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.
^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. PMID 9844008.
^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. PMID 9700966. S2CID 37020086.
^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.
^. 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.
^Beal, MF; Cleren, C; Calingasan, NY; Yang, L; Klivenyi, P; Lorenzl, S (2005). . U.S. Army Medical Research and Material Command Fort Detrick, Maryland 21702-5012. Archived from the original on 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. 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.
^ 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]
^ ab"DALIRESP (roflumilast) tablet [Forest Laboratories, Inc.]". DailyMed. Forest Laboratories, Inc. August 2013. Retrieved 13 November 2013.
^Brooks, M (21 March 2014). "FDA Clears Apremilast (Otezla) for Psoriatic Arthritis". Medscape Medical News. WebMD. Retrieved 28 March 2014.
^Lowes, R (23 September 2014). "FDA Approves Apremilast (Otezla) for Plaque Psoriasis". Medscape Medical News. WebMD. Retrieved 13 October 2014.
^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. S2CID 2216800.
^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.
^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.
^"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. from the original on 1 August 2022. Retrieved 1 August 2022 – via GlobeNewswire.
December 15, 2023
phosphodiesterase, inhibitor, phosphodiesterase, inhibitor, commonly, referred, pde4, inhibitor, drug, used, block, degradative, action, phosphodiesterase, pde4, cyclic, adenosine, monophosphate, camp, member, larger, family, inhibitors, pde4, family, enzymes,. 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 Rolipram the prototypical PDE4 inhibitor Contents 1 Therapeutic utility 2 Adverse reactions 3 Examples 4 Mode of action 5 See also 6 ReferencesTherapeutic utility editThe 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 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 reactions editNausea 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 Examples editSee also List of phosphodiesterase inhibitors Apremilast a phthalimide derivative that was approved by the U S FDA in March 2014 for use as a treatment for psoriatic arthritis 21 and in September 2014 for the treatment of plaque psoriasis under the brand name Otezla 22 Cilomilast in clinical development by GlaxoSmithKline for treatment of COPD 23 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 Glaucine an aporphine alkaloid low potency PDE4 inhibitor calcium channel blocker dopamine antagonist and 5 HT2A positive allosteric modulator used as antitussive in 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 possesses IGF 1 properties 29 Mesembrenone an alkaloid from the herb Sceletium 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 by Merck amp 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 Mesembrine an alkaloid present in Sceletium tortuosum kanna Mode of action editPDE4 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 editDevelopment of analogs of thalidomide ForskolinReferences edit 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 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 PMC 24568 PMID 9844008 Lelkes Z Alfoldi 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 PMID 9700966 S2CID 37020086 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 S2CID 2768440 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 PMC 3313447 PMID 17081698 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 from the original on 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 PMC 2743726 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 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 a b c d Francis 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 ISBN 978 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 PMID 18394866 S2CID 32661995 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 PMC 3539205 PMID 21833500 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 PMC 4335658 PMID 22671516 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 PMC 3106141 PMID 21450351 a b DALIRESP roflumilast tablet Forest Laboratories Inc DailyMed Forest Laboratories Inc August 2013 Retrieved 13 November 2013 Brooks M 21 March 2014 FDA Clears Apremilast Otezla for Psoriatic Arthritis Medscape Medical News WebMD Retrieved 28 March 2014 Lowes R 23 September 2014 FDA Approves Apremilast Otezla for Plaque Psoriasis Medscape Medical News WebMD Retrieved 13 October 2014 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 S2CID 2216800 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 a b Boswell 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 PMC 1760738 PMID 16402111 Collado M C Beleta J Martinez E Miralpeix M Domenech T Palacios J M Hernandez 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 PMC 1565256 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 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 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 Retrieved from https en wikipedia org w index php title Phosphodiesterase 4 inhibitor amp oldid 1184620767, wikipedia, wiki, book, books, library,
