Denufosol: A review of studies with inhaled P2Y2 agonists that led to Phase 3

Kellerman, Donald J.; Mospan, Andrea R.; Engels, Jean; Schaberg, A.; Gorden, JoAnn C.; Smiley, Lynn

doi:10.1016/j.pupt.2007.12.003

Cited by 84 publications

(59 citation statements)

References 20 publications

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“…In phase 2 European trials, Moli1901 was well tolerated in most patients (one participant experienced a transient decrease in pulmonary function). Those receiving treatment of 2.5 mg daily of inhaled Moli1901 showed significant improvement in lung function measured as forced expiratory volume in one second (FEV 1 ; Grasemann et al, 2007).Initially promising, Denufosol, a P2Y2 agonist developed by Inspire, was believed to rehydrate the airway surface liquid, bypassing the basic CFTR protein defect, producing improvement in pulmonary function (Kellerman et al, 2008). However, the most recent clinical trial found it to be without effect.…”

Section: Mucolytics/airway-rehydrating Agentsmentioning

confidence: 99%

Channel Replacement Therapy for Cystic Fibrosis

Tomich¹,

Bukovnik²,

Layman³

et al. 2012

Cystic Fibrosis - Renewed Hopes Through Research

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Section: Mucolytics/airway-rehydrating Agentsmentioning

confidence: 99%

Channel Replacement Therapy for Cystic Fibrosis

Tomich¹,

Bukovnik²,

Layman³

et al. 2012

Cystic Fibrosis - Renewed Hopes Through Research

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“…3A) may be ideal for treating resistant Gram-negative lung infections. To treat cystic fibrosis (CF), an inhaled adenosine triphosphate (ATP) analog, Denufosol, targeted at lung chloride channel purinergic P2Y receptors with the goal of compensating for dysfunctional CF transmembrane conductance regulator (CFTR) ion flow, is showing excellent promise in clinical trials (34). Covalent linkage of ATP or an analog such as Denufosol to SP-B1-25 ( Fig.…”

Section: Discussionmentioning

confidence: 99%

A human surfactant peptide-elastase inhibitor construct as a treatment for emphysema

Guarnieri

Spencer²,

Lucey³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Two million Americans suffer from pulmonary emphysema, costing $2.5 billion/year and contributing to 100,000 deaths/year. Emphysema is thought to result from an imbalance between elastase and endogenous inhibitors of elastase, leading to tissue destruction and a loss of alveoli. Decades of research have still not resulted in an effective treatment other than stopping cigarette smoking, a highly addictive behavior. On the basis of our previous work, we hypothesize that small molecule inhibitors of human neutrophil elastase are ineffective because of rapid clearance from the lungs. To develop a long-acting elastase inhibitor with a lung pharmacodynamic profile that has minimal immunogenicity, we covalently linked an elastase inhibitor, similar to a trifluoro inhibitor that was used in clinical trials, to a 25-amino-acid fragment of human surfactant peptide B. We used this construct to prevent human neutrophil elastaseinduced emphysema in a rodent model. The elastase inhibitor alone, although in a 70-fold molar excess to elastase in a mixture with <0.6% residual elastase activity, provided no protection from elastase-induced emphysema. Covalently combining an endogenous peptide from the target organ with a synthetic small molecule inhibitor is a unique way of endowing an active compound with the pharmacodynamic profile needed to create in vivo efficacy.lung cancer | resistant infections | tuberculosis | asthma I nhalation is an important means of systemically delivering drugs that require immediate onset of action because the lungs provide a facile conduit to the bloodstream (1). Conversely, rapid lung clearance of small molecules causes a significant challenge for the development of pulmonary therapeutics. Rodent models of elastase-induced emphysema, for example, highlight the challenges for the development of effective drugs for pulmonary diseases. Potent in vitro human neutrophil elastase (HNE) inhibitors are cleared from the animals' lungs in minutes and may even exacerbate HNEinduced emphysema (2), whereas one intratracheally instilled dose of elastase causes maximum lung damage after 4 wk (3). The combination of long-term chronic pulmonary damage that characterizes the progression of emphysema with the rapid lung clearance (4) and potential nephrotoxicity (5) of small molecule drugs indicates that there is a profound need for new ways of producing pulmonary therapeutics with long lung residence time pharmacodynamics.Because emphysema is a chronic disease, any treatment will likely be administered over the course of the patient's life, and thus long-acting agents may induce an immune response that would negate the therapeutic effect. The ability of the treatment to access all regions of the vast lung surface area must also be considered. One way to slow the clearance of a small molecule inhibitor from the lung is to attach it to a larger polymer (6). For instance, the covalent linkage of a hydrophilic polymer to a peptidyl carbamate inhibitor increases the half-life by 100-fold in the lungs of hamsters and pro...

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“…Nebulised uridine triphosphate aerosol in the presence or absence of amiloride has been shown to provide enhanced mucociliary clearance in healthy subjects [21]. P2Y2 purinergic receptor agonists have been recently developed and phase 3 studies are currently in progress [22].…”

Section: Ion Channel Modifiersmentioning

confidence: 99%

Mucoactive drugs

Balsamo¹,

Lanata²,

Egan³

2010

Eur Respir Rev

125

102

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Mucus hypersecretion is a clinical feature of severe respiratory diseases such as asthma, cystic fibrosis and chronic obstructive pulmonary disease. Airway mucosal infection and/ or inflammation associated with these diseases often gives rise to inflammatory products, including neutrophil-derived DNA and filamentous actin, in addition to bacteria, apoptotic cells and cellular debris, that may collectively increase mucus production and viscosity. Mucoactive agents have been the medication of choice for the treatment of respiratory diseases in which mucus hypersecretion is a clinical complication. The main purpose of mucoactive drugs is to increase the ability to expectorate sputum and/or decrease mucus hypersecretion. Many mucoactive drugs are currently available and can be classified according to their putative mechanism of action. Mucoactive medications include expectorants, mucoregulators, mucolytics and mucokinetics. By developing our understanding of the specific effects of mucoactive agents, we may result in improved therapeutic use of these drugs. The present review provides a summary of the most clinically relevant mucoactive drugs in addition to their potential mechanism of action.

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Denufosol: A review of studies with inhaled P2Y2 agonists that led to Phase 3

Cited by 84 publications

References 20 publications

Channel Replacement Therapy for Cystic Fibrosis

Channel Replacement Therapy for Cystic Fibrosis

A human surfactant peptide-elastase inhibitor construct as a treatment for emphysema

Mucoactive drugs

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