http://hdl.handle.net/10366/4001 2026-07-20T09:38:04Z http://hdl.handle.net/10366/172223 Background: Invasive aspergillosis (IA) is an opportunistic infection that affects immuno compromised patients. While voriconazole is commonly used for IA treatment, it presents the risk of drug interactions, particularly in patients on polytherapy. Isavuconazole may serve as a safer alternative with fewer interactions. However, the use of isavuconazole is typically limited to the parenteral route for patients without access to the enteral route, due to recommendations against tablet handling for enteral administration. The objective of this study was to evaluate the suitability of isavuconazole administration via an enteral tube, by therapeutic drug monitoring of isavuconazole plasma concentrations. Methods: This case study examines a patient with diffuse large B-cell lym phoma who was diagnosed with IA and treated with isavuconazole via an enteral tube. Therapeutic pharmacokinetic monitoring of isavuconazole plasma concentrations was performed to assess the feasibility and safety of enteral administration.The results show that isavuconazole concentrations were maintained within the therapeutic range when administered via an enteral tube. No significant deviations in plasma concentration were noted during the monitoring period. Conclusions: Administering isavuconazole through an enteral tube is a safe and viable alternative for patients that are unable to receive the drug via the oral route. Therapeutic monitoring of plasma concentrations is recommended to ensure proper dosing and efficacy. 2024-01-01T00:00:00Z http://hdl.handle.net/10366/172222 Background: Isavuconazole is a broad-spectrum antifungal agent used for treating invasive fungal infections (IFIs). Its pharmacokinetics may be impacted in hematologic patients due to concomitant clinical and therapeutic factors potentially affecting drug exposure. The aim of this study was to develop a population pharmacokinetic (popPK) model of isavuconazole in adult hematologic patients to support model-informed precision dosing. Materials and method: Prospective, non-controlled study performed in adult hematologic patients receiving isa vuconazole for IFIs and followed up by a therapeutic drug monitoring (TDM) program. Isavuconazole plasma concentrations were quantified using an ultra-high-performance liquid chromatography (UPLC) with UV de tector. A popPK model was developed using NONMEM v.7.5.0. Simulations were based on the final model to evaluate the differences across physiological variables with impact on drug exposure. Results: A one-compartment model with first-order absorption and elimination described adequately 121 isa vuconazole concentrations from 52 patients. Body surface area (BSA) and serum albumin (ALB) significantly influenced drug clearance. The final popPK model showed good precision, robustness, and predictive perfor mance, supporting its use for individualized isavuconazole dosing in this population. Conclusions: BSA and serum ALB were identified as covariates influencing isavuconazole clearance in adult he matologic patients. Further studies are needed to better characterize the absorption of isavuconazole and im plications on dosage recommendations, especially for higher proposed doses. 2025-01-01T00:00:00Z http://hdl.handle.net/10366/172221 Therapeutic drug monitoring (TDM) is routinely recommended for most antifungal triazoles to ensure efficacy and safety. Isavuconazole, however, was initially approved without this recommendation due to its predictable pharmacokinetic profile. Later clinical data have raised concerns about subtherapeutic exposures in certain populations. This prospective, single-center study aimed to assess the need for TDM of isavuconazole in critically ill and hematologic patients with invasive fungal infections. Between March 2022 and November 2023, patients receiving standard dosing of isavuconazole were enrolled, and plasma concentrations were measured to determine the proportion of patients with values outside the therapeutic range (1–4 µg/mL), particularly focusing on subtherapeutic levels. A total of 65 isavuconazole plasma concentrations from 24 patients (9 critically ill and 15 hematologic) were analyzed. Critically ill patients had lower initial concentrations than hematologic patients (median [range]: 0.75 [not detectable (ND)–5.18] vs. 3.03 [1.03–6.65] µg/mL), with 66.7% showing levels outside the therapeutic range and 55.5% having subtherapeutic concentrations. The coefficient of variation (CV%) of concentrations values at the first TDM was 124.7% in critically ill patients and 57.3% in hematologic patients. After dose adjustment in critically ill patients, the proportion with levels outside the therapeutic range decreased to 28.6%. These findings suggest that, despite initial assumptions, isavuconazole exhibits considerable pharmacokinetic variability in specific populations, particularly in critically ill patients, and the findings support the implementation of TDM to optimize antifungal therapy and improve patient outcomes in real-world clinical settings. 2025-01-01T00:00:00Z http://hdl.handle.net/10366/172220 Purpose Drug (or medicine) recalls represent a public health risk and may contribute to shortages, potentially affecting sup ply continuity and, consequently, patient care. This study analyzed drug recalls issued by the Spanish Agency of Medicines and Medical Devices (AEMPS) and conducted an additional descriptive recall-related shortage assessment to estimate their potential impact on supply continuity in Spain. Methods A descriptive retrospective regulatory analysis was conducted on drug recalls in Spain over a 14-year period (2010–2023). Data from the AEMPS website were analyzed, and drug recalls recorded during the last 4 years of the study period (2020–2023) were cross‑referenced with national shortage records to assess their supply impact. Results A total of 1,120 drug recalls were identified, 87.86% (n = 984) involved prescriptions and 57.32% (n = 642) were classified as Class 2, recalls with a moderate risk of temporary or medically reversible adverse health consequences. The presence of nitrosamines (22.50%, n = 252) was the leading cause of recalls, driven by a phase-specific crisis (2018–2019), with the highest number of issued recalls (19.19%, n = 215) observed in 2018. Five manufacturers of active substances and finished products accounted for 27.32% (n = 306) of all recalls. Drug recalls issued between 2020 and 2023 (n = 195) resulted in a total of 55 drug shortages. Of these shortages, 10.91% (n = 6) were considered to have a high clinical impact on supply continuity. Conclusion Nitrosamines emerged as the leading cause of recalls in Spain during the study period. A subset of recalls was linked to shortages affecting supply continuity, posing a potential risk to patients’ health. These findings underscore the importance of monitoring recalls and addressing supply chain vulnerabilities to mitigate negative effects on patients’ health and access to essential medications 2026-01-01T00:00:00Z http://hdl.handle.net/10366/172219 Background In this study, the efficacy of three essential oil extraction techniques steam entrainment, Soxhlet extraction, and supercritical fluid extraction (SCF) was evaluated. Aim Determine the most effective method for obtaining bioactive compounds from Cymbopogon citratus, Origanum vulgare, and Coriandrum sativum, plant species recognized for their antimicrobial and anti-inflammatory properties with potential applications in dentistry. The selected plants, identified based on scientific evidence, were certified and lyophilized prior to extraction. The efficiency of each technique was assessed in terms of essential oil yield, purity, and biological activity. Methodology The plant species were selected for their therapeutic properties based on scientific reports, certified, and lyophilized before proceeding with the different extraction methods. The efficacy of each technique was compared in terms of the purity and yield of the essential oils obtained. The statistical analysis was performed using SPSS version 25. Results It was shown that FSC extraction is the method that allows obtaining essential oils with the highest purity and yield, followed by steam entrainment, with the Soxhlet method being the least efficient. However, in the microbiological analysis, the essential oil obtained by steam entrainment showed a greater inhibitory effect against Candida albicans ATCC 90028. Conclusion In this study, the FSC and steam entrainment techniques are the most suitable for obtaining essential oils for therapeutic applications in dentistry, since they allow better preservation of the bioactive components and reduce the environmental impact. These results position FSC and vapor entrainment extraction as promising options for the development of therapeutic products in dentistry. 2025-01-01T00:00:00Z http://hdl.handle.net/10366/162163 Objective: Our objective was to validate and compare the automated and chromatography methods for determining imatinib levels in plasma, in terms of linearity, precision, accuracy and specificity, for therapeutic drug monitoring. Methods: Imatinib patterns were prepared in human plasma and were analysed by both methods to determine the calibration curve of each method. The methods were validated for linearity, extraction recovery, intra- and inter-day precision (relative standard deviation, RSD%), accuracy, and specificity of imatinib analysis. Method comparison study was carried out using the imatinib concentrations determined in the 25 patient samples by Deming regression and Bland–Altman analysis. Results: The calibration curve of the automated and chromatography methods were linear over the range 500–2750 ng/ml (r = 0.996) and 500–3000 ng/ml (r = 0.999), respectively. Intra- and inter-day precision showed that not all the CV values of the drug were below 15% for the automated method, recommended by the EMA and the FDA. In contrast, all CV values for precision of the chromatography method are below 6.0%. Average recovery percentage is 94.4% and 100.8 for the automated and chromatography methods, respectively. Agreement between the two methods was illustrated using Bland–Altman plot with a mean difference (Immunoassay—UPLC-UV) of 191.28 ng/ml and a 95% confidence interval of − 201.41 to 583.97 ng/ml. Deming regression analysis showed that the correlation coefficient for the automated method versus the chromatography method was 0.927 Conclusions: The chromatographic technique was the better option for therapeutic drug monitoring of imatinib in clinical practice in patients with Chronic Myeloid Leukemia (CML). 2021-01-01T00:00:00Z http://hdl.handle.net/10366/162162 Therapeutic drug monitoring (TDM) of voriconazole is recommended for personalizing doses. The objective of this study was to compare the enzyme immunoassay developed by ARKTM Diagnostics Inc. for the quantification of voriconazole adapted to the Architect C4000 autoanalyzer (Abbott®) with ultra-performance liquid chromatography using ultraviolet detector (UPLC-UV) method. Materials and Methods: Linearity, precision and accuracy of both methods were validated according to the Food and Drug Administration (FDA) and European Medicines Agency guidelines. The limit of quantification (LOQ) of the UPLC-UV method was determined experimentally. Both methods were applied to the analysis of 62 samples from patients. Correlation was evaluated by Passing-Bablok analysis and the concordance by the Bland–Altman method. Dosage recommendations were generated; the discordances according to the technique were evaluated. Results: All validation parameters determined for UPLC-UV met the criteria set out and LOQ of 0.1 μg/mL was established. However, when the enzyme immunoassay was used to determine concentrations ≤1 μg/ml, CVs were >20%. A linear correlation between both methods was found. However, an overestimation of immunoassay (systematic error of 0.39 μg/mL) was detected. In 11.3% of the samples, the differences in concentrations when they were determined by different techniques would imply a different therapeutic regime. These samples had concentrations close to 1 μg/mL. Conclusion: Although both techniques can be used for TDM of voriconazole, when a value close to the lower limit of the therapeutic range is determined by the ARKTM immunoassay, it would be better to verify the result by a non-automated technique to avoid possible underdosing. 2021-01-01T00:00:00Z http://hdl.handle.net/10366/162161 Resveratrol is currently considered for chemoprevention and treatment of oral cancer, but unfavorable properties of this molecule hinder its clinical use. The present study deals with preparation of resveratrol liposomes by a method that preserves stability and provides payload high enough for chemoprevention and/or treatment of oral cancer. Different temperatures, resveratrol concentrations and molar fractions, as well as the presence or absence of vitamin C in the hydration media were assayed. Liposome hydrodynamic diameter, polydispersity and zeta potential were evaluated by dynamic light scattering. In vitro cytotoxicity, antioxidant activity, and permeability were evaluated using TR146 cells and PermeaPad® membranes. Liposomes were included in hydrogels and films, and their suitability for buccal application was evaluated by in vitro assays. A temperature of 37 °C was optimal to efficiently produce resveratrol liposomes. Vitamin C was found to influence liposome size, while resveratrol concentration significantly influenced entrapment efficiency. Cytotoxicity assay showed high biocompatibility while potent antioxidant activity, the inclusion of vitamin C reinforcing the latter effect. High permeation across membranes and efficient uptake by cells was proved for resveratrol liposomes. Liposomal hydrogels and films were obtained with payload high enough to produce mucosa concentrations above resveratrol IC50 values reported for cancer cells. 2024-01-01T00:00:00Z http://hdl.handle.net/10366/162160 A pharmaceutical vehicle based on lyophilized liposomes is proposed for the buccal administration of drugs aimed at systemic delivery through the sublingual mucosa. Liposomes made of egg phosphatidylcholine and cholesterol (7/3 molar ratio) were prepared and lyophilized in the presence of different additive mixtures with mucoadhesive and taste-masking properties. Palatability was assayed on healthy volunteers. The lyophilization cycle was optimized, and the lyophilized product was compressed to obtain round and capsule-shaped tables that were evaluated in healthy volunteers. Tablets were also assayed regarding weight and thickness uniformities, swelling index and liposome release. The results proved that lyophilized liposomes in unidirectional round tablets have palatability, small size, comfortability and buccal retention adequate for sublingual administration. In contact with water fluids, the tablets swelled, and rehydrated liposomes were released at a slower rate than permeation efficiency determined using a biomimetic membrane. Permeability efficiency values of 0.72 ± 0.34 µg/cm2/min and 4.18 ± 0.95 µg/cm2/min were obtained for the liposomes with and without additives, respectively. Altogether, the results point to the vehicle proposed as a liposomal formulation suitable for systemic drug delivery through the sublingual mucosa. 2022-01-01T00:00:00Z http://hdl.handle.net/10366/162159 The pathologies produced by fungi in the oral cavity in recent decades have become a health problem, with factors such as an imbalance of the local microbiota being the cause for their propagation. Conventional antifungal treatments, instead of being beneficial, have generated alterations that have led to antifungal resistance. The aim of this study was to investigate and describe phytotherapy resources as a possible solution to oral antifungal resistance. A bibliographic search was carried out on platforms such as PubMed, Scopus, ScienceDirect, Web of Science, and Google scholar. A total of 248 scientific articles were obtained, of which 108 met the inclusion criteria. Microorganisms of fungal origin currently show resistance to the different antifungals of conventional use, which is undoubtedly altering the oral health of human beings, but there are new therapeutic possibilities such as the active principles of various natural species. 2022-01-01T00:00:00Z http://hdl.handle.net/10366/162158 Imatinib is considered the standard first-line treatment in newly diagnosed patients with chronic-phase myeloid leukaemia (CML). Several imatinib population pharmacokinetic (popPK) models have been developed. However, their predictive performance has not been well established when extrapolated to different populations. Therefore, this study aimed to perform an external evaluation of available imatinib popPK models developed mainly in adult patients, and to evaluate the improvement in individual model-based predictions through Bayesian forecasting computed by each model at different treatment occasions. Methods: A literature review was conducted through PubMed and Scopus to identify popPK models. Therapeutic drug monitoring data collected in adult CML patients treated with imatinib was used for external evaluation, including prediction- and simulated-based diagnostics together with Bayesian forecasting analysis. Results: Fourteen imatinib popPK studies were included for model-performance evaluation. A total of 99 imatinib samples were collected from 48 adult CML patients undergoing imatinib treatment with a minimum of one plasma concentration measured at steady-state between January 2016 and December 2020. The model proposed by Petain et al showed the best performance concerning prediction-based diagnostics in the studied population. Bayesian forecasting demonstrated a significant improvement in predictive performance at the second visit. Inter-occasion variability contributed to reducing bias and improving individual model-based predictions. Conclusions: Imatinib popPK studies developed in Caucasian subjects including α1-acid glycoprotein showed the best model performance in terms of overall bias and precision. Moreover, two imatinib samples from different visits appear sufficient to reach an adequate model-based individual prediction performance trough Bayesian forecasting. 2021-01-01T00:00:00Z http://hdl.handle.net/10366/162157 Enteric coating is a common procedure in the development of oral pharmaceutical dosage forms. The main advantage of enteric coating is that it protects the drug from acidic pH and enzymatic degradation in the stomach while protecting it from the undesirable effects of some drugs. There is certain controversy regarding the real influence of enteric coating on the bioavailability of many drugs. Various scientific articles have demonstrated an improvement in the extent of bioavailability of some drugs when enteric coating is used. In recent years, there have been many studies examining different formulation strategies for monolithic and multiparticulate systems, including different pharmaceutical oral dosage forms and delivery systems based on the combined use of enteric coating and other methods that improve the bioavailability of drugs administered orally. However, the real bioavailability, serum levels and therapeutic effect of these drugs may be influenced by gastrointestinal pH values, gastrointestinal environment, inter-individual or intra-individual variability in gastric emptying and gastrointestinal transit time, interpatient variability associated with the type of polymer used for enteric coating or other formulation variables. It deserves special attention to know the real influence of enteric coating on the bioavailability of new oral dosage forms. 2019-01-01T00:00:00Z http://hdl.handle.net/10366/162004 For decades infections have been treated easily with drugs. However, in the 21st century, they may become lethal again owing to the development of antimicrobial resistance. Pathogens can become resistant by means of different mechanisms, such as increasing the time they spend in the intracellular environment, where drugs are unable to reach therapeutic levels. Moreover, drugs are also subject to certain problems that decrease their efficacy. This requires the use of high doses, and frequent administrations must be implemented, causing adverse side effects or toxicity. The use of nanoparticle systems can help to overcome such problems and increase drug efficacy. Accordingly, there is considerable current interest in their use as antimicrobial agents against different pathogens like bacteria, virus, fungi or parasites, multidrug-resistant strains and biofilms; as targeting vectors towards specific tissues; as vaccines and as theranostic systems. This review begins with an overview of the different types and characteristics of nanoparticles used to deliver drugs to the target, followed by a review of current research and clinical trials addressing the use of nanoparticles within the field of infectious diseases. 2016-02-28T00:00:00Z http://hdl.handle.net/10366/162002 The human immunodeficiency virus (HIV) continues to be a global pandemic and there is an urgent need for innovative treatment. Immune cells represent a major target of virus infection, but are also therapeutic targets. Currently, no antiretroviral therapy targets macrophages, which function as portal of entry and as major long-term deposit of HIV. It has been shown before that human macrophages efficiently internalize gold nanoparticles, a fact which might be used to target them with drug-nanoparticle conjugates. Here, the authors use gold nanocarriers to facilitate delivery of stavudine, a widely used antiretroviral drug, to primary human macrophages. Using an ease-of-use coupling method, a striking potentiation of stavudine intake by macrophages using gold nanocarriers is shown. Further, the carriers induce a specific subtype of proinflammatory activation indicative for antiviral activity of macrophages, which suggests promising novel treatment options for HIV. 2017-03-01T00:00:00Z http://hdl.handle.net/10366/162000 The objectives of this study were to conduct a comparative pharmacokinetic/pharmacodynamic (PK/PD) evaluation using Monte Carlo simulation of conventional versus high-dose extended-interval dosage (HDED) regimens of amikacin (AMK) in intensive care unit (ICU) patients for an Acinetobacter baumannii infection model. The simulation was performed in five populations (a control population and four subpopulations of ICU patients). Using a specific AMK PK/PD model and Monte Carlo simulation, the following were generated: simulated AMK steady-state plasma level curves; PK/PD efficacy indexes [time during which the serum drug concentration remains above the minimum inhibitory concentration (MIC) for a dosing period (%T>MIC) and ratio of peak serum concentration to MIC (Cmax/MIC)]; evolution of bacterial growth curves; and adaptive resistance to treatment. A higher probability of bacterial resistance was observed with the HDED regimen compared with the conventional dosage regimen. A statistically significant increase in Cmax/MIC and a statistically significant reduction in %T>MIC with the HDED regimen were obtained. A multiple linear relationship between CFU values at 24h with Cmax/MIC and %T>MIC was obtained. In conclusion, with the infection model tested, the likelihood of resistance to treatment may be higher against pathogens with a high MIC with the HDED regimen, considering that in many ICU patients the %T>MIC may be limited. If a sufficient value of %T>MIC (≥60%) is not reached, even though the Cmax/MIC is high, the therapeutic efficacy of the treatment may not be guaranteed. This study indicates that different AMK dosing strategies could directly influence the efficacy results in ICU patients. 2013-08-01T00:00:00Z http://hdl.handle.net/10366/161998 2014-01-01T00:00:00Z