Eric Heidel

A Binding-Site Barrier Affects Imaging Efficiency of High Affinity Amyloid-Reactive Peptide Radiotracers In Vivo

Amyloid is a complex pathology associated with a growing number of diseases including Alzheimer’s disease, type 2 diabetes, rheumatoid arthritis, and myeloma. The distribution and extent of amyloid deposition in body organs establishes the prognosis and can define treatment options; therefore, determining the amyloid load by using non-invasive molecular imaging is clinically important. We have identified a heparin-binding peptide designated p5 that, when radioiodinated, was capable of selectively imaging systemic visceral AA amyloidosis in a murine model of the disease. The p5 peptide was posited to bind effectively to amyloid deposits, relative to similarly charged polybasic heparin-reactive peptides, because it adopted a polar α helix secondary structure. We have now synthesized a variant, p5R, in which the 8 lysine amino acids of p5 have been replaced with arginine residues predisposing the peptide toward the α helical conformation in an effort to enhance the reactivity of the peptide with the amyloid substrate. The p5R peptide had higher affinity for amyloid and visualized AA amyloid in mice by using SPECT/CT imaging; however, the microdistribution, as evidenced in micro-autoradiographs, was dramatically altered relative to the p5 peptide due to its increased affinity and a resultant “binding site barrier” effect. These data suggest that radioiodinated peptide p5R may be optimal for the in vivo detection of discreet, perivascular amyloid, as found in the brain and pancreatic vasculature, by using molecular imaging techniques; however, peptide p5, due to its increased penetration, may yield more quantitative imaging of expansive tissue amyloid deposits.

Phagocyte depletion inhibits AA amyloid accumulation in AEF-induced huIL-6 transgenic mice

Abstract Objective: Determine the role of phagocytosis in the deposition of acute phase SAA protein in peripheral organs as AA amyloid. Methods: AA amyloidosis was induced by injection of amyloid enhancing factor (AEF) in huIL-6 transgenic mice. Clodronate liposomes were injected at different times, and the amyloid load evaluated by Congo red birefringence staining and monitoring with the amyloid specific probe 125I-labeled peptide p5R. Results: Injection of clodronate containing liposomes depleted Iba-1 positive and F4/80 positive phagocytic cells in liver and spleen for up to 5 days. Treatment prior to administration of intravenous AEF did not alter the pattern of deposition of the AEF in spleen, but inhibited the catabolism of the 125I-labeled AEF. Clodronate treatment 1 day before or 1 day after AEF administration had little effect on AA amyloid accumulation at 2 weeks; however, mice treated with clodronate liposomes 5 days after AEF induction and evaluated at 2 weeks post-AEF induction showed reduced amyloid load relative to controls. At 6 weeks post-AEF there was no significant effect on amyloid load following a single clodronate treatment. Conclusion: Macrophages have been shown to be instrumental in both accumulation and clearance of AA amyloid after cessation of inflammation. Our data indicate that when SAA protein is continuously present, depletion of phagocytic cells during the early course of the disease progression temporarily reduces amyloid load.

Peptide p5 binds both heparinase-sensitive glycosaminoglycans and fibrils in patient-derived AL amyloid extracts

In previously published work, we have described heparin-binding synthetic peptides that preferentially recognize amyloid deposits in a mouse model of reactive systemic (AA) amyloidosis and can be imaged by using positron and single photon emission tomographic imaging. We wanted to extend these findings to the most common form of visceral amyloidosis, namely light chain (AL); however, there are no robust experimental animal models of AL amyloidosis. To further define the binding of the lead peptide, p5, to AL amyloid, we characterized the reactivity in vitro of p5 with in situ and patient-derived AL amyloid extracts which contain both hypersulfated heparan sulfate proteoglycans as well as amyloid fibrils. Histochemical staining demonstrated that the peptide specifically localized with tissue-associated AL amyloid deposits. Although we anticipated that p5 would undergo electrostatic interactions with the amyloid-associated glycosaminoglycans expressing heparin-like side chains, no significant correlation between peptide binding and glycosaminoglycan content within amyloid extracts was observed. In contrast, following heparinase I treatment, although overall binding was reduced, a positive correlation between peptide binding and amyloid fibril content became evident. This interaction was further confirmed using synthetic light chain fibrils that contain no carbohydrates. These data suggest that p5 can bind to both the sulfated glycosaminoglycans and protein fibril components of AL amyloid. Understanding these complex electrostatic interactions will aid in the optimization of synthetic peptides for use as amyloid imaging agents and potentially as therapeutics for the treatment of amyloid diseases.

Pharmacy student knowledge retention after completing either a simulated or written patient case

Objective. To determine pharmacy students’ knowledge retention from and comfort level with a patient-case simulation compared with a written patient case. Design. Pharmacy students were randomly assigned to participate in either a written patient case or a simulated patient case in which a high-fidelity mannequin was used to portray a patient experiencing a narcotic and acetaminophen overdose. Assessment. Participants’ responses on a multiple-choice test and a survey instrument administered before the case, immediately after the case, and 25 days later indicated that participation in the simulated patient case did not result in greater knowledge retention or comfort level than participation in the written patient case. Students’ knowledge improved post-intervention regardless of which teaching method was used. Conclusions. Although further research is needed to determine whether the use of simulation in the PharmD curriculum is equivalent or superior to other teaching methods, students’ enthusiasm for learning in a simulated environment where they can safely apply patient care skills make this technology worth exploring.

A novel method for quantifying peripheral tissue amyloid load by using the radiolabeled amyloidophilic peptide, p5

Abstract Quantitation of peripheral amyloid deposits by non-invasive molecular imaging can be useful for diagnosis, prognostication and monitoring response to therapy. In order to obtain reliable quantitative data, it is necessary to show a linear positive correlation between the uptake of the molecular probe and the tissue amyloid load. The transgenic H-2/IL-6 mouse model of AA amyloidosis was used to generate animals with varied stages of visceral amyloid disease. The mice were injected with 125I-labeled peptide p5 and tissues analyzed 2 h post-injection using Congo red (CR) staining, radioisotope biodistribution and micro-autoradiography (ARG). Micro-ARG confirmed that 125I-p5 was deposited at all amyloid deposits and sites of Congophilia but not at amyloid-free sites within the tissues evaluated. Furthermore, biodistribution studies revealed that the amount of 125I deposited in liver and spleen correlated with the amount of CR birefringence (expressed as 0–4+ or as tissue area [µm2]) in these tissues with correlation coefficients of r > 0.7 (p < 10−6). Deposition of 125I-p5 is a quantitative measure of the amount of AA amyloid in liver and spleen in this mouse model. The p5 peptide has potential as a quantitative amyloid imaging agent in human disease. Abbreviations: AEF, amyloid enhancing factor; CR, Congo red; HSPG, heparan sulfate proteoglycan; PET, positron emission tomography; SAA, serum amyloid protein A; SPECT, single photon emission computed tomography

Impact of an educational intervention on steroid prescribing and dosing effect on patient outcomes in COPD exacerbations

The increasing number of patients affected by chronic obstructive pulmonary disease (COPD) and associated exacerbations has led to both rising hospital admissions and significant economic impact. Evidence-based guidelines have been formulated for COPD management recommending the use of low dose, oral corticosteroid therapy in the treatment of exacerbations. However, fewer than 50% of physicians’ prescribing practices appropriately reflect the published clinical guidelines on the use of systemic corticosteroids in these patients. Objective The purpose of this study was to evaluate the impact of a pharmacist-led educational intervention on prescribing practices and patient outcomes when using systemic corticosteroids in patients with COPD exacerbations. Methods This retrospective case-control study included patients admitted to an inpatient family medicine service with a COPD exacerbation who received systemic corticosteroids. Two pharmacist-led educational interventions were delivered to prescribers to review current guidelines for managing COPD exacerbations with systemic corticosteroids. Patients were retrospectively identified over a three month span prior to and following the educational intervention. Data was collected via chart review to evaluate prescribing practices prior to and following the educational sessions. In addition, data was collected to evaluate the effects of an educational intervention on length of stay, adverse events, and cost of treatment. Results A total of 23 pre-intervention patients and 18 post-intervention patients met inclusion criteria. After pharmacist-led interventions, guidelines were not more likely to be adhered to by prescribers when compared to guideline adherence in the pre-intervention patients. Because no statistically significant change in guideline adherence was observed, there was no impact on secondary outcomes. Conclusion Pharmacist-led didactic educational interventions and guideline dissemination do not improve guideline adherence and prescribing practices with respect to systemic corticosteroids in COPD exacerbations.

Evaluation of the Hemodynamic Effects of Intravenous Amiodarone Formulations During the Maintenance Phase Infusion

Background: Two of the excipients in intravenous formulations of amiodarone, polysorbate 80 and benzyl alcohol, have been shown to cause hypotension. A newer formulation of amiodarone, which contains cyclodextrin, is devoid of these excipients. Objective: To evaluate the change in mean arterial pressure when utilizing 2 intravenous amiodarone formulations. Methods: This was a retrospective cohort analysis conducted at an academic medical center. Patients received intravenous amiodarone containing either polysorbate 80/benzyl alcohol (control) or cyclodextrin (cyclodextrin). Patients received these formulations based on a standard institutional protocol of 1 mg/min for 6 hours, followed by 0.5 mg/min for at least 18 hours or until discontinued by the provider. All data were collected from the medical record and included changes in blood pressures, time to lowest systolic blood pressure, concurrent antihypertensive use, and number of patients requiring treatment for hypotension. Results: A total of 160 patients (120 control, 40 cyclodextrin) were included. There was a statistically significant difference in mean arterial pressure between the groups receiving the control formulation of amiodarone compared with the cyclodextrin formulation across the 24-hour maintenance phase infusion (P < 0.001). There was a significant difference between formulations with regard to the change in mean arterial pressure during the 0- to 6-hour and 12- to 18-hour time blocks. There was a statistically significant difference in the number of patients receiving fluid boluses for treatment of hypotension (P = 0.001). Conclusions: The excipients in the formulation of intravenous amiodarone may have a significant role in the hypotensive effects seen throughout the duration the maintenance phase infusion.

Laparoscopic approach for the treatment of chronic groin pain after inguinal hernia repair: Laparoscopic approach for inguinodynia

BackgroundTraditional methods of clinical research may not be adequate to improve the value of care for patients with complex medical problems such as chronic pain after inguinal hernia repair. This problem is very complex with many potential factors contributing to the development of this complication.MethodsWe have implemented a clinical quality improvement (CQI) effort in an attempt to better measure and improve outcomes for patients suffering with chronic groin pain (inguinodynia) after inguinal hernia repair. Between April 2011 and June 2016, there were 93 patients who underwent 94 operations in an attempt to relieve pain (1 patient had two separate unilateral procedures). Patients who had prior laparoscopic inguinal hernia repair (26) had their procedure completed laparoscopically. Patients who had open inguinal hernia repair (68) had a combination of a laparoscopic and open procedure in an attempt to relieve pain. Initiatives to attempt to improve measurement and outcomes during this period included the administration of pre-operative bilateral transversus abdominis plane and intra-operative inguinal nerve blocks using long-acting local anesthetic as a part of a multimodal regimen, the introduction of a low pressure pneumoperitoneum system, and the expansion of a pre-operative questionnaire to assess emotional health pre-operatively.ResultsThe results included the assessment of how much improvement was achieved after recovery from the operation. Forty-five patients (48%) reported significant improvement, 39 patients (41%) reported moderate improvement, and 10 patients (11%) reported little or no improvement. There were 3 (3%) complications, 13 (11%) hernia recurrences, and 15 patients (13%) developed a new pain in the inguinal region after the initial pain had resolved.ConclusionsThe principles of CQI can be applied to a group of patients suffering from chronic pain after inguinal hernia repair. Based on these results additional process improvement ideas will be implemented in an attempt to improve outcomes.

Reading Demands of Commercial Patient Educational Materials

Commercial information products often have patient education handouts built into their systems. How readable are they to the average patient? This study attempts to answer this question by sampling and scoring handouts from three different producers. The patient education handouts from MD Consult, Micromedex Care Notes, and ADAM were analyzed and scored using the average of three reading level formulas. The results indicate that most handouts are above the average reading level of most patients, with Micromedex Care Notes scoring the best in this study.

Quick and accessible: The highly correlated Cognitive Self-Test (CST)

Background: The CogState brief battery consists of four card playing tasks, which assesses the cognitive domains of psychomotor function, attention, visual learning, and visual working memory. Previous studies have demonstrated the utility and sensitivity of the CogState brief battery for detection of cognitive impairment in Alzheimer’s disease (AD) and mild cognitive impairment (MCI), and for the measurement of cognitive change in the preclinical stages of AD. Thus, the CogState brief battery may be a useful screening tool to assist the management of cognitive function in clinical settings. This study aimed to determine the clinical utility of the CogState brief battery. Methods: Healthy older adults (n 1⁄4 653), adults with MCI (n 1⁄4 68), and adults with AD (n 1⁄4 44) who completed the CogState brief battery were recruited from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) Study of Ageing, and the AIBL-Rate of Change sub-study (AIBL-ROCS). The four performance measures of the CogState brief battery were reduced to two composites a psychomotor/attention composite and a learning/working memory composite. Sensitivity and specificity analyses were conducted on the two composites to determine their clinical utility. Results: Large impairments inMCI (d1⁄4 1.20) and AD (d1⁄4 2.20) were identified for the learning/working memory composite but not the psychomotor/attention composite (MCI d 1⁄4 0.40; AD d 1⁄4 0.50). Using a cutscore of -1.96, the learning/working memory composite showed 85.71% sensitivity and 96.81% specificity to a clinical classification of AD. Both composite scores showed high test-retest reliability (0.95) over four months. Performance on the memory composite was also related to performance on the MMSE, with worse scores on the MMSE associated with worse performance on the CogState memory composite. Additionally, increasing severity on the CDR, sum of boxes score was also associated with worse performance on the CogState memory composite. Conclusions: The results of this study suggest that the CogState memory composite is a useful tool for the identification of AD related memory impairment, and correlates well with traditional measures of disease classification.