Breath of Fresh Air: Feature Articles

In November 1996 the first of a new class of asthma medications became available in the United States, the first entirely new type of asthma therapy in more than 20 years. At that time worldwide experience with the use of these medications — leukotriene [pronounced: lew - ko -TRY - een] blocking drugs — was limited to a few thousand patients. Now, one year later, hundreds of thousands of persons with asthma have been treated with these drugs. What have we learned about their safety and effectiveness?

The first question to be addressed is: what are leukotrienes? In asthmatic reactions of the bronchial tubes, chemicals are released by inflammatory cells and cause swelling of the tubes, constriction of the bronchial muscles, and excess mucus production. The effect of these chemicals is narrowing and swelling of the bronchial tubes, causing the cough, wheezing, chest tightness, and shortness of breath that we recognize as asthma.

Several years ago scientists discovered that one group of chemicals causing these asthmatic effects in the bronchial tubes are the leukotrienes. They are very powerful in their effects; very small amounts cause asthmatic-type reactions that are relatively long lasting. Compared to the better known chemical involved in allergic reactions, histamine, one one-thousandth the amount of leukotrienes brings about the same response in the bronchial tubes. Until last year no medication was available to block the action of these leukotrienes.Then, scientists working at pharmaceutical companies discovered two types of medication that block these leukotrienes. One drug, zileuton (Zyflo®) reduces the amount of leukotriene that the body produces. Another, zafirlukast (Accolate®) [and now montelukast (Singulair®)], blocks the action of leukotrienes before they exert their effects (as antihistamines block the action of histamine). Other leukotriene-blocking medications of these two types will likely become available in the near future.

Leukotrienes are chemicals that cause swelling of the bronchial tubes, constriction of the bronchial muscles, and excess mucus production.

Then, scientists working at pharmaceutical companies discovered two types of medication that block these leukotrienes. One drug, zileuton (Zyflo®) reduces the amount of leukotriene that the body produces. Another, zafirlukast (Accolate®) [and now montelukast (Singulair®)], blocks the action of leukotrienes before they exert their effects (as antihistamines block the action of histamine). Other leukotriene-blocking medications of these two types will likely become available in the near future.

Zyflo®, Accolate®, and Singulair® are leukotriene-blocking medications.

Yes, but how well do these drugs work in treating asthma? For some persons they are highly effective. Asthma symptoms lessen, breathing capacity improves, and the frequency of asthmatic attacks goes down. The advantages of the leukotriene blocking drugs include the following. They have few unpleasant side effects, they are tablets to be swallowed (no coordination of inhaler devices is needed), and they are not corticosteroids ("steroids") and so have none of the potentially harmful effects of steroid tablets.

Zafirlukast is prescribed as one tablet twice daily taken "on an empty stomach." Montelukast is recommended for use once daily at bedtime (without regard to food). Zileuton is to be taken four times a day, with or without food.

Advantages of leukotriene blockers include their few side effects, tablet form, and not being a steroid.

Not everyone with asthma benefits from taking leukotriene blocking medications. Some persons with asthma probably make only relatively small amounts of leukotrienes in their bronchial tubes; other chemicals involved in asthmatic inflammation play a greater role in causing their asthma. Perhaps in as many as 40% of adults with asthma, no improvement derives from taking the leukotriene blocking medications. That is to say, some persons respond to the leukotriene blocking drugs, others do not. At present we have no method to predict who will and who won't be a "responder" -- with one small exception. Persons whose asthma is made worse by taking aspirin or related drugs (the non-steroidal anti-inflammatory drugs such as ibuprofen and naproxen) generally make relatively large amounts of leukotrienes and would be expected to benefit from use of the leukotriene blocking drugs.

Although they have generally been well tolerated, the leukotriene blocking drugs are not without some risk of side effects. Zileuton can cause liver inflammation (in approximately 2-4% of persons), although this reaction is generally mild and resolves when the medication is stopped. Very rare cases of a serious allergic pneumonia and blood vessel inflammation have occurred in persons taking zafirlukast [and montelukast]. Because these medications have only newly become available worldwide, no studies of their long-term effects (over several years) are yet available.

Ultimately, your doctors learn about the effects of new medications in three basic ways. First, they listen to the feedback provided by their patients who have taken these drugs. Second, they conduct or read about research experiments in which the effects of the medications are evaluated and compared to other treatments according to careful scientific protocols. Such research trials are presently being conducted around the world, including at the Asthma Research Center of the Partners Asthma Center.

Third, researchers seek to develop new understandings about how these medications work, in whom, and why. Such basic research is also being conducted by members of the Partners Asthma Center. Without doubt, a year from now we will be able to report a still better understanding of the role of the leukotriene blocking drugs in the treatment of asthma.