Binding profile of SM-9018, a novel antipsychotic candidate

The present study employed various receptor-binding assays to clarify the biochemical characteristics of SM-9018. SM-9018 possessed very high affinity for 5-HT2, D2 and 5-HT1A receptors (Ki = 0.61, 1.4 and 2.9 nM, respectively), and it had moderate affinity for alpha 1 and D1 receptors (Ki = 17 and 41 nM, respectively). However, SM-9018 had only negligible affinity for alpha 2, opiate, glutamate, phencyclidine, benzodiazepine and GABAA receptors. These results suggest that SM-9018 may be a novel antipsychotic agent with binding affinity for 5-HT2 and 5-HT1A receptors.     

Novel benzamides as selective and potent gastric prokinetic agents. 1. Synthesis and structure-activity relationships of N-[(2-morpholinyl)alkyl]benzamides

With the purpose of obtaining more potent and selective gastric prokinetic than metoclopramide (1), a new series of N-[(2-morpholinyl)alkyl]benzamides (17-52) were synthesized and their gastric prokinetic activity was evaluated by determining effects on the gastric emptying of phenol red semisolid meal and of resin pellets solid meal in rats and mice. The morpholinyl moiety was newly designed after consideration of the side-chain structure of cisapride (2) and produced the desired activity when coupled with the 4-amino-5-chloro-2-methoxybenzoyl group of both metoclopramide and cisapride. Modification of the substituents of the benzoyl group markedly influenced the activity. In particular, 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-methoxybenzamide (17) and the 4-(dimethylamino) and 2-ethoxy analogues (25 and 29) of 17 showed potent and selective gastric prokinetic activity along with a weak dopamine D2 receptor antagonistic activity.     

Thoracic duct cyst in supraclavicular region.

A 28-year-old female attended an outpatient clinic in October, 1989, because of a tumor in the left supraclavicular fossa, detected in a health examination. Following exploratory puncture of the tumor which yielded milky-white fluid, suggesting a cyst in the thoracic duct, she was admitted to our department. The cyst was unilocular measuring about 6 cm in diameter, and the fluid content was chyle-rich in lipids. Lymphography demonstrated a lymphatic structure adjacent to the lesion and scattered lymph vessels on the cyst surface. On November 16 the cyst was resected. A restiform structure was observed between the cyst and the thoracic duct, but the presence or absence of communication was unclear. The histological diagnosis was thoracic duct cyst. Thoracic duct cyst occurring in the cervical region is very rare. Our case may provide useful information as to its pathogenesis and the mode of retention of cyst fluid.     

Volume of tarsal bones in congenital clubfoot

To elucidate the growth of the tarsal bones in congenital clubfoot, relative to the growth of these bones in the unaffected feet and compared to growth in the feet of normal volunteers, we used a computed tomography (CT) scanner to measure the volume of all tarsal bones. The subjects of the study were 10 adults (7 men and 3 women) with unilateral congenital clubfoot (average age 20 years and 1 month). As controls, we examined 11 healthy volunteers. We calculated the ratio of the volume of each tarsal bone to the total bone volume and the ratio of the volume of each tarsal bone in clubfoot to the corresponding bone in the unaffected foot. The volume ratio of each tarsal bone was compared between clubfeet and unaffected feet because the differences of each tarsal bone ratio between the normal foot group and unaffected foot group were not significant. In the clubfeet (n=10), the talus and the medial cuneiform bones were smaller than those in the unaffected feet (n=10) but the cuboid bone was larger. The growth of the navicular did not differ from as that in unaffected feet. Our results suggested hypoplasia on the medial side of the foot in adult patients with congenital clubfoot. The 3 patients who had undergone medial release showed particularly marked hypoplasia of the medial side. In congenital clubfoot cases with severe deformities who had undergone wide soft-tissue release operations, there were clear growth suppressions in the talus and the medial cuneiform. We could not determine whether the cause of the growth suppression was the hypoplastic nature of tarsal bones themselves or the surgical obstacles to tarsal bone growth.     

Effect of magnetic field on pineal gland volume and pinealocyte size in the rat

Abstract: Light microscopic observations on the superficial pineal gland of Wistar-King rats were made to examine whether or not pineal volume and pinealocyte size, expressed as nuclear density, at daytime or nighttime are affected by long-term exposure to 50 Hz rotating magnetic field (MF) at 5.0 μT. Determinations of pineal volume and pinealocyte size were repeated twice (April and October) during the year. Size of pinealocytes in MF-exposed and sham-exposed rats exhibited, in addition to the difference between peripheral and central regions, regional differences in a proximodistal direction; pinealocytes in the distal and middle-peripheral regions were usually larger than those in the proximal and middle-central regions at daytime or nighttime. In October, distal and proximal pinealocytes showed significant day-night changes in size in sham-exposed rats, but not in MF-exposed animals. The situations in the two groups were almost reversed in April. Significant day-night differences were scarcely found in pinealocyte size in the middle region in the two groups. Throughout the study, pineal volume and pinealocyte size in each region were generally the same between MF-exposed and sham-exposed rats at daytime or nighttime. The results suggest that pinealocytes in the distal and proximal regions, but not those in the middle region, are affected by MF-exposure; day-night differences in sizes of distal and proximal pinealocytes appear in April and disappear in October under the influence of MF. MF may exert an effect on mechanisms controlling day-night rhythms of pinealocyte size in the rat.     

Biochemical evidence for the involvement of central serotonergic neurotransmission in the action of the antidepressant drug Medifoxamine

Medifoxamine, an antidepressant agent which has an original chemical structure, has been shown through in vitro studies, utilising radioligand binding in tissue homogenates, to bind with moderately high affinity to 5-HT_1c and 5-HT₂ receptor subtypes and to 5-HT uptake sites (IC₅₀ 950, 980, and 1,500 nM, respectively). It has been shown to bind in vivo to rat brain 5-HT₂ receptors after acute treatment with high dose (50 mg/kg, i.e., 133.9 μmol/kg). After 14 days continuous treatment with low dose (20 mg/kg, 53.6 μmol/kg), a decrease in the capacity of [³H]-5-HT uptake and a dose-dependent down-regulation of 5-HT₂ receptors in rat cerebral cortex were observed. These results indicate that medifoxamine, which has been shown previously to act through dopaminergic systems, interacts also with central serotonergic neurotransmission and particularly with the 5-HT₂ receptors, which could contribute to its antidepressant effect.     

Mu rhythm: clinical assessment of the atypical type]

Of 5,218 patients who received EEG examination at our laboratory during a 9-month period in 1989, 241 showed the 7-13 Hz arch-shaped activity originating from over the Rolandic area known as mu rhythm. These subjects were divided into two groups as follows: Group 1, 171 subjects showing typical mu rhythm, i.e., recorded during wakefulness and not affected by visual stimulation but blocked voluntary movements or tactile stimuli; and, Group 2, 70 subjects showing atypical mu rhythm, i.e., accentuated or activated by drowsiness, photic stimuli, or hyperventilation. No difference between the two groups was found with regard to frequency, amplitude or origin of the mu rhythm. Age distribution for Group 1 showed a peak between the ages of 6 and 15 (67.5%), while that for Group 2 peaked between the ages of 11 and 15 (35.7%) considering high incidence in older age range. There was no significant difference between the two groups in regard to gender. Although both groups showed a high incidence of epilepsy, Group 2 showed higher incidence of intractable epilepsy (p less than 0.05), as well as of severe intracranial trauma and of organic brain disease. On EEG recorded among epileptic patients, paroxysmal discharge was more frequent in Group 2 (p less than 0.01), although no other difference between the two groups was observed. Atypical mu rhythm may indicate more severe epilepsy, and careful observation of patients with atypical mu rhythm is recommended.     

A case of aneurysm of the inferior left ventricular wall

Aneurysms of the inferior left ventricular wall represent only a small fraction of all aneurysms that have been reported in surgical series. And in comparison to anterior left ventricular aneurysms, a comparatively higher percentage of reported inferior wall aneurysms was classified as false. A 73-year-old male was admitted for acute inferior myocardial infarction. Three weeks after admission, cardiac catheterization was carried out. Coronary arteriography revealed triple vessel disease and left ventriculography showed an aneurysm of the inferior left ventricular wall, whose feature near the mitral annulus was multiple fenestrations. Left ventricular aneurysmectomy and aortocoronary bypass grafting to the left anterior descending artery were simultaneously performed under cardiopulmonary bypass with moderate hypothermia. The pathological feature was a true aneurysm. The postoperative course was uneventful.     

A simple method for screening assessment of acute toxicity of chemicals

We proposed a simple method for screening assessment of acute oral and dermal toxicity using only three rats and mice of each sex at each dose level. Animals were first treated with chemicals at a dose of 2000 mg/kg and were carefully observed for compound-related morbidity and mortality. If none of the animals died, the following toxicity tests were suspended. If some of the animals died, toxicity tests at doses of 200 and 20 mg/kg were performed. The approximate LD₅₀ values calculated by this method showed little difference between two separate laboratories and were in good agreement with LD₅₀ values reported in the literature. Our toxicological data also showed that LD₅₀ values were about 2–2.5 times the MNLD (maximum non lethal dose) in acute oral and dermal toxicity. This meant that a chemical could be regarded as having an LD₅₀ of about 4000 mg/kg or higher when there was no mortality at the dose of 2000 mg/kg. A chemical with such low toxicity would not require further testing for lethal effects. Therefore, this simple method combining the fixed-dose procedure with the limit test is suitable for determination of approximate LD₅₀ values of chemicals and for screening for necessity for classical full LD₅₀ test using many animals.This work was supported by a grant from Ministry of Health and Welfare in Japan (No. 467 and 511)