RESUMO
Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) represent promising alternatives for drug delivery to the central nervous system. In the present work, four different nanoformulations of the antiepileptic drug Carbamazepine (CBZ) were designed and prepared by the homogenization/ultrasonication method, with encapsulation efficiencies ranging from 82.8 to 93.8%. The formulations remained stable at 4⯰C for at least 3 months. Physicochemical and microscopic characterization were performed by photon correlation spectroscopy (PCS), transmission electron microscopy (TEM), atomic force microscopy (AFM); thermal properties by differential scanning calorimetry (DSC), thermogravimetry (TGA) and X-ray diffraction analysis (XRD). The results indicated the presence of spherical shape nanoparticles with a mean particle diameter around 160â¯nm in a narrow size distribution; the entrapped CBZ displayed an amorphous state. The in vitro release profile of CBZ fitted into a Baker-Lonsdale model for spherical matrices and almost the 100% of the encapsulated drug was released in a controlled manner during the first 24â¯h. The apparent permeability of CBZ-loaded nanoparticles through a cell monolayer model was similar to that of the free drug. In vivo experiments in a mice model of seizure suggested protection by CBZ-NLC against seizures for at least 2â¯h after intraperitoneal administration. The developed CBZ-loaded lipid nanocarriers displayed optimal characteristics of size, shape and drug release and possibly represent a promising tool to improve the treatment of refractory epilepsy linked to efflux transporters upregulation.
Assuntos
Anticonvulsivantes/química , Carbamazepina/química , Lipídeos/química , Nanopartículas/química , Nanoestruturas/química , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacocinética , Varredura Diferencial de Calorimetria , Carbamazepina/administração & dosagem , Carbamazepina/farmacocinética , Cães , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Células Madin Darby de Rim Canino , Camundongos , Microscopia de Força Atômica , Microscopia Eletrônica de Transmissão , Nanopartículas/ultraestrutura , Nanoestruturas/ultraestrutura , Tamanho da Partícula , Termogravimetria , Difração de Raios XRESUMO
Current medical treatments against recurrent pulmonary infections caused by Pseudomonas aeruginosa, such as cystic fibrosis (CF) disorder, involve the administration of inhalable antibiotics. The main challenge is, however, the eradication of microbial biofilms immersed in dense mucus that requires high and recurrent antibiotic doses. Accordingly, the development of novel drug delivery systems capable of providing local and controlled drug release in the lungs is a key factor to improve the therapeutic outcome of such therapeutic molecules. Inhalable hybrid carriers were prepared by co-precipitation of CaCO3 in the presence of alginate and the resulting microparticles were treated with alginate lyase (AL) in order to modify their porosity and enhance the drug loading. The hybrid microparticles were loaded with DNase (mucolytic agent) and levofloxacin (LV, wide-spectrum antibiotic) in the range of 20-40% for LV and 28-67% for DNase, depending on the AL treatment. In vitro studies demonstrated that microparticles were able to control the DNase release for 24 h, while 30-50% of LV was released in 3 days. The morphological characterization was performed by optical, fluorescence and scanning electron microscopies, showing a narrow size distribution (5 µm). FTIR, XRD, DSC and nitrogen adsorption isotherm studies revealed the presence of the drugs in a non-crystalline state. A microcidal effect of microparticles was found on P. aeruginosa in agar plates and corroborated by Live/Dead kit and TEM observations. Finally, to study whether the microparticles improved the localization of LV in the lungs, in vivo studies were performed by pulmonary administration of microparticles to healthy mice via nebulization and dry powder inhalation, followed by the quantification of LV in lung tissue. The results showed that microparticles loaded with LV delivered the antibiotic at least 3 times more efficiently than free LV. The developed system opens the gateway to new drug delivery systems that may provide enhanced therapeutic solutions against bacterial infections and in particular as a potential tool in CF pathology.
RESUMO
Patient-ventilator dyssynchrony is common during mechanical ventilation. Dyssynchrony decreases comfort, prolongs mechanical ventilation and intensive care unit stays, and might lead to worse outcome. Dyssynchrony can occur during the triggering of the ventilator, the inspiration period after triggering, the transition from inspiration to expiration, and the expiratory phase. The most common dyssynchronies are delayed triggering, autotriggering, ineffective inspiratory efforts (which can occur at any point in the respiratory cycle), mismatch between the patient's and ventilator's inspiratory times, and double triggering. At present, the detection of dyssynchronies usually depends on healthcare staff observing ventilator waveforms; however, performance is suboptimal and many events go undetected. To date, technological complexity has made it impossible to evaluate patient-ventilator synchrony throughout the course of mechanical ventilation. Studies have shown that a high index of dyssynchrony may increase the duration of mechanical ventilation. Better training, better ventilatory modes, and/or computerized systems that permit better synchronization of patients' demands and ventilator outputs are necessary to improve patient-ventilator synchrony.
Assuntos
Respiração Artificial/métodos , Ventiladores Mecânicos , Pressão do Ar , Falha de Equipamento/estatística & dados numéricos , Humanos , Pacientes , Respiração Artificial/efeitos adversos , Mecânica Respiratória/fisiologia , Ventiladores Mecânicos/efeitos adversos , Trabalho RespiratórioRESUMO
CNS drug development is characterized by an especially high attrition rate, despite clear unmet medical needs in the field of neuro-pharmacology and significant investment in R of novel CNS drug treatments. Here, we overview the issues underlying the intrinsic difficulty of CNS drugs development, including obstacles of pharmacokinetic nature and lack of predictivity of preclinical tests. We highlight current efforts to overcome these limitations, with an emphasis on modeling opportunities towards early recognition of CNS candidates (stressing the possibilities of multi-target directed ligands or "magic shotguns") and different approaches to improve CNS bioavailability.
Assuntos
Fármacos do Sistema Nervoso Central/química , Fármacos do Sistema Nervoso Central/farmacologia , Doenças do Sistema Nervoso Central/tratamento farmacológico , Descoberta de Drogas/métodos , Animais , Sistema Nervoso Central/efeitos dos fármacos , Desenho Assistido por Computador , HumanosRESUMO
Mechanical ventilation is a therapeutic intervention involving the temporary replacement of ventilatory function with the purpose of improving symptoms in patients with acute respiratory failure. Technological advances have facilitated the development of sophisticated ventilators for viewing and recording the respiratory waveforms, which are a valuable source of information for the clinician. The correct interpretation of these curves is crucial for the correct diagnosis and early detection of anomalies, and for understanding physiological aspects related to mechanical ventilation and patient-ventilator interaction. The present study offers a guide for the interpretation of the airway pressure and flow and volume curves of the ventilator, through the analysis of different clinical scenarios.
Assuntos
Respiração Artificial , Insuficiência Respiratória/fisiopatologia , Insuficiência Respiratória/terapia , Doença Aguda , Humanos , RespiraçãoRESUMO
The Health System is in crisis and critical care (from transport systems to the ICU) cannot escape from that. Lack of integration between ambulances and reference Hospitals, a deep shortage of critical care specialists and assigned economical resources that increase less than critical care demand are the cornerstones of the problem. Moreover, the analysis of the situation anticipated that the problem will be worse in the future. "Closed" ICUs in which critical care specialists direct patient care outperform "open" ones in which primary admitting physicians direct patient care in consultation with critical care specialists. However, the current paradigm in which a critical care specialist is close to the patient is in the edge of the trouble so, only a new paradigm could help to increase the number of patients under intensivist care. Current information technology and networking capabilities should be fully exploited to improve both the extent and quality of intensivist coverage. Far to be a replacement of the existing model Telemedicine might be a complimentary tool. In fact, to centralize medical data into servers has many additional advantages that could even improve the way in which critical care physicians take care of their patients under the traditional system.
Assuntos
Cuidados Críticos/métodos , Serviços Médicos de Emergência/métodos , Medicina de Emergência/métodos , Unidades de Terapia Intensiva/organização & administração , Garantia da Qualidade dos Cuidados de Saúde , Telemedicina , Alarmes Clínicos , Redes de Comunicação de Computadores/organização & administração , Instrução por Computador , Custos e Análise de Custo , Cuidados Críticos/economia , Serviços Médicos de Emergência/economia , Medicina de Emergência/economia , Medicina de Emergência/educação , Previsões , Necessidades e Demandas de Serviços de Saúde , Sistemas de Comunicação no Hospital/organização & administração , Humanos , Unidades de Terapia Intensiva/economia , Monitorização Fisiológica/economia , Monitorização Fisiológica/instrumentação , Controle de Qualidade , Espanha , Telemedicina/economia , Telemedicina/organização & administração , Telemedicina/tendências , Recursos HumanosRESUMO
As part of our search for potential anticonvulsant agents, a set of compounds were designed, synthesized, and evaluated against MES and PTZ tests. Bioisosteric functional group information was used to design a new functionality, sulfamides, that complies with the requirements of the pharmacophore previously defined. Some of the molecules showed a promising anticonvulsant profile as selective anti-MES drugs, being active at low concentrations (30mg/kg). The biological data were confirmed in Phase II of the Anticonvulsant Drug Development Program of the National Institute of Health.
Assuntos
Amidas/química , Amidas/farmacologia , Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Desenho de Fármacos , Enxofre/química , Amidas/síntese química , Animais , Anticonvulsivantes/química , Elétrons , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Ventilator-induced lung injury (VILI) is associated to a high rate of mortality with an important social impact. Mechanical ventilation induces structural and ultrastructural alterations in all cell types of the lung and can derive in the transduction of intracellular signals, as well as in changes in the expression of genes, a process known as mechanotransduction. Some of the conditions involved, such as inflammation and/or coagulation, apoptosis/necrosis can lead to the propagation of the injury outside the lung, resulting in multiorganic failure. VILI can be modulated by means of diverse interventions as the use of protective ventilatory modes, therapeutic approaches based on vasoactive and antioxidative drugs, and more recently treatments based on the use of repairing substances of the surfactant like poloxamers among others. Knowledge of the mechanisms involved in VILI is definitive for a better approach to this condition.
Assuntos
Respiração Artificial/efeitos adversos , Síndrome do Desconforto Respiratório/etiologia , Animais , Antioxidantes/uso terapêutico , Fenômenos Biofísicos , Biofísica , Cálcio/metabolismo , Fragilidade Capilar , Síndrome de Vazamento Capilar/etiologia , Membrana Celular/ultraestrutura , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Citoesqueleto/ultraestrutura , Elasticidade , Epoprostenol/uso terapêutico , Humanos , Pulmão/irrigação sanguínea , Pulmão/patologia , Modelos Biológicos , Insuficiência de Múltiplos Órgãos/etiologia , Respiração com Pressão Positiva , Edema Pulmonar/etiologia , Coelhos , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/patologia , Síndrome do Desconforto Respiratório/fisiopatologia , Síndrome do Desconforto Respiratório/prevenção & controle , Transdução de Sinais , Estresse MecânicoRESUMO
A topological virtual screening (tvs) test is presented, which is capable of identifying new drug leaders with anticonvulsant activity. Molecular structures of both anticonvulsant-active and non active compounds, extracted from the Merck Index database, were represented using topological indexes. By means of the application of a linear discriminant analysis to both sets of structures, a topological anticonvulsant model (tam) was obtained, which defines a connectivity function. On the basis of this model, 41 new structures with anticonvulsant activity have been identified by a topological virtual screening.
Assuntos
Anticonvulsivantes/química , Simulação por Computador , Bases de Dados Factuais , Análise Discriminante , Desenho de Fármacos , Estrutura Molecular , Relação Quantitativa Estrutura-AtividadeRESUMO
A large number of structurally different classes of ligands, many of them sharing the main characteristics of the benzodiazepine (BDZ) nucleus, are active in the modulation of anxiety, sedation, convulsion, myorelaxation, hypnotic and amnesic states in mammals. These compounds have high affinity for the benzodiazepine binding site (BDZ-bs) of the GABA(A) receptor complex. Since 1989 onwards our laboratories established that some natural flavonoids were ligands for the BDZ-bs which exhibit medium to high affinity in vitro and anxiolytic activity in vivo. Further research resulted in the production of synthetic flavonoid derivatives with increased biochemical and pharmacological activities. The currently accepted receptor/pharmacophore model of the BDZ-bs (Zhang, W.; Koeler, K. F.; Zhang, P.; Cook, J. M. Drug Des. Dev. 1995, 12, 193) accounts for the general requirements that should be met by this receptor for ligand recognition. In this paper we present a model pharmacophore which defines the characteristics for a ligand to be able to interact and bind to a flavone site, in the GABA(A) receptor. closely related to the BDZ-bs. A model of a flavone binding site has already been described (Dekermendjian, K.; Kahnberg, P.; Witt, M. R.; Sterner, O.; Nielsen, M.; Liljerfors, T. J. Med. Chem. 1999, 42, 4343). However, this alternative model is based only on graphic superposition techniques using as template a non-BDZ agonist. In this investigation all the natural and synthetic flavonoids found to be ligands for the BDZ-bs have been compared with the classical BDZ diazepam. A QSAR regression analysis of the parameters that describe the interaction demonstrates the relevance of the electronic effects for the ligand binding, and shows that they are associated with the negatively charged oxygen atom of the carbonyl group of the flavonoids and with the nature of the substituent in position 3'.
Assuntos
Benzodiazepinas/metabolismo , Flavonoides/metabolismo , Receptores de GABA-A/metabolismo , Animais , Ansiolíticos/metabolismo , Sítios de Ligação , Diazepam/química , Interações Medicamentosas , Flunitrazepam/metabolismo , Ligantes , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Ensaio Radioligante , Ratos , Sinaptossomos/metabolismoRESUMO
The anticonvulsant activity of 5-tertbutyloxycarbonylamido-1,3,4-thiadiazole-2-sulfonamide (B-H2ats) and 5-amino-1,3,4-thiadiazole-2-sulfonamide (Hats) was compared in mice, to that of acetazolamide (H2acm). These compounds exhibit potent anticonvulsant activity and low minimal motor impairment.