Investigating the Acute and Chronic Effects of Known and Novel Opioid Ligands

Acute and chronic pain are widespread and debilitating diseases that, for a large population, cannot be adequately managed with current pain treatments. Opioid analgesics, such as morphine, have long been used to treat pain and exert their effects by activating the mu-opioid receptor (MOR). While effective, these MOR agonists produce on-target adverse effects such as tolerance, physical dependence, and euphoria. Overall, the experiments described in the current thesis evaluated ways of minimizing opioid tolerance by targeting multiple opioid receptor types simultaneously (chapters 1 and 2) or different populations of opioid receptors in vivo (chapter 3). Previous studies demonstrated that simultaneous modulation of both the MOR and the delta-opioid receptor (DOR) could improve the therapeutic profile of opioid ligands. These experiments sought to further characterize mixed-efficacy opioid ligands, specifically ligands binding to both MORs and DORs with nearly equal affinity. These studies utilized multiple pre-clinical pain models to determine antinociceptive properties of the mixed efficacy opioid ligands, AMB67 and AAH8, following acute and chronic administration. To evaluate the antinociceptive effects of AMB67 and AAH8, we used models of thermal, chemical, and mechanical nociception. In C57BL/6 mice, AMB67 produced dose-dependent antinociceptive effects in all three models of nociception. Mice chronically administered AMB67 failed to develop tolerance to the antinociceptive effects. Chronic administration of AMB67 produced physical dependence as mice exhibited naltrexone-precipitated withdrawal-like behaviors; however, these effects were significantly less than morphine. AMB67 was also less potent than morphine in multiple models assessing abuse potential. In contrast to AMB67, AAH8 significantly attenuated chemical-induced visceral pain following system administration but failed to produce antinociceptive effects in other pain models. Repeated administration of small doses of AAH8 failed to produce tolerance to the antinociceptive effects of AAH8; however, chronic treatment with more frequent, larger doses produced tolerance to the antinociceptive effects of AAH8. These data provide support that mixed-efficacy MOR-DOR ligands may offer improvement over current pharmacotherapies for pain management. Additionally, this study assessed the involvement of peripheral opioid receptors in the development of tolerance to the centrally-mediated antinociceptive effects of MOR agonists. This study used a model of acute, peripherally-mediated visceral pain, acetic acid stretch assay (AASA) and a centrally-mediated thermal reflex assay, warm water tail withdrawal (WWTW). Morphine and the peripherally restricted MOR agonist loperamide produced acute antinociceptive effects in the AASA, and NLX, a non-selective opioid receptor antagonist, blocked these effects. However, only morphine produced opioid-receptor mediated antinociceptive effects in the WWTW. Chronic administration of morphine (3x/day for five days) shifted the ED50 of the morphine dose-effect curve 2.5-fold to the right in the WWTW. Naloxone-methiodide pretreatments to chronic morphine prevented the rightward shift in the morphine dose-effect curve. Conversely, chronic administration of a peripherally active dose of loperamide (3.2 mg/kg, 4x per day for five days) shifted the morphine dose-effect (DE) curve to the right. Pretreatments with naloxone-methiodide completely reversed loperamide-induced cross-tolerance to the antinociceptive effects of morphine. Overall, these data suggest the involvement of peripheral opioid receptors in tolerance development to centrally acting opioids. Overall, the work presented in this thesis furthers our understanding of the in vivo mechanisms of opioid tolerance and potentially identifies novel, safer opioid analgesics. Minimizing the adverse effects of chronic opioid use would significantly improve opioid-based treatment, improve the lives of those who require opioids for everyday function, and help fight the current opioid epidemic.PHDPharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/167905/1/searsbry_1.pd

A General Synthesis of Tris-Indole Derivatives as Potential Iron Chelators

The development of a novel route for the synthesis of a new class of compounds is described. The first tripodal, tris-indole amines are prepared by straightforward routes

Digital Security & Grantcraft Guide : an Introduction Guide for Funders

Digital security breaches can cause harm to grantees, as well as their clients, beneficiaries, and partner organizations. These threats also pose a risk to grantmakers and to the larger strategies of impacted organizations. Security leaks can compromise an organization's ability to carry out its work, and can erode trust between civil society actors.This guide is to help grant­makers both assess and address digital security concerns. It explores the types of digital threats against civil society and the obstacles to addressing them. It explains how to conduct a digital security "triage" of grants to elevate the digital security of your whole grant portfolio; while playing special attention to the highest risk grantees. And it provides suggestions for pathways to think more systematically about digital security

Anti-malarial prescription practices among outpatients with laboratory-confirmed malaria in the setting of a health facility-based sentinel site surveillance system in Uganda.

BACKGROUND: Most African countries have adopted artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated malaria. The World Health Organization now recommends limiting anti-malarial treatment to those with a positive malaria test result. Limited data exist on how these policies have affected ACT prescription practices. METHODS: Data were collected from all outpatients presenting to six public health facilities in Uganda as part of a sentinel site malaria surveillance programme. Training in case management, encouragement of laboratory-based diagnosis of malaria, and regular feedback were provided. Data for this report include patients with laboratory confirmed malaria who were prescribed anti-malarial therapy over a two-year period. Patient visits were analysed in two groups: those considered ACT candidates (defined as uncomplicated malaria with no referral for admission in patients ≥ 4 months of age and ≥ 5 kg in weight) and those who may not have been ACT candidates. Associations between variables of interest and failure to prescribe ACT to patients who were ACT candidates were estimated using multivariable logistic regression. RESULTS: A total of 51,355 patient visits were included in the analysis and 46,265 (90.1%) were classified as ACT candidates. In the ACT candidate group, 94.5% were correctly prescribed ACT. Artemether-lumefantrine made up 97.3% of ACT prescribed. There were significant differences across the sites in the proportion of patients for whom there was a failure to prescribe ACT, ranging from 3.0-9.3%. Young children and woman of childbearing age had higher odds of failure to receive an ACT prescription. Among patients who may not have been ACT candidates, the proportion prescribed quinine versus ACT differed based on if the patient had severe malaria or was referred for admission (93.4% vs 6.5%) or was below age or weight cutoffs for ACT (41.4% vs 57.2%). CONCLUSIONS: High rates of compliance with recommended ACT use can be achieved in resource-limited settings. The unique health facility-based malaria surveillance system operating at these clinical sites may provide a framework for improving appropriate ACT use at other sites in sub-Saharan Africa

Saccharide Display on Microtiter Plates

AbstractNew insight into the importance of carbohydrates in biological systems underscores the need for rapid synthetic and screening procedures for them. Development of an organic synthesis-compatible linker that would attach saccharides to microtiter plates was therefore undertaken to facilitate research in glycobiology. Galactosyllipids containing small, hydrophobic groups at the anomeric position were screened for noncovalent binding to microtiter plates. When the lipid component was a saturated hydrocarbon between 13 and 15 carbons in length, the monosaccharide showed complete retention after aqueous washing and could be utilized in biological assays. This alkyl chain was also successfully employed with more complex oligosaccharides in biological assays. In light of these findings, this method of attachment of oligosaccharides to microtiter plates should be highly efficacious to high-throughput synthesis and analyses of carbohydrates in biological assays

Anti-malarial prescription practices among children admitted to six public hospitals in Uganda from 2011 to 2013.

BACKGROUND: In 2011, Uganda's Ministry of Health switched policy from presumptive treatment of malaria to recommending parasitological diagnosis prior to treatment, resulting in an expansion of diagnostic services at all levels of public health facilities including hospitals. Despite this change, anti-malarial drugs are often prescribed even when test results are negative. Presented is data on anti-malarial prescription practices among hospitalized children who underwent diagnostic testing after adoption of new treatment guidelines. METHODS: Anti-malarial prescription practices were collected as part of an inpatient malaria surveillance program generating high quality data among children admitted for any reason at government hospitals in six districts. A standardized medical record form was used to collect detailed patient information including presenting symptoms and signs, laboratory test results, admission and final diagnoses, treatments administered, and final outcome upon discharge. RESULTS: Between July 2011 and December 2013, 58,095 children were admitted to the six hospitals (hospital range 3294-20,426).A total of 56,282 (96.9 %) patients were tested for malaria, of which 26,072 (46.3 %) tested positive (hospital range 5.9-57.3 %). Among those testing positive, only 84 (0.3 %) were first tested after admission and 295 of 30,389 (1.0 %) patients who tested negative at admission later tested positive. Of 30,210 children with only negative test results, 11,977 (39.6 %) were prescribed an anti-malarial (hospital range 14.5-53.6 %). The proportion of children with a negative test result who were prescribed an anti-malarial fluctuated over time and did not show a significant trend at any site with the exception of one hospital where a steady decline was observed. Among those with only negative test results, children 6-12 months of age (aOR 3.78; p < 0.001) and those greater than 12 months of age (aOR 4.89; p < 0.001) were more likely to be prescribed an anti-malarial compared to children less than 6 months of age. Children with findings suggestive of severe malaria were also more likely to be prescribed an anti-malarial after a negative test result (aOR 1.98; p < 0.001). CONCLUSIONS: Despite high testing rates for malaria at all sites, prescription of anti-malarials to patients with negative test results remained high, with the exception of one site where a steady decline occurred

To promote or not to promote fundamental British values? Teachers' standards, diversity and teacher education

In this article we seek to problematize the presence of the requirement within the teachers’ standards (DfE, 2012), that they ‘should not undermine fundamental British values’ in the context of initial teacher education in England. The inclusion of this statement within the teachers’ code of conduct has made its way from the counter-terrorism strategy, Prevent and raises questions about Britishness, values and the relationship between the state and the profession more generally. We argue that the inclusion of the phrase within a statutory document that regulates the profession is de facto a politicization of the profession by the state thereby instilling the expectation that teachers are state instruments of surveillance. The absence of any wider debate around the inclusion of the statement is also problematic as is the lack of training for pre-service and inservice teachers since it means this concept of fundamental British values is unchallenged and its insidious racialising implications are unrecognised by most teachers

Diversifying Selection in Plant Breeding

Natural variation rather than genetic modification - is this the way to achieve global food security