Schwartz: Could you comment on a sort of anecdotal impression I had. You mentioned a comparison of antihistamines and lipoxygenase (LO) antagonists or inhibitors. My impression is that the efficacy of the LO inhibition drugs increases with severity of asthma, whereas the efficacy of antihistamine therapy decreases with severity of asthma. Is that your impression?
Grant: My impression is as anecdoctal as yours. We occasionally get a patient who needs antihistamines. We put them on cetirizine and they respond, but that has little relevance. To my knowledge there have been no studies done with antihistamines in patients with more severe asthma. When Chris Nicodemus was designing the study that I reported, the FDA told him he couldn’t use more severe patients, he had to use mild asthmatics. So that was a direct requirement, and I think that some of the LO inhibition drug studies were done in more severe patients and maybe that’s why they found a wider profile of responses.
Lichtenstein: I think there is a tremendous potential for using the antihistamines with the leukotriene antagonists. As far as I know there is only one study done by, I believe, John Warren in the UK, showing really excellent synergism.
Busse: There were some in vitro studies done by Sven E. Dahlen a number of years ago showing both the in vitro antihistamines and leukotriene inhibitors on airway smooth mast cells, and again the additive effect was very effective. But, as you indicated, I don’t think the clinical trials have been done.
Grant: I think that would be a wonderful idea. Getting funding for these studies is still difficult.
Busse: The antihistamines are not effective in reducing airways smooth muscle tone, at least in vitro. Could you speculate as to what its mode of action could be, particularly in the study by Sheldon Spector showing an almost 10% improvement in FEV1 in about 4 hours. What could be the mechanism? I’d appreciate Alkis Togias’ comments in this regard also.
Grant: I think it would be pure speculation. We do have some data that cetirizine is a more potent drug than the others. And it could be that there is some reversal of histamine and then perhaps it’s either due to effects on the nose or to the turning off of some inflammatory mechanism that’s taking place in asthma.
Togias: There are quite convincing recent data from Brad Undem’s laboratory that antihistamines are indeed very effective in reducing intrinsic smooth muscle tone in human airways, as effective as a leukotriene antagonist, and there is a paper that he and his group have published recently on that. I believe that primarily the effects that Sheldon Spector published are related to a direct bronchodilatory effect. In the clinical studies, the effect may have something to do with circulating histamine, for example.
Grant: Do you think that the acute effects are due to H1 antagonism on the smooth muscle cell?
Togias: That’s what Brad Undem has shown quite convincingly.
Platts-Mills: If there’s a nasal bronchial reflex, and perhaps for a whole relationship between the nose and the lungs, do you think there is any evidence of patients who have severe nasal disease where it’s having an effect on a normal lung? Is this always patients who have nasal disease and who have indeed got inflammatory disease of the lung, and the nose is triggering an already inflamed and hyper-reactive lung?
Grant: I would suspect that there are changes throughout the airways and that in some patients the nose is worse; with high antigen challenge there is a carry over to the lungs, and with the viral infection there is an activation of this. I think there is a continuum, and that virtually all possibilities could be seen clinically.
Platts-Mills: Are there any studies where someone has shown a nasal effect either by putting balloons in an ancillary sinus when the lung itself is not inflamed?
Grant: Yes, there are studies of that sort. Changes in the nose can directly affect the lungs. We reviewed the nasal allergen challenge model in which the allergen is thought to be just in the nose, and this increases methacholine response.
Platts-Mills: Did they have biopsy or lavage evidence that the lung was uninflamed?
Schwartz: Just a comment: histamine can lower the threshold for stimulating nerves in the airway. That could fit better with the delayed time course of bronchodilatation if there was some effect on the neurogenic control of airway tone.
Togias: To respond to Tom’s question. There are two interesting observations: first the nasobronchial reflex, which, in the past, has been a very debatable issue, has been quite well demonstrated in a number of recent studies. In the study by Fontanari normal volunteers were challenged with cold air in the nose. In that study, there were changes in airway resistance which were then blocked by prior treatment with lidocaine in the nose. That’s quite convincing that a nasobronchial reflex exists in humans. As for the issue whether there could be effects on a non-inflamed lung, there is an interesting, very provocative, study by Aubier showing that in rhinitics who have no asthma symptoms but have methacholine reactivity, nasal corticosteroids were more effective than inhaled corticosteroids in reducing that lower airway reactivity. I believe there was an Italian group that didn’t manage to reproduce these findings. But that is the only study that has been published.
Grant: But aren’t there about three reports of nasal steroids that have improved asthma?
Rihoux: A last comment about the anti-allergic effect of the H1antihistamines. Some H1antihistamines were shown to block histamine release from mast cells. It’s not the case with cetirizine, but it’s the case for cromoglycate to inhibit also. What is interesting is that cromoglycate does not penetrate into the membranes and this was also demonstrated for cetirizine. So some H1 blockers, importantly, accumulate into the membranes and via such accumulation it’s possible to induce many different effects and also the blockade of histamine release, the blockade of the methylation of phospholipids and so on. It’s difficult to define precisely the limits between toxicity and pharmacological activity. So I think that the important point is to find new drugs that don’t accumulate into the cells, don’t induce any disturbances in the phospholipids and are effective.