Effects of antipsychotics on intravenous sedation with midazolam and propofol during dental treatment for patients with intellectual disabilities.

BACKGROUND: Some patients with intellectual disabilities (ID) are prescribed antipsychotic drugs for symptomatic treatment of behavioural disorders. Nevertheless, it can still prove difficult to perform dental treatments safely for some patients with ID. In such cases, treatment under intravenous sedation (IVS) is one option. Sedative, hypnotic and α-blocking effects of antipsychotic drugs may cause adverse events, such as severe hypotension, among patients who take antipsychotic drugs regularly. This study aimed to investigate the effects of oral antipsychotic medication on cardiovascular function during IVS. Accordingly, we compared mean blood pressure (MBP) and heart rate (HR) between patients who regularly take antipsychotic drugs and patients who do not. METHODS: Thirty-seven patients with ID were enrolled in this study. All participants were outpatients of Special Care Dentistry of general hospital and received dental treatment under IVS performed with a combination of midazolam and propofol. Eighteen patients regularly took antipsychotics (medication group), and 19 patients were not currently taking antipsychotics (non-medication group). MBP, HR, dose, and effect-site concentration of intravenous sedative medications were measured at three points: 'before IVS', 'at optimal sedation', and 'during dental treatment'. RESULTS: The magnitude of reduction of MBP was significantly smaller in the medication group than in the non-medication group (P < 0.023). However, there were no differences in MBP, HR, dose, and effect-site concentration of midazolam and propofol between groups at any point. CONCLUSION: These results suggest that antipsychotic medication may not have clinically significant adverse effects on cardiovascular fluctuations during dental treatment under IVS for persons with ID.

Inhibitory effect of cyclooxygenase inhibitors on the step-through passive avoidance performance in mice treated with NC-1900, an arginine-vasopressin fragment analog.

To examine the participation of endogenous cyclooxygenase (COX) in the mnemonic effect of NC-1900, an arginine-vasopressin fragment analog, the latencies of mice in the step-through passive avoidance (PA) task were determined following the administration of COX inhibitors and/or NC-1900 (1 ng/kg). When administered immediately after the acquisition trial (Acq) in the PA task, indomethacin (20 mg/kg), a nonspecific COX inhibitor, and NS-398 (10 and 20 mg/kg), a specific COX-2 inhibitor, but not piroxicam (10 and 20 mg/kg), a specific COX-1 inhibitor, decreased the latency on the retention trial (Ret). The mnemonic effect of 1 ng/kg NC-1900 on the Ret in the PA task was also inhibited by the administration of either indomethacin (20 mg/kg) or NS-398 (20 mg/kg) but not by piroxicam. However, when 20 mg/kg indomethacin and NS-398 were administered 3 h after the Acq, the increase in Ret latency induced by NC-1900 was not inhibited. These results suggested that the action of NC-1900 on the early stage of memory formation in the PA task may be modulated by endogenous COX-2 but not by COX-1.

Ketamine-induced anesthesia involves the N-methyl-D-aspartate receptor-channel complex in mice.

The role of the N-methyl-D-aspartate (NMDA) receptor-channel complex in ketamine-induced anesthesia was examined in mice. General anesthetic potencies were evaluated on a rating scale, which provided the data for anesthetic scores, loss of righting reflex, sleeping time and recovery time. All drugs were administered intraperitoneally. NMDA (60-300 mg/kg), an NMDA receptor agonist, dose-dependently antagonized the general anesthetic potencies of ketamine at a dose of 100 mg/kg which produced loss of righting reflex in more than 90% of the mice. On the other hand, a high dose of N-methyl-L-aspartate (400 mg/kg), a stereoisomer of NMDA, did not. A dose of 300 mg/kg of NMDA significantly shifted the dose-response curve of ketamine for loss of righting reflex to the right. A high dose of D-cycloserine (200 mg/kg), an agonist at the glycine site on the NMDA receptor complex, slightly but significantly shortened the sleeping time caused by ketamine (100 mg/kg). However, neither a critical subconvulsive dose of kainate (15 mg/kg), a kainate receptor agonist, nor a subconvulsive dose of quisqualate (120 mg/kg), an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor agonist, reversed general anesthesia induced by 100 mg/kg of ketamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of purified (Na+,K+)-ATPase activity from porcine cerebral cortex by NO generating drugs.

We tested the effects of several nitric oxide (NO) generating compounds on the activity of sodium-potassium adenosine 5'-triphosphatase [(Na+,K+)-ATPase] purified from porcine cerebral cortex. Sodium nitroprusside (SNP), S-nitroso-N-acetylpenicillamine (SNAP), 3-morpholinosydnonimine (SIN-1) and (d1)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide (NOR 3) inhibited the (Na+,K+)-ATPase activity dose dependently. Superoxide dismutase, a NO scavenger, and sulfhydryl (SH) compounds, reduced-form glutathione (rGSH) and dithiothreitol (DTT), prevented the inhibitory action of SNAP, SIN-1 and NOR 3 but not of SNP, when applied simultaneously with NO generating compounds, and this enzyme inhibition could be reactivated by the incubation with these SH compounds but not with SOD. The inhibitory action by SNP was magnified by simultaneous application of DTT. These results suggest that NO generating compounds, SNAP, SIN-1 and NOR 3 but not SNP, may release NO or NO-derived products and may inhibit (Na+,K+)-ATPase activity by interacting with a SH group at the active site of the enzyme.

Effects of ketamine on dopamine metabolism during anesthesia in discrete brain regions in mice: comparison with the effects during the recovery and subanesthetic phases.

The effects of ketamine on the levels of dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT, serotonin) and their metabolites were examined in discrete brain regions in mice. A high dose of ketamine (150 mg/kg, i.p.) did not change DA metabolism in the frontal cortex, nucleus accumbens, striatum and hippocampus, but did decrease it in the brainstem during anesthesia. In contrast, during recovery from the ketamine anesthesia, the high dose increased the level of homovanillic acid (HVA) in all brain regions. A low subanesthetic dose of ketamine (30 mg/kg, i.p.) increased the concentrations of both 3,4-dihydroxyphenylacetic acid (DOPAC) and HVA only in the nucleus accumbens. The DA level was not affected by any ketamine treatment. During ketamine anesthesia, the content of 3-methoxy-4-hydroxy-phenylglycol (MHPG) was decreased in the brainstem, whereas during recovery from anesthesia, the MHPG level was increased in the frontal cortex, nucleus accumbens and brainstem. The NE content was not altered in any region by ketamine treatment. The concentration of 5-hydroxyindoleacetic acid (5-HIAA) was reduced in the frontal cortex, striatum, hippocampus and brainstem during ketamine anesthesia. The 5-HT level was unaltered in all regions except the brainstem where it was reduced. In contrast, after anesthesia, the concentrations of both 5-HT and 5-HIAA were increased in the striatum. During the subanesthetic phase, however, the levels of NE, 5-HT and their metabolites were unchanged. These neurochemical results are consistent with the electrophysiological findings that a high dose of ketamine does not change the basal firing rates of nigrostriatal DA neurons during anesthesia, while low subanesthetic doses significantly increase those of ventral tegmental DA neurons.

Nasal mucosa sensitization with toluene diisocyanate (TDI) increases preprotachykinin A (PPTA) and preproCGRP mRNAs in guinea pig trigeminal ganglion neurons.

Toluene diisocyanate (TDI) induces respiratory allergy in mammals. Using immunohistochemistry and in situ hybridization histochemistry, the present study examined effects of nasal mucosa sensitization by TDI on the immunoreactivity for substance P (SP) and calcitonin gene-related peptide (CGRP) and on the expression of their mRNAs in guinea pig trigeminal ganglion and their terminals. Single intranasal application of TDI (acute experiment) did not induce nasal allergy-like behaviours and failed to cause changes of SP and CGRP immunoreactivity and in the expression of preprotachykinin A (PPTA) mRNA and preproCGRP mRNA coding for SP and CGRP respectively in the trigeminal ganglion neurons. However, repeated application of TDI (chronic experiment) caused a dramatic increase of SP and CGRP immunoreactivity in peripheral neurites of sensory nerves in the nasal mucosa but a slight increase in the spinal trigeminal nucleus, a decrease of the same immunoreactivities in the cell bodies of the trigeminal ganglion neurons, and an increase of the expression of PPTA and preproCGRP mRNA in the same neurons. These findings suggest that chronic exposure of the nasal mucosa to TDI apparently causes enhancement of both the biosynthesis of SP and CGRP and their axonal transport in the trigeminal system.

Effects of talipexole on motor behavior in normal and MPTP-treated common marmosets.

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 0.5 mg/animal i.v. once or twice) to common marmosets induced persistent parkinsonian motor deficits. The postsynaptic dopamine D2 receptor agonist properties of talipexole (B-HT 920, 2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]-azepine), which is believed to be a dopamine autoreceptor agonist, were examined using normal and MPTP-treated marmosets and were compared to these properties of bromocriptine, a selective dopamine D2 receptor agonist. Talipexole (20-160 micrograms/kg i.p.) dose dependently increased motor activity and reversed the akinesia and incoordination of movement in MPTP-treated marmosets. In normal marmosets, higher doses of talipexole (80-160 micrograms/kg i.p.) produced a dose-dependent increase in motor activity, while the lowest dose (20 micrograms/kg i.p.) depressed this activity. These data for talipexole were very similar to those for bromocriptine. Talipexole had, however, several properties different from those of bromocriptine; it had a rapid onset of antiparkinsonian activity compared to bromocriptine; it had more than 25 times as much activity potency as bromocriptine; a dose of talipexole (80 micrograms/kg i.p.) sufficient to produce the activity did not induce emesis as strongly as an insufficient dose of bromocriptine (0.5 mg/kg i.p.). These results suggest that talipexole has postsynaptic dopamine D2 receptor agonist properties and that these properties of talipexole may be favorable in the treatment of Parkinson's disease.

Effects of GBR 12909 on locomotor activity and dopamine turnover in mice: comparison with apomorphine.

The effects of GBR 12909 1-[2-[bis(4-fluorophenyl)methoxy]-ethyl]-4- [3-phenylpropyl]piperazine, a very potent and selective dopamine uptake inhibitor, and apomorphine, a dopamine receptor agonist, alone and in combination were investigated on locomotor activity and dopamine turnover in discrete brain regions of mice. The levels of dopamine and its metabolites were examined 40 min after the administration of GBR 12909 and/or apomorphine, when the effects of the drugs on locomotor activity were approximately at a peak. GBR 12909 (10 mg/kg i.p.) reversed a low dose of apomorphine (0.05 mg/kg s.c.)-induced suppression in locomotor activity and significantly increased this activity. Despite the dramatic change in the behavior, GBR 12909 did not influence the decrease in 3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine ratio (which is one of the indications of transmitter turnover) induced by a low dose of apomorphine in the nucleus accumbens and striatum. In contrast, GBR 12909 did not enhance the high-dose apomorphine (2 mg/kg s.c.)-induced hyperlocomotion, and did not modify the larger decrease in dopamine turnover produced by the high dose of apomorphine in the frontal cortex, nucleus accumbens and striatum. This suggests that postsynaptic dopamine receptors may reach maximum stimulation at a high dose of apomorphine. These results indicate that a behavioral change induced via stimulation of postsynaptic dopamine receptors does not necessarily lead to an alteration in dopamine turnover.

Antiparkinsonian activity of talipexole in MPTP-treated monkeys: in combination with L-dopa and as chronic treatment.

We examined whether or not the antiparkinsonian activity of talipexole (B-HT 920, 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]-azepine) could be optimised by combination with L-3,4-dihydroxyphenylalanine (L-dopa). Additionally, the effects of chronic treatment with talipexole on motor behavior were investigated using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated and normal common marmosets. Administration of MPTP (0.5 mg/animal i.v. once or twice) to marmosets induced persistent parkinsonian motor deficits. The antiparkinsonian activity of talipexole (40 micrograms/kg s.c.) was significantly enhanced by its combination with L-dopa (30 mg/kg i.p.). This may further support the postulated postsynaptic dopamine D2 receptor agonist properties of talipexole. Chronic treatment with talipexole (a daily dose of 40 micrograms/kg s.c. for 21 days) did not lead to tolerance to the antiparkinsonian activity in MPTP-treated animals. No obvious dyskinesia was seen throughout the chronic treatment. In contrast, in normal marmosets, talipexole at a dose of 80 micrograms/kg which is a dose sufficient to induce hyperactivity did not increase motor activity during the treatment repeated for 21 days. These results suggest that talipexole is a selective dopamine D2 receptor agonist drug of potential use in the treatment of Parkinson's disease.

Effects of bifemelane on parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the common marmoset.

The effects of bifemelane on parkinsonism were shown in MPTP-treated common marmosets. The administration of bifemelane increased locomotor activity in MPTP-treated marmosets but not in normal control marmosets. In a microdialysis study, extracellular levels of dopamine and its metabolites increased following the administration of bifemelane. These results indicate that it is worth studying the effects of bifemelane hydrochloride on patients with Parkinson's disease.

Effects of volatile and intravenous anesthetics on the uptake of GABA, glutamate and dopamine by their transporters heterologously expressed in COS cells and in rat brain synaptosomes.

Although the neurotransmitter uptake system is considered a possible target for the presynaptic action of anesthetic agents, observations are inconsistent concerning effects on the transporter and their clinical relevance. The present study examined the effects of volatile and intravenous anesthetics on the uptake of GABA, glutamate and dopamine in COS cells heterologously expressing the transporters for these neurotransmitters and in the rat brain synaptosomes. Halothane and isoflurane, but not thiamylal or thiopental, significantly inhibited uptake by COS cell systems of GABA, dopamine and glutamic acid in a concentration-dependent manner within clinically relevant ranges for anesthesia induced by these agents. Similarly, in synaptosomes halothane and isoflurane but not thiopental significantly suppressed the uptake of GABA and glutamic acid, respectively. These results do not support the hypothesis that volatile and intravenous anesthetics exert their action via specific inhibition of GABA uptake to enhance inhibitory GABAergic neuronal activity. Rather, they suggest that presynaptic uptake systems for various neurotransmitters including GABA may be the molecular targets for volatile anesthetic agents.

Ketamine-induced hyperlocomotion associated with alteration of presynaptic components of dopamine neurons in the nucleus accumbens of mice.

The underlying mechanisms of ketamine-induced hyperlocomotion were examined in mice. An intraperitoneal (IP) injection of ketamine (3-150 mg/kg) increased locomotor activity in a dose-dependent fashion. A low dose of ketamine (30 mg/kg) produced peak locomotion within the first 10 min followed by a rapid decline. In contrast, a high dose (150 mg/kg) inhibited locomotor activity to the control level during the first 30 min. Thereafter the activity gradually increased and reached a peak at approximately 2 h followed by a gradual decline. The hyperactivities induced by both low and high doses of ketamine were inhibited by a low dose of haloperidol (0.10 mg/kg, IP), a dopamine (DA) receptor antagonist. However, neither a high dose of phenoxybenzamine (10 mg/kg, IP), an alpha-blocker nor a high dose of propranolol (20 mg/kg, IP), a beta-blocker inhibited the hyperactivities. Destruction of catecholaminergic terminals by 6-hydroxydopamine suppressed ketamine-induced hyperlocomotion. Regional brain monoamine assays revealed that, at peak locomotion, a low dose of ketamine (30 mg/kg) selectively increased DA turnover in the nucleus accumbens which is a forebrain region believed to be involved in the initiation and regulation of locomotor activity, while a high dose (150 mg/kg) increased not only DA but also norepinephrine and serotonin turnover in many regions of the brain. In vitro, ketamine slightly provoked [3H]DA release from nucleus accumbens and striatal slices to a similar extent, but inhibited synaptosomal uptake of [3H]DA in the nucleus accumbens to a greater degree than in the striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

Involvement of N-methyl-D-aspartate (NMDA) receptors in noncompetitive NMDA receptor antagonist-induced hyperlocomotion in mice.

The role of the N-methyl-D-aspartate (NMDA) receptors in hyperlocomotion induced by (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), a potent and selective noncompetitive NMDA receptor antagonist, was examined in male ddY mice. A low dose of MK-801 [0.2 mg/kg, intraperitoneally (IP)] produced a marked increase in locomotor activity without obvious staggering gait. In contrast, a high dose (1 mg/kg, IP) induced a typical motor syndrome characterized by increased locomotor activity, stereotyped behavior, and severe ataxia. NMDA (60-120 mg/kg, IP), an NMDA receptor agonist, dose dependently antagonized hyperlocomotion induced by a low dose of MK-801 (0.2 mg/kg). However, even a high convulsive dose of NMDA (240 mg/kg, IP) could not completely antagonize the hyperactivity induced by MK-801. On the other hand, neither a high dose of N-methyl-L-aspartate (400 mg/kg, IP), a stereoisomer of NMDA, nor a critical subconvulsive dose of kainate (10 mg/kg, IP), a non-NMDA receptor agonist, reversed MK-801-induced hyperlocomotion. The activity induced by MK-801 was potently suppressed by low doses of haloperidol (0.05-0.1 mg/kg, IP), a dopamine (DA) receptor antagonist, in a dose-dependent manner. These data for MK-801 were similar to those for phencyclidine and ketamine, other noncompetitive NMDA receptor antagonists. These results suggest that noncompetitive NMDA receptor antagonist-induced hyperlocomotion is mediated, at least in part, by NMDA receptor antagonism, although this hyperactivity may also involve dopaminergic mechanisms through indirect (perhaps by reducing NMDA receptor-mediated neurotransmission) and/or direct (by inhibiting DA uptake) effects on DA neurons.

Histamine metabolism in nasal polyps.

We attempted to determine the relationship of nasal polyps to histamine (HA) metabolism. Compared to that in allergy-related nasal polyps and infection-related nasal polyps, the level of HA in aspirin-induced asthma-related polyps was significantly lower. Large differences between the groups were not observed in HA-synthesizing enzyme activity, but degradative enzyme activity was much higher in aspirin-induced asthma-related polyps than in other types of nasal polyps tested. These findings suggest the possibility that the amount of HA in polyps associated with aspirin-induced asthma was less because of greatly enhanced degradation. We found, in addition, that in nasal tissues such as polyps, histamine-N-methyl transferase, rather than histaminase, was the principal degradative enzyme.

Effects of capsaicin desensitization on nasal allergy-like symptoms and histamine release in the nose induced by toluene diisocyanate in guinea pigs.

Intranasal application of toluene diisocyanate (TDI) induced nasal allergy-like symptoms of sneezing and watery rhinorrhea and decreased the histamine content of the nasal mucosa in guinea pigs. However, in the animals pretreated with capsaicin (capsaicin desensitization) before sensitization with TDI, nasal allergy-like symptoms were not induced. Capsaicin desensitization also inhibited histamine release in the nasal mucosa induced by TDI. These findings suggest that antidromic impulses of capsaicin-sensitive sensory nerves stimulated by TDI cause histamine release from mast cells in the nasal mucosa, resulting in nasal discharge and sneezing in guinea pigs. Thus neurogenic inflammation via an axon reflex in the nose may contribute to the pathogenesis of vasomotor rhinitis.

Nasal allergy in medical students.

The incidence of nasal allergy in medical students was studied in our University from 1983 to 1987. Intradermal skin tests were performed using six allergens: house dust (HD), ragweed, Japanese cedar, orchard grass, candida and broncasma berna. 154 out of 471 students (32.7%) had symptoms indicative of nasal allergy. HD and Japanese cedar were the main allergens and their positive rates were 66.4% and 51.0%, respectively in symptomatic cases. However, 34.4% of asymptomatic students also showed positive reactions to HD and 19.6% to Japanese cedar. In nasal provocation tests, 53.8% of symptomatic students who reacted positively to HD skin test showed positive reactions, while even 34.8% of asymptomatic students also showed positive reactions. The same results were obtained for Japanese cedar. It seemed that some asymptomatic students who had positive reactions to skin tests have latent allergies. A long-term follow-up would be necessary for these cases.

Evaluation of allergen-specific IgE antibodies by MAST for the diagnosis of nasal allergy.

Multiple-antigen simultaneous test (MAST) is a new system for detecting allergen-specific IgE antibodies. Multiple antigens can be examined simultaneously in a short period of time by this method. The purpose of this study is to evaluate the usefulness of this method and to compare the results of MAST with those of RAST and intradermal skin test using 133 serum samples obtained from patients with nasal allergy. The positive rates of the main allergens detected by the MAST system are 56% for Japanese cedar, 31 for Dermatophagoides farinae (DF), 30% for Dermatophagoides pteronyssinus (DP), 27% for house dust (HD), and 27% for timothy grass. The positive rates of food allergens are very low. An average of 3.5 different allergens can be simultaneously detected in one serum. We have compared MAST and RAST with respect to nine allergens: HD, DF, cat, Japanese cedar, timothy, bahia, sweet vernal, velvet, and ragweed. There are statistically significant correlations between MAST and RAST for all allergens except ragweed, the correlation coefficients in the eight allergens are greater than r = 0.60, and total agreements exceed over 70%. Similarly, there also is a good correlation between MAST and skin test for the allergens: HD, cat, Japanese cedar, timothy grass, and ragweed. These results indicate the clinical usefulness of the MAST system for detecting specific IgE antibodies in patients with nasal allergy.

Topical treatment of nasal polyps with a beclomethasone dipropionate powder preparation.

The clinical efficacy of a topical preparation consisting of beclomethasone dipropionate (BDP) powder and a mucous membrane adhesive agent (hydroxypropylcellulose, HPC) for nasal polyps was examined. For 1 week, in 31 patients with bilateral nasal polyposis, the clinical efficacy of the topical BDP-HPC powder treatment was examined. The effect of this treatment on the histology of the nasal polyps was also investigated. The controls were six patients with bilateral nasal polyposis, who underwent identical surgery without prior use of the topical steroid therapy. Polyp shrinkage and improvement of some nasal symptoms (rhinorrhea, ease of noseblowing, and nasal blockage) were observed with the topical treatment. Significant clinical improvement (P < 0.05) was seen in the group treated with topical BDP HPC powder compared with the untreated control group. Histological examination of the excised nasal polyps in both groups demonstrated no clear differences attributable to BDP HPC powder. The topical treatment of nasal polyps with BDP HPC powder is a useful conservative therapy.

[Dermal application of lisuride on parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the common marmoset and on cases with Parkinson's disease].

Dermal administration is a nonoral drug delivery system that can keep the concentration of a drug in the body at a proper level for a long time. This is suitable especially in patients in the advanced stages of Parkinson's disease with a wearing-off phenomenon (short duration of effects on antiparkinsonian drugs), or in postoperative patients who cannot be treated with oral administration. We studied the effects of lisuride, a dopamine receptor agonist, in the dermal application on MPTP-treated common marmosets and on 5 patients with Parkinson's disease. Lisuride was applied to 4 x 5 cm of skin of the abdomen of monkeys. In patients with Parkinson's disease, lisuride was applied to the skin of the chest. The agent reversed akinesia of MPTP-treated animals within 30 min following the application and relieved the animal of parkinsonism for 5 days at a dose of 2 mg/kg. In patients, the dermal application of lisuride increased the duration of the ON period at doses of 1 to 2 mg/kg. These results suggest that the dermal application of lisuride is a useful treatment in parkinsonism.

[Seven cases of tuberculous otitis media].

Tuberculous otitis media (TOM) is a variable and puzzling infectious disease that is sometimes confused with other chronic middle ear diseases. A series of 7 cases (9 ears) of TOM recently treated at Osaka Prefectural Habikino Hospital is reviewed to assess the recent features of the disease. In most cases, the pathogenetic mechanism was probably aspiration of tubercle bacilli through the eustachian tube. In most cases, abundant granulations were observed in the middle and external ears, but multiple perforations of the tympanic membrane were not seen. The manifestations were variable, such as otorrhea from the perforation and otitis media with effusion. In their early stage, most cases of TOMs due to transmission via the eustachian tube are tend to resemble otitis media with effusion. Smear tests, culture, PCR, and histopathological examinations, each of which has advantages and disadvantages, must be repeated to achieve a definitive diagnosis. Tuberculin tests can be unreliable, but a chest x-ray is indispensable whenever TOM is suspected. Antitubercular chemotherapy and 2% kanamycin earwash yielded good results. Since the classical criteria for the diagnosis of TOM are no longer valid, we propose a new criterion for diagnosis in the early stage of the disease.