longterm therapyThe results of the present investigation demonstrate that the use of single standard doses of S and M in combination provide greater protection against the obstructive consequences of isocapnic HV of frigid air more than either drug alone. Within 60 min of administration, M and S individually attenuated between 30% and 54% of the airflow limitation in the control trial, respectively; however, the mixture blunted 82%, indicating an additive effect. Since thermal events, particularly exercise-induced bron-chospasm (EIB), are real-world stimuli that can adversely influence the lives of virtually all patients with asthma information of this type, when appropriately validated, could ultimately prove to be of great clinical value.

(P-adrenergic agonists have been the treatment of choice for EIB for a considerable time. In the last 15 years, the therapeutic benefits of the antileukotriene agents in the treatment of this condition have been recognized. However, there are some subjects who have little response to leukotrienes. The comparative effectiveness of each type of drug was not examined until the past few years. All of the available data to date, including those reported herein, indicate that, on average, both classes of compounds offer statistically similar degrees of prophylaxis. It was not until the work of Coreno and associates, however, that the amounts and duration of treatment required to produce benefits have been addressed. These investigators showed that longterm therapy with leukotriene blockers was not essential and that single doses of either a 5-lipoxygenase inhibitor or a cysteinyl leukotriene 1 receptor antagonist initiated sustained effects. In their study, protection developed within 60 min of ingestion of the available agents, including M, and remained stable for 8 to 12 h. The present findings concur nicely with these results. In addition, Dempsey et al and Hui and Barnes, as also reported in the present investigation, reported that therapy with a mixture of S and M produced greater bronchodilatation than therapy with M alone. Finally, these two drugs have been shown to provide additive protection against other bronchoprovocations. Dempsey et al found that single doses of M and S, when administered together to asthmatic individuals, blunted challenges with adenosine monophosphate more than the individual compounds. New ideas, new thoughts, new investigations and new technologies are overcroweded the web world nowadays. All news that you need at Canadian health care website, these news will help you to find a way out from such a deadlock from which you cannot have found the way for a long time.

Airway hyperresponsivenessThe mechanisms by which M and S work together have not been established. One possibility is that S may change the initiation threshold for airflow limitation to begin and M may alter the biochemical elements that follow signal activation. Besides reducing smooth muscle tone, S also dilates the airway microcirculation. Since it appears that bronchial blood flow is important in the regulation of intrathoracic heat exchange, any such elevations can potentially limit the degree of airway cooling that occurs at a given Ve. As a result, after S administration, a far greater Ve would be needed to produce the critical thermal gradients that induced airflow limitation pretreatment. Based on BAL studies, there is controversy as to whether the airways release leukotrienes in response to thermal stimuli. Direct measurements in airway surface fluid, however, suggest that they do (E.R. McFadden, Jr., MD; unpublished data). To the extent that there is less cooling, the airways may possibly release fewer cysteinyl leukotrienes. These compounds are generated in the epithelium and mediate heightened mucus production, increased vascular permeability, smooth muscle contraction, and the recruitment of inflammatory cells. Many of these activities are believed to be key elements in the pathophysiology of thermally induced asthma, and urinary concentrations of LTE4 have been found to rise in some studies following thermal challeng-es. Thus, the blockade of leukotriene receptor activity may interfere with the development of fundamental components of the reaction. The data in Figure 3 indirectly support this reasoning. S provided protection by changing ventilatory thresholds, suggesting an alteration in an initiating or entry phenomenon, whereas the effect of M developed without influencing this parameter implies a reduction in a sustaining component.

Thermally induced asthmaThe present study was designed to provide pharmacologic proof of concept, and not as a therapeutic trial. Given the heterogeneity of some of the individual responses seen in Figure 2, we appreciate that our relatively small numbers of subjects raise the possibility of unrecognized type 1 and type 2 statistical errors, and that larger comparative investigations will be needed to determine those who will derive maximum benefit. Nonetheless, the current pilot data demonstrate promise. Isocapnic HV was employed because it is a well-established means of simulating the hyperpnea of exercise. Both forms of ventilation produce identical changes in intrathoracic thermal fluxes and bronchial narrowing while sharing similar therapeutic sensitivities. In addition, unlike exercise, HV provides the advantage of being able to examine responsiveness over a range of stimulation without unduly stressing the sub-jects.

Again, because this was not a clinical trial, we chose to simplify our protocol by not using placebo or double-dummy techniques. This decision was unlikely to adversely influence our results because the obstructive response to both exercise and HV over time is known to be highly reproducible with minimal within-subject variability when the critical determinants (VE, and the inspired temperature and water contents) are matched between chal-lenges.

In summary, the combination of standard single doses of M and S appear to provide additive protection against thermal stimuli. It remains to be determined whether such a mixture will provide additional clinical benefits to patients over the single agents. Further studies are also needed to ascertain whether the combination will increase the duration of the protective benefits and/or will blunt the tachyphylaxis that may occur when EIB is treated with S over time.