Contact allergy caused by acrylates in nail cosmetics: A pilot study from Greece.

BACKGROUND: The growing popularity of nail techniques based on acrylates has led to a higher frequency of sensitization in both nail technicians and users. OBJECTIVES: The study aimed to assess cases of allergic contact dermatitis (ACD) caused by acrylates in individuals with occupational or non-occupational exposure to nail techniques. METHODS: A preliminary study was conducted on 30 patients with ACD caused by acrylates in nail techniques, who were patch tested from September 2022 to March 2023 at the First Department of Dermatology and Venereology of Andreas Syggros Hospital, Athens, Greece. RESULTS: Thirty female patients with ACD to acrylates were documented (15 users and 15 nail technicians and users). The most common allergens were: 2-hydroxyethyl methacrylate (HEMA), 2-hydroxypropyl methacrylate (HPMA) and ethyleneglycol dimethacrylate (EGDMA), which tested positive in all 30 patients (100.0%). Twenty patients (66.7%) had been exposed to dental procedures involving acrylates, before the onset of ACD. Nail technicians exhibited extensive skin lesions, 40.0% experienced ACD within the first year of work and 13.3% during their professional practice. Three of them (20.0%) had to discontinue their work. CONCLUSION: Acrylates have been identified as potent allergens, necessitating the implementation of safety measures for the use of these chemicals in nail techniques.

Ropivacaine pharmacokinetics in the arterial and venous pools after ultrasound-guided continuous thoracic paravertebral nerve block.

Background and Aims: Although thoracic paravertebral blockade (TPVB) is employed in thoracic surgery to ensure satisfactory postoperative analgesia, large doses of anesthetics are required and manifestations of local anesthetic systemic toxicity (LAST) may appear. Currently, there are limited data on the pharmacokinetics of ropivacaine after continuous TPVB. The aim of this prospective study was to investigate ropivacaine kinetics, in the arterial and venous pools, after continuous TPVB and assess the risk of LAST. Material and Methods: Immediately after induction of general anesthesia, an ultrasound-guided continuous TPVB at T5 or T6 or T7 thoracic level was performed in 18 adult patients subjected to open thoracotomy. A 25-ml single bolus injection of ropivacaine 0.5% was administered through thoracic paravertebral catheter, followed by a 14 ml/h continuous infusion of ropivacaine 0.2% starting at the end of surgery. Quantification of total ropivacaine concentrations was performed using a validated high-performance liquid chromatography method. Population pharmacokinetic models were developed separately for arterial and venous ropivacaine data. Results: The best model was one-compartment disposition with an additional pre-absorption compartment corresponding to thoracic paravertebral space. Gender had a significant effect on clearance, with females displaying lower elimination than males. Some patients had ropivacaine concentrations above the toxic threshold, but none displayed evidence of LAST. Continuous thoracic paravertebral nerve blocks provided adequate postoperative analgesia. Conclusion: Ropivacaine doses at the upper end of clinical use (800 mg/d) did not inflict the manifestations of LAST and provided adequate postoperative pain control. Pharmacokinetic models were developed, and the effect of gender was identified.

A Retrospective Analysis to Investigate Contact Sensitization in Greek Population Using Classic and Machine Learning Techniques.

Allergic contact dermatitis (ACD) is an inflammatory reaction affecting all age groups and both sexes. ACD is characterized by a delayed-type hypersensitivity reaction IV caused by skin contact with haptens. Chronic exposure typically leads to a decrease in erythema accompanied by lichenification (thickening and hardening of the skin) and persistent itching. The current study aims to investigate the patterns of contact sensitization in the Greek population using patch test data analysis. Patch test data from 240 patients (120 Males/120 Females) with allergic contact dermatitis were collected at the Laboratory for Patch Testing, National Reference Center for Occupational Dermatoses "Andreas Syggros" Hospital in Athens Greece. The contact allergic reactions were caused by ethylenediamine dihydrochloride 1%, thimerosal 0.5%, and methyldibromo-glutaronitrile 0.1% from the European baseline series of allergens; information was also collected for ICDRG evaluation, an extended MOAHLFA index and patient-reported outcomes (daily routine questionnaire). The chi-square test for independence and Spearman's rank were used to evaluate the association and correlation, respectively, between patient characteristics and ACD-related factors. Multiple correspondence analysis (MCA), which is a data analysis approach, was used to find and depict underlying structures in the data collection for nominal categorical data. Statistically significant associations were found between the following pairs of characteristics: eczema triggers and gender and eczema triggers and hand dermatitis. The results from MCA showed that there is correlation between allergic contact dermatitis onset, allergens, and demographic variables.

SARS-CoV-2 humoral responses following booster BNT162b2 vaccination in patients with B-cell malignancies.

Patients with B-cell malignancies have suboptimal immune responses to SARS-CoV-2 vaccination and are a high-risk population for severe COVID19 disease. We evaluated the effect of a third booster BNT162b2 vaccine on the kinetics of anti- SARS-CoV-2 neutralizing antibody (NAbs) titers in patients with B-cell malignancies. Patients with NHL (n = 54) Waldenström's macroglobulinemia (n = 90) and chronic lymphocytic leukemia (n = 49) enrolled in the ongoing NCT04743388 study and compared against matched healthy controls. All patient groups had significantly lower NAbs compared to controls at all time points. 1 month post the third dose (M1P3D) NAbs increased significantly compared to previous time points (median NAbs 77.9%, p < .05 for all comparisons) in all patients. NAbs ≥ 50% were seen in 59.1% of patients, 34.5% of patients with suboptimal responses post-second dose, elicited a protective NAb titer ≥50%. Active treatment, rituximab, and BTKi treatment were the most important prognostic factors for a poor NAb response at 1MP3D; only 25.8% of patients on active treatment had NAbs ≥ 50%. No significant between-group differences were observed. Patients with B-cell malignancies have inferior humoral responses against SARS-CoV-2 and booster dose enhances the NAb response in a proportion of these patients.

Ulvan-Based Nanofibrous Patches Enhance Wound Healing of Skin Trauma Resulting from Cryosurgical Treatment of Keloids.

Keloids are skin fibroproliferative disorders, resulting from abnormal healing of deep cutaneous injuries. Cryosurgery, the most common treatment for keloids, causes skin traumas. Even though the clinical practice of cryosurgery has increased, effective wound healing therapy is still lacking. In this investigation, nonwoven nanofibrous patches composed of ulvan, a marine sulfated polysaccharide exhibiting anti-inflammatory and antioxidant activities, and polyethylene oxide (PEO) were fabricated through electrospinning and characterized. Their wound healing efficacy on skin traumas resulting from cryosurgical treatment of keloids was clinically tested and evaluated in comparison to a reference product. Twenty-four volunteer patients undergoing cryosurgery as a treatment of keloids were selected to apply either the ulvan/PEO patch or the reference product for 21 days. The ulvan/PEO patch, 21 days after cryosurgery, showed significant wound healing, elimination of skin inflammation, restoration of biophysical parameters similar to normal values and significant decrease in haemoglobin concentration, skin texture and volume, while no discomfort or adverse reaction was observed. In contrast, the reference product showed inferior performance in all evaluated parameters. The designed ulvan/PEO patch represents the first wound dressing to effectively heal skin trauma after cryosurgical treatment of keloids.

Colchicine for the treatment of COVID-19 patients: efficacy, safety, and model informed dosage regimens.

Colchicine is widely investigated for cardioprotection of COVID-19 patients since it can prevent the phenomenon of 'cytokine storm' and may reduce the complications arising from COVID-19. Despite the potentially beneficial effects of colchicine, there is no consensus on the appropriate dosage regimen and numerous schemes are currently used.In this study, simulations were performed to identify the ability of dosage regimens to attain plasma levels in CVOID-19 patients, known to be generally safe and efficacious. Since renal and hepatic impairment, as well as, drug-drug interactions have been identified to be the most significant factors increasing colchicine toxicity, the impact of these interactions was assessed in the simulations.Some dosage regimens lead to high colchicine concentrations, while others result in sub-therapeutic levels. Additional dosage schemes were proposed in this study aiming to be applied in patients with clearance insufficiency. Colchicine administration of 0.5 mg twice daily, can be considered safe and effective. In cases of clearance impairment, doses as low as 0.25 mg thrice or twice daily should be applied.Colchicine is a narrow therapeutic index drug and dosage regimens tailored to patients' needs should be designed.

Optimization of hydroxychloroquine dosing scheme based on COVID-19 patients' characteristics: a review of the literature and simulations.

During the recent COVID-19 outbreak hydroxychloroquine (HCQ) has been proposed as a safe and effective therapeutic option. However, a wide variety of dosing schemes has been applied in the clinical practice and tested in clinical studies. An extended literature survey was performed investigating the pharmacokinetics, the efficacy and safety of HCQ in COVID-19 treatment. Population pharmacokinetic models were retrieved from the literature and after evaluation and assessment one was selected in order to perform simulations. The most commonly applied dosing schemes were explored for patients with different weights and different levels of HCQ clearance impairment. Model-based simulations of HCQ concentrations revealed that high initial doses followed by low and sparse doses may offer significant benefits to patients by decreasing the viral load without reaching levels considered to produce adverse effects. For instance, the dosing scheme proposed for a 70 kg adult with moderate COVID-19 symptoms would be 600 mg upon diagnosis, 400 mg after 12 h, 300 mg after 24 h, 200 mg after 36 h, followed by 200 mg BID for 4 d, followed by 200 mg OD for 5 d. Based on the results from simulations performed and the currently published knowledge regarding HCQ in COVID-19 treatment, this study provides evidence that a high loading dose followed by sparse doses could offer significant benefits to the patients.

Validation of population pharmacokinetic models: a comparison of internal and external validation approaches for hydrochlorothiazide.

1. Model evaluation is an important issue in population analyses. Our aim was to perform and illustrate metrics and techniques for internal and external evaluation with an application to population pharmacokinetics of hydrochlorothiazide (HCTZ).2. A nonlinear mixed effects model was used to study the pharmacokinetics of HCTZ. In addition, different types of internal assessment tools and external metrics were used for model evaluation. External evaluation was performed using an alternative dataset that included data from an independent group of subjects. For comparison, a previously published population pharmacokinetic model for HCTZ was applied to the same data.3. A two-compartment model with first-order oral absorption using a constant time delay between administration and absorption and first-order elimination best described HCTZ pharmacokinetics. Age had a statistically significant effect on HCTZ clearance. The final model performed adequately in the internal and external assessment tests. The final model showed better predictive performance than the other previously published HCTZ model.4. Finally, a robust population pharmacokinetic model for HCTZ in adults was constructed and validated internally and externally. Incorporating analytical assessment of nonlinear pharmacokinetics into the modelling may be a promising approach to improve the predictive power of the model.

Pharmacokinetic and pharmacodynamic modeling of levetiracetam: investigation of factors affecting the clinical outcome.

This study aimed to evaluate the pharmacokinetics and pharmacodynamics of oral levetiracetam therapy in drug refractory adult epileptic outpatients, as well as factors affecting them. Concentration-time data were collected at steady state, while seizure recurrence was monitored for 13 months. Non-linear mixed effects modeling was applied, and covariates assessed included weight, height, age, daily dose and creatinine clearance.Plasma concentrations of levetiracetam were best described by a one-compartment pharmacokinetic model (V/F = 34.7 L) with first-order absorption (ka = 0.616 h-1) and clearance (CL/F = 3.26 L/h). Patient's CrCL was found to significantly affect levetiracetam clearance (beta = 0.795). Time to seizure occurrence followed an exponential distribution and the mean time to seizure occurrence was estimated Te = 22.08 days. Seizure rate per month followed a Poisson distribution, while mean seizure rate per month was estimated λ = 1.33. Daily dose significantly affected the mean estimated time to seizure (beta = -2.2) and the mean monthly seizure rate (beta = 2.27) in a reverse way. Using discrete time Markov chains, it was shown that the transition probability from focal seizures to focal to bilateral tonic-clonic is significantly altered in relation to patient's CrCL.Simulations showed that dose should be adjusted in relation to CrCL, while low doses of levetiracetam are more effective for seizure control. Modeling and simulation in every-day clinical practice may provide significant information for the optimization of seizure control using well-known agents.

On the population pharmacokinetics and the enterohepatic recirculation of total ezetimibe.

Ezetimibe is a potent cholesterol absorption inhibitor, with an erratic pharmacokinetic (PK) profile, attributed to an extensive enterohepatic recirculation (EHC). The aim of this study was to develop a population PK model able to adequately characterize the complex distribution processes of total ezetimibe. The analysis was performed on the individual concentration-time data obtained from 28 healthy subjects who participated in a bioequivalence study comparing two oral ezetimibe formulations. The population PK analysis was performed using nonlinear mixed effect modeling, where different EHC models were developed and evaluated for their performance. Total ezetimibe pharmacokinetics was best described by a four-compartment model featuring EHC through the inclusion of an additional gallbladder compartment, which was assumed to release drug at specific time-intervals consistent with food intake. The final PK model was able to adequately estimate the population pharmacokinetic parameters and to allow for a formal characterization of the pharmacokinetic profile and the secondary peaks due to enterohepatic recirculation.

Hematocrit effect on dried blood spots in adults: a computational study and theoretical considerations.

Dried blood spots (DBS) are formed by deposition of a small amount of blood on specific adsorbent paper and its physical drying. DBS are employed as a sampling method in several fields of life sciences and drug research. A concern about DBS is the so-called 'Hematocrit (Ht) effect', as a different Ht leads, due to different viscosity, to different spot size, affecting assay bias. Solutions have been proposed, including the correction of quantified concentrations with a suitable correction factor. In order to quantitatively assess Ht impact on the DBS measurements, a computational approach was developed and implemented in R® language. First, the % relative error was modeled with respect to Ht. Then, Monte Carlo simulations were performed in virtual men/women populations with different Ht levels and the % relative error in relation to the Ht used for calibrators was quantified. An upper level for % relative error being a 'tolerable contribution' of Ht effect to % total analytical error was finally suggested, defining, for the first time, a potential Ht range for analysis of adults' samples, where correction of concentrations of unknown samples may be omitted. Such tolerable level for % relative error may be defined in each laboratory, also based on experimental parameters (type of paper and blood volume). Using a Ht calibration value representing the study population is fully rationalized, leading to reduced probability for concentration corrections. Regulatory criteria for bioanalysis can thus be targeted, moving towards wider utilization of DBS in human pharmacokinetic and clinical trials.

Pharmacokinetic analysis of inhaled salmeterol in asthma patients: Evidence from two dry powder inhalers.

Salmeterol (SAL) is a long-acting ß2-adrenergic agonist, which is widely used in the therapy of asthma. The aim of this study was to investigate the pharmacokinetics (PK) of inhaled salmeterol in asthma patients using two different dry powder inhalers. This analysis was based on data from 45 subjects who participated in a two-sequence, four-period crossover bioequivalence (BE) study after single administration of the test (T) and reference (R) products. In order to mimic more closely the real treatment conditions, activated charcoal was not co-administered. Plasma concentration-time (C-t) data were initially analysed using classic non-compartmental PK approaches, while the main objective of the study was to apply population PK modeling. The relative fraction of the dose absorbed via the lungs (RL ) was set as a parameter in the structural model. The plasma C-t profiles of salmeterol showed a biphasic time course indicating a parallel pulmonary and gastrointestinal (GI) absorption. A two-compartment disposition model with first order absorption from the GI and very rapid absorption from lungs (like an i.v. bolus) was found to describe successfully the C-t profiles of salmeterol. The estimated RL value was 13% suggesting a high gut deposition of inhaled salmeterol. Women were found to exert less capability to eliminate salmeterol than men, while body weight (in allometric form) was found to be an important covariate on the peripheral volume of distribution.

Ropivacaine, Interleukin-6 and Tumor Necrosis Factor Alpha Plasma Levels during Intermittent Epidural and Continuous Wound Infusion of Ropivacaine for Analgesia after Hysterectomy or Myomectomy: An Observational Study.

BACKGROUND/AIMS: The concentration-time profile of the long-acting local anesthetic ropivacaine after epidural (EP) administration at fixed time intervals or continuous subcutaneous (SC) infusion has not been fully evaluated. The objective of this work was to determine total plasma concentrations of ropivacaine and changes in cytokine interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels during EP and SC. METHODS: In this prospective randomized controlled trial, 18 patients undergoing abdominal hysterectomy or myomectomy were randomly selected to receive ropivacaine either every 6 h via an EP catheter or by continuous wound infusion along the skin incision, after a bolus dose, for 48 h. Total plasma ropivacaine concentrations were measured before the bolus and 2, 4, 8, 24, 48, and 50 h after the bolus using high-performance liquid chromatography-UV and IL-6 and TNF-α levels were measured at 0, 8 and 24 h with ELISA and analyzed statistically. RESULTS: During EP, mean ± SD ropivacaine concentrations were relatively stable up to 50 h postoperatively, that is, 239 ± 89 ng/ml, while during SC, initial concentrations between 2 and 8 h were comparatively lower (101.5 ± 42.9 ng/ml) than 24-50 h concentrations (437.1 ± 206 ng/ml). An increase in IL-6 levels was noted between 0 and 24 h during EP and SC, but TNF-α levels increased slightly, between 0 and 24 h, only during EP. CONCLUSION: Ropivacaine plasma concentrations with both EP and SC were found to be safe throughout the administration time interval. IL-6 levels increased during the same time interval, while TNF levels varied only slightly.

Preservative contact allergy in occupational dermatitis: a machine learning analysis.

Occupational dermatoses impose a significant socioeconomic burden. Allergic contact dermatitis related to occupation is prevalent among healthcare workers, cleaning service personnel, individuals in the beauty industry and industrial workers. Among risk factors, the exposure to preservatives is frequent, since they are extensively added in products for occupational use. The goal of this study is to investigate the contact allergy patterns in order to understand the linkage among hypersensitivity to preservatives, occupational profiles, patients' clinical and demographic characteristics. Patch test results were collected from monosensitized patients to Formaldehyde 2%, KATHON 0.02%, thimerosal 0.1%, and MDBGN 0.5%; information was also collected for an extended MOAHLFA (Male-Occupational-Atopic-Hand-Leg-Face-Age) index. To assess the relationship between allergen group and occupational-related ACD, the chi-square test for independence was utilized. To uncover underlying relationships in the data, multiple correspondence analysis (MCA) and categorical principal components analysis (CATPCA), which are machine learning approaches, were applied. Significant relationships were found between allergen group and: occupation class, atopy, hand, leg, facial, trunk, neck, head dermatitis, clinical characteristics, ICDRG 48 h and ICDRG 72 h clinical evaluation. MCA and CATPCA findings revealed a link among allergen group, occupation class, patients' demographic and clinical characteristics, the MOAHLFA index, and the ICDRG scores. Significant relationships were identified between the allergen group and various manifestations of dermatitis. The utilization of machine learning techniques facilitated the discernment of meaningful patterns in the data.

An insight into the properties of a two-stage design in bioequivalence studies.

PURPOSE: Unveil the properties of a two-stage design (TSD) for bioequivalence (BE) studies. METHODS: A TSD with an upper sample size limit (UL) is described and analyzed under different conditions using Monte Carlo simulations. TSD was split into three branches: A, B1, and B2. The first stage included branches A and B1, while stage two referred to branch B2. Sample size re-estimation at B2 relies on the observed GMR and variability of stage 1. The properties studied were % BE acceptance, % uses and % efficiency of each branch, as well as the reason of BE failure. RESULTS: No inflation of type I error was observed. Each TSD branch exhibits different performance. Stage two exhibits the greatest % BE acceptances when highly variable drugs are assessed with a low starting number of subjects (N1) or when formulations differ significantly. Branch A is more frequently used when variability is low, drug products are similar, and a large N1 is included. BE assessment at branch A is very efficient. CONCLUSIONS: The overall acceptance profile of TSD resembles the typical pattern observed in single-stage studies, but it is actually different. Inclusion of a UL is necessary to avoid inflation of type I error.

An In Silico Approach toward the Appropriate Absorption Rate Metric in Bioequivalence.

In bioequivalence, the maximum plasma concentration (Cmax) is traditionally used as a metric for the absorption rate, despite the fact that there are several concerns. The idea of "average slope" (AS) was recently introduced as an alternative metric to reflect absorption rate. This study aims to further extend the previous findings and apply an in silico approach to investigate the kinetic sensitivity of AS and Cmax. This computational analysis was applied to the C-t data of hydrochlorothiazide, donepezil, and amlodipine, which exhibit different absorption kinetics. Principal component analysis (PCA) was applied to uncover the relationships between all bioequivalence metrics. Monte Carlo simulations of bioequivalence trials were performed to investigate sensitivity. The appropriate programming codes were written in Python for the PCA and in MATLAB® for the simulations. The PCA verified the desired properties of AS and the unsuitability of Cmax to reflect absorption rate. The Monte Carlo simulations showed that AS is quite sensitive to detecting differences in absorption rate, while Cmax has almost negligible sensitivity. Cmax fails to reflect absorption rate, and its use in bioequivalence gives only a false impression. AS has the appropriate units, is easily calculated, exhibits high sensitivity, and has the desired properties of absorption rate.

Dried Blood Spots in Neonatal Studies: A Computational Analysis for the Role of the Hematocrit Effect.

Dried blood spot (DBS) microsampling is extensively employed in newborn screening (NBS) and neonatal studies. However, the impact of variable neonatal hematocrit (Ht) values on the results can be a source of analytical error, and the use of fixed Ht for calibration (Htcal) is not representative of all neonatal subpopulations. A computational approach based on neonatal demographics was developed and implemented in R® language to propose a strategy using correction factors to address the Ht effect in neonatal DBS partial-spot assays. A rational "tolerance level" was proposed for the Ht effect contribution to the total analytical error and a safe Ht range for neonatal samples, where the correction of concentrations can be omitted. Furthermore, an "alert zone" for a false positive or negative result in NBS was proposed, where the Ht effect has to be considered. Results point toward the use of Htcal values closely representative of populations under analysis and an acceptable level of percentage relative error can be attributed to the Ht effect, diminishing the probability of correction. Overall, the impact of the Ht effect on neonatal studies is important and future work may further investigate this parameter, correlated to other clinical variables potentially affecting results.