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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 [[Phosphodiesterase inhibitor|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.<ref>{{cite journal|doi=10.1038/bjp.2008.307|title=PDE4 inhibitors: current status|journal=[[British Journal of Pharmacology]]|year=2008|first=D|last= Spina|volume=155|issue=3|pages=308–315|pmid=18660825|pmc=2567892}}</ref>
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 [[Phosphodiesterase inhibitor|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.<ref>{{cite journal|doi=10.1038/bjp.2008.307|title=PDE4 inhibitors: current status|journal=[[British Journal of Pharmacology]]|year=2008|first=D|last= Spina|volume=155|issue=3|pages=308–315|pmid=18660825|pmc=2567892}}</ref>


==Background==
==Introduction==
The prototypical PDE4 inhibitors is [[rolipram]]. PDE4 inhibitors have been investigated as treatments for a diverse group of different diseases, including central nervous system disorders such as [[major depressive disorder]] (clinical depression), [[schizophrenia]], [[Parkinson's disease]], [[Alzheimer's disease]], [[multiple sclerosis]] and inflammatory conditions such as [[chronic obstructive pulmonary disease]] (COPD), [[asthma]] and [[rheumatoid arthritis]].<ref>{{cite journal|title=Phosphodiesterase type 4 inhibitors: potential in the treatment of multiple sclerosis?|journal=BioDrugs|date=February 2000|volume=13|issue=2|pages=87-94|author=Dinter, H|pmid=18034515}}</ref><ref>{{cite journal|title=Update on the therapeutic potential of PDE4 inhibitors|journal=Expert Opinion on Investigational Drugs|date=January 2002|volume=11|issue=1|pages=1-13|doi=10.1517/13543784.11.1.1|pmid=11772317|author=Dyke, HJ; Montana, JG}}</ref><ref>{{cite journal|title=PDE inhibitors in psychiatry – future options for dementia, depression and schizophrenia?|journal=Drug Discovery Today|volume=12|issue=19-20|date=October 2007|pages=870-878|doi=10.1016/j.drudis.2007.07.023|author=Halene, TB; Siegel, SJ|pmid=17933689}}</ref><ref name = BK>{{cite book|title=Phosphodiesterases as Drug Targets|series=Handbook of Experimental Pharmacology|volume=204|date=2011|doi=10.1007/978-3-642-17969-3|isbn=978-3-642-17968-6|url=http://link.springer.com.elibrary.jcu.edu.au/content/pdf/10.1007%2F978-3-642-17969-3.pdf|format=PDF|publisher=Springer Berlin Heidelberg|editors=Francis, SH; Conti, M; Houslay, MD}}</ref> The clinical development of PDE4 inhibitors has been hampered by their potent emetic effects.<ref name = BK/>
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|date=October 2010}} Clinical development of rolipram was abandoned due to the side-effects associated with its dosing.{{Citation needed|date=October 2010}} 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==
==Indications==

Revision as of 15:46, 12 November 2013

Rolipram, the prototypical 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]

Introduction

The prototypical PDE4 inhibitors is rolipram. PDE4 inhibitors have been investigated as treatments for a diverse group of different diseases, including central nervous system disorders such as major depressive disorder (clinical depression), schizophrenia, Parkinson's disease, Alzheimer's disease, multiple sclerosis and inflammatory conditions such as chronic obstructive pulmonary disease (COPD), asthma and rheumatoid arthritis.[2][3][4][5] The clinical development of PDE4 inhibitors has been hampered by their potent emetic effects.[5]

Indications

PDE4 inhibitors have shown a wide range of therapeutic potential including treatment of:

Some have also shown benefits such as antipsychotic effects,[8][9] improved long term memory,[10] increased wakefulness[11] and increased neuroprotection.[12][13] Because PDE4 breaks down cAMP in immune cells, PDE4 is also involved in regulating Inflammation.[14]

Adverse reactions

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

Examples

  • Apremilast, a drug being developed for inflammatory disorders
  • 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.[15]
  • Luteolin, supplement extracted from peanuts that also possesses IGF-1 properties.[16]
  • Roflumilast, licensed for the treatment of severe chronic obstructive pulmonary disease in the EU by Merck Sharp & Dohme using the tradename Daxas[17] and in the US under the name Daliresp.[18]
  • Cilomilast, in clinical development by GlaxoSmithKline for treatment of COPD[citation needed]
  • Diazepam[19]

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.

See also

Discovery and development of thalidomide and its analogs

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.
  2. ^ Dinter, H (February 2000). "Phosphodiesterase type 4 inhibitors: potential in the treatment of multiple sclerosis?". BioDrugs. 13 (2): 87–94. PMID 18034515.
  3. ^ Dyke, HJ; Montana, JG (January 2002). "Update on the therapeutic potential of PDE4 inhibitors". Expert Opinion on Investigational Drugs. 11 (1): 1–13. doi:10.1517/13543784.11.1.1. PMID 11772317.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Halene, TB; Siegel, SJ (October 2007). "PDE inhibitors in psychiatry – future options for dementia, depression and schizophrenia?". Drug Discovery Today. 12 (19–20): 870–878. doi:10.1016/j.drudis.2007.07.023. PMID 17933689.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ a b Phosphodiesterases as Drug Targets (PDF). Handbook of Experimental Pharmacology. Vol. 204. Springer Berlin Heidelberg. 2011. doi:10.1007/978-3-642-17969-3. ISBN 978-3-642-17968-6. {{cite book}}: Unknown parameter |editors= ignored (|editor= suggested) (help)
  6. ^ Smith, Donna L (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. Retrieved 2009-11-13. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  7. ^ MF, Beal (2005). "Oxidative Damage in Parkinson's Disease". U.S. Army Medical Research and Material Command Fort Detrick, Maryland 21702-5012. Retrieved 2009-11-13. {{cite web}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  8. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ 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 Sciences of the United States of America. 95 (25): 15020–5. doi:10.1073/pnas.95.25.15020. PMC 24568. PMID 9844008.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ "Intracellular Mechanisms of Inflammation:PDE4 Promotes the Release of Proinflammatory Mediators". Celgene Corporation. 2012. Retrieved 2012-07-24.
  15. ^ de Visser, Y. P.; Walther, F. J.; Laghmani E. H.; van Wijngaarden, S.; Nieuwland, K.; Wagenaar, G. T. (2008). "Phosphodiesterase-4 inhibition attenuates pulmonary inflammation in neonatal lung injury". European Respiratory Journal. 31 (3): 633–644. doi:10.1183/09031936.00071307. PMID 18094015.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ Yu, M. C.; Chen, J. H.; Lai, C. Y.; Han, C. Y.; Ko, W. C. (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". European Journal of Pharmacology. 627 (1–3): 269–275. doi:10.1016/j.ejphar.2009.10.031. PMID 19853596.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ http://emc.medicines.org.uk/medicine/23416/SPC/DAXAS 500 micrograms film-coated tablets
  18. ^ http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=022522&DrugName=DALIRESP&ActiveIngred=ROFLUMILAST&SponsorApplicant=FOREST%20RES%20INST%20INC&ProductMktStatus=1&goto=Search.DrugDetails
  19. ^ Collado, M. C.; Beleta, J.; Martinez, E.; Miralpeix, M.; Domènech, T.; Palacios, J. M.; Hernández, J. (1998). "Functional and biochemical evidence for diazepam as a cyclic nucleotide phosphodiesterase type 4 inhibitor" (pdf). British Journal of Pharmacology. 123 (6): 1047–1054. doi:10.1038/sj.bjp.0701698. PMC 1565256. PMID 9559885.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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