Pelo presente instrumento particular de um lado a OTOSUL tinnitus

Document Sample
Pelo presente instrumento particular de um lado a OTOSUL  tinnitus Powered By Docstoc
					                                         RESEARCH PROJECT

                     TITLE: “Tinnitus treatment with piribedil guided by eletro-
                     cochleography and acoustic otoemissions”
                     RESPONSIBLE RESEARCHER: Andréia A. Azevedo ,MD
                     INSTITUTIONS: OTOSUL, Otorrinolaringologia Sul-
                     ADRESS: OTOSUL, Otorrinolaringologia Sul-Fluminense, Rua
                     40, n 20, Shopping 33, Vila Santa Cecília, Volta Redonda,RJ.


                     AIM: Establish eficcacy and safety of piribedil in sensori-
                     neural tinnitus` treatment, guided by eletrocochleography
                     and acoustic otoemissions
Rua 40, 20
Salas 216 a 218      ESTIMATED DURATION: 18 to 24 months
Shopping 33
Vila Santa Cecília          Aug 2006 to Feb 2008-       ministration of the drug
Volta Redonda -RJ
                                                        Complementary methods
(24) 3348-6382                                          Clinical evaluation
Homepage                                                Side effects control

                            August 2007 to September 2007 – data compilation
                            October 2007- statistical evaluation
                            November 2007- final compilation


                     Tinnitus is a very common symptom in patients that have a
                     sensori-neural hearing loss. An electrical stimulus in the audi-
                     tory pathway can induce or inhibit temporary auditory sensa-
                     A hearing loss can be originated from the external ear, middle
                     ear, inner ear and central auditory pathways. Associations
                     between these places are frequent.
                     The majority (about 90 %) of tinnitus is associated with a
                     hearing loss.
                     There is consensus in the literature about tinnitus generation
                     as an aberrant activity in the auditory pathways, with some
                     changes in the hair cell`s and neuron`s membrane electro-
                     chemical gradients, damaging the cochlear mechanics and it
                     can be checked by the evoked oto-emissions (EAOE).
                     There are some particularities that can help us getting closer
                     to which area is damaged:
                     1) Metz Recruitment-Hearing loss is associated. It occurs due
                     to inner ear elements` loss. So, more fibers have to be re-
                     cruited to perceive the same intensity in sound.
                     2)Hyperacusis-Normal hearing most of the times ,but there is
                     an intolerance to the lower sounds to moderate intensity.
Endereço             There is damage at the central processing to the sounds, and
Rua 40, 20           the cochlea is preserved.
Salas 216 a 218      3)Hyperacusis and hearing loss
Shopping 33
Vila Santa Cecília   Hyperacusis is a particular form of tinnitus, associated or not
Volta Redonda -RJ    to a conscient tinnitus.
Telefone             The peripheric origin can be associated in some cases:
(24) 3348-6382       3.a) Stapedium reflex dysfunction
Homepage             3.b) Cochlear origined -outer hair cells dysfunction
                     probably caused by traumatic noise.

                     3.c) Central abnormal gain at the auditory central neuron
                     (Jastreboff et Azell 1993), which makes it easier to detect the
                     signal not pertinent to the back sound, explaining a tinnitus
                     associated to hyperacusis.
                     Some authors (Klein et ALL ,1990; Phillips et Carr, 1998)
                     suggest that a central hyperacusis means a incapacity of the
                     Central Nervous System to suit the alarm answer(Marriage et
                     Barnes 1995).
                     Sound`s intolerance without periphery auditory symptons is
                     linked to serotonin metabolic reduction, which is responsible
                     for the cortical excitation gain.(Jacobs et Azmetri, 1992)
                     25 to 40% of the patients with tinnitus have hyperacusis and
                     they use to say it is the worst symptom.
                     Patients with hyperacusis and normal hearing can present
                     similar hearing thresholds. The intensity that causes discom-
                     fort is what change due tolerance to sounds reduction.
                     Hyperacusis can occur in normal hearing, in hearing loss and
                     in patients with severe tinnitus.
                     Most of the patients that have hearing losses have associated
                     tinnitus and many patients that have tinnitus have also
                     Our proposal is to approximate the most we can, to the poss-
                     ible damaged site, to make a better decision in drugs choice.
                     In this study, our aim is to focus our attention at the lateral
                     olivo- cochlear efferent system. Efferent inhibition lowers the
                     effective sensitivity of an efferent fiber, shifting its response
                     curve to higher sound pressure.
                     One of the consequences of this fact, is that the ear is them
                     able to encode a range of loud sounds that would ordinarily
                     saturate the cochlear response.
                     The efferent neurons are medial and lateral nuclei of the su-
                     perior olivary complex in the brainstem.
                     The medial make synapse contact directly on to outer hair
Rua 40, 20
Salas 216 a 218      cells in the cochlea.
Shopping 33          The second group, which is the focus of this study, is a small-
Vila Santa Cecília   er efferent arise in the lateral olive and forms synapses on
Volta Redonda -RJ
                     afferent fibers beneath the inner hair cells.
                     Dopamine is the principal efferent neurotransmitter at the
(24) 3348-6382
                     lateral olivoco-chlear bundle. It is not present in the medial
Homepage             olivo-cochlear bundle (Eybolim,1993;Puel, 1995).

                     Dopamine cause a neuron activity`s suppression and an an-
                     swer threshold capacity increase, suggesting that dopamine is
                     an inhibitory neurotransmitter at the primary auditory neu-
                     In other way, dopamine antagonists, increase the neurons`
                     activity and reduce the threshold, due to inhibition of dopa-
                     Dopamine exercises an inhibition in the initial auditory mes-
                     This system is a permanent gain suit adjusting the threshold
                     and the dynamic neurons answer due an entrance.
                     A dysfunction of this system could affect fibers from the the
                     cochlear nerve and could be the cause of some kinds of tinni-
                     This inhibitory action can be a protector mechanism to the
                     cochlear damage from glutamate excess.
                     Excitotoxicity involves the activation of glutamate receptors
                     in the central nervous system. The glutamate excess acting in
                     the same receptors, cause cell death because of the exces-
                     sive activation of these receptors. In physiological conditions,
                     the presence of glutamate in the synapse is regulated by ac-
                     tive ATP-dependent transporter in neurons or glia.
                     The neurons from the inner cells affected by the excitotoxicity
                     can regenerate and have the capacity to recover the synapse
                     with the inner hair cells. (Puel et al, 1995)
                     In this recover, the neurons modulate glutamate receptors, in
                     special NMDA (Puel, 1995; D`aldin 1997)
                     Glutamate will act without inhibition by the efference.
                     With double innervations the inner hair cells could be the
                     cause of some tinnitus. The efference directly contacting the
                     inner hair cells stimulate more the afference.
                     The eletrococleography (ECogh) demonstrates the real coch-
                     lear auditive thresholds and the cochlear recruitment.
Rua 40, 20
Salas 216 a 218      The Ecogh is important to register the electrical answer of the
Shopping 33          additive nerve. The auditive stimulus is followed by some
Vila Santa Cecília   peaks with an amplitude less than 01 Microvolt during 06 mil-
Volta Redonda -RJ
                     liseconds after the sound presentation.
(24) 3348-6382


                     Piribedil is a dopamin agonist that acts in the lateral olivo-
                     cochlear bundle. It is indicated in Parkinson disease, dizziness
                     and tinnitus and the usual prescription is 50 mg once a day
                     after the main meal. Adverse effects occur in about 4 % of
                     the cases, most of the gastro-intestinal, like nausea and dys-

                     MATERIAL AND METHOD:

                           100 patients with sensori-neural tinnitus will be se-
                     lected. The inclusion criteria are: exclusion of para-auditory
                     tinnitus (muscular and vascular tinnitus); exclusion of pa-
                     tients with TMJ disorders; normal otoscopy; exclusion of con-
                     ductive and mixed hearing losses; A-n tympanogram. Pa-
                     tients will have to quantify their tinnitus with a subjective
                     visual-analog scale (from 1 to 10) and also with the THI (Tin-
                     nitus Handicap Inventory). Evokated Acoustic oto-emissions
                     distortion products (EAOEPD) with and without contra-lateral
                     noise suppression will also be done, to determine if the outer
Endereço             hair cells are damaged. ABR and eletrocochleography will
Rua 40, 20
Salas 216 a 218      show how much the afference is affected and if the summat-
Shopping 33
Vila Santa Cecília   ing potential (and, thus, the inner hair cells) is affected. The
Volta Redonda -RJ
                     100 patients will be divided in two groups, according to the
(24) 3348-6382       the EAOEPD and ECoCh: Group 1, with 50 patients, will have
Homepage             patients   with   normal   summating   potential   and   altered
                     EAOEPD; Group 2 , also with 50 patients, will have patients
                     with altered summating potentials. In both groups, patients
                     will be randomized, so that 25 will receive piribedil, 50 mg
                     once a day (after lunch) and 25 placebo. They will be ana-
                     lyzed monthly for theirs THI and AVE grades. After 3 months,
                     we will have a 30 days period of wash-out and after that pa-
                     tients who received placebo will have piribedil and vice-versa
                     for 3 months more. We will monitore the grades for more 3
                     months after the end of medication. Our aim, with this selec-
                     tion, is to evaluate the drug therapy guided by the comple-
                     mentary methods (ECoch and EAOPD, in this case). Theoreti-
                     cally, piribedil should work better in patients with altered in-
                     ner hair cells function. Adverse effects will be noted. Data will
                     be statistically analyzed for efficacy and safety of the drug,
                     and   for statistically significant differences   between    the

                     INFRA-STRUCTURE:           Our      private     clinic    (OTO-
                     SUL,Otorrinolaringologia Sul-Fluminense) has all the equip-
                     ment necessary for the study.

Endereço             Double-channel audiometer AMPLAID A-177 Plus
Rua 40, 20
Salas 216 a 218      Automatic Imitanciometer AMPLAID 750
Shopping 33
Vila Santa Cecília   Acoustic Oto-emissions OTO-READ, INTERACOUSTICS
Volta Redonda -RJ
                     ABR and Eletrocochleography ECLIPSE, INTERACOUSTICS
(24) 3348-6382


                      1- Azevedo,AA e Figueiredo,RR: “Atualização em
                        zumbido”, Revista Brasileira de ORL, 2004,
                        70(1),Caderno de Debates, 27-40.
                      2- Breuel,MFB; Sanchez,T.G.; Bento,R.F.: “Vias Auditivas
                        Eferentes e seu papel no Sistema Auditivo”. Arq. Otor-
                        rin., 2001; 5(2): 62-7.
                      3- Parks, TN: “The AMPA receptors of auditory neurons”
                        Hearing Research, 2000, 147, 77-91.
                      4- Centre Régional D‟Imagerie Cellulaire (CRIC) http://
                      5- Anatomia e Audição:
                      6- Bonfils,P.;Puel,J-L, “Synapses cochléaires et
                        acouphènes”, in Meyer, B. et al. “Acouphènes et
Endereço                hyperacusie”, Société Française d‟Oto-rhino-laryngologie
Rua 40, 20
Salas 216 a 218         et de Chirurgie de la Face et du Cou, 2001, 96-106.
Shopping 33
Vila Santa Cecília    7- Peng,BG et al.: “Group I Metabotropic Glutamate recep-
Volta Redonda -RJ
                        tors in spiral ganglion neurons contribute to excitatory
(24) 3348-6382          neurotransmissions in cochlea”. Neuroscience,
Homepage                2004,123, 221-30

                     8- Angulo et al. “Subunit composition, kinetic and permea-
                       tion properties of AMPA receptors in single neocortical
                       nonpyramidal cells”. J. Neuroscience,1997,17, 6685-96.
                     9- Feldman, DE; Knudsen, EI: “NMDA and non-NMDA glu-
                       tamate receptors in auditory neurotransmission in the
                       barn owl inferior colliculus”. J. Neuroscience,1994,14,
                     10-    Molitor,SC; Manis,PB: “Evidence for functional me-
                       tabotropic glutamate receptors in the dorsal cochlear
                       nucleus”, J. Neurophysiology, 1997,77, 1889-1905.
                     11-    Fujino, K; Oertel,D.: „Bidirectional synaptic plastici-
                       ty in the cerebellum-like dorsal cochlear nucleus”. Proc
                       Natl Acad Sci USA, 2003,100,265-70
                     12-    Cunha,N.T.; Puel,J-L. “Zumbidos,presente e futuro
                       da investigação à aplicação clínica”, Associação
                       Portuguesa de Otoneurologia- Fórum-
                     13-    Boureau, F.;Meyer,B., “Analogies avec la douleur”,
                       in Meyer, B. et al. “Acouphènes et hyperacusie”, Société
                       Française d‟Oto-rhino-laryngologie et de Chirurgie de la
                       Face et du Cou, 2001,107-20.
Endereço             14-    Denk, DM; Heinzl,H; Franz P; Ehrenberger, K: “Ca-
Rua 40, 20
Salas 216 a 218        roverine in tinnitus treatment: a placebo-controlled
Shopping 33
Vila Santa Cecília     blinded study”. Acta Otolaryngol, 1997,117(6), 825-30.
Volta Redonda -RJ
                     15-    Oestreicher,E; Arnold,W; Ehrenberger, K; Felix,D:
(24) 3348-6382         “Memantine suppresses the glutamatergic neurotrans-
Homepage               mission of mammalian inner hair cells”. Journal for ORL
                       and related spec., 1998, 60 (1), 18-21.
                     16-    Westerberger, BD; Roberson, JB; Stach, BA. “A
                       double-blind placebo-controlled trial of baclofen in the
                       treatment of tinnitus”. Am Journal of Otolaryng ,1996,
                       17 (6), 896-903.
                     17-    Szczepaniak, WS; Moller, AR: “Effects of L- Baclo-
                       fen and D-Baclofen on the auditory system : a study of
                       click-evoked potentials from the inferior colliculus in the
                       rat:. Ann Otol Rhinol Laryng, 1995, 104 (5), 399-404.
                     18-    Monografia do Acamprosato, MERCK
                     19-    Azevedo,AA; Figueiredo, RR: “Uso do
                       Acamprosato no tratamento do zumbido”. Revista
                       Brasileira de ORL, 2005, 71 (5): 618-23.
                     20-    Parsons CG; Danysz W; Quack C: “Memantine is a
                       clinically well tolerated NMDA receptor antagonist- a re-
                       view of pre-clinical data”: Neuropharmacology, 1999,
                       38 (6): 735-67.
                     21-    Washington University of Saint Louis- School of
                     22-    Figueiredo, RR; Azevedo,AA: “Aminoácidos
                       neurotransmissores nas vias auditivas, Revista da
                       Sociedade de ORL do Rio de Janeiro, 2004 Abr/Jun, 4
Endereço               (2), 49-54
Rua 40, 20
Salas 216 a 218      23-    Azevedo,AA; Figueiredo,RR: “Uso da
Shopping 33
Vila Santa Cecília     trimetizidina no tratamento do zumbido”, Revista da
Volta Redonda -RJ
                       Sociedade de ORL do Rio de Janeiro, 2005 Jan/ Abr, 5
(24) 3348-6382         (1), 13-16.

                       24-     Fávero,ML: “Estudo das vias auditivas eferentes em
                          indivíduos com zumbido”, tese de
                          Doutorado,Universidade de São Paulo,2003.
                       25-     Eybalin,M: “Neurotransmitters and neuromodula-
                          tors of the mammalian cochlea”,Physiol. Rev, 73: 309-
                          73, 1993
                       26-     Puel,JL: “Chemical synaptic transmission in the
                          cochlea”, Prog Neurobiol 447:449-76,1995
                       27-     Ruel,J et al. “AMPA-preffering glutamate receptors
                          in cochlear physiology of adult guinea-pig”, J Physiology,
                          518 (pt3): 667-80,1999
                       28-     Ruel,J et al. “The selective AMPA receptor antagon-
                          ist GYKI 53784 blocks action potential generation and
                          excitotoxicity in the guinea pig cochlea, Neuropharma-
                          cology, 39 (11): 1959-73, 2000
                       29-     D`Aldin,CG et al. “Implication of NMDA type gluta-
                          mate receptors in neural regeneration and neoformation
                          of synapses after excitotoxicity injuries in the guinea pig
                          cochlea”, Int J Dev Neurosci, 15: 619-29, 1997

Rua 40, 20
Salas 216 a 218
Shopping 33
Vila Santa Cecília   ETHICAL ASPECTS
Volta Redonda -RJ
(24) 3348-6382
Homepage             RISKS AND BENEFITS: Piribedil is a safe drug, with rare
                     and mild side effects. Expected benefits are decrease of tinni-
                     tus, with an improvement in quality of life and psychological
                     aspects, and also achieving a more rational guideline for drug
                     therapy. The possibility that piribedil could worse tinnitus is
                     very remote. The study has the approval of the Ethical Medi-
                     cal Research Comitee of the Valença Medical School, in Va-
                     lença, state of Rio de Janeiro. Every patient will sign the Term
                     of Consentiment

                     PLACEBO: The use of placebo is fundamental to evaluate the
                     real action of the drug, eliminating other improvement fac-
                     tors, like psychologic factors and physician-patient interac-
                     tion. We will use amid, which is safe and has no action in
                     sensori-neural tinnitus.

                                                               Andréia Azevedo,MD
                                                             Ricardo Figueiredo,MD

Rua 40, 20
Salas 216 a 218
Shopping 33
Vila Santa Cecília
Volta Redonda -RJ
(24) 3348-6382


Shared By:
Description: Pelo presente instrumento particular de um lado a OTOSUL tinnitus