A Promising Drug therapy for Cochlear Synaptic Tinnitus

1. “CAROVERINE” A Promising Drug therapy for Cochlear Synaptic Tinnitus INTRODUCTION Tinnitus, referred as the ringing or noise in the ear is a purely subjective experience. 60% of the inner ear diseases cause tinnitus. Symptoms may include hearing buzzing, roaring, ringing, whistling, or hissing sounds. These sounds may be intermittent, continuous, or pulsatile. Tinnitus may interfere with the normal activities and sleep, and there may be an associated decrease in the ability to hear conversations or other sounds in the environment. Tinnitus is estimated to affect about 35 to 45% of adults over 17 years of age at some point of time in their lives as a temporary or permanent disturbance. Around 8% people find ringing in the ear as a nuisance in their everyday lives and about 1% is incapacitated by the condition. Unfortunately, no consistently effective and well-tolerated drug was available for the treatment of tinnitus. Till date some anti epileptics, anti anxiety agents, antidepressants, and vasodilators were used in tinnitus with some vague, empirical success. 1

2. The neurotransmitter glutamate is implicated in the pathophysiology of cochlear synaptic tinnitus. As the name suggests, it is caused due to functional disturbances of the synapse between the internal hair cells and the afferent dendrites of the auditory nerves. The cochlear synapse has the following characteristics: ● Glutamate is responsible for neurotransmission (Felix and Ehrenberger, 1990; Ehrenberger and Felix 1991 and 1995; Pujol R et al., 1993). ● Two different receptor types work as a dual receptor system: NMDA (N-methyl-D-aspartate) and non-NMDA-receptors (Quisqualate, Kainate) on the sub synaptic membrane (Felix and Ehrenberger, 1990; Ehrenberger and Felix 1991 and 1995; Pujol R et al., 1993). 2

3. In a physiological state​​, a typical pattern of depolarization results from the interplay of the dual receptor mechanism which is responsible for the normal undisturbed hearing. ​Under pathological conditions​​, spontaneous receptor-dependent depolarization patterns mimic sound-induced patterns, which are different from the normal pattern. These sound induced patterns are perceived as tinnitus (Felix and Ehrenberger, 1990; Ehrenberger and Felix 1991 and 1995; Pujol R et al., 1993; Ehrenberger K, D. -M.Denk and Felix D 1995). These forms of tinnitus occur when the physiological activity of the NMDA and AMPA receptors at the sub synaptic membranes of inner hair cell afferents is disturbed (Felix and Ehrenberger, 1990; Ehrenberger and Felix 1991 and 1995; Pujol R et al., 1993; Ehrenberger K, D. -M.Denk and Felix D 1995). Since Caroverine had a quinoxaline-dione structure, it was investigated for glutamate antagonistic activity and later on was developed as a therapy for cochlear synaptic tinnitus. Caroverine acted as a potent competitive (AMPA) receptor antagonist. In higher doses, it acts as a non-competitive (NMDA) antagonist. Glutamate is believed to be the neurotransmitter of the afferent cochlear synapses of the hair cell of the inner ear, which has a key function in tinnitus. Due to the property of glutamate antagonism, Caroverine, has a neuroprotective action by reversing the spontaneous depolarization state in tinnitus cases. (Felix D and Ehrenberger K, 1990). The therapeutic benefits of Caroverine in tinnitus have been confirmed in clinical trials sponsored by Phafag AG, Schaanwald, Liechtenstein. 3

4. These clinical studies have confirmed the above hypothesis and established Caroverine as an effective treatment available for cochlear synaptic tinnitus​. Tinnitus relief was achieved in 55-66% of patients in these trials and the treatment was generally well tolerated. Who can be benefited? Step 1 Diagnosis: (Confirmation of Cochlear Synaptic Tinnitus) Cochlear origin subjective tinnitus ​(Cochlear Synaptic tinnitus) is the only condition where Caroverine will work. Please note that 90% of the patients coming to the ENT surgeon with tinnitus are of cochlear synaptic tinnitus. For the purpose of perfect diagnosis and differentiating cochlear synaptic tinnitus from Middle ear and retro-cochlear tinnitus, following investigations are must. ● High frequency audiometry 0-16KHz (PTA- HF) ● Impedance audiometry (IA) ● Eustachian Tube Function Test (ETFT) ● Acoustic Reflexes (AR) Ipsi & Contra both ● Clinching Reflex Test- To rule out tinnitus of middle ear origin ● Reflex decay (RD) – to rule out cochlear Synaptic tinnitus ● Tinnitus matching (Frequency of tinnitus what patient hears) ● Tinnitus grading (Intensity of tinnitus) ● SISI Test (additional confirmatory test for cochlear pathology) ● ENG, E.CochG, BERA, are additional investigations which some patients may need. 4

5. Step II Who can have benefit with Caroverine? ● Age of patient – Any age group ● Sex – any sex ● Tinnitus diagnosed (unilateral or bilateral) ● Type: only subjective (cochlear synaptic) ● Duration of tinnitus – any duration: recent origin to since several years ● Hearing loss – with or without hearing loss Exclusion criteria: The following characteristics should be excluded before starting Caroverine therapy: ● Objective tinnitus ● Persistent presence of causative pathology, which may cause immediate recurrence of tinnitus by creating spontaneous depolarization again. Foe example: active middle ear pathology. ● Retro cochlear hearing defect ● Conductive hearing defect – with active middle ear pathology ● Masticatory movements influencing subjective tinnitus sensation (Tinnitus of middle ear origin) ● Reasonable doubts as to patient’s ability or intention to co-operate – Psychologically disturbed patients ● Concomitant disorder that might influence the results. For example: multiple sclerosis or similar neural disorders 5

6. ● Pregnancy or plans of having children ● Hydrops cochleae or Meiniere’s disease – in such cases, Cure vertigo first ● Pulse-synchronous tinnitus (Pulsatile tinnitus ) ● Excessive consumption of alcohol, drugs or nicotine ● Intolerance/ sensitivity to Caroverine ● Concomitant medication that might influence the result, and ● Medical therapy of tinnitus within one week of medication. The following groups of drugs should be prohibited during 7 days prior to the infusion and until 1 week after the infusion. ● Cytotoxic drugs (ototoxic) ● Furosemide (ototoxic) ● Streptomycin (ototoxic) ● Psychopharmaceuticals ● Muscle relaxants Any other treatment concurrently is not allowed. Medication and administration: Ampoules containing Caroverine (as hydrochloride) 160 mg in 8 ml in 100 ml of normal saline and administered as infusion at a rate of 2 ml/min till the therapeutic effect was achieved or complete dose was administered. (i.e. up to 1 hour). 6

7. Patients should be examined prior to infusion, immediately after the infusion and 4 weeks after the infusion. Antidote:- In case of worsening of tinnitus, an antidote infusion containing glutamic acid should be kept ready. The maximum dosage that can be administered is 160 mg for Caroverine. Please note: serious toxic dose is 156 mg/kg body weight as established in preclinical trials. Hence, the recommended dose here is very safe. Efficacy assessment:​​ (Result assessment) Efficacy assessment should be carried out before infusion, immediately after the infusion and 4 weeks after the infusion. Post therapy hearing evaluation is recommended. 7

8. Gradation of Tinnitus (Gradation card) Patients are asked to rate their tinnitus on a scale of 0-10 where; 0 = no tinnitus 10 = tormenting tinnitus Subsequent to the infusion the evaluation of drug response was made on the basis of subjective rating by the patients on the scale of 0-10. The patient showing improvement of 2 points on the subjective scale of 0-10 was assessed to be the responder. DISCUSSION ● As per the results of the clinical trials 55 to 66 % patients with cochlear synaptic tinnitus showed positive results in the form of cure of tinnitus or reduction in the intensity of tinnitus. ● The causes of NO response could be: 1. With False diagnosis (Non cochlear lesion) 2. Combined lesions (Cochlear and retro cochlear) 3. Persistent existence of damaging pathology ● Associated hearing problems, sleep disturbances, vertigo, and duration of tinnitus had no significant relationship with response to Caroverine. 8

9. ● Delay responder mechanism is unexplained. ● No Correlation between the demographic characteristics of patients and response obtained. (age, sex, caste, etc) The fact that only a single Caroverine injection produced the desired long term effect may be explained by a pharmacological tuning of different ionotropic glutamate receptors, re-establishing physiological depolarization patterns (Ehrenberger K, Felix D Acta Otolaryngol 1995, Denk D-M, Felix D, Ehrenberger K. 1994). The findings support the working hypothesis that cochlear-synaptic tinnitus can be treated with glutamate antagonists like Caroverine. Our Results are consistent to other published clinical trials. References: 1. Denk D-M, Felix D, Ehrenberger K. Caroverine for therapy of cochlear synaptic tinnitus. In: Proceedings of Inner Ear Neuropharmacology, Montpellier, 1994 2. Denk D-M, Brix R, Felix D, Ehrenberger K.Tinnitus therapy with transmitters .In: Aran JM, Dauman R, eds Tinnitus 91.Amsterdam: Kugler, 1992:119-21. 3. Doris –Maria Denk, Herald Heinzl, Peter Franz and Klaus. Caroverine in tinnitus treatment, a placebo controlled blind study. Acta Otolaryngol (Stockh) 1997; 117; 825-830 9

10. 4. Drian M. -J., Kamenka J. -M, Pirat J. -L. and Privat A. Non-competitive antagonists of N-Methyl-D aspartate prevent spontaneous neuronal death in primary cultures of embryonic rat cortex. J. Neurosci Res 1991; 29: 133-138 5. Dubinsky J M and Rothman St.M. Intracellular calcium concentrations during “chemical hypoxia” and excitotoxic neuronal injury. J Neurosci. 1991; 11:2545-2551 6. Ehrenberger K, Felix D.Receptor pharmacological models for inner ear therapies with emphasis on glutamate receptor: A survey. Acta Otolaryngol (Stockh) 1995; 115:236-40 7. Ehrenberger K, D. -M.Denk. Felix D. Receptor pharmacological models for a causal tinnitus therapy. Otorhinologia Nova 1995; pages 148-152.. 8. Ehrenberger K, Felix D. Glutamate receptors in afferent cochlear neurotransmission in guinea pigs. Hear Res 1991; 52; 73-80 9. Ehrenberger K, FelixD. Glutamate receptors in afferent cochlear neurotransmission in guinea pigs. Hear Res 1991; 52; 73-80 10. Ehrengberger K and Felix D. Caroverine depresses the activity of cochlear glutamate receptors in guinea pigs: in vivo model for drug-induced neuroprotection? Neuropharmacology 1992; 31(12): 1259-1263. 11. Eybalin M. Neurotransmission and neuromodulators of the mammalian cochlea . Physiol Rev 1993; 73:309-73 10

11. 12. Felix D and Ehrenberger K (1990) a microiontophoretic study of the role of excitatory amino acids at the afferent synapses of mammalian inner hair cells. Eur Arch Otorhinololaryngol 1990; 248:1-3. 13. Pujol R, Puel JL, Gervais d’Aldin C, EybalinM. Pathophysiology of the glutaminergic synapses in the cochlea. Acta Otolaryngol (Stockh) 1993; 113:330-4 Contact address: - Dr.Vinod Khandhar, ​​MD.,D.L.O.,M.S. (ENT),M.S. (General Surgery),LL.B., “Swarsudha Cochlear Implant Research Foundation And Microsurgery Clinic” 5​th​ Floor, Medicare Building, Behind Town Hall, Ahmedabad 380 006 Ph: - +91 79 6575330 / 6585330 /6588330 M: - +919824047807 Email: - ​khandhar@satyam.net.in 11