The stratum corneum represents the main barrier to transdermal drug delivery, particularly for hydrophilic and ionized compounds such as aminophylline. In this study, the solubility-permeability-matrix interplay was investigated using aminophylline and theophylline as model drugs in various matrix-type transdermal patches based on either hydroxypropyl methylcellulose (HPMC) or silicone-based Bio-PSA (Biomedical Pressure-Sensitive Adhesive). Franz diffusion cells with porcine ear skin were used to evaluate in vitro skin permeation, and complementary release studies were conducted using dialysis membranes. Aminophylline exhibited significantly higher transdermal flux than theophylline in both matrix systems, despite its increased hydrophilicity and ionization. This effect is attributed to its capacity to maintain high thermodynamic activity when formulated as a suspension, thereby intensifying chemical potential gradients and supporting aqueous pathway permeation. Penetration enhancers showed distinct mechanisms of action. Geraniol, a lipophilic terpene alcohol, significantly increased skin permeation by disrupting stratum corneum lipid lamellae and facilitating transient hydrophilic channels. In contrast, Transcutol P acted primarily by increasing drug solubility within the matrix and forming a reservoir in the stratum corneum. However, its enhancing effect remained modest due to limited interaction with the barrier and slow release from the silicone matrix. These findings highlight the critical role of drug solubility and enhancer molecular properties in the transdermal delivery of hydrophilic drugs. In addition, matrix parameters like thickness, hydration and release properties need to be properly engineered for making optimal use of the involved solubility-permeability interplay.

Background: The appropriate identification of target patients for methylxanthine therapy may optimize resource allocation and improve clinical outcomes, but data on routine care in low-resource settings are limited. Our study assessed methylxanthine use in clinical practice in two Sub-Saharan settings. Methods: This retrospective, registry-based study investigated methylxanthine use in newborns who were admitted to Tosamaganga Hospital (Tanzania) and Wolisso Hospital (Ethiopia) in 2022-2023. The prevalence and type of methylxanthine treatment were investigated. Neonates receiving methylxanthine were compared to those not receiving it in terms of baseline characteristics, clinical data, treatments, and discharge information. All data were retrieved from local registries. Results: Aminophylline was administered to 196/1674 neonates (11.7%), while caffeine was not available in these settings. This treatment was more common in preterm and smaller infants (p < 0.0001), asphyxiated neonates (p < 0.0001), and the sickest patients (p < 0.001). The need for respiratory support (p < 0.0001), intravenous lines (p < 0.0001), and antibiotic therapy (p < 0.0001), as well as the length of hospital stay (p < 0.0001) and mortality rate (p < 0.0001), were higher in neonates receiving aminophylline. Conclusions: In two Sub-Saharan settings, methylxanthine treatment was limited to aminophylline, which was given to around 12% of infants admitted to the special care units. Overall, the treatment was appropriately given to most eligible neonates, although a considerable subgroup of very preterm infants did not receive aminophylline prophylaxis. Further studies may investigate the reasons for protocol incompliance regarding aminophylline treatment and healthcare staff's opinions on such an aspect.

We studied cytotoxicity and the effect on cell viability in in vitro incubated mammalian embryonic cells of purine derivative aminophylline, indole derivative ergotamine tartrate, as well as the phosphoric acid derivatives 3-ethyl-2-hydroxy-2-oxa-1,4,2-oxazaphosphorinane (EHOOP) and α-ethyl-α-N-(hydroxyethylamino)methylphosphonic acid (ENHEAMPA) after inoculation of the cells with vaccine avipoxviral strain FK (fowl) with initial infectious titer 106 CCID50/ml for 24 or 48 h. The tested substances were applied for 24 or 48 h at concentrations of 10-11-10-2 mol/ml (aminophylline and ergotamine tartrate), as well as at 10-11-10-3 mol/ml (EHOOP and ENHEAMPA). In cell suspensions, the cytotoxic concentrations CC50 (mol/ml) were determined corresponding to the death or alterations in half of the cells. They were 10-3 and 10-2 mol/ml for purine and indole analogues, respectively, whereas similar values for two phosphoric acid derivatives were 10-5-10-4 mol/ml. At low concentrations of the test substances, a decrease in cell viability was observed when exposure was prolonged from 24 to 48 h, which can be explained by pathogenic action of the inoculated virus. A decrease in cell viability was also observed when the concentration of the test agents was elevated, which can be explained by their intrinsic cytotoxic action at high concentrations. Overall, purine and indole analogues were less toxic for cultured mammalian cells than the test phosphoric acid derivatives. Purine analogue aminophylline had the lowest cytotoxicity, but exhibited maximum antiviral activity.

BACKGROUND Ceftriaxone is a cephalosporin antibiotic administered by injection, and although it is widely used, there have been rare reports of anaphylaxis and cardiac arrest, with some fatal outcomes. This report describes the case of a 61-year-old woman with anaphylaxis and cardiac arrest on initial intravenous administration of ceftriaxone who recovered following cardiopulmonary resuscitation. CASE REPORT A 61-year-old woman with a 3-day history of cough and dizziness presented to the emergency room. She had been taking cefuroxime and aminophylline, with no known antibiotic allergies. On examination, mild leukocytosis was observed, and chest computed tomography (CT) revealed right lower-lobe consolidation, consistent with pneumonia. Intravenous ceftriaxone was administered. Within 30 seconds, she developed severe respiratory distress and cyanosis. Ceftriaxone was immediately discontinued, and she rapidly progressed to asystole, and advanced cardiovascular life support (ACLS) was initiated. Spontaneous circulation was restored after 2 minutes. She stabilized with corticosteroids and supportive care and her respiratory status and oxygenation improved. One hour after onset, a transient truncal urticaria occurred and resolved spontaneously. She was then transferred to the intensive care unit (ICU) and discharged in good health after 3 days. No complications were noted at 1-month follow-up. CONCLUSIONS An initial intravenous dose of ceftriaxone may trigger rare but serious anaphylactic reactions, even in patients without a history of drug allergy, underscoring the need for vigilant monitoring during administration.

Apnoea-the cessation of breathing-is a common condition in preterm infants due to the immaturity of their lungs, airway and brainstem respiratory drivers. Consequently, many preterm infants will receive pharmacological interventions for the treatment of apnoea. Caffeine (or in some developing countries, aminophylline or theophylline) is usually given as first-line treatment, whereas doxapram is sometimes used as an adjunct therapy. These treatments reduce apnoeas and improve neurodevelopmental outcomes. However, there is substantial variation in individual infants' requirement for treatment (not all infants will experience apnoea nor to the same degree). Moreover, there are considerable differences in how infants respond to treatment, for example, some infants continue to experience episodes of apnoea despite treatment. Clinical guidelines for pharmacological treatment (in particular, for caffeine) are often based on the age or weight of the infant, and there are currently no biomarkers for treatment requirement or dosing. There is a need for personalised treatment for apnoea of prematurity through the identification of suitable pharmacodynamic biomarkers. Here we narratively review current knowledge of the treatment of apnoea, focusing on caffeine, aminophylline and doxapram. We propose potential pharmacodynamic biomarkers and explore avenues for future research which will enable the testing and translation of these biomarkers for use in the neonatal unit. A personalised approach for apnoea treatment is essential to mitigate the negative short and long-term effects of both apnoea and its treatment in premature infants, ensuring that treatment can be provided at the right time and with the correct dose.

Background: Apnea of prematurity affects at least 85% of infants born before 34 weeks' gestation and represents a significant clinical challenge in neonatal intensive care. Methylxanthines, including caffeine, theophylline, and aminophylline, have emerged as the primary pharmacological intervention for this condition. Objective: To conduct a comprehensive systematic review of the use of methylxanthine in the treatment and prevention of apnea episodes in preterm infants, evaluating efficacy, safety, and long-term outcomes. Methods: We searched multiple databases including PubMed, Embase, Web of Science for randomized controlled trials, retrospective studies, or case-control studies of methylxanthine effects in preterm apnea. Risk of bias was assessed using the Cochrane Risk of Bias tool. Results were summarized narratively and grouped by methylxanthine type, study design, and primary outcomes (reduction in frequency and severity of apnea episodes, success of extubation, risk of bronchopulmonary dysplasia). Results: Twenty-five studies (n = 4599 preterm infants) were included. The landmark Caffeine for Apnea of Prematurity (CAP) trial (n = 2006) demonstrated that caffeine therapy significantly reduced bronchopulmonary dysplasia (36.3% vs. 46.9%, adjusted OR 0.63) and facilitated the earlier discontinuation of positive airway pressure (median 1 week earlier). Studies with a smaller number of cases have consistently demonstrated the efficacy of methylxanthines in reducing the incidence of bronchopulmonary dysplasia and apneic episodes and in supporting successful extubation. Long-term follow-up at 11 years showed improved pulmonary function (FEV1 z-score -1.00 vs. -1.53). Discussion: Limitations of this review include heterogeneity in outcome definitions, small sample sizes in early studies, and the dominance of evidence from the CAP trial. Methylxanthines, particularly caffeine, are an evidence-based intervention used for apnea of prematurity, with demonstrated benefits that extend beyond reducing the frequency and severity of apnea episodes, including decreasing the risk of bronchopulmonary dysplasia as well as reducing the need for mechanical ventilation. No external funding was received for this review. No registration record exists for this systematic review.

Sepsis is a life-threatening organ dysfunction syndrome caused by a dysregulated host response to infection. As a leading cause of mortality in intensive care units patients, it still lacks sensitive biomarkers. Therefore, this study aimed to develop a diagnostic model for sepsis and identify key driver biomarkers. Using single-cell RNA sequencing (scRNA-seq) data from the GEO database, we constructed a diagnostic model through 113 machine learning (ML) frameworks, supplemented with Shapley additive explanations (SHAP) analysis to identify pivotal genes. Results revealed a significant increase in myeloid cells, particularly neutrophils, in the peripheral blood of sepsis patients. Screening identified 70 upregulated and 762 downregulated neutrophil-associated genes, which were intersected with differentially expressed genes (DEGs) between healthy controls and sepsis patients, yielding 13 overlapping genes - including S100A12 - as potential drivers. These 13 genes were incorporated into 113 ML models. The Random Forest (RF) model, which included S100A12, PIK3AP1, HLA-DMB, and RETN, achieved the highest mean C-index with fewer features. Its robust diagnostic performance was validated using receiver operator characteristic curves, calibration curves, and decision curve analysis. SHAP analysis highlighted S100A12 as the most influential driver gene and identified theophylline, aspirin, and aminophylline as potential targeting compounds. In conclusion, sepsis patients show increased peripheral neutrophils, an RF model based on 4 neutrophil-associated genes demonstrates strong diagnostic ability, and S100A12 serves as a key biomarker for sepsis.