An account on the history of pharmacology in Spain.

Here we present an account on the history of pharmacology in Spain. Pharmacology as an independent science in Europe began with the creation of university chairs. Of particular relevance was the appointment in 1872 of Osswald Shmiedeberg as chairman of an Institute of Pharmacology at the University of Strassbourg, Germany. Teófilo Hernando pioneered in Spain the new emerging pharmacology at the beginning of the XX Century. He made a posdoctoral stay in the laboratory of Schmiedeberg, working on digitalis. In 1912 he won the chair of "Materia Médica y Arte de Recetar" at "Universidad Central of Madrid" (today, "Universidad Complutense de Madrid", UCM). He soon decided to transform such subject to the emerging modern pharmacology, with the teaching of experimental pharmacology in the third course of medical studies and clinical therapeutics (today clinical pharmacology) in the sixth course. This was the status of pharmacology in 1920, supporting the view that Hernando was a pioneer of clinical pharmacology. However, the Spanish Civil War and the II Word War interropted this division of preclinical and clinical pharmacology; only in the 1980's was clinical pharmacolgy partially developed in Spain. From a scientific point of view, Hernando directly trained various young pharmacologists that extended the new science to various Spanish universities. Some of his direct disciples were Benigno Lorenzo Velázquez, Francisco García Valdecasas, Rafael Méndez, Tomás Alday, Gabriel Sánchez de la Cuesta, Dámaso Gutiérrez or Ramón P é rez-Cirera. One of the central research subject was the analysis of the effects of digitalis on the cat and frog heart. In the initiation of the 1970 s pharmacologists trained by those Hernando's students grew throughout various universities and the "Consejo Superior de Investigaciones Científicas" (CSIC). And hence, in 1972 the "Sociedad Española de Farmacología" (SEF) emerged. Later on, in the 1990's the "Sociedad Española de Farmacología Clínica (SEFC) also emerged. The relationship between the two societies is still weak. Out of the vast scope of the pharmacological sciences, Spanish pharmacologists have made relevant contributions in two areas namely, neuropsychopharmacology and cardiovacular pharmacology. Nonetheless, in other areas such as smooth muscle, gastroenterology, pharmacogenetics and hepatic toxicity, Spanish pharmacologists have also made relevant contributions. A succint description of such contributions is made. Finally, some hints on perspectives for the further development of preclinical and clinical pharmacology in Spain, are offered.

Recent progress in the development of porous carbon-based electrodes for sensing applications.

Electrochemical (bio)sensors are considered clean and powerful analytical tools capable of converting an electrochemical reaction between analytes and electrodes into a quantitative signal. They are an important part of our daily lives integrated in various fields such as healthcare, food and environmental monitoring. Several strategies including the incorporation of porous carbon materials in its configuration have been applied to improve their sensitivity and selectivity in the last decade. The porosity, surface area, graphitic structure as well as chemical composition of materials greatly influence the electrochemical performance of the sensors. In this review, activated carbons, ordered mesoporous carbons, graphene-based materials, and MOF-derived carbons, which are used to date as crucial elements of electrochemical devices, are described, starting from their textural and chemical compositions to their role in the outcome of electrochemical sensors. Several relevant and meaningful examples about material synthesis, sensor fabrication and applications are illustrated and described. The closer perspectives of these fascinating materials forecast a promising future for the electrochemical sensing field.

Health Care Workers' Reasons for Choosing Between Two Different COVID-19 Prophylaxis Trials in an Acute Pandemic Context: Single-Center Questionnaire Study.

BACKGROUND: In April 2020, two independent clinical trials to assess SARS-CoV-2 prophylaxis strategies among health care workers were initiated at our hospital: MeCOVID (melatonin vs placebo) and EPICOS (tenofovir disoproxil/emtricitabine vs hydroxychloroquine vs combination therapy vs placebo). OBJECTIVE: This study aimed to evaluate the reasons why health care workers chose to participate in the MeCOVID and EPICOS trials, as well as why they chose one over the other. METHODS: Both trials were offered to health care workers through an internal news bulletin. After an initial screening visit, all subjects were asked to respond to a web-based survey. RESULTS: In the first month, 206 health care workers were screened and 160 were randomized. The survey participation was high at 73.3%. Health care workers cited "to contribute to scientific knowledge" (n=80, 53.0%), followed by "to avoid SARS-CoV-2 infection" (n=33, 21.9%) and "the interest to be tested for SARS-CoV-2" (n=28, 18.5%), as their primary reasons to participate in the trials. We observed significant differences in the expected personal benefits across physicians and nurses (P=.01). The vast majority of volunteers (n=202, 98.0%) selected the MeCOVID trial, their primary reason being their concern regarding adverse reactions to treatments in the EPICOS trial (n=102, 69.4%). CONCLUSIONS: Health care workers' reasons to participate in prophylaxis trials in an acute pandemic context appear to be driven largely by their desire to contribute to science and to gain health benefits. Safety outweighed efficacy when choosing between the two clinical trials.

Effect of confinement of horse heart cytochrome c and formate dehydrogenase from Candida boidinii on mesoporous carbons on their catalytic activity.

This study reports the immobilization of two biocatalysts (e.g., cytochrome c-Cyt c-and the non-metalloenzyme formate dehydrogenase from Candida boidinii-cbFDH) on a series of mesoporous carbons with controlled pore sizes. The catalytic activity of the nanoconfined proteins was correlated with the pore size distribution of the carbon materials used as supports. The electrochemical behaviour of nanoconfined Cyt c showed direct electron transfer electroactivity in pore sizes matching tightly the protein dimension. The pseudo-peroxidase activity towards H2O2 reduction was enhanced at pH 4.0, due to the protein conformational changes. For cbFDH, the reduction of CO2 towards formic acid was evaluated for the nanoconfined protein, in the presence of nicotinamide adenine dinucleotide (NADH). The carbons displayed different cbFDH uptake capacity, governed by the dimensions of the main mesopore cavities and their accessibility through narrow pore necks. The catalytic activity of nanoconfined cbFDH was largely improved, compared to its performance in free solution. Regardless of the carbon support used, the production of formic acid was higher upon immobilization with lower nominal cbFDH:NADH ratios.

Glucose Biosensor Based on Disposable Activated Carbon Electrodes Modified with Platinum Nanoparticles Electrodeposited on Poly(Azure A).

Herein, a novel electrochemical glucose biosensor based on glucose oxidase (GOx) immobilized on a surface containing platinum nanoparticles (PtNPs) electrodeposited on poly(Azure A) (PAA) previously electropolymerized on activated screen-printed carbon electrodes (GOx-PtNPs-PAA-aSPCEs) is reported. The resulting electrochemical biosensor was validated towards glucose oxidation in real samples and further electrochemical measurement associated with the generated H2O2. The electrochemical biosensor showed an excellent sensitivity (42.7 µA mM-1 cm-2), limit of detection (7.6 µM), linear range (20 µM-2.3 mM), and good selectivity towards glucose determination. Furthermore, and most importantly, the detection of glucose was performed at a low potential (0.2 V vs. Ag). The high performance of the electrochemical biosensor was explained through surface exploration using field emission SEM, XPS, and impedance measurements. The electrochemical biosensor was successfully applied to glucose quantification in several real samples (commercial juices and a plant cell culture medium), exhibiting a high accuracy when compared with a classical spectrophotometric method. This electrochemical biosensor can be easily prepared and opens up a good alternative in the development of new sensitive glucose sensors.

Design and Characterization of Effective Ag, Pt and AgPt Nanoparticles to H2O2 Electrosensing from Scrapped Printed Electrodes.

The use of disposable screen-printed electrodes (SPEs) has extraordinarily grown in the last years. In this paper, conductive inks from scrapped SPEs were removed by acid leaching, providing high value feedstocks suitable for the electrochemical deposition of Ag, Pt and Ag core-Pt shell-like bimetallic (AgPt) nanoparticles, onto screen-printed carbon electrodes (ML@SPCEs, M = Ag, Pt or AgPt, L = metal nanoparticles from leaching solutions). ML@SPCEs were characterized by scanning electron microscopy, cyclic voltammetry and electrochemical impedance spectroscopy. The results were compared to those obtained when metal nanoparticles were synthesised using standard solutions of metal salts (MS@SPCEs). Both ML@SPCEs and MS@SPCEs exhibited similar cyclic voltammetric patterns referred to the electrochemical stripping of silver or the adsorption/desorption of hydrogen/anions in the case of platinum, proving leaching solutions extremely effective for the electrodeposition of metallic nanoparticles. The use of both ML@SPCEs and MS@SPCEs proved effective in enhancing the sensitivity for the detection of H2O2 in phosphate buffer solutions (pH = 7). The AgPtL@SPCE was used as proof of concept for the validation of an amperometric sensor for the determination of H2O2 within laundry boosters and antiseptic samples. The electrochemical sensor gave good agreement with the results obtained by a spectrophotometric method with H2O2 recoveries between 100.6% and 106.4%.

An alternative to hydrogenation processes. Electrocatalytic hydrogenation of benzophenone.

The electrocatalytic hydrogenation of benzophenone was performed at room temperature and atmospheric pressure using a polymer electrolyte membrane electrochemical reactor (PEMER). Palladium (Pd) nanoparticles were synthesised and supported on a carbonaceous matrix (Pd/C) with a 28 wt % of Pd with respect to carbon material. Pd/C was characterised by transmission electron microscopy (TEM), and thermogravimetric analysis (TGA). Cathodes were prepared using Pd electrocatalytic loadings (LPd) of 0.2 and 0.02 mg cm-2. The anode consisted of hydrogen gas diffusion for the electrooxidation of hydrogen gas, and a 117 Nafion exchange membrane acted as a cationic polymer electrolyte membrane. Benzophenone solution was electrochemically hydrogenated in EtOH/water (90/10 v/v) plus 0.1 M H2SO4. Current densities of 10, 15 and 20 mA cm-2 were analysed for the preparative electrochemical hydrogenation of benzophenone and such results led to the highest fractional conversion (XR) of around 30% and a selectivity over 90% for the synthesis of diphenylmethanol upon the lowest current density. With regards to an increase by ten times the Pd electrocatalytic loading the electrocatalytic hydrogenation led neither to an increase in fractional conversion nor to a change in selectivity.

Pencil it in: pencil drawn electrochemical sensing platforms.

Inspired by recent reports concerning the utilisation of hand drawn pencil macroelectrodes (PDEs), we report the fabrication, characterisation (physicochemical and electrochemical) and implementation (electrochemical sensing) of various PDEs drawn upon a flexible polyester substrate. Electrochemical characterisation reveals that there are no quantifiable electrochemical responses upon utilising these PDEs with an electroactive analyte that requires an electrochemical oxidation step first, therefore the PDEs have been examined towards the electroactive redox probes hexaammineruthenium(iii) chloride, potassium ferricyanide and ammonium iron(ii) sulfate. For the first time, characterisation of the number of drawn pencil layers and the grade of pencil are examined; these parameters are commonly overlooked when utilising PDEs. It is demonstrated that a PDE drawn ten times with a 6B pencil presented the most advantageous electrochemical platform, in terms of electrochemical reversibility and peak height/analytical signal. In consideration of the aforementioned limitation, analytes requiring an electrochemical reduction as the first process were solely analysed. We demonstrate the beneficial electroanalytical capabilities of these PDEs towards p-benzoquinone and the simultaneous detection of heavy metals, namely lead(ii) and cadmium(ii), all of which are explored for the first time utilising PDEs. Initially, the detection limits of this system were higher than desired for electroanalytical platforms, however upon implementation of the PDEs in a back-to-back configuration (in which two PDEs are placed back-to-back sharing a single connection to the potentiostat), the detection limits for lead(ii) and cadmium(ii) correspond to 10 µg L(-1) and 98 µg L(-1) respectively within model aqueous (0.1 M HCl) solutions.

Can the mechanical activation (polishing) of screen-printed electrodes enhance their electroanalytical response?

The mechanical activation (polishing) of screen-printed electrodes (SPEs) is explored and shown to exhibit an improved voltammetric response (in specific cases) when polished with either commonly available alumina slurry or diamond spray. Proof-of-concept is demonstrated for the electrochemical sensing of nitrite where an increase in the voltammetric current is found using both polishing protocols, exhibiting an improved limit of detection (3σ) and a two-fold increase in the electroanalytical sensitivity compared to the respective un-polished counterpart. It is found that mechanical activation/polishing increases the C/O ratio which significantly affects inner-sphere electrochemical probes only (whereas outer-sphere systems remain unaffected). Mechanical activation/polishing has the potential to be a simple pre-treatment technique that can be extended and routinely applied towards other analytes for an observable improvement in the electroanalytical response.

Electrodegradation of the Acid Green 28 dye using Ti/ß-PbO2 and Ti-Pt/ß-PbO2 anodes.

The statistical Response Surface Methodology (RSM) is applied to investigate the effect of different parameters (current density, j, NaCl concentration, [NaCl], pH, and temperature, θ) and their interactions on the electrochemical degradation of the Acid Green (AG) 28 dye using a Ti/ß-PbO2 or Ti-Pt/ß-PbO2 anode in a filter-press reactor. LC/MS is employed to identify intermediate compounds. For both anodes, the best experimental conditions are j = 50 mA cm(-2), [NaCl] = 1.5 g L(-1), pH = 5, and θ = 25 °C. After 3 h of electrolysis, a dye solution treated under these conditions presents the following parameters: electric charge per unit volume of the electrolyzed solution required for 90% decolorization (Q(90)) of 0.34-0.37 A h L(-1), %COD removal of ∼100%, specific energy consumption of 18-20 kW h m(-3), and %TOC removal of 32-33%. No loss of the ß-PbO2 film is observed during all the experiments. The ß-PbO2 films present excellent stability for solutions with pH ≥ 5 ([Pb(2+)] < 0.5 mg L(-1)). Chloroform is the only volatile organic halo compound present in the treated solution under those optimized conditions. Hydroxylated anthraquinone derivatives, aromatic chloramines, and naphthoquinones are formed during the electrolyses. The Ti/ß-PbO2 and Ti-Pt/ß-PbO2 anodes show significantly better performance than a commercial DSA anode for the electrochemical degradation of the AG 28 dye. The Ti/ß-PbO2 anode, prepared as described in this work, is an excellent option for the treatment of textile effluents because of its low cost of fabrication and good performance.

Graphite Screen-Printed Electrodes Applied for the Accurate and Reagentless Sensing of pH.

A reagentless pH sensor based upon disposable and economical graphite screen-printed electrodes (GSPEs) is demonstrated for the first time. The voltammetric pH sensor utilizes GSPEs which are chemically pretreated to form surface immobilized oxygenated species that, when their redox behavior is monitored, give a Nernstian response over a large pH range (1-13). An excellent experimental correlation is observed between the voltammetric potential and pH over the entire pH range of 1-13 providing a simple approach with which to monitor solution pH. Such a linear response over this dynamic pH range is not usually expected but rather deviation from linearity is encountered at alkaline pH values; absence of this has previously been attributed to a change in the pKa value of surface immobilized groups from that of solution phase species. This non-deviation, which is observed here in the case of our facile produced reagentless pH sensor and also reported in the literature for pH sensitive compounds immobilized upon carbon electrodes/surfaces, where a linear response is observed over the entire pH range, is explained alternatively for the first time. The performance of the GSPE pH sensor is also directly compared with a glass pH probe and applied to the measurement of pH in "real" unbuffered samples where an excellent correlation between the two protocols is observed validating the proposed GSPE pH sensor.

Electroanalytical detection of pindolol: comparison of unmodified and reduced graphene oxide modified screen-printed graphite electrodes.

Recent work has reported the first electroanalytical detection of pindolol using reduced graphene oxide (RGO) modified glassy carbon electrodes [S. Smarzewska and W. Ciesielski, Anal. Methods, 2014, 6, 5038] where it was reported that the use of RGO provided significant improvements in the electroanalytical signal in comparison to a bare (unmodified) glassy carbon electrode. We demonstrate, for the first time, that the electroanalytical quantification of pindolol is actually possible using bare (unmodified) screen-printed graphite electrodes (SPEs). This paper addresses the electroanalytical determination of pindolol utilising RGO modified SPEs. Surprisingly, it is found that bare (unmodified) SPEs provide superior electrochemical signatures over that of RGO modified SPEs. Consequently the electroanalytical sensing of pindolol is explored at bare unmodified SPEs where a linear range between 0.1 µM-10.0 µM is found to be possible whilst offering a limit of detection (3σ) corresponding to 0.097 µM. This provides a convenient yet analytically sensitive method for sensing pindolol. The optimised electroanalytical protocol using the unmodified SPEs, which requires no pre-treatment (electrode polishing) or electrode modification step (such as with the use of RGO), was then further applied to the determination of pindolol in urine samples. This work demonstrates that the use of RGO modified SPEs have no significant benefits when compared to the bare (unmodified) alternative and that the RGO free electrode surface can provide electro-analytically useful performances.

Cysteine-cystine redox cycling in a gold-gold dual-plate generator-collector microtrench sensor.

Thiols and disulfides are ubiquitous and important analytical targets. However, their redox properties, in particular on gold sensor electrodes, are complex and obscured by strong adsorption. Here, a gold-gold dual-plate microtrench dual-electrode sensor with feedback signal amplification is demonstrated to give well-defined (but kinetically limited) steady-state voltammetric current responses for the cysteine-cystine redox cycle in nondegassed aqueous buffer media at pH 7 down to micromolar concentration levels.

Screen-printed graphite macroelectrodes for the direct electron transfer of cytochrome c: a deeper study of the effect of pH on the conformational states, immobilization and peroxidase activity.

The direct electron transfer of cytochrome c has been studied at screen-printed graphite macroelectrodes without recourse to mediators or the need for any electrode pre-treatment as is commonly employed within the literature. A wide range of pH values from 2.0 to 11.0 have been explored upon the electrochemical response of cytochrome c and different voltammetric signatures have been observed. The direct electron transfer of the alkaline transition of cytochrome c was found impeded within alkaline media leading to either an irreversible redox process or even no voltammetric responses. In acidic aqueous media the electrochemical process is observed to undergo a mixed diffusion and adsorption controlled process rather than a purely diffusional process of the native conformation as observed at pH 7.0. Interestingly, at pH 3.5 a new conformational state is revealed in cooperation with the native conformation. The immobilization of the protein was satisfactorily obtained using a simple method by cycling the protein at specific solution pH values allowing amperometric responses to be obtained and gives rise to useful pseudo-peroxidase activity for sensing H2O2. Apparent Michaelis-Menten constant values (Km) were calculated via the Lineweaver-Burk method with deduced values of 25 ± 4, 98 ± 12 and 230 ± 30 mM, respectively for pH values of 2.0, 3.0 and 7.0. Such work is important for those utilising cytochrome c in bio-electrochemical and related applications.

Screen-printed electrode-based electrochemical detector coupled with in-situ ionic-liquid-assisted dispersive liquid-liquid microextraction for determination of 2,4,6-trinitrotoluene.

A novel method is reported, whereby screen-printed electrodes (SPELs) are combined with dispersive liquid-liquid microextraction. In-situ ionic liquid (IL) formation was used as an extractant phase in the microextraction technique and proved to be a simple, fast and inexpensive analytical method. This approach uses miniaturized systems both in sample preparation and in the detection stage, helping to develop environmentally friendly analytical methods and portable devices to enable rapid and onsite measurement. The microextraction method is based on a simple metathesis reaction, in which a water-immiscible IL (1-hexyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide, [Hmim][NTf2]) is formed from a water-miscible IL (1-hexyl-3-methylimidazolium chloride, [Hmim][Cl]) and an ion-exchange reagent (lithium bis[(trifluoromethyl)sulfonyl]imide, LiNTf2) in sample solutions. The explosive 2,4,6-trinitrotoluene (TNT) was used as a model analyte to develop the method. The electrochemical behavior of TNT in [Hmim][NTf2] has been studied in SPELs. The extraction method was first optimized by use of a two-step multivariate optimization strategy, using Plackett-Burman and central composite designs. The method was then evaluated under optimum conditions and a good level of linearity was obtained, with a correlation coefficient of 0.9990. Limits of detection and quantification were 7 µg L(-1) and 9 µg L(-1), respectively. The repeatability of the proposed method was evaluated at two different spiking levels (20 and 50 µg L(-1)), and coefficients of variation of 7 % and 5 % (n = 5) were obtained. Tap water and industrial wastewater were selected as real-world water samples to assess the applicability of the method.

All-in-one continuous electrochemical monitoring of 2-phenylphenol removal from water by electro-Fenton treatment.

The biggest allure of heterogeneous electro-Fenton (HEF) processes largely fails on its high efficiency for the degradation of a plethora of hazardous compounds present in water, but still challenging to search for good and cost-effective electrocatalyst. In this work, carbon black (CB) and oxidised carbon black (CBox) materials were investigated as cathodes in the electrochemical production of hydrogen peroxide involved in HEF reaction for the degradation of 2-phenylphenol (2PP) as a target pollutant. The electrodes were fabricated by employing carbon cloth as support, and the highest H2O2 production yields were obtained for the CBox, pointing out the beneficial effect of the hydrophilic character of the electrode and oxygen-type functionalization of the carbonaceous surface. HEF degradation of 2PP was explored at -0.7 V vs. Ag/AgCl exhibiting the best conversion rates and degradation grade (total organic carbon) for the CBox-based cathode. In addition, the incorporation of an electrochemical sensor of 2PP in line with the HEF reactor was accomplished by the use of screen-printed electrodes (SPE) in order to monitor the pollutant degradation. The electrochemical sensor performance was evaluated from the oxidation of 2PP in the presence of Fe2+ ions by using square wave voltammetry (SWV) technique. The best electrochemical sensor performance was based on SPE modified with Meldola Blue showing a high sensitivity, low detection limit (0.12 ppm) and wide linear range (0.5-21 ppm) with good reproducibility (RSD 2.3 %). The all-in-one electrochemical station has been successfully tested for the degradation and quantification of 2PP, obtaining good recoveries analysing spiked waters from different water matrices origins.

Efficacy and Safety of Calcifediol in Young Adults with Vitamin D Deficiency: A Phase I, Multicentre, Clinical Trial-POSCAL Study.

Vitamin D deficiency is highly prevalent, and recent evidence suggests a possible association between vitamin D deficiency and various health conditions. The aim of this study was to assess monthly calcifediol treatments for vitamin D deficiency (or biweekly, if the deficiency was severe) in a young adult population with no associated comorbidities. This multicentre phase I trial started with a four month open-label treatment phase (TP) that included 101 participants (65% women with mean age 29.8 years). Eighty-two percent of the subjects (79/96) achieved 25(OH)D levels within the target range (20-60 ng/mL) by the end of the TP, and they were subsequently randomised and subjected to a double-blind, placebo-controlled, five month follow-up phase (FP). At the end of the FP, 89% of participants maintained vitamin D levels of >20 ng/mL with calcifediol, versus 49% with placebo (p < 0.001). Subjects receiving monthly calcifediol during both phases (n = 32) maintained 25(OH)D levels >20 ng/mL, whereas those on the placebo during the FP (n = 38) exhibited deficiency levels of 25(OH)D by the end of the study. No clinically relevant changes in bone metabolism parameters or toxic 25(OH)D levels were observed, and no serious adverse events were reported throughout the study. Calcifediol is a safe and effective treatment for vitamin D deficiency in the young adult population, but long-term use may be required to sustain optimal 25(OH)D levels.

Immunogenicity, reactogenicity, and safety of a second booster with BNT162b2 or full-dose mRNA-1273: A randomized VACCELERATE trial in adults aged ≥75 years (EU-COVAT-1-AGED Part B).

OBJECTIVES: To assess the safety and immunogenicity of a fourth vaccination (second booster) in individuals aged ≥75 years. METHODS: Participants were randomized to BNT162b2 (Comirnaty, 30 µg) or messenger RNA (mRNA)-1273 (Spikevax, 100 µg). The primary end point was the rate of two-fold antibody titer increase 14 days after vaccination, targeting the receptor binding domain (RBD) region of wild-type SARS-CoV-2. The secondary end points included changes in neutralizing activity against wild-type and 25 variants. Safety was assessed by monitoring solicited adverse events (AEs) for 7 days. RESULTS: A total of 269 participants (mean age 81 years, mRNA-1273 n = 135/BNT162b2 n = 134) were included. Two-fold anti-RBD immunoglobulin (Ig) G titer increase was achieved by 101 of 129 (78%) and 116 of 133 (87%) subjects in the BNT162b2 and the mRNA-1273 group, respectively (P = 0.054). A second booster of mRNA-1273 provided higher anti-RBD IgG geometric mean titer: 21.326 IU/mL (95% confidence interval: 18.235-24.940) vs BNT162b2: 15.181 IU/mL (95% confidence interval: 13.172-17.497). A higher neutralizing activity was noted for the mRNA-1273 group. The most frequent AE was pain at the injection site (51% in mRNA-1273 and 48% in BNT162b2). Participants in the mRNA-1273 group had less vaccine-related AEs (30% vs 39%). CONCLUSIONS: A second booster of either BNT162b2 or mRNA-1273 provided substantial IgG increase. Full-dose mRNA-1273 provided higher IgG levels and neutralizing capacity against SARS-CoV-2, with similar safety profile for subjects of advanced age.

Conversion from Prograf to Advagraf in adolescents with stable liver transplants: comparative pharmacokinetics and 1-year follow-up.

The recommended dose of Advagraf for conversion from Prograf is considered to be 1:1 on a milligram basis. However, the long-term equivalence of Prograf and Advagraf has been questioned. The relative bioavailability of Advagraf and Prograf was evaluated in a single-center, open-label study of Prograf-to-Advagraf conversion in 20 patients, ranging in age from 12 to 18 years, who had a stable liver transplant and were receiving Prograf. After the supervised administration of Prograf for 7 days, the patients were converted to Advagraf. On days 7 and 14, serial blood samples were obtained for tacrolimus determinations. The pharmacokinetic parameters were calculated with a noncompartmental approach, and the relative bioavailability of both formulations was calculated according to standard statistical methods. Polymorphisms in cytochrome P450 3A5 (rs776746), adenosine triphosphate-binding cassette B1 (rs1045642), POR*28 (rs1057868), and POR (rs2868177) were determined with standard methods. The clinical and analytical data from a 1-year follow-up period were collected for all patients 30, 90, 180, and 360 days after conversion. The mean ratios for Cmax and AUC0-24 were 96.9 (90% confidence interval = 85.37-110.19) and 100.1 (90% confidence interval = 90.8-112.1), respectively. No relationship was found between the patients' genotypes and the pharmacokinetic tacrolimus values. During the follow-up, biochemical parameters (aspartate aminotransferase, alanine aminotransferase, bilirubin, cystatin C, and creatinine) did not change significantly; 3 patients presented with relevant clinical events, but no event was considered to be related to tacrolimus. A decrease in tacrolimus blood levels and an increase in dose/level ratios were observed 3 and 6 months after conversion, but they returned to basal levels by month 12. In conclusion, conversion from Prograf to Advagraf with a 1:1 dose equivalence is appropriate as an initial guideline. Our 1-year follow-up showed a transient decrease in tacrolimus levels, so closer monitoring of tacrolimus levels may be required after conversion.