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1 University of Alabama Lung Health Center, University of Alabama at Birmingham, Birmingham, Alabama; and 2 David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California
Correspondence and requests for reprints should be addressed to William C. Bailey, M.D., UAB Lung Health Center, 620 South 20th Street, Suite NHB 104, Birmingham, AL 35249–7337. E-mail: wcbailey{at}uab.edu
ABSTRACT
Chronic obstructive pulmonary disease (COPD) is increasing in the United States and throughout the world. There have been a number of advances in the treatment of this disease within the last several decades, and these improved therapies continue to become available, making the prospects for the future encouraging. Bronchodilation is the treatment of choice, and we point out in this article the potential availability of many new bronchodilators. There will be several options in the ß2-agonist and the anticholinergic categories for once-a-day preparations. There will also be a number of products combining these categories of bronchodilators and inhaled steroids, and the combination products will be available in once-a-day preparations. Also under development are several candidates for specific and effective antiinflammatory agents in COPD. It is likely that our ability to control the inflammation underlying COPD will be a reality in the future. Although many new cases of COPD are being diagnosed in former smokers, for patients who smoke, the most important treatment is smoking cessation. A number of new drugs are available, and more will be brought to market in the future. We have highlighted the details of this important area.
Key Words: chronic obstructive pulmonary disease • bronchodilators • therapy • antiinflammatory agents • smoking cessation
This article covers drugs for chronic obstructive pulmonary disease (COPD) not presented elsewhere in this issue, with particular emphasis on drugs under development and those likely to become important. There is no longer reason for therapeutic nihilism. We believe that the products discussed in this section point toward a much brighter future for the treatment of COPD. The first section focuses on new drugs for smoking cessation. These products have become progressively more effective. Even though many new diagnoses of COPD are being made in former smokers, smoking cessation is the most important treatment for patients with COPD who smoke.
The next section on new bronchodilators offers real hope. Once-a-day preparations are likely for all the inhaled medications, and it is just a matter of time before the various combinations are available in once-a-day formulations. Phosphodiesterase-4 (PDE-4) inhibitors will probably be available within a year. They are the first class of medications likely to inhibit neutrophilic inflammation in the airways.
Antioxidants are another category of agents for which there is at least a good theoretical basis for their functional effectiveness. Anti–tumor necrosis factor-
(anti–TNF-) is one of the first monoclonal antibodies to be tested in COPD, and the progress in this area is covered. Finally, retinoids are mentioned as a possible approach, but the clinical trials have not been encouraging.
NEW PHARMACOLOGIC AIDS FOR SMOKING CESSATION
The vast majority of COPD cases are attributable to tobacco smoking, and smoking cessation has been shown to be the most effective method of slowing the progression of COPD (1, 2). Although 35% of cigarette smokers attempt to quit each year, only a small percentage succeed in quitting and remaining abstinent (3). Commonly used smoking cessation strategies include physician advice, telephone quit-lines, and face-to-face individual and group counseling (which are aimed at behavior modification), and pharmacotherapy. Effective pharmacotherapy for smoking cessation became available in the mid-1980s with the introduction of nicotine replacement therapy (NRT), initially as nicotine gum and subsequently in a variety of other forms (Table 1).
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Ten years ago, the first non–nicotine-containing pharmacologic agent (bupropion) with proven efficacy in facilitating smoking cessation was introduced. The mechanism of action of bupropion is unclear, but it is believed to act by inhibiting reuptake of dopamine and norepinephrine, thereby reducing craving and withdrawal symptoms (4). NRT seems to be only approximately twice as effective as placebo in achieving abstinence from smoking at 6 months (5), with some additional relapse to smoking between 6 and 12 months. Bupropion yields results similar to those of NRT, although there is a suggestion of an additive effect of bupropion and NRT (6). Bupropion has also been shown to be effective in achieving higher smoking cessation rates than placebo in a study of smokers with COPD (7), who are believed to represent a subgroup of smokers who encounter greater difficulties in quitting and remaining abstinent than smokers without this tobacco-related disease. Nonetheless, the benefits of pharmacotherapy are limited, with average 6-month abstinence rates of only 20 to 30%; therefore, there is a need for more effective pharmacologic aids to smoking cessation.
The most recently approved drug for smoking cessation is varenicline, a partial agonist-antagonist that is highly selective for the predominant brain nicotinic acetylcholine receptor 4ß2 subtype that is responsible for mediating the reinforcing effects of nicotine. Binding of nicotine to this receptor in the ventral tegmental area is believed to cause the release of dopamine at the nucleus accumbens, which is responsible for the satisfaction and "reward" derived from smoking. Because varenicline is a partial agonist/antagonist, it may relieve nicotine craving and withdrawal symptoms due to its agonist properties. Because of its receptor antagonism, varenicline may reduce the psychogenic reward associated with smoking in patients who relapse. In a multicenter, double-blind, randomized controlled trial of varenicline 1 mg twice daily, bupropion 150 mg twice daily, or placebo administered for 12 weeks in 1,025 smokers followed for up to 52 weeks, 44.0% of the varenicline subjects were continuously abstinent from smoking for the last 4 weeks of the 12-week treatment period, compared with 29.5 and 17.7% for the subjects receiving bupropion and placebo, respectively (8). The differences from placebo and bupropion were highly significant (p < 0.001) and correspond to a 3.85 and 1.93 greater odds of achieving continuous abstinence during this period than placebo and bupropion, respectively. Approximately half of the subjects in each treatment group who were continuously abstinent from 9 to 12 weeks relapsed to smoking during the post-treatment period of 12 to 52 weeks, although the differences in the proportions of subjects who remained abstinent through 52 weeks were essentially the same as those who achieved continuous abstinence during the period of active treatment. Thus, at 52 weeks, 21.9, 16.1, and 8.4% of subjects in the varenicline, bupropion, and placebo groups, respectively, maintained continuous abstinence.
Similar results were obtained in a companion study of 1,027 smokers (9). In another trial in which smokers who achieved continuous abstinence during 12 weeks of therapy with varenicline, extension of varenicline therapy for an additional 12 weeks resulted in greater sustained abstinence rates through 52 weeks compared with placebo (43.6 vs. 36.9%, respectively), suggesting an added benefit of 24 weeks over 12 weeks of therapy, at least among subjects who achieve continuous abstinence during the initial 12 weeks of treatment (10). Although the incidence of adverse events in these studies was similar across treatment groups, nausea occurred more often in the varenicline group (28.1%) compared with the bupropion and placebo groups (12.5 and 8.4%, respectively) and was the commonest varenicline-related adverse event (8).
Varenicline represents a new class of smoking-cessation drug with a different mechanism of action from NRT or bupropion. However, as pointed out by Klesges and colleagues (11), it is not a panacea for smoking cessation because most of the patients in the varenicline trials remained smokers at 1 year. Moreover, many subjects experienced adverse events, discontinued the study medication, and withdrew prematurely from the studies. Therefore, additional research is needed to improve on current strategies to achieve lasting smoking cessation, including newer approaches to behavioral therapy and newer and more effective pharmacologic aids.
A promising new area of smoking cessation research involves the development of nicotine vaccines that generate nicotine-specific antibodies. These antibodies bind to free nicotine (derived from cigarette smoke) in the circulation, creating an antigen–antibody complex that is too large to cross the blood–brain barrier. As a result, nicotine from cigarette smoke is prevented from reaching receptors in the brain that mediate smoking satisfaction, thereby reducing nicotine absorption by the brain and the associated addictive potential. One nicotine vaccine is already in phase IIb clinical trials.
NEW BRONCHODILATORS
Long-Acting ß-Agonists
A number of new, long-acting ß2-agonists are in various stages of development. Formoterol and salmeterol have been available for some time. They are generally considered safe and effective, although some questions have been raised about the possibility of infrequent side affects leading to death in postmarketing studies subject to effects of confounders that were not adequately controlled for in the studies available. Both of these drugs are effective for 12 hours and are discussed elsewhere in this issue. Newer agents on the horizon are as follows:
Arformoterol (R,R-formoterol) is a single-isomer version of racemic formoterol. It has been developed by Sepracor and was recently approved by the U.S. Food and Drug Administration for use as a nebulized solution. It will probably be available in the marketplace in early 2007. It is a safe and effective bronchodilator that is characterized by a rapid onset of bronchodilation. Although the duration of its major effect is less than 24 hours, patients receiving the higher dose in phase III studies showed improvements of FEV1 of 15% after 24 hours (12). This drug will fill a niche for patients who need a nebulized, long-acting ß2-agonist. It will generally be used twice a day, although there may be certain situations for which once-a-day treatment will be appropriate.
Arformoterol has been shown to reduce IL-8 production from small airways epithelial cells stimulated by various antigens (13). Whether this action will result in an antiinflammatory effect that is clinically meaningful is unclear.
Carmoterol is a long-acting (24 h or longer) ß2-agonist. It is a pure (R,R) isomer that is highly potent and selective for the ß2 versus the ß1 receptor. It has a rapid onset of action and a high potency for the ß2 receptor. Carmoterol is licensed to Chiesi from Tanabe Seiyaku. Plans are for the drug to be administered in a single daily dose via the inhaled route. Dose-escalating studies range from 0.8 to 12.8 µg. Early results from clinical trials show excellent safety and efficacy. There is a greater than 24-hour duration of effect at the 3-µg dose (14). Other studies have shown sustained improvement in the FEV1 up to 30 hours (15). There seems to be a positive interaction between budesonide and carmoterol that may justify the development of a new fixed-dose combination.
Indacaterol is a 24-hour ß-agonist being developed by Novartis (16). It is characterized by a rapid onset and 24-hour duration of action. The molecular structure is similar to that of carmoterol. Indacaterol has shown an excellent safety profile in single daily doses from 50 to 600 µg, and the clinical efficacy was dose dependent. Phase III studies are underway, and this drug will probably be available as monotherapy and as a component of several possible combination products.
Several other long-acting ß-agonists are under development through the collaborative efforts of GlaxoSmithKline (GSK) and Theravance. One such agent, GSK-159797, is known to have excellent efficacy throughout a 24-hour evaluation period and was well tolerated with no increase in heart rate (15). There is a strong possibility that this drug will be combined with GSK-685698, which is a new long-acting inhaled corticosteroid, although limited details are available. Several other long-acting ß-agonists are under development through the GSK-Theravance collaborative effort. These include GSK-597901, GSK-159802, GSK-642444, and GSK-678007.
Other once-daily ß-agonists under development include several long-chain formoterol analogs with variations in the terminal ether residue and several other novel molecular structures. All seem to have a long-acting effect.
Two anticholinergic drugs are available: ipratropium, a bronchodilator effective for 6 hours, and tiotropium, a safe and effective 24-hour agent. These agents and the general pharmacology of anticholinergic bronchodilators are well described in the article on bronchodilators elsewhere in this symposium (17).
Several additional anticholinergic drugs are in development stages, including Novartis (NVA 237) (glycopyrrolate), OrM3, LAS-34273, LAS-35201, TD-5742, GSK-656398, and GSK-233705. The only drug in this group with sufficient data in human subjects to justify discussion is NVA 237. This drug was developed by Arakis and Vectura, two U.K. companies. Novartis has a global license for the compound and plans to use this agent as monotherapy and perhaps as combination therapy with the once-daily ß-agonist indacaterol. NVA 237 is an antimuscarinic bronchodilator that was developed for the treatment of COPD. NVA 237 has a high affinity for the muscarinic receptors (M1 and M3). This affinity, together with slow disassociation from the M3 receptor, provides for long duration of bronchodilator activity in patients with COPD.
Studies have shown that this agent provides early and sustained 24-hour bronchodilation in patients with moderate COPD in doses ranging from 125 to 480 µg. No clinically significant safety problems in this dose range have emerged. This anticholinergic agent produced comparable bronchodilation to that of albuterol over the first 40 minutes postdose. In single doses of 480 µg, sustained bronchodilation has been noted for 32 hours postdose (18, 19).
The only combination therapy available in the United States is Advair (fluticasone/salmeterol) in three dosage forms. This combination of a long-acting ß-agonist and an inhaled steroid has been shown to be safe and effective for selected patients with asthma and COPD. Another product approved in the United States but not available commercially is Symbicort, which is a combination of formoterol and budesonide. This combination agent is widely available and popular in Europe and Canada and is expected to be available in the United States in early 2007. The only combination anticholinergic/beta agonist available in the United States is Combivent (ipratropium/albuterol). Many of the long-acting agents had been used together but with separate dosing for some time; combination products of these agents are inevitable.
Few data in humans have been reported on the combination products not already available, but several combinations are known to be under development. Plans are being made for several more ß2-agonists to be combined with inhaled steroids. These include carmoterol and budesonide, which may be particularly effective based on animal model evidence of a positive interaction between these two agents in the control of bronchoconstriction induced by acetaldehyde (20).
One proposed combination ß2-agonist/inhaled steroid is that of GSK-159797 and GSK-685698 (a long-acting inhaled steroid). This will be a once-a-day preparation if it is successfully brought to market. Another proposed new combination in this class is indacaterol, from Novartis, combined with mometasone, a Schering Plough product. This combination agent also will be a once-daily preparation and is proposed to be delivered via the Twisthaler device, a multidose dry powder inhaler.
Several proposed combination products using long-acting ß-agonists and long-acting anticholinergics are being developed. The combination of carmoterol, a long-acting ß-agonist, and tiotropium is under consideration and will be available as a once-daily dose. This combination includes one drug in the intermediate stages of approval and one drug that is already approved.
Another similar combination by Novartis is indacaterol and NVA 237. Neither of these drugs has been approved, but both look promising. Once-a-day dosing is planned. Finally, the combination of GSK-159797 (a long-acting ß-agonist) and GSK-233705 (a long-acting anticholinergic) is under consideration. Neither of these drugs has been approved, and neither is far along in clinical development. Once-a-day dosing is expected.
PDE-4 is the predominant PDE isoenzyme that is expressed in a variety of inflammatory cells, including neutrophils, CD4 and CD8 lymphocytes, monocytes, and macrophages, in which it hydrolyzes cAMP, leading to elevations of cAMP and impairing the inflammatory activity of these cells (21). Therefore, it is a potentially useful target in COPD, in which these inflammatory cells are believed to play an important pathogenetic role. Selective PDE-4 inhibitors have been developed and have been found to possess an antiinflammatory effect in animal models (22, 23). These agents have been investigated in clinical trials for COPD and asthma, but their clinical development has been hampered by side effects, particularly nausea, emesis, and abdominal pain, that have limited the dose that can be administered. Therefore, their potential efficacy is questionable.
Two selective PDE-4 inhibitors, cilomilast and roflumilast, are in phase III clinical trials. A 12-week, placebo-controlled study of the antiinflammatory and physiologic effects of cilomilast was conducted in 59 patients with COPD (mean FEV1: 58.2 and 53.9% predicted in cilomilast and placebo patients, respectively) who underwent bronchial biopsies at baseline and Week 10 and serial lung function testing (24). By the end of the 12-week study, mean FEV1 in the placebo group fell from baseline by 10 ± 0.03 ml (SEM), whereas it rose by 60 ± 0.04 ml (SEM) in the cilomilast group, a difference of 70 ml that did not reach statistical significance in this small-scale study. Cilomilast was also associated with significant reductions compared with placebo in subepithelial CD4+ (42%; p = 0.025), CD8+ (48%; p = 0.004), and CD68+ (55%; p < 0.001) cells and with subepithelial neutrophils (37%; p = 0.049), but it had no effect on the numbers of epithelial neutrophils or on IL-8 mRNA+ or TNF- mRNA+ cells. More cilomilast than placebo patients complained of diarrhea and nausea, but the differences in this small study were not statistically significant. These findings indicate that cilomilast has the capability of reducing airway tissue inflammatory cells found in COPD, but this antiinflammatory effect seems to be associated with only modest benefits with respect to lung function change.
In a recently published 24-week, randomized, double-blind trial of cilomilast (15 mg twice daily) versus placebo in 647 patients with COPD (mean FEV1, 47% predicted), cilomilast resulted in a stable FEV1 (
10 ml improvement) over the course of the study, whereas placebo led to a decline in FEV1 of approximately 70 ml. The treatment difference between cilomilast and placebo (80 ml) was modest but statistically significant (p < 0.001) (25). Cilomilast-treated patients also experienced significantly more improvement in dyspnea after standardized exercise testing than placebo patients (Borg scale difference after six-minute-walk test, 0.24; p < 0.03), greater freedom from acute exacerbations (74 vs. 62%, respectively; p = 0.008), and a greater improvement in disease-specific quality of life (clinically meaningful difference in St. George Respiratory Questionnaire [SGRQ] total score of 4.1 U; p < 0.001). On the other hand, a higher proportion of subjects receiving cilomilast (49%) experienced gastrointestinal side effects (diarrhea, nausea, and abdominal pain) compared with those receiving placebo (25%), although most of these events were mild to moderate.
Cilomilast is believed to be somewhat selective for the D subtype of PDE-4, which is predominantly expressed in cells in the brain stem that mediate nausea and emesis and is less well expressed in inflammatory cells (26). In contrast, rolumilast is nonselective for PDE-4 isoenzyme subtypes D and B (B is more important than D in inflammatory cells) (27,28) and therefore has a more favorable therapeutic/side-effect ratio than cilomilast. Roflumilast in two doses (250 and 500 µg once daily) was compared with placebo in a 24-week randomized, double-blind trial conducted in 1,411 patients with COPD (mean FEV1, 50–51% predicted) (29). At the end of the trial, patients receiving roflumilast in the 250-µg and 500-µg doses showed significant improvements in FEV1 (74 ± 18 [SD] ml and 97 ± 18 ml, respectively) compared with those receiving placebo (p < 0.001) and numerically but not statistically greater improvements in quality of life (–3.4 and –3.5 units, respectively) than with placebo (–1.8 units). The mean number of moderate and severe exacerbations per patient (a coprimary endpoint) was low and not different between groups.
In summary, the results of clinical trials with cilomilast and roflumilast show only relatively modest efficacy with respect to improvement in FEV1, with variable effects on patient-centered outcomes and with some decrease in inflammatory cells in the airways. These beneficial effects must be weighed against the relatively high incidence of gastrointestinal side effects. Future studies should be directed toward developing and testing newer PDE-4 inhibitors that have more antiinflammatory activity and less gastrointestinal toxicity. Such newer agents could include drugs selective for the B subtype of PDE-4 inhibitors that do not cross the blood–brain barrier and thus can be given in higher and more effective but still tolerable doses, and agents that are effective by inhalation with low oral bioavailability.
Another category of novel agents includes the antioxidants. Because oxidative stress plays an important role in the pathogenesis of COPD (30, 31), it is possible that antioxidants, such as N-acetylcysteine (NAC; which provides cysteine for increased production of the antioxidant glutathione), may have a beneficial effect in COPD by reducing oxidative stress (32). The latter possibility has been supported by meta-analyses and retrospective analyses of the results of several older trials that showed that long-term therapy with oral NAC was associated with a significant (22–29%) reduction in acute exacerbations of chronic bronchitis or COPD or in readmission to the hospital for COPD (33–36).
To further explore this possibility, a large-scale, multicenter, rigorously designed, prospective, 3-year, randomized, placebo-controlled trial of oral NAC (BRONCUS [Bronchitis Randomized on NAC Cost-Utility Study]) was recently conducted to assess the effects of NAC on COPD progression and exacerbation frequency (37). In this trial, 523 patients with moderate to severe COPD (mean FEV1, 57% predicted) were randomized to receive 600 mg/day oral NAC or placebo. Patients were followed for 3 years with serial spirometry and clinical assessments. Because of the large number of patients in the study who were receiving inhaled corticosteroids (ICS), patients were randomly stratified on study entry according to their ICS use. Results indicated that the course of COPD (as defined by the annual rate of decline in FEV1) did not differ between the NAC and placebo groups (54 ± 6 [SEM] vs. 47 ± 6 [SEM] ml, respectively; difference in slopes 8 ± 9 ml; 95% confidence interval, –25 to 10). No significant difference between the two groups was noted in the number of exacerbations per year (1.25 ± 1.35 vs. 1.29 ± 146; p = 0.85) or in health-related quality of life. Subgroup analysis showed a significantly lower exacerbation rate in the subset of patients not receiving ICS who were treated with NAC (relative risk, 0.78; 95% confidence interval, 0.63–0.99; p = 0.04), suggesting a possible benefit of NAC on this important outcome that was independent of, but not additive to, the benefit of ICS. NAC was associated with a significant decline in hyperinflation (reduction in functional residual capacity of 374 ml), which was not seen in the placebo group. Few adverse effects were noted. Because NAC was well tolerated and some beneficial effects were noted, the authors concluded that higher doses of NAC (1,200 or 1,800 mg) should be studied in future trials.
TNF- inhibitors are another area of investigation. TNF-, a proinflammatory cytokine that induces IL-8 and other chemokines in airway cells, is believed to play a role in the pathobiology of COPD, particularly because TNF- has been found to be elevated in the sputum, bronchoalveolar lavage fluid, and peripheral blood (38, 39) of patients with COPD. TNF- has also been incriminated in the severe wasting of some patients with advanced COPD through an effect on skeletal muscle apoptosis (39). It has been hypothesized, therefore, that the humanized monoclonal TNF antibody (infliximab), which is effective in other inflammatory diseases such as rheumatoid arthritis, might also be effective in COPD. A randomized, controlled trial of anti–TNF- monoclonal antibody (infliximab) therapy was recently completed in 234 patients with moderate to severe COPD who were allocated to receive inflixamab in one of two doses (3 or 5 mg/kg) or placebo and followed for 24 months with serial spirometry, questionnaires, and 6-minute walk tests and for an additional 20 weeks to evaluate safety parameters (40). No beneficial effect of either dose of infliximab (or of both doses pooled) compared with placebo was noted on the course of FEV1, health-related quality of life (Chronic Respiratory Questionnaire), or exercise performance. These findings suggest that inhibiting the action of single cytokine targets might not be an effective strategy in a disease with the pathogenetic complexity of COPD.
Retinoids, such as vitamin A and all-trans-retinoic acid (ATRA), activate genes involved in lung development and promote alveolarization and growth in the pre- and postnatal periods (41, 42). A decade ago, while studying mature rats, Massaro and Massaro reported that systemic administration of ATRA reversed morphometric and physiologic evidence of emphysema induced by elastase (43), presumably by up-regulating retinoic acid receptors and stimulating the growth and development of regenerative alveolar tissue. Similar results in a rodent model were subsequently reported by another group with ATRA and 9-cis-retinoic acid (44).
Retinoic acid has been shown to suppress the expression of collagenases and proteases, to stimulate tissue inhibitors of metalloproteinases, to increase elastic/collagen gene expression, to stimulate secretion of surfactant proteins, and to promote angiogenesis. Because of the implications of these findings for the treatment of human emphysema and the differences between the elastase-induced animal model of emphysema and human emphysema, controlled clinical trials have been carried out to examine the effects of retinoids in smoking-related emphysema.
The first of these human studies was a pilot randomized, double-blind, placebo-controlled, crossover trial of ATRA in 20 patients with severe smoking-related emphysema who were treated for 3 months with ATRA (50 mg/m2/d) or placebo and then crossed over to receive the alternate treatment for the next 3 months (45). Although the treatment was well tolerated and associated with only mild side effects (transient headaches, hyperlipidemia, transaminase elevations, and musculoskeletal complaints), serial physiologic (FEV1, lung volumes, static lung compliance, and diffusing capacity) and thoracic high-resolution computed tomography (CT) measurements did not change appreciably in response to treatment, although a trend toward improvement in health-related quality of life (SGRQ scores) were noted 3 months after treatment, implying a possible delayed effect. The lack of apparent efficacy could have been due to the short duration of treatment and difficulty in maintaining stable plasma levels of ATRA due to the fact that ATRA induces its own oxidative catabolism, leading to pronounced reductions in plasma concentrations.
As a follow-up to the latter study, the NIH-funded FORTE (Feasibility of Retinoid Therapy for Emphysema) trial was carried out. For the FORTE trial, 300 patients with moderate to severe emphysema (mean FEV1, 42.5% predicted; diffusing capacity of carbon monoxide [DLCO], 37% predicted; total lung capacity, 118% predicted) were enrolled and randomized in double-blind fashion to receive low- or high-dose ATRA (1 mg/kg/d or 2 mg/kg/d, respectively), cis-retinoic acid, or placebo for 6 months (46). No overall effects of any of the retinoic acid agents were noted on lung function or high-resolution CT imaging, except for dose-, drug-, and time-dependent changes in DLCO (early decline and later recovery), consistent with drug toxicity or early remodeling. A delayed improvement in SGRQ was also noted in the high-dose ATRA group; moreover, a delayed improvement in CT measures was observed in a subset of the high-dose ATRA group, which exhibited the highest ATRA blood levels. These preliminary findings suggest some biological activity of retinoic acid agents that warrant further study. Such studies could be longer term; enroll patients with less severe disease; and use high-dose ATRA, liposomal ATRA (novel synthetic retinoid derivatives with better pharmacokinetics), or the combination of ATRA with a stem cell–mobilizing agent.
CONCLUSIONS
There are new drugs to come, many of which will be effective, and our treatment of COPD will improve over the next decade. A good chance exists that we will be able to substantially affect the specific inflammatory components of COPD with one or more of the products discussed in this article. We no longer have an excuse for not aggressively approaching smoking cessation in any of our patients with COPD who smoke. There are a number of products that work, and there are more to come. Combining these products with the appropriate behavioral approaches will lead to success in many cases.
Before the end of the decade, many bronchodilators should be available for once-a-day dosing. They are likely to be safe and effective. Their widespread and appropriate use will depend primarily on product cost and on the diffusion of knowledge to the primary care community. As disease severity increases, requiring more than one bronchodilator and/or the addition of inhaled steroids to one or two bronchodilators, there is good reason to suspect that a single inhaler combining these ingredients will be available for any recommended combination.
Finally, there is at least a hope that lung regeneration can be accomplished. Although we do not know if retinoids will do this, the animal studies with them show that this is at least theoretically possible.
FOOTNOTES
Conflict of Interest Statement: W.C.B. has been reimbursed by Boehringer-Ingelheim, GlaxoSmithKline, and Pfizer for attending several meetings. His organization does several pharmaceutical research projects for several pharmaceutical companies. He has participated as a speaker in scientific meetings or courses organized and financed by various pharmaceutical companies (GlaxoSmithKline, Boehringer-Ingelheim, AstraZeneca, etc.). He has a research grant for participation in a multicenter clinical trial. D.P.T. has served as a consultant for Boehringer-Ingelheim ($2,400 in 2004; $2,400 in 2005, and $1,200 in 2006), Schering-Plough (no payment), and Dey Laboratories ($2,500 in 2006). He served on an Advisory Board for AstraZeneca ($1,500 in 2004, 2005, and 2006). He has received lecture fees from Boehringer-Ingelheim ($7,500 in 2004, $6,000 in 2006, and $4,000 in 2006) and Pfizer ($3,000 in 2004, $3,000 in 2005, and $1,500 in 2006) and has received through the Regents of the University of California multicenter research grants during the period 2003–2006 in the following amounts: $138,000 from Boehringer-Ingelheim, $27,000 from Schering-Plough, $17,000 from Dey Laboratories, $42,000 from Astra-Zeneca, and $25,000 from GlaxoSmithKline.
(Received in original form January 16, 2007; accepted in final form February 28, 2007)
REFERENCES
4ß2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 2006;296:56–63.This article has been cited by other articles:
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