Identifying vagal bronchopulmonary afferents mediating cough response to inhaled sulfur dioxide in mice.

Sulfur dioxide (SO2), a common environmental and industrial air pollutant, possesses a potent effect in eliciting cough reflex, but the primary type of airway sensory receptors involved in its tussive action has not been clearly identified. This study was carried out to determine the relative roles of three major types of vagal bronchopulmonary afferents [slowly adapting receptors (SARs), rapidly adapting receptors (RARs), and C-fibers] in regulating the cough response to inhaled SO2. Our results showed that inhalation of SO2 (300 or 600 ppm for 8 min) evoked an abrupt and intense stimulatory effect on bronchopulmonary C-fibers, which continued for the entire duration of inhalation challenge and returned toward the baseline in 1-2 min after resuming room air-breathing in anesthetized and mechanically ventilated mice. In stark contrast, the same SO2 inhalation challenge generated a distinct and consistent inhibitory effect on both SARs and phasic RARs; their phasic discharges synchronized with respiratory cycles during the baseline (breathing room air) began to decline progressively within 1-3 min after the onset of SO2 inhalation, ceased completely before termination of the 8-min inhalation challenge, and then slowly returned toward the baseline after >40 min. In a parallel study in awake mice, inhalation of SO2 at the same concentration and duration as that in the nerve recording experiments evoked cough responses in a pattern and time course similar to that observed in the C-fiber responses. Based on these results, we concluded that stimulation of vagal bronchopulmonary C-fibers is primarily responsible for triggering the cough response to inhaled SO2.NEW & NOTEWORTHY This study demonstrated that inhalation of a high concentration of sulfur dioxide, an irritant gas and common air pollutant, completely and reversibly inhibited the neural activities of both slowly adapting receptor and rapidly adapting receptor, two major types of mechanoreceptors in the lungs with their activities conducted by myelinated fibers. Furthermore, the results of this study suggested that stimulation of vagal bronchopulmonary C-fibers is primarily responsible for triggering the cough reflex responses to inhaled sulfur dioxide.

The prevalence and severity of upper gastrointestinal complications among patients with chronic diseases: a cross-sectional study from Palestine.

BACKGROUND: Many old people have at least one chronic disease. As a result, multiple drugs should be used. Gastrointestinal complications may occur because of the harmful effects of these chronic drugs on the stomach. The study aimed to assess the prevalence of upper gastrointestinal complications in patients taking chronic medications, the severity of these symptoms, and whether they take any gastro-protective drugs or not. METHODOLOGY: This was a cross-sectional study through face-to-face questionnaires from internal outpatient clinics at a specialized hospital. Patients with chronic diseases who were taking at least one chronic medication were included in the study. Data Collection Form was used to gather information. The Short-Form Leeds Dyspepsia Questionnaire (SF-LDQ) was used to evaluate the severity of the upper gastrointestinal symptoms. Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) version 21. RESULTS: A total of 400 patients with chronic diseases and using multiple medications were included. Among them, 53.8% were females and 56% were married, 58.5% were unemployed, 70% were not smokers, the mean age was 54.7 ± 17.5 years. The most common comorbid diseases among the patients were diabetes, hypertension, and arthritis, with percentages of 44.3%, 38%, and 27.3%, respectively. The mean number of chronic medications used was 3.36 ± 1.6 with a range of 1 to 9. The most commonly used was aspirin with a percentage of 50%, followed by atorvastatin, bisoprolol, and insulin with percentages of 29.5%, 25%, and 20.3%, respectively. Among the 400 participants, 362 (90.5%) suffered from upper gastrointestinal side effects like indigestion (65.8%), heartburn (78.3%), nausea (48.8%), and regurgitation (52.0%). Based on SF-LDQ scoring, of the 400 respondents, 235(58.8%), 109(27.3%) and 18(4.5%) suffered from mild, moderate and severe dyspepsia, respectively. A high percentage 325 (81.3%) of participants were prescribed gastro-protective medications. Proton pump inhibitors were the most prescribed group in 209 (52.3%) patients. Dyspepsia was significantly associated with older age (p-value = 0.001), being educated (p-value = 0.031), not being single (p-value < 0.001), having health insurance (p-value = 0.021), being a smoker (p-value = 0.003), and using ≥ 5 medications (p-value < 0.001). CONCLUSION: Upper gastrointestinal complications among patients with chronic diseases were very common. Fortunately, the symptoms were mild in most cases. The risk increased with age and using a higher number of medications. It is important to review patients' medications and avoid overuse of them, in addition to use gastro-protective agents when needed.

Skin- and airway-deliverable TRPA1 inhibitor.

This study explored the potential of perfumery compounds as sources of transient receptor potential ankyrin 1 (TRPA1) inhibitors that could be formulated for effective delivery to the skin and airways. A highly potent, small, and selective TRPA1 inhibitor, 2-methyl-4-phenyl-1-pentanol (1), was discovered in perfumery compounds. Compound 1 demonstrated promising inhibitory activity against a broad range of TRPA1 agonists. A single stereoisomer of 1 was identified as the most effective TRPA1 inhibitor, indicating the potential for stereoselective synthesis to enhance its potency. Additionally, the structure-activity relationship of 1 was evaluated to elucidate the structural features of TRPA1 inhibitors within the fragrance-like compounds. Notably, the topical application of 1 alleviated sensory irritation in individuals with sensitive skin, while the inhalation of 1 resulted in a significant reduction in ammonia irritation, underscoring its efficacy in both skin and airway applications.

Gamma-Irradiated Gum Arabic Grafted with 2-Hydroxyethyl Methacrylate: A Novel Superabsorbent Polymer for Controlled Folic Acid Release.

This study explores the synthesis and characterization of superabsorbent hydrogels derived from chemically modified gum Arabic, designed for controlled folic acid release. The synthesis involves a two-step process: carboxymethylation followed by grafting with 2-hydroxyethyl methacrylate via gamma irradiation. The resulting hydrogels exhibit enhanced mechanical strength and controlled diffusivity, essential for nutrient delivery systems. Key factors such as copolymer composition and irradiation dose are investigated, affecting the synthesis process. Systematic studies of swelling behaviors reveal that the hydrogel achieves a maximum swelling of 888.1% at 40 °C. The hydrogels are loaded with folic acid, and in vitro, sustained release profiles are examined under various pH conditions. The maximum release of 83.3% is observed after 24 h at pH 7.0, following a Korsmeyer-Peppas release mechanism. Different characterization techniques, confirm the successful synthesis and unique properties of the superabsorbent hydrogels. Rheological behavior analysis, scanning electron microscopy, and biocompatibility assessments provide a comprehensive understanding of the hydrogel structures. Gamma irradiation ensures a homogeneous network structure, crucial for optimal swelling behavior and mechanical properties. This research highlights the potential of eco-friendly biopolymer hydrogels in precise drug delivery applications, leveraging the safety and process control benefits of gamma irradiation.

Substrate Modification for Atrial Fibrillation Induced by Mechanical Irritation That May Be Associated With Non-Pulmonary Vein Foci.

The importance of treating non-pulmonary vein (PV) foci is increasing with improvements in the durability of PV isolation. We describe two cases wherein non-PV foci were induced by mechanical irritation and conventional induction in the same area, which was impossible to induce after ablation, suggesting a relationship between mechanical irritation and induction of non-PV foci. In a recurrent case of non-PV foci, atrial fibrillation (AF) was induced only by mechanical irritation. No recurrence has been observed since the ablation of the area. Thus, treatment of the AF induction site with mechanical irritation could be considered an effective therapy for non-PV foci.

Content validity of the EQ-5D-5L with skin irritation and self-confidence bolt-ons in patients with atopic dermatitis: a qualitative think-aloud study.

OBJECTIVES: Two bolt-on dimensions (skin irritation, self-confidence) have been developed for the EQ-5D-5L to improve its content validity and responsiveness in psoriasis. However, the two bolt-ons are not strictly psoriasis-specific and are potentially relevant in other skin conditions. This study aims to explore the content validity of the EQ-5D-5L with two bolt-ons in patients with atopic dermatitis (AD). METHODS: In 2021-2022, qualitative, semi-structured interviews were conducted with 20 adult AD patients at a university dermatology clinic in Hungary. We aimed for a heterogeneous sample in terms of age, gender, education and disease severity. Patients completed the EQ-5D-5L with two bolt-ons using a think-aloud protocol. Probing questions were posed to investigate item relevance, potential conceptual overlaps, missing concepts and the appropriateness of the recall period. Interview transcripts were subjected to thematic analysis. RESULTS: The EQ-5D-5L with the two bolt-ons covered the most important aspects of health-related quality of life in AD patients. Most patients found both the skin irritation and self-confidence bolt-ons relevant. Fifteen potential missing concepts were identified, but only two (social relationships, judgement by others) were identified by more than one patient. A smaller conceptual overlap was found between the skin irritation and pain/discomfort dimensions in 7 patients (35%). Half the patients expressed a preference for a recall period of 1 week rather than of 'today'. CONCLUSIONS: The EQ-5D-5L with skin irritation and self-confidence bolt-ons showed good relevance, comprehensiveness and comprehensibility in patients with AD. However, in terms of comprehensiveness, social relationships and judgement by others (stigma) may be missing from the questionnaire.

Exposure limits for indoor volatile substances concerning the general population: The role of population-based differences in sensory irritation of the eyes and airways for assessment factors.

Assessment factors (AFs) are essential in the derivation of occupational exposure limits (OELs) and indoor air quality guidelines. The factors shall accommodate differences in sensitivity between subgroups, i.e., workers, healthy and sick people, and occupational exposure versus life-long exposure for the general population. Derivation of AFs itself is based on empirical knowledge from human and animal exposure studies with immanent uncertainty in the empirical evidence due to knowledge gaps and experimental reliability. Sensory irritation in the eyes and airways constitute about 30-40% of OELs and is an abundant symptom in non-industrial buildings characterizing the indoor air quality and general health. Intraspecies differences between subgroups of the general population should be quantified for the proposal of more 'empirical' based AFs. In this review, we focus on sensitivity differences in sensory irritation about gender, age, health status, and vulnerability in people, based solely on human exposure studies. Females are more sensitive to sensory irritation than males for few volatile substances. Older people appear less sensitive than younger ones. However, impaired defense mechanisms may increase vulnerability in the long term. Empirical evidence of sensory irritation in children is rare and limited to children down to the age of six years. Studies of the nervous system in children compared to adults suggest a higher sensitivity in children; however, some defense mechanisms are more efficient in children than in adults. Usually, exposure studies are performed with healthy subjects. Exposure studies with sick people are not representative due to the deselection of subjects with moderate or severe eye or airway diseases, which likely underestimates the sensitivity of the group of people with diseases. Psychological characterization like personality factors shows that concentrations of volatile substances far below their sensory irritation thresholds may influence the sensitivity, in part biased by odor perception. Thus, the protection of people with extreme personality traits is not feasible by an AF and other mitigation strategies are required. The available empirical evidence comprising age, lifestyle, and health supports an AF of not greater than up to 2 for sensory irritation. Further, general AFs are discouraged for derivation, rather substance-specific derivation of AFs is recommended based on the risk assessment of empirical data, deposition in the airways depending on the substance's water solubility and compensating for knowledge and experimental gaps. Modeling of sensory irritation would be a better 'empirical' starting point for derivation of AFs for children, older, and sick people, as human exposure studies are not possible (due to ethical reasons) or not generalizable (due to self-selection). Dedicated AFs may be derived for environments where dry air, high room temperature, and visually demanding tasks aggravate the eyes or airways than for places in which the workload is balanced, while indoor playgrounds might need other AFs due to physical workload and affected groups of the general population.

The effect of electrical stimulation on skin vulnerability to irritants.

PURPOSE: Electrical stimulation (ES) is a widely used technique in the medical field for various purposes. The effect of ES on several skin properties has been investigated; however, its effect on skin vulnerability to irritants remains unknown. This study aimed to investigate the effects of ES application on skin vulnerability to external irritants. MATERIALS AND METHODS: An experimental study on 12 healthy male subjects (Mean ± SD, 22.9 ± 3.6 years) who completed the study. The subjects were free of skin abnormalities in the volar aspect of both forearms. Three areas were allocated to each forearm and marked as areas 1, 2, and A in the treated forearm, and areas 3, 4, and B in the control forearm. ES was applied to the volar aspect of the treated forearm for 30 min three times a week, for 2 weeks. The effect of ES on skin vulnerability was investigated using 5% and 0.5% sodium lauryl sulfate (SLS) patches applied to both treated and control forearms. The skin response to irritants was evaluated using transepidermal water loss (TEWL) and a visual erythema score 24 h after patch removal. RESULTS: Compared to the control forearm, ES increased skin permeability and erythema in response to external irritants (SLS), as measured by the visual analog score (Z = 2.75, p = 0.006) and TEWL (p < 0.05), respectively. CONCLUSIONS: ES escalates skin reactions to low concentrations of irritant substances, such as SLS, in the area between the two electrodes. This emphasizes the use of this substance, and similar irritants should be avoided in areas treated with ES.

Multispectral near-infrared spectroscopy study evaluating the effect of razor design on shaving-induced erythema.

BACKGROUND: While shaving-induced erythema is a common inflammatory skin issue, there is a lack of quantitative information on how well a shaving product performs in this regard. In this study, multispectral near-infrared spectroscopy (NIRS) imaging was used to quantitatively and qualitatively measure the extent of shaving-induced erythema. The research compares a safety razor and a cartridge razor to evaluate their impact on skin irritation. MATERIALS AND METHODS: Fifty-nine healthy male volunteers without pre-existing skin conditions were enrolled. Basic demographics were recorded, and participants' faces or necks were imaged before shaving. Shaving was conducted on the right side of the face/neck with the safety razor and on the left side of the face/neck using the 3-blade cartridge razor. Images were captured immediately after shaving, at 5 and 10 min post-shaving. RESULTS: Tissue oxygen saturation (StO2) measurements demonstrated that the safety razor induced significantly less erythema than the cartridge razor. Immediately after shaving, 40.3% of skin shaved with the safety razor had erythema compared to 57.6% for the cartridge razor. At 5 min post-shaving, 36.5% of skin shaved with the safety razor had erythema, compared to 53.8% of cartridge razor. CONCLUSIONS: Multispectral NIRS revealed significant differences in shaving-induced erythema between safety and cartridge razors. Safety razors demonstrated a lower incidence of erythema, suggesting a potential advantage for individuals prone to skin irritation. This study contributes valuable insights into skin irritation and highlights the potential of multispectral NIRS in dermatology research.

Retrospective evaluation of the eye irritation potential of agrochemical formulations.

Multiple in vitro eye irritation methods have been developed and adopted as OECD health effects test guidelines. However, for predicting the ocular irritation/damage potential of agrochemical formulations there is an applicability domain knowledge gap for most of the methods. To overcome this gap, a retrospective evaluation of 192 agrochemical formulations with in vivo (OECD TG 405) and in vitro (OECD TG 437, 438, and/or 492) data was conducted to determine if the in vitro methods could accurately assign United Nations Globally Harmonized System for Classification and Labelling of Chemicals (GHS) eye irritation hazard classifications. In addition, for each formulation the eye irritation classification was derived from the classification of the contained hazardous ingredients and their respective concentration in the product using the GHS concentration threshold (CT) approach. The results herein suggest that the three in vitro methods and the GHS CT approach were highly predictive of formulations that would not require GHS classification for eye irritation. Given most agrochemical formulations fall into this category, methods that accurately identify non-classified agrochemical formulations could significantly reduce the use of animals for this endpoint.

Sensory irritation and use of the best available science in setting exposure limits: Issues raised by a scientific panel review of formaldehyde human research studies.

As a high production volume chemical with recognized sensory irritation and widespread exposure, the human health risk potential of formaldehyde has been reviewed by many international regulatory agencies and scientific advisory bodies. A scientific panel, the Human Studies Review Board, under the auspices of the EPA's Toxic Substances Control Act (TSCA) program recently reviewed the sensory irritation studies included in the 2022 Draft Integrated Risk Information System (IRIS) Formaldehyde Hazard Assessment in the context of their use in a weight of evidence evaluation of acute inhalation health effects. This panel issued a series of recommendations on the use of these studies for the purposes of calculating exposure limits (e.g., study design preferences; uncertainty adjustment). Considering that these recommendations might reflect topic areas with varying degrees of scientific consensus, this commentary reflects on commonalities and distinctions amongst international formaldehyde exposure limits based on sensory irritation. Notably, each review panel charged with an assessment of the science recommended that no adjustment was needed to account for either exposure duration or human variability. These areas of scientific consensus should be considered as the best available science for the purposes of setting exposure limits in the anticipated TSCA Risk Evaluation on formaldehyde.

Research progress in the development of 3D skin models and their application to in vitro skin irritation testing.

Toxicological assessment of chemicals is crucial for safeguarding human health and the environment. However, traditional animal experiments are associated with ethical, technical, and predictive limitations in assessing the toxicity of chemicals to the skin. With the recent development of bioengineering and tissue engineering, three-dimensional (3D) skin models have been commonly used as an alternative for toxicological studies. The skin consists of the subcutaneous, dermis, and epidermis. All these layers have crucial functions such as physical and biological protection and thermoregulation. The epidermis is the shallowest layer protecting against external substances and media. Because the skin is the first contact point for many substances, this organ is very significant for assessing local toxicity following skin exposure. According to the classification of the United Nations Global Harmonized System, skin irritation is a major potentially hazardous characteristic of chemicals, and this characteristic must be accurately assessed and classified for enhancing chemical safety management and preventing and reducing chemical accidents. This review discusses the research progress of 3D skin models and introduces their application in assessing chemical skin irritation.

A comparative study on the effect of alcohol-based hand sanitizers in spray and gel formulation on the skin: A prospective, randomised, crossover trial.

BACKGROUND: Many formulations of Alcohol-based hand rubs (ABHRs), such as liquid, gel, and spray have been developed and used for preventing infections. This study aimed to compare skin irritation from using ABHRs in gel and spray formulations. METHOD: This was a prospective, randomised, crossover trial conducted to investigate the effect of skin irritation caused by ABHRs in gel compared to spray formulation after 21 days of using each formulation. Clinical outcomes were assessed using subjective Larson's skin assessment score and Frosch and Kligman observer skin assessment score, as well as bioengineering measures: transepidermal water loss (TEWL) and skin capacitance on days 3, 7, 14, and 21. RESULTS: Among 38 participants, both formulations showed no significant change in clinical scores and skin capacitance during the study. However, TEWL increased significantly from baseline on day 3 (p = 0.029) for the spray formulation and on day 21 (p = 0.019) for the gel formulation, with no statistically significant difference between the formulations (p = 0.46). CONCLUSION: Our research supports the safety of gel and spray ABHRs for regular use, with the only potential issue being mild skin irritation. For those with sensitive skin, the gel formulation is preferable.

Analysis of early clinical signs and risk factors for severe hemorrhagic cystitis after stem cell transplantation in children.

INTRODUCTION: To analyze the characteristics of early clinical symptoms of hemorrhagic cystitis (HC) after hematopoietic stem cell transplantation (HSCT) and the risk factors of severe HC. METHODS: We retrospectively analyzed 77 children with post-HSCT HC treated at our hospital between June 2013 and June 2021. Clinical characteristics were collected and catalogued. RESULTS: Among the children with urinary tract irritation symptoms (UTIS) as the first symptom, symptoms appeared earlier than hematuria symptoms (28 day vs. 31 day, p = 0.027), and the time progressing to severe HC was significantly longer in these children (12 day vs. 7 day, p = 0.038), but there was no significant difference in the number of participants (57.8% vs. 59.4%, p = 0.889). BK polyomavirus (BKV) infection was an independent risk factor (hazard ratio [HR] = 2.782, p = 0.035) for severe HC, which was also positively associated with multi-viral infection (HR = 2.215, p = 0.020). CONCLUSIONS: In HC children, when the first urinary tract symptom was UTIS, it appeared earlier than hematuria, and the time of progression to severe HC was significantly longer, suggesting that we still need more aggressive treatment for these children to prevent the worsening of symptoms. The severity of HC was positively correlated with BKV infection and multiple infections.

Opisthotonic posturing in Guillian-Barre syndrome.

INTRODUCTION: Here we report a child of Gullian Barre syndrome (GBS) with opisthotonic posturing and we subsequently detected Scrub typhus in him. CASE REPORT: An 11-year-old boy presented with progressive motor quadriparesis with transient bladder retention, bilateral facial weakness, diminished gag reflex, absent reflexes and his nerve conduction studies suggested Acute Motor Axonal Neuropathy (AMAN) GBS. His power gradually started recovering after one week. However, he had opisthotonus and signs of meningeal irritation. The child's CSF examination was consistent with GBS. His bacterial, fungal, tubercular microscopy and cultures and viral markers were negative. IgM for Borrelia and Leptospira and HIV ELISA were negative. IgM for scrub typhus, however, came out to be positive. Hence, we gave him azithromycin and he recovered almost completely in 3 months. CONCLUSIONS: To our knowledge there is no previous report of opisthotonic posturing in GBS patients. This could be due to radicular involvement in immune mediated etiology of GBS.

Assessment of Intranasal Function of the Trigeminal Nerve in Daily Clinical Practice.

BACKGROUND: The trigeminal nerve is a mixed cranial nerve responsible for the motor innervation of the masticatory muscles and the sensory innervation of the face, including the nasal cavities. Through its nasal innervation, we perceive sensations, such as cooling, tingling, and burning, while the trigeminal system mediates the perception of airflow. However, the intranasal trigeminal system has received little attention in the clinical evaluation of patients with nasal pathology. SUMMARY: Testing methods that enable the clinical assessment of intranasal trigeminal function have recently been developed. This study aims to present the current clinical methods that can be utilised in everyday practice, as described in the literature. These methods include four assessment techniques: (1) the quick screening test of trigeminal sensitivity involves patients rating the intensity of ammonium vapour presented in a lipstick-like container. (2) The lateralisation test requires subjects to identify which nasal cavity is being stimulated by a trigeminal stimulus, such as eucalyptol or menthol, while the other side receives an odourless stimulus. (3) The trigeminal sticks test evaluates the trigeminal function similarly to the olfactory function using sticks filled with trigeminal stimulant liquids. (4) The automated CO2 stimulation device is used for measuring trigeminal pain thresholds, utilising intranasal CO2 stimuli to define the pain threshold. KEY MESSAGES: Assessing intranasal trigeminal function clinically may prove useful in evaluating rhinology patients, particularly those who encounter nasal obstruction without anatomical blockage and those experiencing olfactory disorders with suspected trigeminal dysfunction. Despite their limitations, the presented methods may provide useful information about nasal patency, chemosensitivity, and pain sensation in the daily clinical practice of such patients, leading to better therapeutic decisions.

Optimisation and in-vivo evaluation of extracted Karanjin loaded liposomal topical formulation for treatment of psoriasis in tape-stripped mouse model.

AIM: The present work is focus on development of anti-psoriasis activity of Karanjin (isolated from Pongamia pinnata seed oil) loaded liposome based lotion for enhancement of skin permeation and retention. METHOD: Karanjin was isolated using liquid-liquid extraction method and characterised by HPLC analysis and partition coefficient. Further, isolated Karanjin was loaded into liposomes using thin-film hydration technique and optimised by Box-Behnken design. Selected optimised batch was characterised their mean diameter, PDI, zeta potential, and entrapment efficiency, morphology (by TEM), FTIR and ex-vivo skin retention. Additionally, Karanjin loaded liposomes were formulated into lotion and characterise their rheological, spreadability, texture, ex-vivo skin permeation & retention, stability and anti-psoriatic activity in mouse tail model. RESULT: The yield of Karanjin from seed oil was 0.1% w/v and have lipophilic nature. The optimised liposomal formulation showed 195 ± 1.8 nm mean diameter, 0.271 ± 0.02 PDI, -27.0 ± 2.1 mV zeta potential and 61.97 ± 2.5% EE. TEM image revel the spherical shap of liposome surrounded by single phospholipid bilayer and no interection between drug and excipients. Further, lotion was prepared by 0.1% w/v carbopol and found to 615 mPa.sec viscosity, good thixotropic behaviour, spreadability and texture. There was 22.44% increase in drug permeation for Karanjin loaded liposomal lotion compared to pure Karanjin lotion, confirm by ex-vivo permeation and retention. While, in-vivo study revel the liposomal lotion of Karanjin was found to have 16.09% higher drug activity then 5% w/w conventional Karanjin lotion. CONCLUSION: Karanjin loaded liposomal lotion have an effective anti-psoriatic agent and showed better skin permeation and retention than the conventional Karanjin lotion.

Development of Sensitive In Vitro Protocols for the Biocompatibility Testing of Medical Devices and Pharmaceuticals Intended for Contact with the Eyes: Acute Irritation and Phototoxicity Assessment.

This study introduces a novel in vitro methodology that employs the 3-D reconstructed tissue model, EpiOcular, to assess the irritation and phototoxicity potential of medical devices and drugs in contact with the eye. Our study evaluated diverse test materials, including medical devices, ophthalmological solutions and an experimental drug (cemtirestat), for their potential to cause eye irritation and phototoxicity. The protocols used in this study with the EpiOcular tissue model were akin to those used in the ultra-mildness testing of cosmetic formulations, which is challenging to predict with standard in vivo rabbit tests. To design these protocols, we leveraged experience gained from the validation project on the EpiDerm skin irritation test for medical devices (ISO 10993-23:2021) and the OECD TG 498 method for photo-irritation testing. The predictions were based on the tissue viability and inflammatory response, as determined by IL-1α release. By developing and evaluating these protocols for medical devices, we aimed to expand the applicability domain of the tests referred to in ISO 10993-23. This will contribute to the standardisation and cost-effective safety evaluation of ophthalmic products, while reducing reliance on animal testing in this field. The findings obtained from the EpiOcular model in the photo-irritation test could support its implementation in the testing strategies outlined in OECD TG 498.

A Novel Ex Vivo Blinking Method for Comparing the Corneal Residence Time of New Shampoo Formulations.

In the cosmetics sector, many products such as shampoos have a probability of accidental ocular exposure during their routine use. One very specific safety parameter is the residence time of the substance on the corneal surface, as prolonged exposure may cause injury. In this study, we developed a system that simulates corneal exposure to blinking and tear flow, for comparing the corneal clearance times of viscous detergent formulations. The Ex Vivo Eye Irritation Test (EVEIT), which uses corneal explants from discarded rabbit eyes from an abattoir, was used as the basis for the new system. To simulate blinking, we developed a silicone wiping membrane to regularly move across the corneal surface, under conditions of constant addition and aspiration of fluid, to mimic tear flow. Six shampoo formulations were tested and were shown to differ widely in their corneal clearance time. Three groups could be identified according to the observed clearance times (fast, intermediate and slow); the reference shampoo had the shortest clearance time of all tested formulations. With this new system, it is now possible to investigate an important physicochemical parameter, i.e. corneal clearance time, for the consideration of ocular safety during the development of novel cosmetic formulations.

Establishment and Validation of a Transdermal Drug Delivery System for the Anti-Depressant Drug Citalopram Hydrobromide.

To enhance the bioavailability and antihypertensive effect of the anti-depressant drug citalopram hydrobromide (CTH) we developed a sustained-release transdermal delivery system containing CTH. A transdermal diffusion meter was first used to determine the optimal formulation of the CTH transdermal drug delivery system (TDDS). Then, based on the determined formulation, a sustained-release patch was prepared; its physical characteristics, including quality, stickiness, and appearance, were evaluated, and its pharmacokinetics and irritation to the skin were evaluated by applying it to rabbits and rats. The optimal formulation of the CTH TDDS was 49.2% hydroxypropyl methyl cellulose K100M, 32.8% polyvinylpyrrolidone K30, 16% oleic acid-azone, and 2% polyacrylic acid resin II. The system continuously released an effective dose of CTH for 24 h and significantly enhanced its bioavailability, with a higher area under the curve, good stability, and no skin irritation. The developed CTH TDDS possessed a sustained-release effect and good characteristics and pharmacokinetics; therefore, it has the potential for clinical application as an antidepressant.