Background

We explored whether clinical outcomes differ by treatment strategy following initial antidepressant treatment failure among patients with and without clinically relevant symptom clusters.

Methods

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial was used to examine depression remission and response in patients with coexisting anxiety, atypical features, insomnia, and low energy. We applied propensity scoring to control for selection bias that precluded comparisons between augmentation and switch strategies in the original trial. Binomial regressions compared the likelihood of remission or response among patients with and without symptom clusters for switch versus augmentation strategies (n=269 per arm); augmentation strategy type (n=565); and switch strategy type (n=727).

Results

We found no statistically significant difference in remission or response rates between augmentation or switch strategies. However, symptom clusters did distinguish among augmentation and switch strategies, respectively. For patients with low energy, augmentation with buspirone was less likely to produce remission than augmentation with bupropion (remission Risk Ratio [RR]:0.54, 95% CI: 0.35–0.85, response RR:0.67, 95% CI 0.43, 1.03). Also, for patients with low energy, switching to venlafaxine or bupropion was less likely to produce remission than switching to sertraline (RR: 0.59, 95% CI: 0.36–0.97; RR: 0.63, 95% CI: 0.38–1.06, respectively).

Conclusions

Remission and response rates following initial antidepressant treatment failure did not differ by treatment strategy for patients with coexisting atypical symptoms or insomnia. However, some second-step treatments for depression may be more effective than others in the presence of coexisting low energy. Subsequent prospective testing is necessary to confirm these initial findings.

Background

Nonsteroidal anti-inflammatory drugs (NSAIDs) may disrupt control of blood pressure in hypertensive patients and increase their risk of morbidity, mortality, and the costs of care. The objective of this study was to examine the association between incident use of NSAIDs and blood pressure in patients with hypertension.

Methods

We conducted a retrospective cohort study of adult hypertensive patients to determine the effects of their first prescription for NSAID on systolic blood pressure and antihypertensive drug intensification. Data were collected from an electronic medical record serving an academic general medicine practice in Indianapolis, Indiana, USA. Using propensity scores to minimize bias, we matched a cohort of 1,340 users of NSAIDs with 1,340 users of acetaminophen. Propensity score models included covariates likely to affect blood pressure or the use of NSAIDs. The study outcomes were the mean systolic blood pressure measurement after starting NSAIDs and changes in antihypertensive therapy.

Results

Compared to patients using acetaminophen, NSAID users had a 2 mmHg increase in systolic blood pressure (95% CI, 0.7 to 3.3). Ibuprofen was associated with a 3 mmHg increase in systolic blood pressure compared to naproxen (95% CI, 0.5 to 4.6), and a 5 mmHg increase compared to celecoxib (95% CI, 0.4 to 10). The systolic blood pressure increase was 3 mmHg in a subgroup of patients concomitantly prescribed angiotensin converting enzyme inhibitors or calcium channel blockers and 6 mmHg among those prescribed a beta-adrenergic blocker. Blood pressure changes in patients prescribed diuretics or multiple antihypertensives were not statistically significant.

Conclusion

Compared to acetaminophen, incident use of NSAIDs, particularly ibuprofen, is associated with a small increase in systolic blood pressure in hypertensive patients. Effects in patients prescribed diuretics or multiple antihypertensives are negligible.

Limited neuromuscular input results in muscle weakness in neuromuscular disease either because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission1. We developed a small molecule fast skeletal troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neuromuscular input is diminished secondary to a neuromuscular disease. Binding selectively to the fast skeletal troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium. As a consequence, the force-calcium relationship of muscle fibers shifts leftwards as does the force-frequency relationship of a nerve-muscle pair. In vitro and in vivo, CK-2017357 increases the production of force at sub-maximal stimulation rates. Importantly, we show that sensitization of the fast skeletal troponin complex to calcium improves muscle force and grip strength immediately after single doses of CK-2017357 in a model of neuromuscular disease, myasthenia gravis. Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised.

Objective. To assess the extent to which US colleges and schools of pharmacy are incorporating interprofessional education into their introductory pharmacy practice experiences (IPPEs), and to identify barriers to implementation; characterize the format, structure, and assessment; and identify factors associated with incorporating interprofessional education in IPPEs.

Methods. An electronic survey of 116 US colleges and schools of pharmacy was conducted from March 2011 through May 2011.

Results. Interprofessional education is a stated curricular goal in 78% of colleges and schools and consistently occurred in IPPEs in 55%. Most colleges and schools that included interprofessional education in IPPEs (70%) used subjective measures to assess competencies, while 17.5% used standardized outcomes assessment instruments. Barriers cited by respondents from colleges and schools that had not implemented interprofessional education in IPPEs included a lack of access to sufficient healthcare facilities with interprofessional education opportunities (57%) and a lack of required personnel resources (52%).

Conclusions. Many US colleges and schools of pharmacy have incorporated interprofessional education into their IPPEs, but there is a need for further expansion of interprofessional education and better assessment related to achievement of interprofessional education competencies in IPPEs.

SUMMARY

Background

Selective cyclooxygenase-2 (COX-2) inhibitors have been linked to cardiac death. The mechanism for this adverse effect appears to be by ischemic insult; however another mechanism could involve hyperkalemia. The objective of this study was to determine the effects of selective COX-2 inhibitors and non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) on serum potassium concentration and the electrocardiogram.

Methods

A retrospective cohort study was conducted using propensity score matching of patients from an inner-city academic medical center at Indianapolis, Indiana. Two hundred and two patients prescribed selective COX-2 inhibitors were matched to 202 patients prescribed non-selective NSAIDs using propensity scores methods. Outcomes included change in serum potassium concentration from baseline and the risk of an abnormal electrocardiogram.

Results

Compared to patients prescribed non-selective NSAIDs, those prescribed a selective COX-2 inhibitor had a higher risk of serum potassium increase greater than 5 mEq/L (OR, 2.56; 95%CI, 1.03–6.36). However, patients prescribed selective COX-2 inhibitors had no greater risk of electrocardiogram abnormality (OR, 1.16; 95%CI, 0.74–1.82).

Conclusions

Selective COX-2 inhibitors may have a greater risk of hyperkalemia than non-selective NSAIDs. This study was exploratory with small numbers of patients. Further studies are needed to confirm these results and any association with cardiovascular events.

Purpose

The beneficial properties of β-glucans have been recognized for centuries. Their proposed mechanisms of action in cancer therapy occur via stimulation of macrophages and priming of innate neutrophil complement receptor 3 (CR3) for eliciting CR3-dependent cellular cytotoxicity of iC3b-opsonized tumor cells. The current study is to investigate whether β-glucan therapy has any impact on anti-tumor adaptive T cell responses.

Experimental Design

We first examined the trafficking of orally administered particulate yeast-derived β-glucan and its interaction with dendritic cells (DCs) that captured tumor materials. Antigen-specific T cells were adoptively transferred into recipient mice to determine whether oral β-glucan therapy induces augmented T cell responses. Lewis lung carcinoma and RAM-S lymphoma models were used to test oral β-glucan therapeutic effect. Further mechanistic studies including tumor-infiltrating T cells and cytokine profiles within the tumor milieu were determined.

Results

Orally administered particulate β-glucan trafficked into spleen and lymph nodes and activated DCs that captured dying tumor cells in vivo, leading to the expansion and activation of antigen-specific CD4 and CD8 T cells. In addition, IFN-γ production of tumor-infiltrating T cells and CTL responses were significantly enhanced upon β-glucan treatment, which ultimately resulted in significantly reduced tumor burden. Moreover, β-glucan-treated tumors had significantly more DC infiltration with the activated phenotype and significant levels of Th1-biased cytokines within the tumor microenvironment.

Conclusions

These data highlight the ability of yeast-derived β-glucan to bridge innate and adaptive anti-tumor immunity and suggest that it can be used as an adjuvant for tumor immunotherapy.

Inflammatory bowel disease (IBD) arises in genetically susceptible individuals as a result of an unidentified environmental trigger, possibly a hitherto unknown bacterial pathogen. Twenty-six clinical isolates of Sutterella wadsworthensis were obtained from 134 adults and 61 pediatric patients undergoing colonoscopy, of whom 69 and 29 respectively had IBD. S. wadsworthensis was initially more frequently isolated from IBD subjects, hence this comprehensive study was undertaken to elucidate its role in IBD. Utilizing these samples, a newly designed PCR was developed, to study the prevalence of this bacterium in adult patients with ulcerative colitis (UC). Sutterella wadsworthensis was detected in 83.8% of adult patients with UC as opposed to 86.1% of control subjects (p = 0.64). Selected strains from IBD cases and controls were studied to elicit morphological, proteomic, genotypic and pathogenic differences. This study reports Scanning Electron Microscopy (SEM) appearances and characteristic MALDI-TOF MS protein profiles of S. wadsworthensis for the very first time. SEM showed that the bacterium is pleomorphic, existing in predominantly two morphological forms, long rods and coccobacilli. No differences were noted in the MALDI-TOF mass spectrometry proteomic analysis. There was no distinct clustering of strains identified from cases and controls on sequence analysis. Cytokine response after monocyte challenge with strains from patients with IBD and controls did not yield any significant differences. Our studies indicate that S. wadsworthensis is unlikely to play a role in the pathogenesis of IBD. Strains from cases of IBD could not be distinguished from those identified from controls.

Introduction

The critical role of bacteria in the pathogenesis of ulcerative colitis (UC) is well recognized, but an individual causative microorganism has not been singled out so far. Campylobacter concisus and other non-jejuni species of Campylobacter have been implicated as putative aetiological agents in inflammatory bowel disease in children, but such studies have not been addressed in adults. This study investigated the prevalence of Campylobacter species in colonic biopsy samples from adults with UC and healthy controls.

Methods

Adult patients who were undergoing diagnostic colonoscopy were recruited for the study, which included 69 patients with histologically proven UC and 65 healthy controls. DNA was extracted from the biopsy samples and subjected to Campylobacter genus specific and Campylobacter concisus specific polymerase chain reaction and sequencing.

Results

Detection of all Campylobacter DNA utilising genus specific primers was significantly higher in cases of UC, with a prevalence of 73.9% (51/69) compared to 23.1% (15/65) in controls (p = 0.0001). Nested PCR for C. concisus DNA was positive in 33.3% (23/69) of biopsy samples from subjects with UC, which was significantly higher than the prevalence rate of 10.8% (7/65) from controls (p = 0.0019). Sequencing of the remaining Campylobacter positive samples revealed that Campylobacter ureolyticus was positive in 21.7% (15/69) of samples from UC subjects as opposed to 3.1% (2/65) in controls (p = 0.0013). Mixed Campylobacter species were more common in UC patients, 20.3% (14/69) as compared to controls 4.6% (3/65) (p = 0.0084).

Conclusion

The higher prevalence of Campylobacter genus and more specifically C. concisus and C. ureolyticus in biopsy samples from adults with UC suggests these genera of bacteria may be involved in the chronic inflammation that is characteristically seen in UC. To the best of our knowledge this is the first report of this association of C. concisus and C. ureolyticus with UC in adults.

Purpose

Non-adherence is a significant problem with antidepressants. Identifying patients at highest risk for discontinuing antidepressant treatment can be used to target clinical management. Accordingly, our purpose was to determine the shortest gap in medication supply that is predictive of discontinuation, while minimizing false positive results.

Methods

A retrospective cohort study of medical and prescription claims from a national health plan affiliated with i3 Innovus. Sensitivities, specificities, and positive and negative predictive values were calculated for gap lengths to assess how well they predicted discontinuation. Continuously insured individuals aged 18–65 with newly diagnosed major depression and an antidepressant prescription within 45 days of diagnosis were included. Gap length was defined as the maximum number of continuous days without medication supply during acute phase treatment. Discontinuation was defined as a continuous gap of 30 or more days between an expected refill and actual refill.

Results

Of 4,545 eligible patients, 73% discontinued antidepressant treatment during the study period. A maximum continuous gap of 14 days had a sensitivity of 87% and a specificity of 82% for predicting discontinuation. In analyses that varied the way gaps and discontinuation were defined, gap lengths between 8 and 19 days were highly predictive of discontinuation without exceeding a 20% false positive rate.

Conclusions

Based on administrative pharmacy records, screening for gaps in medication supply of at least 14 days can accurately identify 4 of every 5 patients at risk for discontinuing. This early indicator can be used to target clinical interventions.

Background

Changes in bacterial populations termed “dysbiosis” are thought central to ulcerative colitis (UC) pathogenesis. In particular, the possibility that novel Helicobacter organisms play a role in human UC has been debated but not comprehensively investigated. The aim of this study was to develop a molecular approach to investigate the presence of Helicobacter organisms in adults with and without UC.

Methodology/Principal Findings

A dual molecular approach to detect Helicobacter was developed. Oligonucleotide probes against the genus Helicobacter were designed and optimised alongside a validation of published H. pylori probes. A comprehensive evaluation of Helicobacter genus and H. pylori PCR primers was also undertaken. The combined approach was then assessed in a range of gastrointestinal samples prior to assessment of a UC cohort. Archival colonic samples were available from 106 individuals for FISH analysis (57 with UC and 49 non-IBD controls). A further 118 individuals were collected prospectively for dual FISH and PCR analysis (86 UC and 32 non-IBD controls). An additional 27 non-IBD controls were available for PCR analysis. All Helicobacter PCR-positive samples were sequenced. The association between Helicobacter and each study group was statistically analysed using the Pearson Chi Squared 2 tailed test. Helicobacter genus PCR positivity was significantly higher in UC than controls (32 of 77 versus 11 of 59, p = 0.004). Sequence analysis indicated enterohepatic Helicobacter species prevalence was significantly higher in the UC group compared to the control group (30 of 77 versus 2 of 59, p<0.0001). PCR and FISH results were concordant in 74 (67.9%) of subjects. The majority of discordant results were attributable to a higher positivity rate with FISH than PCR.

Conclusions/Significance

Helicobacter organisms warrant consideration as potential pathogenic entities in UC. Isolation of these organisms from colonic tissue is needed to enable interrogation of pathogenicity against established criteria.

Objective

To describe the implementation and evaluation of a web‐based medication error reporting system.

Design

Evaluation study.

Setting

Long‐term care.

Participants

25 nursing homes in the US state of North Carolina.

Intervention

Detailed information about all medication errors occurring in a facility during a 1 year period was entered into a web‐based reporting system. An evaluation survey was conducted to assess usability and the potential for the system to prevent errors.

Main outcome measures

Number and specific characteristics of medication errors reported. A survey evaluating ease of use of the system and whether the participants thought it would help improve medication safety.

Results

23 (92%) sites entered 631 error reports for 2731 discrete error instances when weighted by the number of times the errors were repeated. 51 (8%) errors were classified as having a serious patient impact requiring monitoring/intervention or worse. The most common errors were dose omission (203, 32%), overdose (91, 14%), underdose (43, 7%), wrong patient (38, 6%), wrong product (38, 6%), and wrong strength (38, 6%). Errors most commonly occurred during medication administration (296, 47%) and were attributed to basic human error (402, 48%). Seven drugs were implicated in a third (175, 28%) of all errors: lorazepam, oxycodone, warfarin, furosemide, hydrocodone, insulin and fentanyl. 20 sites (86% of respondents) completed the evaluation survey and participants found the system easy to use and thought it would increase accuracy of reporting and improve patient safety.

Conclusions

The web‐based medication error reporting system was easy to use, with strong indications that it would be a valuable tool for preventing future errors.

Background & Aims

Direct to consumer advertisement (DTCA) and physician promotion of drugs can influence patient and physician behaviors. We sought to determine the relationship between promotion of tegaserod and the number of office visits for abdominal pain, constipation, and bloating; diagnoses of irritable bowel syndrome (IBS); and tegaserod prescriptions.

Methods

We used an Integrated Promotional Services database to estimate tegaserod DTCA and promotion expenditures, The National Ambulatory/Hospital Medical Care Surveys (1997–2005) to estimate the number of ambulatory care visits for abdominal pain, constipation, and bloating and diagnoses of IBS, and IMS Health's National Prescription Audit Plus to estimate the number of prescriptions. We constructed segmented and multivariate regression models to analyze the data.

Results

In the 3 months immediately following the start of tegaserod DTCA, there was a significant increase in physician visits (by 1 million; 95% CI 0.5–1.6 million) and IBS diagnoses (by 397,025; 95% CI 3,909–790,141). Subsequently, the trend of visits and IBS diagnoses reduced. In multivariate analyses that examined the overall relationship of promotion with visits, diagnoses, and prescriptions, only the relationship between physician promotion and tegaserod prescribing was significant; every $1 million spent on physician promotion resulted in an additional 4,108 prescriptions (95% CI: 2,526–5,691).

Conclusions

The initial DTCA of tegaserod was associated with a significant, immediate increase in physician visits and IBS diagnoses. This trend reversed and in multivariate models, neither DTCA nor physician promotion correlated with visits or diagnoses. Physician promotion (though not DTCA) correlated with tegaserod prescription volume.

β-Glucan is an immuno-stimulating agent that has been used to treat cancer and infectious disease for many years with varying and unpredictable efficacy. Recent studies have unraveled the action mode of yeast-derived β-glucan in combination with anti-tumor monoclonal antibodies (mAbs) in cancer therapy. It has demonstrated that particulate or large molecular weight soluble β-glucans are ingested and processed by macrophages. These macrophages secrete the active moiety that primes neutrophil complement receptor 3 (CR3) to kill iC3b-opsonized tumor cells. In vitro and in vivo data demonstrate that successful combination therapy requires complement activation and deposition on tumors and CR3 expression on granulocytes. Pre-clinical animal studies have demonstrated the efficacy of combined β-glucan with anti-tumor mAbs therapy in terms of tumor regression and long-term survival. Clinical trials are underway using anti-epidermal growth factor receptor mAb (Erbitux) in combination with β-glucan for metastatic colorectal cancer. This review provides a brief overview of this combination therapy in cancer and describes in detail the β-glucan composition and structure, mechanism of action, and preclinical studies in human carcinoma xenograft models. It is proposed that the addition of β-glucan will further improve the therapeutic efficacy of anti-tumor mAbs in cancer patients.

Background

Anemia is common in chronic kidney disease (CKD), and suboptimal management of anemia can lead to serious health complications and poor quality of life.

Objectives

1) To describe health-related and overall quality of life among patients entering a clinic focused on anemia management; 2) to compare their baseline quality of life with other relevant populations; 3) to explore predictors of quality of life prior to anemia management; and 4) to explore changes in quality of life over 1 year for patients managed in the clinic.

Methods

The Kidney Disease Quality of Life questionnaire – short form (KDQOL™-SF) was used to measure kidney disease specific and overall quality of life in a cohort of pre-dialysis CKD patients (n=79) enrolled in the clinic from January 2003 to September 2004. Baseline measures were compared to previously published measurements. The influence of demographic and clinical characteristics on baseline quality of life was explored. Changes in quality of life were evaluated over time.

Results

Patients with CKD entering the clinic had lower overall quality of life compared with estimates from the general US population (physical composite 35.7 vs. 48.4 and mental composite 46.0 vs. 50.2, respectively). Clinic patients had better kidney disease specific scores than patients with end stage kidney disease. General quality of life scores were similar regardless of kidney disease severity, with the exception of physical functioning which was lowest for patients with end-stage disease. Hemoglobin was the only factor predictive of quality of life. Over time, quality of life improved among patients managed in the CKD clinic, with statistically significant improvements in sleep (change of 6.2 ± 15.2; p < 0.05) and social function (change of 11.6 ± 27.7; p < 0.05).

Conclusions

Patients with anemia of chronic kidney disease reported reduced quality of life compared to populations without kidney disease, but better quality of life compared to populations with end stage kidney disease on dialysis. Quality of life generally improved among patients managed in the multidisciplinary anemia clinic.

Objective

To review data on the efficacy and effectiveness of second-generation antidepressants for preventing major depression relapse and recurrence during continuation and maintenance phase treatment, respectively.

Methods

MEDLINE®, EMBASE, and PsychLit; the Cochrane Library; and the International Pharmaceutical Abstracts were searched from January 1980 through April 2007 for reviews, randomized controlled trials, meta-analyses, and observational studies. Two persons independently reviewed abstracts and full text articles using a structured data abstraction form to ensure consistency in appraisal and data extraction.

Findings

Four comparative trials and 23 placebo controlled trials that addressed relapse or recurrence prevention were included. Results of comparative trials have not demonstrated statistically significant differences between duloxetine and paroxetine, fluoxetine and sertraline, fluvoxamine and sertraline, and trazodone and venlafaxine. Pooled data for the class of second-generation antidepressants compared with placebo suggest a relatively large effect size that persists over time. The number needed to treat to prevent one additional relapse or recurrence is 5 (95% CI 4 to 6). Differences in the length of open-label treatment prior to randomization, drug type, and trial duration did not affect pooled estimates of relapse rates (P = 0.716, P = 0.507, and P = 0.480, respectively). Across all trials, 7% of patients randomized to active treatment and 5% of patients randomized to placebo discontinued treatment because of adverse events.

Conclusions

This review demonstrates the overall benefits of continuation- and maintenance-phase treatment of major depression with second-generation antidepressants, and stresses the need for additional studies on comparative differences among drugs.

Purpose

To describe a method for quantitatively dealing with drug dose in comparative effectiveness reviews. Second-generation antidepressants are used as an example to illustrate this method, and to determine whether dose influences conclusions on comparative effectiveness.

Methods

Studies previously identified in a systematic review of second-generation antidepressants were included if data on drug dose were available. The usual dosing range for each drug was defined, and then used to create 2- and 3-level dose categories. Placebo-controlled data were used to calculate overall effect sizes for the drug class and effect sizes stratified by drug dose. Meta-regression tested the impact of dose on effect size. Weighted mean differences and risk ratios were calculated for comparative studies, stratifying by whether compared doses were equivalent.

Results

The dose classification method was able to identify dose-response trends in the context of meta-analysis. Compared to low dose studies, medium and high dose studies had a 1 to 2 point greater differential in mean HAM-D change (P<0.001). Dose was not a statistically significant predictor of categorical HAM-D response. Among comparative trials with non-equivalent doses, trends favored higher dose categories, but generally were not statistically significant.

Conclusions

A structured method for quantitatively dealing with drug dose in comparative effectiveness reviews is described, with application to the second-generation antidepressants. Dose-dependent reductions in HAM-D scores were identified, although differences did not translate into better response rates for higher doses. Dose equivalency was not a significant factor among comparative studies in second-generation antidepressants.

Objective

To systematically review the general and comparative efficacy and safety of anakinra for rheumatoid arthritis.

Methods

We searched MEDLINE®, Embase, The Cochrane Library, and the International Pharmaceutical Abstracts from 1980 to April 2009. We manually searched reference lists of pertinent review articles and explored the Center for Drug Evaluation and Research database. For efficacy we included randomized controlled trials (RCTs) comparing anakinra with placebo or other biologics. For safety both experimental and observational studies were eligible. Two persons independently reviewed abstracts and full text articles and extracted relevant data.

Results

We included data from 3 RCTs comparing anakinra with placebo for rheumatoid arthritis (RA). The pooled relative risk (RR) of an ACR50 (American College of Rheumatology) response for anakinra compared with placebo is 2.28 (95% CI 1.41 to 3.67). Adjusted indirect comparisons of ACR50 response rates of anakinra and anti-TNF agents showed a RR of 0.67 (95% CI 0.38 to 1.17) favoring the anti-TNF drugs. This result did not reach statistical significance. For safety, we included 9 experimental and observational studies of 24 weeks to 3 years duration. Up to 30% of patients withdrew from the studies due to adverse events. 67.2% (95% CI 38.7 to 95.7) of patients experienced an injection site reaction.

Conclusions

Anakinra is an effective drug for treating RA. Indirect comparisons with adalimumab, etanercept and infliximab, however, showed a trend towards greater efficacy for the anti-TNF drugs. Anakinra also seems to be associated with comparably high rates of injection site reactions. These results should be taken into account when considering biologic therapy for patients with RA.

Study Objective

Previous studies suggest a risk of gastrointestinal events in patients prescribed oral corticosteroids, but gastrointestinal events have not commonly been documented in patients prescribed inhaled corticosteroids. We explored whether patients prescribed inhaled corticosteroids are at risk of adverse gastrointestinal effects.

Design

A retrospective cohort study was conducted using 25 years of electronic medical record data.

Setting

An urban health center with an academic affiliation.

Patients

The incidence of adverse gastrointestinal events in patients prescribed inhaled corticosteroids and albuterol (n = 7,156) was compared to those prescribed albuterol alone (n = 12,287).

Measurements and Main Results

Adverse gastrointestinal outcomes included events such as gastritis, ulcers, and bleeding. Cox proportional hazards models were used to determine the risk of adverse events controlling for possible confounders such as alcohol use or non-steroidal anti-inflammatory drug use. Adverse gastrointestinal events were observed in 461 (6.4%) patients prescribed inhaled corticosteroids and albuterol and in 302 (2.5%) patients prescribed only albuterol. Patients prescribed inhaled albuterol and inhaled corticosteroids had an increased risk of adverse gastrointestinal events compared to patients prescribed only albuterol [hazard ratio 1.26 (95% confidence interval 1.02 to 1.56)] after controlling for potential confounders. A prescription for a spacer device reduced this risk among patients prescribed inhaled steroid [hazard ratio 0.26 (95% confidence interval 0.20 to 0.34)].

Conclusions

Patients prescribed inhaled corticosteroids appear to have a slight risk of adverse gastrointestinal events that is mitigated in patients prescribed a spacer device.

A systematic review and meta-analysis was conducted to evaluate the comparative efficacy and tolerability of second-generation antidepressants in social anxiety disorder. Studies were identified by searching MEDLINE®, Embase, The Cochrane Library, PsychLit, and the International Pharmaceutical Abstracts from January 1980 through October 2006. Comparative evidence was summarized and indirect comparisons were made using network meta-analysis. Only three head-to-head trials were identified; comparative trials found only minimal differences in efficacy between escitalopram and paroxetine, and no statistically significant differences in efficacy between extended-release venlafaxine and paroxetine. Pooled evidence from 15 placebo-controlled trials suggests that escitalopram (relative benefit 1.3; 95% CI 1.2 to 1.5), paroxetine (relative benefit 1.9; 95% CI 1.5 to 2.3), sertraline (relative benefit 1.8; 95% CI 1.5 to 2.2), and venlafaxine (relative benefit 1.7; 95% CI 1.5 to 1.9) all produce significantly more responders than placebo; evidence favored fluvoxamine over placebo but was not significant (relative benefit 1.5; 95% CI 0.9 to 2.4). Network meta-analysis did not reveal differences in efficacy among drugs. Overall, fair evidence supports the efficacy of escitalopram, fluvoxamine, paroxetine, sertraline, and venlafaxine in social anxiety disorder. The drugs do not differ in efficacy, although their adverse event profiles do.

Pharmacologic treatments for Alzheimer’s disease include the cholinesterase inhibitors donepezil, galantamine, and rivastigmine. We reviewed their evidence by searching MEDLINE, Embase, The Cochrane Library, and the International Pharmaceutical Abstracts from 1980 through 2007 (July) for placebo-controlled and comparative trials assessing cognition, function, behavior, global change, and safety. Thirty-three articles on 26 studies were included in the review. Meta-analyses of placebo-controlled data support the drugs’ modest overall benefits for stabilizing or slowing decline in cognition, function, behavior, and clinical global change. Three open-label trials and one double-blind randomized trial directly compared donepezil with galantamine and rivastigmine. Results are conflicting; two studies suggest no differences in efficacy between compared drugs, while one study found donepezil to be more efficacious than galantamine, and one study found rivastigmine to be more efficacious than donepezil. Adjusted indirect comparison of placebo-controlled data did not find statistically significant differences among drugs with regard to cognition, but found the relative risk of global response to be better with donepezil and rivastigmine compared with galantamine (relative risk = 1.63 and 1.42, respectively). Indirect comparisons also favored donepezil over galantamine with regard to behavior. Across trials, the incidence of adverse events was generally lowest for donepezil and highest for rivastigmine.

Purpose

Bevacizumab is a recombinant IgG1humanized monoclonal antibody against vascular endothelial growth factor (VEGF). Its proposed mechanism of action is independent of immune effector functions. Many human carcinomas not only secrete VEGF but also express membrane-bound VEGF. In addition, VEGF receptors are expressed on tumor cells. It is hypothesized that bevacizumab could bind membrane-bound VEGF or VEGF-VEGF receptor complexes on tumors, thereby initiating potential immunologic consequences. We previously showed that yeast-derived β-glucan functions with antitumor antibodies that activate complement to recruit complement receptor 3– expressing leukocytes capable of mediating complement receptor 3– dependent cellular cytotoxicity of tumors opsonized with iC3b. In the current study, the therapeutic efficacy mediated by combining bevacizumab with yeast-derived β-glucan was studied in human carcinoma xenograft models.

Experimental Design

Human tumor cell lines were screened for membrane-bound VEGF expression both in vitro and in vivo. Complement activation mediated by bevacizumab was examined. Tumor cell lines positive or negative for membrane-bound VEGF expression were implanted in severe combined immunodeficient mice to establish xenograft models. Tumor-bearing mice were treated with different regimens. Tumor regression and long-term survival were recorded.

Results

Human ovarian carcinoma SKOV-3 cells expressed membrane-bound VEGF both in vitro and in vivo. Bevacizumab was bound to membrane-bound VEGF, activated complement, and synergized with β-glucan to elicit cellular cytotoxicity in vitro. In vivo study showed that β-glucan could significantly augment the therapeutic efficacy mediated by bevacizumab.

Conclusions

Yeast-derived β-glucan can synergize with anti-VEGF monoclonal antibody bevacizumab for the treatment of cancer with membrane-bound VEGF expression.

INTRODUCTION

Exisulind is an apoptotic agent with preclinical activity in non-small cell lung cancer (NSCLC). Vinorelbine is safe and effective in older patients with advanced NSCLC. We assessed these agents together as palliative treatment for older patients with advanced NSCLC.

METHODS

Chemotherapy-naïve patients ≥ 70 years old with stage IIIB-IV NSCLC and a performance status (PS) ≤ 2 were eligible. Primary endpoints were the maximum tolerated dose (MTD, phase I) and time-to-progression (TTP, phase II) of oral exisulind with 25 mg/m2/week of intravenous (IV) vinorelbine on a 28-day cycle. Patients with clinical benefit after six cycles of this combination received exisulind alone.

RESULTS

Fourteen phase I patients (median PS 1; median age 78 years) were enrolled. Dose-limiting toxicities included grade 3 constipation (one patient), grade 3 febrile neutropenia (one patient) and grade 3 diarrhea (one patient). The MTD of oral exisulind with 25 mg/m2/week of IV vinorelbine was 125 mg twice daily. Thirty phase II patients (median PS 1; median age 78 years) were enrolled. Grade ≥ 3 neutropenia occurred in 14/30 patients. Two patients experienced neutropenic fever. There were no complete responses, one partial response and 12 patients with stable disease as their best response. The objective response rate was 4.0% (95% CI: 0.1–20.4%). Phase II median TTP was 4.7 months (95% CI: 3.1 – 9.3 months) and median OS was 9.6 months (95% CI: 6.6 – 19.1 months).

CONCLUSIONS

This combination is safe, appears to have activity in the elderly with advanced NSCLC and a PS ≤ 2, and warrants further investigation.

The therapeutic benefits of fungal β-glucans have been demonstrated as immuno-stimulating agents. In this study, we aimed to explore the mechanisms used by yeast β-glucan-rich particles to activate murine resident macrophages for cytokine secretion. We demonstrated that resident macrophages were effectively activated by whole yeast β-glucan particles (WGPs), such as with the up-regulation of co-stimulatory molecules and the secretion of cytokines. The binding ability of WGPs and the levels of cytokine secretion in resident macrophages were significantly inhibited by soluble yeast β-glucan but not by blockade of zymosan glucan receptor dectin-1. In addition, WGP-stimulated cytokine secretion was partially dependent on the MyD-88 pathway but was not significantly affected in CR3-deficient (CR3−/−) mice. Furthermore, we showed that Syk kinase was recruited upon WGP stimulation and was required for the production of cytokines. Taken together, these observations suggest that β-glucan recognition is necessary but not sufficient to induce inflammatory response on resident macrophages. In addition, β-glucan particles may use differential mechanisms for cytokine secretion in resident macrophages that may modulate both innate and adaptive immunity.

Administration of a combination of yeast-derived β-glucan with antitumor monoclonal antibodies (mAb) has significant therapeutic efficacy in a variety of syngeneic murine tumor models. We have now tested this strategy using human carcinomas implanted in immunocompromised severe combined immunodeficient mice. Combined immunotherapy was therapeutically effective in vivo against NCI-H23 human non–small-cell lung carcinomas, but this modality was surprisingly ineffective against SKOV-3 human ovarian carcinomas. Whereas NCI-H23 tumors responded to this combination therapy with increased intratumoral neutrophil infiltration and C5a production, these responses were lacking in treated SKOV-3 tumors. Further results suggested that SKOV-3 tumors were protected by up-regulation of the membrane complement regulatory protein CD55 (decay-accelerating factor). Blockade of CD55 in vitro led to enhanced deposition of C activation product C3b and increased cytotoxicity mediated by β-glucan–primed neutrophils. In vivo, administration of anti-CD55 mAb along with β-glucan and anti–Her-2/neu mAb caused tumor regression and greatly improved long-term survival in animals bearing the previously resistant SKOV-3 tumors. This was accompanied by increased intratumoral neutrophil accumulation and C5a production. We conclude that CD55 suppresses tumor killing by antitumor mAb plus β-glucan therapy (and, perhaps, in other circumstances). These results suggest a critical role for CD55 to regulate iC3b and C5a release and in turn to influence the recruitment of β-glucan–primed neutrophils eliciting killing activity.

Pharmacologic treatments for Alzheimer’s disease include the cholinesterase inhibitors donepezil, galantamine, and rivastigmine. We reviewed their evidence by searching MEDLINE®, Embase, The Cochrane Library, and the International Pharmaceutical Abstracts from 1980 through 2007 (July) for placebo-controlled and comparative trials assessing cognition, function, behavior, global change, and safety. Thirty-three articles on 26 studies were included in the review. Meta-analyses of placebo-controlled data support the drugs’ modest overall benefits for stabilizing or slowing decline in cognition, function, behavior, and clinical global change. Three open-label trials and one double-blind randomized trial directly compared donepezil with galantamine and rivastigmine. Results are conflicting; two studies suggest no differences in efficacy between compared drugs, while one study found donepezil to be more efficacious than galantamine, and one study found rivastigmine to be more efficacious than donepezil. Adjusted indirect comparison of placebo-controlled data did not find statistically significant differences among drugs with regard to cognition, but found the relative risk of global response to be better with donepezil and rivastigmine compared with galantamine (relative risk = 1.63 and 1.42, respectively). Indirect comparisons also favored donepezil over galantamine with regard to behavior. Across trials, the incidence of adverse events was generally lowest for donepezil and highest for rivastigmine.