Effects of an Intervention to Improve Evidence-Based Care for People With Diabetes and Cardiovascular Disease Across Sex, Race, and Ethnicity Subgroups: Insights From the COORDINATE-Diabetes Trial.

BACKGROUND: Results from the COORDINATE-Diabetes trial (Coordinating Cardiology Clinics Randomized Trial of Interventions to Improve Outcomes - Diabetes) demonstrated that a multifaceted, clinic-based intervention increased prescription of evidence-based medical therapies to participants with type 2 diabetes and atherosclerotic cardiovascular disease. This secondary analysis assessed whether intervention success was consistent across sex, race, and ethnicity. METHODS: COORDINATE-Diabetes, a cluster randomized trial, recruited participants from 43 US cardiology clinics (20 randomized to intervention and 23 randomized to usual care). The primary outcome was the proportion of participants prescribed all 3 groups of evidence-based therapy (high-intensity statin, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and sodium-glucose cotransporter-2 inhibitor or glucagon-like peptide 1 receptor agonist) at last trial assessment (6 to 12 months). In this prespecified analysis, mixed-effects logistic regression models were used to assess the outcome by self-reported sex, race, and ethnicity in the intervention and usual care groups, with adjustment for baseline characteristics, medications, comorbidities, and site location. RESULTS: Among 1045 participants with type 2 diabetes and atherosclerotic cardiovascular disease, the median age was 70 years, 32% were female, 16% were Black, and 9% were Hispanic. At the last trial assessment, there was an absolute increase in the proportion of participants prescribed all 3 groups of evidence-based therapy in women (36% versus 15%), Black participants (41% versus 18%), and Hispanic participants (46% versus 18%) with the intervention compared with usual care, with consistent benefit across sex (male versus female; Pinteraction=0.44), race (Black versus White; Pinteraction=0.59), and ethnicity (Hispanic versus Non-Hispanic; Pinteraction= 0.78). CONCLUSIONS: The COORDINATE-Diabetes intervention successfully improved delivery of evidence-based care, regardless of sex, race, or ethnicity. Widespread dissemination of this intervention could improve equitable health care quality, particularly among women and minority communities who are frequently underrepresented in clinical trials. REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03936660.

Epidemiology and Clinical Outcomes of Fusobacterium Infections: A Six-Year Retrospective Study.

Background and Objectives: Anaerobic bacteria like Fusobacterium can lead to severe and life-threatening infections. The inherent complexities in the isolation of these bacteria may result in diagnostic and therapeutic delays, thereby escalating both morbidity and mortality rates. We aimed to examine data from patients with infections due to Fusobacterium to gain insights into the epidemiology and clinical outcomes of patients with these infections. Methods and Results: We conducted a retrospective analysis of clinical data from a cohort of patients with cultures positive for Fusobacterium species at a tertiary care medical center in the United States. Between 2009 and 2015, we identified 96 patients with cultures positive for Fusobacterium. Patients could be categorized into three groups based on the site of primary infection. Patients with head and neck infections constituted 37% (n 36). Patients with infections of other soft tissue sites accounted for 38.5% (n 37). Patients with anaerobic bacteremia due to Fusobacterium formed 24% (n 23) of the cohort. Surgical intervention coupled with antibiotic therapy emerged as cornerstones of management for patients with head and neck or other soft tissue infections, who generally exhibited more favorable outcomes. Patients with bacteremia were older, more likely to have malignancy, and had a high mortality rate. When speciation was available, Fusobacterium necrophorum was the most frequently isolated species. Conclusions: Our retrospective analysis of epidemiology and clinical outcomes of Fusobacterium infections revealed three distinct cohorts. Patients with head, neck, or soft tissue infections had better outcomes than those with bacteremia. Our findings highlight the importance of employing management strategies based on infection site and underlying comorbidities in patients with Fusobacterium infections. Further research is needed to investigate the optimal therapeutic strategies and identify prognostic indicators to improve clinical outcomes for these complex infections.

Coordinating Cardiology clinics randomized trial of interventions to improve outcomes (COORDINATE) - Diabetes: rationale and design.

Several medications that are proven to reduce cardiovascular events exist for individuals with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease, however they are substantially underused in clinical practice. Clinician, patient, and system-level barriers all contribute to these gaps in care; yet, there is a paucity of high quality, rigorous studies evaluating the role of interventions to increase utilization. The COORDINATE-Diabetes trial randomized 42 cardiology clinics across the United States to either a multifaceted, site-specific intervention focused on evidence-based care for patients with T2DM or standard of care. The multifaceted intervention comprised the development of an interdisciplinary care pathway for each clinic, audit-and-feedback tools and educational outreach, in addition to patient-facing tools. The primary outcome is the proportion of individuals with T2DM prescribed three key classes of evidence-based medications (high-intensity statin, angiotensin converting enzyme inhibitor or angiotensin receptor blocker, and either a sodium/glucose cotransporter-2 inhibitor (SGLT-2i) inhibitor or glucagon-like peptide 1 receptor agonist (GLP-1RA) and will be assessed at least 6 months after participant enrollment. COORDINATE-Diabetes aims to identify strategies that improve the implementation and adoption of evidence-based therapies.

Coordinated Care to Optimize Cardiovascular Preventive Therapies in Type 2 Diabetes: A Randomized Clinical Trial.

Importance: Evidence-based therapies to reduce atherosclerotic cardiovascular disease risk in adults with type 2 diabetes are underused in clinical practice. Objective: To assess the effect of a coordinated, multifaceted intervention of assessment, education, and feedback vs usual care on the proportion of adults with type 2 diabetes and atherosclerotic cardiovascular disease prescribed all 3 groups of recommended, evidence-based therapies (high-intensity statins, angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers [ARBs], and sodium-glucose cotransporter 2 [SGLT2] inhibitors and/or glucagon-like peptide 1 receptor agonists [GLP-1RAs]). Design, Setting, and Participants: Cluster randomized clinical trial with 43 US cardiology clinics recruiting participants from July 2019 through May 2022 and follow-up through December 2022. The participants were adults with type 2 diabetes and atherosclerotic cardiovascular disease not already taking all 3 groups of evidence-based therapies. Interventions: Assessing local barriers, developing care pathways, coordinating care, educating clinicians, reporting data back to the clinics, and providing tools for participants (n = 459) vs usual care per practice guidelines (n = 590). Main Outcomes and Measures: The primary outcome was the proportion of participants prescribed all 3 groups of recommended therapies at 6 to 12 months after enrollment. The secondary outcomes included changes in atherosclerotic cardiovascular disease risk factors and a composite outcome of all-cause death or hospitalization for myocardial infarction, stroke, decompensated heart failure, or urgent revascularization (the trial was not powered to show these differences). Results: Of 1049 participants enrolled (459 at 20 intervention clinics and 590 at 23 usual care clinics), the median age was 70 years and there were 338 women (32.2%), 173 Black participants (16.5%), and 90 Hispanic participants (8.6%). At the last follow-up visit (12 months for 97.3% of participants), those in the intervention group were more likely to be prescribed all 3 therapies (173/457 [37.9%]) vs the usual care group (85/588 [14.5%]), which is a difference of 23.4% (adjusted odds ratio [OR], 4.38 [95% CI, 2.49 to 7.71]; P < .001) and were more likely to be prescribed each of the 3 therapies (change from baseline in high-intensity statins from 66.5% to 70.7% for intervention vs from 58.2% to 56.8% for usual care [adjusted OR, 1.73; 95% CI, 1.06-2.83]; ACEIs or ARBs: from 75.1% to 81.4% for intervention vs from 69.6% to 68.4% for usual care [adjusted OR, 1.82; 95% CI, 1.14-2.91]; SGLT2 inhibitors and/or GLP-1RAs: from 12.3% to 60.4% for intervention vs from 14.5% to 35.5% for usual care [adjusted OR, 3.11; 95% CI, 2.08-4.64]). The intervention was not associated with changes in atherosclerotic cardiovascular disease risk factors. The composite secondary outcome occurred in 23 of 457 participants (5%) in the intervention group vs 40 of 588 participants (6.8%) in the usual care group (adjusted hazard ratio, 0.79 [95% CI, 0.46 to 1.33]). Conclusions and Relevance: A coordinated, multifaceted intervention increased prescription of 3 groups of evidence-based therapies in adults with type 2 diabetes and atherosclerotic cardiovascular disease. Trial Registration: ClinicalTrials.gov Identifier: NCT03936660.

Incorporating SGLT2i and GLP-1RA for Cardiovascular and Kidney Disease Risk Reduction: Call for Action to the Cardiology Community.

Multiple sodium glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to impart significant cardiovascular and kidney benefits, but are underused in clinical practice. Both SGLT-2i and GLP-1RA were first studied as glucose-lowering drugs, which may have impeded uptake by cardiologists in the wake of proven cardiovascular efficacy. Their significant effect on cardiovascular and kidney outcomes, which are largely independent of glucose-lowering effects, must drive a broader use of these drugs. Cardiologists are 3 times more likely than endocrinologists to see patients with both type 2 diabetes and cardiovascular disease, thus they are ideally positioned to share responsibility for SGLT-2i and GLP-1RA treatment with primary care providers. In order to increase adoption, SGLT-2i and GLP-1RA must be reframed as primarily cardiovascular and kidney disease risk-reducing agents with a side effect of glucose-lowering. Coordinated and multifaceted interventions engaging clinicians, patients, payers, professional societies, and health systems must be implemented to incentivize the adoption of these medications as part of routine cardiovascular and kidney care. Greater use of SGLT-2i and GLP-1RA will improve outcomes for patients with type 2 diabetes at high risk for cardiovascular and kidney disease.

Considerations for the design and conduct of pediatric obesity pharmacotherapy clinical trials: Proceedings of expert roundtable meetings.

Anti-obesity medications (AOMs) have emerged as one element of comprehensive obesity clinical care intended to improve long-term health outcomes for children and adolescents. The number of pediatric AOM clinical trials has burgeoned in recent years as new pharmacotherapeutics have been developed. Factors related to growth and development in children and adolescents can present unique challenges in terms of designing and conducting clinical trials investigating the safety and efficacy of AOMs. These barriers can delay the AOM development and evaluation process, increase the cost of performing trials, create challenges in the interpretation of results, influence the generalizability of the findings and present ethical dilemmas. In an effort to address these issues and provide guidance to streamline the process of designing and conducting pediatric AOM clinical trials, relevant key stakeholders convened a series of roundtable meetings to discuss, debate and achieve harmonization on design features. Stakeholder participants included a multidisciplinary group of international pediatric obesity experts, patient (parent) representatives and representatives from academic medicine, key regulatory agencies and industry. Topics of discussion included primary efficacy end-points, secondary end-points, eligibility criteria, trial run-in and follow-up phases, use of active comparators and guidelines for down-titration and/or stopping rules for excessive weight reduction. Consensus recommendations were agreed upon. Regarding end-points, emphasis was placed on moving away from BMI z-score as a primary outcome, incorporating multiple alternative BMI-related outcomes and measuring adiposity/body fat as a prominent secondary end-point. Trial eligibility criteria were carefully considered to maximize generalizability while maintaining safety. The limited value of trial run-in phases was discussed. It was also underscored that designing trials with extended follow-up periods after AOM withdrawal should be avoided owing to ethical issues (including possible psychological harm) related to weight regain without providing the opportunity to access other treatments. The panel emphasized the value of the randomized, placebo-controlled trial but recommended the thoughtful consideration of the use of active comparators in addition to, or instead of, placebo to achieve clinical equipoise when appropriate. Finally, the panel recommended that clinical trial protocols should include clear guidance regarding AOM down-titration to avoid excessive weight reduction when applicable.

The use of selexipag, a prostacyclin receptor analog, for treatment of severe pulmonary artery hypertension during pregnancy, a case report.

Pregnancy in patients with pulmonary artery hypertension (PAH) is associated with high mortality and morbidity. Despite the risks, more patients with PAH are becoming pregnant. Case reports and case series have described the use of IV epoprostenol in these patients with some success. However, there are no published reports regarding the use of oral prostacyclins and prostacyclin receptor agonists in pregnancy. We describe the use of selexipag, an oral prostacyclin receptor agonist, for treating severe PAH during pregnancy in a patient who refused IV prostacyclin therapy. She remained stable throughout pregnancy and delivered a healthy baby girl; however, she died 13 days after her delivery by cesarean section due to developing worsening heart failure. While there is data and support for IV prostacyclins in pregnancy, patients may opt for oral formulations, like in our case. Registry data on the use of oral prostacyclins and prostacyclin receptor agonists in pregnancy may help improve patient outcomes.

Use of Lipid-, Blood Pressure-, and Glucose-Lowering Pharmacotherapy in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease.

Importance: Based on contemporary estimates in the US, evidence-based therapies for cardiovascular risk reduction are generally underused among patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD). Objective: To determine the use of evidence-based cardiovascular preventive therapies in a broad US population with diabetes and ASCVD. Design, Setting, and Participants: This multicenter cohort study used health system-level aggregated data within the National Patient-Centered Clinical Research Network, including 12 health systems. Participants included patients with diabetes and established ASCVD (ie, coronary artery disease, cerebrovascular disease, and peripheral artery disease) between January 1 and December 31, 2018. Data were analyzed from September 2020 until January 2021. Exposures: One or more health care encounters in 2018. Main Outcomes and Measures: Patient characteristics by prescription of any of the following key evidence-based therapies: high-intensity statin, angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) and sodium glucose cotransporter-2 inhibitors (SGLT2I) or glucagon-like peptide-1 receptor agonist (GLP-1RA). Results: The overall cohort included 324 706 patients, with a mean (SD) age of 68.1 (12.2) years and 144 169 (44.4%) women and 180 537 (55.6%) men. A total of 59 124 patients (18.2% ) were Black, and 41 470 patients (12.8%) were Latinx. Among 205 885 patients with specialized visit data from the prior year, 17 971 patients (8.7%) visited an endocrinologist, 54 330 patients (26.4%) visited a cardiologist, and 154 078 patients (74.8%) visited a primary care physician. Overall, 190 277 patients (58.6%) were prescribed a statin, but only 88 426 patients (26.8%) were prescribed a high-intensity statin; 147 762 patients (45.5%) were prescribed an ACEI or ARB, 12 724 patients (3.9%) were prescribed a GLP-1RA, and 8989 patients (2.8%) were prescribed an SGLT2I. Overall, 14 918 patients (4.6%) were prescribed all 3 classes of therapies, and 138 173 patients (42.6%) were prescribed none. Patients who were prescribed a high-intensity statin were more likely to be men (59.9% [95% CI, 59.6%-60.3%] of patients vs 55.6% [95% CI, 55.4%-55.8%] of patients), have coronary atherosclerotic disease (79.9% [95% CI, 79.7%-80.2%] of patients vs 73.0% [95% CI, 72.8%-73.3%] of patients) and more likely to have seen a cardiologist (40.0% [95% CI, 39.6%-40.4%] of patients vs 26.4% [95% CI, 26.2%-26.6%] of patients). Conclusions and Relevance: In this large cohort of US patients with diabetes and ASCVD, fewer than 1 in 20 patients were prescribed all 3 evidence-based therapies, defined as a high-intensity statin, either an ACEI or ARB, and either an SGLT2I and/or a GLP-1RA. These findings suggest that multifaceted interventions are needed to overcome barriers to the implementation of evidence-based therapies and facilitate their optimal use.

Estimating the number of preventable cardiovascular disease events in the United States using the EMPA-REG OUTCOME trial results and National Health and Nutrition Examination Survey.

AIM: We examined eligibility and preventable cardiovascular disease events in US adults with diabetes mellitus from the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME). METHODS: We identified adults with diabetes mellitus eligible for EMPA-REG OUTCOME based on trial eligibility criteria available from the National Health and Nutrition Examination Surveys, 2007-2016. We estimated composite cardiovascular disease endpoints, as well as all-cause deaths, death from cardiovascular disease and hospitalizations for heart failure from trial treatment and placebo event rates, the difference indicating the preventable events. RESULTS: Among 29,629 US adults aged ⩾18 years (representing 231.9 million), 4672 (27.3 million) had diabetes mellitus, with 342 (1.86 million) meeting eligibility criteria of EMPA-REG OUTCOME. We estimated from trial primary endpoint event rates of 10.5% and 12.1% in the empagliflozin and placebo groups, respectively, that based on the 'treatment' of our 1.86 million estimated EMPA-REG OUTCOME eligible subjects, 12,066 (95% confidence interval: 10,352-13,780) cardiovascular disease events could be prevented annually. Estimated annual preventable deaths from any cause, cardiovascular causes and hospitalizations from heart failure were 17,078 (95% confidence interval: 14,652-19,504), 14,479 (95% confidence interval: 12,422-16,536) and 9467 (95% confidence interval: 8122-10,812), respectively. CONCLUSION: Empagliflozin, if provided to EMPA-REG OUTCOME eligible US adults, may prevent many cardiovascular disease events, cardiovascular and total deaths, as well as heart failure hospitalizations.

Primary Care Physicians' Knowledge of the Cardiovascular Effects of Diabetes Medications: Findings from an Online Survey.

INTRODUCTION: Cardiovascular (CV) outcomes trial (CVOT) results have led to changes in indications for some glucose-lowering agents, with recommendations based on the presence of comorbidities. OBJECTIVE: This study aimed to understand internal medicine (IM) and family medicine (FM) physicians' knowledge of CVOTs and beliefs about type 2 diabetes mellitus (T2DM) medications, excluding insulin, for CV disease risk reduction. METHODS: WebMD, LLC, fielded a 23-item online survey from September 18 to 20, 2018, to 47,534 Medscape members (US IM and FM physicians) who were invited to participate via e-mail (quota = 500). RESULTS: Of the 702 physicians who responded, 503 were eligible and completed the survey. Overall, 39% of respondents were not familiar with the 2018 American Diabetes Association treatment recommendations for those with T2DM and atherosclerotic CV disease. Respondents reported they were most familiar with TECOS (42%), LEADER (39%), EMPA-REG OUTCOME (33%), and CANVAS (30%). Many respondents did not know which CVOT showed superiority for major adverse CV events (26%) or CV mortality (31%). When provided with a list of seven treatment priorities, 33% of respondents ranked using T2DM medications with CV benefits as least important. CONCLUSIONS: Findings from this 2018 survey suggest that there are knowledge gaps among IM and FM physicians regarding the results from CVOTs, with implications for the treatment of patients with T2DM and CV disease.

The Association Between Type 2 Diabetes and Cardiovascular Disease: The "For Your SweetHeart™" Survey.

INTRODUCTION: It is unclear whether patients and their loved ones appreciate that cardiovascular disease (CVD) is the major cause of morbidity and mortality in type 2 diabetes mellitus (T2DM). The purpose of this survey was to evaluate the degree of awareness regarding the link between T2DM and CVD. METHODS: An online survey was conducted among US adults (general population) and adults with self-reported T2DM. RESULTS: Of 13,027 participants recruited, 1505 completed the survey (12% response rate): 501 with T2DM and 1004 from the general population, of whom 364 knew someone with T2DM (e.g., partner, friend, relative, colleague: "SweetHearts"). Of those with T2DM, 52% were unaware that patients with T2DM are at increased risk of CVD and related macrovascular events. People with T2DM were more likely to be aware of the increased risk of microvascular disease (blindness [57%], nephropathy [57%], neuropathy [64%]) than macrovascular disease (myocardial infarction [41%], stroke [43%]). Despite CVD being the leading cause of death in T2DM, 67% of those with T2DM and 69% of SweetHearts were unaware of this, similar figures to those of the general population (74%). People with T2DM indicated they would take preventive measures if they were aware of their increased CVD risk: 88% would modify their diet and 81% would talk to their healthcare provider. Respondents with T2DM (73%) indicated that a desire to live longer/spend more time with family would motivate them to decrease their CVD risk. CONCLUSIONS: Findings indicate that education regarding the association between T2DM and CVD in patients and their loved ones is warranted. Plain language summary available for this article. Please see Fig. 1 and the following link: https://doi.org/10.6084/m9.figshare.7546817 . FUNDING: The "For Your SweetHeart™" survey was supported by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance, and was developed in partnership with KRC Research.

The long-term effects of nefiracetam on learning in older rabbits.

Classical conditioning of the nictitating membrane (NM)/eyeblink response has proven utility in the study of age-related memory disorders. The 750 ms delay eyeblink conditioning procedure was used to investigate the magnitude and duration of the nootropic drug nefiracetam's effect on retention and relearning. After administering daily injections of 0 (vehicle), 5, 10, or 15 mg/kg nefiracetam to 34 retired breeder rabbits during 15 days of acquisition, we tested retention and relearning 1, 5, and 12 weeks post-training. Rabbits received no drug after the initial 15 daily injections. Significant relearning was observed in the 10 mg/kg nefiracetam group 1 and 5 weeks after initial acquisition. Differences in tone-alone retention did not achieve statistical significance, although responses were numerically greater in the 10 mg/kg nefiracetam group. The effect of nefiracetam upon the ability of older rabbits to relearn a previously learned task is apparent up to 5 weeks after drug administration. Under normal conditions, a drug is administered continuously. In this experiment, nefiracetam had a significant effect long after drug administration had ceased. Prolonged administration of nefiracetam may have ameliorating effects greater than those observed in only 15 days of drug administration.

Effect of a single course of isotretinoin therapy on bone mineral density in adolescent patients with severe, recalcitrant, nodular acne.

BACKGROUND: Adverse changes in bone have been reported for patients undergoing high-dose, long-term (several years) isotretinoin therapy for disorders of cornification. The effect of short-term (4-5 months) therapy at the lower dose recommended for acne on bone development in younger, growing adolescent (12-17 years) patients has not been well studied. OBJECTIVE: The purpose of the study was to evaluate the effect of a standard, single course of isotretinoin (Accutane) therapy on bone mineral density (BMD) of the lumbar spine and hip in adolescents ages 12 to 17 years with severe, recalcitrant, nodular acne. METHODS: In this open-label, multicenter study, 217 adolescents (81 girls) with severe, recalcitrant, nodular acne were enrolled and treated with isotretinoin twice daily with food at the recommended total dose of approximately 1 mg/kg for 16 to 20 weeks. BMD in the lumbar spine and hip was measured at baseline and at the end of therapy by dual energy radiograph absorptiometry. RESULTS: There was no clinically significant mean change in BMD measured at the lumbar spine (+1.4%, range: -4.9% to +12.3%) or total hip (-0.26%, range: -11.3% to +15.0%). Hyperostosis was not observed in any patient. Typical efficacy expected in the treatment of acne was observed. CONCLUSIONS: A 16- to 20-week course of isotretinoin treatment at the recommended dose for severe acne has no clinically significant effect on lumbar spine and total hip BMD in the adolescent (12-17 years) population.

The effect of scopolamine in older rabbits tested in the 750 ms delay eyeblink classical conditioning procedure.

We investigated the effect of several doses of scopolamine in older rabbits that were trained for 20 days in the 750 ms delay eyeblink classical conditioning procedure. Our aim was to determine if the scopolamine-injected older rabbit would be a useful model for testing drugs for cognition enhancement in Alzheimer's disease (AD). A total of 39 rabbits with a mean age of 31 months received classical eyeblink conditioning with daily injections of 0.25, 0.75, or 1.5 mg/kg scopolamine hydrobromide or sterile saline vehicle. Doses of 0.75 and 1.5 mg/kg scopolamine significantly impaired acquisition, whereas acquisition was not significantly impaired with 0.25 mg/kg scopolamine. Results exhibit parallels in performance on delay eyeblink classical conditioning between scopolamine-treated older rabbits and human patients diagnosed with AD.

Nefiracetam ameliorates associative learning impairment in the scopolamine-injected older rabbit.

BACKGROUND: The cognition-enhancing drug, nefiracetam, is in Phase III clinical trials to treat memory impairment in Alzheimer's disease (AD). Nefiracetam ameliorates acquisition of delay eyeblink classical conditioning in older rabbits, a form of associative learning with striking behavioral and neurobiological similarities in rabbits and humans. In both species, delay eyeblink conditioning engages the septo-hippocampal cholinergic system and is disrupted when the cholinergic system is antagonized. Delay eyeblink classical conditioning is impaired in normal aging and severely disrupted in AD. MATERIAL/METHODS: To test further the efficacy of nefiracetam in an animal model that mimics some of the neurobiological and behavioral effects present in AD, we tested 56 older rabbits assigned to 7 treatment groups in the 750 ms delay eyeblink conditioning procedure. Older rabbits were injected with 1.5 mg/kg scopolamine to simulate disruption of the cholinergic system in AD. Three doses of nefiracetam (5, 10, or 15 mg/kg) were also injected in older rabbits receiving 1.5 mg/kg scopolamine. Control groups were treated with 1.5 mg/kg scopolamine + vehicle, vehicle alone, or explicitly unpaired presentations of conditioning stimuli and vehicle or 1.5 mg/kg scopolamine + 15 mg/kg nefiracetam. RESULTS: Rabbits injected with 1.5 mg/kg scopolamine alone were impaired, but a dose of 15 mg/kg nefiracetam reversed significantly the behavioral impairment. CONCLUSIONS: Nefiracetam had ameliorating effects on a task impaired in AD in an animal model of AD: older rabbits with cholinergic system antagonism.