Theophylline with ethylenediamine

Caffeine is used medicinally as a CNS stimulant, usually combined with another therapeutic agent, as in compound analgesic preparations. Theobromine is of value as a diuretic and smooth muscle relaxant, but is not now routinely used. Theophylline is an important smooth muscle relaxant for relief of bronchospasm, and is frequently dispensed in slow-release formulations to reduce side-effects. It is also available as aminophylline (a more soluble preparation containing theophylline with ethylenediamine) and choline theophyllinate (theophylline and choline). The alkaloids may be isolated from natural sources, or obtained by total or partial synthesis. 

Aminophylline (Theophylline with Ethylenediamine). This substance is prepared by evaporating a solution of theophylline in ethylenediamine to dryness. 

Tablets of Aminophylline, B.P, The usual strength of these tablets is 0 1 g of theophylline with ethylenediamine. The assay is exactly as for the parent substance given above using about 0 5 g of the powdered sample.

Methylxanthines are ineffective by aerosol and must be taken systemically (orally or IV). Sustained-release theophylline is the preferred oral preparation, whereas its complex with ethylenediamine (ammophylline) is the preferred parenteral product due to increased solubility. IV theophylline is also available. 

Several modified-release formulations are available. Maximum serum concentrations occur at 1-3 hours with most of the standard formulations and at up to 6 hours with modified-release formulations. In aminophyl-line, the most widely used theophylline derivative, theophylline is combined with ethylenediamine to enhance its solubility. Since ethylenediamine is therapeutically inert, all the effects of aminophyUine, except for allergic reactions, are considered to stem from the theophyUine component. 

MUSCLE relaxant, CARDIAC STIMULANT and VASODILATOR properties. Clinically, it can be used as a BRONCHODILATOR in treating obstructive airways disease, including as an ANTIASTHMATIC in acute attacks. It is often used in the form of derivatives, especially aminophylline. theophylline ethylenediamine aminophylline. theophylline sodium glycinate [usan] is a compound of theophylline with sodium glycinate. It has CARDIAC STIMULANT, SMOOTH MUSCLE RELAXANT and VASODILATOR properties. 

Theophylline occurs in such a low concentration in all xanthine drugs that extraction is not profitable. Theophylline can be produced by demethylation of caffeine or by total synthesis. Theophylline has a spasmolytic effect on smooth muscles, which is apparent in a pronounced bronchodilating action, hence it is used in asthma either on its own or combined with ethylenediamine to produce aminophylline. Furthermore, theophylline has a diuretic action. 

Theophylline can be dissolved by salt formation with ethylenediamine or other amines. Previously, ethylene-diamine theofyllinate (aminophylline) was used in oral preparations. Soluble double salts of theophylline can be prepared using sodium acetate and sodium glycinate. However, excellent absorption is achieved after oral administration of theophylline as such, for example in capsules, so... 

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. 

Theophylline, given as the soluble ethylenediamine salt aminophylline, offers some help in relieving the paroxysmal dyspnea that is often associated with left heart failure. A major portion of its efficacy may be due to the relief of bronchospasm secondary to pulmonary vascular congestion. Theophylline increases myocardial contractile force and has occasionally been used in the treatment of refractory forms of congestive heart fail-... 

Aminophylline (theophylline ethylenediamine), given intravenously, is used in patients with status asthmaticus who do not respond to epinephrine. In addition, epinephrine may be administered subcutaneously for acute asthma attacks. Epinephrine may also be given along with theophylline. It is thought that the bronchodilation is associated with me enhanced concentration of cyclic AMP, which is metabolized according to the following sequence ... 

A stable mixture containing 78 to 84% of anhydrous theophylline and 13 to 14% of ethylenediamine with a variable quantity of water. 

Methylxanthines have a few valid therapeutic uses, including treatment of asthma and relief of dyspnea (see Antiasthmatic agents). The CNS stimulatory effects are also utilized for the treatment of the prolonged apnea that may be observed in premature infants. Theophylline may be combined with doxapram (13) for this use (20). The methylxanthine most widely used therapeutically is theophylline, although caffeine may also be used. For parenteral administration, a salt of theophylline is employed. There are several salts available, including theophylline ethylenediamine (aminophylline [317-34-0]) and oxtriphylline (choline theophyllinate). Other synthetic xanthines that are used include dyphylline [479-18-5] and enprofylline [410784)2-8] (21). Caffeine is obtained in pure form from tea waste, from the manufacture of caffeine coffee, and by total synthesis (22,23). 

The analeptic action of theophylline-diethanolamine is much less effective in the rabbit than that of theophylline-ethylenediamine. Diethanolamine scarcely modifies the respiratory rate and amplitude but it slightly increases the total respiratory volume. This phenomenon is seen equally with or without denervation of the chemoceptors of the carotid sinuses (200). 

Ethylenediamine is used in numerous industrial processes as a solvent for casein or albumin, as a stabilizer in rubber latex and as a textile lubricant. It can be found in epoxy-resin hardeners, cooling oils, fungicides, and waxes. Contact dermatitis from ethylenediamine is almost exclusively due to topical medicaments. Occupational contact dermatitis in epoxy-resin systems is rather infrequent. Ethylenediamine can cross react with triethylenetetramine and diethylenetriamine. Ethylenediamine was responsible for sensitization in pharmacists handling aminophylline suppositories, in nurses preparing and administering injectable theophylline, and in a laboratory technician in the manufacture of aminophylline tablets. 

The titration of aminophylline, which is the salt of theophylline (the acid) and ethylenediamine (the base), is performed in water with hydrochloric acid in the presence of bromocresol green (3.8[Pg.177]

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