Intratympanic dexamethasone treatment for control of subjective idiopathic tinnitus: our clinical experience.

In this report, we summarize our clinical experience with intratympanic dexamethasone treatment (IDT) for control of tinnitus. From March 2000 through February 2001, we observed 54 patients (23 women, 31 men; mean age, 49.6 +/- 7.2 years; range, 24-71 years) suffering from subjective idiopathic tinnitus (SIT). After common audiological tests had been performed; all patients underwent specific topodiagnostic tests to verify the cochlear SIT genesis. The 50 subjects with positive results from a furosemide test and negative results from caraverine and carbamazepine tests were selected for the IDT, consisting of transtympanic perfusion of 4 mg dexamethasone to the round window via the middle ear. The treatment was repeated three times daily for 3 consecutive months. Its short-term effects were evaluated 2 weeks after the last perfusion. In 17 of 50 of these patients (34%), the SIT disappeared; 20 of the 50 (40%) reported a significant decrease of the symptom; and the remaining 13 of the 50 (26%) did not experience any improvement. Therefore, we believe that IDT represents an effective drug delivery system for SIT control, as long as the condition arises from inner ear disorders only and treatment occurs within 3 months of symptom onset.

Regulation of inner ear fluid in the rat by vasopressin.

The anti-diuretic hormone vasopressin has been shown to be important in regulating inner ear fluid. The diuretic hormone, CNP, and its receptor, ANP-B receptor, may also function in the regulation of inner ear fluid. To determine whether vasopressin directly affects the fluid level, we infused this hormone to rat and assay of V2-AVP receptor mRNA by semiquantitative RT-PCR demonstrated a significantly lower level of this transcript in vasopressin-infused animals than in saline-infused animals. The levels of CNP and ANP-B receptors mRNA, however, were the same in both groups of rats. Results suggest that high plasma levels of vasopressin may be a principal causal factor of endolymphatic hydrops in Meniere's disease, perhaps by down-regulating the number of vasopressin receptors.

Effect of glycerol on pressure difference between perilymph and endolymph.

The pressure difference between the perilymph and the endolymph following administration of 50% glycerol (12 ml/kg) was studied in guinea pigs. The perilymphatic and endolymphatic pressures were measured simultaneously with two sets of a servo-nulling system. Glycerol was administered for about one minute via a gastrocatheter. Both the perilymphatic and endolymphatic pressures began to decrease about 5 min after the administration of glycerol, and thereafter the decrease continued for about one hour with no significant difference between the two pressures. We concluded from the results that the glycerol-induced pressure difference between the perilymph and the endolymph, if present, is only a very small one, although a collapse of the scala media after glycerol intake was reported in guinea pigs and chinchillas.

[Dehydration therapy in low tone hearing loss. An alternative to rheologic therapy?]. / Die Dehydratationstherapie des Tieftonhörverlustes. Eine Alternative zur rheologischen Therapie?

Patients with acute low-tone sensorineural hearing loss were treated by rheology or dehydration after recording of the summation and compound action potentials by electrocochleography. Patients treated in the acute phase, as well as patients with chronic disease (that is the interval between onset of hearing loss and therapy was more than 1 week) clearly responded better to dehydration than to conventional rheological treatment. This was especially striking in those patients showing an enhanced SP/AP ratio indicating endolymphatic hydrops.

Turnover of sulphated macromolecules in the murine endolymphatic sac after long-term kanamycin treatment.

Radioactively labeled sulphur was injected into 12 mice of the NMRI strain 20 days after pretreatment with kanamycin. The animals were decapitated after intervals ranging from 2 minutes to 24 hours after injection. After a routine autoradiographic procedure, darkly stained silver grains were detected in the endolymphatic sac (ES) and its surroundings. One hour after injection, the grains were found in the surrounding blood vessels. Eleven hours later, maximal uptake was seen in the epithelial cells of the ES in the kanamycin-treated animals. Twenty-four hours after injection, a faint S35 uptake in the ES could still be detected. An increase in the ES activity, indicated by an increased number of free-floating cells and the secretion of a sulphur-containing intraluminal substance, did not occur. The spreading pattern of sulphur, as shown in this investigation, does not support the theory that waste products from the inner ear, transported to the ES by the longitudinal flow, produces an increased activity in the sac after long pretreatment with kanamycin. In 12 control animals, no difference in the distribution of labeling was observed, but there was an additional uptake in the free intraluminal cells which was not seen in the kanamycin group.

The preparation of acetic acid for use in otic drops and its effect on endocochlear potential and pH in inner ear fluid.

The ototoxicity of an otic drop preparation containing 2% acetic acid and 3% propylene glycol (VoSol, Denver Chemical Co., Humacao, PR) was investigated according to measurements of endocochlear potential (EP) and inner ear fluid pH. The application of this preparation to the round window membrane for 30 minutes caused a depression in EP from 80.5 +/- 2.5 mV (mean +/- SD; n = 6) to 11.7 +/- 7.7 mV, and lowered inner ear fluid pH from 7.55 +/- 0.09 to 5.06 +/- 0.19 (n = 6) in perilymph and from 7.52 +/- 0.07 to 5.88 +/- 0.63 (n = 6) in endolymph. Two percent acetic acid produced similar changes after 30 minutes: EP was reduced from 83.0 +/- 2.2 mV to 34.0 +/- 2.9 mV and endolymphatic pH from 7.49 +/- 0.04 to 6.83 +/- 0.21 (n = 4). However, the application of artificial perilymph of pH 4 titrated with HCl induced no significant changes in either EP or endolymphatic pH. We suggest that the mechanisms of ototoxicity in the otic drop preparation are Na+ and K+-ATPase inhibition, and that such inhibition is due to the intracellular acidification of strial cells resulting from the penetration of acetic acid across the cell membrane, and to the direct and synergistic actions of propylene glycol.

Effects of nitrogen mustard-N-oxide on ionic activities of inner ear fluid and ionic permeabilities of the cochlear partition in the guinea pig.

The effect of nitrogen mustard-N-oxide (NMO) on the endocochlear potential (EP) was investigated from the aspect of the ion concentrations and permeabilities in the cochlea. Compared with the untreated animals, in NMO-treated animals 20 to 30 hours after administration, the EP was decreased (30.8 +/- 3.5 mV in NMO versus 82.4 +/- 1.6 mV in control), the K+ concentration in perilymph of the scala tympani was increased (8.2 +/- 1.0 mM versus 5.3 +/- 0.7 mM), the K+ concentration in endolymph was decreased (128.5 +/- 10.6 mM versus 157.9 +/- 7.9 mM), and the Na+ concentration in endolymph was increased (9.6 +/- 3.6 mM versus 2.5 +/- 0.4 mM). The permeability coefficient for Na+ of the cochlear partition in the NMO-treated animals significantly decreased, while that for Cl- significantly increased. The negative EP, which presumably exists in the normal state, diminished further (-2.7 mV versus -27.8 mV), and the calculated electrogenic potential of the EP was depressed remarkably (33.5 mV versus 110.2 mV). The results suggest that the effects of NMO involved changes in ion permeabilities of the partition and the inhibition of electrogenic transport processes in the cochlea.

Simultaneous investigations of elemental changes in individual cells of the stria vascularis and in endolymph.

Using the microprobe for energy dispersive X-ray microanalysis, the elemental compositions of both the individual cells of the stria vascularis and of the endolymph were followed simultaneously under normal conditions and after the administration of 120 mg/kg ethacrynic acid (EA). Marginal cells and intermediate cells showed reversible increases in potassium and decreases in sodium concentrations. Shifts in the ionic composition of endolymph occurred later than after elemental changes in the strial cells. The present results indicate that the marginal and the intermediate cells are the primary target for EA-induced ototoxicity. However, generalized toxic effects of EA are also indicated, with a general leakage of different elements occurring during the 30-60 min period after EA administration.

Effects of prostaglandins on perilymphatic oxygenation. Enhancement of cochlear autoregulation by prostacyclin.

Effects of prostaglandin E1, prostacyclin, a prostacyclin analogue (OP-2507), and an inhibitor of thromboxane A2 synthetase (OKY-046) on the perilymphatic oxygen tension were measured in the feline tympanic perilymph under various respiratory conditions and blood pressure ranges. Factors influencing the capacity of the autoregulative properties of the inner ear vessels to accommodate changes in systemic blood pressure were also examined. Intravenous administration of prostacyclin, OP-2507, and OKY-046 prevented a decrease in perilymphatic oxygen tension when the systemic blood pressure decreased. Even a negative correlation of the differential coefficients between the perilymphatic oxygen tension and the systemic blood pressure was noticed during the administration of prostacyclin. Thus, prostacyclin enhanced the autoregulative property of the inner ear vessels. Furthermore, correlation studies between perilymphatic oxygen tension and cochlear blood flow demonstrated a partial dissociation, indicating the presence of autoregulation in the mean systemic blood pressure range under 80 mmHg.

The effects of cetrimide and potassium bromate on the potassium ion concentration in the inner ear fluid of the guinea-pig.

The mammalian inner ear is located deep within the temporal bone. The organ of Corti, the delicate sensory system for sound, is surrounded by two fluid systems; the potassium-rich endolymph and the sodium-rich perilymph. The pathogenesis of inner ear deafness is thought to be largely due to an imbalance of potassium and sodium ions in the inner ear fluids. Dynamic changes in K+ in the endolymph and perilymph were studied in the guinea-pig following cetrimide (cetrimonium bromide, a powerful cationic detergent which shows ototoxicity) applications on the round window membrane, intramuscular injection of potassium bromate (bread whitener, known to cause renal damage and permanent deafness in animals and man). Maximum fall in K+ concentration in the endolymoh (mM/min) and maximum K+ conductance (mM/min/mV) were 3.54 +/- 1.65 and 0.036 +/- 0.02 in cetrimide, and 1.85 +/- 0.35 and 0.021 +/- 0.009 in potassium bromate, respectively. In view of these findings, the influence of the active transport mechanism to K+ concentrations are discussed in comparison with dynamic changes in endolymph K+ induced by asphyxia and ethacrynic acid.

Effect of glycerol on inner ear fluid electrolytes and osmolalities in guinea pigs.

Endolymph of the scala media (SM) and perilymph of the scala vestibuli (SV) and scala tympani (ST) were collected from the basal turn of anesthetized guinea pigs before and after intravenous administration of glycerol (3 g/kg). Sound-evoked responses were recorded during the test periods. Blood, CSF, and perilymph of the ST were also collected continuously after the injection. The osmolalities and chloride concentrations of the collected samples were determined. In another experiment, the continuous changes of potassium and chloride concentrations in endolymph and perilymph of the ST before and after the injection were measured by ion-selective electrodes. The osmolalities in CSF and perilymph lagged behind the increase in serum osmolality. The osmolalities in endolymph and perilymph increased gradually after the injection, reached maximum values after 90 minutes, and then decreased. The changes in chloride and potassium concentrations in endolymph and perilymph had similar tendencies. But the increases in chloride concentrations in perilymph of the SV and ST were much less than that in endolymph. We propose that most of the osmolality increase in perilymph is due to glycerol or other osmotically active substances and that the osmolality increase in endolymph is due to water shift.

The osmotic effect of glycerol on the stria vascularis and endolymph.

In the chinchilla, quantitative changes in strial thickness, area of the endolymphatic space, serum osmolality, and serum levels of glycerol, glucose, total protein sodium, potassium and chloride were determined at 1, 2, 3 and 5 h after the intraperitoneal administration of 6 g/kg glycerol. The serum osmolality, glycerol, glucose and potassium levels increased, while serum sodium and chloride decreased. Quantitative changes in cochlear structure included an increase in strial thickness and a decrease in area of the endolymphatic space. In all the animals (n = 50), the increase in strial thickness was closely correlated (correlation coefficient r = 0.57) to an increase in serum osmolality. This correlation with strial thickness improved (R = 0.71) when the interval between injection and animal sacrifice was used in combination with serum osmolality. The increase in stria thickness was also closely correlated to an increase in serum glycerol and to a decrease in serum chloride. A decrease in endolymphatic volume was found most consistently at 3 h after the i.p. administration of glycerol.

Effects of isosorbide on perilymphatic pressure and oxygenation.

Using a servocontrolled micropipet pressure measuring system, the effect of intravenous and oral administration of isosorbide, a hyperosmolar agent that is an anhydrate of sorbitol, was examined in 11 fasting cats. Following intravenous administration of 2 g/kg of the agent, perilymphatic pressure has shown, on the average, a significant reduction of 136% of the initial value (3.6 +/- 0.3 mm Hg). A strong rebound phenomenon, however, with a 61% rise to the initial value, was noted, and this did not come down in 3 hours. On the contrary, no rebound phenomenon was noted after oral administration, which caused a significant 60% drop in perilymphatic pressure for more than 90 minutes. Using polarographic technique, perilymphatic oxygen tension was measured and showed a maximal increase of 145% to the initial value. The time it took to reach the maximal PO2 tension was equal to the time it took to come down to the minimal perilymphatic pressure. This is a strong indication that isosorbide improves perfusion and increases blood flow of the inner ear vessels.

[Effects of mannitol on the fluids of the internal ear. Use in the treatment of deafness]. / Effets du mannitol sur les liquides de l'oreille interne. Application au traitement des surdités.

The action of mannitol upon the inner ear fluids was studied experimentally by means of kinetics of mannitol entry into cochlear perilymph and endolymph in rats. A daily two hours infusion of 10% mannitol induces an osmotic water flow from cochlear fluids toward plasma. Following this therapeutic protocol, progressive, non-tumoral sensorineural hearing loss is enhanced in 32% of the cases. The rate of hearing improvement is larger than 50% in case of Ménière's disease. For sudden hearing loss, 75% of the cases are improved by mannitol, and 92% of the cases when the delay between the hearing loss onset and the mannitol therapy is less than two weeks. Sudden hearing loss should be considered as a sensory emergency.

Biochemical aspects of inner ear fluids and possible implications for pharmacological treatment.

Inner ear fluids are in dynamic equilibrium with surrounding fluids, namely blood and cerebrospinal fluid. It is known that substances injected into the blood stream or cerebrospinal fluid are transported into the inner ear fluids. The rate of transport from blood into perilymph is inversely related to the molecular weight or molecular size. There appears to exist a blood-labyrinth barrier. In general, the morphology of capillaries in the spiral ligament and stria vascularis is similar to that of brain capillaries which contribute to formation of the blood-brain barrier. Information on the volume of the inner ear fluids is necessary for estimating the toxicity of the drugs as well as the effective concentration of systemically injected substances. Recently, alteration of the levels of arachidonic acid metabolites, especially the prostaglandins, in perilymph under experimental conditions has been reported. The responses of prostaglandin levels in perilymph to these experimental conditions (aspirin injection, antidiuretic hormone or epinephrine infusion) suggest that prostaglandins may play an important role under physiological conditions. Possible mechanisms of auditory dysfunction due to abnormal prostaglandin metabolism in the auditory system are discussed.

Effects of hyperosmotic solutions on endolymphatic pressure.

Hydrostatic pressure changes in endolymph as well as perilymph and cerebrospinal fluid (CSF) following intravenous injection of glycerol, urea, and mannitol were studied in the guinea pig using a servo-controlled micropipet system. After the initial rise in pressure observed during and immediately after injection of each hyperosmotic agent, all pressures fell below baseline levels for about 20 minutes. The largest reductions in pressure with each of the hyperosmotics showed no significant difference between CSF and labyrinth. In the glycerol and urea studies, labyrinthine pressures stabilized at their minimum levels 20 to 40 minutes after injection, while CSF pressure recovered slowly. However, alteration of labyrinthine pressures induced by mannitol paralleled that of CSF. These results may suggest a possible osmotic dehydration effect in the labyrinth for glycerol and urea, but an ambiguous effect for mannitol.

Effect of peroral glycerol administration on inner ear fluid electrolytes of guinea pigs.

After the oral administration of 50% glycerol (12 mL/kg), serum, CSF and inner ear fluids from scala tympani perilymph, scala vestibuli perilymph, and scala media endolymph were collected from normal guinea pigs under sodium pentobarbital anesthesia (25-35 mg/kg). The sodium and potassium concentrations were determined by microflame photometry. Increases in sodium concentrations were found in CSF, scala tympani perilymph, scala vestibuli perilymph, and cochlear endolymph. No significant change was observed in the serum. These sodium increases were considered to be due to the dehydration caused by the osmotic action of glycerol. Potassium concentration was increased only in scala tympani perilymph. Oral administration of glycerol was found to be more gradual and effective in dehydration compared to intravenous injection.

Effects of intravenous glycerol injection on inner ear fluid electrolytes.

Under sodium pentrobarbital anesthesia (20-30 mg/kg, i.p.), normal guinea pigs received an intravenous injection of glycerol (1.0 ml/kg). Serum, cerebrospinal fluids (CSF) and inner ear fluids were collected from the scala tympani perilymph, scala vestibuli perilymph and the scala media endolymph. The sodium and potassium concentrations were assessed using microflame photometry. Increases in sodium concentration were found in the CSF and the scala tympani perilymph; no significant changes were observed in the serum, scala vestibuli perilymph or the scala media endolymph. These sodium increases were considered to be a result of the dehydration process caused by the osmotic agent glycerol. Increases in potassium concentration were found only in the scala vestibuli perilymph.

Probenecid reduces cochlear effects and perilymph penetration of furosemide in chinchilla.

Previous investigation has suggested that the ototoxicity of furosemide is related to penetration of the drug into the inner ear and that active drug transport out of the inner ear may be responsible for maintaining the serum-perilymph drug concentration gradient. We further tested this hypothesis by investigating the endocochlear potential (ototoxicity) and furosemide perilymph concentrations after furosemide administration to chinchillas pretreated with the organic anion transport inhibitor, probenecid. Probenecid pretreatment attenuated the fall in endocochlear potential seen after furosemide (25 mg/kg i.v.): untreated, 58.6 +/- 27.0 mV; probenecid pretreatment, 14.1 +/- 11.9 mV (P less than .01). Furosemide concentrations in perilymph were correspondingly lower after probenecid (P less than .003), although serum furosemide concentrations were not affected by probenecid pretreatment. Diuresis, measured over an 8-hr period after furosemide, was also uneffected by probenecid. These results confirm the proposed relationship between inner ear furosemide concentrations and the occurrence of ototoxicity due to this drug. However, the determinants of penetration of this drug into the inner ear are unclear. The observation that probenecid pretreatment attenuates the ototoxic effect of furosemide while the diuretic effect is preserved suggests this drug combination warrants further investigation.