Antioxidant and Radical Scavenging Properties of 8-Oxo Derivatives of Xanthine Drugs Pentoxifylline and Lisofylline

Abstract

The antioxidant and radical scavenging properties of 8-oxo derivatives of pentoxifylline, lisofylline, enprofylline (3-propyl xanthine), and 1,7-dimethyl enprofylline were studied in vitro. The results show that 8-oxopentoxifylline and 8-oxolisofylline are significantly better hydroxyl and peroxyl radical scavengers and more potent inhibitors of t-butylhydroperoxide-induced lipid peroxidation in human erythrocyte membranes than the parent drugs. The hydroxyl radical scavenging property of 8-oxoenprofylline and its analogue 1,7-dimethyl-8-oxoenprofylline is marginally better than their corresponding xanthines. Interestingly, 1,7-dimethyl-8-oxoenprofylline is an effective inhibitor of lipid peroxidation whereas enprofylline, 1,7-dimethylenprofylline, and 8-oxoenprofylline exhibit significantly less activity. All the 8-oxo derivatives tested are better hydroxyl radical scavengers than uric acid, a natural antioxidant and a free radical scavenger in humans. The rate constant for the reaction between 8-oxopentoxifylline and hydroxyl radical is 1.6-4.2 x 10(10) M(-1) s(-1) which is comparable to that of dimethyl sulfoxide (1.4-1.6 x 10(10) M(-1) s(-1)) and better than that of mannitol (1.9-2.5 x 10(9) M(-1) s(-1)), the known hydroxyl radical scavengers. Both 8-oxo pentoxifylline (IC(50), 1.8 +/- 0.08 microM) and 8-oxolisofylline (IC(50), 2.2 +/- 0.13 microM) are as efficient peroxyl radical scavengers as uric acid (IC(50), 1.9 +/- 0.05 microM). The results presented clearly indicate that the anti-inflammatory property of pentoxifylline and lisofylline is exerted more through their 8-oxo derivatives than through the parent drugs.

Cerebroprotective activity of 3-benzylxanthine derivative - compound Ale-15, in conditions of bilateral common carotid arteries ligation (ischemic stroke)

“…6,8,9,12 Substituted xanthine derivatives are an important class of pharmacologically active compounds that are known to exhibit various pharmacological properties including antioxidant. 13,14 Earlier we mentioned about the synthesis of Ale-15 compound -(morpholin-4-ium 3-benzylxanthinyl-8-methylthioacetate) (Figure 1), that shows high antioxidant qualities in vitro. 15 The goal of this research was to study in vivo neuroprotective action of Ale-15 compound in conditions of bilateral common carotid arteries ligation (ischemic stroke) and in comparison with pharmacological standard of neuroprotector-antioxidant -Mexidol.…”

Effect of pentoxifylline on histological activity and fibrosis of nonalcoholic steatohepatitis patients: A one year randomized control trial

“…[27] So, regarding the improvement of fibrosis, Telmisartan is superior to pentoxifylline. As PTX is known to decrease oxidative stress, [10] have hydroxyl and peroxyl radical scavenging effects [11] and specifically inhibit lipid peroxidation. [12] PTX blocks the second hit that includes oxidative stress that leads to the secretion of proinflammatory cytokines such as TNF-α and adiponectin, an anti-inflammatory cytokine.…”

“…Pentoxifylline (PTX) is known to decrease oxidative stress. [10] PTX also has hydroxyl and peroxyl radical scavenging effects [11] and specifically inhibits lipid peroxidation. [12] Moreover, pentoxifylline has anti-inflammatory properties and it is also known to definitely suppress TNF-α gene transcription, preventing TNF -α synthesis.…”

Topical Combinations Aimed at Treating Microvascular Dysfunction Reduce Allodynia in Rat Models of CRPS-I and Neuropathic Pain

“…Also, clonidine's anti-allodynic effects were mimicked by apraclondine, which does not cross the blood brain barrier 83 . In addition, the many of the various anti-inflammatory activities of pentoxifylline and lisofylline are linked with their vascular effects 7,62,76,91 , as microvascular function is key to various processes involved in the inflammatory response, including plasma extravasation, platelet aggregration, leukocyte migration, cytokine activation, among others.…”

“…However, α 2A receptor agonists, NO donors and PDE inhibitors have been used systemically in patients or preclinical animal models to treat pain associated with angina 13,43,66 , PAD 19,52,82 , CRPS 18,40,63,74 , neuropathic pain 32,53,60 and PDN 16,24,48,84 indicating their usefulness in these syndromes. PA inhibitors have not been used to treat chronic pain, but should be equally or more effective than PDE inhibitors since they have anti-oxidant 7,34 , anticytokine 68,76 , anti-chemotaxic 70,91 , immunosuppressant 15,23 , and mitochondrial protective 12 effects, in addition to the vasodilator 61 , anti-ischemic 90 and anti-platelet aggregation 62 effects they share with PDE inhibitors.…”