DOCSLIB.ORG

Pharmacokinetics, Safety, and Tolerability of Saroglitazar (ZYH1), a Predominantly Ppara Agonist with Moderate Pparc Agonist Activity in Healthy Human Subjects

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Pharmacokinetics, Safety, and Tolerability of Saroglitazar (ZYH1), a Predominantly Ppara Agonist with Moderate Pparc Agonist Activity in Healthy Human Subjects Clin Drug Investig DOI 10.1007/s40261-013-0128-3 ORIGINAL RESEARCH ARTICLE Pharmacokinetics, Safety, and Tolerability of Saroglitazar (ZYH1), a Predominantly PPARa Agonist with Moderate PPARc Agonist Activity in Healthy Human Subjects Rajendra H. Jani • Kevinkumar Kansagra • Mukul R. Jain • Harilal Patel Ó The Author(s) 2013. This article is published with open access at Springerlink.com Abstract subjects (8 males from part I of the study and 8 females) in Background and Objectives Dyslipidaemia is a major part II. cardiovascular risk factor associated with type 2 diabetes Results Saroglitazar was rapidly and well absorbed across mellitus. Saroglitazar (ZYH1) is a novel peroxisome pro- all doses in the single-dose pharmacokinetic study, with a liferator-activated receptor (PPAR) agonist with predomi- median time to the peak plasma concentration (tmax) of less nant PPARa and moderate PPARc activity. It has been than 1 h (range 0.63–1 h) under fasting conditions across developed for the treatment of dyslipidaemia and has the doses studied. The maximum plasma concentration favourable effects on glycaemic parameters in type 2 dia- ranged from 3.98 to 7,461 ng/mL across the dose range. betes mellitus. The objective of this phase 1 study was to The area under the plasma concentration–time curve evaluate the pharmacokinetics, safety and tolerability of increased in a dose-related manner. The average terminal saroglitazar in healthy human subjects. half-life of saroglitazar was 5.6 h. Saroglitazar was not Methods This was a randomized, double-blind, placebo- eliminated via the renal route. There was no effect of sex controlled, single-centre, phase I study in healthy human on the pharmacokinetics of saroglitazar, except for the volunteers, and was performed in two parts; part I evalu- terminal half-life, which was significantly shorter in ated single ascending oral doses of saroglitazar (0.125, females than in males. Food had a small effect on the 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64 and 128 mg) in healthy pharmacokinetics; however, it was not consistent in males subjects, and part II measured the effects of food and sex and females. Single oral doses of saroglitazar up to 128 mg on the pharmacokinetics of 1 mg saroglitazar, the human were well tolerated. No serious adverse events were equivalent efficacy dose derived from pre-clinical studies. reported. Adverse events were generally mild and moderate A total of 96 subjects were enrolled in the study, which in nature. Saroglitazar did not show any clinically relevant included 88 healthy male subjects in part I and 16 healthy findings in clinical laboratory investigations, physical examinations, vital signs and electrocardiograms. Conclusion The highest dose of saroglitazar evaluated in R. H. Jani (&) Á K. Kansagra this study was 128 mg, several times the estimated thera- Clinical R&D, Zydus Research Centre, Cadila Healthcare peutic doses (1–4 mg). The pharmacokinetics of saroglit- Limited, Sarkhej-Bavla N.H. No. 8A, Moriya, Ahmedabad 382 213, Gujarat, India azar support a once daily dosage schedule. Saroglitazar was e-mail: [email protected] found to be safe and well tolerated in this study. M. R. Jain Pharmacology & Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H. No. 8A, Moriya, 1 Introduction Ahmedabad 382 213, Gujarat, India Cardiovascular disease is the most common underlying H. Patel cause of death, accounting for about 50 % of mortality in Drug Metabolism & Pharmacokinetics, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H. No. 8A, Moriya, type 2 diabetes mellitus (T2DM) [1, 2]. The results of the Ahmedabad 382 213, Gujarat, India ACCORD (Action to Control Cardiovascular risk in R. H. Jani et al. Diabetes) and ADVANCE (Action in Diabetes and Vascular 2 Methods Disease; Preterax and Diamicron Modified Release Con- trolled Evaluation) studies showed that intensive glycaemic The study was conducted (from 16 June 2005 to control reduced microvascular complications (new or 29 November 2005) in accordance with accepted standards worsening nephropathy or retinopathy) but not macrovas- for the protection of subject safety and welfare, and the cular complications (cardiovascular death, nonfatal myo- principles of the Declaration of Helsinki and its amend- cardial infarction or nonfatal stroke) [3, 4]. Diabetic ments, and was in compliance with Good Clinical Practice. dyslipidaemia is characterized by elevation of serum tri- The study was initiated after obtaining approval from the glyceride (TG) levels ([150 mg/dL), reduced high-density Drug Controller General of India (DCGI; no. 12-05/05- lipoprotein (HDL) cholesterol levels (\40 mg/dL in males DC, dated 27 May 2005) and an independent ethics com- and\50 mg/dL in females) and normal or elevated levels of mittee (IEC), Aditya, Ahmedabad, Gujarat, India. low-density lipoprotein (LDL) cholesterol ([100 mg/dL) [5, 6]. Low levels of serum HDL cholesterol have been corre- 2.1 Study Design lated with cardiovascular disease [7–9], and identification of agents that elevate HDL cholesterol in diabetic patients is an This was a randomized, double-blind, placebo-controlled, area of active interest. The American Diabetes Association single-centre study to evaluate the pharmacokinetics, safety (ADA) recommends control of diabetic dyslipidaemia. It has and tolerability of single ascending oral doses of saroglit- been well established that dyslipidaemia is a major cardio- azar under fasting conditions in healthy subjects. In addi- vascular risk factor associated with T2DM [7]. tion, the effects of food and sex on the pharmacokinetics of The potential of peroxisome proliferator-activated saroglitazar were also studied. receptor (PPAR) agonists to reduce the risk of cardiovas- Eligible healthy subjects (aged 18–45 years, weighing cular disease in T2DM patients has remained an area of 50–70 kg) with normal medical history, physical exami- continuous medical interest. PPARa and PPARc agonists nation, electrocardiogram (ECG) and clinical laboratory are approved for lipid and glycaemic control, respectively findings were enrolled. Eligible healthy female subjects [10, 11]. Numerous dual PPAR agonists have been devel- were enrolled if they had undergone surgical sterilization oped for management of both glycaemic and lipid abnor- (tubectomy, hysterectomy or tubal ligation). The subjects malities in T2DM. However, none of these agents has so had not received any medications within 14 days prior to far been successful [11, 12]. Saroglitazar, [(S)-a-ethoxy-4- the current study and had not participated in any study {2-[2-methyl-5-(4-methylthio) phenyl)]-1H-pyrrol-1-yl]- within 3 months prior to the current study. ethoxy})-benzenepropanoic acid magnesium salt], is the In each cohort, eight subjects were randomized to first glitazar that has been granted marketing authorization receive either saroglitazar or a matching placebo (3:1) by a in India and is indicated for treatment of diabetic dyslip- computer-generated block randomization (SAS Ver- idaemia. Saroglitazar is a dual PPAR agonist with pre- sion 9.1, SAS Institute Inc., Cary, NC, USA). Subjects dominant PPARa and moderate PPARc activity [13]. It were admitted to the clinical pharmacology unit on the was developed with an expectation to achieve optimum evening prior to dosing and were confined until 72 h after anti-dyslipidaemic and anti-hyperglycaemic effects, while the last dose. The study drugs, saroglitazar (0.125–0.5 mg avoiding peripheral oedema and weight gain. The structural oral suspension or 1–128 mg tablets) or the matching formula of saroglitazar is given in Fig. 1. placebo, were administered orally. The purpose of this first-in-humans phase 1 study was to The study was divided into two parts: (i) a single- assess the pharmacokinetics, safety and tolerability of sa- ascending-dose study; and (ii) a study of the effects of food roglitazar in healthy volunteers. and sex. 2.1.1 Part I: Single-Ascending-Dose Study Saroglitazar [versus the matching placebo (3:1)] was studied in 11 cohorts; each cohort comprised eight healthy male subjects. In the first three cohorts, saroglitazar (0.125, 0.25 and 0.5 mg) or the placebo was administered as an oral suspension (0.5 mg/mL). In subsequent cohorts, sa- roglitazar (1, 2, 4, 8, 16, 32, 64 and 128 mg) or a matching placebo tablet was orally administered. Study drugs were administered with 240 mL of water after overnight fasting Fig. 1 Structural formula of saroglitazar for at least 10 h (Fig. 2). Pharmacokinetics, Safety and Tolerability of Saroglitazar 217 male subjects screened 58 failed screening 88 randomized 71 did not report to the facility N=71,2 N=81 N=81 N=83 N=83 N=83 N=83 N=83 N=83 N=83 N=83 0.125 mg 0.25 mg 0.5 mg 1 mg 2 mg 4 mg 8 mg 16 mg 32 mg 64 mg 128 mg N=73,4 20 female subjects screened, 8 randomized 1 mg 14 eligible 5 N=75,6 Crossover food effect study N=8 1 mg 1 mg 1. Saroglitazar suspension in fasting condition. 2. N=8 randomized but one subject withdrew because of ectopic beats before dosing. 3. Saroglitazar tablet in fasting condition 4. N=8 randomized but one subject withdrew informed consent for period I of the crossover food effect study. 5. Saroglitazar after food intake. 6. One subject did not report to the facility for period II of the crossover food effect study. Fig. 2 Study design and subject disposition. The pharmacokinetics of saroglitazar in male and female subjects were compared at 1 mg doses. In each group, 6 subjects received saroglitazar and 2 received placebo 2.1.2 Part II: Study of the Effects of Food and Sex 2.2 Blood Sampling for Pharmacokinetics The effects of food and sex were studied with the sarog- In part I and part II, venous blood samples (7 mL) were litazar 1 mg tablet.
Load more

Recommended publications
  • Muraglitazar Bristol-Myers Squibb/Merck Daniella Barlocco
    Muraglitazar Bristol-Myers Squibb/Merck Daniella Barlocco Address Originator Bristol-Myers Squibb Co University of Milan . Istituto di Chimica Farmaceutica e Tossicologica Viale Abruzzi 42 Licensee Merck & Co Inc 20131 Milano . Italy Status Pre-registration Email: [email protected] . Indications Metabolic disorder, Non-insulin-dependent Current Opinion in Investigational Drugs 2005 6(4): diabetes © The Thomson Corporation ISSN 1472-4472 . Actions Antihyperlipidemic agent, Hypoglycemic agent, Bristol-Myers Squibb and Merck & Co are co-developing Insulin sensitizer, PPARα agonist, PPARγ agonist muraglitazar, a dual peroxisome proliferator-activated receptor-α/γ . agonist, for the potential treatment of type 2 diabetes and other Synonym BMS-298585 metabolic disorders. In November 2004, approval was anticipated as early as mid-2005. Registry No: 331741-94-7 Introduction [579218], [579221], [579457], [579459]. PPARγ is expressed in Type 2 diabetes is a complex metabolic disorder that is adipose tissue, lower intestine and cells involved in characterized by hyperglycemia, insulin resistance and immunity. Activation of PPARγ regulates glucose and lipid defects in insulin secretion. The disease is associated with homeostasis, and triggers insulin sensitization [579216], older age, obesity, a family history of diabetes and physical [579218], [579458], [579461]. PPARδ is expressed inactivity. The prevalence of type 2 diabetes is increasing ubiquitously and has been found to be effective in rapidly, and the World Health Organization warns that, controlling dyslipidemia and cardiovascular diseases unless appropriate action is taken, the number of sufferers [579216]. PPARα agonists are used as potent hypolipidemic will double to over 350 million individuals by the year compounds, increasing plasma high-density lipoprotein 2030. Worryingly, it is estimated that only half of sufferers (HDL)-cholesterol and reducing free fatty acids, are diagnosed with the condition [www.who.int].
    [Show full text]
  • 7-Azaindoles and Their Use As Ppar Agonists 7-Azaindole Und Ihre Verwendung Als Ppar-Agonisten 7-Azaindoles Et Leur Utilisation Comme Agonistes De Ppar
    (19) TZZ___T (11) EP 1 794 159 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 471/04 (2006.01) A61K 31/437 (2006.01) 01.08.2012 Bulletin 2012/31 A61P 3/10 (2006.01) (21) Application number: 05778246.8 (86) International application number: PCT/EP2005/009269 (22) Date of filing: 27.08.2005 (87) International publication number: WO 2006/029699 (23.03.2006 Gazette 2006/12) (54) 7-AZAINDOLES AND THEIR USE AS PPAR AGONISTS 7-AZAINDOLE UND IHRE VERWENDUNG ALS PPAR-AGONISTEN 7-AZAINDOLES ET LEUR UTILISATION COMME AGONISTES DE PPAR (84) Designated Contracting States: • GLIEN, Maike AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 65195 Wiesbaden (DE) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • SCHAEFER, Hans-Ludwig SK TR 65239 Hochheim (DE) • WENDLER, Wolfgang (30) Priority: 11.09.2004 EP 04021667 65618 Selters (DE) • BERNARDELLI, Patrick (43) Date of publication of application: F-78450 Villepreux (FR) 13.06.2007 Bulletin 2007/24 • TERRIER, Corinne F-93190 Livry Gargan (FR) (73) Proprietor: Sanofi-Aventis Deutschland GmbH • RONAN, Baptiste 65929 Frankfurt am Main (DE) F-92140 Clamart (FR) (72) Inventors: (56) References cited: • KEIL, Stefanie EP-A- 1 445 258 WO-A-2004/074284 65719 Hofheim (DE) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations.
    [Show full text]
  • The Leading Source of Diabetes Business News the Long View Fall
    The Leading Source of Diabetes Business News The Long View Fall 2011 • No. 108 Although change isn’t literally in the air for me – here in San Francisco, we still get a few more weeks of summer – autumn brings some notable shifts in the world of diabetes, and I’m looking forward to hearing all about them in companies’ third-quarter financial updates. Perhaps most importantly, Amylin/Lilly/Alkermes’ Bydureon, the first once-weekly diabetes therapy, has now made its debut in several European countries. That means this earnings’ season will be the first chance to hear how the launch has gone, and we’ll get our first real indicator of what to expect in the quarters to come. Will patients flock to the every-seven-days dosage schedule, forcing rival GLP-1 companies to accelerate development of their own once-weekly products (and encouraging Amylin/Lilly/Alkermes to stay on course with their phase 2 once-monthly exenatide)? Or will factors like needle size, injection simplicity – and even the regularity of daily dosing, considered an advantage by some – give the edge to Victoza? (Novo Nordisk certainly isn’t resting on the success of this soon-to- be-blockbuster, having most recently launched Victoza in the swiftly growing Chinese market – a topic we explore in this issue’s interview with Novo Nordisk’s head of China, Ron Christie.) The global GLP-1 contest was already intensely competitive and has become more so, even before Bydureon’s entry to the US or the arrival of new players (e.g., Sanofi’s Lyxumia).
    [Show full text]
  • S 26948: a New Specific Peroxisome Proliferator–Activated Receptor
    ORIGINAL ARTICLE S 26948: a New Specific Peroxisome Proliferator–Activated Receptor ␥ Modulator With Potent Antidiabetes and Antiatherogenic Effects Maria Carmen Carmona,1 Katie Louche,1 Bruno Lefebvre,2 Antoine Pilon,3 Nathalie Hennuyer,3 Ve´ronique Audinot-Bouchez,4 Catherine Fievet,3 Ge´rard Torpier,3 Pierre Formstecher,2 Pierre Renard,5 Philippe Lefebvre,2 Catherine Dacquet,5 Bart Staels,3 Louis Casteilla,1 and Luc Pe´nicaud1 on behalf of the Consortium of the French Ministry of Research and Technology OBJECTIVE—Rosiglitazone displays powerful antidiabetes benefits but is associated with increased body weight and adipo- genesis. Keeping in mind the concept of selective peroxisome he peroxisome proliferator–activated receptors proliferator–activated receptor (PPAR)␥ modulator, the aim of this (PPARs) (1) are transcription factors belonging study was to characterize the properties of a new PPAR␥ ligand, S to the nuclear receptor transcription factor fam- 26948, with special attention in body-weight gain. Tily (1). Three isoforms, PPAR␣,-␦, and -␥, have RESEARCH DESIGN AND METHODS—We used transient been described to have tissue-specific patterns of expres- transfection and binding assays to characterized the binding sion and function—the latter being highly expressed in characteristics of S 26948 and GST pull-down experiments to adipocytes and macrophages among other cell types (2–5). investigate its pattern of coactivator recruitment compared with The role of PPAR␥ on adipocyte differentiation has been rosiglitazone. We also assessed its adipogenic capacity in vitro extensively studied in vitro and in vivo (2,3,6,7). Forced using the 3T3-F442A cell line and its in vivo effects in ob/ob mice ␥ (for antidiabetes and antiobesity properties), as well as the expression of PPAR in nonadipogenic cells is sufficient to homozygous human apolipoprotein E2 knockin mice (E2-KI) (for induce adipocyte differentiation on treatment with specific antiatherogenic capacity).
    [Show full text]
  • Role of Dual PPAR Gamma and Alpha Agonists in Diabetes Mellitus
    23 Role of Dual PPAR γ and α Agonists in Diabetes Mellitus—Have They Met a Road Block or They Are Dead? Mohd Ashraf Ganie, Abdul Hamid Zargar Abstract: There are three peroxisome proliferator-activated receptors (PPARs) subtypes which are commonly designated PPAR alpha, PPAR gamma and PPAR beta/delta. PPAR alpha activation increases high density lipoprotein (HDL) cholesterol synthesis, stimulates “reverse” cholesterol transport and reduces triglycerides. PPAR gamma activation results in insulin sensitization and antidiabetic action. Combined treatments with PPAR gamma and alpha agonists may potentially improve insulin resistance and alleviate atherogenic dyslipidemia, whereas PPAR delta properties may prevent the development of overweight which typically accompanies “pure” PPAR gamma ligands. The new generation of dual-action PPARs—the glitazars, which target PPAR-gamma and PPAR-alpha (like muraglitazar and tesaglitazar) were on deck in late-stage clinical trials for sometime and were considered effective in reducing cardiovascular risk, but their long-term clinical effects were unknown. Thus glitazars offered a hope of a new approach to diabetes care addressing not just glycemia, but dyslipidemia and other components of the metabolic syndrome, though the side effect profile remains unknown. No human data is available, and so it remains highly speculative. The glitazars and on the newly published results for muraglitazar and tesaglitazar. “The PPAR-alpha is a good target and is being developed to yield more potent drugs that work through PPAR-alpha, and at the same time, improve on the PPAR-gamma. Efforts is on to get the glucose lowering with few of the adverse effects. This thinking has met with problems as many clinical trials have been terminated due to dominant side effects.
    [Show full text]
  • A Role of Peroxisome Proliferator‐Activated Receptor Γ in Non‐Alcoholic Fatty Liver Disease
    A role of peroxisome proliferator-activated receptor gamma in non-alcoholic fatty liver disease Skat-Rordam, Josephine; Ipsen, David Hojland; Lykkesfeldt, Jens; Tveden-Nyborg, Pernille Published in: Basic & Clinical Pharmacology & Toxicology DOI: 10.1111/bcpt.13190 Publication date: 2019 Document version Publisher's PDF, also known as Version of record Document license: CC BY Citation for published version (APA): Skat-Rordam, J., Ipsen, D. H., Lykkesfeldt, J., & Tveden-Nyborg, P. (2019). A role of peroxisome proliferator- activated receptor gamma in non-alcoholic fatty liver disease. Basic & Clinical Pharmacology & Toxicology, 124(5), 528-537. https://doi.org/10.1111/bcpt.13190 Download date: 29. sep.. 2021 Received: 23 October 2018 | Accepted: 2 December 2018 DOI: 10.1111/bcpt.13190 MINIREVIEW A role of peroxisome proliferator‐activated receptor γ in non‐alcoholic fatty liver disease Josephine Skat‐Rørdam | David Højland Ipsen | Jens Lykkesfeldt | Pernille Tveden‐Nyborg Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Abstract Denmark Non‐alcoholic fatty liver disease is becoming a major health burden, as prevalence increases and there are no approved treatment options. Thiazolidinediones target the Correspondence Pernille Tveden‐Nyborg, Experimental nuclear receptor peroxisome proliferator‐activated receptor γ (PPARγ) and have Pharmacology and Toxicology, Faculty of been investigated in several clinical trials for their potential in treating non‐alcoholic Health and Medical Sciences, University fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH). PPARγ has of Copenhagen, Copenhagen, Denmark. Email: [email protected] specialized roles in distinct tissues and cell types, and although the primary function of PPARγ is in adipose tissue, where the highest expression levels are observed, hepatic expression levels of PPARγ are significantly increased in patients with NAFLD.
    [Show full text]
  • George Grunberger, M.D., F.A.C.P., F.A.C.E
    GEORGE GRUNBERGER, M.D., F.A.C.P., F.A.C.E. Chairman, Grunberger Diabetes Institute Clinical Professor, Department of Internal Medicine Clinical Professor, Center for Molecular Medicine & Genetics Wayne State University School of Medicine Professor, Department of Internal Medicine Oakland University William Beaumont School of Medicine Visiting Professor, First Faculty of Medicine Charles University, Prague (Czech Republic) Phone: (248) 335-7740 43494 Woodward Ave, ste 208, Bloomfield Hills, MI 48302 Fax: (248) 338-7979 e-mail: [email protected] EDUCATION 1973 BA degree (Biochemistry), Columbia College, New York, NY 1977 MD degree, New York University School of Medicine, New York, NY TRAINING 1977-1980 Residency, Internal Medicine Case Western Reserve University University Hospitals of Cleveland, Cleveland, Ohio 1980-1983 Fellowship (clinical and basic research), Endocrinology and Metabolism, Diabetes Branch, National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases National Institutes of Health, Bethesda, Maryland FACULTY APPOINTMENTS, Wayne State University, Detroit, Michigan 1986-1992 Associate Professor (tenured), Department of Internal Medicine Associate Professor (tenured), Department of Molecular Biology and Genetics 1992-2002 Professor (tenured), Department of Internal Medicine 1995-1996 Interim Chairman, Department of Internal Medicine 1992-1994 Professor (tenured), Department of Molecular Biology & Genetics 1994-present Professor (tenured), Center for Molecular Medicine & Genetics 1986-present Regular member
    [Show full text]
  • Oral Hypoglycemic Drugs in the Management of Type 2 Diabetes Mellitus: a Review
    Journal of Health, Medicine and Nursing www.iiste.org ISSN 2422-8419 An International Peer-reviewed Journal Vol.44, 2017 Oral Hypoglycemic Drugs in the Management of Type 2 Diabetes Mellitus: A Review Nikesh Mani Shrestha 1* Bang Zhu Meng 2 1.School of Clinical Medicine, Inner Mongolia University for the Nationalities,536 West Huo Lin He Street, Horqin District, Tongliao City, Inner Mongolia, China 2.Affiliated Hospital of Inner Mongolia University for the Nationalities, 1742 Huo Lin He Street, Horqin District, Tongliao City, Inner Mongolia, China Abstract Diabetes mellitus is a chronic, progressive, heterogeneous group of metabolic disorder mainly characterized by hyperglycemia. T2DM results due to insulin resistance or secretory defects of a beta cell or both and gradually progress to a state characterized by complete loss of pancreatic beta cells secretion. 2hour oral glucose tolerance test or HbA1c testing is performed for the screening for diabetes mellitus. In this review, we attempt to outline the basic pharmacological and non-pharmacological principles for the management of T2DM. Keywords: diabetes, clinical management, non-pharmacological management, primary care 1. Introduction Diabetes mellitus is one of the common chronic metabolic diseases which is mainly characterized by hyperglycemia. It is a progressive disease. So, as a disease progresses there is a high chance of developing microvascular and macrovascular complications. Many studies have been conducted to find the effective measure to reduce these complications. Based on the pathology, there are different types of diabetes mellitus. Among them, type 2 diabetes (T2D) is very common accounting for approximately 90% of diabetic cases worldwide. The prevalence rate of T2DM is increasing due to a sedentary lifestyle, increasing obesity and an aging population (Johnson JA et al, 2006).
    [Show full text]
  • 'Made in India': the Saroglitazar Story
    indian heart journal 67 (2015) 23e26 Available online at www.sciencedirect.com ScienceDirect journal homepage: www.elsevier.com/locate/ihj Original Article Observational study to evaluate the safety and efficacy of saroglitazar in Indian diabetic dyslipidemia patients Sadanand R. Shetty a, Soumitra Kumar b, R.P. Mathur c, Kamal H. Sharma d, Ashok D. Jaiswal e,* a Professor & Ex HOD, Department of Medicine, D.Y. Patil University, CMD, Sadanand Healthy Living Center, Mumbai, India b Professor (Cardiology), Department of Medicine, Vivekananda Institute of Medical Sciences, Kolkata, India c Professor & HOD, Department of Endocrinology, Osmania Medical College, Hyderabad, India d Associate Professor, UN Mehta Institute of Cardiology, BJ Medical College, Ahmedabad, India e Zydus Tower, Near Satellite Cross Road, Opposite Iscon Temple, Satellite, Ahmedabad, India article info abstract Article history: Saroglitazar is a dual PPAR a/g agonist approved in India for the management of diabetic Received 22 January 2015 dyslipidemia. Accepted 3 February 2015 Aims: The objective of this study was to evaluate the safety and efficacy of saroglitazar 4 mg Available online 26 February 2015 once daily in clinical practice. Methods: This was an observational, multicenter, single-arm study. Patients with type 2 Keywords: diabetes (with on-going antidiabetic medication), age above 18 years, and triglycerides Saroglitazar 200 mg/dL were included. Diabetic dyslipidemia Results: A total 2804 patients with a mean duration of diabetes 6.29 yrs were included in this Triglycerides analysis. The baseline demographic profile was: mean age of 53 yrs, mean body weight PPAR 72.3 kg and mean BMI of 27 kg/m2. 62.5% patients were male and 57.8% were reported to be on statin therapy at baseline.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9,533,022 B2 Mehta Et Al
    USO09533022B2 (12) United States Patent (10) Patent No.: US 9,533,022 B2 Mehta et al. (45) Date of Patent: *Jan. 3, 2017 (54) PEPTIDE ANALOGS FOR TREATING (56) References Cited DISEASES AND DISORDERS U.S. PATENT DOCUMENTS (71) Applicants: Nozer M. Mehta, Randolph, NJ (US); 4,764,589 A 8, 1988 Orlowski William Stern, Tenafly, NJ (US); Amy 9,006,172 B2 * 4/2015 Mehta .................... A61K 38.23 M. Sturmer, Towaco, NJ (US); Morten 514/1.1 Asser Karsdal, Kobenhavn (DK); Kim 2002/0065255 A1* 5/2002 Bay .................. A61K 47, 183 Henriksen, Hillerod (DK) 514,166 2010/0311650 A1* 12/2010 Mehta .................... CO7K 1400 (72) Inventors: Nozer M. Mehta, Randolph, NJ (US); 514,49 William Stern, Tenafly, NJ (US); Amy M. Sturmer, Towaco, NJ (US); Morten FOREIGN PATENT DOCUMENTS Asser Karsdal, Kobenhavn (DK); Kim Henriksen, Hillerod (DK) WO 2010O85700 A2 T 2010 (73) Assignee: KeyBioscience A/S, Stans (CH) OTHER PUBLICATIONS Lee et al., “Metformin Decreases Food Consumption and Induces (*) Notice: Subject to any disclaimer, the term of this Weight Loss in Subjects with Obesity with Type Il Non-Insulin patent is extended or adjusted under 35 Dependent Diabetes,” Obes. Res. 6:47-53 (1998).* U.S.C. 154(b) by 0 days. Feigh et al., “A novel oral form of Salmon calcitonin improves glucose homeostasis and reduces body weight in diet-induced obese This patent is Subject to a terminal dis rats' Diab. Obesity Metab. 13:911-920 (2011).* claimer. Unigene Laboratories Inc. Unigene Laboratories Inc. Corporate Overview 2010, URL: www.getfillings.com/sec-filings/100325/ (21) Appl.
    [Show full text]
  • 09.Subjectindex ADA 13.Indd
    SUBJECT INDEX (-)-Epigallocatechin-3-gallate 2919-PO Add-on to basal insulin 1102-P Aggressiveness factor 2526-PO 1,5-Anhydroglucitol 928-P Add-on to metformin 1092-P Aging 1284-P, 1396-P, 1399-P, 1797-P, 1966-P, 11 β-HSD 1993-P Add-on to metformin + SU 1082-P 1972-P, 1981-P, 2007-P, 2209-P, 2308-PO, 11beta-HSD, glucocorticosteroids, type 2 diabetes Add-on to pioglitazone 1120-P 2481-PO, 2693-PO, 2697-PO 1128-P Adenine nucleotide translocase 28-OR, 29-OR Aging society 2657-PO 11β-HSD1 1875-P Adenosine A1 receptor 1854-P Agreement 2508-PO SUBJECT INDEX 12(S)-HETE 2057-P Adenovirus, shrna, over expression 340-OR Agrp neurons 1917-P 12/15-Lipoxygenase 2057-P Adherence 652-P, 789-P, 802-P, 814-P, 821-P, 857-P, AICAR 1815-P 12-Lipoxygenase 338-OR 889-P, 894-P, 1227-P, 1259-P, 1423-P, 2504-PO Akita 1643-P 14-3-3 142-OR Adhesive capsulitis 2887-PO Akt 25-OR 18FDG PET 2026-P Adipocyte 100-OR, 1644-P, 1748-P, 1748-P, 1749-P, Akt mediated signaling pathway 2321-PO 18F-TTCO-cys40-exendin-4 2163-P 1751-P, 1752-P, 1755-P, 1756-P, 1758-P, 1761-P, Akt, glucose uptake 1802-P 1-h plasma glucose 1457-P, 2808-PO 1763-P, 1765-P, 1769-P, 1769-P, 2056-P, 2943-PO Akt/GSK3 signaling pathway 488-P 25(OH)D 679-P Adipocyte differentiation 144-OR, 1745-P, 1745-P, Akt2 1818-P 25-hydroxivitamin D 2035-P 2013-P Alanine 1916-P 26S Proteasomes 498-P Adipocyte fatty acid-binding protein 2003-P Alanine aminotransferase 1460-P, 2860-PO 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid Adipocyte precursor cells 2081-P Alaska native people 183-OR 2079-P Adipocytes 94-OR, 95-OR,
    [Show full text]
  • Peroxisome Proliferator-Activated Receptors and Their Novel Ligands As Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease
    cells Review Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease Anne Fougerat 1,*, Alexandra Montagner 1,2,3, Nicolas Loiseau 1 , Hervé Guillou 1 and Walter Wahli 1,4,5,* 1 Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; [email protected] (A.M.); [email protected] (N.L.); [email protected] (H.G.) 2 Institut National de la Santé et de la Recherche Médicale (Inserm), Institute of Metabolic and Cardiovascular Diseases, UMR1048 Toulouse, France 3 Institute of Metabolic and Cardiovascular Diseases, University of Toulouse, UMR1048 Toulouse, France 4 Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Clinical Sciences Building, 11 Mandalay Road, Singapore 308232, Singapore 5 Center for Integrative Genomics, Université de Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland * Correspondence: [email protected] (A.F.); [email protected] (W.W.); Tel.: +33-582066376 (A.F.); +41-79-6016832 (W.W.) Received: 29 May 2020; Accepted: 4 July 2020; Published: 8 July 2020 Abstract: Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD.
    [Show full text]