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https://www.readbyqxmd.com/read/28528968/amylin-and-its-g-protein-coupled-receptor-a-probable-pathological-process-and-drug-target-for-alzheimer-s-disease
#1
REVIEW
Wei Qiao Qiu
G-protein-coupled receptors (GPCRs) are shown to be involved in Alzheimer's disease (AD) pathogenesis. However, because GPCRs include a large family of membrane receptors, it is unclear which specific GPCR or pathway with rational ligands can become effective therapeutic targets for AD. Amylin receptor (AmR) is a GPCR that mediates several activities, such as improving glucose metabolism, relaxing cerebrovascular structure, modulating inflammatory reactions and potentially enhancing neural regeneration. Recent studies show that peripheral treatments with amylin or its clinical analog, pramlintide, reduced several components of AD pathology, including amyloid plaques, tauopathy, neuroinflammation and other components in the brain, corresponding with improved learning and memory in AD mouse models...
May 18, 2017: Neuroscience
https://www.readbyqxmd.com/read/28503657/an-amylin-analog-used-as-a-challenge-test-for-alzheimer-s-disease
#2
Haihao Zhu, Robert A Stern, Qiushan Tao, Alexandra Bourlas, Maritza D Essis, Meenakshi Chivukula, James Rosenzweig, Devin Steenkamp, Weiming Xia, Gustavo A Mercier, Yorghos Tripodis, Martin Farlow, Neil Kowall, Wei Qiao Qiu
INTRODUCTION: Preclinical studies demonstrate the potential of amylin in the diagnosis of Alzheimer's disease (AD). We aimed to lay the foundation for repurposing the amylin analog and a diabetes drug, pramlintide, for AD in humans. METHODS: We administered a single subcutaneous injection of 60 μg of pramlintide to nondiabetic subjects under fasting conditions. RESULTS: None of the participants developed hypoglycemia after the injection of pramlintide...
January 2017: Alzheimer's & Dementia: Translational Research & Clinical Interventions
https://www.readbyqxmd.com/read/28415672/efficacy-and-safety-of-pramlintide-injection-adjunct-to-insulin-therapy-in-patients-with-type-1-diabetes-mellitus-a-systematic-review-and-meta-analysis
#3
Yong-Chao Qiao, Wei Ling, Yan-Hong Pan, Yin-Ling Chen, Dan Zhou, Yan-Mei Huang, Xiao-Xi Zhang, Hai-Lu Zhao
AIMS: We aim to assess the efficacy and safety of pramlintide plus insulin therapy in patients with type 1 diabetes. METHODS: We included clinical studies comparing pramlintide plus insulin to placebo plus insulin. Efficacy was reflected by glycemic control and reduction in body weight and insulin use. Safety concerns were hypoglycemia and other adverse events. Subgroup analysis was performed for different doses (30, 60, 90 µg/meal) and durations (≤4, 26, 29, >29 weeks) of the treatment...
March 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28363773/amylin-receptor-ligands-reduce-the-pathological-cascade-of-alzheimer-s-disease
#4
Haihao Zhu, Xiehua Xue, Erming Wang, Max Wallack, Hana Na, Jacob M Hooker, Neil Kowall, Qiushan Tao, Thor D Stein, Benjamin Wolozin, Wei Qiao Qiu
Amylin is an important gut-brain axis hormone. Since amylin and amyloid-β peptide (Aβ) share similar β sheet secondary structure despite not having the same primary sequences, we hypothesized that the accumulation of Aβ in the brains of subjects with Alzheimer's disease (AD) might compete with amylin for binding to the amylin receptor (AmR). If true, adding exogenous amylin type peptides would compete with Aβ and reduce the AD pathological cascade, improving cognition. Here we report that a 10-week course of peripheral treatment with human amylin significantly reduced multiple different markers associated with AD pathology, including reducing levels of phospho-tau, insoluble tau, two inflammatory markers (Iba1 and CD68), as well as cerebral Aβ...
March 28, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28245771/current-drug-targets-in-obesity-pharmacotherapy-a-review
#5
Sangeeta P Bhat, Arun Sharma
Obesity, an impending global pandemic, is not being effectively controlled by current measures such as lifestyle modifications, bariatric surgery or available medications. Its toll on health and economy compels us to look for more effective measures. Fortunately, the advances in biology and molecular technology have been in our favour for delineating new pathways in the pathophysiology of obesity and have led to subsequent development of new drug targets. Development of anti-obesity drugs has often been riddled with problems in the past...
February 27, 2017: Current Drug Targets
https://www.readbyqxmd.com/read/28241453/synthesis-of-reusable-silica-nanosphere-supported-pt-iv-complex-for-formation-of-disulfide-bonds-in-peptides
#6
Xiaonan Hou, Xiaowei Zhao, Yamei Zhang, Aiying Han, Shuying Huo, Shigang Shen
Some peptide-based drugs, including oxytocin, vasopressin, ziconotide, pramlintide, nesiritide, and octreotide, contain one intramolecular disulfide bond. A novel and reusable monodispersed silica nanosphere-supported Pt(IV) complex (SiO₂@TPEA@Pt(IV)); TPEA: N-[3-(trimethoxysilyl)propyl]ethylenediamine) was synthesized via a four-step procedure and was used for the formation of intramolecular disulfide bonds in peptides. Transmission electron microscopy (TEM) and chemical mapping results for the Pt(II) intermediates and for SiO₂@TPEA@Pt(IV) show that the silica nanospheres possess a monodisperse spherical structure and contain uniformly-distributed Si, O, C, N, Cl, and Pt...
February 22, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28223444/basal-glucose-can-be-controlled-but-the-prandial-problem-persists-it-s-the-next-target
#7
Matthew C Riddle
Both basal and postprandial elevations contribute to the hyperglycemic exposure of diabetes, but current therapies are mainly effective in controlling the basal component. Inability to control postprandial hyperglycemia limits success in maintaining overall glycemic control beyond the first 5 to 10 years after diagnosis, and it is also related to the weight gain that is common during insulin therapy. The "prandial problem"-comprising abnormalities of glucose and other metabolites, weight gain, and risk of hypoglycemia-deserves more attention...
March 2017: Diabetes Care
https://www.readbyqxmd.com/read/28118069/rationale-for-treatment-options-for-mealtime-glucose-control-in-patients-with-type-2-diabetes
#8
REVIEW
Stephen L Aronoff
While glycemic control is routinely assessed using HbA1c and fasting glucose measures, postprandial glucose (PPG) is also an important contributor of overall glycemia. Furthermore, PPG excursions have been linked to complications of diabetes. This review examines the effects of glucose-lowering therapies (including treatments administered at mealtime) on postprandial hyperglycemia in patients with type 2 diabetes. A PubMed search was conducted to identify clinical studies of treatments for mealtime glucose control in type 2 diabetes...
March 2017: Postgraduate Medicine
https://www.readbyqxmd.com/read/28097882/antidiabetic-agents-and-cardiovascular-outcomes-in-patients-with-heart-diseases
#9
Judy W M Cheng, Hisham A Badreldin, Dhiren K Patel, Snehal H Bhatt
INTRODUCTION: This article reviews evidence of the benefits and risk of antidiabetic agents in cardiovascular (CV) outcomes, with a focus on medications approved by the FDA since 2008. STUDY SELECTION: Peer-reviewed articles were identified from MEDLINE and Current Content databases (both 1966 to 1 October 2016) using the search terms insulin, metformin, rosiglitazone, pioglitazone, glyburide, glipizide, glimepiride, acarbose, miglitol, albiglutide, exenatide, liraglutide, lixisenatide, dulaglutide, pramlintide, meglitinide, alogliptin, linagliptin, saxagliptin, sitagliptin, canagliflozin, dapagliflozin, empagliflozin, colesevalam, bromocriptine, mortality, myocardial infarction (MI), heart failure (HF), and stroke...
June 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28093996/challenges-related-to-glycemic-control-in-type-2-diabetes-mellitus-patients
#10
Masoumeh Kheirandish, Hamidreza Mahboobi, Maryam Yazdanparast, Mohammad Amjad Kamal
Diabetes mellitus (DM) is a chronic disease with long-term complications. Glycemic control is an important part in management of DM. The first line in treatment of type 2 DM (T2DM) is diet and life style change. Metformin is the first choice of medication in T2DM patients. Sulfonylureas have high risk of hypoglycemia. Glinides are associated with lower risk of hypoglycemia in comparison to sulfonylureas. Also α-glucosidase inhibitors decrease the polysacarides digestion in small intestine and less effective in comparison to metformin and sulfonylureas in lowering hemoglobin A1c (HbA1c)...
January 15, 2017: Current Drug Metabolism
https://www.readbyqxmd.com/read/27815568/diabetes-drug-effects-on-the-skeleton
#11
Manju Chandran
Diabetes be it type 1 or type 2 is associated with an increased risk of fragility fractures. The mechanisms underlying this increased risk are just being elucidated. Anti-diabetes medications are crucial for maintaining glucose control and for preventing micro- and macrovascular complications in diabetes. However, they may modulate fracture risk in diabetes in different ways. Thiazolidinediones have demonstrated an unfavorable effect on the skeleton, while metformin and sulfonylureas may have a neutral if not beneficial effect on bone...
November 4, 2016: Calcified Tissue International
https://www.readbyqxmd.com/read/27665170/amyloidogenesis-of-the-amylin-analogue-pramlintide
#12
Dayana Cabral da Silva, Giselle N Fontes, Luiza C S Erthal, Luís Maurício T R Lima
Amylin is a pancreatic peptide hormone co-secreted along with insulin by the β-cells. It is found in amyloid deposits in both type 2 diabetic individuals and elder non-diabetic. The triple proline amylinomimetic compound (25,28,29-Pro-human amylin) named pramlintide was designed aiming to solve the solubility and amyloid characteristics of human amylin. We have found by using ion mobility spectrometry-based mass spectrometry that pramlintide is able to assembly into multimers. Pramlintide formed amyloid fibrils in vitro in a pH-dependent kinetic process within a few hours, as followed by thioflavin T, quantification of soluble peptide and further characterized by transmission electron microscopy, atomic force microscopy and X-ray diffraction...
December 2016: Biophysical Chemistry
https://www.readbyqxmd.com/read/27208332/mitigating-meal-related-glycemic-excursions-in-an-insulin-sparing-manner-during-closed-loop-insulin-delivery-the-beneficial-effects-of-adjunctive-pramlintide-and-liraglutide
#13
Jennifer L Sherr, Neha S Patel, Camille I Michaud, Miladys M Palau-Collazo, Michelle A Van Name, William V Tamborlane, Eda Cengiz, Lori R Carria, Eileen M Tichy, Stuart A Weinzimer
OBJECTIVE: Closed-loop (CL) insulin delivery effectively maintains glucose overnight but struggles when challenged with meals. Use of single-day, 30-μg/meal pramlintide lowers meal excursions during CL. We sought to further elucidate the potential benefits of adjunctive agents after 3-4 weeks of outpatient dose titration. RESEARCH DESIGN AND METHODS: Two CL studies were conducted: one evaluating adjunctive pramlintide and the other liraglutide. Ten subjects (age 16-23 years; A1C 7...
July 2016: Diabetes Care
https://www.readbyqxmd.com/read/27139251/synthesis-and-amylin-receptor-activity-of-glycomimetics-of-pramlintide-using-click-chemistry
#14
Lauren R Yule, Rebekah L Bower, Harveen Kaur, Renata Kowalczyk, Debbie L Hay, Margaret A Brimble
Pramlintide (Symlin®), a synthetic analogue of the neuroendocrine hormone amylin, is devoid of the tendency to form cytotoxic amyloid fibrils and is currently used in patients with type I and type II diabetes mellitus as an adjunctive therapy with insulin or insulin analogues. As part of an on-going search for a pramlintide analogue with improved pharmacokinetic properties, we herein report the synthesis of mono- and di-glycosylated analogues of pramlintide and their activity at the AMY1(a) receptor. Introduction of N-glycosylated amino acids into the pramlintide sequence afforded the native N-linked glycomimetics whilst use of Cu(i)-catalysed azide-alkyne 1,3-dipolar cycloaddition (click) chemistry delivered 1,2,3-triazole linked glycomimetics...
June 21, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27071768/impact-of-disease-duration-on-the-effects-of-pramlintide-in-type-1-diabetes-a-post-hoc-analysis-of-three-clinical-trials
#15
Kathrin Herrmann, Steven C Brunell, Yan Li, Ming Zhou, David G Maggs
INTRODUCTION: Adjunctive mealtime use of the amylin analog pramlintide improves postprandial hyperglycemia in patients with type 1 diabetes. This post hoc analysis of three randomized trials evaluated whether disease duration affected responses to pramlintide. METHODS: Patients received mealtime pramlintide 30 or 60 µg (n = 714) or placebo (n = 537) as an adjunct to insulin and were stratified into tertiles by diabetes duration at baseline. Efficacy and safety end points were assessed at week 26 using analysis of covariance and logistic regression models...
May 2016: Advances in Therapy
https://www.readbyqxmd.com/read/27071617/addressing-unmet-medical-needs-in-type-1-diabetes-a-review-of-drugs-under-development
#16
Friedrich Mittermayer, Erica Caveney, Claudia De Oliveira, G Alexander Fleming, Loukas Gourgiotis, Mala Puri, Li-Jung Tai, J Rick Turner
The incidence of type 1 diabetes (T1D) is increasing worldwide and there is a very large need for effective therapies. Besides pramlintide, there are essentially no pharmacologic therapies other than insulin currently approved for the treatment of T1D. Drugs already in use for type 2 diabetes and many new drugs are under clinical development for T1D, including compounds with both established and new mechanisms of action. Most of the new compounds in clinical development are currently in Phase 1 and Phase 2...
April 13, 2016: Current Diabetes Reviews
https://www.readbyqxmd.com/read/27061187/amylin-structure-function-relationships-and-receptor-pharmacology-implications-for-amylin-mimetic-drug-development
#17
REVIEW
Rebekah L Bower, Debbie L Hay
Amylin is an important, but poorly understood, 37 amino acid glucoregulatory hormone with great potential to target metabolic diseases. A working example that the amylin system is one worth developing is the FDA-approved drug used in insulin-requiring diabetic patients, pramlintide. However, certain characteristics of pramlintide pharmacokinetics and formulation leave considerable room for further development of amylin-mimetic compounds. Given that amylin-mimetic drug design and development is an active area of research, surprisingly little is known about the structure/function relationships of amylin...
June 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/26969516/non-insulin-drugs-to-treat-hyperglycaemia-in-type-1-diabetes-mellitus
#18
REVIEW
Christian Seerup Frandsen, Thomas Fremming Dejgaard, Sten Madsbad
Insulin treatment of individuals with type 1 diabetes has shortcomings and many patients do not achieve glycaemic and metabolic targets. Consequently, the focus is on novel non-insulin therapeutic approaches that reduce hyperglycaemia and improve metabolic variables without increasing the risk of hypoglycaemia or other adverse events. Several therapies given in conjunction with insulin have been investigated in clinical trials, including pramlintide, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter inhibitors, metformin, sulfonylureas, and thiazolidinediones...
September 2016: Lancet Diabetes & Endocrinology
https://www.readbyqxmd.com/read/26930181/effect-of-pramlintide-on-postprandial-glucose-fluxes-in-type-1-diabetes
#19
Ling Hinshaw, Michele Schiavon, Vikash Dadlani, Ashwini Mallad, Chiara Dalla Man, Adil Bharucha, Rita Basu, Jennifer R Geske, Rickey E Carter, Claudio Cobelli, Ananda Basu, Yogish C Kudva
CONTEXT: Early postprandial hyperglycemia and delayed hypoglycemia remain major problems in current management of type 1 diabetes (T1D). OBJECTIVE: Our objective was to investigate the effects of pramlintide, known to suppress glucagon and delay gastric emptying, on postprandial glucose fluxes in T1D. DESIGN: This was a single-center, inpatient, randomized, crossover study. PATIENTS: Twelve patients with T1D who completed the study were analyzed...
May 2016: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/26922873/amylin-mediated-control-of-glycemia-energy-balance-and-cognition
#20
REVIEW
Elizabeth G Mietlicki-Baase
Amylin, a peptide hormone produced in the pancreas and in the brain, has well-established physiological roles in glycemic regulation and energy balance control. It improves postprandial blood glucose levels by suppressing gastric emptying and glucagon secretion; these beneficial effects have led to the FDA-approved use of the amylin analog pramlintide in the treatment of diabetes mellitus. Amylin also acts centrally as a satiation signal, reducing food intake and body weight. The ability of amylin to promote negative energy balance, along with its unique capacity to cooperatively facilitate or enhance the intake- and body weight-suppressive effects of other neuroendocrine signals like leptin, have made amylin a leading target for the development of novel pharmacotherapies for the treatment of obesity...
August 1, 2016: Physiology & Behavior
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