Alteraciones del comportamiento como contenido en la formación de estudiantes para la orientación a las familias

La formación de estudiantes para la prevención de las alteraciones del comportamiento en los niños de la primera infancia, es imprescindible porque contribuye a elevar la calidad de la atención educativa de salud y educación en ambas modalidades de atención educativa de la primera infancia. El artículo que se presenta tiene como objetivo exponer acciones dirigidas a los estudiantes en formación que los prepara para la orientación de las familias, en función de la prevención de las alteraciones del comportamientoen niños de infancia preescolar. Las acciones se aplicaron durante el periodo del 2019 al 2022 como parte de la preparación para la práctica laboral, lo que posibilitó que se elevara la calidad de la orientación familiar en función de la prevención de las alteraciones del comportamiento en los niños de infancia preescolar, en ambas modalidades de atención educativa.

The training of students for the prevention of behavioral disorders in early childhood children is essential because it contributes to raising the quality of educational health care and education in both modalities of early childhood educational care. The article that is presented aims to expose actions aimed at students in training that prepare them for the orientation of families, based on the prevention of behavioral disorders in preschool children. The actions were applied during the period from 2019 to 2022 as part of the preparation for labor practice, which made it possible to raise the quality of family guidance based on the prevention of behavioral disorders in preschool children, in both modalities of educational attention.

Development and Pharmacokinetic Evaluation of Two Parenteral Formulations of Albendazole Using Prodrug and Cosolvent Approaches.

Albendazole is a broad-spectrum anthelmintic drug used for parasitic infections. In addition, due to its mechanism of action, it has been studied as an anticancer agent. However, poor and highly variable bioavailability are limiting factors for its use in systemic illnesses. The present study aimed to develop two parenteral formulations of albendazole and to compare its pharmacokinetic profile with the conventional oral administration. Parenteral formulations were developed using two different approaches: a phosphonooxymethylated prodrug and cosolvents. For the albendazole prodrug, once synthetized, its solubility and hydrolysis with alkaline phosphatase were evaluated. A factorial design of experiments was used for the cosolvent formulation. Stability and hemolytic activity were assessed. A pharmacokinetic study was performed on New Zealand rabbits. Both formulations were administered intravenously, and the prodrug was also administered intramuscularly. Results were compared with those obtained after the oral administration of albendazole. A 20,000-fold and 6000-fold increase in albendazole solubility was found with the prodrug and cosolvent formulations, respectively. Both parenteral formulations displayed higher albendazole plasma concentrations for the first 2 h compared with oral administration, even when the oral dose was doubled. The absolute bioavailability of oral albendazole was 15.5% while for the intramuscular administration of the prodrug was 102.6%. Both parenteral formulations showed a significant decrease in the formation of albendazole sulfoxide (ANOVA p<0.05) and allowed greater exposure to albendazole. Albendazole cosolvent parenteral formulation could be a promising option in systemic illnesses considering its ease of preparation and superb pharmacokinetic performance.

Analysis of the effect of in vitro dissolution on the pharmacokinetics of albendazole

Abstract Albendazole is an anthelmintic drug commonly used in parenchymal neurocysticercosis and cystic echinococcosis. The aim of this study was to explore whether disparities in the dissolution profiles of albendazole products lead to significant differences in pharmacokinetic parameters. Three generic products and the innovator were evaluated in vitro. Quality control tests were performed, and dissolution profiles were obtained according to the Mexican Pharmacopeia. Although all products passed the quality control tests, none of the generic products complied with the similarity factor (f 2). The product with the lowest f 2 value in respect to the reference was chosen for in vivo evaluation. The study was carried out in 12 healthy volunteers who received 400 mg of the generic or reference product according to a crossover design. No significant differences were found in Cmax and AUC for albendazole and its main metabolite, albendazole sulfoxide, between products. Two absorption peaks were observed in the pharmacokinetic profile, and a population (22%) with different absorption rates and delay time for the the second peak was found. Based on the results, due to the high variability in the absorption process the differences observed in vitro could not be observed in vivo.

Giardia duodenalis: Flavohemoglobin is involved in drug biotransformation and resistance to albendazole.

Giardia duodenalis causes giardiasis, a major diarrheal disease in humans worldwide whose treatment relies mainly on metronidazole (MTZ) and albendazole (ABZ). The emergence of ABZ resistance in this parasite has prompted studies to elucidate the molecular mechanisms underlying this phenomenon. G. duodenalis trophozoites convert ABZ into its sulfoxide (ABZSO) and sulfone (ABZSOO) forms, despite lacking canonical enzymes involved in these processes, such as cytochrome P450s (CYP450s) and flavin-containing monooxygenases (FMOs). This study aims to identify the enzyme responsible for ABZ metabolism and its role in ABZ resistance in G. duodenalis. We first determined that the iron-containing cofactor heme induces higher mRNA expression levels of flavohemoglobin (gFlHb) in Giardia trophozoites. Molecular docking analyses predict favorable interactions of gFlHb with ABZ, ABZSO and ABZSOO. Spectral analyses of recombinant gFlHb in the presence of ABZ, ABZSO and ABZSOO showed high affinities for each of these compounds with Kd values of 22.7, 19.1 and 23.8 nM respectively. ABZ and ABZSO enhanced gFlHb NADH oxidase activity (turnover number 14.5 min-1), whereas LC-MS/MS analyses of the reaction products showed that gFlHb slowly oxygenates ABZ into ABZSO at a much lower rate (turnover number 0.01 min-1). Further spectroscopic analyses showed that ABZ is indirectly oxidized to ABZSO by superoxide generated from the NADH oxidase activity of gFlHb. In a similar manner, the superoxide-generating enzyme xanthine oxidase was able to produce ABZSO in the presence of xanthine and ABZ. Interestingly, we find that gFlHb mRNA expression is lower in albendazole-resistant clones compared to those that are sensitive to this drug. Furthermore, all albendazole-resistant clones transfected to overexpress gFlHb displayed higher susceptibility to the drug than the parent clones. Collectively these findings indicate a role for gFlHb in ABZ conversion to its sulfoxide and that gFlHb down-regulation acts as a passive pharmacokinetic mechanism of resistance in this parasite.

ß-cyclodextrin dendritic derivatives as permeation mediators to enhance the in vitro albendazole cysticidal activity by the improvement of the diffusion component.

The improvement of permeation of drugs across parasites' membranes to promote their diffusion component represents a challenge to achieve better therapeutic effects, including the avoidance of drug resistance. In the context of medicinal chemistry, suitable structural modifications can be made, either on a drug or a nanocarrier, to trigger different mechanisms that promote the influx across membranes. This study aimed to demonstrate the potential of a set of dendritic derivatives of ß-cyclodextrin (m2G, h2G, and m3G) as nanocarriers, based on their physicochemical and biological behavior in terms of (i) stability, monitored by 1H NMR at pH 7 for seven days, (ii) ability to complex, and subsequently release around 50-80% of the cargo molecule (albendazole) in a biphasic medium and (iii) the absence of in vitro cysticidal effect in cysticercus cultures. The albendazole/nanocarrier inclusion complexes (ICs) were proved in the T. crassiceps model. According to the EC50 values related to the cysticidal activity of albendazole, either free or complexed, the potency of this drug in the ICs experienced a significant increase, which may be attributed to the enhancement of its solubility but also to a better permeation mediated by the amphiphilic dendritic moieties, which ultimately positively impacts the diffusion of this drug through the tegument of the cysticerci. Additional considerations akin to synthetic ease of the dendritic nanocarriers, and production cost, along with the obtained outcomes, allowed us to place m2G followed by m3G as the best options to be considered for further in vivo assays.

Leading causes of excess mortality in Mexico during the COVID-19 pandemic 2020-2021: A death certificates study in a middle-income country.

Background: The death toll after SARS-CoV-2 emergence includes deaths directly or indirectly associated with COVID-19. Mexico reported 325,415 excess deaths, 34.4% of them not directly related to COVID-19 in 2020. In this work, we aimed to analyse temporal changes in the distribution of the leading causes of mortality produced by COVID-19 pandemic in Mexico to understand excess mortality not directly related to the virus infection. Methods: We did a longitudinal retrospective study of the leading causes of mortality and their variation with respect to cause-specific expected deaths in Mexico from January 2020 through December 2021 using death certificate information. We fitted a Poisson regression model to predict cause-specific mortality during the pandemic period, based on the 2015-2019 registered mortality. We estimated excess deaths as a weekly difference between expected and observed deaths and added up for the entire period. We expressed all-cause and cause-specific excess mortality as a percentage change with respect to predicted deaths by our model. Findings: COVID-19 was the leading cause of death in 2020-2021 (439,582 deaths). All-cause total excess mortality was 600,590 deaths (38⋅2% [95% CI: 36·0 to 40·4] over expected). The largest increases in cause-specific mortality, occurred in diabetes (36·8% over expected), respiratory infections (33·3%), ischaemic heart diseases (32·5%) and hypertensive diseases (25·0%). The cause-groups that experienced significant decreases with respect to the expected pre-pandemic mortality were infectious and parasitic diseases (-20·8%), skin diseases (-17·5%), non-traffic related accidents (-16·7%) and malignant neoplasm (-5·3%). Interpretation: Mortality from COVID-19 became the first cause of death in 2020-2021, the increase in other causes of death may be explained by changes in the health service utilization patterns caused by hospital conversion or fear of the population using them. Cause-misclassification cannot be ruled out. Funding: This study was funded by Conacyt.

Estimación del exceso de mortalidad por todas las causas durante la pandemia del Covid-19 en México.

 Objetivo. Estimar el exceso de defunciones por todas las causas en México durante 2020. Material y métodos. Se construyó un canal endémico con las defunciones (2015- 2019), estableciendo el umbral epidémico en el percentil 90, y se comparó con las actas de defunción para estimar el exceso de mortalidad. Resultados. A la semana 53, ocurrieron 326 612 defunciones en exceso (45.1%), con un máximo en la semana 28 (98.0%) y un mínimo en la semana 41 (35.2%); después de la semana 4 los hombres (51.3%), principalmente de 45-64 años de edad, sin embargo, en los de 60 años o más ocurrió el mayor nú-mero de defunciones. Conclusión. En México, el exceso de mortalidad ha sido prolongado en comparación con otros países, con alta variabilidad interestatal. Esto podría deberse a las condiciones socioeconómicas y a la alta prevalencia de comorbilidades que aumentan el riesgo de morir en la población mexicana.

Estimación del exceso de mortalidad por todas las causas durante la pandemia del Covid-19 en México / All-cause excess mortality during the Covid-19 pandemic in Mexico

Resumen: Objetivo: Estimar el exceso de defunciones por todas las causas en México durante 2020. Material y métodos: Se construyó un canal endémico con las defunciones (2015-2019), estableciendo el umbral epidémico en el percentil 90, y se comparó con las actas de defunción para estimar el exceso de mortalidad. Resultados: A la semana 53, ocurrieron 326 612 defunciones en exceso (45.1%), con un máximo en la semana 28 (98.0%) y un mínimo en la semana 41 (35.2%); después de la semana 42, la tendencia vuelve a ser ascendente por el resto del año. Esto fue proporcionalmente mayor en los hombres (51.3%), principalmente de 45-64 años de edad, sin embargo, en los de 60 años o más ocurrió el mayor número de defunciones. Conclusión: En México, el exceso de mortalidad ha sido prolongado en comparación con otros países, con alta variabilidad interestatal. Esto podría deberse a las condiciones socioeconómicas y a la alta prevalencia de comorbilidades que aumentan el riesgo de morir en la población mexicana.

Abstract: Objective: To estimate excess mortality from all causes in Mexico in 2020. Materials and methods: We constructed an endemic channel with deaths (2015-2018) establishing the epidemic threshold at the 90th percentile, comparing with death certificates counts to estimate excess mortality. Results: At week 53, there were 326 612 excess deaths (45.1%), with a maximum in week 28 (98.0%) and a minimum at week 41 (35.2%); after week 42, the increasing trend remained for the rest of the year. It was proportionally higher in men, mainly aged 45-64 years, however, in those aged 60 and over, the highest number of deaths occurred. Conclusion: In Mexico, excess mortality has been prolonged compared to other countries, with high interstate variability. This could be explained by socioeconomic conditions and the high prevalence of comorbidities in the Mexican population.

Adherence to self-administering interferon-ß1a using RebiSmart® device in Mexican patients with relapsing multiple sclerosis.

BACKGROUND: Adherence to disease-modifying therapies is determinant to attain maximal clinical benefit in multiple sclerosis (MS). RebiSmart® is an electronic auto-injector for subcutaneous delivery of interferon ß-1a (INF-ß1a) that monitors adherence by featuring a log of each drug administration for objective evaluation. The aim of this study was to assess long-term adherence to INF-ß1a by using the RebiSmart® device in Mexican patients with relapsing MS. METHODS: This is an observational multicenter study on patients with relapsing MS treated with INF-ß1a subcutaneously delivered by the RebiSmart® device. Adherence was computed as the number of injections received during the study period divided by the number of injections scheduled and expressed as percent. RESULTS: A total of 66 patients from 6 specialized MS centers were evaluated (45 females and 21 males, mean age 43.91±13.32 years). Mean adherence was 79.51±18% (median: 85.54%, range: 34.4-100%). During a median follow-up of 27.5 months (mean 33.36±29.39 months) the annualized relapse rate had a mean of 0.50±1.63. Mean initial EDSS was 1.90±1.52, and mean EDSS at the end of follow-up was 1.80±1.74. Compared with their counterparts, the mean number of relapses was significantly lower among patients with high (>80%) adherence (0.25±0.44 vs 0.67±92 relapses, respectively; P = 0.03). The proportion of relapse-free patients was 75.0% among patients with high adherence and 53.3% in low-compliant patients (P = 0.06). High adherence patients presented lower rates of EDSS worsening ≥1.0 at the end of treatment, as compared with low-compliant patients (11.1% vs 43.3%, respectively; P = 0.003). High schooling (>12 years) was the only predictor of a high adherence (OR: 2.97, 05% CI: 1.08-1.18; P = 0.03) and of being relapse-free during follow-up (OR: 3.22, 05% CI: 1.12-9.23; P = 0.03). CONCLUSION: Adherence to INF-ß1a using RebiSmart® in this Mexican cohort with MS was moderate, but associated with low relapse rate and influenced by high schooling.

Evaluation of New Benzimidazole Derivatives as Cysticidal Agents: In Vitro, in Vivo and Docking Studies.

Based on our previous research on cysticidal drugs, we report the synthesis and evaluation of three new benzimidazole derivatives. In these compounds, the amido group was used as a bioisosteric replacement of the ester group. The molecular docking on ß-tubulin revealed that the derivatives interacted through hydrogen bonding with N165, E198 and V236. All compounds showed in vitro activity against Taenia crassiceps cysts. Among them, benzimidazole 3 was found to be the most potent of the series (EC50 0.86 µM). This compound also exhibited the highest probability of binding and the lowest binding free energy score and was therefore selected for in vivo evaluation. Results indicated that the efficacy of compound 3 was comparable to that of the reference drug, albendazole (50.39 vs. 47.16% parasite reduction). Animals treated with compound 3 seemed to tolerate this benzimidazole well, with no changes in behavior, or food and water consumption. These findings are consistent with the in silico prediction results, which indicated low toxicity risks. The pharmacokinetic study showed that the half-life and mean residence time (6.06 and 11.9 h, respectively) were long after oral administration. Together, these results indicate that this new benzimidazole derivative represents a promising structure with cysticidal activity.

α-Synuclein Expression Is Preserved in Substantia Nigra GABAergic Fibers of Young and Aged Neurotoxin-Treated Rhesus Monkeys.

α-Synuclein (α-syn) is a small presynaptic protein distributed ubiquitously in the central and peripheral nervous system. In normal conditions, α-syn is found in soluble form, while in Parkinson's disease (PD) it may phosphorylate, aggregate, and combine with other proteins to form Lewy bodies. The purpose of this study was to evaluate, in nonhuman primates, whether α-syn expression is affected by age and neurotoxin challenge. Young adult (n = 5, 5-10 years old) and aged (n = 4, 23-25 years old) rhesus monkeys received a single unilateral carotid artery injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Three months post-MPTP the animals were necropsied by transcardiac perfusion, and their brains extracted and processed with immunohistochemical methods. Quantification of tyrosine hydroxylase (TH)-positive substantia nigra (SN) neurons showed a significant 80-89% decrease in the side ipsilateral to MPTP administration in young and old animals. Optical density of TH- immunoreactivity (-ir) in the caudate and putamen presented a 60-70% loss compared with the contralateral side. α-Syn-ir was present in both ipsi- and contra- lateral MPTP-treated nigra, caudate, and putamen, mostly in fibers; its intracellular distribution was not affected by age. Comparison of α-syn-ir between MPTP-treated young and aged monkeys revealed significantly higher optical density for both the ipsi- and contralateral caudate and SN in the aged animals. TH and α-syn immunofluorescence confirmed the loss of nigral TH-ir dopaminergic neurons in the MPTP-treated side of intoxicated animals, but bilateral α-syn expression. Colabeling of GAD67 and α-syn immunofluorescence showed that α-syn expression was present mainly in GABAergic fibers. Our results demonstrate that, 3 months post unilateral intracarotid artery infusion of MPTP, α-syn expression in the SN is largely present in GABAergic fibers, regardless of age. Bilateral increase of α-syn expression in SN fibers of aged, compared with young rhesus monkeys, suggests that α-syn-ir may increase with age, but not after neurotoxin-induced dopaminergic nigral cell loss.

Factors Associated With Cysticidal Treatment Response in Extraparenchymal Neurocysticercosis.

Extraparenchymal neurocysticercosis is the most severe form of cysticercosis, and response to treatment is suboptimal. We sought to determine how demographic and clinical characteristics and albendazole sulfoxide concentrations were related to cysticidal treatment response. We conducted a longitudinal study of 31 participants with extraparenchymal vesicular parasites who received the same treatment, albendazole 30 mg/kg/day for 10 days with dexamethasone 0.4 mg/kg/day for 13 days, followed by a prednisone taper. Response to treatment was determined by parasite volumes before and 6 months after treatment. Eight participants (25.8%) had a complete treatment response, 16 (51.6%) had a treatment response > 50% but < 100%, and 7 (22.6%) had a treatment response < 50%. Complete treatment response was significantly associated with higher concentrations of albendazole sulfoxide (P = .032), younger age (P = .032), fewer cysts (P = .049) and lower pretreatment parasite volume (P = .037). Higher number of previous cysticidal treatment courses was associated with a noncomplete treatment response (P = .023). Although the large proportion of participants with less than a complete response emphasizes the need to develop more efficacious pharmacologic regimens, the association of albendazole sulfoxide concentrations with treatment response highlights the importance of optimizing existing therapeutic regimens. In addition, the association of treatment response with parasite volume emphasizes the importance of early diagnosis.

Mycobacterium "habana" TMC 5135 as a vaccine candidate against tuberculosis: In vitro studies.

Background: Tuberculosis (TB) is one of the biggest problems of global health, at present. Bacillus-Calmette-Guérin is the only vaccine available against this disease. It protects only against the severe forms of TB in the childhood, which is a challenge in the search of new vaccine candidates. Taking into account the protective history of Mycobacterium "habana" against experimental TB, we proposed to provide the elements that support the use of M. "habana" TMC 5135 as a vaccine candidate against TB by infection studies in murine macrophages cell cultures. Methods: The production of microbicidal compounds dependent on oxygen metabolism as nitric oxide and hydrogen peroxide by murine peritoneal macrophages was detected. The invasive and toxigenic capacity of M. "habana" to infect this cell type was also evaluated through the quantification of intracellular alive bacillus and 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay, respectively. Results: The results suggest that M. "habana" TMC 5135 is able to persist into peritoneal macrophages, to resist the effectors mechanisms of respiratory burst, and to keep the viability of the target cell. The demonstration of these effector mechanisms and the survival capacity of M. "habana" in this niche are relevant aspects of this research assuring the continuity of this candidate to next phases of preclinical development. Conclusion: The present investigation contributes to the characterization of the infection by this mycobacteria in its main target cells of innate immunity and it suggest future investigations to evaluate the activation of effector mechanisms of the innate immunity against this candidate.

Diferencias en la fagocitosis de Mycobacterium habana TMC 5135 en cultivos celulares de macrófagos murinos / Differences in phagocytosis of Mycobacterium ´habana´ TMC 5135 by murine macrophages cellular cultures

La tuberculosis es uno de los mayores problemas que enfrenta la salud mundial en la actualidad. La única vacuna disponible contra esta enfermedad es la BCG, esta protege solo contra la tuberculosis grave de la infancia, lo cual plantea un reto en la búsqueda de nuevos candidatos vacunales. Teniendo en cuenta el antecedente protector de Mycobacterium ´habana´ contra la tuberculosis experimental, nos propusimos aportar elementos que avalen el empleo de M. ´habana´ TMC 5135 como candidato vacunal contra la tuberculosis, mediante estudios de infección en cultivos celulares de macrófagos murinos. Se caracterizó el proceso de fagocitosis de esta micobacteria por cultivos primarios de macrófagos peritoneales murinos y por la línea celular RAW 264.7, para lo cual se determinó el porcentaje de fagocitosis y el número fagocítico. El presente trabajo demostró que el proceso de fagocitosis de M. ´habana´ TMC 5135 está influenciado por la fuente celular empleada como célula hospedadora, así como por la carga bacteriana infectante y el tiempo de exposición a la misma. La presente investigación contribuye a la caracterización de la infección por esta micobacteria en sus principales células blanco de la inmunidad innata y traza el camino de futuras investigaciones para evaluar la activación de mecanismos efectores de la inmunidad innata frente a este candidato(AU)

Tuberculosis remains as a major problem in the global health. BCG is the available vaccine against tuberculosis but only protects against severe form of disease during childhood, so the search for new vaccine candidates is a challenge. Taking into account the protective capacity of Mycobacterium ´habana´ against experimental tuberculosis, we proposed in vitro experiments using murine macrophages (peritoneal macrophages and cell line Raw 264.7) to characterize phagocytic process of this candidate. Phagocitic index and phagocytic number were calculated. The present work demonstrated that the phagocytosis process of M. ‘habana’ TMC 5135 is influenced by the cellular source used as host cell, as well as by the infecting bacterial load and the time of exposure. The present investigation contributes to the characterization of the infection by this mycobacteria in its main target cells of innate immunity and it suggest future investigations to evaluate the activation of effector mechanisms of the innate immunity against this candidate(AU)

Diferencias en la fagocitosis de Mycobacterium habana TMC 5135 en cultivos celulares de macrófagos murinos / Differences in phagocytosis of Mycobacterium ´habana´ TMC 5135 by murine macrophages cellular cultures

La tuberculosis es uno de los mayores problemas que enfrenta la salud mundial en la actualidad. La única vacuna disponible contra esta enfermedad es la BCG, esta protege solo contra la tuberculosis grave de la infancia, lo cual plantea un reto en la búsqueda de nuevos candidatos vacunales. Teniendo en cuenta el antecedente protector de Mycobacterium habana contra la tuberculosis experimental, nos propusimos aportar elementos que avalen el empleo de M. habana TMC 5135 como candidato vacunal contra la tuberculosis, mediante estudios de infección en cultivos celulares de macrófagos murinos. Se caracterizó el proceso de fagocitosis de esta micobacteria por cultivos primarios de macrófagos peritoneales murinos y por la línea celular RAW 264.7, para lo cual se determinó el porcentaje de fagocitosis y el número fagocítico. El presente trabajo demostró que el proceso de fagocitosis de M. habana TMC 5135 está influenciado por la fuente celular empleada como célula hospedadora, así como por la carga bacteriana infectante y el tiempo de exposición a la misma. La presente investigación contribuye a la caracterización de la infección por esta micobacteria en sus principales células blanco de la inmunidad innata y traza el camino de futuras investigaciones para evaluar la activación de mecanismos efectores de la inmunidad innata frente a este candidato(AU)

Tuberculosis remains as a major problem in the global health. BCG is the available vaccine against tuberculosis but only protects against severe form of disease during childhood, so the search for new vaccine candidates is a challenge. Taking into account the protective capacity of Mycobacterium ´habana´ against experimental tuberculosis, we proposed in vitro experiments using murine macrophages (peritoneal macrophages and cell line Raw 264.7) to characterize phagocytic process of this candidate. Phagocitic index and phagocytic number were calculated. The present work demonstrated that the phagocytosis process of M. habana TMC 5135 is influenced by the cellular source used as host cell, as well as by the infecting bacterial load and the time of exposure. The present investigation contributes to the characterization of the infection by this mycobacteria in its main target cells of innate immunity and it suggest future investigations to evaluate the activation of effector mechanisms of the innate immunity against this candidate(AU)

Effect of nitazoxanide on albendazole pharmacokinetics in cerebrospinal fluid and plasma in rats.

Background: Although albendazole is the drug-of-choice for the treatment of neurocysticercosis, its efficacy is limited due to its low bioavailability. An alternative for optimizing pharmacological treatment is through drug combinations. In vitro studies have shown that nitazoxanide and tizoxanide (the active metabolite of nitazoxanide) exhibit cysticidal activity and that the combination of tizoxanide with albendazole sulfoxide (the active metabolite of albendazole) produced an additive effect. Objectives: (1) To assess the concentration profile of tizoxanide in plasma and in cerebrospinal fluid; and (2) to evaluate the influence of nitazoxanide on the pharmacokinetics of albendazole in plasma and in cerebrospinal fluid. Methods: Two different studies were conducted. In study 1, 10 male Sprague-Dawley rats received a single oral dose of 7.5 mg/kg of nitazoxanide and serial blood and cerebrospinal fluid samples were collected over a period of 4 h. In study 2, 38 healthy male Sprague-Dawley rats were randomly divided into two groups: one of these received a single dose of albendazole (15 mg/kg) and, in the other group, albendazole (15 mg/kg) was co-administered with nitazoxanide (7.5 mg/kg). Plasma and cerebrospinal fluid samples were collected from 0 to 16 h after administration. Albendazole sulfoxide and tizoxanide levels were assayed by using HPLC or LC/MS techniques. Results: In study 1, tizoxanide reached a maximum plasma concentration of 244.42 ± 31.98 ng/mL at 0.25 h; however, in cerebrospinal fluid, this could be detected only at 0.5 h, and levels were below the quantification limit (10 ng/mL). These data indicate low permeation of tizoxanide into the blood brain barrier. In study 2, Cmax, the area under the curve, and the mean residence time of albendazole sulfoxide in plasma and cerebrospinal fluid were not affected by co-administration with nitazoxanide. Conclusion: The results of the present study indicate that in rats at the applied doses, tizoxanide does not permeate into the cerebrospinal fluid. Furthermore, nitazoxanide does not appear to alter significantly the pharmacokinetics of albendazole in plasma or in cerebrospinal fluid.

In vitro and in vivo cysticidal activity of extracts and isolated flavanone from the bark of Prunus serotina: A bio-guided study.

Currently, neurocysticercosis treatment involves two drugs: albendazole and praziquantel; however, their efficacy is suboptimal and new cysticidal drugs are needed. The present paper reports the cysticidal activity of extracts of the bark from Prunus serotina against Taenia crassiceps cysts and the isolation and identification of the main components of the most active extract. Results showed that all extracts displayed in vitro cysticidal activity (EC50=17.9-88.5µg/mL), being the methanolic the most active and selective. Also, methanolic extract exhibited in vivo efficacy at 300mg/kg which was similar to that obtained with albendazole. Bio-guided fractionation of methanolic extract led the isolation of 2,3-dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one (naringenin, NGN), 3,4,5-trimethoxybenzoic acid and 1,3,5-trimethoxybenzene. NGN exhibited in vitro activity, in a time-concentration-dependent manner (EC50=89.3µM]. Furthermore, NGN at a dose of 376.1µmol/kg displayed similar in vivo efficacy than those obtained with albendazole at 188.4µmol/kg. NGN also caused a high level of damage in all parasite tissue in a similar manner than that observed with the methanolic extract. This study represents the first report of the cysticidal properties of the bark of P. serotina. NGN was identified as the main active compound of this specie and other studies are required to explore the potential of this flavanone as cysticidal agent.

Cysticidal activity of extracts and isolated compounds from Teloxys graveolens: In vitro and in vivo studies.

In the search of new alternatives for neurocysticercosis treatment, the cysticidal activity of organic extracts of Teloxys graveolens was evaluated. The in vitro activity of hexane, ethyl acetate and methanol extracts against Taenia crassiceps cysts was tested and the selectivity index relative to human fibroblasts was determined. Subsequently, the in vivo efficacy of the methanolic extract at doses of 200 and 500 mg/kg in the murine cysticercosis model was evaluated. The ultrastructural effects in vitro and in vivo of the methanolic extract were also investigated using scanning electron microscopy. Additionally, a bioassay-guided fractionation for the isolation of the cysticidal components was performed. Our in vitro findings revealed that all extracts exhibited good cysticidal activity with EC50 values from 44.8 to 67.1 µg/mL. Although the ethyl acetate and methanolic extracts displayed low cytotoxicity, the methanolic extract was the most selective. The methanolic extract also showed in vivo efficacy which was similar to that obtained with ABZ. Significant alterations were found on the germinal layer of the cysts, with a high accumulation of granules of glycogen and vacuoles. The bioguided fractionation of methanolic extract led to the isolation of three flavonoids: chrysin, pinocembrin and pinostrobin; among them, pinocembrin was the compound that displayed cysticidal activity. This is the first study which reveals that T. graveolens could be a potential source for cysticidal and non-toxic compounds.

Utility of electrocorticography in the surgical treatment of cavernomas presenting with pharmacoresistant epilepsy.

AIM: To describe the general aspects of cavernomas and epilepsy and review the available literature on the utility of electrocorticography (ECoG) in cerebral cavernoma surgery. METHODS: We searched studies in PubMed, MedLine, Scopus, Web of Science, and Google Scholar (from January 1969 to December 2013) using the keywords "electrocorticography" or "ECoG" or "prognosis" or "outcome" and "cavernomas". Original articles that reported utility of ECoG in epilepsy surgery were included. Four review authors independently selected the studies, extracted data, and assessed the methodological quality of the studies using the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions, PRISMA guidelines, and Jadad Scale. A meta-analysis was not possible due to methodological, clinical, and statistical heterogeneity of included studies. We analysed six articles with a total of 219 patients. RESULTS: The most common surgical approach was lesionectomy using ECoG in the temporal lobe with Engel I outcome range from 72.7 to 100%. CONCLUSIONS: Small controlled studies suggest that ECoG-guided resection offers the best functional results in seizure control for subjects undergoing cavernoma surgery, especially in the temporal lobe.