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https://www.readbyqxmd.com/read/28245771/current-drug-targets-in-obesity-pharmacotherapy-a-review
#1
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
#2
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
#3
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
#4
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...
January 24, 2017: Postgraduate Medicine
https://www.readbyqxmd.com/read/28097882/antidiabetic-agents-and-cardiovascular-outcomes-in-patients-with-heart-diseases
#5
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...
February 15, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28093996/challenges-related-to-glycemic-control-in-type-2-diabetes-mellitus-patients
#6
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
#7
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
#8
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...
September 20, 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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
https://www.readbyqxmd.com/read/26655697/hypothalamic-amylin-acts-in-concert-with-leptin-to-regulate-food-intake
#17
Zhiying Li, Leah Kelly, Myriam Heiman, Paul Greengard, Jeffrey Michael Friedman
In this report we evaluated the functions of hypothalamic amylin in vivo and in vitro. Profiling of hypothalamic neurons revealed that islet amyloid polypeptide (Iapp, precursor to amylin) is expressed in neurons in the lateral hypothalamus, arcuate nucleus, medial preoptic area, and elsewhere. Hypothalamic expression of lapp is markedly decreased in ob/ob mice and normalized by exogenous leptin. In slices, amylin and leptin had similar electrophysiologic effects on lateral hypothalamic leptin receptor ObRb-expressing neurons, while the amylin antagonist AC187 inhibited their activity and blunted the effect of leptin...
December 1, 2015: Cell Metabolism
https://www.readbyqxmd.com/read/26652033/novel-therapeutic-interventions-for-p53-altered-tumors-through-manipulation-of-its-family-members-p63-and-p73
#18
Avinashnarayan Venkatanarayan, Payal Raulji, William Norton, Elsa R Flores
TP53 is highly mutated in human cancers, thus targeting this tumor suppressor pathway is highly desirable and will impact many cancer patients. (1,2) Therapeutic strategies to reactivate the p53-pathway have been challenging, (3,4) and no effective treatment exists. (5) We utilized the p53-family members, p63 and p73, which are not frequently mutated in cancer, to treat p53-defective cancers. The N-terminal splice variants of p63 and p73 are denoted as the TA and ΔN isoforms. We recently demonstrated that deletion of either ΔNp63 or ΔNp73 in p53-deficient mouse tumors results in tumor regression mediated by metabolic programming...
2016: Cell Cycle
https://www.readbyqxmd.com/read/26589105/immunogenicity-associated-with-metreleptin-treatment-in-patients-with-obesity-or-lipodystrophy
#19
Jean L Chan, Joy Koda, Joseph S Heilig, Elaine K Cochran, Phillip Gorden, Elif A Oral, Rebecca J Brown
OBJECTIVE: Recombinant human leptin (metreleptin) improves glycaemia and hypertriglyceridaemia in patients with generalized lipodystrophy; antibody development with in vitro neutralizing activity has been reported. We aimed to characterize antimetreleptin antibody development, including in vitro neutralizing activity. DESIGN: Two randomized controlled studies in patients with obesity (twice-daily metreleptin ± pramlintide for 20-52 weeks; 2006-2009); two long-term, open-label studies in patients with lipodystrophy (once-daily or twice-daily metreleptin for 2 months to 12·3 years; 2000-2014)...
July 2016: Clinical Endocrinology
https://www.readbyqxmd.com/read/26424675/role-of-amylin-in-type-1-and-type-2-diabetes
#20
REVIEW
Laura Hieronymus, Stacy Griffin
PURPOSE: The pathophysiology of diabetes has historically focused on alterations in insulin secretion and function; however, diabetes involves multiple hormonal alterations, including abnormal regulation of amylin. This review discusses the physiologic functions of amylin in glucose homeostasis and the rationale for amylin replacement in type 1 and 2 diabetes. The use of pramlintide, a synthetic amylin analog, is also discussed. CONCLUSIONS: Amylin, formed primarily in pancreatic islet β cells, is cosecreted with insulin in response to caloric intake...
December 2015: Diabetes Educator
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