Theophylline with adenosine

Despite the fact that the last mechanism may be basic for theophylline, a few xanthines, which in general lack the ability to bind with adenosine receptors, express the same, if not more broncholytic activity than theophylline. 

C Methyixanthines such as theophylline are adenosine receptor antagonists. In the presence of methyixanthines, larger doses of adenosine may be required or some patients may be refractory to adenosine. The other drugs are not likely to interfere with adenosine s efficacy. 

Experimental studies in healthy subjects, on the way xanthine drugs possibly interact with adenosine, have shown that caffeine and theophylline (but not enprofylline) reduced the increased heart rate and the changes in blood pressure caused by infusions of adenosine, and attenuated adenosine-induced vasodilatation. Theophylline also attenuated adenosine-induced respiratory effects and chest pain. Similarly, an adenosine infusion antagonised the haemodynamic effects of a single dose of theophylline in healthy subjects, but did not reduce the metabolic effects (reductions in plasma potassium and magnesium). ... 

IL-10 production after hydrogen peroxide and IPS stimulation and dose-dependently inhibited TNF secretion. The enhanced IL-10 production was not observed when cells were preincubated with adenosine Ai or Aj receptor agonists (E-phenylisopro-pyladenosine, 5 -N-ethylcarboxamide-adenosine, and 2-chloroadenosine) and was not affected by pre-treatment with theophylline, an antagonist of both Ai and Aj receptors, or with dipyridamole, an inhibitor of adenosine cellular uptake (Le Moine et al. 1996). 

The inhibition of [ H]chloroadenosine binding by adenosine receptor antagonists was studied. Isobutylmethylxanthine was a more potent inhibitor than theophylline with a Kd of 23 ]M as compared to... 

Kinoshita, Imoto etal.11 14) synthesized other anionic models, 5 (APVP), CPVP, UPVP, TPVA, HPVA, THPVA, and 6 (AMPPVA), by the polymer reaction of N-eoupled(2-dihydrogenphosphate)-ethylderivatives of nucleic acid bases (or adenosine-5 -phosphate, AMP) with polyvinylaleohol. A, C, U, T, H, and TH denote adenine, cytosine, uracil, thymin, hypoxanthine, and theophylline, respectively. The authors reported the apparent hypochromities of 3 to 16% for many kinds of mixtures of the models and DNA or RNA, as compiled in Table 1. However, for the mixtures APVA + RNA, HPVA + RNA HPVA + DNA, THPVA + RNA, CPVA + DNA and CPVA + RNA, no hypochromicity was detected. 

It is perhaps not surprising that, sinee adenosine has been presented as an endogenous inhibitor of neuronal funetion with its antagonists, like theophylline, being stimulants (see Chapter 13), it should have been implieated in sleep induetion. 

Theophylline is also considered an alternative to inhaled corticosteroids for the treatment of mild persistent asthma however, limited efficacy compared to inhaled corticosteroids, a narrow therapeutic index with life-threatening toxicity, and multiple clinically important drug interactions have severely limited its use. Theophylline causes bronchodilation through inhibition of phosphodiesterase and antagonism of adenosine and appears to have anti-inflammatory and immunomodulatory properties as well.36... 

Kuhne T., Homstein A., Semple J., et al. Flow cytometric evaluation of platelet activation in blood collected into EDTA vs. Diatube-H, a sodium citrate solution supplemented with theophylline, adenosine and dipyridamole. Am J Hematol 1995 50,40-5. 

Caffeine and theophylline decrease total sleep time, time spent in SWS and REM sleep and increase the number of intrasleep arousals. Withdrawal of caffeine in regular users leads to daytime sleepiness, increased slow wave (delta) activity on the EEC and headaches. The mechanism of action appears to be antagonism of central adenosine Ai and A2 receptors which normally exert a CNS depressant action, with consequent interference with the sleep-inducing action of adenosine (Chapter 6). 

Smooth muscle relaxation, central nervous system (CNS) excitation, and cardiac stimulation are the principal pharmacological effects observed in patients treated with theophylline. The action of theophylline on the respiratory system is easily seen in the asthmatic by the resolution of obstruction and improvement in pulmonary function. Other mechanisms that may contribute to the action of theophylline in asthma include antagonism of adenosine, inhibition of mediator release, increased sympathetic activity, alteration in immune cell function, and reduction in respiratory muscle fatigue. Theophylline also may exert an antiinflammatory effect through its ability to modulate inflammatory mediator release and immune cell function. 

Use of caffeine has also been recommended to lower the threshold in patients who do not experience an adequate seizure (104,105 and 106). One report, however, found that caffeine appeared to produce neuronal damage in rats receiving ECS (107). Because adenosine may have neuroprotective effects, one postulated mechanism is the ability of methyixanthines (e.g., caffeine, theophylline) to block adenosine receptors. On a positive note, studies have not found a difference in cognitive disruption between patients receiving ECT with or without caffeine (108). Although the implications of the animal data for humans are not clear, and because shorter seizures may be effective in some patients, a conservative approach would be to augment with caffeine only when seizure duration is less than 20 seconds and response is inadequate ( 38). Alternatively, it may be appropriate to switch to BILAT electrode placement or from methohexital to etomidate when UND electrode stimulation produces inadequate seizure duration (even at maximal stimulus intensity) and response is insufficient ( 97, 98). 

ATP, ADP, and adenosine are among the purines that are present in some synapses and activate a variety of receptors. Adenosine receptors are blocked specifically by methylated xanthines such as caffeine (Fig. 25-18) and theophylline.808 80813 A drug almost 105 times as potent as theophylline is l,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine.809 Adenosine receptors, which are present in large numbers in the hippocampus,149 form functional complexes with metabotropic glutamate receptors.678 Adenosine... 

A3 receptors are present on human eosinophils and couple to signalling pathways that lead to cell activation ( Kohno et al. 1996a Reeves et al. 2000). Despite this it has not proven easy to demonstrate the functional consequences of activation of these sites (Reeves et al. 2000). Nevertheless, the chronic inflammation in asthma is characterised by extensive infiltration of the airways by activated eosinophils (Holgate 1999 Pearlman 1999) and it remains possible that the elevated adenosine concentrations associated with asthma would contribute to eosinophil activation through stimulation of A3 receptors. In addition, it has been speculated that activation of A3 receptors may protect eosinophils from apoptosis (Gao et al. 2001). Thus, blockade of A3 receptors may reduce the numbers of eosinophils and their activation thereby reducing the pro-inflammatory burden in the lung. Consistent with this, following 6 weeks treatment of mild asthmatics with theophylline there was a... 

This neurotransmitter has diverse functions throughout the brain that are also related to our sleep—wake cycles. We know a lot about it because of the ready availability of a very safe, highly effective adenosine receptor antagonist that is served hot or cold, with or without cream, throughout the world—caffeinated coffee Caffeine is also commonly found with theophylline (a molecule that is very similar to caffeine) in tea. Indeed, although caffeine is found in at least 63 plant species, 54% of the world s... 

Many people drink coffee to reduce drowsiness. How does caffeine achieve this effect in the brain The answer begins with a consideration of the function of the acetylcholine neurons that control your ability to pay attention. Adenosine negatively controls the activity of these neurons, meaning that when adenosine binds to its receptor on acetylcholine neurons, their activity slows. The production and release of adenosine in your brain is linked to metabolic activity while you are awake. Therefore, the concentration of adenosine in the neighborhood of acetylcholine neurons increases constantly while your brain is active during the day. As the levels of adenosine increase, they steadily inhibit your acetylcholine neurons, your brain s activity gradually slows, and you begin to feel drowsy and ultimately fall asleep. Caffeine comes to the rescue because it, like theophylline... 

Finally, purines such as caffeine (including dietary caffeine in coffee, tea, colas, and chocolate) and synthetic derivatives, such as theophylline, can interfere with the vascular actions of dipyridamole, These agents act to inhibit the adenosine A2A receptor, which serves to further emphasize the role of adenosine in the pharmacologic actions of dipyridamole (41-43), It has also been shown that this effect on A2A receptors is restricted to the vessel wall the direct anti-aggregatory actions of dipyridamole are not blocked by purines and may, if anything, be enhanced by the indirect effect of purines to upregulate A2A receptors (44,45). 

I I Ban G, Brereton GC, Fulwood M, et al. Effect of prosaglandin E, alone and incombination with theophylline or aspirin on collagen induced platelet aggregation and on platelet nucleotides including adenosine 3 5 -cydic monophosphate. Biochem J 1970 120 709-718. 

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). 

Figure S. Effects of adenosine antagonists (theophylline, SO pM and 3,7-dimediyl-l-piopaigylxantfiine, DMPX, 20 pM) on vasopressin-induced platelet aggregation in PRP with normal amounts of adenosine (blood collected in presence of dCF and dilazep from a female donor). (Reproduced with permission poblication of Agarwal, KC Ref. 49).

Daly, JW, Dkena, D, Jacobson, KA, Analogues of adenosine, theophylline, and caffeine Selective interactions with A, and A, adenosine receptors. In Topics and perspectives in adenosine research (eds Gerlach, E and Backer, BF), Springer-Verlag, Heidelberg, 1987,23-36. 

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