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Debut of `Right-Handed' Albuterol.

CHICAGO -- As the good book says, "... let not thy left hand know what thy right hand doeth."

The developers of a "right-handed" formulation of albuterol have taken that proverb to heart.

Last spring they launched an albuterol formulation that contains only the right-handed (R) isomer of the compound. The left-handed (S) molecules, which have little [beta]-agonist activity and may be proinflammatory, have been extracted.

In a study involving 362 asthmatic patients, single-isomer albuterol, called 1evalbuterol, was therapeutically equivalent to standard albuterol formulations, which are racemic (50:50) mixtures of R and S isomers but at one-quarter the dose and with fewer side effects.

Marketed by Sepracor Inc. as Xopenex, levalbuterol is approved for treating asthma in patients 12 years and older and is available so far only as a nebulized solution. The drug generated considerable excitement at the annual meeting of the American College of Allergy, Asthma, and Immunology.

"The S isomer of albuterol does not provide any symptom relief, and may cause problems," Dr. Bob Lanier, vice president of the college, said at a press briefing during the meeting.

Most endogenous compounds produced in the body are "pure" single isomers, while most synthetic drugs are racemic mixtures. "We have known for a long time that, physiologically, the isomers behave very differently," explained Dr. Lanier of the University of Texas in Dallas. He is also on the speakers' board of Marlborough, Mass.-based Sepracor.

Some attendees at the ACAAI conference said that levalbuterol will not catch on widely until it becomes available via a metered-dose inhaler (MDI).

Sepracor spokeswoman Jonae Barnes said that the MDI formulation is in phase I and II trials and is expected to launch in 2002. The company also is developing syrup, tablet, and dry-powder inhaler forms of levalbuterol.

Nebulized levalbuterol, at an average wholesale price of $1.98 per unit-dose vial, is intended to be competitive with racemic albuterol products such as Schering's Proventil ($1.71 per vial), Glaxo Weilcome's Ventolin ($1.63), or generic formulations (average $1.21), according to Ms. Barnes.

Levalbuterol is one of many applications of chiral chemistry by Sepracor. The company is working on a host of drugs to develop proprietary "improved chemical entities," or pure single-isomer or active metabolite formulations.

The list--a veritable pharmaceutical hit-parade--includes loratadine (Claritin), astemizole (Hismanal), cetirizine (Zyrtec), fluoxetine (Prozac), doxazosin (Cardura), itraconazole (Sporanox), bupropion (Zyban), amlodipine (Norvasc), and formoterol (Foradil). The latter, which will be a once-daily form of the long-acting [beta]agonist, is in phase II testing. Sepracor projects that the loratadine, astemizole, and cetirizine products will launch in the next 3 years.

Single-isomer drugs have strong support from the Food and Drug Administration, which issued a policy statement in 1992 encouraging their development.

In the case of albuterol, the R isomer "shows a decrease in the movement of intracellular calcium in smooth muscle cells, predisposing the airway to relaxation, whereas S-albuterol increases intracellular calcium... predisposing the airway to hyperreactivity," Dr. Lanier said at 1 of 16 sessions at the meeting that were sponsored by Sepracor.

Bronchial tissue treated with the S isomer is 35% more reactive in terms of histamine-induced bronchospasm than tissue treated with the R isomer, he added.

The initial 33-center levalbuterol trial, led by Dr. Harold Nelson of the National Jewish Medical and Research Center, Denver, included 424 asthmatic patients aged 12 years and up. They were randomized to 4 weeks of thrice-daily nebulizer therapy with placebo, levalbuterol 0.625 mg or 1.25 mg, or racemic albuterol 1.25 mg or 2.5 mg.

The doses were selected to facilitate comparison between single-isomer and racemic albuterol. The racemic form is a 50:50 mixture, so 1.25 mg of racemic contains 0.625 mg of R isomer; 2.5 mg of racemic contains 1.25 mg of R isomer.

All patients underwent a 1-week placebo washout to establish baseline asthma symptom measurements; 362 patients finished the trial.

At 4 weeks, improvements in [FEV.sub.1] were similar for 0.625-mg levalbuterol and 2.5mg racemic albuterol; both gave an [FEV.sub.1] increase of just under 35%.

Nearly 17% of patients on levalbuterol 0.625 mg had side effects, compared with 27% of those on racemic albuterol 2.5 mg and 18.7% of those on placebo. Nervousness was reported by 2.8% of levalbuterol 0.625-mg patients and by 8.1% of those on racemic 2.5 mg. None of those on low-dose levalbuterol had tremors, compared with 2,7% of those on the equivalent racemic mixture.

Tachycardia occurred with equal frequency, at just under 3%, in the low-dose levalbuterol and the high-dose racemic groups. Headache was slightly more common (4.2% versus 2.7%) with the low-dose levalbuterol.

Levalbuterol 1.25 mg yielded the greatest increase in [FEV.sub.1] (mean of 36%) but also had the highest incidence of adverse effects (31.5%). Side effects were mild for the majority in all groups, Dr. Nelson and his associates reported (J. Allergy Clin. Immunol. 102[6, pt. 1]:943-52, 1998)

Levalbuterol is not approved for pediatric use, but studies in children have begun, Dr. Lanier said. In one recent trial involving 33 asthmatic children, levalbuterol 0.625 mg and 0.31 mg were comparable with racemic albuterol 1.25 mg and 2.5 mg in the ability to increase [FEV.sub.1]. There were no major differences in side effects between single-isomer and racemic albuterol (J. Allergy Clin. Immunol. 103[4]:615-21, 1999).
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Publication:Family Practice News
Article Type:Brief Article
Date:Jan 1, 2000
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