Biomedical subjects
J Shimada
Publications and source records attributed to J Shimada.
Photoisomerization of a potent and selective adenosine A2 antagonist, (E)-1,3-Dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthine.
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Adenosine A1 antagonists. 3. Structure-activity relationships on amelioration against scopolamine- or N6-((R)-phenylisopropyl)adenosine-induced cognitive disturbance.
The effects of a variety of adenosine A1 and A2 antagonists on N6-((R)-phenylisopropyl)adenosine (R-PIA)- and scopolamine-induced amnesias were investigated in rodents in order to clarify the role of adenosine receptors in learning and memory. Some of the selective adenosine A1 antagonists exhibited antiamnesic activities at several doses where they did not induce an increase of spontaneous locomotion. These results suggest that the blockade of A1 receptors is more important than that of A2 receptors in learning and memory. Detailed studies of structure-activity relationships of adenosine A1 antagonists in two amnesia models demonstrated that there were three types of adenosine A1 antagonists: (A) Compounds 3-5 (8-substituted 1,3-dipropylxanthines) ameliorated the shortened latency in both models. (B) Compounds 7-11 (8-substituted 1,3-dialkylxanthines) and 19-21 (imidazo[2,1-i]purin-5(4H)-one derivatives) ameliorated the shortened latency in the (R)-PIA-induced amnesia model but not in the scopolamine-induced amnesia model. (C) Compounds 14-16 ameliorated the shortened latency in the scopolamine model but not in the (R)-PIA model. Aminophenethyl-substituted compounds C did not exhibit adenosine A1 antagonism in vivo presumably due to rapid metabolism. The dramatic change in the activities of A and B could not be explained by their simple pharmacokinetic differences because both types of compounds showed clear blockade of central adenosine A1 receptors in the (R)-PIA model. 8-(3-Dicyclopropylmethyl)-1,3-dipropylxanthine (5) (KF15372) was chosen for further studies and is currently under preclinical development as a cognition enhancer.
[Management of patients with urinary catheter and prevention of cross infections].
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Effects of protein binding on the isomerization of ceftibuten.
Isomerization of ceftibuten to trans-ceftibuten, a less active isomer of ceftibuten, was observed in human serum in vitro. Investigation of the isomerization mechanism in the serum clarified that albumin accelerated the isomerization. The isomerization rate constant correlated significantly with the percent of binding to albumin, suggesting the binding of ceftibuten to albumin might be the driving force for the isomerization under in vitro conditions. This isomerization was also observed in clinical studies in humans. Results of physiological model analysis indicate that the isomerization catalyzed by albumin contributes significantly to the overall isomerization in the human body following oral administration.
Carnitine status and safety after administration of S-1108, a new oral cephem, to patients.
The metabolism and clinical safety of the pivalic acid-containing antibiotic S-1108, an orally active pro-drug cephalosporin, were investigated to assess the clinical effects, with special emphasis on the influence of carnitine consumption in 15 patients with various infectious diseases receiving S-1108 three times a day at a 300- or 600-mg total daily dose for 3 to 7 days. The free carnitine concentrations in plasma were greatly reduced to approximately 65% of pretreatment levels, and the plasma pivaloylcarnitine (the main metabolite of pivaloyloxymethyl ester) concentrations were increased during the 200-mg (three times a day) regimens but returned to the pretreatment levels within 3 to 5 days after the cessation of treatment. In three elderly patients with declining renal function (creatinine clearance rate, 31 to 50 ml/min), the acylcarnitine/free carnitine ratio increased from 0.1 to 0.4 up to 0.7 to 1.5 at day 5 during the 7-day treatment, showed a tendency to decrease, and then returned to the pretreatment ratio 4 days after discontinuation of the drug. The degree of free carnitine reduction and increase of the acylcarnitine/free carnitine ratio depended mostly on the dose and the duration of S-1108 treatment. The increased acylcarnitine/free carnitine ratio in elderly patients was due to reduction of the free carnitine concentration in plasma and mainly to the retardation of nontoxic pivaloylcarnitine excretion. This study indicated that there was a decrease in free carnitine levels in plasma, but there were no clinical symptoms or adverse effects associated with carnitine reduction in patients during the 7-day multiple administration of S-1108.
Clinical pharmacokinetics of sparfloxacin.
Sparfloxacin is a recently developed fluoroquinolone. The drug has shown potent antimicrobial activity against a wide range of Gram-positive and Gram-negative bacteria, glucose non-fermenters, anaerobes, Legionella spp., Mycoplasma spp., Chlamydia spp. and Mycobacterium spp. Methicillin-resistant Staphylococcus aureus is also susceptible to sparfloxacin. Plasma sparfloxacin concentrations reach a peak (Cmax) of approximately 0.7 mg/L at 3 to 5 hours after a 200mg oral dose. This is followed by a monophasic slow decrease, with an elimination half-life (t1/2) of 15 to 20 hours. The Cmax and area under the plasma concentration-time curve show dose-related increases. Food intake does not affect the absorption and pharmacokinetics of sparfloxacin. Sparfloxacin binds weakly to plasma protein (37%), and exhibits excellent tissue distribution and effective penetration into extracellular fluids. Concentrations of the drug in most tissues are similar to, or higher than, concomitant plasma concentrations. Sparfloxacin distributes slightly into cerebrospinal fluid. The drug is metabolised to a glucuronide. The urinary excretion of the unchanged drug accounts for 10 to 14% of the given dose. The ratio of Cmax values after multiple and single oral doses is 1.3 to 1.4, but other pharmacokinetic parameters of sparfloxacin are not influenced by multiple doses. Even in patients with severe renal failure, no significant prolongation of the half-life is observed after oral administration. Sparfloxacin appears unlikely to affect the pharmacokinetics of theophylline. Antacids containing aluminium hydroxide reduce the oral bioavailability of sparfloxacin by 25 to 35%. Probenecid does not affect sparfloxacin pharmacokinetics. The pharmacokinetic properties of sparfloxacin allow once-daily administration in the treatment of various infections.
Effect of cephalosporins on gamma-aminobutyric acid receptor binding with or without non-steroidal anti-inflammatory drugs.
Cephalosporins have been well known to have potent convulsant activity. We studied the mechanism of the convulsions induced by cephalosporins. Cefazolin, cephaloridine, cefpirome and cefmetazole inhibited the receptor binding of gamma-aminobutyric acid (GABA), an inhibitory transmitter in the mammalian central nervous system. As fluoroquinolones also inhibited GABA receptor binding and this inhibition was enhanced in the presence of non-steroidal anti-inflammatory drugs (NSAIDs), we studied the effect of cephalosporins on GABA receptor binding in the presence of NSAIDs. The inhibitory activity of cephalosporins was not enhanced in the presence of NSAIDs. These results suggested that cephalosporins might induce convulsions through the inhibition of GABA receptor binding, and that concurrent administration of cephalosporins and NSAIDs might not enhance the convulsant activity of cephalosporins.
[Antisense DNA].
Antisense DNA has been given a big attention as future therapeutic reagents. However, there are several shortcomings including biological instability and low membrane permeability. In order to overcome these shortcomings, the first generation of oligonucleotides has been synthesized. The efficacy of these analogues in vitro or in vivo seems to be promising. In this reviewing article, we mainly describe the intracellular delivery of oligonucleotides from the pharmaceutical point of view.
Clinical staging and gadolinium-DTPA enhanced images of the wrist in rheumatoid arthritis.
The usefulness of gadolinium (Gd)-DTPA enhanced magnetic resonance imaging (MRI) of the wrist joint for predicting articular destruction was investigated in 49 patients with rheumatoid arthritis (RA). On T1 weighted images with Gd-DTPA enhancement, the synovium showed a localized or diffuse pattern of enhancement. Many patients classed as stage II or higher by plain radiography had diffuse enhancement on MRI, while all except one stage I patient had relatively confined localized enhancement. Our study showed that MRI of the carpus could detect soft tissue changes in patients with RA earlier than anything revealed by radiography, and suggested that contrast MRI may be useful for predicting articular destruction.
[Tissue and serum levels of 5-FU in the patients with head and neck malignant tumors--influence of a streptococcal preparation OK-432].
Concentrations of Tegafur, 5-FU, and Uracil were measured in the tissues and serum of 32 patients with malignant head and neck tumors after administration of UFT or UFT and OK-432. Of the 32 patients, 15 patients were treated with UFT alone and 17 patients with a combination of UFT and a clinical dose of OK-432. The level of 5-FU was higher in the tissues and serum in the patients who received the combined administration of UFT and OK-432 than in those the received UFT alone. In particular, levels of 5-FU in tumor tissue and metastatic lymph node tissue were higher than 0.05 micrograms/g even 14.6 hours after the last administration of UFT. No significant undesirable interactions between UFT and OK-432 were exhibited during combination therapy of these agents in clinically administered doses. From our satisfactory results, clinical cures would be expected by the combined immuno-chemotherapeutic action of these agents.
[Antimicrobial activity of clarithromycin and its effect on bacterial adherence to medical material].
Antimicrobial activity of clarithromycin (CAM) in comparison with other 6 macrolides was determined against 419 recent clinical isolates including Streptococci, Enterococci, Staphylococci, Moraxella, Haemophilus and Bacteroides strains. MICs80's of CAM against Streptococcus pneumoniae, Streptococcus pyogenes and Streptococcus agalactiae were 0.78, 0.10 and 0.10 microgram/ml, respectively. MICs80's against Moraxella catarrhalis and Haemophilus influenzae were 0.05 and 1.56 micrograms/ml, respectively. Laboratory-induced resistance to CAM in strains of S. pneumoniae, Enterococcus faecalis or methicillin-sensitive Staphylococcus epidermidis occurred in stepwise fashion and at a very low rate. Adherence to silicon filter of strains of Pseudomonas aeruginosa or S. epidermidis was strongly repressed by the addition of sub-MIC of CAM or other macrolides. Although tosufloxacin (TFLX) alone had no bactericidal activity against the sessile cells of P. aeruginosa strains tested, TFLX showed synergistic bactericidal activity when combined with sub-MICs of CAM or erythromycin.
7,8-Dihydro-8-ethyl-2-(3-noradamantyl)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one: a potent and water-soluble adenosine A1 antagonist.
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Adenosine A1 antagonists. 2. Structure-activity relationships on diuretic activities and protective effects against acute renal failure.
Diuretic activities of xanthine or nonxanthine adenosine antagonists and their ameliorative effects against glycerol-induced acute renal failure in rats were investigated in order to clarify the physiological and pathological function of adenosine receptors in the kidney. Diuretic and natriuretic activities of a variety of adenosine antagonists clarified systematically for the first time that the blockade of A1 receptors is more important than that of A2 receptors in sodium and water excretion and support the hypothesis that endogenous intrarenal levels of adenosine directly enhance tubular sodium readsorption. Studies of structure-activity relationships of 8-substituted xanthines in the acute renal failure demonstrated that the activation of adenosine A1 receptor was an important factor in developing such a renal failure. A series of 8-(3-noradamantyl)xanthines exhibited the extremely potent diuretic and natriuretic activities (24; 2.5 micrograms/kg, po, the ratio of urinary excretion value in treated rats to urinary excretion value in control rats = 1.69, the ratio of Na+/K+ in treated rats to Na+/K+ in control rats = 1.76) and potent ameliorative effects against glycerol-induced acute renal failure (24; 10 micrograms/kg, ip, 55% inhibition). From our detailed studies of structure-activity relationships, we can speculate that some tissue differences of the adenosine A1 receptor might exist between kidney and brain and sites of action for adenosine antagonists could be different between two renal pharmacological assays. 1,3-Dipropyl-8-(3-noradamantyl)xanthine, KW-3902 (24), was chosen for further studies and is under development as a drug for treating the acute renal failure.
(E)-1,3-dialkyl-7-methyl-8-(3,4,5-trimethoxystyryl)xanthines: potent and selective adenosine A2 antagonists.
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[Angiographic features of alveolar soft-part sarcoma].
The angiographic findings were analyzed in five patients with alveolar soft-part sarcoma. The angiographic appearance of the tumors was the same in all five cases: hypervascularity of the tumor including encasement, dilatation, tortuosity and displacement of feeding arteries, remarkable tumor stain and early venous filling. These angiographic findings are considered to be characteristic of alveolar soft-part sarcoma in the differential diagnosis of hypervascular soft tissue mass.
8-Polycycloalkyl-1,3-dipropylxanthines as potent and selective antagonists for A1-adenosine receptors.
With the aim of characterizing the hydrophobic interactions between xanthines and the A1 receptor site, 1,3-dipropyl-8-substituted xanthines were synthesized. Introduction of a quaternary carbon and the conformationally restricted cyclopentyl moiety into the 8-position of xanthines enhanced the adenosine A1 antagonism. 1,3-Dipropyl-8-(3-noradamantyl)xanthine was identified to be a selective and the most potent A1 receptor antagonist reported to date. Under our structure-activity relationship, the 8-substituent of xanthine antagonists and the N6-substituent of adenosine agonists appears to bind to the same region of the A1 receptor.
Effects of antacids, ferrous sulfate, and ranitidine on absorption of DR-3355 in humans.
This study examined the effects of widely used antacids (aluminum hydroxide, magnesium oxide, and calcium carbonate), ferrous sulfate, and ranitidine on the absorption of a fluorinated quinolone, (-)-(S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro- 7H- pyrido-[1,2,3,-de][1,4]benzoxazine-6-carboxylic acid hemihydrate (DR-3355), in healthy male volunteers enrolled in three separate randomized crossover studies. Study 1 used 100-mg doses of DR-3355 and concurrent doses of aluminum hydroxide (1 g) or magnesium oxide (500 mg), while study 2 used DR-3355 (100 mg) and concurrent ferrous sulfate (160 mg) or calcium carbonate (1 g). Study 3 used DR-3355 (100 mg) and concurrent ranitidine (150 mg). Each study included control doses of DR-3355 (100 mg) alone. When aluminum hydroxide, ferrous sulfate, and magnesium oxide were coadministered with DR-3355, the relative bioavailability of DR-3355 was decreased to 56, 81, and 78%, respectively, of that for DR-3355 (100 mg) alone. Urinary excretion of DR-3355 was also significantly decreased by coadministration of these drugs. Thus, the magnitude of the decrease in the area under the concentration-time curve for DR-3355 varied among antacids, and the ranking of their inhibitory effects correlated with previously reported rankings of stability constants for chelate formation. DR-3355 bioavailability was not influenced by the concurrent administration of calcium carbonate and ranitidine, indicating that changes in gastric pH do not affect DR-3355 absorption.