DOCSLIB.ORG

Revisiting Baclofen for the Treatment of Severe Chronic Tinnitus

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Revisiting Baclofen for the Treatment of Severe Chronic Tinnitus View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central OPINION ARTICLE published: 09 March 2012 doi: 10.3389/fneur.2012.00034 Revisiting baclofen for the treatment of severe chronic tinnitus Paul F. Smith*, Yiwen Zheng and Cynthia L. Darlington Department of Pharmacology and Toxicology, School of Medical Sciences, University of Otago Medical School, and Brain Health Research Centre, University of Otago, Dunedin, New Zealand *Correspondence: [email protected] Subjective tinnitus is a phantom sensation of the study appeared to have more severe raises the possibility that the use of racemic of sound, which has been estimated to occur tinnitus to begin with. Another was that baclofen to treat tinnitus, as was the case in in 25.3% of people in the USA, with 7.9% the study was potentially underpowered the study by Westerberg et al. (1996), may experiencing it frequently (Shargorodsky statistically due to the inclusion of sev- have actually undermined the effects of et al., 2010). Drugs are one of a number eral different types of tinnitus, some of the l-baclofen. An obvious question is why of potential treatment avenues for severe which might not have responded to the racemic baclofen would be manufactured chronic tinnitus. However, to date, there is drug (Møller, 1997). The possibility that if there was evidence that d-baclofen is less relatively little agreement about which par- the study was underpowered was carefully potent than l-baclofen? One consideration ticular drugs might be best used to alleviate acknowledged by the authors themselves, is probably that racemic baclofen is easier to the condition (see Darlington and Smith, who performed power calculations for dif- manufacture, because the separation of the 2007; Hoekstra et al., 2011 for reviews). ferent scenarios (Westerberg et al., 1996). l- and d-isomers requires additional steps. On the assumption that chronic tinnitus In addition, Westerberg et al. (1996) appar- The potential utility of l-baclofen, as is associated with neuronal hyperactivity at ently used racemic baclofen (i.e., a mixture opposed to d-baclofen or racemic baclofen, different levels of the central auditory path- of the L- and D-isomers of baclofen, also is supported by a recent study in which we ways, such as the dorsal cochlear nucleus, the known as R- and S-isomers), which was found that l-baclofen dose-dependently inferior colliculus, and the auditory cortex the only licensed form in 1996 (Szczepaniak reduced the behavioral signs of chronic tin- (see Moller, 2000; Eggermont and Roberts, and Møller, 1995), and d-baclofen has been nitus in an animal model caused by acoustic 2004; Eggermont, 2005; Kaltenbach, 2006; reported to be less potent than l-baclofen trauma (Zheng et al., 2012). Although the Roberts et al., 2010 for reviews; see Dong in reducing tone- and click-evoked hyper- lowest effective dose for clear suppression et al., 2010; Middleton et al., 2011; Vogler excitability in neurons of the inferior colli- of tinnitus was 3 mg/kg, using the dose et al., 2011; Wang et al., 2011 and Mulders culus (Szczepaniak and Møller, 1995, 1996). adjustment calculation employed by the and Robertson, 2011 for recent examples), In fact, a number of studies have FDA to calculate human equivalent doses drugs that increase inhibitory neuro- reported that D-baclofen can reduce the (Regan-Shaw et al., 2007), this was approxi- transmission or block excitatory neuro- effects of L-baclofen. This has been reported mately equivalent to 34.1 mg/day for a 70-kg transmission, are often used. Aside from in the trigeminal nucleus (Terrence et al., adult. This is above the effective dose of anti-epileptic drugs, which are an obvious 1983; Fromm et al., 1990), but not in the 6–12 mg of l-baclofen reported by Fromm choice, the anti-spasticity agent and GABAB hippocampus or neocortex (Howe and and Terrence (1987) for the treatment of receptor agonist, baclofen, has also been Zieglgänsberger, 1986). In the spinal cord, trigeminal neuralgia but is lower than the used occasionally. d-baclofen has been reported to antago- twice daily 20 or 30 mg doses of racemic Unfortunately, as Hoekstra et al. (2011) nize the effects of l-baclofen (Sawynok baclofen employed by Westerberg et al. concluded in a recent review, the evidence and Dickson, 1984, 1985). In a double (1996) in patients with tinnitus, which were supporting the efficacy of anti-epileptic blind crossover trial with 15 patients suf- the highest doses used in the second and drugs in treating tinnitus is not very con- fering from trigeminal neuralgia, in 9 third weeks of their study (in the first week vincing. Even less convincing is the evi- patients l-baclofen was reported to be five they used 10 mg twice daily). Therefore, the dence supporting the use of baclofen. The times more effective in relieving the symp- effective dose of l-baclofen in our animal only published clinical trial of baclofen in toms than racemic baclofen (Fromm and model study was within the dose range patients with tinnitus, yielded inconsistent Terrence, 1987). In addition, the adverse of racemic baclofen that has been used in results. The patients’ subjective ratings of side effects of l-baclofen were better tol- humans. tinnitus were significantly reduced follow- erated than those of the racemic baclofen While baclofen is not likely to be a ing drug administration compared to before (Fromm and Terrence, 1987). Although the drug of first choice for tinnitus due to drug administration; however, there was idea that d-baclofen is an antagonist, at least its adverse side effects, such as sedation, no significant difference compared to the at some GABAB receptors, is still unresolved confusion, and dizziness (Jorns and placebo group (Westerberg et al., 1996). (Froestl, 2010), at the very least it can be Zakrzewska, 2007), the significance of Nonetheless, interest in the possible use of concluded that its agonist effects are much the potential underestimation of GABAB baclofen to treat tinnitus remained (Møller, less potent than l-baclofen, which appears receptor agonists for the treatment of 1997). One potential problem with the trial to be the case in the inferior colliculus tinnitus, extends beyond baclofen itself. was that the patients in the baclofen arm (Szczepaniak and Møller, 1995, 1995). This Arbaclofen placarbil is a novel l- (or r-) www.frontiersin.org March 2012 | Volume 3 | Article 34 | 1 Smith et al. Tinnitus and baclofen baclofen prodrug with improved phar- Hoekstra, C. E., Rynja, S. P., van Zanten, G. A., and Rovers, Sawynok, J., and Dickson, C. (1985). D-baclofen is an macokinetics that may be useful in the M. M. (2011). Anticonvulsants for tinnitus. Cochrane antagonist at baclofen receptors mediating antinoci- Database Syst. Rev. 6, CD007960. ception in the spinal cord. Pharmacology 31, 248–259. treatment of neurological disorders (Lal Howe, J. R., and Zieglgänsberger, W. (1986). D-baclofen Shargorodsky, J., Curhan, G. C., and Farwell, W. R. (2010) et al., 2009). There is also a new genera- does not antagonize the actions of L-baclofen on Prevalence and characteristics of tinnitus among US rat neocortical neurons in vitro. Neurosci. Lett. 72, adults. Am. J. Med. 123, 711–718. tion of novel GABAB receptor agonists, such as CGP7930 (Adams and Lawrence, 99–104. Szczepaniak, W. S., and Møller, A. R. (1995). Effects of 2007), which do not have the adverse side Jorns, T. P., and Zakrzewska, J. M. (2007). Evidence-based L-baclofen and D-baclofen on the auditory system: a approach to the medical management of trigeminal study of click-evoked potentials from the inferior collic- effects of baclofen but which may be use- neuralgia. Br. J. Neurosurg. 21, 253–261. ulus in the rat. Ann. Otol. Rhinol. Laryngol. 104, 399–404. ful for the treatment of tinnitus. It would Kaltenbach, J. A. (2006). The dorsal cochlear nucleus as a Szczepaniak, W. S., and Møller, A. R. (1996). Effects of unfortunate if the extensive use of race- participant in the auditory, attentional and emotional (-)-baclofen, clonazepam, and diazepam on tone components of tinnitus. Hear. Res. 216–217, 224–234. exposure-induced hyperexcitability of the inferior mic baclofen prevented these new GABAB receptor agonists from being investigated Lal, R., Sukbuntherng, J., Tai, E. H. L., Upadhyay, S., Yao, colliculus in the rat: possible therapeutic implica- F., Warren, M. S., Luo, W., Bu, L., Nguyen, S., Zamora, tions for pharmacological management of tinnitus for their efficacy against tinnitus. J., Peng, G., Dias, T., Bao, Y., Ludwikow, M., Phan, and hyperacusis. Hear. Res. 97, 46–53. T., Scheuerman, R. A., Yan, H., Gao, M., Wu, Q. Q., Terrence, C. F., Sax, M., Fromm, G. H., Chang, C. H., and ACKNOWLEDGMENTS Annamalai, T., Raillard, S. P., Koller, K., Gallop, M. Yoo, C. S. (1983). Effect of baclofen enantiomorphs on This research was supported by grants A., and Cundy, K. C. (2009). Arbaclofen placarbil, the spinal trigeminal nucleus and steric similarities of from the Jean Cathie Estate and the New a novel R-baclofen prodrug: improved absorption, carbamazepine. Pharmacology 27, 85–94. distribution, metabolism and elimination properties Vogler, D. P., Robertson, D., and Mulders, W. H. (2011). Zealand Neurological Foundation grant to compared with R-baclofen. J. Pharmacol. Exp. Ther. Hyperactivity in the ventral cochlear nucleus after Paul F. Smith, Yiwen Zheng, and Cynthia 330, 911–921. cochlear trauma. J. Neurosci. 31, 6639–6645. L. Darlington. Middleton, J. W., Kiritani, T., Pedersen, C., Turner, J. G., Wang, H., Brozoski, T. J., and Caspary, D. M. (2011). Shepherd, G. M., and Tzounopoulos, T. (2011). Mice Inhibitory neurotransmission in animal models of REFERENCES with behavioral evidence of tinnitus exhibit dorsal tinnitus: maladaptive plasticity.
Load more

Recommended publications
  • Cell Surface Mobility of GABAB Receptors Saad Bin
    Cell surface mobility of GABAB receptors Saad Bin Hannan September 2011 A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy of the University College London Department of Neuroscience, Physiology, and Pharmacology University College London Gower Street London WC1E 6BT UK Declaration ii ‘I, Saad Hannan confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis.' ____________________ Saad Hannan September 2011 To Ammu, Abbu, Polu Abstract ivi Abstract Type-B γ-aminobutyric acid receptors (GABABRs) are important for mediating slow inhibition in the central nervous system and the kinetics of their internalisation and lateral mobility will be a major determinant of their signalling efficacy. Functional GABABRs require R1 and R2 subunit co-assembly, but how heterodimerisation affects the trafficking kinetics of GABABRs is unknown. Here, an α- bungarotoxin binding site (BBS) was inserted into the N-terminus of R2 to monitor receptor mobility in live cells. GABABRs are internalised via clathrin- and dynamin- dependent pathways and recruited to endosomes. By mutating the BBS, a new technique was developed to differentially track R1a and R2 simultaneously, revealing the subunits internalise as heteromers and that R2 dominantly-affects constitutive internalisation of GABABRs. Notably, the internalisation profile of R1aR2 heteromers, but not R1a homomers devoid of their ER retention motif (R1ASA), is similar to R2 homomers in heterologous systems. The internalisation of R1aASA was slowed to that of R2 by mutating a di-leucine motif in the R1 C-terminus, indicating a new role for heterodimerisation, whereby R2 subunits slow the internalization of surface GABABRs.
    [Show full text]
  • Pharmacological Agents Currently in Clinical Trials for Disorders in Neurogastroenterology
    Pharmacological agents currently in clinical trials for disorders in neurogastroenterology Michael Camilleri J Clin Invest. 2013;123(10):4111-4120. https://doi.org/10.1172/JCI70837. Clinical Review Esophageal, gastrointestinal, and colonic diseases resulting from disorders of the motor and sensory functions represent almost half the patients presenting to gastroenterologists. There have been significant advances in understanding the mechanisms of these disorders, through basic and translational research, and in targeting the receptors or mediators involved, through clinical trials involving biomarkers and patient responses. These advances have led to relief of patients’ symptoms and improved quality of life, although there are still significant unmet needs. This article reviews the pipeline of medications in development for esophageal sensorimotor disorders, gastroparesis, chronic diarrhea, chronic constipation (including opioid-induced constipation), and visceral pain. Find the latest version: https://jci.me/70837/pdf Review Pharmacological agents currently in clinical trials for disorders in neurogastroenterology Michael Camilleri Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA. Esophageal, gastrointestinal, and colonic diseases resulting from disorders of the motor and sensory functions represent almost half the patients presenting to gastroenterologists. There have been significant advances in under- standing the mechanisms of these disorders, through basic and translational research, and in targeting the recep- tors or mediators involved, through clinical trials involving biomarkers and patient responses. These advances have led to relief of patients’ symptoms and improved quality of life, although there are still significant unmet needs. This article reviews the pipeline of medications in development for esophageal sensorimotor disorders, gastropa- resis, chronic diarrhea, chronic constipation (including opioid-induced constipation), and visceral pain.
    [Show full text]
  • Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
    US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .
    [Show full text]
  • Copyrighted Material
    Subject index Note: page numbers in italics refer to fi gures, those in bold refer to tables Abbreviations used in subentries abdominal mass patterns 781–782 GERD – gastroesophageal refl ux disease choledochal cysts 1850 perception 781 IBD – infl ammatory bowel disease mesenteric panniculitis 2208 periodicity 708–709 mesenteric tumors 2210 peripheral neurogenic 2429 A omental tumors 2210 pharmacological management 714–717 ABCB1/MDR1 484 , 633 , 634–636 abdominal migrane (AM) 712 , 2428–2429 physical examination 709–710 , 710 ABCB4 abdominal obesity 2230 postprandial 2498–2499 c h o l e s t e r o l g a l l s t o n e s 1817–1818 , abdominal pain 695–722 in pregnancy 842 1819–1820 a c u t e see acute abdominal pain prevalence 695 functions 483–484 , 1813 acute cholecystitis 784 rare/obscure causes 712–713 , 712 intrahepatic cholestasis of pregnancy 848 acute diverticulitis 794–796 , 795 , 1523–1524 , red fl ags 713 low phospholipid-associated 1527 relieving/aggravating factors 709 cholelithiasis 1810 , 1819–1820 , 2393 acute mesenteric ischemia 2492 right lower quadrant 794 m u t a t i o n p h e n o t y p e s 2392 , 2393 a c u t e p a n c r e a t i t i s 795 , 1653 , 1667 right upper quadrant 794 progressive familial intrahepatic cholestasis-3 acute suppurative peritonitis 2196 sickle cell crisis 2419 494 adhesions 713 s i t e 703 , 708 ABCB11 see bile salt export pump (BSEP) AIDS 2200 special pain syndromes 718–720 ABCC2/MRP2 485 , 494 , 870 , 1813 , 2394 , 2395 anxiety 706–707 sphincter of Oddi dysfunction 1877 ABCG2/BCRP 484–485 , 633
    [Show full text]
  • April 5, 2019
    Scott M. Lassman Goodwin Procter LLP +1 202 346 4134 901 New York Avenue NW [email protected] Washington, DC 20001 goodwinlaw.com +1 202 346 4000 April 5, 2019 VIA ELECTRONIC SUBMISSION Division of Dockets Management Department of Health and Human Services Food and Drug Administration 5630 Fishers Lane, Room 1061 Rockville, MD 20852 Re: Citizen Petition Requesting the Food and Drug Administration (“FDA”) to Revoke Orphan Drug Designation for Sublocade (Buprenorphine Extended- Release) Injection for Treatment of Opiate Addiction in Opiate Users Dear Sir or Madam: On behalf of Braeburn, Inc. (“Braeburn”), the undersigned hereby submits this Citizen Petition pursuant to 21 C.F.R. §§ 10.30 and 316.29 and section 526 of the Federal Food, Drug, and Cosmetic Act (“FFDCA”), 21 U.S.C. § 360bb, to request the Commissioner of Food and Drugs to revoke orphan drug designation (“ODD”) for Sublocade (buprenorphine extended- release) injection for treatment of opiate addiction in opiate users (currently referred to as opioid use disorder (“OUD”)). Such action is necessary to (1) preserve the integrity of the Orphan Drug Act against inappropriate, unintended and abusive “evergreening” tactics, and (2) prevent such tactics from stifling the development and marketing of innovative new buprenorphine treatments to combat the growing opioid epidemic. The foundation of this request is based on the following critical factors: • Sublocade is not now, nor was it ever, a bona fide orphan drug, particularly since more than two million Americans currently are afflicted by opioid addiction. • Sublocade, which is expected to be a “blockbuster” drug with peak sales of more than $1 billion per year, nevertheless received ODD from FDA.
    [Show full text]
  • Pharmaceutical Appendix to the Harmonized Tariff Schedule
    Harmonized Tariff Schedule of the United States Basic Revision 3 (2021) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States Basic Revision 3 (2021) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known.
    [Show full text]
  • Arbaclofen Placarbil, a Novel R-Baclofen Prodrug: Improved ADME
    JPET Fast Forward. Published on June 5, 2009 as DOI: 10.1124/jpet.108.149773 JPETThis Fast article Forward. has not been Published copyedited and on formatted. June 5, The 2009 final asversion DOI:10.1124/jpet.108.149773 may differ from this version. JPET#149773 Arbaclofen Placarbil, A Novel R-Baclofen Prodrug: Improved ADME Properties Compared to R-Baclofen. Ritu Lal, Juthamas Sukbuntherng, Ezra H.L. Tai, Shubhra Upadhyay, Fenmei Yao, Mark S. Warren, Wendy Luo, Lin Bu, Son Nguyen, Jeanelle Zamora, Ge Peng, Tracy Dias, Ying Bao, Maria Ludwikow, Thu Phan, Randall A. Scheuerman, Hui Yan, Mark Gao, Downloaded from Quincey Q. Wu, Thamil Annamalai, Stephen P. Raillard, Kerry Koller, Mark A. Gallop, and Kenneth C. Cundy jpet.aspetjournals.org XenoPort, Inc., Santa Clara, CA, U.S.A. at ASPET Journals on September 26, 2021 1 Copyright 2009 by the American Society for Pharmacology and Experimental Therapeutics. JPET Fast Forward. Published on June 5, 2009 as DOI: 10.1124/jpet.108.149773 This article has not been copyedited and formatted. The final version may differ from this version. JPET#149773 Running Title: Arbaclofen Placarbil: ADME and Pharmacokinetics Corresponding Author: Ritu Lal, Ph.D. XenoPort, Inc. 3410 Central Expressway Santa Clara, CA 95051 Phone: 408-616-7199 FAX: 408-616-7212 Downloaded from E-mail: [email protected] jpet.aspetjournals.org Number of text pages: 40 Number of Tables: 8 Number of Figures: 5 at ASPET Journals on September 26, 2021 Number of References: 22 Number of words in Abstract: 214 Number of words in Introduction: 478 Number of words in Discussion: 1494 List of Abbreviations: AUC, area under the blood concentration versus time curve; AUC(0-inf), area under the blood concentration versus time curve extrapolated to infinity; C0, concentration in blood extrapolated to time zero following intravenous administration; Cmax, maximum concentration in blood; Caco-2, human colonic adenocarcinoma cell line; CSF, cerebrospinal fluid; GABAB, gamma-aminobutyric acid-B; GERD, gastroesophageal 2 JPET Fast Forward.
    [Show full text]
  • DRUG DELIVERY Review and Outlook I N D U S T R Y G R O W T H T O C O N T I N U E T H R O U G H N E W Technologies
    SPECIAL REPORT DECEMBER 2011 DRUG DELIVERY REVIEW AND OUTLOOK INDUSTRY GROWTH TO CONTINUE THROUGH NEW TECHNOLOGIES The worldwide drug-delivery arena is growing each year as the increasing aging population is in need of improved methods of administration for products and therapies. Drug-delivery industry growth is being led by the United States as well as emerging markets. Oral forms remain the preferred method of drug-delivery administration. Gaining in popularity are parenteral, inhalation and implantable systems. Elements impacting the development of drug-delivery systems include reimbursement, environmental factors, and regulatory processes. Product developers are coming up with better ways to improve therapy performance and safety as patients become more involved in their treatments in an effort to cut down on costs. New electronic technologies for reusable systems and disposable devices are leading to improved sales of auto-injectors. Microneedle technology is on the rise so that medicine can be precisely delivered to areas in need of treatment. UBM CANON DATA PRODUCTS TABLE OF CONTENTS 828B Newtown-Yardley Road, Suite B Drug-Delivery Industry Overview . Page 3 Newtown, PA 18940 Drug-Delivery Company Overview . 8 United States Phone: +1 .215 .944 .9800 Drug-Delivery Prescription Products Fax: +1 .215 .867 .0053 Website: PharmaLive .com Awaiting Approval . 26 Steve Corrick Phase III . 29 VP and Executive Director UBM Canon Publishing Phase II/III . 36 steve .corrick@ubm .com Phase II . 37 Roger Burg Phase I/II . 46 VP, Operations Publications Division Phase I . 47 roger .burg@ubm .com +1 .310 .445 .4221 Preclinical Development . 50 Glenn Glasberg Companies . 52 Circulation and Marketing Director glenn .glasberg@ubm .com Drug-Delivery Medical Devices +1 .215 .944 .9810 Class I Devices – General Controls – 510(k) Exempt .
    [Show full text]
  • The GABAB Receptor—Structure, Ligand Binding and Drug Development
    molecules Review The GABAB Receptor—Structure, Ligand Binding and Drug Development Linn Samira Mari Evenseth * , Mari Gabrielsen and Ingebrigt Sylte Molecular Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, NO-9037 Tromsø, Norway; [email protected] (M.G.); [email protected] (I.S.) * Correspondence: [email protected] Academic Editor: Mercedes Alfonso-Prieto Received: 29 May 2020; Accepted: 6 July 2020; Published: 7 July 2020 Abstract: The γ-aminobutyric acid (GABA) type B receptor (GABAB-R) belongs to class C of the G-protein coupled receptors (GPCRs). Together with the GABAA receptor, the receptor mediates the neurotransmission of GABA, the main inhibitory neurotransmitter in the central nervous system (CNS). In recent decades, the receptor has been extensively studied with the intention being to understand pathophysiological roles, structural mechanisms and develop drugs. The dysfunction of the receptor is linked to a broad variety of disorders, including anxiety, depression, alcohol addiction, memory and cancer. Despite extensive efforts, few compounds are known to target the receptor, and only the agonist baclofen is approved for clinical use. The receptor is a mandatory heterodimer of the GABAB1 and GABAB2 subunits, and each subunit is composed of an extracellular Venus Flytrap domain (VFT) and a transmembrane domain of seven α-helices (7TM domain). In this review, we briefly present the existing knowledge about the receptor structure, activation and compounds targeting the receptor, emphasizing the role of the receptor in previous and future drug design and discovery efforts. Keywords: GABAB receptors; orthosteric binding site; allosteric binding site; structural mechanisms; drug development; baclofen 1.
    [Show full text]
  • Addiction Treatment Company …With Enormous Future Potential
    A World Leading Addiction Treatment Company …with enormous future potential Jefferies Healthcare Conference 2014 Disclaimer . For the purposes of this disclaimer the "Presentation" shall mean and include these slides, the oral presentation of the slides, any document that follows, any oral briefing, the question and answer session that follows the oral briefing, and any material distributed at, or in connection with, the presentation. By attending or reading the Presentation, you will be deemed to have agreed to the obligations and restrictions set out below. The Presentation is strictly private and confidential and is intended solely for the information of analysts and/or investors in connection with the proposed demerger by Reckitt Benckiser Group plc of its pharmaceutical business (the “Demerger”). It is not an offer or invitation to the public and should not be reproduced or circulated or used for any purpose other than assisting with the assessment of the Demerger. It should not be shared with or disclosed to any third party without the prior written permission of Reckitt Benckiser Group plc or Indivior PLC. Under no circumstances may any person contact the management or employees of Reckitt Benckiser Group plc or Indivior PLC, or its shareholders, or visit any sites used by the Reckitt Benckiser Group plc or Indivior PLC. The Presentation is not a prospectus. It does not constitute an offer of securities for sale or a solicitation of an offer to purchase securities in any jurisdiction. The shares of Indivior PLC have not been, and will not be, registered under the US Securities Act of 1933, and may not be offered or sold within the United States, except pursuant to an applicable exemption from, or in a transaction not subject to, the registration requirements of the US Securities Act of 1933 and in compliance with any applicable securities laws of any state or other jurisdiction of the US.
    [Show full text]
  • The Effects of Early L-Baclofen Administration on the Development of Tinnitus Induced by Acoustic Trauma, And
    The Effects Of Early L-Baclofen Administration On The Development Of Tinnitus Induced By Acoustic Trauma, And GABAB-R2 Expression, In Rats Kate McPherson A Thesis Submitted For The Degree Of Master Of Science At The University Of Otago, Dunedin, New Zealand August 2013 i Acknowledgements Firstly, I’d like to thank my supervisor Professor Paul Smith for his guidance throughout all aspects of this process. Your wealth of knowledge on all-things-tinnitus continued to astound and aid me as I not only carried out this research, but also wrote my thesis. Furthermore, you were somewhat of a god-send when it came to navigating my way through the statistics and SPSS program, and for that I am truly grateful. I would also like to thank Dr Yiwen Zheng for her constant support and encouragement. You made yourself available at all times, and were the calm amidst the storm when I was learning how to do things in the lab. Furthermore, I would like to express my thanks for your help with the brain perfusions of my rats, which could not have been carried out without your expertise. To Lucy Stiles, I will be forever in your debt. I cannot thank you enough for not only your help with the brain perfusions and data analysis, but for also being the go-to within the lab. If I didn’t know something, I could always count on you to be there and to have the answer. To Phillip Aitkin, for teaching me the ins-and-outs of acoustic brainstem responses and immunohistochemistry, as well as your involvement in the brain perfusions.
    [Show full text]
  • Fighting Apathy and Lack of Awareness in the Struggle Against Substance
    ADVERTISEMENT FEATURE Indivior Inc. www.indivior.com Fighting apathy and lack of awareness in the struggle against substance use disorder Taking a patient-centered approach, Indivior is developing innovative treatments for addiction to opioids, alcohol, and stimulants, as well as accompanying illnesses such as schizophrenia. Drug addiction is a chronically relapsing disorder Despite the availability of medications to treat opioid The FDA approval of SUBLOCADE last year was characterized by long-lasting changes in the brain. use disorder, only a minority of patients have ever only the first step of a long commitment to better Dysfunction in the neural circuits that control cogni- received treatment. Even for those receiving treat- understand how to address the unmet needs of tive regulatory processes leads to the compulsion to ment, the high rate of nonadherence to daily medi- patients suffering from opioid use disorder. Indivior profile seek and take the drug, the loss of control in limit- cations has been associated with increased odds of recently established a partnership with Virginia ing intake, and the emergence of a negative emo- relapse and higher total health-care costs compared Commonwealth University, Inova Fairfax Hospital tional state when access to the drug is withdrawn. with adherent patients. and Virginia Tech Carilion Research Institute to study Substance use disorder is a global health crisis that Indivior has a long history of supporting the addic- the effects of SUBLOCADE in the emergency room has reached epidemic proportions. Despite the avail- tion treatment community through education on environment to prevent repeated opioid overdoses ability of medications, many individuals who struggle the importance of continuity of care and through and potentially change standards of care.
    [Show full text]