Of theophylline

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,... 

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). 

Equimolecular proportions of theophylline and 2-emino-2-mathyl-1 -propanol are dissolved in water and the water is evaporated until crystallization is almost complete. Tha crystals are filtered off and dried. Tha product has a malting point of 254°-256°C, softening at 245°C. 

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... 

When Hie cholinesterase inhibitors are administered with the anticholinergic drugp, there is a potential decrease in activity of the anticholinergic drug. There is an increased risk of toxicity of theophylline when the cholinesterase inhibitors are administered with tacrine There is a synergistic effect when tacrine is administered with succinyl-choline, cholinesterase inhibitors, or cholinergic agonists (eg, bethanechol). 

The therapeutic range of theophylline blood levels is 10 to 20 p,g/mL. Levels greater than 20 pig/mL may cause toxicity. In some patients, toxicity may occur with levels between 15 and 20 pg/mL. Toxicity is more likely to occur in patients requiring high doses or during prolonged dierapy. 

Notify the primary health care provider immediately if any of the following signs of theophylline toxicity develop anorexia, nausea, vomiting, diarrhea, confusion, abdominal cramping, headache, restlessness insomnia, tachycardia, arrhythmias or seizures... 

Remember that frequent monitoring of theophylline serum levels is important. 

Fig. 1 Fluorescence scan of a chromatogram track with 500 ng each of theophylline (1), theobromine (2) and caffeine (3) per chromatogram zone.

Jubran A, Gross N, Ramsdell J, et al. Comparative cost-effectiveness analysis of theophylline and ipratropium bromide in chronic obstructive pulmonary disease. A three-center study. Chest 1993 103 678-84. 

Other Formulations. Neural networks have been applied to the modeling of pellet formulations to control the release of theophylline [63] and to control the rate of degradation of omeprazole [64]. They have also been applied to the preparation of acrylic microspheres [65] and to model the release of insulin from an implant [66]. In arecent study from Brazil, the release of hydrocortisone from a biodegradable matrix has been successfully modeled [67]. 

Another example of the use of small particle silica is in the analysis of theophylline in plasma, as shown in Figure 5 (40). The clean-up procedure is simply a single extraction of the plasma with an organic solvent. This analysis has also been achieved by reverse phase chromatography (41), and this points out the fact that in some separations (e.g. with components of moderate polarity) either the adsorption or reverse phase mode can be used. 

Use of zileuton is uncommon due to the need for dosing four times a day, potential drug interactions, and the potential for hepatotoxicity with the resulting need for frequent monitoring of liver enzymes. In patients started on zileuton, serum alanine aminotransferase concentrations should be monitored before treatment begins, monthly for the first 3 months, every 2 to 3 months for the remainder of the first year, and then periodically thereafter for as long as the patient continues to receive the medication. Zileuton also inhibits the cytochrome P-450 (CYP) mixed function enzyme system and has been shown to decrease the clearance of theophylline, R-warfarin and propranolol.34... 

Theophylline COCs decrease theophylline clearance by 34% and increase the t1/2 by 33% Increase side effects of theophylline... 

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. 

The determination of theophylline in plasma can also be accomplished by various immunoassay techniques.66-67 Theophylline was also determined by a polarization fluoroimmunoassays but found to have a caffeine interference.88. In a more research oriented application, the interaction of caffeine with L-tryptophan was studied using h NMR with the results indicating that caffeine interacted with tryptophan in a 1 1 molar ratio through parallel stacking.69... 

Schack, J.A. and Waxier, S.H., Ultraviolet spectrophotometric method for the determination of theophylline and theobromine in blood and tissues, J. Pharmacol. Exp. Ther., 97,283,1949. 

Jatlow, P., Ultraviolet spectrophotometry of theophylline in plasma in the presence of barbiturates, Clin. Chem., 21,1518,1975. 

Gupta, R.C. and Lundberg, G.D., Qualitative determination of theophylline in blood by differential spectrophotometry, Anal Chem., 45,2402,1973. 

Peng, G.W., Gadalia, M.A.F., and Chiou, W.L., High performance liquid chromatographic determination of theophylline in plasma, Clin. Chem., 24,357,1978. 

Sommadossi, J.P., Aubert, C., Cano, J.P., Durand, A., and Viala, A., Determination of theophylline in plasma by high performance liquid chromatography, J Liquid Chromatogr., 4,97,1981. 

Hieda, Y., Kashimura, S., Hara, K., and Kageura, M., Highly sensitive and rapid determination of theophylline, theobromine and caffeine in human plasma and urine by high performance liquid chromatography frit fast atom bombardment spectrometry, J. Chromatogr., 667,241,1995... 

Koup, J.R. and Brodsky, B., Comparison of homogeneous enzyme immunoassay and high pressure liquid chromatography for the determination of theophylline concentration in serum, Am. Rev. Respir. Dis., 117,1135,1978. 

Oellerich, M., Klupmann, W.R., Beneking, M., Sybrecht, G.W., Staib, A.H., and Schuster, R., Determination of theophylline in serum by nonisotopic immunoassays (EMIT, SLFIA, NIIA) and HPLC-CA comparative study, Fresenius Z. Anal. Chem., 311,355,1982. 

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. 

According to Schutz, it is well known that cocoa contains about 2.5% by weight of theobromine and caffeine.29 Although the presence of theophylline has been demonstrated, its concentration is so low that it is generally ignored. In a summary of the literature values for 27 commercial cocoa powders and cocoa masses, Hadorn found that the mean total alkaloid content was 3.36 0.48%.23 Theobromine and caffeine content of several cocoa powders is shown in Table 6. HPLC analyses by DeVries et... 

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. 

The percentage of binding to plasma protein is low for caffeine (35%) and theobromine (15 to 25%), but fairly high for theophylline (55 to 67%). This higher binding of theophylline should be considered when it is used as a prescription drug. 

Theophylline is used pharmacologically to manage asthma. Therapeutic effect is seen at concentrations in plasma above 10 mg/L. At 20 mg/ L, adverse effects limit the usefulness of theophylline. 

Figure 3 shows the amount of theophylline released at time t (Mt) relative to the total amount loaded (Moo) (i.e., Mt/Mco) as a function of time. Evidently theophylline-loaded PDMAAm-i-PIB networks are efficient drug delivery systems, and nearly complete release requires 24 hours. 

Figure 3. Release of theophylline as a function of time from PDMAAm-1.-PIB amphiphilic networks.

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