Methylxanthins

Pentoxifylline is stmcturaHy related to other methylxanthine derivatives such as caffeine [58-02-2] (1,3,7-trimethylxanthine), theobromine [83-67-0] (3,7-dimethylxanthine), and theophylline [58-55-9] (3,7-dihydro-1,3-dimethyl-1 H-piirine-2,6-dione or 1,3-dimethylxanthine), which also show radioprotective activity in some instances, suggesting that methylxanthines as a dmg class may radioprotect through a common mechanism (see Alkaloids). In a retrospective analysis of cervical and endometrial cancer patients receiving primary or adjuvant XRT, no association between caffeine consumption and incidence of acute radiation effects has been found. However, there was a decreased incidence of severe late radiation injury in cervical cancer patients who consumed higher levels of caffeine at the time of thek XRT (121). The observed lack of correlation between caffeine consumption and acute radiation effects is consistent with laboratory investigations using pentoxifylline. 

The mechanism by which the methylxanthines produce CNS stimulation is not clearly estabUshed. These agents may function, ia part, to limit chloride channel activation ia a manner similar to that of pentylenetetra2ol (7) or hicuculline (8). Another possibiUty is a specific antagonism of the inhibitory neurotransmitter adenosiae [58-61-7] (19) (19). 

The leaves of Camellia sinensis are similar to most plants in general morphology and contain all the standard enzymes and stmctures associated with plant cell growth and photosynthesis (10—12). Unique to tea plants are large quantities of flavonoids and methylxanthines, compounds which impart the unique flavor and functional properties of tea. The general composition of fresh tea leaves is presented ia Table 1. 

Methybcanthine Diuretics. The mild diuretic effect of drinking coffee, from caffeine, and tea, mainly from theophylline, has been recogni2ed for along time. But the methylxanthines (Table 5) are of very limited efficacy when used as diuretics. The excretion of sodium and chloride ions are increased, but the potassium excretion is normal. Methylxanthines do not alter the urinary pH. Even though the methylxanthines have been demonstrated to have minor direct effects in the renal tubules, it is beUeved that they exert their diuretic effects through increased renal blood flow and GER (71). 

Isobutyl-l-methylxanthine (3-isobutyl-l-methylpurine-2,6-dione) [28822-58-4] M 222.3, m 199-210°, 202-203°, pK ,t 6.7 (acidic NH). Recrystd from aqueous EtOH. 

With hydrobromic acid and potassium bromate 7-methylxanthine (159 X = H) gave the 2-bromo derivative (159 X = Br) in 83% yield (84CHE924). Conversion of a variety of 2-substituted-6-trifluoromethyl-purines into the anions, followed by treatment with NBS in hot dimethyl-formamide, gave 20-60% yields of 2-bromo derivatives (90JHC1505). 

Adenosine is produced by many tissues, mainly as a byproduct of ATP breakdown. It is released from neurons, glia and other cells, possibly through the operation of the membrane transport system. Its rate of production varies with the functional state of the tissue and it may play a role as an autocrine or paracrine mediator (e.g. controlling blood flow). The uptake of adenosine is blocked by dipyridamole, which has vasodilatory effects. The effects of adenosine are mediated by a group of G protein-coupled receptors (the Gi/o-coupled Ai- and A3 receptors, and the Gs-coupled A2a-/A2B receptors). Ai receptors can mediate vasoconstriction, block of cardiac atrioventricular conduction and reduction of force of contraction, bronchoconstriction, and inhibition of neurotransmitter release. A2 receptors mediate vasodilatation and are involved in the stimulation of nociceptive afferent neurons. A3 receptors mediate the release of mediators from mast cells. Methylxanthines (e.g. caffeine) function as antagonists of Ai and A2 receptors. Adenosine itself is used to terminate supraventricular tachycardia by intravenous bolus injection. 

Methylxanthines have relaxing and anti-inflammatory effects. Accumulation of intracellular cAMP by inhibition of PDE3 (phosphodiesterase-3) relaxes airway... 

Mehtylxanthines are naturally occurring drugs, including theophylline, theobromine and caffeine. Methylxanthines at relatively high doses inhibit phosphodiesterases, which results in an increase in intracellular cAMP... 

Examples of the xanthine derivatives (drag that stimulate the central nervous system [CNS] resulting in bronchodilation, also called methylxanthines) are theophylline and aminophylline. Additional information concerning the xanthine derivatives is found in the Summary Drag Table Bronchodilators. 

Caffeine and nicotine have more complex reinforcing effects on dopamine. Caffeine, a methylxanthine compound, appears to exert its central ac-... 

Figure 33-8. Caffeine, a trimethyixanthine. The di-methylxanthines theobromine and theophylline are similar but lack the methyl group at N-1 and at N-7, respectively.

Tea leaf contains 2.5-4.0% caffeine (1,3,7-trimethylxanthine) on a dry weight basis and smaller quantities of the related methylxanthines, theobromine (3,7-dimethylxanthine 0.2-0.4%) and theophylline (1,3-dimethylxanthine ca. 0.02%). Although it is said that var. sinensis is slightly lower in caffeine than var. assamica, black, green and oolong tea beverages all contain about the same levels of caffeine (Cheng and Chen, 1994). 

Ia+ Murine class II major histocompatibility complex antigen IB4 Anti-CD 18 monoclonal antibody IBD Inflammatory bowel disease IBMX 3-isobutyl-l-methylxanthine IBS Inflammatory bowel syndrome iC3 Inactivated C3 iC4 Inactivated C4 IC50 Concentration producing 50% inhibition... 

Methylxanthine Theophylline Oral 0.5-2 hours Up to 24 hours, depending on formulation 6-24 hours 400-600 mg/day divided every... 

Drug- or toxin-induced3 Catecholamines Doxapram Methylphenidate Methylxanthines Nicotine Progesterone Salicylates... 

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