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.     

Morphological Analysis of the Early Development of the Chick Neural Tube Separated from the Floor Plate and Notochord

When the neural tube of avian embryos is separated from the notochord and floor plate, motoneurons in the spinal cord fail to develop. In order to investigate the factors involved in this phenomenon, cell proliferation activity and cell death were observed following paramedian incision of the neural tube at the level of the segmental plate using colchicine, BrdU, and TUNEL methods. If the notochord and/or floor plate produces a substance(s) that promotes cell division in the basal plate neuroepithelium or that supports the survival of the motoneuron's neuroblasts, mitotic figures should not be present in the neuroepithelium nor should substantial cell death be observed in the ventral aspect of the notochord- and floor plate-deprived neural tube. Surprisingly, however, neither result was observed in the present experiments, with the exception of a considerable amount of homogeneously distributed cell death. Neuroepithelial cells continued to proliferate and gave rise to neuroblasts. Nevertheless, motoneurons failed to develop, and the neural tube was enveloped by only the basement membrane of the alar plate (S. Hirano and H. Tanaka, 1994,Dev. Growth Differ.36, 481–488). These morphological results revealed that the cause of the development of the anterior horn lacking a neural tube in the notochord- and neural tube-eliminated embryos is not the elimination of the source of the surviving factor(s) of the motoneuron's neuroblasts, but rather the elimination of the signals to induce the motoneurons, derived from the notochord and/or floor plate. The larger amount of cell death in the neural tube on the experimental side suggests that a nonspecific survival factor(s), necessary for the survival of a variety of types of neuroblasts, is also produced by the notochord and/or floor plate.     

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.     

Hard metal asthma: cross immunological and respiratory reactivity between cobalt and nickel?

Eight asthmatic patients with hard metal asthma due to cobalt underwent bronchial provocation challenge with nickel sulphate. Seven patients developed a fall in FEV1 of 20% or more after inhaling nickel sulphate, four showing an immediate response and three a late response. Eight control subjects, including six asthmatic patients, with no history of hard metal exposure, showed no bronchoconstriction in response to a provocation challenge with nickel sulphate. Specific antibodies to nickel conjugated human serum albumin were present in four of the eight patients with sensitivity to cobalt conjugated human serum albumin but were absent from the serum of 60 unexposed asthmatic patients and 25 exposed symptom free workers. These results suggest that nickel as well as cobalt sensitivity plays a part in hard metal asthma.     

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.