A phosphodiesterase-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]
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. Indeed, one experiment has found that intake of a PDE4 oral medication for psoriasis has significantly reduced alcohol consumption in serious human drinkers compared with those taking the placebo.[18] A few different lines of evidence suggests the therapeutic utility in the treatment of brain tumours.[19]
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 reactionsedit
Nausea, vomiting, 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.[20]
Crisaborole (AN2728), a boron-containing drug for the topical treatment of psoriasis and atopic dermatitis.[24][25] It was approved by the FDA on December 14, 2016 under the brand name Eucrisa for the treatment of mild-to-moderate atopic dermatitis (eczema) in patients 2 years of age and older.[26]
Caffeine is a weak, non-selective PDE inhibitor.[27] A metabolite of caffeine, theophylline, is a more potent PDE inhibitor.[27]
Diazepam, a benzodiazepine anxiolytic, amnesic, hypnotic, sedative and muscle relaxant.[28]
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.
Luteolin, supplement extracted from peanuts and other plants that also possesses IGF-1 properties.[29]
Roflumilast, licensed for the treatment of severe chronic obstructive pulmonary disease in the EU, Russia and U.S. by Merck & Co. under the trade names Daxas[20] and Daliresp, and for the treatment of plaque psoriasis under the brand name Zoryve.[31]
Rolipram, used as investigative tool in pharmacological research.
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^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. S2CID 25453633.
^"Intracellular Mechanisms of Inflammation:PDE4 Promotes the Release of Proinflammatory Mediators". Celgene Corporation. 2012. Archived from the original on 2019-08-13. Retrieved 2012-07-24.
^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. S2CID 19578277.
^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. PMC3313447. PMID 17081698.
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^Smith, DL; Pozueta, J; Gong, B; Arancio, O; Shelanski, M (September 2009). "Reversal of long-term dendritic spine alterations in Alzheimer disease models". Proceedings of the National Academy of Sciences of the United States of America. 106 (39): 16877–16882. Bibcode:2009PNAS..10616877S. doi:10.1073/pnas.0908706106. PMC2743726. PMID 19805389.
^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. S2CID 23444101.
^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. S2CID 22623399.
^ abHalene, 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.
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^Nazarian, R; Weinberg, JM (November 2009). "AN-2728, a PDE4 Inhibitor for the Potential Topical Treatment of Psoriasis and Atopic Dermatitis". Current Opinion in Investigational Drugs. 10 (11): 1236–42. PMID 19876791.
^Moustafa, F; Feldman, SR (16 May 2014). "A Review of Phosphodiesterase-Inhibition and the Potential Role for Phosphodiesterase 4-Inhibitors in Clinical Dermatology" (PDF). Dermatology Online Journal. 20 (5): 22608. doi:10.5070/D3205022608. PMID 24852768.
^"FDA Approves Eucrisa for Eczema". U.S. Food and Drug Administration. 14 December 2016.
^ abBoswell-Smith, Victoria; Spina, Domenico; Page, Clive P. (January 2006). "Phosphodiesterase inhibitors". British Journal of Pharmacology. 147 (Suppl 1): S252–257. doi:10.1038/sj.bjp.0706495. ISSN 0007-1188. PMC1760738. PMID 16402111.
^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". British Journal of Pharmacology. 123 (6): 1047–1054. doi:10.1038/sj.bjp.0701698. PMC1565256. PMID 9559885.
^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.
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^"FDA Approves Arcutis' Zoryve (Roflumilast) Cream 0.3% For the Treatment of Plaque Psoriasis in Individuals Age 12 and Older" (Press release). Arcutis Biotherapeutics. 29 July 2022. Archived from the original on 1 August 2022. Retrieved 1 August 2022 – via GlobeNewswire.