Search Results (368)

Background: Despite considerable advances in contemporary pharmacotherapy for heart failure (HF), residual congestion continues to drive adverse outcomes in a substantial proportion of patients. Goreisan, a traditional Kampo herbal formulation, has seen growing clinical application as an adjunct for refractory fluid retention; yet the prognostic implications of sustaining versus withdrawing goreisan among patients on tolvaptan-based regimens have not been adequately characterized. Methods: We conducted a retrospective single-center observational analysis enrolling patients with HF who received goreisan alongside tolvaptan-incorporated medical therapy between April 2022 and November 2025. Enrolled patients were classified into a continuation group or a termination group based on their subsequent goreisan treatment course. The primary endpoint was defined as a composite of all-cause death and HF-related hospitalization requiring intravenous diuretic therapy. Results: Among 25 patients, 12 maintained goreisan throughout the observation period while 13 underwent treatment termination. Baseline clinical profiles were broadly similar across the two groups. The continuation group exhibited a significantly reduced cumulative incidence of the primary endpoint relative to the termination group (p = 0.036). Negative binomial regression revealed a markedly elevated event rate in the termination group (incidence rate ratio 9.27; 95% confidence interval 2.05–42.0; p = 0.004), with adverse events demonstrating a pronounced temporal clustering in the immediate post-discontinuation period. Conclusions: Among patients with HF and refractory congestion on tolvaptan-incorporated therapy, maintaining goreisan was associated with a trend toward fewer clinical events and longer periods of hemodynamic stability, whereas its withdrawal appeared to be followed by early adverse outcomes. Given the small sample size and observational design, no definitive conclusions can be drawn, and these findings should be regarded strictly as preliminary and hypothesis generating; prospective controlled studies with larger cohorts are needed before any clinical implications can be established. Full article

Background: Arginine and related amino acids are widely used to suppress protein aggregation, thereby affecting stability, manufacturability, and therapeutic performance. However, their effectiveness remains limited, necessitating the exploration of alternative strategies. Previous studies have shown that N-acetyl-L-arginine (NA-Arg) can improve protein stability; however, the potential of other N-acetylated amino acids has not been fully explored. Methods: This study aimed to investigate the effects of multiple N-acetylated amino acids as alternative excipients on aggregation, colloidal stability, and viscosity in intravenous immunoglobulin (IVIG) formulations. Dynamic light scattering (DLS) was used to evaluate diffusion behavior and aggregation tendencies, while complementary analyses were performed using size-exclusion chromatography (SEC) and flow-imaging microscopy (FI). Results: Overall, N-acetylation of amino acids improved colloidal stability, shifting the kD values from −5.87 to 6.83 mL/g for arginine and from −8.17 to 16.22 mL/g for histidine, and increased the aggregation onset temperature (Tagg) to above 60 °C. Among the tested compounds, N-acetyl-L-histidine (NA-His) showed the most favorable results, increasing the monomer proportion by approximately 4%, reducing high-molecular-weight species to below 2%, and producing a greater than 10-fold decrease in subvisible particles relative to histidine hydrochloride after 5 days of agitation. At 50 mM, both NA-His and NA-Arg reduced the viscosity of highly concentrated 200 mg/mL IVIG formulations, with NA-His exhibiting the lowest viscosity (7.24 ± 0.12 mPa·s). Protein–protein interaction and surface charge analyses indicated improved colloidal stability relative to parent amino acids, attributable to the presence of the acetyl group. Conclusions: These findings support the potential of N-acetylation as a strategy to modulate interaction-driven instability and suggest NA-His as a promising candidate excipient for stabilizing highly concentrated therapeutic proteins at acidic pH. Full article

Background/Objectives: Women and girls, particularly in sub-Saharan Africa, face high risks for both HIV and unintended pregnancy. Inconsistent condom use underscores the need for new multipurpose prevention technologies (MPTs) that combine HIV pre-exposure prophylaxis (PrEP) and contraception. Long-acting (LA) injectables are especially promising. To this end, an LA cabotegravir (CAB)/medroxyprogesterone acetate (MPA) in situ-forming implant (ISFI) has been developed. We report pharmacokinetic (PK) modeling to characterize CAB and MPA disposition and absorption to support the development of the MPT ISFI. Methods: Female BALB/c mice received single intravenous (IV) or subcutaneous (SQ) bolus doses of CAB or MPA. Sparse plasma samples were collected (~3 mice/timepoint) for PK analysis by LC-MS/MS. Noncompartmental analysis assessed SQ bioavailability. Macroparameterized compartmental PK models were fit to IV data to derive unit impulse responses (UIRs) for each drug. Results: CAB and MPA exhibited 61% and 42% bioavailability, respectively. CAB IV PK was best described by a two-compartment model with macroconstant parameters: A = 16,621 ng/mL, α = 4.52 h⁻¹, B = 30,206 ng/mL, and β = 0.053 h⁻¹. MPA IV PK was also best described by a two-compartment model, with A = 2506 ng/mL, α = 10.5 h⁻¹, B = 439 ng/mL, and β = 0.65 h⁻¹. These values define the UIR for CAB and MPA. Conclusions: Our IV PK modeling framework fully characterizes CAB/MPA disposition in mouse, enabling downstream deconvolution-based estimation of absorption from controlled-release formulations. This provides a foundation for in vitro–in vivo correlation, facilitating preclinical evaluation of long-acting formulations such as ISFIs. Full article

Background/Objectives: While intravitreal administration allows for increased ocular exposure to anti-TNF-α monoclonal antibodies, there is still a need for developing delivery systems able to prolong ocular drug exposure and alleviate patient compliance and safety concerns because of repeated injections. Therefore, the objective of this work was to guide the design of sustained-release formulations of anti-TNF-α monoclonal antibodies for intravitreal administration through a model-based strategy in non-infectious uveitis in the preclinical setting. Methods: Using an in-house-developed anterior uveitis disease model in rats, an intravenous reference dose reducing free TNF-α by 90% at the biophase was established. Intravitreal administrations of sustained-release formulations every 24 weeks were then simulated for adalimumab, golimumab and infliximab to evaluate TNF-α kinetics in the anterior chamber of the eye at different release rates. The selected sustained-release formulation was further evaluated for possible formulation issues causing device emptying before the next administration. Results: Intravitreal administration of sustained-release formulations releasing adalimumab, golimumab or infliximab at 1.802, 0.979 and 1.442 μg/week, respectively, met the predefined criteria of ≥90% reduction in free TNF-α at the biophase. TNF-α levels in aqueous humour were anticipated to be the most sensitive to detect possible formulation issues. Formulation emptying 10, 4 or 8 weeks for adalimumab, golimumab and infliximab, respectively, before next administration triggered TNF-α reaching pathological levels at week 24 post-dose. Conclusions: This work underscores the potential of new approach methodologies in the preclinical drug development of sustained-release formulations for intravitreal administration in ocular inflammatory disorders with less animal testing and without compromising the accuracy of model-informed predictions for human translation. Full article

The escalating use of plastic medical products has made medical microplastics (MMPs) contamination an important health concern for specific populations (e.g., patients undergoing medical interventions) and has rendered it a growing focus in global environmental health research. This review systematically summarizes the release characteristics of MMPs throughout their life cycle from device manufacturing and clinical use to waste disposal, and elucidates human exposure pathways. For the general population, environmental exposure and dietary intake are the dominant exposure sources. In patients, however, invasive procedures and intravenous infusions serve as direct, high-concentration routes, enabling MMPs to enter the bloodstream directly. The article focuses on analyzing the molecular mechanisms underlying multisystem pathological effects induced by MMPs, including cardiovascular injury, respiratory dysfunction, digestive disorders, and reproductive toxicity, which involve key pathways such as oxidative stress, inflammatory responses, apoptosis, and dysregulated autophagy. Regarding existing detection technologies, we compare and evaluate the advantages and limitations of microscopic observation, spectral analysis, and chromatography–mass spectrometry in terms of sensitivity, specificity, and applicability, proposing that integrated technical strategies can significantly improve detection reliability. Finally, the review discusses current challenges and future research directions, including the establishment of standardized risk assessment frameworks, the development of highly sensitive in situ detection technologies, and the exploration of targeted intervention strategies. This work provides a theoretical basis for understanding the health risks of MMPs and offers valuable insights for formulating safety management policies for medical plastics. Full article

Microplastics (MPs) are emerging environmental contaminants detected not only in water, soil, and air but also in human biological samples. To date, three main exposure routes have been identified. Currently, the principal exposure routes examined in scholarly works are oral, inhalational, and dermal. This paper explores iatrogenic microplastic exposure (IME) as an underrecognized healthcare-associated source of exposure and suggests that, in certain clinical contexts involving invasive, device-mediated, or direct systemic contact, IME may be considered a possible fourth route of exposure. IME is the introduction of microplastics into the human body through medical interventions. A literature-based conceptual review was conducted focusing on the materials and additives used in pharmaceutical formulations, intravenous systems, and medical devices. Particular attention was given to polymer-based excipients and plasticizers (e.g., phthalates, PEG, triacetin) found in enteric drug coatings and infusion packaging. Findings suggest that polymer-derived particles may enter systemic circulation via intravenous fluids, implantable devices, or oral medications, especially under conditions of heat, pressure, or prolonged contact. Such materials, though deemed biocompatible, may contribute to nanoplastic load and chronic exposure risks. Vulnerable groups such as neonates, oncology patients, and ICU populations may face disproportionate exposure. This calls for re-evaluation of plastic use in medical practice, improved regulatory oversight of pharmaceutical excipients, and innovation in plastic-free biomedical materials. Integrating this route into toxicological and epidemiological frameworks will enrich our understanding of microplastic-related health risks and broaden the scope of environmental health strategies. Full article

N-acetylcysteine (NAC) is a glutathione precursor with established antioxidant and anti-inflammatory properties that has been investigated as a neuroprotective agent across multiple neurological conditions. This systematic review systematically mapped the clinical evidence for NAC across seven neurological disorders. PubMed and Cochrane Library were searched for studies published between 1 January 1995 and 31 December 2025. Twenty-three studies were included: traumatic brain injury (TBI, n = 6), Alzheimer’s disease (AD, n = 5), Parkinson’s disease (PD, n = 5), multiple sclerosis (n = 4), amyotrophic lateral sclerosis (n = 2), and migraine (n = 1); no eligible epilepsy studies were identified. The strongest evidence emerged for acute mild TBI, where early NAC administration significantly improved symptom resolution, and for PD, where combined intravenous/oral NAC improved dopamine transporter binding. In AD, nutraceutical formulations including NAC and other active compounds showed trends toward cognitive stabilization. Most included studies had a high or serious risk of bias, and only eight of 23 assessed oxidative stress biomarkers. NAC demonstrated a favorable safety profile across all conditions. Despite fragmented and heterogeneous evidence, the encouraging signals identified warrant large-scale randomized controlled trials with a standardized biomarker assessment. Full article

Background/Objectives: Infliximab (IFX) is commonly used in chronic inflammatory conditions of the ileo-anal pouch. A subcutaneous (SC) formulation has been developed, with studies in inflammatory bowel disease (IBD) patients showing that switching from intravenous (IV) to SC IFX is safe with a low risk of relapse. However, so far, it has not been specifically investigated in chronic inflammatory pouch conditions. The aim of our study was to evaluate the effectiveness and safety of SC IFX in patients with chronic inflammatory pouch conditions. Methods: This was an observational retrospective study. We included patients with chronic inflammatory pouch conditions, initially treated with IV IFX and subsequently switched to SC IFX, who had a follow-up of at least 1 year. The primary outcome was SC IFX treatment persistence, defined as continuation of SC IFX throughout the study period. The secondary outcome was pouch failure, defined by the need for a defunctioning ileostomy or pouch excision. Results: A total of seven patients were included. The mean age was 50.6 years. The average follow-up length was 101.3 months (range 70.4–132.6 months). All seven patients continued SC IFX throughout the study period. No patient experienced pouch failure. The median IFX serum concentration was 18.1 mg/L. There were no cases of serious infections or malignancy. Conclusions: Switching clinically stable patients with chronic inflammatory pouch conditions from IV to SC IFX formulation appears feasible. These findings warrant confirmation in larger patient cohorts. Full article

Liposomes are widely recognized as versatile nanocarriers in drug delivery due to their biocompatibility, tunable physicochemical properties, and ability to incorporate both hydrophilic and hydrophobic compounds. In this study, the encapsulation and release of diclofenac, a nonsteroidal anti-inflammatory drug (NSAID), using lecithin–cholesterol liposomes are explored. Encapsulation parameters were first optimized with calcein as a model fluorophore, confirming that cholesterol addition enhances encapsulation efficiency by reducing membrane permeability. Guided by these results, liposomes containing equal weight fractions of lecithin and cholesterol were selected as an optimized formulation, providing calcein and diclofenac encapsulation efficiencies up to approximately 35% while maintaining hydrodynamic diameters below 300 nm with low polydispersity (PdI < 0.2), optimal for intravenous administration and prolonged systemic circulation. Release studies demonstrated sustained drug release over 15 days, with cumulative release exceeding 80%. Weibull modeling yielded ${\theta }_{\mathrm{\infty }}$ ≈ 1 and β values up to ~1.6 at higher loadings, with β > 1 indicating a complex, sigmoidal (non-Fickian) release mechanism. These findings support the potential of liposomes as delivery platforms for NSAIDs with solubility and bioavailability limitations. Full article

Background/Objectives: Iron deficiency and associated iron deficiency anaemia represent a major global health burden. Parenteral nutrition (PN) patients are at increased risk of iron deficiency due to inadequate iron supplementation. Currently, iron is added to all-in-one (AIO) PN mostly as low-dose ferric chloride in trace element solutions, limited to 1–2 mg in adults, to ensure emulsion stability and prevent lipid peroxidation. The objective of this study was to evaluate the compatibility and stability of selected, widely used complex-bound iron products added to AIO PN over a 48 h period. Methods: Ferric carboxymaltose and iron sucrose were added as non-biological complex intravenous iron oxide carbohydrate products to two different commercial AIO PN admixtures for adults. The iron concentrations used were 100 and 400 mg/L (1.79 and 7.16 mmol/L), corresponding to approximately 200 mg (3.58 mmol) of iron dose per PN bag. Free and complex-bound iron were separated using 100 kDa dialysis tubes. Free and complex-bound iron were assessed at 4, 24, and 48 h after admixing. pH was measured before and at 0, 4, 24, and 48 h after admixture. Iron quantification was performed by inductively coupled plasma mass spectrometry (ICP-MS). Results: No significant changes in complex-bound iron concentration were observed over the 48 h incubation period (p-value = 0.449; estimate 0.060 mg/L per h, 95% CI −0.089, 0.201 mg/L per h). The concentration of free iron was very low and increased only slightly over time. Iron recovery ranged from 95.8% to 103.9%. The addition of the alkaline iron sucrose significantly increased the pH of the AIO admixture (p-value = 0.033), whereas the addition of ferric carboxymaltose did not affect the pH (p-value = 0.351). After the initial increase, the pH of all conditions remained stable over the 48 h incubation period (p-value = 0.07). Conclusions: Ferric carboxymaltose demonstrated stable intravenous iron admixtures within the PN formulations tested. Before the clinical application of these findings, further studies should specifically evaluate the lipid peroxidation and stability of the lipid emulsions, the most sensitive and important PN compatibility and safety characteristics of AIO PN. Full article

Background/Objectives: Iron-deficiency anemia (IDA) is a common extraintestinal complication of inflammatory bowel disease (IBD). Among high-dose intravenous (IV) iron options, ferric carboxymaltose (FCM) carries a higher risk of treatment-emergent hypophosphatemia than ferric derisomaltose (FDI), with potential clinical consequences. Slovenia’s healthcare setting, characterized by very low IV iron infusion tariffs and recent pricing in which FCM is substantially less expensive than FDI, warrants a setting-specific cost effectiveness evaluation. Methods: We integrated two methodological components: (i) a payer-perspective cost-effectiveness analysis using a patient-level microsimulation model with (ii) an umbrella review of systematic reviews and a targeted search of expert consensus statements on IV-iron-associated hypophosphatemia. Results: In the base case, FDI required fewer infusions than FCM (11.1 vs. 14.2 over 10 years) but generated only €95 in IV iron administration savings due to low tariffs, while drug procurement was €1166 higher with FDI than FCM. When incorporating the clinical impact of hypophosphatemia, incremental quality-adjusted life years (QALYs) were 0.136, yielding an incremental cost-effectiveness ratio (ICER) of €6590/QALY. The umbrella review consistently showed higher hypophosphatemia incidence with FCM (up to 92%) compared with other IV iron formulations (<10%), with recent recommendations emphasizing phosphate monitoring and risk mitigation through alternative formulations. Conclusions: Despite Slovenia’s low IV iron infusion tariffs and lower FCM price, FDI remained cost-effective in this model, largely due to its more favorable hypophosphatemia profile within the model. These findings suggest that hypophosphatemia risk should be considered when selecting IV iron therapy in routine IBD care. Full article

Background/Objectives: Tuberculosis (TB) remains a major global health threat. Current administration methods for anti-TB drugs, including oral or intravenous, suffer from systemic side effects, low lung distribution, and poor patient compliance. Dry powder inhalers (DPIs) offer a promising alternative. This study investigates the aerodynamic performance of co-spray-dried DPIs containing rifampin or pyrazinamide and amino acids by using machine learning. Methods: Firstly, 72 formulations were prepared by varying drug-amino acid combinations, molar ratios, and spray-drying parameters. Subsequently, the aerodynamic performance of all 72 formulations was evaluated using a Next Generation Impactor, and the solid-state characterizations of optimal DPIs were carried out. Finally, four machine learning (ML) models were successfully developed and were utilized to predict the fine particle dose (FPD), FPF, MMAD, and geometric standard deviation (GSD) of DPIs based on the high-quality in-house data above. Results: Key results showed that the aerodynamic performance of DPIs was highly dependent on the specific drug-amino acid combination, with rifampin-L-lysine acetate and pyrazinamide-L-leucine formulations achieving the highest fine particle fraction (FPF, 73.37%, 87.74%) and optimal mass median aerodynamic diameter (MMAD, 2.59 µm, 1.88 µm). Notably, XGBoost (v3.1.3) exhibited the best predictive performance, with R² values ranging from 0.894 to 0.991 in the testing set for the four prediction tasks. Meanwhile, SHapley Additive exPlanations (v0.50.0) was used for model interpretability analysis. The molecular weights and LogP of the drug and amino acid were identified as two of the most important features affecting the prediction of FPD, FPF, MMAD, and GSD. Conclusions: This work demonstrates the feasibility of ML in accelerating the development of inhalable spray-dried anti-TB drugs by enabling the prediction of DPI formulations. Full article

Background/Objectives: In Japan, cancer-related anemia (CRA) is common, and erythropoiesis-stimulating agents (ESAs) are not approved for chemotherapy-induced anemia. Modern intravenous (IV) iron formulations, such as ferric carboxymaltose (FCM) and ferric derisomaltose (FDI), enable high-dose repletion; however, real-world evidence in ESA-free oncology settings remains limited. Methods: This single-center retrospective study included patients with CRA (N = 55) who received high-dose IV iron (FCM or FDI). Iron phenotypes were classified as absolute iron deficiency (ID), functional ID, or non-ID. The primary endpoint was hemoglobin (Hb) change from baseline to approximately 1 month (21–45 days) in the non-transfused patients. Secondary endpoints included responder rate (ΔHb ≥ 1.0 g/dL), transfusion avoidance rate, dosing adequacy relative to Ganzoni-calculated iron deficit, and safety, particularly hypophosphatemia. Results: Among the non-transfused patients, mean Hb increased from 8.76 ± 1.34 g/dL to 9.73 ± 1.75 g/dL (mean ΔHb +0.92 ± 1.44 g/dL; p < 0.001). The responder and transfusion avoidance rates were 48.9% and 81.8%, respectively. Functional ID was most prevalent (52.7%), with clinically meaningful Hb responses. A total of 38.2% achieved approximately 1000 mg dosing. The safety profile was excellent, and no infusion reactions or symptomatic hypophosphatemia was observed (median serum phosphate changed from 3.4 [3.0–3.9] to 3.2 [2.7–3.8] mg/dL). Conclusions: In this real-world Japanese oncology setting where ESAs were not available for chemotherapy-induced anemia, high-dose IV iron monotherapy (FCM or FDI) was well tolerated and was associated with modest short-term Hb increases and a high observed rate of transfusion avoidance within a 21–45-day assessment window. These findings suggest that a proactive, TSAT-guided IV iron therapy approach may be a pragmatic option for selected patients; however, durability beyond 1 month, optimal re-dosing, and generalizability require confirmation in larger, longer prospective studies. Full article

Parenteral nutrition (PN) is essential for patients who are unable to tolerate oral or enteral feeding, providing them with necessary nutrients intravenously, including dextrose, amino acids, electrolytes, vitamins, trace elements, and lipid emulsions. Clinical pharmacists (CPs) play a critical role in PN management by ensuring proper formulation, monitoring therapy, preventing complications, and optimizing patient outcomes. In Saudi Arabia, limited literature exists on CPs’ involvement in total parenteral nutrition (TPN) administration, health information management (HIM) systems, and pharmacist staffing ratios. This paper examines the evolving role of CPs in PN management, addressing key challenges such as the optimal patient-to-CP ratio, the impact of HIM systems on PN prescribing, and the advantages and limitations of centralized versus decentralized PN prescription models. It highlights the need for standardized staffing levels, structured pharmacist training, and improved HIM integration to enhance workflow efficiency and prescribing accuracy. Additionally, the study examines how the adoption of advanced HIM systems can streamline documentation, reduce prescribing errors, and enhance interdisciplinary collaboration. This paper provides a framework for optimizing PN delivery, enhancing healthcare quality, and strengthening CPs’ contributions to nutrition support by addressing these factors. Implementing these recommendations will improve patient outcomes and establish a more efficient PN management system in Saudi Arabia, reinforcing the vital role of CPs in multidisciplinary care. Full article

Therapeutic drug monitoring of the intravenous formulations of infliximab in particular, but also vedolizumab, has become an important means of optimising these agents to minimise primary and secondary loss of response. More recently subcutaneous formulations of both infliximab and vedolizumab have become widely available. These new molecules offer patients the convenience of self-administration, and also have pharmacokinetic benefits via maintaining high drug levels, reducing the risk of the development of immunogenicity. It took many years before recommended therapeutic target ranges for intravenous biologics were agreed on, and it is now clear that target levels for the subcutaneous formulations are different, and further research is required before optimal drug levels are confirmed. This narrative review summarises the current literature of therapeutic drug monitoring of subcutaneous infliximab and vedolizumab, acknowledging that this evidence base is presently incomplete. We also aim to provide clinicians with some practical recommendations for the use of TDM with these formulations in clinical practice today. In summary, we recommend performing TDM of the IV formulations prior to switching and then measuring drug levels at 8 weeks after switching to SC infliximab and at 16 weeks for SC vedolizumab. We suggest provisional target drug levels obtained from post hoc analyses of >14 μg/mL for SC infliximab and 25–35 μg/mL for SC vedolizumab. We recommend performing reactive TDM in cases of loss of response to SC therapy. In conclusion we offer suggested areas for future research. Full article