PENATALAKSANAAN

TINITUS

Dr Widayat Alviandi SpTHT

Sub-Dept
Dr. Widayat Neurotologi THT
Alviandi, Sp. THT
FKUI/RSCM
Jakarta, 20 JulyJakarta
2002
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Tinnitus Retraining Therapy (TRT)
• Model neuropatofisiologi dari Jastreboff
• Tujuan :
1. Menghilangkan fikiran negatif/rasa takut
akibat persepsi tinitus
2. Menghilangkan persepsi bunyi tinitus
• Cara :
1. Konseling terpimpin
2. Terapi akustik (sound therapy)

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Kategori Kriteria
0 Derajat gangguan tidak ada - ringan
Onset akut
Tidak ada gangguan pendengaran &
hiperakusis
1 Derajat gangguan ringan
Tidak ada gangguan pendengaran &
hiperakusis
2 Derajat gangguan sedang
Gangguan pendengaran (+)
Tidak ada hiperakusis atau
perburukan pasca pajanan suara
3 Hiperakusis +
Keluhan subyektif tidak relevan
Tidak ada perburukan pasca pajanan
4 Hiperakusis
Perburukan pasca pajanan suara
Tipe TRT
Konseling terpimpin
Terapi akustik sewaktu – waktu
Konseling terpimpin
Terapi akustik bila perlu wearable sound
generator
Konseling terpimpin
ABD dengan sound generator (intrumen
kombinasi)
Konseling terpimpin
Wearable sound generator atau instrumen
kombinasi
Jarang dijumpai + sulit di terapi
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 Korteks Auditori dan Area Korteks lain
Persepsi & Evaluasi (Kesadaran, Memori, Atensi)

Auditori Bawah Sistim Limbik

Sadar
Deteksi / Proses

Auditorik Perifer
Suara yang dikenal

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 Medikamentosa
• Vasodilator : golongan Histin, Nimodipin,
antagonis Kalsium
• Anti kejang : Gabapentin
• Psikoaktif : Alprazolam
• Vitamin dan mineral :
sianokobalamin/mekobalamin, Zn, Mg, Ca
• Herbal :GINKGOBILOBA

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• Metode : disuntikkan , tuba ventilasi + obat
tetes
• Pilihan : lidokain, steroid, aminoglikosida
• Steroid intratimpani mempunyai efektifitas 70
– 90 %, terutama pada pasien dengan penyakit
Meniere

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• Gangguan vaskularisasi dan oksigenisasi
koklea  gangguan pendengaran + tinitus
• Terapi hiperbarik  meningkatkan kadar
oksigen 5 x
• Fanzca (2005)  perbaikan skor VAS pasca
terapi 3,1 vs 0,4
• Lamm (2003)  50 penelitian klinis, 85,3 %
perbaikan

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Repetitive Transcranial Magnetic Stimulation

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 PERANAN EKSTRAK
GINKGOBILOBA
(EGb)761 PADA TINITUS
Dr. Widayat Alviandi, Sp. THT
Jakarta, 20 July 2002
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CULTIVATION Terstandarisasi
Dari Budidaya
DRYING Sampai Obat
MULTIPLE EXTRACTION STEPS

COATTING

BLISTERING

FINISHED PRODUCT

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 Manufacturing procedure for
EGb 761 ®

Ginkgo Extraction Primary Lipoid

(Acetone/water)
leaves extrakt phase
1. Liquid/liquid extraction
2. Phase separation

1.Removal solvent
Filtration 2. Drying EGb 761® Prepurified
Fraction II extract
1. Precipitation 1. Precipitation
2. Filtration 2. Filtration

Filtration
Proteins Tannins
Fraction I

waste
waste 11
 Production process
• Patented 27-step special extraction procedure
resulting in EGb 761®
• Active Ingredients are concentrated while harmful
compounds such as toxic ginkgolic acids are
eliminated
• EGb 761® is standardized to contain 24 % Ginkgo
flavone glycosides, 6 % terpene lactones and less
than 5 ppm Ginkgolic acids
• Rigorous quality control from cultivation of Ginkgo
trees to the finished product
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 Composition of EGb 761 ®

Various
Unknown
Flavone glycosides

Water, solvent
Inorganic

High molecular Terpene lactones

Proantho-
cyanidines
Nonflavone
glycosides Carbonsäuren
Catechines

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 Comparison of several
constituents in Ginkgo leaves and
EGb 761
[mg/10 g] Ginkgo leaves EGb 761

ginkgo flavone
30 2400
glycosides

ginkgolides 0.5 600

biflavonoids 160 < 10

ginkgolic acids 170 < 0.05

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 Chemical Structure
Flavone glykosides

Proanthocyanidines, Bilobalide,
Shikimic acid Ginkgolides

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Pharmacology

Major Constituents of EGb 761® and

their Pharmacological Profile
Haemodynamic/
Inactivation of
Haemorheologic
toxic free radicals
effects

EGb 761®
Ginkgoflavone- Ginkgolides A, B
glykosides
Bilobalide

Neuro-
protection

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Pharmacology

Haemorheology effect
EGb 761® leads to :
• Decrease in :
– whole blood and plasma viscosity
– erythrocyte aggregation
– fibrinogen values
• Increase in :
– erythocyte flexibility
– leukocyte flexibility

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Pharmacology
Effect of EGb 761 on ®

hemorheological parameters

Erythrocyte flexibility in patients with vascular pathologies,

Group I = EGb 761®, Group II = Placebo

Dominguez & Suarez 1994, randomized, double blind, placebo-controlled,

3 x 80 mg EGb 761 for 60 days, 39 patients
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Pharmacology
Effect of EGb 761® on
hemorheological parameters

Erythrocyte aggregation in patients with vascular

pathologies, Group I = EGb 761®, Group II = Placebo

Dominguez & Suarez 1994, randomized, double blind, placebo-controlled,

3 x 80 mg EGb 761 for 60 days, 39 patients
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Pharmacology
Effect of EGb 761 on ®

hemorheological parameters

Whole blood viscosity in patients with vascular pathologies,

Group I = EGb 761®, Group II = Placebo

Dominguez & Suarez 1994, randomized, double blind, placebo-controlled,

3 x 80 mg EGb 761 for 60 days, 39 patients
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Pharmacology

EGb 761® improves regional

cerebral blood flow
450
400 Control
Regional cerebral blood flow

350 EGb 761

300
[ml/100g/min]

250
200
150
100
50
0
Frontal Okzipital Auditive Hippo- Amygdala Nucleus Substantia
cortex cortex cortex campus accumbens nigra

Measurement of the regional cerebral blood flow by an autoradiographic method.

Rats were treated with 130 mg/kg EGb 761®

Oberpichler et al. 1988

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Pharmacology

Recent study at Institute for

Microcirculation, Berlin
Design: Human-pharmacological
study
Patients: 40 polypathic elderly patients of a geriatric
out-patient department
Duration: 40 days
Dose: 240 mg EGb 761® (20 Patients, the other 20
patients as reference group)
Testmethode: Non-invasive measurement of microcirculation
by means of high-resolution intravital
microscopy in the same tissue region of skin
and rectum
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Pharmacology
Improvement of
Microcirculation

Previous to treatment after treatment

with 240 mg Egb 761 daily over 4 weeks
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Pharmacology

Results of hemorheological effect

• Statistically significant improvement of in-flowing blood into the
microvessels and venular back-flow.
• Improved distribution of blood cells in the networks.
• Improved adaptability of arterioles and venules (vasomotion).
• Significant increase of oxygen partial pressure in the tissue
investigated after already one week.
• Enhanced immunologic defense system through better distribution
of white blood cells in the tissues (postulated)

• Basis for the therapeutic application of our special extract in

circulatory disturbances with different localization (e.g. the brain,
the inner ear or the lower extremities)

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Pharmacology

PAF (Platelet Activating Factor)

ANTAGONIS
PAF contributes to :
• thrombocyte aggregation
• Ca2+ accumulation in cell
• edema formation in brain
• post-ischemic cell lesion
• leukocyte activation
PAF inhibition by EGb 761® can prevent those
effects and the subsequent damage to the body
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Pharmacology

Free radicals scavenging

• Inhibitory effect on :
– lipid peroxidation
– radical production by granulocytes
– radical-induced membrane lesions
• Increase of prostacylin synthesis
• Acceleration of postischemic reparation
processes

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Pharmacology

Experimental Effects of EGb

761 ®
• Neuroprotection (Integrity/Function)
– Cell survival
– Energy metabolism
– Membrane integrity and function
– Prevention of amyloid deposition
• Enhancement of Neurotransmission
– Acetylcholine
– Serotonin

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Pharmacology
Neuroprotective action of
Ginkgolide B after hypoxia in
80 rats Vehicle
Ginkgolide B pre
70
Ginkgolide B post
60
Damage [%]

50
40
30
20
10
0
Striatum Hippocampus Cortex

Liu et al. 1996, neuroprotective action of Ginkgolide B (25 mg/kg) after right carotid artery
ligation in rats. Immediately before and 1 h after hypoxia = Ginkgolide B pre, immediately
after and 2 h after hypoxia = Ginkgolide B post.
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Pharmacology

Neuroprotective properties of
bilobalide
40
35 p<0,05

30
25
20
15
NaCN + 1µM
10 control NaCN bilobalide

5
0

Krieglstein et al. 1995, Cultured neuron chicken cells were damaged by 1mM
NaCN for 30 min and were allowed to recover for 3 days. Bilobalide treatment was
performed 30 min prior to and up to 24 h after intoxication.

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Pharmacology

Cell Protection by EGb 761 ®

80
70
cytotoxicity [%]

60
50
40
30
20
10
0
0 5 10 20 40 100 200 300 300 400
Concentration of EGb 761 [µg/ml]
Sellak et al. 1994, Protective effect of EGb 761 on vascular endothelial cell
cultures from cell toxicity of oxygen radicals measured as LDH release

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Pharmacology

Summary „Pharmacology“
EGb 761®
• is a complex mixture of different ingredients with different
pharmacological actions
• scavenges free radicals (Ginkgo flavone glycosides)

• has a PAF-antagonistic action (ginkgolides)

• has a neuroprotective action (bilobalide and ginkgolides)

• influences rheological parameters of the blood and vessel tone

• is orally not toxic up to 10 g/kg in rats

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HASIL PENELITIAN &
UJI KLINIS

DIDUKUNG > 400 HASIL PENELITIAN

(BASIC STUDY & CLINICAL TRIAL)

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 EGb 761 is effective in the
®

treatment of Tinnitus
70
frequency of tinnitus [%]

60
50 0 weeks of
treatment
40 6 weeks of
treatment
30
12 weeks of
20 treatment

10
0
non mild moderate severe very
existent severe
Gomez 1997, open study with 202 patients, 3 x 40 mg EGb 761 for 12 weeks
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Efficacy of EGb 761 in Patients ®

with Tinnitus
Reduction of sound volume (dB)
0

-1

-2
Placebo
EGb 761
-3

-4

-5 week 4 week 8 week 12

Morgenstern C, Biermann E, 1997
99 patients suffering from tinnitus for at least 2 months were treated in a randomized, placebo-
controlled, double-blind study with 120 mg EGb 761 p.o./d for 12 weeks. Prior to treatment a 2
weeks wash-out phase was conducted

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SAFETY

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Safety Evaluation of EGb 761 ®

• If 5.000 patients take Ginkgo extract

EGb 761® continuously for 10 years
only 1 (one) of them will (once) have
experienced a side effect.

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 EGb 761 has no effect on
®

bleeding time
• randomized placebo controlled clinical trial with 50
healthy male volunteers (crossover)
• 7 days treatment with either placebo, EGb 761®
(240 mg/day), ASA/Acetyl Salicylic Acid (500
mg/day) or ASA and EGb 761® (wash-out at least
three weeks)
• no clinically relevant effect of EGb 761® on blood
coagulation was detectable, neither when
administered alone nor in combination with ASA

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 Ginkgo biloba extract does not
interact with warfarin in patients
on stable long-term warfarin
treatment
• Engelsen J, Dalsgaard Nielsen J, Winther K
• Coagulation Laboratory, Department of Clinical
Biochemistry, Copenhagen County Hospital,
Denmark
Second Conference of the International Coenenzyme Q Association, 2000
10

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 Post marketing surveillance
study
Tolerance as rated by the physician [%]

80
70 Cardiac
insufficiency (n=628)
60 Control group
(n=2161)
50
40
30
20
10
0
not reported very good good satisfactory adequate inadequate

Tolerance of EGb 761 in patients with and without cardiac insufficiency evaluated in
a post marketing surveillance study (120 mg EGb 761/ day for 12 weeks)
[Honold et al. 1992]
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Post marketing surveillance study
Tolerance as rated by the physician [%]
80
70
Essential hypertension
60 (n=769)
50 Control group (n=2020)

40
30
20
10
0
not reported very good good satisfactory adequate inadequate

Tolerance of EGb 761 in patients with and without essential hypertension evaluated
in a post marketing surveillance study (120 mg EGb 761/ day for 12 weeks)

[Honold et al. 1992]

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Post marketing surveillance study
80
Tolerance as rated by the physician [%]

70
60
concomitant
50 treatment (n=2104)
control group
40 (n=685)

30
20
10
0
not reported very good good satisfactory adequate inadequate

Tolerance of EGb 761 in patients with and without concomitant treatment evaluated
in a post marketing surveillance study (120 mg EGb 761/ day for 12 weeks)
[Honold et al. 1992]

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The Adverse effect of EGB 761 has reported
from 44 clinical trial (9,772 patients)
Adverse Event Number of Adverse event

Gastrointestinal 21
Headache 7
Dizziness 6
Vascular 5
Cardiovascular 3
General Intolerance 3
Allergy 2
Sleep Disorder 2

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 Frequency of possible ADR (Adverse effect Rate)
in relation to concomitant treatment of 469 patients
in 14 clinical trials
Patients receiving Patients not receiving
concomitant medication this medication
No. of No. of No. of No. of
Concomitant treatment patients possible patients possible
ADRs ADRs
Antihipertensive drugs (incl.
105 4 (3.8%) 252 2 (0.8%)
Ca2+ antagonist)
Digitalis glycosides 62 2 (3.2%) 381 8 (2.1%)
Acetylsalicylic acid 42 0 (0.0%) 143 5 (3.5%)
Glucose – Lowering agents
55 3 (5.5%) 318 8 (2.5%)
(incl. insulin)
Oral anticoagulant 5 0(0.0%) 124 5(4.0%)
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 Concomitant medication in a postmarketing
surveillance study involving 3,044 patients
(Hanold et al. 1992)
Patients receiving Patients not
concomitant receiving this
medication medication
No. of No. of No. of No. of
Concomitant treatment patients possible patients possible
ADRs ADRs
Antihipertensive drugs (incl.
829 4 (0.5%) 2,215 10 (0.5%)
Ca2+ antagonist)
Digitalis glycosides 612 3 (0.5%) 2,432 11 (0.5%)
Acetylsalicylic acid 40 1 (2.5%) 3,004 13 (0.4%)
Glucose – Lowering agents
392 1 (0.3%) 2,652 13 (0.5%)
(incl. insulin)
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Oral anticoagulant 9 0(0.0%) 3,035 14 (0.5%)
 Dosage and Administration

• 120 mg – 240 mg daily (2 BID) for tinnitus and

vertigo for 8 – 12 weeks
• Usual dosage 3 tablet per day for Cognitive
impairment

• Adverse effects have been reported rarely

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Kemasan :
Dos 3 blister @ 10 tablet,
40 mg dan 80mg
POM TL. 022500151
Diproduksi oleh :
PT. Phapros Tbk.,
Semarang, Indonesia
Atas lisensi dari :
Dr. Willmar Schwabe GmbH
& Co.
Karlsruhe, Germany.

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