DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2010/013.6614 A1 Luo Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) Patent Application Publication (10) Pub. No.: US 2010/013.6614 A1 Luo Et Al US 2010O136614A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/013.6614 A1 Luo et al. (43) Pub. Date: Jun. 3, 2010 (54) DENDRIMER-LIKE MODULAR DELIVERY Publication Classification VECTOR (51) Int. Cl. CI2P 2L/00 (2006.01) (76) Inventors: Dan Luo, Ithaca, NY (US); Yougen C08G 83/00 (2006.01) Li, Pasadena, CA (US) (52) U.S. Cl. ...…. 435/68.1: 525/54.2 (57) ABSTRACT Correspondence Address: WILSON, SONSINI, GOODRICH & ROSATI Various nucleic acid-based matrixes are provided, compris 650 PAGE MILL ROAD ing nucleic acid monomers as building blocks, as well as PALO ALTO, CA 94304-1050 (US) nucleic acids encoding proteins, so as to produce novel bio materials. The nucleic acids are used to form dendrimers that are useful as Supports, vectors, carriers or delivery vehicles (21) Appl. No.: 11/583,990 for a variety of compounds in biomedical and biotechnologi cal applications. In particular, the macromolecules may be (22) Filed: Oct. 18, 2006 used for the delivery of drugs, genetic material, imaging components or other functional molecule to which they can Related U.S. Application Data be conjugated. An additional feature of the macromolecules is their ability to be targeted for certain organs, tumors, or types (60) Provisional application No. 60/727.961, filed on Oct. of tissues. Methods of utilizing such biomaterials include 18, 2005. delivery of functional molecules to cells. Patent Application Publication Jun. 3, 2010 Sheet 1 of 13 US 2010/013.6614 A1 Patent Application Publication Jun. 3, 2010 Sheet 2 of 13 US 2010/013.6614 A1 Patent Application Publication Jun. 3, 2010 Sheet 4 of 13 US 2010/013.6614 A1 Patent Application Publication Jun. 3, 2010 Sheet 5 of 13 US 2010/013.6614 A1 Patent Application Publication Jun. 3, 2010 Sheet 6 of 13 US 2010/013.6614 A1 Patent Application Publication Jun. 3, 2010 Sheet 7 of 13 US 2010/013.6614 A1 FIG.7 SECR D NO:96 Patent Application Publication Jun. 3, 2010 Sheet 8 of 13 US 2010/013.6614 A1 FIG. 11 Patent Application Publication Jun. 3, 2010 Sheet 9 of 13 US 2010/013.6614 A1 FIG. 12 FG, 13 Patent Application Publication Jun. 3, 2010 Sheet 10 of 13 US 2010/013.6614 A1 FIG.15. J SEG ID NO:100 SEQD NO:97. P, GTGAGTAGTGA AATTGACTCATGGACTAs #élé SEO D NO:99 SEOQ ID NO:98 ? · DNA FIG. 16 SEO ID NO: 104 *woravovouvogvlowaaoauvoiejewou'257 0LLLLLLLLLSLLLLLLLLLLLLLL SEOQ ID NO: 103 <-R dumbbel-DNA. SEOQ ID NO 102 FIG. 17 SEGQD NO: 1 .....................................3????????????????????”“ **` SEOQ ID NO:3 SEO DI NO:2 ? Patent Application Publication Jun. 3, 2010 Sheet 11 of 13 US 2010/013.6614 A1 Plasmid DNA as CnC , ! Schema of viral and non-viral hybrid system Patent Application Publication Jun. 3, 2010 Sheet 12 of 13 US 2010/013.6614 A1 Patent Application Publication Jun. 3, 2010 Sheet 13 of 13 US 2010/013.6614 A1 FIG. 21. Seberinë , BOTN-spacer-DNA. (Bio-5p-SP). BioTN-spacer-DNA * GGCG---TCSACF-5° Yo-ONA . Step. Bio-5p-CCGG AAC3. tggcor-TTGACT's ... US 2010/013.6614 A1 Jun. 3, 2010 and DNA-mediated supramolecular structures (Taton et al., polynucleotide is complementary to at least a portion of the Journal of the American Chemical Society 122:6305-6306 third polynucleotide, and where the first, second, and third (2000)), DNA sensing via gold nanoparticles (Elghanian et polynucleotides are associated together to form a multimer, al., Science 277:1078-81 (1997)), Y-shape DNA molecules and at least one of the first, second and third polynucleotides (Eckardt et al., Nature 420:286 (2002)) and DNA patterning are linked to at least one bioactive agent. In some embodi via dip-pen nanolithography (Demers et al., Science 296. ments, the multimers are trimers that are Y-shape or T-shape. 1836-8 (2002)). However, the preceding prior art DNA-based In one embodiment, all the trimers are Y-shape. In another structures are are further limited to linear DNA. Linear DNA embodiment, the all the trimers are T-shape. In yet other was first used to construct an artificial nano-structure (Chenet embodiments, the trimers are Y- and T-shape. al., Nature 350,631 (1991)). Using “double crossover DNA (two crossovers connecting two helical domains), a variety of 0012. In other aspects of the invention, a multimer mol geometric objects, periodic arrays and nanoscale mechanical ecule comprises a first, a second, a third and a fourth poly devices have been constructed (Yan et al., Nature 415, 62 nucleotide, where at least a portion of the first polynucleotide (2002):Yan et al., Science 301, 1882 (2003); Seeman, Trends is complementary to at least a portion of the second poly Biochem Sci 30, 119 (2005); Pinto et al., Nano Lett 5, 2399 nucleotides, where at least a portion of the first polynucle (2005)). Recently Lin et al. used a linear DNA molecule as a otide is complementary to at least a portion of the fourth cross-linker to construct a thermal-stimulative polyacryla polynucleotide, where at least a portion of the third poly mide hydrogel, creating a DNA-polymer hybrid hydrogel nucleotide is complementary to at least a portion of second system (Lin et al., J Biomech Eng 126, 104 (2004)). polynucleotide and where at least a porting of the third poly 0009. However, dendrimer-like nucleic acid compositions nucleotide is complementary to at least a portion of the fourth have not been utilized to effect delivery of bioactive agents to polynucleotides, and where at least one of the first, second, cells (either in a targeted or nonspecific manner). Therefore third and fourth polynucleotides are linked to at least one there is a need for new biomaterials that have applications in bioactive agent. In some embodiments, the multimers are diverse areas of biotechnology and medicine, and which pro tetramers that are X-shape or dumbbell shape. For dumbbell vide more effecient modular delivery, sufficient release and shapes, the second polynucleotide comprises at least portions effective cellular/tissue targeting. The present invention pro vides compositions and methods that provide dendrimer-like that are complementary to the first, third and fourth nucle nucleic acid-based products useful in biotechnology and otides. Similarly, the fourth polynucleotide comprises at least medicine as modular delivery vectors for a multitidue of Some portions that are complementary to the first, second and compounds. third polynucleotides. In one embodiment, all the tetramers are X-shape. In another embodiment, the all the tetramers are SUMMARY OF THE INVENTION dumbbell-shape. In yet other embodiments, the tetramers are X- and dumbbell-shape. 0010 Certain aspects of the present invention provide a 0013. In some aspects of the invention also provide a multivalent vector capable of providing a plurality of attach method of making a nucleic acid assembly by associating at ment points for a plurality of the same or distinct bioactive least two mutlimers together. In some embodiments, the mul agents. Such bioactive agents include without limitation, timers so assembled are all of one shape (i.e., Y, T, X- or therapeutics (e.g., drugs, nucleic acids, Small organic mol dumbbell shape). In yet, other embodiments, the multimers so ecules, inorganic molecules), targeting or delivery moieties assembled are of one or more different shape. Such Y, T, X (e.g., signal peptides, nucleic acid condensing peptides, anti or dumbbell-shape molecules are building blocks which form bodies, one or more receptor/ligand or other binding pair an assembled structure. In some embodiments, a multimer members, biotin or nucleic acids), labeling/staining moieties building block comprises at least one polynucleotide having a (e.g., quantum dots, dyes, stains, selection markers), as well Sticky end. In other embodiments, a multimer comprises as Solid Substrates (e.g., agarose beads, magnetic beads, etc.). polynucleotides, each of which comprises a sticky end. Therefore, a key feature of a multivalent vector is that any number of different chemical/biochemical entities can be 0014. In some embodiments, a nucleic acid assembly is linked directly or indirectly to the multivalent vector. Den produced by associating a plurality of multimers together. In drimers as described herein provide a multivalent and/or Some embodiments, such associations produce Dendrimer monodisperse structure that provides multiple sites for addi Like-Nucleic Acid Molecules (DL-NAMs). In yet other tion of one or more molecules of interest, including without embodiments, DL-NAMs comprise at least some linear linker limitation bioactive agents, targeting agents, selection mark nucleic acid molecules. In various embodiments, DL-NAMs ers, antibiotics, detection signals/labels, drugs ora combina are comprised of a single shape or at least two different shape tion thereof. In various embodiments, such vectors can be building block molecules. utilized to deliver one or more bioactive agents to a cell or [0015] In certain embodiments, the DL-NAMs are pro animal. In other embodiments, such Vectors can also be uti duced in a controlled fashion, by adding multimer building lized in diagnostics by targeting specific cells related to dis blocks in Successive rounds to producea highly branched, ease (e.g., pathogens, cancer, etc.). Moreover, such multiva tree-shape DL-NAMs. In some embodiments, DL-NAMs are lent vectors are utilized in vivo as well as in vitro. produced that are either isotropic or anisotropic, providing 0011. In some aspects of the invention a composition com molecules that are linked to various other biochemical/ prises a multimer molecule, including a first, a second, and a chemical entities (e.g., therapeutics, targeting/delivery third polynucleotide, where at least a portion of the first agents, labeling/staining agents, binding pair members, etc.). polynucleotide is complementary to at least a portion of the 0016.
Load more

Recommended publications
  • Sustained Release Tablet Comprising Pramipexole
    (19) & (11) EP 2 172 199 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 07.04.2010 Bulletin 2010/14 A61K 31/428 (2006.01) A61K 9/20 (2006.01) A61K 9/28 (2006.01) (21) Application number: 09178277.1 (22) Date of filing: 25.07.2003 (84) Designated Contracting States: • Lee, Ernest, J. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Kalamazoo, MI 49009 (US) HU IE IT LI LU MC NL PT RO SE SI SK TR • Martino, Alice, C. Kalamazoo, MI 49009 (US) (30) Priority: 25.07.2002 US 398427 P • Noack, Robert, M. 25.07.2002 US 398447 P Grand Rapids, MI 49506 (US) 28.08.2002 US 406609 P • Reo, Joseph, P. 18.06.2003 US 479387 P Kalamazoo, MI 49009 (US) • Skoug, Connie, J. (62) Document number(s) of the earlier application(s) in Portage, MI 49024 (US) accordance with Art. 76 EPC: 03771898.8 / 1 536 791 (74) Representative: Summers, Victoria Clare Pfizer Limited (71) Applicant: Pharmacia Corporation European Patent Department Peapack, NJ 07977 (US) Ramsgate Road Sandwich, Kent CT13 9NJ (GB) (72) Inventors: • Amidon, Gregory, E. Remarks: Portage, MI 49024 (US) This application was filed on 08-12-2009 as a • Ganorkar, Loksidh, D. divisional application to the application mentioned Kalamazoo, MI 49009 (US) under INID code 62. • Heimlich, John, M. Portage, MI 49002 (US) (54) Sustained release tablet comprising pramipexole (57) A sustained - release pharmaceutical composi- hydrophilic polymer and astarch having a tensile strength tion in a form of an orally deliverable tablet comprising of at least about 0.15kNcm -2 at a solid fraction represent- an active pharmaceutical agent having solubility not less ative of the tablet.
    [Show full text]
  • The Activation of the Glucagon-Like Peptide-1 (GLP-1) Receptor by Peptide and Non-Peptide Ligands
    The Activation of the Glucagon-Like Peptide-1 (GLP-1) Receptor by Peptide and Non-Peptide Ligands Clare Louise Wishart Submitted in accordance with the requirements for the degree of Doctor of Philosophy of Science University of Leeds School of Biomedical Sciences Faculty of Biological Sciences September 2013 I Intellectual Property and Publication Statements The candidate confirms that the work submitted is her own and that appropriate credit has been given where reference has been made to the work of others. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. The right of Clare Louise Wishart to be identified as Author of this work has been asserted by her in accordance with the Copyright, Designs and Patents Act 1988. © 2013 The University of Leeds and Clare Louise Wishart. II Acknowledgments Firstly I would like to offer my sincerest thanks and gratitude to my supervisor, Dr. Dan Donnelly, who has been nothing but encouraging and engaging from day one. I have thoroughly enjoyed every moment of working alongside him and learning from his guidance and wisdom. My thanks go to my academic assessor Professor Paul Milner whom I have known for several years, and during my time at the University of Leeds he has offered me invaluable advice and inspiration. Additionally I would like to thank my academic project advisor Dr. Michael Harrison for his friendship, help and advice. I would like to thank Dr. Rosalind Mann and Dr. Elsayed Nasr for welcoming me into the lab as a new PhD student and sharing their experimental techniques with me, these techniques have helped me no end in my time as a research student.
    [Show full text]
  • Human Histamine H2 Receptor, Frozen Cells Product No.: ES-391-AF
    TECHNICAL AequoZen® DATA SHEET Research use only. Not for use in diagnostic procedures. You are authorized to utilize these frozen cell preparations one time only. Any attempt to transfer, re-use, or propagate these cells is expressly unauthorized and a violation of the product terms and conditions of sale. Human Histamine H2 Receptor, Frozen Cells Product No.: ES-391-AF Lot No.: 2562845 Material Provided Cells: 1 x 1 mL frozen aliquot Format: ~10 x 106 cells/mL in Ham’s F12, 10% FBS with 10 % DMSO Product Information Cellular Background: CHO-K1 Parental Frozen Cells (control): A19 (replaced with Cat # ES-000-A2F) Frozen Cells Info: Frozen recombinant, CHO-K1 cells expressing mitochondrially- targeted Aequorin, Gα16 and the human Histamine H2 receptor. DNA Sequence: Identical to coding sequence of GenBank NM_022304.2. Corresponding Protein Sequence: Identical to GenBank NP_071640.1. Storage Conditions: Store in liquid nitrogen (vapor phase) immediately upon receipt, or maximum 15 days at -80°C. AequoZen® is designed for single use only. Do not refreeze. Quality Control ® EC50 for a reference agonist is determined using an AequoScreen assay (Figure 1). Mycoplasma test is performed using MycoAlert® Mycoplasma detection kit. We certify that these results meet our quality release criteria. Amthamine dihydrobromide (EC50): 6.9 nM Mycoplasma: This cell line tested negative for Mycoplasma. TDS-ES-391-AF-04 Page 1 of 5 Recommended Thawing Conditions and Handling of Frozen Cells Carefully follow instructions below to obtain the expected results. Most Frozen cells are intended to be assayed immediately upon thawing. Exceptionally, where specified, some frozen cell products require an overnight incubation in Cell Medium to enable them to perform optimally.
    [Show full text]
  • Type 2 Diabetes Mellitus: a Review of Multi-Target Drugs
    Molecules 2020, 25, 1987 1 of 20 Review Type 2 Diabetes Mellitus: A Review of Multi-Target Drugs Angelica Artasensi, Alessandro Pedretti, Giulio Vistoli and Laura Fumagalli * Dipartimento di Scienze Farmaceutiche, University Degli Studi di Milano, 20133 Milano, Italy; [email protected] (A.A.); [email protected] (A.P.); [email protected] (G.V.) * Correspondence: [email protected]; Tel.: +39-02-5031-9303 Academic Editor: Massimo Bertinaria, Derek J. McPhee Received: 01 April 2020; Accepted: 21 April 2020; Published: 23 April 2020 Abstract: Diabetes Mellitus (DM) is a multi-factorial chronic health condition that affects a large part of population and according to the World Health Organization (WHO) the number of adults living with diabetes is expected to increase. Since type 2 diabetes mellitus (T2DM) is suffered by the majority of diabetic patients (around 90–95%) and often the mono-target therapy fails in managing blood glucose levels and the other comorbidities, this review focuses on the potential drugs acting on multi-targets involved in the treatment of this type of diabetes. In particular, the review considers the main systems directly involved in T2DM or involved in diabetes comorbidities. Agonists acting on incretin, glucagon systems, as well as on peroxisome proliferation activated receptors are considered. Inhibitors which target either aldose reductase and tyrosine phosphatase 1B or sodium glucose transporters 1 and 2 are taken into account. Moreover, with a view at the multi-target approaches for T2DM some phytocomplexes are also discussed. Keywords: diabetes mellitus; type 2 diabetes mellitus; multi-target compounds; multi-target drugs 1.
    [Show full text]
  • List of Approved Ndas for Biological Products That Were Deemed to Be Blas on March 23, 2020
    List of Approved NDAs for Biological Products That Were Deemed to be BLAs on March 23, 2020 On March 23, 2020, an approved application for a biological product under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) was deemed to be a license for the biological product under section 351 of the Public Health Service Act (PHS Act) (see section 7002(e)(4)(A) of the Biologics Price Competition and Innovation Act of 2009). To enhance transparency and facilitate planning for the March 23, 2020, transition date, FDA compiled a preliminary list of approved applications for biological products under the FD&C Act that were listed in FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book) and that would be affected by this transition provision. FDA posted this list on the FDA website in December 2018, and periodically updated this list before the March 23, 2020, transition date. The September 2019 update to this preliminary list added certain administratively closed applications related to approved applications for biological products that were on the December 2018 version of this list. The January 2020 update to the preliminary list reflected a change to the definition of “biological product” made by the Further Consolidated Appropriations Act, 2020, which was enacted on December 20, 2019. Section 605 of this Act further amended the definition of a “biological product” in section 351(i) of the PHS Act to remove the parenthetical “(except any chemically synthesized polypeptide)” from the statutory category of “protein.” FDA has provided below a list of each approved application for a biological product under the FD&C Act that was deemed to be a license (i.e., an approved biologics license application (BLA)) for the biological product on March 23, 2020.
    [Show full text]
  • Chapter 2 Molecular Aspects of Histamine Receptors
    VU Research Portal Shedding Light on the Histamine H3 Receptor Mocking, T.A.M. 2020 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Mocking, T. A. M. (2020). Shedding Light on the Histamine H3 Receptor: Photopharmacology and bioluminescent assays to study GPCRs. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 06. Oct. 2021 Chapter 2 Molecular aspects of histamine receptors Histamine mediates a multitude of physiological effects in the human body by activating four histamine receptor subtypes. Histamine receptors have proven to be promising drug targets in the treatment of a variety of diseases, including hay fever, gastric ulcers, inflammatory and neuropathological diseases. In this chapter the molecular aspects of histamine receptors are described, including expression profile, intracellular signaling, and how histamine receptor activity can be attenuated by ligands targeting the histamine receptor binding sites.
    [Show full text]
  • Corticorelin Acetate, a Synthetic Corticotropin-Releasing Factor with Preclinical Antitumor Activity, Alone and with Bevacizumab, Against Human Brain Tumor Models
    ANTICANCER RESEARCH 30: 5037-5042 (2010) Corticorelin Acetate, a Synthetic Corticotropin-releasing Factor with Preclinical Antitumor Activity, alone and with Bevacizumab, against Human Brain Tumor Models IDOIA GAMEZ1, ROBERT P. RYAN1 and STEPHEN T. KEIR2 1Celtic Pharmaceutical Development Services America, Inc., New York, NY 10022, U.S.A.; 2The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC 27710, U.S.A. Abstract. Background: Corticorelin acetate (CrA) is a brain tumors. The cause of PBE is believed to result in part synthetic form of corticotropin-releasing factor that is from the leakage of edematous brain tumor fluid from currently undergoing clinical trials in the treatment of abnormal tumor vasculature into the surrounding tissue (1, peritumoral brain edema (PBE). This study preclinically 2). The mechanism(s) of action by which CrA exerts its investigated its potential as an antitumor agent against beneficial effect in the therapy of PBE has not been human brain tumor xenografts. Materials and Methods: The elucidated, but two factors appear to be relevant: decreased in vivo efficacy of CrA as a single agent and in combination vascular leakage and preserved integrity of the endothelial with the antiangiogenic agent, bevacizumab, was examined cells, which ultimately helps to maintain the blood-brain in three different patient-derived human brain tumor barrier (3, 4). xenografts implanted orthotopically (intracranially) or CrA appears to mediate its activity through two subtypes subcutaneously in athymic mice. Results: CrA significantly of G-protein coupled receptors: CRF receptor-1 (CRFR1) increased the lifespan of mice implanted orthotopically with and CRF receptor-2 (CRFR2) (5). These CRFRs are widely two different pediatric brain tumor xenograft models.
    [Show full text]
  • Dualism of Peroxisome Proliferator-Activated Receptor Α/Γ: a Potent Clincher in Insulin Resistance
    AEGAEUM JOURNAL ISSN NO: 0776-3808 Dualism of Peroxisome Proliferator-Activated Receptor α/γ: A Potent Clincher in Insulin Resistance Mr. Ravikumar R. Thakar1 and Dr. Nilesh J. Patel1* 1Faculty of Pharmacy, Shree S. K. Patel College of Pharmaceutical Education & Research, Ganpat University, Gujarat, India. [email protected] Abstract: Diabetes mellitus is clinical syndrome which is signalised by augmenting level of sugar in blood stream, which produced through lacking of insulin level and defective insulin activity or both. As per worldwide epidemiology data suggested that the numbers of people with T2DM living in developing countries is increasing with 80% of people with T2DM. Peroxisome proliferator-activated receptors are a family of ligand-activated transcription factors; modulate the expression of many genes. PPARs have three isoforms namely PPARα, PPARβ/δ and PPARγ that play a central role in regulating glucose, lipid and cholesterol metabolism where imbalance can lead to obesity, T2DM and CV ailments. It have pathogenic role in diabetes. PPARα is regulates the metabolism of lipids, carbohydrates, and amino acids, activated by ligands such as polyunsaturated fatty acids, and drugs used as Lipid lowering agents. PPAR β/δ could envision as a therapeutic option for the correction of diabetes and a variety of inflammatory conditions. PPARγ is well categorized, an element of the PPARs, also pharmacological effective as an insulin resistance lowering agents, are used as a remedy for insulin resistance integrated with type- 2 diabetes mellitus. There are mechanistic role of PPARα, PPARβ/δ and PPARγ in diabetes mellitus and insulin resistance. From mechanistic way, it revealed that dual PPAR-α/γ agonist play important role in regulating both lipids as well as glycemic levels with essential safety issues.
    [Show full text]
  • Comparative Transcriptional Network Modeling of Three PPAR-A/C Co-Agonists Reveals Distinct Metabolic Gene Signatures in Primary Human Hepatocytes
    Comparative Transcriptional Network Modeling of Three PPAR-a/c Co-Agonists Reveals Distinct Metabolic Gene Signatures in Primary Human Hepatocytes Rene´e Deehan1, Pia Maerz-Weiss2, Natalie L. Catlett1, Guido Steiner2, Ben Wong1, Matthew B. Wright2*, Gil Blander1¤a, Keith O. Elliston1¤b, William Ladd1, Maria Bobadilla2, Jacques Mizrahi2, Carolina Haefliger2, Alan Edgar{2 1 Selventa, Cambridge, Massachusetts, United States of America, 2 F. Hoffmann-La Roche AG, Basel, Switzerland Abstract Aims: To compare the molecular and biologic signatures of a balanced dual peroxisome proliferator-activated receptor (PPAR)-a/c agonist, aleglitazar, with tesaglitazar (a dual PPAR-a/c agonist) or a combination of pioglitazone (Pio; PPAR-c agonist) and fenofibrate (Feno; PPAR-a agonist) in human hepatocytes. Methods and Results: Gene expression microarray profiles were obtained from primary human hepatocytes treated with EC50-aligned low, medium and high concentrations of the three treatments. A systems biology approach, Causal Network Modeling, was used to model the data to infer upstream molecular mechanisms that may explain the observed changes in gene expression. Aleglitazar, tesaglitazar and Pio/Feno each induced unique transcriptional signatures, despite comparable core PPAR signaling. Although all treatments inferred qualitatively similar PPAR-a signaling, aleglitazar was inferred to have greater effects on high- and low-density lipoprotein cholesterol levels than tesaglitazar and Pio/Feno, due to a greater number of gene expression changes in pathways related to high-density and low-density lipoprotein metabolism. Distinct transcriptional and biologic signatures were also inferred for stress responses, which appeared to be less affected by aleglitazar than the comparators. In particular, Pio/Feno was inferred to increase NFE2L2 activity, a key component of the stress response pathway, while aleglitazar had no significant effect.
    [Show full text]
  • CDR Clinical Review Report for Soliqua
    CADTH COMMON DRUG REVIEW Clinical Review Report Insulin glargine and lixisenatide injection (Soliqua) (Sanofi-Aventis) Indication: adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus inadequately controlled on basal insulin (less than 60 units daily) alone or in combination with metformin. Service Line: CADTH Common Drug Review Version: Final (with redactions) Publication Date: January 2019 Report Length: 118 Pages Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services. While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document.
    [Show full text]
  • Histamine Receptors
    Tocris Scientific Review Series Tocri-lu-2945 Histamine Receptors Iwan de Esch and Rob Leurs Introduction Leiden/Amsterdam Center for Drug Research (LACDR), Division Histamine is one of the aminergic neurotransmitters and plays of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit an important role in the regulation of several (patho)physiological Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam, The processes. In the mammalian brain histamine is synthesised in Netherlands restricted populations of neurons that are located in the tuberomammillary nucleus of the posterior hypothalamus.1 Dr. Iwan de Esch is an assistant professor and Prof. Rob Leurs is These neurons project diffusely to most cerebral areas and have full professor and head of the Division of Medicinal Chemistry of been implicated in several brain functions (e.g. sleep/ the Leiden/Amsterdam Center of Drug Research (LACDR), VU wakefulness, hormonal secretion, cardiovascular control, University Amsterdam, The Netherlands. Since the seventies, thermoregulation, food intake, and memory formation).2 In histamine receptor research has been one of the traditional peripheral tissues, histamine is stored in mast cells, eosinophils, themes of the division. Molecular understanding of ligand- basophils, enterochromaffin cells and probably also in some receptor interaction is obtained by combining pharmacology specific neurons. Mast cell histamine plays an important role in (signal transduction, proliferation), molecular biology, receptor the pathogenesis of various allergic conditions. After mast cell modelling and the synthesis and identification of new ligands. degranulation, release of histamine leads to various well-known symptoms of allergic conditions in the skin and the airway system. In 1937, Bovet and Staub discovered compounds that antagonise the effect of histamine on these allergic reactions.3 Ever since, there has been intense research devoted towards finding novel ligands with (anti-) histaminergic activity.
    [Show full text]
  • BCBSVT Specialty Drug List Effective 2021.07.01.Xlsx
    Effective Date: 07/01/2021 SPECIALTY DRUG LIST Revised Date: 05/07/2021 DOSAGE EXCLUDED ON NATIONAL DRUG CLASS DRUG NAME GENERIC NAME FORM PERFORMANCE FORMULARY ANEMIA ARANESP SOLN DARBEPOETIN ALFA SOLN INJ ANEMIA ARANESP SOSY DARBEPOETIN ALFA SOLN PREFILLED SYRINGE ANEMIA EPOGEN SOLN EPOETIN ALFA INJ X ANEMIA PROCRIT SOLN EPOETIN ALFA INJ X ANEMIA REBLOZYL SOLR LUSPATERCEPT-AAMT FOR SUBCUTANEOUS INJ ANEMIA RETACRIT SOLN EPOETIN ALFA-EPBX INJ ANTI-GOUT AGENT KRYSTEXXA SOLN PEGLOTICASE INJ (FOR IV INFUSION) ANTI-INFECTIVE PREVYMIS SOLN LETERMOVIR IV SOLN ANTI-INFECTIVE PREVYMIS TABS LETERMOVIR TAB ASTHMA CINQAIR SOLN RESLIZUMAB IV INFUSION SOLN ASTHMA FASENRA SOSY BENRALIZUMAB SUBCUTANEOUS SOLN PREFILLED SYRINGE ASTHMA FASENRA PEN SOAJ BENRALIZUMAB SUBCUTANEOUS SOLN AUTO-INJECTOR ASTHMA NUCALA SOAJ MEPOLIZUMAB SUBCUTANEOUS SOLUTION AUTO-INJECTOR ASTHMA NUCALA SOLR MEPOLIZUMAB FOR INJ ASTHMA NUCALA SOSY MEPOLIZUMAB SUBCUTANEOUS SOLUTION PREF SYRINGE ASTHMA XOLAIR SOLR OMALIZUMAB FOR INJ ASTHMA XOLAIR SOSY OMALIZUMAB SUBCUTANEOUS SOLN PREFILLED SYRINGE CARDIOVASCULAR VYNDAMAX CAPS TAFAMIDIS CAP CARDIOVASCULAR VYNDAQEL CAPS TAFAMIDIS MEGLUMINE (CARDIAC) CAP CENTRAL NERVOUS SYSTEM AGENTS AUSTEDO TABS DEUTETRABENAZINE TAB CENTRAL NERVOUS SYSTEM AGENTS ENSPRYNG SOSY SATRALIZUMAB-MWGE SUBCUTANEOUS SOLN PREF SYRINGE CENTRAL NERVOUS SYSTEM AGENTS HETLIOZ CAPS TASIMELTEON CAPSULE CENTRAL NERVOUS SYSTEM AGENTS HETLIOZ LQ SUSP TASIMELTEON ORAL SUSP CHEMOTHERAPY PROTECTANT AMIFOSTINE SOLR AMIFOSTINE CRYSTALLINE FOR INJ CHEMOTHERAPY PROTECTANT ELITEK
    [Show full text]