[Clinical dose dependence of anti-anxiety agents].
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Anti-Anxiety Agents↗
Biomedical subjects
M Murasaki
Publications and source records attributed to M Murasaki.
A comparative study of the psychological effects of DN-2327, a partial benzodiazepine agonist, and alprazolam.
The effects of single oral doses of DN-2327 (DN, 2 mg or 3 mg), a newly developed partial benzodiazepine receptor agonist, and alprazolam (APZ, 0.8 mg), a full receptor agonist, on psychomotor function and short-term memory were assessed using three psychometric tests: letter cancellation, visual vigilance and Sternberg's memory scanning task. Twelve healthy male volunteers participated in this study. Randomized, double-blind, cross-over test sessions were conducted at 2-week intervals. Both 3 mg DN and 0.8 mg APZ increased the time to completion of the letter cancellation task at 3 h after administration, but neither had any effect on accuracy of response. In the visual vigilance task, which required relatively intense concentration and continuous attention, both the number of errors and reaction times to correct responses significantly increased from 1.5 to 3.5 h after administration of 3 mg DN and at 3.5 h after administration with 0.8 mg APZ. DN at 2 mg also significantly increased the number of errors from 1.5 to 3.5 h after administration, but it did not affect reaction times. In the memory scanning task, 3 mg DN, but not 2 mg DN or APZ, significantly increased overall reaction times at 2 h after administration. These performance deficits paralleled the time-course changes in serum concentrations of both drugs and appeared to be associated with the hypnotic-sedative effects of the drugs tested. These findings did not support those of previous preclinical studies of DN, indicating superiority of DN over conventional full benzodiazepine agonists/anxiolytics in terms of adverse behavioral consequences.
Adult↗
[Problematic points of psychotropic drugs].
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Drug Interactions↗
[Recent progress in development of psychotropic drugs (2)--antipsychotics].
The discovery of chlorpromazine led to rapid progress in drug therapy for schizophrenia. However, conventional neuroleptics frequently induce EPS and tardive dyskinesia in addition to the drawback of having little effect against negative symptoms. New types of atypical antipsychotics has been actively developed in Japan to overcome these drawbacks. Firstly, serotonin-dopamine antagonist (SDA) is most actively developed. Eight SDAs have been introduced into clinical trials: risperidone's trials have been finished and a NDA has been filed, Org 5222 has been dropped because of worsening of significant cases, and 6 SDAs (SM-9018, sertindole, seroquel, AD-5423, ziprasidone and olanzapine) are now under development. Secondly, OPC-14597, a unique atypical antipsychotic has been advanced to the phase 3 study, which has both DA autoreceptor-agonistic and D2-receptor blocking actions. Thirdly, we have much interest in NE-100, a selective sigma receptor antagonist which potently suppresses the phencyclidine-induced behaviors. Finally. a 5-HT3 receptor antagonist, alosetron was already dropped because it showed no antipsychotic effects, although it was introduced with great expectations. We hope that as many as possible new antipsychotics will be approved for the battle against schizophrenia.
Animals↗
[Drug therapy of manic-depressive disorders].
Much more depressed patients visit general practitioners or internists than psychiatrists. Therefore, all doctors have to master the method how to treat depression. There are many cases who shift to protracted or chronic depression and intractable ones, because of insufficient medications. For example, antidepressants should be increased to the well-responded dosage, considering any side-effects, and should be continued till getting full recovery. On the other hand, manic patients should be treated by psychiatrists, because they usually lack the insight of disorders and refuse to receive any treatment. Most cases are obliged to hospitalize and to take mood stabilizers and sedative neuroleptics added on.
Antidepressive Agents↗
The printing of that article in our dental journal was a slap in the face to us Big Island dentists.
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Dental Care↗
Effects of tandospirone, a 5-HT1A receptor-related anxiolytic, on daytime sleepiness and psychomotor functions: a comparative double-blind study with diazepam.
A double-blind cross-over placebo-controlled study was designed to compare the effects of a single oral dose of tandospirone (30 mg), a new 5-HT1A receptor-related anxiolytic, on daytime sleepiness, psychomotor function and short-term memory with those of diazepam (5 mg), a benzodiazepine, in 12 healthy Japanese volunteers. A dose of 5 mg of diazepam significantly shortened sleep latencies measured by the Multiple Sleep Latency Test during the periods of 3 to 7 h after the medication, with no influence on the self-estimated sleepiness on the Stanford Sleepiness Scale. The elevated daytime sleepiness under the diazepam treatment was correlated with impaired psychomotor performance; performance on the visual vigilance task significantly declined 1.5 to 3.5 h after the administration of 5 mg of diazepam. In contrast, 30 mg of trandospirone did not impair objective measures of daytime wakefulness or performances. The differential effects of the two anxiolytics on daytime sleepiness and psychomotor functions could be ascribable to the differences in their pharmacological mechanisms of actions. The findings also suggested the superiority of tandospirone to the benzodiazepine in terms of behavioral side effects.
Adult↗
[Drug-induced movement disorders].
Many drugs have been known to cause movement disorders with different mechanisms of action. Most of these drugs interfere with dopaminergic transmission within the basal ganglia. However, numerous other drugs are capable of producing movement disorders, whose mechanism is not at all clearly understood. Neuroleptic drugs-induced extrapyramidal symptoms such as dystonia, akathisia, parkinsonism have been related to sudden imbalance between the striatal dopamine and cholinergic systems, causing a relative preponderance of acetylcholine. Some calcium channel blockers and H2 blockers induced or aggravated parkinsonism and other extrapyramidal symptoms. It has been suggested that calcium channel blockers-induced extrapyramidal symptoms are much more common in elderly patients. In H2 blockers induced movement disorders, renal and liver dysfunction is the risk factor of them, but the mechanism is not clearly understood.
Antipsychotic Agents↗
The future of 5-HT1A receptor agonists. (Aryl-piperazine derivatives).
At present the dominant position among anti-anxiety medications has changed from meprobamate to the benzodiazepine derivatives. In order to avoid benzodiazepine's (BZ) undesirable side effects such as impairment of psycho-motor function, memory impairment, low dose dependence and withdrawal symptoms, a third generation anxiolytic agent, buspirone, the focus of the aryl-piperazine group of anti-anxiety agents, has been introduced recently. Aryl-piperazine derivatives work as 5-HT1A receptor partial agonists and are known as serotonin normalizers. Therefore, they are expected to have not only an anxiolytic function but also an anti-depressant effect as well. A characteristic of the aryl-piperazine derivatives is that they have no sedative and muscle relaxant effects, and they do not have BZ's undesirable side-effects, especially in regard to withdrawal symptoms. However they have a rather weak anxiolytic action and a slow onset of action. Aryl-piperazine derivatives will not take the place of BZ, but the use of BZ and buspirone as bridge medications, making the most of the strong points of both, can be proposed as a way to compensate for their respective clisadvantages.
Animals↗
Single- and multiple-dose pharmacokinetics of nefiracetam, a new nootropic agent, in healthy volunteers.
The pharmacokinetic profile of nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide), a new nootropic agent, was studied in healthy Japanese male volunteers. Nefiracetam was administered orally at doses of 10-200 mg in the single-dose studies, and at doses of 200 mg three times a day for seven days in the multiple-dose study. An HPLC method was used to determine the concentrations of nefiracetam in serum, urine and faecal samples. Linear kinetic behaviour was obtained after single oral administration. Serum concentrations of nefiracetam reached maximum values (Cmax) within 2 h for all dosage groups, and declined monophasically after Cmax with half-lives of 3-5 h. The area under the concentration-time curve (AUC infinity) and Cmax were linearly related to the dose. The apparent clearance (CL) values were 94.4-140.3 mL min-1. Urinary excretion of nefiracetam was independent of the administered dose, and less than 10% of the dose was recovered in urine as the unchanged form within 24 h after administration. Renal clearance (CLR) did not change significantly as dose increased from 10 to 1200 mg. Faecal excretion of nefiracetam was less than 0.1% of the dose up to 24 h after a 300 mg oral dose. Food intake delayed the absorption of nefiracetam but did not significantly modify its pharmacokinetics. No clinically significant accumulation of nefiracetam in the body was observed during and after multiple doses.
Administration, Oral↗
Abuse of "BRON": a Japanese OTC cough suppressant solution containing methylephedrine, codeine, caffeine and chlorpheniramine.
1. The paper describes the mental disturbances of 44 abusive cases of "BRON," an over-the-counter (OTC) cough suppressant solution containing methylephedrine, codeine, caffeine, and chlorpheniramine. 2. Major psychiatric symptoms observed included hallucinatory-paranoid state and affective disorder. There also were groups which exhibited a combination of the two states and abuse only. 3. The hallucinatory-paranoid state group had a relatively small BRON usage amount, short usage term and few withdrawal symptoms. The affective disorder group, in contrast, had large usage amount, longer usage term, and showed significant autonomic nerve disorders during withdrawal. These tendencies were seen more clearly in the mixed state group. 4. The hallucinatory-paranoid state group showed little or no physical dependence, while that of the affective disorder group was thought to be firmly established. Thus, in the former group, methylephedrine was considered the major behavior modifying drug, while in the latter, it was thought to be codeine.
Adult↗
Pharmacokinetic study of iminodibenzyl antipsychotic drugs, clocapramine and Y-516 in dog and man.
The pharmacokinetic properties of the iminodibenzyl antipsychotic drugs clocapramine (CCP, 3-chloro-5-[3-(4-carbamoyl-4-piperidino piperidino) propyl]-10, 11-dihydro-5H-dibenzo[b, f]azepine) and Y-516 (3-chloro-5-[3-(2-oxo-1, 2, 3, 5, 6, 7, 8, 8a-octahydroimidazo [1,2-a] pyridine-3-spiro-4'-piperidino) propyl]-10, 11-dihydro-5H-dibenzo[b, f]azepine) were investigated in dog and man. Dogs were administered CCP and Y-516 intravenously, intraperitoneally, and orally, and the concentrations of the parent drugs and their metabolites in the plasma and urine were determined. Half-life (t1/2) was approximately the same by all three administration routes, being approximately 5 h for CCP and 3 h for Y-516. Bioavailability following oral administration was 0.16 +/- 0.01 (mean +/- SD, n = 3) for CCP and 0.29 +/- 0.07 for Y-516. The fractions of dose absorbed following oral administration were 0.43 +/- 0.07 and 0.79 +/- 0.24, and the fractions of dose metabolized in the liver due to the first-pass effect were 0.63 +/- 0.05 and 0.63 +/- 0.04 for CCP and Y-516, respectively. Y-516 was detected in the plasma after intraperitoneal and oral administration of CCP. The ratio of the AUC of Y-516 to that of CCP was 0.06 following intraperitoneal administration and 0.40 following oral administration. This indicated that while the metabolism of CCP into Y-516 may occur partly in the liver due to the first-pass effect, it occurs mostly within the gastrointestinal tract itself or its mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Phase I study of a new antianxiety drug, buspirone.
1. A phase I study of buspirone was conducted in 7 healthy male volunteers. 2. Diazepam was selected as the control drug and administered in equipotent doses to buspirone. Dosage was initiated at 2.5mg and doubled until a maximum dosage of 20mg was attained. Subsequently, 10mg was administered once a day for three consecutive days. 3. Clinico-pharmacologically both drugs produced sleepiness/drowsiness, but dizziness, light-headed feeling and feeling of drunkenness were marked only in the diazepam group. 4. No drug-related abnormalities were observed in clinical laboratory test values, endocrinological tests and ECG. 5. On the Uchida-Kraepelin test, no change with the control values was observed under buspirone but subjects administered diazepam exhibited marked deterioration during the latter half of the test. Moreover, in the tapping test, significant impairment was observed in the diazepam group whereas buspirone had no effect. 6. On the EEG some fast waves were observed with diazepam whereas buspirone exhibited slow waves.
Buspirone↗
Comparison of therapeutic efficacy of neuroses between CM6912 (ethyl loflazepate) and diazepam in a double-blind trial.
1. The therapeutic efficacy on several neuroses between CM6912 and diazepam (DZP) was comparatively investigated by means of intergroup comparison method in a double-blind trials. CM6912 was given to CM-1 group on the basis of twice daily dose of 1 mg each in the morning and evening and to CM-2 group on the basis of once daily dose of 2 mg only in the evening and DZP was given to another group on the basis of three times each dose of 2 mg. 2. As for the overall evaluation, no significant differences were found in the percentages of final global improvement rating among three groups. It resulted in "markedly improved" by 22% in CM-2 group, 18% in CM-1 group and 15% in DZP group in order, and "more than moderately improved" by 62% in CM-2 group, 56% in DZP group and 51% in CM-1 group in order. 3. As for the overall safety rating, no differences were found in the incidence of adverse reactions. 4. As for the global utility rating, it resulted in "extremely useful" by 22% in CM-2 group, 14% in CM-1 group and 8% in DZP group in order, showing significant superiority of CM-2 group to DZP group (p less than 0.05). It resulted in "more than useful" by 58% in CM-2 group, 52% in DZP group and 50% in CM-1 group in order.
Anti-Anxiety Agents↗
Phase 1 study of a new antipsychotic drug, OPC-4392.
1. A phase I study of OPC-4392 (OPC), a quinolinone derivative recently developed in Japan and recognized to have an agonistic effect on dopamine autoreceptors, was performed in 7 male healthy volunteers in comparison with chlorpromazine (CPZ). 2. Clinical pharmacology The main clinical symptoms of OPC were sleepiness, weakness, fatigability, heavy headedness, disturbance of concentration, nausea, etc. The severity of these symptoms increased dose-dependently, and the upper limit dosage of OPC was considered to be 5 mg for the healthy volunteers. 3. Endocrinological research The serum prolactin level decreased dose-dependently in the OPC group, whereas it rose in the CPZ group. A significant negative correlation was recognized between the OPC-plasma level and serum prolactin level as well. 4. Psychological tests In the Kraepelin test, a decrease in the average work quantity was observed in both groups, but it was less in the OPC group. 5. Pharmacokinetic study From the pharmacokinetic parameters measured, two features were recognized: one was the slowness of Tmax (4-6 hours) and the other was the length of its biological half-life (56-88 hours). It was estimated that the plasma level of OPC-4392 would take 2 weeks to reach a steady state.
Adult↗
Complex partial status epilepticus.
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Electroencephalography↗
A sporadic case of benign myoclonus epilepsy of adult onset: its clinical aspects and electroencephalographic, polygraphic study.
A sporadic case of myoclonus epilepsy of adult onset with a benign course is presented. Its clinical implications were discussed symptomatologically and nosologically. EEG findings consisted of the slowing of basic activity, characteristic polyspike and wave discharges or other paroxysmal patterns and photomyoclonic response (PMR). The PMR was well evoked by flashes of 6-21 Hz and of yellow or red color. Clinical similarities of this case to those of hereditary myoclonus epilepsy without progressive dementia and cerebellar ataxia, and pathognomonic characteristics of electrophysiological findings indicated that the myoclonic epilepsy syndrome might share basic properties, which are state-dependent, but independent of underlying neuropathology or heredity. During sleep, paroxysmal discharges with spike(s) significantly decreased in slow-wave sleep and almost recovered in REM sleep. This finding suggests that the brain stem may be responsible for the epileptogeneity in this case.
Adult↗