Theophyllinate

Broh-Kahn, E.H. and Sasmor, E.J. U.S. Patent 3,069,321 December IB, 1962 assigned to Laboratories for Pharmaceutical Development, Inc. 

Therapeutic Function Smooth muscle relaxant Chemical Name Theophylline cholinate Common Name Oxotriphylline oxytrimethylline 

Trade Name Manufacturer Country Year Introduced 

IB parts by weight of theophylline are added to 37.8 parts by weight of aqueous choline bicarbonate (47% assay) and the mixture stirred and heated at B0°C to 90°C until the evolution 

Chemical Name [ (3-(2-(Diethylamino)ethy ] -4-methyl-2-oxo-2H-1 -benzopyran-7-yl] oxy) acetic acid ethyl ester hydrochloride 

18 Parts by weight of theophylline are added to 37.8 parts by weight of aqueous choline bi- 

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This experiment describes the quantitative analysis of the asthma medication Quadrinal for the active ingredients theophylline, salicylic acid, phenobarbital, ephedrine HGl, and potassium iodide. Separations are carried out using a Gi8 column with a mobile phase of 19% v/v acetonitrile, 80% v/v water, and 1% acetic acid. A small amount of triethylamine (0.03% v/v) is included to ensure the elution of ephedrine HGl. A UV detector set to 254 nm is used to record the chromatogram. 

This experiment describes a quantitative analysis for caffeine, theobromine, and theophylline in tea, pain killers, and cocoa. Separations are accomplished by MEKC using a pH 8.25 borate-phosphate buffer with added SDS. A UV detector set to 214 nm is used to record the electropherogram. An internal standard of phenobarbital is included for quantitative work. 

The leaf and leaf buds of Cammelia sinensis (L.) O Kuntze and other related plants and most teas contain, depending upon climate, specific variety, time of harvest, etc, somewhat less than 5% caffeine (16) and smaller amounts of theophylline (133, Rj = Rg = CHg Rg = H) and theobromine (133,... 

Two other commonly found sources of caffeine (16) are kola Cold) from the seeds of, for example. Cola nitida (Vent.) Schott and Engl., which contains 1—4% of the alkaloid, but Httie theophylline or theobromine, and cocoa (from the seeds of Theobroma cacao L.), which generally contains about 3% theobromine and significantiy less caffeine. 

AH three of these materials are apparentiy central nervous system (CNS) stimulants. It is beheved that for most individuals caffeine causes greater stimulation than does theophylline. Theobromine apparentiy causes the least stimulation. There is some evidence that caffeine acts on the cortex and reduces drowsiness and fatigue, although habituation can reduce these effects. 

Caffeine. About 3% by weight of the roasted coffee bean is caffeine (16). The second U.S. Department of Agriculture world coffee crop estimate for 1988—1989 was 4.24 x 10 kg (93.3 million 100-lb bags) (102). World coffee consumption was predicted to rise in the foreseeable future at the rate of 1—2% per year and thus the total amount of caffeine and related alkaloids ingested from this source can also be expected to increase. Caffeine and related bases (eg, theophylline) are also found in various teas but, because most of the major producers (India, China, etc) export relatively Htfle of thek crops and keep most for domestic consumption, accurate figures on year-to-year production are more difficult to obtain. Nevertheless, these crops are of significant economic import (103). 

Ai,A/-bis(hydroxymethyl) formamide [6921-98-8] (21), which in solution is in equiUbrium with the monomethylol derivative [13052-19-2] and formaldehyde. With ben2aldehyde in the presence of pyridine, formamide condenses to yield ben2yhdene bisformamide [14328-12-2]. Similar reactions occur with ketones, which, however, requite more drastic reaction conditions. Formamide is a valuable reagent in the synthesis of heterocycHc compounds. Synthetic routes to various types of compounds like imida2oles, oxa2oles, pyrimidines, tria2ines, xanthines, and even complex purine alkaloids, eg, theophylline [58-55-9] theobromine [83-67-0], and caffeine [58-08-2], have been devised (22). 

Otherwise cyanoacetic acid is directiy converted as a solution with 1,3-dimethylurea [96-31-1] iato 2-cyano-A/,AT-dimethylcarbamoyl acetamide [39615-79-7] which is further upgraded iato the diuretics theophylline [58-55-9] (33 where R = H) and caffeiae [58-08-2] (33, where R = CH3) (63). 

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. 

Historically, the use of xanthines has been hampered by poor aqueous solubiUty, rapid but highly variable metaboHsm, and the existance of a low therapeutic index. SolubiUty problems were partially solved by the preparation of various salt forms, eg, aminophylline. However, it was since recognized that the added base in aminophylline only increases solubiUty by increasing pH and thus does not affect the rate of absorption from the gut (65). Thus, in more recent medical practice, theophylline is commonly dispensed in anhydrous form and aminophylline is only recommended for iv adrninistration. 

The development of easy-to-use assays for determining theophylline blood levels afforded a handle on maintenance of effective but nontoxic levels. The relatively good availabihty of such assays in the United States probably contributed to the historical preference for theophylline treatment by U.S. physicians. Careful titration of the dose must be done on a patient-by-patient basis because individual rates of metaboHsm vary widely. Most ( 85%) of an oral dose of theophylline is metabolized by Hver microsomal enzymes. As a result many dmgs, eg, cimetidine [51481-61-9], anticonvulsants, or conditions, eg, fever, cigarette smoking, Hver disease, which affect Hver function alter theophylline blood levels. 

Common side effects of theophylline therapy include headache, dyspepsia, and nausea. More serious side effects such as lethal seizures or cardiac arrythmias can occur if blood levels are too high. Many derivatives of theophylline have been prepared in an effort to discover an analogue without these limitations (60,61). However, the most universal solution has resulted from the development of reHable sustained release formulations. This technology limits the peaks and valleys in semm blood levels that occur with frequent dosing of immediate release formulations. ControUed release addresses the problems inherent in a dmg which is rapidly metabolized but which is toxic at levels ( >20 7g/mL) that are only slightly higher than the therapeutically efficacious ones (10—20 p.g/mL). Furthermore, such once-a-day formulations taken just before bedtime have proven especially beneficial in the control of nocturnal asthma (27,50,62). 

The effectiveness of theophylline in the treatment of asthma seems to result from a combination of biological properties which are not clearly understood (63). Detailed discussions of the possible role of xanthines in asthma may be found in references 64—66. 

Theophylline s predominant mode of action appears to be bronchocHlation. However, it has also been shown that prophylactic acHriinistration of theophylline provides some protection from asthma attacks and suppresses the late-phase response (67,68). Some researchers beHeve that at therapeutic semm concentrations theophylline may inhibit the development of airway inflammation (69). There are conflicting reports on the effect of theophylline on allergen-induced bronchial hyperresponsiveness some clinical stucHes report a reduction in hyper-responsiveness, others do not (69,70). Theophylline clearly does not reverse the general bronchial hyperresponsiveness over the course of long-term therapy (71). Because of the relationship between... 

Initially, it was beheved that the abiUty of xanthines phosphodiesterase (PDF) led to bronchodilation (Fig. 2). One significant flaw in this proposal is that the concentration of theophylline needed to significantly inhibit PDE in vitro is higher than the therapeutically useful semm values (72). It is possible that concentration of theophylline in airways smooth muscle occurs, but there is no support for this idea from tissue distribution studies. Furthermore, other potent PDE inhibitors such as dipyridamole [58-32-2] are not bronchodilators (73). EinaHy, although clinical studies have shown that neither po nor continuous iv theophylline has a direct effect on circulating cycHc AMP levels (74,75), one study has shown that iv theophylline significant potentiates the increase in cycHc AMP levels induced by isoproterenol (74). 

C. G. A. Persson, Agents and Actions (Suppl.) 13, 115 (1983). A review on Theophylline stmcture-activity relationships. 

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. 

Enzyme immunosensors are employed for the determination of Hepatitis B surface antigen, IgG, alpha-fetoprotein, estradiol, theophylline, insulin [9004-10-8] and alburnin (69,70). However, these immunosensors generally have slow response times and slow reversibiUty (57). 

Others. Other choline salts available as commercial products include choline bicarbonate [78-73-9] choline saUcylate [2016-36-6] and the bronchodilator choline theophyllinate [4499-40-5]. 

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