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1.
Crit Care Explor ; 3(2): e0338, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33604579

RESUMO

Objectives: Effective treatment options for surfactant therapy in acute respiratory distress syndrome and coronavirus disease 2019 have not been established. To conduct preclinical studies in vitro and in vivo to evaluate efficiency, particle size, dosing, safety, and efficacy of inhaled surfactant using a breath-synchronized, nebulized delivery system in an established acute respiratory distress syndrome model. Design: Preclinical study. Setting: Research laboratory. Subjects: Anesthetized pigs. Intervention: In vitro analysis included particle size distribution and inhaled dose during simulated ventilation using a novel breath-synchronized nebulizer. Physiologic effects of inhaled aerosolized surfactant (treatment) were compared with aerosolized normal saline (control) in an adult porcine model (weight of 34.3 ± 0.6 kg) of severe acute respiratory distress syndrome (Pao2/Fio2 <100) with lung lavages and ventilator-induced lung injury during invasive ventilation. Measurements and Main Results: Mass median aerosol diameter was 2.8 µm. In vitro dose delivered distal to the endotracheal tube during mechanical ventilation was 85% ± 5%. Nebulizers were functional up to 20 doses of 108 mg of surfactant. Surfactant-treated animals (n = 4) exhibited rapid improvement in oxygenation with nearly full recovery of Pao2/Fio2 (~300) and end-expiratory lung volumes with nominal dose less than 30 mg/kg of surfactant, whereas control subjects (n = 3) maintained Pao2/Fio2 less than 100 over 4.5 hours with reduced end-expiratory lung volume. There was notably greater surfactant phospholipid content and lower indicators of lung inflammation and pathologic lung injury in surfactant-treated pigs than controls. There were no peridosing complications associated with nebulized surfactant, but surfactant-treated animals had progressively higher airway resistance post treatment than controls with no differences in ventilation effects between the two groups. Conclusions: Breath-synchronized, nebulized bovine surfactant appears to be a safe and feasible treatment option for use in coronavirus disease 2019 and other severe forms of acute respiratory distress syndrome.

2.
Int J Toxicol ; 39(5): 433-442, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32787636

RESUMO

Currently, off-label continuous administration of inhaled epoprostenol is used to manage hemodynamics during mitral valve surgery. A toxicology program was developed to support the use of inhaled epoprostenol during mechanical ventilation as well as pre- and postsurgery via nasal prongs. To support use in patients using nasal prongs, a Good Laboratory Practice (GLP), 14-day rat, nose-only inhalation study was performed. No adverse findings were observed at ∼50× the dose rate received by patient during off-label use. To simulate up to 48 hours continuous aerosol exposure during mechanical ventilation, a GLP toxicology study was performed using anesthetized, intubated, mechanically ventilated dogs. Dogs inhaled epoprostenol at approximately 6× and 13× the dose rate reported in off-label human studies. This novel animal model required establishment of a dog intensive care unit providing sedation, multisystem support, partial parenteral nutrition, and management of the intubated mechanically ventilated dogs for the 48-hour duration of study. Aerosol was generated by a vibrating mesh nebulizer with novel methods required to determine dose and particle size in-vitro. Continuous pH 10.5 epoprostenol was anticipated to be associated with lung injury; however, no adverse findings were observed. As no toxicity at pH 10.5 was observed with a formulation that required refrigeration, a room temperature stable formulation at pH 12 was evaluated in the same ventilated dog model. Again, there were no adverse findings. In conclusion, current toxicology findings support the evaluation of inhaled epoprostenol at pH 12 in surgical patients with pulmonary hypertension for up to 48 hours continuous exposure.


Assuntos
Anti-Hipertensivos/toxicidade , Epoprostenol/toxicidade , Administração por Inalação , Aerossóis , Animais , Anti-Hipertensivos/química , Cães , Desenvolvimento de Medicamentos , Epoprostenol/química , Feminino , Concentração de Íons de Hidrogênio , Hipertensão Pulmonar/tratamento farmacológico , Pulmão/anatomia & histologia , Pulmão/efeitos dos fármacos , Masculino , Nebulizadores e Vaporizadores , Ratos Sprague-Dawley , Respiração Artificial , Testes de Toxicidade/métodos
4.
J Cardiovasc Pharmacol ; 72(3): 129-135, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29923887

RESUMO

We compared the pharmacokinetic (PK) profile and electrocardiographic (ECG) changes in response to intratracheal instillation of flecainide acetate into the left atrium and ventricle with intravenous (IV) flecainide acetate administration. In 12 closed-chest anesthetized Yorkshire pigs, we monitored the QRS complex and PR, JTc, and QTc intervals during sinus rhythm and correlated changes with venous plasma drug concentrations before and at 2, 5, 10, 15, and 30 minutes after drug administration. Intratracheal instillation of flecainide (0.75 and 1.5 mg/kg, rapid bolus) caused dose/concentration-dependent increases in the QRS complex duration of 10% and 19%, respectively, at 2 minutes, coinciding with peak venous plasma levels (1688 ± 177 and 2808 ± 217 ng/mL, respectively). IV infusion of flecainide (2 mg/kg) over 2 or 10 minutes similarly prolonged QRS complexes and PR intervals (both, P < 0.001). Intratracheal flecainide instillation increased PR interval briefly at 5 minutes. Neither intratracheal nor IV flecainide affected JTc or QTc intervals. Thus, the PK pattern of intratracheal instillation of flecainide is comparable to IV administration, although the absolute plasma concentrations were higher with IV infusion. Both modes of delivery elicited ECG changes that were consistent with the expected pharmacological activity of flecainide.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Antiarrítmicos/administração & dosagem , Antiarrítmicos/farmacocinética , Eletrocardiografia , Flecainida/administração & dosagem , Flecainida/farmacocinética , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Administração por Inalação , Anestesia Geral , Animais , Sistema de Condução Cardíaco/fisiologia , Infusões Intravenosas , Masculino , Sus scrofa
5.
J Pharmacol Exp Ther ; 363(1): 104-113, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28778859

RESUMO

The increasing availability of prescription opioid analgesics for the treatment of pain has been paralleled by an epidemic of opioid misuse, diversion, and overdose. The development of abuse-deterrent formulations (ADFs) of conventional opioids such as oxycodone and morphine represents an advance in the field and has had a positive but insufficient impact, as most opioids are still prescribed in highly abusable, non-ADF forms, and abusers can tamper with ADF medications to liberate the abusable opioid within. The abuse liability of mu-opioid agonists appears to be dependent on their rapid rate of entry into the central nervous system (CNS), whereas analgesic activity appears to be a function of CNS exposure alone, suggesting that a new opioid agonist with an inherently low rate of influx across the blood-brain barrier could mediate analgesia with low abuse liability, regardless of formulation or route of administration. NKTR-181 is a novel, long-acting, selective mu-opioid agonist with structural properties that reduce its rate of entry across the blood-brain barrier compared with traditional mu-opioid agonists. NKTR-181 demonstrated maximum analgesic activity comparable to that of oxycodone in hot-plate latency and acetic-acid writhing models. NKTR-181 was distinguishable from oxycodone by its reduced abuse potential in self-administration and progressive-ratio break point models, with behavioral effects similar to those of saline, as well as reduced CNS side effects as measured by the modified Irwin test. The in vitro and in vivo studies presented here demonstrate that NKTR-181 is the first selective mu-opioid agonist to combine analgesic efficacy and reduced abuse liability through the alteration of brain-entry kinetics.


Assuntos
Analgésicos Opioides/farmacologia , Morfinanos/farmacologia , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle , Analgésicos Opioides/química , Analgésicos Opioides/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Células CACO-2 , Relação Dose-Resposta a Droga , Composição de Medicamentos , Humanos , Masculino , Morfinanos/química , Morfinanos/metabolismo , Permeabilidade , Ratos , Ratos Sprague-Dawley , Receptores Opioides mu/metabolismo , Fatores de Tempo
6.
Bioorg Med Chem Lett ; 24(13): 2871-6, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24835980

RESUMO

A multivalent approach focused on amine-based secondary binding groups was applied to the discovery of long-acting inhaled ß2-agonists. Addition of amine moieties to the neutral secondary binding group of an existing ß2-agonist series was found to provide improved in vivo efficacy, but also led to the formation of biologically active aldehyde metabolites which were viewed as a risk for the development of these compounds. Structural simplification of the scaffold and blocking the site of metabolism to prevent aldehyde formation afforded a potent series of dibasic ß2-agonists with improved duration of action relative to their monobasic analogs. Additional optimization led to the discovery of 29 (TD-4306), a potent and selective ß2-agonist with potential for once-daily dosing.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Asma/tratamento farmacológico , Difenilamina/análogos & derivados , Descoberta de Drogas , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolonas/farmacologia , Receptores Adrenérgicos beta 2/metabolismo , Agonistas de Receptores Adrenérgicos beta 2/síntese química , Agonistas de Receptores Adrenérgicos beta 2/química , Animais , Asma/metabolismo , Linhagem Celular , Difenilamina/síntese química , Difenilamina/química , Difenilamina/farmacologia , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Cobaias , Humanos , Estrutura Molecular , Doença Pulmonar Obstrutiva Crônica/metabolismo , Quinolonas/síntese química , Quinolonas/química , Ratos , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 24(12): 2625-30, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24813741

RESUMO

A series of potent ß2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical ß2-agonist primary binding group linked via a phenethylamine linker to a hydrophilic secondary binding group, served as an initiation point. A more hydrophobic set of secondary binding groups was explored, prepared rapidly from a common intermediate by Buchwald-Hartwig amination. TD-5471 (25), a potent and selective full agonist of the human ß2-adrenoceptor, was identified as the most promising agent. It is potent, with slow onset in an in vitro guinea pig trachea model and shows a dose-dependent and long duration of action in an in vivo guinea pig model of bronchoprotection. TD-5471 is structurally differentiated from milveterol and its long duration of action is consistent with a correlation with hydrophobicity observed in other long-acting ß2-agonist discovery programs.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/síntese química , Aminas/síntese química , Desenho de Fármacos , Agonistas de Receptores Adrenérgicos beta 2/química , Aminas/química , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Cobaias , Humanos , Pneumopatias Obstrutivas/tratamento farmacológico , Estrutura Molecular
8.
J Antimicrob Chemother ; 67(4): 970-6, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22240402

RESUMO

OBJECTIVES: Amphotericin B inhalation powder (ABIP) is a novel dry-powder amphotericin B formulation that is directly delivered to the lung, resulting in elevated lung tissue drug concentrations of this polyene. We evaluated the prophylactic efficacy of single dose administration of ABIP in a guinea pig model of invasive pulmonary aspergillosis. METHODS: Guinea pigs were immunosuppressed with cyclophosphamide and cortisone acetate and challenged with Aspergillus fumigatus conidia in an aerosol chamber. Guinea pigs received prophylaxis with a single inhaled dose of ABIP at 0.05, 0.5, 4 or 10 mg/kg administered 24 h prior to infection. Treatment with oral voriconazole at doses of 5 or 10 mg/kg twice daily beginning 24 h post-challenge served as the positive control. RESULTS: Improvements in survival were observed with ABIP prophylaxis. A single inhaled dose of 4 mg/kg ABIP and treatment with 5 mg/kg voriconazole both improved median and percentage survival compared with untreated controls. In addition, pulmonary fungal burden, as assessed by cfu, quantitative PCR and galactomannan, was also reduced in a dose-dependent fashion with ABIP prophylaxis as well as with both doses of voriconazole treatment. CONCLUSIONS: Single-dose prophylaxis with inhaled ABIP as prophylaxis demonstrated a significant survival advantage and reductions in pulmonary fungal burden in this model of invasive pulmonary aspergillosis. Optimization of the dose and dosing frequency of ABIP dose may help to further enhance the anti-Aspergillus activity of this novel amphotericin B formulation.


Assuntos
Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Aspergillus fumigatus/patogenicidade , Quimioprevenção/métodos , Aspergilose Pulmonar Invasiva/prevenção & controle , Administração por Inalação , Animais , Aspergillus fumigatus/efeitos dos fármacos , Contagem de Colônia Microbiana , Cortisona/administração & dosagem , Cortisona/análogos & derivados , Ciclofosfamida/administração & dosagem , Modelos Animais de Doenças , Cobaias , Imunossupressores/administração & dosagem , Pulmão/microbiologia , Masculino , Pirimidinas/administração & dosagem , Análise de Sobrevida , Triazóis/administração & dosagem , Voriconazol
9.
Bioorg Med Chem Lett ; 22(2): 1213-8, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22178551

RESUMO

A multivalent approach was applied to the design of long-acting inhaled ß(2)-adrenoceptor agonists. A series of dimeric arylethanolamines based on the short acting ß(2)-adrenoceptor agonist albuterol were prepared, varying the nature and length of the linker between the basic nitrogens. None of the C(2)-symmetric dimers demonstrated increased potency, however dimer 5j, derived from 4-phenethylamine, was found to have increased binding potency in vitro relative to the parent monomer. Optimization of this structure led to the identification of 22 (milveterol) which demonstrates high potency in vitro and long duration of action in a guinea pig model of bronchoprotection.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Descoberta de Drogas , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 2/síntese química , Agonistas de Receptores Adrenérgicos beta 2/química , Animais , Antiasmáticos/síntese química , Antiasmáticos/química , Linhagem Celular , Cobaias , Humanos , Estrutura Molecular , Estereoisomerismo
10.
J Pharm Sci ; 98(8): 2847-56, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19408293

RESUMO

Polyethylene glycol (PEG) polymers are large amphiphilic molecules that are highly hydrated in solution. To explore the permeability properties of different sized PEG polymers across epithelial membranes in vivo, we examined the absorption of fluorescently labeled PEG conjugates sized 0.55-20 kDa from the lung, since this system provides a reservoir that limits rapid diffusion of molecules away from the site of delivery and enables permeability over longer times to be examined. Following intratracheal delivery in rats, the PEG polymers underwent absorption with first-order kinetics described by single exponential decay curves. PEG size produced a marked influence on the rate of uptake from the lung, with half-lives ranging from 2.4 to 13 h, although above a size of 5 kDa, no further change in rate was observed. PEG size likewise affected retention in alveolar macrophages and in lung tissue; whereas smaller PEG sizes (<2 kDa) were effectively cleared within 48 h, larger PEG sizes (>5 kDa) remained in lung cells and tissue for up to 7 days. These data demonstrate that PEG polymers can be absorbed across epithelial membranes and that PEG size plays a dominant role in controlling the rate and mechanism of absorption.


Assuntos
Polietilenoglicóis/química , Polietilenoglicóis/metabolismo , Absorção/efeitos dos fármacos , Absorção/fisiologia , Animais , Relação Dose-Resposta a Droga , Masculino , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Polietilenoglicóis/farmacologia , Polímeros/química , Polímeros/metabolismo , Ratos , Ratos Sprague-Dawley , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo
11.
Am J Pathol ; 162(6): 2069-78, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12759261

RESUMO

Increased mucus production in asthma is an important cause of airflow obstruction during severe exacerbations. To better understand the changes in airway epithelium that lead to increased mucus production, ovalbumin-sensitized and -challenged mice were used. The phenotype of the epithelium was dramatically altered, resulting in increased numbers of mucous cells, predominantly in the proximal airways. However, the total numbers of epithelial cells per unit area of basement membrane did not change. A 75% decrease in Clara cells and a 25% decrease in ciliated cells were completely compensated for by an increase in mucous cells. Consequently, by day 22, 70% of the total epithelial cell population in the proximal airways was mucous cells. Electron microscopy illustrated that Clara cells were undergoing metaplasia to mucous cells. Conversely, epithelial proliferation, detected with 5-chloro-2-deoxyuridine immunohistochemistry, was most marked in the distal airways. Using ethidium homodimer cell labeling to evaluate necrosis and terminal dUTP nick-end labeling immunohistochemistry to evaluate apoptosis, this proliferation was accompanied by negligible cell death. In conclusion, epithelial cell death did not appear to be the stimulus driving epithelial proliferation and the increase in mucous cell numbers was primarily a result of Clara cell metaplasia.


Assuntos
Asma/patologia , Mucosa Respiratória/patologia , Animais , Asma/imunologia , Brônquios/imunologia , Brônquios/patologia , Divisão Celular , Modelos Animais de Doenças , Células Epiteliais/patologia , Células Epiteliais/ultraestrutura , Masculino , Metaplasia/etiologia , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica , Ovalbumina/imunologia , Mucosa Respiratória/ultraestrutura
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