Effect of Duloxetine on Urethral Resting Pressure and on Sphincter Contractility in Response to Coughing and Magnetic Stimulation in Healthy Women.

OBJECTIVES: As a proof-of-mechanism (POM) study of drugs developed to treat stress urinary incontinence (SUI) has not been conducted, this urodynamic study in healthy women was performed to determine an appropriate method to confirm POM, and to evaluate the effect of duloxetine, a serotonin and noradrenaline reuptake inhibitor, on urethral resting pressure and on sphincter contractility in response to coughing and magnetic stimulation. METHODS: The urethral pressure profiles at rest, during coughing and during sacral root magnetic stimulation (SMS), and the motor threshold (MT) for urethral sphincter contraction in response to transcranial magnetic stimulation (TMS) were measured before and 6 h after the administration of 40 mg duloxetine in 10 healthy female subjects. RESULTS: Oral administration of duloxetine significantly increased the mean and maximal urethral closure pressures at rest over the proximal and middle third of the urethra. During coughing, duloxetine marginally significantly increased the mean distal urethral pressure and significantly reduced the mean delay in the distal urethral pressure peak relative to the vesical peak. Although duloxetine did not change amplitudes of pressure spikes in response to SMS, this drug significantly lowered the MT in response to TMS. CONCLUSION: The proposed method for measuring the urethral resistance in healthy women can be used in POM studies of new drugs developed to treat SUI. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000009096.

A comparison of the expression and contractile function of α1-adrenoceptors in seminal vesicle and vas deferens from normotensive and hypertensive rats.

Because hypertension related alterations occur in the properties of α(1)-adrenoceptor in several mammalian tissues and hypertension may impact ejaculatory function, we investigated hypertension related alterations in the functional, biochemical and molecular properties of α(1)-adrenoceptor in the rat seminal vesicle and vas deferens. Spontaneous seminal emission in male spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats was studied during the 3-day observation period. The characteristics of α(1)-adrenoceptor in the seminal vesicle and epididymal and prostatic portion of vas deferens of the two strains were determined using an isolated muscle bath, radioligand receptor binding and real-time reverse transcription-polymerase chain reaction techniques. SHRs had significantly higher serum testosterone than WKY rats. However, the daily mean number of ejaculatory plugs emitted and their dry weight in SHRs were significantly lower than those in WKY rats. Although there was no significant difference in the properties of α(1)-adrenoceptor in the prostatic portion of vas deferens between SHRs and WKY rats, the maximum contractile responses to phenylephrine, total α(1)-adrenoceptor density and expression of α(1A)-adrenoceptor mRNA were significantly higher in the seminal vesicle and epididymal portion of vas deferens of SHRs vs. WKY rats. Our data demonstrate the presence of hypertension related alterations in serum testosterone and in α(1)-adrenergic responsiveness of the rat seminal vesicle and vas deferens and suggest that ejaculatory function in SHRs does not mirror these hypertension related alterations.

Effects of age and hypertension on α1-adrenoceptors in the major source arteries of the rat bladder and penis.

α(1)-Adrenoceptors regulate blood pressure, regional vascular resistance and tissue blood flow. As aging and hypertension may impact pelvic arterial blood flow resulting in bladder and penile dysfunction, we investigated effects of age and hypertension on α(1)-adrenoceptors in the major source arteries of the rat bladder and penis. Using radioligand receptor binding, real-time reverse transcription-polymerase chain reaction (RT-PCR) and fluorescent microsphere infusion techniques, we compared 3 and 22-month-old male Fischer rats, and male normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). Twenty-two-month-old rats and SHRs had significantly higher total α(1)-adrenoceptor density in the internal iliac artery and lower blood flow to the bladder and penis than 3-month-old and WKY rats, respectively. RT-PCR data showed an age and hypertension related increase in the expression of α(1B)-adrenoceptor mRNA in the internal iliac, vesical and internal pudendal arteries and a switch from α(1A) predominance in 3-month-old and WKY rats to α(1B)>α(1A) in 22-month-old rats and SHRs. Our data indicate the presence of age and hypertension related alterations in vascular α(1)-adrenoceptor subtype distribution and in blood flow to the rat bladder and penis. These findings suggest that pharmacological blockade of the vascular α(1B)-adrenoceptor, which could increase pelvic blood flow, may contribute to the improvement of bladder and penile dysfunctions in animal models for aging and hypertension.

Bioavailability of acetate from two vinegar supplements: capsule and drink.

The bioavailability of acetate in various vinegar supplements, e.g. as capsules and drinks, remains unclear. Thus, we conducted a cross-over clinical study in 30 healthy subjects. After an overnight fast, subjects received each test sample in a randomised sequence: 9 vinegar capsules (containing 750 mg acetic acid in total) with 150 mL of water, 100 mL of vinegar drink (containing 750 mg acetic acid), and 150 mL of water as reference. Blood samples were collected before (defined as 0 min), at 15, 30, 45, 60, 90, 120 and 180 min after each test sample intake. In the vinegar drink group, serum acetate concentration increased immediately after intake, peaked at 15 min and returned to baseline at 90 min. That in the vinegar capsule group rose slowly, peaked at 30 min and returned to baseline at 120 min. The peak values in both groups exceeded 200 µmol/L, the physiologically active concentration confirmed by in vitro experiment. In the reference group, levels remained constant throughout the 180-min period. The amount of absorbed acetate from the vinegar capsule group and the drink group was evaluated by the difference value of the area under the serum acetate concentration-time curve (AUC) between in each vinegar group and in the reference group (expressed as AUC(capsule-ref) and AUC(drink-ref ), respectively). AUC(capsule-ref) was about 80% of AUC(drink-ref ), but there was no significant difference between them.

Protective effects of exogenous GM-1 ganglioside on acoustic injury of the mouse cochlea.

GM-1 ganglioside (GM-1), a glycosphingolipid, is embedded in the lipid layer of neuronal membranes and is one of the neuroprotective agents. To the best of our knowledge, the role of GM-1 has never been examined in hair cell injury. The purpose of this study was therefore to evaluate the effects of GM-1 on acoustic injury of the cochlea. Mice were exposed to 4-kHz pure tone of 128dB SPL (sound pressure level) for 4h. GM-1 was intraperitoneally administered immediately before the onset of acoustic overexposure. The threshold shift of the auditory brainstem response (ABR) and hair cell loss were then evaluated 2 weeks after acoustic overexposure. Immunostaining for 4-hydroxynonenal (4-HNE), indicative of lipid peroxidation, was also examined in animals subjected to acoustic overexposure. GM-1 treatment significantly decreased the ABR threshold shifts and hair cell loss after acoustic overexposure. And immunostaining for 4-HNE was reduced by GM-1 treatment. These findings suggest that GM-1 is involved in the protection of the cochlea against acoustic injury through inhibiting lipid peroxidation.

The effect of a GABAA agonist muscimol on acoustic injury of the mouse cochlea.

Gamma-aminobutyric acid (GABA) is one of major inhibitory neurotransmitter in the central nervous system and constitutes the cochlear efferent system. Glutamate excitotoxicity is implicated in the pathogenesis of acoustic injury of the cochlea. The present work investigated whether GABA(A) agonist muscimol can alleviate acoustic injury. Mice were exposed to a 4 kHz pure tone of 128 dB SPL for 4h. Muscimol and/or bicuculline, a GABA(A) antagonist, were intraperitoneally administered immediately before the onset of acoustic overexposure. The threshold shifts of the auditory brainstem response (ABR) and cochlear morphology after acoustic overexposure were then evaluated. Muscimol significantly decreased the ABR threshold shift and inhibited swelling of the afferent dendrites induced by acoustic overexposure. In addition, bicuculline inhibited the effects of muscimol. These findings suggest that activation of GABA(A) receptors reduces acoustic injury of the cochlea.

The importance of postoperative radiotherapy against polymorphous low-grade adenocarcinoma of the parotid gland: case report and review of the literature.

Polymorphous low-grade adenocarcinoma (PLGA) of the salivary gland is a disease entity that is a recently described form of adenocarcinoma. PLGA most commonly arises in the minor salivary glands. We report two cases of PLGA of the parotid gland. Case 1: A 52-year-old female visited the University of Tsukuba Hospital with a painless mass in the left parotid region. A superficial parotidectomy and postoperative radiotherapy were performed. The patient has been free from disease for 50 months. Case 2: A 55-year-old female initially noticed a painless slowly growing mass in the left parotid region. The tumor was removed with a superficial parotidectomy. The local recurrence was found 6 years after the initial surgery. The recurrent tumor was removed, and radiotherapy was administered thereafter. The patient has been free from the disease for 33 months since the last treatment. The treatment for the primary lesion is crucial for the prognosis since metastasis to the regional lymph node or to distant region is unusual in PLGA. Although surgical extirpation is the recommended modality for treatment of PLGA, wide resection with a safety margin is often difficult in the parotid gland because of the presence of the facial nerve. Our two cases were successfully treated with surgery and postoperative radiotherapy. Although our literature search revealed 32 previously reported cases of PLGA of the parotid gland, only five of the 32 cases were treated postoperative radiotherapy. We highlight the importance of postoperative radiotherapy for PLGA of the parotid gland.

Successful treatment of eosinophilic otitis media using ramatroban: report of two cases.

OBJECTIVE: The pathogenesis of eosinophilic otitis media is not yet fully understood. The purpose of this paper is to describe the clinical course of our two patients with eosinophilic otitis media and to discuss the pathogenesis and treatment of this intractable condition. METHODS: Two cases of eosinophilic otitis media were treated with ramatroban. RESULTS: The middle ear effusion has been well controlled in both patients for more than 1 year with minimal corticosteroid therapy. CONCLUSIONS: Our experience suggests that the pathogenesis of eosinophilic otitis media is related to the pharmaceutical effects of ramatroban, i.e., inhibition of the thromboxane A2 receptor (TP) and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2).

Protective effects of glucocorticoids on ischemia-reperfusion injury of outer hair cells.

OBJECTIVE: This animal study aimed to investigate effects of glucocorticoids on the functional recovery of outer hair cells (OHCs) after transient ischemia. METHODS: Distortion-product otoacoustic emission (DPOAE) was examined before, during, and after transient cochlear ischemia of 30 minutes using albino guinea pigs. RESULTS: DPOAE decreased to noise level during ischemia. On recirculation, DPOAE initially recovered with time until 20 minutes after the onset of reperfusion, but thereafter, the DPOAE level gradually decreased toward the noise level in the control animals. Prednisolone and methylprednisolone significantly improved the DPOAE level 60 minutes after the onset of reperfusion. CONCLUSIONS: The present findings suggest that glucocorticoids possess protective effects against ischemia-reperfusion injury of OHCs.

The effects of tempol, 3-aminobenzamide and nitric oxide synthase inhibitors on acoustic injury of the mouse cochlea.

Oxygen free radicals have been implicated in the pathogenesis of acoustic injury of the cochlea. The purpose of this study was to evaluate the effects of tempol (a superoxide anion scavenger), 3-aminobenzamide (a poly (ADP-ribose) synthetase (PARS) inhibitor), N-nitro-l-arginine (a non-selective nitric oxide synthase (NOS) inhibitor), 7-nitroindazole (a selective neuronal NOS inhibitor) and aminoguanidine (a selective inducible NOS inhibitor) on acoustic injury. Mice were exposed to a 4 kHz pure tone of 110-128 dB SPL for 4h. Tempol, 3-aminobenzamide or N-nitro-l-arginine was intraperitoneally administered immediately before the onset of acoustic overexposure, while 7-nitroindazole or aminoguanidine was intraperitoneally administered every 12h starting immediately before the onset of acoustic overexposure. The threshold shift of the auditory brainstem response (ABR) and hair cell loss were then evaluated one and two weeks after acoustic overexposure. Tempol and 3-aminobenzamide significantly protected the cochlea against acoustic injury, whereas the NOS inhibitors did not exert any protective effect. These findings suggest that reactive oxygen species and PARS are involved in acoustic injury of the cochlea. However, further study is necessary to elucidate the roles of nitric oxide and nitric oxide synthase in acoustic injury.

Coexistence of pemphigus vulgaris and bullous pemphigoid in the upper aerodigestive tract.

Pemphigus vulgaris and bullous pemphigoid are autoimmune blistering diseases of the skin and the mucosa characterized by circulating autoantibodies. Coexistence of these lesions is extremely uncommon. We report herein a case of both pemphigus vulgaris and bullous pemphigoid which occurred in the upper aerodigestive tract. The diagnosis was made based on the circulating autoantibodies and direct immunofluorescent studies. The literature on this subject is reviewed.

Dehydroepiandrosterone sulfate reduces acoustic injury of the guinea-pig cochlea.

The present study was performed to determine effects of dehydroepiandrosterone sulfate (DHEAS), a neurosteroid, on acoustic injury. Albino guinea pigs were exposed to a 2 kHz pure tone of 120 or 125 dB sound pressure level for 10 min immediately after intravenous administration of DHEAS. Statistically significant improvement in the compound action potential threshold shifts and in amplitude reduction of distortion-product otoacoustic emissions was observed 1 week after the acoustic overexposure in the animals treated with DHEAS. The present results suggest that DHEAS has a protective effect against acoustic injury of the cochlea.

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.

Outer hair cells functionally and structurally deteriorate during reperfusion.

Transient ischemia of the cochlea was induced in 65 albino guinea pigs by pressing the labyrinthine artery, and the effects of cochlear reperfusion on cochlear potentials (endocochlear potential, compound action potential and cochlear microphonics (CM)) and structural changes in hair cells were examined. Although 15 min ischemia did not elevate the post-ischemic CM pseudo-threshold as compared with the pre-ischemic value, ischemia of 30 min or longer significantly elevated the CM pseudo-threshold. CM amplitude tended to progressively decrease during the reperfusion period in the animals subjected to 45 or 60 min ischemia. After transient ischemia, outer hair cells (OHCs) were swollen and exhibited alterations of the nucleus. Severer structural deterioration of OHCs was induced by 4 h reperfusion than ischemia itself when the ischemic period was 45 or 60 min. Perilymphatic perfusion of dimethylthiourea, a hydroxyl radical scavenger, partially ameliorated the elevation of the CM pseudo-thresholds and the structural changes of OHCs. These results indicate that cochlear reperfusion induces functional and structural deterioration of OHC probably by hydroxyl radical generation.

Long-term observations on the reversibility of cochlear dysfunction after transient ischemia.

To examine the reversibility of functional damage to the cochlea after transient ischemia, cochlear ischemia of 0-60 min was induced in 34 albino guinea pigs. Thresholds of auditory brainstem response (ABR) were then followed for 5 days after ischemia. Although the ABR threshold returned to almost the pre-ischemic value after 15 min ischemia, ischemia of 30 and 60 min duration induced irreversible dysfunction. Aminoguanidine, an inducible NO synthase (iNOS) inhibitor, significantly ameliorated the post-ischemic cochlear dysfunction induced by 60 min ischemia. Morphological findings of the hair cells were consistent with these functional results. These results indicate that ischemia of 30 min or longer induces irreversible damage to the cochlea and that iNOS plays injury-producing roles in this type of injury.

Does endogenous or exogenous adenosine facilitate the functional recovery of the cochlea after ischemia?

The present study was undertaken to determine whether adenosine attenuates cochlear dysfunction induced by transient ischemia. Adenosine or erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase inhibitor, was administered by perilymphatic perfusion to albino guinea pigs that were subjected to cochlear ischemic episodes of 30-minute duration. The threshold shift of the compound action potential (CAP) from the preischemic value was significantly reduced in the animals perfused with EHNA 1 hour after the onset of reperfusion. However, perfusion of adenosine at concentrations of 100 micromol/L to 10 mmol/L did not reduce the postischemic CAP threshold shift by either 1 hour or 4 hours after the onset of reperfusion. These results suggest that the elevation of the adenosine concentration did not exert a protective effect on the cochlear ischemia-reperfusion injury, and that the protective action of EHNA is unrelated to elevating the adenosine concentration.

Effect of ketamine, dextromethorphan, and MK-801 on cochlear dysfunction induced by transient ischemia.

Overstimulation of the N-methyl-D-aspartate (NMDA) glutamate receptor has been implicated as a factor in the pathogenesis of hypoxic-ischemic injury in the central nervous system. To evaluate the role played by NMDA antagonists in ischemia-reperfusion injury of the cochlea, 3 noncompetitive NMDA antagonists--ketamine, dextromethorphan, and MK-801--were administered to 53 albino guinea pigs subjected to transient ischemia of 30 minutes' duration, and the threshold shifts of the compound action potential were compared with those of nontreated animals 4 hours after the onset of recirculation. Ketamine and dextromethorphan moderately ameliorated the compound action potential threshold shifts, whereas MK-801, the most potent NMDA receptor antagonist among these 3 agents, did not show any protective effect. These results indicate that the action antagonizing the NMDA receptor has no protective effect against ischemia-reperfusion injury of the cochlea, and that ketamine and dextromethorphan act as protective agents for the cochlea via other pathways.