Effectiveness of Lemon Verbena (Cymbopogon citratus) in Oral Candidiasis: A Systematic Review.

The rise of phytotherapy has enabled the utilization of various plant species for medicinal purposes, such as Cymbopogon citratus (C. citratus), providing solutions for oral pathologies, such as oral candidiasis. The PubMed, Web of Science, Scopus, and SciELO databases were searched. In vivo and in vitro studies on the action of C. citratus against oral candidiasis were included, and ROBINS-I was used to determine study quality and risk of bias. The search yielded 1922 articles, of which 10 met the inclusion criteria. Limited scientific evidence exists regarding the use of C. citratus for oral candidiasis. However, studies have indicated its potent antifungal effects. Further studies, preferably clinical trials, are necessary to confirm this effect and to enable its clinical use as a therapeutic option.

Validation and clinical evaluation of an ultra-performance liquid chromatography with ultraviolet detector method for plasma quantification of micafungin.

BACKGROUND: Factors associated with interindividual variability in the pharmacokinetics of micafungin have been identified. This variability can cause underexposure and loss of drug efficacy. For this reason, a simple, fast, cost-effective and sensitive ultra-performance liquid chromatography ultraviolet detector (UPLC-UV) method was developed and validated for the quantification of micafungin. METHODS: The method involves simple plasma precipitation by UPLC with a reversed phase C18 column at 40°C coupled with ultraviolet detection set at a wavelength of 264 nm. The mobile phase consisted of a mixture 42/58 of potassium phosphate 20 mm and acetonitrile. RESULTS: The method was validated over the concentration range of 0.25-15.0 mg/L and proved to be reliable and reproducible with an average percentage of recoveries of 101.59 ± 3.93% and inter and intraday variation coefficients lower than 15% in all cases. The method was successfully applied in determining 30 samples from 10 patients being treated with micafungin. CONCLUSIONS: The method proposed could be useful to facilitate the implementation of therapeutic drug monitoring for personalizing micafungin treatment in invasive fungal infections.

Development of a Mucoadhesive Vehicle Based on Lyophilized Liposomes for Drug Delivery through the Sublingual Mucosa.

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.

Phytotherapy: A Solution to Decrease Antifungal Resistance in the Dental Field.

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.

Population pharmacokinetics of a posaconazole tablet formulation in transplant adult allogeneic stem cell recipients.

BACKGROUND: Posaconazole is an antifungal agent extensively used as a prophylaxis for invasive fungal infections (IFIs) in allogeneic stem cell transplant (SCT) recipients. Low posaconazole concentrations have been associated with reduced clinical response. The aim of this study was to develop a population pharmacokinetic (popPK) model of a posaconazole tablet formulation in allogeneic SCT adult recipients for supporting model-informed precision dosing (MIPD). MATERIALS AND METHOD: Prospective observational study performed in adult allogeneic SCT recipients receiving posaconazole as prophylaxis for IFIs and followed up by a therapeutic drug monitoring (TDM) program. Posaconazole plasma concentrations were quantified using an ultra-high-performance liquid chromatography (UPLC) with UV detector. A popPK model was developed using NONMEM v.7.4.0. Deterministic and stochastic simulations were carried out with the final model to evaluate the differences across physiological variables with impact on drug exposure. RESULTS: A one-compartment model with sequential absorption (zero and first order) and first order elimination described adequately 55 posaconazole concentrations from 36 patients. Higher doses of posaconazole were found to be required by males and patients with lower values of total serum proteins. A nomogram to estimate the posaconazole daily dose based on pharmacokinetic/pharmacodynamic (PKPD) criterion for males and females for different values of total proteins was developed. CONCLUSIONS: Gender and total serum proteins have been identified as covariates influencing posaconazole CL/F in adult allogeneic SCT recipients receiving the delay-released tablet formulation. Additional studies are required to better characterize the absorption of posaconazole and implications on dosage recommendations together with potential safety concerns.

External evaluation of population pharmacokinetic models of imatinib in adults diagnosed with chronic myeloid leukaemia.

AIMS: 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.

Comparison of ultra-performance liquid chromatography and ARK immunoassay for therapeutic drug monitoring of voriconazole.

BACKGROUND: 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.

Albumin micro/nanoparticles entrapping liposomes for itraconazole green formulation.

Itraconazole-loaded micro/nanoparticles containing albumin and liposomes were prepared by a technological process that avoids the use of organic solvents and crosslinker agents. The particles were characterized, lyophilized and formulated as tablets. Dynamic light scattering was used to determine the hydrodynamic diameter and zeta potential of the particles; optical and scanning-electron microscopy was used to evaluate their morphology. Spherical shaped particles of different sizes and zeta potential were obtained. An exponential relationship between the zeta potential and the albumin/cationic lipid molar ratio was established. Drug entrapment efficiency values were in the range of 51-68%, with no statistical differences among albumin feeding concentrations. Mannitol was used as lyophilization additive and the freeze-dried cake was directly compressed into tablets, suitable for vaginal administration. The results from the in vitro drug delivery assay show the influence of albumin on the itraconazole delivery profile; a rapid release was observed for particles with higher albumin amount compared to those with lower protein content. According to the results of this study, albumin particles entrapping liposomes prove to be a green pharmaceutical vehicle with a high potential for delivery of hydrophobic and highly albumin-bound drugs.

Pharmacokinetics and biodistribution of amikacin encapsulated in carrier erythrocytes.

OBJECTIVES: To study the changes in the pharmacokinetics and tissue distribution of the aminoglycoside amikacin in rats using amikacin carrier erythrocytes as a delivery system. METHODS: Amikacin-loaded erythrocytes were obtained using a hypotonic dialysis method. The pharmacokinetic and tissue distribution of amikacin were studied in three groups of rats receiving intravenous amikacin in saline solution, amikacin-loaded erythrocytes and amikacin-loaded erythrocytes treated with glutaraldehyde. Pharmacokinetic analysis was accomplished using model-independent methods. RESULTS: Administration of the antibiotic using carrier erythrocytes elicited a sustained release effect, with an increase in the plasma half-life and in the area under the curve of the antibiotic. The tissue pharmacokinetics of amikacin using carrier erythrocytes in comparison with a control group revealed an accumulation of the antibiotic in specific tissues such as the liver and spleen, a similar pharmacokinetics in the lung and moderate changes in the pharmacokinetics in the kidney. Studies of tissue concentrations after the injection of glutaraldehyde-treated loaded erythrocytes demonstrated important changes in organs of the reticulo-endothelial system (RES) in comparison with the results observed for standard carrier erythrocytes, higher levels being observed in the liver whereas spleen levels decreased. CONCLUSIONS: The administration of amikacin in loaded erythrocytes in rats leads to significant changes in the pharmacokinetic behaviour of the antibiotic, a greater accumulation being observed in RES organs such as liver and spleen. This shows that loaded erythrocytes are potentially useful for the delivery of antibiotics in phagocytic cells located in the RES.

Factors associated with the performance of carrier erythrocytes obtained by hypotonic dialysis.

Carrier erythrocytes containing drugs, enzymes or peptides can be used as a delivery system that allows changes in the kinetic behaviour and selective biodistribution of the substances encapsulated. Hypotonic dialysis is the method most commonly used in the preparation of carrier erythrocytes, but many factors affect the yield and characteristics of the ghost erythrocytes obtained using this method. This review analyses the factors that affect the performance of carrier erythrocytes prepared by hypotonic dialysis. Factors such as the composition and osmolality range of the hypotonic buffer used, the duration of the hypotonic dialysis, temperature, the volume ratio between the erythrocyte suspension and the dialysis buffer, the inclusion in the process of an annealing phase, the composition and osmolality of the resealing buffer, and the conditions under which the final washing of the erythrocytes is carried out may all affect the morphological properties and the later in vivo behaviour of the ghost erythrocytes obtained. Changes in the yield of the encapsulation process, the in vitro drug or enzyme controlled delivery, the pharmacokinetic properties or the in vivo tissue targeting may be modified depending on the conditions under which the preparation of carrier erythrocytes by hypotonic dialysis is carried out. Chemical alterations to the membrane of carrier erythrocytes obtained by hypotonic dialysis with substances such as glutaraldehyde, band 3 cross-linking reagents, trypsin or NHS-biotin, among others, may affect the release rate of the substances encapsulated and may increase the uptake of cells by macrophages both in vitro and in vivo.

Pharmacokinetics of ciprofloxacin as a tool to optimise dosage schedules in community patients.

OBJECTIVE: To evaluate the dosage regimens of ciprofloxacin prescribed for outpatients by applying the principles of antibacterial therapy. DESIGN: Retrospective analysis of prescription and demographic data. SETTING: Community pharmacy in Valladolid, Spain. PATIENTS: Fifty male and female patients aged 18-93 years and with bodyweight 41-95kg. METHODS: Prescribed dosage regimen, age, weight, height, type of infection, comorbidity and coadministered drugs were recorded for each patient. Plasma concentration curves were simulated from literature values of the pharmacokinetic parameters of the drug and the age and weight of the patients. Urine concentrations were estimated from simulated plasma concentrations, literature values of renal clearance and an average urinary flow rate of 2 L/day. The potential efficacy of the prescribed treatment was evaluated from the ratio of the simulated peak plasma concentration (C(max)) to the literature value of the minimum inhibitory concentration (MIC) for the bacterium most probably responsible for the infection (C(max) /MIC). The ratio of area under the plasma concentration-time curve over 24 hours to MIC (AUC24 /MIC) was also estimated for non-urinary infections. RESULTS: Demographic variables such as age or bodyweight do not seem to be taken in consideration when ciprofloxacin is prescribed, at least in the patients considered here, leading to wide interindividual variability in plasma concentrations. This may not be relevant for urinary infections, since ciprofloxacin concentrates in the urine, leading to high Cmax /MIC ratios in all patients. Simulated plasma concentration-time curves revealed consistent underdosing for systemic infections in young patients over 60kg, for whom the plasma concentrations achieved led to Cmax /MIC and AUC24 /MIC ratios lower than those associated with clinical efficacy and minimal spread of bacterial resistance. CONCLUSIONS: The standard regimen of ciprofloxacin 250mg every 12 hours prescribed for urinary infections may not be the best choice, since a more convenient regimen of 500mg once daily leads to a higher Cmax /MIC ratio, which is associated with a more significant postantibiotic effect and higher efficacy of fluoroquinolones. For non-urinary infections, the age and weight of patients should be taken into account to achieve optimum plasma concentrations.