Tetsuro Wada

The Effect of Methylprednisolone on Acoustic Trauma

The effect of methylprednisolone (mPSL) upon acoustic trauma was studied using albino guinea pigs which were exposed to 2 kHz pure tone of 110, 115 or 120 dB SPL for 10 min. After the exposure to intense sound, mPSL of 6, 12 or 40 mg/kg was intraperitoneally given daily for 7 days and the threshold of the compound action potential (CAP) was examined on the 8th day. Compared with CAP of the control animals given physiological saline solution, no significant difference was observed in the CAP threshold shift between the mPSL group and the controls following exposures to the sound of 115 and 120 dB SPL, respectively. However, when the animals were exposed to the sound of 110 dB SPL, the CAP threshold shift was significantly smaller in the mPSL animals than in the controls. The present results indicate that mPSL possesses a therapeutic effect in cases of mild acoustic overstimulation.

Glucocorticoids and dehydroepiandrosterone sulfate ameliorate ischemia-induced injury of the cochlea

This study aimed to evaluate the effects of steroidal drugs on the functional recovery of the cochlea after transient ischemia. Albino guinea pigs were subjected to transient cochlear ischemia of 30 min duration, and the threshold shifts of the compound action potential (CAP) from the pre-ischemic values were evaluated 4 h after ischemia. Pre-ischemic administration of a glucocorticoid, prednisolone or methylprednisolone, significantly ameliorated the post-ischemic CAP threshold shifts as compared with control animals at a relatively wide range of doses. Post-ischemic administration of these glucocorticoids also exhibited protective effects. Pre-ischemic administration of dehydroepiandrosterone sulfate significantly decreased the post-ischemic CAP threshold shifts 4 h after ischemia. The present results indicate that glucocorticoids and dehydroepiandrosterone sulfate possess therapeutic effects against ischemic injury of the cochlea, such as idiopathic sudden sensorineural hearing loss.

The effect of mannitol upon cochlear dysfunction induced by transient local anoxia

Transient local anoxia of the cochlea was induced by pressing the labyrinthine artery, and compound action potential (CAP) or endocochlear potential (EP) was measured before and after transient local anoxia ranging from 5 to 60 min using 106 albino guinea pigs. The complete interruption of the cochlear blood flow by this procedure and its full restoration after releasing the pressure on the artery was confirmed by a laser-Doppler flowmeter. The anoxia of less than 10 min induced no post-anoxic cochlear dysfunction, whereas the anoxia of a longer duration induced an irreversible dysfunction of the cochlea. It was evident that the post-anoxic recovery of the CAP threshold was worse as the anoxia period was prolonged, and CAP was almost completely abolished after 60-min anoxia. In animals which were administered mannitol intravenously just after the restoration of the cochlear blood circulation, the recovery of the CAP threshold was significantly better than that in the control animals, when the animals were subjected to local anoxia of 15- to 30-min duration. No beneficial effect, however, was observed in the 60-min anoxia group. In conclusion, local anoxia of 10 min or longer caused cochlear dysfunction, which was partially but significantly alleviated by mannitol.

Steroid-sensitive nephrotic syndrome associated with Kimura disease.

Abstract We report an 11-year-old Japanese boy with Kimura disease and associated nephrotic syndrome. Before the diagnosis of Kimura disease was established, the patient had three episodes of swelling on the left cheek with subsequent nephrotic syndrome. Steroids were effective for both conditions. However, both conditions recurred within months of discontinuation of steroids. For the fourth episode of swelling on the left cheek, cyclosporine (CsA) was used. The subcutaneous tumor responded to CsA and disappeared within a few days. There has been no subsequent relapse of the nephrotic syndrome to date.

Effect of nitric oxide synthase inhibitor on cochlear dysfunction induced by transient local anoxia

To evaluate whether nitric oxide (NO) plays a role in the mechanism of generation of cochlear dysfunction induced by anoxia and reperfusion, the effects of a nitric oxide synthase (NOS) inhibitor, N-nitro-L-arginine, were examined using 71 albino guinea pigs. Transient cochlear anoxia of different duration (15, 30 or 60 min) was induced by pressing the labyrinthine artery and compound action potential (CAP) was measured before and 4 h after anoxia. N-nitro-L-arginine (1-30 mg/kg) administered intraperitoneally 1 h before the onset of anoxia alleviated the cochlear dysfunction when the anoxic period was 15 or 30 min. No beneficial effect was observed, however, in the 60-min anoxia. These results indicate that NO contributes to the generation of anoxia-induced cochlear dysfunction and that NOS inhibitor has a protective effect on the cochlear injury induced by anoxia of moderate duration.

Effect of 7-Nitroindazole upon Cochlear Dysfunction Induced by Transient Local Anoxia

The purpose of the present study was to further elucidate how nitric oxide (NO) is involved in cochlear anoxia-reperfusion injury. Transient local anoxia of the cochlea was induced in albino guinea pigs for 15, 30, or 60 minutes by transiently compressing the labyrinthine artery through a skull base approach. 7-Nitroindazole (7NI), a relatively selective neuronal nitric oxide synthase (nNOS) inhibitor, was intraperitoneally administered to the guinea pigs 30 minutes before the onset of local anoxia. The compound action potential (CAP) thresholds were measured before the administration of 7NI and 4 hours after the onset of reperfusion. A statistically significant reduction in the postanoxic CAP threshold shift from the preadministration value was observed in the 7NI-administered animals as compared with the control animals after 15- and 30-minute periods of anoxia. These results confirm the involvement of NO and nNOS in the cochlear injury induced by transient local anoxia.

The Effect of Crossed Olivo-cochlear Bundle Stimulation on Acoustic Trauma

To investigate whether the crossed olivo-cochlear bundle (COCB) functions in a protective manner, albino guinea pigs were exposed to sounds of varying intensity (110-130 dB SPL, 3-30 min) with or without electric stimulation of COCB, and the threshold shifts of the compound action potential (CAP) were examined. A statistically significant protective effect was observed in animals exposed to stimuli of intermediate intensity which induce threshold shifts of 50 to 55 dB on average. No protective effect was observed in the groups exposed to greater or milder stimuli. These results are discussed in the light of the available literature.

Effects of voriconazole co-administration on oxycodone-induced adverse events: a case in the retrospective survey.

Letter to the editor Oxycodone, a semisynthetic μ-opioid receptor agonist, is widely used for acute and chronic pain [1]. Because oxycodone is a substrate of cytochrome P450 (CYP) 2D6 and 3A4 [2–4], pharmacokinetic drug interaction may occur under concomitant use of CYP inhibitors, such as azole antifungals. Hagelberg et al. recently reported a drug interaction between oxycodone and voriconazole, an antifungal agent with potent CYP3A4 inhibitory activity, in a pharmacokinetic study employing healthy individuals, where the area under the drug concentration-time curve for oxycodone increased by 2.7–5.6 fold under co-administration of voriconazole [5]. This finding suggests that voriconazole potentially enhances both the efficacy of and the occurrence of related adverse events when both drugs are used concomitantly. To assess the clinical impact of this drug interaction, we present a typical case and clinical survey of nine cancer patients who were treated simultaneously with oxycodone and voriconazole. The study was approved by the Ethical Committee of Tsukuba University Hospital (Tsukuba, Japan). A 41-year-old man (63.6 kg) with Burkitt’s lymphoma received oxycodone per os for his thigh pain. Dosage was maintained at 20 mg d after admission. As he was feverish due to possible Aspergillosis, with positive Aspergillus antigen, voriconazole iv was administered for 5 days (700 mg d; day 7, 400 mg d; day 8–11). The fever gradually declined, and serum Aspergillus antigen turned negative on day 13. The patient complained of nausea and vomited just after starting voriconazole (on days 8 and 9). A sudden reduction in heart rate was also observed on day 9. Although he had required additional oxycodone (rapid-release preparation) as the rescue dose (2.5–5.0 mg d) both before starting and after stopping voriconazole, he needed no rescue dose during voriconazole co-administration (Fig. 1). These observations suggested that voriconazole co-administration enhanced both the efficacy of and the adverse symptoms relating to oxycodone, resulting in no need for a rescue dose of oxycodone but inducing nausea and vomiting while both drugs were used concomitantly. The dosing schedule for other drugs (omeprazole, gabapentin, zolpidem, magnesia oxide) was unchanged before and after voriconazole administration. Liver and kidney function (aspartate aminotransferase, 52 IU L; alanine aminotransferase, 97 IU L; blood urea nitrogen, 6.5 mg dl; serum creatinine 0.49 mg dl), and other laboratory data were also unchanged throughout the study. M. Watanabe :M. Homma (*) :K. Momo :Y. Kohda Department of Pharmacy, Tsukuba University Hospital, 2-1-1 Amakubo, Tsukuba, Ibaraki 305-8576, Japan e-mail: masatoh@md.tsukuba.ac.jp

The protective effect of the sympathetic nervous system against acoustic trauma

OBJECTIVE the cochlea is innervated by the sympathetic nerve fibers. However, the functions of those fibers in the cochlea are still controversial. The present study was designed to determine whether the sympathetic nervous system (SNS) exerts a protective or enhancing effect on acoustic trauma. METHODS acoustic overstimulation (either of 110, 115, or 130 dB SPL for 10 min) was performed in guinea pigs during electrical stimulation of the ipsilateral cervical SNS, after its surgical elimination or in the non-treated condition. The threshold shift of the compound action potential (CAP) from the pre-exposure value was measured at 1 h and at 1 week after acoustic overstimulation. Two-way analyses of variance (ANOVAs) were completed for the SNS conditions and the frequencies. RESULTS although no significant difference was found at 1 h after overstimulation among these three groups, the CAP threshold shift at 1 week (110 and 115 dB SPL) was significantly smaller in the SNS stimulation group than in the other two groups. CONCLUSION a protective effect was observed in the SNS stimulation group 1 week after the exposure to acoustic overstimulation of moderate intensity (from 110 to 115 dB SPL for 10 min).

Effect of A1 adenosine receptor agonist upon cochlear dysfunction induced by transient ischemia.

The present study was undertaken to determine whether 2-chloro-N6-cyclopentyladenosine (CCPA), a highly selective A1 adenosine receptor agonist, attenuated cochlear dysfunction induced by transient ischemia or not. Ischemia of different durations (15, 30 or 60 min) was induced in 46 albino guinea pigs by transiently pressing the labyrinthine artery. CCPA or physiological saline solution was intraperitoneally administered to the animals 15 min prior to ischemia. The post-ischemic CAP threshold shift from the pre-administration value was measured 4 h after the onset of reperfusion to assess post-ischemic cochlear dysfunction. A statistically significant reduction in the CAP threshold shift was seen in CCPA-given animals after 15- and 30-min ischemia, whereas there was no statistical difference after 60-min ischemia. These results suggest that A1 adenosine receptor agonist exerts a protective effect on the cochlear injury induced by transient ischemia of intermediate duration.