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]
PDE4D inhibition, along withPDE4A inhibition also appears to be responsible for the antidepressant effects of PDE4 inhibitors.[14] SimilarlyPDE4B 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 andbipolar disorder in a postmortem study.[15] PDE4 also regulates theD1/PKA/DARPP-32 signalling cascade in thefrontal cortex, which may contribute to the antipsychotic and procognitive effects of PDE4 inhibitors.[16] WhereasPDE4C 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 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 potentemetic effects, which appear to be related to their inhibition ofPDE4D which is expressed in thearea postrema.[14]
Nausea,vomiting, and related general gastrointestinalside 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 ofroflumilast.[20]
Crisaborole (AN2728), aboron-containing drug for the topical treatment ofpsoriasis andatopic dermatitis.[24][25] It was approved by the FDA on December 14, 2016 under the brand nameEucrisa for 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]
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-1 properties.[29]
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 psoriasis under the brand nameZoryve.[31]
Rolipram, used as investigative tool in pharmacological research.
^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.
^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 original on May 23, 2012.
^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.
^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.
