353 results on '"Benson CT"'
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2. Effect of Food Consumption on the Pharmacokinetics, Safety, and Tolerability of Once-Daily Orally Administered Orforglipron (LY3502970), a Non-peptide GLP-1 Receptor Agonist.
- Author
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Ma X, Liu R, Pratt EJ, Benson CT, Bhattachar SN, and Sloop KW
- Abstract
Introduction: We assessed the effect of the prandial state on the pharmacokinetics, safety, and tolerability of single and multiple doses of orforglipron (LY3502970), an oral, non-peptide glucagon-like peptide 1 receptor agonist (GLP-1 RA), in two studies (A and B)., Methods: Study A and study B were phase 1, randomized, crossover studies in healthy adults aged 18-65 years and 21-70 years, respectively. Participants received single (3 mg, study A) or multiple (16 mg, study B) oral doses of orforglipron under fasted and fed conditions. Blood samples were collected pre- and postdose to assess area under the concentration-time curve (AUC), maximum observed drug concentration (C
max ), time of Cmax (tmax ), and half-life (t1/2 ) associated with terminal rate constant. AUC and Cmax were analyzed using a linear mixed-effects model. Treatment differences were presented as ratios of geometric least squares means (GLSM). Treatment-emergent adverse events (TEAEs), adverse events of special interest, and serious adverse events were assessed., Results: Study A included 12 participants (mean age 45.0 years; male 66.7%); study B included 34 participants (mean age 42.8 years; male 88.2%). GLSM AUC and Cmax were lower by 23.7% and 23.2% in study A, and 17.6% and 20.9% in study B, in the fed versus fasted states, respectively. In both studies, t1/2 and median tmax were comparable between fed and fasted states. The majority of TEAEs in both studies were gastrointestinal tract-related conditions. No serious adverse events or deaths were reported in either study., Conclusion: The observed pharmacokinetic differences due to the prandial state are unlikely to contribute to clinically meaningful differences in the efficacy of orforglipron. The safety profile was consistent with the known profiles of other GLP-1 RAs. Given the absence of prandial restrictions, orforglipron may emerge as a convenient oral treatment option for patients with type 2 diabetes or obesity., Trial Registration: ClinicalTrials.gov identifiers, NCT03929744 and NCT05110794., (© 2024. The Author(s).)- Published
- 2024
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3. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial.
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Urva S, Coskun T, Loh MT, Du Y, Thomas MK, Gurbuz S, Haupt A, Benson CT, Hernandez-Illas M, D'Alessio DA, and Milicevic Z
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- Adult, Humans, Body Weight, Gastric Inhibitory Polypeptide, Glucagon, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Glucose, Obesity, Young Adult, Middle Aged, Aged, Double-Blind Method, Diabetes Mellitus, Type 2 drug therapy, Receptors, Glucagon
- Abstract
Background: Treating hyperglycaemia and obesity in individuals with type 2 diabetes using multi-receptor agonists can improve short-term and long-term outcomes. LY3437943 is a single peptide with agonist activity for glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) receptors that is currently in development for the treatment of type 2 diabetes and for the treatment of obesity and associated comorbidities. We investigated the safety, pharmacokinetics, and pharmacodynamics of multiple weekly doses of LY3437943 in people with type 2 diabetes in a 12-week study., Methods: In this phase 1b, proof-of-concept, double-blind, placebo-controlled, randomised, multiple-ascending dose trial, adults (aged 20-70 years) with type 2 diabetes for at least 3 months, a glycated haemoglobin A
1c (HbA1c ) value of 7·0-10·5%, body-mass index of 23-50 kg/m2 , and stable bodyweight (<5% change in previous 3 months) were recruited at four centres in the USA. Using an interactive web-response system, participants were randomly assigned to receive once-weekly subcutaneous injections of LY3437943, placebo, or dulaglutide 1·5 mg over a 12-week period. Five ascending dose cohorts were studied, with randomisation in each cohort such that a minimum of nine participants received LY3437943, three received placebo, and one received dulaglutide 1·5 mg within each cohort. The top doses in the two highest dose cohorts were attained via stepwise dose escalations. The primary outcome was to investigate the safety and tolerability of LY3437943, and characterising the pharmacodynamics and pharmacokinetics were secondary outcomes. Safety was analysed in all participants who received at least one dose of study drug, and pharmacodynamics and pharmacokinetics in all participants who received at least one dose of study drug and had evaluable data. This trial is registered at ClinicalTrials.gov, NCT04143802., Findings: Between Dec 18, 2019, and Dec 28, 2020, 210 people were screened, of whom 72 were enrolled, received at least one dose of study drug, and were included in safety analyses. 15 participants had placebo, five had dulaglutide 1·5 mg and, for LY3437943, nine had 0·5 mg, nine had 1·5 mg, 11 had 3 mg, 11 had 3/6 mg, and 12 had 3/6/9/12 mg. 29 participants discontinued the study prematurely. Treatment-emergent adverse events were reported by 33 (63%), three (60%), and eight (54%) participants who received LY3437943, dulaglutide 1·5 mg, and placebo, respectively, with gastrointestinal disorders being the most frequently reported treatment-emergent adverse events. The pharmacokinetics of LY3437943 were dose proportional and its half-life was approximately 6 days. At week 12, placebo-adjusted mean daily plasma glucose significantly decreased from baseline at the three highest dose LY3437943 groups (least-squares mean difference -2·8 mmol/L [90% CI -4·63 to -0·94] for 3 mg; -3·1 mmol/L [-4·91 to -1·22] for 3/6 mg; and -2·9 mmol/L [-4·70 to -1·01] for 3/6/9/12 mg). Placebo-adjusted sHbA1c also decreased significantly in the three highest dose groups (-1·4% [90% CI -2·17 to -0·56] for 3 mg; -1·6% [-2·37 to -0·75] for 3/6 mg; and -1·2% [-2·05 to -0·45] for 3/6/9/12 mg). Placebo-adjusted bodyweight reduction with LY3437943 appeared to be dose dependent (up to -8·96 kg [90% CI -11·16 to -6·75] in the 3/6/9/12 mg group)., Interpretation: In this early phase study, LY3437943 showed an acceptable safety profile, and its pharmacokinetics suggest suitability for once-weekly dosing. This finding, together with the pharmacodynamic findings of robust reductions in glucose and bodyweight, provides support for phase 2 development., Funding: Eli Lilly and Company., Competing Interests: Declaration of interests SU, TC, MTL, YD, SG, AH, CTB, and ZM are employees and shareholders of Eli Lilly and Company. MKT is an employee and shareholder of Eli Lilly and Company, and reports being industry chair of a steering committee on Accelerating Medicines Partnership-Type 2 Diabetes, and a steering committee member on Accelerating Medicines Partnership-Common Metabolic Diseases. DAD reports research grants and advisory fees from Eli Lilly and Company; research grants from Merck; consulting fees from Intarcia and Sun Pharmaceuticals; and editorial fees from American Diabetes Association journals. MH-I is an employee of QPS and was the principal investigator of this study. We declare no other competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2022
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4. Effects of Hepatic Impairment on the Pharmacokinetics of the Dual GIP and GLP-1 Receptor Agonist Tirzepatide.
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Urva S, Quinlan T, Landry J, Ma X, Martin JA, and Benson CT
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- Area Under Curve, Glucagon-Like Peptide-1 Receptor agonists, Humans, Serum Albumin, Diabetes Mellitus, Type 2 drug therapy, Gastric Inhibitory Polypeptide pharmacokinetics, Hypoglycemic Agents pharmacokinetics, Liver Diseases complications
- Abstract
Background and Objective: Tirzepatide, a novel, once-weekly, dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, is approved in the US as a treatment for type 2 diabetes and is under development for long-term weight management, heart failure with preserved ejection fraction, and nonalcoholic steatohepatitis. This study evaluated the pharmacokinetics and tolerability of tirzepatide in participants with hepatic impairment (with or without type 2 diabetes) versus healthy participants with normal hepatic function., Methods: Participants in this parallel, single-dose, open-label study were categorized by hepatic impairment defined by the baseline Child-Pugh (CP) score A (mild impairment; n = 6), B (moderate impairment; n = 6), or C (severe impairment; n = 7) or normal hepatic function (n = 13). All participants received a single subcutaneous 5-mg dose of tirzepatide. Blood samples were collected to determine tirzepatide plasma concentrations to estimate pharmacokinetic parameters. The primary pharmacokinetic parameters of area under the drug concentration-time curve from zero to infinity (AUC
0-∞ ) and maximum observed drug concentration (Cmax ) were evaluated using an analysis of covariance. The geometric least-squares means (LSM) and mean ratios for each group, between control and hepatic impairment levels, and the corresponding 90% confidence intervals (CIs) were estimated. The analysis of the time to maximum observed drug concentration was based on a nonparametric method. The relationships between the pharmacokinetic parameters and CP classification parameters (serum albumin level, total bilirubin level, and international normalized ratio) were also assessed. Adverse events were monitored to assess safety and tolerability., Results: Tirzepatide exposure, based on AUC0-∞ and Cmax , was similar across the control and hepatic impairment groups. Statistical analysis showed no difference in the geometric LSM AUC0-∞ or Cmax between participants in the control group and the hepatic impairment groups, with the 90% CI for the ratios of geometric LSM spanning unity (AUC0-∞ ratio of geometric LSM vs control [90% CI 1.08 [0.879, 1.32], 0.960 [0.790, 1.17], and 0.852 [0.699, 1.04] and Cmax ratio of geometric LSM vs control [90% CI]: 0.916 [0.726, 1.16], 1.00 [0.802, 1.25], and 0.972 [0.784, 1.21] for mild, moderate and severe hepatic impairment groups, respectively). There was no change in median time to Cmax of tirzepatide across all groups (time to Cmax median difference vs control [90% CI]: 0 [- 4.00, 12.00], 0 [- 12.00, 12.00], and 0 [- 11.83, 4.17], respectively). There was no significant relationship between the exposure of tirzepatide and the CP score (p > 0.1 for AUC0-∞ , Cmax , and apparent total body clearance). Similarly, there was no clinically relevant relationship between the exposure of tirzepatide and serum albumin level, total bilirubin level, or international normalized ratio. The geometric LSM half-life values were also similar across the control and hepatic impairment groups. No notable differences in safety profiles were observed between participants with hepatic impairment and healthy control participants., Conclusions: Tirzepatide pharmacokinetics was similar in participants with varying degrees of hepatic impairment compared with healthy participants. Thus, people with hepatic impairment treated with tirzepatide may not require dose adjustments., Clinical Trial Registration: ClinicalTrials.gov identifier number NCT03940742., (© 2022. The Author(s).)- Published
- 2022
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5. Pharmacokinetics and Pharmacodynamics of Human Regular U-500 Insulin Administered via Continuous Subcutaneous Insulin Infusion Versus Subcutaneous Injection in Adults With Type 2 Diabetes and High-Dose Insulin Requirements.
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Ma X, Benson CT, Prescilla R, Zhang S, Linnebjerg H, LaBell ES, Morrow LA, Jackson JA, Nguyen A, Ilag LL, Johnson JL, and Leishman D
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- Adult, Blood Glucose, Humans, Hypoglycemic Agents, Injections, Subcutaneous, Insulin, Insulin Infusion Systems, Diabetes Mellitus, Type 2 drug therapy
- Abstract
Introduction: Human regular U-500 insulin (U-500R) is approved for subcutaneous (SC) injection in patients with diabetes requiring >200 units/day of insulin. Here, pharmacokinetic and pharmacodynamic (PK/PD) profiles following U-500R administered by continuous subcutaneous insulin infusion (CSII) and SC injection in adults with type 2 diabetes (T2D) on high-dose insulin were studied., Methods: In this randomized, crossover, euglycemic clamp study, patients received a 100-unit bolus of U-500R via SC injection or CSII with basal infusion using a U-500R specific pump. PK parameters were estimated using non-compartmental methods. PD estimates were derived from the glucose infusion rate during the euglycemic clamp procedure., Results: When corrected for the basal infusion, the PK profiles for the 100-unit bolus of U-500R were similar for CSII and SC injection. Without correction for basal infusion, PK and PD profiles showed a greater insulin concentration and effect when U-500R was administered via CSII compared to SC injection, primarily due to basal insulin infusion for CSII. The ratio of geometric least squares AUC
0-tlast means SC:CSII (90% CI) is 0.857 (0.729, 1.01) with correction (mean AUC0-tlast : 5230 pmol*L/h [SC injection] and 6070 pmol*L/h [CSII, with correction]) and 0.424 (0.361, 0.499) without correction (mean AUC0-tlast : 12300 pmol*L/h [CSII, without correction]). Median time-to-peak insulin concentration was six hours (range 0.5-8 hours) via SC injection and five hours (0.5-12 hours) via CSII., Conclusions: In adults with T2D on high-dose insulin, U-500R PK/PD parameters were similar for a 100-unit bolus when given by SC injection or CSII via a U-500R pump.- Published
- 2022
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6. Time for a Fully Integrated Nonclinical-Clinical Risk Assessment to Streamline QT Prolongation Liability Determinations: A Pharma Industry Perspective.
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Vargas HM, Rolf MG, Wisialowski TA, Achanzar W, Bahinski A, Bass A, Benson CT, Chaudhary KW, Couvreur N, Dota C, Engwall MJ, Michael Foley C, Gallacher D, Greiter-Wilke A, Guillon JM, Guth B, Himmel HM, Hegele-Hartung C, Ito M, Jenkinson S, Chiba K, Lagrutta A, Levesque P, Martel E, Okai Y, Peri R, Pointon A, Qu Y, Teisman A, Traebert M, Yoshinaga T, Gintant GA, Leishman DJ, and Valentin JP
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- Animals, Arrhythmias, Cardiac chemically induced, Drug Development methods, Drug Industry methods, Electrocardiography methods, Humans, Risk Assessment, Torsades de Pointes chemically induced, Drugs, Investigational adverse effects, Long QT Syndrome chemically induced
- Abstract
Defining an appropriate and efficient assessment of drug-induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc-prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical evaluations of delayed repolarization still minimally influence ICH E14-based strategies for assessing clinical QTc prolongation and defining proarrhythmic risk. In particular, the value of ICH S7B-based "double-negative" nonclinical findings (low risk for hERG block and in vivo QTc prolongation at relevant clinical exposures) is underappreciated. These nonclinical data have additional value in assessing the risk of clinical QTc prolongation when clinical evaluations are limited by heart rate changes, low drug exposures, or high-dose safety considerations. The time has come to meaningfully merge nonclinical and clinical data to enable a more comprehensive, but flexible, clinical risk assessment strategy for QTc monitoring discussed in updated ICH E14 Questions and Answers. Implementing a fully integrated nonclinical/clinical risk assessment for compounds with double-negative nonclinical findings in the context of a low prevalence of clinical QTc prolongation would relieve the burden of unnecessary clinical QTc studies and streamline drug development., (© 2020 Amgen, Inc.; Pfizer, Inc.; Takeda Inc.; Bayer; Novartis; Merck; Bristol-Myers Squibb; and Janssen. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2021
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7. Shared Learnings on the New EMA First-in-Human and Early Clinical Trial Guideline: Proceedings From a DIAlogue Session at DIA Europe 2018.
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van der Laan JW, Benson CT, Janssens W, Bos J, Stahl E, Brady JT, Wändel-Liminga U, Corriol-Rohou S, Forster R, Hartmann A, Pertel PE, Robertson SM, Silva-Lima B, Malik RE, and Chibout SD
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- Europe, Humans, Switzerland, Pharmaceutical Preparations
- Abstract
The EU is a member of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), and therefore adopts the ICH Guidelines, including the ICH M3 Guideline on Nonclinical Safety Studies. Following the 2016 incident in France with BIA 10-2474, and in light of the substantial evolvement of how early clinical development has been undertaken during the last 10 years, for example, conducting integrated (FIH) studies that include multiple parts (eg, single ascending doses, multiple ascending doses, food effect), EMA decided to update the existing 2007 FIH guideline. The key revisions to the 2007 guideline, now titled "Guideline on Strategies to Identify and Mitigate Risks for First-in-Human and Early Clinical Trials With Investigational Medicinal Products," include additional information. The revision reinforces the importance and impact of pharmacologic data, which supports the intended efficacy of the compound, risk assessment, and protocol design. The updates, effective February 2018, are intended to provide additional guidance and clarity for Sponsors developing FIH and early phase clinical research programs, and ultimately support subject safety. At the 2018 DIA Europe Annual Meeting in Basel, Switzerland, European regulators, industry representatives and academics convened a DIAlogue Session on April 17 to discuss how the revised 2017 guideline is being applied, and to establish recommendations for its application. Using two case studies as examples, the session participants discussed the nonclinical and clinical considerations for applying the newly revised recommendations, and interacted with a panel including regulators and industry representatives. The proceedings from this session reflect practical considerations for the implementation of the revised guideline.
- Published
- 2020
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8. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept.
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Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, Cabrera O, Roell WC, Kuchibhotla U, Moyers JS, Benson CT, Gimeno RE, D'Alessio DA, and Haupt A
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- Adult, Animals, Appetite drug effects, Blood Glucose metabolism, Body Weight, Diarrhea etiology, Female, Gastric Inhibitory Polypeptide adverse effects, Gastric Inhibitory Polypeptide pharmacology, Humans, Hypoglycemic Agents adverse effects, Hypoglycemic Agents pharmacology, Incretins adverse effects, Incretins pharmacology, Male, Mice, Mice, Inbred C57BL, Middle Aged, Vomiting etiology, Diabetes Mellitus, Type 2 drug therapy, Gastric Inhibitory Polypeptide therapeutic use, Glucagon-Like Peptide-1 Receptor agonists, Hypoglycemic Agents therapeutic use, Incretins therapeutic use, Receptors, Gastrointestinal Hormone agonists
- Abstract
Objective: A novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists in type 2 diabetes mellitus (T2DM)., Methods: LY3298176 is a fatty acid modified peptide with dual GIP and GLP-1 receptor agonist activity designed for once-weekly subcutaneous administration. LY3298176 was characterised in vitro, using signaling and functional assays in cell lines expressing recombinant or endogenous incretin receptors, and in vivo using body weight, food intake, insulin secretion and glycemic profiles in mice. A Phase 1, randomised, placebo-controlled, double-blind study was comprised of three parts: a single-ascending dose (SAD; doses 0.25-8 mg) and 4-week multiple-ascending dose (MAD; doses 0.5-10 mg) studies in healthy subjects (HS), followed by a 4-week multiple-dose Phase 1 b proof-of-concept (POC; doses 0.5-15 mg) in patients with T2DM (ClinicalTrials.gov no. NCT02759107). Doses higher than 5 mg were attained by titration, dulaglutide (DU) was used as a positive control. The primary objective was to investigate safety and tolerability of LY3298176., Results: LY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist. A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25-15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean [LSM] difference [95% CI]: -49.12 mg/dL [-78.14, -20.12] and -43.15 mg/dL [-73.06, -13.21], respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference [95% CI]: -1.75 kg [-3.38, -0.12], -5.09 kg [-6.72, -3.46] and -4.61 kg [-6.21, -3.01], respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference [95% CI]: -2.62 kg [-3.79, -1.45] and -2.07 kg [-3.25, -0.88], respectively. The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity., Conclusions: Based on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity., (Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2018
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9. Development of a selective androgen receptor modulator for transdermal use in hypogonadal patients.
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Krishnan V, Patel NJ, Mackrell JG, Sweetana SA, Bullock H, Ma YL, Waterhouse TH, Yaden BC, Henck J, Zeng QQ, Gavardinas K, Jadhav P, Saeed A, Garcia-Losada P, Robins DA, and Benson CT
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- Administration, Cutaneous, Animals, Fracture Healing drug effects, Guinea Pigs, Haplorhini, Humans, Hypogonadism, Male, Muscle, Striated drug effects, Rats, Androgens pharmacology, Aniline Compounds pharmacology, Drug Discovery, Nitriles pharmacology
- Abstract
We have identified a non-steroidal selective androgen receptor modulator (SARM), termed LY305, that is bioavailable through a transdermal route of administration while highly cleared via hepatic metabolism to limit parent compound exposure in the liver. Selection of this compound and its transdermal formulation was based on the optimization of skin absorption properties using both in vitro and in vivo skin models that supported PBPK modeling for human PK predictions. This molecule is an agonist in perineal muscle while being a weak partial agonist in the androgenic tissues such as prostate. When LY305 was tested in animal models of skeletal atrophy it restored the skeletal muscle mass through accelerated repair. In a bone fracture model, LY305 remained osteoprotective in the regenerating tissue and void of deleterious effects. Finally, in a small cohort of healthy volunteers, we assessed the safety and tolerability of LY305 when administered transdermally. LY305 showed a dose-dependent increase in serum exposure and was well tolerated with minimal adverse effects. Notably, there were no statistically significant changes to hematocrit or HDL after 4-week treatment period. Collectively, LY305 represents a first of its kind de novo development of a non-steroidal transdermal SARM with unique properties which could find clinical utility in hypogonadal men., (© 2018 American Society of Andrology and European Academy of Andrology.)
- Published
- 2018
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10. Τhe story of sclerostin inhibition: the past, the present, and the future.
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Anastasilakis AD and Tsourdi E
- Abstract
Sclerostin inhibits osteoblast activity by hampering activation of the canonical Wnt signaling pathway and simultaneously stimulates osteoclastogenesis through upregulation of the receptor activator of NFκB ligand (RANKL). Thus, antibodies against sclerostin (Scl-Abs), besides promoting bone formation, suppress bone resorption and dissociate bone formation from resorption. This dual action results in remarkable increases of bone mineral density which are of a greater magnitude compared to the other antiosteoporotic treatments and are accompanied by decreases of fracture risk at all skeletal sites. The anabolic effect subsides after the first few months of treatment and a predominantly antiresorptive effect remains after this period, limiting its use to 12 months. Furthermore, these effects are largely reversible upon discontinuation; therefore, subsequent treatment with antiresorptives is indicated to maintain or further increase the bone gains achieved. Romosozumab is currently the only Scl-Ab approved for the treatment of severe postmenopausal osteoporosis. Indications for use in other populations, such as males, premenopausal women, and patients with glucocorticoid-induced osteoporosis, are pending. Additionally, the efficacy of Scl-Abs in other bone diseases, such as osteogenesis imperfecta, hypophosphatasia, X-linked hypophosphatemia, and bone loss associated with malignancies, is under thorough investigation. Cardiovascular safety concerns currently exclude patients at high cardiovascular risk from this treatment., (© 2024. The Author(s), under exclusive licence to Hellenic Endocrine Society.)
- Published
- 2024
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11. A Phase 2 Randomized Study Investigating the Efficacy and Safety of Myostatin Antibody LY2495655 versus Placebo in Patients Undergoing Elective Total Hip Arthroplasty.
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Woodhouse L, Gandhi R, Warden SJ, Poiraudeau S, Myers SL, Benson CT, Hu L, Ahmad QI, Linnemeier P, Gomez EV, and Benichou O
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- Absorptiometry, Photon, Aged, Dose-Response Relationship, Drug, Double-Blind Method, Drug Monitoring methods, Female, Humans, Injections, Subcutaneous, Male, Middle Aged, Osteoarthritis surgery, Recovery of Function drug effects, Treatment Outcome, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized therapeutic use, Arthroplasty, Replacement, Hip adverse effects, Arthroplasty, Replacement, Hip methods, Muscle, Skeletal drug effects, Muscular Atrophy diagnosis, Muscular Atrophy etiology, Muscular Atrophy metabolism, Muscular Atrophy prevention & control, Myostatin antagonists & inhibitors, Postoperative Complications diagnosis, Postoperative Complications metabolism, Postoperative Complications prevention & control
- Abstract
Background: Total hip arthroplasty relieves joint pain in patients with end stage osteoarthritis. However, postoperative muscle atrophy often results in suboptimal lower limb function. There is a need to improve functional recovery after total hip arthroplasty., Objectives: To assess safety and efficacy of LY2495655, a humanized monoclonal antibody targeting myostatin, in patients undergoing elective total hip arthroplasty., Design: Phase 2, randomized, parallel, double-blind, 12-week clinical trial with a 12-week follow-up period., Setting: Forty-two sites in 11 countries., Participants: Individuals (N=400) aged ≥50 years scheduled for elective total hip arthroplasty for osteoarthritis within 10 ± 6 days after randomization., Intervention: Placebo or LY2495655 (35 mg, 105 mg, or 315 mg) subcutaneous injections at weeks 0 (randomization date), 4, 8, and 12 with follow up until week 24., Measurements: Primary endpoint: probability that LY2495655 increases appendicular lean mass (operated limb excluded) by at least 2.5% more than placebo at week 12, using dual-energy x-ray absorptiometry. Exploratory endpoints: muscle strength, performance based and self-reported measures of physical function, and whole body composition over time., Results: Participants: 59% women, aged 69 ± 8 years, BMI 29 ± 5 kg/m2. Groups were comparable at baseline. The primary objective was not reached as LY2495655 changes in lean mass did not meet the superiority threshold at week 12. However, LY2495655 105 and LY2495655 315 experienced progressive increases in appendicular lean mass that were statistically significant versus placebo at weeks 8 and 16. Whole body fat mass decreased in LY2495655 315 versus placebo at weeks 8 and 16. No meaningful differences were detected between groups in other exploratory endpoints. Injection site reactions occurred more often in LY2495655 patients than in placebo patients. No other safety signals were detected., Conclusion: Dose-dependent increases in appendicular lean body mass and decreases in fat mass were observed, although this study did not achieve the threshold of its primary objective.
- Published
- 2016
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12. Myostatin antibody (LY2495655) in older weak fallers: a proof-of-concept, randomised, phase 2 trial.
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Becker C, Lord SR, Studenski SA, Warden SJ, Fielding RA, Recknor CP, Hochberg MC, Ferrari SL, Blain H, Binder EF, Rolland Y, Poiraudeau S, Benson CT, Myers SL, Hu L, Ahmad QI, Pacuch KR, Gomez EV, and Benichou O
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- Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Double-Blind Method, Female, Gait drug effects, Hand Strength, Humans, Injections, Subcutaneous, Male, Myostatin immunology, Treatment Outcome, Accidental Falls, Antibodies, Monoclonal, Humanized therapeutic use, Muscle Weakness drug therapy, Muscle, Skeletal drug effects, Myostatin antagonists & inhibitors
- Abstract
Background: Myostatin inhibits skeletal muscle growth. The humanised monoclonal antibody LY2495655 (LY) binds and neutralises myostatin. We aimed to test whether LY increases appendicular lean body mass (aLBM) and improves physical performance in older individuals who have had recent falls and low muscle strength and power., Methods: In this proof-of-concept, randomised, placebo-controlled, double-blind, parallel, multicentre, phase 2 study, we recruited patients aged 75 years or older who had fallen in the past year from 21 investigator sites across Argentina, Australia, France, Germany, Sweden, and the USA. Eligible patients had low performance on hand grip strength and chair rise tests, tested with the procedure described by Guralnik and colleagues. Participants were stratified by country, age, hand grip strength, and performance on the chair rise test, and were randomly assigned (1:1) by a computer-generated random sequence to receive subcutaneous injections of placebo or 315 mg LY at weeks 0 (randomisation visit), 4, 8, 12, 16, and 20, followed by 16 weeks observation. The primary outcome was change in aLBM from baseline to 24 weeks. We measured physical performance as secondary outcomes (four-step stair climbing time, usual gait speed, and time to rise five times from a chair without arms, or with arms for participants unable to do it without arms) and exploratory outcomes (12-step stair climbing test, 6-min walking distance, fast gait speed, hand grip strength, and isometric leg extension strength). Efficacy analyses included all randomly assigned patients who received at least one dose and had a baseline and at least one subsequent measure. The primary analysis and all other tests of treatment effect (except physical performance tests) were done at a two-sided alpha level of 0·05. Tests of treatment effect on physical performance tests were done at a pre-specified two-sided alpha level of 0·1. This trial is registered with ClinicalTrials.gov, number NCT01604408., Findings: Between June 19, 2012, and Dec 12, 2013, we screened 365 patients. 99 were randomly assigned to receive placebo and 102 to receive LY. Treatment was completed in 85 (86%) of patients given placebo and in 82 (80%) given LY. At 24 weeks, the least-squares mean change in aLBM was -0·123 kg (95% CI -0·287 to 0·040) in the placebo group and 0·303 kg (0·135 to 0·470) in the LY group, a difference of 0·43 kg (95% CI 0·192 to 0·660; p<0·0001). Stair climbing time (four-step and 12-step tests), chair rise with arms, and fast gait speed improved significantly from baseline to week 24 with differences between LY and placebo of respectively -0·46 s (p=0·093), -1·28 s (p=0·011), -4·15 s (p=0·054), and 0·05 m/s (p=0·088). No effect was detected for other performance-based measures. Injection site reactions were recorded in nine (9%) patients given placebo and in 31 (30%) patients given LY (p<0·0001), and were generally mild, and led to treatment discontinuation in two patients given LY., Interpretation: Our findings show LY treatment increases lean mass and might improve functional measures of muscle power. Although additional studies are needed to confirm these results, our data suggest LY should be tested for its potential ability to reduce the risk of falls or physical dependency in older weak fallers., Funding: Eli Lilly and Company., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
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- 2015
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13. The Effect of Discontinuing Treatment With Blosozumab: Follow-up Results of a Phase 2 Randomized Clinical Trial in Postmenopausal Women With Low Bone Mineral Density.
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Recknor CP, Recker RR, Benson CT, Robins DA, Chiang AY, Alam J, Hu L, Matsumoto T, Sowa H, Sloan JH, Konrad RJ, Mitlak BH, and Sipos AA
- Subjects
- Adaptor Proteins, Signal Transducing, Aged, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal, Humanized blood, Bone Density Conservation Agents administration & dosage, Bone Density Conservation Agents blood, Bone Morphogenetic Proteins immunology, Bone Resorption, Double-Blind Method, Drug Administration Schedule, Female, Follow-Up Studies, Genetic Markers immunology, Humans, Middle Aged, Osteogenesis, Steroids chemistry, Time Factors, Antibodies, Monoclonal, Humanized administration & dosage, Bone Density, Bone Morphogenetic Proteins blood, Osteoporosis, Postmenopausal drug therapy, Postmenopause
- Abstract
Administration of blosozumab, a humanized monoclonal antibody that binds sclerostin, increases bone formation and bone mineral density (BMD) in postmenopausal women with low BMD. To evaluate the effect of discontinuing blosozumab, we studied women enrolled in a 1-year randomized, placebo-controlled phase 2 trial for an additional year after they completed treatment. Of the 120 women initially enrolled in the study, 106 women completed treatment and continued into follow-up; 88 women completed 1 year of follow-up. At the beginning of follow-up, groups remained balanced for age, race, and body mass index, but lumbar spine and total hip BMD were increased in prior blosozumab groups, reflecting an anabolic treatment effect. At the end of follow-up, 1 year after discontinuing treatment, lumbar spine BMD remained significantly greater than placebo in women initially treated with blosozumab 270 mg every 2 weeks (Q2W) and blosozumab 180 mg Q2W (6.9% and 3.6% above baseline, respectively). Total hip BMD also declined after discontinuation of treatment but at 1 year after treatment remained significantly greater than placebo in women initially treated with blosozumab 270 mg Q2W and blosozumab 180 mg Q2W (3.9% and 2.6% above baseline, respectively). During follow-up, median serum P1NP was not consistently different between the prior blosozumab groups and placebo. A similar pattern was apparent for median serum C-terminal telopeptide of type 1 collagen (CTx) levels, with more variability. Mean serum total sclerostin concentration increased with blosozumab, indicating target engagement, and declined to baseline after discontinuation. There were no adverse events considered related to prior treatment with blosozumab. Anti-drug antibodies generally declined in patients who had detectable levels during prior treatment. These findings support the continued study of blosozumab as an anabolic therapy for treatment of osteoporosis., (© 2015 American Society for Bone and Mineral Research.)
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- 2015
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14. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density.
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Recker RR, Benson CT, Matsumoto T, Bolognese MA, Robins DA, Alam J, Chiang AY, Hu L, Krege JH, Sowa H, Mitlak BH, and Myers SL
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- Adaptor Proteins, Signal Transducing, Aged, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized therapeutic use, Biomarkers metabolism, Bone Remodeling drug effects, Double-Blind Method, Female, Humans, Osteoporosis, Postmenopausal drug therapy, Placebos, Treatment Outcome, Antibodies, Monoclonal, Humanized pharmacology, Bone Density drug effects, Bone Morphogenetic Proteins immunology, Genetic Markers immunology, Postmenopause drug effects
- Abstract
Sclerostin, a SOST protein secreted by osteocytes, negatively regulates formation of mineralized bone matrix and bone mass. We report the results of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin, in postmenopausal women with low bone mineral density (BMD). Postmenopausal women with a lumbar spine T-score -2.0 to -3.5, inclusive, were randomized to subcutaneous blosozumab 180 mg every 4 weeks (Q4W), 180 mg every 2 weeks (Q2W), 270 mg Q2W, or matching placebo for 1 year, with calcium and vitamin D. Serial measurements of spine and hip BMD and biochemical markers of bone turnover were performed. Overall, 120 women were enrolled in the study (mean age 65.8 years, mean lumbar spine T-score -2.8). Blosozumab treatment resulted in statistically significant dose-related increases in spine, femoral neck, and total hip BMD as compared with placebo. In the highest dose group, BMD increases from baseline reached 17.7% at the spine, and 6.2% at the total hip. Biochemical markers of bone formation increased rapidly during blosozumab treatment, and trended toward pretreatment levels by study end. However, bone specific alkaline phosphatase remained higher than placebo at study end in the highest-dose group. CTx, a biochemical marker of bone resorption, decreased early in blosozumab treatment to a concentration less than that of the placebo group by 2 weeks, and remained reduced throughout blosozumab treatment. Mild injection site reactions were reported more frequently with blosozumab than placebo. In conclusion, treatment of postmenopausal women with an antibody targeted against sclerostin resulted in substantial increases in spine and hip BMD. These results support further study of blosozumab as a potential anabolic therapy for osteoporosis., (© 2014 American Society for Bone and Mineral Research.)
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- 2015
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15. Tirzepatide a novel anti diabetic molecule unfold dual action.
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Sweta, Gupta, Sumeet, Bansal, Seema, Devi, Siwani, Sharma, Sheenam, Laxmi, and Deepa
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CARDIOVASCULAR disease prevention ,KIDNEY disease prevention ,GLUCAGON-like peptide-1 agonists ,NON-alcoholic fatty liver disease ,INCRETINS ,GLYCEMIC control ,BODY weight ,PANCREATIC beta cells ,HYPOGLYCEMIC agents ,INSULIN ,GASTROINTESTINAL hormones ,PHARMACY information services ,TYPE 2 diabetes ,MOLECULAR structure ,DRUG interactions ,DRUG efficacy ,OBESITY ,CELL receptors ,PHARMACODYNAMICS ,CHEMICAL inhibitors - Abstract
This review article provides an in-depth examination of various aspects related to tirzepatide, a synthetic peptide given the positive signal by the "United States Food and Drug Administration" for managing type 2 diabetes. Beginning with an overview of diabetes introduction, epidemiology, and issues related to β-cell dysfunction, is explored in the narrative. It further delves into the significance of incretins in the context of diabetes and introduces tirzepatide as a novel "twincretin" owing to its dual agonistic activity on the glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) receptors. The document delves into the chemistry and structure of tirzepatide, providing insights into its unique composition of 39 amino acids derived from native GLP-1, GIP, and semaglutide sequences. Tirzepatide's pharmacology, with a focus on its pharmacokinetic characteristics, and its mechanism of action (MOA) are extensively discussed. Notably, tirzepatide exhibits a preference for GIP receptors, leading to effective reduction of hyperglycemia and positive effects on pancreatic β-cells. Clinical trials examining tirzepatide's impact on glycemic and obesity control are detailed, demonstrating its efficacy in reducing body weight and appetite. Furthermore, the review article explores tirzepatide's effects on cardiovascular and kidney function, highlighting potential renal benefits for diabetic and elevated cardiovascular risk individuals. The narrative also addresses the association between tirzepatide and NAFLD, emphasizing potential benefits in mitigating NAFLD outcomes. Additionally, a comprehensive overview of tirzepatide's side effects, supported by scientific trials, is presented in this article. In conclusion, this review article provides a thorough examination of tirzepatide's multifaceted impact on diabetes management, shedding light on its pharmacological properties, clinical implications, and potential side effects. The information presented contributes to a comprehensive understanding of tirzepatide's role in the evolving landscape of T2D therapeutics. [ABSTRACT FROM AUTHOR]
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- 2024
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16. Gut hormone multi-agonists for the treatment of type 2 diabetes and obesity: advances and challenges.
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Xianxian Huang, Jing Liu, Guangquan Peng, Mingyue Lu, Zhongbo Zhou, Neng Jiang, and Zhiming Yan
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TYPE 2 diabetes ,GLUCAGON receptors ,GASTROINTESTINAL hormones ,WEIGHT loss ,HORMONE receptors ,GLUCAGON-like peptide-1 agonists ,GASTRIC inhibitory polypeptide - Abstract
The rapidly rising incidence of obesity, coupled with type 2 diabetes mellitus (T2DM), is a growing concern. Glucagonlike peptide 1 (GLP-1), an endogenous peptide secreted by enteroendocrine L-cells, demonstrates exceptional pharmacological potential for the treatment of T2DM and obesity, primarily through its pivotal roles in regulating glucose homeostasis, stimulating glucose-dependent insulin secretion, and promoting satiety. Considering its proven efficacy in glucoregulation and weight loss, GLP-1 receptor agonists (GLP-1RAs) have emerged as a revolutionary breakthrough in the arena of diabetes management and weight control. Additional gastrointestinal hormones, such as glucose-dependent insulinotropic peptide (GIP) and glucagon, exhibit structural similarities to GLP-1 and work synergistically to lower blood glucose levels or aid in weight loss. Today, various classes of gut hormone receptor multiple agonists are steadily progressing through development and clinical trials, including dual GLP-1/glucagon receptor agonists (first discovered in 2009), dual GLP-1/GIP receptor agonists (first described in 2013), and triple GLP-1/GIP/glucagon receptor agonists (initially designed in 2015). The GLP-1/GIP receptor co-agonist, tirzepatide, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of T2DM, outperforming basal insulin or selective GLP-1RAs by providing superior HbA1c reductions. Remarkably, tirzepatide also facilitated unprecedented weight loss of up to 22.5% in non-diabetic individuals living with obesity. This result is comparable to those achieved with certain types of bariatric surgery. Therefore, the advent of gut hormone multi-agonists signifies the dawn of an exciting new era in peptide-based therapy for obesity and T2DM. This review offers a comprehensive summary of the various types of gut hormone multiple agonists, including their discovery, development, action of mechanisms, and clinical effectiveness. We further delve into potential hurdles, limitations, and prospective advancements in the field. [ABSTRACT FROM AUTHOR]
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- 2024
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17. Relationship Between Osteoporosis and Serum Sclerostin Levels in Kidney Transplant Recipients.
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Basir, Hasan, Altunoren, Orcun, Erken, Ertugrul, Kilinc, Metin, Sarisik, Feyza Nur, Isiktas, Songul, and Gungor, Ozkan
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- 2024
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18. Reduced incretin receptor trafficking upon activation enhances glycemic control and reverses obesity in diet-induced obese mice.
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Bauri, Rathin, Bele, Shilpak, Edelli, Jhansi, Reddy, Neelesh C., Kurukuti, Sreenivasulu, Devasia, Tom, Ibrahim, Ahamed, Rai, Vishal, and Mitra, Prasenjit
- Subjects
GLYCEMIC control ,INSULIN ,GLUCAGON-like peptide-1 receptor ,N-terminal residues ,INSULIN receptors ,PEPTIDES ,OBESITY ,INSULIN derivatives - Abstract
Activation of incretin receptors by their cognate agonist augments sustained cAMP generation both from the plasma membrane as well as from the endosome. To address the functional outcome of this spatiotemporal signaling, we developed a nonacylated glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor dual agonist I-M-150847 that reduced receptor internalization following activation of the incretin receptors. The incretin receptor dual agonist I-M-150847 was developed by replacing the tryptophan cage of exendin-4 tyrosine substituted at the amino terminus with the C-terminal undecapeptide sequence of oxyntomodulin that placed lysine 30 of I-M-150847 in frame with the corresponding lysine residue of GIP. The peptide I-M-150847 is a partial agonist of GLP-1R and GIPR; however, the receptors, upon activation by I-M-150847, undergo reduced internalization that promotes agonist-mediated iterative cAMP signaling and augments glucose-stimulated insulin exocytosis in pancreatic β cells. Chronic administration of I-M-150847 improved glycemic control, enhanced insulin sensitivity, and provided profound weight loss in diet-induced obese (DIO) mice. Our results demonstrated that despite being a partial agonist, I-M-150847, by reducing the receptor internalization upon activation, enhanced the incretin effect and reversed obesity. NEW & NOTEWORTHY: Replacement of the tryptophan cage (Trp-cage) with the C-terminal oxyntomodulin undecapeptide along with the tyrosine substitution at the amino terminus converts the selective glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 to a novel GLP-1R and GIPR dual agonist I-M-150847. Reduced internalization of incretin receptors upon activation by the GLP-1R and GIPR dual agonist I-M-150847 promotes iterative receptor signaling that enhances the incretin effect and reverses obesity. [ABSTRACT FROM AUTHOR]
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- 2024
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19. Cardiac Safety Research Consortium: can the thorough QT/QTc study be replaced by early QT assessment in routine clinical pharmacology studies? Scientific update and a research proposal for a path forward.
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Darpo B, Garnett C, Benson CT, Keirns J, Leishman D, Malik M, Mehrotra N, Prasad K, Riley S, Rodriguez I, Sager P, Sarapa N, and Wallis R
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- Anti-Arrhythmia Agents pharmacokinetics, Anti-Arrhythmia Agents pharmacology, Arrhythmias, Cardiac chemically induced, Arrhythmias, Cardiac diagnosis, Drug Evaluation, Preclinical standards, Humans, Long QT Syndrome prevention & control, Patch-Clamp Techniques, Research Design, Anti-Arrhythmia Agents therapeutic use, Drug Evaluation, Preclinical methods, Electrocardiography, Heart Conduction System drug effects, Long QT Syndrome diagnosis
- Abstract
The International Conference on Harmonization E14 guidance for the clinical evaluation of QT/QTc interval prolongation requires almost all new drugs to undergo a dedicated clinical study, primarily in healthy volunteers, the so-called TQT study. Since 2005, when the E14 guidance was implemented in United States and Europe, close to 400 TQT studies have been conducted. In February 2012, the Cardiac Safety Research Consortium held a think tank meeting at Food and Drug Administration's White Oak campus to discuss whether "QT assessment" can be performed as part of routine phase 1 studies. Based on these discussions, a group of experts convened to discuss how to improve the confidence in QT data from early clinical studies, for example, the First-Time-in-Human trial, through collection of serial electrocardiograms and pharmacokinetic samples and the use of exposure response analysis. Recommendations are given on how to design such "early electrocardiogram assessment," and the limitation of not having a pharmacologic-positive control in these studies is discussed. A research path is identified toward collecting evidence to replace or provide an alternative to the dedicated TQT study., (Copyright © 2014 Mosby, Inc. All rights reserved.)
- Published
- 2014
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20. Mathematical model formulation and validation of water and solute transport in whole hamster pancreatic islets.
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Benson JD, Benson CT, and Critser JK
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- Animals, Cricetinae, Mesocricetus, Osmosis, Video Recording, Biological Transport physiology, Cryopreservation methods, Cryoprotective Agents pharmacology, Islets of Langerhans physiology, Models, Biological, Water physiology
- Abstract
Optimization of cryopreservation protocols for cells and tissues requires accurate models of heat and mass transport. Model selection often depends on the configuration of the tissue. Here, a mathematical and conceptual model of water and solute transport for whole hamster pancreatic islets has been developed and experimentally validated incorporating fundamental biophysical data from previous studies on individual hamster islet cells while retaining whole-islet structural information. It describes coupled transport of water and solutes through the islet by three methods: intracellularly, intercellularly, and in combination. In particular we use domain decomposition techniques to couple a transmembrane flux model with an interstitial mass transfer model. The only significant undetermined variable is the cellular surface area which is in contact with the intercellularly transported solutes, Ais. The model was validated and Ais determined using a 3×3 factorial experimental design blocked for experimental day. Whole islet physical experiments were compared with model predictions at three temperatures, three perfusing solutions, and three islet size groups. A mean of 4.4 islets were compared at each of the 27 experimental conditions and found to correlate with a coefficient of determination of 0.87±0.06 (mean ± SD). Only the treatment variable of perfusing solution was found to be significant (p<0.05). We have devised a model that retains much of the intrinsic geometric configuration of the system, and thus fewer laboratory experiments are needed to determine model parameters and thus to develop new optimized cryopreservation protocols. Additionally, extensions to ovarian follicles and other concentric tissue structures may be made., (Copyright © 2014 Elsevier Inc. All rights reserved.)
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- 2014
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21. Pharmacological Advances in Incretin-Based Polyagonism: What We Know and What We Don't.
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Novikoff, Aaron and Müller, Timo D.
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GLUCAGON-like peptide-1 receptor ,GLUCAGON-like peptide-1 agonists ,TYPE 2 diabetes ,GLUCOSE metabolism ,ENERGY metabolism - Abstract
The prevalence of obesity continues to rise in both adolescents and adults, in parallel obesity is strongly associated with the increased incidence of type 2 diabetes, heart failure, certain types of cancer, and all-cause mortality. In relation to obesity, many pharmacological approaches of the past have tried and failed to combat the rising obesity epidemic, particularly due to insufficient efficacy or unacceptable side effects. However, while the history of antiobesity medication is plagued by failures and disappointments, we have witnessed over the last 10 years substantial progress, particularly in regard to biochemically optimized agonists at the receptor for glucagon-like peptide-1 (GLP-1R) and unimolecular coagonists at the receptors for GLP-1 and the glucose-dependent insulinotropic polypeptide (GIP). Although the GIP receptor:GLP-1R coagonists are being heralded as premier pharmacological tools for the treatment of obesity and diabetes, uncertainty remains as to why these drugs testify superiority over best-in-class GLP-1R monoagonists. Particularly with regard to GIP, there remains great uncertainty if and how GIP acts on systems metabolism and if the GIP system should be activated or inhibited to improve metabolic outcome in adjunct to GLP-1R agonism. In this review, we summarize recent advances in GLP-1- and GIP-based pharmacology and discuss recent findings and open questions related to how the GIP system affects systemic energy and glucose metabolism. [ABSTRACT FROM AUTHOR]
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- 2024
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22. The antiemetic actions of GIP receptor agonism.
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Borner, Tito, De Jonghe, Bart C., and Hayes, Matthew R.
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GASTRIC inhibitory polypeptide ,ANTIEMETICS ,TERMINATION of treatment ,GLUCAGON-like peptide-1 receptor ,REGULATION of body weight ,VOMITING - Abstract
Nausea and vomiting are primitive aspects of mammalian physiology and behavior that ensure survival. Unfortunately, both are ubiquitously present side effects of drug treatments for many chronic diseases with negative consequences on pharmacotherapy tolerance, quality of life, and prognosis. One of the most critical clinical examples is the profound emesis and nausea that occur in patients undergoing chemotherapy, which continue to be among the most distressing side effects, even with the use of modern antiemetic medications. Similarly, antiobesity/diabetes medications that target the glucagon-like peptide-1 system, despite their remarkable metabolic success, also cause nausea and vomiting in a significant number of patients. These side effects hinder the ability to administer higher dosages for optimal glycemic and weight management and represent the major reasons for treatment discontinuation. Our inability to effectively control these side effects highlights the need to anatomically, molecularly, and functionally characterize novel neural substrates that drive and inhibit nausea and emesis. Here, we discuss clinical and preclinical evidence that highlights the glucose-dependent insulinotropic peptide receptor system as a novel therapeutic central target for the management of nausea and emesis. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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23. Teriparatide has no effect on the calcium-mediated pharmacodynamics of digoxin.
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Benson CT and Voelker JR
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- Adult, Cardiotonic Agents metabolism, Cardiotonic Agents pharmacology, Cross-Over Studies, Digoxin metabolism, Digoxin pharmacology, Double-Blind Method, Female, Humans, Injections, Subcutaneous, Male, Middle Aged, Reference Values, Teriparatide administration & dosage, Time Factors, Blood Pressure drug effects, Calcium Channels drug effects, Cardiotonic Agents pharmacokinetics, Digoxin pharmacokinetics, Heart Rate drug effects, Teriparatide pharmacology
- Abstract
Background: Teriparatide (recombinant human parathyroid hormone [1-34]) stimulates bone formation and causes small transient increases in serum calcium concentration. We assessed whether teriparatide causes a change in digoxin pharmacodynamic effects by measuring systolic time intervals and heart rate., Methods: Measurements were made by echocardiographic Doppler that examined 3 systolic time intervals, as follows: QS(2) (time from Q wave on electrocardiogram to the closure of the aortic valve), left ventricular ejection time, and pre-ejection period, all corrected for changes in heart rate. Fifteen healthy subjects (2 men and 13 women) were administered a single subcutaneous teriparatide dose (20 microg) on day 1 and then equilibrated on a daily oral dose of digoxin for 15 days. Subcutaneous placebo and teriparatide, 20 microg, were given in a randomized crossover design with the 14th (day 15) and 15th (day 16) digoxin doses. Serial systolic time interval and heart rate measurements were obtained on days 1, 15, and 16., Results: After subjects were dosed to steady state with digoxin, there were statistically significant reductions in QS(2) corrected for heart rate (QS(2)c) of 23 to 25 ms and heart rate of 4 to 6 beats/min. However, there was no difference between treatment with digoxin plus placebo versus digoxin plus teriparatide. The study was powered to find a difference in QS(2)c as small as 6 ms (alpha =.05, beta =.2)., Conclusion: Teriparatide, 20 microg subcutaneously, does not alter the cardiac effect of digoxin.
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- 2003
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24. Hydraulic conductivity (Lp) and its activation energy (Ea), cryoprotectant agent permeability (Ps) and its Ea, and reflection coefficients (sigma) for golden hamster individual pancreatic islet cell membranes.
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Benson CT, Liu C, Gao DY, Critser ES, Benson JD, and Critser JK
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- Animals, Biophysical Phenomena, Biophysics, Cricetinae, Cryopreservation, Dimethyl Sulfoxide pharmacokinetics, Ethylene Glycol pharmacokinetics, Humans, In Vitro Techniques, Islets of Langerhans Transplantation, Mesocricetus, Thermodynamics, Water metabolism, Cell Membrane Permeability, Cryoprotective Agents pharmacokinetics, Islets of Langerhans metabolism
- Abstract
Long-term cryopreservation of islets of Langerhans would be advantageous to a clinical islet transplantation program. Fundamental cryobiology utilizes knowledge of basic biophysical characteristics to increase the understanding of the preservation process and possibly increase survival rate. In this study several of these previously unreported characteristics have been determined for individual islet cells isolated from Golden hamster islets. Using an electronic particle counting device and a temperature control apparatus, dynamic volumetric response of individual islet cells to anisosmotic challenges of 1.5 M dimethyl sulfoxide (DMSO) and 1.5 M ethylene glycol (EG) were recorded at four temperatures (8, 22, 28, and 37 degreesC). The resulting curves were fitted using Kedem and Katchalsky equations which describe water flux and cryoprotectant agent (CPA) flux based on hydraulic conductivity (Lp), CPA permeability (Ps), and reflection coefficient (final sigma) for the membrane. For Golden hamster islet cells, Lp, Ps, and final sigma for DMSO at 22 degreesC were found to be 0.23 +/- 0.06 microm/min/atm, 0.79 +/- 0.32 x 10(-3) cm/min, and 0.55 +/- 0.37 (n = 11) (mean +/- SD), respectively. For EG at 22 degreesC, Lp equaled 0.23 +/- 0.06 microm/min/atm, Ps equaled 0.63 +/- 0.20 x 10(-3) cm/min, and final sigma was 0.75 +/- 0.17 (n = 9). Arrhenius plots (ln Lp or ln Ps versus 1/temperature (K)) were created by adding the data from the other three temperatures and the resulting linear regression yielded correlation coefficients (r) of 0.99 for all four plots (Lp and Ps for both CPAs). Activation energies (Ea) of Lp and Ps were calculated from the slopes of the regressions. The values for DMSO were found to be 12.43 and 18.34 kcal/mol for Lp and Ps (four temperatures, total n = 52), respectively. For EG, Ea of Lp was 11.69 kcal/mol and Ea of Ps was 20.35 kcal/mol (four temperatures, total n = 58)., (Copyright 1998 Academic Press.)
- Published
- 1998
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25. Development of a novel microperfusion chamber for determination of cell membrane transport properties.
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Gao DY, Benson CT, Liu C, McGrath JJ, Critser ES, and Critser JK
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- Animals, Biological Transport, Active drug effects, Biophysical Phenomena, Biophysics, Cell Membrane drug effects, Cell Membrane Permeability drug effects, Cell Size, Cricetinae, Dimethyl Sulfoxide pharmacology, Evaluation Studies as Topic, Female, In Vitro Techniques, Islets of Langerhans cytology, Islets of Langerhans drug effects, Islets of Langerhans metabolism, Kinetics, Mesocricetus, Mice, Mice, Inbred ICR, Oocytes cytology, Oocytes drug effects, Oocytes metabolism, Thermodynamics, Water metabolism, Cell Membrane metabolism, Perfusion instrumentation
- Abstract
A novel microperfusion chamber was developed to measure kinetic cell volume changes under various extracellular conditions and to quantitatively determine cell membrane transport properties. This device eliminates modeling ambiguities and limitations inherent in the use of the microdiffusion chamber and the micropipette perfusion technique, both of which have been previously validated and are closely related optical technologies using light microscopy and image analysis. The resultant simplicity should prove to be especially valuable for study of the coupled transport of water and permeating solutes through cell membranes. Using the microperfusion chamber, water and dimethylsulfoxide (DMSO) permeability coefficients of mouse oocytes as well as the water permeability coefficient of golden hamster pancreatic islet cells were determined. In these experiments, the individual cells were held in the chamber and perfused at 22 degrees C with hyperosmotic media, with or without DMSO (1.5 M). The cell volume change was videotaped and quantified by image analysis. Based on the experimental data and irreversible thermodynamics theory for the coupled mass transfer across the cell membrane, the water permeability coefficient of the oocytes was determined to be 0.47 micron. min-1. atm-1 in the absence of DMSO and 0.65 microns. min-1. atm-1 in the presence of DMSO. The DMSO permeability coefficient of the oocyte membrane and associated membrane reflection coefficient to DMSO were determined to be 0.23 and 0.85 micron/s, respectively. These values are consistent with those determined using the micropipette perfusion and microdiffusion chamber techniques. The water permeability coefficient of the golden hamster pancreatic islet cells was determined to be 0.27 microns. min-1. atm-1, which agrees well with a value previously determined using an electronic sizing (Coulter counter) technique. The use of the microperfusion chamber has the following major advantages: 1) This method allows the extracellular condition(s) to be readily changed by perfusing a single cell or group of cells with a prepared medium (cells can be reperfused with a different medium to study the response of the same cell to different osmotic conditions). 2) The short mixing time of cells and perfusion medium allows for accurate control of the extracellular osmolality and ensures accuracy of the corresponding mathematical formulation (modeling). 3) This technique has wide applicability in studying the cell osmotic response and in determining cell membrane transport properties.
- Published
- 1996
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26. Water permeability and its activation energy for individual hamster pancreatic islet cells.
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Liu C, Benson CT, Gao D, Haag BW, McGann LE, and Critser JK
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- Animals, Cell Size, Cricetinae, Evaluation Studies as Topic, In Vitro Techniques, Mesocricetus, Osmosis, Pancreas cytology, Permeability, Thermodynamics, Water metabolism, Cryopreservation methods, Islets of Langerhans cytology, Islets of Langerhans metabolism
- Abstract
Coupled with the rapid development of clinical pancreatic islet transplantation, there is an increasing requirement for cryopreservation of viable islets. Fundamental cryobiology requires determination of several cryobiophysical parameters to predict optimal cryopreservation procedures. These include water permeability or hydraulic conductivity (Lp) and its activation energy (Ea), the permeability of the cell plasma membrane to a cryoprotectant(s) (Ps) and its Ea, the osmotically inactive fraction of cell volume (Vb), and the intracellular ice formation temperature. For islet cells, these parameters have not previously been reported. In the present studies, the Lp, its Ea, and Vb were determined for isolated individual golden hamster pancreatic islet cells. The Lp and Vb parameters were also measured for corresponding exocrine cells. Both islet and the exocrine cells appeared to be ideal osmometers over the experimental range when examined by the Boyle Van't-Hoff relationship (linear regression, r = 0.99 for both types of cells). Extrapolation of these plots generated Vb values of 0.40 for the islet cells and 0.45 for the pancreatic exocrine cells. To determine the Lp, kinetic changes of cell volume over time (dv/dt) in response to anisoosmotic conditions (ranging from 145 mOsm/kg to 1.35 Osm/kg) were measured using an electronic particle counter. The experimental data were fitted to generate the Lp values by least-squares curve fitting to a differential equation describing osmotic water movement across the plasma membrane. For pancreatic islet cells, the Lp was determined to be 0.25 +/- 0.03 microns/min/atm (mean +/- SD, n = 14) at 22 degrees C, 0.54 +/- 0.07 (n = 10), 0.06 +/- 0.008 (n = 9), and 0.01 +/- 0.001 (n = 9) at 37, 8 and 0 degrees C, respectively. The Ea for Lp was calculated from the slope of the Arrhenius plot based upon the mean Lp values at the four different temperatures. The Ea was 16.21 Kcal/mol between 0 and 37 degrees C. Based upon these values, an optimal cooling rate for cryopreserving pancreatic islet cells is predicted to be approximately 0.5 degrees C min. The Lp for the individual exocrine cells was determined to be 3.73 +/- 1.75 microns/min/atm (n = 13) at 22 degrees C, which was approximately 10 times the Lp value of the corresponding islet cells.
- Published
- 1995
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27. High water permeability of human spermatozoa is mercury-resistant and not mediated by CHIP28.
- Author
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Liu C, Gao D, Preston GM, McGann LE, Benson CT, Critser ES, and Critser JK
- Subjects
- Aquaporin 1, Blood Group Antigens, Blotting, Western, Erythrocytes drug effects, Humans, Male, Spermatozoa drug effects, Spermatozoa ultrastructure, Aquaporins, Cell Membrane Permeability drug effects, Ion Channels physiology, Mercuric Chloride pharmacology, Spermatozoa physiology, Water metabolism
- Abstract
A novel integral membrane protein with an apparent molecular mass of 28 kDa (CHIP28) was first isolated from human erythrocytes and is now recognized as a water channel protein. The expression of this protein has been found in several other cell types that all require high water permeability for their functions. Recent studies have shown that the water permeability (Lp) of human spermatozoa is among the highest reported for mammalian cells. Together with the low activation energy of human spermatozoa for Lp, this suggests that CHIP28 water channel may be present in the plasma membrane of human spermatozoa. However, our current studies do not support this hypothesis. Results from Western blot analysis on human sperm plasma membrane proteins, performed through use of an antibody against human erythrocyte CHIP28 protein, indicated that human spermatozoa do not express CHIP28 protein on their cell surface (n = 10). Consistent with the Western blot finding, mercuric chloride (HgCl2), a known water channel blocker, failed to reduce the osmotic water permeability of human spermatozoa. The calculated Lp values were 1.30 +/- 0.29 micron/min/atm (n = 16; mean +/- SEM) for the control group and 1.31 +/- 0.29 (n = 9; mean +/- SEM), 1.04 +/- 0.27 (n = 11; mean +/- SEM), and 1.34 +/- 0.19 (n = 6; mean +/- SEM), respectively, for the 10 microM, 30 microM, and 50 microM HgCl2-treated groups. These Lp values are not different (p > 0.05). In contrast, the same concentration of HgCl2 significantly blocked the osmotic water transport across the membrane of human erythrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1995
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28. Membrane transport properties of mammalian oocytes: a micropipette perfusion technique.
- Author
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Gao DY, McGrath JJ, Tao J, Benson CT, Critser ES, and Critser JK
- Subjects
- Animals, Biological Transport, Cell Membrane metabolism, Equipment and Supplies, Female, Image Processing, Computer-Assisted, Mathematics, Mice, Mice, Inbred ICR, Models, Biological, Oocytes cytology, Perfusion, Video Recording, Oocytes metabolism
- Abstract
A perfusion technique using micropipette methodology was developed to determine quantitatively the membrane transport properties of mammalian oocytes. This method eliminates modelling ambiguities inherent in microdiffusion, a closely related technology, and should prove to be especially valuable for study of the coupled transport of water and cryoprotectant through mammalian oocytes and embryos. The method is described and evidence given for validity of the method for the simple case of uncoupled flow of water through the mouse oocyte membrane. The zona pellucida of a mouse oocyte was held by a micropipette with an 8-10 microns diameter tip opening and perfused by hyperosmotic media. The kinetic volume change of the cell was videotaped and quantified by image analysis. Experimental data and mathematical modelling were used to determine the hydraulic conductivity of the oocyte membrane (Lp) found to be 1.05, 0.45 and 0.26 microns min-1 atm-1 at 30 degrees C, 22 degrees C and 12 degrees C, respectively. The corresponding activation energy, Ea, for Lp was calculated to be 13.0 kcal mol-1. These values are in agreement with data obtained by other techniques. One of the major advantages of this technique is that the extracellular osmotic condition can be changed readily by perfusing a single cell with a prepared medium. To study the response of the same cell to different osmotic conditions, the old perfusion medium can be removed easily and the cell reperfused with a different medium.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1994
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29. Variation of water permeability (Lp) and its activation energy (Ea) among unfertilized golden hamster and ICR murine oocytes.
- Author
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Benson CT and Critser JK
- Subjects
- Analysis of Variance, Animals, Cell Membrane Permeability, Cricetinae, Cryopreservation, Female, In Vitro Techniques, Mesocricetus, Mice, Mice, Inbred ICR, Thermodynamics, Oocytes metabolism, Water metabolism
- Abstract
Oocytes provide an excellent model cell type for the exploration of the hypothesis that there is a genetic influence to inter-animal variability in plasma membrane water permeability (Lp) and its activation energy (Ea). Although variability among oocytes pooled across animals has been previously published, variability of oocyte Lp and its Ea among individual animals has yet to be determined. Using a microdiffusion chamber, individual oocytes from five Golden hamsters and six ICR mice were exposed to a 900-mOsm NaCl solution at 37, 22, or 3 degrees C. The resulting change in cell volume over time (dv/dt) was analyzed and hydraulic conductivity (Lp) estimated. The Arrhenius plots (lnLp vs (1/K) x 1000) of the oocytes from each animal were determined and the Ea's were found not to be different among individual Golden hamsters (P > 0.05) with a mean of 7.96 +/- 0.96 Kcal/mol (mean +/- SD). However, the Ea's of the oocytes among individual ICR mice were shown to be significantly different (P < 0.05), with a mean of 11.38 +/- 2.2 Kcal/mol (mean +/- SD). Furthermore, an analysis of the within-mouse and among-mouse variability of Lp was undertaken. The results demonstrated that there was significant variability among ICR mouse oocyte Lp values at all temperatures; however, there was no significant variability within animals. In summary, these data support the hypothesis that significant variability exists in the Lp of ova among mice of the outbred ICR strain. In contrast, the data from the inbred Golden hamster oocyte donors do not show significant variability.
- Published
- 1994
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- View/download PDF
30. Determination of the osmotic characteristics of hamster pancreatic islets and isolated pancreatic islet cells.
- Author
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Benson CT, Liu C, Gao DY, Critser ES, and Critser JK
- Subjects
- Animals, Body Water metabolism, Cell Size, Cricetinae, Cryopreservation methods, Diffusion, Islets of Langerhans drug effects, Islets of Langerhans metabolism, Osmosis, Sodium Chloride pharmacology, Islets of Langerhans cytology, Mesocricetus anatomy & histology
- Abstract
The ability to store pancreatic islets using cryopreservation methodology would greatly assist the application of clinical islet transplantation to Type 1 (insulin-dependent) diabetics. It is our working thesis that the illumination of fundamental biophysical characteristics of these cells will lead to increased cryosurvival rates through theoretically predicted and experimental testing of optimal freezing protocol; as has been found for cells and tissues such as mammalian and Drosophila embryos. Pancreatic islets were isolated from Golden hamsters and their osmometric behavior, including inactive cell volume (Vb), was determined for either whole islets or isolated individual islet cells. When islets or islet cells were exposed to various concentrations of NaCl, they were found to exhibit a "classic" "Boyle-Van't Hoff" osmometric response. The Boyle-Van't Hoff representation of the volume curve (relative cell volume vs. 1/osmolality) yields a linear response with r values of .99 for each curve. Extrapolations to the normalized osmotically inactive volumes (Vb) were .43 and .22 for whole islets and individual islet cells, respectively. These data regarding the fundamental cryobiological characteristics of islets and islet cells should provide the foundation upon which to further the investigation of osmotic parameters of these cells and eventually lead to the determination of optimal freezing protocols.
- Published
- 1993
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31. Population pharmacokinetics of the GIP/GLP receptor agonist tirzepatide.
- Author
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Schneck, Karen and Urva, Shweta
- Subjects
GLUCAGON-like peptide-1 receptor ,TYPE 2 diabetes ,GLUCAGON-like peptide-1 agonists ,PHARMACOKINETICS ,ALLOMETRY ,PEPTIDE receptors ,BODY size ,GLUCAGON receptors - Abstract
Tirzepatide is a first‐in‐class glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1 receptor agonist approved as for the treatment of type 2 diabetes mellitus. A population‐based pharmacokinetic (PK) model was developed from 19 pooled studies. Tirzepatide pharmacokinetics were well‐described by a two‐compartment model with first order absorption and elimination. The tirzepatide population PK model utilized a semimechanistic allometry model to describe the relationship between body size and tirzepatide PK. The half‐life of tirzepatide was ~5 days and enabled sustained exposure with once‐weekly subcutaneous dosing. The covariate analysis suggested that adjustment of the dose regimen based on demographics or subpopulations was unnecessary. The tirzepatide PK model can be used to predict tirzepatide exposure for various scenarios or populations. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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- View/download PDF
32. Reduction of prevalence of patients meeting the criteria for metabolic syndrome with tirzepatide: a post hoc analysis from the SURPASS Clinical Trial Program.
- Author
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Nicholls, Stephen J., Tofé, Santiago, le Roux, Carel W., D'Alessio, David A., Wiese, Russell J., Pavo, Imre, Brown, Katelyn, Weerakkody, Govinda J., Zeytinoglu, Meltem, and Romera, Irene C.
- Subjects
METABOLIC syndrome ,WEIGHT loss ,DYSLIPIDEMIA ,CARDIOVASCULAR diseases risk factors ,CLINICAL trials ,INSULIN resistance - Abstract
Background: Metabolic syndrome is characterized as the co-occurrence of interrelated cardiovascular risk factors, including insulin resistance, hyperinsulinemia, abdominal obesity, dyslipidemia and hypertension. Once weekly tirzepatide is approved in the US and EU for the treatment of type 2 diabetes (T2D) and obesity. In the SURPASS clinical trial program for T2D, tirzepatide demonstrated greater improvements in glycemic control, body weight reduction and other cardiometabolic risk factors versus placebo, subcutaneous semaglutide 1 mg, insulin degludec, and insulin glargine. This post hoc analysis assessed the effect of tirzepatide use on the prevalence of patients meeting the criteria for metabolic syndrome across SURPASS 1–5. Methods: Metabolic syndrome was defined as having ≥ 3 of 5 criteria according to the US National Cholesterol Education Program: Adult Treatment Panel III. Analyses were based on on-treatment data at the primary endpoint from patients adherent to treatment (taking ≥ 75% study drug). A logistic regression model with metabolic syndrome status as the response variable, metabolic syndrome status at the baseline visit as an adjustment, and randomized treatment as fixed explanatory effect was used. The effect of tirzepatide use on the prevalence of patients meeting the criteria for metabolic syndrome by categorical weight loss, background medication and gender were assessed. Results: In SURPASS, the prevalence of patients meeting the criteria for metabolic syndrome at baseline was 67–88% across treatment groups with reductions at the primary endpoint to 38–64% with tirzepatide versus 64–82% with comparators. Reductions in the prevalence of patients meeting the criteria for metabolic syndrome was significantly greater with all tirzepatide doses versus placebo, semaglutide 1 mg, insulin glargine, and insulin degludec (p < 0.001). Individual components of metabolic syndrome were also reduced to a greater extent with tirzepatide vs comparators. Greater reductions in body weight were associated with greater reductions in the prevalence of patients meeting the criteria for metabolic syndrome and its individual components. Background SGLT2i or sulfonylurea use or gender did not impact the change in prevalence of patients meeting the criteria for metabolic syndrome. Conclusions: In this post hoc analysis, tirzepatide at all doses studied was associated with a greater reduction in the prevalence of patients meeting the criteria for metabolic syndrome compared to placebo, semaglutide 1 mg, insulin degludec, and insulin glargine. Although more evidence is needed, these data would support greater potential improvement in cardiovascular risk factor profile with tirzepatide treatment in people across the continuum of T2D. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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- View/download PDF
33. The Body weight Reducing Effects of Tirzepatide in People with and without Type 2 Diabetes: A Review on Efficacy and Adverse Effects.
- Author
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Jensen, Thomas Leth, Brønden, Andreas, Karstoft, Kristian, Sonne, David Peick, and Christensen, Mikkel Bring
- Subjects
WEIGHT loss ,TYPE 2 diabetes ,BODY weight ,POSTOPERATIVE nausea & vomiting ,GLYCEMIC control ,GLYCOSYLATED hemoglobin - Abstract
Obesity is becoming more frequent and has several negative health impacts. Recent advances in weight management strategies have primarily resided in pharmaceutical treatments, and the glucagon-like peptide-1 (GLP-1) receptor agonists have shown great potential in terms of body weight reduction in addition to improving glycemic control in patients with type 2 diabetes (T2D). Recently, the dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide has been developed. Tirzepatide has shown strong effects on glycated hemoglobin (HbA1
C ) levels in several clinical trials including participants with T2D (SURPASS program). In addition to its lowering effect on HbA1C , tirzepatide leads to substantial reductions in body weight, and a series of clinical trials (SURMOUNT program) have investigated the effects on body weight as the primary outcome. In these two trial programs, tirzepatide in doses of 5 mg to 15 mg administered subcutaneously once weekly resulted in body weight reduction of up to 15% in participants with T2D and up to 21% in participants without T2D, despite comparable baseline bodyweight. Across the two trial programs, adverse effects were mainly gastrointestinal (nausea, diarrhea, and vomiting) occurring with similar incidences of vomiting and lower incidences of diarrhea and nausea in trial participants with T2D compared to trials participants without T2D. Overall, discontinuation due to adverse events occurred in 3– 7% of participants with no major differences between individuals with and without T2D. The higher weight-reducing efficacy of tirzepatide in trial participants without T2D is currently unexplained and may be partly reflected in dissimilarities in frequencies of gastrointestinal adverse events. The weight reducing effects of tirzepatide hold great promise for weight management in obese patients regardless of the presence of T2D. [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF
34. Safety, pharmacokinetics, and target engagement of a brain penetrant RIPK1 inhibitor, SAR443820 (DNL788), in healthy adult participants.
- Author
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Hincelin‐Mery, Agnes, Nicolas, Xavier, Cantalloube, Cathy, Pomponio, Robert, Lewanczyk, Pascale, Benamor, Myriam, Ofengeim, Dimitry, Krupka, Emmanuel, Hsiao‐Nakamoto, Jennifer, Eastenson, Amy, and Atassi, Nazem
- Subjects
AMYOTROPHIC lateral sclerosis ,PHARMACOKINETICS ,CEREBROSPINAL fluid examination ,TERMINATION of treatment ,PROTEIN kinases ,MULTIPLE sclerosis - Abstract
SAR443820 (DNL788) is a selective, orally bioavailable, brain penetrant inhibitor of receptor‐interacting serine/threonine protein kinase 1 (RIPK1). This phase I first‐in‐human healthy participant study (NCT05795907) was comprised of three parts: randomized, double‐blind, placebo‐controlled single ascending dose (SAD; part 1a); 14‐day multiple ascending dose (MAD; part 2) parts that evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of SAR443820; and a separate open‐label, single‐dose part 1b (PK‐cerebrospinal fluid [CSF]) to assess SAR443820 levels in CSF. SAR443820 was well‐tolerated in healthy participants, and no treatment discontinuation related to an adverse event (AE) occurred. Most common AEs were dizziness and headache. No clinically meaningful changes were noted in laboratory values, vital signs, or electrocardiogram parameters. SAR443820 had a favorable PK profile, with plasma half‐lives (geometric mean) ranged between 5.7–8.0 h and 7.2–8.9 h after single and repeated doses, respectively. There were no major deviations from dose proportionality for maximum concentration and area under the curve across SAR443820 doses. Mean CSF‐to‐unbound plasma concentration ratio ranged from 0.8 to 1.3 over time (assessed up to 10 h postdose), indicating high brain penetrance. High levels of inhibition of activated RIPK1, as measured by decrease in pS166‐RIPK1, were achieved in both SAD and MAD parts, with a maximum median inhibition from baseline close to 90% at predose (Ctrough) after multiple dosing in MAD, reflecting a marked RIPK1 target engagement at the peripheral level. These results support further development of SAR443820 in phase II trials in amyotrophic lateral sclerosis (NCT05237284) and multiple sclerosis (NCT05630547). [ABSTRACT FROM AUTHOR]
- Published
- 2024
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- View/download PDF
35. Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets.
- Author
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Folli, Franco, Finzi, Giovanna, Manfrini, Roberto, Galli, Alessandra, Casiraghi, Francesca, Centofanti, Lucia, Berra, Cesare, Fiorina, Paolo, Davalli, Alberto, Rosa, Stefano La, Perego, Carla, and Higgins, Paul B.
- Subjects
GASTRIC inhibitory polypeptide ,ISLANDS of Langerhans ,GLUCAGON-like peptide-1 receptor ,GLUCAGON receptors ,PEPTIDE receptors ,G protein coupled receptors - Abstract
Simultaneous activation of the incretin G-protein-coupled receptors (GPCRs) via unimolecular dual-receptor agonists (UDRA) has emerged as a new therapeutic approach for type 2 diabetes. Recent studies also advocate triple agonism with molecules also capable of binding the glucagon receptor. In this scoping review, we discuss the cellular mechanisms of action (MOA) underlying the actions of these novel and therapeutically important classes of peptide receptor agonists. Clinical efficacy studies of several UDRAs have demonstrated favorable results both as monotherapies and when combined with approved hypoglycemics. Although the additive insulinotropic effects of dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic peptide receptor (GIPR) agonism were anticipated based on the known actions of either glucagon-like peptide-1 (GLP-1) or glucose-dependent insulinotropic peptide (GIP) alone, the additional benefits from GCGR were largely unexpected. Whether additional synergistic or antagonistic interactions among these G-protein receptor signaling pathways arise from simultaneous stimulation is not known. The signaling pathways affected by dual- and tri-agonism require more trenchant investigation before a comprehensive understanding of the cellular MOA. This knowledge will be essential for understanding the chronic efficacy and safety of these treatments. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
36. "The Future Ain't What It Used to Be": Anesthesia Research, Practice, and Management in 2050.
- Author
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Pandit, Jaideep J.
- Published
- 2024
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37. A potential therapeutic drug for osteoporosis: prospect for osteogenic LncRNAs.
- Author
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Fanjin Meng, Yang Yu, Ye Tian, Meng Deng, Kaiyuan Zheng, Xiaolan Guo, Beilei Zeng, Jingjia Li, Airong Qian, and Chong Yin
- Subjects
MICRORNA ,BONE growth ,GENOME editing ,LINCRNA - Abstract
Long non-coding RNAs (LncRNAs) play essential roles in multiple physiological processes including bone formation. Investigators have revealed that LncRNAs regulated bone formation through various signaling pathways and micro RNAs (miRNAs). However, several problems exist in current research studies on osteogenic LncRNAs, including sophisticated techniques, high cost for in vivo experiment, as well as low homology of LncRNAs between animal model and human, which hindered translational medicine research. Moreover, compared with gene editing, LncRNAs would only lead to inhibition of target genes rather than completely knocking them out. As the studies on osteogenic LncRNA gradually proceed, some of these problems have turned osteogenic LncRNA research studies into slump. This review described some new techniques and innovative ideas to address these problems. Although investigations on osteogenic LncRNAs still have obtacles to overcome, LncRNA will work as a promising therapeutic drug for osteoporosis in the near future. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
38. Sclerostin small-molecule inhibitors promote osteogenesis by activating canonical Wnt and BMP pathways.
- Author
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Sangadala, Sreedhara, Chi Heon Kim, Fernandes, Lorenzo M., Makkar, Pooja, Beck, George R., Boden, Scott D., Drissi, Hicham, and Presciutti, Steven M.
- Published
- 2023
- Full Text
- View/download PDF
39. Development of consensus-driven SPIRIT and CONSORT extensions for early phase dose-finding trials: the DEFINE study.
- Author
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Solovyeva, Olga, Dimairo, Munyaradzi, Weir, Christopher J., Hee, Siew Wan, Espinasse, Aude, Ursino, Moreno, Patel, Dhrusti, Kightley, Andrew, Hughes, Sarah, Jaki, Thomas, Mander, Adrian, Evans, Thomas R. Jeffry, Lee, Shing, Hopewell, Sally, Rantell, Khadija Rerhou, Chan, An-Wen, Bedding, Alun, Stephens, Richard, Richards, Dawn, and Roberts, Lesley
- Subjects
CRIME & the press ,GREY literature ,THEMATIC analysis ,MEDICAL protocols ,QUANTITATIVE research - Abstract
Background: Early phase dose-finding (EPDF) trials are crucial for the development of a new intervention and influence whether it should be investigated in further trials. Guidance exists for clinical trial protocols and completed trial reports in the SPIRIT and CONSORT guidelines, respectively. However, both guidelines and their extensions do not adequately address the characteristics of EPDF trials. Building on the SPIRIT and CONSORT checklists, the DEFINE study aims to develop international consensus-driven guidelines for EPDF trial protocols (SPIRIT-DEFINE) and reports (CONSORT-DEFINE). Methods: The initial generation of candidate items was informed by reviewing published EPDF trial reports. The early draft items were refined further through a review of the published and grey literature, analysis of real-world examples, citation and reference searches, and expert recommendations, followed by a two-round modified Delphi process. Patient and public involvement and engagement (PPIE) was pursued concurrently with the quantitative and thematic analysis of Delphi participants' feedback. Results: The Delphi survey included 79 new or modified SPIRIT-DEFINE (n = 36) and CONSORT-DEFINE (n = 43) extension candidate items. In Round One, 206 interdisciplinary stakeholders from 24 countries voted and 151 stakeholders voted in Round Two. Following Round One feedback, one item for CONSORT-DEFINE was added in Round Two. Of the 80 items, 60 met the threshold for inclusion (≥ 70% of respondents voted critical: 26 SPIRIT-DEFINE, 34 CONSORT-DEFINE), with the remaining 20 items to be further discussed at the consensus meeting. The parallel PPIE work resulted in the development of an EPDF lay summary toolkit consisting of a template with guidance notes and an exemplar. Conclusions: By detailing the development journey of the DEFINE study and the decisions undertaken, we envision that this will enhance understanding and help researchers in the development of future guidelines. The SPIRIT-DEFINE and CONSORT-DEFINE guidelines will allow investigators to effectively address essential items that should be present in EPDF trial protocols and reports, thereby promoting transparency, comprehensiveness, and reproducibility. Trial registration: SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network (https://www.equator-network.org/). [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
40. Molecular changes in skeletal muscle in chronic kidney disease: A systematic review.
- Author
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Wong, Limy, Kenny, Rachel, Howard, Jennifer, and McMahon, Lawrence P.
- Published
- 2023
- Full Text
- View/download PDF
41. Concentration-QTcF Modeling of Icenticaftor from a Randomized, Placebo- and Positive-Controlled Thorough QT Study in Healthy Participants.
- Author
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Iyer GR, Darpo B, Xue H, Lecot J, Zack J, Bebrevska L, Weis W, Jones I, and Drollmann A
- Subjects
- Adult, Humans, Male, Middle Aged, Young Adult, Administration, Oral, Dose-Response Relationship, Drug, Double-Blind Method, Heart Rate drug effects, Long QT Syndrome chemically induced, Models, Biological, Cross-Over Studies, Electrocardiography drug effects, Healthy Volunteers, Moxifloxacin administration & dosage, Moxifloxacin adverse effects
- Abstract
Icenticaftor (QBW251) is a potentiator of the cystic fibrosis transmembrane receptor. Based on its mechanism of action, icenticaftor is expected to provide benefits in patients with chronic obstructive pulmonary disease by restoring mucociliary clearance, which would eventually lead to a reduction of bacterial colonization and related inflammatory cascade. A placebo- and positive-controlled, 4-way crossover thorough QT study was conducted in 46 healthy participants with the objective to assess the effect of therapeutic (300 mg twice daily for 6 days) and supratherapeutic (750 mg twice daily for 6 days) oral doses of icenticaftor on electrocardiogram parameters, including concentration-corrected QT (QTc) analysis. Moxifloxacin (400 mg, oral) was used as a positive control. In the concentration-QTc analysis performed on pooled data from Day 1 and Day 6 (steady state), the estimated population slope was shallow and slightly negative: -0.0012 ms/ng/mL. The effect on the Fridericia corrected QT (QTcF) interval (∆ΔQTcF) was predicted to be -1.3 milliseconds at the icenticaftor 300-mg twice-daily peak concentration (geometric mean was 1094 ng/mL) and -5.5 milliseconds at the 750-mg twice-daily peak concentration (geometric mean C
max was 4529 ng/mL) indicated a mild shortening effect of icenticaftor on QTcF interval length. The results of the by-time-point analysis indicated least squares placebo corrected mean ∆∆QTcF across time points ranged from -7.9 to 0.1 milliseconds at 1 and 24 hours after dosing both on Day 6 in the 750-mg dose group compared with -3.7 to 1.6 milliseconds at 1.5 and 24 hours after dosing on Day 1 in the 300-mg dose group. Assay sensitivity was demonstrated with moxifloxacin. The large accumulation of exposures, especially the 4.3-fold increase in peak plasma concentration observed at the icenticaftor 750-mg twice-daily dosage compared with Icenticaftor 300 mg twice daily (2.3-fold) on Day 6 provided a large concentration range (up to 9540 ng/mL) to evaluate the effect of icenticaftor on ΔΔQTcF. Based on the concentration-QTc analysis, an effect on ΔΔQTcF exceeding 10 milliseconds can be excluded within the full observed ranges of plasma concentrations on icenticaftor, up to approximately 9540 ng/mL. Icenticaftor at the studied doses demonstrated a mild shortening in QTcF, which is unlikely to be of clinical relevance in a therapeutic setting., (© 2024 Novartis Pharmaceuticals. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)- Published
- 2024
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42. Advances in sarcopenia: mechanisms, therapeutic targets, and intervention strategies.
- Author
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Zheng Y, Feng J, Yu Y, Ling M, and Wang X
- Subjects
- Humans, Animals, Muscle, Skeletal drug effects, Muscle, Skeletal metabolism, Myostatin antagonists & inhibitors, Myostatin metabolism, Drug Development methods, Sarcopenia drug therapy, Sarcopenia metabolism, Sarcopenia therapy
- Abstract
Sarcopenia is a multifactorial condition characterized by loss of muscle mass. It poses significant health risks in older adults worldwide. Both pharmacological and non-pharmacological approaches are reported to address this disease. Certain dietary patterns, such as adequate energy intake and essential amino acids, have shown positive outcomes in preserving muscle function. Various medications, including myostatin inhibitors, growth hormones, and activin type II receptor inhibitors, have been evaluated for their effectiveness in managing sarcopenia. However, it is important to consider the variable efficacy and potential side effects associated with these treatments. There are currently no drugs approved by the Food and Drug Administration for sarcopenia. The ongoing research aims to develop more effective strategies in the future. Our review of research on disease mechanisms and drug development will be a valuable contribution to future research endeavors., (© 2024. The Pharmaceutical Society of Korea.)
- Published
- 2024
- Full Text
- View/download PDF
43. Mathematical Modeling and Optimization of Cryopreservation in Single Cells.
- Author
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Benson JD
- Subjects
- Algorithms, Animals, Computer Simulation, Humans, Cryopreservation methods, Cryopreservation standards, Cryoprotective Agents pharmacology, Freeze Drying methods, Models, Theoretical, Single-Cell Analysis methods
- Abstract
Cryobiology is a multiscale and interdisciplinary field. The scope and scale of interactions limit the gains that can be made by one theory or experiment alone. Because of this, modeling has played a critical role in both explaining cryobiological phenomena and predicting improved protocols. Modeling facilitates understanding of the biophysical and some of the biochemical mechanisms of damage during all phases of cryopreservation including CPA equilibration and cooling and warming. Moreover, as a tool for optimization of cryopreservation protocols, modeling has yielded many successes. Modern cryobiological modeling includes very detailed descriptions of the physical phenomena that occur during freezing, including ice growth kinetics and spatial gradients that define heat and mass transport models. Here we reduce the complexity and approach only a small but classic subset of these problems. Namely, here we describe the process of building and using a mathematical model of a cell in suspension where spatial homogeneity is assumed for all quantities. We define the models that describe the critical cell quantities used to describe optimal and suboptimal protocols and then give an overview of classical methods of how to determine optimal protocols using these models. We include practical considerations of modeling in cryobiology, including fitting transport models to cell volume data, performing optimization with cell volume constraints, and a look at expanding cost functions to cooling regimes.
- Published
- 2021
- Full Text
- View/download PDF
44. Medikamentöse Therapie der Adipositas – Konkurrenz zur bariatrischen Chirurgie oder sinnvolle Ergänzung?
- Author
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Mazaheri, Tina, Ansari, Saleem, Nallagonda, Madhavi, Kollmann, Lars, Nickel, Felix, Seyfried, Florian, and Miras, Alexander Dimitri
- Abstract
Copyright of Chirurgie (2731-6971) is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2023
- Full Text
- View/download PDF
45. Novel insights on the effect of sclerostin on bone and other organs.
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Dreyer, Timothy J., Keen, Jacob A. C., Wells, Leah M., and Roberts, Scott J.
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SCLEROSTIN ,CHRONIC kidney failure ,BONE remodeling ,BONE growth ,BONE diseases - Abstract
As a key regulator of bone homeostasis, sclerostin has garnered a lot of interest over the last two decades. Although sclerostin is primarily expressed by osteocytes and is well known for its role in bone formation and remodelling, it is also expressed by a number of other cells and potentially plays a role in other organs. Herein, we aim to bring together recent sclerostin research and discuss the effect of sclerostin on bone, cartilage, muscle, liver, kidney and the cardiovascular and immune systems. Particular focus is placed on its role in diseases, such as osteoporosis and myeloma bone disease, and the novel development of sclerostin as a therapeutic target. Anti-sclerostin antibodies have recently been approved for the treatment of osteoporosis. However, a cardiovascular signal was observed, prompting extensive research into the role of sclerostin in vascular and bone tissue crosstalk. The study of sclerostin expression in chronic kidney disease was followed by the investigation of its role in liver–lipid– bone interactions, and the recent discovery of sclerostin as a myokine prompted new research into sclerostin within the bone–muscle relationship. Potentially, the effects of sclerostin reach beyond that of bone alone. We further summarise recent developments in the use of sclerostin as a potential therapeutic for osteoarthritis, osteosarcoma and sclerosteosis. Overall, these new treatments and discoveries illustrate progress within the field, however, also highlight remaining gaps in our knowledge. [ABSTRACT FROM AUTHOR]
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- 2023
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46. Crosstalk between bone and muscle in chronic kidney disease.
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Wong, Limy and McMahon, Lawrence P.
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CHRONIC kidney failure ,MUSCLE metabolism ,MUSCULOSKELETAL system ,ENDOCRINE system ,EXERCISE therapy ,BONE metabolism - Abstract
With increasing life expectancy, the related disorders of bone loss, metabolic dysregulation and sarcopenia have become major health threats to the elderly. Each of these conditions is prevalent in patients with chronic kidney disease (CKD), particularly in more advanced stages. Our current understanding of the bone-muscle interaction is beyond mechanical coupling, where bone and muscle have been identified as interrelated secretory organs, and regulation of both bone and muscle metabolism occurs through osteokines and myokines via autocrine, paracrine and endocrine systems. This review appraises the current knowledge regarding biochemical crosstalk between bone and muscle, and considers recent progress related to the role of osteokines and myokines in CKD, including modulatory effects of physical exercise and potential therapeutic targets to improve musculoskeletal health in CKD patients. [ABSTRACT FROM AUTHOR]
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- 2023
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47. Multiple doses of SHR-1222, a sclerostin monoclonal antibody, in postmenopausal women with osteoporosis: A randomized, double-blind, placebocontrolled, dose-escalation phase 1 trial.
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Zhijie Dai, Ronghua Zhu, Zhifeng Sheng, Guijun Qin, Xianghang Luo, Qun Qin, Chunli Song, Liping Li, Ping Jin, Guoping Yang, Yanxiang Cheng, Danhong Peng, Chong Zou, Lijuan Wang, Jianzhong Shentu, Qin Zhang, Zhe Zhang, Xiang Yan, Pingfei Fang, and Qiangyong Yan
- Subjects
TERIPARATIDE ,OSTEOPOROSIS in women ,SCLEROSTIN ,MONOCLONAL antibodies ,POSTMENOPAUSE ,BONE growth - Abstract
SHR-1222, a novel humanized monoclonal antibody targeting sclerostin, has been shown to induce bone formation and decrease bone resorption at a single dose ranging 50-400 mg in our previous phase 1 trial. This study was a randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial, which further investigated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of multiple ascending doses of SHR-1222 in women with postmenopausal osteoporosis (POP). A total of 105 women with POP were enrolled and randomly assigned. Twenty-one received placebo and eighty-four received SHR-1222 sequentially (100 mg QM, n=4; 200 or 300 mg QM, n=20; and 400 or 600 mg Q2M, n=20). The most common adverse events included increased blood parathyroid hormone, increased low-density lipoprotein, increased blood alkaline phosphatase, increased blood cholesterol, back pain, and arthralgia, the majority of which were mild in severity without noticeable safety concerns. Serum SHR-1222 exposure (C
max,ss and AUC0-tau,ss ) increased in a greater than dose-proportional manner. Following multiple doses of SHR-1222, the bone formation markers (terminal propeptide of type I procollagen, bonespecific alkaline phosphatase, and osteocalcin) increased in a dosedependent manner, whereas the bone resorption marker (b-C-telopeptide) was downregulated. Accordingly, BMD gains in the lumbar spine, total hip, and femoral neck were observed. The maximum BMD increase from baseline at the lumbar spine was detected in the 300 mg QM cohort (14.6% vs. 0.6% in the placebo group on day 169). Six (6/83; 7.2%) subjects developed anti-SHR- 1222 antibodies with no discernible effects on PKs, PDs, and safety. Thus, multiple doses of SHR-1222 showed an acceptable safety profile and dosedependent plasma exposure in women with POP, and could improve their BMD rapidly and prominently by promoting bone formation and inhibiting bone resorption. These findings further support SHR-1222 as a potential alternative agent for the treatment of POP. [ABSTRACT FROM AUTHOR]- Published
- 2023
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48. Cardiovascular effects of incretins: focus on glucagon-like peptide-1 receptor agonists.
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Madsbad, Sten and Holst, Jens J
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GLUCAGON-like peptide-1 receptor ,GLUCAGON-like peptide-1 agonists ,WEIGHT loss ,DIABETIC nephropathies ,CARDIOVASCULAR diseases risk factors - Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been used to treat patients with type 2 diabetes since 2005 and have become popular because of the efficacy and durability in relation to glycaemic control in combination with weight loss in most patients. Today in 2022, seven GLP-1 RAs, including oral semaglutide are available for treatment of type 2 diabetes. Since the efficacy in relation to reduction of HbA1c and body weight as well as tolerability and dosing frequency vary between agents, the GLP-1 RAs cannot be considered equal. The short acting lixisenatide showed no cardiovascular benefits, while once daily liraglutide and the weekly agonists, subcutaneous semaglutide, dulaglutide, and efpeglenatide, all lowered the incidence of cardiovascular events. Liraglutide, oral semaglutide and exenatide once weekly also reduced mortality. GLP-1 RAs reduce the progression of diabetic kidney disease. In the 2019 consensus report from European Association for the Study of Diabetes/American Diabetes Association, GLP-1 RAs with demonstrated cardio-renal benefits (liraglutide, semaglutide and dulaglutide) are recommended after metformin to patients with established cardiovascular diseases or multiple cardiovascular risk factors. European Society of Cardiology suggests starting with a sodium-glucose cotransprter-2 inhibitor or a GLP-1 RA in drug naïve patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (CVD) or high CV Risk. However, the results from cardiovascular outcome trials (CVOT) are very heterogeneous suggesting that some GLP-1RAs are more suitable to prevent CVD than others. The CVOTs provide a basis upon which individual treatment decisions for patients with T2D and CVD can be made. [ABSTRACT FROM AUTHOR]
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- 2023
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49. Efficacy and Safety of Tirzepatide in Adults With Type 2 Diabetes: A Perspective for Primary Care Providers.
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Kushner, Pamela, Anderson, John E., Simon, Jörg, Boye, Kristina S., Ranta, Kari, Torcello-Gómez, Amelia, and Levine, Joshua A.
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DRUG efficacy ,GLYCOSYLATED hemoglobin ,GLUCAGON-like peptide 1 ,HYPOGLYCEMIC agents ,PHYSICIANS' attitudes ,CELL receptors ,TYPE 2 diabetes ,SOCIOECONOMIC factors ,TREATMENT effectiveness ,RESEARCH funding ,PATIENT safety ,PEPTIDES ,PHARMACODYNAMICS ,ADULTS - Abstract
This article reviews the efficacy and safety data of tirzepatide, a once-weekly, novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 (GLP-1) receptor agonist approved in the United States, the European Union, and other regions for the treatment of type 2 diabetes. All doses of tirzepatide demonstrated superiority in reducing A1C and body weight from baseline versus placebo or active comparators. The safety profile of tirzepatide was consistent with that of the GLP-1 receptor agonist class, with mild to moderate and transient gastrointestinal side effects being the most common adverse events. With clinically and statistically significant reductions in A1C and body weight without increased risk of hypoglycemia in various populations, tirzepatide has demonstrated potential as a first-in-class treatment option for many people with type 2 diabetes. [ABSTRACT FROM AUTHOR]
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- 2023
- Full Text
- View/download PDF
50. Η επίδραση των νεότερων αντιδιαβητικών παραγόντων στην μη αλκοολική λιπώδης νόσος του ήπατος
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Εμινίδου, Βαλέρια and Παπαζαφειροπούλου, Αθανασία
- Abstract
Copyright of Scientific Chronicles / Epistimonika Chronika is the property of Tzaneio General Hospital and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2023
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