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Ginkgo biloba extract in the treatment of tinnitus: A systematic review

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Tinnitus is a symptom frequently encountered by ear, nose, and throat practitioners. A causal treatment is rarely possible, and drug and nondrug treatment options are limited. One of the frequently prescribed treatments is Ginkgo biloba extract. Therefore, randomized, placebo-controlled clinical trials of Ginkgo biloba extract preparations were searched for and reviewed systematically. There is evidence of efficacy for the standardized extract, EGb 761(®) (Dr Willmar Schwabe GmbH & Co KG Pharmaceuticals, Karlsruhe, Germany), in the treatment of tinnitus from three trials in patients in whom tinnitus was the primary complaint. Supportive evidence comes from a further five trials in patients with age-associated cognitive impairment or dementia in whom tinnitus was present as a concomitant symptom. As yet, the efficacy of other ginkgo preparations has not been proven, which does not necessarily indicate ineffectiveness, but may be due to flawed clinical trials. In conclusion, EGb 761(®), a standardized Ginkgo biloba extract, is an evidence-based treatment option in tinnitus.
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open access to scientific and medical research
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http://dx.doi.org/10.2147/NDT.S22793
Ginkgo biloba extract in the treatment of tinnitus:
a systematic review
Alexander von Boetticher
Ear, Nose and Throat Surgery,
Lueneburg, Germany
Correspondence: Alexander von
Boetticher
Ear, Nose and Throat Surgery,
Willy-Brandt-Str 2, 21335 Lueneburg,
Germany
Tel +49 4131 47178
Fax +49 4131 404891
Email alexander@boetticher.net
Abstract: Tinnitus is a symptom frequently encountered by ear, nose, and throat practitioners.
A causal treatment is rarely possible, and drug and nondrug treatment options are limited.
One of the frequently prescribed treatments is Ginkgo biloba extract. Therefore, randomized,
placebo-controlled clinical trials of Ginkgo biloba extract preparations were searched for and
reviewed systematically. There is evidence of efficacy for the standardized extract, EGb 761
®
(Dr Willmar Schwabe GmbH & Co KG Pharmaceuticals, Karlsruhe, Germany), in the treatment
of tinnitus from three trials in patients in whom tinnitus was the primary complaint. Supportive
evidence comes from a further five trials in patients with age-associated cognitive impairment
or dementia in whom tinnitus was present as a concomitant symptom. As yet, the efficacy of
other ginkgo preparations has not been proven, which does not necessarily indicate ineffective-
ness, but may be due to flawed clinical trials. In conclusion, EGb 761
®
, a standardized Ginkgo
biloba extract, is an evidence-based treatment option in tinnitus.
Keywords: tinnitus, Ginkgo biloba, EGb 761
®
, systematic review
Introduction
In an ear, nose, and throat office, one is confronted every day with patients suffering
from tinnitus. The prevalence of tinnitus in adults is between 10% and 15%.
1
According
to the 1999–2004 National Health and Nutrition Examination Surveys, 50 million
people in the US suffer from this condition.
1
A British study involving 48,313 sub-
jects reported a 10.1% prevalence of tinnitus in the adult population,
2
which increases
with age.
3
Tinnitus has been found to affect more men than women.
4
Approximately
25% of patients with tinnitus report an increase in severity over time.
5
The 2010
Australian Blue Mountains Hearing Study with over 2000 individuals observed over
5 years that nearly one in five older adults suffered from tinnitus.
6
Classication and characteristics
The patients showing up in the ear, nose, and throat office suffer from various degrees
of tinnitus. Subjective tinnitus is the perception of sound in the absence of external
acoustic stimulation. In contrast, objective tinnitus is where an external source, such as
blood streaming phenomena or muscular cramps inside the middle ear, can be identified.
Subjective tinnitus is detectable only by the patient and can often be described as
crackling, ringing, or whistling. It can be continuous or intermittent, and the onset may
be acute with or without hearing loss.
4
Full or partial spontaneous remission is possible,
but tinnitus often becomes a chronic condition.
7
Tinnitus may have a considerable
impact on mood, and cause depression, anger, and anxiety, which in turn may enhance
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attention to tinnitus.
8
The hearing sensation can be very
annoying, so that the patient suffers from a compromised
ability to concentrate and relax. This situation is considered a
decompensated, pathological chronic tinnitus. A compensated
chronic tinnitus is described as a hearing sensation without
any disturbing quality.
9
Etiology
Jastreboff and Hazell suggest a neurophysiological model for
tinnitus,
10
ie, an abnormal processing of signals generated in
the auditory nervous system, beginning at the sensory level
of the cochlear hair cell to cochlear fibers and the nucleus in
higher brain structures. In this model, tinnitus could be gen-
erated at different levels in the auditory processing system.
Hyperactivity or damage to the cochlear hair cells resulting
in senseless signals would be translated by the brain into a
kind of phantom hearing sensation associated with hearing
loss. Depending on the site of damage, the tinnitus is called
peripheral, in contrast with central tinnitus originating from
higher central nervous damage. Many environmental, iatro-
genic, and genetic factors have been described as a potential
cause of hearing impairment and tinnitus, the most relevant
being acoustic trauma, chronic exposure to occupational or
work-related noise, and drug-related impairment caused by
loop diuretics, antibiotics, chemotherapeutics, and salicy-
lates.
4
An overview of possible causes is provided in Table 1.
However, in 10%–20% of patients no cause for tinnitus can
be found, and this is commonly referred to as “idiopathic
tinnitus”.
11
The pathological changes at the level of the inner ear
hair cells include damage to the mitochondrial DNA or
endothelial damage with dysfunction of microcirculation.
12,13
The underlying mechanism of ototoxicity varies with
different drugs. According to Schacht, for example,
aminoglycoside antibiotics can cause loss of cochlear outer
hair cells secondary to damage from free radicals and accu-
mulation of calcium and potassium ions.
14,15
Treatment
Tinnitus is complex and multifactorial, and involves many
etiological loci.
3
Until now, there has been no specific
therapy for all the different kinds of tinnitus. Current
schemes include the use of hearing aids, counseling, sup-
portive therapy including tinnitus retraining therapy, and
different medications such as vasodilators, corticosteroids,
anticonvulsants, spasmolytic drugs, lidocaine, benzodiaz-
epines, and Gingko biloba preparations.
4
EGb 761
®
(Dr Willmar Schwabe GmbH & Co KG
Pharmaceuticals, Karlsruhe, Germany) is a dry extract from
Ginkgo biloba leaves (35-67:1), extraction solvent: acetone
60% (w/w). The extract is adjusted to 22.0–27.0% ginkgo
flavonoids calculated as ginkgo flavone glycosides and
5.0–7.0% terpene lactones consisting of 2.8–3.4% ginkgolides
A, B, C and 2.6–3.2% bilobalide and contains less than 5 ppm
ginkgolic acids. It is known to enhance microperfusion by
increasing red blood cell deformability and decreasing whole
blood viscosity.
16,17
In a cat model, it specifically increased
the blood flow in the cochlea.
18
Moreover, EGb 761
®
protects
Table 1 Causes of tinnitus (according to Lockwood)
4
TYPE CAUSES
Subjective tinnitus
Otologic Noise-induced hearing loss, presbycusis, otosclerosis, otitis, impacted cerumen, sudden
deafness, Ménière’s disease, and other causes of hearing loss
Neurologic Head injury, whiplash, multiple sclerosis, vestibular schwannoma (commonly called an
acoustic neuroma) or other cerebellar-pontine-angle tumors
Infectious Otitis media and sequelae of Lyme disease, meningitis, syphilis, and other infectious or
inammatory processes that affect hearing
Drug-related Common side effect of many drugs, such as salicylates, nonsteroidal antiinammatory
drugs, aminoglycoside antibiotics, loop diuretics, and chemotherapy agents (eg. platins and
vincristine)
Other Temporomandibular-joint dysfunction and other dental disorders
Objective Tinnitus
Pulsatile Carotid stenosis, arteriovenous malformations, other vascular anomalies, vascular tumors
(eg., of the glomus jugulare), valvular heart disease (usually aortic stenosis), states of
high cardiac output (anemia and drug-induced high output), and other conditions causing
turbulent blood ow
Muscular or anatomical Palatal myoclonus, spasm of stapedius or tensor tympani muscle, patulous eustachian tube
Spontaneous Spontaneous otoacoustic emissions
Note: Reproduced with permission from Lockwood AH, Salvi RJ, Burkard RF. Tinnitus. N Engl J Med. 2002;347(12):904–910. © 2002 The New England Journal of Medicine.
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Ginkgo biloba in tinnitus
the mitochondria from oxidative stress and improves energy
metabolism,
19,20
thus attenuating damage to cochlear cells
subject to increased energy demand or decreased perfusion.
In a rat model of salicylate-induced tinnitus, Jastreboff et al
demonstrated that EGb 761
®
treatment resulted in a signifi-
cant decrease in the behavioral manifestations of tinnitus.
21
Cisplatin-induced hair cell loss in rats, as well as subsequent
alterations of endocochlear potentials and auditory brain stem
responses, could be prevented by EGb 761
®
.
22
Randomized controlled trials of a variety of Ginkgo biloba
extracts in the treatment of tinnitus have shown different
results, and reviews published during recent years have arrived
at different conclusions. The objective of this review was to
assess the methodological quality of available randomized
controlled trials of Ginkgo biloba extract in tinnitus, and to
provide a synopsis of the evidence of efficacy for each specific
extract. The results will be discussed in the context of former
reviews, the scientific soundness of which will be evaluated.
Methods
Randomized, placebo-controlled, double-blind trials that met the
following criteria were eligible for inclusion in this review:
• Use of an identifiable, standardized Ginkgo biloba extract,
the composition of which is described adequately
• Dosing and duration of treatment appropriate for type
of tinnitus
• Enrollment of inpatients or outpatients suffering from
tinnitus as the primary or concomitant complaint
• No major methodological shortcomings or bias
• Publication in English, French, German, Spanish, or
Italian language.
Trials of interest were identified by searching the PubMed
database (from the beginning up to October 2010) using the
search terms “Ginkgo” and “tinnitus”, by hand searching ref-
erences listed in such identified reviews and trial reports, and
by requesting information on randomized controlled trials of
any Ginkgo product on tinnitus from a manufacturer.
Characteristics of included and excluded studies are
described in tabular format and reasons for exclusion of
studies are provided. An overview of details and results of
included studies is depicted in tabular format and summarized
in a descriptive manner.
Results
The PubMed search yielded 57 hits, of which 46 could be
ruled out as irrelevant by title and abstract. The search identi-
fied seven review articles dealing to a substantial degree with
Ginkgo and tinnitus and four randomized controlled trials of
Ginkgo extract and tinnitus. Another randomized, placebo-
controlled trial of the special extract, EGb 761
®
, in tinnitus
was identified from the references given in one of the review
articles and five randomized, placebo-controlled trials of
EGb 761
®
in dementia or age-related cognitive impairment
(including one for which publication was pending) were
identified by the manufacturer contacted.
Three studies of patients with tinnitus as a primary com-
plaint fulfilled the inclusion criteria and were included in the
review. Five studies on patients suffering from dementia or
age-associated cognitive decline with tinnitus as a concomi-
tant complaint met the inclusion criteria and were included
in the review. Details are provided in Table 2. The standard-
ized extract, EGb 761
®
, was used in all studies that fulfilled
Table 2 Characteristics of included trials
Reference Patients Diagnoses
Tinnitus as primary complaint
Morgenstern and Biermann
23
57 patients, median age approximately
46 years, 57% male
Chronic tinnitus, mean duration approximately
3 years
Morgenstern and Biermann
24
99 patients, mean age 45.5 years Chronic tinnitus, mean duration 4.5 years
Meyer
25
100 patients, mean age 50.4 years, 52% male Acute or subchronic tinnitus, mean duration 134 days
Tinnitus as concomitant complaint in dementia or aging-related cognitive impairment
Ihl et al
26
404 patients, mean age 65 years, 33% male Mild to moderate dementia (Alzheimer’s
disease, vascular dementia or mixed form)
associated with neuropsychiatric symptoms
Napryeyenko et al
27
395 patients, mean age 64 years, 28% male Mild to moderate dementia (Alzheimer’s
disease, vascular dementia or mixed form)
associated with neuropsychiatric symptoms
Schneider et al
*
72 patients, mean age 78 years, 47% male Tinnitus associated with Alzheimer’s disease
Halama et al
28
40 patients, mean age 66 years Mild to moderate cerebrovascular insufciency
Eckmann and Schlag
29
32 patients, aged 45–74 years, 60% male Tinnitus associated with cerebro vascular insufciency
Note: *Schneider LS, DeKosky ST, Farlow MR, Tariot PN, Hoerr R, Kieser M.
Ginkgo biloba (EGb 761®) effects on mood and neurosensory symptoms (dizziness, tinnitus)
in elderly, demented patients: secondary results of a randomized, placebo-controlled, double-blind trial [unpublished data].
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all quality criteria set to determine eligibility for this review.
Three randomized controlled trials were excluded from the
review due to major shortcomings in study conduct and/or
reporting.
In the open-label part of the trial reported by Holgers
et al,
30
80 patients with chronic tinnitus were treated with
29.2 mg per day of a Ginkgo product for two weeks.
Treatment responders (20 patients) were then treated for
two weeks each with 29.2 mg per day of the Ginkgo product
and placebo in randomized order. The Ginkgo product was
identifiable, but not described adequately. The daily dose
of 29.2 mg seems rather low compared with the daily doses
of 120–240 mg of the standardized extract EGb 761
®
. A
treatment period of 2 weeks is too short for chronic tin-
nitus, which is associated with cortical reorganization.
Hence, patients reporting subjective improvement after 2
week’s treatment were most likely to be those experiencing
the largest placebo effect. Selection of such patients for the
placebo-controlled part of the trial does not seem appropriate
from a methodological point of view. A crossover design is
not state of the art for proof of efficacy because of the pos-
sibility of carryover effects.
In a randomized, double-blind, placebo-controlled trial
reported by Drew and Davies,
31
1243 patients with chronic
tinnitus were enrolled and treated with LI 1370 150 mg
per day or placebo for 12 weeks. This study did not meet
minimal standards of Good Clinical Practice. No personal
contact between physicians and patients was required;
as a consequence, the actual existence and identity of the
patients could not be verified, nor was any medical or
audiological examination performed. Of 1426 patients who
were not excluded from the study, 183 were not selected and
122 were withdrawn without reasons being given. Although
patients were paired and then allocated treatment codes, 155
patients who received study medication were unpaired at
the end of the study, and only 363 pairs (726 patients) were
accounted for in the primary analysis.
Rejali et al
32
reported a randomized, placebo-controlled,
double-blind trial involving 66 outpatients with tinnitus who
were treated with 120 mg per day of a Ginkgo preparation or
placebo for 12 weeks. Neither the type of Ginkgo prepara-
tion used is described nor is any information provided about
composition or standardization. After 12 weeks’ treatment,
51% of patients treated with placebo and 21% of those
treated with Ginkgo were unable to attend the final visit.
Concomitant illness was the reason for this in 27% and 12%
of placebo-treated and Ginkgo-treated patients, respectively.
There is reason to assume that concomitant illness, which
was severe enough to prevent patients from clinic visits,
interfered with the subjective self-assessment of tinnitus
handicap and health status.
All eight randomized, placebo-controlled trials of the
standardized Ginkgo biloba extract EGb 761
®
showed
statistically significant superiority of the active treatment
over placebo. This holds for change in tinnitus volume/inten-
sity (assessed and significant in three studies) as well as for
overall severity (assessed in six, significant in five studies).
Hence, there is evidence of efficacy for this specific prepara-
tion in patients with tinnitus as a single or major complaint,
as well as in subjects suffering from tinnitus associated with
dementia or aging-related cognitive impairment. Details of
individual studies and outcomes are provided in Table 3.
Discussion
In all identified and retrieved studies using the standardized
Ginkgo biloba extract, EGb 761
®
, this specific preparation was
found to be superior to placebo in the treatment of tinnitus.
None of the identified studies using other Ginkgo products
found a difference from placebo. However, considering the
methodological flaws of these studies, it would be imprudent
to conclude that all these products are ineffective.
Several reviews addressing the efficacy of Ginkgo biloba
have been published in recent years. Smith et al uncriti-
cally lumped together studies of different Ginkgo biloba
preparations irrespective of their quality and dosage.
33
They did not address the serious problems of the study by
Drew and Davies,
31
and concluded that there is no proven
support for the efficacy of Ginkgo biloba treatment. They
may have relied on publication in a peer-reviewed journal
as proof of quality rather than going into the detection of
flaws in the different publications. In a meta-analysis of
trials of Ginkgo biloba in the treatment of tinnitus, Rejali
et al also pooled studies using various Ginkgo products of
different and partly unknown quality.
32
Their conclusion was
that Ginkgo biloba does not benefit patients with tinnitus.
Similarly, Hilton and Stewart included three clinical trials
with three different products in their Cochrane Review.
34
Although they contend that they applied rigorous meth-
odological criteria for study selection, they accepted two
seriously flawed trials. They concluded that there was no
statistical proof of an effective tinnitus treatment with
Gingko. On the contrary, Holstein, who only included
studies with Gingko biloba extract EGb 761
®
in his review,
found evidence of efficacy for this standardized extract
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Ginkgo biloba in tinnitus
Table 3 Results of included trials
Reference Treatment (orally
unless stated otherwise)
Type of analysis, results (means ± SD or 95% CI
unless stated otherwise)
Morgenstern
and Biermann
23
Part I:
EGb 761
®
:
57 patients,
200 mg/d IV
10 days
Part II:
EGb 761
®
:
30 patients,
160 mg/day;
placebo:
27 patients;
12 weeks
ITT-LOCF
Part I: Tinnitus volume decreased by approximately 8 dB on average
Part II: (changes after end of part I)
Change in tinnitus volume week 12: EGb 761
®
-3.5 ± 17.8 dB,
Plc -1.9 ± 17.3 dB, P , 0.05
Change in tinnitus volume week 8: EGb 761
®
-3.0 ± 17.6 dB,
Plc -1.3 ± 16.2 dB, P , 0.05
Change in tinnitus volume week 4: EGb 761
®
-5.8 ± 13.0 dB,
Plc 0.0 ± 17.7 dB, P , 0.05
Hearing loss at 3.0 kHz: EGb 761
®
-0.5 ± 7.1 dB,
Plc +3.7 ± 7.7 dB, P , 0.05
Hearing loss at 4.0 kHz: EGb 761
®
-4.8 ± 11.4 dB,
Plc +4.3 ± 9.8 dB, P , 0.01
Hearing loss at 6.0 kHz: EGb 761
®
-1.8 ± 13.8 dB,
Plc +1.7 ± 6.4 dB, ns
Hearing loss at 8.0 kHz: EGb 761
®
-2.2 ± 12.0 dB,
Plc +1.7 ± 3.9 dB, ns
(negative change in hearing loss means improvement)
Rates of patients with self-assessed intensity of permanent tinnitus as annoying
or very annoying: EGb 761
®
59% at baseline, 37.9% at week 12; Plc 43.4% at baseline,
47.8% at week 12
Morgenstern
and Biermann
24
EGb 761
®
:
49 patients,
120 mg/day;
placebo:
50 patients;
12 weeks
ITT-LOCF
Change in tinnitus volume in the more severely affected ear (baseline/week 12):
EGb 761
®
from 42.2 (36.6, 48.1) to 39.0 (31.9, 46.1),
Plc from 44.3 (39.2, 49.4) to 45.1 (39.1, 51.2),
P = 0.015
Patients’ global impression of change: EGb 761
®
31% improved, Plc 14% improved
No signicant differences between treatment groups regarding tinnitus volume in the less
severely affected ear, subjective rating of tinnitus intensity and hearing loss.
Meyer
25
EGb 761
®
:
55 patients,
160 mg/day;
placebo:
45 patients
3 months
Type of analysis not specied
Global rating of change: EGb 761
®
40% much improved,
Plc 24% much improved, P = 0.05
Duration until disappearance or signicant improvement in 50% of patients:
EGb 761
®
70 days, Plc 119 days (medians), P = 0.03
Change in tinnitus intensity (scale 0–3): EGb 761
®
-1.0, Plc -0.67, P = 0.03
Change in nuisance (scale 0–3): EGb 761
®
-0.84, Plc -0.59, P = 0.08
Ihl et al
26
EGb 761
®
:
202 patients,
240 mg/day;
placebo:
202 patients;
24 weeks
ITT-LOCF
11-point box scale* for tinnitus:
EGb 761
®
: -0.5 (-0.6, -0.3), Plc: -0.1 (-0.2, 0.0), P , 0.001
Napryeyenko
et al
27
EGb 761
®
:
198 patients,
240 mg/day;
placebo:
197 patients;
22 weeks
ITT-LOCF
11-point box scale for tinnitus:
EGb 761
®
: -1.1 ± 1.6
Plc: -0.0 ± 0.9
P = 0.003
Schneider
et al
**
EGb 761
®
high dose:
19 patients, 240 mg/day;
EGb 761
®
low dose:
29 patients, 120 mg/day;
placebo:
24 patients;
26 weeks
ITT-LOCF
11-point box scale for tinnitus:
EGb 761
®
high dose: -2.1 ± 2.1, P = 0.003 vs Plc
EGb 761
®
low dose: -1.1 ± 2.1, P = 0.09 vs Plc
Plc: -0.2 ± 1.7
(Continued)
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Table 3 (Continued)
Reference Treatment (orally
unless stated otherwise)
Type of analysis, results (means ± SD or 95% CI
unless stated otherwise)
Halama et al
28
EGb 761
®
:
20 patients,
120 mg/day;
placebo:
20 patients;
12 weeks
Type of analysis not specied
Severity rating tinnitus (scale 0–3): EGb 761
®
from 1.05 ± 1.05 to 0.45 ± 0.83,
Plc from 1.25 ± 0.91 to 1.10 ± 0.97, P = 0.035
Eckmann and
Schlag
29
EGb 761
®
:
12 patients,
120 mg/day;
placebo:
20 patients;
30 days
Type of analysis not specied
Tinnitus disappeared: EGb 761
®
100%, Plc 50%, P , 0.005
Notes: *Consisting of 11 boxes numbered 0 to 10, with 0 representing no tinnitus and 10 representing extremely severe tinnitus. **Schneider LS, DeKosky ST, Farlow MR,
Tariot PN, Hoerr R, Kieser M. Ginkgo biloba (EGb 761®) effects on mood and neurosensory symptoms (dizziness, tinnitus) in elderly, demented patients: secondary results
of a randomized, placebo-controlled, double-blind trial [unpublished data]. Bold print = primary outcome measure, if dened.
Abbreviations: CI, condence interval; SD, standard deviation; IV, intravenous; ITT-LOCF, intention-to-treat, last value carried forward; Plc, placebo; ns, not signicant.
from randomized, placebo-controlled trials, supported by
findings from reference-controlled and uncontrolled trials
in a more true-to-life setting.
35
The efficacy of a plant extract depends on its composi-
tion, which is determined by the extraction process, the bio-
availability of its active compounds, which depends on the
composition and the galenical formulation, and its dosage.
Products made from the same plant species by different
production processes cannot be assumed to be bioequiva-
lent. Therefore, it is not possible to generalize findings from
studies of one specific extract to other products. Hence,
lumping together studies of different Ginkgo products and
trying to draw an overall conclusion about the efficacy of
all of these products is not reasonable and is also contradic-
tory to the principles of evidence-based medicine (“… the
conscientious, explicit, and judicious use of current best
evidence in making decisions about the care of individual
patients”).
36
The question is not whether any treatment may
benefit the individual patient but which treatment is most
appropriate.
There are studies of various Gingko preparations which
have shown no effect but these were of poor methodological
quality. However, the currently available literature shows
that there is evidence for the successful treatment of tinnitus
with the Ginkgo biloba extract, EGb 761
®
. Of note, all trials
using this extract consistently demonstrate its superiority
over placebo. The average treatment effects may be limited
in magnitude and not all patients seem to respond to the drug,
yet, given the annoying and often disabling nature of tinnitus,
even moderate improvements may have a considerable impact
on patient quality of life. It is the ear, nose, and throat special-
ist’s responsibility to offer patients counseling, supportive
care, and the best alternatives in treatments available for each
individual patient. Considering the limited data from meth-
odologically sound, well controlled trials of other therapeutic
options, the robust and consistent data available for tinnitus
treatment with EGb 761
®
should be appreciated.
Disclosure
The author reports no conflicts of interest in this work.
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... Treatment is necessary in cases with severe tinnitus that interferes with the QOL, but there is no consensus on the optimum treatment modality. Various treatments have been proposed for tinnitus, such as pharmacological agents, intratympanic injection of steroids, tinnitus retraining therapy, hearing aid fitting, sound masking, transcranial stimulation of the brain, acupuncture, and surgical destruction of the vestibular system (8)(9)(10)(11)(12)(13)(14). Medications frequently used include anticonvulsants, antidepressants, vasomodulators, and Ginkgo biloba (8)(9)(10). ...
... Various treatments have been proposed for tinnitus, such as pharmacological agents, intratympanic injection of steroids, tinnitus retraining therapy, hearing aid fitting, sound masking, transcranial stimulation of the brain, acupuncture, and surgical destruction of the vestibular system (8)(9)(10)(11)(12)(13)(14). Medications frequently used include anticonvulsants, antidepressants, vasomodulators, and Ginkgo biloba (8)(9)(10). Betahistine is another pharmacological agent that may have beneficial effects in the treatment of tinnitus (15)(16)(17). ...
... As yet, no drug has been approved for tinnitus by the European Medicines Agency or the United States Food and Drug Administration (18). Nonetheless, drug therapies are frequently used to reduce the severity of tinnitus or manage complaints associated with this condition (8)(9)(10)(15)(16)(17)(18). Betahistine is one of the most prescribed drugs for tinnitus both across the world and in Turkey. ...
Article
Objective: This study aimed to evaluate betahistine treatment efficacy and factors affecting the success of betahistine treatment in patients with subjective idiopathic tinnitus. Methods: A total of 91 patients diagnosed with subjective idiopathic tinnitus were included in the study. The study group consisted of 61 patients treated with betahistine for three months. The control group consisted of 30 patients who did not receive any treatment. The severity of tinnitus and its effects on quality of life (QOL) and sleep were evaluated using the Tinnitus Handicap Inventory (THI) and Visual Analog Scale. Results: According to the THI results, there was clinical improvement in 25 of 61 patients (41%) treated with betahistine and in 6 of 30 patients (20%) in the control group, which indicated a significant difference (p<0.05). Compared with the control group, there was a statistically significant decrease regarding the duration of tinnitus and annoyance in the treatment group (p<0.05). According to the multivariate analysis, improvement in tinnitus was increased by the absence of a history of betahistine use within the past year, by having a normal level of vitamin B12, by every one-year reduction in age, and by having stable tinnitus loudness. Conclusion: Betahistine treatment applied for three months in patients with subjective idiopathic tinnitus improves the QOL and reduces the severity of tinnitus. Keywords: Betahistine, THI, tinnitus, treatment, VAS
... [10][11][12][13] In a case-control study of elderly patients with neurological disorders, those with dementia had a particularly high rate of falls (60% in 1 year), which may indicate a higher prevalence of dizziness and impaired equilibrium control. 14 Given the high comorbidity of tinnitus and dizziness in dementia and the findings from earlier studies in which Ginkgo biloba extract EGb 761 ® (Dr Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany) alleviated tinnitus and dizziness or vertigo, 15,16 measures of tinnitus and dizziness were included in recent clinical trials of EGb 761 ® in patients with dementia. ...
... Overall, we found EGb 761 ® to be clearly superior to placebo in alleviating both tinnitus and dizziness. This is in line with the results of earlier trials in patients with tinnitus or vertigo, 15,16 in whom these neurosensory symptoms were the main complaints. It is also in line with conclusions from systematic reviews that found EGb 761 ® , but not other G. biloba extracts, to be effective in the treatment of tinnitus and vertigo. ...
... It is also in line with conclusions from systematic reviews that found EGb 761 ® , but not other G. biloba extracts, to be effective in the treatment of tinnitus and vertigo. 15,16 EGb 761 ® is a defined extract of G. biloba leaves that is obtained by a proprietary multi-step extraction procedure during which pharmacodynamically active molecules are enriched and harmful compounds are removed. EGb 761 ® is adjusted to 22.0%-27.0% ...
... 5 Penelitian yang dilakukan di Jerman, didapatkan bahwa ekstrak Ginkgo biloba Egb 761 bisa meringankan gejala tinnitus dan juga vertigo atau pusing pada pasien demensia. 6,7 Dalam mempertimbangkan mengapa ekstrak G.biloba EGb761 bisa meringankan tinnitus, pusing, atau vertigo pada pasien demensia, kita harus memperhatikan patomekanisme yang mendasari. Neuron dari sistem vestibular dan sistem pendengaran, sel-sel rambut koklea, dan sel-sel sensorik vestibular memiliki energy yang tinggi untuk mempertahankan dan terus menerus memperbaiki potensi listrik transmembran mereka. ...
Article
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Ginkgo Biloba adalah Salah satu tanaman yang tergolong sebagai fitofarmaka atau obat-obatan yang berasal dari tanaman ialah Ginkgo biloba Tanaman G.biloba (Gb) termasuk dalam familia Ginkgoceae. Di dalam ekstrak G.biloba terdapat antioksidan, antivirus, antiinflamasi, dan juga antikarsinogenik. Dan juga telah dinyatakan bahwa ekstrak G.biloba mempunyai efek yang baik terhadap fungsi SSP (sistem saraf pusat). Untuk mengetahui manfaat G.biloba dalam penanganan gangguan neurologis. Dibuat dengan menggunakan metode studi pustaka untuk mengumpulkan referensi yang valid mengenai tanaman Ginkgo Biloba yang dapat digunakan sebagai penanganan gangguan Neurologi. Hasil literature reviewberdasarkan studi pustaka yang dilakukan menunujukkan bahwa tanaman Ginkgo Biloba yang dapat digunakan sebagai penanganan penyakit neuorologis dengan kandungan dan efek terhadap tubuh. Dalam literature review ini didapatkan tanaman Ginkgo Biloba yang dapat digunakan sebagai penanganan gangguan neurologis
... Extensive means of treating tinnitus have been developed, which include medications (Bhatt et al., 2016;von Boetticher, 2011), counselling and cognitive behaviour therapy, transcranial magnetic stimulation (Formanek et al., 2018;Kreuzer et al., 2017), transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) (Bae et al., 2020), tinnitus retraining therapy Lee et al., 2019;Scherer et al., 2014), relaxation therapy, hearing aids (Searchfield et al., 2010) and sound therapy (Blakley, 2016;Hall et al., 2015;Langguth, 2015;Makar et al., 2017;Plein et al., 2016). According to the clinical practice guidelines of tinnitus, sound therapy is one of the recommended treatments (Tunkel et al., 2014) and is used as a standard treatment in the UK (Baguley et al., 2013). ...
Article
Full-text available
To determine the neural mechanism underlying the effects of sound therapy on tinnitus, we hypothesize that sound therapy may be effective by modulating both local neural activity and functional connectivity that is associated with auditory perception, auditory information storage or emotional processing. In this prospective observational study, thirty tinnitus patients underwent resting-state functional magnetic resonance imaging scans at baseline and after 12 weeks of sound therapy. Thirty-two age- and gender-matched healthy controls also underwent two scans over a 12-week interval; thirty of these healthy controls were enrolled for data analysis. The amplitude of low-frequency fluctuation was analysed, and seed-based functional connectivity measures were shown to significantly alter spontaneous local brain activity and its connections to other brain regions. Interaction effects between the two groups and the two scans in local neural activity as assessed by the amplitude of low-frequency fluctuation were observed in the left parahippocampal gyrus and the right Heschl's gyrus. Importantly, local functional activity in the left parahippocampal gyrus in the patient group was significantly higher than that in the healthy controls at baseline and was reduced to relatively normal levels after treatment. Conversely, activity in the right Heschl's gyrus was significantly increased and extended beyond a relatively normal range after sound therapy. These changes were found to be positively correlated with tinnitus relief. The functional connectivity between the left parahippocampal gyrus and the cingulate cortex was higher in tinnitus patients after treatment. The alterations of local activity and functional connectivity in the left parahippocampal gyrus and right Heschl’s gyrus were associated with tinnitus relief. Resting-state functional magnetic resonance imaging can provide functional information to explain and “visualize” the mechanism underlying the effect of sound therapy on the brain.
... Over the past two decades, various randomized controlled studies have been conducted on Ginkgo biloba and its extract on various diseases and indications including asthma, bronchitis, tinnitus as well as for memory improvement (Huntley and Ernst, 2000;von Boetticher, 2011;Montes et al., 2015;Zhang et al., 2016). While Ginkgo biloba has been used in traditional Chinese medicine to treat ischemic stroke, conventional medicine only recently examined the use of gingko biloba on the neuroprotective role against the ischemic brain injury caused by AIS. ...
Article
Ginkgo biloba and its extract have been suggested to have a neuroprotective role in patients with acute ischemic stroke. We aimed to examine the efficacy and safety of Ginkgo biloba use in patients with acute ischemic stroke. We searched seven databases for randomized controlled studies examining the use of Ginkgo biloba in patients with acute ischemic stroke. Relevant studies were retrieved, screened, and data were extracted independently by two reviewers. Random effects meta-analyses were performed to evaluate the efficacy and safety outcomes of Ginkgo biloba. We subsequently assessed the certainty of evidence using the GRADE (Grading of Recommendation Assessment, Development and Evaluation) methodology. We found 12 randomized controlled studies enrolling 1466 patients. Pooled results suggest that Ginkgo biloba use was associated with an improvement in neurological function among individuals with AIS with a reduction of 2.87 points on the National Institute of Health Stroke Scale score (95% CI: [Formula: see text]–[Formula: see text], [Formula: see text]). Ginkgo biloba use was also associated with an improvement in activities of daily living and functional outcome (Mean Difference: 9.52; 4.66–14.33, [Formula: see text]). Subgroup analysis suggest that the impact was larger when using an injectable formulation of Ginkgo biloba compared to the oral formulation. There was no apparent impact of Ginkgo biloba use on all-cause mortality (Risk ratio (RR): 1.21; 0.29–5.09, [Formula: see text]) or cerebrovascular bleeding (RR: 0.82; 0.43–1.57, [Formula: see text]). There was limited evidence on to support the use of gingko biloba in terms of improving quality of life and other stroke events. As such, more studies are needed before it can be recommended for routine use in improving neurological and cognitive function in patients with acute ischemic stroke.
... Administration of psychopharmacological treatment might limit validity of treatment effectiveness, although there is still insufficient evidence to underline antidepressant drug therapy to improve tinnitus (44). In essence, the effects of medication in this study remain unclear, although evidence suggests Ginkgo biloba extract having an effect on the treatment of tinnitus (45). No control group for comparison was included, which lies within the naturalistic study design where we offer treatment to any referred patient. ...
Article
Full-text available
Aim: Tinnitus and hyperacusis are phenomena with a considerable prevalence in the general population, leading to high levels of suffering. It is a symptom that can present itself comorbidly with a variety of psychiatric and medical illnesses. We established a treatment of tinnitus and hyperacusis, which is based on a multimodal approach including a specific cognitive behavioral therapy (CBT) method in an inpatient setting. This approach includes education on tinnitus and hyperacusis, applying coping strategies and techniques of relaxation, directed attention, and music therapy. We aim to evaluate the efficacy of this treatment approach. Materials and methods: We included retrospective data of 268 patients who underwent tinnitus treatment throughout the 10-year existence of the treatment program. We assessed routine clinical data pretreatment and posttreatment with parameters concerning tinnitus-distress, hyperacusis, and psychological well-being. To determine these variables, we used validated instruments including the Tinnitus Questionnaire (TQ), Questionnaire on Hypersensitivity to Sound (QHS), Brief Symptom Inventory (BSI), and the Beck Depression Inventory (BDI-II). Results: Patients showed highly significant reduction in all of the examined clinical outcomes. Reduction of TQ, the primary outcome measure, was 15.39 (SD 21.88) from a mean baseline value of 35.72 (p < 0.001). The QHS showed a reduction of 6.72 (SD 8.23) from a mean baseline value of 18.98 (p < 0.001). Moreover, psychological strain was also reduced with high significance, as illustrated in reduction of BSI and BDI-II; reduction in BSI from 49.63 by 24.41 (SD 26.88; p < 0.001) and BDI-II from 16.89 by 7.47 (SD 8.76; p < 0.001). Discussion: The multimodal treatment program for tinnitus and hyperacusis including a specific CBT method proves to be a highly effective means of significantly reducing not only tinnitus and hyperacusis but also accompanying distress. Furthermore, it also enables considerable reduction of concomitant psychiatric symptoms such as depression. Conclusions: Our results underline the importance of intensive and multimodal approaches to the treatment of tinnitus and hyperacusis.
... [12][13][14] In a systematic review of the efficacy of standard Gingko biloba extracts in patients of tinnitus, in which a randomized, placebocontrolled clinical trials of Ginkgo biloba extract preparations were searched for and reviewed systematically. 15 There is evidence of efficacy for the standardized extract, in the treatment of tinnitus from three trials in patients in whom tinnitus was the primary complaint. Supportive evidence comes from a further five trials in patients with age-associated cognitive impairment or dementia in whom tinnitus was present as a concomitant symptom. ...
Article
Full-text available
p class="abstract"> Background: Cochlear synaptic tinnitus (CST), also referred to as sensorineural type III tinnitus, is a type of transformation tinnitus, resulting due to aberrant signal transduction between Inner hair cells and afferent nerve fibres owing to excessive and pathologic glutamate release and subsequent spontaneous receptor depolarization (NMDA and AMPA receptors). Of the various pharmacologic agents used for treatment for CST, Gingko biloba and Caroverine have stood the test of time. Methods: A total 48 selected patients of CST, otherwise free from any medical or surgical co-morbidity, were included in the study and divided randomly in two groups, one group receiving oral formulation of Caroverine and the other group receiving oral Gingko biloba in appropriate doses. Both the groups were followed up for 12 weeks. Treatment outcomes were measured in terms of improvement in subjective symptoms (tinnitus grading) and psycho-acoustic measure (tinnitus matching). Results: Although oral caroverine yielded promising results in the initial month of treatment in terms of improved tinnitus matching, long term effect was found to be dissatisfying. Oral Gingko biloba , at the completion of 12 weeks of therapy was found to be more effective in terms of improvement of mean tinnitus grading and matching (p<0.05). Side effects of the test drugs were not noted in either group. Conclusions: Gingko biloba is thus found to be more effective treatment modality for CST for long term basis and is also readily available in the market, cost effective and free of side effects as well.</p
Article
Full-text available
Altered functional connectivity (FC) of the thalamus has been proven to be an important finding in tinnitus patients. Tinnitus can be effectively desensitized by sound therapy. However, it is still unclear whether and how sound therapy affects the FC of the thalamus. Resting-state functional magnetic resonance imaging data and anatomical data were longitudinally collected from 25 idiopathic tinnitus patients before and after 12 weeks of sound therapy by using adjusted narrow band noise and from 25 matched healthy controls at the same time interval without any intervention. The FC of bilateral thalami were analyzed by setting the left and right thalamus as the regions of interest. Significant main effect of group on the FC of the thalamus were found mainly in the key components of the default mode network, limbic network, salience network, cognitive control network, auditory network and occipital region. FC values between the thalamus, inferior frontal gyrus (IFG), and anterior cingulate cortex (ACC) featured higher values in the tinnitus group at baseline compared to the healthy controls and restoration in tinnitus patients after treatment. Decreased Tinnitus Handicap Inventory (THI) scores and decreased FC values between the right thalamus and right IFG were positively correlated (r = 0.476, P = 0.016). Abnormal FC of the thalamus is associated with multiple brain networks. Sound therapy has a normalizing effect on the enhanced FC of the thalamus-IFG and thalamus-ACC, representing decreased tinnitus attention control and less involvement of the noise-canceling system.
Article
Ginkgo biloba extract (GBE) is widely used as herbal medicine. Preventive effect of GBE against dementia, including Alzheimer’s disease, has been reported. The bioactive compounds in GBE that impart these beneficial effects, flavonoids and terpene lactones, have poor bioavailability. Our previous study found distribution of bioactive compounds of sesame extract in mice brain after mixing it with turmeric oil. Here, we evaluate the distribution of bioactive compounds of GBE by combining it with the mixture of sesame extract and turmeric oil (MST). The content of terpene lactones in mice serum was significantly increased in a dose-dependent manner after administration of GBE. However, the contents of terpene lactones in mice brain were not significantly changed. Concentration of ginkgolide A in mice brain increased significantly when GBE was co-administrated with MST than when GBE was administered alone. These results suggest that MST may be effective in enhancing the bioavailability of ginkgolide A in GBE.
Article
Full-text available
Previous resting-state functional magnetic resonance imaging (fMRI) studies have shown neural connectivity alterations after the treatment of tinnitus. We aim to study the value of the baseline functional connectivity features of neural network nodes to predict outcomes of sound therapy through adjusted narrow band noise. The fMRI data of 27 untreated tinnitus patients and 27 matched healthy controls were analyzed. We calculated the graph-theoretical metric degree centrality (DC) to characterize the functional connectivity of the neural network nodes. Therapeutic outcomes are determined by the changes in the Tinnitus Handicap Inventory (THI) score after a 12-week intervention. The connectivity of 10 brain nodes in tinnitus patients was significantly increased at baseline. The functional connectivity of right insula, inferior parietal lobule (IPL), bilateral thalami, and left middle temporal gyrus was significantly modified with the sound therapy, and such changes correlated with THI changes in tinnitus patients. Receiver operating characteristic curve analyses revealed that the measurements from the five brain regions were effective at classifying improvement after therapy. After age, gender, and education correction, the adjusted area under the curve (AUC) values for the bilateral thalami were the highest (left, 0.745; right, 0.708). Our study further supported the involvement of the fronto-parietal-cingulate network in tinnitus and found that the connectivity of the thalamus at baseline is an object neuroimaging-based indicator to predict clinical outcome of sound therapy through adjusted narrow band noise.
Article
Tinnitus is defined as the erroneous perception of sounds and noises in the absence of a relevant external stimulus. It is a common phenomenon that almost everyone has experienced at some time or other. Some 4% of the German population suffers from chronic noises in the ear/head (tinnitus persisting for more than 1 year), with approximately 15% of them claiming serious interference with their daily activities (decompensated tinnitus). Clinically, a differentiation is made between subjective and objective tinnitus, the latter being very rare and the sounds are "real" (due to vascular disorders, palatal myoclonus or an open Eustachian tube, etc.), and may be heard with a stethoscope applied to the head or auditory canal. It is therefore not "true" tinnitus, and is better termed "body noise" Subjective tinnitus is usually associated with a hearing disorder or is associated with vertigo (Meniere's disease). Only 10-20% of the patients have no concomitant hearing loss. Options for acute treatment are few. In the chronic stage, treatment measures aimed at coping with the problem must be favoured (e.g. Tinnitus Retraining Therapy, and the use of noise, including the use of hearing aids to achieve a partial masking effect; in cases causing intolerable suffering, hospitalisation in special clinics providing psychotherapeutic treatment is indicated.
Article
In this study, we investigated the effect of ginkgoglycoside in two different doses (19.2 mg/day and 28.8 mg/day) on blood viscosity and erythrocyte deformability in 27 patients suffering from cerebrovascular insufficiency. The patients were divided into two groups randomly consisting of 13 and 14 patients respectively. Both groups received 28.8 mg/day ginkgoglycoside between the 1st and 15th day. The first group received the same dose until the end of the 30th day, whereas the dose administrated to the second group was reduced to 19.2 mg/day. In the first group, during 30 days a significant decrease in blood viscosity and a significant increase in erythrocyte deformability were observed. In the second group on the other hand, after dose reduction, the effect of the drug on blood viscosity and erythrocyte deformability were diminished. Improvement of symptoms including vertigo, tinnutus, headache and forgetfulness in the first group was found to be significantly different from the 2nd group at day 30 in a dose dependent manner.
Article
The efficacy of Gingko biloba extract on the relevant symptoms was tested on 40 out-patients with the diagnosis of 'mild to medium cerebrovascular insufficiency' (dosage: 1 film coated tablet, 40 mg extract, t.i.d., duration of treatment 12 weeks) in a randomized, placebocontrolled, double blind trial. In the group receiving active substance, the values for total SCAG Score (Sandoz Clinical Assessment - Geriatric) dropped on average by 9 points, whereas they remained unchanged in the placebo group. This difference is highly significant (p = 0.00005, one-sided, χ2 test). Evaluation of the separate items showed an effect particularly on disturbances of short-term memory and mental awareness as well as on dizziness as a symptom. Superior effects were also shown in the symptoms of headaches and tinnitus (noise in the ears), as well as through Syndrome Kurztest.
Article
In a randomized open and placebo-controlled clinical trial including 48 patients with vascular dementia, the effects of infusions of the Ginkgo biloba special extract EGb 761 at doses of 50, 100 and 200 mg were investigated as against placebo infusions. For this purpose, the 48 patients were randomly alloted to 4 groups with group I receiving placebo, group II 50 mg EGb 761, group III 100 mg EGb 761 and group IV 200 mg EGb 761. Primary variables chosen were microperfusion of the skin as well as whole-blood viscosity and elasticity. The values were determined previous to the beginning of the infusion and then 10, 20, 30, 45, 60, 80 and 120 minutes later; microperfusion of the skin was additionally measured 5 minutes after the beginning of the infusion. No statistically significant differences were found between group I (placebo) and group II (50 mg EGb 761) as concerns microperfusion. The comparison between group III (100 mg EGb 761) and group IV (200 mg EGb 761) showed significant differences after 45 and 120 minutes in favor of the higher dose. Furthermore, it was possible to demonstrate an increase in microperfusion in groups III and IV which was significant as compared to group I from 20 and 30 minutes on after infusion beginning as well as over the subsequent period till 120 minutes. Whole-blood viscoelasticity also showed dose-dependent changes with statistically significant differences between group IV and group I after 60 minutes as well as between group IV and group II after 45 minutes in each case in favor of the higher dose.
Chapter
People with tinnitus hear sounds such as crackling or whistling in the absence of external noise. Noises appear to arise in the ears or inside the head and may be experienced all of the time, or only intermittently. The causes of tinnitus are not yet fully understood and a variety of treatments are offered including medication, psychotherapy, noise 'maskers' and Tinnitus Retraining Therapy. The review of trials assessed the effectiveness of extract of Ginkgo biloba. Few good quality trials were found and there was no evidence that Ginkgo biloba is effective for tinnitus. Further research is needed.
Article
Previous studies have shown contradictory results of Ginkgo biloba extract (GBE) treatment of tinnitus. The present study was divided into two parts: first an open part, without placebo control (n = 80), followed by a double-blind placebo-controlled study (n = 20). The patients included in the open study were patients who had been referred to the Department of Audiology, Sahlgren's Hospital, Goteborg, Sweden, due to persistent severe tinnitus. Patients reporting a positive effect on tinnitus in the open study were included in the double-blind placebo-controlled study (20 out of 21 patients participated). 7 patients preferred GBE to placebo, 7 placebo to GBE and 6 patients had no preference. Statistical group analysis gives no suppport to the hypothesis that GBE has any effect on tinnitus, although it is possible that GBE has an effect on some patients due to several reasons, e.g. the diverse etiology of tinnitus. Since there is no objective method to measure the symptom, the search for an effective drug can only be made on an individual basis. © 1994 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.