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OBJECTIVES: The objectives of this qualitative study were to explore participant experiences of doula training programs offered by a prisoner health advocacy organization and Indigenous and Black community groups. DESIGN: This investigation employed a qualitative design. Recruitment was conducted through email. Interviews were conducted in Winter 2020. Data were analyzed using thematic analysis. SAMPLE: A total of 12 participants were recruited to participate in this study. Six participants identify as Black and six identify as Indigenous. All participants identify as women. MEASUREMENTS: Qualitative interviews were conducted using a semi-structured interview guide to elicit a breadth of information. RESULTS: Key themes included training experiences, training improvements and ''bridging the gap''. The training validated participants' experiences of birth and began to address the exclusion of Black and Indigenous people from birth work. However, participants expressed concerns about not being adequately positioned for sustained participation in birth work. CONCLUSIONS: Participants expressed receiving great value from the training programs. These trainings, which were fully subsidized, removed a financial barrier. However, these trainings do not address the exclusion of Black and Indigenous people from perinatal work or the lack or sustainable support systems for Black and Indigenous communities. This study makes several recommendations for future interventions.
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Doulas , Femenino , Humanos , Nueva Escocia , Embarazo , Investigación CualitativaRESUMEN
Retinal diseases, such as age-related macular degeneration and diabetic retinopathy, are the leading causes of blindness worldwide. The mainstay of treatment for these blinding diseases remains to be surgery, and the available pharmaceutical therapies on the market are limited, partially owing to various biological barriers in hindering the delivery of therapeutics to the retina. The nanoparticulate drug delivery system confers the capability for delivering therapeutics to the specific ocular targets and, hence, potentially revolutionizes the current treatment landscape of retinal diseases. While the research to date indicates the enormous therapeutics potentials of the nanoparticulate delivery systems, the successful translation of these systems from the bench to bedside is challenging and requires a combined understanding of retinal pathology, physiology of the eye, and particle and formulation designs of nanoparticles. To this end, the review begins with an overview of the most prevalent retinal diseases and related pharmacotherapy. Highlights of the current challenges encountered in ocular drug delivery for each administration route are provided, followed by critical appraisal of various nanoparticulate drug delivery systems for the retinal diseases, including their formulation designs, therapeutic merits, limitations, and future direction. It is believed that a greater understanding of the nano-biointeraction in eyes will lead to the development of more sophisticated drug delivery systems for retinal diseases.
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Ceguera/prevención & control , Nanopartículas/química , Soluciones Oftálmicas/administración & dosificación , Enfermedades de la Retina/tratamiento farmacológico , Administración Intravenosa , Administración Oftálmica , Administración Oral , Animales , Ceguera/etiología , Barrera Hematorretinal/metabolismo , Coroides/metabolismo , Conjuntiva/metabolismo , Córnea/metabolismo , Modelos Animales de Enfermedad , Liberación de Fármacos , Humanos , Soluciones Oftálmicas/farmacocinética , Permeabilidad , Retina/patología , Enfermedades de la Retina/complicaciones , Enfermedades de la Retina/patología , Esclerótica/metabolismoRESUMEN
N-methyl-D-aspartate receptors (NMDARs) play critical roles in the physiological function of the mammalian central nervous system (CNS), including learning, memory, and synaptic plasticity, through modulating excitatory neurotransmission. Attributed to etiopathology of various CNS disorders and neurodegenerative diseases, GluN2B is one of the most well-studied subtypes in preclinical and clinical studies on NMDARs. Herein, we report the synthesis and preclinical evaluation of two 11C-labeled GluN2B-selective negative allosteric modulators (NAMs) containing N,N-dimethyl-2-(1H-pyrrolo[3,2-b]pyridin-1-yl)acetamides for positron emission tomography (PET) imaging. Two PET ligands, namely [11C]31 and [11C]37 (also called N2B-1810 and N2B-1903, respectively) were labeled with [11C]CH3I in good radiochemical yields (decay-corrected 28% and 32% relative to starting [11C]CO2, respectively), high radiochemical purity (>99%) and high molar activity (>74 GBq/µmol). In particular, PET ligand [11C]31 demonstrated moderate specific binding to GluN2B subtype by in vitro autoradiography studies. However, because in vivo PET imaging studies showed limited brain uptake of [11C]31 (up to 0.5 SUV), further medicinal chemistry and ADME optimization are necessary for this chemotype attributed to low binding specificity and rapid metabolism in vivo.
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Acetamidas/metabolismo , Pirimidinas/metabolismo , Pirroles/metabolismo , Radiofármacos/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Acetamidas/síntesis química , Acetamidas/farmacocinética , Animales , Encéfalo/metabolismo , Radioisótopos de Carbono/química , Femenino , Ligandos , Masculino , Metilación , Ratones Endogámicos ICR , Tomografía de Emisión de Positrones , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Pirroles/síntesis química , Pirroles/farmacocinética , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
Cholesterol 24-hydroxylase, also known as CYP46A1 (EC 1.14.13.98), is a monooxygenase and a member of the cytochrome P450 family. CYP46A1 is specifically expressed in the brain where it controls cholesterol elimination by producing 24S-hydroxylcholesterol (24-HC) as the major metabolite. Modulation of CYP46A1 activity may affect Aß deposition and p-tau accumulation by changing 24-HC formation, which thereafter serves as potential therapeutic pathway for Alzheimer's disease. In this work, we showcase the efficient synthesis and preliminary pharmacokinetic evaluation of a novel cholesterol 24-hydroxylase inhibitor 1 for use in positron emission tomography.
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Dióxido de Carbono/química , Isótopos de Carbono , Colesterol 24-Hidroxilasa/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Radiofármacos/síntesis química , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Ratones , Estructura Molecular , Neuroimagen , Tomografía de Emisión de Positrones , Radiofármacos/química , Radiofármacos/farmacocinética , Distribución TisularRESUMEN
Fluorine-18 labeled N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide ([18 F]FDPA) is a potent and selective radiotracer for positron-emission tomography (PET) imaging of the translocator protein 18 kDa (TSPO). Our previous in vitro and in vivo evaluations have proven that this tracer is promising for further human translation. Our study addresses the need to streamline the automatic synthesis of this radiotracer to make it more accessible for widespread clinical evaluation and application. Here, we successfully demonstrate a one-step radiolabeling of [18 F]FDPA based on a novel spirocyclic iodonium ylide (SCIDY) precursor using tetra-n-butyl ammonium methanesulfonate (TBAOMs), which has demonstrated the highest radiochemical yields and molar activity from readily available [18 F]fluoride ion. The nucleophilic radiofluorination was completed on a GE TRACERlab FX2 N synthesis module, and the formulated [18 F]FDPA was obtained in nondecay corrected (n.d.c) radiochemical yields of 15.6 ± 4.2%, with molar activities of 529.2 ± 22.5 GBq/µmol (14.3 ± 0.6 Ci/µmol) at the end of synthesis (60 minutes, n = 3) and validated for human use. This methodology facilitates efficient synthesis of [18 F]FDPA in a commercially available synthesis module, which would be broadly applicable for routine production and widespread clinical PET imaging studies.
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Receptores de GABA/metabolismo , Compuestos de Espiro/química , Automatización , Técnicas de Química Sintética , Humanos , Tomografía de Emisión de Positrones , Trazadores Radiactivos , RadioquímicaRESUMEN
The Managing Medicines for People With Dementia version 2 website was developed in three languages, English, Italian, and Macedonian, to assist informal caregivers in the task of managing medications. Medication management is a complex task with potentially high stakes health outcomes, including hospitalization and death. A mixed-methods evaluation was carried out. A survey was available to site users and Web log data were collected over a 3-month period. Subsequently, the quality and suitability of the information and readability and usability of the Web site were evaluated. Focus groups and interviews were conducted with end users from all three language groups. Data collected from the evaluation surveys during the pilot test showed that users were generally satisfied with site usability (77%). The results of the readability testing indicate that future versions could be improved. Feedback from the focus groups and interviews was generally positive. The use of multiple methodologies provided comprehensive testing that is likely to have identified the majority of usability issues. Ways in which the site can be maintained with up-to-date information and be promoted to the target population, informal carers, need to be explored.
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Cuidadores/educación , Demencia/tratamiento farmacológico , Servicios de Información sobre Medicamentos , Internet , Retroalimentación , Femenino , Grupos Focales , Humanos , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
Fluorine-18-labelled 6-(fluoro)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([18 F]MK-6240) is a novel potent and selective positron emission tomography (PET) radiopharmaceutical for detecting human neurofibrillary tangles, which are made up of aggregated tau protein. Herein, we report the fully automated 2-step radiosynthesis of [18 F]MK-6240 using a commercially available radiosynthesis module, GE Healthcare TRACERlab FXFN . Nucleophilic fluorination of the 5-diBoc-6-nitro precursor with potassium cryptand [18 F]fluoride (K[18 F]/K222 ) was performed by conventional heating, followed by acid deprotection and semipreparative high-performance liquid chromatography under isocratic conditions. The isolated product was diluted with formulation solution and sterile filtered under Current Good Manufacturing Practices, and quality control procedures were established to validate this radiopharmaceutical for human use. At the end of synthesis, 6.3 to 9.3 GBq (170-250 mCi) of [18 F]MK-6240 was formulated and ready for injection, in an uncorrected radiochemical yield of 7.5% ± 1.9% (relative to starting [18 F]fluoride) with a specific activity of 222 ± 67 GBq/µmol (6.0 ± 1.8 Ci/µmol) at the end of synthesis (90 minutes; n = 3). [18 F]MK-6240 was successfully validated for human PET studies meeting all Food and Drug Administration and United States Pharmacopeia requirements for a PET radiopharmaceutical. The present method can be easily adopted for use with other radiofluorination modules for widespread clinical research use.
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Radioisótopos de Flúor , Isoquinolinas/química , Ovillos Neurofibrilares/metabolismo , Tomografía de Emisión de Positrones/métodos , Radioquímica/métodos , Radiofármacos/química , Halogenación , Humanos , Isoquinolinas/síntesis química , Control de Calidad , Radiofármacos/síntesis químicaRESUMEN
Continuous-flow microfluidics has shown increased applications in radiochemistry over the last decade, particularly for both pre-clinical and clinical production of fluorine-18 labeled radiotracers. The main advantages of microfluidics are the reduction in reaction times and consumption of reagents that often result in increased radiochemical yields and rapid optimization of reaction parameters for 18F-labeling. In this paper, we report on the two-step microfluidic radiosynthesis of the high affinity partial agonist of the serotonin 1A receptor, [18F]FEMPT (pKi = 9. 79; Ki = 0.16 nM) by microfluidic radiochemistry. [18F]FEMPT was obtained in ≈7% isolated radiochemical yield and in >98% radiochemical and chemical purity. The molar activity of the final product was determined to be >148 GBq/µmol (>4 Ci/µmol).
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Activation of retinoid X receptors (RXRs) has been proposed as a therapeutic mechanism for the treatment of neurodegeneration, including Alzheimer's and Parkinson's diseases. We previously reported radiolabeling of a Food and Drug Administration-approved RXR agonist, bexarotene, by copper-mediated [(11)C]CO2 fixation and preliminary positron emission tomography (PET) neuroimaging that demonstrated brain permeability in nonhuman primate with regional binding distribution consistent with RXRs. In this study, the brain uptake and saturability of [(11)C]bexarotene were studied in rats and nonhuman primates by PET imaging under baseline and greater target occupancy conditions. [(11)C]Bexarotene displays a high proportion of nonsaturable uptake in the brain and is unsuitable for RXR occupancy measurements in the central nervous system.
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Encéfalo/diagnóstico por imagen , Neuroimagen/métodos , Tetrahidronaftalenos/farmacología , Animales , Bexaroteno , Encéfalo/metabolismo , Radioisótopos de Carbono/química , Masculino , Tomografía de Emisión de Positrones , Primates , Radiofármacos/química , Ratas , Receptores X Retinoide/agonistas , Receptores X Retinoide/metabolismo , Tetrahidronaftalenos/químicaRESUMEN
Spirocyclic hypervalent iodine(III) ylides have proven to be synthetically versatile precursors for efficient radiolabelling of a diverse range of non-activated (hetero)arenes, highly functionalised small molecules, building blocks and radiopharmaceuticals from [18F]fluoride ion. Herein, we report the implementation of these reactions onto a continuous-flow microfluidic platform, thereby offering an alterative and automated synthetic procedure of a radiopharmaceutical, 3-[18F]fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ([18F]FPEB) and a routinely used building block for click-radiochemistry, 4-[18F]fluorobenzyl azide. This new protocol was applied to the synthesis of [18F]FPEB (radiochemical conversion (RCC) = 68 ± 5%) and 4-[18F]fluorobenzyl azide (RCC=68 ± 5%; isolated radiochemical yield = 24±0%). We anticipate that the high throughput microfluidic platform will accelerate the discovery and applications of 18F-labelled building blocks and labelled compounds prepared by iodonium ylide precursors as well as the production of radiotracers for preclinical imaging studies.
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Distal limb contractures (DLC) represent a heterogeneous clinical and genetic condition. Overall, 20-25% of the DLC are caused by mutations in genes encoding the muscle contractile apparatus. Large interstitial deletions of the 3p have already been diagnosed by standard chromosomal analysis, but not associated with a specific phenotype. We report on four patients with syndromic DLC presenting with a de novo 3p14.1p13 microdeletion. The clinical features associated multiple contractures, feeding problems, developmental delay, and intellectual disability. Facial dysmorphism was constant with low-set posteriorly rotated ears and blepharophimosis. Review of previously reported cases with a precise mapping of the deletions, documented a 250 kb smallest region of overlap (SRO) necessary for DLC. This region contained one gene, EIF4E3, the first three exons of the FOXP1 gene, and an intronic enhancer of FOXP1 named hs1149. Sanger sequencing and locus quantification of hs1149, EIF4E3, and FOXP1 in a cohort of 11 French patients affected by DLC appeared normal. In conclusion, we delineate a new microdeletion syndrome involving the 3p14.1p13 locus and associated with DLC and severe developmental delay.
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Artrogriposis/epidemiología , Aberraciones Cromosómicas , Cromosomas Humanos Par 3/genética , Contractura/epidemiología , Contractura/genética , Extremidades/patología , Animales , Proteínas Portadoras/genética , Hibridación Genómica Comparativa , Contractura/patología , Femenino , Factores de Transcripción Forkhead/genética , Francia/epidemiología , Humanos , Masculino , Ratones , Ratones Noqueados , Proteínas Represoras/genética , SíndromeRESUMEN
PURPOSE: To evaluate the anatomical, functional and post-operative outcomes of polypropylene mesh (Prolift™) in the surgical management of pelvic organ prolapse (POP). METHODS: A single-centre observational study of 106 successive patients, who underwent Prolift™ mesh repair (POP ≥ 2) with a median follow-up of 4 years, was performed. Outcomes of interest measured included patient demographics, intra and post-operative complications, concomitant procedures for POP or urinary incontinence. Using the Baden-Walker classification, grade ≥2 prolapses in the operated compartment were deemed as surgical failure. Validated questionnaires including ICIQ-VS and ICIQ-UI were used to assess functional outcome. RESULTS: Of the 106 patients, 56 had an anterior, 36 a posterior and 14 a total Prolift™. 101 patients were available for follow-up (median 4 years). 82 women underwent a clinical follow-up whilst 19 underwent a telephonic follow-up. Peri-operative bladder injury was noted in 2 (1.9 %) cases. Six (5.6 %) patients developed mesh exposure post-operatively. Re-operation rates for recurrent prolapse in the operated compartment were 2.8 % (n = 3). At follow-up, prolapse recurrence in the operated compartment was noted in another 7.3 % (n = 6) patients. Combining re-operations for POP and recurrences noted during follow-up, the revised failure rate was 10.1 % (n = 9). De novo prolapse in the non-operated compartment occurred in 19.5 % (n = 16) women. CONCLUSION: Our study demonstrates that Prolift™ vaginal mesh surgery offers anatomical cure rates of 89.9 %. A higher rate of de novo recurrence in the non-operated compartment was noted suggesting that surgical correction in one compartment may exacerbate recurrence in other compartments.
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Procedimientos Quirúrgicos Ginecológicos/instrumentación , Prolapso de Órgano Pélvico/cirugía , Polipropilenos , Mallas Quirúrgicas/efectos adversos , Incontinencia Urinaria/etiología , Adulto , Anciano , Femenino , Estudios de Seguimiento , Procedimientos Quirúrgicos Ginecológicos/efectos adversos , Encuestas de Atención de la Salud , Humanos , Tiempo de Internación , Persona de Mediana Edad , Complicaciones Posoperatorias , Prótesis e Implantes , Estudios Retrospectivos , Encuestas y Cuestionarios , Centros de Atención TerciariaRESUMEN
BACKGROUND: Management of prelabour rupture of membranes at term (37 weeks gestation or later) (TPROM) remains complicated in the absence of a rapid assay for group B streptococcus (GBS) colonisation. AIMS: To evaluate the accuracy and clinical utility of a commercial PCR assay, compared with culture, for detection of GBS colonisation in pregnant women presenting with TPROM. METHODS: A prospective study of women presenting with TPROM conducted in a large tertiary hospital (Westmead Hospital, Australia). Five hundred and seventy-four consecutive women with TPROM were enrolled between July 2006 and November 2007. Paired low vaginal and anal swabs were collected from women presenting with TPROM for PCR and culture on GBS selective agar following broth enrichment. Primary outcomes were sensitivity and specificity of PCR compared with GBS selective enrichment culture. Secondary analyses included comparison with a historical but otherwise similar cohort regarding clinical utility, maternal and neonatal outcomes. RESULTS: PCR sensitivity and specificity were 89.0% (95% CI - 82.8-93.6%) and 97.9% (95% CI - 96.0-99.0%), respectively, compared with culture. 72.3% of women were aware of their GBS PCR status within 3 h of presentation. Compared with the historical cohort, PCR reduced the requirement for intrapartum antibiotics by 25.6% (P < 0.001). There were no significant differences in maternal outcomes or combined rates of admissions to neonatal intensive care or special care nursery. CONCLUSIONS: Group B streptococcus PCR is an accurate, rapid, safe and practical alternative to culture for detection of GBS colonisation in pregnant women at the time of TPROM. This method has the potential advantage to reduce costs associated with length of hospital stay.
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Reacción en Cadena de la Polimerasa , Complicaciones Infecciosas del Embarazo/diagnóstico , Infecciones Estreptocócicas/diagnóstico , Streptococcus agalactiae/aislamiento & purificación , Adolescente , Adulto , Canal Anal/microbiología , ADN Bacteriano/análisis , Femenino , Rotura Prematura de Membranas Fetales/microbiología , Humanos , Recién Nacido , Embarazo , Sensibilidad y Especificidad , Streptococcus agalactiae/genética , Vagina/microbiología , Adulto JovenRESUMEN
The etiology of spina bifida, a neural tube birth defect, is largely unknown, but a majority of cases are thought to be genetic in origin. Although maternal blood type was found not to be associated with the occurrence of spina bifida, the analysis was never extended to other aspects of the disorder. The purpose of this descriptive study was to determine if maternal blood type was related to characteristics of children with spina bifida. The blood type of 221 mothers of children with spina bifida enrolled on the Arkansas Spinal Cord Disability Registry from 1995 to 2008 was obtained by mailed questionnaire. All children were community-dwelling and from singleton pregnancies. As expected, analysis of mother-child data showed that the distribution of mothers' blood type was not statistically different from the general population (chi-squared, P = 0.9203). However, the blood type of these mothers was associated with their child's lesion level (chi-squared, P = 0.011). Mothers with blood type A more frequently had children with thoracic lesions; mothers with non-A blood types more frequently had children with lumbar and sacral lesions. In addition, mean birthweight differed by mothers' blood type (analysis of variance, P = 0.025). Children of mothers with blood type A had the highest mean birthweight, while those of mothers with blood type AB had the lowest. Also, hydrocephalus was present more frequently in children with thoracic lesions compared to those with lumbar and sacral lesions (chi-squared, P = 0.001). Interestingly, these results were significant for female children but not for male children. In conclusion, maternal blood type was associated with lesion level and birthweight of children with spina bifida.
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Sistema del Grupo Sanguíneo ABO , Peso al Nacer , Disrafia Espinal , Humanos , Disrafia Espinal/sangre , Femenino , Sistema del Grupo Sanguíneo ABO/sangre , Masculino , Madres , Recién Nacido , Niño , Adulto , Arkansas/epidemiologíaRESUMEN
PURPOSE: Prediction of the early treatment response is important in neovascular age-related macular degeneration (nAMD). Hence, we aimed to test if non-invasive measurements of the retinal vascular structure were able to predict a successful outcome of initial intravitreal treatment. METHODS: In 58 eyes of 58 patients with treatment-naïve nAMD, advanced markers of retinal vascular structure were measured by Singapore I Vessel Assessment prior to initial intravitreal treatment with three monthly injections of aflibercept with subsequently categorization of patients as full treatment responders (FTR) or non/partial treatment responders (N/PR), with the former defined as loosing fewer than five Early Treatment Diabetic Retinopathy Study letters and having no residual intra- or subretinal fluid or macular haemorrhage. RESULTS: Of 54 eyes attending follow-up, 44.4% were categorized as FTR. Patients with FTR were older (81.5 vs. 77 years, p = 0.04), and prior to treatment those eyes had a lower retinal arteriolar fractal dimension (Fd) (1.21 vs. 1.24 units, p = 0.02) and venular length-diameter ratio (LDR) (7.3 vs. 15.9 units, p = 0.006), but did not differ with respect to other retinal vascular parameters. In multiple logistic regression models, a lower chance of FTR was independently predicted by a higher retinal venular LDR (odds ratio [OR] 0.91, 95% CI 0.82-0.99, p = 0.03, for each 1 unit increment) and marginally by a higher retinal arteriolar Fd (OR 0.83, 95% CI 0.68-1.00, p = 0.05, for each 0.01 unit increment). CONCLUSION: Retinal venular LDR independently predicted the initial treatment response in nAMD. If confirmed by long-term, prospective studies, this might help to guide treatment.
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Degeneración Macular , Degeneración Macular Húmeda , Humanos , Inhibidores de la Angiogénesis/uso terapéutico , Factor A de Crecimiento Endotelial Vascular , Estudios Prospectivos , Retina , Degeneración Macular/tratamiento farmacológico , Inyecciones Intravítreas , Receptores de Factores de Crecimiento Endotelial Vascular , Proteínas Recombinantes de Fusión/uso terapéutico , Resultado del Tratamiento , Degeneración Macular Húmeda/diagnóstico , Degeneración Macular Húmeda/tratamiento farmacológicoRESUMEN
Polymeric nanoparticles (NPs), specifically those comprised of biodegradable and biocompatible polyesters, have been heralded as a game-changing drug delivery platform. In fact, poly(α-hydroxy acids) such as polylactide (PLA), poly(lactide-co-glycolide) (PLGA), and poly(ε-caprolactone) (PCL) have been heavily researched in the past three decades as the material basis of polymeric NPs for drug delivery applications. As materials, these polymers have found success in resorbable sutures, biodegradable implants, and even monolithic, biodegradable platforms for sustained release of therapeutics (e.g., proteins and small molecules) and diagnostics. Few fields have gained more attention in drug delivery through polymeric NPs than cancer therapy. However, the clinical translational of polymeric nanomedicines for treating solid tumors has not been congruent with the fervor or funding in this particular field of research. Here, we attempt to provide a comprehensive snapshot of polyester NPs in the context of chemotherapeutic delivery. This includes a preliminary exploration of the polymeric nanomedicine in the cancer research space. We examine the various processes for producing polyester NPs, including methods for surface-functionalization, and related challenges. After a detailed overview of the multiple factors involved with the delivery of NPs to solid tumors, the crosstalk between particle design and interactions with biological systems is discussed. Finally, we report state-of-the-art approaches toward effective delivery of NPs to tumors, aiming at identifying new research areas and re-evaluating the reasons why some research avenues have underdelivered. We hope our effort will contribute to a better understanding of the gap to fill and delineate the future research work needed to bring polyester-based NPs closer to clinical application. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.
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Nanopartículas , Neoplasias , Poliésteres , Poliésteres/química , Humanos , Neoplasias/tratamiento farmacológico , Nanopartículas/química , Animales , Antineoplásicos , Sistemas de Liberación de Medicamentos , NanomedicinaAsunto(s)
Potasio , Animales , Dieta , Femenino , Humanos , Leche , Leche Humana , Sacarosa/análogos & derivados , TiazinasRESUMEN
BACKGROUND: We investigated in a porcine model whether measuring both the flow distal to an anastomosis and the graft transit time flow (TTF) gives a more accurate picture of the true blood flow in the left anterior descending artery (LAD) than graft TTF measurement alone. METHODS: We performed off-pump coronary artery bypass grafting (CABG)-left internal mammary artery (LIMA) to the LAD-on 5 Yorkshire-Landrace pigs. Snares were placed both proximal and distal to the anastomosis. Flow was measured with ultrasound and TTF. This was carried out on the LIMA and at 2 locations on the LAD. Measurements were performed at the following times: baseline, during proximal snaring, after proximal snare loosening, during distal snaring, after distal snare loosening, and during both proximal and distal snaring. RESULTS: During distal snaring, the TTF dropped (P = .047), and the pulsatile index (PI) increased (P = .025), while the ultrasound flow in the LAD dropped (P = .002). During proximal and distal snaring, the ultrasound flow dropped (P = .005), but the TTF value did not change significantly, compared with baseline. CONCLUSION: A high flow and a low PI were seen in the graft, both proximal and distal to the anastomosis, despite a fully occluded LAD. This result suggests that graft TTF measurement alone is not sufficient when performing CABG, and measurement of flow distal to the anastomosis is also necessary to determine the true blood flow in the LAD.
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Velocidad del Flujo Sanguíneo/fisiología , Puente de Arteria Coronaria/métodos , Circulación Coronaria/fisiología , Vasos Coronarios/fisiología , Vasos Coronarios/cirugía , Oclusión de Injerto Vascular/fisiopatología , Análisis de la Onda del Pulso/métodos , Animales , Porcinos , Resultado del TratamientoRESUMEN
The brain remains one of the most challenging therapeutic targets due to the low and selective permeability of the blood-brain barrier and complex architecture of the brain tissue. Nanomedicines, despite their relatively large size compared to small molecules and nucleic acids, are being heavily investigated as vehicles to delivery therapeutics into the brain. Here we elaborate on how nanomedicines may be used to treat rare neurodevelopmental disorders, using Krabbe disease (globoid cell leukodystrophy) to frame the discussion. As a monogenetic disorder and lysosomal storage disease affecting the nervous system, the lessons learned from examining nanoparticle delivery to the brain in the context of Krabbe disease can have a broader impact on the treatment of various other neurodevelopmental and neurodegenerative disorders. In this review, we introduce the epidemiology and genetic basis of Krabbe disease, discuss current in vitro and in vivo models of the disease, as well as current therapeutic approaches either approved or at different stage of clinical developments. We then elaborate on challenges in particle delivery to the brain, with a specific emphasis on methods to transport nanomedicines across the blood-brain barrier. We highlight nanoparticles for delivering therapeutics for the treatment of lysosomal storage diseases, classified by the therapeutic payload, including gene therapy, enzyme replacement therapy, and small molecule delivery. Finally, we provide some useful hints on the design of nanomedicines for the treatment of rare neurological disorders.
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Leucodistrofia de Células Globoides , Enfermedades por Almacenamiento Lisosomal , Humanos , Leucodistrofia de Células Globoides/tratamiento farmacológico , Leucodistrofia de Células Globoides/genética , Galactosilceramidasa/genética , Galactosilceramidasa/metabolismo , Nanomedicina , Encéfalo/metabolismo , Barrera Hematoencefálica/metabolismo , Enfermedades por Almacenamiento Lisosomal/tratamiento farmacológicoRESUMEN
Assessing the mechanical behavior of nano- and micron-scale particles with complex shapes is fundamental in drug delivery. Although different techniques are available to quantify the bulk stiffness in static conditions, there is still uncertainty in assessing particle deformability in dynamic conditions. Here, a microfluidic chip is designed, engineered, and validated as a platform to assess the mechanical behavior of fluid-borne particles. Specifically, potassium hydroxide (KOH) wet etching was used to realize a channel incorporating a series of micropillars (filtering modules) with different geometries and openings, acting as microfilters in the direction of the flow. These filtering modules were designed with progressively decreasing openings, ranging in size from about 5 down to 1 µm. Discoidal polymeric nanoconstructs (DPNs), with a diameter of 5.5 µm and a height of 400 nm, were realized with different poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) ratios (PLGA/PEG), namely, 5:1 and 1:0, resulting in soft and rigid particles, respectively. Given the peculiar geometry of DPNs, the channel height was kept to 5 µm to limit particle tumbling or flipping along the flow. After thorough physicochemical and morphological characterization, DPNs were tested within the microfluidic chip to investigate their behavior under flow. As expected, most rigid DPNs were trapped in the first series of pillars, whereas soft DPNs were observed to cross multiple filtering modules and reach the micropillars with the smallest opening (1 µm). This experimental evidence was also supported by computational tools, where DPNs were modeled as a network of springs and beads immersed in a Newtonian fluid using the smoothed particle hydrodynamics (SPH) method. This preliminary study presents a combined experimental-computational framework to quantify, compare, and analyze the characteristics of particles having complex geometrical and mechanical attributes under flow conditions.