Efficacy and safety of omalizumab in patients with moderate-to-severe asthma: An analytic comparison of data from randomized controlled trials between Chinese and Caucasians.

BACKGROUND: Omalizumab has > 15 years of real-world evidence of effectiveness in Caucasian patients. In August 2017, it was approved as an add-on therapy for the management of moderate-to-severe asthma in China. OBJECTIVE: To compare the efficacy and safety of omalizumab in Chinese and Caucasian patients. METHODS: This analysis included clinical trial data from a Chinese study (NCT01202903) and four studies with predominantly Caucasian patients (008, 009, EXTRA and INNOVATE). The following outcomes were analyzed: change from baseline in morning peak expiratory flow (mPEF), percentage predicted forced expiratory volume in one second (FEV1), patient-reported outcomes (PROs), asthma exacerbation and safety. Further, a population pharmacokinetic/pharmacodynamic (PK/PD) was also assessed. RESULTS: In the Chinese study, omalizumab significantly improved the mPEF from baseline vs placebo at Weeks > 4-8 through > 16-20; however, the change in mPEF did not reach statistical significance at Week 24. A similar trend towards improvement in mPEF was observed in the studies with Caucasians (INNOVATE, 008 and 009). In all studies, omalizumab showed greater improvement in %predicted FEV1, AQLQ score, and GETE score vs placebo. In addition, asthma symptom scores and seasonal exacerbations were lower, especially during winter, in the Chinese study, and was comparable to studies in Caucasians. PK/PD analyses showed that steady-state PK of omalizumab; free or total immunoglobulin E levels were similar in all studies. CONCLUSIONS: The clinical efficacy and safety of omalizumab was comparable among Chinese and Caucasian patients with moderate-to-severe asthma supporting therapeutic effectiveness, irrespective of race, ethnicity and geographical factors.

Efficacy and Safety of Indacaterol/Glycopyrronium (IND/GLY) Versus Salmeterol/Fluticasone in Chinese Patients with Moderate-to-Severe Chronic Obstructive Pulmonary Disease: The Chinese Cohort from the LANTERN Study.

Inhaled indacaterol/glycopyrronium fixed-dose combination (IND/GLY) is approved in over 80 countries, including the EU, Japan, Australia and Switzerland and the US. The LANTERN study evaluated the efficacy of IND/GLY compared with inhaled long-acting ß2-agonist (LABA)/inhaled corticosteroid (ICS) or salmeterol/fluticasone (SFC) in patients with moderate-to-severe COPD with a history of ≤1 exacerbation in the previous year. Here we present the efficacy and safety of IND/GLY versus SFC in the Chinese cohort from the LANTERN study. LANTERN was a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group study conducted in patients with moderate-to-severe COPD with a history of ≤1 exacerbation in the previous year. The patients were randomized (1:1) to once-daily IND/GLY (110/50 µg) or twice-daily SFC (50/500 µg). The primary endpoint was non-inferiority of IND/GLY versus SFC in terms of trough FEV1. Of the total 744 patients randomized in the LANTERN study, 598 (80.4%) were from Mainland China and randomized to IND/GLY (n = 298) or SFC (n = 300), and 553 (92.5%) completed the study. IND/GLY showed superiority over SFC with a statistically significant and clinically meaningful improvement in trough FEV1, FEV1 AUC0-4h, peak FEV1 and trough forced vital capacity (FVC) change from the baseline. Annualized rate of moderate or severe COPD exacerbations was significantly lower (43%) with IND/GLY compared with SFC (rate ratio: 0.57, p = 0.015). Overall, adverse events were lower for IND/GLY (34.6%) versus SFC (43.1%). IND/GLY was superior in achieving bronchodilation versus SFC in a Chinese subgroup of patients from this study. Clinicaltrials.gov identifier: NCT01709903.

Real-world ALK Testing Trends in Patients With Advanced Non-Small-Cell Lung Cancer in the United States.

INTRODUCTION: Patients with non-small-cell lung cancer (NSCLC) whose tumors harbor anaplastic lymphoma kinase (ALK) rearrangements can be treated with ALK tyrosine kinase inhibitors. We assessed real-world ALK biomarker testing and treatment patterns of patients with NSCLC in the United States. PATIENTS AND METHODS: Data were extracted from the Flatiron Health electronic health record-derived deidentified database for patients aged ≥18 years with stage IIIB or IV NSCLC and ≥2 clinic visits between January 2011 and December 2019. RESULTS: Among 60,025 eligible patients, tumors from 36,691 (61.1%) patients were tested for ALK rearrangements, and 1042 (2.8%) tested positive (ALK+). From 2011 to 2019, ALK testing rates increased from 33.1% to 73.0%; testing via fluorescence in situ hybridization declined from 68.3% to 32.1% while next-generation sequencing increased from <1% to 52.2%. Although tissue samples were more commonly used than blood (85.1% vs. 13.5% of tests), blood sample testing increased from 0.1% in 2011 to 28.2% in 2019. Median (interquartile range) time from diagnosis of advanced NSCLC to first ALK+ test result was 23 (13-43) days, including laboratory processing time of 9 (6-14) days. For the 24.7% of patients with an ALK+ test result who began treatment before receiving the positive result, chemotherapy was initiated most often overall until 2018 when immuno-oncology agents became most common. CONCLUSION: Although ALK testing in NSCLC increased over time, testing rates among eligible patients did not reach 100% during the study period. Treatment decisions for some patients with NSCLC may have been made without important, guideline-recommended biomarker data.

Regulated binding of importin-α to protein kinase Cδ in response to apoptotic signals facilitates nuclear import.

PKCδ translocates into the nucleus in response to apoptotic agents and functions as a potent cell death signal. Cytoplasmic retention of PKCδ and its transport into the nucleus are essential for cell homeostasis, but how these processes are regulated is poorly understood. We show that PKCδ resides in the cytoplasm in a conformation that precludes binding of importin-α. A structural model of PKCδ in the inactive state suggests that the nuclear localization sequence (NLS) is prevented from binding to importin-α through intramolecular contacts between the C2 and catalytic domains. We have previously shown that PKCδ is phosphorylated on specific tyrosine residues in response to apoptotic agents. Here, we show that phosphorylation of PKCδ at Tyr-64 and Tyr-155 results in a conformational change that allows exposure of the NLS and binding of importin-α. In addition, Hsp90 binds to PKCδ with similar kinetics as importin-α and is required for the interaction of importin-α with the NLS. Finally, we elucidate a role for a conserved PPxxP motif, which overlaps the NLS, in nuclear exclusion of PKCδ. Mutagenesis of the conserved prolines to alanines enhanced importin-α binding to PKCδ and induced its nuclear import in resting cells. Thus, the PPxxP motif is important for maintaining a conformation that facilitates cytosplasmic retention of PKCδ. Taken together, this study establishes a novel mechanism that retains PKCδ in the cytoplasm of resting cells and regulates its nuclear import in response to apoptotic stimuli.

The cost-effectiveness of brigatinib in adult patients with ALK inhibitor-naive ALK-positive non-small cell lung cancer from a US perspective.

BACKGROUND: The discovery of specific oncogenic drivers in non-small cell lung cancer (NSCLC) has led to the development of highly targeted anaplastic lymphoma kinase tyrosine kinase inhibitors (ALKis). Brigatinib is a next-generation ALKi associated with prolonged progression-free survival in patients with ALKi-naive ALK+ NSCLC. OBJECTIVE: To estimate the cost-effectiveness of brigatinib compared with crizotinib and alectinib in patients with ALKi-naive ALK+ NSCLC, from a US payer perspective. METHODS: A lifetime area under the curve-partitioned survival model with 4 health states was used to evaluate the relative cost-effectiveness of brigatinib in the ALKi-naive ALK+ NSCLC setting. Brigatinib was compared with crizotinib within a cost-effectiveness framework and compared with alectinib in a cost-comparison framework, where all efficacy outcomes were assumed equal. The efficacy of brigatinib and crizotinib was informed by the ALTA-1L trial, and an indirect treatment comparison was performed to inform the efficacy of brigatinib vs alectinib owing to a lack of head-to-head data. Costs were derived from public sources. The main outcomes of the model were total costs, quality-adjusted life-years (QALYs), life-years, and incremental cost-effectiveness ratios. Univariate and probabilistic sensitivity analyses, in addition to multiple scenario analyses, were conducted to assess the robustness of the model outcomes. RESULTS: The improved outcomes observed in ALTA-1L translated into QALY gains (+0.97) in the comparison of brigatinib vs crizotinib. The superior efficacy profile was associated with increased time on treatment with brigatinib, which drove the increase in costs vs crizotinib (+$210,519). The resulting base-case incremental cost-effectiveness ratio was $217,607/QALY gained. Compared with alectinib, brigatinib was associated with a cost difference of -$8,546. Sensitivity analysis suggested that extrapolation of overall survival, the assumptions relating to time on treatment, and subsequent therapy costs were the most influential determinants of results. Probabilistic sensitivity analysis suggested brigatinib had the highest probability of being cost-effective beyond willingness-to-pay thresholds of $236,000 per QALY vs crizotinib and alectinib. CONCLUSIONS: At list prices and under base-case assumptions in the current analysis, brigatinib was associated with cost-savings vs alectinib, and QALY gains but at higher costs vs crizotinib. Additional research into the real-world efficacy of ALKis is warranted to further understand the comparative cost-effectiveness of these therapies. DISCLOSURES: Ms Cranmer and Ms Kearns are employees of Takeda UK Ltd. Dr Young is a former employee of Takeda Pharmaceuticals America, Inc. Dr Humphries is an employee of Takeda Pharmaceuticals U.S.A., Inc. Mr Trueman is an employee of Source Health Economics, the consultancy company that provided health economic and writing services. This work was funded by ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Work by Source Health Economics was funded by ARIAD Pharmaceuticals, Inc. Professional medical writing assistance was provided by Phillipa White, of Source Health Economics, and funded by ARIAD Pharmaceuticals, Inc.

Catching the GIST: Massive Gastrointestinal Stromal Tumor Presenting as Acute Dyspnea.

We present a case of a 55-year-old woman presenting with worsening shortness of breath and constipation over the course of three days. Initial computed tomography scan showed a large, complex abdominal mass with a vascular pedicle and possible pedunculated origin along the inferior aspect of the greater curvature of the stomach. The mass was further evaluated on magnetic resonance imaging showing an active hemorrhage. The patient became hemodynamically unstable and general surgery was consulted for evaluation. Mass resection was performed, and biopsy revealed KIT/CD117+ and DOG1/ANO1+ gastrointestinal stromal tumor staged as T4. Although definitive diagnosis of a gastrointestinal stromal tumor requires biopsy, prompt clinical and radiological recognition is critical for patients to receive definitive treatment of mass resection.

Single-agent inhibition of Chk1 is antiproliferative in human cancer cell lines in vitro and inhibits tumor xenograft growth in vivo.

Chk1 is a serine/threonine kinase that plays several important roles in the cellular response to genotoxic stress. Since many current standard-of-care therapies for human cancer directly damage DNA or inhibit DNA synthesis, there is interest in using small molecule inhibitors of Chk1 to potentiate their clinical activity. Additionally, Chk1 is known to be critically involved in cell cycle progression of unperturbed cells. Therefore, it is plausible that treatment with a Chkl inhibitor alone could also be an efficacious cancer therapy. Here we report that Chk1-A, a potent and highly selective small molecule inhibitor of Chk1, is antiproliferative as a single agent in a variety of human cancer cell lines in vitro. The inhibition of proliferation is associated with collapse of DNA replication and apoptosis. Rapid decreases in inhibitory phosphorylation of CDKs and a concomitant increase in CDK kinase activity and chromatin loading of Cdc45 suggest that the antiproliferative and proapoptotic activity of Chk1-A is at least in part due to deregulation of DNA synthesis. We extend these in vitro studies by demonstrating that Chk1-A inhibits the growth of tumor xenografts in vivo in a treatment regimen that is well tolerated. Together, these results suggest that single-agent inhibition of Chk1 may be an effective treatment strategy for selected human malignancies.

Timing and Duration of Sleep in Hospitalized Children: An Observational Study.

BACKGROUND AND OBJECTIVES: Sleep during hospitalization is important, but data on children's sleep quality during hospitalization are lacking. We sought to document sleep duration and awakenings in hospitalized children and explore associations between sleep and chronic care complexity, home sleep quality, and late-night food consumption. METHODS: Children aged 2 to 17 years admitted to a hospitalist service for at least 24 hours were approached for participation. Children were video recorded from 20:00 to 08:00. Paired investigators reviewed recordings and extracted data. Investigators blinded to sleep data separately extracted clinical and demographic information. Analyses included Spearman correlations and linear and generalized linear regression models with t and Wald χ2 tests. RESULTS: The mean time subjects (n = 57) initiated sleep was 22:35 (range: 20:00-02:47), with a mean sleep duration of 475 minutes (89-719 minutes). Subjects awakened 2.2 times (0-7 times, SD: 1.9) per night, on average, with the average total time awake during those awakenings of 55.7 minutes (2-352 minutes, SD: 75 minutes). In multivariate analysis, children with private insurance had longer sleep duration. Additionally, subjects who ate a snack after 21:00 went to sleep much later (odds ratio: 9.5; confidence interval: 2.6 to 34.9) and had 64 minutes less total sleep time and spent less time in bed than patients who did not eat late (P = .007). CONCLUSIONS: Hospitalized children sleep less than recommended and experience frequent awakenings. Some demographic variables are related to sleep. Many hospitalized children also consume food at night, which is associated with later bedtime and less sleep. Future efforts to improve sleep in hospitalized children are needed.

Indacaterol/glycopyrronium versus salmeterol/fluticasone in Asian patients with COPD at a high risk of exacerbations: results from the FLAME study.

BACKGROUND: The FLAME study demonstrated that indacaterol/glycopyrronium (IND/GLY), the fixed-dose combination of a long-acting ß2-agonist (LABA, IND) and a long-acting muscarinic antagonist (LAMA, GLY), was superior to salmeterol/fluticasone combination (SFC) in preventing exacerbations in COPD patients with a high risk of exacerbations. In this study, we report a prespecified analysis of the efficacy and safety of IND/GLY versus SFC in Asian patients from the FLAME study. PATIENTS AND METHODS: Patients from Asian centers with moderate-to-very severe COPD and ≥1 exacerbation in the previous year from the 52-week, randomized FLAME study were included. IND/GLY was compared versus SFC for effects on exacerbations, lung function (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC]), health status (St George's Respiratory Questionnaire [SGRQ]), rescue medication use, and safety. RESULTS: A total of 510 Asian patients (IND/GLY, n=250 or SFC, n=260) were included. Compared to the overall FLAME population, the Asian cohort had more males, a shorter duration of COPD, fewer patients using inhaled corticosteroid (ICS) at screening, fewer current smokers, and more patients with very severe COPD. IND/GLY significantly reduced the rate of moderate/severe exacerbations (rate ratio: 0.75; 95% confidence interval: 0.58-0.97; P=0.027) and prolonged time to first moderate/severe exacerbation versus SFC (hazard ratio: 0.77; 95% confidence interval: 0.59-1.01; P=0.055). Predose trough FEV1 and FVC significantly improved in Asian patients (P<0.001). IND/GLY improved SGRQ for COPD (SGRQ-C score; P=0.006) and reduced rescue medication use (P=0.058) at week 52. Pneumonia incidence was 3.6% with IND/GLY and 7.7% with SFC (P=0.046). CONCLUSION: In exacerbating Asian COPD patients, IND/GLY was more effective than SFC.

Suppression of cell migration by protein kinase Cdelta.

The ability of cancer cells to migrate is strongly correlated with malignant progression and metastasis. Survival signals that suppress apoptosis have also been linked to increased cell motility. We previously reported that suppression of protein kinase Cdelta (PKCdelta) provided survival signals in a rat fibroblast model system. These studies have been extended to human breast cancer cells with differential cell motilities and PKCdelta levels. BT-549 cells, which lack detectable expression of PKCdelta, migrate very efficiently, whereas MCF-7 cells, which express high levels of PKCdelta, migrate very poorly. Ectopic expression of PKCdelta suppressed cell migration in the BT-549 cells, and downregulation of PKCdelta enhanced cell migration in the MCF-7 cells. Downregulation of PKCdelta in the MCF-7 cells also led to increased secretion of the matrix metalloprotease MMP-9. The migration of mouse embryo fibroblasts (MEFs) from wild type and PKCdelta knockout mice was also examined and MEFs from PKCdelta knockout mice had a five-fold increase in cell migration relative to the wild-type MEFs. These data provide evidence that PKCdelta suppresses cell migration in both human breast cancer cells and in primary mouse fibroblasts, and indicate that the loss of PKCdelta in human cancers could contribute to both cell survival and metastasis.

Indacaterol/glycopyrronium in symptomatic patients with COPD (GOLD B and GOLD D) versus salmeterol/fluticasone: ILLUMINATE/LANTERN pooled analysis.

BACKGROUND: Indacaterol/glycopyrronium (IND/GLY) is approved for maintenance treatment of adult patients with COPD. This post hoc analysis explored the efficacy and safety of IND/GLY versus salmeterol/fluticasone (SFC) in symptomatic (Global Initiative for Chronic Obstructive Lung Disease [GOLD] B and GOLD D) patients with moderate-to-severe COPD. PATIENTS AND METHODS: Data from LANTERN and ILLUMINATE studies were pooled and analyzed. In both studies, symptomatic COPD patients were randomized to once-daily IND/GLY 110 µg/50 µg or twice-daily SFC 50 µg/500 µg. End points were pre-dose trough forced expiratory volume in one second (FEV1), standardized area under the curve for FEV1 from 0 to 12 hours (FEV1 AUC0-12 hours), peak FEV1, peak forced vital capacity (FVC), pre-dose trough FVC, Transition Dyspnea Index (TDI) total score, St George's Respiratory Questionnaire total score, rescue medication use and safety. RESULTS: A total of 1,263 patients were classified as either GOLD B (n=809) or GOLD D (n=454). At week 26, IND/GLY demonstrated statistically significant improvement in all lung function parameters versus SFC in patients in both the GOLD B and GOLD D subgroups. TDI total score and rescue medication use were significantly improved with IND/GLY versus SFC in the overall population and in the GOLD B (TDI total score only) and GOLD D (rescue medication only) subgroups. IND/GLY also reduced the rate of exacerbations in the pooled population. Overall safety profile was comparable with a higher incidence of pneumonia in the SFC-treated group. CONCLUSION: In this pooled analysis, IND/GLY demonstrated superior efficacy compared with SFC in patients in the GOLD B and GOLD D subgroups and supported its use in symptomatic COPD patients.

Omalizumab Improves Quality of Life and Asthma Control in Chinese Patients With Moderate to Severe Asthma: A Randomized Phase III Study.

PURPOSE: Omalizumab is the preferred add-on therapy for patients with moderate-to-severe persistent allergic asthma and has demonstrated efficacy and safety in various ethnicities. This study evaluated the efficacy and safety of omalizumab in Chinese patients with moderate-to-severe allergic asthma. METHODS: This randomized, double-blind, parallel-group, placebo-controlled, phase III study assessed lung function, quality of life, asthma control, and safety of omalizumab after 24-week therapy in Chinese patients (18-75 years of age). RESULTS: A total of 616 patients were randomized (1:1) to omalizumab or placebo. The primary endpoint, least squares mean treatment difference (LSM-TD) in morning peak expiratory flow (PEF) (omalizumab vs placebo), at Weeks >20-24 was 8.85 L/min (Full analysis set; P=0.062). Per-protocol analysis set showed significant improvements with LSM-TD of 11.53 L/min in mean mPEF at Weeks >20-24 (P=0.022). The FEV1 % predicted was significantly improved with omalizumab vs placebo from 8 to 24 weeks (after 24-week treatment: LSM-TD=4.12%; P=0.001). At Week 24, a higher proportion of omalizumab-treated patients achieved clinically relevant improvements in standardized AQLQ (58.2% vs 39.3%; LSM=0.51 vs 0.10; P<0.001) and ACQ (49.5% vs 35.5%; LSM=-0.51 vs -0.34; P=0.002) scores vs placebo. Total and nighttime symptom scores reduced significantly with omalizumab vs placebo (LSM-TD=-0.21, P=0.048 and -0.12, P=0.011, respectively). Although the study was not powered to study differences in exacerbation rates (P=0.097), exacerbations in winter months were less frequent in the omalizumab vs placebo group (2 vs 21). Adverse event and severe adverse event rates were comparable between omalizumab and placebo. CONCLUSIONS: Omalizumab improves lung function, quality of life, and asthma control in Chinese patients with moderate-to-severe persistent allergic asthma and has a good safety profile.

LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD.

BACKGROUND: The current Global initiative for chronic Obstructive Lung Disease (GOLD) treatment strategy recommends the use of one or more bronchodilators according to the patient's airflow limitation, their history of exacerbations, and symptoms. The LANTERN study evaluated the effect of the long-acting ß2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) dual bronchodilator, QVA149 (indacaterol/glycopyrronium), as compared with the LABA/inhaled corticosteroid, salmeterol/fluticasone (SFC), in patients with moderate-to-severe COPD with a history of ≤1 exacerbation in the previous year. METHODS: In this double-blind, double-dummy, parallel-group study, 744 patients with moderate-to-severe COPD with a history of ≤1 exacerbations in the previous year were randomized (1:1) to QVA149 110/50 µg once daily or SFC 50/500 µg twice daily for 26 weeks. The primary endpoint was noninferiority of QVA149 versus SFC for trough forced expiratory volume in 1 second (FEV1) at week 26. RESULTS: Overall, 676 patients completed the study. The primary objective of noninferiority between QVA149 and SFC in trough FEV1 at week 26 was met. QVA149 demonstrated statistically significant superiority to SFC for trough FEV1 (treatment difference [Δ]=75 mL; P<0.001). QVA149 demonstrated a statistically significant improvement in standardized area under the curve (AUC) from 0 hours to 4 hours for FEV1 (FEV1 AUC0-4h) at week 26 versus SFC (Δ=122 mL; P<0.001). QVA149 and SFC had similar improvements in transition dyspnea index focal score, St George Respiratory Questionnaire total score, and rescue medication use. However, QVA149 significantly reduced the rate of moderate or severe exacerbations by 31% (P=0.048) over SFC. Overall, the incidence of adverse events was comparable between QVA149 (40.1%) and SFC (47.4%). The incidence of pneumonia was threefold lower with QVA149 (0.8%) versus SFC (2.7%). CONCLUSION: These findings support the use of the LABA/LAMA, QVA149 as an alternative treatment, over LABA/inhaled corticosteroid, in the management of moderate-to-severe COPD patients (GOLD B and GOLD D) with a history of ≤1 exacerbation in the previous year.

Efficacy and safety of once-daily glycopyrronium in predominantly Chinese patients with moderate-to-severe chronic obstructive pulmonary disease: the GLOW7 study.

BACKGROUND: Glycopyrronium is a once-daily (od) long-acting muscarinic antagonist for the maintenance treatment of chronic obstructive pulmonary disease (COPD). The GLOW7 study evaluated the efficacy and safety of od glycopyrronium 50 µg in predominantly Chinese patients with moderate-to-severe COPD. METHODS: In this 26-week, multi-center, double-blind, placebo-controlled, parallel-group study, men and women ≥40 years with moderate-to-severe COPD were randomized to glycopyrronium 50 µg od or placebo (2:1). The primary objective was to confirm the significant improvement of trough forced expiratory volume in 1 second (FEV1) following 12 weeks of treatment with glycopyrronium compared with placebo. Secondary objectives included the effect of glycopyrronium on health status (St George's Respiratory Questionnaire), breathlessness (Transition Dyspnea Index), other lung function parameters, rescue medication use, and COPD exacerbations. Safety and tolerability were also evaluated. RESULTS: Of the 460 patients randomized, 459 were included in the full analysis set (glycopyrronium, n=306; placebo, n=154; mean age 64.7 years; mean post-bronchodilator FEV1: 50.8% predicted); 425 (92.4%) completed the study. At Week 12, glycopyrronium signifcantly improved trough FEV1 with a least square means treatment difference of 141 mL (95% confidence interval 111 mL, 171 mL; P<0.001) compared with placebo. The mean treatment effect of glycopyrronium was greater than the minimum clinically important difference versus placebo in both St George's Respiratory Questionnaire total score (-4.92; P<0.001) and Transition Dyspnea Index focal score (1.0; P<0.001) at week 26. Glycopyrronium reduced the risk of exacerbations in terms of time to first moderate or severe exacerbation by 28% (P=0.153) and rate of moderate or severe COPD exacerbation by 29% (P=0.119) compared with placebo. Incidence of death was 1.3% with glycopyrronium and 0% in placebo during the treatment period. Overall incidence of adverse events (glycopyrronium 43.6%; placebo 47.4%) and serious adverse events (glycopyrronium 5.6%; placebo 9.1%) were similar. CONCLUSION: In predominantly Chinese patients with moderate-to-severe COPD, od glycopyrronium 50 µg significantly improved lung function, dyspnea, and health status compared with placebo. The safety and tolerability profile of glycopyrronium was comparable to placebo.

Salmeterol/Fluticasone Propionate in a Single Inhaler is Superior to Budesonide Alone in Control of Chinese Asthmatic Adults : An Open-Label, Randomised, 6-Week Study.

OBJECTIVE AND DESIGN: There is comparatively little information on asthma management in China. A multicentre, randomised, open-label, parallel-group, 6-week treatment study was conducted to evaluate the efficacy and safety of salmeterol/fluticasone propionate combination treatment in Chinese adult asthmatic patients. SETTING AND PATIENTS: 398 patients with a documented history of moderate-to-severe asthma were randomised to treatment. INTERVENTIONS: Salmeterol 50mug/fluticasone propionate 100mug twice daily for 6 weeks via Accuhaler((R)) (Diskustrade mark) inhaler and budesonide 400mug twice daily for 6 weeks via Turbuhaler((R)) inhaler. MAIN OUTCOME MEASURES AND RESULTS: Morning peak expiratory flow (PEF) was investigated as the primary efficacy endpoint; evening PEF, use of salbutamol (albuterol) as rescue medication, and day- and night-time asthma symptom scores were secondary efficacy endpoints. Safety was assessed according to adverse events recorded. Over the 6-week treatment period, salmeterol/fluticasone propionate led to a significantly greater increase in morning (p < 0.0001) and evening (p = 0.0066) PEF compared with budesonide. Moreover, the significant benefit of salmeterol/fluticasone propionate was evident from the first week. Similarly, salmeterol/fluticasone propionate led to significantly greater improvements in the use of rescue medication and day- and night-time asthma symptom scores, compared with budesonide. Both treatments were well tolerated, with a similar incidence (23%) of adverse events in both treatment groups and no serious adverse events. CONCLUSIONS: Salmeterol/fluticasone propionate 50mug /100mug twice daily was significantly more effective than budesonide 400mug twice daily in improving lung function and reducing symptoms and use of rescue medication in Chinese asthmatic patients who were poorly controlled on low-dose inhaled corticosteroids. This confirms the findings of superior efficacy of this combination product over budesonide in other populations.

Induction of apoptosis is driven by nuclear retention of protein kinase C delta.

Protein kinase C delta (PKC delta) mediates apoptosis downstream of many apoptotic stimuli. Because of its ubiquitous expression, tight regulation of the proapoptotic function of PKC delta is critical for cell survival. Full-length PKC delta is found in all cells, whereas the catalytic fragment of PKC delta, generated by caspase cleavage, is only present in cells undergoing apoptosis. Here we show that full-length PKC delta transiently accumulates in the nucleus in response to etoposide and that nuclear translocation precedes caspase cleavage of PKC delta. Nuclear PKC delta is either cleaved by caspase 3, resulting in accumulation of the catalytic fragment in the nucleus, or rapidly exported by a Crm1-sensitive pathway, thereby assuring that sustained nuclear accumulation of PKC delta is coupled to caspase activation. Nuclear accumulation of PKC delta is necessary for caspase cleavage, as mutants of PKC delta that do not translocate to the nucleus are not cleaved. However, caspase cleavage of PKC delta per se is not required for apoptosis, as an uncleavable form of PKC delta induces apoptosis when retained in the nucleus by the addition of an SV-40 nuclear localization signal. Finally, we show that kinase negative full-length PKC delta does not translocate to the nucleus in apoptotic cells but instead inhibits apoptosis by blocking nuclear import of endogenous PKC delta. These studies demonstrate that generation of the PKC delta catalytic fragment is a critical step for commitment to apoptosis and that nuclear import and export of PKC delta plays a key role in regulating the survival/death pathway.

Suppression of apoptosis in the protein kinase Cdelta null mouse in vivo.

Protein kinase C (PKC) delta is an essential regulator of mitochondrial dependent apoptosis in epithelial cells. We have used the PKCdelta(-/-) mouse to ask if loss of PKCdelta protects salivary glands against gamma-irradiation-induced apoptosis in vivo and to explore the mechanism underlying protection from apoptosis. We show that gamma-irradiation in vivo results in a robust induction of apoptosis in the parotid glands of wild type mice, whereas apoptosis is suppressed by greater than 60% in the parotid glands of PKCdelta(-/-) mice. Primary parotid cells from PKCdelta(-/-) mice are defective in mitochondrial dependent apoptosis as indicated by suppression of etoposide-induced cytochrome c release, poly(ADP-ribose) polymerase cleavage, and caspase-3 activation. Notably, apoptotic responsiveness can be restored by re-introduction of PKCdelta by adenoviral transduction. Etoposide and gamma-irradiation-induced activation of p53 is similar in primary parotid cells and parotid glands from PKCdelta(+/+) and PKCdelta(-/-) mice, indicating that PKCdelta functions downstream of the DNA damage response. In contrast, activation of the c-Jun amino-terminal kinase is reduced in primary parotid cells from PKCdelta(-/-) cells and in parotid C5 cells, which express a dominant inhibitory mutant of PKCdelta. Similarly, c-Jun amino-terminal kinase activation is suppressed in vivo in gamma-irradiated parotid glands from PKCdelta(-/-) mice. These studies indicate an essential role for PKCdelta downstream of the p53 response and upstream of the c-Jun amino-terminal kinase activation in DNA damage-induced apoptosis in vivo and in vitro.