PDE4 inhibitor
Aphosphodiesterase-4 inhibitor,commonly referred to as aPDE4 inhibitor,is a drug used to block the degradative action ofphosphodiesterase 4(PDE4) oncyclic adenosine monophosphate(cAMP). It is a member of the larger family ofPDE inhibitors.The PDE4 family of enzymes are the most prevalent PDE inimmune cells.They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system.[1]
Therapeutic utility
[edit]The prototypical PDE4 inhibitor isrolipram.PDE4 inhibitors are known to possess procognitive (includinglong 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 asmajor 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,autismand inflammatory conditions such aschronic obstructive pulmonary disease(COPD),asthmaandrheumatoid arthritis.[12][13][14]
PDE4D inhibition, along withPDE4Ainhibition also appears to be responsible for the antidepressant effects of PDE4 inhibitors.[14]SimilarlyPDE4Binhibition 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 andbipolar disorderin a postmortem study.[15]PDE4 also regulates theD1/PKA/DARPP-32signalling cascade in thefrontal cortex,which may contribute to the antipsychotic and procognitive effects of PDE4 inhibitors.[16]WhereasPDE4Cis 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 ofalcohol 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 potentemeticeffects, which appear to be related to their inhibition ofPDE4Dwhich is expressed in thearea postrema.[14]
Adverse reactions
[edit]Nausea,vomiting,and related general gastrointestinalside effectsare 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 ofroflumilast.[20]
Examples
[edit]- Apremilast,aphthalimidederivative that was approved by the U.S. FDA in March 2014 for use as a treatment forpsoriatic arthritis,[21]and in September 2014 for the treatment ofplaque psoriasisunder the brand nameOtezla.[22]
- Cilomilast,in clinical development byGlaxoSmithKlinefor treatment of COPD.[23]
- Crisaborole(AN2728), aboron-containing drug for the topical treatment ofpsoriasisandatopic dermatitis.[24][25]It was approved by the FDA on December 14, 2016 under the brand nameEucrisafor the treatment of mild-to-moderateatopic 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]
- Glaucine,anaporphinealkaloid, low-potency PDE4 inhibitor,calcium channel blocker,dopamine antagonistand5-HT2Apositive allosteric modulator, used asantitussivein Eastern Europe and Iceland.
- 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 possessesIGF-1properties.[29]
- Mesembrenone,an alkaloid from the herbSceletium tortuosum(Kanna).
- Piclamilast,a more potent inhibitor than rolipram.[30]
- Roflumilast,licensed for the treatment of severe chronic obstructive pulmonary disease in the EU, Russia and U.S. byMerck & Co.under the trade namesDaxas[20]andDaliresp,and for the treatment ofplaque psoriasisunder the brand nameZoryve.[31]
- Rolipram,used as investigative tool in pharmacological research.
- Mesembrine,analkaloidpresent inSceletium tortuosum(kanna).
- Ensifentrine
Mode of action
[edit]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
[edit]References
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- ^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.Bibcode:1998PNAS...9515020B.doi:10.1073/pnas.95.25.15020.PMC24568.PMID9844008.
- ^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 Behavior.60(4): 835–9.doi:10.1016/S0091-3057(98)00038-0.PMID9700966.S2CID37020086.
- ^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.PMID11388438.S2CID2768440.
- ^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.PMID17398001.S2CID25453633.
- ^"Intracellular Mechanisms of Inflammation:PDE4 Promotes the Release of Proinflammatory Mediators".Celgene Corporation. 2012. Archived fromthe originalon 2019-08-13.Retrieved2012-07-24.
- ^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.PMID15489033.S2CID19578277.
- ^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.PMID17081698.
- ^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. Archived fromthe originalon May 23, 2012.
- ^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.PMID19805389.
- ^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.PMID18034515.S2CID23444101.
- ^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.PMID11772317.S2CID22623399.
- ^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.PMID17933689.
- ^abcdFrancis, SH; Conti, M; Houslay, MD, eds. (2011).Phosphodiesterases as Drug Targets(PDF).Handbook of Experimental Pharmacology. Vol. 204. Springer Berlin Heidelberg.doi:10.1007/978-3-642-17969-3.ISBN978-3-642-17968-6.[dead link]
- ^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.PMID18394866.S2CID32661995.
- ^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".Psychopharmacology.219(4): 1065–1079.doi:10.1007/s00213-011-2436-8.PMC3539205.PMID21833500.
- ^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.PMC4335658.PMID22671516.
- ^Wilson, C. (2021). Psoriasis drug may cut alcohol misuse.New Scientist,250(3340), p.16
- ^Sengupta, R; Sun, T; Warrington, NM; Rubin, JB (June 2011)."Treating brain tumors with PDE4 inhibitors".Trends in Pharmacological Sciences.32(6): 337–344.doi:10.1016/j.tips.2011.02.015.PMC3106141.PMID21450351.
- ^ab"DALIRESP (roflumilast) tablet [Forest Laboratories, Inc.]".DailyMed.Forest Laboratories, Inc. August 2013.Retrieved13 November2013.
- ^Brooks, M (21 March 2014)."FDA Clears Apremilast (Otezla) for Psoriatic Arthritis".Medscape Medical News.WebMD.Retrieved28 March2014.
- ^Lowes, R (23 September 2014)."FDA Approves Apremilast (Otezla) for Plaque Psoriasis".Medscape Medical News.WebMD.Retrieved13 October2014.
- ^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.PMID19105585.S2CID2216800.
- ^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.PMID19876791.
- ^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.PMID24852768.
- ^"FDA Approves Eucrisa for Eczema".U.S. Food and Drug Administration. 14 December 2016.
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- ^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.PMID19853596.
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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.Archivedfrom the original on 1 August 2022.Retrieved1 August2022– via GlobeNewswire.