Skip to main content

Advertisement

SpringerLink
Log in

Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open-label study in youth with fragile X syndrome

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Fragile X syndrome (FXS) is an inherited form of developmental disability and a single gene cause of autism. As a disorder with increasingly understood pathophysiology, FXS is a model form of developmental disability for targeted drug development efforts. Preclinical animal model findings have focused targeted drug treatment development in FXS on an imbalance between excessive glutamate and deficient gamma-aminobutyric acid (GABA) neurotransmission.

Methods

We conducted a prospective open-label 10-week trial of acamprosate in 12 youth aged 6–17 years (mean age: 11.9 years) with FXS.

Results

Acamprosate use (mean dose: 1,054 ± 422 mg/day) was associated with treatment response (defined by a Clinical Global Impressions Improvement (CGI-I) scale score of “very much improved” or “much improved”) in nine of 12 (75 %) subjects. Improvement was noted in social behavior and inattention/hyperactivity using multiple standard behavioral outcome measures. No significant adverse effects or changes in vital signs, including weight or laboratory measures, occurred during treatment with acamprosate. Additionally, pre- and post-treatment blood biomarker analyses looking at brain-derived neurotrophic factor (BDNF) levels found a significant increase in BDNF with treatment. In our pilot sample, treatment response did not correlate with change in BDNF with treatment.

Conclusions

Acamprosate was generally safe and well tolerated and was associated with a significant improvement in social behavior and a reduction in inattention/hyperactivity. The increase in BDNF that occurred with treatment may be a useful pharmacodynamic marker in future acamprosate studies. Given these findings, a double-blind, placebo-controlled study of acamprosate in youth with FXS is warranted.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Aman MG, Singh NN, Stewart AW, Field CJ (1985) The Aberrant Behavior Checklist: a behavior rating scale for the assessment of treatment effects. Am J Ment Defic 5:485–491

    Google Scholar 

  • Bailey DB Jr, Hatton DD, Tassone F, Skinner M, Taylor AK (2001) Variability in FMRP and early development in males with fragile X syndrome. Am J Ment Retard 106:16–27

    Article  PubMed  Google Scholar 

  • Bailey DB Jr, Raspa M, Olmsted M, Holiday DB (2008) Co-occurring conditions associated with FMR1 gene variations: findings from a national parent survey. Am J Med Genet A 146A:2060–2069

    Article  PubMed  CAS  Google Scholar 

  • Balu DT, Hoshaw BA, Malberg JE, Rosenzweig-Lipson S, Schechter LE, Lucki I (2008) Differential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments. Brain Res 1211:37–43

    Article  PubMed  CAS  Google Scholar 

  • Bear MF, Huber KM, Warren ST (2004) The mGluR theory of fragile X mental retardation. Trends Neurosci 27:370–377

    Article  PubMed  CAS  Google Scholar 

  • Berry-Kravis E, Krause SE, Block SS, Guter S, Wuu J, Leurgans S, Decle P, Potanos K, Cook E, Salt J, Maino D, Weinberg D, Lara R, Jardini T, Cogswell J, Johnson SA, Hagerman R (2006) Effect of CX516, an AMPA-modulating compound, on cognition and behavior in fragile X syndrome: a controlled trial. J Child Adolesc Psychopharmacol 16:525–540

    Article  PubMed  Google Scholar 

  • Berry-Kravis E, Hessl D, Coffey S, Hervey C, Schneider A, Yuhas J, Hutchison J, Snape M, Tranfaglia M, Nguyen DV, Hagerman R (2009) A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. J Med Genet 46:266–271

    Article  PubMed  CAS  Google Scholar 

  • Blednov YA, Adron Harris R (2008) Metabotropic glutamate receptor 5 (mGluR5) regulation of ethanol sedation, dependence and consumption: relationship to acamprosate actions. Int J Neuropsychopharmacol 11:775–793

    Article  PubMed  CAS  Google Scholar 

  • Castren M, Lampinen KE, Miettinen R, Koponen E, Sipola I, Bakker CE, Oostra BA, Castren E (2002) BDNF regulates the expression of fragile X mental retardation protein mRNA in the hippocampus. Neurobiol Dis 11:221–229

    Article  PubMed  CAS  Google Scholar 

  • Chuang SC, Zhao W, Bauchwitz R, Yan Q, Bianchi R, Wong RK (2005) Prolonged epileptiform discharges induced by altered group I metabotropic glutamate receptor-mediated synaptic responses in hippocampal slices of a fragile X mouse model. J Neurosci 25:8048–8055

    Article  PubMed  CAS  Google Scholar 

  • Constantino JN, Davis SA, Todd RD, Schindler MK, Gross MM, Brophy SL, Metzger LM, Shoushtari CS, Splinter R, Reich W (2003) Validation of a brief quantitative measure of autistic traits: comparison of the social responsiveness scale with the autism diagnostic interview-revised. J Autism Dev Disord 33:427–433

    Article  PubMed  Google Scholar 

  • Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE, Stone EF, Chen C, Fak JJ, Chi SW, Licatalosi DD, Richter JD, Darnell RB (2011) FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146:247–261

    Article  PubMed  CAS  Google Scholar 

  • de Vrij FM, Levenga J, van der Linde HC, Koekkoek SK, De Zeeuw CI, Nelson DL, Oostra BA, Willemsen R (2008) Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice. Neurobiol Dis 31:127–132

    Article  PubMed  Google Scholar 

  • Devys D, Lutz Y, Rouyer N, Bellocq JP, Mandel JL (1993) The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation. Nat Genet 4:335–340

    Article  PubMed  CAS  Google Scholar 

  • D’Hulst C, Kooy RF (2007) The GABAA receptor: a novel target for treatment of fragile X? Trends Neurosci 30:425–431

    Article  PubMed  Google Scholar 

  • D’Hulst C, De Geest N, Reeve SP, Van Dam D, De Deyn PP, Hassan BA, Kooy RF (2006) Decreased expression of the GABAA receptor in fragile X syndrome. Brain Res 1121:238–245

    Article  PubMed  Google Scholar 

  • D’Hulst C, Heulens I, Brouwer JR, Willemsen R, De Geest N, Reeve SP, De Deyn PP, Hassan BA, Kooy RF (2008) Expression of the GABAergic system in animal models for fragile X syndrome and fragile X associated tremor/ataxia syndrome (FXTAS). Brain Res

  • Dolen G, Bear MF (2008) Role for metabotropic glutamate receptor 5 (mGluR5) in the pathogenesis of fragile X syndrome. J Physiol 586:1503–1508

    Article  PubMed  CAS  Google Scholar 

  • El Idrissi A, Ding XH, Scalia J, Trenkner E, Brown WT, Dobkin C (2005) Decreased GABA(A) receptor expression in the seizure-prone fragile X mouse. Neurosci Lett 377:141–146

    Article  PubMed  CAS  Google Scholar 

  • El Idrissi A, Boukarrou L, Dokin C, Brown WT (2009) Taurine improves congestive functions in a mouse model of fragile X syndrome. Adv Exp Med Biol 643:191–198

    Article  PubMed  CAS  Google Scholar 

  • El Idrissi A, Yan X, L’Amoreaux W, Brown WT, Dobkin C (2012) Neuroendocrine alterations in the fragile X mouse. Results Probl Cell Differ 54:201–221

    Article  PubMed  CAS  Google Scholar 

  • Erickson CA, Mullett JE, McDougle CJ (2009) Open-label memantine in fragile X syndrome. J Autism Dev Disord

  • Erickson CA, Mullett JE, McDougle CJ (2010) Brief report: acamprosate in fragile X syndrome. J Autism Dev Disord 40:1412–1416

    Article  PubMed  Google Scholar 

  • Erickson CA, Early M, Stigler KA, Wink LK, McDougle CJ (2011) An open-label naturalistic pilot study of acamprosate in youth with autistic disorder. J Child Adolesc Psychopharmacol

  • Greenough WT, Klintsova AY, Irwin SA, Galvez R, Bates KE, Weiler IJ (2001) Synaptic regulation of protein synthesis and the fragile X protein. Proc Natl Acad Sci U S A 98:7101–7106

    Article  PubMed  CAS  Google Scholar 

  • Gupta T, Syed YM, Revis AA, Miller SA, Martinez M, Cohn KA, Demeyer MR, Patel KY, Brzezinska WJ, Rhodes JS (2008) Acute effects of acamprosate and MPEP on ethanol Drinking-in-the-Dark in male C57BL/6 J mice. Alcohol Clin Exp Res 32:1992–1998

    PubMed  CAS  Google Scholar 

  • Guy W (1976) ECDEU assessment manual for psychopharmacology, publication no. 76-338. U.S. DHEW, NIMH, Washington

    Google Scholar 

  • Harris BR, Prendergast MA, Gibson DA, Rogers DT, Blanchard JA, Holley RC, Fu MC, Hart SR, Pedigo NW, Littleton JM (2002) Acamprosate inhibits the binding and neurotoxic effects of trans-ACPD, suggesting a novel site of action at metabotropic glutamate receptors. Alcohol Clin Exp Res 26:1779–1793

    Article  PubMed  CAS  Google Scholar 

  • Henderson C, Wijetunge L, Kinoshita MN, Shumway M, Hammond RS, Postma FR, Brynczka C, Rush R, Thomas A, Paylor R, Warren ST, Vanderklish PW, Kind PC, Carpenter RL, Bear MF, Healy AM (2012) Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABAB receptors with arbaclofen. Sci Transl Med 4:152ra128

    Article  PubMed  Google Scholar 

  • Heulens I, D’Hulst C, Van Dam D, De Deyn PP, Kooy RF (2012) Pharmacological treatment of fragile X syndrome with GABAergic drugs in a knockout mouse model. Behav Brain Res 229:244–249

    Article  PubMed  CAS  Google Scholar 

  • Hong A, Zhang A, Ke Y, El Idrissi A, Shen CH (2012) Downregulation of GABA(A) beta subunits is transcriptionally controlled by Fmr1p. J Mol Neurosci 46:272–275

    Article  PubMed  CAS  Google Scholar 

  • Jacquemont S, Curie A, des Portes V, Torrioli MG, Berry-Kravis E, Hagerman RJ, Ramos FJ, Cornish K, He Y, Paulding C, Neri G, Chen F, Hadjikhani N, Martinet D, Meyer J, Beckmann JS, Delange K, Brun A, Bussy G, Gasparini F, Hilse T, Floesser A, Branson J, Bilbe G, Johns D, Gomez-Mancilla B (2011) Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med 3:64ra61

    Article  Google Scholar 

  • Klein AB, Williamson R, Santini MA, Clemmensen C, Ettrup A, Rios M, Knudsen GM, Aznar S (2011) Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int J Neuropsychopharmacol 14:347–353

    Article  PubMed  CAS  Google Scholar 

  • Kotlinska J, Bochenski M (2008) The influence of various glutamate receptors antagonists on anxiety-like effect of ethanol withdrawal in a plus-maze test in rats. Eur J Pharmacol 598:57–63

    Article  PubMed  CAS  Google Scholar 

  • Lanz TA, Bove SE, Pilsmaker CD, Mariga A, Drummond EM, Cadelina GW, Adamowicz WO, Swetter BJ, Carmel S, Dumin JA, Kleiman RJ (2012) Robust changes in expression of brain-derived neurotrophic factor (BDNF) mRNA and protein across the brain do not translate to detectable changes in BDNF levels in CSF or plasma. Biomarkers 17:524–531

    Article  PubMed  CAS  Google Scholar 

  • Lauterborn JC, Rex CS, Kramar E, Chen LY, Pandyarajan V, Lynch G, Gall CM (2007) Brain-derived neurotrophic factor rescues synaptic plasticity in a mouse model of fragile X syndrome. J Neurosci 27:10685–10694

    Article  PubMed  CAS  Google Scholar 

  • Lindemann L, Jaeschke G, Michalon A, Vieira E, Honer M, Spooren W, Porter R, Hartung T, Kolczewski S, Buttelmann B, Flament C, Diener C, Fischer C, Gatti S, Prinssen EP, Parrott N, Hoffmann G, Wettstein JG (2011) CTEP: a novel, potent, long-acting, and orally bioavailable metabotropic glutamate receptor 5 inhibitor. J Pharmacol Exp Ther 339:474–486

    Article  PubMed  CAS  Google Scholar 

  • Lord C, Rutter M, Goode S, Heemsbergen J, Jordan H, Mawhood L, Schopler E (1989) Autism diagnostic observation schedule: a standardized observation of communicative and social behavior. J Autism Dev Disord 19:185–212

    Article  PubMed  CAS  Google Scholar 

  • Louhivuori V, Vicario A, Uutela M, Rantamaki T, Louhivuori LM, Castren E, Tongiorgi E, Akerman KE, Castren ML (2011) BDNF and TrkB in neuronal differentiation of Fmr1-knockout mouse. Neurobiol Dis 41:469–480

    Article  PubMed  CAS  Google Scholar 

  • Mann K, Kiefer F, Spanagel R, Littleton J (2008) Acamprosate: recent findings and future research directions. Alcohol Clin Exp Res 32:1105–1110

    Article  PubMed  CAS  Google Scholar 

  • Mayer S, Harris B, Gibson DA, Blanchard J, Prendergast MA, Holley RC, Littleton J (2002) Acamprosate has no effect on NMDA-induced toxicity but reduces toxicity induced by spermidine or by changing the medium in organotypic hippocampal slice cultures from rat. Alcohol Clin Exp Res 26:655–662

    Article  PubMed  CAS  Google Scholar 

  • Michalon A, Sidorov M, Ballard TM, Ozmen L, Spooren W, Wettstein JG, Jaeschke G, Bear MF, Lindemann L (2012) Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron 74:49–56

    Article  PubMed  CAS  Google Scholar 

  • Morichi S, Kashiwagi Y, Takekuma K, Hoshika A, Kawashima H (2013) Expressions of brain-derived neurotrophic factor (BDNF) in cerebrospinal fluid and plasma of children with meningitis and encephalitis/encephalopathy. Int J Neurosci 123:17–23

    Article  PubMed  CAS  Google Scholar 

  • Muma JR (1984) Semel and Wiig’s CELF: construct validity? J Speech Hear Disord 49:101–104

    PubMed  CAS  Google Scholar 

  • Naassila M, Hammoumi S, Legrand E, Durbin P, Daoust M (1998) Mechanism of action of acamprosate. Part I. Characterization of spermidine-sensitive acamprosate binding site in rat brain. Alcohol Clin Exp Res 22:802–809

    Article  PubMed  CAS  Google Scholar 

  • Niederhofer H, Staffen W (2003) Acamprosate and its efficacy in treating alcohol dependent adolescents. European Child Adolesc Psychiatry 12:144–148

    Article  Google Scholar 

  • Olmos-Serrano JL, Paluszkiewicz SM, Martin BS, Kaufmann WE, Corbin JG, Huntsman MM (2010) Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome. J Neurosci 30:9929–9938

    Article  PubMed  CAS  Google Scholar 

  • Olmos-Serrano JL, Corbin JG, Burns MP (2011) The GABA(A) receptor agonist THIP ameliorates specific behavioral deficits in the mouse model of fragile X syndrome. Dev Neurosci 33:395–403

    Article  PubMed  CAS  Google Scholar 

  • Palucha-Poniewiera A, Pilc A (2012) Involvement of mGlu5 and NMDA receptors in the antidepressant-like effect of acamprosate in the tail suspension test. Prog Neuropsychopharmacol Biol Psychiatry 39:102–106

    Article  PubMed  CAS  Google Scholar 

  • Pierrefiche O, Daoust M, Naassila M (2004) Biphasic effect of acamprosate on NMDA but not on GABAA receptors in spontaneous rhythmic activity from the isolated neonatal rat respiratory network. Neuropharmacology 47:35–45

    Article  PubMed  CAS  Google Scholar 

  • Pillai A, Kale A, Joshi S, Naphade N, Raju MS, Nasrallah H, Mahadik SP (2010) Decreased BDNF levels in CSF of drug-naive first-episode psychotic subjects: correlation with plasma BDNF and psychopathology. Int J Neuropsychopharmacol 13:535–539

    Article  PubMed  CAS  Google Scholar 

  • Pilpel Y, Kolleker A, Berberich S, Ginger M, Frick A, Mientjes E, Oostra BA, Seeburg PH (2008) Synaptic ionotropic glutamate receptors and plasticity are developmentally altered in the CA1 field of FMR1 KO mice. J Physiol

  • Price DR, Herbert DA, Walsh ML, Law JG Jr (1990) Study of WAIS-R, Quick Test and PPVT IQS for neuropsychiatric patients. Percept Mot Skills 70:1320–1322

    PubMed  CAS  Google Scholar 

  • Ray B, Gaskins DL, Sajdyk TJ, Spence JP, Fitz SD, Shekhar A, Lahiri DK (2011a) Restraint stress and repeated corticotrophin-releasing factor receptor activation in the amygdala both increase amyloid-beta precursor protein and amyloid-beta peptide but have divergent effects on brain-derived neurotrophic factor and pre-synaptic proteins in the prefrontal cortex of rats. Neuroscience 184:139–150

    Article  PubMed  CAS  Google Scholar 

  • Ray B, Long JM, Sokol DK, Lahiri DK (2011b) Increased secreted amyloid precursor protein-alpha (sAPPalpha) in severe autism: proposal of a specific, anabolic pathway and putative biomarker. PLoS One 6:e20405

    Article  PubMed  CAS  Google Scholar 

  • Reilly MT, Lobo IA, McCracken LM, Borghese CM, Gong D, Horishita T, Harris RA (2008) Effects of acamprosate on neuronal receptors and ion channels expressed in Xenopus oocytes. Alcohol Clin Exp Res 32:188–196

    Article  PubMed  CAS  Google Scholar 

  • Sansone SM, Widaman KF, Hall SS, Reiss AL, Lightbody A, Kaufmann WE, Berry-Kravis E, Lachiewicz A, Brown EC, Hessl D (2012) Psychometric study of the aberrant behavior checklist in fragile x syndrome and implications for targeted treatment. J Autism Dev Disord 42:1377–1392

    Article  PubMed  Google Scholar 

  • Scahill L, McDougle CJ, Williams SK, Dimitropoulos A, Aman MG, McCracken JT, Tierney E, Arnold LE, Cronin P, Grados M, Ghuman J, Koenig K, Lam KS, McGough J, Posey DJ, Ritz L, Swiezy NB, Vitiello B (2006) Children’s Yale-Brown Obsessive Compulsive Scale modified for pervasive developmental disorders. J Am Acad Child Adolesc Psychiatry 45:1114–1123

    Article  PubMed  Google Scholar 

  • Schmidt HD, Duman RS (2010) Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models. Neuropsychopharmacology 35:2378–2391

    Article  PubMed  CAS  Google Scholar 

  • Sparrow SS, Cicchetti DV (1985) Diagnostic uses of the Vineland Adaptive Behavior Scales. J Pediatr Psychol 10:215–225

    Article  PubMed  CAS  Google Scholar 

  • Uutela M, Lindholm J, Louhivuori V, Wei H, Louhivuori LM, Pertovaara A, Akerman K, Castren E, Castren ML (2012) Reduction of BDNF expression in Fmr1 knockout mice worsens cognitive deficits but improves hyperactivity and sensorimotor deficits. Genes Brain Behav 11:513–523

    Article  PubMed  CAS  Google Scholar 

  • Wei H, Dobkin C, Sheikh AM, Malik M, Brown WT, Li X (2012) The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome. PLoS One 7:e36981

    Article  PubMed  CAS  Google Scholar 

  • Yan QJ, Rammal M, Tranfaglia M, Bauchwitz RP (2005) Suppression of two major fragile X syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology 49:1053–1066

    Article  PubMed  CAS  Google Scholar 

  • Zhang S, Faries DE, Vowles M, Michelson D (2005) ADHD Rating Scale IV: psychometric properties from a multinational study as a clinician-administered instrument. Int J Methods Psychiatr Res 14:186–201

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work is supported by a grant from the Indiana Clinical and Translational Sciences Institute (CTSI; Dr. Erickson). The work is also supported, in part, by the Division of Disability & Rehabilitative Services, Indiana Family and Social Services Administration (Drs. Erickson, Wink); National Institute of Health grant KL2 UL1 RR025761 Indiana University Clinical, and Translational Sciences Institute Career Development Award (Dr. Erickson); NIH grant 5R01 AG 018884-10 (Dr. Lahiri); and NIMH grants R01 MH072964, R01 MH077600, and R01 MH083739 (Dr. McDougle). We would like to thank J.T. Diener, Jennifer Mullett, and Arlene Kohn for their assistance with this project.

Conflict of interest

Dr. Erickson is the inventor on intellectual property held by Indiana University related to use of acamprosate in fragile X syndrome and autism. Dr. Erickson holds equity in Confluence Pharmaceuticals, a company that has licensed this intellectual property from Indiana University.

Author information

Author notes

  1. Craig A. Erickson & Logan K. Wink

    Present address: Division of Child and Adolescent Psychiatry, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

Authors and Affiliations

  1. Department of Psychiatry, Indiana University School of Medicine, and James Whitcomb Riley Hospital for Children, Indianapolis, IN, USA

    Craig A. Erickson, Logan K. Wink, Balmiki Ray, Maureen C. Early, Elizabeth Stiegelmeyer, Lauren Mathieu-Frasier, Vanessa Patrick, Debomoy K. Lahiri & Christopher J. McDougle

  2. Lurie Center for Autism, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Christopher J. McDougle

  3. Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 4002, Cincinnati, OH, 45229, USA

    Craig A. Erickson

Authors
  1. Craig A. Erickson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Logan K. Wink
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Balmiki Ray
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maureen C. Early
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elizabeth Stiegelmeyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lauren Mathieu-Frasier
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vanessa Patrick
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Debomoy K. Lahiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christopher J. McDougle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Craig A. Erickson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Erickson, C.A., Wink, L.K., Ray, B. et al. Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open-label study in youth with fragile X syndrome. Psychopharmacology 228, 75–84 (2013). https://doi.org/10.1007/s00213-013-3022-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-013-3022-z

Keywords

Search

Navigation