|S. E. Wenzel, MD, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colo, described leukotriene modulation as a newly available option for treating asthma. Leukotriene receptor antagonists and 5-lipoxygenase (5-LOX) inhibitors improve pulmonary function in about 50 percent of study patients. However, clinicians need help in selecting that asthma patient expected to benefit from this new class of drugs.|
|Leukotriene biology||Airway inflammatory cells produce leukotrienes via the arachidonic acid (AA) pathway of metabolism starting with cell-membrane phospholipids. One of the key enzymes in the process is 5-LOX which helps convert AA to 5-hydroperoxyeicosatetranoic acid (5-HPETE). Later, metabolism of 5-HPETE results in the formation of three important cysteinyl leukotrienes (LTs): LTC4, LTD4, and LTE4, as well as LTB4. This LT group is capable of inducing hyperresponsiveness, mucus secretion, edema, and eosinophilia -- all seen in asthma.|
|Satisfying Koch's postulates||
Using a modified version of Koch's postulates helps describe
the role of the leukotrienes in clinical asthma. Koch specified
the evidence needed to associate an organism with a given
disease. This approach, supported by research data, links the
leukotrienes with asthma:
|Cysteinyl leukotriene receptor antagonists||
Zafirlukast, pranlukast, and montelukast primarily prevent the
activity of LTD4. To a lesser degree, the drugs also block LTC4
and LTE4 receptors.
Wenzel described the results of a 13-week unpublished placebo-controlled study with zafirlukast given as 20 mg twice daily to very mild asthma patients. There was a significant improvement in pulmonary function (FEV1) and a decrease in symptom scores. Treated patients also used less beta agonist medication and reported fewer nighttime awakenings. Comparative studies with zafirlukast and other leukotriene receptor antagonists are needed to uncover clinically important differences.
By inhibiting the enzyme 5-LOX, zileuton leads to a decrease
in the production of the three cysteinyl leukotrienes and LTB-4.
The latter is a neutrophil and eosinophil chemoattractant, and
cell activator. Zileuton resembles some of the LTD4 receptor
antagonists in producing immediate bronchodilation and in
adding to the effect of beta agonists.
In a 6-month clinical study, zileuton produced a sustained average improvement in FEV1 of 15 to 18 per cent and a decrease in asthma symptom scores. Also, there was a possible additive effect to inhaled glucocorticoids and a marginal improvement in nocturnal asthma (Wenzel; Am Rev Crit Care Med 1995,152:897-905).
|Beyond asthma||Perhaps the leukotriene modulators will prove useful in treating other diseases having prominent inflammation. Wenzel suggests studying pulmonary hypertension, interstitial lung disease, acute respiratory distress syndrome, pulmonary edema, chronic sinusitis, and allergic rhinitis.|
|Identifying the responder||
To date, about 50 percent of asthma patients treated with a leukotriene
modulator responded to treatment using a 12 percent or
more increase in FEV1 as the end-point. How can clinicians
identify that asthma patient expected to respond? No definite
answer is yet available, according to Wenzel.
Leukotriene urinary levels, although decreased in response to treatment, and invasive laboratory tests (bronchial biopsy or BAL) are not practical for routine use. As with many new asthma drugs, the patient uncontrolled with a beta agonist, cromolyn, theophylline, etc may benefit from a leukotriene modulator, but the drug will have to be tried before a decision can be made.
For professional correspondence, please contact Dr. Wenzel at: email@example.com
Presented at the Annual Meeting of the American College of
Allergy, Asthma and Immunology on 8 November 1996
CONRAD NOTES, © January 1997 All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078 / posted 8-Feb-1997