Reproducibility of airway response to inhaled bradykinin and effect of the neurokinin receptor antagonist FK-24 in asthmatic subjects

Objective: Inhaled neurokinins have been shown to induce bronchoconstriction in asthmatic subjects. We have investigated the effect of a neurokinin receptor antagonist, FK-224, on bradykinin (BK)-induced bronchoconstriction, and have compared its effect with the spontaneous variability of BK responsiveness. Methods: Thirteen subjects with mild extrinsic bronchial asthma participated in the study. Four BK inhalation challenge tests (Study Days 2 to 5) were performed over a period of several weeks. On Study Days 4 and 5 subjects inhaled either 2 mg FK-224 or placebo 30 min before the BK challenge. Results: The geometric mean PC₂₀FEV₁ of BK was 0.04, 0.06, and 0.10 mg⋅ml⁻¹ on the first and second BK challenge and after placebo. Mean PC₂₀FEV₁ after FK-224 was 0.20 mg⋅ml⁻¹ and was not different from placebo, whereas there was a significant effect in PC₁₅FEV₁. The mean shift in PC₂₀FEV₁ after FK-224 vs placebo was 1.0 doubling concentrations. The mean changes in BK responsiveness on the second BK challenge and placebo days compared to the first BK challenge were 0.6 and 1.3 doubling concentrations. We observed a significant fall in FEV₁ after inhalation of saline plus ethanol, which was the diluent for BK (mean decrease 4.2%). Conclusion: The data demonstrate that inhalation of 2 mg FK-224 is only marginally effective against BK-induced bronchoconstriction in mild asthmatic subjects and that its effect is similar to the variability in BK responsiveness assessed over several weeks. Received: 18 August 1995/Accepted in revised form: 3 January 1996     

Relative efficacy of three different inhalers containing salbutamol in patients with asthma

Objective: To investigate the relative efficacy of three inhalers containing salbutamol: Turbuhaler (TBH), Rotahaler (RH) and Diskhaler (DH). Methods: A randomized, open, three-way crossover, cumulative dose response study was performed in 20 patients with asthma with mean forced expiratory volume in 1s (FEV₁) values of 60% of predicted (range 41–90%) and a 27% reversibility in FEV₁ (range 15–61%). Four doses of salbutamol were inhaled at 30-min intervals: 50 μg, 50 μg, 100 μg and 200 μg by TBH and 200 μg, 200 μg, 400 μg and 800 μg by both RH and DH. FEV₁ was measured at baseline and 25 min after each dose. Results: The increases in FEV₁ after the first doses (50 μg by TBH, 200 μg by RH and by DH) were not statistically significantly different (23.6%, 25.1% and 28%, respectively). Based on the parallel shift in the dose response curves, salbutamol TBH was calculated to be 2.4 times as potent as salbutamol RH (95% confidence interval 1.4–3.3) and 2.2 times as potent as salbutamol DH (90% CI 1.3–3.3). Additionally, during dosing with TBH, fewer patients experienced adverse events than during dosing with RH or DH. Conclusion: Turbuhaler is a twofold more efficient inhaler for salbutamol than Rotahaler or Diskhaler as measured by its bronchodilating effect. Received: 15 February 1996/Accepted in revised form: 16 February 1996     

The efficacy of a low-dose, monodisperse parasympathicolytic aerosol compared with a standard aerosol from a metered-dose inhaler

Objective: In previous experiments we showed that monodisperse bronchodilator aerosols with a median mass aerodynamic diameter of 2.8 μm induced stronger bronchodilatations than larger aerosols and that the dilatations were clinically relevant at low doses. To discover whether the bronchodilator effects of these low-dose monodisperse aerosols differed from those of standard dosages delivered by metered-dose inhalers, we carried out a comparative trial. Methods: Ten stable outpatients with a mean forced expiratory volume in 1 s (FEV₁) of 58.1% of the predic-ted value inhaled a placebo aerosol, 8 μg of a 2.8-μm monodisperse ipratropium bromide aerosol and 40 μg from a metered-dose inhaler plus spacer; lung-function measurements followed. Data were analysed with repeated measurements analysis of variance (ANOVA). Results: Greater improvements than with placebo were evident for the forced vital capacity (FVC), the FEV₁, the specific airway conductance (sGaw), the peak flow (PEF) and the maximum expiratory flow at 75% of the forced vital capacity (MEF₇₅). In these cases, the low-dose 2.8-μm aerosol proved to be equivalent to the higher-dose metered-dose inhaler. Conclusion: By changing the polydisperse characteristic of inhaled aerosols to a monodisperse pattern, the dose of the drug administered can be reduced without loss of efficacy. Received: 5 August 1997 / Accepted in revised form: 25 October 1997     

Evaluation of plasma and urinary salbutamol levels in COPD

Objective: To evaluate the use of trough plasma salbutamol and overnight urinary salbutamol excretion in the assessment of nebulised salbutamol delivery in patients with chronic obstructive pulmonary disease (COPD). Methods: Twenty in-patients with COPD receiving nebulised salbutamol, age 69.7 years, FEV₁ 38.1% predicted, were studied on two consecutive days, receiving four 2.5 mg doses of nebulised salbutamol on day 1 and four 5 mg doses of nebulised salbutamol on day 2, the first dose at 8.00 h the last dose at 22.00 h. Salbutamol delivery was assessed after the last dose by trough plasma salbutamol 8.00 h and overnight urinary excretion of salbutamol (22.00–8.00 h). Results: Levels of urinary salbutamol were detectable in all 20 patients at both doses, whereas for plasma salbutamol detectable levels were only found in 16/20 cases at the 2.5 mg dose and in all cases at the 5 mg dose. For overnight urinary salbutamol (μg⋅10 h⁻¹  n = 20) the results were 141 for 2.5 mg and 249 for 5 mg. The dose ratio for urinary salbutamol between 2.5 mg and 5 mg doses was 1.83. Results for plasma salbutamol (ng/ml, n = 16) were 1.58 at 2.5 mg and 2.43 at 5 mg: dose ratio (geometric mean) 1.49. Conclusion: Overnight urinary salbutamol provides a simple and effective measure of nebulised salbutamol delivery in patients with COPD, which would be suitable for studying nebuliser performance and compliance. Received: 14 March 1996/Accepted in revised form: 14 May 1996     

Oral bambuterol compared to inhaled salmeterol in patients with partially reversible chronic obstructive pulmonary disease

Objective: There is now good evidence that inhaled salmeterol is an effective agent in chronic obstructive pulmonary disease (COPD),but, at the present time, data on the effects of bambuterol, which is an oral tarbutaline pro-drug, in patients with COPD are scarce. Moreover, no comparative study between bambuterol and salmeterol in patients with chronic obstructive airway disorders has been published. The objective of this research was, consequently, to compare the efficacy and safety of 20 mg oral bambuterol and 50 μg inhaled salmeterol in patients with partially reversible COPD. Methods: The speed and length of bronchodilation with 20 mg bambuterol and 50 μg inhaled salmeterol were compared in 16 patients with partially reversible COPD. The investigation and designed as a double-blind, double-dummy, cross-over, placebo controlled and randomised study. Lung function (FEV₁, FVC) and systemic variables (subjective tremor, heart rate, blood pressure) were monitored prior to the administration of the drug and for 12 h after each agent on 3 non-consecutive days. Results: Inhalation of salmeterol induced a significant (P < 0.05) increase of lung function when compared with placebo. In addition, oral bambuterol elicited good bronchodilation, with its maximum slightly later than for salmeterol. The mean (±SE) AUC_0–12 hs for all patients were 3.134 1 ± 0.553 for salmeterol and 1963 1 ± 0.573 for bambuterol. Both AUC_0–12 h s were significantly greater than for placebo (P < 0.05), but there was no significant difference (P = 0.077) between the salmeterol and bambuterol AUC_0–12 hs. Bambuterol, but not salmeterol, caused tremor in four patients. Moreover, it induced a higher heart rate when compared with salmeterol at each considered time after the administration of the drug; differences after 9 and 12 h  were statistically significant (P < 0.05). Conclusion: Both oral bambuterol and inhaled salmeterol resulted in good bronchodilation in patients with stable COPD. However, bambuterol, but not salmeterol, caused tremor in several subjects and elicited a more pronounced tachycardia. Received: 11 May 1998 / Accepted in revised form: 13 September 1998     

Survey to determine the efficacy and safety of guideline-based pharmacological therapy for chronic obstructive pulmonary disease patients not previously receiving maintenance treatment

Objective: To investigate the potential beneficial effects of guideline-based pharmacological therapy on pulmonary function and quality of life (QOL) in Japanese chronic obstructive pulmonary disease (COPD) patients without prior treatment.

Research design and methods: Multicenter survey, open-label study of 49 Japanese COPD patients aged ≥ 40 years; outpatients with >10 pack years of smoking history; ratio of forced expiratory volume in 1 s (FEV₁)/forced vital capacity (FVC) < 70%; predicted FEV₁ < 80%; treated with bronchodilators and/or inhaled corticosteroids as maintenance therapy until week 48.

Main outcome measures: The primary endpoint was change in pulmonary function (trough FEV₁, trough FVC); secondary endpoints were QOL and physical activity at 48 weeks after initiation of therapy.

Results: Airway reversibility was confirmed in untreated patients. Significant changes over time were not observed for FEV₁ and FVC, indicating lung function at initiation of treatment was maintained during the observation period. COPD assessment test scores showed statistical and clinical improvements. Cough, sputum, breathlessness, and shortness of breath were significantly improved.

Conclusions: Lung function and QOL of untreated Japanese COPD patients improved and improvements were maintained by performing a therapeutic intervention that conformed to published guidelines.     

茶碱缓释片联合噻托溴铵干粉治疗稳定期慢性阻塞性肺疾病的临床研究

目的 探讨茶碱缓释片联合噻托溴铵干粉治疗稳定期慢性阻塞性肺疾病（COPD）的临床疗效,并分析其对患者肺功能和气道重塑的影响。方法 选择2013年4月-10月稳定期COPD患者90例,随机分为对照组（43例）和治疗组（47例）。对照组口服茶碱缓释片0.1 g/次,每12小时1次。治疗组在对照组治疗基础上应用噻托溴铵,1 粒/次,1次/d。两组均连续治疗2个月。治疗结束后,评估患者治疗前后1秒钟用力呼气量（FEV₁）、FEV₁占预计值的百分比（FEV₁%Pred）、FEV₁/用力肺活量（FVC）,采用呼吸疾病问卷（SGRQ）进行生活质量评估;应用6 min步行距离（6MWD）观察两组患者运动耐力的变化情况。检测治疗前后两组患者痰液中基质金属蛋白酶-9（MMP-9）和白介素-8（IL-8）的水平变化。结果 治疗后两组FEV₁、FEV₁%Pred、FEV₁/FVC均高于同组治疗前,经统计学分析,差异均有统计学意义（P<0.05）。治疗后,治疗组FEV₁、FEV₁%Pred、FEV₁/FVC均高于对照组,两组比较差异有统计学意义（P<0.05）。治疗后,两组6MWD高于治疗前,同组治疗前后比较差异有统计学意义（P<0.05）,且治疗组6MWD明显高于对照组,两组比较差异有统计学意义（P<0.05）。治疗后两组SGRQ评分、MMP-9、IL-8均低于同组治疗前,差异有统计学意义（P<0.05）;治疗后治疗组SGRQ评分、MMP-9、IL-8显著低于对照组,两组比较差异有统计学意义（P<0.05）结论 茶碱缓释片联合噻托溴铵干粉对稳定期COPD具有显著的治疗效果,能够改善患者肺功能和气道重塑,值得临床推广应用。     

β-adrenoceptor blockers and pulmonary function in the general population: the Rotterdam Study

Aim

β-adrenoceptor blockers have been used with caution in patients with obstructive lung diseases such as asthma or chronic obstructive pulmonary disease (COPD), due to the potentially increased airway reactivity and risk of bronchial obstruction. Cardioselective β-adrenoceptor blockers have a more beneficial profile than non-cardioselective β-adrenoceptor blockers and can be safely prescribed to patients with both cardiovascular disease and COPD. We hypothesized that cardioselective β-adrenoceptor blockers also affect pulmonary function.

Methods

This study was performed within the Rotterdam Study, a prospective population-based cohort study. Effects of cardioselective and non-cardioselective β-adrenoceptor blockers on pulmonary function were analysed using regression techniques with multivariable adjustment for potential confounders.

Results

Current use of non-cardioselective β-adrenoceptor blockers was significantly associated with a lower forced expiratory volume in 1 s (FEV₁) of −198 ml (95% CI −301, −96), with a lower forced vital capacity (FVC) of −223 ml (95% CI −367, −79) and with a decreased FEV₁ : FVC of −1.38% (95% CI −2.74, −0.13%). Current use of cardioselective β-adrenoceptor blockers was significantly associated with a lower FEV₁ of −118 ml (95% CI −157, −78) and with a lower FVC of −167 ml (95% CI −222, −111), but did not affect FEV₁ : FVC. After exclusion of patients with COPD, asthma and heart failure the effects of cardioselective β-adrenoceptor blockers remained significant for FEV₁ (−142 ml [95% CI −189, −96]) and for FVC (−176 ml [95% CI −236, −117]).

Conclusion

In our study both non-cardioselective and cardioselective β-adrenoceptor blockers had a clinically relevant effect on both FEV₁ and FVC. In contrast to cardioselective β-adrenoceptor blockers, use of non-cardioselective β-adrenoceptor blockers was associated with a significantly lower FEV₁ : FVC.     

Dose-dependent influence of buspirone on the activities of selective serotonin reuptake inhibitors in the mouse forced swimming test

Recent clinical data suggest that buspirone may enhance the efficacy and/or reduce the latency to therapeutic effect of selective serotonin reuptake inhibitors (SSRIs) in unipolar major depressive disorder. The present study, using the mouse forced swimming test, was performed to investigate further the mechanisms involved in the potential antidepressant-enhancing effects of buspirone. Prior administration of buspirone (0.06 mg kg⁻¹, IP) significantly enhanced the anti-immobility effects of subactive doses of fluvoxamine (4 mg kg⁻¹, IP; P < 0.01), paroxetine (4 mg kg⁻¹, IP; P < 0.01), citalopram (4 mg kg⁻¹, IP; P < 0.01) and sertraline (2 mg kg⁻¹, IP; P < 0.01) in the forced swimming test. However, pretreatment with buspirone did not induce antidepressant-like effects when tested in combination with fluoxetine (4 mg kg⁻¹, IP). Each antidepressant tested reduced immobility time in the forced swimming test [citalopram (16 mg kg⁻¹, IP; P < 0.01), fluoxetine (32 mg kg⁻¹, IP; P < 0.01), fluvoxamine (32 mg kg⁻¹, IP; P < 0.01), paroxetine (16 mg kg⁻¹, IP; P < 0.01) and sertraline (16 mg kg⁻¹, IP; P < 0.01)]. Pretreatment with buspirone (0.5 mg kg⁻¹, IP), or its major metabolite 1-PP (0.5 mg kg⁻¹, IP), attenuated all SSRI-induced anti-immobility effects (P < 0.01). Concomitant studies of locomotor activity ruled out any stimulant or sedative effects of the interactions. The results of the present study suggested that low dose buspirone enhanced the activity of subactive doses of SSRIs in the mouse forced swimming test, probably via an action at 5-HT_1A receptors. On the other hand, a high dose of buspirone attenuated the antidepressant-like effects of active doses of these drugs, possibly via the generation of an active metabolite (1-PP) acting at alpha₂-adrenoreceptors. Received: 19 October 1997 / Final version: 16 December 1997     

Effects of histamine H3 receptor ligands in experimental models of anxiety and depression

Histamine H₃ receptor ligands have been proposed to be of potential therapeutic interest for the treatment of different central nervous system disorders; however, the psychopharmacological properties of these drugs have not been studied extensively. In this work, we investigated the possible involvement of histamine H₃ receptor function in experimental models of anxiety (elevated plus-maze) and depression (forced swimming test). Male Sprague-Dawley rats were treated IP with the histamine H₃ receptor agonist R-α-methylhistamine (10 mg/kg) or the histamine H₃ receptor antagonist thioperamide (0.2, 2 and 10 mg/kg) and 30 min afterwards the time spent in the open arms of an elevated plus-maze was registered for 5 min. The immobility time of male OF1 mice in the forced swimming test was recorded for 6 min, 1 h after the IP administration of R-α-methylhistamine (10 and 20 mg/kg), thioperamide (0.2, 2, 10 and 20 mg/kg) or another histamine H₃ receptor antagonist, clobenpropit (5 mg/kg). The locomotor activity of mice was checked in parallel by means of an activity meter. Both saline controls and active drug controls were used in all the paradigms. Neither thioperamide nor R-α-methylhistamine significantly changed animal behaviour in the elevated plus-maze. R-α-methylhistamine and the higher dose of thioperamide assayed (20 mg/kg) were also inactive in the forced swimming test. By contrast, thioperamide (0.2–10 mg/kg) dose-dependently decreased immobility, the effect being significant at 10 mg/kg (33% reduction of immobility); clobenpropit produced an effect qualitatively similar (24% reduction of immobility). None of these histamine H₃ receptor antagonists affected locomotor activity. These preliminary results suggest that the histamine H₃ receptor blockade could be devoid of anxiolytic potential but have antidepressant effects. Besides, the stimulation of these receptors does not seem to be followed by changes in the behavioural parameters studied. Received: 1 July 1998/Final version: 8 September 1998     

Phenacetin O-deethylation by human liver microsomes in vitro: inhibition by chemical probes,SSRI antidepressants,nefazodone and venlafaxine

Biotransformation of phenacetin via O-deethylation to acetaminophen, an index reaction reflecting activity of Cytochrome P450-1A2, was studied in microsomal preparations from a series of human livers. Acetaminophen formation was consistent with a double Michaelis-Menten system, with low-K_m (mean K_m1 = 68 μM) and high-K_m (mean K_m2 = 7691 μM) components. The low-K_m enzyme accounted for an average of 96% of estimated intrinsic clearance, and was predicted to contribute more than 50% of net reaction velocity at phenacetin concentrations less than 2000 μM. Among index inhibitor probes, α-naphthoflavone was a highly potent inhibitor of the low-K_m enzyme (K_i1 = 0.013 μM); furafylline also was a moderately active inhibitor (K_i1 = 4.4 μM), but its inhibiting potency was increased by preincubation with microsomes. Ketoconazole was a relatively weak inhibitor (K_i1 = 32 μM); quinidine and cimetidine showed minimal inhibiting activity. Among six selective serotonin reuptake inhibitor (SSRI) antidepressants, fluvoxamine was a potent inhibitor of 1A2 (mean K_i1 = 0.24 μM). The other SSRIs were more than tenfold less potent. Mean K_i1 values were: fluoxetine, 4.4 μM; norfluoxetine, 15.9 μM; sertraline, 8.8 μM; desmethylsertraline, 9.5μM; paroxetine, 5.5 μM. The antidepressant nefazodone and four of its metabolites (meta-chloro-phenylpiperazine, two hydroxylated derivatives, and a triazoledione) were very weak inhibitors of P450-1A2. Venlafaxine and its O- and N-desmethyl metabolites showed minimal inhibitory activity. Received: 18 March 1996/Final version: 10 July 1996     

The optimal particle size for parasympathicolytic aerosols in mild asthmatics

Background: the optimal particle size of a parasympathicolytic aerosol is unknown. Methods: eight stable asthmatics with a mean FEV₁ of 72% of the predicted value inhaled three types of monodisperse ipratropium bromide aerosols, with particle sizes of 1.5, 2.8 and 5 μm, respectively, and a placebo aerosol. The volunteers inhaled 8 μg ipratropium bromide, after which lung function improvement was determined. The changes in lung function were analysed with repeated measurements ANOVA. Results: according to the changes in FEV₁ and MEF_50/25 the 1.5/2.8 μm aerosol induced significantly better bronchodilatation than the 5 μm aerosol. No particle size effect was noticeable with regard to changes in R_cot, VC, FVC and PEF. Conclusions: in mild asthmatics the particle size of choice for a parasympathicolytic aerosol should be ≤ 2.8 μm.     

The effect of oxitropium bromide on neurokinin A-induced bronchoconstriction in asthmatic subjects

In some animal species substance P and neurokinin A (NKA) cause bronchoconstriction by the release of acetylcholine from postganglionic cholinergic nerve endings. The aim of the present study was to investigate the effect of an anticholinergic drug, oxitropium bromide, on bronchoprovocation with NKA in asthmatics. Eleven mild asthmatics (mean % predicted FEV₁ 85.5) received on 2 separate days, double blind, in a randomised order, 400 mcg oxitropium bromide or placebo, 90 min before challenge with NKA. NKA was inhaled at 3 concentrations (10⁻⁴, 3.10⁻⁴ and 10⁻³ M). Specific airways conductance (sGaw) and forced expiratory volume in 1 s (FEV₁) were used as parameters of airway calibre. Compared to the placebo-aerosol, oxitropium bromide caused a significant increase in sGaw and FEV₁. On the placebo-treatment day, NKA caused a concentration-dependent decrease in sGaw and FEV₁. The percentage changes in sGaw and FEV₁ on the oxitropium day were not statistically different from those occurring on the placebo day. We conclude that oxitropium bromide caused a significant bronchodilation but offered no significant protection against NKA-induced bronchoconstriction in mild asthmatic subjects.     

Systemic and bronchodilator effects of inhaled rac-formoterol in subjects with chronic obstructive pulmonary disease: a dose-response study

AIMS

Rac-formoterol is effective as maintenance treatment for both asthma and chronic obstructive pulmonary disease (COPD) and is now used as relief therapy in asthma. Using rac-formoterol for relief and maintenance treatment could involve inhalation of high doses, and whether this is of benefit in COPD is uncertain. Our aim was to determine whether higher doses of inhaled rac-formoterol produce systemic adverse effects that outweigh the limited bronchodilator benefit seen in subjects with COPD.

METHODS

We examined airway and systemic effects of 6, 12, 24 and 48 μg rac-formoterol and placebo on separate days in 20 subjects with symptomatic COPD [forced expiratory volume in 1 s (FEV₁) 47% predicted]. FEV₁, oxygen saturation, dyspnoea, 6-min walk distance, patient satisfaction and systemic effects were measured and treatment was assessed against placebo and for dose–response effects.

RESULTS

FEV₁[area under the time–response curve (AUC)] and satisfaction scores increased with all formoterol doses compared with placebo, as did AUC tremor with the 24- and 48-μg doses and AUC heart rate with the 48-μg dose. A dose–response relationship was seen with FEV₁ and tremor, but not with satisfaction scores. There was no difference between placebo and rac-formoterol for other variables.

CONCLUSIONS

Our results show that in patients with COPD rac-formoterol improves FEV₁ and patient satisfaction without a corresponding reduction in dyspnoea. Since the systemic effects from a relatively high dose were minimal, its use as relief medication in COPD merits further evaluation.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The long-acting inhaled β₂-agonist formoterol has systemic effects when taken in high doses.
• It can be used as relief medication in asthma and there is interest in this approach in chronic obstructive pulmonary disease (COPD).
• Relief medication can involve high doses, and in subjects with COPD who have limited ability to bronchodilate the adverse effects can outweigh the benefits.
• There are concerns with the overall safety of high-dose β₂-agonists in subjects with COPD, and this study looks at the balance of beneficial and adverse effects of a range of doses of inhaled formoterol.

WHAT THIS STUDY ADDS

• Among subjects with COPD, high-dose inhaled formoterol produced a dose-related increase in forced expiratory volume in 1 s without a corresponding reduction in dyspnoea or increase in walk distance.
• Systemic effects were modest, however, and high doses did not appear to reduce patient satisfaction.
• Although further safety data are needed, inhaled formoterol may have a role as relief medication in COPD.

     

Once-daily glycopyrronium bromide (Seebri Breezhaler®) for the treatment of chronic obstructive pulmonary disease (COPD)

Introduction: Long-acting bronchodilators are the mainstay of pharmacological therapy for patients with chronic obstructive pulmonary disease (COPD). The choice of optimal bronchodilator therapy for COPD is increasingly difficult for clinicians as new treatments are marketed.Areas covered: Inhaled glycopyrronium bromide (Seebri Breezhaler®) is a well-tolerated long-acting anti-muscarinic agent (LAMA) with a fast onset of action. In patients with moderate to severe COPD, glycopyrronium bromide has clinically important effects on level of FEV₁, use of relief medication, day-time dyspnea scores, and probably also on health status. Furthermore, glycopyrronium bromide also has beneficial effects on dynamic hyperinflation and, probably by that, exercise tolerance. Glycopyrronium bromide has been shown to reduce the rate of exacerbations in patients with moderate to severe COPD, although as a secondary outcome only. Expert opinion: Once-daily inhaled glycopyrronium bromide has positive impact on important COPD outcomes, comparable to the effects of other marketed LAMAs. Once-daily administration may improve adherence, and glycopyrronium bromide has the potential for a role in the future management of COPD similar to that of other long-acting anti-muscarinic agents, including tiotropium. Studies of glycopyrronium bromide with exacerbation rate as the primary outcome of interest is needed.     

参麦注射液联合沙美特罗替卡松治疗慢性阻塞性肺疾病合并呼吸衰竭的临床研究

目的探讨参麦注射液联合沙美特罗替卡松粉吸入剂治疗慢性阻塞性肺疾病(COPD)合并呼吸衰竭的临床疗效。方法选取2013年6月—2015年6月重庆三博长安医院呼吸内科收治的COPD合并呼吸衰竭患者78例,按治疗方案的差别分为对照组和治疗组,每组各39例。对照组患者在常规治疗基础上雾化吸入沙美特罗替卡松粉吸入剂,1吸/次,2次/d。治疗组在对照组的基础上静脉输注参麦注射液,100 m L/次,1次/d。两组患者均治疗14 d。观察两组临床疗效,并比较两组患者的动脉血气指标、肺功能指标,白细胞(WBC)、C反应蛋白(CRP)和降钙素原(PCT)的变化。结果治疗后,对照组与治疗组患者的总有效率分别为79.49%、94.87%,两组总有效率比较差异有统计学意义(P0.05)。治疗后,两组患者的p H值和p O2均较治疗前显著升高,而p CO2却较治疗前显著降低,同组治疗前后差异具有统计学意义(P0.05);且治疗组这些观察指标的改善程度明显优于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者FEV1、FVC以及FEV1/FVC均较治疗前显著升高,同组治疗前后差异具有统计学意义(P0.05);且治疗组这些观察指标的改善程度明显优于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者的WBC、CRP和PCT均较治疗前显著下降,同组治疗前后差异具有统计学意义(P0.05);且治疗组这些观察指标的改善程度明显好于对照组,两组比较差异具有统计学意义(P0.05)。结论参麦注射液联合沙美特罗替卡松粉吸入剂治疗COPD合并呼吸衰竭具有较好的临床疗效,能降低呼吸道中的炎症反应,明显改善肺功能,具有一定的临床推广应用价值。     

Gepirone and 1-(2-pyrimidinyl)-piperazine in vitro: human cytochromes mediating transformation and cytochrome inhibitory effects

Biotransformation of gepirone to its principal metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP), was studied in human liver microsomes and in microsomes from cDNA-transfected human lymphoblastoid cells. Formation of 1-PP from gepirone in liver microsomes proceeded with a mean apparent K _m ranging from 335 to 677 μM. Coincubation with 1 μM ketoconazole reduced reaction velocity to less than 5% of control values at a gepirone concentration of 250 μM. Three other metabolites, presumed to be hydroxylated products, were also formed from gepirone. Formation of all three products was reduced to approximately 20% of control values by 1 μM ketoconazole; quinidine at 1 μM produced a small reduction in formation (91–94% of control) of two of the metabolites. 1-PP was formed from gepirone exclusively by pure P450-3A4 with a K _m of 849 μM; K _m values for the other metabolites were 245, 240, and 415 μM. Two of the products were also formed by P450-2D6. The results indicate that 3A4 is the principal cytochrome mediating 1-PP formation, as well as formation of the other metabolites. The properties of gepirone and 1-PP themselves as cytochrome inhibitors were tested in human liver microsomes using index reactions representing activitiy of P450-1A2, -2C9, -2C19, -2D6, -2E1 and -3A. Gepirone and 1-PP produced negligible inhibition of all these reactions. Thus gepirone at therapeutic doses in humans has a low likelihood of inhibiting P450-mediated drug metabolism involving these cytochromes. Received: 26 November 1997/Final version: 6 February 1998     

The effect of aerosolized SK&F 104353-Z2 on the bronchoconstrictor effect of leukotriene D4 in asthmatics

Leukotriene D₄ (LTD₄) is a potent bronchoconstrictor and vasoactive mediator that has been implicated in the pathogenesis of bronchial asthma. We have studied the effect of SK&F 104353-Z₂, a specific LTD₄ antagonist, on LTD₄-induced bronchoconstriction in asthmatics. A total of 12 mild asthmatics (mean baseline FEV1 ± SEM: 85.9% ± 2.6) received on 2 separate days, double-blind and cross-over, 800 μg SK&F 104353-Z₂ or placebo via aerosol. After 30 min, doubling concentrations of LTD₄ (0.078 to 20.1 μM in the first 4 patients and up 80.4 μM in the other patients) were inhaled with intervals of 30 min. Specific airways conductance (sGaw) and forced expiratory volume in 1 s (FEV₁) were measured. On the placebo-day LTD₄ inhalation caused a concentration dependent bronchoconstriction. The effect of SK&F 104353-Z₂ on baseline sGaw and FEV₁ could be evaluated in 10 patients. After inhalation of SK&F 104353-Z₂ a small, but significant increase, in sGaw (0.107 ± 0.013 to 0.132 ± 0.011 cm H2O⁻¹s⁻¹) and FEV₁ (3.39 ±0.23 to 3.56 ±0.25 liter) was observed. The effect of SK&F 104353-Z₂ on the dose-response curve for LTD₄ was evaluated in the six patients who inhaled concentrations of LTD₄ up to 80 μM. On the active treatment day, the dose-response curve for LTD₄ was significantly shifted to the right. Geometric mean PC₂₀ LTD₄ (FEV₁) (μM) was 4.4 (range 1.5–11.6) on the placebo and 54.1 (2.8–81) on the active treatment day (p < 0.05). Geometric mean PC₃₅ LTD₄ (sGaw) (μM) was 2.75 (0.2–80.4) on the placebo and 22.7 (0.1–81.0) on the active treatment day (NS). We conclude that inhaled SK&F 104353-Z₂ is able to antagonize the bronchoconstrictor effect of inhaled LTD₄ in asthmatics.     

Human cytochromes mediating N-demethylation of fluoxetine in vitro

Biotransformation of the selective serotonin reuptake inhibitor antidepressant, fluoxetine, to its principal metabolite, norfluoxetine, was evaluated in human liver microsomes and in microsomes from transfected cell lines expressing pure human cytochromes. In human liver microsomes, formation of norfluoxetine from R,S-fluoxetine was consistent with Michaelis-Menten kinetics (mean K_m = 33 μM), with evidence of substrate inhibition at high substrate concentrations in a number of cases. The reaction was minimally inhibited by coincubation with chemical probes inhibitory for P450-2D6 (quinidine), -1A2 (furafylline, α-naphthoflavone), and -2E1 (diethyldithiocarbamate). Substantial inhibition was produced by coincubation with sulfaphenazole (K_i = 2.8 μM), an inhibitory probe for P450-2C9, and by ketoconazole (K_i = 2.5 μM) and fluvoxamine (K_i = 5.2 μM). However, ketoconazole, relatively specific for P450-3A isoforms only at low concentrations, reduced norfluoxetine formation by only 20% at 1 μM, and triacetyloleandomycin (≥ 5 μM) reduced the velocity by only 20–25%. Microsomes from cDNA-transfected human lymphoblastoid cells containing human P450-2C9 produced substantial quantities of norfluoxetine when incubated with 100 μM fluoxetine. Smaller amounts of product were produced by P450-2C19 and -2D6, but no product was produced by P450-1A2, -2E1, or 3A4. Cytochrome P450-2C9 appears to be the principal human cytochrome mediating fluoxetine N-demethylation. P450-2C19 and -3A may make a further small contribution, but P450-2D6 is unlikely to make an important contribution. Received: 23 December 1996 / Final version: 4 March 1997     

盐酸丙卡特罗口服或硫酸特布他林雾化联合布地奈德雾化治疗儿童咳嗽变异性哮喘的有效性及经济性研究

目的 比较盐酸丙卡特罗口服溶液口服联合布地奈德雾化与硫酸特布他林雾化液雾化吸入联合布地奈德雾化治疗儿童咳嗽变异性哮喘患儿的有效性和经济性。方法 纳入2020年1月—2020年12月上海中医药大学附属龙华医院收治的120例咳嗽变异性哮喘患儿,按随机数字表法将其分为丙卡特罗组与特布他林组,每组各60例。丙卡特罗组予以布地奈德雾化联合盐酸丙卡特罗口服溶液口服治疗,特布他林组予以布地奈德联合硫酸特布他林雾化治疗。评估两组疗效和安全性。比较两组治疗前后1秒用力呼气容积（FEV₁）、用力肺活量（FVC）、呼气峰值流速（PEF）、嗜酸性粒细胞（EOS）、免疫球蛋白E（IgE）水平。比较两组成本-效果。结果 特布他林组总有效率（96.67%）显著高于丙卡特罗组（86.67%,P＜0.05）。两组患儿治疗后FEV₁、FVC、PEF显著高于治疗前（P＜0.05）,特布他林组患儿FEV₁、FVC、PEF显著高于丙卡特罗组（P＜0.05）。两组患儿治疗后EOS和IgE水平显著低于治疗前（P＜0.05）,特布他林组患儿EOS和IgE水平显著低于丙卡特罗组（P＜0.05）。特布他林组患儿不良反应发生率与丙卡特罗组比较差异无统计学意义（P＞0.05）。丙卡特罗组治疗经济学显著优于特布他林组（P＜0.05）。结论 与丙卡特罗口服液相比,硫酸特布他林雾化吸入治疗儿童咳嗽变异性哮喘可能具有较好效果及安全性,但丙卡特罗口服液具有更高经济价值。