The aging brain and late onset drug-refractory epilepsies.

While late-onset epilepsies are characterized by a good pharmacoresponsiveness, a relevant subgroup of this patient population suffers from drug-refractory epilepsy with its impact on overall quality of life and a high risk of seizure-related injuries. Particular attention should be paid to accurate diagnosis and thorough exclusion of pseudoresistance. Challenges include the likelihood of multimorbidities and polypharmacotherapy in an elderly patient population. Network, cellular, molecular, and metabolic alterations associated with aging and age-related disorders have the potential to affect the intrinsic severity of late-onset epilepsies, neural network function, and the pharmacodynamics and pharmacokinetics of antiseizure medications (ASMs). Whereas age-related changes in pharmacokinetics tend to favor responsiveness to low doses, respective changes in network excitability and pharmacodynamics of ASMs are more likely to contribute to drug resistance. There are particular gaps in our knowledge of the mechanisms of drug resistance and the impact of influencing factors in this patient population. Therefore, experimental and clinical research needs to be intensified to advance our understanding of drug-resistant epilepsy in patients with late-onset epilepsies and to develop multivariate prediction algorithms. In this context, the heterogeneity of an elderly patient population should be taken into account, considering differences in etiology, comorbidities, co-medications, frailty, activity and environmental factors.

[Study of the practice of prescribing phenosanic acid in epilepsy accompanied by asthenic disorders]. / Izuchenie effektivnosti primeneniya fenozanovoi kisloty pri epilepsii, soprovozhdayushcheisya astenicheskimi narusheniyami.

OBJECTIVE: To evaluate the experience of prescribing phenosanic acid in the practice of a neurologist/epileptologist when prescribing the second, third anticonvulsant drug (AED) as part of combination therapy for patients with manifestations of fatigue due to epilepsy. MATERIAL AND METHODS: 501 patients with focal epilepsy accompanied by asthenic disorders were included in the observational program. The observation program protocol included 5 visits, including visit 1, at which screening and inclusion in the OP took place. The observation period was 10 months. At baseline and at the end of the 10-month follow-up, the patients' condition was assessed according to the following indicators: frequency and transformation of attacks with focal onset, severity of fatigue (self-assessment scale MFI-20); quality of life (questionnaire QoLiE-10-P); frequency of attacks with focal onset. The safety of phenosanic acid (Dibufelon) was also assessed. RESULTS: In 10 months after the inclusion of Dibufelon as the 2nd, 3rd AED in the treatment regimen, a statistically significant (p<0.01) decrease in the frequency of seizures was observed: in general - in 88% of patients; by 50% or more - in 76% of patients; transition from the group with a large number of seizures to the group with a smaller number of seizures - 74% of patients. Also when taking phenosanic acid, a positive dynamics of seizure type was noted: a reliable decrease in the proportion of patients with seizures with secondary generalization from 70% to 56%; a decrease in the number of focal seizures with impaired consciousness from 65% to 53%. In addition, there was a 38% decrease in the severity of fatigue on the MFI-20 scale (the greatest decrease on the «Mental fatigue¼ scale), improvement in the quality of life - a 2.7-fold increase in the mean values of the QOLIE-10 questionnaire. CONCLUSION: The addition of phenosanic acid to antiepileptic therapy as a second or third AED allows for better control of seizures, leading to a decrease the frequency and severity of attacks and the severity of fatigue both, and an increase of the quality of life of patients with epilepsy.

Potential impact on mental health in patients with treatment-resistant schizophrenia - clozapine augmentation with long-acting parenteral antipsychotics: a case series.

INTRODUCTION: The rate of pharmacoresistance among in patients diagnosed with schizophrenia is around 30%. Clozapineis the drug of choice for these patients; however, an adequate response to treatment doesn't always occur. One of the possible augmentation approaches, specifically for non-adherent patients, is the administration of long-acting parenteral antipsychotics. Our goal was to evaluate previous experiences of administering a combination of the atypical antipsychotic clozapine and long-acting injectable antipsychotics to pharmacoresistant patients at the Department of Psychiatry the Czech Republic and to assess the safety and effectiveness of such administration. METHODS: A retrospective evaluation of patient case studies was conducted for those who were hospitalized in the Ward for the therapy of Psychotic disorders between 2016 and 2020 and had a medication history of combining clozapine and depot antipsychotics. RESULTS: Over half of the patients had no illness relapses during the observed period. The clinical manifestation of adverse effects from combination therapy appears low in our patient sample, primarily involving mild and pharmacologically manageable side effects (tachycardia). Only one of the cases recorded neutropenia, which led to discontinuation of clozapine; the patient was maintained on long-acting injectable antipsychotics medication. CONCLUSION: From our findings, it can be inferred that augmenting clozapine with depot antipsychotics is a potential therapeutic intervention that pharmacoresistant patients could benefit from. However, it is essential to emphasize that this therapeutic approach should only be administered after carefully considering the patient's existing treatment. It should be strictly individualized based on the treating physician's or clinical pharmacist's sufficient professional experience.

Age-Dependent Phenomena of 6-Hz Corneal Kindling Model in Mice.

Although numerous studies have acknowledged disparities in epilepsy-related disease processes between young and aged animals, little is known about how epilepsy changes from young adulthood to middle age. This study investigates the impact of aging on 6-Hz corneal kindling in young-adult mice and middle-aged mice. We found that the kindling acquisition of the 6-Hz corneal kindling model was delayed in middle-aged mice when compared to young-adult mice. While the seizure stage and incidence of generalized seizures (GS) were similar between the two age groups, the duration of GS in the kindled middle-aged mice was shorter than that in the kindled young-adult mice. Besides, all kindled mice, regardless of age, were resistant to phenytoin sodium (PHT), valproate sodium (VPA), and lamotrigine (LGT), whereas middle-aged mice exhibited higher levetiracetam (LEV) resistance compared to young-adult mice. Both age groups of kindled mice displayed hyperactivity and impaired memory, which are common behavioral characteristics associated with epilepsy. Furthermore, middle-aged mice displayed more pronounced astrogliosis in the hippocampus. Additionally, the expression of Brain-Derived Neurotrophic Factor (BDNF) was lower in middle-aged mice than in young-adult mice prior to kindling. These data demonstrate that both the acquisition and expression of 6-Hz corneal kindling are attenuated in middle-aged mice, while hippocampal astrogliosis and pharmacological resistance are more pronounced in this age group. These results underscore the importance of considering age-related factors when utilizing the 6-Hz corneal kindling model in mice of varying age groups.

Proposal of pharmacophore model for HIV reverse transcriptase inhibitors: Combined mutational effect analysis, molecular dynamics, molecular docking and pharmacophore modeling study.

OBJECTIVES: Antiretroviral therapy (ART) efficacy is jeopardized by the emergence of drug resistance mutations in HIV, compromising treatment effectiveness. This study aims to propose novel analogs of Effavirenz (EFV) as potential direct inhibitors of HIV reverse transcriptase, employing computer-aided drug design methodologies. METHODS: Three key approaches were applied: a mutational profile study, molecular dynamics simulations, and pharmacophore development. The impact of mutations on the stability, flexibility, function, and affinity of target proteins, especially those associated with NRTI, was assessed. Molecular dynamics analysis identified G190E as a mutation significantly altering protein properties, potentially leading to therapeutic failure. Comparative analysis revealed that among six first-line antiretroviral drugs, EFV exhibited notably low affinity with viral reverse transcriptase, further reduced by the G190E mutation. Subsequently, a search for EFV-similar inhibitors yielded 12 promising molecules based on their affinity, forming the basis for generating a pharmacophore model. RESULTS: Mutational analysis pinpointed G190E as a crucial mutation impacting protein properties, potentially undermining therapeutic efficacy. EFV demonstrated diminished affinity with viral reverse transcriptase, exacerbated by the G190E mutation. The search for EFV analogs identified 12 high-affinity molecules, culminating in a pharmacophore model elucidating key structural features crucial for potent inhibition. CONCLUSION: This study underscores the significance of EFV analogs as potential inhibitors of HIV reverse transcriptase. The findings highlight the impact of mutations on drug efficacy, particularly the detrimental effect of G190E. The generated pharmacophore model serves as a pivotal reference for future drug development efforts targeting HIV, providing essential structural insights for the design of potent inhibitors based on EFV analogs identified in vitro.

Main Pathogens Causing Infections and Antibiotic Resistance Profile in Major Burns in Brazil Comparing Two Periods: 2015/2016 and 2019/2020.

Sepsis is the main cause of death in major burns. In this retrospective study conducted in a reference hospital in Brazil, the main agents causing infection and the resistance profile to antibiotics were identified. In addition, the epidemiological profile, length of hospital stay, type of burn, and total body surface area (TBSA) in major burns were collected from medical records, comparing the years 2015/2016 and 2019/2020. In both time periods, there was a predominance of males with a mean age of 43 years. Burns with less than 30% of TBSA predominated. There was a significant increase in positive cultures (P = .00026), from 58.7% to 80%, and an increase in skin punch culture collection from 25.6% to 43.9% in the years 2019/2020. The predominant etiological agent was Pseudomonas aeruginosa, followed by Acinetobacter baumannii resistant to carbapenems, and Staphylococcus aureus in both evaluated periods. The percentage of deaths was higher in 2019/2020 (26.2% vs. 14.6%; P = .026). The length of hospital stay was shorter in the latter period (P = .0081). Sepsis was the cause of death in 81.2% of cases in 2015/2020 and 78.3% in 2019/2020. Among the deaths, P. aeruginosa was the main agent identified. There was no change in the main pathogens and bacterial antibiotic resistance between the 2 time periods.

Microbiological environmental contamination in a Pediatric Intensive Care Unit / Contaminação ambiental microbiológica em Unidade de Terapia Intensiva Pediátrica / Contaminación ambiental microbiológica en una Unidad de Cuidados Intensivos Pediátricos

Background and objectives: inanimate surfaces and equipment in the hospital environment are considered reservoirs of resistant and pathogenic microorganisms. In Pediatric Intensive Care Units, the risk of infection is also related to the severity of pathologies associated with the immaturity of the immune system of this population. This study aimed to investigate microbiological environmental contamination in a Pediatric Intensive Care Unit. Method: this is an exploratory cross-sectional study, carried out in a Pediatric Intensive Care Unit of a highly complex university hospital, located in southern Brazil. To assess environmental contamination, sterile swabs were rubbed on surfaces corresponding to the patient unit and in the common area. Results: twenty-eight surfaces were analyzed, 12 of which were located in units occupied by patients at the time of collection and 16 surfaces in the common use area. In the total number of surfaces analyzed by microbiological cultures, the patient unit showed 66.67% contamination by microorganisms, while surfaces in the common area showed 56.25%. Regarding the microbiological profile, all isolated microorganisms were Gram-positive and showed resistance, namely Staphylococcus aureus and coagulase-negative Staphylococcus. Conclusion: there was evidence of a high frequency of contamination on inanimate surfaces and equipment near and far from patients, essentially by pathogenic and multi-resistant microorganisms to antimicrobials.(AU)

Justificativa e objetivos: superfícies e equipamentos inanimados no ambiente hospitalar são considerados reservatórios de microrganismos resistentes e patogênicos. Nas Unidades de Cuidados Intensivos Pediátricos, o risco de infeção também está relacionado com a gravidade das patologias associadas à imaturidade do sistema imunitário desta população. Este estudo teve como objetivo investigar a contaminação microbiológica ambiental em uma Unidade de Terapia Intensiva Pediátrica. Método: trata-se de um estudo exploratório transversal, realizado em uma Unidade de Terapia Intensiva Pediátrica de um hospital universitário de alta complexidade, localizado no Sul do Brasil. Para avaliar a contaminação ambiental, foram esfregados swabs estéreis nas superfícies correspondentes à unidade do paciente e na área comum. Resultados: foram analisadas vinte e oito superfícies, sendo 12 localizadas em unidades ocupadas por pacientes no momento da coleta e 16 superfícies em área de uso comum. No total de superfícies analisadas por culturas microbiológicas, a unidade paciente apresentou 66,67% de contaminação por microrganismos, enquanto as superfícies da área comum apresentaram 56,25%. Quanto ao perfil microbiológico, todos os microrganismos isolados eram Gram-positivos e apresentavam resistência, nomeadamente Staphylococcus aureus e Staphylococcus coagulase-negativa. Conclusão: houve evidência de elevada frequência de contaminação em superfícies inanimadas e equipamentos próximos e distantes dos pacientes, essencialmente por microrganismos patogênicos e multirresistentes aos antimicrobianos.(AU)

Fundamento y objetivos: las superficies y equipos inanimados del ambiente hospitalario son considerados reservorios de microorganismos resistentes y patógenos. En las Unidades de Cuidados Intensivos Pediátricos el riesgo de infección también se relaciona con la gravedad de patologías asociadas a la inmadurez del sistema inmunológico de esta población. Este estudio tuvo como objetivo investigar la contaminación ambiental microbiológica en una Unidad de Cuidados Intensivos Pediátricos. Método: se trata de un estudio exploratorio transversal, realizado en una Unidad de Cuidados Intensivos Pediátricos de un hospital universitario de alta complejidad, ubicado en el sur de Brasil. Para evaluar la contaminación ambiental se frotaron hisopos estériles en las superficies correspondientes a la unidad de pacientes y en el área común. Resultados: se analizaron veintiocho superficies, 12 de las cuales estaban ubicadas en unidades ocupadas por los pacientes en el momento de la recogida y 16 superficies en el área de uso común. Del total de superficies analizadas por cultivos microbiológicos, la unidad de pacientes presentó un 66,67% de contaminación por microorganismos, mientras que las superficies del área común presentaron un 56,25%. En cuanto al perfil microbiológico, todos los microorganismos aislados fueron Gram positivos y presentaron resistencia, concretamente Staphylococcus aureus y Staphylococcus coagulasa negativo. Conclusión: se evidenció alta frecuencia de contaminación en superficies inanimadas y equipos cercanos y lejanos de los pacientes, esencialmente por microorganismos patógenos y multirresistentes a los antimicrobianos.(AU)

Revisiting the concept of drug-resistant epilepsy: A TASK1 report of the ILAE/AES Joint Translational Task Force.

Despite progress in the development of anti-seizure medications (ASMs), one third of people with epilepsy have drug-resistant epilepsy (DRE). The working definition of DRE, proposed by the International League Against Epilepsy (ILAE) in 2010, helped identify individuals who might benefit from presurgical evaluation early on. As the incidence of DRE remains high, the TASK1 workgroup on DRE of the ILAE/American Epilepsy Society (AES) Joint Translational Task Force discussed the heterogeneity and complexity of its presentation and mechanisms, the confounders in drawing mechanistic insights when testing treatment responses, and barriers in modeling DRE across the lifespan and translating across species. We propose that it is necessary to revisit the current definition of DRE, in order to transform the preclinical and clinical research of mechanisms and biomarkers, to identify novel, effective, precise, pharmacologic treatments, allowing for earlier recognition of drug resistance and individualized therapies.

Trends in referral patterns to presurgical evaluation at a European reference center.

PURPOSE: To determine if growing evidence for epilepsy surgery as an early treatment option is reflected in the decrease of latencies between epilepsy onset and referral for presurgical evaluation METHODS: Retrospective analysis of latencies in 1646 patients (children and adults) from the time of epilepsy diagnosis to first presurgical workup in the period from 1999 to 2019 based on electronic patient charts at a tertiary epilepsy center. Time spans 1999-2009 and 2010-2019, prior to and following the ILAE definition of pharmacoresistance, and the role of etiological factors were assessed. RESULTS: Over the whole period, the mean latency between diagnosis and a presurgical workup was 15.3 y. There was a significant reduction in the latencies between the periods 1999-2009 (16.9 y) and 2010-2019 (13.4 y), (p < 0.0001). In a linear regression analysis, the latency decreased by 2.6 months/year from 17.4 in 1999 to 13.1 y in 2019 (p < 0.001). Subgroup analyses showed significant decreases in latency to presurgical evaluation in patients with hippocampal sclerosis from 24.4 to 19.5 y, in malformations of cortical development from 16.4 to 13.2 y, and in nonlesional patients from 18.1 to 12.8 y, in contrast to patients with MR evidence for brain tumors with similar latencies across time (10.5 vs. 9.5 y, n.s.). CONCLUSION: The reduction of the time span to a first presurgical evaluation was highly significant over time, yet moderate in its degree. Overall, the aim of early diagnostic evaluation for epilepsy surgery options after established pharmacoresistance was only achieved for a minority of patients.

Pathophysiology of drug-resistant canine epilepsy.

Drug resistance continues to be a major clinical problem in the therapeutic management of canine epilepsies with substantial implications for quality of life and survival times. Experimental and clinical data from human medicine provided evidence for relevant contributions of intrinsic severity of the disease as well as alterations in pharmacokinetics and -dynamics to failure to respond to antiseizure medications. In addition, several modulatory factors have been identified that can be associated with the level of therapeutic responses. Among others, the list of potential modulatory factors comprises genetic and epigenetic factors, inflammatory mediators, and metabolites. Regarding data from dogs, there are obvious gaps in knowledge when it comes to our understanding of the clinical patterns and the mechanisms of drug-resistant canine epilepsy. So far, seizure density and the occurrence of cluster seizures have been linked with a poor response to antiseizure medications. Moreover, evidence exists that the genetic background and alterations in epigenetic mechanisms might influence the efficacy of antiseizure medications in dogs with epilepsy. Further molecular, cellular, and network alterations that may affect intrinsic severity, pharmacokinetics, and -dynamics have been reported. However, the association with drug responsiveness has not yet been studied in detail. In summary, there is an urgent need to strengthen clinical and experimental research efforts exploring the mechanisms of resistance as well as their association with different etiologies, epilepsy types, and clinical courses.

Risk factors for drug-resistant epilepsy in adult patients.

INTRODUCTION: Drug-resistant epilepsy occurs in about 30% of epilepsy patients. It has been suggested that etiology or seizure type would increase the risk of pharmacoresistance. This study aims to compare the characteristics of patients with drug-sensitive epilepsy with patients with drug-resistant epilepsy to identify risk factors. PATIENT AND METHODS: A multicentric cohort study was conducted between 2019 and 2022. We included patients >18 years-old with epilepsy but excluded psychogenic non-epileptic seizures and less than 2 years of follow-up. RESULTS: We included 128 patients, of whom 46 had drug-resistance epilepsy, and 82 responding to medication. Both groups showed similar characteristics. Febrile seizures (OR: 7.25), focal epilepsy (OR: 2.4), focal seizures with loss of consciousness (OR: 2.36), structural etiology (OR: 2.2) and abnormal MRI (OR: 4.6) were significant risk factors for drug-resistance epilepsy. CONCLUSION: Following other studies, we observed that factors such as epilepsy type, seizure type, structural etiology, abnormal MRI, and febrile seizure increased the risk for drug-resistance epilepsy, in our population.

Acute and chronic convection-enhanced muscimol delivery into the rat subthalamic nucleus induces antiseizure effects associated with high responder rates.

Intracerebral drug delivery is an emerging treatment strategy aiming to manage seizures in patients with systemic drug-resistant epilepsies. In rat seizure and epilepsy models, the GABAA receptor agonist muscimol has shown powerful antiseizure potential when injected acutely into the subthalamic nucleus (STN), known for its capacity to provide remote control of different seizure types. However, chronic intrasubthalamic muscimol delivery required for long-term seizure suppression has not yet been investigated. We tested the hypothesis that chronic convection-enhanced delivery (CED) of muscimol into the STN produces long-lasting antiseizure effects in the intravenous pentylenetetrazole seizure threshold test in female rats. Acute microinjection was included to verify efficacy of intrasubthalamic muscimol delivery in this seizure model and caused significant antiseizure effects at 30 and 60 ng per hemisphere with a dose-dependent increase of responders and efficacy and only mild adverse effects compared to controls. For the chronic study, muscimol was bilaterally infused into the STN over three weeks at daily doses of 60, 300, or 600 ng per hemisphere using an implantable pump and cannula system. Chronic intrasubthalamic CED of muscimol caused significant long-lasting antiseizure effects for up to three weeks at 300 and 600 ng daily. Drug responder rate increased dose-dependently, as did drug tolerance rates. Transient ataxia and body weight loss were the main adverse effects. Drug distribution was comparable (about 2-3 mm) between acute and chronic delivery. This is the first study providing proof-of-concept that not only acute, but also chronic, continuous CED of muscimol into the STN raises seizure thresholds.

Treatment of cholinergic-induced status epilepticus with polytherapy targeting GABA and glutamate receptors.

Despite new antiseizure medications, the development of cholinergic-induced refractory status epilepticus (RSE) continues to be a therapeutic challenge as pharmacoresistance to benzodiazepines and other antiseizure medications quickly develops. Studies conducted by Epilepsia. 2005;46:142 demonstrated that the initiation and maintenance of cholinergic-induced RSE are associated with trafficking and inactivation of gamma-aminobutyric acid A receptors (GABAA R) thought to contribute to the development of benzodiazepine pharmacoresistance. In addition, Dr. Wasterlain's laboratory reported that increased N-methyl-d-aspartate receptors (NMDAR) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) contribute to enhanced glutamatergic excitation (Neurobiol Dis. 2013;54:225; Epilepsia. 2013;54:78). Thus, Dr. Wasterlain postulated that targeting both maladaptive responses of reduced inhibition and increased excitation that is associated with cholinergic-induced RSE should improve therapeutic outcome. We currently review studies in several animal models of cholinergic-induced RSE that demonstrate that benzodiazepine monotherapy has reduced efficacy when treatment is delayed and that polytherapy with drugs that include a benzodiazepine (eg midazolam and diazepam) to counter loss of inhibition, concurrent with an NMDA antagonist (eg ketamine) to reduce excitation provide improved efficacy. Improved efficacy with polytherapy against cholinergic-induced seizure is demonstrated by reduction in (1) seizure severity, (2) epileptogenesis, and (3) neurodegeneration compared with monotherapy. Animal models reviewed include pilocarpine-induced seizure in rats, organophosphorus nerve agent (OPNA)-induced seizure in rats, and OPNA-induced seizure in two mouse models: (1) carboxylesterase knockout (Es1-/- ) mice which, similarly to humans, lack plasma carboxylesterase and (2) human acetylcholinesterase knock-in carboxylesterase knockout (KIKO) mice. We also review studies showing that supplementing midazolam and ketamine with a third antiseizure medication (valproate or phenobarbital) that targets a nonbenzodiazepine site rapidly terminates RSE and provides further protection against cholinergic-induced SE. Finally, we review studies on the benefits of simultaneous compared with sequential drug treatments and the clinical implications that lead us to predict improved efficacy of early combination drug therapies. The data generated from seminal rodent studies of efficacious treatment of cholinergic-induced RSE conducted under Dr. Wasterlain's guidance suggest that future clinical trials should treat the inadequate inhibition and temper the excess excitation that characterize RSE and that early combination therapies may provide improved outcome over benzodiazepine monotherapy.

CRISPR/Cas9 targeting liposomes knocked down multidrug resistance proteins in brain endothelial cells as a model to predict potential pharmacoresistance.

This investigation aimed to use CRISPR-Cas9 gene-editing to knock down P-glycoprotein (P-gp) expression and then establish a feasible cell line to evaluate the potential pharmacoresistance of therapeutic agents mediated by efflux. A cationic liposome was prepared as a "smart bomb" by conjugating with a peptide-based targeting ligand (THRPPMWSPVWP), specifically binding to transferrin receptors at the blood-brain barrier (BBB), and then formed a nanocomplex with P-gp knockdown CRISPR/Cas9 plasmid. Higher uptakes of targeted and stable liposomes in bEND.3 cells were observed compared to non-peptide conjugated ones (p < 0.05). The P-gp transporters were successfully knocked down by the cell-nontoxic CRISPR/Cas9 targeted liposomes and P-gp associated ATP activities were higher in the transfected cells (p < 0.05). Functional studies of knocked down cells were evaluated by using prototypical P-gp substrates rhodamine 123 and doxorubicin. More accumulation of rhodamine 123 and higher cytotoxic sensitivity of doxorubicin was observed in the transfected cells as compared with those in the wild-type cells.

Perfil da prevalência de infecções enterocócicas e de resistência bacteriana aos antimicrobianos em infecções urinárias comunitárias / Profile of the prevalence of enterococcal infections and bacterial resistance to antibiotics in public urinary infections

As infecções do trato urinário causadas por bactérias resistentes aos antimicrobiano são o terceiro tipo de infecção mais comum em humanos, descritas em todo o mundo. Trata-se de estudo de série temporal realizado a partir de registros de urocultura positiva, no período de 1º de janeiro de 2011 a 31 de dezembro de 2019, na região metropolitana do município de Goiânia, Centro-Oeste do Brasil, em pessoas de todas as idades e sexos, com objetivo de avaliar a prevalência as infeções urinárias, o padrão de resistência aos antimicrobianos e a tendência do crescimento da resistência em Enterococcus faecalis. A análise descritiva e o teste Qui-quadrado de Pearson foram utilizados para avaliar o crescimento da prevalência da resistência aos antimicrobianos e a análise de correlação pelo método de Poisson foi usada para avaliar a tendência do crescimento da resistência bacteriana. De 22.034 registros de uroculturas positivas, 646 (2,9%) eram E. faecalis. Os achados demonstraram que as infeções urinárias são mais prevalentes em mulheres com idade superior a 19 anos. A prevalência da resistência foi elevada para as fluoroquinolonas e significante crescimento da resistência para Gentamicina (p=0,02%) e diminuição para Ampicilina (p<0,001) e Tobramicina (p<0,001). A tendência de crescimento positiva foi significante para a Gentamicina e negativa para Ampicilina e Tobramicina. Os achados demonstram que é necessária a criação de programas de vigilância que objetivam monitorar o crescimento do padrão de resistência nas ITUs comunitárias, levando em consideração o local de estudo.

Urinary tract infections caused by antibiotic-resistant bacteria are the third most common type of infection in humans described worldwide. This is a time series study carried out from positive urine culture records, from January 1, 2011, to December 31, 2019, in the metropolitan region of the municipality of Goiania, Midwest Brazil, in people of all ages and sexes. The aim was to assess the prevalence of urinary tract infections, the pattern of resistance to antibiotics, and the trend of increasing resistance in Enterococcus faecalis. Descriptive analysis and Pearson's chi-square test were used to assess the growth in the prevalence of antibiotic resistance, and a correlation analysis by the Poisson method was used to assess the trend in the growth of bacterial resistance. Of 22,034 positive urine cultures, 646 (2.9%) were of E. faecalis. The findings showed that urinary tract infections are more prevalent in women aged over 19 years old. The prevalence of resistance was high for the fluoroquinolone drugs and a significant increase in resistance against Gentamicin (p=0.02%) and a decrease toward Ampicillin (p<0.001) and Tobramycin (p<0.001). The increasing trend was significant for Gentamicin and negative for Ampicillin and Tobramycin. The findings demonstrate that it is necessary to create surveillance programs that aim to monitor the growth of the resistance patterns in public UTIs, while considering the study site.

Cannabidiol in canine epilepsy.

The anticonvulsant effect of cannabidiol (CBD), which has been confirmed by findings from animal models and human trials, has attracted the interest of veterinary practitioners and dog owners. Moreover, social media and public pressure has sparked a renewed awareness of cannabinoids, which have been used for epilepsy since ancient times. Unfortunately, at this moment veterinarians and veterinary neurologists have difficulty prescribing cannabinoids because of the paucity of sound scientific studies. Pharmacokinetic studies in dogs have demonstrated a low oral bioavailability of CBD and a high first-pass effect through the liver. Administering CBD in oil-based formulations and/or with food has been shown to enhance the bioavailability in dogs, rats and humans. Tolerability studies in healthy dogs and dogs with epilepsy have demonstrated that CBD was safe and well tolerated with only mild to moderate adverse effects. In this context, it should be noted that the quality of available CBD varies widely, underscoring the importance of pharmaceutical quality and its control. One clinical trial in dogs with drug-resistant idiopathic epilepsy failed to confirm a difference in response rates between the CBD group and the placebo group, while in another cross-over trial a ≥ 50 % reduction in epileptic seizure frequency was found in six of 14 dogs in the treatment phase, a reduction that was not observed during the placebo phase. Based on the current state of knowledge it is not possible to provide clear-cut recommendations for the use of CBD in canine epilepsy. Randomized controlled canine trials with large sample sizes are needed to determine the range of therapeutic plasma concentrations, develop evidence-based dosing regimens, determine the efficacy of cannabidiol in drug-refractory epilepsy, and explore potential associations between treatment effects and different etiologies, epilepsy types, and drug combinations.

Innovative treatments for epilepsy: Venom peptides, cannabinoids, and neurostimulation.

Antiepileptic drugs have been successfully treating epilepsy and providing individuals sustained seizure freedom. However, about 30% of the patients with epilepsy present drug resistance, which means they are not responsive to the pharmacological treatment. Considering this, it becomes extremely relevant to pursue alternative therapeutic approaches, in order to provide appropriate treatment for those patients and also improve their quality of life. In the light of that, this review aims to discuss some innovative options for the treatment of epilepsy, which are currently under investigation, addressing strategies that go from therapeutic compounds to clinical procedures. For instance, peptides derived from animal venoms, such as wasps, spiders, and scorpions, demonstrate to be promising antiepileptic molecules, acting on a variety of targets. Other options are cannabinoids and compounds that modulate the endocannabinoid system, since it is now known that this network is involved in the pathophysiology of epilepsy. Furthermore, neurostimulation is another strategy, being an alternative clinical procedure for drug-resistant patients who are not eligible for palliative surgeries.

Dysfunction of ABC Transporters at the Surface of BBB: Potential Implications in Intractable Epilepsy and Applications of Nanotechnology Enabled Drug Delivery.

Epilepsy is a chronic neurological disorder affecting 70 million people globally. One of the fascinating attributes of brain microvasculature is the (BBB), which controls a chain of distinct features that securely regulate the molecules, ions, and cells movement between the blood and the parenchyma. The barrier's integrity is of paramount importance and essential for maintaining brain homeostasis, as it offers both physical and chemical barriers to counter pathogens and xenobiotics. Dysfunction of various transporters in the (BBB), mainly ATP binding cassette (ABC), is considered to play a vital role in hampering the availability of antiepileptic drugs into the brain. ABC (ATP-binding cassette) transporters constitute a most diverse protein superfamily, which plays an essential part in various biological processes, including cell homeostasis, cell signaling, uptake of nutrients, and drug metabolism. Moreover, it plays a crucial role in neuroprotection by out-flowing various internal and external toxic substances from the interior of a cell, thus decreasing their buildup inside the cell. In humans, forty-eight ABC transporters have been acknowledged and categorized into subfamilies A to G based on their phylogenetic analysis. ABC subfamilies B, C, and G, impart a vital role at the BBB in guarding the brain against the entrance of various xenobiotic and their buildup. The illnesses of the central nervous system have received a lot of attention lately Owing to the existence of the BBB, the penetration effectiveness of most CNS medicines into the brain parenchyma is very limited (BBB). In the development of neurological therapies, BBB crossing for medication delivery to the CNS continues to be a major barrier. Nanomaterials with BBB cross ability have indeed been extensively developed for the treatment of CNS diseases due to their advantageous properties. This review will focus on multiple possible factors like inflammation, oxidative stress, uncontrolled recurrent seizures, and genetic polymorphisms that result in the deregulation of ABC transporters in epilepsy and nanotechnology-enabled delivery across BBB in epilepsy.