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Improvement in cochlear flow with Pycnogenol in patients with tinnitus: a pilot evaluation
M. G. GROSSI, G. BELCARO, M. R. CESARONE, M. DUGALL, M. HOSOI, M. CACCHIO, E. IPPOLITO, P. BAVERA

Aim. The aim of this preliminary evaluation was to study the efficacy of Pycnogenol in improving cochlear flow in patients with mild-to-moderate tinnitus present for at least two weeks (without vertigo or important hearing loss), possibly associated with cochlear hypo-perfusion. Methods. Patients with mild-to-moderate, idiopatic, monolateral tinnitus present for at least 2 weeks were included; no vertigo or important hearing loss had been found in a specific examination. The origin of tinnitus had been sudden (hours or days). Fifty-eight patients used Pycnogenol: 24 used 150 mg/day (group A; mean age 43.24.3) and 34 patients 100 mg/day (group B: mean age 42.43.8). Controls included 24 patients (mean age 42.34.5). The groups were comparable for their clinical problem and age and sex. The average duration of treatment was 34.33.1 days. No side effects were observed and no drop-outs occurred. Results. The variations in cochlear flow velocity (in cm/s at the cochlear artery), at inclusion and after four weeks of treatment indicated that flow velocity at the level of the affected ear was significantly lower (both the diastolic and systolic components; P<0.05) in comparison with the other ear. The treatment favored an improvement in systolic (P<0.05) and diastolic flow velocity (P<0.05) in the two treatment groups A+B. The increase in flow velocity was very limited and not significant in controls. Conclusion. These results suggest that in selected patients with tinnitus and altered perfusion, Pycnogenol is effective in a short period of time in relieving tinnitus symptoms by improving cochlear blood flow. The effect is more pronounced with higher Pycnogenol dosage. More studies should be planned to better evaluate the pathology and potential applications of
Conflict of interest.None. Received on April 13, 2010. Accepted for publication on June 4, 2010. Corresponding author: G. Belcaro, MD, PhD, Irvine3 Circulation/ Vascular Labs, Chieti-Pescara University, SS 16bis, 94 (A), Spoltore, 65100 Pescara, Italy. E-mail: cardres@abol.it

Irvine3 Labs Department of Biomedical Sciences Chieti-Pescara University, Pescara, Italy

Pycnogenol in a larger number of patients who are currently without a real therapeutic solution. KEY WORDS: Cochlea - Tinnitus - Ultrasonography - Ventricular function - Pycnogenol.

innitus originates within the ear and may affect one or both ears. The sounds have been variously described by patients as a buzzing sound, humming noise, a whistling sound, and so on. Tinnitus may be associated with several ear or systemic problems. It is difficult to determine its cause as many disorders may produce it. Tinnitus may be associated with a block of the ear canal or a block of the eustachian tube and with different types of infections. Otosclerosis is a common cause of tinnitus. Also, Menieres disease, characterized by an association of dizziness and deafness, is also associated with tinnitus.1-6 In most patients, one ear is affected. Tinnitus may be associated with drug treatments such as aspirin and antibiotics (i.e., aminoglycosides). An associated hearing loss may be present, with different degrees of gravity. Several types of trauma, a chronic exposition to noise or vibrations in working conditions, or injury caused by explosions are also linked to tinnitus. Temporo-mandibular joint syndrome is also considered a cause of tinnitus. This symptom also occurs in association with other clinical conditions such as anemia, hypertension and atherosclerosis in its several local-

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izations, hypothyroidism, and head and vertebral traumas. Presbycusis (hearing loss and hearing problems related to advanced age) can also be associated with tinnitus.2-6 The broad range of possible patho-mechanisms involved makes the diagnosis and treatment of this condition very difficult with very subjective results to treatment, despite several available technological measurements. The basis for measuring tinnitus is based on the brains tendency to select out only the loudest sounds heard. The amplitude of tinnitus is measured by playing sample sounds of defined amplitude and asking the patient which he/she hears. The tinnitus will always be equal to or less than sample noises heard by the patient. This method is effective to define and measure objective tinnitus.1-6 Although objective tinnitus is not frequent, subjective tinnitus, which cannot be tested by comparative methods, is very frequent. Subjective noises may often be present, becoming very intrusive and severely impairing attention and the quality of life of otherwise healthy patients. These noises are not usually related to identified ear problems or hearing loss, and most patients have great difficulty coping with tinnitus. Several patients have a combination of good hearing and tinnitus. In other subjects, tinnitus may be related to cognitive function impairment, altered memory or temporary situations linked to anxiety, fatigue and underlying disease. Both retina and cochlear tissue are basically brain-related structures, and in some situations, such as retinal circulation problems, tinnitus may be an early expression of important neurological problems. In previous studies 7-9 we have anecdotally observed that some patients both diabetics and non diabetics who showed signs of tinnitus with vertigo and defined or undiagnosed inner ear problems related to microcirculation improved when using Pycnogenol (trademark of Horphag Research) prescribed for vascular problems. These patients showed an improvement in their tinnitus that was independent from the main clinical/preventive application of Pycnogenol. At the moment, patients with tinnitus constitute a very large group without a real and specific therapeutic solution. In severe cases PGE1 (prostaglandin E1) can be used to obtain relief. With a noninvasive technique (color-Duplex ultrasonography), it is now possible to measure flow in the cochlear artery and to follow Duplex flow changes due to treatments in most

patients. The aim of this preliminary evaluation was to study the efficacy of Pycnogenol in improving cochlear blood flow in patients with mild-to-moderate tinnitus, present for at least two weeks (without vertigo or important hearing loss), possibly associated with cochlear hypoperfusion.
Materials and methods

Inclusion criteria Patients with mild-to-moderate, idiopatic, monolateral tinnitus present for at least two weeks were included; no vertigo or important hearing loss had been found in a specific ear. The origin of tinnitus had been sudden (hours or days). The specialist had suggested that in the absence of any other defined cause, tinnitus was possibly associated with cochlear hypoperfusion. By inclusion criteria, the cochlear systolic and diastolic flow velocities were significantly decreased (>30%) in comparison with the other, nonaffected ear. This was considered an indication of hypoperfusion. No other medical treatment was used at inclusion or during the previous weeks. No metabolic condition (i.e., diabetes, requiring specific treatment) was present, and no smoking or other important cardiovascular risk factors had been detected at inclusion. Patients had no history of trauma. As reported, a specialized ear examination was substantially negative without infection or history of infection. No obstruction of the ear canal was reported, and no apparent other significant disease had been diagnosed. Routine blood tests were all within the normal range. Also, there were no significant previous episodes or ear surgery in the medical history. The inclusion age range was between 35 and 55 years.

Cochlear imaging and color-Duplex ultra-sonography

A high-resolution, linear probe (10-13 Mhz) was used for imaging.10, 11 The probe was placed anteriorly to the ear, and image and flow detection were made with the color-Duplex and slow flow option. A Preirus, Hitachi ultrasound scanner was used (Tokio, Japan). The Pycnogenol dose was 100 mg/day (50 mg bid) in group B and 150 mg (50 mg tid)/day in group A, and a comparable group of subjects not using Pycnogenol or any other specific treatments were evaluated at inclusion and four weeks.

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TABLE I.The Tinnitus Scale.

No tinnitus 10 cm Tinnitus as bad as possible (i.e., requiring hospital admission)
Irvine3 Subjective Tinnitus Scale: (0-15) Signs/Symptom Score 0 1 2 3

Figure 1.The Analogue Scale line for tinnitus.

A specific, Visual Analogue Scale (VAS) was designed to define subjective tinnitus. This scale, particularly appropriate for pain and tinnitus (which can be considered similar to pain in its expression), is highly subjective and influenced by several external causes. This measurement provides the subjects with a simple rating scale. Respondents had to mark the appropriate point on a 10-centimeter line corresponding to the severity of tinnitus they experience (Figure 1). This scale offers freedom to choose the exact intensity of tinnitus as perceived and the maximum opportunity for subjects to express a personal response. VAS data of this type is recorded as the number of cm from the left origin of the line with a defined range from 0 to 10 cm.

Presence Intensity Duration Changes in QOL Use of drugs

Uncommon Low Minutes None None

Monthly Mild Hours Mild Occasional

Weekly Moderate Days Moderate Frequent

Always Severe Always Severe Always

QOL: quality of life.

TABLE II.The variations in cochlear flow velocity (in cm/s at the cochlear artery), at inclusion and after four weeks of treatment are shown in Table I.
Normal ear Systolic Diastolic Affected ear Systolic Diastolic

Pycnogenol (100 mg) Pycnogenol (150 mg) Controls

Bef 4W Bef 4W Bef Aft

24.22.2 23.12.4 22.22.1 23.113.2 21.61.3 22.11.23

12.11.9 13.12.3 12.22.3 12.81.7 14.21.4 15.31.7

14.32 21.22.4* 13.22.4 24.31.4* 13.62.1 13.31.3

4.221.1 8.231.3* 3.22.2 12.51.4* 4.120.9 3.221.1

Irvine3 subjective tinnitus scale

Table I shows the items in the tinnitus scale ranging from 0 to15. The scale has been validated for evaluating subjective tinnitus and vertigo in previous studies.

Values are given as meanstandard deviation. Asterisk indicates significance compared to baseline

Statistical analysis
The results considered non-parametric were evaluated using analysis of variance (ANOVA with the Bonferroni correction). At least 15 subjects should have been observed in the study (with at least 10 completing the study/observation period in each group). These numbers were defined in order to overcome spontaneous or intraindividual variations and interindividual variability. A condition such as tinnitus may have periods of very high intensity followed by other periods of low levels of intensity. These variations are due to several factors including individual, psychological and environmental conditions.
Results

(group B: mean age 42.43.8; 22 females). Controls included 24 patients (mean age 42.34.5 years; 15 females). Groups were comparable for their clinical problem and age/sex. The average duration of treatment was 34.33.1 days. No side effects due to treatment were observed, and no drop-outs were recorded. The variations in cochlear blood flow velocity (in cm/s at the cochlear artery) at inclusion and after 4 weeks of treatment are shown in Table II. Flow velocity at the affected ear was significantly lower (both the diastolic and systolic components, P<0.05) in comparison with the other ear. This was considered an indication of the vascular origin of the tinnitus. With treatment there was a significant improvement in both systolic (P<0.05) and diastolic flow velocity (P<0.05) in the two groups versus baseline values. The increase in flow velocity was very limited and statistically not significant in the control group.

A group of 58 patients using Pycnogenol was evaluated; 24 used the high dose of Pycnogenol (group A: mean age 43.24.3; 18 females) and 34 the low dose

Analogue Scale Line

The score in the low dose group (B) was 7.62.2 at inclusion; it decreased to 5.12.1 after four weeks treat-

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ment (P<0.05). In the high dose group (A) it was 7.92.1 at inclusion and decreased to 4.11.3 after four weeks (P<0.05). The score was 7.82.4 in controls at inclusion, and after four weeks the value was 7.92.5 (the difference was not significant). Therefore, the differences before/after were statistically significant for both groups A and B, with group A, which received a higher dose, showing a significantly more important improvement (P<0.05 vs. B).

Tinnitus Scale
The value at inclusion in group A was 8.83.1 and 8.82.8 in group B, and 7.93.1 in the control group. After four weeks the score was reduced to 5.21.3 (P<0.05) in the low dose group (B); and 3.32.1 in the high dose group (A) (P<0.05). In the control group the score was reduced to 6.64.4 (not significant).
Discussion

Perhaps the only current source of limited but explicit documentation of tinnitus is the post-deployment health assessment questionnaire (DD Form 2796) used for the United States Army. Reports defining the characteristics of tinnitus vary. Tinnitus induced by noise exposure may be high-pitched, whereas tinnitus associated with Mnires disease may be a lowpitched sound. Tinnitus can be transient or persistent. Persistent or prolonged tinnitus lasts at least five minutes and is perceived continuously (all or most of the time) or occasionally. A given episode of tinnitus may also resolve, with new repeating episodes. Currently tinnitus is considered a symptom rather than an illness. Its association with several clinical conditions, including hearing loss, is still unclear. In some patients; however, tinnitus is a clinical entity without a context.12-15 In previous studies 10, 11 the vascular origin of tinnitus was evaluated measuring cochlear blood flow with color-Duplex ultrasonography. The efficacy of a vasodilating agent, Pentoxifylline (used for four weeks), in improving perfusion within the inner ear circulation was associated with an improvement in signs/symptoms, including tinnitus. Also PGE1 had been used on a compassionate basis (no other treatment is actually available) in subjects with acute or chronic hypoacusia and vertigo or balance disorders often associated with tinnitus. These signs/symptoms may be asso-

ciated to cochlear infarctions or angina episodes that can be treated with a perfusional increase (obtained with PGE1, intravenous infusion). It is important to note that the measurement of cochlear blood flow, as for any intracranial blood flow measurement, is possibile only if an adequate osteal window allows ultrasound to penetrate the cochlear area. In general, a good acousting window is available in some 80% of normal subjects.16-19 This pilot study indicates a potentially important dose-related effect of Pycnogenol on cochlear blood flow and on tinnitus. The study also indicates the parallel efficacy of Pycnogenol on blood flow and tinnitus symptoms. As anecdotally observed, this may also be true for other signs/symptoms such as impaired hearing (particularly the acute form associated with balance problems, as seen in cochlear infarctions). Results show that in selected patients with persistent tinnitus and altered inner ear perfusion, Pycnogenol is effective in relieving tinnitus in a relatively short period of time, possibly by improving cochlear blood flow. The effect appears to be related to dosage, as the higher dose was more effective. More studies should be planned to further evaluate the use of Pycnogenol in this very interesting field affecting a very large number of patients who are currently without a real therapeutic solution. References
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