Eosinophilic oesophagitis is a long-term complication of oesophageal atresia (EA), an uncommon condition that affects approximately 1 in 3500 infants. An exploratory, open-label phase 2 clinical trial was conducted in paediatric eosinophilic oesophagitis after oesophageal atresia (EoE-EA) to assess the safety, pharmacokinetics, and efficacy of oral viscous budesonide (OVB). In total, eight patients were enrolled in the study and assigned to a twice-daily dosing regimen of either 0.8 or 1 mg OVB, depending on age and height, administered for 12 weeks. OVB was safe and effective in the treatment of EoE-EA. The current investigation focuses on the pharmacokinetics of budesonide and the impact of an oral viscous formulation on its absorption and bioavailability. Using a non-linear mixed effects approach, two distinct absorption profiles were identified, despite marked interindividual variability in drug concentrations. Budesonide exposure was higher than previously reported in children following oral inhalation. Even though no significant effect has been observed on serum cortisol levels, future studies should consider exploring different doses, schedules, and/or treatment durations, as there may be an opportunity to reduce the risk of cortisol suppression.

The second part of this CME article discusses sunscreen regulation and safety considerations for humans and the environment. First, we provide an overview of the history of the United States Food and Drug Administration\'s regulation of sunscreen. Recent Food and Drug Administration studies clearly demonstrate that organic ultraviolet filters are systemically absorbed during routine sunscreen use, but to date there is no evidence of associated negative health effects. We also review the current evidence of sunscreen\'s association with vitamin D levels and frontal fibrosing alopecia, and recent concerns regarding benzene contamination. Finally, we review the possible environmental effects of ultraviolet filters, particularly coral bleaching. While climate change has been shown to be the primary driver of coral bleaching, laboratory-based studies suggest that organic ultraviolet filters represent an additional contributing factor, which led several localities to ban certain organic filters.

No previous studies have investigated the systemic absorption of bupivacaine when used topically for posttonsillectomy pain. The present study was undertaken to investigate the pharmacokinetics of bupivacaine after administration by a swab in the tonsillar fossae over 4 min after tonsillectomy. Eleven adult patients undergoing elective tonsillectomy were recruited. After removal of both tonsils, each of the two tonsillar fossae was covered with a swab moistened with 2 mL of bupivacaine 5 mg/mL, that is, a total of 20 mg bupivacaine. Blood samples were drawn after 0, 5, 10, 20, 30, 45, and 60 min. Bupivacaine was analyzed with an ultra-high-performance liquid chromatography-tandem mass spectrometry method. The highest single measured bupivacaine serum concentration was 23.2 ng/mL and took place 10 min after drug administration. Mean (±SD) Cmax was 11.4 ± 6.0 ng/mL and mean tmax was 11.3 ± 4.7 min. Mean t1/2 was 31.6 ± 9.3 min. As the toxic concentration threshold has been reported to be in the interval 1500-4500 ng/mL, the concentrations measured were well below 2% of the lowest cited toxic threshold. In conclusion, this study shows that applying 4 mL of bupivacaine 5 mg/mL by a swab in the tonsillar fossae posttonsillectomy yields very low plasma concentrations, suggesting its safe application without any risk of systemic toxic effects.

BACKGROUND: Budesonide high-volume saline irrigations (HVSIs) are routinely used to treat chronic rhinosinusitis (CRS) due to improved sinonasal delivery and efficacy compared to intranasal corticosteroid sprays. The off-label use of budesonide is assumed to be safe, with several studies suggesting the systemically absorbed dose of budesonide HVSI is low. However, the actual budesonide dose retained in the sinonasal cavity following HVSI is unknown. The objective of this study was to quantify the retained dose of budesonide after HVSI.
METHODS: Adult patients diagnosed with CRS who had undergone endoscopic sinus surgery (ESS) and were prescribed budesonide HVSI were enrolled into a prospective, observational cohort study. Patients performed budesonide HVSI (0.5 mg dose) under supervision in an outpatient clinic, and irrigation effluent was collected. High-performance liquid chromatography was employed to determine the dose of budesonide retained after HVSI.
RESULTS: Twenty-four patients met inclusion criteria. The average corrected retained dose of budesonide across the cohort was 0.171 ± 0.087 mg (37.9% of administered budesonide). Increased time from ESS significantly impacted the measured retained dose, with those 3 months post-ESS retaining 27.4% of administered budesonide (P = .0004).
CONCLUSIONS: The retained dose of budesonide in patients with CRS after HVSI was found to be significantly higher than previously estimated and decreased with time post-ESS. Given that budesonide HVSI is a cornerstone of care in CRS, defining the retained dose and the potential systemic implications is critical to understanding the safety of budesonide HVSI.

Nebivolol (NBV), a BCS class II anti-hypertensive drug, suffers from limited solubility and oral bioavailability. Nanosized ethosomes were adopted as an approach to solubilize and deliver NBV transdermally, as a substitute to oral route. Ethosomal dispersions were prepared employing thin film hydration method. Formulation variables were adjusted to obtain entrapment efficiency; EE > 50%, particle size; PS < 100 nm, zeta potential; ZP > ±25 mV, and polydispersity index; PDI < 0.5. The optimized ethosomal dispersion (OED) showed accepted EE 86.46 ± 0.15%, PS 73.50 ± 0.08 nm, ZP 33.75 ± 1.20 mV, and PDI 0.31 ± 0.07. It also showed enhanced cumulative amount of NBV permeated at 8 h (Q8) 71.26 ± 1.46% and 24 h (Q24) 98.18 ± 1.02%. TEM images denoted spherical vesicles with light colored lipid bi-layer and dark core. Confocal laser scanning microscopy showed deeply localized intradermal and transfollicular permeation of the fluorolabelled OED (FL-OED). Nanosized FL-OED (<100 nm) can permeate through hair follicles creating a drug reservoir for enhanced systemic absorption. OED formulated into transdermal patch (OED-TP1) exhibited accepted physicochemical properties including; thickness 0.14 ± 0.01 mm, folding endurance 151 ± 0.07, surface pH 5.80 ± 0.15, drug content 98.64 ± 2.01%, mucoadhesion 8534 ± 0.03, Q8 87.61 ± 0.11%, and Q24 99.22 ± 0.24%. In vivo pharmacokinetic studies showed significantly enhanced bioavailability of OED-TP1 by 7.9 folds compared to oral Nevilob® tablets (p = 0.0002). It could be concluded that OED-TP1 can be a promising lipid nanocarrier TDDS for NBV and an efficacious alternative route of administration for hypertensive patients suffering from dysphagia.
Ethosomes loaded with lipophilic drugs, as NBV, can have two possible pathways of permeation through the skin; intradermal and transfollicular.Nanosized ethosomes (< 100 nm) can produce efficient intradermal and transfollicular reservoirs for sustained drug delivery.The formulated transdermal patch loaded with the optimized ethosomal dispersion (OED) showed enhanced bioavailability by 7.9 folds compared to Nevilob® oral tablets.

Systemic absorbtion of topically applied mitomycin C (MMC) during trabeculectomy needs to be evaluated to look for any systemic toxicity, which might be a major concern in certain conditions like pregnancy.
After obtaining ethical committee clearance, female patients in the reproductive age group undergoing trabeculectomy with MMC were included. Pregnant/lactating patients, patients with any systemic illness were excluded. During trabeculectomy, 0.02% MMC was applied subconjunctivally for 2 min and then washed. Blood samples were withdrawn at 1, 2, 4, 8, 12, and 24 hrs after the surgery and analyzed of MMC levels using Liquid chromatography-tandem mass spectroscopy (LC-MS/MS).
The mean age of the participants was 29 ± 12 years. MMC was not detected in any of the plasma samples analyzed as it was less than the detection limit (<1.56 ng/mL) of the employed LC-MS/MS assay.
It can be deduced that the systemic absorption of MMC is negligible or the plasma concentration is less than 1.56 ng/ml (1000 times less than the concentration where systemic toxicity was not observed).

Protection against sunburn, skin damage and the carcinogenic effects of ultraviolet light are the primary health benefits associated with UV filters used in topical sunscreen drug products. Countries such as Europe have 30+ UV filters approved for sunscreen products while the US has about 10, greatly reducing the options to provide diverse, effective sun protection products. Bemotrizinol (BEMT) is the first new sunscreen active ingredient to be evaluated for inclusion in the Over-The-Counter (OTC) sunscreen monograph using FDA\'s new Generally Recognized as Safe and Effective (GRASE) testing guidelines. An in vitro skin permeation test (IVPT) and clinical pilot pharmacokinetic Maximum Usage Trial (MUsT) were completed to support the GRASE determination for 6% BEMT. IVPT results indicated an oil +10% ethanol as the model sunscreen intervention for the pilot MUsT. The open-label trial revealed: BEMT concentrations rarely exceeded FDA\'s defined threshold (0.5 ng/mL) in plasma; no evidence for BEMT accumulation or steady-state concentrations above threshold; only one moderate and few mild treatment emergent adverse events (TEAEs). Therefore, maximal topical applications of 6% BEMT in a model sunscreen formulation did not contribute to meaningful systemic exposure. These results support the safety of BEMT 6% for human sunscreen use.

An in vivo pharmacokinetic study was conducted using consumer antiseptic wash containing 0.13% benzalkonium chloride (BAC) to assess the effect of dermal absorption on long-term systemic exposure to BAC. The objective of the study was to determine blood levels of BAC under maximal use conditions. Subjects were enlisted to wash their hands 60 s with soap containing 0.13% BAC 30 times per day over an 8-9 h time period for 5 consecutive days. The test product with the highest absorption potential was selected based on market share and results from in vitro permeation testing. Blood plasma was collected from subjects on 32 occasions over the 6-day study period. Plasma samples were analyzed for the C12 and C14 homologs of BAC using LC-MS/MS with a lower limit of quantitation (LLOQ) of 106.9 and 32.6 ng/L, respectively. For the 32 subjects, C12 homolog was detected above the LLOQ in only four of 1,024 plasma samples at 117.8-191.7 ng/L, and C14 homolog was detected in only one sample at 59.5 ng/L. Consequently, systemic exposure to BAC in antimicrobial soap is very low and below the level of concern identified by the U.S. Food and Drug Administration (500 ng/L) even under maximal use conditions.

The study aimed to determine the tear film pharmacokinetics following topical administration of 1% prednisolone acetate-assessing whether two drops would provide a superior kinetic profile compared to one drop-and to determine the fraction of an eye drop that reaches the systemic circulation in dogs. Two separate experiments were conducted in eight healthy Beagle dogs: (i) Instillation of 1 drop (35 μL) or 2 drops (70 μL) of 1% prednisolone acetate ophthalmic suspension in each eye, followed by tear collections with Schirmer strips from 0 to 720 min; (ii) Instillation of 1 or 2 drops of 1% prednisolone acetate in both eyes 4 times daily for 3 days, followed by blood collection 10-15 min after each topical administration on Day 3. Tear and blood samples were analyzed with high performance liquid chromatography to determine the levels of prodrug (prednisolone acetate), active metabolite (prednisolone) and total prednisolone (prednisolonetotal = prodrug + active metabolite). Prednisolone levels represented 10 and 72% of prednisolonetotal concentrations in tears and plasma, respectively, indicating a greater hydrolysis of prodrug in the blood vs. tear compartment. For eyes receiving one or two drops, tear film prednisolonetotal concentrations were high (~3.1 mg/mL) immediately following topical administration but rapidly decreased by ~45% at 1 min and ~95% at 15 min. No differences were noted between 1 vs. 2 drops in tear film prednisolonetotal concentrations (including maximal concentration, Cmax) or residual drug levels in tears at any time point (P ≥ 0.097); however, instillation of 2 drops provided a higher average tear concentration (Cavg) and overall drug exposure to the ocular surface (AUClast) over the 12-h sampling period (P = 0.009). Average plasma prednisolonetotal concentration represented ≤ 2% of the dose applied to the ocular surface, and did not differ significantly for dogs receiving 1 drop (17 ng/mL) or 2 drops (20 ng/mL) 4 times daily for 3 days (P = 0.438). In sum, topical corticotherapy is beneficial for inflammatory conditions of the canine anterior segment given the relatively high concentrations achieved in tears, although caution is warranted to prevent unwanted local or systemic adverse effects.

Although curcumin\'s effect on head and neck cancer has been studied in vitro and in vivo, to the authors\' knowledge its efficacy is limited by poor systemic absorption from oral administration. APG-157 is a botanical drug containing multiple polyphenols, including curcumin, developed under the US Food and Drug Administration\'s Botanical Drug Development, that delivers the active components to oromucosal tissues near the tumor target.
A double-blind, randomized, placebo-controlled, phase 1 clinical trial was conducted with APG-157 in 13 normal subjects and 12 patients with oral cancer. Two doses, 100 mg or 200 mg, were delivered transorally every hour for 3 hours. Blood and saliva were collected before and 1 hour, 2 hours, 3 hours, and 24 hours after treatment. Electrocardiograms and blood tests did not demonstrate any toxicity.
Treatment with APG-157 resulted in circulating concentrations of curcumin and analogs peaking at 3 hours with reduced IL-1β, IL-6, and IL-8 concentrations in the salivary supernatant fluid of patients with cancer. Salivary microbial flora analysis showed a reduction in Bacteroidetes species in cancer subjects. RNA and immunofluorescence analyses of tumor tissues of a subject demonstrated increased expression of genes associated with differentiation and T-cell recruitment to the tumor microenvironment.
The results of the current study suggested that APG-157 could serve as a therapeutic drug in combination with immunotherapy.
Curcumin has been shown to suppress tumor cells because of its antioxidant and anti-inflammatory properties. However, its effectiveness has been limited by poor absorption when delivered orally. Subjects with oral cancer were given oral APG-157, a botanical drug containing multiple polyphenols, including curcumin. Curcumin was found in the blood and in tumor tissues. Inflammatory markers and Bacteroides species were found to be decreased in the saliva, and immune T cells were increased in the tumor tissue. APG-157 is absorbed well, reduces inflammation, and attracts T cells to the tumor, suggesting its potential use in combination with immunotherapy drugs.