Biomedical subjects
Publications and source records attributed to H Fujimura.
An oxazole compound, tioxaprofen, exerted a strong anti-mycotic activity against Trichophyton mentagrophytes and T. rubrum, which were major dermatophytes from patients. It was found that tioxaprofen was a potent uncoupling agent of mitochondrial respiration.
Opioid receptor bindings of four different ligands, dihydromorphine (DHM), D-Ala2-D-Leu5-enkephalin (DADLE), ethylketocyclazocine (EKC) and phencyclidine (PCP), were investigated with the treatment of 5,5'-dithiobis-(2-nitrobenzoic acid), DTNB, and 5,5'-dithiobis-(2-nitro-N-2'-hydroxyethylbenzamide), DTNHEB; a relative positive charged analog of DTNB. DTNB and DTNHEB effectively inhibited the binding of DHM and DADLE. Despite the presence of maximally effective concentrations of DTNB for DHM and DADLE, the receptor binding of EKC decreased intermediately, like effect of a partial agonist. DTNHEB inactivated the binding of EKC in a similar fashion to that of DHM. DTNB did not alter the intensity of the decrease of EKC binding by DTNHEB, even given concurrently. It suggests that an anionic center of the receptor has multiple active sulfhydryl sites. The ability of GTP to inhibit DADLE binding to the receptor disappeared by the pre-treatment of DTNB, and DTNB-induced inactivation of opioid agonist binding was potentiated in the presence of NaCl. DTNB-sensitive site may couple a mechanism of ligand binding that GTP regulated. The receptor binding of PCP was not influenced by DTNB and/or DTNHEB.
A series of novel diphenylethylpiperazines were synthesized, and analgesic activities and opioid receptor interactions were evaluated. Analgesic activity of S(+) enantiomer of 1-cyclohexyl analogues (I-C6) was as potent as morphine. This compound showed narcotic properties. Racemate of I-C6 demonstrated the most potent analgesic activities among the enantiomorphic pairs. The R(-) isomer and (-) spa, NN-dimethyl-1, 2-diphenylethylamine, had mu-agonist like character. The S(+) isomer possessed high affinity for all types of the receptor, especially favorable for delta and kappa, in the different manner from opiate-like analgesics. It is conceivable that opioid receptor has various subsites, and this S(+) enantiomer alter the conformation of the receptor.
Platelet aggregation response to various stimulants was examined in 18 unmedicated schizophrenic patients, 13 medicated patients, and 13 control subjects. Platelet aggregation response to epinephrine decreased only in unmedicated schizophrenic patients. Clinical improvement in seven patients after neuroleptic medication was significantly correlated with an increase in platelet aggregation response to arachidonic acid, and nonsignificantly to epinephrine, dopamine, and serotonin. The inhibitory effect of prostaglandin E1 on platelet aggregation response to adenosine diphosphate was investigated in seven unmedicated schizophrenic patients, six medicated patients, and eight controls. The inhibitory effect of prostaglandin E1 on platelet aggregation response to adenosine diphosphate was significantly reduced in all unmedicated schizophrenic patients. Neuroleptic medication had some effect in normalizing aberrant sensitivity to prostaglandin E1 in those patients, although acute medication induced an adverse reaction in the controls.
The present study was carried out to elucidate the effect of clove and its active principles in view of cholagogue. The cholagogue effect was observed in acetone extract of clove and eugenol. Acetyl-eugenol also possessed cholagogue property.
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This study was performed to develop a topical ointment of diclofenac-Na which has a potent anti-inflammatory activity by oral administration. At first, research was carried out on the ointment base which influences the external anti-inflammatory effect of the drug. Ointments of diclofenac-Na were prepared with three kinds of bases: lipophilic, emulsion (cream) and gel bases; and their anti-inflammatory effects were compared. The cream was found to have the most potent effect. Therefore, in the next experiment, an optimum concentration of diclofenac-Na in cream was determined comparing the anti-inflammatory effect among the cream preparations containing 0.5, 0.75, 1.0 and 1.5% of the drug. Obvious effects were observed with the cream containing 1.0% and 1.5% of the drug concentration, and there was no significant difference in the anti-inflammatory activities of these two concentrations. Based on these results, the cream preparation containing 1.0% of diclofenac-Na (DF cream) was adopted as the external ointment of the drug. The anti-inflammatory effect of this cream was compared with that of existing anti-inflammatory ointments, i.e., indomethacin gel (IM gel), bufexamac cream (BM cream) and mobilat ointment (ML ointment). DF cream produced obvious inhibition on increased vascular permeability and on acute edema and remarkable suppression of ultraviolet erythema. These activities of DF cream were similar to those of IM gel and more potent than those of BM cream and ML ointment. The inhibitory effect of DF cream on the proliferation of granulation tissue was almost equal to that of ML ointment and more distinguishable than that of IM gel and BM cream. In adjuvant arthritis, DF cream reduced the swelling remarkably in the treated paw and slightly in the untreated paw. The anti-adjuvant activity of DF cream was equal to that of IM gel and more potent than that of BM cream and ML ointment. In pain to pressure stimulation, an analgesic effect was observed in the early stage of DF cream application, and its activity was slightly stronger than that of the other ointments. These results show that DF cream has an obvious anti-inflammatory effect as an external preparation, and the activity is comparable or superior to that of similar existing anti-inflammatory ointments. This cream may be considered as useful in the clinical field as a topical anti-inflammatory preparation.
Prostaglandins (PGs) increase the intestinal fluid to result in diarrhea. Some laxatives are known to exert their actions partially by stimulating the PGs biosynthesis. On the other hand, it is well documented that nonsteroidal anti-inflammatory drugs (NSAID) inhibit markedly the PGs biosynthesis. Since endotoxin (ETX) also produces diarrhea similarly in all species of experimental animals, we investigated the effect of various NSAID and steroidal anti-inflammatory drugs (SAID) on ETX-induced diarrhea in mice. ETX given p.o. did not produce diarrhea, but it could induce it after parenteral administration, especially intravenous injection. ALL NSAID and SAID tested inhibited ETX-induced diarrhea at dose levels similar to or lower than those commonly producing an acute anti-inflammatory effect. The anti-diarrheal effects were found in not only acidic NSAID, but also in basic NSAID and SAID which did not inhibited ultraviolet erythema, acute death induced by arachidonic acid injection and PGs biosynthesis. Therefore, this test using ETX-induced diarrhea in mice may be used as a new and desirable method for screening or evaluating anti-inflammatory drugs. The mechanism of diarrheogenic action of ETX is poorly understood, but may be attributed to inhibition of PGs biosynthesis besides other unknown actions.
In conscious rabbits, the intravenous administration of pindolol (1.25 mg/kg), propranolol (1 mg/kg) and alprenolol (2 mg/kg) induced a highly significant decrease of mean arterial blood pressure and significant bradycardia. In the same model, the intravenous administration of saline, indomethacin, and clidanac did not affect the mean arterial blood pressure and heart rate. Pretreatment with indomethacin and clidanac reduced the effect of these beta-blockers on the mean arterial blood pressure and had no effect on the heart rate. Treating of the guinea pig heart homogenate with 1 microM indomethacin or clidanac decreased the number of beta-adrenoceptors without changing their affinity. These results suggest that indomethacin and clidanac interfere with beta-adrenoceptor-mediated effects.
The Opioid receptor affinities of butorphanol (BT) and its main metabolites, norbutorphanol (NB) and hydroxybutorphanol (HB), were determined by an in vitro receptor binding assay using crude synaptosomal membrane preparations of rat brain. BT showed high affinities to all types of the receptor except the alpha type (phencyclidine binding site), resulting in displacements of the bindings of mu (dihydromorphine)-, delta (D-Ala2-D-Leu5-enkephalin)- and kappa (ethylketocyclazocine)-ligands with more potency than morphine and ketocyclazocine, and it preferentially bound to mu- and kappa-opioid receptors. NB bound to the mu-binding site with affinity higher than that of pentazocine and to the kappa-binding site with the lowest affinity. HB exclusively bound to the mu-binding site with lower affinity. The affinities of BT, NB, HB and morphine to the alpha-site were smaller than those of pentazocine and ketocyclazocine. In the presence of 100 mM NaCl or by treating with 500 microM 5,5'-dithiobis (2-nitrobenzoic acid), the binding capacity of the membrane preparation was altered, and BT behaved as a typical antagonist. NB showed an agonistic property, and HB behaved as an antagonist. BT appears to be a mu-opioid receptor antagonist and has a kappa-receptor agonist-like character.
A study was attempted to establish a screening method for detecting cholelitholytic ingredients from a wide variety of natural substances. Although mice were selected as a suitable pathological model of cholelithiasis to detect a small amount of the ingredients, all the conventional lithogenic diets caused unfavorable influence on the animals. Therefore, as the first step we formulated a new lithogenic diet consisting of butter, cholesterol, cholic acid, etc, which was adequate for mice. Subsequently, the pathological characteristics and persistence of cholelithiasis were examined in the animals; the changes in bile compositions including free and conjugated bile acids, cholesterol and phospholipids were observed before and at the onset of cholelithiasis. Following confirmation of the stone formation, a normal diet was substituted for the lithogenic diet to likewise assess the bile compositions 4 and 6 weeks later. An increasing tendency for deoxycholic acid, disappearance of chenodeoxycholic acid and decrease in ursodeoxycholic acid were seen under the condition of cholelithiasis. In addition, the cholic acid-glycine conjugate which should not exist in the normal state and the increase in free and tauring-conjugated cholic acid were noticed. The biliary cholesterol level in treated mice increased to about 4 times higher than that in untreated mice, while the biliary phospholipids and total bile acids levels increased to only about 1.5 and about 2 times the control levels, respectively. The incidence of stone formation rose sharply at an experimental period between 2 and 3 weeks after starting the lithogenic diet. Gallstones die not disappear even at the 6th week after substituting a normal diet for the lithogenic one. However, the cholic acid-glycine conjugate disappeared, and deoxycholic acid as well as chenodeoxycholic acid and ursodeoxycholic acid tended to recover to the normal levels in the bile.
After the intravenous injection of butorphanol or norbutorphanol in rats every 1 hr for 3 days, naloxone-induced body weight loss and withdrawal syndrome were observed to some degree. A slow-released emulsion containing each of the test drugs was injected subcutaneously in guinea-pigs, and naloxone was administered after 2 or 3 days. BT caused little jumping response even at a dose of 600 mg/kg, and the reaction was significantly weaker than that of pentazocine. No jumping responses were recognized in the cases of NB (600 mg/kg). In morphinized rats, the injection of BT or HB caused potent body weight loss, and these rats exhibited withdrawal syndrome which was more potent than that by pentazocine at the same dose. The body weight losses by the injection of NB and pentazocine were to the same degree, and these changes were significantly different from that of the saline control. BT inhibited the adenylate cyclase activity of the rat caudate nuclei, and the effect was weaker than that of pentazocine. NB showed a slight inhibition, and HB had no effect on the activity. These results suggest that the physical dependence liability of butorphanol is less than that of pentazocine, and the potent mu-antagonistic character of butorphanol is based on the liability. NB, a mu-agonist, makes dependence production possible. The ability of HB is negligible.
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This paper describes a unique case of combined malignant lymphoma of the jejunum and multiple synchronous carcinomas of colon and rectum. The jejunal tumor developed obstructive growth without regional lymph node involvement. Histologically, it was a malignant lymphoma corresponding to medium-sized cell type of follicular lymphoma, suggesting B cell origin in the bowel wall. In the colon and rectum, except for the transverse segment, there were three encircling, annular infiltrative tumors, and six polyps with malignant change. They developed independently, separated by an intact mucosa suggesting multiple synchronous cancers. Histologically they showed adenocarcinoma with or without mucus production, adenosquamous cell carcinoma, and villotubular adenocarcinoma. A case report is presented with a brief review of the incidence and pathogenesis of both jejunal and colonic tumors.
Platelet aggregation response to epinephrine, dopamine, serotonin, adenosine diphosphate, arachidonic acid, and collagen was examined in seven patients with Huntington's disease and nine of their relatives. All patients, except for two cases that were in terminal states, showed enhanced response to all the stimulants, especially to dopamine and epinephrine. The platelet aggregation response in many relatives also deviated from the normal limit. The relationship between platelet aggregation abnormality in Huntington's disease and the pathophysiology of the disease was discussed from the view of a generalized membrane defect hypothesis in Huntington's disease, and of disturbed cathecholamine metabolism, both in the CNS and periphery. A possibility that platelet aggregation response examination will be a useful screening test of offspring at risk was proposed.
Anti-inflammatory properties of paeoniflorin and its derivatives were examined in experimental animals. Paeoniflorin, desbenzoylpaeoniflorin and new monoterpene glucoside 'paeonon' inhibited experimental contact hypersensitivities and passive cutaneous anaphylaxis reaction. Paeonon inhibited tissue swelling in the adjuvant arthritis, while paeoniflorin and its related compounds were ineffective in inhibiting non-allergic inflammatory response.
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