Assessment of cytochrome P450 induction in canine intestinal organoid models.

Understanding cytochrome P450 (CYP) enzymes in the canine intestine is vital for predicting drug metabolism and developing safer oral medications. This study evaluates canine colonoids as a model to assess the expression and induction of essential intestinal CYP enzymes.Canine colonoids were cultured in expansion medium (EM) with Wnt-3A and in differentiation medium (DM) without Wnt-3A. We assessed the mRNA expression of CYP2B11, CYP2C21, CYP3A12, and CYP3A98 using qPCR and examined the effects of rifampicin and phenobarbital as inducers.Our findings show that DM significantly increased the mRNA expression of CYP3A98 and CYP2B11, but not CYP3A12, compared to EM. CYP2C21, not typically expressed in the intestine, remained unexpressed in colonoids. Rifampicin induced CYP3A98, aligning with pregnane x receptor (PXR) regulation, while phenobarbital did not, suggesting no constitutive androstane receptor (CAR) involvement. CYP2B11 did not respond to either inducer, suggesting alternative regulatory pathways in canine colonoids.This study is a pioneering effort to establish conditions for studying P450 expression in canine colonoids, confirming significant CYP3A98 expression in the canine intestine. It demonstrated colonoids can induce CYP activity post drug treatments. Further research is needed to enhance species-specific drug metabolism understanding and validate this model for broader applications.

Eficacia y seguridad de lacosamida como tratamiento complementario en pacientes pediátricos con epilepsia focal refractaria / Efficacy and safety of lacosamide as adjunctive treatment in pediatric patients with refractory focal epilepsy

ANTECEDENTES: En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Institución de Evaluación de Tecnologías en Salud e Investigación N° 97-IETSI-ESSALUD-2022, se ha elaborado el presente dictamen que expone la evaluación de la eficacia y seguridad de lacosamida para el tratamiento de pacientes pediátricos con epilepsia focal refractaria. Así, el médico Dr. Edwin Martín Lazo Rivera, especialista en neurología pediátrica del Hospital Nacional Carlos Alberto Seguín Escobedo - Red Asistencial Arequipa y la Dra. Rebeca Fiorella Valdivia Bravo, especialista en pediatría del Hospital Nacional Alberto Sabogal Sologuren de la Red Prestacional Sabogal, siguiendo la Directiva N° 003-IETSI-ESSALUD-2016, enviaron al Instituto de Evaluación de Tecnologías en Salud e Investigación ­ IETSI sus respectivas solicitudes de autorización de uso del producto farmacéutico lacosamida no incluido en el Petitorio Farmacológico de EsSalud. ASPECTOS GENERALES: La epilepsia es una condición del sistema nervioso central caracterizada por crisis epilépticas recurrentes y no provocadas por desencadenantes inmediatos identificables. Así, la crisis epiléptica es aquel acontecimiento transitorio de signos y/o síntomas originados por una actividad neuronal cerebral sincrónica anormal o excesiva, que puede manifestarse por fenómenos sensitivos, motores, sensoriales o autonómicos con o sin pérdida de la conciencia, ya que dependen del área cerebral donde se originan. En ese sentido, las crisis convulsivas se clasifican según tres posibilidades de origen: las de inicio focal, generalizado y desconocido. Las crisis focales, a su vez, se pueden subclasificar en aquellas que tienen pérdida o no de la consciencia, para posteriormente categorizar si los síntomas son motores o no motores. En consecuencia, los especialistas deciden el abordaje terapéutico de los pacientes con epilepsia focal teniendo en cuenta esta clasificación, adicional a la etiología y a las comorbilidades asociadas (Reséndiz-Aparicio et al.,2019, Fisher et al.,2017, INSN.,2020). En todo el mundo, la epilepsia afecta aproximadamente a 65 millones de personas, reportándose una incidencia de la epilepsia de 67,8 por 100 000 habitantes en los países en desarrollo (Mohammadzadeh et al., 2022). En el Perú, se estima que la prevalencia de epilepsia es de 11,9 a 32,1 por cada 1000 personas (Burneo et al., 2017). Asimismo, es conocido que la incidencia de la epilepsia en la población pediátrica es de aproximadamente 0,5 % a 1 % de la población general. Además, algunos estudios sugieren que hasta el 60 % de los pacientes pediátricos con epilepsia presentarán remisión de su condición, mientras que alrededor del 20 % a 30 % de los pacientes con epilepsia serán refractarios al tratamiento médico (Ortiz de la Rosa et al., 2015). METODOLOGÍA: La búsqueda bibliográfica exhaustiva se llevó a cabo con el objetivo de identificar la mejor evidencia disponible sobre la eficacia y seguridad de lacosamida para el tratamiento de pacientes pediátricos con epilepsia focal refractaria a los FAE disponibles en EsSalud. La búsqueda bibliográfica se realizó en las bases de datos PubMed, The Cochrane Library. Web of Science y LILACS. Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas (RS), evaluaciones de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC) de: la National Institute for Health and Care Excellence (NICE), la American Academy of Neurology (ANN), la American Epilepsy Society (AES), la Scottish Intercollegiate Guidelines Network (SIGN), la Internacional Database of GRADE Guideline (BIGG), la Canadian Agency for Drugs and Technologies in Health (CADTH), la Comissáo Nacional de Incorporadáo de Tecnologias no Sistema Único de Saúde (CONITEC) y el Ministerio de Salud del Perú (MINSA). Adicionalmente, se realizó una búsqueda manual en las bases el portal de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), y el repositorio institucional de la Dirección General de Medicamentos, Insumos y Drogas (DIGEMID). Finalmente, se realizó una búsqueda en el portal ClinicalTrials.govdel National Institutes of Health (NIH) para identificar ensayos clínicos en desarrollo o que aún no hayan sido publicados. La metodología de tipo escalonada fue utilizada para la selección de documentos a ser incluidos en el presente dictamen. De acuerdo con los criterios de elegibilidad, se priorizaron durante la selección: GPC, ETS, RS de ensayos clínicos (EC) con o sin metaanálisis (MA), y ensayos clínicos aleatorizados (ECA) de fase III. Se elaboraron estrategias de búsqueda sensibles en bases de datos bibliográficas y sitios web para obtener la evidencia científica que permita responder a la pregunta PICO. Las estrategias de búsqueda incluyeron términos relacionados con la intervención y población de interés. Se emplearon términos MeSH4, así como términos de lenguaje libre, junto con operadores booleanos para cada una de las bases de datos elegidas para la búsqueda. Los registros obtenidos de la búsqueda bibliográfica fueron importados al aplicativo web Rayyan (http://rayyan.qcri.org/) para una revisión manual por título y resumen. La selección de los estudios se realizó en una primera fase por dos evaluadores del Equipo Técnico del IETSI de manera independiente (búsqueda par); evaluando los títulos y resúmenes en relación con la pregunta PICO y seleccionando aquellos que serían evaluados a texto completo en una segunda fase por un único evaluador. En la segunda fase, uno de los evaluadores revisó los documentos a texto completo incluidos en la primera fase y realizó la selección final de los estudios. RESULTADOS: Luego de la búsqueda bibliográfica, se incluyó una GPC elaborada por la National Institute for Health and Care Excellence (NICE 2022), y un ECA de fase III, NCT01921205 (Farkas et al., 2019). CONCLUSIÓN: Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación aprueba el uso de lacosamida para el tratamiento complementario en pacientes pediátricos con epilepsia focal refractaria, como producto farmacéutico no incluido en el Petitorio Farmacológico de EsSalud, según lo establecido en el Anexo N° 1. La vigencia del presente informe preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de mayor evidencia que pueda surgir en el tiempo.

Assessment of porphyrogenicity of drugs and chemicals in selected hepatic cell culture models through a fluorescence-based screening assay.

Compounds that induce 5-aminolevulinic acid [ALA] synthase-1 and/or cytochromes P-450 may induce acute porphyric attacks in patients with the acute hepatic porphyrias [AHPs]. Currently, there is no simple, robust model used to assess and predict the porphyrogenicity of drugs and chemicals. Our aim was to develop a fluorescence-based in vitro assay for this purpose. We studied four different hepatic cell culture models: HepG2 cells, LMH cells, 3D HepG2 organoids, and 3D organoids of primary liver cells from people without known disease [normal human controls]. We took advantage of the fluorescent properties of protoporphyrin IX [PP], the last intermediate of the heme biosynthesis pathway, performing fluorescence spectrometry to measure the intensity of fluorescence emitted by these cells treated with selected compounds of importance to patients with AHPs. Among the four cell culture models, the LMH cells produced the highest fluorescence readings, suggesting that these cells retain more robust heme biosynthesis enzymes or that the other cell models may have lost their inducibility of ALA synthase-1 [ALAS-1]. Allyl isopropyl acetamide [AIA], a known potent porphyrogen and inducer of ALAS-1, was used as a positive control to help predict porphyrogenicity for tested compounds. Among the tested compounds (acetaminophen, acetylsalicylic acid, ß-estradiol, hydroxychloroquine sulfate, alpha-methyldopa, D (-) norgestrel, phenobarbital, phenytoin, sulfamethoxazole, sulfisoxazole, sodium valproate, and valsartan), concentrations greater than 0.314 mM for norgestrel, phenobarbital, phenytoin, and sodium valproate produced fluorescence readings higher than the reading produced by the positive AIA control. Porphyrin accumulation was also measured by HPLC to confirm the validity of the assay. We conclude that LMH cell cultures in multi-well plates are an inexpensive, robust, and simple system to predict the porphyrogenicity of existing or novel compounds that may exacerbate the AHPs.

Biological system considerations for application of toxicogenomics in next-generation risk assessment and predictive toxicology.

There is increasing interest in using modern 'omics technologies, such as whole transcriptome sequencing, to inform decisions about human health safety and chemical toxicity hazard. High throughput methodologies using in vitro assays offer a path forward in reducing or eliminating animal testing. However, many aspects of these technologies need assessment before they will gain the trust of regulators and the public as viable alternative test methods for human health and safety. We used a high throughput whole transcriptome sequence assay (TempO-Seq) to assess the use of three widely used cancer cell lines (HepG2, MCF7, and Ishikawa cells) as in vitro systems for determination of cellular modes of action for two well studied compounds with canonical liver responses: ketoconazole and phenobarbital. We evaluated transcriptomic data to infer points of departure for use in risk analyses of compounds. Both compounds displayed shortcomings in evidence for canonical liver-related responses in any cell line, despite a strong dose response in all three. This raises questions about the competence of simple, mono-cultured cancer cell lines as appropriate surrogates for some adverse effects or toxic endpoints. Points of departure derived from benchmark doses were highly consistent across all three cell lines however, indicating the use of transcriptomic BMD analyses for such purposes would be a reliable and consistent approach.

Development of an antiepileptogenesis drug screening platform: Effects of everolimus and phenobarbital.

OBJECTIVE: The kainic acid (KA)-induced status epilepticus (SE) model in rats is a well-defined model of epileptogenesis. This model closely recapitulates many of the clinical and pathological characteristics of human temporal lobe epilepsy (TLE) that arise following SE or another neurological insult. Spontaneous recurrent seizures (SRS) in TLE can present after a latent period following a neurological insult (traumatic brain injury, SE event, viral infection, etc.). Moreover, this model is suitable for preclinical studies to evaluate the long-term process of epileptogenesis and screen putative disease-modifying/antiepileptogenic agents. The burden of human TLE is highly variable, similar to the post-KA SE rat model. In this regard, this model may have broad translational relevance. This report thus details the pharmacological characterization and methodological refinement of a moderate-throughput drug screening program using the post-KA-induced SE model of epileptogenesis in male Sprague Dawley rats to identify potential agents that may prevent or modify the burden of SRS. Specifically, we sought to demonstrate whether our protocol could prevent the development of SRS or lead to a reduced frequency/severity of SRS. METHODS: Rats were administered either everolimus (2-3 mg/kg po) beginning 1, 2, or 24 h after SE onset, or phenobarbital (60 mg/kg ip) beginning 1 h after SE onset. All treatments were administered once/day for 5-7 days. Rats in all studies (n = 12/treatment dose/study) were then monitored intermittently by video-electroencephalography (2 weeks on, 2 weeks off, 2 weeks on epochs) to determine latency to onset of SRS and disease burden. RESULTS: Although no adverse side effects were observed in our studies, no treatment significantly modified disease or prevented the presentation of SRS by 6 weeks after SE onset. SIGNIFICANCE: Neither phenobarbital nor everolimus administered at several time points after SE onset prevented the development of SRS. Nonetheless, we demonstrate a practical and moderate-throughput screen for potential antiepileptogenic agents in a rat model of TLE.

COVID-19 et les soins palliatifs en contexte de pénuries pendant la pandémie / COVID-19 and palliative care in the context of shortages during the pandemic

CONTEXTE: Le présent document ainsi que les constats qu'il énonce ont été rédigés en réponse à une interpellation du ministère de la Santé et des Services sociaux dans le contexte de l'urgence sanitaire liée à la maladie à coronavirus (COVID-19) au Québec. L'objectif est de réaliser une recension sommaire des données publiées et de mobiliser les savoirs clés afin d'informer les décideurs publics et les professionnels de la santé et des services sociaux. Vu la nature rapide de cette réponse, les constats ou les positions qui en découlent ne reposent pas sur un repérage exhaustif des données publiées, une évaluation de la qualité méthodologique des études avec une méthode systématique ou sur un processus de consultation élaboré. Dans les circonstances d'une telle urgence de santé publique, l'INESSS reste à l'affût de toutes nouvelles données susceptibles de lui faire modifier cette réponse rapide. PRÉSENTATION DE LA DEMANDE: Le midazolam (VersedMC), lorazépam (AtivanMC) ainsi que le phénobarbital font partie des médicaments administrés en soins palliatifs. Le contexte actuel d'urgence sanitaire lié à la COVID-19 exerce une forte pression sur l'usage de ces médicaments. Afin d'être en mesure d'offrir des soins palliatifs de qualité aux personnes qui le nécessitent, et ce, même en cas de pénurie, le MSSS a demandé à l'INESSS de rechercher les médicaments pouvant constituer des alternatives au lorazépam, midazolam et au phénobarbital en soins palliatifs, tout en tenant compte des ruptures de stock actuelles et anticipées de ces médicaments. Une attention particulière a été portée aux moyens permettant de limiter les pertes de produits, ainsi que l'usage du matériel pouvant être appelé à manquer, tels les pompes volumétriques. MÉTHODOLOGIE: Revue de littérature Questions d'évaluation: 1. Quelles sont les alternatives au midazolam (VersedMC), au lorazépam (AtivanMC) et au phénobarbital en soins palliatifs? 2. Quels seraient les moyens permettant de limiter les pertes de ces médicaments? Repérage des publications : Date de la recherche: 9 avril. Une recherche rapide a été effectuée en utilisant les bases de données Pubmed, Medline, Embase, EBM Reviews et le moteur de recherche Google avec les mots-clés suivants: midazolam, lorazepam, phenobarbital, palliative care, palliative sedation, drug shortage. Une recherche manuelle de la littérature a également été effectuée en consultant les sites Web des agences règlementaires, d'agences d'évaluation des technologies de la santé ainsi que ceux d'organismes gouvernementaux, d'associations ou ordres professionnels en lien avec le thème des travaux. CONSTATS DE L'INESSS: Basé sur la documentation scientifique disponible au moment de sa rédaction, et sur les consultations menées, malgré l'incertitude existante dans cette documentation et dans la démarche utilisée, l'INESSS met en lumière que: La pénurie de médicaments, réelle ou potentielle, doit être communiquée localement dès maintenant aux différents intervenants et des actions mises en place immédiatement, si ce n'est pas déjà fait, dans tous les centres hospitaliers du Québec, qu'ils reçoivent ou non des patients atteints de la COVID-19. L'utilisation des options alternatives devrait donc être favorisée dès maintenant afin d'éviter une pression à la baisse sur les stocks des molécules déjà à risque de pénurie. Dans un contexte d'approvisionnement limité et incertain, il faut éviter le gaspillage et minimiser les pertes; de plus, l'usage de certains produits critiques devrait être priorisé et réservé aux situations pour lesquelles les options alternatives sont peu ou pas envisageables. Il est important de bien adapter le choix des médicaments en fonction des symptômes que l'on souhaite soulager, de l'état du patient et du degré de sédation désiré. Pour soutenir les plus petits centres hospitaliers dans l'usage des options alternatives en soins palliatifs, il serait important de faciliter le partage des connaissances développées dans les grands centres hospitaliers au moyen, par exemple, d'un programme de mentorat. Les patients atteints de COVID-19 chez qui l'approche préconisée est palliative devront faire l'objet d'une prise en charge adaptée qui tient compte de la mitigation des risques de transmission ou contamination. Considérant l'évolution de la pandémie et les milieux d'exercice des soins de fin de vie, les pratiques devront néanmoins s'adapter en tenant compte des éléments d'expertise locale et de capacité du milieu à offrir certains soins.

Avaliação do perfil dos tumores de mama localmente avançados de estadiamento inicial T4N0 no Instituto Nacional de Câncer José Alencar Gomes da Silva / Profile assessment of locally advanced T4N0 breast tumors at the National Cancer Institute José Alencar Gomes da Silva

"Introdução: O câncer de mama localmente avançado é uma forma de apresentação ainda bastante frequente em países em desenvolvimento, correspondendo a um grupo heterogêneo de tumores com comportamento biológico variado. As pacientes são tratadas com abordagem multidisciplinar, incluindo tratamento sistêmico, cirurgia radical e radioterapia. Objetivo: Avaliar se há características presentes em tumores de estadiamento clínico T4N0 que poderiam dar respaldo à realização de biópsia de linfonodo sentinela. Método: Estudo retrospectivo incluindo 50 pacientes com carcinoma invasivo de mama localmente avançado matriculadas no Instituto Nacional de Câncer no período entre fevereiro de 2008 a agosto de 2010. Todas as pacientes foram submetidas a tratamento cirúrgico com mastectomia radical modificada e todas as pacientes foram submetidas à radioterapia adjuvante. Utilizadas variáveis como tamanho do tumor, número de linfonodos acometidos, subtipo molecular e ocorrência de linfedema. Resultados: A média de idade foi 59,42 anos. O tamanho médio do tumor pré-tratamento foi 5,83 cm e pós-tratamento foi 3,2 cm. Terapia neoadjuvante sistêmica foi administrada a 40 pacientes. Trinta e seis casos tinham receptor de estrogênio positivo, 19 pacientes eram receptor de progesterona positivo, 10 pacientes apresentavam HER2 positivo, 5 casos de tumores receptor hormonal negativo e HER2 positivo, 9 pacientes tumores triplo negativos e cinco pacientes com tumores do tipo luminal híbrido. Vinte e três pacientes não apresentaram linfonodos positivos na peça cirúrgica; 18 pacientes apresentaram 1 a 3 linfonodos positivos, 6 pacientes apresentaram de 4 a 9 linfonodos comprometidos e 3 pacientes com 10 ou mais linfonodos comprometidos. Apresentaram linfedema 34% das pacientes, sendo que 41,1% não apresentaram doença axilar na patologia pós-operatória. Das vinte e três pacientes com ausência de doença axilar, 82,6% das pacientes apresentavam, ao exame clínico na triagem, apenas edema cutâneo como característica para classificação T4. Conclusão: A biópsia de linfonodo sentinela poderia ser considerada em casos selecionados de pacientes classificadas como T4b que apresentam como alteração apenas o edema de pele, e com o tratamento sistêmico apresentam resposta terapêutica e resolução completa da alteração cutânea, mantendo-se com axila clinicamente negativa, podendo se beneficiar de um procedimento menos invasivo na axila"(AU)

"Introduction: Locally advanced breast cancer is a form of presentation that is still quite frequent in developing countries, corresponding to a heterogeneous group of tumors with varied biological behavior. Patients are usually treated with a multidisciplinary approach, including systemic treatment, radical surgery and radiation therapy. Objective: To evaluate if there are characteristics present in T4N0 clinical staging tumors that could support the performance of sentinel lymph node biopsy. Method: Retrospective study including 50 patients with locally advanced invasive breast carcinoma enrolled at the National Cancer Institute from February 2008 to August 2010. All patients underwent surgical treatment with modified radical mastectomy and all patients underwent adjuvant radiotherapy. Variables such as tumor size, number of affected lymph nodes, molecular subtype and occurrence of lymphedema were assessed. Results: The average age was 59.42 years. The average size of the pretreatment tumor was 5.83 cm and post-treatment was 3.2 cm. Systemic neoadjuvant therapy was administered to 40 patients. Thirty-six cases had positive estrogen receptor, 19 patients were positive progesterone receptor, 10 patients had HER2 positive, 5 cases of negative hormone receptor and positive HER2 tumors, 9 patients with triple negative tumors and 5 patients with hybrid luminal tumors. 23 patients did not present positive lymph nodes in the surgical specimen; 18 patients had 1 to 3 positive lymph nodes, 6 patients had 4 to 9 compromised lymph nodes and 3 patients with 10 or more compromised lymph nodes. 34% of the patients had lymphedema, and 41.1% of them had no axillary disease in the postoperative pathology. Of the 23 patients with no axillary disease, 82.6% of the patients presented, at screening, on clinical examination, only cutaneous edema as a characteristic for T4 classification. Conclusion: Sentinel lymph node biopsy could be considered in selected cases of patients classified as T4b who present only skin edema as an alteration, and with systemic treatment present therapeutic response and complete resolution of the skin alteration, maintaining a clinically negative armpit and may benefit from a less invasive procedure in the armpit."(AU)

Meta-analysis and cost-effectiveness of second-line antiepileptic drugs for status epilepticus.

OBJECTIVE: Compare the cost and effectiveness of nonbenzodiazepine antiepileptic drugs (non-BZD AEDs) for treatment of BZD-resistant convulsive status epilepticus (SE). METHODS: Decision analysis model populated with effectiveness data from a systematic review and meta-analysis of the literature, and cost data from publicly available prices. The primary outcome was cost per seizure stopped ($/SS). Sensitivity analyses evaluated the robustness of the results across a wide variation of the input parameters. RESULTS: We included 24 studies with 1,185 SE episodes. The most effective non-BZD AED was phenobarbital (PB) with a probability of SS of 0.8 (95% confidence interval [CI]: 0.69-0.88), followed by valproate (VPA) (0.71 [95% CI: 0.61-0.79]), lacosamide (0.66 [95% CI: 0.51-0.79]), levetiracetam (LEV) (0.62 [95% CI: 0.5-0.73]), and phenytoin/fosphenytoin (PHT) (0.53 [95% CI: 0.39-0.67]). In pairwise comparisons, PB was more effective than PHT (p = 0.002), VPA was more effective than PHT (p = 0.043), and PB was more effective than LEV (p = 0.018). The most cost-effective non-BZD AED was LEV (incremental cost-effectiveness ratio [ICER]: $18.55/SS), followed by VPA (ICER: $94.44/SS), and lastly PB (ICER: $847.22/SS). PHT and lacosamide were not cost-effective compared to the other options. Sensitivity analyses showed marked overlap in cost-effectiveness, but PHT was consistently less cost-effective than LEV, VPA, and PB. CONCLUSION: VPA and PB were more effective than PHT for SE. There is substantial overlap in the cost-effectiveness of non-BZD AEDs for SE, but available evidence does not support the preeminence of PHT, neither in terms of effectiveness nor in terms of cost-effectiveness.

Home Palliative Sedation Using Phenobarbital Suppositories: Time to Death, Patient Characteristics, and Administration Protocol.

BACKGROUND: Most people in the United States and other countries cite their preferred location of death as their homes. However, intractable symptoms sometimes require hospitalization, especially if significant sedation becomes necessary. For over a decade, Hospice of Central New York has been using compounded phenobarbital suppositories with individuals in whom adequate sedation has not been achieved using sufficient doses of antipsychotics or benzodiazepines but prefer to remain in their homes. OBJECTIVES: (1) Describe the use of phenobarbital suppositories in homes for the purpose of sedation. (2) Understand patient characteristics of potential users and those in whom suppositories were actually used. (3) Measure time to death after initiating the phenobarbital suppositories. SETTING: Medicare-certified not-for-profit hospice organization in New York State. METHOD: Retrospective case series. RESULTS: Of 1675 patients enrolled in hospice over an 18-month period, phenobarbital suppositories were placed in the homes of 90 patients for potential use. Suppositories were initiated in 31 of the 90 patients. Agitated delirium was the major symptom for which suppositories were placed and initiated. Both groups had a greater prevalence of cancer diagnoses than the target population. The mean time to death after initiation of phenobarbital suppositories was 38.8 hours. None of the users were hospitalized. CONCLUSION: The use of compounded phenobarbital suppositories for the purpose of palliative sedation is an alternative for patients and families who desire to remain home despite refractory symptoms.

Interventional programs to improve therapeutic management of people with epilepsy in low- and middle-income countries.

OBJECTIVE: To assess the current status of initiatives carried out in developing countries to improve therapeutic management of people with epilepsy. METHODS: A literature review was performed in 2015 to identify and analyze interventional programs carried out in countries with low- and middle-income economies. Electronic databases were reviewed with no time restriction. Each intervention was categorized according to the level of evidence achieved (A: blind randomized controlled trial, B: randomized controlled trial, C1: randomized trial, C2: controlled trial, D: prospective cohort, E: retrospective evaluation). RESULTS: A total of 46 intervention projects were identified, 13 with no quantitative assessment. The 31 remaining projects were carried out in 18 countries, 52% (16) in Africa, 42% (13) in Asia, and 6% (2) in Latin America. Among those, 13% (4) were level B, 3% (1) C1, 6% (2) C2, 74% (23) D, and 3% (1) were level E. The effectiveness of the intervention, assessed by the efficacy of antiepileptic drugs, was the primary objective in 81% (25). People with epilepsy were on average seizure-free in 44.6%±14.4% of cases at one year, ranging from 25.0% to 78.4%. At two years, on average 50.9%±29.7% are seizure-free, ranging from 4.6 to 92.7%. The median compliance was 79.3% with a minimum of 21.6% and a maximum of 100.0%. DISCUSSION: No blind randomized controlled trial has been used to assess the efficacy of a program to improve access to antiepileptic drugs (AEDs) in developing countries, and the level of evidence was globally low. Phenobarbital remains the AED predominantly used in programs. Adherence to treatment management has been pointed out to be a key element in the success of a program, sometimes not sufficiently considered. Monthly supply of AEDs, at specific and community level, reducing the costs and time spent traveling, appeared to be the most effective strategies. Homogenization and standardization of evaluation practices of programs to improve the management of epilepsy in resource-limited settings would lead to comparison and meta-analysis which would ultimately improve strategies of support for not only epilepsy but also other noncommunicable diseases in developing countries.

Cytochrome P450 1A2 Messenger RNA is a More Reliable Marker than Cytochrome P450 1A2 Activity, Phenacetin O-Deethylation, for Assessment of Induction Potential of Drug-Metabolizing Enzymes Using HepaRG Cells.

BACKGROUND: The HepaRG cells have key drug metabolism functionalities comparable to those of primary human hepatocytes. Many studies have reported that this cell line can be used as a reliable in vitro model for human drug metabolism studies, including the assessment of cytochrome P450 (CYP) induction. OBJECTIVES: The objective of this study is to determine whether CYP mRNA level measurement is superior to the CYP enzyme activity measurement as a convenient high-throughput method for evaluating CYP induction potential using HepaRG cells. METHODS: QuantiGene Plex 2.0 Assay and LC/MS/MS. mRNA expression levels and enzyme activities of CYP1A2, CYP2B6, and CYP3A in HepaRG cells treated with prototypical inducers of each CYP isoform [omeprazole (OME) for CYP1A2, phenobarbital (PB) for CYP2B6, and rifampicin (RIF) for CYP3A] were evaluated. RESULTS: Although the activities of CYP2B6 and CYP3A were induced by treatment with PB and RIF, we found that the activity of phenacetin O-deethylase (PHOD), which is known as a marker of the activity of CYP1A2, was also enhanced by treatment with these non-CYP1A2 inducers in HepaRG cells. Based on previously published reports, we hypothesized that the expression ratio of CYP3A to CYP1A2 is much higher in HepaRG cells than in human hepatocytes; this may result in a nonnegligible contribution of CYP3A to the PHOD reaction in HepaRG cells. Studies using CYP3A inhibitor and pregnane X receptor-knockout HepaRG cells supported this hypothesis. CONCLUSION: The measurement of mRNA serves as a higher reliable indicator for the evaluation of CYP induction potential when using HepaRG cells.

Implementation of a Neurocritical Care Program: Improved Seizure Detection and Decreased Antiseizure Medication at Discharge in Neonates With Hypoxic-Ischemic Encephalopathy.

BACKGROUND: We report the impact of implementing continuous video electroencephalography monitoring for neonates with hypoxic-ischemic encephalopathy via a protocol in the context of neonatal neuro-critical care program. METHODS: Neonates with hypoxic-ischemic encephalopathy were studied retrospectively two years before and after implementing continuous video electroencephalography for 72 hours as a care protocol. Before continuous video electroencephalography, a 60-minute routine electroencephalography was performed at the discretion of the provider. PRIMARY OUTCOME: electrographic seizure detection; secondary outcome: use of maintenance antiseizure medications, discharge antiseizure medications, and cumulative burden for each antiseizure medication defined as total mg/kg during hospital stay. RESULTS: A total of 157 patients with a median gestation of 40 weeks were analyzed; 103 (66%) underwent therapeutic hypothermia. Baseline and clinical characteristics including disease severity and cooling were similar. Before continuous video-electroencephalography (n = 86), 44 (51.2%) had clinical seizures, of those 35 had available routine electroencephalography; 12 of 35 (34%) had electrographic seizures. None of the infants without clinical seizures showed electrographic seizures. After continuous video-electroencephalography (n = 71), 34 (47.9%) had clinical seizures, of those 18 (53%) had electrographic seizures; five of 37 (14%) of infants with no clinical seizures had electrographic seizures. The introduction of continuous video-electroencephalography significantly increased electrographic seizure detection (P = 0.016). Although there was no significant difference in the initiation and maintenance use of antiseizure medications after continuous video-electroencephalography, fewer infants were discharged on any antiseizure medication (P = 0.008). Also, the mean phenobarbital burden reduced (P = 0.04), without increase in other antiseizure medications use or burden. CONCLUSION: Use of continuous video-electroencephalography as part of the neonatal neuro-critical care program was associated with improved electrographic seizure detection, decreased phenobarbital burden, and antiseizure medication use at discharge.

Overview of accessibility and quality of antiepileptic drugs in Madagascar.

PURPOSE: To determine the accessibility of treatment and the quality of antiepileptic drugs (AEDs) in the Haute Matsiatra district of Madagascar. METHODS: Cross-sectional descriptive study and interviews. Samples of 10 units of each available AED were collected, and the active ingredient was quantified by reversed-phase high-performance liquid chromatography (RP-HPLC) with photodiode-array UV detection. The quality of an AED was considered satisfactory if the quantity of active ingredient in each tablet was in the range ±15% of the average value according to the European Pharmacopeia (6th edition, 2008). RESULTS: The area was well served with health infrastructure but rescue facilities were poorly distributed. Available AEDs were all first-generation, and 73% were generic formulations. People with epilepsy (PWE) surveyed consulted traditional healers and most were treated with plants. PWE did not consider themselves sick but believed they were "possessed"; they consulted a doctor only immediately after a seizure, following the advice of traditional healers. The most prescribed AED was phenobarbital, costing between 0.03 and 0.12 US Dollar (US$) per 100mg. The purchase of full treatment was difficult for 77% of PWE and as a result, 39% took nothing. The quality of AEDs were considered unsatisfactory in 2.8% of cases. CONCLUSION: The AEDs collected in Haute Matsiatra were globally of good quality. The main limiting elements were a lack of knowledge among PWE that epilepsy is a disease, and the cost of traditional treatments.

Development of an in vitro high content imaging assay for quantitative assessment of CAR-dependent mouse, rat, and human primary hepatocyte proliferation.

Rodent liver tumors promoted by constitutive androstane receptor (CAR) activation are known to be mediated by key events that include CAR-dependent gene expression and hepatocellular proliferation. Here, an in vitro high content imaging based assay was developed for quantitative assessment of nascent DNA synthesis in primary hepatocyte cultures from mouse, rat, and human species. Detection of DNA synthesis was performed using direct DNA labeling with the nucleoside analog 5-ethynyl-2'-deoxyuridine (EdU). The assay was multiplexed to enable direct quantitation of DNA synthesis, cytotoxicity, and cell count endpoints. An optimized defined medium cocktail was developed to sensitize hepatocytes to cell cycle progression. The baseline EdU response to defined medium was greatest for mouse, followed by rat, and then human. Hepatocytes from all three species demonstrated CAR activation in response to the CAR agonists TCPOBOP, CITCO, and phenobarbital based on increased gene expression for Cyp2b isoforms. When evaluated for a proliferation phenotype, TCPOBOP and CITCO exhibited significant dose-dependent increases in frequency of EdU labeling in mouse and rat hepatocytes that was not observed in hepatocytes from three human donors. The observed species differences are consistent with CAR activators inducing a proliferative response in rodents, a key event in the liver tumor mode of action that is not observed in humans.

Rooming-In to Treat Neonatal Abstinence Syndrome: Improved Family-Centered Care at Lower Cost.

BACKGROUND AND OBJECTIVE: The incidence and associated costs of neonatal abstinence syndrome (NAS) have recently risen sharply; newborns with NAS occupy 4% of NICU beds. We implemented a coordinated program for NAS including standardized protocols for scoring, medications and weaning, and a calm rooming-in environment, to improve family-centered care and to decrease both length of stay (LOS) and hospital costs. METHODS: In early 2013, a multidisciplinary quality improvement team began consecutive plan-do-study-act (PDSA) cycles. We trained nurses in modified Finnegan scoring, ensured scoring only after on-demand feeds during skin-to-skin care, and standardized physician score interpretation. We provided prenatal family education, increased family involvement in symptom monitoring and nonpharmacologic treatment, and treated otherwise healthy infants on the inpatient pediatric unit instead of in the NICU. We measured outcomes using statistical process control methods. RESULTS: At baseline, 46% of inborn infants at-risk for NAS were treated with morphine; by 2015, this decreased to 27%. Adjunctive use of phenobarbital decreased from 13% to 2% in the same period. Average LOS for morphine-treated newborns decreased from 16.9 to 12.3 days, average hospital costs per treated infant decreased from $19 737 to $8755, and costs per at-risk infant dropped from $11 000 to $5300. Cumulative morphine dose decreased from 13.7 to 6.6 mg per treated newborn. There were no adverse events, and 30-day readmission rates remained stable. CONCLUSIONS: A coordinated, standardized NAS program safely reduced pharmacologic therapy, LOS, and hospital costs. Rooming-in with family and decreased use of NICU beds were central to achieved outcomes.

[Therapeutic drug monitoring of three antiepileptic drugs - Back on twenty years of experience]. / Suivi thérapeutique pharmacologique de trois médicaments antiépileptiques: retour sur vingt années d'expérience.

INTRODUCTION: The therapeutic drug monitoring (TDM) of antiepileptic drugs is a tool widely used in the management of epilepsy. In Morocco, this monitoring is carried out by the Centre Anti Poison et Pharmacovigilance (CAPM) since April 1995. METHODS: This is a retrospective study spanning 20 years. It concerns the therapeutic drug monitoring of Phenobarbital (PB) of carbamazepine (CBZ) and valproic acid (VPA). RESULTS: Therapeutic drug monitoring of the 3 antiepileptic drugs represent 58.85% of all applications received by the CAPM. The dosage of PB was ranked first followed by that of CBZ and finally by the VPA. Weak demand for therapeutic drug monitoring in Morocco could be explained by the low number of neurologists in addition to social factors. With its affordable price by patients, PB is the most prescribed antiepileptic drug in our country, which explains the high demand for its dosage. As for the therapeutic drug monitoring of the antiepileptic drug, they were mainly related to age, the occurrence of adverse effects, the association antiepileptic drugs or in the case of verification of patient compliance. CONCLUSION: Efforts are required for promoting the interests of therapeutic drug monitoring of antiepileptic drug in the management of epilepsy in Morocco.

Variation in treatment of neonatal abstinence syndrome in US children's hospitals, 2004-2011.

OBJECTIVE: Neonatal abstinence syndrome (NAS) is a drug withdrawal syndrome experienced by opioid-exposed infants. There is no standard treatment for NAS and surveys suggest wide variation in pharmacotherapy for NAS. Our objective was to determine whether different pharmacotherapies for NAS are associated with differences in outcomes and to determine whether pharmacotherapy and outcome vary by hospital. STUDY DESIGN: We used the Pediatric Health Information System Database from 2004 to 2011 to identify a cohort of infants with NAS requiring pharmacotherapy. Mixed effects hierarchical negative binomial models evaluated the association between pharmacotherapy and hospital with length of stay (LOS), length of treatment (LOT) and hospital charges, after adjusting for socioeconomic variables and comorbid clinical conditions. RESULT: Our cohort included 1424 infants with NAS from 14 children's hospitals. Among hospitals in our sample, six used morphine, six used methadone and two used phenobarbital as primary initial treatment for NAS. In multivariate analysis, when compared with NAS patients initially treated with morphine, infants treated with methadone had shorter LOT (incidence rate ratio (IRR) = 0.55; P < 0.0001) and LOS (IRR = 0.60; P < 0.0001). Phenobarbital as a second-line agent was associated with increased LOT (IRR = 2.09; P<0.0001), LOS (IRR = 1.78; P < 0.0001) and higher hospital charges (IRR = 1.84; P < 0.0001). After controlling for case-mix, hospitals varied in LOT, LOS and hospital charges. CONCLUSION: We found variation in hospital in treatment for NAS among major US children's hospitals. In analyses controlling for possible confounders, methadone as initial treatment was associated with reduced LOT and hospital stay.

Home-based detoxification for neonatal abstinence syndrome reduces length of hospital admission without prolonging treatment.

AIM: Neonatal abstinence syndrome (NAS) is a drug withdrawal syndrome, secondary to in utero chemical exposure and characterised by tremor, irritability and feed intolerance. It often requires prolonged hospital treatment and separation of families. Outpatient therapy may reduce this burden, but current literature is sparse. This review aimed to evaluate the safety and efficacy of our home-based detoxification programme and compare it with standard inpatient care. METHODS: Infants requiring treatment for NAS between January 2004 and December 2010 were reviewed. Data on demographics, drug exposure, length of stay and type of therapy were compared between infants selected for home-based therapy and those treated conventionally. RESULTS: Of the 118 infants who were admitted for treatment of NAS, 38 (32%) were managed at home. Infants receiving home-based detoxification had shorter hospital stays (mean 19 days vs. 39 days), with no increase in total duration of treatment (mean 36 days vs. 41 days), and were more likely to be breastfeeding on discharge from hospital care (45% vs. 22%). CONCLUSION: In selected infants, home-based detoxification is associated with reduced hospital stays and increased rates of breastfeeding, without prolonging therapy. Safety of the infants remains paramount, which precludes many from entering such a programme.

Drugs, money, and power: the Canadian drug shortage.

This article describes the shortage of generic injectable medications in Canada that affected hospitals in 2012. It traces the events leading up to the drug shortage, the causes of the shortage, and the responses by health administrators, pharmacists, and ethicists. The article argues that generic drug shortages are an ethical problem because health care organizations and governments have an obligation to avoid exposing patients to resource scarcity. The article also discusses some options governments could pursue in order to secure the drug supply and thereby fulfill their ethical obligations.