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1.
Adv Neonatal Care ; 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38986129

RESUMO

BACKGROUND: Necrotizing enterocolitis (NEC) is common in preterm infants, especially infants less than 32 weeks gestation. Mortality from NEC is 7% and occurs in 1 out of 1000 preterm infants. Studies have shown the efficacy of an exclusive milk from mother diet in decreasing rates of NEC and associated mortality. PURPOSE: To evaluate the effectiveness of an existing exclusive human milk diet (EHMD) protocol on the incidence of NEC in extremely premature infants. EHMD, for the purposes of this project is defined as breast milk of mother, with or without human milk-based fortifier. METHODS: A single-center retrospective quasi-experimental study. The sample included 201 infants born less than 32 weeks gestation, weighing less than 1250 grams, small for gestational age (SGA) and with low Apgar scores. Outcomes measured included incidences of NEC, mortality, and co-morbidities in infants pre- and postinitiation of an EHMD protocol. RESULTS: Just 4.8% of the EHMD group had a NEC diagnosis compared to 10.5% of the bovine-based (BOV) group. There was a 1% mortality rate of the EHMD group as compared to 6% in the BOV group. The EHMD group had a statistically significant greater weight gain during hospitalization as compared to infants fed BOV (P = < .05). IMPLICATIONS FOR PRACTICE AND RESEARCH: Neonatal intensive care units should consider EHMDs for use in this infant population. Future research is needed to support dissemination of the use of EHMD as standard of practice.

2.
Artigo em Inglês | MEDLINE | ID: mdl-38735431

RESUMO

OBJECTIVE: More than 200 million children and adolescents live in countries affected by violent conflict, are likely to have complex mental health needs, and struggle to access traditional mental health services. Digital mental health interventions have the potential to overcome some of the barriers in accessing mental health support. We performed a scoping review to map existing digital mental health interventions relevant for children and adolescents affected by war, to examine the strength of the evidence base, and to inform the development of future interventions. METHOD: Based on a pre-registered strategy, we systematically searched MEDLINE, Embase, Global Health, APA PsychInfo, and Google Scholar from the creation of each database to September 30, 2022, identifying k = 6,843 studies. Our systematic search was complemented by extensive consultation with experts from the GROW Network. RESULTS: The systematic search identified 6 relevant studies: 1 study evaluating digital mental health interventions for children and adolescents affected by war, and 5 studies for those affected by disasters. Experts identified 35 interventions of possible relevance. The interventions spanned from universal prevention to specialist-guided treatment. Most interventions directly targeted young people and parents or carers/caregivers and were self-guided. A quarter of the interventions were tested through randomized controlled trials. Because most interventions were not culturally or linguistically adapted to relevant contexts, their implementation potential was unclear. CONCLUSION: There is very limited evidence for the use of digital mental health interventions for children and adolescents affected by war at present. The review provides a framework to inform the development of new interventions. DIVERSITY & INCLUSION STATEMENT: We actively worked to promote sex and gender balance in our author group. STUDY PREREGISTRATION INFORMATION: Digital mental health interventions for children and young people affected by war: a scoping review; https://osf.io/; hrny9.

4.
J Affect Disord ; 347: 445-452, 2024 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-38007105

RESUMO

The goal of this work was to explore associations of constituent factors of alexithymia on mental health and potential mediating effects of emotion regulation strategies, specifically suppression and reappraisal. Data were collected through the crowd-sourcing platform Amazon Mechanical Turk (MTURK). Three hundred seventy-seven individuals completed questionnaires related to distress (Depression Anxiety Stress Scales [DASS]), emotion regulation (Emotion Regulation Questionnaire [ERQ]) and Alexithymia (Bermond-Vorst Alexithymia Questionnaire [BVAQ]). Three mediation models were constructed for depression, anxiety and stress, with BVAQ subscales (verbalizing, identifying, emotionalizing, fantasizing, and analyzing) as predictors and ERQ subscales (suppression and reappraisal) as mediators. Results indicated 37.3 % variance in depression, 25.2 % variance in anxiety, and 35.3 % variance in stress was explained by each model. Direct associations revealed emotionalizing and fantasizing were negatively associated with depression, anxiety, and stress, while verbalizing was additionally associated with depression, identifying was additionally associated with anxiety, and all four BVAQ subscales were associated with stress. BVAQ subscales demonstrated negative associations with reappraisal and positive associations with suppression that mediated anxiety and depression. However, suppression did not mediate relationships between BVAQ subscales with stress. Findings support the importance of examining multiple factors of alexithymia and associations with emotion regulation strategies and distress.


Assuntos
Sintomas Afetivos , Depressão , Humanos , Sintomas Afetivos/epidemiologia , Sintomas Afetivos/psicologia , Depressão/epidemiologia , Transtornos de Ansiedade/epidemiologia , Inquéritos e Questionários , Ansiedade/epidemiologia
5.
Contemp Nurse ; 59(4-5): 402-412, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37801549

RESUMO

BACKGROUND: Most recently, it has been reported that 1.4 million adults in the United States identify as transgender. This number is double what was reported just five years earlier. What little research has been completed on this vulnerable population indicates that people who identify as transgender experience higher rates of depression, suicide, and social stigmatization than the cisgender population. Stigmatization of transgender people and lack of access to quality care is often the root for these disparities. Very few studies have examined the experience of transition. OBJECTIVE: The purpose of this phenomenological study was to explore the experience of transitioning from one gender to another. METHODS: Non-structured, in-depth interviews were conducted via an online platform with 11 male-to-female transgender adults who gave their informed consent to participate. RESULTS: Through a process of group data analysis, four major themes emerged: (a) Everybody Saw the Mask; (b) A Turning Point; (c) Shedding My Skin; and (d) Navigating the Way. CONCLUSIONS: These findings can heighten healthcare personnel's sensitivity to this vulnerable population, as well as guide students and providers to provide culturally appropriate care, which can lead to a decrease in health disparities.


Assuntos
Assistência à Saúde Culturalmente Competente , Pessoas Transgênero , Adulto , Humanos , Masculino , Feminino , Estados Unidos , Atenção à Saúde , Qualidade da Assistência à Saúde , Desigualdades de Saúde
6.
Nurse Educ Today ; 129: 105900, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37480672

RESUMO

BACKGROUND: Human trafficking is characterized as a violation of human rights that exploits males and females of any age for personal or financial gain. Recently, health care professionals have been identified as feasible change agents in this global issue. However, many health care professionals are not trained in identifying and treating human trafficking victims. Through human trafficking education, health care professionals have the potential to be better equipped to recognize and assist trafficking victims and guide them to the specialized care they need. OBJECTIVE: The purpose of this study was to measure the effect of a trauma-informed human trafficking education intervention and the impact of this training on the self-efficacy of health care professionals in identifying and recognizing human trafficking victims in healthcare settings. DESIGN: The study was a quasi-experimental research design with snowball and convenience recruitment SETTING: 100 % virtual, online. PARTICIPANTS: Health care professionals (N = 30) including Nurse Practitioners, Physician Assistants, Registered Nurses, Licensed Practical Nurses, Certified Medical Assistants, Certified Nursing Assistants, Emergency Medical Technicians, and Paramedics from a variety of healthcare settings. METHODS: 30 min total program to include Qualtrics pre-intervention Violence Against Women Health Care Provider survey, 20 min educational intervention on YouTube©, and an identical Qualtrics post-intervention survey. RESULTS: Total of 30 sets of paired data. The results showed statistically significant improvement in self-efficacy in all survey questions pre- and post-human trafficking educational intervention (p < .001). CONCLUSIONS: An increase in health care professionals' self-efficacy in identifying and treating human trafficking victims yields better patient and health care system outcomes. Trauma-informed human trafficking education for all health care professionals is recommended.


Assuntos
Tráfico de Pessoas , Autoeficácia , Masculino , Feminino , Humanos , Tráfico de Pessoas/prevenção & controle , Pessoal de Saúde/educação , Inquéritos e Questionários , Pessoal Técnico de Saúde
7.
J Am Acad Child Adolesc Psychiatry ; 62(11): 1188-1190, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37328140

RESUMO

Trauma-exposed young people are about twice as likely as their unexposed peers to develop mental health problems, which, if left untreated, can have long-term negative consequences.1 There is robust evidence for the effectiveness of individual trauma-focused psychological therapies to improve trauma-related psychopathology, particularly posttraumatic stress disorder (PTSD), in young people.2 However, there are minimal services that provide such specialist treatments in low/middle-income countries where most young people live,3 and services may be severely disrupted at times of extreme stressors, such as war, natural disasters, and other humanitarian crises, when need is greatest.4 Moreover, even in high-income stable regions where child mental health services are established and treatments are available, these health care resources are limited, and can only be accessed by a minority of affected trauma-exposed young people.5 There is therefore a need for research to indicate effective interventions that are more accessible and can be delivered on a greater scale to treat more young people with trauma-related psychopathology.6 The recent meta-analysis by Davis et al.7 focused on the more accessible intervention of group-based psychological treatment for child PTSD symptoms, and found evidence of effectiveness compared with control conditions. The study provides an important advancement in this field, and also highlights the need for further research to better understand how group interventions can be most usefully implemented.


Assuntos
Psicoterapia , Transtornos de Estresse Pós-Traumáticos , Criança , Humanos , Adolescente , Transtornos de Estresse Pós-Traumáticos/psicologia , Psicopatologia
8.
Nurs Womens Health ; 27(2): 110-120, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36773629

RESUMO

OBJECTIVE: To determine whether implementation of a written communication tool in labor and delivery during high-risk births improves communication, preparation, and satisfaction of responding neonatal resuscitation team members. DESIGN: Quality improvement project with a pretest and posttest design. SETTING/LOCAL PROBLEM: Two labor and delivery units and a third labor-delivery-recovery-postpartum unit within a health care system in the southeastern United States. PARTICIPANTS: Nurses, nurse practitioners, respiratory therapists, and physicians who are part of the neonatal resuscitation team. INTERVENTIONS/MEASUREMENTS: A researcher-designed, written communication tool titled the High-Risk Delivery Communication Tool was implemented in the settings. A researcher-designed measurement tool titled the Neonatal High-Risk Delivery Communication Scale was used as a before-and-after survey to measure communication to the neonatal resuscitation team, preparation for high-risk births, and satisfaction with communication from labor and delivery nurses. RESULTS: Findings from all portions of the Neonatal High-Risk Delivery Communication Scale indicated statistically significant improvements in communication, preparation, and neonatal resuscitation team member neonatal resuscitation team satisfaction while attending high-risk births. Scores improved on every item regarding hand-off, risk factor communication, preparation, and satisfaction. CONCLUSION: Implementing a communication tool for use in high-risk births may improve communication to neonatal resuscitation team members, enhance preparation for neonatal care, and increase team members' satisfaction with interprofessional communication.


Assuntos
Comunicação , Ressuscitação , Feminino , Recém-Nascido , Humanos , Sudeste dos Estados Unidos , Período Pós-Parto , Equipe de Assistência ao Paciente
9.
J Child Psychol Psychiatry ; 64(4): 708-710, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36789471

RESUMO

In their annual research review, McAdams, Cheesman, and Ahmadzadeh (2023) provide a thorough overview of how the use of novel genetically informative approaches can increase our knowledge about the intergenerational transmission of psychopathology. Many JCPP readers will already be familiar with genetically sensitive family-based designs, such as twin and adoption studies, as well as with newer molecular-genetic approaches, such as polygenic-score studies. McAdams et al.'s (2023) review discusses the innovative combination of family-based and molecular-genetic methods, and what this combination can reveal about developmental psychopathology.


Assuntos
Saúde Mental , Psicopatologia , Humanos , Genômica
10.
Child Youth Care Forum ; 52(4): 829-853, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36092528

RESUMO

Background: Youth-serving organizations in the United States provide programs, activities, and opportunities for young people before school, during school, after school, in summer, and on weekends. At the core of youth-serving organizations are the adults; that is, youth development staff. Objective: In this explanatory sequential mixed methods study we explored youth development staff's stress and worries, their compassion satisfaction, and whether stress and compassion satisfaction varied by race/ethnicity and gender during the early months of the COVID-19 pandemic - a collective trauma event. Methods: We surveyed 283 youth development staff and interviewed a subset of 25. Results: Results suggest that youth development staff experienced stress and compassion satisfaction during the COVID-19 pandemic. Conclusion: We recommend organizational leaders provide youth development staff with support before a collective trauma event. They can work to change, add, or remove policies, practices, and routines to help decrease stress and increase compassion satisfaction. In addition, based on our results from this study our primary recommendation specific to collective trauma events, after taking care of their own personal wellness, is for youth development staff to focus on what is in their control and work to do those things for as many young people as they can.

12.
ACS Chem Biol ; 17(7): 1824-1830, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35730734

RESUMO

Fungus-growing ants are defended by antibiotic-producing bacterial symbionts in the genus Pseudonocardia. Nutrients provisioned by the ants support these symbionts but also invite colonization and competition from other bacteria. As an arena for chemically mediated bacterial competition, this niche offers a window into ecological antibiotic function with well-defined competing organisms. From multiple colonies of the desert specialist ant Trachymyrmex smithi, we isolated Amycolatopsis bacteria that inhibit the growth of Pseudonocardia symbionts under laboratory conditions. Using bioassay-guided fractionation, we discovered a novel analog of the antibiotic nocamycin that is responsible for this antagonism. We identified the biosynthetic gene cluster for this antibiotic, which has a suite of oxidative enzymes consistent with this molecule's more extensive oxidative tailoring relative to similar tetramic acid antibiotics. High genetic similarity to globally distributed soil Amycolatopsis isolates suggest that this ant-derived Amycolatopsis strain may be an opportunistic soil strain whose antibiotic production allows for competition in this specialized niche. This nocamycin analog adds to the catalog of novel bioactive molecules isolated from bacterial associates of fungus-growing ants, and its activity against ant symbionts represents, to our knowledge, the first putative ecological function for the widely distributed enoyl tetramic acid family of antibiotics.


Assuntos
Formigas , Animais , Antibacterianos/farmacologia , Formigas/microbiologia , Bactérias , Fungos , Policetídeos , Solo , Simbiose
13.
Clin Trials ; 19(4): 452-463, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35730910

RESUMO

BACKGROUND/AIMS: There are increasing pressures for anonymised datasets from clinical trials to be shared across the scientific community, and differing recommendations exist on how to perform anonymisation prior to sharing. We aimed to systematically identify, describe and synthesise existing recommendations for anonymising clinical trial datasets to prepare for data sharing. METHODS: We systematically searched MEDLINE®, EMBASE and Web of Science from inception to 8 February 2021. We also searched other resources to ensure the comprehensiveness of our search. Any publication reporting recommendations on anonymisation to enable data sharing from clinical trials was included. Two reviewers independently screened titles, abstracts and full text for eligibility. One reviewer extracted data from included papers using thematic synthesis, which then was sense-checked by a second reviewer. Results were summarised by narrative analysis. RESULTS: Fifty-nine articles (from 43 studies) were eligible for inclusion. Three distinct themes are emerging: anonymisation, de-identification and pseudonymisation. The most commonly used anonymisation techniques are: removal of direct patient identifiers; and careful evaluation and modification of indirect identifiers to minimise the risk of identification. Anonymised datasets joined with controlled access was the preferred method for data sharing. CONCLUSIONS: There is no single standardised set of recommendations on how to anonymise clinical trial datasets for sharing. However, this systematic review shows a developing consensus on techniques used to achieve anonymisation. Researchers in clinical trials still consider that anonymisation techniques by themselves are insufficient to protect patient privacy, and they need to be paired with controlled access.


Assuntos
Confidencialidade , Anonimização de Dados , Humanos , Disseminação de Informação/métodos , Pesquisadores
14.
Mol Psychiatry ; 27(6): 2700-2708, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35365801

RESUMO

Recent years have seen the rapid proliferation of clinical prediction models aiming to support risk stratification and individualized care within psychiatry. Despite growing interest, attempts to synthesize current evidence in the nascent field of precision psychiatry have remained scarce. This systematic review therefore sought to summarize progress towards clinical implementation of prediction modeling for psychiatric outcomes. We searched MEDLINE, PubMed, Embase, and PsychINFO databases from inception to September 30, 2020, for English-language articles that developed and/or validated multivariable models to predict (at an individual level) onset, course, or treatment response for non-organic psychiatric disorders (PROSPERO: CRD42020216530). Individual prediction models were evaluated based on three key criteria: (i) mitigation of bias and overfitting; (ii) generalizability, and (iii) clinical utility. The Prediction model Risk Of Bias ASsessment Tool (PROBAST) was used to formally appraise each study's risk of bias. 228 studies detailing 308 prediction models were ultimately eligible for inclusion. 94.5% of developed prediction models were deemed to be at high risk of bias, largely due to inadequate or inappropriate analytic decisions. Insufficient internal validation efforts (within the development sample) were also observed, while only one-fifth of models underwent external validation in an independent sample. Finally, our search identified just one published model whose potential utility in clinical practice was formally assessed. Our findings illustrated significant growth in precision psychiatry with promising progress towards real-world application. Nevertheless, these efforts have been inhibited by a preponderance of bias and overfitting, while the generalizability and clinical utility of many published models has yet to be formally established. Through improved methodological rigor during initial development, robust evaluations of reproducibility via independent validation, and evidence-based implementation frameworks, future research has the potential to generate risk prediction tools capable of enhancing clinical decision-making in psychiatric care.


Assuntos
Modelos Estatísticos , Psiquiatria , Viés , Humanos , Prognóstico , Reprodutibilidade dos Testes
15.
Br J Psychiatry ; 220(3): 107-108, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35049481

RESUMO

Childhood adversities are major preventable risk factors for poor mental and physical health. Scientific advances in this area are not matched by clinical gains for affected individuals. We reflect on novel research directions that could accelerate clinical impact.


Assuntos
Experiências Adversas da Infância , Humanos , Fatores de Risco
16.
Am J Prev Med ; 62(3): 427-432, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34635382

RESUMO

INTRODUCTION: Adverse childhood experiences confer an increased risk for physical and mental health problems across the population, prompting calls for routine clinical screening based on reported adverse childhood experience exposure. However, recent longitudinal research has questioned whether adverse childhood experiences can accurately identify ill health at an individual level. METHODS: Revisiting data collected for the Adverse Childhood Experience Study between 1995 and 1997, this study derived approximate area under the curve estimates to test the ability of the retrospectively reported adverse childhood experience score to discriminate between adults with and without a range of common health risk factors and disease conditions. Furthermore, the classification accuracy of a recommended clinical definition for high-risk exposure (≥4 versus 0-3 adverse childhood experiences) was evaluated on the basis of sensitivity, specificity, positive and negative predictive values, and positive likelihood ratios. RESULTS: Across all health outcomes, the levels of discrimination for the continuous adverse childhood experience score ranged from very poor to fair (area under the curve=0.50-0.76). The binary classification of ≥4 versus 0-3 adverse childhood experiences yielded high specificity (true-negative detection) and negative predictive values (absence of ill health among low-risk adverse childhood experience groups). However, sensitivity (true-positive detection) and positive predictive values (presence of ill health among high-risk adverse childhood experience groups) were low, whereas positive likelihood ratios suggested only minimal-to-moderate increases in health risks among individuals reporting ≥4 adverse childhood experiences versus that among those reporting 0-3. CONCLUSIONS: These findings suggest that screening based on the adverse childhood experience score does not accurately identify those individuals at high risk of health problems. This can lead to both allocation of unnecessary interventions and lack of provision of necessary support.


Assuntos
Experiências Adversas da Infância , Adulto , Humanos , Programas de Rastreamento , Estudos Retrospectivos , Fatores de Risco
17.
Br J Psychiatry ; 219(2): 448-455, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34538875

RESUMO

Background: Complex traumas are traumatic experiences that involve multiple interpersonal threats during childhood or adolescence, such as repeated abuse. Complex traumas are hypothesized to lead to more severe psychopathology and poorer cognitive function than other non-complex traumas. However, empirical testing of this hypothesis has been limited to clinical/convenience samples and cross-sectional designs. Aims: To investigate psychopathology and cognitive function in young people exposed to complex, non-complex, or no trauma from a population-representative longitudinal cohort, and to consider the role of pre-existing vulnerabilities. Method: Participants were from the Environmental Risk (E-Risk) Longitudinal Twin Study, a population-representative birth-cohort of 2,232 British children. At age 18 years (93% participation), we assessed lifetime exposure to complex and non-complex trauma, past-year psychopathology, and current cognitive function. We also prospectively assessed early childhood vulnerabilities: internalizing and externalizing symptoms at age 5, IQ at age 5, family history of mental illness, family socioeconomic status, and sex. Results: Participants exposed to complex trauma had more severe psychopathology and poorer cognitive function at age 18 compared to both trauma-unexposed participants and those exposed to non-complex trauma. Early childhood vulnerabilities predicted risk of later complex trauma exposure, and largely explained associations of complex trauma with cognitive deficits, but not with psychopathology. Conclusions: By conflating complex and non-complex traumas, current research and clinical practice under-estimate the severity of psychopathology, cognitive deficits, and pre-existing vulnerabilities linked with complex trauma. A better understanding of the mental health needs of people exposed to complex trauma could inform the development of new effective interventions.


Assuntos
Transtornos Mentais , Psicopatologia , Adolescente , Criança , Pré-Escolar , Cognição , Estudos de Coortes , Estudos Transversais , Humanos , Estudos Longitudinais , Transtornos Mentais/epidemiologia
18.
JAC Antimicrob Resist ; 3(1): dlab022, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34223097

RESUMO

BACKGROUND: Early in vitro studies suggested that flavophospholipol has plasmid-curing effects and could inhibit conjugation by disrupting pilus formation between bacteria. OBJECTIVES: This 36-day controlled-challenge study aimed to evaluate the anti-conjugative and plasmid-curing effect of flavophospholipol in vivo on plasmid-mediated antimicrobial resistance (AMR) in MDR transconjugant Salmonella Enteritidis in chickens. METHODS: A total of 270-day-old chicks were randomly assigned to four control and four treatment groups with two doses of in-feed flavophospholipol (10 ppm and 64 ppm) and in the presence and absence of ampicillin in drinking water. Chicks were orally challenged with Salmonella Enteritidis with known plasmid-encoded AMR factors. Cloacal swabs were collected on Day 7, 14 and 23. On Day 35, all chickens were euthanized, and caecal tissue and content were collected. Antimicrobial susceptibility testing was done with a panel of 12 antimicrobials and interpreted according to CLSI breakpoints. RESULTS: Flavophospholipol given in-feed at 64 ppm had an anti-conjugative effect. There was a significant reduction of acquisition of resistance to ampicillin, streptomycin and tetracycline by the recipient strains of Salmonella Enteritidis in treatment groups given flavophospholipol in-feed at 64 ppm (P < 0.05). This was not seen with flavophospholipol given in-feed at 10 ppm. CONCLUSIONS: The results demonstrate that flavophospholipol given in-feed at 64 ppm had an anti-conjugative effect. The results also suggest that AMR is reduced through other mechanisms of action, which are yet to be determined. There is insufficient evidence that flavophospholipol at 64 ppm in feed alone or with sub-therapeutic levels of antibiotics had a plasmid-curing effect.

20.
AAPS J ; 22(4): 92, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32676788

RESUMO

In this study, we characterized the pharmacokinetics of OSU-2S, a fingolimod-derived, non-immunosuppressive phosphatase activator, in mice, rats, and dogs, as well as tolerability and food effects in dogs. Across all species tested, plasma protein binding for OSU-2S was > 99.5%, and metabolic stability and hepatic intrinsic clearance were in the moderate range. OSU-2S did not significantly modulate CYP enzyme activity up until 50 µM, and Caco-2 data suggested low permeability with active efflux at 2 µM. Apparent oral bioavailability in mice was 16% and 69% at 10 and 50 mg/kg, respectively. In rats, bioavailability was 24%, 35%, and 28% at 10, 30, and 100 mg/kg, respectively, while brain/plasma ratio was 36 at 6-h post-dose at 30 mg/kg. In dogs, OSU-2S was well tolerated with oral capsule bioavailability of 27.5%. Plasma OSU-2S exposures increased proportionally over a 2.5-20 mg/kg dose range. After 4 weeks of 3 times weekly, oral administration (20 mg/kg), plasma AUClast (26.1 µM*h), and Cmax (0.899 µM) were nearly 2-fold greater than those after 1 week of dosing, and no food effects were observed. The elimination half-life (29.7 h), clearance (22.9 mL/min/kg), and plasma concentrations of repeated oral doses support a 3-times weekly dosing schedule in dogs. No significant CBC, serum biochemical, or histopathological changes were observed. OSU-2S has favorable oral PK properties similar to fingolimod in rodents and dogs and is well tolerated in healthy animals. This work supports establishing trials of OSU-2S efficacy in dogs with spontaneous tumors to guide its clinical development as a cancer therapeutic for human patients.


Assuntos
Análise de Dados , Cloridrato de Fingolimode/farmacocinética , Imunossupressores/farmacocinética , Propilenoglicóis/farmacocinética , Esfingosina/análogos & derivados , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Cães , Relação Dose-Resposta a Droga , Cloridrato de Fingolimode/administração & dosagem , Haplorrinos , Humanos , Imunossupressores/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Propilenoglicóis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Esfingosina/administração & dosagem , Esfingosina/farmacocinética
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