Belladonna alkaloids-induced behavioral changes and amnesia on open-field and step-through in 18-, 28-, and 38-day-old mice.
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AIM: To study the age-related changes of atropine (Atr), scopolamine (Sco), anisodine (AT3), and anisodamine (Ani) on behaviors and memories. METHODS: The behaviors and memories were measured with open-field test and step-through task. M-cholinergic receptors were determined by [3H] quinuclidinyl benzilate ([3H] QNB). RESULTS: During acquisition session (d 1) the 18-, 28-, and 38-d-old mice pretreated with Atr, Sco, and AT3 (0.02, 0.2, 2, or 20 mg.kg-1, i.p.) in open-field test showed increase in walking counts by 26%-42%, but decrease in rearing, grooming, and defecating counts for 50%-92%, 67%-100%, and 75%-100%, respectively. On recall session (d 2) the walking and rearing behaviors in the 18- and 28-d-old mice receiving Atr, Sco, and AT3 on d 1 were higher than those in the mice receiving saline. But a lower grooming behavior on d 2 was found in the mice receiving the drugs on d 1. On d 1 Ani 20 mg.kg-1 reduced the rearing behavior by 50% in 18-d-old mice and defecation by 33%-36% in 18- and 28-d-old mice. All the 4 belladonna alkaloids increased the number of avoidance-response errors and decreased the retention latencies in step-through task. Bmax of [3H] QNB binding sites in frontal cortex and hippocampus regions in the 38-d-old mice increased 7% and 23% vs in the mice of 18 d of age, respectively. CONCLUSION: 1) The effects of the belladonna alkaloids on behaviors and memories in adult mice were weaker than those in young mice. 2) The belladonna alkaloids-induced amnesia on passive avoidance-response in step-through was more sensitive than behavioral changes and amnesia on open-field. 3) According to the lowest effective doses which insulted the behaviors or memories in young mice, Sco was about 10, 100, and 1000 times more potent than Atr, AT3, and Ani, respectively. (+info)
Acute effect of pretreatment with single conventional dose of salmeterol on dose-response curve to oxitropium bromide in chronic obstructive pulmonary disease.
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BACKGROUND: An earlier study documented that, in patients with chronic obstructive pulmonary disease (COPD), addition of ipratropium bromide at the clinically recommended dose (40 microg) does not produce any further bronchodilation than that achieved with salmeterol 50 microg alone. However, the dose of ipratropium bromide needed to produce near maximal bronchodilation is several times higher than the customary dosage. The full therapeutic potential of combined salmeterol plus an anticholinergic drug can therefore only be established using doses higher than those currently recommended in the marketing of these agents. A study was undertaken to examine the possible acute effects of higher than conventional doses of an anticholinergic agent on the single dose salmeterol induced bronchodilation in patients with stable and partially reversible COPD. METHODS: Thirty two outpatients received 50 microg salmeterol or placebo. Two hours after inhalation a dose-response curve to inhaled oxitropium bromide (100 microg/puff) or placebo was constructed using one puff, one puff, two puffs, and two puffs-that is, a total cumulative dose of 600 microg oxitropium bromide. Dose increments were given at 20 minute intervals with measurements being made 15 minutes after each dose. On four separate days all patients received one of the following: (1) 50 microg salmeterol + 600 microg oxitropium bromide; (2) 50 microg salmeterol + placebo; (3) placebo + 600 microg oxitropium bromide; (4) placebo + placebo. RESULTS: Salmeterol induced a good bronchodilation (mean increase 0.272 l; 95% CI 0.207 to 0.337) two hours after its inhalation. Oxitropium bromide elicited an evident dose-dependent increase in forced expiratory volume in one second (FEV(1)) and this occurred also after pretreatment with salmeterol with a further mean maximum increase of 0.152 l (95% CI of differences 0.124 to 0.180). CONCLUSIONS: This study shows that acute pretreatment with 50 microg salmeterol does not block the possibility of inducing more bronchodilation with an anticholinergic agent when a higher than normal dosage of the muscarinic antagonist is used. (+info)
A randomised controlled comparison of tiotropium nd ipratropium in the treatment of chronic obstructive pulmonary disease. The Dutch Tiotropium Study Group.
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BACKGROUND: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. (+info)
Effects of clausenamide on anisodine-induced acetylcholine decrease and memory deficits in the mouse brain.
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OBJECTIVES: To study the action mechanism of a new cognition enhancer clausenamide and the effect of clausenamide on regional acetylcholine (ACh) levels, and to examine anisodine-induced ACh decrease in mice of memory deficits, and to compare the effect of (-)clausenamide on ACh with that of (+)clausenamide. METHODS: Animal amnesia model was induced by i.p. anisodine and brain ACh content was measured by high performance liquid chromatography with electrochemical detection. RESULTS: Single administration of (-)clausenamide or (+)clausenamide (10, 20, 50 mg/kg, i.g.) had no effect on the ACh level in the frontal cortex, hippocampus and striatum. However, pretreatment with (-)clausenamide (10, 20, 50 mg/kg, i.g.) significantly ameliorated the reduction of ACh induced by anisodine (10 mg/kg, i.p.) in a dose-dependent manner. Physostigmine (0.2 mg/kg, s.c.), as a cholinesterase inhibitor significantly increased the ACh levels and reversed the anisodine-induced ACh decrease. In contrast, (+)clausenamide had no effect on ACh decrease in all examined brain regions. (-)Clausenamide ameliorated anisodine-induced memory deficits in step-through test in mice. CONCLUSION: There is significant difference in the action of (-)clausenamide and (+)clausenamide. The protective action of (-)clausenamide against anisodine-induced amnesia is due to its ability to reverse the ACh reduction. (+info)
Learning deficits induced by 4 belladonna alkaloids are preferentially attenuated by tacrine.
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AIM: To examine the antagonism of tacrine on the amnesic effects of scopolamine (Sco), anisodine (AT3), atropine (Atr), and anisodamine (Ani). METHODS: Cognitive functions and locomotor activities were determined using two sessions of step-through and open-field tests, respectively. Mice were injected with one of the belladonna alkaloids (0.05-50 mumol.kg-1, i.p.) and tacrine (50 mumol.kg-1, s.c.) 30 min before the first session. RESULTS: Tacrine completely blocked the avoidance-learning deficit caused by Sco 0.5 mumol.kg-1, AT3 and Atr 5 mumol.kg-1, or Ani 50 mumol.kg-1. But tacrine partly antagonized the learning deficit induced by Sco 5-50 mumol.kg-1 or Atr and AT3 50 mumol.kg-1. The avoidance-memory deficit caused by Sco 0.05-5 mumol.kg-1 or Atr 5 mumol.kg-1 was completely or partly attenuated by tacrine, which did not antagonize the memory deficit elicited by Sco and Atr 50 mumol.kg-1, AT3 5 and 50 mumol.kg-1, and Ani 50 mumol.kg-1. During the acquisition, the locomotor activity of the mice was inhibited by tacrine. This reduction was completely antagonized by Sco 0.5-50 mumol.kg-1, AT3 5-50 mumol.kg-1, Atr 5-50 mumol.kg-1, and only partly antagonized by AT3 and Atr 0.5 mumol.kg-1 or Ani 50 mumol.kg-1. CONCLUSION: Compared with the avoidance-memory deficit, the avoidance-learning deficit caused by belladonna alkaloids is more preferentially attenuated by tacrine. (+info)
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)
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)