Jump to content

PDE4 inhibitor

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by Rjwilmsi (talk | contribs) at 19:45, 1 February 2016 (Journal cites: format journal names, using AWB (11852)). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

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]

Therapeutic utility

The prototypical PDE4 inhibitor is rolipram. PDE4 inhibitors are known to possess procognitive (including long-term memory-improving),[2] wakefulness-promoting,[3] neuroprotective,[4][5] and anti-inflammatory effects.[6] Consequently, 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), anxiety disorders, schizophrenia,[7][8] Parkinson's disease,[9] Alzheimer's disease,[10] multiple sclerosis,[11] attention deficit-hyperactivity disorder, Huntington's disease, stroke, autism and inflammatory conditions such as chronic obstructive pulmonary disease (COPD), asthma and rheumatoid arthritis.[12][13][14] PDE4D inhibition, along with PDE4A inhibition also appears to be responsible for the antidepressant effects of PDE4 inhibitors.[14] Similarly PDE4B inhibition appears to be required for the antipsychotic effects of PDE4 inhibitors,[13] in line with this view PDE4B polymorphisms and altered gene expression in the central nervous system have been associated with schizophrenia and bipolar disorder in a postmortem study.[15] PDE4 also regulates the D1/PKA/DARPP-32 signalling cascade in the frontal cortex, which may contribute to the antipsychotic and procognitive effects of PDE4 inhibitors.[16] Whereas PDE4C is expressed primarily in the periphery and hence may be partly responsible for the peripheral effects of PDE4 inhibitors (e.g. their anti-inflammatory effects).[14] PDE4 inhibition is also known to attenuate ethanol seeking and consumption in rats,[17] hence suggesting its possible utility in the treatment of alcohol dependence. A few different lines of evidence suggests the therapeutic utility in the treatment of brain tumours.[18]

The clinical development of PDE4 inhibitors has been hampered by their potent emetic effects, which appear to be related to their inhibition of PDE4D which is expressed in the area postrema.[14]

Adverse reactions

Nausea, emesis, and related general gastrointestinal side-effects are the most commonly implicated side-effects of PDE4 inhibitors. Other possible side effects include respiratory and urinary tract infections, which have been discovered from the clinical use of roflumilast.[19]

Examples

See also: List of phosphodiesterase inhibitors

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.[citation needed]

See also

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. ^ 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)
  3. ^ 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)
  4. ^ 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)
  5. ^ 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)
  6. ^ "Intracellular Mechanisms of Inflammation:PDE4 Promotes the Release of Proinflammatory Mediators". Celgene Corporation. 2012. Retrieved 2012-07-24.
  7. ^ 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)
  8. ^ 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. PMC 3313447. PMID 17081698.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Beal, MF; Cleren, C; Calingasan, NY; Yang, L; Klivenyi, P; Lorenzl, S (2005). "Oxidative Damage in Parkinson's Disease". U.S. Army Medical Research and Material Command Fort Detrick, Maryland 21702-5012.
  10. ^ Smith, DL; Pozueta, J; Gong, B; Arancio, O; Shelanski, M (September 2009). "Reversal of long-term dendritic spine alterations in Alzheimer disease models" (PDF). Proceedings of the National Academy of Sciences of the United States of America. 106 (39): 16877–16882. doi:10.1073/pnas.0908706106. PMC 2743726. PMID 19805389.
  11. ^ Dinter, H (February 2000). "Phosphodiesterase type 4 inhibitors: potential in the treatment of multiple sclerosis?". BioDrugs. 13 (2): 87–94. doi:10.2165/00063030-200013020-00002. PMID 18034515.
  12. ^ 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)
  13. ^ a b 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)
  14. ^ a b c d 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) [dead link‍]
  15. ^ Fatemi, SH; King, DP; Reutiman, TJ; Folsom, TD; Laurence, JA; Lee, S; Fan, YT; Paciga, SA; Conti, M; Menniti, FS (April 2008). "PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia". Schizophrenia Research. 101 (1–3): 36–49. doi:10.1016/j.schres.2008.01.029. PMID 18394866.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ Kuroiwa, M; Snyder, GL; Shuto, T; Fukuda, A; Yanagawa, Y; Benavides, DR; Nairn, AC; Bibb, JA; Greengard, P; Nishi, A (February 2012). "Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex" (PDF). Psychopharmacology (Berl). 219 (4): 1065–1079. doi:10.1007/s00213-011-2436-8. PMC 3539205. PMID 21833500.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ Wen, RT; Zhang, M; Qin, WJ; Liu, Q; Wang, WP; Lawrence, AJ; Zhang, HT; Liang, JH (December 2012). "The Phosphodiesterase-4 (PDE4) Inhibitor Rolipram Decreases Ethanol Seeking and Consumption in Alcohol-Preferring Fawn-Hooded Rats". Alcoholism: Clinical and Experimental Research. 36 (12): 2157–2167. doi:10.1111/j.1530-0277.2012.01845.x. PMID 22671516.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Sengupta, R; Sun, T; Warrington, NM; Rubin, JB (June 2011). "Treating brain tumors with PDE4 inhibitors" (PDF). Trends in Pharmacological Sciences. 32 (6): 337–344. doi:10.1016/j.tips.2011.02.015. PMC 3106141. PMID 21450351.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ a b "DALIRESP (roflumilast) tablet [Forest Laboratories, Inc.]". DailyMed. Forest Laboratories, Inc. August 2013. Retrieved 13 November 2013.
  20. ^ Anacor AN2728 at Anacor website Page accessed May 15, 2015
  21. ^ Nazarian, R (2009). "AN-2728, a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis". Curr Opin Investig Drugs. 11: 1236–1242. PMID 19876791.
  22. ^ a b Moustafa F, Feldman SR (May 2014). "A review of phosphodiesterase-inhibition and the potential role for phosphodiesterase 4-inhibitors in clinical dermatology". Dermatol Online J. 20 (5): 22608. PMID 24852768.
  23. ^ Brooks, M (21 March 2014). "FDA Clears Apremilast (Otezla) for Psoriatic Arthritis". Medscape Medical News. WebMD. Retrieved 28 March 2014.
  24. ^ Lowes, R (23 September 2014). "FDA Approves Apremilast (Otezla) for Plaque Psoriasis". Medscape Medical News. WebMD. Retrieved 13 October 2014.
  25. ^ Rennard, S; Knobil, K; Rabe, KF; Morris, A; Schachter, N; Locantore, N; Canonica, WG; Zhu, Y; Barnhart, F (2008). "The efficacy and safety of cilomilast in COPD". Drugs. 68 (Suppl 2): 3–57. doi:10.2165/0003495-200868002-00002. PMID 19105585.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  26. ^ 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)
  27. ^ 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)
  28. ^ 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)
  29. ^ Clinical trial number NCT01300052 at ClinicalTrials.gov
  30. ^ 6. Furue M. Safety and efficacy of topical E6005, a phosphodiesterase 4 inhibitor, in Japanese adult patients with atopic dermatitis: Results of a randomized, vehicle-controlled, multicenter clinical trial. Journal of Dermatology. 2014; 41: 577–585.
Retrieved from "https://en.wikipedia.org/w/index.php?title=PDE4_inhibitor&oldid=702805289"