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Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.).
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Proteínas de Transporte de Membrana/genética , Mutagénesis Insercional , Lipofuscinosis Ceroideas Neuronales/tratamiento farmacológico , Lipofuscinosis Ceroideas Neuronales/genética , Oligonucleótidos Antisentido/uso terapéutico , Medicina de Precisión , Enfermedades Raras/tratamiento farmacológico , Biopsia , Niño , Desarrollo Infantil , Descubrimiento de Drogas , Drogas en Investigación/uso terapéutico , Electroencefalografía , Femenino , Humanos , Pruebas Neuropsicológicas , ARN Mensajero , Convulsiones/diagnóstico , Convulsiones/tratamiento farmacológico , Piel/patología , Secuenciación Completa del GenomaRESUMEN
The consideration of polar interactions is of vital importance for the development of predictive and accurate thermodynamic models for polar fluids, as they govern most of their thermodynamic properties, making them highly non-ideal fluids. We present here for the first time the extension of the soft-SAFT equation of state (EoS), named polar soft-SAFT, to explicitly model intermolecular polar interactions (dipolar and quadrupolar), using the approach of Jog and Chapman (P. K. Jog and W. G. Chapman, Mol. Phys., 1999, 97(3), 307-319). The theory is first validated using molecular simulation data for a wide range of polar model systems including Stockmayer fluids, LJ dimers with dipole, and quadrupolar LJ fluids, for a wide range of thermophysical properties such as liquid density, vapour pressure, surface tension and heat capacities. Excellent agreement between polar soft-SAFT and simulation data has been obtained for all examined fluids and properties for systems exhibiting low to intermediate polar strength, while the agreement deteriorates at very high polar strengths. Once validated with simulations, the equation has been applied to calculate vapour-liquid equilibria (VLE), surface tension and second-order derivative properties of systems such as 2-ketone and methane chloride families as showcases for dipolar fluids and the benzene family for quadrupolar fluids, finding very good agreement with experimental data. In order to preserve the robustness of the model, the experimental value of the dipole or quadrupole was used in these calculations, while the additional parameter for the polar fluids was set a priori rather than included in the fitting procedure. The excellent agreement found with simulations and experiments empowers the soft-SAFT equation with new capabilities for the development of robust and accurate molecular models of polar fluids of industrial relevance.
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BACKGROUND: Although immunomodulatory effects of anesthetics have been increasingly recognized, their underlying molecular mechanisms are not completely understood. Toll-like receptors (TLRs) are one of the major receptors to recognize invading pathogens and danger signals from damaged host tissues to initiate immune responses. Among the TLR family, TLR2 and TLR4 recognize a wide range of ligands and are considered to be important players in perioperative pathophysiology. Based on our recent finding that volatile anesthetics modulate TLR4 function, we tested our hypothesis that they would also modulate TLR2 function. METHODS: The effect of anesthetics isoflurane, sevoflurane, propofol, and dexmedetomidine on TLR2 activation was examined by reporter assays. An anesthetic that affected the activation was subjected to in silico rigid docking simulation on TLR2. To test our prediction that sevoflurane and a TLR1/TLR2 ligand Pam3CSK4 would compete for the same pocket of TLR2, we performed Pam3CSK4 competitive binding assay to TLR2 using HEK cells stably transfected with TLR2 (HEK-TLR2) with or without sevoflurane. We examined the effect of different anesthetics on the functions of human neutrophils stimulated with TLR2 ligands. Kruskal-Wallis test and Mann-Whitney U test were used for statistical analysis. RESULTS: We observed that the attenuation of TLR1/TLR2 activation was seen on sevoflurane exposure but not on isoflurane, propofol, or dexmedetomidine exposure. The attenuation of TLR2/TLR6 activation was not seen in any of the anesthetics tested. The rigid docking simulation predicted that sevoflurane and Pam3CSK4 bound to the same pocket of TLR1/TLR2 complex. The binding of Pam3CSK4 to HEK-TLR2 cells was impaired in the presence of sevoflurane, indicating that sevoflurane and Pam3CSK4 competed for the pocket, as predicted in silico. The stimulation of neutrophils with Pam3CSK4 induced L-selection shedding but did not affect phagocytosis and reactive oxygen species production. L-selectin shedding from neutrophils was attenuated only by sevoflurane, consistent with the result of our reporter assays. CONCLUSIONS: We found that TLR1/TLR2 activation was attenuated by sevoflurane, but we found no evidence for attenuation by isoflurane, propofol, or dexmedetomidine at clinically relevant concentrations. Our structural analysis and competition assay supported that sevoflurane directly bound to TLR2 at the interphase of the TLR1/TLR2 complex. Sevoflurane attenuated neutrophil L-selectin shedding, an important step for neutrophil migration.
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Anestésicos por Inhalación/farmacología , Sevoflurano/farmacología , Receptor Toll-Like 1/antagonistas & inhibidores , Receptor Toll-Like 2/antagonistas & inhibidores , Línea Celular Tumoral , Células HEK293 , Humanos , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Estructura Secundaria de Proteína , Receptor Toll-Like 1/química , Receptor Toll-Like 1/metabolismo , Receptor Toll-Like 2/química , Receptor Toll-Like 2/metabolismoRESUMEN
OBJECTIVES: Shunt thrombosis, a potential complication of aortopulmonary shunting, is associated with high mortality. Commonly used oral antiplatelet drugs such as aspirin demonstrate variable absorption and inconsistent antiplatelet effect in critically ill patients early after surgery. IV glycoprotein IIb/IIIa inhibitors are antiplatelet agents with rapid and reproducible effect that may be beneficial as a bridge to oral therapy. DESIGN: Retrospective review of pediatric patients undergoing treatment with IV tirofiban. Discarded blood samples were used to determine pharmacokinetic parameters. SETTING: Pediatric cardiac ICU at a single institution. PATIENTS: Fifty-two pediatric patients (< 18 yr) undergoing surgical aortopulmonary shunt procedure who received tirofiban infusion as a bridge to oral aspirin. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome measures were shunt thrombosis and bleeding events, whereas secondary outcomes included measurement of platelet inhibition by thromboelastography with platelet mapping and pharmacokinetic analysis (performed in a subset of 15 patients). Shunt thrombosis occurred in two of 52 patients (3.9%) after prophylaxis treatment with tirofiban; both thrombosis events occurred after discontinuation of the drug. One patient (1.9%) experienced bleeding complication during the infusion. A tirofiban bolus of 10 µg/kg and infusion of 0.15 µg/kg/min resulted in significantly increased platelet inhibition via adenosine diphosphate pathway (median 66% [43-96] pre-tirofiban compared with 97% [92-99%] at 2 hr; p < 0.05). Half-life of tirofiban in plasma was 142 ± 1.5 minutes, and the average steady-state concentration was 112 ± 62 ng/mL. Age and serum creatinine were significant covariates associated with systemic clearance. Dosing simulations were generated based upon one compartment model. CONCLUSIONS: IV glycoprotein IIb/IIIa inhibitor as a bridge to oral antiplatelet therapy is safe in pediatric patients after aortopulmonary shunting. Dosing considerations should include both age and renal function. Randomized trials are warranted to establish efficacy compared with current anticoagulation practices.
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Preparaciones Farmacéuticas , Trombosis , Niño , Humanos , Inhibidores de Agregación Plaquetaria/efectos adversos , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria , Estudios Retrospectivos , Trombosis/etiología , Trombosis/prevención & control , Resultado del Tratamiento , TirosinaRESUMEN
BACKGROUND: Intraperitoneal (IP) administration of local anesthetics is used in adults and children for postoperative analgesia after laparoscopic surgery. Population pharmacokinetics (PK) of IP bupivacaine has not been determined in children. Objectives of this study were (1) to develop a population PK model to compare IP bupivacaine administered via manual bolus atomization and micropump nebulization and (2) to assess postoperative morphine requirements after intraoperative administration. We hypothesized similar PK profiles and morphine requirements for both delivery methods. METHODS: This was a prospective, sequential, observational study. After institutional review board (IRB) approval and written informed parental consent, 67 children 6 months to 6 years of age undergoing robot-assisted laparoscopic urological surgery received IP bupivacaine at the beginning of surgery. Children received a total dose of 1.25 mg/kg bupivacaine, either diluted in 30-mL normal saline via manual bolus atomization over 30 seconds or undiluted bupivacaine 0.5% via micropump nebulization into carbon dioxide (CO2) insufflation tubing over 10-17.4 minutes. Venous blood samples were obtained at 4 time points between 1 and 120 minutes intraoperatively. Samples were analyzed by liquid chromatography with mass spectrometry. PK parameters were calculated using noncompartmental and compartmental analyses. Nonlinear regression modeling was used to estimate PK parameters (primary outcomes) and Mann-Whitney U test for morphine requirements (secondary outcomes). RESULTS: Patient characteristics between the 2 delivery methods were comparable. No clinical signs of neurotoxicity or cardiotoxicity were observed. The range of peak plasma concentrations was 0.39-2.44 µg/mL for the manual bolus atomization versus 0.25-1.07 µg/mL for the micropump nebulization. IP bupivacaine PK was described by a 1-compartment model for both delivery methods. Bupivacaine administration by micropump nebulization resulted in a significantly lower Highest Plasma Drug Concentration (Cmax) and shorter time to reach Cmax (Tmax) (P < .001) compared to manual bolus atomization. Lower plasma concentrations with less interpatient variability were observed and predicted by the PK model for the micropump nebulization (P < .001). Adjusting for age, weight, and sex as covariates, Cmax and area under the curve (AUC) were significantly lower with micropump nebulization (P < .001). Regardless of the delivery method, morphine requirements were low at all time points. There were no differences in cumulative postoperative intravenous/oral morphine requirements between manual bolus atomization and micropump nebulization (0.14 vs 0.17 mg/kg; P = .85) measured up to 24 hours postoperatively. CONCLUSIONS: IP bupivacaine administration by micropump nebulization demonstrated lower plasma concentrations, less interpatient variability, low risk of toxicity, and similar clinical efficacy compared to manual bolus atomization. This is the first population PK study of IP bupivacaine in children, motivating future randomized controlled trials to determine efficacy.
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Analgésicos Opioides/administración & dosificación , Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacocinética , Bupivacaína/administración & dosificación , Bupivacaína/farmacocinética , Modelos Biológicos , Morfina/administración & dosificación , Dolor Postoperatorio/prevención & control , Aerosoles , Factores de Edad , Anestésicos Locales/sangre , Bupivacaína/sangre , Niño , Preescolar , Esquema de Medicación , Femenino , Humanos , Lactante , Cuidados Intraoperatorios , Laparoscopía/efectos adversos , Masculino , Nebulizadores y Vaporizadores , Dimensión del Dolor , Dolor Postoperatorio/diagnóstico , Dolor Postoperatorio/etiología , Estudios Prospectivos , Procedimientos Quirúrgicos Robotizados/efectos adversos , Resultado del Tratamiento , Procedimientos Quirúrgicos Urológicos/efectos adversosRESUMEN
Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40-120 µg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.
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Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , Síndrome de Rett/tratamiento farmacológico , Niño , Preescolar , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/efectos adversos , Factor I del Crecimiento Similar a la Insulina/farmacocinética , Péptidos y Proteínas de Señalización Intercelular/efectos adversos , Péptidos y Proteínas de Señalización Intercelular/farmacocinética , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapéuticoRESUMEN
Background: The del Nido cardioplegia solution (dNCS) was originally developed for pediatric cardiac surgery, being now also used for adult patients. Hospital pharmacies frequently resort to internal dNCS production which has led to an increase in the need for validated parameters for compounding and storage. Objective: This report defines in-house production standards, as well as the stability of dNCS under optimal storage conditions. Methods: All ingredients were sterile and United States Pharmacopeia (USP)/National Formulary (NF) certified. All final bags were quarantined at 4°C for quality control, when 3 of 33 weekly bags were randomly assayed for potassium content. Each lot was only released if all 3 samples were within ±5% of target. Stability testing was performed per USP 797 guidance. Over a 6-month period, 4 different lots and 4 bags from each lot of dNCS were assayed. Each bag was assessed for physical and chemical stability while refrigerated at 4°C, at 35°C in an incubator, and at 70°C under 80% relative humidity. A light exposure arm was also set up at 25°C under 150 lumens. Calibrators of lidocaine, mannitol, and gluconate were freshly prepared and assayed with the samples by Liquid chromatography/Mass spectrometry (LC/MS). Results: Lidocaine concentrations averaged 0.117 mg/mL (95.8% of theoretical) at 4°C for 30 days. At 35°C, they decayed by 67% in 30 days, while at 70°C nearly 50% was lost after the first day. A first-order kinetics was observed with an Arrhenius activation energy of 25 kcal/mol. Degradation products identified under stress conditions were absent in the stable product. Conclusions: The dNCS is stable for at least 30 days under 4°C refrigeration in ethylene vinyl acetate (EVA) bags.
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BACKGROUND: Tranexamic acid (TXA) is one of the most commonly used antifibrinolytic medications in children undergoing repair of congenital heart defects. However, a pharmacokinetics analysis of TXA has never been performed in neonates or young children undergoing complex cardiac surgeries using cardiopulmonary bypass, hypothermia, circulatory arrest, and ultrafiltration. A comprehensive pharmacokinetics study was performed in this patient population. METHODS: Fifty-five patients ranging from 2 days through 4 yr old were categorized into three groups: children less than 2 months old, infants 2 months to 1 yr old, and children greater than 1 yr old and weighing up to 20 kg. TXA was given as a bolus of 100 mg/kg followed by an infusion of 10 mg · kg · h throughout the surgery. A dose of 100 mg/kg was placed in the cardiopulmonary bypass prime. A total of 16 to 18 samples were obtained from all patients throughout surgery. Plasma TXA concentrations were measured by high-performance liquid chromatography and modeled under a nonlinear mixed-effects framework with a two-compartment structural model. RESULTS: Cardiopulmonary bypass had a statistically significant impact on all pharmacokinetic parameters. Age was a better covariate than body weight, affecting both the distribution and the elimination of TXA. However, weight performed well in some cases. Other covariates including body surface area, pump prime volume, ultrafiltrate volume, and body temperature did not improve the model. CONCLUSIONS: This TXA pharmacokinetic analysis is reported for the first time in neonates and young children undergoing complex cardiac surgeries with cardiopulmonary bypass. Dosing recommendations are provided as guidance for maintaining desired target concentrations.
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Antifibrinolíticos/farmacocinética , Puente Cardiopulmonar , Modelos Biológicos , Ácido Tranexámico/farmacocinética , Antifibrinolíticos/uso terapéutico , Procedimientos Quirúrgicos Cardíacos/métodos , Puente Cardiopulmonar/métodos , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Ácido Tranexámico/uso terapéuticoRESUMEN
BACKGROUND: Adherence to once daily oral preexposure prophylaxis (PrEP) for HIV prevention can be challenging for men who have sex with men (MSM) with substance use. Digital pill systems (DPS) comprise a radiofrequency emitter integrated into a gelatin capsule containing PrEP, which transmits data to a wearable Reader following ingestion, thereby enabling direct, real-time adherence measurement. This study evaluated the feasibility, acceptability, and accuracy of a DPS to measure PrEP adherence. METHODS: A 90-day, single-arm, open-label, pilot demonstration trial was conducted with adult, cisgender, HIV-negative MSM on PrEP with nonalcohol substance use. Feasibility was measured via DPS engagement and timeline followback. Acceptability was assessed via qualitative user experience interviews. Accuracy was evaluated via DPS performance metrics, pill counts, and DBS to quantify tenofovir diphosphate. RESULTS: Sixteen MSM enrolled (median age, 32 years), and 15 completed the study. Engagement remained stable over time. Emergent nonadherence patterns included intercurrent substance use. The DPS was largely acceptable based on interviews; the predominant barrier to use was the Reader. DPS-recorded ingestions totaled 1099, including 83.9% were detected by Reader and 16.1% were reported manually. The DPS recorded 92.2% of 1192 total expected ingestions per pill counts. Point-biserial correlation (R = 0.58; 95% CI: 0.21 to 0.80; P = 0.047) and Pearson correlation (month 1: R = 0.85; 95% CI: 0.57 to 0.95; P = 0.0002; month 3: R = 0.75; 95% CI: 0.17 to 0.94; P = 0.0197) showed strong correlations between DPS-recorded adherence and tenofovir diphosphate in dried blood spots. CONCLUSION: DPS are a feasible, acceptable, and accurate method of measuring PrEP adherence in MSM with substance use. Future investigations should incorporate DPS into behavioral interventions targeting nonadherence.
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Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Minorías Sexuales y de Género , Adulto , Fármacos Anti-VIH/uso terapéutico , Estudios de Factibilidad , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Homosexualidad Masculina , Humanos , Masculino , Cumplimiento de la Medicación , Proyectos Piloto , Profilaxis Pre-Exposición/métodosRESUMEN
BACKGROUND: Extensive blood loss is common in pediatric craniosynostosis reconstruction surgery. Tranexamic acid (TXA) is increasingly used to reduce perioperative blood loss in various settings, but data on its efficacy are limited in children. The purpose of this randomized, double-blind, placebo-controlled, parallel trial was to evaluate the efficacy of TXA in pediatric craniosynostosis correction surgery. The primary and secondary outcome variables were reduction in perioperative blood loss and reduction in blood transfusion, respectively. METHODS: Forty-three children, ages 2 months to 6 yr, received either placebo or TXA in a loading dose of 50 mg·kg(-1), followed by an infusion of 5 mg·kg·h(-1) during surgery. TXA plasma concentrations were measured. RESULTS: The TXA group had significantly lower perioperative mean blood loss (65 vs. 119 ml·kg(-1), P < 0.001) and lower perioperative mean blood transfusion (33 vs. 56 ml· kg(-1), P = 0.006) compared to the placebo group. The mean difference between the TXA and placebo groups for total blood loss was 54 ml·kg(-1) (95% CI for the difference, 23-84 ml·kg(-1)) and for packed erythrocytes transfused was 23 ml·kg(-1) (95% CI for the difference, 7-39 ml·kg(-1)). TXA administration also significantly diminished (by two thirds) the perioperative exposure of patients to transfused blood (median, 1 unit vs. 3 units; P < 0.001). TXA plasma concentrations were maintained above the in vitro thresholds reported for inhibition of fibrinolysis (10 µg·ml(-1)) and plasmin-induced platelet activation (16 µg·ml(-1)) throughout the infusion. CONCLUSIONS: TXA is effective in reducing perioperative blood loss and transfusion requirement in children undergoing craniosynostosis reconstruction surgery.
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Antifibrinolíticos/uso terapéutico , Pérdida de Sangre Quirúrgica/prevención & control , Craneosinostosis/cirugía , Ácido Tranexámico/uso terapéutico , Transfusión Sanguínea/estadística & datos numéricos , Niño , Preescolar , Método Doble Ciego , Femenino , Humanos , Lactante , Cuidados Intraoperatorios , Masculino , Resultado del TratamientoRESUMEN
Cardiopulmonary bypass (CPB) circuits can significantly sequester intravenous anesthetics. Adsorption of medications by our institution's standard circuit (Terumo CAPIOX FX05 oxygenator; noncoated polyvinylchloride tubing) has not been described. We prepared ex vivo CPB circuits with and without oxygenators. Medication combinations studied included midazolam (0.5 mg), fentanyl (50 µg), midazolam (0.5 mg) with morphine (0.5 mg), and midazolam (0.5 mg) with fentanyl (50 µg). Medications were administered after obtaining baseline samples. Samples were drawn at 2, 5, 15, 30, 60, 120, and 180 minutes, and analyzed for concentration of injected medications. Midazolam demonstrated no sequestration after 180 minutes. Fentanyl concentration at 180 minutes was lower with an oxygenator (52.7 ± 12.5 vs. 110.9 ± 12.0 ng/ml, P = 0.00432). More fentanyl was found in solution after 180 minutes when given with midazolam compared to fentanyl given alone in the presence of an oxygenator (101 ± 22.3 vs. 52.7 ± 12.5 ng/ml, P = 0.044). Less midazolam was present after 180 minutes when given with morphine compared to midazolam given alone in the absence of an oxygenator (1264.9 ± 425.6 vs. 2124 ± 254 ng/ml, P = 0.037). We successfully characterized the adsorption of various combinations of midazolam, fentanyl, and morphine to our CPB circuit, showing that fentanyl and midazolam behave differently based on other medications present.
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Fentanilo , Midazolam , Puente Cardiopulmonar , Morfina , OxigenadoresRESUMEN
BACKGROUND: Enteral nutrition (EN) intolerance and delayed gastric emptying are prevalent in pediatric critical illness and limit EN delivery. Gastrointestinal (GI) hormones may be associated with EN intolerance and delayed gastric emptying in this cohort. METHODS: We determined GI hormone levels, time to achieve 50% of EN goal, and gastric emptying in critically ill children. Total amylin, active ghrelin, total glucagon-like peptide-1 (GLP-1), total gastric inhibitory polypeptide, glucagon, and total peptide-YY (PYY) were measured by multiplex assay and cholecystokinin by ELISA. Lower concentrations of acetaminophen at 1 hour (C1h, µg/mL) using the acetaminophen absorption test defined delayed gastric emptying. Correlation, regression analyses, and a principal component analysis were used to examine the association between GI hormones and time to 50% EN goal and C1h. RESULTS: GI hormones were measured in 14 of 21 patients with gastric emptying testing; median age of 11.2 years (6.74-16.3) and 50% male. Increasing hormone levels from GI hormone profile 1 (GLP-1, glucagon, and amylin) correlated with greater time to reach 50% EN goal (R2 = 0.296, P = 0.04). Decreasing hormone levels from GI hormone profile 2 (PYY and ghrelin) correlated with lower C1h and slower gastric emptying (R2 = 0.342, P = 0.02). CONCLUSION: GI hormone profiles are associated with time to achieve 50% of EN goal and gastric emptying in critically ill children. We have described a feasible model to study the role of GI hormones in this cohort, including the potential clinical applicability of GI hormone measurement in the management of delayed gastric emptying.
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Enfermedad Crítica , Nutrición Enteral , Hormonas Gastrointestinales , Niño , Femenino , Vaciamiento Gástrico , Humanos , Masculino , Proyectos PilotoRESUMEN
The clinical outcomes of primary immunodeficiencies (PIDs) are greatly improved by accurate diagnosis early in life. However, it is not common to consider PIDs before the manifestation of severe clinical symptoms. Including PIDs in the nation-wide newborn screening programs will potentially improve survival and provide better disease management and preventive care in PID patients. This calls for the detection of disease biomarkers in blood and the use of dried blood spot samples, which is a part of routine newborn screening programs worldwide. Here, we developed a newborn screening method based on multiplex protein profiling for parallel diagnosis of 22 innate immunodeficiencies affecting the complement system and respiratory burst function in phagocytosis. The proposed method uses a small fraction of eluted blood from dried blood spots and is applicable for population-scale performance. The diagnosis method is validated through a retrospective screening of immunodeficient patient samples. This diagnostic approach can pave the way for an earlier, more comprehensive and accurate diagnosis of complement and phagocytic disorders, which ultimately lead to a healthy and active life for the PID patients.
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Enfermedades por Deficiencia de Complemento Hereditario/diagnóstico , Síndromes de Inmunodeficiencia/diagnóstico , Tamizaje Neonatal/métodos , Disfunción de Fagocito Bactericida/diagnóstico , Fagocitos/fisiología , Diagnóstico Precoz , Humanos , Recién Nacido , Fagocitosis , Estudios RetrospectivosRESUMEN
Patient sedation and analgesia on extracorporeal membrane oxygenation (ECMO) is vital for safety and comfort. However, adsorption to the circuit may alter drug pharmacokinetics and remains poorly characterized. This study characterizes drug adsorption of morphine, fentanyl, midazolam, and dexmedetomidine in an ex vivo infant ECMO circuit utilizing polymethylpentene (PMP) membrane oxygenator (MO) with protein-bounded polyvinylchloride (PVC) tubing. Twelve closed-loop ex vivo ECMO circuits were prepared using P.h.i.s.i.o (phosphorylcholine)-coated PVC tubing (Sorin Group USA, Inc.) and a Quadrox-iD pediatric polymethylpentene MO (Maquet Cardiopulmonary AG). Once the circuits were primed and running, a single medication was injected as a bolus into the circuit with three circuits per drug. Drug samples were drawn following injection, at 2, 5, 15, 30, 60, 120 minutes and at 4, 12, 24, 36, and 48 hours and analyzed using ultra high-performance liquid chromatography with mass spectrometry. Compared with morphine, the other drugs are highly sequestered with fentanyl 68.5%, dexmedetomidine 50.8%, and midazolam 26.2% affecting the availability of free drug in the circuit. Sequestration of fentanyl, midazolam, and dexmedetomidine in an ECMO circuit with P.h.i.s.i.o-coated PVC tubing and PMP MO may limit drug delivery to infants. Future in vivo studies are needed to determine the clinical impact of sequestration.
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Adsorción , Analgésicos/química , Oxigenación por Membrana Extracorpórea , Hipnóticos y Sedantes/química , Oxigenación por Membrana Extracorpórea/métodos , Humanos , Técnicas In Vitro , LactanteRESUMEN
Digital pills, gelatin capsules with radiofrequency transmitters activated by stomach chloride ions, directly measure antiretroviral therapy adherence. In individuals with substance use disorders and HIV, real-time nonadherence detected by digital pills creates a platform to deliver substance use and adherence interventions. In this study, we determined the bioequivalence of tenofovir (TFV), administered as tenofovir disoproxil fumarate (TDF) in healthy human volunteers administered a commercial drug product and a digital pill formulation. We adhered generally to the US FDA Analytical Procedures and Methods for Validation for Drugs and Biologics guidelines. Ten HIV-uninfected adults without reported allergy to TFV, emtricitabine, or rilpivirine were enrolled. Participants ingested a digital pill containing TDF/emtricitabine/rilpivirine. Peripheral venous blood samples were collected at 0.5, 1, 2, 4, 8, and 24 h postingestion. After a 14-day washout period, the same participants ingested Complera™. Serial venous blood samples were collected using the same protocol as the digital pill. Liquid chromatography/mass spectrometry was used to determine a maximum concentration (Cmax), area under curve from time zero to last measured concentration (AUCo-t), and area under curve from time zero to infinity (AUCoo) of TFV. Ten participants with an average age of 27 and body mass index of 25.4 successfully completed the study. Predose TFV was undetectable before the second administration of Complera confirming adequate washout period after ingestion of the digital pill. The geometric means of AUCo-t, AUCoo, and Cmax for test and reference products were within the 95% confidence intervals and, therefore, bioequivalent. TFV overencapsulated in digital pills are bioequivalent to TFV in commercial formulations.
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Fármacos Anti-VIH/farmacocinética , Sistemas de Liberación de Medicamentos , Emtricitabina/farmacocinética , Rilpivirina/farmacocinética , Tenofovir/farmacocinética , Adulto , Cápsulas , Combinación Emtricitabina, Rilpivirina y Tenofovir/farmacocinética , Femenino , Infecciones por VIH/prevención & control , Voluntarios Sanos , Humanos , Masculino , Cumplimiento de la Medicación , Ondas de Radio , Equivalencia Terapéutica , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Axotomy results in permanent loss of function after brain and spinal cord injuries due to the minimal regenerative propensity of the adult central nervous system (CNS). To identify pharmacological enhancers of axon regeneration, 960 compounds were screened for cortical neuron axonal regrowth using an in vitro cortical scrape assay. Diltiazem, verapamil, and bromopride were discovered to facilitate axon regeneration in rat cortical cultures, in the presence of chondroitin sulfate proteoglycans (CSPGs). Diltiazem, an L-type calcium channel blocker (L-CCB), also promotes axon outgrowth in adult primary mouse dorsal root ganglion (DRG) and induced human sensory (iSensory) neurons.
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Axones/fisiología , Diltiazem/farmacología , Regeneración Nerviosa/efectos de los fármacos , Amidas/farmacología , Animales , Axones/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo L/metabolismo , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Sinergismo Farmacológico , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Humanos , Ratones Endogámicos C57BL , Piridinas/farmacología , Ratas Sprague-DawleyRESUMEN
A clarification is due about the paper by Chelminiak [Phys. Rev. E 72, 031903 (2005)]. In changing notation at the beginning, the authors incur an unfortunate error that significantly impacts the rest of the paper.
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BACKGROUND AND OBJECTIVES: Neurological complications of spinal anesthesia are rare conditions. Headache caused by low pressure of the cerebrospinal fluid is one of the most frequent, which occurs after post-dural puncture. A comprehensive history and physical exam must be carried out before making the diagnosis of Post-Dural Puncture Headache (PDPH) and additional tests are necessary to exclude the possibility of developing serious neurological complications such as Dural Sinus Thrombosis (DST). According to the Case Report a differential diagnosis between Dural Sinus Thrombosis with PDPH is discussed. CASE REPORT: A 22 year-old lady, ASA Physical Status Class I was admitted at 39 weeks of gestation for delivery. For labor pain relief she requested epidural for analgesia, but unfortunately accidental dural puncture occurred. She developed an occipital headache and neck pain in the second day postpartum which was relieved by both lying down and supporting treatment such as rehydration, analgesics and caffeine. On day third postpartum she was discharged without complaints. On day fifth postpartum the pain returned and became more intense and less responsive to oral analgesics. She was admitted to the hospital to do a complete neurological and image investigation that showed a lesion consistent with the diagnosis of cortical vein thrombosis and Duhral Sinus Thrombosis (TSD). She was treated with oral anticoagulants. After two days, a repeated magnetic resonance image (MRI) showed partial canalization of the central sinus thrombus. The patient was discharged from hospital five days after her admission without any of the initial symptoms. CONCLUSION: The report describes a patient who developed severe headache following continuous epidural analgesia for delivery. Initially it was diagnosed as PDPH, however with the aid of an MRI the diagnosis of TSD was later established and treated. TSD is a rare condition and is often underdiagnosed. Because of its potentially lethal complications, it should always be considered in acute headache differential diagnosis.
RESUMEN
BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a prevalent pathogen in patients with cystic fibrosis (CF) associated with increased morbidity. Ceftaroline fosamil is an intravenous (IV) cephalosporin with activity against MRSA. There are minimal data regarding dosing in the CF population. The objective of this study was to determine the pharmacokinetic and pharmacodynamic profile of IV ceftaroline in patients with CF. METHODS: We conducted a single-center prospective study of children and young adults with CF receiving ceftaroline (15mg/kg IV up to 600mg every 8h) as part of treatment for a CF pulmonary exacerbation between June 2016 and April 2017. Seven patients were enrolled for a total of 10 treatment courses. For each treatment course, up to 8 plasma samples were assayed for ceftaroline using ultra-high performance liquid chromatography with mass spectrometry. Maximum plasma concentration, systemic clearance, and elimination half-life were calculated. The area under the curve (AUC) above the minimum inhibitory concentration (MIC) and the percent time above the MIC (%fT>MIC) were determined for each subject using MICs of 0.5, 1, and 2µg/mL and the measured MIC if available. RESULTS: The mean (SD) age for the 7 patients was 20.3 (8.0) years. Mean (SD) maximum plasma concentration of ceftaroline was 22.7 (9.6) µg/mL, systemic clearance 7.9 (3.3) L/h, and half-life 1.1 (0.4) hours. Using a MIC of 1 µg/mL, accepted as the MIC 90 of MRSA isolates, AUC above MIC mean (SD) was 53.6 (19.5) µg·h/mL, mean (SD) %fT>MIC was 75.7 (10.4), and all subjects had >60%fT>MIC. CONCLUSIONS: In this cohort of CF patients, mean ceftaroline half-life was 1.1h, which is notably lower than the general population. The dosing regimen studied, which exceeds the recommended dosing in the non-CF population, was adequate to achieve >60% time above the MIC in all patients.
Asunto(s)
Antibacterianos , Cefalosporinas , Fibrosis Quística , Staphylococcus aureus Resistente a Meticilina , Adolescente , Adulto , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Cefalosporinas/administración & dosificación , Cefalosporinas/farmacocinética , Niño , Cromatografía Liquida/métodos , Fibrosis Quística/diagnóstico , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/microbiología , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas/métodos , Femenino , Semivida , Humanos , Masculino , Espectrometría de Masas/métodos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Pruebas de Sensibilidad Microbiana/métodos , Estudios Prospectivos , Resultado del Tratamiento , CeftarolinaRESUMEN
BACKGROUND: Delayed gastric emptying (GE) impedes enteral nutrient (EN) delivery in critically ill children. We examined the correlation between (a) bedside EN intolerance assessments, including gastric residual volume (GRV); (b) delayed GE; and (c) delayed EN advancement. MATERIALS AND METHODS: We prospectively enrolled patients ≥1 year of age, eligible for gastric EN and without contraindications to acetaminophen. Gastric emptying was determined by the acetaminophen absorption test, specifically the area under the curve at 60 minutes (AUC60). Slow EN advancement was defined as delivery of <50% of the prescribed EN 48 hours after study initiation. EN intolerance assessments (GRV, abdominal distension, emesis, loose stools, abdominal discomfort) were recorded. RESULTS: We enrolled 20 patients, median 11 years (4.4-15.5), 50% male. Sixteen (80%) patients had delayed GE (AUC60 <600 mcg·min/mL) and 7 (35%) had slow EN advancement. Median GRV (mL/kg) for patients with delayed vs normal GE was 0.43 (0.113-2.188) vs 0.89 (0.06-1.91), P = .9635. Patients with slow vs rapid EN advancement had median GRV (mL/kg) of 1.02 mL/kg (0.20-3.20) vs 0.27 mL/kg (0.06-1.62), P = .3114, and frequency of altered EN intolerance assessments of 3/7 (42.9%) vs 5/13 (38.5%), P = 1. Median AUC60 for patients with slow vs rapid EN advancement was 91.74 mcg·min/mL (53.52-143.1) vs 449.5 mcg·min/mL (173.2-786.5), P = .0012. CONCLUSIONS: A majority of our study cohort had delayed GE. Bedside EN intolerance assessments, particularly GRV, did not predict delayed GE or rate of EN advancement. Delayed gastric emptying predicted slow EN advancement. Novel tests for delayed GE and EN intolerance are needed.