PDE4 inhibitor

Piclamilast, a common PDE4 inhibitor

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.^[1]

Background

One of the first thoroughly elaborated PDE4 inhibitors is rolipram. It was initially tested for effects on the central nervous system as a potential treatment for depression and later for Parkinson's.^{[citation needed]} Clinical development of rolipram was abandoned due to the side-effects associated with its dosing.^{[citation needed]} 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 disease (COPD)
• Bronchopulmonary dysplasia (BPD)
• Asthma
• Depression
• Alzheimer's^[2]
• Parkinson's^[3]

Some have also shown benefits such as antipsychotic effects,^[4][5] improved long term memory,^[6] increased wakefulness^[7] and increased neuroprotection.^[8][9]

Adverse reactions

Nausea, emesis, and related general intestinal side-effects are the most commonly implicated side-effects of PDE4 inhibitors.

Examples

• Mesembrine, an alkaloid from the herb Sceletium tortuosum
• Rolipram, used as investigative tool in pharmacological research
• Ibudilast, 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.
• Piclamilast, a more potent inhibitor than rolipram.^[10]
• Luteolin, supplement extracted from peanuts that also possesses IGF-1 properties.^[11]
• Roflumilast, licensed for the treatment of severe chronic obstructive pulmonary disease in the EU by Merck Sharp & Dohme using the tradename Daxas^[12]
• Cilomilast, in clinical development by GlaxoSmithKline for treatment of COPD
• Diazepam 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.

Mode of action

PDE4 hydrolyzes cyclic adenosine monophosphate (cAMP) to inactive adenosine monophosphate (AMP). Inhibition of PDE4 blocks hydrolysis of cAMP, thereby increasing levels of cAMP within cells.

References

1. ^ Spina, D (2008). "PDE4 inhibitors: current status". British Journal of Pharmacology 155 (3): 308–315. doi:10.1038/bjp.2008.307. PMC 2567892. PMID 18660825. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2567892. 
2. ^ Smith, Donna L; Pozueta J, Gong B, Arancio O, Shelanski M (September 14, 2009). "Reversal of long-term dendritic spine alterations in Alzheimer disease models". Proceedings of the National Academy of Sciences of the United States 106 (39): 16877–16882. doi:10.1073/pnas.0908706106. PMC 2743726. PMID 19805389. http://www.pnas.org/content/106/39/16877.full. Retrieved 2009-11-13. 
3. ^ MF, Beal; Cleren C, Calingasan NY, Yang L, Klivenyi P, Lorenzl S (2005). "Oxidative Damage in Parkinson's Disease". U.S. Army Medical Research and Materiel CommandFort Detrick, Maryland 21702-5012. http://handle.dtic.mil/100.2/ADA434051. Retrieved 2009-11-13. 
4. ^ Maxwell CR, Kanes SJ, Abel T, Siegel SJ. (2004). "Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications". Neuroscience. 129 (1): 101–7. doi:10.1016/j.neuroscience.2004.07.038. PMID 15489033. 
5. ^ Kanes SJ, Tokarczyk J, Siegel SJ, Bilker W, Abel T, Kelly MP. (2006). "Rolipram: A specific phosphodiesterase 4 inhibitor with potential antipsychotic activity". Neuroscience. 144 (1): 239–246. doi:10.1016/j.neuroscience.2006.09.026. PMID 17081698. 
6. ^ Barad M, Bourtchouladze R, Winder DG, Golan H, Kandel E. (1998). "Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory". Proceedings of the National Academy of Science of the USA. 95 (25): 15020–5. doi:10.1073/pnas.95.25.15020. PMC 24568. PMID 9844008. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=24568. 
7. ^ Lelkes Z, Alföldi P, Erdos A, Benedek G. (1998). "Rolipram, an antidepressant that increases the availability of cAMP, transiently enhances wakefulness in rats". Pharmacology, Biochemistry and Behaviour. 60 (4): 835–9. doi:10.1016/S0091-3057(98)00038-0. PMID 9700966. 
8. ^ Block F, Schmidt W, Nolden-Koch M, Schwarz M. (2001). "Rolipram reduces excitotoxic neuronal damage". Neuroreport. 12 (7): 1507–11. doi:10.1097/00001756-200105250-00041. PMID 11388438. 
9. ^ Chen RW, Williams AJ, Liao Z, Yao C, Tortella FC, Dave JR. (2007). "Broad spectrum neuroprotection profile of phosphodiesterase inhibitors as related to modulation of cell-cycle elements and caspase-3 activation". Neuroscience Letters. 418 (2): 165–9. doi:10.1016/j.neulet.2007.03.033. PMID 17398001. 
10. ^ de Visser YP, Walther FJ, Laghmani EH, van Wijngaarden S, Nieuwland K, Wagenaar GT. (2008). "Phosphodiesterase-4 inhibition attenuates pulmonary inflammation in neonatal lung injury". Eur Respir J 31 (3): 633–644. doi:10.1183/09031936.00071307. PMID 18094015. 
11. ^ Yu MC, Chen JH, Lai CY, Han CY, Ko WC. (2009). "Luteolin, a non-selective competitive inhibitor of phosphodiesterases 1-5, displaced [(3)H]-rolipram from high-affinity rolipram binding sites and reversed xylazine/ketamine-induced anesthesia". Eur J Pharmacol. ? (?): 269–75. doi:10.1016/j.ejphar.2009.10.031. PMID 19853596. 
12. ^ http://emc.medicines.org.uk/medicine/23416/SPC/DAXAS 500 micrograms film-coated tablets