PDE4 inhibitor
Encyclopedia
A phosphodiesterase type 4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate
(cAMP). It is a member of the larger family of PDE inhibitors
. The PDE4 family of enzymes are the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system.
. It was initially tested for effects on the central nervous system
as a potential treatment for depression and later for Parkinson's. Clinical development of rolipram was abandoned due to the side-effects associated with its dosing. Despite the problems associated with rolipram as a drug, it remains as a valuable standard for research into PDE4 inhibitors because of its potent activity toward PDE4.
Some have also shown benefits such as antipsychotic effects, improved long term memory, increased wakefulness and increased neuroprotection.
, emesis, and related general intestinal side-effects are the most commonly implicated side-effects of PDE4 inhibitors.
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
(cAMP). It is a member of the larger family of PDE inhibitors
Phosphodiesterase inhibitor
A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase , therefore preventing the inactivation of the intracellular second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate by the respective PDE...
. The PDE4 family of enzymes are the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system.
Background
One of the first thoroughly elaborated PDE4 inhibitors is rolipramRolipram
Rolipram is a PDE4-inhibitor. Like most PDE4-inhibitors, it is an anti-inflammatory drug. Rolipram is being studied as a possible alternative to current antidepressants. Recent studies show that rolipram may have antipsychotic effects...
. It was initially tested for effects on the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
as a potential treatment for depression and later for Parkinson's. Clinical development of rolipram was abandoned due to the side-effects associated with its dosing. Despite the problems associated with rolipram as a drug, it remains as a valuable standard for research into PDE4 inhibitors because of its potent activity toward PDE4.
Indications
PDE4 inhibitors have shown a wide range of therapeutic potential including treatment of:- Chronic obstructive pulmonary diseaseChronic obstructive pulmonary diseaseChronic obstructive pulmonary disease , also known as chronic obstructive lung disease , chronic obstructive airway disease , chronic airflow limitation and chronic obstructive respiratory disease , is the co-occurrence of chronic bronchitis and emphysema, a pair of commonly co-existing diseases...
(COPD) - Bronchopulmonary dysplasiaBronchopulmonary dysplasiaBronchopulmonary dysplasia is a chronic lung disorder that is most common among children who were born prematurely, with low birthweights and who received prolonged mechanical ventilation to treat respiratory distress syndrome...
(BPD) - AsthmaAsthmaAsthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
- Depression
- Alzheimer's
- Parkinson's
Some have also shown benefits such as antipsychotic effects, improved long term memory, increased wakefulness and increased neuroprotection.
Adverse reactions
NauseaNausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, emesis, and related general intestinal side-effects are the most commonly implicated side-effects of PDE4 inhibitors.
Examples
- MesembrineMesembrineMesembrine is an alkaloid present in Sceletium tortuosum. Mesembrine acts as a serotonin reuptake inhibitor. Mesembrine may contribute to the antidepressant effects of kanna....
, an alkaloid from the herb Sceletium tortuosumSceletium tortuosumSceletium tortuosum is a succulent herb commonly found in South Africa, which is also known as Kanna, Channa, Kougoed - which literally means, 'chew things/goodies' or 'something to chew'... - RolipramRolipramRolipram is a PDE4-inhibitor. Like most PDE4-inhibitors, it is an anti-inflammatory drug. Rolipram is being studied as a possible alternative to current antidepressants. Recent studies show that rolipram may have antipsychotic effects...
, used as investigative tool in pharmacological research - IbudilastIbudilastIbudilast is an antiinflammatory drug used mainly in Japan, which acts as a phosphodiesterase inhibitor, inhibiting the PDE-4 subtype to the greatest extent, but also showing significant inhibition of other PDE subtypes.Ibudilast has bronchodilator, vasodilator and neuroprotective effects, and is...
, a neuroprotective and bronchodilator drug used mainly in the treatment of asthma and stroke. It inhibits PDE4 to the greatest extent, but also shows significant inhibition of other PDE subtypes, and so acts as a selective PDE4 inhibitor or a non-selective phosphodiesterase inhibitor, depending on the dose. - PiclamilastPiclamilastPiclamilast , is a selective PDE4 inhibitor. It is comparable to other PDE4 inhibitors for its anti-inflammatory effects. It has been investigated for its applications to the treatment of conditions such as chronic obstructive pulmonary disease, bronchopulmonary dysplasia and asthma...
, a more potent inhibitor than rolipram. - LuteolinLuteolinLuteolin is a yellow crystalline compound. It is a flavonoid; to be specific, it is one of the more common flavones. From preliminary research, it is thought to play a role in the human body possibly as an antioxidant, a free radical scavenger, a promoter of carbohydrate metabolism, or an immune...
, supplement extracted from peanuts that also possesses IGF-1 properties. - RoflumilastRoflumilastRoflumilast is a drug which acts as a selective, long-acting inhibitor of the enzyme PDE-4. It has antiinflammatory effects and is under development as an orally administered drug for the treatment of inflammatory conditions of the lungs such as asthma, and chronic obstructive pulmonary disease...
, licensed for the treatment of severe chronic obstructive pulmonary disease in the EU by Merck Sharp & Dohme using the tradename Daxas - CilomilastCilomilastCilomilast is a drug which was developed for the treatment of respiratory disorders such as asthma and Chronic Obstructive Pulmonary Disease...
, in clinical development by GlaxoSmithKlineGlaxoSmithKlineGlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
for treatment of COPD - DiazepamDiazepamDiazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
Carmen Collado, M., Beleta, J., Martinez, E., Miralpeix, M., Domènech, T., Maria Palacios, J. and Hernández, J. (1998), Functional and biochemical evidence for diazepam as a cyclic nucleotide phosphodiesterase type 4 inhibitor. British Journal of Pharmacology, 123: 1047–1054.