Skip to main content
Log in

Effects of extracochlear gacyclidine perfusion on tinnitus in humans: a case series

  • Otology
  • Published:
European Archives of Oto-Rhino-Laryngology Aims and scope Submit manuscript

Abstract

Gacyclidine, a non-competitive NMDA receptor antagonist, is a phencyclidine derivative with neuroprotective properties. It has been previously safely administered intravenously to acute traumatic brain-injured patients. Experiments in guinea pigs have shown that local administration of gacyclidine to the cochlea can suppress salicylate-induced tinnitus. Thus, we thought that patients with therapy-resistant sensorineural tinnitus might benefit from a local therapy with gacyclidine. As a compassionate treatment, we administered aqueous gacyclidine solution via a Durect RWμCathTM into the round window niche in six patients with unilateral deafness associated with tinnitus. The response of each patient to the drug treatment was given a numerical value by the use of a visual analogue scale (VAS) on a scale of 0–10 for tinnitus intensity, where 0 represented no tinnitus and 10 represented unbearable tinnitus-intensity or -annoyance (subjective). After constant perfusion of gacyclidine for 40–63 h, four out of six patients experienced a temporary relief from their tinnitus. No serious side effects were recorded in any of the cases. Gacyclidine might present a potent drug for the suppression of sensorineural tinnitus in humans and therefore should be considered for future double-blinded, placebo-controlled clinical trials. For lasting effective treatment, controlled intracochlear and long-term delivery of the drug seems to be necessary. Further studies investigating the toxicological effects of gacyclidine intracochlear perfusion as well as different dosages and therapy durations are under way to ensure the safety of the drug for long-term human use and warrant clinical trials.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Andersson G, Lyttkens L (1996) Acupuncture for tinnitus: time to stop? Scand Audiol 25:273–275

    CAS  PubMed  Google Scholar 

  2. Chen Z, Ulfendahl M, Ruan R, Tan L, Duan M (2003) Acute treatment of noise trauma with local caroverine application in the guinea pig. Acta Otolaryngol 123:905–909

    CAS  PubMed  Google Scholar 

  3. Chen Z, Ulfendahl M, Ruan R, Tan L, Duan M (2004) Protection of auditory function against noise trauma with local caroverine administration in guinea pigs. Hear Res 197:131–136

    Article  CAS  PubMed  Google Scholar 

  4. Costa E (1998) From GABAA receptor diversity emerges a unified vision of GABAergic inhibition. Annu Rev Pharmacol Toxicol 38:321–350

    Article  CAS  PubMed  Google Scholar 

  5. Czuczwar SJ, Patsalos PN (2001) The new generation of GABA enhancers. Potential in the treatment of epilepsy. CNS Drugs 15:339–350

    Article  CAS  PubMed  Google Scholar 

  6. Denk DM, Heinzl H, Franz P, Ehrenberger K (1997) Caroverine in tinnitus treatment. A placebo-controlled blind study. Acta Otolaryngol 117:825–830

    Article  CAS  PubMed  Google Scholar 

  7. Dobie RA, Sakai CS, Sullivan MD, Katon WJ, Russo J (1993) Antidepressant treatment of tinnitus patients: report of a randomized clinical trial and clinical prediction of benefit. Am J Otol 14:18–23

    CAS  PubMed  Google Scholar 

  8. Duckert LG, Rees TS (1984) Placebo effect in tinnitus management. Otolaryngol Head Neck Surg 92:697–699

    CAS  PubMed  Google Scholar 

  9. Ehrenberger K (2005) Topical administration of caroverine in somatic tinnitus treatment: proof-of-concept study. Int Tinnitus J 11:34–37

    CAS  PubMed  Google Scholar 

  10. Feldblum S, Arnaud S, Simon M, Rabin O, D’Arbigny P (2000) Efficacy of a new neuroprotective agent, gacyclidine, in a model of rat spinal cord injury. J Neurotrauma 17:1079–1093

    Article  CAS  PubMed  Google Scholar 

  11. Galici R, Pinna G, Stephens DN, Schneider HH, Turski L (1998) Tolerance to and dependence on alprazolam are due to changes in GABAa receptor function and are independent of exposure to experimental set-up. Restor Neurol Neurosci 12:233–237

    CAS  PubMed  Google Scholar 

  12. Goldstein BA, Shulman A (2003) Tinnitus outcome profile and tinnitus control. Int Tinnitus J 9:26–31

    PubMed  Google Scholar 

  13. Guitton MJ, Caston J, Ruel J, Johnson RM, Pujol R, Puel JL (2003) Salicylate induces tinnitus through activation of cochlear NMDA receptors. J Neurosci 23:3944–3952

    CAS  PubMed  Google Scholar 

  14. Henry JA, Schechter MA, Loovis CL, Zaugg TL, Kaelin C, Montero M (2005) Clinical management of tinnitus using a “progressive intervention” approach. J Rehabil Res Dev 42:95–116

    Article  PubMed  Google Scholar 

  15. Hesse G (2008) Neurootologic and psychosomatic habituation therapy. Treatment approaches in chronic tinnitus. HNO 56:686–693

    Article  CAS  PubMed  Google Scholar 

  16. Hester TO, Theilman G, Green W, Jones RO (1998) Cyclandelate in the management of tinnitus: a randomized, placebo-controlled study. Otolaryngol Head Neck Surg 118:329–332

    Article  CAS  PubMed  Google Scholar 

  17. Hirbec H, Gaviria M, Vignon J (2001) Gacyclidine: a new neuroprotective agent acting at the N-methyl-d-aspartate receptor. CNS Drug Rev 7:172–198

    CAS  PubMed  Google Scholar 

  18. Hirbec H, Kamenka JM, Privat A, Vignon J (2001) Characterization of ‘non-N-methyl-d-aspartate’ binding sites for gacyclidine enantiomers in the rat cerebellar and telencephalic structures. J Neurochem 77:190–201

    CAS  PubMed  Google Scholar 

  19. Hirbec H, Mausset AL, Kamenka JM, Privat A, Vignon J (2002) Re-evaluation of phencyclidine low-affinity or “non-NMDA” binding sites. J Neurosci Res 68:305–314

    Article  CAS  PubMed  Google Scholar 

  20. Holgers KM, Axelsson A, Pringle I (1994) Ginkgo biloba extract for the treatment of tinnitus. Audiology 33:85–92

    Article  CAS  PubMed  Google Scholar 

  21. Hulshof JH, Vermeij P (1987) The effect of nicotinamide on tinnitus: a double-blind controlled study. Clin Otolaryngol Allied Sci 12:211–214

    Article  CAS  PubMed  Google Scholar 

  22. Hulshof JH, Vermeij P (1985) The value of carbamazepine in the treatment of tinnitus. ORL J Otorhinolaryngol Relat Spec 47:262–266

    CAS  PubMed  Google Scholar 

  23. Hulshof JH, Vermeij P (1986) The value of flunarizine in the treatment of tinnitus. ORL J Otorhinolaryngol Relat Spec 48:33–36

    CAS  PubMed  Google Scholar 

  24. Hulshof JH, Vermeij P (1985) The value of tocainide in the treatment of tinnitus. A double-blind controlled study. Arch Otorhinolaryngol 241:279–283

    Article  CAS  PubMed  Google Scholar 

  25. Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vockler J, Dikranian K, Tenkova TI, Stefovska V, Turski L, Olney JW (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283:70–74

    Article  CAS  PubMed  Google Scholar 

  26. Johnson RM, Brummett R, Schleuning A (1993) Use of alprazolam for relief of tinnitus. A double-blind study. Arch Otolaryngol Head Neck Surg 119:842–845

    CAS  PubMed  Google Scholar 

  27. Kay NJ (1981) Oral chemotherapy in tinnitus. Br J Audiol 15:123–124

    Article  CAS  PubMed  Google Scholar 

  28. Kopke RD, Coleman JK, Liu J, Campbell KC, Riffenburgh RH (2002) Candidate’s thesis: enhancing intrinsic cochlear stress defenses to reduce noise-induced hearing loss. Laryngoscope 112:1515–1532

    Article  CAS  PubMed  Google Scholar 

  29. Krystal JH, D’Souza DC, Mathalon D, Perry E, Belger A, Hoffman R (2003) NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology (Berl) 169:215–233

    Article  CAS  Google Scholar 

  30. Lenarz T (1986) Treatment of tinnitus with lidocaine and tocainide. Scand Audiol Suppl 26:49–51

    CAS  PubMed  Google Scholar 

  31. Lenarz T, Gulzow J (1985) Tinnitus therapy with lidocaine and tocainide. Laryngol Rhinol Otol (Stuttg) 64:604–608

    Article  CAS  Google Scholar 

  32. Lepeintre JF, D’Arbigny P, Mathe JF, Vigue B, Loubert G, Delcour J, Kempf C, Tadie M (2004) Neuroprotective effect of gacyclidine. A multicenter double-blind pilot trial in patients with acute traumatic brain injury. Neurochirurgie 50:83–95

    PubMed  Google Scholar 

  33. Moller AR (1997) A double-blind placebo-controlled trial of baclofen in the treatment of tinnitus. Am J Otol 18:268–269

    CAS  PubMed  Google Scholar 

  34. Muly SM, Gross JS, Potashner SJ (2004) Noise trauma alters d-[3H]aspartate release and AMPA binding in chinchilla cochlear nucleus. J Neurosci Res 75:585–596

    Article  CAS  PubMed  Google Scholar 

  35. Newman CW, Sandridge SA, Jacobson GP (1998) Psychometric adequacy of the tinnitus handicap inventory (THI) for evaluating treatment outcome. J Am Acad Audiol 9:153–160

    CAS  PubMed  Google Scholar 

  36. Niedzielski AS, Safieddine S, Wenthold RJ (1997) Molecular analysis of excitatory amino acid receptor expression in the cochlea. Audiol Neurootol 2:79–91

    Article  CAS  PubMed  Google Scholar 

  37. Nordang L, Cestreicher E, Arnold W, Anniko M (2000) Glutamate is the afferent neurotransmitter in the human cochlea. Acta Otolaryngol 120:359–362

    Article  CAS  PubMed  Google Scholar 

  38. Oestreicher E, Arnold W, Ehrenberger K, Felix D (1998) Memantine suppresses the glutamatergic neurotransmission of mammalian inner hair cells. ORL J Otorhinolaryngol Relat Spec 60:18–21

    CAS  PubMed  Google Scholar 

  39. Oestreicher E, Arnold W, Ehrenberger K, Felix D (1999) New approaches for inner ear therapy with glutamate antagonists. Acta Otolaryngol 119:174–178

    Article  CAS  PubMed  Google Scholar 

  40. Oestreicher E, Ehrenberger K, Felix D (2002) Different action of memantine and caroverine on glutamatergic transmission in the mammalian cochlea. Adv Otorhinolaryngol 59:18–25

    CAS  PubMed  Google Scholar 

  41. Oliver D, Ludwig J, Reisinger E, Zoellner W, Ruppersberg JP, Fakler B (2001) Memantine inhibits efferent cholinergic transmission in the cochlea by blocking nicotinic acetylcholine receptors of outer hair cells. Mol Pharmacol 60:183–189

    CAS  PubMed  Google Scholar 

  42. Olney JW (2002) New insights and new issues in developmental neurotoxicology. Neurotoxicology 23:659–668

    Article  CAS  PubMed  Google Scholar 

  43. Paaske PB, Pedersen CB, Kjems G, Sam IL (1991) Zinc in the management of tinnitus. Placebo-controlled trial. Ann Otol Rhinol Laryngol 100:647–649

    CAS  PubMed  Google Scholar 

  44. Perucca E, Jackson P (1985) A controlled study of the suppression of tinnitus by lidocaine infusion: (relationship of therapeutic effect with serum lidocaine levels). J Laryngol Otol 99:657–661

    Article  CAS  PubMed  Google Scholar 

  45. Pujol R, Puel JL (1999) Excitotoxicity, synaptic repair, and functional recovery in the mammalian cochlea: a review of recent findings. Ann N Y Acad Sci 884:249–254

    Article  CAS  PubMed  Google Scholar 

  46. Rosenberg SI, Silverstein H, Rowan PT, Olds MJ (1998) Effect of melatonin on tinnitus. Laryngoscope 108:305–310

    Article  CAS  PubMed  Google Scholar 

  47. Rowland LM, Astur RS, Jung RE, Bustillo JR, Lauriello J, Yeo RA (2005) Selective cognitive impairments associated with NMDA receptor blockade in humans. Neuropsychopharmacology 30:633–639

    Article  CAS  PubMed  Google Scholar 

  48. Schwab B, Lenarz T, Heermann R (2004) Use of the round window micro cath for inner ear therapy—results of a placebo-controlled, prospective study on chronic tinnitus. Laryngorhinootologie 83:164–172

    Article  CAS  PubMed  Google Scholar 

  49. Schwarz JB, Gibbons SE, Graham SR, Colbry NL, Guzzo PR, Le VD, Vartanian MG, Kinsora JJ, Lotarski SM, Li Z, Dickerson MR, Su TZ, Weber ML, El-Kattan A, Thorpe AJ, Donevan SD, Taylor CP, Wustrow DJ (2005) Novel cyclopropyl beta-amino acid analogues of pregabalin and gabapentin that target the alpha2-delta protein. J Med Chem 48:3026–3035

    Article  CAS  PubMed  Google Scholar 

  50. Sekiya T, Shimamura N, Hatayama T, Suzuki S (2000) Effectiveness of preoperative administration of an N-methyl-d-aspartate antagonist to enhance cochlear neuron resistance to intraoperative traumatic stress: an experimental study. J Neurosurg 93:90–98

    Article  CAS  PubMed  Google Scholar 

  51. Simpson JJ, Donaldson I, Davies WE (1998) Use of homeopathy in the treatment of tinnitus. Br J Audiol 32:227–233

    CAS  PubMed  Google Scholar 

  52. Soholm B (1998) Clinical improvement of memory and other cognitive functions by Ginkgo biloba: review of relevant literature. Adv Ther 15:54–65

    CAS  PubMed  Google Scholar 

  53. Spangler EL, Bresnahan EL, Garofalo P, Muth NJ, Heller B, Ingram DK (1991) NMDA receptor channel antagonism by dizocilpine (MK-801) impairs performance of rats in aversively motivated complex maze tasks. Pharmacol Biochem Behav 40:949–958

    Article  CAS  PubMed  Google Scholar 

  54. Stahl SM (2004) Anticonvulsants and the relief of chronic pain: pregabalin and gabapentin as alpha(2)delta ligands at voltage-gated calcium channels. J Clin Psychiatry 65:596–597

    Article  PubMed  Google Scholar 

  55. Stoney PJ, Callaghan DE, Walker FS, Stephens SD (1991) A controlled trial of azapropazone in tinnitus. Br J Audiol 25:415–417

    Article  CAS  PubMed  Google Scholar 

  56. Sugimoto M, Uchida I, Mashimo T (2003) Local anaesthetics have different mechanisms and sites of action at the recombinant N-methyl-d-aspartate (NMDA) receptors. Br J Pharmacol 138:876–882

    Article  CAS  PubMed  Google Scholar 

  57. Sullivan M, Katon W, Russo J, Dobie R, Sakai C (1993) A randomized trial of nortriptyline for severe chronic tinnitus. Effects on depression, disability, and tinnitus symptoms. Arch Intern Med 153:2251–2259

    Article  CAS  PubMed  Google Scholar 

  58. Taylor CP (1997) Mechanisms of action of gabapentin. Rev Neurol (Paris) 153(Suppl 1):S39–S45

    Google Scholar 

  59. Vandame D, Desmadryl G, Becerril Ortega J, Teigell M, Crouzin N, Buisson A, Privat A, Hirbec H (2007) Comparison of the pharmacological properties of GK11 and MK801, two NMDA receptor antagonists: towards an explanation for the lack of intrinsic neurotoxicity of GK11. J Neurochem 103:1682–1696

    Article  CAS  PubMed  Google Scholar 

  60. Westerberg BD, Roberson JB Jr, Stach BA (1996) A double-blind placebo-controlled trial of baclofen in the treatment of tinnitus. Am J Otol 17:896–903

    CAS  PubMed  Google Scholar 

  61. Zenner HP, Ruppersberg JP, Busch A (2000) Method for treating diseases of the inner ear using adamantane derivatives. US Patent No. 6,066,652

Download references

Acknowledgments

We herein thank NeuroSystec-Company for providing gacyclidine, Thomas J. Lobl for valuable comments and Isaac Ruperto Ayala for the illustration in Fig. 1.

Conflict of interest statement

The compassionate treatment has been sponsored by the Medical University.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gentiana Ioana Wenzel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wenzel, G.I., Warnecke, A., Stöver, T. et al. Effects of extracochlear gacyclidine perfusion on tinnitus in humans: a case series. Eur Arch Otorhinolaryngol 267, 691–699 (2010). https://doi.org/10.1007/s00405-009-1126-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00405-009-1126-1

Keywords

Navigation