Medical Pharmacology Commons^™

Impact Of Cyp2d6 Genotype On Amitriptyline Efficacy For The Treatment Of Diabetic Peripheral Neuropathy: A Pilot Study., Mamoonah Chaudhry, Marco Alessandrini, Jacobus Rademan, Tyren M. Dodgen, Francois E. Steffens, Danie G. Van Zyl, Andrea Gaedigk, Michael S. Pepper

Manuscripts, Articles, Book Chapters and Other Papers

AIM: Therapy with low-dose amitriptyline is commonly used to treat painful diabetic peripheral neuropathy. There is a knowledge gap, however, regarding the role of variable CYP2D6-mediated drug metabolism and side effects (SEs). We aimed to generate pilot data to demonstrate that SEs are more frequent in patients with variant CYP2D6 alleles.

METHOD: To that end, 31 randomly recruited participants were treated with low-dose amitriptyline for painful diabetic peripheral neuropathy and their CYP2D6 gene sequenced.

RESULTS: Patients with predicted normal or ultra-rapid metabolizer phenotypes presented with less SEs compared with individuals with decreased CYP2D6 activity.

CONCLUSION: Hence, CYP2D6 genotype contributes to …

In Vivo Characterization Of Cyp2d6*12, *29 And *84 Using Dextromethorphan As A Probe Drug: A Case Report., Andrea Gaedigk, Greyson P. Twist, Emily G. Farrow, Jennifer Lowry, Sarah E. Soden, Neil A. Miller

Manuscripts, Articles, Book Chapters and Other Papers

CYP2D6*84 was first described in a Black South African subject, however, its function remains unknown. Astrolabe, a probabilistic scoring tool developed in our laboratory to call genotypes from whole genome sequence, identified CYP2D6*84 in a trio. The father presented with intermediate metabolism when challenged with the CYP2D6 probe drug dextromethorphan (DM/dextrorphan [DX] = 0.0839). Since his second allele, CYP2D6*12, is nonfunctional, the observed activity is derived by CYP2D6*84. This finding suggests that the allele's hallmark P267H causes decreased activity toward DM and that this allele should receive a value of 0.5 for Activity Score calculations. The mother's DM/DX of 0.0543 …

Metabolic And Molecular Insights Into An Essential Role Of Nicotinamide Phosphoribosyltransferase., Li Q. Zhang, Leon Van Haandel, Min Xiong, Peixin Huang, Daniel P. Heruth, Chengpeng Bi, R Gaedigk, Xun Jiang, Ding-You Li, Gerald Wyckoff, Dmitry N. Grigoryev, Li Gao, Linheng Li, Min Wu, J Steven Leeder, Shui Qing Ye

Manuscripts, Articles, Book Chapters and Other Papers

Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein implicated in the pathogenesis of acute respiratory distress syndrome, aging, cancer, coronary heart diseases, diabetes, nonalcoholic fatty liver disease, obesity, rheumatoid arthritis, and sepsis. However, the underlying molecular mechanisms of NAMPT in these physiological and pathological processes are not fully understood. Here, we provide experimental evidence that a Nampt gene homozygous knockout (Nampt-/-) resulted in lethality at an early stage of mouse embryonic development and death within 5-10 days in adult mice accompanied by a 25.24±2.22% body weight loss, after the tamoxifen induction of NamptF/F × Cre mice. These results substantiate that Nampt …

Topical Anaesthetics For Pain Control During Repair Of Dermal Laceration., Baraa O. Tayeb, Anthony Eidelman, Cristy L. Eidelman, Ewan D. Mcnicol, Daniel B. Carr

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Topical local anaesthetics provide effective analgesia for patients undergoing numerous superficial procedures, including repair of dermal lacerations. The need for cocaine in topical anaesthetic formulations has been questioned because of concern about adverse effects, thus novel preparations of cocaine-free anaesthetics have been developed. This review was originally published in 2011 and has been updated in 2017.

OBJECTIVES: To assess whether benefits of non-invasive topical anaesthetic application occur at the expense of decreased analgesic efficacy. To compare the efficacy of various single-component or multi-component topical anaesthetic agents for repair of dermal lacerations. To determine the clinical necessity for topical application …

M2 Polarization Of Macrophages Facilitates Arsenic-Induced Cell Transformation Of Lung Epithelial Cells, Jiajun Cui, Wenhua Xu, Jian Chen, Hui Li, Lu Dai, Jacqueline A. Frank, Shaojun Peng, Siying Wang, Gang Chen

Pharmacology and Nutritional Sciences Faculty Publications

The alterations in microenvironment upon chronic arsenic exposure may contribute to arsenic-induced lung carcinogenesis. Immune cells, such as macrophages, play an important role in mediating the microenvironment in the lungs. Macrophages carry out their functions after activation. There are two activation status for macrophages: classical (M1) or alternative (M2); the latter is associated with tumorigenesis. Our previous work showed that long-term arsenic exposure induces transformation of lung epithelial cells. However, the crosstalk between epithelial cells and macrophages upon arsenic exposure has not been investigated. In this study, using a co-culture system in which human lung epithelial cells are cultured with …

Newborn Sequencing In Genomic Medicine And Public Health., Jonathan S. Berg, Pankaj B. Agrawal, Donald B. Bailey, Alan H. Beggs, Steven E. Brenner, Amy M. Brower, Julie A. Cakici, Ozge Ceyhan-Birsoy, Kee Chan, Flavia Chen, Robert J. Currier, Dmitry Dukhovny, Robert C. Green, Julie Harris-Wai, Ingrid A. Holm, Brenda Iglesias, Galen Joseph, Stephen F. Kingsmore, Barbara A. Koenig, Pui-Yan Kwok, John Lantos, J Steven Leeder, Megan A. Lewis, Amy L. Mcguire, Laura V. Milko, Sean D. Mooney, Richard B. Parad, Stacey Pereira, Josh E. Petrikin, Bradford C. Powell, Cynthia M. Powell, Jennifer M. Puck, Heidi L. Rehm, Neil Risch, Myra Roche, Joseph T. Shieh, Narayanan Veeraraghavan, Michael S. Watson, Laurel K. Willig, Timothy W. Yu, Tiina Urv, Anastasia L. Wise

Manuscripts, Articles, Book Chapters and Other Papers

The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing …

Metronidazole Metabolism In Neonates And The Interplay Between Ontogeny And Genetic Variation., Laura A. Wang, Daniel Gonzalez, J Steven Leeder, Rachel F. Tyndale, Robin E. Pearce, Daniel K. Benjamin, Gregory L. Kearns, Michael Cohen-Wolkowiez, Best Pharmaceuticals For Children Act-Pediatric Trials Network Steering Committee

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.

Prediction Of Cyp2d6 Phenotype From Genotype Across World Populations., Andrea Gaedigk, Katrin Sangkuhl, Michelle Whirl-Carrillo, Teri Klein, J Steven Leeder

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: Owing to its highly polymorphic nature and major contribution to the metabolism and bioactivation of numerous clinically used drugs, CYP2D6 is one of the most extensively studied drug-metabolizing enzymes and pharmacogenes. CYP2D6 alleles confer no, decreased, normal, or increased activity and cause a wide range of activity among individuals and between populations. However, there is no standard approach to translate diplotypes into predicted phenotype.

METHODS: We exploited CYP2D6 allele-frequency data that have been compiled for Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines (>60,000 subjects, 173 reports) in order to estimate genotype-predicted phenotype status across major world populations based on …

A Novel Compound-Heterozygous Epithelial Cell Adhesion Molecule Mutation In Tufting Enteropathy., Valentina Shakhnovich, Darrell Dinwiddie, Amber Hildreth, Thomas M. Attard, Stephen Kingsmore

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.

Tgf-Β Signaling: New Insights Into Aortic Aneurysms, Sean E. Thatcher

Pharmacology and Nutritional Sciences Faculty Publications

No abstract provided.

Bioactivation Of Trimethoprim To Protein-Reactive Metabolites In Human Liver Microsomes., Jennifer Goldman, Yakov M. Koen, Steven A. Rogers, Kelin Li, J Steven Leeder, Robert P. Hanzlik

Manuscripts, Articles, Book Chapters and Other Papers

The formation of drug-protein adducts via metabolic activation and covalent binding may stimulate an immune response or may result in direct cell toxicity. Protein covalent binding is a potentially pivotal step in the development of idiosyncratic adverse drug reactions (IADRs). Trimethoprim (TMP)-sulfamethoxazole (SMX) is a combination antibiotic that commonly causes IADRs. Recent data suggest that the contribution of the TMP component of TMP-SMX to IADRs may be underappreciated. We previously demonstrated that TMP is bioactivated to chemically reactive intermediates that can be trapped in vitro by N-acetyl cysteine (NAC), and we have detected TMP-NAC adducts (i.e., mercapturic acids) in the …

Ontogeny Of Hepatic Drug Transporters As Quantified By Lc-Ms/Ms Proteomics., B Prasad, Andrea Gaedigk, M Vrana, R Gaedigk, J Steven Leeder, L Salphati, X Chu, G Xiao, Ceca Hop, R Evers, L Gan, J D Unadkat

Manuscripts, Articles, Book Chapters and Other Papers

Protein expression of major hepatic uptake and efflux drug transporters in human pediatric (n = 69) and adult (n = 41) livers was quantified by liquid chromatography / tandem mass spectroscopy (LC-MS/MS). Transporter protein expression of OCT1, OATP1B3, P-gp, and MRP3 was age-dependent. Particularly, significant differences were observed in transporter expression (P < 0.05) between the following age groups: neonates vs. adults (OCT1, OATP1B3, P-gp), neonates or infants vs. adolescents and/or adults (OCT1, OATP1B3, and P-gp), infants vs. children (OATP1B3 and P-gp), and adolescents vs. adults (MRP3). OCT1 showed the largest increase, of almost 5-fold, in protein expression with age. Ontogenic expression of OATP1B1 was confounded by genotype and was revealed only in livers harboring SLCO1B1*1A/*1A. In livers >1 year, tissues harboring SLCO1B1*14/*1A showed 2.5-fold higher (P < 0.05) protein expression than SLCO1B1*15/*1A. Integration of these ontogeny data in physiologically based pharmacokinetic (PBPK) models will be a crucial step in predicting hepatic drug disposition in children.

Thrombospondin 1 Deficiency Ameliorates The Development Of Adriamycin-Induced Proteinuric Kidney Disease, Hasiyeti Maimaitiyiming, Qi Zhou, Shuxia Wang

Pharmacology and Nutritional Sciences Faculty Publications

Accumulating evidence suggests that thrombospondin 1 (TSP1) is an important player in diabetic nephropathy. However, the role of TSP1 in podocyte injury and the development of non-diabetic proteinuric kidney disease is largely unknown. In the current study, by using a well-established podocyte injury model (adriamycin-induced nephropathy mouse model), we examined the contribution of TSP1 to the development of proteinuric kidney disease. We found that TSP1 was up-regulated in the glomeruli, notably in podocytes, in adriamycin injected mice before the onset of proteinuria. ADR treatment also stimulated TSP1 expression in cultured human podocytes in vitro. Moreover, increased TSP1 mediated ADR-induced …

Network-Driven Plasma Proteomics Expose Molecular Changes In The Alzheimer's Brain, Philipp A. Jaeger, Kurt M. Lucin, Markus Britschgi, Badri Vardarajan, Ruo-Pan Huang, Elizabeth D. Kirby, Rachelle Abbey, Bradley F. Boeve, Adam L. Boxer, Lindsay A. Farrer, Nicole Finch, Neill R. Graff-Radford, Elizabeth Head, Matan Hofree, Ruochun Huang, Hudson Johns, Anna Karydas, David S. Knopman, Andrey Loboda, Eliezer Masliah, Ramya Narasimhan, Ronald C. Petersen, Alexei Podtelezhnikov, Suraj Pradhan, Rosa Rademakers, Chung-Huan Sun, Steven G. Younkin, Bruce L. Miller, Trey Ideker, Tony Wyss-Coray

Pharmacology and Nutritional Sciences Faculty Publications

Background: Biological pathways that significantly contribute to sporadic Alzheimer’s disease are largely unknown and cannot be observed directly. Cognitive symptoms appear only decades after the molecular disease onset, further complicating analyses. As a consequence, molecular research is often restricted to late-stage post-mortem studies of brain tissue. However, the disease process is expected to trigger numerous cellular signaling pathways and modulate the local and systemic environment, and resulting changes in secreted signaling molecules carry information about otherwise inaccessible pathological processes.

Results: To access this information we probed relative levels of close to 600 secreted signaling proteins from patients’ blood samples using …

Big Data Transforms Discovery-Utilization Therapeutics Continuum., Scott A. Waldman, Andre Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Enabling omic technologies adopt a holistic view to produce unprecedented insights into the molecular underpinnings of health and disease, in part, by generating massive high-dimensional biological data. Leveraging these systems-level insights as an engine driving the healthcare evolution is maximized through integration with medical, demographic, and environmental datasets from individuals to populations. Big data analytics has accordingly emerged to add value to the technical aspects of storage, transfer, and analysis required for merging vast arrays of omic-, clinical-, and eco-datasets. In turn, this new field at the interface of biology, medicine, and information science is systematically transforming modern therapeutics across …

Bioinnovation Enterprise: An Engine Driving Breakthrough Therapies., Scott A. Waldman, Andre Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Biological advances have radically expanded our insights into the underpinnings of health and disease. New knowledge has formed the substrate for translation-expedited in turn by the biotechnology and pharmaceutical industry into novel therapeutic solutions impacting the management of patients and populations. Indeed, this Bioinnovation Enterprise has become the dominant growth sector in drug development and the engine driving the translation of breakthrough therapies worldwide. This annual Therapeutic Innovations issue highlights recent exceptional advances by the Bioinnovation Enterprise in translating molecular insights in pathobiology into transformative therapies.

Selective Vip Receptor Agonists Facilitate Immune Transformation For Dopaminergic Neuroprotection In Mptp-Intoxicated Mice., Katherine E. Olson, Lisa M. Kosloski-Bilek, Kristi M. Anderson, Breha J. Diggs, Barbara E. Clark, John M. Gledhill, Scott J. Shandler, R. Lee Mosley, Howard Gendelman

Journal Articles: Pharmacology & Experimental Neuroscience

UNLABELLED: Vasoactive intestinal peptide (VIP) mediates a broad range of biological responses by activating two related receptors, VIP receptor 1 and 2 (VIPR1 and VIPR2). Although the use of native VIP facilitates neuroprotection, clinical application of the hormone is limited due to VIP's rapid metabolism and inability to distinguish between VIPR1 and VIPR2 receptors. In addition, activation of both receptors by therapeutics may increase adverse secondary toxicities. Therefore, we developed metabolically stable and receptor-selective agonists for VIPR1 and VIPR2 to improve pharmacokinetic and pharmacodynamic therapeutic end points. Selective agonists were investigated for their abilities to protect mice against MPTP-induced neurodegeneration …

Chronic Ethanol Exposure Enhances The Aggressiveness Of Breast Cancer: The Role Of P38Γ, Mei Xu, Siying Wang, Zhenhua Ren, Jacqueline A. Frank, Xiuwei H. Yang, Zhuo Zhang, Zun-Ji Ke, Xianglin Shi, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Both epidemiological and experimental studies suggest that ethanol may enhance aggressiveness of breast cancer. We have previously demonstrated that short term exposure to ethanol (12–48 hours) increased migration/invasion in breast cancer cells overexpressing ErbB2, but not in breast cancer cells with low expression of ErbB2, such as MCF7, BT20 and T47D breast cancer cells. In this study, we showed that chronic ethanol exposure transformed breast cancer cells that were not responsive to short term ethanol treatment to a more aggressive phenotype. Chronic ethanol exposure (10 days - 2 months) at 100 (22 mM) or 200 mg/dl (44 mM) caused the …

Emerging Immunopharmacological Targets In Multiple Sclerosis., Mojtaba Farjam, Guang-Xian Zhang, Bogoljub Ciric, Abdolmohamad Rostami

Department of Neurology Faculty Papers

Inflammatory demyelination of the central nervous system (CNS) is the hallmark of multiple sclerosis (MS), a chronic debilitating disease that affects more than 2.5 million individuals worldwide. It has been widely accepted, although not proven, that the major pathogenic mechanism of MS involves myelin-reactive T cell activation in the periphery and migration into the CNS, which subsequently triggers an inflammatory cascade that leads to demyelination and axonal damage. Virtually all MS medications now in use target the immune system and prevent tissue damage by modulating neuroinflammatory processes. Although current therapies such as commonly prescribed disease-modifying medications decrease the relapse rate …

Cd151-Α3Β1 Integrin Complexes Are Prognostic Markers Of Glioblastoma And Cooperate With Egfr To Drive Tumor Cell Motility And Invasion, Pengcheng Zhou, Sonia Erfani, Zeyi Liu, Changhe Jia, Yecang Chen, Bingwei Xu, Xinyu Deng, Jose E. Alfáro, Li Chen, Dana L. Napier, Michael Lu, Jian-An Huang, Chunming Liu, Olivier Thibault, Rosalind Segal, Binhua P. Zhou, Natasha Kyprianou, Craig Horbinski, Xiuwei H. Yang

Pharmacology and Nutritional Sciences Faculty Publications

Glioblastoma, one of the most aggressive forms of brain cancer, is featured by high tumor cell motility and invasiveness, which not only fuel tumor infiltration, but also enable escape from surgical or other clinical interventions. Thus, better understanding of how these malignant traits are controlled will be key to the discovery of novel biomarkers and therapies against this deadly disease. Tetraspanin CD151 and its associated α3β1 integrin have been implicated in facilitating tumor progression across multiple cancer types. How these adhesion molecules are involved in the progression of glioblastoma, however, remains largely unclear. Here, we examined an in-house tissue microarray-based …

Pharmacodynamics Of Folic Acid Receptor Targeted Antiretroviral Nanotherapy In Hiv-1-Infected Humanized Mice., Pavan Puligujja, Mariluz Araínga, Prasanta Dash, Diana L. Palandri, R. Lee Mosley, Santhi Gorantla, Larisa Y Poluektova, Joellyn Mcmillan, Howard Gendelman

Journal Articles: Pharmacology & Experimental Neuroscience

Long-acting nanoformulated antiretroviral therapy (nanoART) can sustain plasma drug levels and improve its biodistribution. Cell targeted-nanoART can achieve this and bring drug efficiently to viral reservoirs. However, whether such improvements affect antiretroviral responses remains unknown. To these ends, we tested folic acid (FA)-linked poloxamer407-coated ritonavir-boosted atazanavir (FA-nanoATV/r) nanoparticles for their ability to affect chronic HIV-1 infection in humanized mice. Following three, 100mg/kg FA-nanoATV/r intramuscular injections administered every other week to infected animals, viral RNA was at or below the detection limit, cell-associated HIV-1p24 reduced and CD4+ T cell counts protected. The dosing regimen improved treatment outcomes more than two fold …

Oseltamivir-Warfarin Interaction In Hypoplastic Left Heart Syndrome: Case Report And Review., Jonathan B. Wagner, Susan M. Abdel-Rahman

Manuscripts, Articles, Book Chapters and Other Papers

An 8-year-old boy with hypoplastic left heart syndrome with a previous history of thrombosis within the inferior vena cava receiving stable warfarin dosing for anticoagulation was diagnosed with influenza B. He was subsequently placed on oseltamivir therapy according to the Centers for Disease Control and Prevention clinical practice guidelines. During the hospitalization, his international normalized ratio steadily increased to supratherapeutic levels and returned to baseline after discontinuation of oseltamivir therapy. This case represents a drug-drug interaction that has not been previously reported in children or adolescents. An extensive review of the pharmacokinetic and pharmacodynamic literature did not uncover a definitive …

Opposing Regulation Of Endolysosomal Pathways By Long-Acting Nanoformulated Antiretroviral Therapy And Hiv-1 In Human Macrophages., Mariluz Araínga, Dongwei Guo, Jayme Wiederin, Pawel Ciborowski, Joellyn Mcmillan, Howard Gendelman

Journal Articles: Pharmacology & Experimental Neuroscience

BACKGROUND: Long-acting nanoformulated antiretroviral therapy (nanoART) is designed to improve patient regimen adherence, reduce systemic drug toxicities, and facilitate clearance of human immunodeficiency virus type one (HIV-1) infection. While nanoART establishes drug depots within recycling and late monocyte-macrophage endosomes, whether or not this provides a strategic advantage towards viral elimination has not been elucidated.

RESULTS: We applied quantitative SWATH-MS proteomics and cell profiling to nanoparticle atazanavir (nanoATV)-treated and HIV-1 infected human monocyte-derived macrophages (MDM). Native ATV and uninfected cells served as controls. Both HIV-1 and nanoATV engaged endolysosomal trafficking for assembly and depot formation, respectively. Notably, the pathways were deregulated …

Opposing Regulation Of Endolysosomal Pathways By Long-Acting Nanoformulated Antiretroviral Therapy And Hiv-1 In Human Macrophages., Mariluz Araínga, Dongwei Guo, Jayme Wiederin, Pawel Ciborowski, Joellyn Mcmillan, Howard Gendelman

Journal Articles: Pharmacology & Experimental Neuroscience

BACKGROUND: Long-acting nanoformulated antiretroviral therapy (nanoART) is designed to improve patient regimen adherence, reduce systemic drug toxicities, and facilitate clearance of human immunodeficiency virus type one (HIV-1) infection. While nanoART establishes drug depots within recycling and late monocyte-macrophage endosomes, whether or not this provides a strategic advantage towards viral elimination has not been elucidated.

RESULTS: We applied quantitative SWATH-MS proteomics and cell profiling to nanoparticle atazanavir (nanoATV)-treated and HIV-1 infected human monocyte-derived macrophages (MDM). Native ATV and uninfected cells served as controls. Both HIV-1 and nanoATV engaged endolysosomal trafficking for assembly and depot formation, respectively. Notably, the pathways were deregulated …

Cd151-Α3Β1 Integrin Complexes Suppress Ovarian Tumor Growth By Repressing Slug-Mediated Emt And Canonical Wnt Signaling, Lauren A. Baldwin, John T. Hoff, Jason Lefringhouse, Michael Zhang, Changhe Jia, Zeyi Liu, Sonia Erfani, Hongyan Jin, Mei Xu, Qing-Bai She, John R. Van Nagell Jr., Chi Wang, Li Chen, Rina Plattner, David M. Kaetzel, Jia Luo, Michael Lu, Dava West, Chunming Liu, Fred R. Ueland, Ronny Drapkin, Binhua P. Zhou, Xiuwei H. Yang

Pharmacology and Nutritional Sciences Faculty Publications

Human ovarian cancer is diagnosed in the late, metastatic stages but the underlying mechanisms remain poorly understood. We report a surprising functional link between CD151-α3β1 integrin complexes and the malignancy of serous-type ovarian cancer. Analyses of clinical specimens indicate that CD151 expression is significantly reduced or diminished in 90% of metastatic lesions, while it remains detectable in 58% of primary tumors. These observations suggest a putative tumor-suppressing role of CD151 in ovarian cancer. Indeed, our analyses show that knocking down CD151 or α3 integrin enhances tumor cell proliferation, growth and ascites production in nude mice. These changes are accompanied by …

Long-Acting Antituberculous Therapeutic Nanoparticles Target Macrophage Endosomes., Benson J. Edagwa, Dongwei Guo, Pavan Puligujja, Han Chen, Joellyn Mcmillan, Xinming Liu, Howard Gendelman, Prabagaran Narayanasamy

Journal Articles: Pharmacology & Experimental Neuroscience

Eradication of Mycobacterium tuberculosis (MTB) infection requires daily administration of combinations of rifampin (RIF), isoniazid [isonicotinylhydrazine (INH)], pyrazinamide, and ethambutol, among other drug therapies. To facilitate and optimize MTB therapeutic selections, a mononuclear phagocyte (MP; monocyte, macrophage, and dendritic cell)-targeted drug delivery strategy was developed. Long-acting nanoformulations of RIF and an INH derivative, pentenyl-INH (INHP), were prepared, and their physicochemical properties were evaluated. This included the evaluation of MP particle uptake and retention, cell viability, and antimicrobial efficacy. Drug levels reached 6 μg/10(6) cells in human monocyte-derived macrophages (MDMs) for nanoparticle treatments compared with 0.1 μg/10(6) cells for native drugs. …

Pupillometry: A Non-Invasive Technique For Pain Assessment In Paediatric Patients., Mark A. Connelly, Jacob T. Brown, Gregory L. Kearns, Rawni A. Anderson, Shawn D. St Peter, Kathleen A. Neville

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: Pupillometry has been used to assess pain intensity and response to analgesic medications in adults. The aim of this observational study was to explore proof of concept for the use of this technique in paediatric patients. Changes in pupil parameters before and after opioid exposure also were evaluated.

DESIGN AND SETTING: This was a single-centre, prospective study conducted at an academic paediatric medical centre.

PATIENTS: Children 9-17 years of age undergoing elective surgical correction of pectus excavatum were enrolled into a protocol approved by the human ethical committee (institutional review board).

INTERVENTIONS: Pupil size and reactivity were measured using …

Neuroinflammation And Neurologic Deficits In Diabetes Linked To Brain Accumulation Of Amylin, Sarah Srodulski, Savita Sharma, Adam B. Bachstetter, Jennifer M. Brelsfoard, Conrado Pascual, Xinmin Simon Xie, Kathryn E. Saatman, Linda J. Van Eldik, Florin Despa

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: We recently found that brain tissue from patients with type-2 diabetes (T2D) and cognitive impairment contains deposits of amylin, an amyloidogenic hormone synthesized and co-secreted with insulin by pancreatic β-cells. Amylin deposition is promoted by chronic hypersecretion of amylin (hyperamylinemia), which is common in humans with obesity or pre-diabetic insulin resistance. Human amylin oligomerizes quickly when oversecreted, which is toxic, induces inflammation in pancreatic islets and contributes to the development of T2D. Here, we tested the hypothesis that accumulation of oligomerized amylin affects brain function.

METHODS: In contrast to amylin from humans, rodent amylin is neither amyloidogenic nor cytotoxic. …

Cc2d1a Regulates Human Intellectual And Social Function As Well As Nf-Κb Signaling Homeostasis., M. Chiara Manzini, Lan Xiong, Ranad Shaheen, Dimira E Tambunan, Stefania Di Costanzo, Vanessa Mitisalis, +15 Additional Authors

Pharmacology and Physiology Faculty Publications

Autism spectrum disorder (ASD) and intellectual disability (ID) are often comorbid, but the extent to which they share common genetic causes remains controversial. Here, we present two autosomal-recessive "founder" mutations in the CC2D1A gene causing fully penetrant cognitive phenotypes, including mild-to-severe ID, ASD, as well as seizures, suggesting shared developmental mechanisms. CC2D1A regulates multiple intracellular signaling pathways, and we found its strongest effect to be on the transcription factor nuclear factor κB (NF-κB). Cc2d1a gain and loss of function both increase activation of NF-κB, revealing a critical role of Cc2d1a in homeostatic control of intracellular signaling. Cc2d1a knockdown in neurons …

Cardioprotection By Controlling Hyperamylinemia In A "Humanized" Diabetic Rat Model, Sanda Despa, Savita Sharma, Todd R. Harris, Hua Dong, Ning Li, Nipavan Chiamvimonvat, Heinrich Taegtmeyer, Kenneth B. Margulies, Bruce D. Hammock, Florin Despa

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Chronic hypersecretion of the pancreatic hormone amylin is common in humans with obesity or prediabetic insulin resistance and induces amylin aggregation and proteotoxicity in the pancreas. We recently showed that hyperamylinemia also affects the cardiovascular system. Here, we investigated whether amylin aggregates interact directly with cardiac myocytes and whether controlling hyperamylinemia protects the heart.

METHODS AND RESULTS: By Western blot, we found abundant amylin aggregates in lysates of cardiac myocytes from obese patients, but not in controls. Aggregated amylin was elevated in failing hearts, suggesting a role in myocyte injury. Using rats overexpressing human amylin in the pancreas (HIP …