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Abnormalities of auditory steady-state responses (ASSRs) and the effects of antipsychotic drugs on ASSRs have been investigated in patients with schizophrenia. It is presumed that drugs do not directly affect ASSRs because its abnormalities are associated with schizophrenia. Therefore, to investigate the direct effect of drugs on ASSRs, we established an ASSR evaluation system for common marmosets in a naïve state. Dopamine D1 receptor stimulation (SKF-81297, 2 mg/kg ip) significantly increased evoked power (EP) at 40 Hz. The phase locking factor (PLF) was increased significantly at 20, 30, 40, and 80 Hz. However, administration of a dopamine D1 receptor antagonist (SCH-39166, 0.3 mg/kg ip) resulted in a significant decrease in EP and PLF at 30 Hz. Dopamine D2 receptor stimulation (quinpirole, 1 mg/kg im) tended to increase EP and induced power (IP) at all frequencies, and a significant difference was observed at 30 Hz IP. There was no change in PLF at all frequencies. In addition, dopamine D2 receptor blockade (raclopride, 3 mg/kg ip) reduced EP and PLF at 30 Hz. Subcutaneous administration of the serotonin dopamine antagonist, risperidone (0.3 mg/kg), tended to increase IP and decrease PLF, but not significantly. Taken together, it is possible to compare the differences in the mode of action of drugs on ASSRs using naïve nonhuman primates.

The ameliorating effect of risperidone on apomorphine-induced stereotyped behavior and inhibition of auditory sensory gating was investigated using rhesus monkeys. The total duration of the stereotyped behavior observed in the control group was 43.7 ± 23.0 s (n = 3) between 10 and 25 min after vehicle administration, whereas the duration in the apomorphine-treated (0.1 or 0.15 mg/kg i.m., n = 3) group was observed to be significantly prolonged to 413.0 ± 150.6 s. Administration of 0.01, 0.03, 0.1 mg/kg of risperidone 60 min before apomorphine, significantly reduced the duration of this apomorphine-induced stereotyped behavior to 327 ± 104.9 s (n = 3), 8.3 ± 4.2 s (n = 3), and 0.0 ± × 0.0 s (n = 3, t-test: p 0.05), respectively. Next, the auditory sensory gating test/conditioning (T/C) ratio was used as a bio-marker. The T/C ratio was 0.598 ± 0.0802 in the vehicle-administered control group (n = 4) and was significantly increased to 2.098 ± 0.254 (n = 4) by apomorphine (0.15 mg/kg, i.m.). Administering of risperidone (0.1 mg/kg, s.c.) 30 min before apomorphine treatment significantly restricted the T/C ratio to 0.571 ± 0.0886 (n = 4), compared to the T/C ratio in the vehicle-administered control group. The above results demonstrate, not only behaviorally but also electrophysiologically, the ameliorating effect of risperidone on the induction of schizophrenia-like symptoms by apomorphine in non-human primates.

The pharmacological activity of DSP-6952, a novel compound was investigated, compared to that of clinically efficacious gastrointestinal (GI) prokinetic 5-hydroxytryptamine 4 (5-HT 4 ) receptor agonists. DSP-6952 had a strong affinity of K i = 51.9 nM for 5-HT 4(b) receptor, and produced contraction in the isolated guinea pig colon with EC 50 of 271.6 nM and low intrinsic activity of 57%, similar to tegaserod and mosapride. In the development of the 5-HT 4 receptor agonists, cardiovascular risk was deliberately evaluated, because some related prokinetics were reported to cause with cardiovascular adverse events, such as ventricular arrhythmias or ischemia. DSP-6952 showed minimal effects up to 100 μM in human ether-a-go-go-related gene (hERG) channels or guinea pig cardiomyocytes. In telemetered conscious monkeys, DSP-6952 did not affect blood pressure or any electrocardiogram (ECG) up to 180 mg/kg, p.o.; however, DSP-6952 transiently increased heart rate, as well as in anesthetized dogs. The positive chronotropic effects of DSP-6952 were completely antagonized by a 5-HT 4 receptor antagonist, and another 5-HT 4 receptor agonist, TD-5108 also increased heart rate. These effects are considered a class effect seen in clinically developing and marketed 5-HT 4 receptor agonists, and have not been regarded as a critical issue in clinical use. DSP-6952 did not induce contraction in the rabbit coronary artery up to 100 μM, which differed from tegaserod or sumatriptan. These results show that DSP-6952 does not have cardiac ischemic risk via coronary vasoconstriction. In conclusion, DSP-6952 is a promising GI prokinetic compound with partial 5-HT 4 receptor agonistic activity as well as a favorable cardiovascular safety profile.

The pharmacological activity of DSP-6952, a novel compound was investigated, compared to that of clinically efficacious gastrointestinal (GI) prokinetic 5-hydroxytryptamine

Background. A number of studies have indicated that the ki-67 proliferation index is of important prognostic significance for a variety of neoplasias. It was the aim of this study to investigate whether any correlation exits between the MIB-1 proliferation index and various clinicopathologic parameters in squamous cell carcinomas of the esophagus from 72 patients (20 women: median age, 64 years; range, 45–79 years; and 52 men: median age, 61 years; range, 43–77 years). Methods. Proliferative activity was determined using an immunohistochemical method with monoclonal antibody MIB-1 (ABC method), for tumor samples obtained from individuals who underwent esophagectomy in the period from 1983 to 1991. The percentage proliferation index (PI) was calculated as the number of positive cells divided by the total number of cells examined. Thirty-nine patients (54%) died of recurrence of esophageal cancer, with a median survival span of 15 months (range, 1–58 months). Thirty-three patients (46%) were still alive at the time of this study; their median follow up was 57 months (range, 40–98 months). Results. Significant differences between proliferative index values were recorded for the following parameters: survival rate, P < 0.0001; presence of lymph node metastasis, P < 0.05; size of the primary esophageal lesion, P < 0.01; proliferation pattern of the tumor, P < 0.01; and age of the patients, P < 0.05. No correlation was found regarding histologic differentiation, clinical stage, location of the lesion, intraepithelial cancerous spread, lymphatic and blood vessel invasion, and sex of the patients. Conclusion. The MIB-1 proliferation index may be a powerful prognostic marker for patients with squamous cell carcinomas of the esophagus. Cancer 1995;76:358–66.

The Image Processor for Analytical Pathology (IPAP), is a computer-based image analysis instrument which uses current technology to provide valuable information to the pathologist. Our own studies using the IPAP system are focussed on the fields of tumor pathology and toxicologic pathology. The spectrum of methods for the characterization of histologic patterns in these fields consists of karyometric and histometric measurements. This paper describes the hardware configuration of the IPAP and the software system which has been developed to allow a flexible and interactive analysis of microscopical images with minimal computer training and experience. Some examples are given to illustrate the possibilities of the IPAP.

In this study, the effects of atropine sulfate (atropine) on swallowing and cough reflex were evaluated in the two experimental models in conscious dogs. To evaluate the effects of atropine on swallowing, 1 mL of marker (contrast medium) was injected into the pharynx under X-ray exposure to induce swallowing. Baclofen, used as a positive control, caused marker congestion in the upper esophagus. In our experimental model, atropine (0.02 and 0.1 mg /kg, i.v.) dose-dependently increased not only the number of marker congestions but also that of the swallows. In addition, atropine significantly shortened the onset of first swallowing. In the evaluation of atropine effects on electrically evoked cough reflex induced by two electrodes implanted into the trachea, atropine strongly inhibited the number of coughs at 0.01 or 0.05 mg/kg accompanied with 0.01 or 0.05 mg/kg per hour (i.v.), respectively. These findings indicate that atropine has the potential of causing aspiration pneumonia through induction of swallowing disorder and inhibition of the cough reflex. Keywords:: swallowing disorder, inhibition of cough reflex, anti-cholinergic agent, dog, aspiration pneumonia