Theophylline 1,3-dimethylxanthine

For many years oral xanthines, shown in Table 2, were the preferred first-line treatment for asthma in the United States, and if the aerosol and oral formulations of P2" go sts are considered separately, as they are in Table 1, this was still the case in 1989. Within this class of compounds theophylline (8), or one of its various salt forms, such as aminophylline [317-34-0] (theophylline ethylenediamine 2 l), have been the predominant agents. Theophylline, 1,3-dimethylxanthine [58-55-9], is but one member of a class of naturally occurring alkaloids. Two more common alkaloids are theobromine (9), isomeric with theophylline and the principal alkaloid in cacao beans, and caffeine, (10), 1,3,7-Trimethylxanthine [58-08-2], found in coffee and tea. 

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). 

The methylxanthines of interest are caffeine (1,3,7-trimethylxanthine), theophylline (1,3-dimethylxanthine), and theobromine (3,7-dimethylxanthine) and they occur in coffee, tea, mate, cocoa products, and cola beverages. This chapter is an introduction to their chemistry, isolation, and biosynthesis. While the class of methylxanthines is large and comprised of more members than these three, this chapter will essentially be limited to caffeine, theobromine, and theophylline. 

Foods derived from cocoa beans have been consumed by humans since at least 460 to 480 AD. The source of cocoa beans, the species Theobroma, contains a variety of biologically active components. These include the purine alkaloids theobromine, caffeine, and theophylline. Structurally, they are methylated xanthines and, thus, are often referred to as methylxanthines. Theobromine (3, 7-dimethylxanthine) is the predominant purine alkaloid in cocoa and chocolate. Caffeine (1, 3, 7-trimethylxanthine), the major purine alkaloid found in coffee and tea, is found in cocoa and chocolate at about one eighth the concentration of theobromine. Only trace amounts of theophylline (1, 3-dimethylxanthine) are detected in cocoa and chocolate products. 

Related xanthines - theobromine (3,7-dimethylxanthin) and theophylline (1,3-dimethylxanthine)... 

Closely related methylxanthines include theophylline (1,3-dimethylxanthine), theobromine (3,7 dimethylxanthine) and paraxanthine (1,7-dimethylxanthine). Theobromine is found primarily in chocolate. These derivatives of caffeine are important because they are pharmacologically active and also are the common metabolites of caffeine. 

The purine nucleus is constructed by a condensation of the pyrimidine and imidazole (glyoxaline) nuclei (Figure 11.12). Xanthine is 2,6-dioxypurine caffeine, 1,3,7-trimethylxanthine theophylline, 1,3-dimethylxanthine and theobromine, 3,7-dimethylxanthine. These alkaloids are found in coffee, tea, cacao, kola, mate, and guarana (Figure 11.13). 

The metabolism of theophylline (1,3-dimethylxanthine) is similar to that of caffeine but less complex (vide supra). Consequently, some consideration has been given to using it as a CYP1A2 probe. However, potential analytical sensitivity problems and, more importantly, safety considerations do not suggest that theophylline has any advantage over caffeine for this purpose (86). 

Methyl derivatives of xanthine (2,3-dioxypurine) namely caffeine (1,3,7-trimethyl-xanthine), theobromine (3,7-dimethylxanthine) and theophylline (1,3-dimethylxanthine) (Section 1, Appendix) are variously found in plants used for stimulatory drinks such as Ilex paraguayensis (mate) (Aquifoliaceae), Coffea species (coffee) (Rubiaceae), Paullinia cupana (guarana) (Sapindaceae), Cola acuminata (cola) and Theabroma cacao (cocoa) (Sterculiaceae) and Camellia sinensis (tea) (Theaceae). These methylxanthines are variously active as inhibitors of... 

Almost identical bell-shaped rate-pH curves are produced by [8- H]theophylline (1,3-dimethylxanthine 8), xanthine (77T803) and 1-methylxanthine (79T663) whereas the characteristic curve shown by 9-isopropylpurine is also reproduced by [8- H]caffeine (1,3,7-trimethylxanthine) (77T803), [8- H]-theobromine (3,7-dimethylxanthine), 7-methylxanthine and xanthosine (79T663) in which substituents also occur in the imidazole ring. 3-Methylxanthine (71) on the other hand shows a rate-pH profile which is exceptional. 

In most studies, the selectivities of the MIPs have been estimated by measuring the amount of each ligand required to displace 50% of the binding of radiolabelled imprint species to the MIP (IC50). The first MIA study reported excellent selectivity of the theophylline method for theophylline (1,3-dimethylxanthine) in the presence of the structurally related compound caffeine (1,3,7-trimethylxanthine) [3]. Despite their close resemblance (they differ by only one methyl group), caffeine showed less than 1 % cross-reactivity. A similar level of specificity was recorded for cortisol and corticosterone MIPs, which were able to detect the absence and presence of single hydroxyl groups and double bonds in the steroid structure [13]. 

Caffeine is rapidly absorbed after an oral dose, with peak levels reached within 1-2 h at therapeutic doses. Onset of clinical effects occurs within 60 min. In adults, caffeine is extensively metabolized by the liver primarily by N-demethylation. It is excreted in the urine primarily as 1-methyluric acid and 1-methylxan-thine. Theophylline (1,3-dimethylxanthine) is a minor product of caffeine metabolism in adults (< 1%). After massive caffeine overdoses, serum levels of theophylline are measurable. The elimination half-life of caffeine is 3-6 h at therapeutic doses. The half-life is shorter in smokers and is prolonged by oral contraceptives, cimetidine, late pregnancy, and in overdose. The half-life of caffeine is much longer in infants and does not approximate that seen in adults until 6 months of age. The half-life of caffeine may exceed 100 h in preterm infants. Only 1-10% of caffeine appears unchanged in the urine in adults. Neonates may excrete up to 85% of caffeine unchanged. 

Taziphilline (Table 13-2) represents a novel approach to the design of second-generation Hrantagonists, hopefully with additional desired properties such as antiasthmatic effects. Theophylline (1,3-dimethylxanthine) has long been known, and used, for its bron-chodilator activity and efficacy in asthma. Several N7-derivatives are also useful... 

As commented above, the use of a surfactant different from SDS is anecdotal in direct injection MLC procedures. For this reason, the comparison of the determination of a drug such as theophylline (1,3 -dimethylxanthine), using two different surfactants, is interesting. Habel et al. [9] reported a procedure for the direct determination of this drug in human serum by using a p-Bondapak phenyl column, a micellar mobile phase of the zwitterionic surfactant C DAPS (10 M) containing 3% 1-propanol and UV detection at 273 nm. Later, Perez Martinez et al. [29] developed a procedure for theophylline, caffeine (1,3,7-trimethylxanthine) and theobromine (3,7-dimethylxanthine), in urine, with a Spherisorb Cl8... 

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