Alcohol-induced dose dumping is a significant concern for modified-release oral dosage forms, as it can compromise the intended release behaviour. For enteric-coated formulations, alcohol exposure may lead to loss of enteric functionality and unintended premature drug release in the stomach. Although previous studies have mainly assessed the loss of enteric performance in delayed-release dosage forms, the mechanisms underlying alcohol-induced changes remain poorly understood. In this study, the behaviour of isolated hydroxypropyl methylcellulose phthalate (HPMC-P) films was investigated in aqueous ethanolic media containing 0-40% v/v ethanol. Film permeability was evaluated using paracetamol, nicotinamide and tritiated water as model permeants. No significant change in permeability was observed at ethanol concentrations up to 20% v/v. However, exposure to 40% v/v ethanol significantly increased permeability. Under these conditions, permeability differences between paracetamol (4.4 ± 0.6 E-05 cm/s) and nicotinamide (2.4 ± 0.3 E-05 cm/s) were observed and were initially attributed to differences in drug solubility in hydroalcoholic medium. However, studies with tritiated water eliminated solubility-related effects and provided direct evidence of ethanol-induced changes in film permeability. Microscopic imaging revealed ethanol concentration dependent pore formation within the films. Mass loss study showed negligible film erosion even at 40% v/v ethanol, despite the substantial increase in permeability. These findings demonstrate that increased film permeability originates primarily from ethanol-induced microstructural changes rather than polymer erosion. Overall, this work provides mechanistic insights into the effects of ethanol exposure on HPMC-P films and improves understanding of alcohol-induced alterations in enteric-coated formulations.

IntroductionMetastasis occurs in almost 50% of patients with uveal melanoma. In patients who are HLA-A*02:01 positive, first line treatment is the Immune mobilizing monoclonal T cell receptor Against Cancer (ImmTAC), tebentafusp, which increases overall survival significantly at one year compared to single-agent immunotherapy or chemotherapy. Hypersensitivity reactions (HSR) to cancer therapeutics are well established. When these therapies offer significant benefits over alternatives, drug desensitization protocols are utilized to improve clinical outcomes in those with suspected IgE-mediated HSRs.Case reportWe present a case of an individual with metastatic uveal melanoma who suffered an anaphylactic HSR to tebentafusp. Given the lack of available ImmTAC therapeutic desensitization protocols, this report's purpose was to create a tebentafusp desensitization protocol based on accepted desensitization protocols for other chemotherapeutic drugs.Management and outcomeThe desensitization procedure consisted of pretreatment with cetirizine, famotidine, diphenhydramine, methylprednisolone, and acetaminophen prior to infusion. Infusions were each given as two diluted infusions limited to 100 mL of reconstitution volume, with cumulative quantities equivalent to standard treatment regimen dosages. Drug was given over no longer than four hours per manufacturer's recommendations. A total of three cycles of three weekly infusions were completed. The patient had no anaphylaxis recurrence. Tebentafusp treatment was withheld after the third cycle due to disease progression.DiscussionFor patients with HLA-A*02:01 positive metastatic uveal melanoma with suspected IgE-mediated HSR to tebentafusp, desensitization can be completed safely. Given the patient's disease progression within two months of treatment, it is unknown whether desensitization impacts the drug's clinical benefit.

Oral delivery of water-repelling drugs for acute liver failure (ALF) often runs into problems like poor solubility, instability, and low absorption. In this work, we found that extracellular vesicles derived from honey (HEVs) can serve as a natural nanocarrier that works orally and targets the liver on its own. After isolating and characterizing these vesicles, we saw they are membrane-bound nanoparticles roughly 160 nm in size with a surface charge around -32 mV, and they contain proteins and RNAs. Oral HEVs mainly ended up in the liver and showed some anti-inflammatory activity without any drug loaded. To get better therapeutic effects, we loaded curcumin (Cur), a hydrophobic anti-inflammatory compound, into HEVs to make Cur@HEVs. These loaded vesicles greatly improved how well curcumin is absorbed and released in a sustained manner. In acetaminophen (APAP) caused ALF mice, oral Cur@HEVs improved liver function and survival much more than plain curcumin or empty HEVs did. Specifically, Cur@HEVs simultaneously put the brakes on pyroptosis (via the NLRP3/GSDMD/caspase-1 route) and necroptosis (through the RIPK1/RIPK3/MLKL pathway), which in turn cut down the release of inflammatory cytokines and kept liver cells from dying. Overall, HEVs come across as a safe, food-based nanocarrier that can be taken orally, and Cur@HEVs offer a bioactive platform for dually targeting inflammatory cell death in ALF. Our findings suggest that dietary extracellular vesicles warrant further investigation as potential therapeutic biomaterials, though additional translational studies are needed.

The occurrence of paracetamol in water motivates the development of treatment processes that combine contaminant removal with reduced dependence on grid electricity. Iron-electrode electrocoagulation was optimized using a regulated direct-current power supply, a face-centered central composite design, and response surface methodology. The initial paracetamol concentration (0.1-0.3 mg·mL[-1]), reaction time (10-30 min), current density (0.95-6.67 A·m[-2]), and initial pH (3.0-10.0) were evaluated. The quadratic model was statistically significant (F = 3.072; p = 0.0293; R[2] = 0.7818; adjusted R[2] = 0.5273) and revealed significant interactions between current density and pH, concentration and current density, concentration and pH, and reaction time and pH. The highest experimental removal was 90.7%, obtained at 0.2 mg·mL[-1], 30 min, 3.81 A·m[-2], and pH 6.5, with a residual concentration of 18.6 mg·L[-1]. Near-zero ζ-potential values and floc growth up to approximately 44 μm were consistent with charge neutralization and sweep coagulation, although they did not establish a unique removal mechanism. The selected condition was subsequently operated using a configuration comprising a photovoltaic module, an MPPT controller, and a battery; photovoltaic supply was not a factor in the experimental design. At the maximum-removal condition, both configurations exhibited the same reactor energy consumption (0.018315 kWh·m[-3]) and theoretical iron dissolution (0.001737 kg·m[-3]). However, when a marginal purchase price of zero was assigned to photovoltaic electricity, the solar configuration was more cost-efficient than the conventional configuration: the partial variable cost decreased from BRL 0.013482·m[-3]to BRL 0.000495·m[-3], corresponding to a 96.33% reduction. This comparison excludes photovoltaic system capital investment, battery replacement, maintenance, sludge management, labor, and life-cycle costs. The results identify a favorable operating region at the batch scale, although the resulting residual concentration does not demonstrate compliance with a discharge criterion.

N-acetyl-p-aminophenol (APAP), or acetaminophen, is the most prescribed analgesic and antipyretic, even used in association with other drugs. Because it is easily bought in drugstores, much evidence about its toxic effects is known due to high doses or continuous use, which can lead to death in cases of intoxication. The present study aimed demonstrate the ability of APAP to change the brain and heart electrical activities, as early as significant increase in liver enzymes. Thus, a toxic dose of 1 g/kg was administered orally, and the animals were assessed every 3 h until 12 h for electroencephalography, electrocardiography and liver function data. The results showed that a toxic dose of APAP was capable of reducing brain electrical activity for the delta, theta, beta and gamma waves; however, the alpha wave activity was increased. In the heart, a reduced electrical activity was observed synchronously with the electroencephalogram. During the 12-h follow-up period, a significant increase in liver enzymes was observed. Taken together, we conclude that high doses of APAP can alter frequency brain oscillations and promote cardiac changes independently of liver damage in the first 12 h.

Oxidative stress is a central driver of acute liver injury, and protein carbonylation and lipid aldehyde formation are among its most direct chemical signatures. Most carbonyl-reactive fluorescent probes have been characterized only in two-dimensional culture, and their behavior in three-dimensional tissue is often unclear. Here we describe a protocol for evaluating carbonyl-reactive fluorescent probes in mouse hepatic organoids grown in suspension in the CERO 3D bioreactor, using acetaminophen (APAP) overdose as a well-established model of acute oxidative liver injury. We demonstrate the assay with P7-Hz, a hydrazine-based probe that reacts with carbonyl groups on oxidatively damaged proteins and lipids to form the fluorescent hydrazone product P7-Hz-Ali. The protocol covers organoid culture and maintenance, APAP dosing to induce injury, probe incubation (labeling), and imaging-based quantification of the fluorescence signal as a readout of carbonylation, together with co-staining viability to distinguish probe-specific signal from cytotoxicity. Although P7-Hz is used as the demonstration probe, the same workflow accommodates other carbonyl-reactive probes whose hydrazone (or analogous) product is spectroscopically distinguishable from the unreacted probe, providing a reproducible three-dimensional platform for probe validation.