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.

MPTP treatment of common marmosets impairs proteasomal enzyme activity and decreases expression of structural and regulatory elements of the 26S proteasome.

Dysfunction of the ubiquitin-proteasome system occurs in the substantia nigra (SN) in Parkinson's disease (PD). However, it is unknown whether this is a primary cause or a secondary consequence of other components of the pathogenic process. We have investigated in nonhuman primates whether initiating cell death through mitochondrial complex I inhibition using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) altered proteasomal activity or the proteasomal components in the SN. Chymotrypsin-like, trypsin-like and peptidylglutamyl-peptide hydrolase (PGPH) activating of 20S proteasome were decreased in SN homogenates of MPTP-treated marmosets compared to naïve animals. Western blotting revealed a marked decrease in the expression of 20S-alpha subunits, but no change in 20S-beta subunits in the SN of MPTP-treated marmoset compared to naïve animals. There was a marked decrease in the expression of the proteasome activator 700 (PA700) and proteasome activator 28 (PA28) regulatory complexes. The 20S-alpha4 subunit immunoreactivity was decreased in the nucleus of colocalized tyrosine hydroxylase (TH)-positive cells of MPTP-treated animals compared to naïve animals but no difference in the intensity of 20S-beta1i subunit staining. Immunoreactivity for PA700-Rpt5 and PA28-alpha subunits within surviving TH-positive cells of MPTP-treated marmoset was reduced compared to naïve controls. Overall, the changes in proteasomal function and structure occurring follow MPTP-induced destruction of the SN in common marmosets were very similar to those found in PD. This suggests that altered proteasomal function in PD could be a consequence of other pathogenic processes occurring in SN as opposed to initiating cell death as previously suggested.

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.

Evidence for GABA(A) receptor agonistic properties of ketamine: convulsive and anesthetic behavioral models in mice.

UNLABELLED: We examined the potentiation by ketamine of the gamma-aminobutyric acid(A) (GABA(A)) receptor function using convulsive and anesthetic behavioral models in adult male ddY mice. General anesthetic potencies were evaluated by a rating scale, which provided the data for anesthetic scores, loss of righting reflex, duration, and recovery time. All drugs were administered intraperitoneally. Small subanesthetic doses of ketamine did inhibit tonic seizures induced by a large dose of the GABA(A) receptor antagonist bicuculline (8 mg/kg). The 50% effective dose value was 15 (95% confidence limits 10-22) mg/kg. Even large anesthetic doses (100-150 mg/kg) did not suppress clonic seizures in 50% of the animals. The GABA(A) receptor agonist, muscimol (0.32-1.12 mg/kg), potentiated ketamine-induced anesthesia in a dose-dependent fashion (P < 0.05). Similarly, the benzodiazepine receptor agonist, diazepam (1-3 mg/kg), augmented ketamine anesthesia in a dose-dependent manner (P < 0.05). Bicuculline (2-5 mg/kg) dose-dependently antagonized ketamine-induced anesthesia (P < 0.05). Neither the benzodiazepine receptor antagonist, flumazenil (2-20 mg/kg), nor the GABA synthesis inhibitor, L-allylglycine (200 mg/kg), affected the anesthetic action of ketamine. These results suggest that ketamine has GABA(A) receptor agonistic properties and that ketamine-induced anesthesia is mediated, at least in part, by GABA(A) receptors. IMPLICATIONS: We examined the potentiation by ketamine of the gamma-aminobutyric acid(A) receptor function using convulsive and anesthetic behavioral models in mice. Subanesthetic doses of ketamine-inhibited tonic convulsions induced by the gamma-aminobutyric acid(A) receptor antagonist bicuculline. The gamma-aminobutyric acid(A) receptor agonist, muscimol, potentiated ketamine-induced anesthesia. Bicuculline antagonized ketamine anesthesia, but the benzodiazepine receptor antagonist, flumazenil, and the gamma-aminobutyric acid synthesis inhibitor, L-allyglycine, did not. The effects of ketamine on the gamma-aminobutyric acid(A) receptors appear to correlate with its anesthetic actions.

[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.

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.

Propofol anaesthesia in mice is potentiated by muscimol and reversed by bicuculline.

We have examined the role of gamma-aminobutyric acid (GABA) neurones in propofol anaesthesia in mice using the righting reflex. Propofol i.p. increased the percentage of loss of the righting reflex in a dose-dependent manner with an ED50 value of 140 (95% confidence limits 123-160) mg kg-1 (n = 40; eight animals per dose, five doses per dose-response curve). The ED50 for propofol decreased significantly to 66 (58-75) mg kg-1 in the presence of the GABAA receptor agonist muscimol 1 mg kg-1 i.p. (n = 40) (P < 0.05). In contrast, the ED50 increased significantly to 240 (211-274) mg kg-1 in the presence of the antagonist bicuculline 5 mg kg-1 i.p. (n = 40) (P < 0.05). Our results suggest that propofol anaesthesia may be mediated, at least in part by GABA neurons.

[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.

Inhibition by diazepam of ketamine-induced hyperlocomotion and dopamine turnover in mice.

PURPOSE: To investigate the effects of the benzodiazepine diazepam on ketamine-induced hyperlocomotion and dopamine turnover. METHODS: Adult male ddY mice were used (n = 218). Locomotor activity was measured with four circular activity cages equipped with three photocell sensor units. Interruptions by a mover of the infrared light Peams were recorded on electromechanical counters, and automatically printed every 10 min for three hours after the ketamine injection. All drugs were administered intraperitoneally (i.p.). The concentrations of dopamine and its metabolites in discrete brain regions were measured by high performance liquid chromatography with electrochemical detection. RESULTS: Ketamine (30 mg.kg-1) increased total locomotor activity counts for three hours to 442% of control in mice (P = 0.0001). Diazepam, 3 and 10 mg.kg-1, inhibited, in a dose-dependent fashion, this ketamine-induced hyperlocomotion by 26% (P = 0.0111) and 59% (P = 0.0001), respectively. Regional brain dopamine assays revealed that ketamine (30 mg.kg-1) increased the homovanillic acid:dopamine ratio (one indicator of dopamine turnover) to 121% of control in the nucleus accumbens (P = 0.0065) and to 111% in the striatum (P = 0.0135) at peak locomotion. Diazepam, 3 and 10 mg.kg-1, returned this increase in dopamine turnover produced by ketamine to control levels both in the nucleus accumbens (P = 0.0061 and P = 0.0117, respectively) and in the striatum (P = 0.0004 and P = 0.0047, respectively). CONCLUSION: These results suggest that the inhibition by diazepam of ketamine-induced hyperlocomotion may be related to its ability to suppress the activation of dopamine neurons in the nucleus accumbens and striatum.

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.

Inhibitory effect of several nitric oxide-generating compounds on purified Na+,K(+)-ATPase activity from porcine cerebral cortex.

Nitric oxide (NO)-generating compounds (NO donors) such as sodium nitroprusside, S-nitroso-N-acetylpenicillamine, S-nitroso-L-glutathione, 3-morpholino-sydnonimine (SIN-1), (DL)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-5-3-hexenamide, and 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene inhibited the Na+,K(+)-ATPase activity purified from porcine cerebral cortex. NO-reducing or -scavenging agents, such as superoxide dismutase or N-(dithiocarbamate)-N-methyl-D-glucamine sodium salt, L-ascorbic acid; and sulfhydryl (SH) compounds, such as dithiothreitol or the reduced form of glutathione, but not alpha-tocopherol, prevented the inhibition of the enzyme activity by all NO donors except sodium nitroprusside. Enzyme inhibition could also be reversed by these SH compounds, but not by superoxide dismutase, L-ascorbic acid, and alpha-tocopherol. 2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazolin-1-oxyl 3-oxide (PTIO), which is able to scavenge NO radicals and generate nitrogen dioxide radicals (.NO2), potentiated the inhibition of this enzyme activity induced by all NO donors (except SIN-1). PTIO did not potentiate, but rather attenuated, the SIN-1-induced inhibition. SIN-1 has been reported to release both NO and superoxide and thereby to rapidly form peroxynitrite (ONOO-). These potentiated and attenuated inhibitions of the enzyme activity induced by PTIO plus all of the NO donors except sodium nitroprusside were prevented by SH compounds, but not by superoxide dismutase, L-ascorbic acid, and alpha-tocopherol. These results suggest that NO donors may release NO or NO-derived products, presumably .NO2 and ONOO-, and may inhibit the Na+,K(+)-ATPase activity by interacting with a SH group at the active site of the enzyme.

Hyperlocomotion during recovery from isoflurane anesthesia is associated with increased dopamine turnover in the nucleus accumbens and striatum in mice.

BACKGROUND: It was recently reported that isoflurane increases dopamine release in the striatum in rats both in vivo and in vitro, and that isoflurane inhibits uptake of dopamine in the rat brain synaptosomes. However, the functional role of these effects of isoflurane on dopamine neurons is uncertain. Dopaminergic mechanisms within the nucleus accumbens and striatum play an important role in the control of locomotor activity, and a change in dopamine turnover depends essentially on a change in impulse flow in the dopamine neurons. In this study, the effects of isoflurane on locomotor activity and on dopamine turnover were investigated in discrete brain regions in mice. METHODS: Mice were placed in individual airtight clear plastic chambers and spontaneously breathed isoflurane in 25% oxygen and 75% nitrogen (fresh gas flow, 4 l/min). Locomotor activity was measured with an Animex activity meter. Animals were decapitated after treatments with or without isoflurane, and the concentrations of monoamines and their metabolites in different brain areas were measured by high-performance liquid chromatography. RESULTS: During the 10 min after the cessation of the 20-min exposure to isoflurane, there was a significant increase in locomotor activity in animals breathing 1.5% isoflurane but not 0.7% isoflurane. This increase in locomotor activity produced by 1.5% isoflurane was abolished by a low dose of haloperidol (0.1 mg/kg), a dopamine receptor antagonist. Regional brain monoamine assays revealed that 1.5% isoflurane significantly increased the 3,4-dihydroxyphenylacetic acid:dopamine ratio (one indicator of transmitter turnover) in the nucleus accumbens and striatum, but a concentration of 0.7% did not. This significant increase in dopamine turnover in these regions continued during 20 min after the cessation of the administration of 1.5% isoflurane. CONCLUSIONS: These results suggest that isoflurane-induced hyperlocomotion during emergence may be associated with increased dopamine turnover in the nucleus accumbens and striatum.

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.

Comparison of multiple-antigen simultaneous test and CAP systems for diagnosis of nasal allergy.

The multiple-antigen simultaneous test (MAST) is a simple system that uses no radioactive agents and allows simultaneous examination of multiple antigens. CAP is a quick new, in vitro system that is more sensitive than the radio-allergosorbent test (RAST). To evaluate their clinical efficacies, we examined the correlation between the MAST and CAP systems. Serum samples were collected from 33 patients with nasal allergies, 13 males and 20 females, mean age 31.1 years. The MAST and CAP were used for 7 inhaled allergens: house dust, Dermatophagoides farinae, Japanese cedar, timothy, sweet vernal grass, ragweed and mugwort. The correlation coefficients found for MAST and CAP were significant for all the allergens tested. In addition, high values for sensitivity, specificity and efficiency were obtained for all the allergens. The MAST system provided the same information as the CAP system. Although CAP tended to have better sensitivity, some of its positive results may clinically be false-positive. We believe that the MAST and CAP are both useful for the detection of allergens but that the diagnosis of allergy must be based on results of detailed examinations such as use of the skin test, the nasal provocation test and clinical symptoms.

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.

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.

Nasal mucociliary clearance in patients with upper and lower respiratory diseases.

The nasal mucociliary clearance was measured in 71 subjects with nasal allergy (NA) (56 subjects without sinusitis and 15 with sinusitis), 12 subjects with bronchial asthma (BA) (7 without, 5 with) and 7 subjects with aspirin-induced asthma (AIA) using a saccharin test. The results were compared with those obtained in a control group of 15 healthy subjects. The saccharin time (ST) values for both NA and BA subjects without sinusitis (16.9 +/- 9.9 and 20.1 +/- 9.4 min, respectively) did not differ from that of the healthy subjects (16.3 +/- 5.3 min). However, ST values in NA and BA subjects with sinusitis (37.6 +/- 22.9 and 57.0 +/- 6.7 min, respectively) were significantly higher than those of healthy subjects (p < 0.01). The ST value of AIA subjects (13.0 +/- 5.4 min) showed no significant difference compared with that of the control group. These results suggest that allergic reactions do not influence the nasal mucociliary clearance and that the property of mucus complicated with sinusitis is important. Also, sinusitis observed in AIA may be somewhat different from ordinary sinusitis complicated with NA and BA.