Metal-Binding Q-Proline Macrocycles.

We introduce the efficient Fmoc-SPPS and peptoid synthesis of Q-proline-based, metal-binding macrocycles (QPMs), which bind metal cations and display nine functional groups. Metal-free QPMs are disordered, evidenced by NMR and a crystal structure of QPM-3 obtained through racemic crystallization. Upon addition of metal cations, QPMs adopt ordered structures. Notably, the addition of a second functional group at the hydantoin amide position (R2) converts the proline ring from Cγ-endo to Cγ-exo, due to steric interactions.

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution.

The rational design of foldable and functionalizable peptidomimetic scaffolds requires the concerted application of both computational and experimental methods. Recently, a new class of designed peptoid macrocycle incorporating spiroligomer proline mimics (Q-prolines) has been found to preorganize when bound by monovalent metal cations. To determine the solution-state structure of these cation-bound macrocycles, we employ a Bayesian inference method (BICePs) to reconcile enhanced-sampling molecular simulations with sparse ROESY correlations from experimental NMR studies to predict and design conformational and binding properties of macrocycles as functional scaffolds for peptidomimetics. Conformations predicted to be most populated in solution were then simulated in the presence of explicit cations to yield trajectories with observed binding events, revealing a highly preorganized all-trans amide conformation, whose formation is likely limited by the slow rate of cis/trans isomerization. Interestingly, this conformation differs from a racemic crystal structure solved in the absence of cation. Free energies of cation binding computed from distance-dependent potentials of mean force suggest Na+ has a higher affinity to the macrocycle than K+, with both cations binding much more strongly in acetonitrile than water. The simulated affinities are able to correctly rank the extent to which different macrocycle sequences exhibit preorganization in the presence of different metal cations and solvents, suggesting our approach is suitable for solution-state computational design.

Radiochemical Approaches to Imaging Bacterial Infections: Intracellular versus Extracellular Targets.

The discovery of penicillin began the age of antibiotics, which was a turning point in human healthcare. However, to this day, microbial infections are still a concern throughout the world, and the rise of multidrug-resistant organisms is an increasing challenge. To combat this threat, diagnostic imaging tools could be used to verify the causative organism and curb inappropriate use of antimicrobial drugs. Nuclear imaging offers the sensitivity needed to detect small numbers of bacteria in situ. Among nuclear imaging tools, radiolabeled antibiotics traditionally have lacked the sensitivity or specificity necessary to diagnose bacterial infections accurately. One reason for the lack of success is that the antibiotics were often chelated to a radiometal. This was done without addressing the ramifications of how the radiolabeling would impact probe entry to the bacterial cell, or the mechanism of binding to an intracellular target. In this review, we approach bacterial infection imaging through the lens of bacterial specific molecular targets, their intracellular or extracellular location, and discuss radiochemistry strategies to guide future probe development.

Development of Spiroligomer-Peptoid Hybrids.

Creating functional macromolecules that possess the diversity and functionality of proteins poses an enormous challenge, as this requires large, preorganized macromolecules to facilitate interactions. Peptoids have been shown to interact with proteins, and combinatorial libraries of peptoids have been useful in discovering new ligands for protein binding. We have created spiroligomer-peptoid hybrids that have a spirocyclic core that preorganizes functional groups in three-dimensional space. By utilizing spiroligomers, we can reduce the number of rotatable bonds between functional groups while increasing the stereochemical diversity of the molecules. We have synthesized 15 new spiroligomer monomer amines that contain two stereocenters and three functional groups (67-84% yields from a common hydantoin starting material) as well as a spiroligomer trimer 25 with six stereocenters and five functional groups. These 16 amines were used to synthesize five first-generation spiroligomer-peptoids hybrids.

Regulation of eDHFR-tagged proteins with trimethoprim PROTACs.

Temporal control of protein levels in cells and living animals can be used to improve our understanding of protein function. In addition, control of engineered proteins could be used in therapeutic applications. PRoteolysis-TArgeting Chimeras (PROTACs) have emerged as a small-molecule-driven strategy to achieve rapid, post-translational regulation of protein abundance via recruitment of an E3 ligase to the target protein of interest. Here, we develop several PROTAC molecules by covalently linking the antibiotic trimethoprim (TMP) to pomalidomide, a ligand for the E3 ligase, Cereblon. These molecules induce degradation of proteins of interest (POIs) genetically fused to a small protein domain, E. coli dihydrofolate reductase (eDHFR), the molecular target of TMP. We show that various eDHFR-tagged proteins can be robustly degraded to 95% of maximum expression with PROTAC molecule 7c. Moreover, TMP-based PROTACs minimally affect the expression of immunomodulatory imide drug (IMiD)-sensitive neosubstrates using proteomic and biochemical assays. Finally, we show multiplexed regulation with another known degron-PROTAC pair, as well as reversible protein regulation in a rodent model of metastatic cancer, demonstrating the formidable strength of this system. Altogether, TMP PROTACs are a robust approach for selective and reversible degradation of eDHFR-tagged proteins in vitro and in vivo.

Effect of exenatide on the pharmacokinetics of a combination oral contraceptive in healthy women: an open-label, randomised, crossover trial.

BACKGROUND: Consistent with its effect on gastric emptying, exenatide, an injectable treatment for type 2 diabetes, may slow the absorption rate of concomitantly administered oral drugs resulting in a decrease in maximum concentration (Cmax). This study evaluated the drug interaction potential of exenatide when administered adjunctively with oral contraceptives, given their potential concomitant use. METHODS: This trial evaluated the effect of exenatide co-administration on single- and multiple-dose pharmacokinetics of a combination oral contraceptive (ethinyl estradiol [EE] 30 µg, levonorgestrel [LV] 150 µg [Microgynon 30®]). Thirty-two healthy female subjects participated in an open-label, randomised, crossover trial with 3 treatment periods (oral contraceptive alone, 1 hour before exenatide, 30 minutes after exenatide). Subjects received a single dose of oral contraceptive on Day 8 of each period and QD doses on Days 10 through 28. During treatment periods of concomitant usage, exenatide was administered subcutaneously prior to morning and evening meals at 5 µg BID from Days 1 through 4 and at 10 µg BID from Days 5 through 22. Single- (Day 8) and multiple-dose (Day 22) pharmacokinetic profiles were assessed for each treatment period. RESULTS: Exenatide did not alter the bioavailability nor decrease daily trough concentrations for either oral contraceptive component. No substantive changes in oral contraceptive pharmacokinetics occurred when oral contraceptive was administered 1 hour before exenatide. Single-dose oral contraceptive administration 30 minutes after exenatide resulted in mean (90% CI) Cmax reductions of 46% (42-51%) and 41% (35-47%) for EE and LV, respectively. Repeated daily oral contraceptive administration 30 minutes after exenatide resulted in Cmax reductions of 45% (40-50%) and 27% (21-33%) for EE and LV, respectively. Peak oral contraceptive concentrations were delayed approximately 3 to 4 hours. Mild-to-moderate nausea and vomiting were the most common adverse events observed during the trial. CONCLUSIONS: The observed reduction in Cmax is likely of limited importance given the unaltered oral contraceptive bioavailability and trough concentrations; however, for oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before exenatide injection. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00254800.

Imaging sensitive and drug-resistant bacterial infection with [11C]-trimethoprim.

BACKGROUNDSeveral molecular imaging strategies can identify bacterial infections in humans. PET affords the potential for sensitive infection detection deep within the body. Among PET-based approaches, antibiotic-based radiotracers, which often target key bacterial-specific enzymes, have considerable promise. One question for antibiotic radiotracers is whether antimicrobial resistance (AMR) reduces specific accumulation within bacteria, diminishing the predictive value of the diagnostic test.METHODSUsing a PET radiotracer based on the antibiotic trimethoprim (TMP), [11C]-TMP, we performed in vitro uptake studies in susceptible and drug-resistant bacterial strains and whole-genome sequencing (WGS) in selected strains to identify TMP resistance mechanisms. Next, we queried the NCBI database of annotated bacterial genomes for WT and resistant dihydrofolate reductase (DHFR) genes. Finally, we initiated a first-in-human protocol of [11C]-TMP in patients infected with both TMP-sensitive and TMP-resistant organisms to demonstrate the clinical feasibility of the tool.RESULTSWe observed robust [11C]-TMP uptake in our panel of TMP-sensitive and -resistant bacteria, noting relatively variable and decreased uptake in a few strains of P. aeruginosa and E. coli. WGS showed that the vast majority of clinically relevant bacteria harbor a WT copy of DHFR, targetable by [11C]-TMP, and that despite the AMR, these strains should be "imageable." Clinical imaging of patients with [11C]-TMP demonstrated focal radiotracer uptake in areas of infectious lesions.CONCLUSIONThis work highlights an approach to imaging bacterial infection in patients, which could affect our understanding of bacterial pathogenesis as well as our ability to better diagnose infections and monitor response to therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT03424525.FUNDINGInstitute for Translational Medicine and Therapeutics, Burroughs Wellcome Fund, NIH Office of the Director Early Independence Award (DP5-OD26386), and University of Pennsylvania NIH T32 Radiology Research Training Grant (5T32EB004311-12).

Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial.

BACKGROUND: Diabetes treatments are needed that are convenient, provide effective glycaemic control, and do not cause weight gain. We aimed to test the hypothesis that improvement in haemoglobin A(1c) (HbA(1c)) achieved with once weekly exenatide was superior to that achieved with insulin glargine titrated to glucose targets. METHODS: In this 26-week, open-label, randomised, parallel study, we compared exenatide with insulin glargine in adults with type 2 diabetes who had suboptimum glycaemic control despite use of maximum tolerated doses of blood-glucose-lowering drugs for 3 months or longer. Patients were randomly assigned to add exenatide (2 mg, once-a-week injection) or insulin glargine (once-daily injection, starting dose 10 IU, target glucose range 4.0-5.5 mmol/L) to their blood-glucose-lowering regimens. Randomisation was with a one-to-one allocation and block size four, stratified according to country and concomitant treatment (70% metformin only; 30% metformin plus sulphonylurea). Participants and clinical investigators were not masked to assignment, but investigators analysing data were. The primary endpoint was change in HbA(1c) from baseline, and analysis of this outcome was by modified intention to treat for all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT00641056. FINDINGS: 456 patients were randomly allocated to treatment and were included in the modified intention-to-treat analysis (233 exenatide, 223 insulin glargine). Participants who received at least one dose of study drug and for whom baseline and at least one postbaseline measurement of HbA(1c) were available were included in the primary efficacy analysis. Change in HbA(1c) at 26 weeks was greater in patients taking exenatide (n=228; -1.5%, SE 0.05) than in those taking insulin glargine (n=220; -1.3%, 0.06; treatment difference -0.16%, 0.07, 95% CI -0.29 to -0.03). 12 (5%) of 233 patients allocated to exenatide and two (1%) of 223 taking insulin glargine discontinued participation because of adverse events (p=0.012). A planned extension period (up to 2.5 years' duration) is in progress. INTERPRETATION: Once weekly exenatide is an important therapeutic option for patients for whom risk of hypoglycaemia, weight loss, and convenience are particular concerns. FUNDING: Amylin Pharmaceuticals; Eli Lilly and Company.

A Chemical Approach for Programmable Protein Outputs Based on Engineered Cell Interactions.

Cell-cell interactions and communication are crucial to the proper function of complex mammalian physiology including neurocognitive and immune system functions. While many tools are available for observing and perturbing intracellular processes, relatively few exist to probe intercellular processes. Current techniques for studying interactions often rely on direct protein contact, and few can manipulate diverse, functional outputs with tunable protein expression. To address these limitations, we have developed a small-molecule approach based on a trimethoprim prodrug-enzyme pair capable of reporting the presence of two different engineered cell populations with programmable protein outputs. The approach relies on bacterial nitroreductase enzyme catalysis, which is orthogonal to normal mammalian biology, and diffusion of trimethoprim from "activator" cells to "receiver" cells. We test this strategy, which can theoretically regulate many different types of proteins, using biochemical and in vitro culture assays with optical and cytokine protein readouts. This describes the first small-molecule approach capable of detecting and controlling engineered cell-cell outputs, and we anticipate future applications that are especially relevant to the field of immuno-oncology.

International integrated database for the evaluation of severe sepsis and drotrecogin alfa (activated) therapy: analysis of efficacy and safety data in a large surgical cohort.

BACKGROUND: The International Integrated Database for the Evaluation of Severe Sepsis and Drotrecogin alfa (activated) Therapy includes an extensive cohort of surgical patients (1659/4459; 37%). This database broadens the experience reported on a comparatively small set of surgical patients from the pivotal Protein C Worldwide Evaluation in Severe Sepsis trial to examine issues of safety and efficacy in a much larger cohort. METHODS: We conducted a retrospective analysis of prospectively defined outcomes from 5 integrated clinical studies of severe sepsis. Multivariable analyses incorporated propensity scores, treatment, and significant baseline risk factors as independent variables in logistic regression models for 2 outcomes: serious adverse events that were observed during infusion and 28-day, all-cause mortality rates. Adjusted odds ratios were calculated for clinically important strata. Multiple subcategories of serious bleeding-event rates are presented. RESULTS: Although surgical patients who were treated with drotrecogin alfa [activated] (DrotAA) experienced a greater proportion of serious bleeding events during the infusion period, most of the patients were treated without fatal consequence. A 10.7% absolute all cause mortality risk reduction (adjusted odds ratio, 0.66; 95% CI, 0.45-0.97) was observed for DrotAA-treated, high-risk (Acute Physiology and Chronic Health Evaluation II, >/= 25) surgical patients. We could not demonstrate a survival benefit in DrotAA-treated, low-risk (Acute Physiology and Chronic Health Evaluation II, <25) surgical patients. When surgical patients were stratified by number of organ dysfunctions, absolute risk reductions were observed in both categories: multiorgan (4.3%) and single (4.5%). CONCLUSION: International Integrated Database for the Evaluation of Severe Sepsis and Drotrecogin alfa (activated) Therapy analyses affirmed the favorable benefit/risk profile of DrotAA for surgical patients. The serious adverse event rate that was experienced by surgical patients during the study drug infusion period was 7.5% in the DrotAA-treated group versus 6.3% in the placebo-treated group (odds ratio, 1.41; 95% CI, 0.89-2.25). The clinical benefit of DrotAA therapy paralleled baseline risk of death and substantiated findings from the Protein C Worldwide Evaluation in Severe Sepsis study. Future analyses are needed to evaluate the special relationships among sepsis severity, bleeding management, and the postoperative timing of DrotAA administration.

Racial similarities in response to standardized offer of influenza vaccination. A MetroNet study.

BACKGROUND: Despite known benefits of influenza vaccination and coverage by Medicare Part B, elderly minority patients are less likely to receive influenza vaccination than whites. OBJECTIVES: To test whether a nonphysician-initiated standardized offer of influenza vaccination to all elderly primary care patients would result in similar proportions of African-American and white patients accepting vaccine. DESIGN: In 7 metropolitan Detroit primary care practices during the 2003 influenza vaccination season, medical assistants assessed influenza immunization status of all patients 65 years and older and collected limited demographic data. Eligible patients were offered vaccination. MEASUREMENTS: Proportion of patients accepting influenza vaccination by race and predictors of vaccine acceptance. RESULTS: Four hundred and fifty-four eligible patients with complete racial information were enrolled: 40% African American, 52% white, 8% other race/ethnicity. Similar proportions of African Americans and whites had already received the 2003 vaccine (11.6% and 11.0%, respectively) or stated vaccination as the reason for visit (23.8% and 30.5%, respectively). Among the remainder, there also were similar proportions who accepted vaccination: 68.9% white and 62.1% African-American patients. History of previous vaccination was the only statistically significant predictor of vaccine acceptance (odds ratio [OR] 8.64, 95% confidence interval [CI] 4.17, 17.91, P<.001). After adjusting for history of previous vaccination, age, gender, and education, the odds of vaccine acceptance were no different for whites and African Americans (OR 1.20, 95% CI 0.63, 2.29, P=.57). CONCLUSIONS: Vaccination acceptance differed little between African-American and white elderly patients. Using nonphysician personnel to identify and offer influenza vaccine to eligible patients is easily accomplished in primary care offices and has the potential to eliminate racial disparities in influenza vaccination.

International integrated database for the evaluation of severe sepsis and drotrecogin alfa (activated) therapy: analysis of efficacy and safety data in a large surgical cohort.

BACKGROUND: The International Integrated Database for the Evaluation of Severe Sepsis and Drotrecogin alfa (activated) Therapy includes an extensive cohort of surgical patients (1659/4459; 37%). This database broadens the experience reported on a comparatively small set of surgical patients from the pivotal Protein C Worldwide Evaluation in Severe Sepsis trial to examine issues of safety and efficacy in a much larger cohort. METHODS: We conducted a retrospective analysis of prospectively defined outcomes from 5 integrated clinical studies of severe sepsis. Multivariable analyses incorporated propensity scores, treatment, and significant baseline risk factors as independent variables in logistic regression models for 2 outcomes: serious adverse events that were observed during infusion and 28-day, all-cause mortality rates. Adjusted odds ratios were calculated for clinically important strata. Multiple subcategories of serious bleeding-event rates are presented. RESULTS: Although surgical patients who were treated with drotrecogin alfa [activated] (DrotAA) experienced a greater proportion of serious bleeding events during the infusion period, most of the patients were treated without fatal consequence. A 10.7% absolute all cause mortality risk reduction (adjusted odds ratio, 0.66; 95% CI, 0.45-0.97) was observed for DrotAA-treated, high-risk (Acute Physiology and Chronic Health Evaluation II, >or=25) surgical patients. We could not demonstrate a survival benefit in DrotAA-treated, low-risk (Acute Physiology and Chronic Health Evaluation II, <25) surgical patients. When surgical patients were stratified by number of organ dysfunctions, absolute risk reductions were observed in both categories: multiorgan (4.3%) and single (4.5%). CONCLUSION: International Integrated Database for the Evaluation of Severe Sepsis and Drotrecogin alfa (activated) Therapy analyses affirmed the favorable benefit/risk profile of DrotAA for surgical patients. The serious adverse event rate that was experienced by surgical patients during the study drug infusion period was 7.5% in the DrotAA-treated group versus 6.3% in the placebo-treated group (odds ratio, 1.41; 95% CI, 0.89-2.25). The clinical benefit of DrotAA therapy paralleled baseline risk of death and substantiated findings from the Protein C Worldwide Evaluation in Severe Sepsis study. Future analyses are needed to evaluate the special relationships among sepsis severity, bleeding management, and the postoperative timing of DrotAA administration.

Pharyngitis clinical prediction rules: effect of interobserver agreement: a MetroNet study.

OBJECTIVE: Pharyngitis clinical prediction rules improve Group A beta-hemolytic streptococcus (GABHS) diagnosis and decrease unnecessary antibiotic use, yet few studies have addressed clinician variability in assessment of sore throat signs and symptoms. STUDY DESIGN AND SETTING: We conducted a cross-sectional study in which two clinicians examined each of 200 adult sore throat patients. Each patient had a rapid GABHS antigen test. Clinicians were blinded to each other's assessment and to the rapid antigen result. Interobserver agreement was estimated using a kappa coefficient. Effect of agreement on sensitivity, specificity, and hypothetic rapid antigen testing and antibiotic prescribing was determined for two clinical prediction rules. RESULTS: We found moderate inter-rater reliability on sore throat history and physical assessments. Clinician agreement was associated with significantly fewer hypothetic rapid antigen tests performed. CONCLUSION: Interobserver agreement enhances the utility of pharyngitis clinical prediction rules. Medical school and residency training should focus on correct assessment of history and physical examination components used in GABHS clinical prediction rules. Correct assessment will result in less GABHS testing and antibiotic prescriptions for sore throat patients.

Herbal product use and menopause symptom relief in primary care patients: a MetroNet study.

OBJECTIVES: The four study objectives were to determine (1) the prevalence of use of four herbal product types promoted to reduce menopause symptoms (phytoestrogens, St. John's wort, Ginkgo biloba, and ginseng) among primary care patients approaching or in menopause, (2) the extent to which women who use these types of herbal products report menopause-related symptoms compared with herbal product nonusers, (3) the frequency of reported symptom reduction after use, and (4) if use was disclosed to their physicians. METHODS: A cross-section of ethnically diverse women 40-55 years of age (35.5% African American, 60.2% Caucasian) who were recruited from eight primary care centers in Michigan to complete a self-report survey. The questionnaire included demographic items, health history, recent use of four herbal product types purported to relieve menopause symptoms and perception of symptom improvement, and interest in additional herbal product information. RESULTS: Of 397 women, 24.9% reported taking, in the previous 6 months, at least one of the four study herbs. Herbal product use did not vary by patient demographics or health characteristics. Herbal product users reported more menopause symptoms than nonusers, and 68% of the users said that the herbs improved their symptoms; 56.4% said that their physician was aware of their herbal product use. CONCLUSIONS: Primary care patients experiencing common menopausal symptoms are likely to use herbal products that are purported to provide menopause symptom relief, and many believe that these products improve their menopausal symptoms. Healthcare providers should be aware of patient's positive attitude, use patterns, and lack of disclosure of use of herbal medicines. Inquiry of herbal product use is another way for physicians to learn about patient self-medication of bothersome symptoms.

Use of on-line evidence-based resources at the point of care.

BACKGROUND AND OBJECTIVES: The utility of on-line evidence-based summary databases for answering clinical questions at the point of care is not well understood. Our objectives were to determine if family physician faculty could answer their questions using on-line resources and the proportion of answers that influenced patient care. METHODS: This was a prospective study in which clinical faculty in an urban residency training office recorded their clinical questions and their search results. RESULTS: Faculty asked 92 questions. Therapy, prognosis, and epidemiology questions were the most common types of inquiries. Fifty-four percent of the questions were fully or partially answered by use of an on-line resource; obtaining an answer required 5-10 minutes of searching. Physicians reported that 62% of the obtained answers modified their opinion, influenced the care of the current patient 56% of the time, and would affect the care of future patients 70% of the time. Slow Internet connection and interruptions were the most frequent barriers reported. DISCUSSION: Practicing physicians inexperienced in the use of on-line evidence-based resources answered a proportion of their clinical questions that was comparable to reports of more-experienced searchers; however, the time required to find answers limits the practical use of these databases during patient care time. On-line summary databases such as those used in this study show promise in providing answers that influence care during the patient's visit. With faster Internet connection (or handheld devices) and improved navigability, such resources have the potential to optimize health care in the primary care setting.

Effects of exenatide and lifestyle modification on body weight and glucose tolerance in obese subjects with and without pre-diabetes.

OBJECTIVE: To assess the effects of exenatide on body weight and glucose tolerance in nondiabetic obese subjects with normal or impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS: Obese subjects (n = 152; age 46 +/- 12 years, female 82%, weight 108.6 +/- 23.0 kg, BMI 39.6 +/- 7.0 kg/m(2), IGT or IFG 25%) were randomized to receive exenatide (n = 73) or placebo (n = 79), along with lifestyle intervention, for 24 weeks. RESULTS Exenatide-treated subjects lost 5.1 +/- 0.5 kg from baseline versus 1.6 +/- 0.5 kg with placebo (exenatide--placebo, P < 0.001). Placebo-subtracted difference in percent weight reduction was -3.3 +/- 0.5% (P < 0.001). Both groups reduced their daily calorie intake (exenatide, -449 cal; placebo, -387 cal). IGT or IFG normalized at end point in 77 and 56% of exenatide and placebo subjects, respectively. CONCLUSIONS: Exenatide plus lifestyle modification decreased caloric intake and resulted in weight loss in nondiabetic obesity with improved glucose tolerance in subjects with IGT and IFG.

Efficacy and safety of exenatide in patients of Asian descent with type 2 diabetes inadequately controlled with metformin or metformin and a sulphonylurea.

AIMS: To evaluate the efficacy of exenatide in Asian patients with type 2 diabetes (T2D) inadequately controlled with oral agents. METHODS: Patients taking metformin (MET) alone or with a sulphonylurea (SU) were randomly assigned to exenatide 5 microg then 10 microg twice-daily for 4 and 12 weeks, respectively, or placebo. The primary endpoint was baseline to endpoint HbA(1c) change. RESULTS: 466 patients (age 54+/-9 years, weight 68.7+/-11.2 kg, BMI 26.3+/-3.3 kg/m(2), and HbA(1c) 8.3+/-1.1%; mean+/-S.D.) were enrolled in the full analysis set. Endpoint HbA(1c) reduction (mean [95% CI]) with exenatide was superior to placebo (-1.2 [-1.3, -1.1]% vs. -0.4 [-0.5, -0.2]%, p<0.001). More exenatide- than placebo-treated patients achieved HbA(1c)

Exploring the substitution of exenatide for insulin in patients with type 2 diabetes treated with insulin in combination with oral antidiabetes agents.

OBJECTIVE: This 16-week study explored the safety of substituting exenatide for insulin in patients with type 2 diabetes using insulin in combination with oral antidiabetes agents. RESEARCH DESIGN AND METHODS: Successful maintenance of glycemic control was predefined as an A1C increase of < 0.5%. A total of 49 patients (aged 53 +/- 8 years, with BMI 34 +/- 4 kg/m2, A1C 8.1 +/- 1.1%, and duration of diabetes 11 +/- 7 years) were randomized to either substitute exenatide for insulin or remain on their current insulin regimen. Patients who either completed > or = 8 weeks of study or discontinued because of loss of glycemic control were included in primary efficacy analysis. RESULTS: A total of 62% (18 of 29) of the exenatide-treated patients maintained glycemic control compared with 81% (13 of 16) of the insulin-treated patients. Of the 11 exenatide-treated patients who did not maintain control, 5 discontinued before week 16 because of loss of glucose control. The overall safety profile was generally consistent with previous exenatide trials. The mean overall hypoglycemia rates were 1.72 and 0.97 events/patient-year for the exenatide and insulin reference groups, respectively. CONCLUSIONS: This pilot study suggests that it is feasible to sustain glycemic control when substituting exenatide for insulin. Although it is not possible to characterize clear predictors of outcome given the size and exploratory nature of the study, the data suggest that patients with longer disease duration, who are taking higher doses of insulin and have less endogenous beta-cell function, may experience deterioration in glucose control if exenatide is substituted for insulin therapy.

Correction and use of biomedical literature affected by scientific misconduct.

The purpose of this study was to identify and describe published research articles that were named in official findings of scientific misconduct and to investigate compliance with the administrative actions contained in these reports for corrections and retractions, as represented in PubMed. Between 1993 and 2001, 102 articles were named in either the NIH Guide for Grants and Contracts ("Findings of Scientific Misconduct") or the U.S. Office of Research Integrity annual reports as needing retraction or correction. In 2002, 98 of the 102 articles were indexed in PubMed. Eighty-five of these 98 articles had indexed corrections: 47 were retracted; 26 had an erratum; 12 had a correction described in the "comment" field. Thirteen had no correction, but 10 were linked to the NIH Guide "Findings of Scientific Misconduct", leaving only 3 articles with no indication of any sort of problem. As of May 2005, there were 5,393 citations to the 102 articles, with a median of 26 citations per article (range 0-592). Researchers should be alert to "Comments" linked to the NIH Guide as these are open access, and the "Findings of Scientific Misconduct' reports are often more informative than the statements about the retraction or correction found in the journals.