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1.
JACS Au ; 3(2): 344-357, 2023 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-36873677

RESUMEN

Design of the next-generation of therapeutics, biosensors, and molecular tools for basic research requires that we bring protein activity under control. Each protein has unique properties, and therefore, it is critical to tailor the current techniques to develop new regulatory methods and regulate new proteins of interest (POIs). This perspective gives an overview of the widely used stimuli and synthetic and natural methods for conditional regulation of proteins.

2.
Br J Pharmacol ; 177(18): 4209-4222, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32562259

RESUMEN

BACKGROUND AND PURPOSE: The macrocyclic tetrapeptide natural product CJ-15,208 (cyclo[Phe-d-Pro-Phe-Trp]) is a multifunctional µ-opioid receptor and κ-opioid receptor agonist and κ-opioid receptor antagonist that produces antinociception and prevents stress-induced reinstatement of extinguished cocaine-conditioned place preference (CPP). We hypothesized that an analogue of CJ-15,208, cyclo[Pro-Sar-Phe-d-Phe], would demonstrate multifunctional µ-opioid receptor and κ-opioid receptor ligand activity, producing potent antinociception with fewer liabilities than selective µ-opioid receptor agonists, while preventing both drug- and stress-induced reinstatement of morphine-induced CPP. EXPERIMENTAL APPROACH: The opioid receptor agonist and antagonist activity of cyclo[Pro-Sar-Phe-d-Phe] was characterized after i.c.v. and i.p. administration to C57BL/6J or transgenic opioid receptor "knockout" mice using the 55°C warm-water tail-withdrawal assay. Liabilities of locomotor coordination, respiration and spontaneous ambulation, and direct rewarding or aversive properties were assessed. Finally, the ability of cyclo[Pro-Sar-Phe-d-Phe] to block morphine- and stress-induced reinstatement of extinguished CPP was determined. KEY RESULTS: cyclo[Pro-Sar-Phe-d-Phe] demonstrated dose-dependent, short-lasting antinociception, with an ED50 (and 95% confidence interval) of 0.15 (0.05-0.21) nmol i.c.v. and 1.91 (0.40-3.54) mg·kg-1 i.p., mediated by µ- and κ-opioid receptors. The macrocyclic tetrapeptide also demonstrated potent dose-dependent κ-opioid receptor antagonist-like activity at 2.5, but not at 4.5, h after administration. cyclo[Pro-Sar-Phe-d-Phe] displayed reduced liabiities compared with morphine, attributed to its additional activity at κ-receptors. Pretreatment with cyclo[Pro-Sar-Phe-d-Phe] prevented stress- and drug-induced reinstatement of extinguished morphine-place preference responses in a time-dependent manner. CONCLUSIONS AND IMPLICATIONS: These data suggest that cyclo[Pro-Sar-Phe-d-Phe] is a promising lead compound for both the treatment of pain with reduced sideeffects and preventing both drug- and stress-induced relapse in morphine-abstinent subjects.


Asunto(s)
Morfina , Preparaciones Farmacéuticas , Receptores Opioides mu , Analgésicos Opioides/farmacología , Animales , Ratones , Ratones Endogámicos C57BL , Morfina/farmacología , Antagonistas de Narcóticos , Receptores Opioides , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inhibidores
3.
ACS Chem Neurosci ; 11(9): 1324-1336, 2020 05 06.
Artículo en Inglés | MEDLINE | ID: mdl-32251585

RESUMEN

Substance abuse remains a serious public health crisis, affecting millions of people worldwide. Macrocyclic tetrapeptides like CJ-15,208 and [d-Trp]CJ-15,208 demonstrate opioid activity shown to attenuate the rewarding effects of cocaine in conditioned place preference assays in mice, making them promising lead compounds for treating substance abuse. In the present study, we report the rational design, synthesis, conformational analysis, and continued pharmacological evaluation of the novel macrocyclic tetrapeptide cyclo[Pro-Sar-Phe-d-Phe] to further explore this unique molecular scaffold. This peptide was rationally designed based on X-ray and NMR structures of related macrocyclic tetrapeptides. Following synthesis, its solution-phase conformations were determined by NMR and molecular modeling. The peptide adopted multiple conformations in polar solvents, but a single conformation in chloroform that is stabilized by intramolecular hydrogen bonding. The peptide is orally bioavailable, producing antinociception and antagonism of kappa opioid receptor (KOR) stimulation following oral administration in a mouse 55 °C warm-water tail-withdrawal assay. Notably, cyclo[Pro-Sar-Phe-d-Phe] blocked both stress- and drug-induced reinstatement of cocaine and morphine conditioned place preference in mice following oral administration, and displayed a decreased side-effect profile compared to morphine. Thus, cyclo[Pro-Sar-Phe-d-Phe] is a promising lead compound for the treatment of substance abuse.


Asunto(s)
Analgésicos Opioides , Antagonistas de Narcóticos , Administración Oral , Animales , Ratones , Ratones Endogámicos C57BL , Oligopéptidos , Péptidos Cíclicos , Receptores Opioides kappa , Receptores Opioides mu
4.
Crit Pathw Cardiol ; 17(4): 184-190, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30418248

RESUMEN

Chest pain can be a challenging complaint to manage in the emergency department. A missed diagnosis can result in significant morbidity or mortality, whereas avoidable testing and hospitalizations can lead to increased health care costs, contribute to hospital crowding, and increase risks to patients. The HEART score is a validated decision aid to identify patients at low risk for acute coronary syndrome who can be safely discharged without admission or objective cardiac testing. In the largest and one of the longest studies to date (N = 31,060; 30 months), we included the HEART score into a larger, newly developed low-risk chest pain decision pathway, using a retrospective observational pre/post study design with the objective of safely lowering admissions. The modified HEART score calculation tool was incorporated in our electronic medical record. A significant increase in discharges of low-risk chest pain patients (relative increase of 21%; p < 0.0001) in the postimplementation period was observed with no significant difference in the rates of major adverse cardiac events between the pre and post periods. There was a decrease in the amount of return admissions for 30 days (4.65% fewer; p = 0.009) and 60 days (3.78% fewer; p = 0.020). No significant difference in length of stay was observed for patients who were ultimately discharged. A 64% decrease in monthly coronary computed tomography angiograms was observed in the post period (p < 0.0001). These findings support the growing consensus in the literature that the adoption of the HEART pathway or similar protocols in emergency departments, including at large and high-volume medical institutions, can substantially benefit patient care and reduce associated health care costs.


Asunto(s)
Dolor en el Pecho/diagnóstico , Toma de Decisiones , Servicio de Urgencia en Hospital/estadística & datos numéricos , Admisión del Paciente/tendencias , Medición de Riesgo/métodos , Triaje/normas , Dolor en el Pecho/terapia , Electrocardiografía , Femenino , Florida , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo
5.
West J Emerg Med ; 18(3): 335-339, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28435481

RESUMEN

INTRODUCTION: A subpopulation of sickle-cell disease patients, termed super-utilizers, presents frequently to emergency departments (EDs) for vaso-occlusive events and may consume disproportionate resources without broader health benefit. To address the healthcare needs of this vulnerable patient population, we piloted a multidisciplinary intervention seeking to create and use individualized patient care plans that alter utilization through coordinated care. Our goals were to assess feasibility primarily, and to assess resource use secondarily. METHODS: We evaluated the effects of a single-site interventional study targeted at a population of adult sickle-cell disease super-utilizers using a pre- and post-implementation design. The pre-intervention period was 06/01/13 to 12/31/13 (seven months) and the post-intervention period was 01/01/14 to 02/28/15 (14 months). Our approach included patient-specific best practice advisories (BPA); an ED management protocol; and formation of a "medical home" for these patients. RESULTS: For 10 subjects targeted initially we developed and implemented coordinated care plans; after deployment, we observed a tendency toward reduction in ED and inpatient utilization across all measured indices. Between the annualized pre- and post-implementation periods we found the following: ED visits decreased by 16.5 visits/pt-yr (95% confidence interval [CI] [-1.32-34.2]); ED length of state (LOS) decreased by 115.3 hours/pt-yr (95% CI [-82.9-313.5]); in-patient admissions decreased by 4.20 admissions/pt-yr (95% CI [-1.73-10.1]); in-patient LOS decreased by 35.8 hours/pt-yr (95% CI [-74.9-146.7]); and visits where the patient left before treatment were reduced by an annualized total of 13.7 visits. We observed no patient mortality in our 10 subjects, and no patient required admission to the intensive care unit 72 hours following discharge. CONCLUSION: This effort suggests that a targeted approach is both feasible and potentially effective, laying a foundation for broader study.


Asunto(s)
Atención Ambulatoria/estadística & datos numéricos , Anemia de Células Falciformes/terapia , Antidrepanocíticos/uso terapéutico , Servicio de Urgencia en Hospital/organización & administración , Servicio de Urgencia en Hospital/estadística & datos numéricos , Mal Uso de los Servicios de Salud/prevención & control , Atención Dirigida al Paciente , Adulto , Atención Ambulatoria/economía , Atención Ambulatoria/organización & administración , Anemia de Células Falciformes/economía , Antidrepanocíticos/economía , Transfusión Sanguínea , Análisis Costo-Beneficio , Servicio de Urgencia en Hospital/economía , Estudios de Factibilidad , Femenino , Florida , Accesibilidad a los Servicios de Salud , Mal Uso de los Servicios de Salud/economía , Humanos , Comunicación Interdisciplinaria , Masculino , Aceptación de la Atención de Salud , Atención Dirigida al Paciente/economía , Atención Dirigida al Paciente/organización & administración , Proyectos Piloto
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