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Mesenchymal stem cells (MSCs) have shown potential as an innovative treatment for pulmonary fibrosis (PF), due to their capability to ameliorate the inflammation and moderate the deterioration of P...

Mesenchymal stem cells (MSCs) have shown potential as an innovative treatment for pulmonary fibrosis (PF), due to their capability to ameliorate the inflammation and moderate the deterioration of PF. The fate of the stem cells transplanted into the lung, including survival, migration, homing, and functions, however, has not been fully understood yet. In this paper, we report the development of a computed tomography/magnetic resonance (CT/MR) dual-modal nanotracer, gold/gadolinium nanoclusters overcoated with a silica shell (Au/GdNC@SiO

ITCA 650 consists of a small titanium osmotic mini-pump that is subdermally placed in the abdominal wall during a brief office procedure. As an investigational product for the treatment of type 2 diabetes (T2D), ITCA 650 provides a continuous subcutaneous infusion of exenatide over 3 or 6 months. An integrated analysis of efficacy and safety was conducted from 2 double-blind, randomized, Phase 3 studies, which evaluated pooled data with ITCA 650 20/60 mcg/d vs. placebo or sitagliptin for the treatment of patients with T2D, inadequately controlled on antidiabetic drugs. The efficacy endpoints were mean change from baseline at Week 39 for HbA1c, body weight, composite endpoints of HbA1c and weight loss, and proportion achieving HbA1c Disclosure L.L. Kjems: Employee; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; Intarcia Therapeutics, Inc.. P. Prabhakar: None. B. Schwartz: Employee; Self; Intarcia Therapeutics, Inc.. H. Huang: None. M.A. Baron: Employee; Self; Intarcia Therapeutics, Inc..

ITCA 650 consists of a small titanium osmotic mini—pump that is subdermally placed in the abdominal wall during a brief in-office procedure. As an investigational product for the treatment of type 2 diabetes (T2D), ITCA 650 provides a continuous subcutaneous infusion of exenatide over 3 or 6 months. Pooled 39-week data from two double-blind, randomized, Phase 3 studies were used to evaluate the efficacy of ITCA 650 20/60 mcg/d in patients with T2D inadequately controlled by oral antidiabetic drugs (OADs). Results in the overall population (N=683) and in subgroups according to age, gender, BMI, ethnicity, time since diagnosis, baseline HbA1c, GI adverse events, presence of anti-drug antibodies, and renal function are reported. As shown in the Figure, the overall mean (standard deviation [SD]) reduction in HbA1c (%) was 1.5% (1.2) with clinically meaningful reductions in HbA1c consistently observed irrespective of age, gender, BMI, ethnicity, time from T2D diagnosis, eGFR and background OADs (data not shown). Patients with a higher baseline HbA1c had a greater response. Mean weight loss was 3.4 kg (SD 4.7), and 40.7% (95% CI 0.36-0.46) of patients achieved a composite endpoint of HbA1c/weight reduction of >0.5%/≥2 kg. Similar changes were likewise seen consistently across subgroups. ITCA 650 demonstrated consistent efficacy across a wide spectrum of patients with T2D. Disclosure P. Prabhakar: None. L.L. Kjems: Employee; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; Intarcia Therapeutics, Inc.. H. Huang: None. B. Schwartz: Employee; Self; Intarcia Therapeutics, Inc. M.A. Baron: Employee; Self; Intarcia Therapeutics, Inc..

ITCA 650 is an investigational titanium osmotic mini pump that is subdermally placed in the abdominal wall during a brief office procedure to continuously deliver exenatide over 3 and 6-month periods and has the potential to improve medication adherence because patients do not self-administer. In this 26 week, open-label phase 3b study, 136 patients with T2D receiving liraglutide (1.2 to 1.8 mg/d) and metformin (≥1000 mg/d) were randomized to either the standard ITCA 650 dose regimen used in phase 3 trials of 20 mcg/d for 13 weeks followed by a 60 mcg/d maintenance dose (for 13 weeks in this study) or starting directly with the maintenance dose of 60 mcg/d for 26 weeks. The last injection of liraglutide occurred 2 days prior to randomization. The primary endpoint compared the incidence of nausea (N) and vomiting (V) between the two dose regimens. Switching from liraglutide to either dose regimen of ITCA 650 had a similar incidence of transient mild to moderate N/V (Table). Of note, 3 sites, which recruited 25% of the study population, accounted for 47% and 68% of the total N/V seen in the study. 4 patients discontinued due to GI AEs. Glycemic control remained stable in both groups. At Week 26, significant weight reduction was observed in both groups (p In conclusion, patients on stable liraglutide therapy can be switched to ITCA 650 60 mcg/d without the need for up-titration from a lower dose. Disclosure N. Rasouli: Consultant; Self; AstraZeneca, Intarcia Therapeutics, Inc. J. Rosenstock: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Consultant; Self; Sanofi. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Merck & Co., Inc., Pfizer Inc., Sanofi, Novo Nordisk Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Intarcia Therapeutics, Inc., Genentech, Inc.. S. Nakhle: None. B. Schwartz: Employee; Self; Intarcia Therapeutics, Inc.. P. Prabhakar: None. S.L. Kruger: None. H. Huang: None. M.A. Baron: Employee; Self; Intarcia Therapeutics, Inc..

This is the first edition of a comprehensive book covering the most recent methodology on innovative clinical trial designs for drugs and biological products. It is a great reference book for stati...

Background A new, hydrofluoroalkane nasal aerosol solution formulation of ciclesonide (CIC-HFA) delivered via a metered dose inhaler is currently in clinical development for treatment of allergic rhinitis. Objective To study tolerability and quality of life following administration of CIC-HFA 74- or 148-μg doses once-daily compared with placebo in patients with perennial allergic rhinitis (PAR) over 26 weeks. Methods Patients ≥12 years of age with a ≥2 year history of PAR were randomized in a placebo-controlled, double-blind, parallel group, multicenter study to CIC-HFA 74 μg, 148 μg, or placebo QD AM for 26 weeks. Safety was assessed by monitoring treatment-emergent adverse events (TEAEs). Quality of life was assessed by using a rhinoconjunctivitis quality of life questionnaire with standardized activities (RQLQ[S]) in patients with baseline RQLQ ≥3.00. Reflective total nasal symptom scores (rTNSS) and instantaneous total nasal symptom scores (iTNSS) over 26 weeks were also evaluated. Results In this study, 1111 patients were randomized. The overall incidence of TEAEs was comparable between the treatment groups. Treatment with CIC-HFA 74- or 148-μg doses showed improvements in RQLQ[S] [least squares (LS) mean change 0.40 and 0.37, respectively from baseline, p < 0.01 versus placebo for both], rTNSS (LS mean change 0.65 and 0.52, respectively from baseline; p ≤ 0.01 versus placebo for both), and iTNSS (LS mean change 0.51 and 0.42, respectively from baseline; p < 0.05 versus placebo for both) from baseline. Conclusion In this study, once-daily treatment with CIC-HFA 74- or 148-μg doses over 26 weeks was well tolerated with comparable incidence of TEAEs between the treatment groups.

Background Insomnia marked by sleep maintenance difficulty is extremely prevalent. Yet, problems staying asleep have been relatively neglected as a research focus compared to problems falling asleep. Insomnia treatment studies typically have not required participants to have a problem specifically with sleep maintenance. It is possible that exclusion of such subjects limits the detection of treatment effects in the overall trial in general, and of effects on sleep maintenance specifically. In order to address these issues we conducted a post hoc analysis of a 6-month placebo-controlled trial in which there were no inclusion criteria that specified sleep maintenance difficulties to assess the variable effects of baseline wake time after sleep onset (WASO – the primary maintenance measure) on the efficacy of eszopiclone 3mg. Methods Patients diagnosed with chronic primary insomnia were randomized to eszopiclone 3mg ( n =593) or placebo ( n =195) nightly for sixmonths. The present analyses of this study consisted of: (1) determination of the distribution of baseline WASO; (2) continuous analysis of the relationship between baseline WASO severity and drug-placebo difference at month 1 and 6; and (3) categorical efficacy analyses of subgroups delimited by the following WASO thresholds: 0, 30, 45, 60, and 90min. Results The baseline WASO distribution was: ⩽30=32.2%; >0 to ⩽45=41.5%; >30 to ⩽90=33.0%; >45 to ⩽90=23.7%; >90=22.6%. A relationship between greater baseline WASO severity and a significantly greater drug-placebo difference in efficacy for WASO was evident in both continuous and categorical analyses. Eszopiclone was found to have significant sleep maintenance efficacy at each time point across the entire range of WASO severity studied. Conclusions As illustrated in this analysis, a significant proportion of chronic insomnia patients in efficacy trials that select on the basis of sleep onset latency and total sleep time criteria may have normative-range WASO. However, even in the subgroup with minimal WASO there was a significant sleep maintenance effect. The absence of any sleep maintenance effect in a drug trial may reflect the inclusion of relatively many insomnia patients with no baseline WASO abnormality. However, treatments with therapeutic effects on sleep maintenance, can still demonstrate improvement in sleep maintenance, even in a population not selected for this type of sleep problem, if adequately powered. Future clinical trials intending to examine sleep maintenance should employ WASO selection criteria that would ensure sufficient power to detect a sleep maintenance effect. Drug-placebo difference increased as a function of baseline WASO severity, suggesting that eszopiclone's clinical effectiveness for insomnia may be enhanced in patients with more severe sleep maintenance symptoms.

A nasal aerosol formulation of ciclesonide with a hydrofluoroalkane propellant (CIC-HFA) is currently in development for treatment of allergic rhinitis (AR). This study evaluated the efficacy and safety of once-daily administration of CIC-HFA 74 or 148 micrograms compared with placebo in patients with seasonal AR (SAR) from mountain cedar pollen. Patients ≥12 years of age with a ≥2-year history of SAR from mountain cedar pollen were randomized in a placebo-controlled, double-blind, parallel group, multicenter study to CIC-HFA 74 micrograms, CIC-HFA 148 micrograms, or placebo once daily in the morning for 2 weeks. Change from baseline in reflective total nasal symptom score (rTNSS), instantaneous TNSS (iTNSS), and reflective total ocular symptom score (rTOSS) in patients with baseline rTOSS ≥5.00 were evaluated. Adverse events (AEs) were monitored throughout the study. A statistically significant improvement in rTNSS (least squares [LS] mean change from baseline 1.04 and 1.02 respectively; p < 0.0001 versus placebo for both) and iTNSS (LS mean change from baseline 0.90 and 0.83 respectively; p < 0.001 vs placebo for both) was observed after treatment with CIC-HFA 74- or 148-microgram doses. Only the CIC-HFA 74-micrograms treatment group showed a statistically significant improvement in rTOSS (LS mean change from baseline 0.52; p = 0.0124) compared with placebo. The overall incidence of AEs was low and comparable between the treatment groups. In this study, statistically significant improvements in nasal symptoms of SAR were observed after treatment with CIC-HFA 74-microgram or CIC-HFA 148-microgram doses. Both active treatments were well tolerated. Clinical trial registry URL and registration number: www.clinicaltrials.gov/ct2/show/NCT01010971.

Ciclesonide hydrofluoroalkane nasal aerosol (CIC-HFA) is currently in development for treatment of allergic rhinitis. This Phase I study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of CIC-HFA in healthy subjects (N = 18) and subjects with perennial allergic rhinitis (PAR, N = 18) in a double-blind, placebo-controlled, 3-period crossover design following treatment with 282 μg or 148 μg CIC-HFA or placebo once-daily for 14 days. The concentrations of desisobutyryl-ciclesonide (des-CIC), the pharmacologically active metabolite of CIC were measured by a validated high performance liquid chromatography with tandem mass spectrometry. Maximum serum concentration (C(max)), area under the serum concentration time curve (AUC), time to maximum serum concentration (t(max)) and elimination half life (t(1/2)) where feasible, were calculated. Serum cortisol (AUC(0-24h)) and adverse events (AE) were also evaluated. The overall systemic exposure of des-CIC was low. The mean C(max) for des-CIC on Day 14 was 35.84 ng/L and 25.98 ng/L for the CIC-HFA 282 μg and CIC-HFA 148 μg treatment groups respectively. Mean AUC((0, last)) for des-CIC on Day 14 was 213 ng·h/L and 112.3 ng·h/L for CIC-HFA 282 μg and 148 μg respectively. Mean serum cortisol (AUC(0-24h)) was similar for CIC-HFA 282 μg (178 μg·h/dL), CIC-HFA 148 μg (169 μg·h/dL), and placebo (174 μg·h/dL) on Day 14. The overall incidence of AEs was low and headache and epistaxis were the most common individual AEs reported. In this study, systemic exposure of des-CIC was low and similar in healthy subjects and subjects with PAR with no evidence of clinically relevant accumulation over the 14 day treatment period in either treatment group. Both doses of CIC-HFA were well tolerated without significant effect on cortisol levels.

OBJECTIVE: To evaluate efficacy and safety of eszopiclone compared with placebo in children and adolescents with insomnia associated with attention-deficit/hyperactivity disorder (ADHD). METHODS: A 12-week, randomized, double-blind, placebo-controlled trial evaluated efficacy and safety of high- or low-dose eszopiclone (1 or 2 mg in children aged 6–11 years, 2 or 3 mg in children ages 12–17 years), given every evening, in 486 patients with ADHD-related insomnia. The primary efficacy variable was change in latency to persistent sleep from baseline to week 12, based on polysomnography. Key secondary measures were polysomnography-measured wake time after sleep onset, Clinical Global Impression Parent/Caregiver and Child scales, and the Conners’ ADHD rating scales. The safety of eszopiclone was further studied over 1 year of open-label treatment in 55 patients who completed the double-blind study, and 249 patients with no previous eszopiclone exposure. RESULTS: Neither low-dose nor high-dose eszopiclone significantly reduced latency to persistent sleep compared with placebo after 12 weeks of treatment. Secondary outcomes were considered nonsignificant based on the hierarchical statistical analysis plan. The most frequent treatment-emergent adverse events over 12 weeks with eszopiclone were headache, dysgeusia, and dizziness. The study results demonstrated that eszopiclone was well tolerated over 1 year of treatment, with 11.2% of patients discontinuing open-label treatment because of an adverse event. CONCLUSIONS: Eszopiclone (up to 3 mg) failed to reduce latency to persistent sleep on polysomnography after 12 weeks in children aged 6 to 17 years with ADHD-related insomnia. Eszopiclone was well tolerated in the 1-year study.

Objective: The purpose of this post hoc analysis was to compare the treatment effect size of eszopiclone 3 mg for insomnia in patients with a diagnosis of primary insomnia and in several of the psychiatric and medical conditions that are most commonly comorbid with insomnia. Method: Data were analyzed from 5 large, multicenter, randomized, double-blind, placebo-controlled studies of adult outpatients of at least 1 month duration published between 2006 and 2009. Diary-derived indices of sleep and daytime functioning and the Insomnia Severity Index were compared for patients with primary insomnia (DSM-IV-TR criteria, n = 828) and for those with insomnia comorbid with major depressive disorder (MDD, DSM-IV-TR criteria, n = 545), generalized anxiety disorder (GAD, DSM-IV-TR criteria, n = 595), perimenopause/postmenopause (Stages of Reproductive Aging Workshop criteria, n = 410), and rheumatoid arthritis (American College of Rheumatology criteria, n = 153). Cohen d effect sizes were calculated for each individual study as the between-treatment difference score divided by the pooled standard deviation. Results: Effect sizes ranged from 0.40 to 0.69 (small–medium) as early as week 1 and were maintained at 0.26–0.63 at week 4 for sleep latency, wake time after sleep onset, and total sleep time. Sleep latency and total sleep time effect sizes increased from week 1 to week 4 in the primary insomnia group. At week 4, effect sizes on all 3 parameters and the Insomnia Severity Index tended to be highest for the primary insomnia patients and tended to be lowest for patients with comorbid GAD and MDD. The effect sizes for daytime functioning were small for all insomnia patient groups. Conclusions: Eszopiclone 3 mg is an effective treatment for insomnia across 5 clinically diverse patient populations; however, magnitude of effect is mediated by underlying comorbidity and their treatments, with largest measures of effect seen in primary insomnia and lowest in MDD and GAD. These consistent results, and the fact that clinical trials were conducted in patients being treated as appropriate for their comorbid clinical conditions, support the results’ real-world generalizability and utility to clinical practice.

A new nasal aerosol solution formulation of ciclesonide containing a hydrofluoroalkane propellant (CIC-HFA) delivered via a metered-dose inhaler is currently in clinical development as a potential treatment for allergic rhinitis (AR). This study evaluated the efficacy and tolerability of CIC-HFA 74- or 148-microgram doses compared with placebo in patients with perennial AR (PAR). Patients ≥12 years of age with a ≥ 2-year history of PAR were randomized in a placebo-controlled, double-blind, parallel-group, multicenter study to CIC-HFA 74 micrograms, CIC-HFA 148 micrograms, or placebo q.d. in the morning (A.M.) for 26 weeks. Change from baseline in reflective total nasal symptom score (rTNSS), instantaneous total nasal symptom score (iTNSS), and rhinoconjunctivitis quality-of-life questionnaire with standardized activities (RQLQ[S]) in patients with baseline RQLQ of ≥3.00 were evaluated for the first 6 weeks of treatment. Treatment-emergent adverse events (TEAEs) were monitored throughout the study. Eleven hundred eleven patients were randomized. CIC-HFA 74- and 148-microgram doses showed statistically significant improvements in rTNSS (least squares [LS] mean change, 0.70 and 0.54, respectively; p ≤ 0.001 versus placebo for both), iTNSS (LS mean change, 0.58 and 0.42, respectively; p < 0.05 versus placebo for both), and RQLQ[S] (LS mean change, 0.55 and 0.37, respectively; p < 0.01 versus placebo for both) from baseline. The overall incidence of TEAEs was comparable between the CIC-HFA treatment groups and placebo. In this study, once-daily treatment with CIC-HFA 74- or 148-micrograms showed statistically significant improvements in nasal symptoms of PAR. Both doses were well tolerated. Clinical trial registration URL and registration number: www.clinicaltrials.gov/ct2/show/NCT00953147.

A hypotonic aqueous nasal spray of ciclesonide is indicated for the treatment of allergic rhinitis (AR). A new nasal aerosol formulation of ciclesonide containing a hydrofluoroalkane propellant delivered via a metered-dose inhaler (CIC-HFA) is currently in clinical development as a potential treatment for AR.To study the efficacy and safety of once-daily administration of CIC-HFA 80 or 160 μg compared with placebo in subjects 12 years and older with seasonal AR (SAR).Subjects 12 years and older with a ≥ 2-year history of SAR were randomized in a placebo-controlled, double-blind, parallel-group, multicenter study to receive CIC-HFA 80 or 160 μg or placebo once daily in the morning for 2 weeks. Changes from baseline in reflective total nasal symptom scores (rTNSSs), instantaneous TNSSs (iTNSSs), and reflective total ocular symptom scores (rTOSSs) in subjects with a baseline rTOSS of ≥ 5.00 were evaluated. Treatment-emergent adverse events were monitored throughout the study.Seven hundred seven subjects were randomized. From baseline, CIC-HFA 80 or 160 μg demonstrated 15.1% and 16.0% reductions in rTNSSs (P.0001, 3.7% for placebo), 14.3% and 15.4% reductions in iTNSSs (P.0001, 3.9% for placebo), and 15.7% and 15.0% reductions in rTOSSs (P.001, 6.8% for placebo). The overall incidence of treatment-emergent adverse events was low and comparable between the CIC-HFA and placebo groups.In this study, once-daily treatment with CIC-HFA 80 or 160 μg demonstrated statistically significant improvements in nasal and ocular symptoms of SAR. Both doses of active treatment were well tolerated.

OBJECTIVE: Patients with major depressive disorder (MDD) and significant anxiety are less responsive to antidepressants than those without anxiety. In this post hoc analysis of patients with insomnia and comorbid anxious depression, eszopiclone cotherapy with a selective serotonin reuptake inhibitor (SSRI) was compared with placebo cotherapy. METHOD: Data were pooled from 2 randomized, double-blind, 8-week trials. One trial (conducted from January 2004 to October 2004) included patients with DSM-IV insomnia and comorbid MDD treated with fluoxetine concurrently with eszopiclone 3 mg/d or placebo. The other trial (conducted from July 2005 to April 2006) included patients with DSM-IV-TR insomnia and comorbid generalized anxiety disorder treated with escitalopram concurrently with eszopiclone 3 mg/d or placebo. Anxious depression was defined as a baseline 17-item Hamilton Depression Rating Scale (HDRS-17) score ≥ 14 (excluding insomnia items) and an anxiety/somatization factor score ≥ 7. Treatment group differences were determined for mean changes in HDRS-17 scores (with and without insomnia items), HDRS anxiety/somatization scores, and response and remission rates. Severity of insomnia was assessed by the Insomnia Severity Index (ISI). RESULTS: In the combined dataset, 347 of 1,136 patients (30.5%) had insomnia and comorbid anxious depression. Significant improvements in insomnia were observed for eszopiclone cotherapy relative to placebo cotherapy (mean change from baseline on the ISI: -11.0 vs -7.8, respectively; P < .001). There were greater reductions in HDRS-17 scores at week 8 following cotherapy with eszopiclone compared with placebo when the insomnia items were included (mean change: -14.1 vs -11.2, respectively; P < .01) or excluded (-10.6 vs -8.9; P < .01), but not for anxiety/somatization (-4.3 vs -4.1; P = .23). Response rates were greater for eszopiclone cotherapy than for placebo cotherapy (55.6% vs 42.0%, respectively; P = .01; 50.0% vs 44.4% when insomnia items were removed; P = .3). Remission rates were not significantly different (32.6% vs 27.2%, respectively; P = .28). CONCLUSIONS: In this post hoc analysis of patients with insomnia and comorbid anxious depression derived from 2 trials, 8 weeks of eszopiclone therapy coadministered with an SSRI resulted in significantly greater improvements in insomnia, significantly greater reductions in HDRS-17 total score, and significantly greater HDRS-17 response rates compared with placebo coadministration. There were no significant differences in response rates (when insomnia items were excluded) and remission rates, as well as in anxiety/somatization scores. Further research is warranted to determine whether these modest antidepressant effects can be replicated, and anxiolytic effects demonstrated, when evaluated in a prospective manner.

SummaryPurposeCurrent guidelines support using in combination more than one class of long-acting bronchodilator for COPD patients whose symptoms are not controlled by mono-therapy. This 2-week, multi-center (34 sites), randomized, modified-blind, parallel group study evaluated the efficacy and safety of concomitant treatment with nebulized arformoterol (the formoterol(R,R)-isomer) BID and tiotropium DPI QD.MethodsCOPD patients (mean FEV1 1.37L, 45.4% predicted) were randomized to receive mono-therapy (either arformoterol 15μg BID [n=76] or tiotropium 18μg QD [n=80]), or combined therapy (sequential dosing of arformoterol 15μg BID and tiotropium 18μg QD [n=78]). Changes in pulmonary function, dyspnea, and rescue levalbuterol use were evaluated, as were safety outcomes.ResultsMean FEV1AUC0–24 (the primary endpoint) improved similarly from baseline for arformoterol (0.10L) and tiotropium (0.08L) treatment groups and greater for the combined therapy group (0.22L; all p-values

The Fc region has two highly conserved methionine residues, Met 33 (C(H)3 domain) and Met 209 (C(H)3 domain), which are important for the Fc's structure and biological function. To understand the effect of methionine oxidation on the structure and stability of the human IgG1 Fc expressed in Escherichia coli, we have characterized the fully oxidized Fc using biophysical (DSC, CD, and NMR) and bioanalytical (SEC and RP-HPLC-MS) methods. Methionine oxidation resulted in a detectable secondary and tertiary structural alteration measured by circular dichroism. This is further supported by the NMR data. The HSQC spectral changes indicate the structures of both C(H)2 and C(H)3 domains are affected by methionine oxidation. The melting temperature (Tm) of the C(H)2 domain of the human IgG1 Fc was significantly reduced upon methionine oxidation, while the melting temperature of the C(H)3 domain was only affected slightly. The change in the C(H)2 domain T m depended on the extent of oxidation of both Met 33 and Met 209. This was confirmed by DSC analysis of methionine-oxidized samples of two site specific methionine mutants. When incubated at 45 degrees C, the oxidized Fc exhibited an increased aggregation rate. In addition, the oxidized Fc displayed an increased deamidation (at pH 7.4) rate at the Asn 67 and Asn 96 sites, both located on the C(H)2 domain, while the deamidation rates of the other residues were not affected. The methionine oxidation resulted in changes in the structure and stability of the Fc, which are primarily localized to the C(H)2 domain. These changes can impact the Fc's physical and covalent stability and potentially its biological functions; therefore, it is critical to monitor and control methionine oxidation during manufacturing and storage of protein therapeutics.

Background:We evaluated the efficacy of eszopiclone (ESZ) and concurrent escitalopram oxalate (EO) in patients with insomnia and co-morbid GAD.Methods:Patients meeting DSM-IV-TR criteria for GAD and insomnia received 10 weeks of EO 10mg and co-therapy with ESZ 3mg or placebo (PBO) for 8 weeks. For the last 2 weeks, ESZ was replaced with single-blind PBO to evaluate discontinuation effects. Sleep, daytime functioning and anxiety measures were captured during the study.Results:ESZ+EO improved sleep and daytime functioning at each week and the double-blind period average (p

Background Ciclesonide hydrofluoroalkane nasal aerosol (CIC-HFA) is currently in development as a potential treatment for allergic rhinitis. The objective of this study was to determine the efficacy and safety of CIC-HFA compared to placebo in subjects with perennial allergic rhinitis (PAR). Methods Subjects ≥12 years of age with a ≥2 year history of PAR were randomized in a placebo-controlled, double-blind, parallel group, multicenter study to CIC-HFA 74 μg (N = 298), CIC-HFA 148 μg (N = 505), or placebo (N = 307) QD AM for 26 weeks. Subject-reported change from baseline in the average of AM and PM reflective total nasal symptom score (rTNSS) and instantaneous total nasal symptom score (iTNSS) averaged over the first 6 weeks of treatment period were key endpoints and were calculated as a sum of the 4 individual nasal symptoms of congestion, runny nose, sneezing, and nasal itching each on a scale of 0 (no signs/symptoms evident) to 3 (severe symptoms). Change from baseline in the individual reflective and instantaneous nasal symptom scores over the first 6 weeks of treatment period were also evaluated. Treatment-emergent adverse events (TEAEs) were assessed throughout the study. Results CIC-HFA 74 μg and CIC-HFA 148 μg doses demonstrated a statistically significant improvement in rTNSS (LS mean change 0.70 & 0.54 respectively, P ≤ 0.001 for both), iTNSS (LS mean change 0.58 & 0.42 respectively, P ≤ 0.05 for both) and improvements in individual reflective and instantaneous nasal symptoms (P ≤ 0.05 for all, unadjusted for multiplicity) at 6 weeks from baseline. The overall incidence of TEAEs was low and comparable between the CIC treatment groups and placebo. The most frequently reported TEAEs (≥2% of subjects in any treatment group) were nausea, headache, sinus headache, cough, upper respiratory tract infection, instillation site discomfort, nasal discomfort, nasopharyngitis, sinusitis, oropharyngeal pain, and epistaxis. Conclusions In this study, once-daily treatment with CIC-HFA 74μg or CIC-HFA 148μg demonstrated statistically significant improvements in the nasal symptoms of PAR. Both active treatments were well tolerated.

Insomnia and generalized anxiety disorder (GAD) are prevalent disorders that may coexist.To determine the efficacy of eszopiclone combined with escitalopram oxalate in treating insomnia comorbid with GAD.Double-blind, randomized, placebo-controlled, parallel-group, add-on therapy 10-week study.Multicenter outpatient study from July 2005 to April 2006.Adults aged 18 to 64 years meeting DSM-IV-TR criteria for GAD and insomnia.Patients received 10 mg of escitalopram oxolate for 10 weeks and were randomized to also receive either 3 mg of eszopiclone (n = 294) or placebo (n = 301) nightly for 8 weeks. For the last 2 weeks, eszopiclone was replaced with a single-blind placebo.Sleep, daytime functioning, psychiatric measures, and adverse events.Compared with treatment with placebo and escitalopram, treatment with eszopiclone and escitalopram resulted in significantly improved sleep and daytime functioning (P.05), with no evidence of tolerance. Patients taking eszopiclone and escitalopram had greater improvements in total Hamilton Anxiety Scale (HAM-A) scores at each week (P.05) and at weeks 4 through 10 with the insomnia item removed. Clinical Global Impressions (CGI) of Improvement scores were improved with eszopiclone and escitalopram at every point (P.02), while CGI of Severity of Illness scores were not significantly different after week 1. The HAM-A response (63% vs 49%, respectively, P = .001) and remission (42% vs 36%, respectively, P = .09) rates at week 8 were higher in patients treated with eszopiclone and escitalopram than those treated with placebo and escitalopram, and median time to onset of anxiolytic response was significantly reduced (Por = .05). After eszopiclone discontinuation, there was no evidence of rebound insomnia, and while treatment differences in anxiety measures were maintained, differences in sleep outcomes were not. Overall adverse event rates were 77.6% with cotherapy and 67.9% with monotherapy. The most common adverse events with cotherapy were unpleasant taste, headache, dry mouth, and somnolence.Coadministration of eszopiclone and escitalopram was well tolerated and associated with significantly improved sleep, daytime functioning, anxiety, and mood in patients with insomnia and GAD.clinicaltrials.gov Identifier: NCT00235508.