Rui Lapa
Universidade do Porto, Faculdade de Farmácia, Faculty Member
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Pharmacokinetic (PK) studies improve the design of dosing regimens in preclinical and clinical settings. In complex diseases like cancer, single-agent approaches are often insufficient for an effective treatment, and drug combination... more
Pharmacokinetic (PK) studies improve the design of dosing regimens in preclinical and clinical settings. In complex diseases like cancer, single-agent approaches are often insufficient for an effective treatment, and drug combination therapies can be implemented. In this work, in silico PK models were developed based on in vitro assays results, with the goal of predicting the in vivo performance of drug combinations in the context of cancer therapy. Combinations of reference drugs for cancer treatment, gemcitabine and 5-fluorouracil (5-FU), and repurposed drugs itraconazole, verapamil or tacrine, were evaluated in vitro. Then, two-compartment PK models were developed based on the previous in vitro studies and on the PK profile reported in the literature for human patients. Considering the quantification parameter area under the dose-response-time curve (AUCeffect) for the combinations effect, itraconazole was the most effective in combination with either reference anticancer drugs. ...
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Pharmacokinetics (PK) is a branch of pharmacology present and of vital importance for the research and development (R&D) of new drugs, post-market monitoring, and continued optimizations in clinical contexts. Ultimately, pharmacokinetics... more
Pharmacokinetics (PK) is a branch of pharmacology present and of vital importance for the research and development (R&D) of new drugs, post-market monitoring, and continued optimizations in clinical contexts. Ultimately, pharmacokinetics can contribute to improving patients’ clinical outcomes, helping enhance the efficacy of treatments, and reducing possible adverse side effects while also contributing to precision medicine. This article discusses the methods used to predict and study human pharmacokinetics and their evolution to the current physiologically based pharmacokinetic (PBPK) modeling and simulation methods. The importance of therapeutic drug monitoring (TDM) and PBPK as valuable tools for Model-Informed Precision Dosing (MIPD) are highlighted, with particular emphasis on antibiotic therapy since dosage adjustment of antibiotics can be vital to ensure successful clinical outcomes and to prevent the spread of resistant bacterial strains.
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The importance of closely observing patients receiving antibiotic therapy, performing therapeutic drug monitoring (TDM), and regularly adjusting dosing regimens has been extensively demonstrated. Additionally, antibiotic resistance is a... more
The importance of closely observing patients receiving antibiotic therapy, performing therapeutic drug monitoring (TDM), and regularly adjusting dosing regimens has been extensively demonstrated. Additionally, antibiotic resistance is a contemporary concerningly dangerous issue. Optimizing the use of antibiotics is crucial to ensure treatment efficacy and prevent toxicity caused by overdosing, as well as to combat the prevalence and wide spread of resistant strains. Some antibiotics have been selected and reserved for the treatment of severe infections, including amikacin, gentamicin, tobramycin, and vancomycin. Critically ill patients often require long treatments, hospitalization, and require particular attention regarding TDM and dosing adjustments. As these antibiotics are eliminated by the kidneys, critical deterioration of renal function and toxic effects must be prevented. In this work, clinical data from a Portuguese cohort of 82 inpatients was analyzed and physiologically b...
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Gemcitabine is an anticancer drug used to treat a wide range of solid tumors and is a first line treatment for pancreatic cancer. Our group has previously developed novel conjugates of gemcitabine with cell-penetrating peptides (CPP), and... more
Gemcitabine is an anticancer drug used to treat a wide range of solid tumors and is a first line treatment for pancreatic cancer. Our group has previously developed novel conjugates of gemcitabine with cell-penetrating peptides (CPP), and here we report some preliminary data regarding the pharmacokinetics of gemcitabine, two gemcitabine-CPP conjugates and respective CPP gathered from GastroPlus™, and analyze these results considering our previous evaluation of gemcitabine release and conjugates’ bioactivity. Additionally, seeking to shed some light on the relation between the penetration ability of CPP and their physicochemical properties, chemical descriptors for the 20 natural amino acids were calculated, a new principal property scale (z-scale) was created and CPP prediction models were developed, establishing quantitative structure-activity relationships (QSAR). The z-scores of the peptides conjugated with gemcitabine are presented and analyzed with the aforementioned data.
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A fully automated Vibrio fischeri methodology based on sequential injection analysis (SIA) has been developed. The methodology was based on the aspiration of 75 μL of bacteria and 50 μL of inhibitor followed by measurement of the... more
A fully automated Vibrio fischeri methodology based on sequential injection analysis (SIA) has been developed. The methodology was based on the aspiration of 75 μL of bacteria and 50 μL of inhibitor followed by measurement of the luminescence of bacteria. The assays were conducted for contact times of 5, 15, and 30 min, by means of three mixing chambers that ensured adequate mixing conditions. The optimized methodology provided a precise control of the reaction conditions which is an asset for the analysis of a large number of samples. The developed methodology was applied to the evaluation of the impact of a set of ionic liquids (ILs) on V. fischeri and the results were compared with those provided by a conventional assay kit (Biotox(®)). The collected data evidenced the influence of different cation head groups and anion moieties on the toxicity of ILs. Generally, aromatic cations and fluorine-containing anions displayed higher impact on V. fischeri, evidenced by lower EC50. The p...
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ABSTRACT The construction and evaluation of an inexpensive flow photometer for clinical analysis, using a bicolour LED and a phototransistor adapted for tubular flow cell, are described. The instrument presents some new features such as:... more
ABSTRACT The construction and evaluation of an inexpensive flow photometer for clinical analysis, using a bicolour LED and a phototransistor adapted for tubular flow cell, are described. The instrument presents some new features such as: automatic zero, electronic calibration and peak-hold signal. When compared with a classical photometer, it is simpler and has the advantages of a flow analysis system: lower volumes of reagents and samples, lower levels of contamination, shorter time for analysis and lower analysis costs. The instrument was used in the determination of the constituents in blood samples. The results obtained agree with those obtained by a classical photometer and the precision was better.
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Research Interests: Engineering, Chemistry, Chromatography, Medicine, Beer, and 13 moreBrewing, Mercury, Gas Chromatography, Agricultural, CHEMICAL SCIENCES, Fermentation, GAS LIQUID CHROMATOGRAPHY, Derivatization, Agricultural and Food Chemistry, Adsorptive Stripping Voltammetry, Electrodes, Diacetyl, and Autoanalysis
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A simple ion-interaction C18 reverse-phase high performance liquid chromatographic method was developed for simultaneous determination of nitrite, nitrate and ascorbic acid in canned vegetable juices. The method makes use of 0.010 M... more
A simple ion-interaction C18 reverse-phase high performance liquid chromatographic method was developed for simultaneous determination of nitrite, nitrate and ascorbic acid in canned vegetable juices. The method makes use of 0.010 M octylammonium orthophosphate as the ion interacting reagent and 20% (v/v) aqueous methanol as the mobile phase. The content of nitrite, nitrate (expressed as nitrite ion and nitrate ion, respectively) and ascorbic acid in commercial brands of canned tomato, carrot and mixed vegetable juices were surveyed. The quantitative results indicated that nitrite was very probably added as a preservative in the canned vegetable juices. The total amount of nitrite and nitrate ion per can in two commercial brands of vegetable juices was found to exceed the acceptable daily intake recommended by the 1996 Joint FAO/WHO Expert Committee on Food Additives for an average adult of 60 kg body weight.
Research Interests: Engineering, Chemistry, Food Science, Medicine, Food Preservation, and 15 moreHumans, Nitrates, Nitrate, Nitrite, Vegetables, High Performance Liquid Chromatography, High Pressure Liquid Chromatography, CHEMICAL SCIENCES, Beverages, Ascorbic Acid, Green Reagent, Preservative, Food Preservatives, Nitrites, and Medical and Health Sciences
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Research Interests: Engineering, Chemistry, Microfluidics, Medicine, Quantitative analysis, and 15 moreBiological Sciences, Chemiluminescence, Ground Water, CHEMICAL SCIENCES, Hydrogen Peroxide, Reproducibility, Correlation coefficient, Analytical and Bioanalytical Chemistry, Quantitative Analysis, Image Sensor, Detector, Biosensing Techniques, Nitrites, Dark Current, and Microfluidic Analytical Techniques
A multicommutated flow system for the indirect fluorimetric determination of isoniazid was proposed. The analytical procedure was based on the oxidation of isoniazid by cerium(IV) and monitoring of the fluorescence intensity of the formed... more
A multicommutated flow system for the indirect fluorimetric determination of isoniazid was proposed. The analytical procedure was based on the oxidation of isoniazid by cerium(IV) and monitoring of the fluorescence intensity of the formed cerium(III). A time-based sample insertion enabled an effective control of the sampled volume and thus of the dispersion level attained. Highly concentrated samples were subject to
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Headspace solid-phase microextraction (SPME) coupled to gas chromatography-flame ionization detection (GC-FID) has been applied to the analysis of six phenolic compounds in water samples. A laboratory-made fiber with... more
Headspace solid-phase microextraction (SPME) coupled to gas chromatography-flame ionization detection (GC-FID) has been applied to the analysis of six phenolic compounds in water samples. A laboratory-made fiber with 25,27-dihydroxy-26,28-oxy(2′,7′-dioxo-3′,6′-diazaoctyl)oxy-p-tert-butylcalix[4]arene/hydroxy-terminated silicone oil (Amide bridged-C[4]/OH-TSO) coating was used to extract the analytes from the aqueous samples. The parameters affecting the sorption of analytes onto the fiber, such as extraction temperature and time,
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Considering recent reports on widespread occurrence and concerns about perfluoroalkyl substances (PFAS) in environmental and biological systems, analysis of these compounds have gained much attention in recent years. Majority of... more
Considering recent reports on widespread occurrence and concerns about perfluoroalkyl substances (PFAS) in environmental and biological systems, analysis of these compounds have gained much attention in recent years. Majority of analyte-specific methods are based on a LC/MS/MS or a GC/MS detection, however many environmental or biological studies would benefit from a total organic fluorine (TOF) determination. Presented work was aimed at developing a method for TOF determination. TOF is determined as an amount of inorganic fluoride obtained after defluorination reaction conducted off-line using sodium biphenyl reagent directly on the sorbent without elution of retained analytes. Recovered fluoride was analyzed using flow-injection system with either fluorimetric or potentiometric detection. The TOF method was tested using perfluorocarboxylic acids (PFCA), including perfluorooctanoic acid (PFOA), as model compounds. Considering low concentrations of PFAS in natural samples, solid-phase extraction as a preconcentration procedure was evaluated. Several carbon-based sorbents were tested, namely multi-wall carbon nanotubes, carbon nanofibres and activated carbon. Good sorption of all analytes was achieved and defluorination reaction was possible to carry out directly on a sorbent bed. Recoveries obtained for PFCAs, adsorbed on an activated carbon sorbent, and measured as TOF, were 99.5+/-1.7, 110+/-9.4, 95+/-26, 120+/-32, 110+/-12 for C4, C6, C8, C10 and C12-PFCA, respectively. Two flow systems that would enable the defluorination reaction and fluoride determination in a single system were designed and tested.
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A flow system based on multicommutation was developed for the determination of folic acid by fluorimetry following irradiation by ultraviolet light. The photochemical reaction was carried out in a reaction coil. Insertion of... more
A flow system based on multicommutation was developed for the determination of folic acid by fluorimetry following irradiation by ultraviolet light. The photochemical reaction was carried out in a reaction coil. Insertion of time-controlled sample volumes enabled the determination of a wide range of concentrations without changing the manifold design, which makes it suitable for application to automated dissolution studies.
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... A 95 mg l −1 Brilliant Green solution was prepared in water. A 1000 mg l −1 chromium(VI) standard stock solution was prepared by dissolving 5.66 g of potassium dichromate in 0.5 mol l −1 H 2 SO 4 and completing the volume to 1 l with... more
... A 95 mg l −1 Brilliant Green solution was prepared in water. A 1000 mg l −1 chromium(VI) standard stock solution was prepared by dissolving 5.66 g of potassium dichromate in 0.5 mol l −1 H 2 SO 4 and completing the volume to 1 l with the same H 2 SO 4 solution. ...
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In this paper, the construction and evaluation of an electrode selective to nitrate with improved sensitivity, constructed like a conventional electrode (ISE) but using an operational amplifier to sum the potentials supplied by four... more
In this paper, the construction and evaluation of an electrode selective to nitrate with improved sensitivity, constructed like a conventional electrode (ISE) but using an operational amplifier to sum the potentials supplied by four membranes (ESOA) is described. The two types of electrodes, without an inner reference solution, were constructed using tetraoctylammonium bromide as sensor, dibutylphthalate as solvent mediator and
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Gemcitabine is a nucleoside analog effective against several solid tumors. Standard treatment consists of an intravenous infusion over 30 min. This is an invasive, uncomfortable and often painful method, involving recurring visits to the... more
Gemcitabine is a nucleoside analog effective against several solid tumors. Standard treatment consists of an intravenous infusion over 30 min. This is an invasive, uncomfortable and often painful method, involving recurring visits to the hospital and costs associated with medical staff and equipment. Gemcitabine’s activity is significantly limited by numerous factors, including metabolic inactivation, rapid systemic clearance of gemcitabine and transporter deficiency-associated resistance. As such, there have been research efforts to improve gemcitabine-based therapy efficacy, as well as strategies to enhance its oral bioavailability. In this work, gemcitabine in vitro and clinical data were analyzed and in silico tools were used to study the pharmacokinetics of gemcitabine after oral administration following different regimens. Several physiologically based pharmacokinetic (PBPK) models were developed using simulation software GastroPlus™, predicting the PK parameters and plasma co...
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Background:: Vancomycin has been in clinical use for nearly 50 years and remains the first-line treatment option for Gram-positive infections, including methicillin-resistant Staphylococcus aureus (MRSA). There are multiple strategies to... more
Background:: Vancomycin has been in clinical use for nearly 50 years and remains the first-line treatment option for Gram-positive infections, including methicillin-resistant Staphylococcus aureus (MRSA). There are multiple strategies to monitor therapy and adjust the dose of this antibiotic. AUC24/MIC ratio has been demonstrated to be the best parameter to predict the effectiveness and safety of vancomycin, and a target ratio of ≥400 is recommended. Still, trough and peak serum levels at steady-state conditions have been used in clinical settings as an accurate and practical method to monitor vancomycin. Methods:: In this work, we collected and analyzed clinical information of patients being treated in a hospital center in Porto (Portugal) and studied the pharmacokinetics of vancomycin in silico, developing several physiologically based pharmacokinetic (PBPK) models using simulation software GastroPlus™. Different dosages and treatment regimens were studied, and the influence of pa...
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Renal elimination is an important part of drugs' excretion. At the same time, renal function can be impaired as a side effect of medication, particularly during prolonged treatments. Thus, the assessment of patients' renal... more
Renal elimination is an important part of drugs' excretion. At the same time, renal function can be impaired as a side effect of medication, particularly during prolonged treatments. Thus, the assessment of patients' renal function is of major consequence, especially in cases where the therapeutic regimen is adjusted taking into consideration renal clearance. Serum creatinine concentration is the most common indicator of renal clearance, since the most accurate indicator, glomerular filtration rate (GFR), is not easily measured. Using equations developed over the last decades, creatinine clearance (CLCr) is readily estimated taking into account patients' biological sex, age, body composition, and sometimes race. In this work, differences in estimated CLCr between different equations were studied and the influence of some patients' characteristics evaluated. Data collected from 82 inpatients receiving antibiotic therapy was analyzed and CLCr was estimated using a tota...
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Cancer is one of the most alarming diseases due to its high mortality and still increasing incidence rate. Currently available treatments for this condition present several shortcomings and new options are continuously being developed and... more
Cancer is one of the most alarming diseases due to its high mortality and still increasing incidence rate. Currently available treatments for this condition present several shortcomings and new options are continuously being developed and evaluated, aiming at increasing the overall treatment efficiency and reducing associated adverse side effects. Gemcitabine has proven activity and is used in chemotherapy. However, its therapeutic efficiency is limited by its low bioavailability as a result of rapid enzymatic inactivation. Additionally, tumor cells often develop drug resistance after initial tumor regression related to transporter deficiency. We have previously developed three gemcitabine conjugates with cell-penetrating hexapeptides (CPP6) to facilitate intracellular delivery of this drug while also preventing enzymatic deamination. The bioactivity of these new prodrugs was evaluated in different cell lines and showed promising results. Here, we assessed the absorption and permeab...
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An amperometric multisite detection flow injection analysis (FIA) system was developed for sequential determination of 2 analytes with a single sample injection and single detector. Tubular composite carbon electrodes with an inner... more
An amperometric multisite detection flow injection analysis (FIA) system was developed for sequential determination of 2 analytes with a single sample injection and single detector. Tubular composite carbon electrodes with an inner diameter similar to that of the FIA manifold tubing were constructed so that measurements could be made without impairing the sample plug hydrodynamic characteristics. The electrochemical behavior of the tubular voltammetric cell in a low-dispersion FIA manifold and the behavior of the FIA system incorporating this type of voltammetric cell intended for multisite detection were evaluated by performing measurements with potassium hexacyanoferrate(II). Feasibility of the approach was demonstrated in the sequential determination of salicylic and acetylsalicylic acids in pharmaceutical products at a fixed potential of 0.98 V. The system allows sequential determination of salicylic acid concentrations ranging from 1.0 × 10−5 to 5.0 × 10−5M and acetylsalicylic ...
Research Interests: Chemistry, Analytical Chemistry, Colorimetry, Chromatography, Electrochemistry, and 13 moreMedicine, Portugal, Flow Injection Analysis, Gas Chromatography, Aspirin, High Performance Liquid Chromatography, High Pressure Liquid Chromatography, Solutions, Food Sciences, Electrodes, Salicylic Acid, Fluorometry, and Amperometry
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Few methods, such as coulometrics, have been developed to produce reagents in situ for analytical purposes. In this work the concept related to the generation of ultrasound-assisted reagents was exploited to yield oxidizing species in... more
Few methods, such as coulometrics, have been developed to produce reagents in situ for analytical purposes. In this work the concept related to the generation of ultrasound-assisted reagents was exploited to yield oxidizing species in batch and flow systems of analysis. To evaluate the efficiency of ultrasound-assisted reagent generation, the conversion of Fe(2+) to Fe(3+) associated with the 1,10-o-phenantroline spectrophotometric method was tested to compare the oxidizing power of the produced species from pure water and aqueous solutions saturated with CCl(4) or CHCl(3) irradiated ultrasonic waves. Irradiation processes were conducted with an ultrasonic bath (40 kHz and 140 W). The borosilicate reactor was used in the batch studies, while the PTFE tube reactor was used for setting up the flow system, with the temperature during irradiation being controlled using a thermostatic bath. The sonochemical production of oxidizing agents was demonstrated to be efficient for chemical analysis in batch and flow systems. This technique was exemplified by oxidation of iodide and ferrous ions. It was observed that after 120 min of sonication approximately 40 microg of Fe(2+) was quantitatively oxidized to Fe(3+). Similar result was obtained by the irradiation of iodine in aqueous-organic medium.
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Analyst, 2000, 125, 333-340 DOI:10.1039/A907917C (Paper). Precipitation titrations using an automatic titrator based on a multicommutated unsegmented flow system. Cristina MNV Almeidaa, MCU Araújob, Rui AS Lapa*a, José ...
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Research Interests: Chemistry, Analytical Chemistry, Chromatography, Pharmaceutical Chemistry, Medicine, and 13 moreDosage Form, Potentiometry, Pharmaceutical, Ascorbic Acid, Flow analysis, Titration, Green Reagent, Potentiometric Titration, Pharmaceutical Formulation, Iodide, Relative Standard Deviation, Confidence Level, and Pharmacology and pharmaceutical sciences
The construction of a microcomputer-controlled electrode switch for use in potentiometric determinations is described. This can be coupled to most of the analytical equipment usually found in laboratories, to enable a setting up of... more
The construction of a microcomputer-controlled electrode switch for use in potentiometric determinations is described. This can be coupled to most of the analytical equipment usually found in laboratories, to enable a setting up of automatic systems capable of performing sequential determinations with several ion-selective electrodes. The assessment of its analytical usage and behaviour are discussed.
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Oxidability determination in waste waters using an automatic titrator based on a multicommutated unsegmented flow system. CMNV Almeida, RAS Lapa, JLFC Lima International Journal of Environmental Analytical Chemistry 78:33, 315-332, 2000.... more
Oxidability determination in waste waters using an automatic titrator based on a multicommutated unsegmented flow system. CMNV Almeida, RAS Lapa, JLFC Lima International Journal of Environmental Analytical Chemistry 78:33, 315-332, 2000. ...
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Research Interests: Chemistry, Chromatography, Calcium, Food Chemistry, Multidisciplinary, and 13 moreWine, Automation, Flow Injection Analysis, Magnesium, Potassium, Atomic Absorption Spectrometry, Development Methodology, Sodium, Atomic Absorption, Sampling Technique, Atomic Absorption Spectroscopy, Relative Standard Deviation, and Dilution
Research Interests: Chemistry, Analytical Chemistry, Photochemistry, Computer Aided Design, Medicine, and 10 moreMethyl Methacrylate, Reproducibility of Results, Fluidics, Sensitivity and Specificity, Photopolymer, Equipment Design, Polymethyl Methacrylate (PMMA), Analytical Sciences, Microfluidic Analytical Techniques, and Ultraviolet Rays
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A full automatic flow system based on potentiometric titration for alkalinity monitoring in wastewater treating plants is presented. Titration to an end-point of pH 5.75 partial alkalinity (PA) and then to pH 4.3 intermediate alkalinity... more
A full automatic flow system based on potentiometric titration for alkalinity monitoring in wastewater treating plants is presented. Titration to an end-point of pH 5.75 partial alkalinity (PA) and then to pH 4.3 intermediate alkalinity (IA) allows to distinguish the relative buffering contributions of both bicarbonate and volatile acids in anaerobic digesters and, thus, the attainment of a IA:PA ratio