF-β, and activated ERK/AKT pathway. This drug combination provides a new therapeutic strategy for androgenetic alopecia, while the newly developed cross-linked CD-MOF has been shown to serve as a promising follicular delivery vehicle.

Anticancer activity and morphological analysis of Pt (II) complexes: Their DFT approach, docking simulation, and ADME‐Tox profiling

A consistent series of Pt (II) polypyridyl complexes (i.e., LDP‐10–25), previously obtained and characterized by our research group, underwent extensive biological investigations to verify their activity profile as target‐based anticancer agents. Preliminary in vitro screening at 10 μM against three tumor cell lines known to overexpress DNA G‐4 (MDA‐MB 231, U87, and U2‐OS) pointed out that four of them, namely, LDP‐15, LDP‐16, LDP‐24, and LDP‐25, had promising cytotoxic activity compared with cisplatin. Therefore, these four compounds were selected for continuous assays against the same three cell lines and morphological analyses on U2‐OS cells that showed IC50 values in the micromolar range and remarkable changes in nuclei shape and cytoskeleton integrity, respectively. Docking studies supported the idea that the antiproliferative activity of the complexes could be attributed to their interaction via a hybrid binding mode with the intended molecular target, DNA G‐4. In addition, in silico ADME‐Tox profiling studies showed no risk of tumorigenic, irritant, or reproductive effects for the title compounds. DFT calculations were used to verify the structural characteristics of the four selected compounds and to investigate their electronic behavior. Overall, the results obtained, both experimentally and theoretically, indicate that LDP‐15, LDP‐16, LDP‐24, and LDP‐25 complexes could be useful for further study as potential therapeutic agents.

Evaluation of the disinfectant “Enzidez” according to indicators of acute toxicity and irritant effect

Despite the fairly large number of disinfectants on the market, there is no perfect drug, as microorganisms adapt to new antibacterial substances quite quickly. In this regard, recently, enzymatic preparations for the hydrolysis of protein contaminants and the destruction of the glycopeptide matrix of the microbial biofilm have been introduced into disinfectants. Therefore, disinfectants that have a wide spectrum of antimicrobial action, actively remove organic contaminants and affect the biofilm forms of bacteria are considered relevant and promising for development. The purpose of the work was to conduct a toxicological evaluation of the developed disinfectant “Enzidez” according to indicators of acute toxicity and irritant effect. Determination of acute toxicity and irritant effect of the native disinfectant and its 1 % solution was carried out according to generally accepted methods. Studies on establishing the parameters of subacute (acute) toxicity of Enzidez disinfectant on white mice revealed that the working 1.0 % concentration of Enzidez disinfectant did not cause the death of mice when administered intragastrically in a dose of 5000 to 13000 mg/kg. This indicates that a dose of 13,000 mg/kg body weight will be tolerated (LD0) for animals, while the median lethal (LD50) dose will be higher than this amount. According to the classification regarding the harmfulness of substances, the disinfectant in a working concentration of 1.0 % will be considered low-toxic (toxicity class 4).In the pathological autopsy of laboratory mice after administering lethal and working doses of the drug “Enzidez” to them, it was established that the mice died from pulmonary insufficiency due to hyperemia and pulmonary edema. According to the degree of danger, the product belongs to class 4 (low-toxic substances). When a working 1.0 % solution of the disinfectant was injected into the stomach, no visible pathological-anatomical changes were detected in experimental mice after euthanasia, which indicates its low toxicity. In addition, it was found that the native solution of the disinfectant causes slight irritation to the skin of white rabbits, so rubber gloves should be used when preparing working concentrations of the solution. The working 1 % solution of Enzidez, in turn, did not cause an irritating effect. In addition, it was found that the native solution of the disinfectant caused a harmful effect of 9 points on the mucous membrane of the eyes, and the working – 1 % solution did not cause visible changes in the mucous membrane. Therefore, when working with the native disinfectant “Enzidez”, it is necessary to use eye protection – glasses.