Theophylline methylxanthine

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

The methylxanthine theophylline (p. 326), the phosphodiesterase inhibitor amrinone (p. 132), prostacyclins (p. 197), and nicotinic acid derivatives (p. 156) also possess vasodilating activity. 

Bronchodilators. Narrowing of bronchioles raises airway resistance, e.g in bronchial or bronchitic asthma Several substances that are employed as bronchodilators are described elsewhere in more detail P2-sympathomimetics (p. 84, given by pulmonary, parenteral, or oral route), the methylxanthine theophylline (p. 326, given parenterally or orally), as well as the parasympatholytic ipratropium (pp. 104, 107, given by inhalation). 

Adenosine binds to adenosine receptors (AD-Rs) (subtypes Ah A2A, A2b and A3). Ap and Ap R activation gives Gai-mediated inhibition of adenylyl cyclase (resulting in decreased cAMP) and Gai/Gao-mediated activation of a K+ channel (with a de-excitatory hyperpolarizing effect). A2A and A2B activation gives Gas-mediated stimulation of adenylate cyclase (resulting in elevated cAMP). Adenosine acting via particular receptors variously has cardioprotective, neuroprotective, sedative, anticonvulsant, soporific, vasodilatory and bronchoconstrictive effects. The plant-derived methylxanthines theophylline and caffeine are adenosine A1 and A2 receptor antagonists (Table 5.1). 

The methylxanthines, theophylline and caffeine, act primarily as antagonists for both adenosine A, and Aj receptors (65-68). Caffeine is a relatively weak adenosine antagonist as compared to foeophylline (69). Studies to examine these methylxanthines as adenosine antagonists on platelet ftinction have been limited. Both theophylline and caffeine are shown to stimulate platelet reactivity in vitro and in vivo studies (49,50,67,69,70). Platelets from subjects after chronic consumption of caffeine show decreased antiplatelet activity of the adenosine analog NECA on thrombin-induced... 

The general properties of the methylxanthines (theophylline, caffeine) are discussed elsewhere (see p. 194). Their mild diuretic action probably depends in part on smooth muscle relaxation in the afferent arteriolar bed increasing renal blood flow, and in part on a direct inhibitory effect on salt reabsorption in the proximal tubule. Their uses in medicine depend on other properties. 

A methylxanthine, theophylline, is used in one proprietary OTC preparation marketed for the treatment of bronchial cough, breathlessness and wheezing. 

Treatment--Bronchodilators. The methylxanthine theophylline and its analogues are widely used in the treatment of CB. 

Both purine and pyrimidine bases occur as constituent parts of nucleic acids and plant products. In addition, a number of free purine and pyrimidine bases have been isolated from plants (Atta-ur-Rahman and Choudhary, 1990 Brown, 1991 Wang, 1973). The pyrimidine glucoside vicine (28) was first isolated from seeds of Vida species in 1870. However, purine bases appear to be much more common that pyrimidine bases in nature. The most important purine alkaloids are derived from the xanthine nucleus. Xanthine itself has not been found naturally, but several of its A -alkyl derivatives are of considerable importance. The most important of these are 1,3,7-trimethylxanthine (caffeine) (29), 1,3-di-methylxanthine (theophylline) (30), and 3,7-dimethylxan-thine (theobromine) (31) (Fig. 37.9). These alkaloids are major constituents of plants used as stimulating beverages by people throughout the world. 

The following methylatlons were observed 7-Methylxanthine + Theobromine 1-Methylxanthine -> Theophylline Theobromine - Caffeine Theophylline -> Caffeine 7-Methylxanthosine -> Theobromine Paraxanthine - Caffeine... 

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. 

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). 

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. 

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). 

Caffeine was conceived for a wide range of readers interested in the effects on human health, nutrition, and physiological function of the methylxanthine beverages and foods—tea, coffee, mate, cola beverages, and cocoa and chocolate products. These products supply one or more of the dietary methylxanthines—caffeine, theobromine and theophylline— and are an integral part of the diet of many people in many countries. The interest in the health effects of both the methylxanthines in isolation and in the products containing them has grown rapidly in recent years. 

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. 

The methylxanthines vary in their ability to form certain metal complexes. For example, theophylline will complex with both copper and silver whereas caffeine will not.16 The interpretation of this is that the metal ion forms a pentacyclic complex involving the phenolic 0 at C-6 and N at 7.18... 

Another scheme for methylxanthine isolation involves the extraction of the dried ground plant with 10% ammonium hydroxide chloroform (1 10). A large proportion of the extraction mixture is used, relative to the sample, to ensure complete extraction of any theobromine. Caffeine and theophylline will be extracted easily under these conditions.20 After removing water from the organic layer, filtration, and solvent removal, any methylxanthines present will be in the residue together with some impurities. An approach to finally isolating these methylxanthines from this... 

Several studies have investigated the biosynthesis of caffeine in tea. The results of a study by Suzuki and Takahashi27 30 suggest a pathway for caffeine biosynthesis in tea from 7-methylxanthine to theobromine and then to caffeine. Additionally they suggest that theophylline is synthesized from 1-methylxanthine. Another study by Ogutuga and Northcote31 proposes a pathway through 7-methylxanthosine to theobromine followed by caffeine. 

Much research has centered on identifying the source of the purine ring in caffeine. Two possible sources are likely methylated nucleotides in the nucleotide pool and methylated nucleotides in nucleic acids. Extensive experimental work by Suzuki and Takahashi27-30 proposes a scheme whereby caffeine is synthesized from methylated purines in the nucleotide pool via 7-methylxanthosine and theobromine. Information relating to the formation of 7-methylxanthine from nucleotides in the nucleotide pool is sparse. They also provide data that demonstrate that theophylline is synthesized from 1-methyladenylic acid through 1-methylxanthine as postulated by Ogutuga and Northcote.31... 

The analysis of the methylxanthines (caffeine, theobromine, and theophylline) is important in the areas of nutrition and clinical chemistry. These three compounds compose the majority of the alkaloids present in coffee, tea, cocoa, cola nuts, and guarana. 

There are numerous methods in the literature for the determination of caffeine, theobromine, and theophylline in food matrices, including coffee, tea, and cocoa. Until recently, methods have emphasized the determination of the major methylxanthines in a commodity, for example, caffeine in coffee or theobromine in cocoa. Present methods range from being specific for one of the compounds in a single matrix to being an all-encompassing assay of major and minor methylxanthines in food products. 

In the clinical area, the largest share of analytical methods development and publication has centered on the determination of theophylline in various body fluids, since theophylline is used as a bronchodilator in asthma. Monitoring serum theophylline levels is much more helpful than monitoring dosage levels.44 Interest in the assay of other methylxanthines and their metabolites has been on the increase, as evidenced by the citations in the literature with a focus on the analysis of various xanthines and methylxanthines. 

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. 

Although low levels of methylxanthines have been detected in the leaves and flowers of T. cacao, the primary storage location is within the seed or bean.16 The cocoa bean is the major natural source of the methylxanthine theobromine, but contains only small amounts of caffeine. Theophylline has been detected in cacao beans, but at such low concentrations that its presence generally is ignored. Together, theobromine and caffeine account for up to 99% of the alkaloid content of T. cacao beans. Alkaloid content is affected by genetic makeup, maturity of beans at harvest, and fermentation process. Analytical methodology also is partially responsible for some of the disparity in methylxanthine values since many early methods were unable to separate theobromine and caffeine. 

This chapter has compiled and evaluated information on the methylxanthine composition of cocoa and various chocolate foods and beverages, as well as the consumption pattern for these commodities. Cacao is the major natural source of the xanthine base theobromine. Small amounts of caffeine are present in the bean along with trace amounts of theophylline. Numerous factors, including varietal type and fermentation process, influence the methylxanthine content of beans. 

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