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Atopic Dermatitis
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Luz Fonacier, Amanda Schneider
Another steroid free option but without the black box warning, crisaborole ointment (EucrisaTM), came on the market at the end of 2016 for children over 2 years of age and adults with mild to moderate AD. This agent works by inhibiting phosphodiesterase-4 (PDE-4), preventing breakdown of cyclic AMP (cAMP), ultimately leading to an increase in anti-inflammatory cytokines. The most common adverse side effect consists of pain (burning or stinging) at the site of application (Yang et al. 2019).
Pharmacological Management of Amyotrophic Lateral Sclerosis
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Shalini Mani, Chahat Kubba, Tanya Sharma, Manisha Singh
In the therapy based upon cell-replacement, transplanting the motor neurons which are derived from stem-cell is measured to be a probable move to treat ALS (Christou et al., 2007). These motor neurons may extend to axons which eventually form neuromuscular junctions (Thonhoff et al., 2009). These transplanted neurons may face the challenge due to inhibitory action of myelin associated proteins such as Nogo-A, myelin associated glycoprotein (MAG) and oligodendrocytemyelin glycoprotein (Omgp). Inhibition may also be due to inhibitory proteins specific for the neurite growth. A winning transplantation outcome came in to lime light a decade back, in which rat spinal cord was injected with motor neurons along with dibutyryl cyclic adenosine monophosphate (dbcAMP)(Deshpande et al., 2006).The systemic administration of phosphodiesterase 4 inhibitor was also performed to obstruct the repulsive outcome of myelin (Deshpande et al., 2006). These studies highlighted that the alteration of the proteins responsible for regulation of growth and guidance of axon is important to re-establish appropriate functioning of motor neurons subsequent to therapy by cell replacement.
Herbs with Antidepressant Effects
Published in Scott Mendelson, Herbal Treatment of Major Depression, 2019
Plants of the genus Scelelium contain a variety of indole alkaloids, most notable of which are mesembrine and mesembranone. Serotonin is itself an indole alkaloid, and those plant alkaloids are potent 5-HT uptake inhibitors. Mesembrine is also a modestly potent inhibitor of phosphodiesterase-4, the enzyme primarily responsible for the degradation of the intracellular second messenger, cAMP.2 PDE4 inhibitors have antidepressant effects in both animals and humans, and the enzyme is seen as a potential target of antidepressant drug action.3 Along with being a potent 5-HT reuptake inhibitor, a high mesembrine extract of sceletium was also found to be a 5-HT releasing agent from both human astrocytes and mouse hippocampal neurons.4
BI 1015550: an investigational phosphodiesterase 4B (PDE4B) inhibitor for lung function decline in idiopathic pulmonary fibrosis (IPF)
Published in Expert Opinion on Investigational Drugs, 2023
Giacomo Sgalla, Jacopo Simonetti, Stefania Cortese, Luca Richeldi
Two antifibrotic agents, nintedanib and pirfenidone, have been approved for use in IPF and represent the mainstay of the current therapeutic approach [6,7]. Whilst these therapies are capable of slowing down the functional decline rate in these patients by approximately 50%, they cannot stop the progression of the disease in most individuals. While the therapeutic scenario of IPF has been deeply transformed in the last decade by the introduction of nintedanib and pirfenidone, pharmaceutical research in IPF continued to grow in search of novel safe, and effective agents. A phase 2 randomized, double-blind, placebo-controlled trial of phosphodiesterase 4 (PDE4) inhibitor BI 1015550 in IPF recently delivered encouraging results with regard to the prevention of functional decline [8]. This review aims to summarize the available evidence on BI 1015550 in IPF and to provide insights into the potential role of this novel compound in the therapeutic scenario of this disease. (Box 1)
Recent advances in IAP-based PROTACs (SNIPERs) as potential therapeutic agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Chao Wang, Yujing Zhang, Lingyu Shi, Shanbo Yang, Jing Chang, Yingjie Zhong, Qian Li, Dongming Xing
Phosphodiesterases (PDE) are a diverse family of enzymes responsible for the degradation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which are involved in several cellular and biochemical functions. Phosphodiesterase 4 (PDE4) is the major isoform within this group and is highly expressed in the mammalian brain. An inverse association between PDE4 and cAMP levels is the key mechanism in various pathophysiological conditions like airway inflammatory diseases-chronic obstruction pulmonary disease (COPD), asthma, psoriasis, rheumatoid arthritis, and neurological disorders. Due to the adverse effects like unbearable nausea and vomiting, dose intolerance and diarrhoea, PDE4 inhibitors have very less clinical compliance. Efforts are being made to develop PDE4 PROTACs having better efficacy and lesser adverse effects105,106.
Biologics and small molecules in the management of psoriatic arthritis: Reproduction related issues in female and male patients
Published in Expert Review of Clinical Pharmacology, 2021
Rebecca Fischer-Betz, Monika Østensen
Apremilast (APR) is an orally administered, small molecule inhibitor of phosphodiesterase 4 (PDE4) and is approved for the treatment of moderate to severe plaque PsO and PsA. Its anti-inflammatory effects are based on the inhibition of the intracellular enzyme Phosphodiesterase-4, leading to an increase in cyclic adenosine monophosphate. The result is a decreased production of pro-inflammatory cytokines, including TNF-α, IL 17 and IL 23. Animal studies have not indicated an increase in congenital anomalies under APR but a dose-dependent increase in miscarriages and reduced birth weight was observed. Within the clinical trial program, women and men were required to use effective contraception for the duration of their participation in apremilast trials and for at least 28 days thereafter. As of September 2017, 21 pregnancies were reported (Celgene Corporation, Data on file 2017). Seven of these pregnancies resulted in the birth of healthy infants. There were 8 elective terminations, one spontaneous abortion, one therapeutic abortion, and 4 pregnancies with unknown outcome. In view of the highly limited data, APR should be discontinued at least 2 days before conception. No studies of APR in human breastmilk have been localized.