DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2008/0124279 A1 Andremont 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 2008/0124279 A1 Andremont Et Al US 2008O124279A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0124279 A1 Andremont et al. (43) Pub. Date: May 29, 2008 (54) COLONIC DELIVERY USING ZN/PECTIN (52) U.S. Cl. .......................................... 424/9.1; 424/493 BEADS WITH AEUDRAGT COATING (76) Inventors: Antoine Andremont, Malakoff (FR); Helene Huguet, Paris (FR) (57) ABSTRACT Correspondence Address: Drug delivery systems that can deliver therapeutic and/or INTELLECTUAL PROPERTY f TECHNOLOGY diagnostic agents to the colon are disclosed. The systems LAW include pectin beads crosslinked with Zinc or any divalent PO BOX 14329 cation of interest, which beads are then coated with RESEARCH TRIANGLE PARK, NC 27709 Eudragit R-type polymers. The drug delivery systems are orally administrable, but can deliver the active agents to the (21) Appl. No.: 11/985.465 colon. In some embodiments, they can administer the agents to various positions in the gastro-intestinal tract, including the (22) Filed: Nov. 15, 2007 colon. The agent can be a small molecule, peptide, protein, nucleic acid, or complex structures of natural, recombinant or Related U.S. Application Data synthetic origin. In still other embodiments, the agent is a diagnostic agent. The agents can be used to diagnose, treat or (60) Provisional application No. 60/859,600, filed on Nov. investigate humans and animals for a variety of conditions, 17, 2006. including infectious diseases, inflammatory diseases, cancers O O and the like. Colon-specific delivery is obtained by formulat Publication Classification ing a prophylactic, therapeutic, and/or diagnostic agent with (51) Int. Cl. specific polymers that degrade in the colon, Such as pectin. A6 IK 49/00 (2006.01) The pectin is gelled/crosslinked with a cation Such as a Zinc A6 IK 9/14 (2006.01) cation. The formulation, typically in the form of ionically A6IP35/00 (2006.01) crosslinked pectin beads, is Subsequently coated with a spe A6IPI/00 (2006.01) cific polymer such as a EudragitR) polymer. Processes for A6IP 43/00 (2006.01) obtaining Such beads are also disclosed. SEM pictures of beads with cross section showing approximate thickness of Eudragit layer Patent Application Publication May 29, 2008 Sheet 1 of 6 US 2008/0124279 A1 Figure I : Efficiency of water rinsing to renove excess in etallic cation for formulation of As-Lacatamase LI E 16 9. 14 ') E 12 S 10 a 8 6 g 4. 5 2 O 0 supernatant after first wash Second wash third wash gelification Sample --Gelification in 6% Zn(Ac)2 bath -- Gelification in 12% Zn(Ac)2 bath Patent Application Publication May 29, 2008 Sheet 2 of 6 US 2008/O124279 A1 Beads mean weight (mg : s Number of rising 2 time of rinsing (min) t Time of gelification (min). 1. Figure 2: Effect of Gelification Time, Rinsing Process, and Drying Time on Recovery of b-Lactamase Ll Activity Patent Application Publication May 29, 2008 Sheet 3 of 6 US 2008/0124279 A1 Linearity of the L1 assay using CENTA y = 0.029a + 0.004 R 0.999 y = 0.028x + 0.006 R - G S. y = 0.033: + .001 R = (.99g L1 Concentration (ughini) Figure 3: Linearity of the assay of the enzymatic activity of B-lactamase Ll using CENTA as a substrate. Patent Application Publication May 29, 2008 Sheet 4 of 6 US 2008/0124279 A1 Figure 4: SEM pictures of beads with cross section showing approximate thickness of Endragit layer Release Kinetics from uncoated beads, or Eudragit-coated beads with or without HPMC pre-coating 150 180 210 240 270 300 Time (min) Figure 5: release kinetics of B-lactamase Ll from uncoated beads, and Eudragit-coated beads with or without HPMC pre-coating. Blue triangles: uncoated beads, red circles: beads coated with 40% Eudragit L30D-55 without pre coating; green squares: beads pre-coated with 5% HPMC and coated with 40% Eudragit L30D-55. Patent Application Publication May 29, 2008 Sheet 5 of 6 US 2008/0124279 A1 withfrom without uncoated HPMC beads, pre-coat or Tirne nin Figure 6: Hydrolysis of amoxicillin by uncoated, and Eudragit-coated beads with or without HPMC pre-coating. Blue triangles: uncoated beads, red circles: beads coated with 40% Eudragit L30D-55 without pre-coating, green squares: beads pre coated with HPMC and coated with Eudragit L30D-55. Patent Application Publication May 29, 2008 Sheet 6 of 6 US 2008/0124279 A1 Effect of beta-lactamase-containing beads on the emergence of bacterial resistance 80 . 7t, 60 Treatment2 duration4 (dayss post Dose 1) Figure 7: Effect of Eu dragit-coated pectin beads containing B-lactamase L1 on the emergence of antibiotic-resistant bacteria in piglets treated with amoxicitlin. Blue triangles: untreated animals (n=12), red diamonds: animals treated with amoxicillin and placebo pectin beads (n=12); green squares: animals treated with amoxicillin together with Eudragit-coated pectin beads containing B-lactamase Ll (n=4). US 2008/O124279 A1 May 29, 2008 COLONIC DELVERY USING ZNAPECTIN bacterial species; more than 10' bacteria per gram of colonic BEADS WITH AEUDRAGIT COATING content) which will be affected by the arrival of active anti biotic residues. The following can be observed: REFERENCE TO RELATED APPLICATION 0007 1. Flora imbalance which is the main cause of banal diarrhea occurring following antibiotic treatments (Bartlett J. 0001. This application claims priority to U.S. Ser. No. G. (2002) Clinical practice. Antibiotic associated diarrhea, 60/859,600, filed on Nov. 17, 2006, the contents of which are New England Journal of Medicine, 346,334). Even though hereby incorporated by reference. this diarrhea is generally not serious and ceases rapidly, either spontaneously, or upon completion of the antibiotic treat FIELD OF THE INVENTION ment, it is adversely perceived by patients and adds to the 0002 The present invention is in the area of oral drug discomfort of the original illness for which the antibiotic was delivery systems to administer active agents to the colon. prescribed: 0008 2. interference with the resistance to colonization by BACKGROUND OF THE INVENTION exogenic bacteria (or “barrier effect”) with possible risk of 0003 Drug delivery systems that specifically deliver infection, such as alimentary salmonella intoxication (Holm active agents to the colon have been recognized as having berg S. D. et al. (1984) Drug resistant Salmonella from ani important therapeutic advantages. A large number of colonic mals fed antimicrobials, New England Journal of Medicine, conditions could effectively be treated more efficaciously if 311, 617); the active ingredient is released locally. Examples of Such 0009. 3. selection of microorganisms resistant to the anti colonic disorders include Crohn's disease, ulcerative colitis, biotic. These microorganisms can be of various types: colorectal cancer and constipation. 0010 a) first they can be pathogenic bacteria such as for 0004 Colonic release can also benefit patients when, from example, Clostridium difficile, a species capable of secreting atherapeutic point of view, a delay in absorption is necessary. toxins causing a form of colitis known as pseudomembranous colitis (Bartlett J. G. (1997) Clostridium difficle infection: Examples include the treatment of disorders such as noctur pathophysiology and diagnosis, Seminar in Gastrointestinal nal asthma or angor (Kinget R. et al. (1998), Colonic Drug Disease, 8, 12); Targeting, Journal of Drug Targeting, 6. 129). 0.011 b) they can also be microorganisms that are rela 0005 Colonic release can also be used to administer thera tively weakly pathogenic, but whose multiplication can peutically active polypeptides. Polypeptides are typically lead to an associated infection (vaginal Candidosis or administered by injection, because they are degraded in the Escherichia coli resistant cystitis). stomach. Because injection is painful, research efforts have 0012 c) they can finally be non-pathogenic commensal focused on using the colon as a site of absorption for active drug-resistant bacteria whose multiplication and fecal elimi polypeptides, including analgesics, contraceptives, vaccines, nation will increase dissemination of antibiotic resistance in insulin, and the like. The absorption of polypeptides in the the environment. It is well documented that antibiotic resis colon appears to be more effective than in other sites in the tance genes are carried by mobile or transposable genetic digestive tract. This is particularly due to the relatively weak elements that may contain up to 5 or 6 antibiotic resistance proteolytic activity in the small intestine and the absence of genes, and are readily transmitted to other bacteria, even peptidase activity associated with the membrane of the across species. Consequently, these resistant commensal bac colonic epithelial cells. teria may constitute an important source leading to drug resis 0006 Following their oral administration, antibiotics pass tance for pathogenic species. This risk is currently considered through the stomach and are then absorbed in the Small intes seminal in terms of the disquieting character of the evolution tine to diffuse in the whole organism and treat the infectious towards drug multiresistance by numerous species patho outbreak site(s) for which they have been administered. All genic for humans. the same, a fraction of antibiotics ingested (the importance of 0013. It would therefore be desirable to have drugs and this fraction varies with the characteristics of each antibiotic) drug delivery systems that would act to reduce the quantity of is not absorbed and continues its progress to the colon before residual antibiotics reaching the colon following oral or being eliminated in the stool. These residual antibiotics are parenteral antibiotic therapy. To this end, it would be advan combined, in the large intestine, with a fraction of the antibi tageous to have drug delivery systems which enable to admin otics absorbed, but which are re-excreted in the digestive tract ister the active agents to the colon. by means of biliary elimination. This fraction is of variable 0014) Numerous strategies exploiting the diverse physi importance as a function of metabolism and elimination path ological parameters of the digestive tract have been devised ways for each antibiotic.
Load more

Recommended publications
  • Evaluation of in Silico Approach for Prediction of Presence of Opioid Peptides in Wheat
    Evaluation of in silico approach for prediction of presence of opioid peptides in wheat This is the Accepted version of the following publication Garg, Swati, Apostolopoulos, Vasso, Nurgali, Kulmira and Mishra, Vijay Kumar (2018) Evaluation of in silico approach for prediction of presence of opioid peptides in wheat. Journal of Functional Foods, 41. 34 - 40. ISSN 1756-4646 The publisher’s official version can be found at https://www.sciencedirect.com/science/article/pii/S1756464617307454 Note that access to this version may require subscription. Downloaded from VU Research Repository https://vuir.vu.edu.au/36577/ 1 1 Evaluation of in silico approach for prediction of presence of opioid peptides in wheat 2 gluten 3 Abstract 4 Opioid like morphine and codeine are used for the management of pain, but are associated 5 with serious side-effects limiting their use. Wheat gluten proteins were assessed for the 6 presence of opioid peptides on the basis of tyrosine and proline within their sequence. Eleven 7 peptides were identified and occurrence of predicted sequences or their structural motifs were 8 analysed using BIOPEP database and ranked using PeptideRanker. Based on higher peptide 9 ranking, three sequences YPG, YYPG and YIPP were selected for determination of opioid 10 activity by cAMP assay against µ and κ opioid receptors. Three peptides inhibited the 11 production of cAMP to varied degree with EC50 values of YPG, YYPG and YIPP were 5.3 12 mM, 1.5 mM and 2.9 mM for µ-opioid receptor, and 1.9 mM, 1.2 mM and 3.2 mM for κ- 13 opioid receptor, respectively.
    [Show full text]
  • INVESTIGATION of NATURAL PRODUCT SCAFFOLDS for the DEVELOPMENT of OPIOID RECEPTOR LIGANDS by Katherine M
    INVESTIGATION OF NATURAL PRODUCT SCAFFOLDS FOR THE DEVELOPMENT OF OPIOID RECEPTOR LIGANDS By Katherine M. Prevatt-Smith Submitted to the graduate degree program in Medicinal Chemistry and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. _________________________________ Chairperson: Dr. Thomas E. Prisinzano _________________________________ Dr. Brian S. J. Blagg _________________________________ Dr. Michael F. Rafferty _________________________________ Dr. Paul R. Hanson _________________________________ Dr. Susan M. Lunte Date Defended: July 18, 2012 The Dissertation Committee for Katherine M. Prevatt-Smith certifies that this is the approved version of the following dissertation: INVESTIGATION OF NATURAL PRODUCT SCAFFOLDS FOR THE DEVELOPMENT OF OPIOID RECEPTOR LIGANDS _________________________________ Chairperson: Dr. Thomas E. Prisinzano Date approved: July 18, 2012 ii ABSTRACT Kappa opioid (KOP) receptors have been suggested as an alternative target to the mu opioid (MOP) receptor for the treatment of pain because KOP activation is associated with fewer negative side-effects (respiratory depression, constipation, tolerance, and dependence). The KOP receptor has also been implicated in several abuse-related effects in the central nervous system (CNS). KOP ligands have been investigated as pharmacotherapies for drug abuse; KOP agonists have been shown to modulate dopamine concentrations in the CNS as well as attenuate the self-administration of cocaine in a variety of species, and KOP antagonists have potential in the treatment of relapse. One drawback of current opioid ligand investigation is that many compounds are based on the morphine scaffold and thus have similar properties, both positive and negative, to the parent molecule. Thus there is increasing need to discover new chemical scaffolds with opioid receptor activity.
    [Show full text]
  • Nitrate Prodrugs Able to Release Nitric Oxide in a Controlled and Selective
    Europäisches Patentamt *EP001336602A1* (19) European Patent Office Office européen des brevets (11) EP 1 336 602 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.7: C07C 205/00, A61K 31/00 20.08.2003 Bulletin 2003/34 (21) Application number: 02425075.5 (22) Date of filing: 13.02.2002 (84) Designated Contracting States: (71) Applicant: Scaramuzzino, Giovanni AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU 20052 Monza (Milano) (IT) MC NL PT SE TR Designated Extension States: (72) Inventor: Scaramuzzino, Giovanni AL LT LV MK RO SI 20052 Monza (Milano) (IT) (54) Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases (57) New pharmaceutical compounds of general effects and for this reason they are useful for the prep- formula (I): F-(X)q where q is an integer from 1 to 5, pref- aration of medicines for prevention and treatment of in- erably 1; -F is chosen among drugs described in the text, flammatory, ischemic, degenerative and proliferative -X is chosen among 4 groups -M, -T, -V and -Y as de- diseases of musculoskeletal, tegumental, respiratory, scribed in the text. gastrointestinal, genito-urinary and central nervous sys- The compounds of general formula (I) are nitrate tems. prodrugs which can release nitric oxide in vivo in a con- trolled and selective way and without hypotensive side EP 1 336 602 A1 Printed by Jouve, 75001 PARIS (FR) EP 1 336 602 A1 Description [0001] The present invention relates to new nitrate prodrugs which can release nitric oxide in vivo in a controlled and selective way and without the side effects typical of nitrate vasodilators drugs.
    [Show full text]
  • Cellular Responses to Erbb-2 Overexpression in Human Mammary Luminal Epithelial Cells: Comparison of Mrna and Protein Expression
    British Journal of Cancer (2004) 90, 173 – 181 & 2004 Cancer Research UK All rights reserved 0007 – 0920/04 $25.00 www.bjcancer.com Cellular responses to ErbB-2 overexpression in human mammary luminal epithelial cells: comparison of mRNA and protein expression SL White1, S Gharbi1, MF Bertani1, H-L Chan1, MD Waterfield1 and JF Timms*,1 1 Ludwig Institute for Cancer Research, Wing 1.1, Cruciform Building, Gower Street, London WCIE 6BT, UK Microarray analysis offers a powerful tool for studying the mechanisms of cellular transformation, although the correlation between mRNA and protein expression is largely unknown. In this study, a microarray analysis was performed to compare transcription in response to overexpression of the ErbB-2 receptor tyrosine kinase in a model mammary luminal epithelial cell system, and in response to the ErbB-specific growth factor heregulin b1. We sought to validate mRNA changes by monitoring changes at the protein level using a parallel proteomics strategy, and report a surprisingly high correlation between transcription and translation for the subset of genes studied. We further characterised the identified targets and relate differential expression to changes in the biological properties of ErbB-2-overexpressing cells. We found differential regulation of several key cell cycle modulators, including cyclin D2, and downregulation of a large number of interferon-inducible genes, consistent with increased proliferation of the ErbB-2- overexpressing cells. Furthermore, differential expression of genes involved in extracellular matrix modelling and cellular adhesion was linked to altered adhesion of these cells. Finally, we provide evidence for enhanced autocrine activation of MAPK signalling and the AP-1 transcription complex.
    [Show full text]
  • Targeting the Deubiquitinase STAMBP Inhibits NALP7 Inflammasome
    ARTICLE Received 19 Jul 2016 | Accepted 8 Mar 2017 | Published 11 May 2017 DOI: 10.1038/ncomms15203 OPEN Targeting the deubiquitinase STAMBP inhibits NALP7 inflammasome activity Joseph S. Bednash1, Nathaniel Weathington1, James Londino1, Mauricio Rojas1, Dexter L. Gulick1, Robert Fort1, SeungHye Han1, Alison C. McKelvey1, Bill B. Chen1 & Rama K. Mallampalli1,2,3 Inflammasomes regulate innate immune responses by facilitating maturation of inflammatory cytokines, interleukin (IL)-1b and IL-18. NACHT, LRR and PYD domains-containing protein 7 (NALP7) is one inflammasome constituent, but little is known about its cellular handling. Here we show a mechanism for NALP7 protein stabilization and activation of the inflammasome by Toll-like receptor (TLR) agonism with bacterial lipopolysaccharide (LPS) and the synthetic acylated lipopeptide Pam3CSK4. NALP7 is constitutively ubiquitinated and recruited to the endolysosome for degradation. With TLR ligation, the deubiquitinase enzyme, STAM-binding protein (STAMBP) impedes NALP7 trafficking to lysosomes to increase NALP7 abundance. STAMBP deubiquitinates NALP7 and STAMBP knockdown abrogates LPS or Pam3CSK4-induced increases in NALP7 protein. A small-molecule inhibitor of STAMBP deubiquitinase activity, BC-1471, decreases NALP7 protein levels and suppresses IL-1b release after TLR agonism. These findings describe a unique pathway of inflammasome regulation with the identification of STAMBP as a potential therapeutic target to reduce pro-inflammatory stress. 1 Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, UPMC Montefiore, NW 628, Pittsburgh, Pennsylvania 15213, USA. 2 Departments of Cell Biology and Physiology and Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. 3 Medical Specialty Service Line, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15240, USA.
    [Show full text]
  • Proquest Dissertations
    Opioid peptide permeation across the blood- brain and blood-cerebrospinal fluid barriers Item Type text; Dissertation-Reproduction (electronic) Authors Abbruscato, Thomas John, 1970- Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 04/10/2021 05:24:05 Link to Item http://hdl.handle.net/10150/282429 INFORMATION TO USERS This manuscript has been reproduced from the microfihn master. UMI fihns the text direct^ from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter &ce, while others may be from any type of computer printer. The quality of this reproductioii is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, b^inning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy.
    [Show full text]
  • A Selective Nociceptin Receptor Antagonist to Treat Depression: Evidence from Preclinical and Clinical Studies
    Neuropsychopharmacology (2016) 41, 1803–1812 © 2016 American College of Neuropsychopharmacology. All rights reserved 0893-133X/16 www.neuropsychopharmacology.org A Selective Nociceptin Receptor Antagonist to Treat Depression: Evidence from Preclinical and Clinical Studies ,1 1 2 3 4 Anke Post* , Trevor S Smart , Judith Krikke-Workel , Gerard R Dawson , Catherine J Harmer , 3,4 1 5 6 6 1 Michael Browning , Kimberley Jackson , Rishi Kakar , Richard Mohs , Michael Statnick , Keith Wafford , 1 6 6 Andrew McCarthy , Vanessa Barth and Jeffrey M Witkin 1 2 3 4 5 Lilly UK, Windlesham, Surrey, UK; Eli Lilly, Netherlands; P1vital Limited, Oxfordshire, UK; University of Oxford, Oxford, UK; Innovative Clinical 6 Research-SICR, Ft. Lauderdale, FL, USA; Neuroscience Research, Eli Lilly and Company, Indianapolis, IN, USA Nociceptin/Orphanin FQ (N/OFQ) is an endogenous ligand of the N/OFQ peptide (NOP) receptor, which is a G protein-coupled receptor in brain regions associated with mood disorders. We used a novel, potent, and selective orally bioavailable antagonist, LY2940094, to test the hypothesis that blockade of NOP receptors would induce antidepressant effects. In this study we demonstrate that targeting NOP receptors with LY2940094 translates to antidepressant-like effects in rodent models and, importantly, to antidepressant efficacy in patients with major depressive disorder (MDD). The proof-of-concept study (POC) was an 8-week, double-blind, placebo- controlled trial that evaluated LY2940094 as a novel oral medication for the treatment of patients with MDD. Once daily oral dosing of LY2940094 at 40 mg for 8 weeks vs placebo provided some evidence for an antidepressant effect based on the change from baseline to week 8 in the GRID-Hamilton Depression Rating Scale-17 item total score, although the predefined POC efficacy criterion (probability of ⩾ LY2940094 being better than placebo 88%) was not met (82.9%).
    [Show full text]
  • 1-(4-Amino-Cyclohexyl)
    (19) & (11) EP 1 598 339 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 211/04 (2006.01) C07D 211/06 (2006.01) 24.06.2009 Bulletin 2009/26 C07D 235/24 (2006.01) C07D 413/04 (2006.01) C07D 235/26 (2006.01) C07D 401/04 (2006.01) (2006.01) (2006.01) (21) Application number: 05014116.7 C07D 401/06 C07D 403/04 C07D 403/06 (2006.01) A61K 31/44 (2006.01) A61K 31/48 (2006.01) A61K 31/415 (2006.01) (22) Date of filing: 18.04.2002 A61K 31/445 (2006.01) A61P 25/04 (2006.01) (54) 1-(4-AMINO-CYCLOHEXYL)-1,3-DIHYDRO-2H-BENZIMIDAZOLE-2-ONE DERIVATIVES AND RELATED COMPOUNDS AS NOCICEPTIN ANALOGS AND ORL1 LIGANDS FOR THE TREATMENT OF PAIN 1-(4-AMINO-CYCLOHEXYL)-1,3-DIHYDRO-2H-BENZIMIDAZOLE-2-ON DERIVATE UND VERWANDTE VERBINDUNGEN ALS NOCICEPTIN ANALOGE UND ORL1 LIGANDEN ZUR BEHANDLUNG VON SCHMERZ DERIVÉS DE LA 1-(4-AMINO-CYCLOHEXYL)-1,3-DIHYDRO-2H-BENZIMIDAZOLE-2-ONE ET COMPOSÉS SIMILAIRES POUR L’UTILISATION COMME ANALOGUES DU NOCICEPTIN ET LIGANDES DU ORL1 POUR LE TRAITEMENT DE LA DOULEUR (84) Designated Contracting States: • Victory, Sam AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Oak Ridge, NC 27310 (US) MC NL PT SE TR • Whitehead, John Designated Extension States: Newtown, PA 18940 (US) AL LT LV MK RO SI (74) Representative: Maiwald, Walter (30) Priority: 18.04.2001 US 284666 P Maiwald Patentanwalts GmbH 18.04.2001 US 284667 P Elisenhof 18.04.2001 US 284668 P Elisenstrasse 3 18.04.2001 US 284669 P 80335 München (DE) (43) Date of publication of application: (56) References cited: 23.11.2005 Bulletin 2005/47 EP-A- 0 636 614 EP-A- 0 990 653 EP-A- 1 142 587 WO-A-00/06545 (62) Document number(s) of the earlier application(s) in WO-A-00/08013 WO-A-01/05770 accordance with Art.
    [Show full text]
  • View Full Page
    The Journal of Neuroscience, October 1, 1997, 17(19):7471–7479 Presynaptic Versus Postsynaptic Localization of m and d Opioid Receptors in Dorsal and Ventral Striatopallidal Pathways M. Foster Olive,1,2 Benito Anton,2 Paul Micevych,3 Christopher J. Evans,2 and Nigel T. Maidment2 1Interdepartmental Neuroscience Ph.D. Program and Departments of 2Psychiatry and Biobehavioral Sciences and 3Neurobiology, University of California at Los Angeles, Los Angeles, California 90024 Parallel studies have demonstrated that enkephalin release of cells that were adjacent to enkephalin and synaptophysin from nerve terminals in the pallidum (globus pallidus and ventral immunoreactivities. Injections of the anterograde tracer pallidum) can be modulated by locally applied opioid drugs. To Phaseolus vulgaris leucoagglutinin (PHA-L) or the retrograde investigate further the mechanisms underlying these opioid tracer Texas Red-conjugated dextran amine (TRD) into the effects, the present study examined the presynaptic and dorsal and ventral striatum resulted in labeling of striatopallidal postsynaptic localization of d (DOR1) and m (MOR1) opioid fibers and pallidostriatal cell bodies, respectively. DOR1 immu- receptors in the dorsal and ventral striatopallidal enkephalin- nostaining in the pallidum co-localized only with TRD and not ergic system using fluorescence immunohistochemistry com- PHA-L, whereas pallidal MOR1 immunostaining co-localized bined with anterograde and retrograde neuronal tracing tech- with PHA-L and not TRD. These results suggest that pallidal niques. DOR1 immunostaining patterns revealed primarily a enkephalin release may be modulated by m opioid receptors postsynaptic localization of the receptor in pallidal cell bodies located presynaptically on striatopallidal enkephalinergic neu- adjacent to enkephalin- or synaptophysin-positive fiber termi- rons and by d opioid receptors located postsynaptically on nals.
    [Show full text]
  • Enkephalin Degradation in Serum of Patients with Inflammatory Bowel Diseases
    Pharmacological Reports 71 (2019) 42–47 Contents lists available at ScienceDirect Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep Original article Enkephalin degradation in serum of patients with inflammatory bowel diseases a, a b Beata Wilenska *, Dagmara Tymecka , Marcin Włodarczyk , b c Aleksandra Sobolewska-Włodarczyk , Maria Wisniewska-Jarosinska , d e b a,d, Jolanta Dyniewicz , Árpád Somogyi , Jakub Fichna , Aleksandra Misicka * a Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Warszawa, Poland b Department of Biochemistry, Medical University of Lodz, Łódz, Poland c Department of Gastroenterology, Medical University of Lodz, Łódz, Poland d Department of Neuropeptides, Mossakowski Medical Research Centre Polish Academy of Science, Warszawa, Poland e Campus Chemical Instrumentation Centre (CCIC), The Ohio State University, Columbus, OH, USA A R T I C L E I N F O A B S T R A C T Article history: Background: Inflammatory bowel diseases (IBD) are a group of chronic and recurrent gastrointestinal Received 18 April 2018 disorders that are difficult to control. Recently, a new IBD therapy based on the targeting of the Received in revised form 10 June 2018 endogenous opioid system has been proposed. Consequently, due to the fact that endogenous Accepted 1 August 2018 enkephalins have an anti-inflammatory effect, we aimed at investigating the degradation of serum Available online 2 August 2018 enkephalin (Met- and Leu-enkephalin) in patients with IBD. Methods: Enkephalin degradation in serum of patients with IBD was characterized using mass Keywords: spectrometry methods. Calculated half-life (T1/2) of enkephalins were compared and correlated with the Inflammatory bowel diseases disease type and gender of the patients.
    [Show full text]
  • Genscript Product Catalog 2013-2014 Genscript Product Catalog
    GenScript Product Catalog 2013-2014 GenScript Product Catalog www.genscript.com GenScript USA Inc. 860 Centennial Ave. Piscataway, NJ 08854USA Tel: 1-732-885-9188 / 1-732-885-9688 Toll-Free Tel: 1-877-436-7274 Fax: 1-732-210-0262 / 1-732-885-5878 Email: [email protected] Nucleic Acid Purification and Analysis Business Development Tel: 1-732-317-5088 PCR PCR and Cloning Email: [email protected] Protein Analysis Antibodies 2013-2014 Peptides Welcome to GenScript GenScript USA Incorporation, founded in 2002, is a fast-growing biotechnology company and contract research organization (CRO) specialized in custom services and consumable products for academic and pharmaceutical research. Built on our assembly-line mode, one-stop solutions, continuous improvement, and stringent IP protection, GenScript provides a comprehensive portfolio of products and services at the most competitive prices in the industry to meet your research needs every day. Over the years, GenScript’s scientists have developed many innovative technologies that allow us to maintain our position at the cutting edge of biological and medical research while offering cost-effective solutions for customers to accelerate their research. Our advanced expertise includes proprietary technology for custom gene synthesis, OptimumGeneTM codon optimization technology, CloneEZ® seamless cloning technology, FlexPeptideTM technology for custom peptide synthesis, BacPowerTM technology for protein expression and purification, T-MaxTM adjuvant and advanced nanotechnology for custom antibody production, as well as our ONE-HOUR WesternTM detection system and eStain® protein staining system. GenScript offers a broad range of reagents, optimized kits, and system solutions to help you unravel the mysteries of biology. We also provide a comprehensive portfolio of customized services that include Bio-Reagent, Bio-Assay, Lead Optimization, and Antibody Drug Development which can be effectively integrated into your value chain and your operations.
    [Show full text]
  • Rubsicolins Are Naturally Occurring G-Protein-Biased Delta Opioid Receptor Peptides
    bioRxiv preprint doi: https://doi.org/10.1101/433805; this version posted October 5, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Title page Title: Rubsicolins are naturally occurring G-protein-biased delta opioid receptor peptides Short title: Rubsicolins are G-protein-biased peptides Authors: Robert J. Cassell1†, Kendall L. Mores1†, Breanna L. Zerfas1, Amr H.Mahmoud1, Markus A. Lill1,2,3, Darci J. Trader1,2,3, Richard M. van Rijn1,2,3 Author affiliation: 1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, 2Purdue Institute for Drug Discovery, 3Purdue Institute for Integrative Neuroscience, West Lafayette, IN 47907 †Robert J Cassell and Kendall Mores contributed equally to this work Corresponding author: ‡Richard M. van Rijn, Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907 (Phone: 765-494- 6461; Email: [email protected]) Key words: delta opioid receptor; beta-arrestin; natural products; biased signaling; rubisco; G protein-coupled receptor Abstract: 187 Figures: 2 Tables: 2 References: 27 1 bioRxiv preprint doi: https://doi.org/10.1101/433805; this version posted October 5, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract The impact that β-arrestin proteins have on G-protein-coupled receptor trafficking, signaling and physiological behavior has gained much appreciation over the past decade. A number of studies have attributed the side effects associated with the use of naturally occurring and synthetic opioids, such as respiratory depression and constipation, to excessive recruitment of β-arrestin.
    [Show full text]