Breath-Synchronized Nebulized Surfactant in a Porcine Model of Acute Respiratory Distress Syndrome.

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.

Novel Toxicology Program to Support the Development of Inhaled VentaProst.

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.

Comparative Pharmacokinetic and Electrocardiographic Effects of Intratracheal and Intravenous Administration of Flecainide in Anesthetized Pigs.

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.

NKTR-181: A Novel Mu-Opioid Analgesic with Inherently Low Abuse Potential.

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.

Discovery of TD-4306, a long-acting β2-agonist for the treatment of asthma and COPD.

A multivalent approach focused on amine-based secondary binding groups was applied to the discovery of long-acting inhaled β2-agonists. Addition of amine moieties to the neutral secondary binding group of an existing β2-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 β2-agonists with improved duration of action relative to their monobasic analogs.

Multivalent design of long-acting β(2)-adrenoceptor agonists incorporating biarylamines.

A series of potent β2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical β2-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.

Prophylactic efficacy of single dose pulmonary administration of amphotericin B inhalation powder in a guinea pig model of invasive pulmonary aspergillosis.

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.

A multivalent approach to the discovery of long-acting β(2)-adrenoceptor agonists for the treatment of asthma and COPD.

A multivalent approach was applied to the design of long-acting inhaled β(2)-adrenoceptor agonists. A series of dimeric arylethanolamines based on the short acting β(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.

Absorption of polyethylene glycol (PEG) polymers: the effect of PEG size on permeability.

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.

Pathogenesis of mucous cell metaplasia in a murine asthma model.

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.