Autoradiographic localization and pharmacological characterization of [3H]tandospirone binding sites in the rat brain.

The regional distribution and pharmacological properties of [3H]tandospirone binding sites in the rat brain were investigated using quantitative autoradiography. [3H]Tandospirone binding was notably high in the dentate gyrus and CA1 area of the hippocampus, lateral septum, entorhinal cortex, interpeduncular nucleus and dorsal raphe nucleus. The distribution profiles of [3H]tandospirone binding sites significantly correlated with that of serotonin (5-HT)1A receptors identified using [3H]8-OH-DPAT. In competitive binding studies, [3H]tandospirone binding was inhibited by 5-HT, 8-OH-DPAT, pindolol, buspirone and N-(a,a,a-trifluoro-m-tolyl)-piperazine. The potencies of these ligands correlated with their affinities for 5-HT1A receptors. In addition, there was no significant difference in the dissociation constant of [3H]tandospirone binding between the dentate gyrus, CA1 area, dorsal raphe nucleus, lateral septum and entorhinal cortex (about 10 nM) suggesting that [3H]tandospirone binds to 5-HT1A receptors with same affinities in these brain structures. The distribution pattern of binding sites for [3H]tandospirone was also compared with that of benzodiazepine receptors identified using [3H]fludiazepam to find common effector sites for different types of anxiolytics. Some similarities were observed. It is evident in the hippocampal formation that an overlap of intense binding occurred. 5-HT1A receptors in the hippocampus may participate in the anxiolytic effects of tandospirone.

Inhibition by 8-hydroxy-2-(di-n-propylamino) tetralin and SM-3997, a novel anxiolytic drug, of the hippocampal rhythmical slow activity mediated by 5-hydroxytryptamine1A receptors.

Electrophysiological studies using spectral analysis techniques were undertaken in rabbits to determine whether or not hippocampal rhythmical slow activity (RSA, theta wave activity) was affected by the 5-hydroxy-tryptamine1A (5-HT1A) agonists 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT) and 3a alpha, 4 beta, 7 beta, 7a alpha-hexahydro-2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)-butyl)-4, 7-methano-1H-isoindole-1,3(2H)-dione dihydrogen citrate (SM-3997, a newly synthesized anxiolytic drug). Intravenous administration of 8-OH-DPAT and SM-3997 induced a desynchronized pattern with low-amplitude slow wave activity in the hippocampal EEG and inhibited RSA generation following stimulation of the midbrain reticular formation. RSA was also inhibited by 5-HT1A related anxiolytics such as buspirone, gepirone, and ipsapirone. The effects of 8-OH-DPAT and SM-3997 on the hippocampal RSA were blocked by pindolol, which has 5-HT1A antagonistic activity. Direct microinjection of these 5-HT1A selective agonists into the hippocampus inhibited generation of the hippocampal RSA. These findings indicated that 8-OH-DPAT and SM-3997 inhibited the hippocampal RSA by acting on hippocampal 5-HT1A receptors.

Characterization of the putative anxiolytic SM-3997 recognition sites in rat brain.

In order to clarify the mechanism of action of the putative nonbenzodiazepine anxiolytic SM-3997 [3a alpha,4 beta,7 beta,7a alpha)-Hexahydro-2-(4-(4-(2-pyrimidinyl)-1- piperazinyl)-butyl)-4,7-methano-1H-isoindole-1,3 (2H)-dione dihydrogen citrate), in vitro binding studies with radiolabeled compound were performed. 3H-SM-3997 bound rapidly, reversibly and in a saturable manner with high affinity to rat brain hippocampal membranes (Kd = 9.4 nM, Bmax = 213 fmol/mg protein). This specific binding was displaced by 5-hydroxytryptamine (5-HT) and related compounds. Especially, 8-OH-DPAT, a 5-HT-1A selective agonist, bound with the highest affinity to these binding sites. 3H-SM-3997 binding, however, was not displaced by a variety of other neurotransmitters, neuropeptides and some other drugs. EDTA and physiological concentration of Na+ inhibited this specific binding, but several divalent cations, Mn2+, Ca2+ and Mg2+, enhanced this binding. GTP decreased the affinity of these binding sites for 3H-SM-3997 without changing the number of binding sites, but GMP and ATP did not influence 3H-SM-3997 binding. Furthermore, 3H-SM-3997 bound with marked regional selectivity to hippocampal membranes. These characteristics and the regional distribution of 3H-SM-3997 binding sites were very similar to those of 3H-8-OH-DPAT binding sites (5-HT-1A receptors). Therefore, these results indicate that SM-3997 binds selectively and with high affinity to 5-HT-1A receptors in rat brain and may be an agonist.

Effects of the putative anxiolytic SM-3997 on central monoaminergic systems.

The effects of SM-3997 on central monoaminergic systems were evaluated by ex vivo measurement of monoamines and their metabolite levels in rat brain after intraperitoneal treatment of drugs and by in vitro measurement of monoamine uptake into rat brain slices. The effects of SM-3997 were also compared with those of other new nonbenzodiazepine anxiolytic compounds. SM-3997, buspirone, gepirone and ipsapirone showed no effects on serotonin uptake and dopamine uptake, and a weak inhibition of norepinephrine uptake at the concentration of 100 microM. SM-3997 decreased the serotonin metabolite (5-hydroxyindole-3-acetic acid) level without changing the serotonin level in hippocampus and increased dopamine metabolite (3,4-dihydroxyphenylacetic acid, homovanillic acid) level with no effect on the dopamine level in striatum. SM-3997 also produced an increase in the norepinephrine metabolite (3-methoxy-4-hydroxyphenylglycol) level with a decrease in the norepinephrine levels in hippocampus. Similar effects on serotonin metabolites and norepinephrine metabolites were observed in several other regions. Although the serotonergic effect of SM-3997 was similar to that of buspirone, gepirone and ipsapirone, the dopaminergic effect of SM-3997 was much weaker than that of buspirone.

Magnetic resonance imaging of lumbar disc herniation. Comparison with myelography.

Fifty-three patients with surgically confirmed lumbar disc herniation at 55 levels were studied retrospectively to compare the diagnostic accuracy of high-field strength surface coil magnetic resonance imaging (MRI) with that of myelography. Disc herniation was classified into three groups according to MRI findings, namely, unilateral single-disc herniation, central single-disc herniation, and multilevel disc herniation. Magnetic resonance imaging diagnosis of unilateral single-disc herniation was extremely reliable, so myelography was considered to be unnecessary. Conversely, MRI findings of central single-disc herniation and multilevel disc herniation were less definite, in that myelography was necessary in locating the disc causing symptoms.

[Peripheral lymphocyte subset of patients with pancreatic diabetes mellitus--about a decreased ratio of T-LGL and ability of host defense].

Patients with diabetes mellitus (DM) often suffer from various and severe infection. Patients with pancreatic DM have malnutrition due to chronic pancreatitis. Therefore it is believed that patients with pancreatic DM have a lower ability of host defence to infectious diseases than normal subjects. We examined the primpheral lymphocyte subsets (T cell, B cell, NK cell, CD3+ 56+ T) of eighteen patients (males, age = 52.8 +/- 12.7 years old, mean +/- SD) with pancreatic DM by two color flow-cytometry to evaluate the lymphocyte function. Ratios of T cell (T%, 66.9 +/- 9.3%, mean +/- SD). B cell (B%, 13.1 +/- 5.8%) and NK cell (Nk%, 19.3 +/- 8.7%) to total peripheral lymphocytes of patients with pancreatic DM were not significantly different from those (T% = 66.4 +/- 7.8%, B% = 13.5 +/- 6.7%, NK% = 19.9 +/- 9.1%) of thirteen normal subjects (males, age = 51.2 +/- 13.1). CD3+56+ T cell % (4.1 +/- 1.9%) of patients with pancreatic DM was lower than that (6.0 +/- 3.0%) of normal subjects (p < 0.05). CD3+56+ T cells have cytotoxic activity and it is likely that this activity is similar to that of NK cells. These results suggested that a decrease in peripheral CD3+56+ T cell % is a factor showing a weak host defense mechanism to infectious diseases in patients with pancreatic DM.

[Superoxide anion (O2-) production by polymorphonuclear leukocytes in insulin dependent diabetes mellitus (IDDM)].

The superoxide anion (O2-) production in polymorphonuclear leukocytes stimulated by phorbol myristate acetate in IDDM and non-insulin dependent diabetes mellitus (NIDDM) was determined by the method of Johnston et al, compared with that of each age matched controls. And the correlation between O2- production and hemoglobin (Hb) A1 and A1c value was investigated. The O2- production in IDDM was 24.4 +/- 7.4 (mean +/- SD, n mol per 4 X 10(5) cells) at 10 min. and 51.4 +/- 8.7 at 30 min., in NIDDM each 31.6 +/- 9.3, 60.2 +/- 14.4, and in controls each 40.5 +/- 4.2, 72.4 +/- 3.1. O2- production in IDDM was significantly lower than that in NIDDM (p less than 0.001 at 10 min. and p less than 0.01 30 min.) and controls (p less than 0.001 at 10 and 30 min.). O2- production at 10 and 30 min. possessed a negative correlation with Hba1 and A1c value (HbA1: p less than 0.01 at 10 min. p less than 0.05 at 30 min., HbA1c: p less than 0.01 at 10 and 30 min.). These findings suggest that impaired O2- production might be one of the factors accounting for depressed bactericidal activity of polymorphonuclear leukocytes in IDDM, and that a protracted hyperglycemia might shed some effect on O2- production.

[In vivo antibacterial activity of cefbuperazone. Synergy of cefbuperazone for bactericidal effect with human polymorphonuclear leukocytes].

Studies were done utilizing E. coli No. 59 which are resistant against human and mouse serum, and the following results were obtained. The therapeutic effect of cefbuperazone (CPBZ) against systemic infections of mice was much higher than that of cefmetazole (CMZ), cefotetan (CTT), latamoxef (LMOX) and cefoperazone (CPZ). Synergistic bactericidal effect with human polymorphonuclear leukocytes was more marked for CBPZ than CMZ.

[Therapeutic effects of SM-4300 and antibiotics combination against severe bacterial infections].

A newly developed human immunoglobulin preparation for intravenous administration (SM-4300) was applied to the severe bacterial infections in the field of internal medicine. Nine cases of severe infections were treated with SM-4300 and antibiotics combination. Clinical effects of SM-4300 were excellent in 1 case, good in 5, poor in 1 and unknown in 2. The efficacy rate was summarized as 86%, and no side effects were observed.

[Free methyltetrazolethiol concentrations in men subjected to intravenous administration of cephems with methyltetrazolethiol].

The disulfiram-like reaction due to cephems with methyltetrazolethiol (tetrazole) moiety was studied in biotransformation of these drugs. The serum tetrazole concentration was determined following intravenous administration of cefoperazone (CPZ) 1 g, latamoxef (LMOX) 1 g, or cefmetazole (CMZ) 2 g to patients suffering infections without liver dysfunction, and of CPZ 1 g to patients with liver cirrhosis. Tetrazole concentrations in normal patients were 0.5-2.0 micrograms/ml after 3 hours, and 0.14-0.26 micrograms/ml after 12 hours, and undetectable after 24 hours. On the other hand, the tetrazole concentration in cirrhotic patients was 0.143 +/- 0.07 micrograms/ml (mean +/- SD) even after 24 hours. Therefore, it is concluded that the disulfiram-like reaction due to cephems with tetrazole moiety closely related to the metabolism of these drugs in liver, and probably be caused by the inhibition of acetaldehyde dehydrogenase activity in liver by the free tetrazole group produced by the metabolism of these drugs in liver.

[Laboratory and clinical studies on cefsulodin (author's transl)].

Laboratory and clinical studies on cefsulodin (CFS), a new antipseudomonal cephalosporin antibiotic, were carried out and the following results were obtained. 1. The MIC of CFS against P. aeruginosa showed the peak of susceptibility at 3.13 mcg/ml in the inoculum size of 10(8) cells/ml and at 1.56 mcg/ml in the inoculum size of 10(8) cells/ml. It has a higher superiority as compared with gentamicin or piperacillin and gentamicin-resistant strains of P. aeruginosa were sensitive to CFS. 2. CFS was given to 3 patients with acute pneumonia and 5 patients with chronic cystitis which were all due to P. aeruginosa. Clinical effects were good in 2 patients and poor in a patient with acute pneumonia, and those were good in 3 patients and poor in 2 patients with chronic cystitis. Side effects were not recognized at all.

[Disulfiram-like reactions resulting from the administration of cephem antibiotics with methyltetrazolethiol moiety examined by using different doses].

The disulfiram-like reactions following the treatment of cephem antibiotics with methyltetrazolethiol moiety (latamoxef (LMOX) and cefoperazone (CPZ) was studied by using large (500 mg/kg) and small (50 mg/kg) doses of the drugs. Normal and fatty liver rats were injected intraperitoneally with the cephem antibiotics. After overnight fasting blood samples were obtained following an administration of 20% ethanol (2g/kg). Blood ethanol and acetaldehyde concentrations, and liver acetaldehyde dehydrogenase activity were determined. Blood ethanol concentration upon the small dose was similar to that obtained upon the large dose in both groups of normal and fatty liver rats. Blood acetaldehyde concentration upon the large dose was higher than that upon the small dose; 2-fold increase in normal rats and 2.6-4.7-fold increase in fatty liver rats were observed after administering LMOX, while 3.7-fold increase in normal rats and 5-5.7-fold increase in fatty liver rats upon administering CPZ. Additionally, liver acetaldehyde dehydrogenase activity (Enzyme 1) observed upon the large dose was lower than that observed upon the small dose; the degree of reduction was 33% in normal and 19% in fatty liver rats upon the administration of LMOX, while 37% in normal and 45% in fatty liver rats upon the administration of CPZ.

[A case of extra-intracranial bypass venous graft for giant internal carotid aneurysm (author's transl)].

A male patient, aged 42, (No. 780624) was admitted to the Department of Neurosurgery of Hirosaki University Hospital, complaining recent weight loss, intolerance to cold and visual disturbance of the right eye. Ophthalmological examination revealed the optic atrophy with decreased visual acuity and concentric visual defect of the right eye. Endocrinological examination showed almost general suppression of adenohypophyseal function except abnormal high level resetting of cortisol diurnal rhythm. Radiological examination revealed the accessory middle cerebral artery and giant internal carotid aneurysm of the right side which was displayed by contrast-enhanced CT scan, with the enlarged sella turcica. Good cross filling was seen in left CAG through the anterior communicating artery. Extra-intracranial end to end anastomosis of the right internal carotid artery was performed with long venous graft under general anesthesia with hypothermia and induced hypotension, on Oct. 26 '78. Unroofing of the right optic canal was very useful to preserve the optic nerve, and the body of the giant aneurysm was opened and sutured tightly to reduce its mass effect. Interlacing suture for the anastomosis of the cervical internal carotid artery was employed successfully. The blood flow of the bypass graft, measured as enough volume with square wave flowmeter during the operation, was also confirmed with postoperative angiography. After the episodes of gastrointestinal bleeding, hypotensive attack and hemorrhagic infarction of right frontal base, the postoperative final result was successful and the patient is doing well, 6 months after the operation.

[A case of adenocarcinoma of lung cancer with multiple brain metastasis and lymphangitis carcinomatosa responding well to chemotherapy with carboplatin, etoposide and ifosfamide].

A 75-year-old male who suffered from adenocarcinoma of lung cancer with multiple brain metastases, developed left hemiplegia. After diagnosis, he was treated with 4,000 cGy whole brain radiation, but soon after advanced lymphangitis carcinomatosa set in and his general condition deteriorated. He was administered carboplatin combination with etoposide and ifosfamide. Lymphangitis carcinomatosa disappeared, and the main tumor of lung and brain metastases were not growing. We recommended carboplatin for an old patient or one in poor condition, because it had less cytotoxicity and retained the same antitumor activity compared with cisplatin.