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Conrad Notes
a timely medical meeting newsletter
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:

  • Leukotrienes can induce changes seen in asthma.

  • Leukotrienes are found in relevant body tissues and fluids.

  • Leukotriene levels correspond to the symptoms, patho- physiology, or inflammation associated with asthma.

  • Specific inhibitors or antagonists inhibit the clinical response or inflammation seen in 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Wenzel described the results of a 13-week unpublished placebo-controlled study with zafirlukast given as 20 mg twice daily to very mild asthma patients.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.

5-LOX inhibition 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: wenzels@njc.org

Eugene A. Conrad

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

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