A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.
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Currently available inhaled bronchodilators used as therapy for chronic obstructive pulmonary disease (COPD) necessitate multiple daily dosing. The present study evaluates the long-term safety and efficacy of tiotropium, a new once-daily anticholinergic in COPD. Patients with stable COPD (age 65.2+/-8.7 yrs (mean+/-SD), n=921) were enrolled in two identical randomized double-blind placebo-controlled 1-yr studies. Patients inhaled tiotropium 18 microg or placebo (mean screening forced expiratory volume in one second (FEV1) 1.01 versus 0.99 L, 39.1 and 38.1% of the predicted value) once daily as a dry powder. The primary spirometric outcome was trough FEV1 (i.e. FEV1 prior to dosing). Changes in dyspnoea were measured using the Transition Dyspnea Index, and health status with the disease-specific St. George's Respiratory Questionnaire and the generic Short Form 36. Medication use and adverse events were recorded. Tiotropium provided significantly superior bronchodilation relative to placebo for trough FEV1 response (approximately 12% over baseline) (p<0.01) and mean response during the 3 h following dosing (approximately 22% over baseline) (p<0.001) over the 12-month period. Tiotropium recipients showed less dyspnoea (p<0.001), superior health status scores, and fewer COPD exacerbations and hospitalizations (p<0.05). Adverse events were comparable with placebo, except for dry mouth incidence (tiotropium 16.0% versus placebo 2.7%, p<0.05). Tiotropium is an effective, once-daily bronchodilator that reduces dyspnoea and chronic obstructive pulmonary disease exacerbation frequency and improves health status. This suggests that tiotropium will make an important contribution to chronic obstructive pulmonary disease therapy. (+info)
Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium.
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Tiotropium, a novel once-daily inhaled anticholinergic, has been shown to improve lung function over a 24-h period. In order to extend these findings, health-outcomes were evaluated over 1 yr in chronic obstructive pulmonary disease (COPD) patients. Spirometric results, peak expiratory flow rate (PEFR), salbutamol use and effects on dyspnoea, health-related quality of life and COPD exacerbations were assessed in two identical 1-yr randomized double-blind double-dummy studies of tiotropium 18 microg once daily (n=356) compared with ipratropium 40 microg q.i.d. (n=179). Screening forced expiratory volume in one second (FEV1) were 1.25+/-0.43 L (41.9+/-12.7% of the predicted value) (tiotropium) and 1.18+/-0.37 L (39.4+/-10.7% pred) (ipratropium). Trough FEV1 at 1 yr improved by 0.12+/-0.01 L with tiotropium and declined by 0.03+/-0.02 L with ipratropium (p<0.001). Significant improvement in PEFR, salbutamol use, Transition Dyspnea Index focal score, and the St George's Respiratory Questionnaire total and impact scores were seen with tiotropium (p<0.01). Tiotropium reduced the number of exacerbations (by 24%, p<0.01), and increased time to first exacerbation (p<0.01) and time to first hospitalization for a COPD exacerbation (p<0.05) compared with ipratropium. Apart from an increased incidence of dry mouth in the tiotropium group, adverse events were similar between treatments. Tiotropium was effective in improving dyspnoea, exacerbations, health-related quality of life and lung function in patients with chronic obstructive pulmonary disease, and exceeds the benefits seen with ipratropium. The data support the use of tiotropium once-daily as first-line maintenance treatment in patients with chronic obstructive pulmonary disease. (+info)
Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas.
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A single nicotine exposure increases dopamine levels in the mesolimbic reward system for hours, but nicotine concentrations experienced by smokers desensitize nAChRs on dopamine neurons in seconds to minutes. Here, we show that persistent modulation of both GABAergic and glutamatergic synaptic transmission by nicotine can contribute to the sustained increase in dopamine neuron excitability. Nicotine enhances GABAergic transmission transiently, which is followed by a persistent depression of these inhibitory inputs due to nAChR desensitization. Simultaneously, nicotine enhances glutamatergic transmission through nAChRs that desensitize less than those on GABA neurons. The net effect is a shift toward excitation of the dopamine reward system. These results suggest that spatial and temporal differences in nicotinic receptor activity on both excitatory and inhibitory neurons in reward areas coordinate to reinforce nicotine self-administration. (+info)
Differential response of wheezes and ruttles to anticholinergics.
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Computerised breath sounds analysis was used to assess the response of infants with wheeze and ruttles to the drug ipratropium bromide. A mean decrease in breath sounds intensity occurred in infants with ruttles after five minutes (20.5 dB), but not until 20 minutes in those with wheeze (8.1 dB). This differential response may be related to different underlying pathophysiology. (+info)
Pharmacodynamic steady state of tiotropium in patients with chronic obstructive pulmonary disease.
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Tiotropium (Spiriva) is a new once-daily inhaled anticholinergic that has its effect through prolonged muscarinic (M)3 receptor antagonism. It has a clinically documented, long duration of action with once-daily dosing in chronic obstructive pulmonary disease (COPD). A single-centre, double-blind, ipratropium-controlled study was conducted in order to characterize the onset of pharmacodynamic steady state of tiotropium in patients with COPD. Thirty-one patients (25 male, six female) with a mean age of 62 yrs and a mean forced expiratory volume in one second (FEV1) of 1.13 L (38% of predicted) were randomly assigned to receive either tiotropium 18 microg once-daily from a dry-powder inhaler (HandiHaler, 20 patients), or ipratropium 40 microg four-times daily from a pressurized metered-dose inhaler (11 patients) for a period of 1 week. FEV1 and forced vital capacity (FVC) were measured 1 h prior to, and just before inhalation (mean value of the two measurements on test-day 1 was the baseline value, while on all other test days it was the trough value), and 0.5, 1, 2, 3, 4, 5, and 6 h after inhalation of the morning dose of the study drug (one capsule and two puffs) on days 1, 2, 3, and 8. Trough FEV1 following 8 days of tiotropium was 0.19 L (18%) above baseline. Approximately 90% of this increase was achieved within 24 h of the first dose (0.17 L, 16%). Trough FVC increased 0.67 L (27%) on test-day 8. Approximately 70% of the improvement was observed after two tiotropium doses (0.47 L, 19%). Achievement of FVC steady state was delayed compared to FEV1. Ipratropium performed typically with an onset of action within 30 min, a peak response between 1-2 h postdosing and a duration of action of approximately 4 h. It was concluded that forced expiratory volume in one second steady state with tiotropium is reached within 48 h, while continued improvements in forced vital capacity can be expected over or beyond the first week of therapy. The continued increases in forced vital capacity beyond 48 h suggests that maintenance bronchodilator therapy is required to achieve maximal changes in hyperinflation. (+info)
Receptor binding studies of soft anticholinergic agents.
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Receptor binding studies were performed on 24 soft anticholinergic agents and 5 conventional anticholinergic agents using 4 cloned human muscarinic receptor subtypes. The measured pK(i) values of the soft anticholinergic agents ranged from 6.5 to 9.5, with the majority being in the range of 7.5 to 8.5. Strong correlation was observed between the pK(i) s determined here and the pA 2 values measured earlier in guinea pig ileum contraction assays. The corresponding correlation coefficients (r2) were 0.80, 0.73, 0.81, and 0.78 for pK(i) (m1), pK(i) (m2), pK(i) (m3), and pK(i) (m4), respectively. Quantitative structure-activity relationship (QSAR) studies were also performed, and good characterization could be obtained for the soft anticholinergics containing at least 1 tropine moiety in their structure. For these compounds, the potency as measured by the pK i values was found to be related to geometric, electronic, and lipophilicity descriptors. A linear regression equation using ovality (O(e)), dipole moment (D), and a calculated log octanol-water partition coefficient (QLogP) gave reasonably good descriptions (r = 0.88) for the pK(i) (m3) values. (+info)
Anticholinergics in the treatment of chronic obstructive pulmonary disease.
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Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality in the world. In the majority of cases, the disease is the result of years of cigarette smoking. Contributing factors leading to bronchial obstruction in COPD include mucus hypersecretion and an increase in bronchial muscle tone, which is triggered mainly by cholinergic mechanisms. Anticholinergic bronchodilators reduce vagal cholinergic tone, the main reversible component of COPD; hence they are the first-line treatment for bronchial obstruction in COPD. In addition to improving lung function, anticholinergics improve dyspnea, quality of life and exercise tolerance, and they reduce exacerbations. When compared with other bronchodilators, anticholinergics show at least equivalent bronchodilator potency, but with fewer side effects. In addition, due to their unique site of action, anticholinergics can be effectively combined with other bronchodilators. The introduction of new, long-acting anticholinergics is a promising addition to the treatment of COPD and is expected to lead to improved treatment outcomes and improved patient compliance. (+info)
Aggregation of actin and cofilin in identical twins with juvenile-onset dystonia.
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The neuropathology of the primary dystonias is not well understood. We examined brains from identical twins with DYT1-negative, dopa-unresponsive dystonia. The twins exhibited mild developmental delays until age 12 years when they began developing rapidly progressive generalized dystonia. Genetic, metabolic, and imaging studies ruled out known causes of dystonia. Cognition was subnormal but stable until the last few years. Death occurred at ages 21 and 22 years. The brains were macroscopically unremarkable. Microscopic examination showed unusual glial fibrillary acidic protein-immunoreactive astrocytes in multiple regions and iron accumulation in pallidal and nigral neurons. However, the most striking findings were 1) eosinophilic, rod-like cytoplasmic inclusions in neocortical and thalamic neurons that were actin depolymerizing factor/cofilin-immunoreactive but only rarely actin-positive; and 2) abundant eosinophilic spherical structures in the striatum that were strongly actin- and actin depolymerizing factor/cofilin-positive. Electron microscopy suggested that these structures represent degenerating neurons and processes; the accumulating filaments had the same dimensions as actin microfilaments. To our knowledge, aggregation of actin has not been reported previously as the predominant feature in any neurodegenerative disease. Thus, our findings may shed light on a novel neuropathological change associated with dystonia that may represent a new degenerative mechanism involving actin, a ubiquitous constituent of the cytoskeletal system. (+info)