These large increases in PD20 are also unlikely to be accounted for by a placebo effect. We have studied the effects of placebo aerosol on the response to 4.5 percent saline aerosol in 11 subjects on two occasions. The pH of the placebo was 9.0 in one study and 5.5 in the other. We found that for those receiving the placebo with a pH of 9.027 the effect was to make the patient more sensitive to the challenge by saline aerosol (geometric mean ± 95 percent Cl, control PD20 1.97 ml 1.07, 3.61 vs placebo PD20 1.32 ml 0.69, 2.53), although the difference was not statistically significant. In the study where the pH of the placebo was 5.5, the expected benefit of increasing airway surface liquid was achieved (placebo PD20 3.19 ml 1.87, 5.44 control PD20 1.58 ml 1.28, 3.2 p < 0.04). The pH of the sodium cromoglycate we used was 6.1. While the possibility exists that a patient may become negative to hyperosmolar challenge after placebo alone, we have found this only once in a patient who had a PD20 of 15 ml on the control day. Most subjects included in our trials have a PD20 less than 10 ml.
While we cannot be sure of subjective influence, we think that it is unlikely because the subjects were not informed of the possible benefit of the drug and the nature of the protocol we used. This involved a progressive increase in time of exposure to the aerosol, rather than a single exposure to the aerosol. This usually results in a progressive reduction in FEV, and, where this was not the case, another period of exposure to the aerosol was made. For each exposure, an FEV, maneuver was performed on at least two occasions and the highest value was the one used. canadian neightbor pharmacy
The mechanism whereby sodium cromoglycate prevents the airways narrowing in response to hyperosmolarity is not known but it may relate to its capacity to act on chloride ion channels. Romanin et al have shown that sodium cromoglycate blocks Cl” ion channels on mast cells and this may be its action in preventing mediator release in response to hyperosmolarity. It may also block Cl’ channels on nerves preventing the release of neuropeptides. Furosemide, a loop diuretic with the capacity to reduce Cl” movement across cells, is also effective in preventing responses to hyperosmolar saline aerosol and mediator release from human lungs. Furosemide is also effective in preventing the airway narrowing caused by metabisulfite that is thought to stimulate sensory nerves. Nedocromil is very effective at inhibiting the asthmatic response to 4.5 percent saline aerosol and recent evidence shows that it blocks Cl” channels on sensory nerves. A unifying concept is that hyperosmolarity causes the release of mast cell mediators and neuropeptides by stimulating Cl” secretion, and sodium cromoglycate, nedocromil sodium, and furosemide act to block this effect. An effect on ion channels would explain the wide variety of action these drugs are reported to have in many different organs.
If the airway responsiveness to hyperosmolarity does reflect airway inflammation and if sodium cromoglycate does prevent responses by its action on Cl” channels, then it may be that a reduction in the voltage threshold for opening Cl” channels may be a result of the inflammatory process. This may explain why regular treatment with sodium cromoglycate and nedocromil has beneficial effects that are not the same as corticosteroids. Corticosteroids are required to be given in the long term and probably act by reducing inflammatory cell number and increasing the expression of neutral endopeptidase in airway epithelium.
In conclusion, we have shown that sodium cromoglycate when acutely given before challenge with 4.5 percent saline aerosol markedly inhibits airway narrowing, and this effect is additional to the effect of aerosol steroids. These findings suggest that these two drugs have different modes of action. Challenge with hyperosmolar saline aerosol may cause airway narrowing by stimulating Cl” channels and causing the release of mast cell mediators and sensory neuropeptides. The potency of sodium cromoglycate in this model may relate to its ability to block this ion channel.