An overview of automated flow systems for total and isotopic analysis of strontium and yttrium in samples of environmental interest.

Due to the different uses of radioactivity during the last decades, there has been an increase in the concentration of natural and artificial radionuclides in the environment. This, along with some accidents with a high affect public opinion (for example, Chernobyl and Fukushima), have led to the growth and establishment of environmental radioactivity monitoring programs. Currently, trends in legislation and research are focused on the development of accurate, precise, reliable and fast analytical methods with low limits of detection (LOD) for radionuclides determination, such as strontium and yttrium, in environmental samples. In this paper, two comprehensive reviews and four automated analytical systems for total and isotopic determination of yttrium and strontium are presented. The developed methods have been applied in the analysis of environmental samples with low concentrations of these analytes. These methodologies have been automated by exploiting flow analysis techniques, such as multi-syringe flow injection analysis (MSFIA), Sequential injection analysis (SIA) and laboratory-on-valve (LOV) systems, achieving a minimal handling and low consumption of samples and reagents, a significant reduction in waste generation and a high frequency of analysis. In the developed methodologies, some spectrometric methods such as ICP-OES and ICP-MS have been implemented as detection techniques instead of radiometric detectors obtaining a fully automated, low-cost and fast yttrium and strontium determinations.

Thiol-Functionalized MIL-100(Fe)/Device for the Removal of Heavy Metals in Water.

The preparation of a functional device based on a functionalized MIL-100(Fe) metal-organic framework for the solid-phase extraction of heavy metals is reported. By a simple and easy straightforward grafting procedure, a thiol-functionalized MIL-100(Fe) material (MIL-100(Fe)-SH) with a S/Fe ratio of 0.80 and a surface area of 840 m2 g-1 was obtained. MIL-100(Fe)-SH exhibited a higher Hg(II) extraction (96 ± 5%) than that of MIL-100(Fe) (78 ± 4%) due to the interaction between thiol groups and Hg(II) ions. For practical applications, the obtained MIL-100(Fe)-SH was integrated by a simple method to a 3D printed support based on a matrix of interconnected cubes using poly(vinylidene fluoride) as binder, obtaining a functional device that simultaneously acts as stirrer and sorbent. The developed device showed high efficiency for the removal of Hg(II), good reusability, and excellent performance for the simultaneous preconcentration and further detection and quantification of Hg(II), Pb(II), and As(V) in tap, well, and lake water samples.

Dynamics of Major and Trace Elements in Water-Soil-Tree Interaction: Translocation in Pyrus malus in Chihuahua, Mexico Using ICP-OES and Its Health Risk Implications.

The transference of metals from water irrigation and soil to plants is a possible pathway of contamination for the trophic chain. This research is focused on the distribution of 16 analytes in the water-soil-tree (Pyrus malus) interaction in an agricultural region in the state of Chihuahua in Mexico from August 2019 (first sampling) to August 2020 (second sampling). The apple variety under investigation was Golden Delicious; it was found that the trace elements of As (0.18-0.34 mg·kg-1) and Cd (0.11-0.14 mg·kg-1) in the apple were above the corresponding permissible limit, according to FAO/WHO, and Cr (0.08-0.86 mg·kg-1) was below the limit. Furthermore, the health risk implications were estimated by the Hazard Quotients (HQ) and carcinogenic risk (CR). For carcinogenic risk, As, Cd, and Cr exceeded the risk limit (CR > 10-4). This investigation as well provides a link for similar research around the globe. Major and trace elements detection was performed with the Inductively Coupled Plasma-Optical Emission Spectrometry (ICP-OES) technique, along with a prior homogenization of samples and microwave acid digestion. To obtain the statistical behavior, an analysis of variance and correlation was performed.

Bone metabolism and osteoporosis during pregnancy and lactation.

PURPOSE: Osteoporosis in pregnancy is an uncommon disease and there is little information regarding its pathogenesis and its effects on the skeleton. This review aims to describe changes in mineral metabolism during pregnancy and lactation as well as their clinical impact. METHODS: We performed a narrative review of the literature using the PubMed and Google Scholar databases for articles published from 1955 to 2021. RESULTS: Mineral metabolism in the mother must adapt to the demand created by the fetus and the placenta, which together absorb calcium and other minerals from the mother to mineralize the developing fetal skeleton; analyses of iliac bone biopsies at the beginning and end of pregnancy have shown that pregnancy significantly modifies maternal bone status. The greatest demand for calcium for the maternal skeleton occurs during lactation; women who breastfeed have an even greater loss of calcium to produce milk. However, it is controversial whether breastfeeding can increase the risk of osteoporotic fractures, and the possible mechanism is considerably complicated. Osteoporosis in pregnancy is an uncommon disease characterized by the occurrence of fragility fractures, most commonly in the vertebral column, in the third trimester of pregnancy, or early postpartum. The pathogenesis of PLO remains unclear owing to its rarity; DXA provides a sensitive and specific method for diagnosing osteoporosis by measuring BMD, one of the parameters that allow a better understanding of fracture risk. One limitation is the controversy in using radiation in pregnant women and the risk to the embryo/fetus; a safe alternative can be MRI. CONCLUSION: Pregnancy and lactation alter the maternal bone status; without a balance in metabolism, this may cause an increased risk of fracture due to changes in BMD. There is little information on BMD during pregnancy; more clinical studies are required to elucidate if this represents a risk factor for osteoporosis.

Automatic multicommuted flow systems applied in sample treatment for radionuclide determination in biological and environmental analysis.

The presence of artificial and natural radioactivity in the environment is currently a topic of great relevance and ecological interest, even in human health issue, due to the increase of different anthropogenic activities. The use of multicommuted flow analysis techniques (e.g. Multi-Syringe Flow Injection Analysis - MSFIA, Lab-On-Valve - LOV and Lab-In-Syringe - LIS) has allowed the automation of radiochemical procedures to separate and preconcentrate radionuclides in environmental and biological samples. In comparison with the manual approach commonly used in routine analysis for radioactivity monitoring, the automation has enabled the development of highly reproducible methodologies with a great analysis frequency. Moreover, during the analytical procedure, the intervention of the analyst is drastically reduced, minimizing the radiological risk. The automation also offers significant advantages such as minimum consumption of time and reagents, reducing the cost and the generation of waste, contributing to the green chemistry. In this review, several multicommuted flow analysis techniques (MSFIA, LOV and LIS) reported in the last decade applied for the development of automatic sample treatment methodologies, used to separate, preconcentrate and quantify 90Sr, 99Tc, natural U and 226Ra in biological and environmental samples are described and critically compared.

Fast-response flow-based method for evaluating 131I from biological and hospital waste samples exploiting liquid scintillation detection.

This paper presents a fast and automatic flow-based method to extract 131I from biological samples and hospital waste, previous to liquid scintillation detection. 131I is a radionuclide extensively used in Nuclear Medicine due to their beta and gamma disintegrations, whereby hospitals have to manage the associated waste generation. The automatic developed system is based on Lab-On-Valve (LOV) flow-technique exploiting Cl-resin (135 mg per extraction). This methodology allows performing sample extractions and measurements on the same day, since the extraction frequency takes 1.4-4 h-1, depending on the analysed sample volume, plus up to 2 h of measurement for each vial. 131I is retained as iodine ion and eluted with sodium sulphide 0.2 mol L-1. The maximum sample volume that can be preconcentrated is 20 mL, reaching an extraction efficiency of 85 ±â€¯5%. The minimum detectable activity (MDA) is 0.05 Bq, showing a precision of 7% RSD (n = 5). Both, biological samples (urine and saliva) and hospital waste samples can be satisfactorily analysed by the proposed system, obtaining recoveries between 90 and 110%. The developed method is then suitable to implement in hospitals, improving the surveillance of the 131I environmental release.

Direct photoimmobilization of extraction disks on "green state" 3D printed devices.

Post-curing is essential to improve the mechanical properties of 3D printed parts fabricated by stereolithography (SLA), since right after 3D printing they remain in a "green state". It means that the 3D printed parts have reached their final shape, but the polymerization reaction has not been yet completed. Herein, we take advantage of the tacky partially polymerized surface of "green state" SLA 3D printed parts to immobilize extraction disks and miniature magnets, which after UV post-curing, become permanently attached to the 3D printed part resulting in a rotating-disk sorptive extraction device (RDSE). The developed "stick & cure" procedure is reagent-free and does not require any additional preparation time, specialized skills, or instrumentation. As proof of concept, 3D printed RDSE devices with immobilized chelating disks have been applied to the simultaneous extraction of 14 trace metals prior to ICP-OES determination, featuring LODs between 0.03 and 1.27 µg L-1, and an excellent device-to-device reproducibility (n = 5, RSD = 2.7-8.3%). The developed method was validated using certified wastewater and soil reference samples, and satisfactory spiking recoveries were obtained in the analysis of highly polluted solid waste treatment plant leachates (89-110%). In addition, exploiting the versatility of 3D printing, nine RDSE devices with different shapes were fabricated. Their performance was evaluated and compared for the fast extraction of the highly toxic Cr (VI) as its 1,5-diphenylcarbazide complex in reversed-phase mode, showing different extraction performance on depending on the shape of the 3D printed RDSE device.

3D printed device for the automated preconcentration and determination of chromium (VI).

A 3D printed device for the fully automated disk-based solid-phase extraction (SPE) of Cr (VI) from water samples has been fabricated. The compatibility of the use of organic solvents for analyte elution with 3D printed flow devices based on polymers fabricated using stereolithograph​y has been evaluated. The developed methodology comprises the complexation of Cr (VI) with 1, 5-diphenylcarbazide (DPC) in acidic medium and the subsequent retention of the complex in a SBD-RPS disk contained within the 3D printed device. A multisyringe flow injection analysis system with online spectrophotometric detection has been used for the automation of the method. The fabricated 3D printed device integrates the different components of the flow analysis manifold, including connectors and mixers, being a powerful approach towards the reproducible construction of highly integrated flow-based manifolds. The extracted Cr (VI)-DPC complex is eluted with a mixture of methanol- sulfuric acid and quantified at 540 nm. The effect on the analytical signal and the optimization of variables were evaluated using multivariate and univariate techniques. A detection limit of 1 ng Cr (VI) and a linear working range of 3.2-600 ng Cr (VI) were obtained using a sample volume of 2 ml. The intra-day and inter-day RSDs were 4.8% (10 µg L-1, n = 12) and 3.4% (n = 5, different day with a different disk), respectively. The applicability of the fabricated 3D printed device has been proved by the determination of Cr (VI) in groundwater, surface water and leachates.

3D printed device including disk-based solid-phase extraction for the automated speciation of iron using the multisyringe flow injection analysis technique.

The development of advanced manufacturing techniques is crucial for the design of novel analytical tools with unprecedented features. Advanced manufacturing, also known as 3D printing, has been explored for the first time to fabricate modular devices with integrated features for disk-based automated solid-phase extraction (SPE). A modular device integrating analyte oxidation, disk-based SPE and analyte complexation has been fabricated using stereolithographic 3D printing. The 3D printed device is directly connected to flow-based analytical instrumentation, replacing typical flow networks based on discrete elements. As proof of concept, the 3D printed device was implemented in a multisyringe flow injection analysis (MSFIA) system, and applied to the fully automated speciation, SPE and spectrophotometric quantification of Fe in water samples. The obtained limit of detection for total Fe determination was 7ng, with a dynamic linear range from 22ng to 2400ng Fe (3mL sample). An intra-day RSD of 4% (n = 12) and an inter-day RSD of 4.3% (n = 5, 3mL sample, different day with a different disk), were obtained. Incorporation of integrated 3D printed devices with automated flow-based techniques showed improved sensitivity (85% increase on the measured peak height for the determination of total Fe) in comparison with analogous flow manifolds built from conventional tubing and connectors. Our work represents a step forward towards the improved reproducibility in the fabrication of manifolds for flow-based automated methods of analysis, which is especially relevant in the implementation of interlaboratory analysis.

Masking Agents Evaluation for Lead Determination by Flow Injection-Hydride Generation-Atomic Fluorescence Spectrometry Technique: Effect of KI, L-Cysteine, and 1,10-Phenanthroline.

Hydride generation (HG) of lead technique presents interferences from foreign ions of complex matrix samples. In order to minimize these interferences, the effect of masking agents such as KI, L-cysteine, and 1,10-phenanthroline was studied in the absence and in the presence of selected interfering species (As, Cr, Cu, and Fe). Different modes of addition of masking agents were accomplished, that is, to either sample or KBH4 reducing solution. The lead determinations were performed using a flow injection analysis (FIA) system coupled to HG and atomic fluorescence spectrometry (AFS). The linearity of calibration curves (1-10 µg Pb L(-1)) was not affected by the addition of the masking agents. The use of KI in the reducing solution diminished interferences from concentrations of As and Cu, while 1,10-phenanthroline showed a positive effect on the interference by As. Moreover, Cr and Cu appeared to be the most serious interfering ions for plumbane (PbH4), because they drastically reduced the analytical signal of lead. Fe did not present any interference under the employed experimental conditions, even at high levels. The accuracy was established through the analysis of certified reference material (i.e., BCR-610, groundwater) using KI as masking agent. The detection limit reached by FIA-HG-AFS proposed methodology was 0.03 µg Pb L(-1).

MSFIA-LOV system for (226)Ra isolation and pre-concentration from water samples previous radiometric detection.

An automatic system based on multisyringe flow injection analysis (MSFIA) and lab-on-valve (LOV) flow techniques for separation and pre-concentration of (226)Ra from drinking and natural water samples has been developed. The analytical protocol combines two different procedures: the Ra adsorption on MnO2 and the BaSO4 co-precipitation, achieving more selectivity especially in water samples with low radium levels. Radium is adsorbed on MnO2 deposited on macroporous of bead cellulose. Then, it is eluted with hydroxylamine to transform insoluble MnO2 to soluble Mn(II) thus freeing Ra, which is then coprecipitated with BaSO4. The (226)Ra can be directly detected in off-line mode using a low background proportional counter (LBPC) or through a liquid scintillation counter (LSC), after performing an on-line coprecipitate dissolution. Thus, the versatility of the proposed system allows the selection of the radiometric detection technique depending on the detector availability or the required response efficiency (sample number vs. response time and limit of detection). The MSFIA-LOV system improves the precision (1.7% RSD), and the extraction frequency (up to 3 h(-1)). Besides, it has been satisfactorily applied to different types of water matrices (tap, mineral, well and sea water). The (226)Ra minimum detectable activities (LSC: 0.004 Bq L(-1); LBPC: 0.02 Bq L(-1)) attained by this system allow to reach the guidance values proposed by the relevant international agencies e.g. WHO, EPA and EC.

Automatic flow analysis method to determine traces of Mn²âº in sea and drinking waters by a kinetic catalytic process using LWCC-spectrophotometric detection.

A new automatic kinetic catalytic method has been developed for the measurement of Mn(2+) in drinking and seawater samples. The method is based on the catalytic effect of Mn(2+) on the oxidation of tiron by hydrogen peroxide in presence of Pb(2+) as an activator. The optimum conditions were obtained at pH 10 with 0.019 mol L(-1) 2'2 bipyridyl, 0.005 mol L(-1) tiron and 0.38 mol L(-1) hydrogen peroxide. Flow system is based on multisyringe flow injection analysis (MSFIA) coupled with a lab-on-valve (LOV) device exploiting on line spectrophotometric detection by a Liquid Waveguide Capillary Cell (LWCC), 1m optical length and performed at 445 nm. Under the optimized conditions by a multivariate approach, the method allowed the measurement of Mn(2+) in a range of 0.03-35 µg L(-1) with a detection limit of 0.010 µg L(-1), attaining a repeatability of 1.4% RSD. The method was satisfactorily applied to the determination of Mn(2+) in environmental water samples. The reliability of method was also verified by determining the manganese content of the certified standard reference seawater sample, CASS-4.

Estimation of seasonal risk caused by the intake of lead, mercury and cadmium through freshwater fish consumption from urban water reservoirs in arid areas of northern Mexico.

Bioavailability and hence bioaccumulation of heavy metals in fish species depends on seasonal conditions causing different risks levels to human health during the lifetime. Mercury, cadmium and lead contents in fish from Chihuahua (Mexico) water reservoirs have been investigated to assess contamination levels and safety for consumers. Muscle samples of fish were collected across the seasons. Lead and cadmium were analyzed by inductively coupled plasma-optical emission spectrometry, and mercury by cold-vapor atomic absorption spectrometry. The highest concentrations of cadmium (0.235 mg/kg), mercury (0.744 mg/kg) and lead (4.298 mg/kg) exceeded the maximum levels set by European regulations and Codex Alimentarius. Lead concentrations found in fish from three water reservoirs also surpassed the limit of 1 mg/kg established by Mexican regulations. The provisional tolerable weekly intake (PTWI) suggested by the World Health Organization for methyl mercury (1.6 µg/kg bw per week) was exceeded in the spring season (1.94 µg/kg bw per week). This might put consumers at risk of mercury poisoning.

Uranium monitoring tool for rapid analysis of environmental samples based on automated liquid-liquid microextraction.

A fully automated in-syringe (IS) magnetic stirring assisted (MSA) liquid-liquid microextraction (LLME) method for uranium(VI) determination was developed, exploiting a long path-length liquid waveguide capillary cell (LWCC) with spectrophotometric detection. On-line extraction of uranium was performed within a glass syringe containing a magnetic stirrer for homogenization of the sample and the successive reagents: cyanex-272 in dodecane as extractant, EDTA as interference eliminator, hydrochloric acid to make the back-extraction of U(VI) and arsenazo-III as chromogenic reagent to accomplish the spectrophotometric detection at 655 nm. Magnetic stirring assistance was performed by a specially designed driving device placed around the syringe body creating a rotating magnetic field in the syringe, and forcing the rotation of the stirring bar located inside the syringe. The detection limit (LOD) of the developed method is 3.2 µg L(-1). Its good interday precision (Relative Standard Deviation, RSD 3.3%), and its high extraction frequency (up to 6 h(-1)) makes of this method an inexpensive and fast screening tool for monitoring uranium(VI) in environmental samples. It was successfully applied to different environmental matrices: channel sediment certified reference material (BCR-320R), soil and phosphogypsum reference materials, and natural water samples, with recoveries close to 100%.

Automation of 99Tc extraction by LOV prior ICP-MS detection: application to environmental samples.

A new, fast, automated and inexpensive sample pre-treatment method for (99)Tc determination by inductively coupled plasma-mass spectrometry (ICP-MS) detection is presented. The miniaturized approach is based on a lab-on-valve (LOV) system, allowing automatic separation and preconcentration of (99)Tc. Selectivity is provided by the solid phase extraction system used (TEVA resin) which retains selectively pertechnetate ion in diluted nitric acid solution. The proposed system has some advantages such as minimization of sample handling, reduction of reagents volume, improvement of intermediate precision and sample throughput, offering a significant decrease of both time and cost per analysis in comparison to other flow techniques and batch methods. The proposed LOV system has been successfully applied to different samples of environmental interest (water and soil) with satisfactory recoveries, between 94% and 98%. The detection limit (LOD) of the developed method is 0.005 ng. The high durability of the resin and its low amount (32 mg), its good intermediate precision (RSD 3.8%) and repeatability (RSD 2%) and its high extraction frequency (up to 5 h(-1)) makes this method an inexpensive, high precision and fast tool for monitoring (99)Tc in environmental samples.

A multisyringe flow-based system for kinetic-catalytic determination of cobalt(II).

A kinetic-catalytic method for cobalt determination based on the catalytic effect of cobalt(II) on the oxidative coupling of 1,2-dihydroxyanthraquinone (alizarin) was automated exploiting multisyringe flow injection analysis (MSFIA). The proposed method was performed at pH 9.2, resulting in a discoloration process in the presence of hydrogen peroxide. The fixed-time approach was employed for analytical signal measurement. The spectrophotometric detection was used exploiting a liquid waveguide capillary cell (LWCC), of 1m optical length at 465 nm. The optimization was carried out by a multivariate approach, reaching critical values of 124 µmol L(-1) and 0.22 mol L(-1) for alizarin and hydrogen peroxide, respectively, and 67°C of reagent temperature. A sample volume of 150 µL was used allowing a sampling rate of 30h(-1). Under optimal conditions, calibration curve was linear in the range of 1-200 µg L(-1) Co, achieving a DL of 0.3 µg L(-1) Co. The repeatability, expressed as relative standard deviation (RSD) was lower than 1%. The proposed analytical procedure was applied to the determination of cobalt in cobalt gluconate and different forms of vitamin B12, cyanocobalamin and hydroxicobalamin with successful results showing recoveries around 95%.

Automated method for simultaneous lead and strontium isotopic analysis applied to rainwater samples and airborne particulate filters (PM10).

A new automated, sensitive, and fast system for the simultaneous online isolation and preconcentration of lead and strontium by sorption on a microcolumn packed with Sr-resin using an inductively coupled plasma mass spectrometry (ICP-MS) detector was developed, hyphenating lab-on-valve (LOV) and multisyringe flow injection analysis (MSFIA). Pb and Sr are directly retained on the sorbent column and eluted with a solution of 0.05 mol L(-1) ammonium oxalate. The detection limits achieved were 0.04 ng for lead and 0.03 ng for strontium. Mass calibration curves were used since the proposed system allows the use of different sample volumes for preconcentration. Mass linear working ranges were between 0.13 and 50 ng and 0.1 and 50 ng for lead and strontium, respectively. The repeatability of the method, expressed as RSD, was 2.1% and 2.7% for Pb and Sr, respectively. Environmental samples such as rainwater and airborne particulate (PM10) filters as well as a certified reference material SLRS-4 (river water) were satisfactorily analyzed obtaining recoveries between 90 and 110% for both elements. The main features of the LOV-MSFIA-ICP-MS system proposed are the capability to renew solid phase extraction at will in a fully automated way, the remarkable stability of the column which can be reused up to 160 times, and the potential to perform isotopic analysis.

Automated total and radioactive strontium separation and preconcentration in samples of environmental interest exploiting a lab-on-valve system.

A novel lab-on-valve system has been developed for strontium determination in environmental samples. Miniaturized lab-on-valve system potentially offers facilities to allow any kind of chemical and physical processes, including fluidic and microcarrier bead control, homogenous reaction and liquid-solid interaction. A rapid, inexpensive and fully automated method for the separation and preconcentration of total and radioactive strontium, using a solid phase extraction material (Sr-Resin), has been developed. Total strontium concentrations are determined by ICP-OES and (90)Sr activities by a low background proportional counter. The method has been successfully applied to different water samples of environmental interest. The proposed system offers minimization of sample handling, drastic reduction of reagent volume, improvement of the reproducibility and sample throughput and attains a significant decrease of both time and cost per analysis. The LLD of the total Sr reached is 1.8ng and the minimum detectable activity for (90)Sr is 0.008Bq. The repeatability of the separation procedure is 1.2% (n=10).

Mercury levels in locally manufactured Mexican skin-lightening creams.

Mercury is considered one of the most toxic elements for plants and animals. Nevertheless, in the Middle East, Asia and Latin America, whitening creams containing mercury are being manufactured and purchased, despite their obvious health risks. Due to the mass distribution of these products, this can be considered a global public health issue. In Mexico, these products are widely available in pharmacies, beauty aid and health stores. They are used for their skin lightening effects. The aim of this work was to analyze the mercury content in some cosmetic whitening creams using the cold vapor technique coupled with atomic absorption spectrometry (CV-AAS). A total of 16 skin-lightening creams from the local market were investigated. No warning information was noted on the packaging. In 10 of the samples, no mercury was detected. The mercury content in six of the samples varied between 878 and 36,000 ppm, despite the fact that the U.S. Food and Drug Administration (FDA) has determined that the limit for mercury in creams should be less than 1 ppm. Skin creams containing mercury are still available and commonly used in Mexico and many developing countries, and their contents are poorly controlled.

Experiencia en la terapia crónica con anticonvulsivantes en niños / Experience on the chronic therapy with anticonvulsivants in children

Objetivo:Identificar efectos adversos del uso de drogas anticonvulsivantes en niños, así como su incidencia.Metodología. Estudio prospectivo,observacional de una muestra aleatoria de niños menores de dos años seleccionados de una población pediátrica en tratamiento con uno o múltiples anticonvulsivantes por un período no menor de seis meses. Se excluyeron pacientes con enfermedad hepática, renal y epilépticos sin tratamiento anticonvulsivante.Resultados.Se excluyeron 160 casos de los cuales 34/100 fueron varones y 34/100 con politerapia.Se observaron efectos secundarios en 10/100 de los pacientes con monoterapia con valproato, 42/100 con fenobarbital, 16/100 difenilhidantoína, 50/100 con primidona y no se reportó ningún caso con carbanacepina.Con politerapia los efectos secundarios se observaron en 30/100 con fenobarbital, 60/100 con valproato, 12.5/100 con difenilhidantoína y 4/100 con carbanacepina.Conclusiones.Los medicamentos anticonvulsivantes presentan una proporción de casos con efectos secundarios variables, que aumentan considerablemente al utilizarse en forma combinada.