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PubMed2001

Tiotropium bromide.

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.

Animals↗

PubMed2004

Tiotropium bromide.

Tiotropium bromide is a novel, inhaled, once-daily anticholinergic bronchodilator that has recently been approved in the United States for use in patients with COPD. Its unique feature is the persistence of bronchodilation for > 24 h due to prolonged M(3) muscarinic receptor blockade. Tiotropium provides significant improvement in spirometry and lung volumes. Clinically relevant outcomes such as the relief of dyspnea, improvement in the quality of life (health status), and reductions in the frequency and severity of acute exacerbations have been consistently obtained with tiotropium in clinical trials. In head-to-head trials, tiotropium administered once daily resulted in bronchodilation (peak, trough, and area under the curve) that was statistically superior to ipratropium administered four times daily and salmeterol administered twice daily. Clinical outcomes (dyspnea, quality of life, exacerbation frequency) were numerically but not always statistically better with tiotropium than salmeterol. Long-term studies of the combination of tiotropium with adrenergic agents, methylxanthines, or inhaled corticosteroids have not been reported in full. Several 1-year studies demonstrate that the only significant side effect of tiotropium was dryness of the mouth, which occurred in approximately 10 to 16% of patients; it is well tolerated by patients and safe.

Acute Disease↗

PubMed2002

Tiotropium bromide.

Tiotropium bromide is an anticholinergic bronchodilator that antagonises muscarinic M(1), M(2) and M(3) receptors. It dissociates more slowly from M(1) receptors and, importantly, from M(3) receptors (which are located in bronchial smooth muscle) than from M(2) receptors and subsequently has a long duration of action permitting once-daily administration. In patients with chronic obstructive pulmonary disease (COPD), tiotropium 18microg once daily significantly improved lung function compared with placebo and ipratropium 40microg four times daily in 1-year trials or salmeterol 50microg twice daily in a 6-month study. The incidence of COPD exacerbations decreased and use of rescue medication was lower with tiotropium compared with placebo or ipratropium. There was no evidence of tachyphylaxis during 1-year treatment with tiotropium. Compared with placebo, salmeterol and ipratropium, tiotropium produced significant improvements in patients' perception of dyspnoea and health-related quality of life. Tiotropium is generally well tolerated; dry mouth is the most common drug-related adverse event, occurring in about 10 to 16% of patients in clinical trials.

Bronchodilator Agents↗

PubMed2005

The role of tiotropium bromide, a long-acting anticholinergic bronchodilator, in the management of COPD.

Bronchodilator therapy forms the mainstay of treatment for symptomatic patients with COPD. Long-acting bronchodilators, which maintain sustained airway patency over a 24-hour period, represent an advance in therapy. Tiotropium bromide is a new long-acting inhaled anticholinergic agent with superior pharmacodynamic properties compared with the short-acting anticholinergic, ipratropium bromide. Tiotropium bromide has been consistently shown to have a greater impact than ipratropium bromide on clinically important outcome measures such as health status. The mechanisms of clinical benefit with tiotropium bromide are multifactorial, but improved airway function, which enhances lung emptying and allows sustained deflation of over-inflated lungs, appears to explain improvements in dyspnea and exercise endurance in COPD. Inhaled tiotropium bromide therapy has also been associated with reduction in acute exacerbations of COPD as well as reduced hospitalizations. The safety profile of tiotropium bromide is impressive: dry mouth is the most common adverse event and rarely necessitates termination of the drug. No tachyphylaxis to tiotropium bromide has been demonstrated in clinical trials lasting up to 1 year. There is preliminary information that the combination of long-acting anticholinergics and long-acting beta2-adrenoceptor agonists provides additive physiological and clinical benefits. According to recent international guidelines, long-acting bronchodilators should be considered early in the management of symptomatic patients with COPD in order to achieve effective symptom alleviation and reduction in activity limitation. Tiotropium bromide, because of its once-daily administration and its established efficacy and tolerability profile, has emerged as an attractive therapeutic option for this condition.

Bronchodilator Agents↗

PubMed1995

Tiotropium bromide (Ba 679 BR), a novel long-acting muscarinic antagonist for the treatment of obstructive airways disease.

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.

Acetylcholine↗

PubMed2002

Tiotropium bromide: a novel once-daily anticholinergic bronchodilator for the treatment of COPD.

Tiotropium bromide (Spiriva, BA679BR, Boehringer Ingelheim) is a novel inhaled, long-acting anticholinergic bronchodilator that is employed as a once-daily maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). Like ipratropium bromide, tiotropium bromide is a quaternary ammonium derivative that binds to muscarinic receptors. However, although tiotropium binds with high affinity to muscarinic receptors of M1-, M2- and M3-subtypes, it dissociates very slowly from M1- and M3-receptors but more rapidly from M2-receptors, thereby giving it a unique kinetic selectivity. To date, the short-acting anticholinergic agents ipratropium and oxitropium bromide have been extensively employed as bronchodilator therapy for patients with COPD. Indeed, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy emphasises the role of bronchodilators in symptomatic management of all stages of COPD. It is encouraging that tiotropium given once daily from a dry powder inhaler at 18 g has been shown to cause greater improvement in lung function and reduction in symptoms than ipratropium bromide given four times daily. Furthermore, clinical studies over a 1-year period have demonstrated that tiotropium has impressive and maintained effects on lung function, symptoms and health-related quality of life, and may also reduce exacerbations. In a recent large scale comparative study over 6 months, tiotropium has been shown to cause superior bronchodilation and symptomatic improvement when compared to twice daily salmeterol in COPD. The only significant reported adverse event is dry mouth, which is found in approximately 10%-15% of subjects, but this is reversible and rarely causes discontinuation of therapy. Based on these promising features, it is likely that tiotropium used alone or in combination with other bronchodilators will emerge as first-line maintenance treatment for patients with airway obstruction due to COPD.

Administration, Inhalation↗

PubMed2004

Tiotropium bromide. A review of its use as maintenance therapy in patients with COPD.

Tiotropium bromide (Spiriva) is a long-acting anticholinergic bronchodilator that maintains bronchodilation for at least 24 hours, allowing once-daily administration. The active moiety is the tiotropium cation (tiotropium); tiotropium bromide 22.5 micrograms is equivalent to 18 micrograms of tiotropium cation. Greater improvements in lung function from baseline (primary endpoint mean trough FEV(1)) were observed with inhaled tiotropium 18 micrograms once daily than with placebo in 6-month and 1-year randomized, double-blind trials in patients with COPD. Tiotropium improved lung function (trough FEV(1) response) more effectively than ipratropium bromide (ipratropium) 40 micrograms four times daily in 1-year clinical trials, and was at least as effective as salmeterol 50 micrograms 12-hourly in 6-month trials. Preliminary data suggest that tiotropium alone or in combination with once-daily formoterol has a greater bronchodilator effect than twice-daily formoterol in patients with COPD. Improvements in patients' perception of health-related quality of life (HR-QOL) or dyspnea were greater with tiotropium than with placebo or ipratropium, and were similar to those with salmeterol. Reductions in the frequency and severity of acute exacerbations and in the use of rescue medication were also greater with tiotropium than with ipratropium or placebo. There was no evidence of tachyphylaxis with tiotropium during 1-year clinical trials. Inhaled tiotropium was generally well tolerated in clinical trials. Apart from dry mouth, the type and incidence of adverse events with tiotropium were similar to those with ipratropium, salmeterol or placebo in patients with COPD. In conclusion, inhaled tiotropium 18 micrograms once daily improved lung function, dyspnea, and HR-QOL, and decreased the incidence of acute COPD exacerbations and the use of rescue medication relative to placebo or ipratropium in clinical trials in patients with COPD. Tiotropium was at least as effective as salmeterol in terms of bronchodilator efficacy and improvements in dyspnea or HR-QOL. With the exception of dry mouth, the tolerability profile of tiotropium was similar to that with placebo, ipratropium, or salmeterol. Consequently, inhaled tiotropium is likely to be a valuable option for first-line, long-term maintenance therapy in the management of bronchoconstriction in patients with symptomatic COPD. Tiotropium bromide has a quaternary ammonium structure and acts as an anticholinergic bronchodilator; the active moiety is the tiotropium cation (tiotropium). A 22.5 micrograms dose of tiotropium bromide provides 18 micrograms of tiotropium. Orally inhaled tiotropium bromide antagonizes the muscarinic M(1), M(2), and M(3) receptors located in airway smooth muscle, reversing vagally mediated bronchoconstriction. Receptor binding assays and in vitro tests indicate that tiotropium bromide is kinetically selective for M(1) and M(3) receptors over the M(2) receptor, unlike ipratropium bromide, which is nonselective. Animal and in vitro studies showed that tiotropium bromide was more potent ( approximate, equals 20-fold) than ipratropium bromide in displacing [(3)H]N-methylscopolamine (NMS) from muscarinic receptors, and had a more sustained protective effect (>70% inhibition) against NMS binding. Tiotropium bromide was a more potent inhibitor of bronchial contraction than atropine ( approximate, equals 23-fold), and had a slower onset and markedly longer duration of action than atropine or an equipotent dose of ipratropium bromide. Aerosol particle penetration is improved with tiotropium, without delaying mucus clearance from the lungs. Tiotropium 4.5-36 micrograms once daily for 4 weeks increased mean trough and average FEV(1) and FVC and mean PEFR values from baseline compared with placebo, with no evidence of tachyphylaxis. Improvements in trough FEV(1) from baseline with tiotropium 4.5-36 micrograms were not dose dependent. Based on a lack of dose response, the optimal once-daily tiotropium dosage is 18 micrograms. Steady-state trough FEV(1) values are achieved within 48 hours of commencing tiotrochodilation (for >/=24 hours) and an attenuation of the nocturnal decline in FEV(1) that were unaffected by timing of the daily tiotropium dose were seen in randomized, double-blind, placebo-controlled studies in patients with stable COPD. The drug improved static and dynamic lung hyperinflation (evidenced by reduced trapped air volume and increased tidal volume and end-of-exercise inspiratory capacity), and improved exertional dyspnea (during activities of daily living and exertion) and exercise tolerance compared with placebo in randomized, double-blind studies. In patients with stable COPD, improved sleep-related oxygen desaturation that was unaffected by the timing of the daily dose was seen with tiotropium but not with placebo. Clinically significant treatment-related disorders of conduction or rhythm, or changes in heart rate were not observed with tiotropium in this patient group. Mean maximal plasma concentrations (C(max)) were observed within 5 minutes of inhalation of a single dose of tiotropium 18 micrograms in patients with COPD. Plasma drug levels declined to minimum concentrations (C(min)) within 1 hour of treatment in healthy volunteers. Mean steady-state C(max) concentrations (16 ng/L) were achieved after 2-3 weeks of once-daily inhaled tiotropium 18 micrograms in elderly patients with COPD; tiotropium does not appear to accumulate once steady-state has been achieved.The estimated absolute bioavailability of tiotropium at steady state in healthy volunteers was approximately 20-25%, and approximately 72% of the drug is bound to plasma proteins. Excretion of tiotropium is predominantly renal (through active secretion by the kidneys), although in vitro studies suggest that cytochrome P450 (CYP) oxidation (possibly involving CYP2D6 and CYP3A4 enzymes) may have a minor role. In patients with COPD, renal excretion of the unchanged drug at 24 hours (Ae(24)) was approximately 7%. The mean plasma elimination half-life after single or multiple doses in healthy volunteers and elderly patients with COPD was approximately 5-6 days. The renal clearance and urinary excretion of tiotropium decrease with increasing age; however, these changes are not considered to be clinically significant. Because of altered steady-state C(max), C(min), area under the concentration-time curve, and Ae(24) values, caution is required with tiotropium administration in patients with moderate-to-severe renal impairment. The pharmacokinetics of tiotropium in patients with severe renal or hepatic impairment have not been studied. Tiotropium does not interact with drugs such as cimetidine or ranitidine, which are also eliminated by active renal secretion. Orally inhaled tiotropium bromide has been evaluated as a bronchodilator for the management of patients with COPD in randomized, double-blind 6-month and 1-year trials, and in several shorter studies. In clinical trials, COPD was diagnosed according to the American Thoracic Society guidelines. The bronchodilator effect was expressed as the trough FEV(1) response (the mean change in FEV(1) from baseline measured 1 hour prior to and immediately before a scheduled dose), and was the primary endpoint in all but two clinical trials. The bronchodilator effect with tiotropium 18 micrograms once daily was superior to that with placebo in several well designed trials in patients with COPD. Moreover, greater improvements in mean peak and average FEV(1) responses occurred with tiotropium but not with placebo. Mean trough, peak, and average FVC responses, and weekly mean morning and evening PEFR values were also improved to a greater extent with tiotropium than with placebo. Tiotropium demonstrated a greater bronchodilator effect than ipratropium bromide (hereafter referred to as ipratropium when used at approved dosages) 40 micrograms four times daily in two 1-year trials in patients with COPD. Mean peak and average FEV(1), mean trough FVC responses, and weekly mean morning and evening PEFR values were also increased to a greater extent with tiotropium than with ipratropium. In one of the two 6-month trials that compared the efficacy of tiotropium with that of inhaled salmeterol 50 micrograms twice daily, greater improvements from baseline in mean trough, peak, and average FEV(1) and FVC responses were seen with tiotropium than with salmeterol. Increases in weekly mean evening, but not morning, PEFR values were generally greater with tiotropium than salmeterol. In the second trial, improvement in the primary endpoint (mean trough FEV(1) response from baseline) with tiotropium or salmeterol was similar, although peak and average responses were superior with tiotropium. Preliminary results from a 6-week crossover study in patients with COPD suggested that tiotropium alone or in combination with once-daily formoterol improved mean trough and average FEV(1) and trough FVC values from baseline to a greater extent than twice-daily formoterol. More patients achieved a clinically important improvement (increase of >/=1 unit) in the transitional dyspnea index focal score (a measure of dyspnea-related impairment) with tiotropium than with placebo in the 1-year trials. Tiotropium was superior to ipratropium in 1-year trials, and was at least as effective as salmeterol in 6-month trials, in achieving a clinically important improvement in focal scores. Tiotropium recipients experienced fewer COPD exacerbations than placebo or ipratropium recipients and had fewer and shorter COPD-related hospitalizations compared with placebo recipients. Unlike salmeterol, tiotropium lengthened the time to onset of the first exacerbation and decreased the number of exacerbations compared with placebo in two 6-month trials. Similar proportions of tiotropium, salmeterol, and placebo recipients required COPD-related hospitalizations. (ABSTRACT TRUNCATED)

Bronchodilator Agents↗

PubMed2006

Evaluating the pharmacoeconomic effect of adding tiotropium bromide to the management of chronic obstructive pulmonary disease patients in Singapore.

OBJECTIVE: To perform a pharmacoeconomic analysis on the treatment of chronic obstructive pulmonary disease (COPD) with the addition of tiotropium bromide. METHODS: Pharmacoeconomic modeling was performed utilizing the efficacy of tiotropium bromide from the literature on different settings and severity of COPD. Reductions in exacerbations, hospitalizations, and number of exacerbation days per year were derived from these studies. Cost of drug treatment, exacerbations, hospitalization, and loss of income were derived from local data in Singapore and reported in Singapore dollars (US$1=S$1.71). A model was constructed to calculate the impact of one-year treatment with tiotropium bromide, and the results were reported for the total incremental cost per year, cost per year needed to reduce one hospitalization in one year, and cost-savings from hospitalizations in one year. Sensitivity analysis were performed for different number of patients treated per year, differing cost of hospitalization, different cost for tiotropium bromide, different impact of tiotropium bromide on clinical outcomes, and the different amount of substitution drug utilized in the comparator group. RESULTS: Using the different clinical effects and looking at the impact on treating 1000, 2000, and 10,000 patients per year, most of the results showed a high level of decrease in overall cost per year that ranged from S$145.40 to S$840.37 per patient treated. Cost per year needed to reduce one hospitalization in one year ranged from S$3217.31 to S$18,148.92. Cost-savings from hospitalizations in one year per patient treated ranged from $57.16 to $322.49. This may contribute as high as 83% of the overall cost saving. Sensitivity analysis supports the cost savings finding. CONCLUSION: Adding tiotropium bromide for severe COPD patients would lead to a significant cost savings for the economy.

Bronchodilator Agents↗

PubMed2006

[Efficacy of tiotropium bromide (Spiriva) in patients with chronic-obstructive pulmonary disease (COPD) of different severities].

BACKGROUND: Aim of this study was to evaluate the efficacy of inhaled Tiotropium bromide in COPD patients of different severities in pneumological practices during a three months clinical trial. METHODS: A randomized, double blind, placebo controlled study including COPD-patients (FEV1/FVC < 70 %, FEV1 < or = 70 % predicted; age > or = 40 years; > or = 10 pack years) of different severities was performed. The efficacy of 18 microg Tiotropium bromide once daily on lung function and exacerbations over 12 weeks was evaluated by respective pulmonary function tests (spirometry) before (trough value) and 2 hours after inhalation of study medication. RESULTS: 1639 patients (1236 Tiotropium bromide, 403 placebo; FEV1 reversibility after 200 microg Ipratropium bromide + 200 microg Fenoterol: 7.9 +/- 7.5 % predicted [mean +/- sd]) were randomized. After 12 weeks of treatment Tiotropium bromide led to significant increases of trough FEV1 (23 - 24 h after last inhalation; + 79 +/- 17 ml), and 2 h after Tiotropium bromide inhalation (+ 128 +/- 19 ml) (all values vs. placebo, adjusted mean +/- se, p < 0.0001). FVC and IVC were also improved significantly. In mild COPD (FEV1 > or = 50 - 70 %) improvements were most pronounced (trough FEV1 + 113 +/- 29 ml, 2 h post-inhalation + 181 +/- 33 ml; all values vs. placebo., p < 0.0001). 14.6 % of patients treated with Tiotropium bromide had a COPD exacerbation vs. 19.9 % of patients treated with placebo (p = 0.0151). The time to first exacerbation was prolonged (p = 0.0092 vs. placebo). CONCLUSION: Tiotropium bromide 18 microg once daily led to a persistent improvement of lung function and a reduction of exacerbations in patients with COPD of different severities.

Adult↗

PubMed1996

Prolonged effect of tiotropium bromide on methacholine-induced bronchoconstriction in asthma.

Inhaled anticholinergic drugs are effective in the treatment of chronic obstructive pulmonary diseases (COPD), of acute asthma, and of some patients with nocturnal asthma. Tiotropium bromide (tiotropium) is a novel anticholinergic agent with a long duration of action and kinetic selectivity for M1- and M3-subtypes of muscarinic receptors. We investigated the duration of protection of a single dose of inhaled tiotropium against methacholine-induced bronchoconstriction in 12 male atopic asthmatic volunteers in a double-blind, placebo-controlled study. On four separate occasions 8 to 24 d apart, methacholine PC20 was measured serially for up to 48 h after placebo and after three doses of tiotropium (10, 40, and 80 microg). Each dose of tiotropium produced mild bronchodilatation as measured by an increase in FEV1 of between 5.5 and 11.1% from baseline, that was sustained for 24 h. There was significant dose-dependent protection against methacholine challenge at 2 h of 5.0 +/- 1.1, 7.1 +/- 0.5, and 7.9 +/- 0.7 (mean +/- SEM) doubling doses after 10, 40, and 80 microg respectively, and this persisted for 48 h. There were no adverse effects reported at any dose. The prolonged bronchodilator response and protection against methacholine challenge suggest that tiotropium may be useful in the treatment of COPD and nocturnal asthma and that once-daily dosing may be sufficient.

Adult↗

PubMed1995

Tiotropium bromide, a new long-acting antimuscarinic bronchodilator: a pharmacodynamic study in patients with chronic obstructive pulmonary disease (COPD). Dutch Study Group.

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.

Administration, Inhalation↗

PubMedDate not supplied

Early protective effects of tiotropium bromide in patients with airways hyperresponsiveness.

Tiotropium is an anticholinergic drug for Chronic Obstructive Pulmonary Disease (COPD) patients, with a peak bronchodilator effect observed after 1.5 to 2 hours and a long duration of action. The aim of our study was to quantify the early protection of a single dose of inhaled tiotropium against methacholine-induced bronchoconstriction in asthmatic patients with airway hyperresponsiveness. Ten subjects (7M, 3F), with history of asthma and a baseline FEV(1) (Forced Expiratory Volume 1 sec) > 80% of predicted, were enrolled in the study. Each subject performed three methacholine challenge tests, with a time of 72 hours between each challenge: Test A (methacholine challenge test), and successively, at random, Test B (methacholine 30 minutes after inhaled Tiotropium) and Test C (methacholine 30 minutes after inhaled Placebo). PD20 (Provocative Dose causing a 20% decrease in basal FEV(1) value) was reached to assess airways responsiveness. All the subjects showed in Test A and Test C a mild-moderate airway hyperresponsiveness. In Test B no PD20 was reached at the inhaled maximum dose of methacholine (1600 microg), FEV(1) before tiotropium was 88.6% +/- 4.4, beginning test FEV(1) 92.6% +/- 4.3, end test FEV(1) 85.7% +/- 4.6. Inhaled tiotropium bromide 18 microg has shown a protective effect against methacholine-induced bronchoconstriction in asthmatic patients, with mild-moderate airways hyperresponsiveness, already 30 minutes after its administration.

Administration, Inhalation↗

PubMed2003

Long-acting beta 2-adrenoceptor agonists or tiotropium bromide for patients with COPD: is combination therapy justified?

Bronchodilators are the mainstay of therapy for patients with established chronic obstructive pulmonary disease (COPD) but, at present, the majority of patients use short-acting agents. There is increasing evidence that long-acting agents, such as the beta(2)-adrenoceptor agonists salmeterol and formeterol, and the new anticholinergic tiotropium bromide provide a better therapeutic option. In the treatment of COPD, long-acting beta(2)-adrenoceptor agonists (LABAs) given twice daily cause the same degree of bronchodilation as tiotropium bromide given once daily. Combined use of an inhaled LABA with tiotropium bromide should provide important therapeutic benefits, as these drugs have distinct and complementary pharmacological actions in the airways. Although clinical trials of this combination have not been performed, clinical experience with Combivent, a combination of a short-acting beta(2)-adrenoceptor agonist (salbutamol) and a short-acting anticholinergic (ipratropium bromide), in COPD is encouraging because the bronchodilation produced is of a magnitude greater than that of either component alone. However, because LABAs are given twice daily but tiotropium bromide is required only once daily, the challenge is to develop a combined inhaler that can be employed on a daily basis.

Adrenergic beta-2 Receptor Agonists↗

PubMed2003

Tiotropium bromide: a long-acting anticholinergic bronchodilator for the treatment of patients with chronic obstructive pulmonary disease.

Prevention and relief of symptoms by regular use of bronchodilators is central to the management of patients with chronic obstructive pulmonary disease (COPD). The bronchodilators in use are beta2-agonists, anticholinergics and theophylline. Since the 1970s the anticholinergic ipratropium bromide has been widely used for the treatment of patients with regular symptoms, but because it has a relatively short duration of action, it needs to be administered four times a day. Tiotropium bromide is a long-acting anticholinergic suitable for once daily administration. It has been developed as a dry powder inhaler for the treatment of patients with COPD. Large clinical trials with administration of the drug for one year have now been published. Compared with placebo and ipratopium bromide, significant and long-lasting bronchodilatation was observed, which was maintained over the year. The bronchodilator effect of tiotropium bromide was accompanied by improvements in other health outcomes. A significant decrease in dyspnoea, improvement in health-related quality of life, and a reduction in the number of COPD exacerbations and hospitalisations were noted. In this review we summarise the clinical development of this compound.

Bronchodilator Agents↗

PubMed2006

[A case of bronchiolitis obliterans syndrome successfully treated by Tiotropium bromide].

A 48-year-old woman was admitted with dyspnea on effort. She suffered from adult T-cell leukemia and received peripheral blood stem cell transplantation (PBSCT). Eight months after the PBSCT, she developed dyspnea on effort and was treated with bronchodilator, inhaled corticosteroid, anti-leukotriene drug, theophylline and oxytropium bromide. However her symptoms progressed and she was admitted. We diagnosed bronchiolitis obliterans syndrome (BOS) because of obstructive pulmonary dysfunction, diffuse patchy high density of the lung field on chest computed tomography and decreased ventilation with peripheral patchy accumulation on ventilation scintigraphy. She was treated with corticosteroid and cyclosporine A and her symptoms and her pulmonary function were improved. However, in parallel with corticosteroid tapering, her symptoms and pulmonary functions worsened. Treatment with Tiotropium bromide was started and her pulmonary function improved significantly. Her pulmonary function did not worsen and tapering steroid dose was successfully achieved. PBSCT was reported to up-regulate the muscarinic receptor activity in lung. Tiotropium bromide might become one additional option for the treatment of BOS.

Bronchiolitis Obliterans↗

PubMed2004

Tiotropium bromide, a new, once-daily inhaled anticholinergic bronchodilator for chronic-obstructive pulmonary disease.

Tiotropium bromide is a quaternary ammonium compound structurally related to ipratropium and has recently been approved in the US for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic-obstructive pulmonary disease (COPD). It is available in a dry powder form, where 18 microg [corrected] of the drug is inhaled once-daily through a device, the HandiHaler). The potency and long duration of effect of this anticholinergic bronchodilator result primarily from a prolonged blockade of the M1 and M3 muscarinic receptors in the airways and a relatively more rapid dissociation from the M2 receptor (which provides inhibitory feedback). Multiple studies of up to a duration of 1 year have demonstrated its effectiveness as a bronchodilator for COPD, with a trough increase (measured approximately 24 h after administration of the drug) in forced expiratory volume in 1 s of approximately 0.12 l and a peak increase of approximately 0.25 l. Tiotropium inhalation also leads to a significant reduction in static lung volumes in hyperinflated patients with COPD; this probably contributes to the reduction in dyspnoea that is associated with long-term use of this maintenance bronchodilator. Regular use of the drug was associated with clinically meaningful increases in the Transitional Dyspnoea Index, which indicate reductions in dyspnoea associated with daily activities. Improvement in the respiratory-specific health status questionnaire, the St George's Respiratory Questionnaire component and total scores was also documented. Finally, pooled data from two 1-year studies and two 6-month studies documented 20 and 28% reductions in the number of exacerbations per patient per year. Side effects have been relatively minimal, with dry mouth the most common symptom, ranging 6 - 16% of patients and rarely leading to discontinuation of the study drug. Limited comparisons of efficacy with other bronchodilators are available. Once-daily tiotropium has been demonstrated to be clearly superior to ipratropium four times daily as a bronchodilator for COPD. Combined results from two studies comparing once-daily tiotropium to twice-daily inhalation of standard doses of salmeterol, indicate a magnitude of the bronchodilator response similar in the two drugs early in the study. However, by 6 months, the bronchodilator effect of tiotropium was somewhat greater than that of the long-acting beta-agonist. Preliminary data suggest that combining tiotropium with long-acting beta-agonists may produce additional bronchodilator action in COPD.

Administration, Inhalation↗

PubMed2005

Tiotropium bromide: a new long-acting bronchodilator for the treatment of chronic obstructive pulmonary disease.

BACKGROUND: Tiotropium bromide is a new inhaled anticholinergic agent approved for once-daily, long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD). OBJECTIVE: This article reviews the pharmacology, pharmacokinetic and pharmacodynamic properties, clinical efficacy, tolerability, and cost of tiotropium therapy in patients with COPD. METHODS: The MEDLINE (1966-October 2004), Iowa Drug Information Service (1966-October 2004), and International Pharmaceutical Abstracts (1970-November 2004) databases were searched for original research and review articles published in English. The search terms were tiotropium, Ba 679 BR, and HandiHaler. Reference lists from these articles were also consulted, as was selected information provided by the manufacturer of tiotropium. All relevant identified studies were included in the review, with preference given to Phase II/III trials. Pharmacoeconomic studies were limited to those conducted in the United States. RESULTS: Tiotropium is a nonselective anticholinergic agent that exhibits kinetic receptor selectivity for the muscarinic M1 and M3 receptors. After inhalation, tiotropium has an onset of action within 30 minutes, a peak effect within 3 to 4 hours, and a > or = 24-hour duration of action that allows once-daily dosing. In clinical trials, patients receiving tiotropium 18 microg QD had significant improvements in trough, peak, and mean forced expiratory volume in 1 second (FEV1), dyspnea, and health-related quality of life, as well as fewer COPD exacerbations and hospitalizations, compared with patients receiving placebo and ipratropium (all, P < 0.05). Improvement in FEV1 was also significantly greater in patients who received tiotropium compared with those who received salmeterol (P < 0.05), although the number of exacerbations and extent of health resource use were comparable between groups. Dry mouth was the most commonly reported adverse effect. One analysis found tiotropium to be cost-effective compared with ipratropium. CONCLUSIONS: Tiotropium offers several advantages over ipratropium in the management of COPD. Long-term (> 1 year) studies are necessary to determine the impact of tiotropium on disease progression and life expectancy.

Adult↗

PubMed2005

[Postoperative intestinal paralysis caused by the muscarinic receptor blocker tiotropium bromide].

Drug-induced manipulation of the different muscarinic receptors is gaining increasing interest in the treatment of various diseases. Despite enhanced specific chemical design of these substances, side effects in other organ systems cannot be avoided completely. The observations presented led to the conclusion that under certain circumstances the bronchodilator tiotropium bromide can cause paralytic ileus.

Aged↗