Denufosol
Encyclopedia
Denufosol is an inhalable drug for the treatment of cystic fibrosis
, being developed by Inspire Pharmaceuticals and sponsored by the Cystic Fibrosis Foundation
. It has been tested in a number of Phase III clinical trial
s, initially with good outcomes, but ultimately showing non-significant results compared with placebo
.
The drug was also investigated for the treatment of retinal detachment
and other retina
l diseases, but trials were terminated in 2006.
("jet nebulizer"). To be effective, it had to reach the deeper parts of the lung (bronchiole
s), making it unsuitable for litte children under about five years of age.
CFTR
(cystic fibrosis transmembrane conductance regulator) on epithelial cells in the lungs. This channel is necessary to regulate the components of sweat, digestive juices, and mucus
. Defects lead to a viscous, dehydrated mucus, hindering mucociliary clearance
. Denufosol is an agonist
at the P2Y2 subtype of purinergic receptor
s, opening an alternative chloride channel and so partly compensating the effects caused by the non-working CFTR.
s (composed of a nucleobase
and a sugar each), 2'-desoxycytidine
and uridine
, linked by four units of phosphoric acid
. It is used in form of its tetrasodium
salt.
Cystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
, being developed by Inspire Pharmaceuticals and sponsored by the Cystic Fibrosis Foundation
Cystic Fibrosis Foundation
The Cystic Fibrosis Foundation is a non-profit organization in the United States established to provide the means to cure and control cystic fibrosis . The Foundation provides information about cystic fibrosis and finances CF research that aims to improve the quality of life for people with the...
. It has been tested in a number of Phase III clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s, initially with good outcomes, but ultimately showing non-significant results compared with placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
.
The drug was also investigated for the treatment of retinal detachment
Retinal detachment
Retinal detachment is a disorder of the eye in which the retina peels away from its underlying layer of support tissue. Initial detachment may be localized, but without rapid treatment the entire retina may detach, leading to vision loss and blindness. It is a medical emergency.The retina is a...
and other retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
l diseases, but trials were terminated in 2006.
Application
The substance was applied three times a day with an inhalerInhaler
An inhaler or puffer is a medical device used for delivering medication into the body via the lungs. It is mainly used in the treatment of asthma and Chronic Obstructive Pulmonary Disease . Zanamivir , used to treat influenza, must be administered via inhaler...
("jet nebulizer"). To be effective, it had to reach the deeper parts of the lung (bronchiole
Bronchiole
The bronchioles or bronchioli are the first airway branches that no longer contain cartilage or glands in their submucosa. They are branches of the bronchi.The bronchioles terminate by entering the circular sacs called alveoli.- Structure :...
s), making it unsuitable for litte children under about five years of age.
Mechanism of action
Cystic fibrosis is characterised by a defect of the chloride channelChloride channel
Chloride channels are a superfamily of poorly understood ion channels consisting of approximately 13 members.Chloride channels display a variety of important physiological and cellular roles that include regulation of pH, volume homeostasis, organic solute transport, cell migration, cell...
CFTR
Cystic fibrosis transmembrane conductance regulator
Cystic fibrosis transmembrane conductance regulator is a protein that in humans is encoded by the CFTR gene.CFTR is a ABC transporter-class ion channel that transports chloride and thiocyanate ions across epithelial cell membranes...
(cystic fibrosis transmembrane conductance regulator) on epithelial cells in the lungs. This channel is necessary to regulate the components of sweat, digestive juices, and mucus
Mucus
In vertebrates, mucus is a slippery secretion produced by, and covering, mucous membranes. Mucous fluid is typically produced from mucous cells found in mucous glands. Mucous cells secrete products that are rich in glycoproteins and water. Mucous fluid may also originate from mixed glands, which...
. Defects lead to a viscous, dehydrated mucus, hindering mucociliary clearance
Mucociliary Clearance
Mucociliary clearance, also referred to as mucociliary apparatus or mucociliar clearance , derived from mucus , cilia and clearance describes the self-clearing mechanism of the bronchi.The main bronchi down to the alveoli are lined with a respiratory epithelium...
. Denufosol is an agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
at the P2Y2 subtype of purinergic receptor
Purinergic receptor
Purinergic receptors, also known as purinoceptors, are a family of newly characterized plasma membrane molecules involved in several cellular functions such as vascular reactivity, apoptosis and cytokine secretion...
s, opening an alternative chloride channel and so partly compensating the effects caused by the non-working CFTR.
Chemistry
Denufosol consists of two nucleosideNucleoside
Nucleosides are glycosylamines consisting of a nucleobase bound to a ribose or deoxyribose sugar via a beta-glycosidic linkage...
s (composed of a nucleobase
Nucleobase
Nucleobases are a group of nitrogen-based molecules that are required to form nucleotides, the basic building blocks of DNA and RNA. Nucleobases provide the molecular structure necessary for the hydrogen bonding of complementary DNA and RNA strands, and are key components in the formation of stable...
and a sugar each), 2'-desoxycytidine
Cytidine
Cytidine is a nucleoside molecule that is formed when cytosine is attached to a ribose ring via a β-N1-glycosidic bond...
and uridine
Uridine
Uridine is a molecule that is formed when uracil is attached to a ribose ring via a β-N1-glycosidic bond.If uracil is attached to a deoxyribose ring, it is known as a deoxyuridine....
, linked by four units of phosphoric acid
Phosphoric acid
Phosphoric acid, also known as orthophosphoric acid or phosphoric acid, is a mineral acid having the chemical formula H3PO4. Orthophosphoric acid molecules can combine with themselves to form a variety of compounds which are also referred to as phosphoric acids, but in a more general way...
. It is used in form of its tetrasodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
salt.