Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

Reitman, Marc L.

doi:10.20944/preprints202004.0115.v1

Cited by 9 publications

(7 citation statements)

References 83 publications

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“…This regimen has now been abandoned, but it has allowed us to identify multiple pathways activated by the drug chemical precursor, salicylate, which include an indirect elevation of extracellular Ado concentrations [ 53 ]. A similar indirect influence on the Ado system has been demonstrated for high doses of other NSAIDs (i.e., sulindac) and for sulfasalazine, a prodrug of 5-amino-salicylic acid acting as a DMARD [ 53 , 54 ].…”

Section: Drugs Targeting the Adenosine System In Autoimmune Disordmentioning

confidence: 60%

Adenosine Signaling in Autoimmune Disorders

Magni

Ceruti

2020

Pharmaceuticals

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The molecular components of the purinergic system (i.e., receptors, metabolizing enzymes and membrane transporters) are widely expressed in the cells of the immune system. Additionally, high concentrations of adenosine are generated from the hydrolysis of ATP in any “danger” condition, when oxygen and energy availability dramatically drops. Therefore, adenosine acts as a retaliatory metabolite to counteract the nucleotide-mediated boost of the immune reaction. Based on this observation, it can be foreseen that the recruitment with selective agonists of the receptors involved in the immunomodulatory effect of adenosine might represent an innovative anti-inflammatory approach with potential exploitation in autoimmune disorders. Quite surprisingly, pro-inflammatory activity exerted by some adenosine receptors has been also identified, thus paving the way for the hypothesis that at least some autoimmune disorders may be caused by a derailment of adenosine signaling. In this review article, we provide a general overview of the roles played by adenosine on immune cells with a specific focus on the development of adenosine-based therapies for autoimmune disorders, as demonstrated by the exciting data from concluded and ongoing clinical trials.

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Section: Drugs Targeting the Adenosine System In Autoimmune Disordmentioning

confidence: 60%

Adenosine Signaling in Autoimmune Disorders

Magni

Ceruti

2020

Pharmaceuticals

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“…AMPK activity has been described to prevent articular cartilage degeneration during mouse aging ( 257 ), and is also required to maintain mitochondrial function and prevent OA ( 213 ). As we have described earlier in this review, metformin can activate AMPK, resulting in an increase in extracellular adenosine ( 194 ). It is known that metformin is beneficial in obese patients with knee OA, but the contribution of AMPK to this effect requires further study.…”

Section: Discussionmentioning

confidence: 81%

“…Metformin, a first-line drug for T2D treatment, is known to affect the energy state of the cell. It has been recently proposed that metformin may be beneficial in obese patients with knee OA ( 193 ) and can also inhibit respiratory chain complex 1, activating AMPK and inhibiting AMP deaminase, which results in an increase in extracellular adenosine ( 194 ). The increased adenosine levels might activate A2AR and could explain the beneficial effect of metformin in obese patients with knee osteoarthritis, but this needs to be explored further.…”

Section: Purinergic System In Oa and Modulation By Metainflammationmentioning

confidence: 99%

Purinergic System Signaling in Metainflammation-Associated Osteoarthritis

et al. 2020

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Inflammation triggered by metabolic imbalance, also called metainflammation, is low-grade inflammation caused by the components involved in metabolic syndrome (MetS), including central obesity and impaired glucose tolerance. This phenomenon is mainly due to excess nutrients and energy, and it contributes to the pathogenesis of osteoarthritis (OA). OA is characterized by the progressive degeneration of articular cartilage, which suffers erosion and progressively becomes thinner. Purinergic signaling is involved in several physiological and pathological processes, such as cell proliferation in development and tissue regeneration, neurotransmission and inflammation. Adenosine and ATP receptors, and other members of the signaling pathway, such as AMP-activated protein kinase (AMPK), are involved in obesity, type 2 diabetes (T2D) and OA progression. In this review, we focus on purinergic regulation in osteoarthritic cartilage and how different components of MetS, such as obesity and T2D, modulate the purinergic system in OA. In that regard, we describe the critical role in this disease of receptors, such as adenosine A2A receptor (A2AR) and ATP P2X7 receptor. Finally, we also assess how nucleotides regulate the inflammasome in OA.

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“…The second step is an attempt to translate these in vitro findings to potential in vivo relevance by looking for accepted biomarkers of NT inhibition. As adenosine represents the main endogenous substrate of NTs, which are essential for adenosine re-uptake, extracellular adenosine levels can be elevated as a result of NT inhibition in vivo, although other mechanisms (e.g., inhibition of adenosine metabolism) can also result in elevated plasma adenosine levels [ 23 ]. Among the NT most relevant for adenosine re-uptake, ENT1 has been identified as a major player.…”

Section: Background and Role Of Nts And Their Inhibitionmentioning

confidence: 99%

Cladribine as a Potential Object of Nucleoside Transporter-Based Drug Interactions

Hermann¹,

Krajcsi²,

Fluck

et al. 2021

Clin Pharmacokinet

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Cladribine is a nucleoside analog that is phosphorylated in its target cells (B and T-lymphocytes) to its active triphosphate form (2-chlorodeoxyadenosine triphosphate). Cladribine tablets 10 mg (Mavenclad ® ), administered for up to 10 days per year in 2 consecutive years (3.5-mg/kg cumulative dose over 2 years), are used to treat patients with relapsing multiple sclerosis. Cladribine has been shown to be a substrate of various nucleoside transporters (NTs). Intestinal absorption and distribution of cladribine throughout the body appear to be essentially mediated by equilibrative NTs (ENTs) and concentrative NTs (CNTs), specifically by ENT1, ENT2, ENT4, CNT2 (low affinity), and CNT3. Other efficient transporters of cladribine are the ABC efflux transporters, specifically breast cancer resistance protein, which likely modulates the oral absorption and renal excretion of cladribine. A key transporter for the intracellular uptake of cladribine into B and T-lymphocytes is ENT1 with ancillary contributions of ENT2 and CNT2. Transporter-based drug interactions affecting absorption and target cellular uptake of a prodrug such as cladribine are likely to reduce systemic bioavailability and target cell exposure, thereby possibly hampering clinical efficacy. In order to manage optimized therapy, i.e., to ensure uncompromised target cell uptake to preserve the full therapeutic potential of cladribine, it is important that clinicians are aware of the existence of NT-inhibiting medicinal products, various lifestyle drugs, and food components. This article reviews the existing knowledge on inhibitors of NT, which may alter cladribine absorption, distribution, and uptake into target cells, thereby summarizing the existing knowledge on optimized methods of administration and concomitant drugs that should be avoided during cladribine treatment.

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Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

Cited by 9 publications

References 83 publications

Adenosine Signaling in Autoimmune Disorders

Adenosine Signaling in Autoimmune Disorders

Purinergic System Signaling in Metainflammation-Associated Osteoarthritis

Cladribine as a Potential Object of Nucleoside Transporter-Based Drug Interactions

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