tiotropium-bromide and Lung-Diseases--Obstructive

Tiotropium bromide is a new long-lasting anticholinergic drug which, like ipratropium bromide, is a quaternary ammonium derivative. It binds with high affinity to muscarinic receptors but dissociates very slowly from M(1)- and M(3)-muscarinic receptors. Pharmacology studies have demonstrated a prolonged protective effect against cholinergic agonists and cholinergic nerve stimulation in animal and human airways. In Phase II studies single inhaled doses of tiotropium bromide have a bronchodilator and bronchoprotective effect in asthmatic and chronic obstructive pulmonary disease (COPD) patients of over 24 h. In Phase III studies, once daily inhaled tiotropium is an effective bronchodilator in COPD patients, giving great improvement in lung function and reduction in symptoms than ipratropium bromide given four times daily. The drug is well-tolerated and the only side effect of note is dryness of the mouth which occurs in approximately 10% of patients. Since, anticholinergics are the bronchodilators of choice in COPD it is likely that tiotropium bromide will become the most widely used bronchodilator for COPD patients in the future.

Topics: Animals; Bronchodilator Agents; Cholinergic Antagonists; Clinical Trials as Topic; Humans; Lung Diseases, Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Inhaled antimuscarinic drugs are the treatment of choice, recommended by guidelines, in chronic obstructive pulmonary disease (COPD). In long-term clinical studies ipratropium shows important effects beyond relaxation of airway smooth muscle, e.g. reduction of exacerbations of COPD. In phase III clinical trials the new generation antimuscarinic tiotropium, inhaled once daily, has provided more than 24 hours of stable bronchodilation, that was sustained over the one year treatment period. In addition, tiotropium in comparison to placebo and even ipratropium, has been shown to provide improvement in dyspnea, reduction of exacerbations of COPD, reduced hospital admissions for exacerbations, reduced duration of hospitalisations as well as improved health-related quality of life. Chronic effects, such as reduction of hospitalisations, are conventionally attributed to an anti-inflammatory action and not to symptomatic bronchodilation. The 24 hour stabilisation of airway patency, avoiding fluctuations of the diameter with occasional closure and consequent need for reopening, may explain the extended therapeutic profile of tiotropium. Inhibition by antimuscarinics of pro-inflammatory cholinergic effects may also occur, e.g. inhibition of 5-HETE release from epithelial cells and inhibition of release of neutrophil and eosinophil chemotactic activity from alveolar macrophages. Antimuscarinics have shown increasing value as a therapeutic approach in COPD. The elucidation of their anti-inflammatory potential constitutes an interesting target for future studies.

Topics: Administration, Inhalation; Anti-Inflammatory Agents, Non-Steroidal; Bronchodilator Agents; Humans; Inflammation Mediators; Ipratropium; Lung Diseases, Obstructive; Mast Cells; Muscarinic Antagonists; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium is a long-acting anticholinergic drug. Studies with cloned human muscarinic receptors show that tiotropium binds equally well to M(1), M(2), and M(3) receptors. However, it dissociates very slowly from M(1) and M(3) receptors compared with ipratropium, and more rapidly from M(2) receptors. Binding studies with [(3)H]tiotropium in human lung show that it is approximately 10-fold more potent than ipratropium. In vitro, tiotropium has a potent inhibitory effect against cholinergic nerve-induced contraction of airways. It dissociates extremely slowly, compared with the dissociation of atropine and ipratropium. Clinical studies with single doses of inhaled tiotropium confirm that it is a potent and long-lasting bronchodilator. Furthermore, it protects against cholinergic bronchoconstriction for > 24 h. Pharmacokinetic studies show that little of the inhaled drug is absorbed, thus predicting a high margin of safety.

Topics: Animals; Bronchodilator Agents; Cholinergic Antagonists; Humans; Lung; Lung Diseases, Obstructive; Receptors, Muscarinic; Scopolamine Derivatives; Tiotropium Bromide

Inhaled antimuscarinics, often called anticholinergics in clinical medicine, are established as first line bronchodilators in COPD. Tiotropium has been developed as a new generation antimuscarinic following ipratropium. Tiotropium is a specific, highly potent antimuscarinic, demonstrating very slow dissociation from muscarinic receptors. Dissociation from M2-receptors is faster than from M3 or M1, which in functional in vitro studies, appeared as kinetic receptor subtype selectivity of M3 and M1 over M2. The high potency and slow receptor dissociation found its clinical correlate in significant and long lasting bronchodilatation and bronchoprotection in patients with COPD and asthma. In asthma, protection against methacholine challenge exceeded the study period of 48 hours. In COPD, bronchodilatation of about 80% of the plateau was demonstrated after the first dose. Following chronic once daily inhalation for 28 days, the improvement in pulmonary function was sustained and there was a further increase in peak effects, but more importantly a rising baseline, achieving steady state within 2 weeks. Tiotropium achieves very stable long lasting effects with comparatively low variation of bronchodilatation between peak and trough (the level before the next administration). Stable 24 hour effectiveness profiles the compound as the first once daily bronchodilator. Clinical correlates of kinetic receptor subtype selective blockade remain to be shown. Plasma levels of tiotropium at trough are in the low pg/ml range and are unlikely to explain the sustained effectiveness in the airways. Slow dissociation from muscarinic receptors is likely to be responsible for the long duration of action.

Topics: Animals; Asthma; Binding Sites; Bronchodilator Agents; Cell Membrane; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Lung Diseases, Obstructive; Muscarinic Agonists; Muscarinic Antagonists; Receptors, Muscarinic; Scopolamine Derivatives; Tiotropium Bromide

Antimuscarinic treatment of airway disease has a long and colorful history leading to its present day use as an effective bronchodilator in chronic obstructed pulmonary disease (COPD) as well as an antisecretory drug for watery rhinorrhea. Present formulations are limited to ipratropium bromide, a safe and effective respiratory therapeutic. The bronchodilation from ipratropium, as documented by spirometry, has been well established both alone and in combination with albuterol. Evidence suggests that anticholinergics can affect other important aspects of COPD, such as dynamic hyperinflation, and further studies are warranted to confirm long-term physiologic effects and associated health outcomes. Finally, current development of the long-acting compound tiotropium has provided hope for the next generation of antimuscarinic agents represented by once-daily therapy.

Topics: Adrenergic beta-Agonists; Albuterol; Bronchodilator Agents; Cholinergic Antagonists; Drug Combinations; Humans; Ipratropium; Lung Diseases, Obstructive; Muscarinic Antagonists; Nasal Mucosa; Respiratory Mechanics; Rhinitis; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Tiotropium bromide (Ba 679 BR) is a novel potent and long-lasting muscarinic antagonist that has been developed for the treatment of chronic obstructive airways disease (COPD). Binding studies with [3H]tiotropium bromide in human lung have confirmed that this is a potent muscarinic antagonist with equal affinity for M1-, M2- and M3-receptors and is approximately 10-fold more potent than ipratropium bromide. Tiotropium bromide dissociates very slowly from lung muscarinic receptors compared with ipratropium bromide. In vitro tiotropium bromide has a potent inhibitory effect against cholinergic nerve-induced contraction of guinea-pig and human airways, that has a slower onset than atropine or ipratropium bromide. After washout, however, tiotropium bromide dissociates extremely slowly compared with the dissociation of atropine and ipratropium bromide. Measurement of acetylcholine (ACh) release from guinea-pig trachea shows that tiotropium bromide, ipratropium bromide and atropine all increase ACh release on neural stimulation and that this effect is washed out equally quickly for the three antagonists. This confirms binding studies to transfected human muscarinic receptors which suggested that tiotropium bromide dissociates slowly from M3-receptors (on airway smooth muscle) but rapidly from M2 autoreceptors (on cholinergic nerve terminals). Clinical studies with inhaled tiotropium bromide confirm that it is a potent and long-lasting bronchodilator in COPD and asthma. Furthermore, it protects against cholinergic bronchoconstriction for > 24 h. This suggests that tiotropium bromide will be a useful bronchodilator, particularly in patients with COPD, and may be suitable for daily dosing. The selectivity for M3- over M2-receptors may also confer a clinical advantage.

Topics: Acetylcholine; Animals; Bronchodilator Agents; Chronic Disease; Guinea Pigs; Humans; Ipratropium; Lung; Lung Diseases, Obstructive; Muscarinic Antagonists; Receptors, Muscarinic; Scopolamine Derivatives; Tiotropium Bromide

A study was undertaken to evaluate and compare the efficacy and safety of tiotropium and ipratropium during long term treatment in patients with stable chronic obstructive pulmonary disease (COPD).. 288 patients of mean (SD) age 65 (8) years and forced expiratory volume in one second (FEV(1)) 41 (12)% predicted participated in a 14 centre, double blind, double dummy, parallel group study and were randomised after a run in period of two weeks to receive either tiotropium 18 microg once daily from a dry powder inhaler (HandiHaler; two thirds of patients) or ipratropium 40 microg four times daily from a metered dose inhaler (one third of patients) for a period of 13 weeks. Outcome measures were lung function, daily records of peak expiratory flow (PEF), and the use of concomitant salbutamol. FEV(1) and forced vital capacity (FVC) were measured one hour before and immediately before inhalation (mean value of the two measurements on test day 1 was the baseline value while on all other test days it was known as the trough FEV(1) and FVC), and 0.5, 1, 2, 3, 4, 5, and 6 hours after inhalation of the study drug on days 1, 8, 50, and 92.. During treatment tiotropium achieved a significantly greater improvement than ipratropium (p<0.05) in trough, average, and peak FEV(1) levels and in trough and average FVC levels. The trough FEV(1) response on days 8, 50, and 92 ranged between 0.15 l (95% CI 0.11 to 0.19) and 0.16 l (95% CI 0.12 to 0.20) for tiotropium and between 0.01 l (95% CI -0.03 to 0.05) and 0.03 l (95% CI 0.01 to 0. 07) for ipratropium. The trough FVC response on days 8, 50, and 92 ranged between 0.34 l (95% CI 0.28 to 0.40) and 0.39 l (95% CI 0.31 to 0.47) for tiotropium and between 0.08 l (95% CI 0.00 to 0.16) and 0.18 l (95% CI 0.08 to 0.28) for ipratropium. On all test days tiotropium produced a greater improvement in FEV(1) than ipratropium starting three hours after inhalation (p<0.05). During treatment weekly mean morning and evening peak expiratory flow (PEF) was consistently better in the tiotropium group than in the ipratropium group, the difference in morning PEF being significant up through week 10 and in evening PEF up through week 7 of treatment (p<0.05). The use of concomitant salbutamol was also lower in the tiotropium group (p<0.05). The only drug related adverse event was dry mouth (tiotropium 14.7%, ipratropium 10.3% of patients).. Tiotropium in a dose of 18 microg inhaled once daily using the HandiHaler was significantly more effective than 40 microg ipratropium four times daily in improving trough, average, and peak lung function over the 13 week period. The safety profile of tiotropium was similar to ipratropium. These data support the use of tiotropium as first line treatment for the long term maintenance treatment of patients with airflow obstruction due to COPD.

Topics: Aged; Cholinergic Antagonists; Female; Forced Expiratory Volume; Humans; Ipratropium; Lung Diseases, Obstructive; Male; Middle Aged; Peak Expiratory Flow Rate; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium (Spiriva; Ba679BR) is a new-generation, long-acting anticholinergic bronchodilator that has muscarinic M(1) and M(3) receptor subtype selectivity. A multicenter, randomized, double-blind, parallel group, placebo-controlled study was conducted to evaluate the dose-response characteristics of tiotropium inhalation powder given once daily to stable patients with chronic obstructive pulmonary disease (COPD). Patients (mean FEV(1) = 1.08 L [42% predicted]) were randomized to receive 0, 4.5, 9, 18, or 36 microg tiotropium once daily at noon for 4 wk, with spirometry done before and hourly for 6 h after dosing. Patients measured and recorded their peak expiratory flow rates (PEFRs) three times each day. Significant dose-related improvement in FEV(1) and significant improvement in FVC occurred within 1 h after the first dose of tiotropium as compared with placebo. Over the 29 d of the study, all doses of tiotropium produced significant increases over placebo in trough (i.e., as measured spirometrically at 20 to 24 h after the previous dose and just before the next dose of tiotropium), peak, and 6-h postdose average FEV(1) and FVC, and in PEFR, without a significant difference among the different doses investigated. PEFR gradually returned to pretreatment baseline levels over a 3-wk evaluation period following the discontinuation of tiotropium. The overall safety profile for the tiotropium doses was similar to that for placebo. In summary, tiotropium was shown to be safe and effective in doses ranging from 4.5 to 36 microg delivered once daily. The improvements in spirometry with once-daily dosing confirm the long duration of action of tiotropium reported in single-dose studies, and its sustained improvement of spirometric measures over the 1 mo of testing in the study points to utility of tiotropium as a maintenance bronchodilator for patients with COPD. On the basis of the comparable bronchodilator response at doses from 9 to 36 microg, and advantages suggested by the safety profile at doses below 36 microg in this study, a dose of 18 microg once daily was selected for use in long-term studies of the safety and efficacy of tiotropium.

Topics: Administration, Inhalation; Aged; Bronchi; Bronchodilator Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Lung Diseases, Obstructive; Male; Peak Expiratory Flow Rate; Scopolamine Derivatives; Spirometry; Time Factors; Tiotropium Bromide

To compare the bronchodilator efficacy and safety of tiotropium and placebo.. A 3-month, randomized, double-blind, placebo-controlled, multicenter trial.. Outpatient.. Four hundred seventy patients with stable COPD (mean FEV(1) = 38.6% predicted).. Tiotropium 18 microg (N = 279) or placebo (N = 191) given once daily via a lactose-based dry-powder inhaler device.. Spirometry was evaluated on days 1, 8, 50, and 92. Data were expressed as the mean trough (ie, before morning dose; 23 to 24 h after previous dose) and average response observed in the 3 h after the dose was received. Tiotropium produced significant improvement in trough FEV(1) and FVC, averaging 12% greater than baseline on day 8; these improvements were maintained on days 50 and 92. The average postdose FEV(1) was 16% greater than baseline on day 1 and 20% greater than baseline on day 92; FVC was 17% greater than baseline on day 1 and 19% greater than baseline on day 92. Tiotropium was significantly more effective than placebo in both trough and average FEV(1) and FVC response (p < 0.001). These spirometric effects were corroborated by significant improvements in daily morning and evening peak expiratory flow rate, as well as a reduction in "as-needed" albuterol use. Symptoms of wheezing and shortness of breath were significantly less in patients receiving tiotropium, and the physician global assessment noted overall improvements with those treated with tiotropium relative to placebo. The most common reported adverse event after tiotropium was dry mouth (9.3% vs 1.6% relative to placebo; p < 0.05).. These data demonstrate that tiotropium is a safe and effective once-daily anticholinergic bronchodilator and should prove useful as first-line maintenance therapy in COPD.

Topics: Aged; Albuterol; Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Dyspnea; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Lung; Lung Diseases, Obstructive; Male; Nebulizers and Vaporizers; Peak Expiratory Flow Rate; Placebos; Respiratory Sounds; Safety; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Vital Capacity; Xerostomia

The objective of the present study was to investigate the dose-dependent bronchodilator efficacy and duration of action of the newly developed antimuscarinic agent tiotropium bromide in patients with chronic obstructive pulmonary disease (COPD). In a randomized, double-blind, placebo-controlled, crossover design, patients inhaled single doses of 10-80 micrograms tiotropium bromide and placebo, formulated in lactose powder capsules. The washout period between test doses was 72 h. Thirty five patients were enrolled in the trial (32 males and 3 females; mean age 64 yrs). Baseline forced expiratory volume in one second (FEV1) (mean 1.34 L) was less than 65% of predicted and was < 70% of forced vital capacity (FVC). All subjects had a smoking history of more than 10 pack-years. The mean reversibility of FEV1 after inhalation of 40 micrograms ipratropium bromide was 28%. Pulmonary function testing was performed before and at regular time intervals for up to 32 h after test drug administration. Compared to placebo, tiotropium bromide produced significant improvements in FEV1, FVC, peak expiratory flow rate (PEFR) and forced mid-expiratory flow (FEF25-75%). The bronchodilator response was almost immediate; peak improvement in FEV1 was reached 1-4 h after test drug inhalation, and the duration of action extended to 32 h after the 20, 40 and 80 micrograms doses. A clear dose-response relationship was seen for peak FEV1 and for the average FEV1 over differing time periods during the 32 h observation period, 80 micrograms of test drug being superior to the 10 micrograms dose. Peak improvement in FEV1 ranged 19-26% of test-day baseline for tiotropium bromide doses compared to 16% for placebo. The large improvement for placebo is probably due to carry-over effect which was significant. After excluding carry-over effect, the peak response to placebo decreased to 11%, whilst for tiotropium bromide doses it ranged 20-25%; standard error for mean difference was about 4%. There was no evidence of systemic anticholinergic effects. In this population of patients with COPD, tiotropium bromide was found to be a safe and long-acting bronchodilator, demonstrating a clear dose-response relationship following single dose administration.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Lung Diseases, Obstructive; Male; Middle Aged; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Treatment Outcome

Preclinical studies with Ba 679 Br have demonstrated a significantly longer duration of action than ipratropium bromide. Following inhalation of single doses, no systemic antimuscarinic effects were noted at doses likely to be bronchodilating in man. The objective of the present pilot-study of Ba 679 Br was to establish the dose-range for its bronchodilatory activity in a small number of chronic obstructive pulmonary disease (COPD) patients, before initiating a formal dose- and time-response study. Employing an open cross-over design, the efficacy of Ba 679 Br was tested, following single inhalational administration of five doses of increasing magnitude on separate days in six patients with COPD. A piezoelectric crystal was used, in order to nebulize an aqueous solution into a mist suitable for inhalation. There was a mean increase in forced expiratory volume in one second (FEV1) of 36% 30 min after inhaling ipratropium bromide 40 micrograms. Pulmonary function tests (FEV1, and specific airways conductance (sGaw)) were performed, at regular time intervals up to 24 h after test drug inhalation. The bronchodilatory activity of Ba 679 Br appeared to be dose-related in the dose-range tested (10-160 micrograms). A peak response was reached in 1.5-2 h, and persisted for 10-15 h in the majority of patients with return to baseline FEV1 approximately 19 h after dosing. No changes in physical examination, electrocardiogram (ECG) and laboratory safety tests from predose values were noted, and no serious adverse events were reported by the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Bronchodilator Agents; Dose-Response Relationship, Drug; Female; Forced Expiratory Volume; Humans; Lung Diseases, Obstructive; Male; Middle Aged; Pilot Projects; Scopolamine Derivatives; Tiotropium Bromide

Although inhaled medications are effective therapies for COPD, many patients and providers use them incorrectly.. We recruited providers who prescribe inhalers or teach inhaler technique and assessed their use of metered-dose inhalers (MDIs), various dry powder inhalers (DPIs), and Respimat using predefined checklists. Then they watched tablet-based multimedia educational videos that demonstrated correct inhaler technique by a clinical pharmacist with teach-back from a patient and were re-evaluated. We also recruited patients with COPD and assessed their use of their prescribed inhalers and then retested them after 3-6 months. Baseline and follow-up respiratory symptoms were measured by the COPD Assessment Test.. Fifty-eight providers and 50 subjects participated. For all providers, correct inhaler technique (reported as percentage correct steps) increased after the videos: MDI without a spacer (72% vs 97%) MDI with a spacer (72% vs 96%), formoterol DPI (50% vs 94%), mometasone DPI (43% vs 95%), tiotropium DPI (73% vs 99%), and Respimat (32% vs 93%) (before vs after, P < .001 for all comparisons). Subjects also improved their inhaler use technique after viewing the educational videos: MDI without a spacer (69% vs 92%), MDI with a spacer (73% vs 95%), and tiotropium DPI (83% vs 96%) (before vs after, P < .001 for all comparisons). The beneficial effect of this educational intervention declined slightly for subjects but was durably improved after several months. COPD Assessment Test scores did not demonstrate any change in respiratory symptoms.. A tablet-based inhaler education tool improved inhaler technique for both providers and subjects. Although this intervention did show durable efficacy for improving inhaler use by patients, it did not reduce their respiratory symptoms.

Topics: Aged; Albuterol, Ipratropium Drug Combination; Anti-Allergic Agents; Bronchodilator Agents; Checklist; Computers, Handheld; Dry Powder Inhalers; Education, Medical; Educational Technology; Female; Follow-Up Studies; Formoterol Fumarate; Humans; Lung Diseases, Obstructive; Male; Metered Dose Inhalers; Middle Aged; Mometasone Furoate; Multimedia; Patient Education as Topic; Physicians; Prospective Studies; Symptom Assessment; Tiotropium Bromide

In spite of growing interest in and knowledge about the causes and progression of COPD, neither the assessment nor pharmacologic treatment of this condition is currently ideal. Tiotropium is the first new treatment for COPD in many years. Tiotropium is a long-acting anticholinergic agent that has a potential role as a once-daily maintenance treatment, and a picture of its effectiveness is gradually emerging. Spirometry data from clinical studies demonstrate that it is a potent bronchodilator in patients with COPD and it is very well tolerated. Further data on health status and quality of life are awaited.

Topics: Bronchodilator Agents; Cholinergic Antagonists; Delayed-Action Preparations; Forecasting; Humans; Lung Diseases, Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide

Topics: Adult; Animals; Asthma; Bronchodilator Agents; Cholinergic Antagonists; Disease Models, Animal; Dogs; Humans; Ipratropium; Lung Diseases, Obstructive; Muscarinic Antagonists; Scopolamine Derivatives; Time Factors; Tiotropium Bromide