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In this large, randomized trial, the investigators compared outcomes in patients with chronic obstructive pulmonary disease (COPD) treated with once-daily inhalation of tiotropium or placebo. There was no benefit of treatment on the rate of loss of lung function over time, although benefits were observed in some secondary end points. These investigators compared outcomes in patients with chronic obstructive pulmonary disease treated with once-daily inhalation of tiotropium or placebo. There was no benefit of treatment on the rate of loss of lung function over time, although benefits were observed in some secondary end points. Prospective studies testing effects on the progression of chronic obstructive pulmonary disease (COPD) through the evaluation of the slope of the forced expiratory volume in 1 second (FEV 1 ) have not shown that inhaled short-acting anticholinergic drugs, inhaled corticosteroids, or N -acetylcysteine alter this marker of disease progression. 1 – 7 To date, only smoking cessation has prospectively been shown to alter the rate of decline of FEV 1 in patients with COPD. 2 Tiotropium is a once-daily, inhaled anticholinergic drug that provides at least 24-hour improvements in airflow and hyperinflation in patients with COPD. 8 – 10 Clinical trials lasting 6 weeks to . . .

Some patients with asthma have frequent exacerbations and persistent airflow obstruction despite treatment with inhaled glucocorticoids and long-acting beta-agonists (LABAs). In two replicate, randomized, controlled trials involving 912 patients with asthma who were receiving inhaled glucocorticoids and LABAs, we compared the effect on lung function and exacerbations of adding tiotropium (a total dose of 5 μg) or placebo, both delivered by a soft-mist inhaler once daily for 48 weeks. All the patients were symptomatic, had a post-bronchodilator forced expiratory volume in 1 second (FEV(1)) of 80% or less of the predicted value, and had a history of at least one severe exacerbation in the previous year. The patients had a mean baseline FEV(1) of 62% of the predicted value; the mean age was 53 years. At 24 weeks, the mean (±SE) change in the peak FEV(1) from baseline was greater with tiotropium than with placebo in the two trials: a difference of 86±34 ml in trial 1 (P=0.01) and 154±32 ml in trial 2 (P<0.001). The predose (trough) FEV(1) also improved in trials 1 and 2 with tiotropium, as compared with placebo: a difference of 88±31 ml (P=0.01) and 111±30 ml (P<0.001), respectively. The addition of tiotropium increased the time to the first severe exacerbation (282 days vs. 226 days), with an overall reduction of 21% in the risk of a severe exacerbation (hazard ratio, 0.79; P=0.03). No deaths occurred; adverse events were similar in the two groups. In patients with poorly controlled asthma despite the use of inhaled glucocorticoids and LABAs, the addition of tiotropium significantly increased the time to the first severe exacerbation and provided modest sustained bronchodilation. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov numbers, NCT00772538 and NCT00776984.).

Sideritis scardica Griseb. and Clinopodium vulgare L., belonging to the Lamiaceae family, are rich in terpenoids and phenolics and exhibit various pharmacological effects, including antioxidant, anti-inflammatory and anti-cancer activities. While the memory-enhancing impacts of S. scardica are well documented, the cognitive benefits of C. vulgare remain unexplored. This study assessed the potential effect of C. vulgare on learning and memory in healthy and scopolamine (Sco)-induced memory-impaired male Wistar rats, comparing it with the effects of S. scardica. Over a 21-day period, rats orally received extracts of cultivated S. scardica (200 mg/kg) and C. vulgare (100 mg/kg), either individually or in combination, with administration starting 10 days before and continuing 11 days simultaneously with Sco injection at a dose of 2 mg/kg intraperitoneally. The results showed that both extracts effectively mitigated Sco-induced memory impairment. Their combination significantly improved recognition memory and maintained monoaminergic function. S. scardica excelled in preserving spatial working memory, while C. vulgare exhibited comparable retention of recognition memory, robust antioxidant activity and acetylcholinesterase inhibitory activity. The extracts alleviated Sco-induced downregulation of p-CREB/BDNF signaling, suggesting neuroprotective mechanisms. The extract combination positively affected most of the Sco-induced impairments, underscoring the potential for further investigation of these extracts for therapeutic development.

This large trial involving patients with chronic obstructive pulmonary disease examined the relative safety of tiotropium inhalation delivered by two different devices. No significant differences in mortality were noted between the two devices. Tiotropium (Spiriva, Boehringer Ingelheim), a long-acting inhaled anticholinergic bronchodilator, improves lung function, quality of life, and exercise endurance and reduces exacerbations in patients with chronic obstructive pulmonary disease (COPD). 1 – 4 Tiotropium is approved and marketed as a dry-powder formulation delivered by means of the HandiHaler inhalation device (at a dose of 18 μg) 5 and as an aqueous solution delivered by means of the Respimat inhaler (at a dose of 5 μg) in many countries. 6 Crossover trials of tiotropium Respimat at a dose of 5 μg and HandiHaler at a dose of 18 μg for up to 4 weeks have shown . . .

In this trial involving adults with asthma that was poorly controlled by a low-dose inhaled glucocorticoid, the addition of inhaled tiotropium was superior to a doubling of the dose of an inhaled glucocorticoid and was not inferior to the addition of inhaled salmeterol. Many adults with asthma have inadequate control of symptoms when receiving a low-to-medium dose of an inhaled glucocorticoid. 1 , 2 Treatment options include the addition of a leukotriene modifier, 2 the addition of a long-acting beta-agonist (LABA), 2 – 4 or an increased dose of an inhaled glucocorticoid. 2 Current guidelines of the National Asthma Education and Prevention Program favor the last two options. 2 In recent communications, however, the Food and Drug Administration (FDA) 5 and asthma experts 6 , 7 have questioned the safety of LABA therapy and suggested strategies to minimize the use of these drugs. Because of such concerns and the heterogeneity of patients with . . .

Tropane alkaloids from nightshade plants are neurotransmitter inhibitors that are used for treating neuromuscular disorders and are classified as essential medicines by the World Health Organization . Challenges in global supplies have resulted in frequent shortages of these drugs . Further vulnerabilities in supply chains have been revealed by events such as the Australian wildfires and the COVID-19 pandemic . Rapidly deployable production strategies that are robust to environmental and socioeconomic upheaval are needed. Here we engineered baker's yeast to produce the medicinal alkaloids hyoscyamine and scopolamine, starting from simple sugars and amino acids. We combined functional genomics to identify a missing pathway enzyme, protein engineering to enable the functional expression of an acyltransferase via trafficking to the vacuole, heterologous transporters to facilitate intracellular routing, and strain optimization to improve titres. Our integrated system positions more than twenty proteins adapted from yeast, bacteria, plants and animals across six sub-cellular locations to recapitulate the spatial organization of tropane alkaloid biosynthesis in plants. Microbial biosynthesis platforms can facilitate the discovery of tropane alkaloid derivatives as new therapeutic agents for neurological disease and, once scaled, enable robust and agile supply of these essential medicines.

Background QVA149 is a once-daily (o.d.) inhaled dual bronchodilator containing a fixed-dose combination of the long-acting β2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium for the treatment of COPD. The QUANTIFY study compared QVA149 with a free-dose bronchodilator combination of tiotropium plus formoterol (TIO+FOR) in improving health-related quality of life (HRQoL) of patients with COPD. Methods This multicentre, blinded, triple-dummy, parallel-group, non-inferiority study randomised patients aged ≥40 years with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1 s (FEV1) ≥30% to <80% predicted) to QVA149 110/50 µg o.d. or TIO 18 µg o.d.+ FOR 12 µg twice daily (1:1) for 26 weeks. The primary endpoint was to demonstrate non-inferiority in HRQoL assessed using St George's Respiratory Questionnaire-COPD (SGRQ-C). The prespecified non-inferiority margin was 4 units. Secondary endpoints included Transition Dyspnoea Index (TDI) score, pre-dose FEV1, forced vital capacity (FVC) and safety. Results Of the 934 patients randomised (QVA149=476 and TIO+FOR=458), 87.9% completed the study. At week 26, non-inferiority was met for SGRQ-C (QVA149 vs TIO+FOR; difference: –0.69 units; 95% CI −2.31 to 0.92; p=0.399). A significantly higher percentage of patients achieved a clinically relevant ≥1 point improvement in TDI total score with QVA149 (49.6%) versus TIO+FOR (42.4%; p=0.033). QVA149 significantly increased pre-dose FEV1 (+68 mL, 95% CI 37 mL to 100 mL; p<0.001) and FVC (+74 mL, 95% CI 24 mL to 125 mL; p=0.004) compared with TIO+FOR at week 26. The incidence of adverse events was comparable between both treatments (QVA149=43.7% and TIO+FOR=42.6%). Conclusions QVA149 is non-inferior to TIO+FOR in improving HRQoL, with clinically meaningful and significant improvements in breathlessness and lung function in patients with COPD. Trial registration number NCT01120717.

Some antidepressant agents generate differential benefit based on gender. Blocking cholinergic muscarinic receptors using scopolamine produces robust and rapid antidepressant effects in males and females combined. This study evaluated if males and females differ in the antidepressant response magnitude following scopolamine administration. A total of 52 male and female outpatients meeting criteria for recurrent major depressive or bipolar disorder participated in a double-blind, randomized, placebo-controlled, crossover clinical trial involving seven i.v. infusions of placebo or scopolamine (4 μg/kg). Following a single-blind placebo lead-in, participants entered either a placebo-block/scopolamine-block or a scopolamine-block/placebo-block sequence. Each block included three sessions. Clinical ratings were acquired before each infusion and included the Montgomery–Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A). A treatment group × block interaction (F=21.0, p <0.001) was observed in MADRS scores across gender, and the reduction was significant by the evaluation following the first scopolamine administration (F=8.4, p =0.006). The treatment group × block interaction was also significant in males (F=3.8, p =0.043) and females (F=35.6, p <0.001) separately. A block × gender interaction (F=7.4, p =0.009) indicated that the response magnitude was larger in women. The treatment × block interaction was significant for the HAM-A across gender (F=12.0, p <0.001), and was significant for females (F=24.9, p <0.001) but not for males (F=1.3, p =0.30). When comparing the baseline block to study end, the block × gender interaction (F=12.6, p =0.001) showed that the antianxiety response was greater in women. Men and women show a rapid antidepressant response following scopolamine, but the magnitude of response is larger in women than in men.

In the 4-year UPLIFT trial, tiotropium improved lung function and health-related quality of life and decreased exacerbations compared with usual respiratory medications except inhaled anticholinergics in patients with chronic obstructive pulmonary disease (COPD). Mortality and its causes was a secondary endpoint in UPLIFT. We describe the effect of tiotropium on survival and analyze differences between mortality during treatment and during follow-up of discontinued patients. This study involved a randomized, double-blind trial comparing tiotropium with placebo in patients with COPD (>or=40 yr of age; postbronchodilator FEV(1)

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