Pediatric tuberculosis in Mexico and the COVID-19 phenomenon: Past and present.

In endemic regions, tuberculosis in children constitutes a bigger fraction of total cases as compared to those in low endemic regions, regardless of the implications, this phenomenon has been historically neglected. Pediatric tuberculosis has an insidious onset and quickly develops into disseminated disease and the young are at a special risk for dissemination. Some studies suggest that measures to contain adult tuberculosis are not enough to manage tuberculosis in children, meaning that pediatric tuberculosis needs dedicated attention. Children are harder to diagnose than adults, because collecting samples is difficult, and their bacterial yield is low. In endemic countries, such as Mexico, where contact with Mycobacterium tuberculosis is common, immunological tests are inconsistent, especially in immunocompromised children. With the disruption of Mexican healthcare services by the COVID-19 pandemic, there is an uncertainty of how the situation has evolved, current data about tuberculosis indicates a drop in the national report of cases: 15.4 per 100,000 persons in 2021, compared with pre-COVID 2019 17.7 per 100,000 persons, a small increase in mortality: 1.7 per 100,000 in 2021 compared with 2019 1.6 per 100,000, a drop in treatment success: 80.4% in 2021 compared with 85.4% in 2019, and a decrease in national vaccination rates: an estimate of 86.6% children between 1 and 2 years-old were vaccinated in 2021 compared with 97.3% reported national rate in 2018-2019. There is a need for new research on regions with high tuberculosis incidence, to clarify the current situation of pediatric tuberculosis and improve epidemiological surveillance.

Phytochemicals That Interfere With Drug Metabolism and Transport, Modifying Plasma Concentration in Humans and Animals.

Phytochemicals (Pch) present in fruits, vegetables and other foods, are known to inhibit or induce drug metabolism and transport. An exhaustive search was performed in five databases covering from 2000 to 2021. Twenty-one compounds from plants were found to modulate CYP3A and/or P-gp activities and modified the pharmacokinetics and the therapeutic effect of 27 different drugs. Flavonols, flavanones, flavones, stilbenes, diferuloylmethanes, tannins, protoalkaloids, flavans, hyperforin and terpenes, reduce plasma concentration of cyclosporine, simvastatin, celiprolol, midazolam, saquinavir, buspirone, everolimus, nadolol, tamoxifen, alprazolam, verapamil, quazepam, digoxin, fexofenadine, theophylline, indinavir, clopidogrel. Anthocyanins, flavonols, flavones, flavanones, flavonoid glycosides, stilbenes, diferuloylmethanes, catechin, hyperforin, alkaloids, terpenes, tannins and protoalkaloids increase of plasma concentration of buspirone, losartan, diltiazem, felodipine, midazolam, cyclosporine, triazolam, verapamil, carbamazepine, diltiazem, aripiprazole, tamoxifen, doxorubicin, paclitaxel, nicardipine. Interactions between Pchs and drugs affect the gene expression and enzymatic activity of CYP3A and P-gp transporter, which has an impact on their bioavailability; such that co-administration of drugs with food, beverages and food supplements can cause a subtherapeutic effect or overdose. Therefore, it is important for the clinician to consider these interactions to obtain a better therapeutic effect.

Protective Effect of Tilia americana var. mexicana Against Kainic Acid-induced Damage in Brain, Liver, and Kidney: Behavioral and Biochemical Changes.

Tiliaamericana var. mexicana (Tilia) possesses anticonvulsant, antioxidant, neuroprotective, and hepatoprotective activities. The spectrum of anticonvulsant activity in status epilepticus models has not been sufficiently explored. We evaluated the effects of ethyl acetate (EAc), and methanol (ME) extracts on kainic acid (KA)-induced seizures by measuring rats'behavior (severity and latency) and lipoperoxidation in different brain areas (cerebellum, brain hemispheres, cortex, and medulla), kidneys, and liver. Male Wistar rats were administered KA (10 mg/kg, i.p.) after three days of pretreatment with Tilia extract (100 mg/kg). The EAc and ME Tilia extracts significantly decreased the severity of phase 1 and phase 2 seizures, respectively. The ME Tilia extract increased the latency to seizure (27 ± 2 min) compared to the control (13 ± 2 min). The ME and EAc Tilia extracts significantly prevented the increased lipid peroxidation caused by KA-induced seizures in the cerebellum, brain hemispheres, cortex, medulla, liver, and kidneys. The vehicle olive oil (OO) also showed anticonvulsant effects, decreasing the severity of seizures to phase 3 and lipoperoxidation levels in the cerebellum, brain hemispheres, cortex, medulla, liver, and kidneys. The anticonvulsant activity of Tilia is mediated by antioxidant effects in central and systemic areas that involve synergistic interactions among the chemical constituents of these extracts (glucosides of quercetin and kaempferol), while vehicle OO showed the same effects, probably due to its constituent oleuropein.

Comparative Bioavailability and Pharmacokinetics Between the Solid Form of Metformin vs a Novel Liquid Extemporaneous Formulation in Children.

Metformin pharmacokinetics in a liquid extemporaneous formulation from commercial tablets was determined in paediatric patients. A randomized, transversal clinical trial was conducted in 34 children and adolescents between 7 and 17 years of age. 17 children were randomized to take metformin in the liquid formulation and, after a 1-week wash period, a 500 mg metformin tablet was administered to them. Blood samples were obtained in Whatman 903® cards at 0, 1, 2, 4, 8, 12 and 24 hours. Extraction was made by direct precipitation with acetonitrile (ACN) and methanol, detection by UPLC and tandem mass spectrometry. The method was accurate, precise, selective and linear from 50 to 1000 ng/mL (r = .9982). Comparative pharmacokinetics, tablet vs formulation, were as follows: Cmax 1503.2 ng/mL vs 1521.4, Tmax 1.5 h vs 2.3, and half-life 8.2 vs 7.5 h. The liquid formulation of metformin showed similar pharmacokinetics to the tablet, and the ratios (90% CI) of geometric mean for metformin were 100.63% (89.13-113.6), 98.08% (88.04-109.2), and 97.52% (84.9-112.01), for Cmax, AUC0-t, and AUC 0-∞, respectively. Pharmacokinetics was determined using WinNonlin Pro 3.1 software. The liquid formulation of metformin showed similar pharmacokinetics to the tablet, allowing a more precise dose adjustment and ease of administration.

In vitro inhibition of brain phosphate-activated glutaminase by ammonia and manganese.

INTRODUCTION: As a consequence of the loss of liver function in chronic liver disease, increased levels of ammonia, manganese, and glutamine have been observed in the brain of hepatic encephalopathy patients. OBJECTIVE: In the present study, we explored phosphate activated glutaminase (PAG) activity in mitochondrial enriched fractions under treatment with ammonia and manganese. METHODS: We dissected out the brain cortex, striatum, and cerebellum of male Wistar rats 250-280 g weight; brain sections were pooled to obtain enriched mitochondrial fractions by differential centrifugation. Aliquots equivalent to 200 µg of protein were incubated with semi-log increasing concentrations of ammonia and/or manganese both as chloride salts (from 0 to 10 000 µM) and glutamine (4 mM) for 30 min. Then, the glutamate produced by the reaction was determined by HPLC coupled with fluorescence detection. RESULTS AND DISCUSSION: Both manganese and ammonia inhibited PAG in a concentration-dependent manner. Non-linear modeling was used to determine IC50 and IC20 for ammonia (120 µM) and manganese (2 mM). We found that PAG activity under the combination of IC20 of ammonia and manganese was equivalent to the sum of the effects of both substances, being PAG inhibition more pronounced in mitochondrial fractions from cerebellum. The PAG inhibition observed here could potentially explain a pathway for glutamine accumulation, by means of the inhibition of PAG activity as a consequence of increased concentrations of manganese and ammonia in the brain under liver damage conditions.

Determination of blood dexmedetomidine in dried blood spots by LC-MS/MS to screen therapeutic levels in paediatric patients.

Dexmedetomidine is an imidazole derivative, with high affinity for α2 adrenergic receptors, used for sedation, analgesia and adjuvant anaesthesia. In this study, an analytical method for the quantification of dexmedetomidine in dried blood spots was developed, validated and applied. The drug was extracted from dried blood spot by liquid extraction; the separation was carried out by ultra high-resolution liquid chromatography in reverse phase coupled to tandem mass spectrometry method. An X Select cyano 5 µm HSS column (2.1 X 150 mm, Waters) and a mobile phase composed of 0.1% formic acid: acetonitrile [50:50 v/v], were used. The test was linear over the concentration range of 50 to 2000 pg/mL. The coefficients of variation for the intra and interday trials were less than 15%. The drug was stable under the conditions tested. The method was successfully applied for the quantification of 6 patients, aged 0 to 2 years, with classification ASA I, who underwent ambulatory surgeries, receiving a dose of 1 µg/Kg dexmedetomidine IV. The drug concentrations in the different sampling times were in the range of 76 to 868 pg/mL.

Dose-Dependent Behavioral and Antioxidant Effects of Quercetin and Methanolic and Acetonic Extracts from Heterotheca inuloides on Several Rat Tissues following Kainic Acid-Induced Status Epilepticus.

Kainic acid (KA) has been used to study the neurotoxicity induced after status epilepticus (SE) due to activation of excitatory amino acids with neuronal damage. Medicinal plants can protect against damage caused by KA-induced SE; in particular, organic extracts of Heterotheca inuloides and its metabolite quercetin display antioxidant activity and act as hepatoprotective agents. However, it is unknown whether these properties can protect against the hyperexcitability underlying the damage caused by KA-induced SE. Our aim was to study the protective effects (with regard to behavior and antioxidant activity) of administration of natural products methanolic (ME) and acetonic (AE) extracts and quercetin (Q) from H. inuloides at doses of 30 mg/kg (ME30, AE30, and Q30 groups), 100 mg/kg (ME100, AE100, and Q100 groups), and 300 mg/kg (ME300, AE300, and Q300 groups) against damage in brain regions of male Wistar rats treated with KA. We found dose-dependent effects on behavioral and biochemical studies in the all-natural product groups vs. the control group, with decreases in seizure severity (Racine's scale) and increases in seizure latency (p < 0.05 in the ME100, AE100, Q100, and Q300 groups and p < 0.01 in the AE300 and ME300 groups); on lipid peroxidation and carbonylated proteins in all brain tissues (p < 0.0001); and on GPx, GR, CAT, and SOD activities with all the treatments vs. KA (p ≤ 0.001). In addition, there were strong negative correlations between carbonyl levels and latency in the group treated with KA and in the group treated with methanolic extract in the presence of KA (r = -0.9919, p = 0.0084). This evidence suggests that organic extracts and quercetin from H. inuloides exert anticonvulsant effects via direct scavenging of reactive oxygen species (ROS) and modulation of antioxidant enzyme activity.

Population Pharmacokinetics and Pharmacodynamics of Dexmedetomidine in Children Undergoing Ambulatory Surgery.

BACKGROUND: Dexmedetomidine (DEX) is an α-2 adrenergic agonist with sedative and analgesic properties. Although not approved for pediatric use by the Food and Drug Administration, DEX is increasingly used in pediatric anesthesia and critical care. However, very limited information is available regarding the pharmacokinetics of DEX in children. The aim of this study was to investigate DEX pharmacokinetics and pharmacodynamics (PK-PD) in Mexican children 2-18 years of age who were undergoing outpatient surgical procedures. METHODS: Thirty children 2-18 years of age with American Society of Anesthesiologists physical status score of I/II were enrolled in this study. DEX (0.7 µg/kg) was administered as a single-dose intravenous infusion. Venous blood samples were collected, and plasma DEX concentrations were analyzed with a combination of high-performance liquid chromatography and electrospray ionization-tandem mass spectrometry. Population PK-PD models were constructed using the Monolix program. RESULTS: A 2-compartment model adequately described the concentration-time relationship. The parameters were standardized for a body weight of 70 kg by using an allometric model. Population parameters estimates were as follows: mean (between-subject variability): clearance (Cl) (L/h × 70 kg) = 20.8 (27%); central volume of distribution (V1) (L × 70 kg) = 21.9 (20%); peripheral volume of distribution (V2) (L × 70 kg) = 81.2 (21%); and intercompartmental clearance (Q) (L/h × 70 kg) = 75.8 (25%). The PK-PD model predicted a maximum mean arterial blood pressure reduction of 45% with an IC50 of 0.501 ng/ml, and a maximum heart rate reduction of 28.9% with an IC50 of 0.552 ng/ml. CONCLUSIONS: Our results suggest that in Mexican children 2-18 years of age with American Society of Anesthesiologists score of I/II, the DEX dose should be adjusted in accordance with lower DEX clearance.

Biochemical and molecular modulation of CCl4-induced peripheral and central damage by Tilia americana var. mexicanaextracts.

Around the world, species from the genus Tilia are commonly used because of their peripheral and central medicinal effects; they are prepared as teas and used as tranquilizing, anticonvulsant, and analgesic agents. In this study, we provide evidence of the protective effects of organic and aqueous extracts (100 mg/kg, i.p.) obtained from the leaves of Tilia americana var. mexicana on CCl4-induced liver and brain damage in the rat. Protection was observed in the liver and brain (cerebellum, cortex and cerebral hemispheres) by measuring the activity of antioxidant enzymes and levels of malondialdehyde (MDA) using spectrophotometric methods. Biochemical parameters were also assessed in serum samples from the CCl4-treated rats. The T. americana var. mexicana leaf extracts provided significant protection against CCl4-induced peripheral and central damage by increasing the activity of antioxidant enzymes, diminishing lipid peroxidation, and preventing alterations in biochemical serum parameters, such as the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-globulin (γ-GLOB), serum albumin (ALB), total bilirubin (BB), creatinine (CREA) and creatine kinase (CK), relative to the control group. Additionally, we correlated gene expression with antioxidant activity in the experimental groups treated with the organic and aqueous Tilia extracts and observed a non-statistically significant positive correlation. Our results provide evidence of the underlying biomedical properties of T. americana var. mexicana that confer its neuro- and hepatoprotective effects.

Intestinal permeability in a patient with liver cirrhosis.

Liver cirrhosis is a worldwide public health problem, and patients with this disease are at high risk of developing complications, bacterial translocation from the intestinal lumen to the mesenteric nodes, and systemic circulation, resulting in the development of severe complications related to high mortality rate. The intestinal barrier is a structure with a physical and biochemical activity to maintain balance between the external environment, including bacteria and their products, and the internal environment. Patients with liver cirrhosis develop a series of alterations in different components of the intestinal barrier directly associated with the severity of liver disease that finally increased intestinal permeability. A "leaky gut" is an effect produced by damaged intestinal barrier; alterations in the function of tight junction proteins are related to bacterial translocation and their products. Instead, increasing serum proinflammatory cytokines and hemodynamics modification, which results in the appearance of complications of liver cirrhosis such as hepatic encephalopathy, variceal hemorrhage, bacterial spontaneous peritonitis, and hepatorenal syndrome. The intestinal microbiota plays a fundamental role in maintaining the proper function of the intestinal barrier; bacterial overgrowth and dysbiosis are two phenomena often present in people with liver cirrhosis favoring bacterial translocation. Increased intestinal permeability has an important role in the genesis of these complications, and treating it could be the base for prevention and partial treatment of these complications.

Enzyme activities involved in the glutamate-glutamine cycle are altered to reduce glutamate after spinal cord injury in rats.

Glutamate (Glu) neurotransmitter is involved in the excitotoxic damage after spinal cord injury (SCI). Glu is transformed into glutamine (Gln) by glutamine synthetase (GS) enzyme in glial cells. Once into the neurons, Gln is transformed back into Glu by phosphate-activated glutaminase (PAG). Glu is also a precursor for the synthesis of γ-aminobutyric acid through the action of the glutamic acid decarboxylase (GAD) enzyme. The contribution of all these Glu biotransformations after SCI has not been determined. The aim of this work is to characterize the role of GS, PAG, and GAD in the acute phase after SCI. Female Wistar rats were subjected to SCI by contusion and killed 2, 4, 8, and 12 h after surgery. Sham-injury animals, killed at the same time points served as controls. PAG and GAD activities were analyzed by high-performance liquid chromatography, whereas GS activity was determined by ultraviolet-visible spectroscopy. GS activity showed a significant decrease in animals with SCI at all time points evaluated versus the sham group. Similarly, the activity of the PAG was decreased at all time points compared with the control group. Finally, GAD activity was significantly increased in the SCI group when measured at 2, 4, and 8 h after lesion. The results of this study suggest that excitotoxicity is highly regulated through Glu/Gln and Glu/γ-aminobutyric acid cycles as an important mechanism to prevent further damage in the acute phase after lesion.

A New Method to Quantify Ifosfamide Blood Levels Using Dried Blood Spots and UPLC-MS/MS in Paediatric Patients with Embryonic Solid Tumours.

Ifosfamide blood concentrations are necessary to monitor its therapeutic response, avoiding any adverse effect. We developed and validated an analytical method by UPLC-MS/MS to quantify ifosfamide in dried blood spots (DBS). Blood samples were collected on Whatman 903® filter paper cards. Five 3 mm disks were punched out from each dried blood spot. Acetonitrile and ethyl acetate were used for drug extraction. Chromatographic separation was carried out in an Acquity UPLC equipment with a BEH-C18 column, 2.1 x 100 mm, 1.7 µm (Waters®). The mobile phase consisted in 5 mM ammonium formate and methanol:acetonitrile (40:48:12 v/v/v) at 0.2 mL/min. LC-MS/MS detection was done by ESI+ and multiple reaction mode monitoring, ionic transitions were m/z1+ 260.99 > 91.63 for ifosfamide and 261.00 > 139.90 for cyclophosphamide (internal standard). This method was linear within a 100-10000 ng/mL range and it was accurate, precise and selective. Ifosfamide samples in DBS were stable for up to 52 days at -80°C. The procedure was tested in 14 patients, ages 1 month to 17 years (9 males and 5 females), with embryonic tumours treated with ifosfamide, alone or combined, at a public tertiary referral hospital. Ifosfamide blood levels ranged from 11.1 to 39.7 µmol/L at 12 hours after the last infusion, while 24-hour levels ranged from 0.7-19.7 µmol/L. The median at 12 hours was 19.5 µmol/L (Q25 14.4-Q75 29.0) and 3.8 µmol/L (Q25 1.5-Q75 9.9) at 24 hours, p<0.001. This method is feasible to determine ifosfamide plasma levels in paediatric patients.

Overview of Nrf2 as Therapeutic Target in Epilepsy.

Oxidative stress is a biochemical state of imbalance in the production of reactive oxygen and nitrogen species and antioxidant defenses. It is involved in the physiopathology of degenerative and chronic neuronal disorders, such as epilepsy. Experimental evidence in humans and animals support the involvement of oxidative stress before and after seizures. In the past few years, research has increasingly focused on the molecular pathways of this process, such as that involving transcription factor nuclear factor E2-related factor 2 (Nrf2), which plays a central role in the regulation of antioxidant response elements (ARE) and modulates cellular redox status. The aim of this review is to present experimental evidence on the role of Nrf2 in this neurological disorder and to further determine the therapeutic impact of Nrf2 in epilepsy.

Extemporaneous Formulations of Metformin for Pediatric Endocrinology: Physicochemical Integrity, Cytotoxicity of Sweeteners, and Quantitation of Plasma Levels.

PURPOSE: In response to the lack of pediatric formulations of metformin to control type 2 diabetes mellitus, hyperinsulinemic obesity, and dyslipidemias, we developed liquid formulations of metformin by dissolving 3 generic brands of 500-mg metformin(*,)(†,)(‡) tablets in water sweetened with sucralose. The physicochemical stabilities of these drugs were assessed and compared with those of formulations made with the innovative brand of metformin.(∥) A method to measure metformin plasma levels was proposed and then tested in 2 healthy subjects. This method may be useful to survey treatment compliance in the future. The biological safety profiles of the metformin solutions were assessed preliminarily in a system of hormone-dependent cancer cells (human breast cancer MCF-7 cells). METHODS: Metformin solutions stored at 25°C exposed to light and at 25°C, 4°C, and 40°C protected from light, underwent physicochemical analysis by ultra-performance liquid chromatography with ultraviolet detection, the mobile phase consisting of 0.2 M potassium monobasic phosphate (pH 6.5), 4.6 mM sodium dodecyl sulphate (SDS), and acetonitrile (63:7:30) at a flow rate of 0.8 mL/min in a Symmetry C8 150 × 4.6 mm column (Milford, Massachusetts) at 40°C (236 nm). MCF-7 cells were grown in 96-well ELISA plates (2 × 10(5) cells/well) and were exposed to 10, 20, and 40 mg/mL sucralose(§), Stevia rebaudiana (Svetia; Metco, S.A. de C.V., México, D.F., Mexico), and metformin (50 mg/mL) for 48 hours. Cytotoxicity was determined using the WST-1 colorimetric assay (Roche, USA) in an Epoch ELISA reader (BioTek, Winooski, Vermont) at 440 nm. FINDINGS: All brands of metformin were stable at all storage conditions for up to 30 days and retained >90% of the initial amount. Sucralose and Stevia rebaudiana caused zero cytotoxicity (ANOVA, P ≤ 0.05). The ultra-performance liquid chromatography with ultraviolet detection method was adapted to determine metformin level in very small blood samples (40 µL), which was linear within the range of 20 to 600 ng/mL metformin (retention time 2 minutes). Metformin was physically and chemically stable within the processed blood for up to 30 days at 4°C. IMPLICATIONS: Extemporaneous formulations of metformin may be developed at low cost from either the innovator or generic brands, and both sucralose and Stevia rebaudiana sweeteners may be well tolerated; however, the minimum amount of sweetener is recommended to avoid any endocrine disturbance. The analytical method is accurate and precise to clinically measure metformin levels in patients taking the extemporaneous formulation orally. Study registry identification number: 100/2013.

Relevance of the glutathione system in temporal lobe epilepsy: evidence in human and experimental models.

Oxidative stress, which is a state of imbalance in the production of reactive oxygen species and nitrogen, is induced by a wide variety of factors. This biochemical state is associated with diseases that are systemic as well as diseases that affect the central nervous system. Epilepsy is a chronic neurological disorder, and temporal lobe epilepsy represents an estimated 40% of all epilepsy cases. Currently, evidence from human and experimental models supports the involvement of oxidative stress during seizures and in the epileptogenesis process. Hence, the aim of this review was to provide information that facilitates the processing of this evidence and investigate the therapeutic impact of the biochemical status for this specific pathology.

Development of a UPLC-MS/MS method for the quantification of sildenafil by DBS, and its use on pediatric pulmonary hypertension.

BACKGROUND: Sildenafil is used for the treatment of pediatric pulmonary hypertension. A dried blood spot (DBS)-based LC-MS method for sildenafil quantitation was developed and applied to a group of patients. RESULTS: DBS showed high portability and stability of samples, and the method was selective and linear for quantitation of sildenafil (5-3,000 ng/ml) and N-desmethyl-sildenafil (3-1,500 ng/ml). After a single oral dose of sildenafil (1 mg/kg), method evidenced poor metabolism in these patients. CONCLUSION: The method was successfully applied in peripheral blood and can be used for both pharmacokinetics and therapeutic drug monitoring. DBS proved to have advantages during sample translation and preservation of analytes. Data suggest that hazardous blood sildenafil levels may be reached in this population.

Contributions of microdialysis to new alternative therapeutics for hepatic encephalopathy.

Hepatic encephalopathy (HE) is a common complication of cirrhosis, of largely reversible impairment of brain function occurring in patients with acute or chronic liver failure or when the liver is bypassed by portosystemic shunts. The mechanisms causing this brain dysfunction are still largely unclear. The need to avoid complications caused by late diagnosis has attracted interest to understand the mechanisms underlying neuronal damage in order to find markers that will allow timely diagnosis and to propose new therapeutic alternatives to improve the care of patients. One of the experimental approaches to study HE is microdialysis; this technique allows evaluation of different chemical substances in several organs through the recollection of samples in specific places by semi-permeable membranes. In this review we will discuss the contributions of microdialysis in the understanding of the physiological alterations in human hepatic encephalopathy and experimental models and the studies to find novel alternative therapies for this disease.

Role of oxidative stress in refractory epilepsy: evidence in patients and experimental models.

Oxidative stress, a state of imbalance in the production of reactive oxygen species and nitrogen, is induced by a wide variety of factors. This biochemical state is associated with systemic diseases, and diseases affecting the central nervous system. Epilepsy is a chronic neurological disorder with refractoriness to drug therapy at about 30%. Currently, experimental evidence supports the involvement of oxidative stress in seizures, in the process of their generation, and in the mechanisms associated with refractoriness to drug therapy. Hence, the aim of this review is to present information in order to facilitate the handling of this evidence and determine the therapeutic impact of the biochemical status for this pathology.

Modulation of antioxidant enzymatic activities by certain antiepileptic drugs (valproic acid, oxcarbazepine, and topiramate): evidence in humans and experimental models.

It is estimated that at least 100 million people worldwide will suffer from epilepsy at some point in their lives. This neurological disorder induces brain death due to the excessive liberation of glutamate, which activates the postsynaptic N-methyl-D-aspartic acid (NMDA) receptors, which in turn cause the reuptake of intracellular calcium (excitotoxicity). This excitotoxicity elicits a series of events leading to nitric oxide synthase (NOS) activation and the generation of reactive oxygen species (ROS). Several studies in experimental models and in humans have demonstrated that certain antiepileptic drugs (AEDs) exhibit antioxidant effects by modulating the activity of various enzymes associated with this type of stress. Considering the above-mentioned data, we aimed to compile evidence elucidating how AEDs such as valproic acid (VPA), oxcarbazepine (OXC), and topiramate (TPM) modulate oxidative stress.

Protective effect of N,N'-dialkylated analogs of 4,4'-diaminodiphenylsulfone in a model of intrastriatal quinolinic acid induced-excitotoxicity.

The bacteriostatic agent 4,4'-diaminodiphenylsulfone or dapsone (DDS) and some of its N,N'-dialkylated analogs have shown anticonvulsant and neuroprotective properties in different experimental models. In this study, we tested the ability of five DDS analogs (N,N'-dimethyldapsone, N,N'-diethyldapsone, N,N'-dipropyldapsone, N,N'-dibutyldapsone and N,N'-ditosyldapsone) to attenuate quinolinic acid-induced toxicity in vivo. Male Wistar rats were treated with either DDS or analogs (12.5mg/kg and equimolar doses respectively) 30 min before quinolinic acid intrastriatal stereotaxic injection (240 nmol/µl). Six days after injury, circling behavior was evaluated by counting ipsilateral turns for 1h after apomorphine challenge (1mg/kg, sc). Twenty-four hours later, rats were sacrificed and their corpora striata were dissected out to determine GABA content. Hemotoxicity of the analogs was assessed as the ability to produce methemoglobin (MHb) in vivo. Blood was sampled from tail vein within 18 h after drugs administration. Methemoglobin levels were determined by visible spectrophotometry and mean profiles of MHb-percentage versus time were obtained. All of the analogs tested decreased the number of ipsilateral turns/hour, reducing up to 67% the turns counting (p<0.05) when compared to those induced in animals receiving quinolinic acid with no treatment. N,N'-dimethylated, N,N'-diethylated and N,N'-dibutylated analogs significantly prevented the decrease of intrastriatal GABA content (p<0.05). Methemoglobin produced by the administration of analogs was significantly lower than the levels of the group receiving dapsone (p<0.05). The neuroprotective effect of analogs and their diminished hemotoxicity make them potential candidates for therapeutic applications.