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I read with interest the excellent update on adenosine by Polosa and Holgate.1 An important use of this challenge agent is demonstrated and adenosine antagonism as a potential treatment for asthma is revisited. However, the role of adenosine as a mediator of asthma is somewhat inconsistent with several functional observations.
Besides the fact that adenosine has dual effects in many systems, data are available— particularly involving the pharmacology of enprofylline (3-methyl xanthine)—which suggest that the therapeutic efficacy of theophylline (1,3-dimethyl xanthine) in asthma may not reflect adenosine antagonism.2 This latter aspect is significant because theophylline, at therapeutic concentrations, effectively antagonises adenosine (at receptors and functionally in vivo).
Qualitatively different from theophylline, enprofylline does not antagonise the physiological/pathophysiological actions of adenosine2 yet enprofylline and theophylline share several pharmacological actions including cardiac stimulation, microvascular anti-exudative activity, and a range of smooth muscle relaxant effects although enprofylline is consistently about three times more potent than theophylline.2 Equally, enprofylline is about three times more potent than theophylline in asthma as a bronchodilator,2 as an inhibitor of histamine-induced broncho constriction,2 3 as an inhibitor of late phase reactions,2 and in maintenance therapy.2 Indeed, it is only under artificial conditions when asthmatic subjects inhale adenosine that theophylline provides greater protection than enprofylline.3
In contrast to its efficacy in the treatment of asthma, enprofylline lacks several well known clinical effects of theophylline such as diuretic activity, CNS arousal effects, free fatty acid releasing effects, and gastric secretory effects.2 This distinct human pharmacology is evidence for the clinically effective adenosine antagonism of theophylline and indicates that enprofylline tonically suppresses volume and acidity of gastric secretion, natriuresis, free fatty acid release, etc.2 One might therefore conclude that adenosine antagonism should probably be avoided in asthma therapy because it may be associated with less desirable excitatory extrapulmonary effects.
Antagonism of A2b adenosine receptors by enprofylllne may explain the “adenosine hypothesis”.1 By inferring this, Polosa and Holgate lend greater weight to in vitro observations that disagree with the anti-asthma potency ratio between enprofylline and theophylline that may require 300 μM drug concentrations for effective function (inhibition of mast cell release) than, for instance, to the work by Clarke et al 3 which showed that theophylline, but not enprofylline, protects against adenosine induced obstruction in asthma (see also references 18 and 21 in the review by Polosa and Holgate1).
If the clinical efficacy of the xanthines in asthma cannot be explained by adenosine antagonism, phosphodiesterase inhibition may offer an alternative explanation but, unfortunately, there are also doubts about this4—hence the widely promoted non-xanthine phosphodiesterase IV inhibitors cannot rely on theophylline for any predictable clinical efficacy. Perhaps both adenosine antagonism and phosphodiesterase inhibition are examples of how theoretically attractive mechanisms may prevent unbiased exploration of truly important in vivo modes of action of anti-asthma drugs.4
Incidentally, enprofylline was discovered by unexpected observations in complex biosystems.4 Such exploratory in vivo work, if allowed, will continue to be a source of novel drugs; when successful, one should not be surprised to learn that the discovered class of drug was not predicted by reductionist research paradigms. The new efficaceous compounds may thus unravel novel mechanisms—for example, omeprazole and the acid pump—or, as with the experimental drug enprofylline, the new properties will seriously question the therapeutic relevance of a widely held mechanism.
authors’ reply We read with interest the letter from Professor Persson but we remain somewhat confused about the point or points he raises. The review we wrote was intended to draw attention to adenosine bronchial provocation as a potential new marker of airway inflammation in asthma, which may be useful both clinically and to assess the action of anti-inflammatory drugs such as topical corticosteroids.1-1 Because it was originally thought that enprofylline was free of A2 receptor antagonist properties it was argued that adverse effects of xanthines operating through this receptor could be avoided.1-2 It was also stated that, because enprofylline did have pharmacological and therapeutic actions in asthma, it was unlikely that adenosine antagonism could be involved. As pointed out in our review, it is now known that there exist two types of adenosine A2 receptor designated A2aand A2b.1-3 1-4 While enprofylline has little or no effect against A2a receptors, it is a selective, albeit weak, antagonist at the A2b receptor—the adenosine receptor subtype found both on canine1-5 and human1-6 1-7 mast cells. Thus, if adenosine is released in pharmacologically active concentrations in asthmatic airways, for which there is good evidence, then enhancement of mast cell mediator release via A2b receptors is a probable scenario. As a consequence, enprofylline could have produced at least some of its therapeutic effect in asthma by inhibiting A2b receptor mediated mast cell releasability. This may or may not have had implications for the clinical efficacy of enprofylline, which is only a weak A2bantagonist, but the A2b receptor does present a potential new therapeutic target for asthma against which new drugs might be developed.1-8
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