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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 26  |  Issue : 4  |  Page : 232-239

Investigating the effect of Hypericum Perforatum L. on hearing in rats: An experimental study


1 Department of Otolaryngology, Faculty of Medicine, Sivas Cumhuriyet University, Sivas, Turkey
2 Department of Otolaryngology, Sami Ulus Pediatric Hospital, Ankara, Turkey
3 Department of Otolaryngology, Faculty of Medicine, Ankara Yıldırım Beyazıt University, Ankara, Turkey

Date of Submission31-Aug-2020
Date of Decision02-Oct-2020
Date of Acceptance28-Oct-2020
Date of Web Publication23-Apr-2021

Correspondence Address:
Prof. Emine Elif Altuntas
Department of Otolaryngology, Faculty of Medicine, Sivas Cumhuriyet University, 58140 Sivas
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/indianjotol.INDIANJOTOL_193_20

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  Abstract 


Objectives: Hypericum perforatum L. (HP) is among the oldest used and most comprehensively studied medicinal herbs. Anti-inflammatory activities of different Hypericum extracts on external auditory canal and also in the prevention of tympanic membrane perforation and myringosclerosis were investigated experimentally in the animal model. This study was to investigate whether or not intratympanic injection of H. perforatum L. in the middle ear of the rats causes ototoxicity, via auditory brainstem response (ABR). Materials and Methods: Rats were assigned to three groups as Group C, S, and D. Excessive external auditory canal edema developed in the rats in Group D as of the 5th day and Group D was excluded from the study by considering that ABR records could be affected. Results: A statistically significant difference was observed mean latency values of the wave V and III at the baseline and on the 7th day in Group S (P < 0.05). A significant shortening was calculated in the interpeak mean latency values of the waves III–V at the baseline and on the 7th day in Group S (P < 0.05). A statistically significant difference was observed between the baseline III–V wave interpeak mean latency values in the between-group evaluation on the 7th day (P < 0.05). A statistically significant difference was detected in the mean values of the wave V/Va amplitude ratios at the baseline and on the 7th day in Group S (P < 0.05).In the between-group evaluation, a statistically significant difference was found in the mean values of the wave V/Va amplitude ratios on the 7th day (P < 0.05). Conclusion: The results of the study conducted in accordance with the hypothesis point out that the intratympanic injection of H. perforatum L. may have an ototoxic effect.

Keywords: Auditory brainstem response, herbal medicine, Hypericum perforatum L, ototoxicity, rat


How to cite this article:
Altuntas EE, Bora A, Durmuş K, Kale H, Kutluhan A. Investigating the effect of Hypericum Perforatum L. on hearing in rats: An experimental study. Indian J Otol 2020;26:232-9

How to cite this URL:
Altuntas EE, Bora A, Durmuş K, Kale H, Kutluhan A. Investigating the effect of Hypericum Perforatum L. on hearing in rats: An experimental study. Indian J Otol [serial online] 2020 [cited 2021 Oct 23];26:232-9. Available from: https://www.indianjotol.org/text.asp?2020/26/4/232/314347




  Introduction Top


The World Health Organization states that traditional or herbal medicine is globally important and usually an underrated part of health services.[1] Having a rich historical background, Hypericum perforatum L. (Hypericaceae), commonly known as St. John's wort, is among the oldest used and most comprehensively studied medicinal herbs. H. perforatum L. has been used for the treatment of various illnesses, such as depression, aging memory impairment, smoking cessation, rheumatism, irritable bowel syndrome, bacterial infection, wound healing, and skin lesions in phytotherapeutic medicine for the centuries.[2] Scientific literature mentions numerous bioactivities and applications of H. perforatum L., including its anti-inflammatory, antibacterial, anxiolytic, antiviral, antidepressant, wound healing, and analgesic effects.[3],[4]

Since the presence of the positive effects of H. perforatum L. on the recovery of surgical wounds due to its epithelizing property is an accepted view in the literature, the hypothesis of “Can Hypericum perforatum L. have a role in the topical medical treatments of the patients with chronic suppurative otitis media before and after surgery?” was established in the study, and a total of six articles were found in the accessible databases during the literature review. In four of these studies, anti-inflammatory activities of different Hypericum extracts on external auditory canal edema experimentally induced in mice and also in the prevention of tympanic membrane perforation and myringosclerosis experimentally induced in the rat model were investigated.[5],[6],[7],[8],[9] The sixth study is a letter to the editor and it was pointed out that the positive effect of the administration of H. perforatum L. in preventing myringosclerosis cannot be underestimated. However, in the same study, investigation of ototoxic effects in topical drug applications with auditory brainstem response (ABR) will make a very important contribution to this issue.[10]

As a result, it is remarkable that even though the efficiency of H. perforatum L. has been investigated in the treatment of different pathologies in various animal models such as ear infections and tympanic membrane perforation in the literature, the ototoxic effect of topical application was not investigated before. Yaşar et al.[7] investigated the curative role of topical H. perforatum (HP) in a rat model of tympanic membrane perforation in a histopathological manner. Moreover, they found that H. perforatum L. was found to be more effective in a wound-healing model of the tympanic membrane. Yaşar et al.[7] revealed that “H. perforatum L. may be applied in clinical practice if it is shown to be safe with regard to ototoxicity.” As a result, based on the results of the study of Yaşar et al.,[7] we aimed to investigate whether or not intratympanic injection of H. perforatum L. in the middle ear of the rats causes ototoxicity by ABR method.


  Materials and Methods Top


Experimental animals

The randomized experimental procedure was used in the study. External auditory canals and tympanum of female Wistar albino (n=30, 16–18 week old, mean weight of 230 ± 10 g) rats were anesthetized with 3-mg/kg xylazine SC and 90-mg/kg ketamine HCL SC. And than external auditory canals were examined using an operation microscope (Zeiss, Germany). After the rats with external and middle ear pathologies were excluded from the study, a total of 24 rats were included in the study (given that α = 0.05, β = 0.20, and [1−β] = 0.80, it was decided to include 8 rats in each group and the power of the test was found as P = 0.80942). Wistar albino rats (n = 24) were randomly assigned to three experimental groups as Group C (control; 0.2 cc/day/intratympanic distilled water; n = 8), Group S (single dose; 0.2/cc/day/intratympanic H. perforatum L), and Group D (double dose; 0.2 mg/cc/day/intratympanic × 2 H. perforatum L). Among all rats in the experimental groups, 0.2 cc distilled water was injected as intratympanic to the rats in Group C using a dental injector at the same hour every day for 7 days and 0.2 cc H. perforatum L was injected as intratympanic once a day in Group S and twice a day in Group D.

Since there was no experimental model in which the effect of H. perforatum L was investigated on the auditory nerve, the drug volume of 0.2 cc that was used in the ototoxicity studies in rats was taken as a basis in the present study. It has been revealed by various studies in the literature that this amount was volume to fill middle ear of the rats completely with the drug and as it was sufficient for its transition to the inner ear through the oval and round window.[11],[12] In the study of Eğilmez et al.,[9] 20 mg/kg H. perforatum extract was applied to the rats in the topical treatment group. Approximately 20 mg/kg H. perforatum L. is administered to the middle ear of rats when 0.2 cc is administered intratympanic.

It was planned to exclude the rats, which died during the experimental stage due to any reason and had edema and inflammation in the external auditory canal (because it could affect the evaluation of hearing with ABR due to edema caused by the trauma that may occur during the injection), from the experiment protocol. Excessive external auditory canal edema developed in the rats in Group D as of the 5th day of the application. Intratympanic injection could not be done because the tympanic membranes were not visible in otoscopy and the rat in Group D was excluded from the study by considering that ABR records could be affected due to the edema. No external auditory canal edema was observed in the rats in Group C and S.

The rats were kept in steel cages under standard laboratory conditions (12-h light/dark cycle, 24°C ± 2°C, 35%–60% humidity) and fed with fresh feed without any nutrient limitation.

Experiments were performed at the Experimental Trial and Animal Laboratory of Sivas Cumhuriyet University, Faculty of Medicine in accordance with the Care and Use of Laboratory Animals Guideline of National Institute of Health (NIH) (NIH Publications No. 80-23 Revised 1996), by obtaining the approval of Animal Experiments Local Ethics Committee of Sivas Cumhuriyet University (date March 01, 2018 and no. 65202830-050.04.04-146).

Drug and chemicals

H. perforatum L was supplied from helvacizade (H. perforatum L; Helvacızade Food Pharmaceutical Chemistry Industry Company, Konya, Turkey).

Study protocol

After the rats were anesthetized with 3 mg/kg xylazine SC and 90 mg/kg ketamine HCL SC, ABR thresholds were recorded on the zeroth day (start of the study) (before the administration of any drug or distilled water via intratympanic injection) and on the 7th day (after the administration of any drug or distilled water via intratympanic injection) using a Neuro-Audio 0710 VX (Neurosoft Ltd., 5, Voronin str. Ivanovo, 153032, Russian) device in a quiet room. In the ABR records performed on the zeroth day, it was planned to exclude the rats whose threshold of hearing could not be determined and replace them with other rats having similar characteristics and a determined threshold.

ABR measurements of all the rats were performed from the right ear. Records of ABR responses were taken by subcutaneous Natus Ultra Subdermal Neddle Electrode (Stainless Steel Needle DIN 42802 Connector. Natus Neurology Incorporated 3150 Pleasant, View Road Middleton, WI. USA. 53562, Indonesia.) electrode was placed in such a way to be on an active electrode vertex, the grounding electrode contralateral mastoid, and the reference electrode ipsilateral mastoid. Stimuli were given by insert earphones. ABR evaluation was performed at 30, 50, and 70 dB stimuli by 8, 12, and 16 kHz tone bursts. The stimulus was started to be given at 70 dB nHL level and it was decreased by 20 dB steps until the intensity level approached to the threshold. When threshold was approached, 10 dB intensity steps were preferred and the threshold was determined. At least two traces were generated for each measurement, behavioral repeatability was tested, and thresholds were crosschecked. In case that no behavior could be obtained at 70 dB nHL level, the stimulus level of 90 dB nHL was used.

The stimuli were submitted at alternating polarity, the filter was adjusted as 30–2000 Hz, the repetition rate as 37/s; time window as 20 ms, and 1024 samples were taken for the signal averaging. The test was started by confirming that impedance had lower values than 1.0 kΩ.

ABR threshold was defined as the minimum intensity level with visible V wave of ABR. 10 dB level of auditory threshold was accepted as the inclusion criteria.

In addition to the threshold values, latency, amplitude and interpeak latency values were recorded on the 0th and 7th days in the ABR records in all the rats.

ABR latency is an additional indicator of auditory sensitivity. The measurement of ABR latencies was performed between stimulus onset and the waveform valley. Latency value was measured in milliseconds. In the study, absolute latencies were evaluated in 70 and 50 dB SPL for the wave III and 70, 50, and 30 dB SPL for the wave V.[13] Interpeak latency is generally accepted as the transmission time of the central auditory canal; interpeak latencies of I–III, III–V and I–V waves reflect the transposition time in caudal, rostral, and the whole brain stem, respectively. The elongation in the interpeak latencies is an indicator of a pathology in central auditory processing.[14] Thus, the stimulus intensity of III–V interpeak latency was measured as 50 and 70 dB in the study. Also, the amplitude ratios of the waves III/V and the amplitude ratios of the waves V/Va were recorded.

Statistical analysis

Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA) for Windows 23.0 package program was used to evaluate the data.

Because the rule of n >30 was not met in the evaluation of the data obtained in the study, Mann–Whitney U test was used for independent samples and Wilcoxon signed test was used for dependent samples for two-category comparisons. The tests were interpreted at confidence level of 95%.


  Results Top


In the baseline and 7th day ABR evaluation of all the 16 rats included in the study; the wave V was observed at 8, 12, and 16 kHz frequencies and at 10 dB stimulus intensity.

Wave latencies

[Table 1] shows V-wave mean latency values of all the rats in Group C and Group S at 8, 12, and 16 kHz frequencies and 30, 50, and 70 dB SPL stimulus intensity in the baseline and 7th day ABR evaluation. It was observed that the groups were homogenous when the groups were compared in terms of V-wave mean latency values at the baseline, 8, 12, and 16 kHz frequencies and at 30, 50, and 70 dB SPL stimulus intensity (P > 0.05).
Table 1: Mean latency values of the Wave V of the rats in Group C and Group S in the baseline and 7th-day auditory brainstem response evaluation

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In the within-group evaluation, no statistically significant difference was observed at all three frequencies and stimulus intensity levels in the mean latency values of the baseline and 7th day wave V in Group C (P > 0.05). However, in the within-group evaluation performed in Group S, a statistically significant difference was observed at all three frequencies and stimulus intensity levels in the mean latency values of the wave V at the baseline and on the 7th day (P < 0.05).

[Table 2] shows the wave III mean latency values of all the rats in Group C and Group C at 8, 12 and 16 kHz frequencies and at 50 and 70 dB SPL stimulus intensity at the baseline and 7th day ABR evaluation. At the baseline ABR evaluation of the groups in terms of the wave III mean latency values, it was observed that it was homogeneous at all the frequencies and stimulus intensity levels (P > 0.05).
Table 2: Mean latency values of the Wave III of the rats in Group C and Group S in the baseline and 7th-day auditory brainstem response evaluation

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In the within-group evaluation, no statistically significant difference was observed at all the frequencies and stimulus intensity levels in the mean latency values of the wave III at the baseline and on the 7th day in Group C (P > 0.05). However, in the within-group evaluation performed in Group S, a statistically significant difference was observed at 8 kHz frequency and all stimulus intensity levels and at 12 kHz and 70 dB in the mean latency values of the wave III at the baseline and on the 7th day (P < 0.05), no statistically significant difference was calculated at the other frequencies and stimulus intensity levels (P > 0.05).

Interpeak intervals

[Table 3] shows the III–V interpeak mean latency values of all the rats in Group C and Group S at different frequencies and stimulus intensity levels in the baseline and 7th day ABR evaluation.
Table 3: Interpeak mean latency values of the Waves III–V of the rats in Group C and Group S in the baseline and 7th-day auditory brainstem response evaluation

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It was observed that the groups were homogeneous when the groups are compared in terms of the interpeak mean latency values of the wave III–V at the baseline 8, 12 and 16 kHz frequencies and at 50 and 70 dB SPL stimulus intensities (P > 0.05).

In the within-group evaluation made in Group C, no statistically significant difference was determined at all the frequencies and stimulus intensity levels in the baseline and 7th-day III–V wave interpeak mean latency values (P > 0.05). However, in the within-group evaluation performed in Group S, a significant shortening was calculated only at 12 kHz frequency and at 70 dB in the interpeak mean latency values of the waves III–V at the baseline and on the 7th day (P < 0.05); whereas, no statistically significant difference was determined at all the other frequencies and stimulus intensity levels (P > 0.05).

Similarly, in the between-group evaluation, no statistically significant difference was observed between the baseline III–V wave interpeak mean latency values (P > 0.05); however on the 7th day, the difference at 8 kHz at all the stimulus intensity levels and at 12 kHz at 70 dB was statistically significant (P < 0.05); and a shortening was observed in the III–V interpeak latency value in Group S.

The ratio of wave amplitudes

It was observed that when the groups were compared in terms of mean values of the wave III/V amplitude ratios at the baseline, 8, 12 and 16 kHz frequencies and at 50 and 70 dB SPL stimulus intensities (P > 0.05), they were homogeneous [Table 4].
Table 4: Mean values of amplitude ratios of the Waves III–V of the rats in Group C and Group S in the baseline and 7th-day auditory brainstem response evaluation

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No statistically significant difference was found at all the three frequencies and stimulus intensity levels in terms of mean values of the wave III/V amplitude ratios at the base line and on the 7th day between and within the groups (P > 0.05).

It was observed that when the groups were compared in terms of the mean values of the wave V/Va amplitude ratios at the baseline, 8, 12, and 16 kHz frequencies and at 50 and 70 dB SPL stimulus intensities (P > 0.05), they were homogeneous [Table 5].
Table 5: Mean values of amplitude ratios of the Waves V–Va of the rats in Group C and Group S in the baseline and 7th-day auditory brainstem response evaluation

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In the within-group evaluation, no statistically significant difference was observed at all three frequencies and stimulus intensity levels in the mean values of the wave V/Va amplitude ratios at the baseline and on the 7th day in Group C (P > 0.05). In Group S, a statistically significant difference was detected at 12 kHz and 16 kHz 50 dB stimulus intensity level (P < 0.05).

In the between-group evaluation, no statistically significant difference was determined between the mean values of the baseline V/Va amplitude ratios (P > 0.05); whereas, a statistically significant difference was found at 12 and 16 kHz frequencies and at 50 dB stimulus intensity level in the mean values of the wave V/Va amplitude ratios on the 7th day (P < 0.05). This difference was associated with the reduction in the amplitude ratios in Group S.


  Discussion Top


Ototoxicity can be defined as the development of complaints of hearing impairment and/or dizziness as a result of the damage occurred in the inner ear due to various chemical substances. Some of these substances are the materials used for medical treatment and about 200 drugs are known to be ototoxic today.[15] Ototoxic drugs and chemicals cause cellular degeneration in the inner ear and also the symptoms such as hearing loss, dizziness, and tinnitus causing the dysfunction of the tissues. Sensorineural hearing loss developing as a result of ototoxicity is an outcome of the permanent damage caused by the drugs in the marginal cells and outer hair cells in stria vascularis.[16] Hearing loss developing due to drugs typically starts at high frequencies. Thus, it is necessary to perform the monitorization of hearing by using otoacoustic emission test (OAE) as it reflects the changes in the outer hair cells in the earlier period and also the high frequency audiometric evaluation in the subclinical period before the symptoms occur in the patients taking ototoxic drugs.[17] Although electrophysiological tests such as ABR do not seem to be appropriate for use as a standard monitoring technique for ototoxicity other than children, elders, and the individuals who are unable to adapt to other tests due to various causes, it is the standard method for measuring the functional ototoxic changes in preclinical animal studies when it is necessary to detect the changes in the central auditory system.[17],[18],[19] In the study of Ekborn et al.,[20] to investigate the effects of the protective agents against the cisplatin ototoxicity in guinea pigs via OAE and an electron microscopic evaluation, they showed that OAE was not an appropriate evaluation method for the evaluation of ototoxicity in animals. For this reason, it is generally thought that electrophysiological tests have more reliable results in the monitorization of hearing in experimental animals in ototoxicity studies in the literature.[21] Therefore, in the present study, ABR was selected as a method of evaluation in order to investigate whether or not intratympanic injection of H. perforatum L. cause ototoxicity in the rats.

H. perforatum L. is a natural drug that has been used in the treatment of many diseases for many centuries. It has been shown in various studies in the literature that H. perforatum L. can be effective in the treatment of tympanic membrane perforation and edema of the external auditory canal edema that are experimentally induced in different animal models and it is not investigated in any of these studies whether or not topical administration causes ototoxicity.[5],[6],[7],[8],[9],[10] And also in the literature reviews, we conducted in databases available to us, none of the studies in which H. perforatum L. was used as an antidepressant, analgesic, anti-inflammatory, antioxidant, antimicrobial, and/or wound healing was not mentioned an ototoxicity. The first one of these studies was performed by Rabanal et al.,[5] in 2005 for the investigation of analgesic and topical anti-inflammatory activities of the infusion of the air fractions and methanol extracts of Hypericum canariense L. and Hypericum glandulosum flowers in the rats. In order to examine the local anti-inflammatory effects in the study, plant extracts to the experimental group and reference drug to the control group were applied 15 min after inducing an edema in the external auditory canal by dripping 12-O-tetradecanoylphorbol 13-acetate in the ears of the mice. The experimental animals were sacrificed after 4 h and their tissue samples were taken. The results obtained revealed that all the plant extracts except for H. canariense reduced the ear edema of the mice in topical application. While the results of the study by Rabanal et al.[5] were interpreted, they pointed out that although their study was the first study to investigate the topical anti-inflammatory effects of different extracts obtained from H. canariense and H. glandulosum, further studies are required to use such extracts routinely in the treatment of various inflammatory diseases. In their study, Sánchez-Mateo et al.,[6] used the otitis model induced by tetradecanoylphorbol acetate in mice and determined that Hypericum reflexum had a topical anti-inflammatory effect and different studies regarding this matter are required, which was similar to the results of Rabanal et al.[5] After these two studies, the third study in the literature was the study by Sosa et al.,[8] and they evaluated the topical anti-inflammatory activities of the hydroalcoholic and lipophilic extracts of the H. perforatum as well as the partially purified hydroalcoholic extract of the flowered supernatants. The results obtained from the study showed that all the three extracts were effective on the ear edema that was induced by Croton-oil in mice. However, while Sosa et al.[8] interpreted the results of their study, they reported that different components could be included in the topical antiphlogistic properties of H. Perforatum due to insufficiency of concentration of the studied compounds for the anti-inflammatory effect. In their studies, Eğilmez et al.,[9] examined the protective effect of H. perforatum L. for inhibiting the development of Myringosclerosis in the rats in which the topical and oral forms of H. perforatum L. extract induced a tympanic membrane perforation and they histopathologically revealed that this extract suppressed inflammation, reduced fibrosis and as a result, inhibited the development of myringosclerosis. However, they pointed out that the results of this study should be supported with clinical studies conducted using different antioxidants and with larger populations. In 2016, Yaşar et al.[7] investigated the effect of H. perforatum L. olive oil extract during the recovery period of tympanic membrane perforation in rats. According to the results obtained from their study, they stated that this extract was effective in the recovery period of acute tympanic membrane perforation; however, further studies were required in order to understand whether or not it is effective on the chronic perforation models when considering this positive effect on wound healing besides its antibacterial and anti-inflammatory effects. Moreover, when it is considered in clinical practice that antibiotics and steroids are recommended for the patients in postoperative period after otologic surgeries, they mentioned in their study that H. perforatum L. may positively contribute to the treatment in postoperative period if it is identified to be nonototoxic, and this matter should be also investigated. Baran and Gokdogan[10] shared an editorial letter based on the study by Eğilmez et al.,[9] with the literature in 2016. In this editorial letter, it was noted that there was no information about the ototoxicity of H. perforatum, and the ABR evaluation to be performed before and after the application of the extract could make this study more valuable.

In the study by Cinci et al.,[22] they showed that H. perforatum hydrophilic extract could be used as a new therapeutic strategy in order to withstand against chemotherapy-induced neuropathy and this suggested that this extract could not have any cochleotoxic effect. However, the results obtained from the studies in the literature investigating the positive effects of different extracts of H. perforatum on both anti-inflammatory and wound healing processes in various ear diseases, have pointed out that the ototoxic effect of the extract should be investigated with ABR in the animal model; therefore, in the present study, it was aimed to investigate whether or not the topical application caused an ototoxic effect by administering intratympanic injection of H. perforatum L. in the middle ear of the rats. First, in the study, attention was paid to the homogeneity of the rats in the control and experimental groups in terms of the parameters evaluated in the baseline ABR evaluation. When the ABR results obtained after a 7-day intratympanic drug administration were statistically evaluated, it was revealed that mean latency values of the wave V were elongated at all the frequency and stimulus levels in the experimental group (Group S), mean latency values of the wave III were elongated at certain frequencies and stimulus intensity levels; interpeak mean latency value of the waves III–V at 70 dB reduced in parallel to the elongation in V and III wave latency values, and while there was no significant difference in the mean values of amplitude ratios of the waves III/V, mean values of amplitude ratios of the waves V/Va shortened at certain frequencies and stimulus intensity levels. These results were remarkable in terms of ototoxicity. However, some limitations of the present study are that the drug volume used in other studies investigating ototoxicity for rats since we cannot reach a study in the literature investigating intratympanic injection of H. perforatum L. was based; a single dose of drug was used since H. perforatum L. extract was not prepared from the plant and its preparation form available in the market was administered; only ABR method was used for evaluating ototoxicity; and cochlea and tympanic membrane were not histopathologically evaluated. We are of the opinion that despite all the limitations of the present study, the results obtained from the study may contribute to the further related studies since it is the first study pointing out that H. perforatum L. may have an ototoxic effect.


  Conclusion Top


The results of the present study conducted in accordance with the hypothesis point out that the intratympanic injection of H. perforatum L. may have an ototoxic effect. However, we think that it would not be suitable to specify an absolute decision regarding this matter due to the limitations of the present study and in order to obtain exact results, further studies are required in which different drug dosages are used and cochlea is histopathologically evaluated along with ABR to evaluate the cochlear effect.

Acknowledgment

We would like to thank Selim Çam for his contribution to statistical evaluation.

Financial support and sponsorship

The authors declared that this study has received no financial support.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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