We studied the mechanism on protective effect of fosfomycin against experimental nephrotoxicity induced by dibekacin. In order to simplify an experimental model, the dehydrated Wistar rats were used, because a single injection of dibekacin at 30 mg/kg induced acute renal failure in the dehydrated rats, characterized by alteration of urinalytic parameters and BUN values, and retarded elimination of dibekacin from blood. When the rats were administered simultaneously with fosfomycin at 120 mg/kg, the rate of elimination was restored almost to normal, accompanied with improvement of the nephrotoxic parameters. However, markedly accelerated elimination over normal one was not observed, indicating that the improved elimination was not the reason of protection but a result of normal kidney function. On the other hand, fosfomycin protected the proximal tubular lysosomes form the injury of aminoglycoside, as evidenced a) in vivo by suppression of myeloid body formation and protection of lysosomal membrane integrity of the rats treated with dibekacin, and b) in vitro by dose-dependent protection of the lysosomal membrane integrity of the kidney cells. A study of structrue-protective activity relation revealed that phosphonate anion possessing an epoxy function was important for protection, and that the mechanism of protection differed from the antibacterial mechanism.

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During 5d following single oral doses of ³H-11-bromovincamine to rats (10 mg/kg), dogs (10 mg/kg) and humans (0.5 mg/kg), about 21 and 66%, 28 and 56% and 64 and 21% of the dose were excreted in the urine and faeces respectively, mainly within 24 and 48h. The urinary excretion of radioactivity in humans was biphasic with half-lives of about 6 and 17h, identical to those observed for decline of plasma radioactivity. The excretion of a larger proportion of the dose in the faeces of rat and dog can be attibuted to the greater extent to which biliary excretion of drugs and/or their metabolites occurs in these species compared to man : about 60% of oral or intravenous doses (10 mg/kg) of ³H-11-bromovincamine was excreted in rat bile. At least about two-thirds of an oral dose of 11-bromovincamine was absorbed in rats and humans respectively. Mean peak plasma concentrations of durg-related radioactivity (adjusted for dose) after single oral doses to rats, dogs and humans were 0.55, 0.58 and 3.0 (μg/ml)/(mg/Kg) at 4, 2 and 1h respectively. Plasma concentrations declined with half-lives of about 10 and 34h in rats and dogs respectively and biphasically in humans with half-lives of about 6 and 17h. Provided that certain assumptions are valid, comparison of the areas under the plasma radioactivity concentration-time curves obtained after oral and intravenous doses of ³H-11-bromovincamine to the animal species indicates that oral doses were well absorbed. Concentrations of total radioactivity in rat tissues after oral doses were higher than those in plasma in only a few tissues such as the liver, kidneys and lungs. After intravenous doses, however, concentrations of radioactivity were higher in most tissues than in plasma, presumably reflecting uptake of parent drug into these tissues. Concentrations of radioactivity in brain were lower than or similar to those in plasma. In all tissues examined, drug-related radioactivity concentrations were<μg eq/g after 48h. The major radioactive component in rat urine and faecal extracts, after single oral doses, corresponded to the parent drug and accounted for a total 12.3% of the dose. The remaining radioactivity was associated with a complex mixture of components. 11-Bromovincamine was only a minor component in dog and human urine (2.8% and 1.6% of the dose respectively), while a major metabolite (11-bromovincaminic acid) in human urine (23% dose) was also detected in dog urine (4.3% dose). 11-Bromovincamine represented 2.7% and 0.4% dose in dog and human faecal extracts respectively. After single oral doses, rat plasma contained a complex mixture of metabolites whereas the major radioactive component in dog and human plasma was associated with 11-bromovincamine : also present was a component corresponding to the major urine metabolite which nad a mass spectrum consistent with that of 11-bromovincaminic acid.

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In order to evaluate the effects of antitussive agents, a new method for inducing the cough reflex in guinea pigs was devised. Male guinea pigs weighing 300-450 g were fixed in a supine position under non-anesthesia. A puncture electrode make by a stainless steel wire (0.2 mm diameter, 10 cm length) was inserted into the trachea through a guiding cannula (needle size 23G, Terumo). The optimal parameters of electrical stimulation given on the tracheal mucous membrane were a square-weve pulse with a 40 Hz frequency, duration of application 5s. Fifty percent of antitussive doses (AtD50) of the drugs used in this study were as follows : codeine, 3.35 mg/kg (i.p.), 7.5 mg/kg (p.o.) ; morphine, 1.2mg/kg (i.p.), 2.5 mg/kg (p.o.) ; picoperidamine, 10.9 mg/kg (i.p.), 22.6 mg/kg (p.o.) ; benproperine, 14.5 mg/kg (i.p.), 22.6 mg/kg (p.o.) ; fominoben, 13.9 mg/kg (i.p.), 477 mg/kg (p.o.). These AtD50s are much less as compared with those obtained using other methods. These results suggest that the present method for inducing the cough reflex in guinea pigs is useful for the first screening of antitussives, especially when only a small quantity of the materials in available.

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This study was designed to determine whether ouabain could inhibit insulinstimulated ion and/or glucose transport in rat ventricular slices. In the slices which were obtained by tearing with forceps from the inside surface of the ventricle, insulin (0.1-100 ng/ml, 20-min treatment) stimulated ATP hydrolysis (nmol inorganic phosphate/mg tissue/20 min) and ⁸⁶Rb uptake (nmol Rb/mg tissue/8 min) in a concentration-dependent fashion by up to about 25%, compared with control experiment. About 10-fold higher concentrations of insulin stimulated glucose-[¹⁴C] uptake by the slices (nmol glucose/mg tissue/30 min). Both the stimulant effects of insulin on ion and glucose transport were inhibited by ouabain (0.1-1 mM, 20-min treatment) in a similar concentration-response relationship. It thus never appears that two or more independent transmembrane signals would be generated simultaneously in response to the insulin-receptor interaction to operate ion and glucose transport system in rat cardiac muscle. In addition, rat ventricular slices were shown to provide a sensitive tool for the evaluation of insulin effects on ion transport systems in the muscle.

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The role of serum albumin in in vitro fertilization of mouse ova was studied relating to the fertilization inhibitory activity of Zn²⁺. The time required for mouse sperm capacitation was dependent on the concentration of serum albumin which was added to the medium. The majority of Zn²⁺ added to the medium was shown to be bound to serum albumin (95% out of 200 μM) by means of equilibrium dialysis. Furthermore, it was suggested that the serum albumin was necessary for the initiation of the sperm capacitation process by the periodic observation of sperm penetration through zona pellucida.

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The mechanism responsible for the deconjugation of the glucuronide of p-phenyl benzoic acid (PPBA) in fetal intestine and amniotic fluid was studied in rats. Non-enzymatic hydrolysis of PPBA glucuronide in intestine was little before birth. The activity of β-glucuronidase (β-G) in fetus was the highest in intestine, followed by lung and skin. The activity of β-G in fetal intestine increased with the day of gestation, and increased remarkably between the 18th and 21st day of gestation. PPBA glucuronide injected intraamniotically distributed as PPBA in fetal skin. The fluid of trachea and esophagus showed high distribution of radioactivity and the ratio of PPBA glucuronide in radioactive substances in fetal lung tended to be higher than that in fetal plasma after intraamniotic injection of ¹⁴C-PPBA glucuronide. In summary, PPBA glucuronide in amniotic fluid is absorbed into fetal body through skin, lung and intestine after deconjugation.

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Pretreatments of rats with the highly toxic compounds such as 3, 4, 5, 3', 4'-pentachlorobiphenyl (PenCB), and 2, 3, 7, 8-tetrachloro(TCDF) and 2, 3, 4, 7, 8-pentachlorodibenzofuran(PenCDF), which are potent 3-methylcholanthrene(MC)-type inducers, increased selectively 7α-hydroxylation, but strongly suppressed 2α-, 6β- and 16α-hydroxylations as well as 5α-reduction of progesterone and testosterone in the liver microsomes. This unique change in the metabolic pattern was accompanied by a marked decrease in total metabolism of both steroids and appeared to correlate apparently with their toxic potency. This kind of change was not shown by pretreatments with not only MC itself but also the phenobarbital-type(2, 4, 5, 2', 4', 5'-hexachlorobiphenyl) and the mixed type PCBs(Kanechlor 400, a PCB mixture with 48% chlorine content), all of which possess only a low acute toxicity. The metabolic change produced by 3, 4, 5, 3', 4'-PenCB, 2, 3, 7, 8, -TCDF and 2, 3, 4, 7, 8, -PenCDF might not be due to their stimulatory or inhibitory effects, because when added to the incubation mixture 3, 4, 5, 3', 4'-PenCB did not change the metabolic pattern with MC-microsomes to that with 3, 4, 5, 3', 4'-PenCB-microsomes. Furthermore, either 2, 3, 7, 8, -TCDF or 2, 3, 4, 7, 8, -PenCDF gave similar metabolic pattern whereas their residual levels in the liver were greatly different from earch other at the time of sacrifice. These results suggest that this kind of unique change of the steroid metabolism produced by highly toxic PCBs and PCDFs may be responsible, at least in part, for the endocrine symptoms caused by these compounds via disturbance of steroid homeostasis.

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Buffalo/Mna rats (Mna rats) with spontaneous thymoma show the motor dysfunction represented by an exacerbated fatigability of hind-limb muscles. In this study fast (extensor digitorum longus, EDL) and slow (soleus) muscles of these rats were examined physiologically and pharmacologically. ACI strain served as a reference. The mechanical fatigability of the EDL muscle during repetitive nerve and direct stimulation in Mna rats was greater than that in ACI rats, but electromyographical fatigabilities of both strains were quite similar. Smaller amplitude of evoked electromyograms, twitch tension (t.t.) and muscle weight (m.w.) and longer twitch relaxing time were observed in the EDL muscles of Mna rats as compared with ACI rats. On the other hand, the soleus muscles of rats of both strains showed similar t.t., and neither mechanical nor electromyographical fatigability. However, smaller t.t./m.w., greater m.w. and lower sensitivity to d-tubocurarine chloride were observed in the soleus muscles of Mna rats as compared with ACI rats. The motor dysfunction seems to result mainly from the muscle weakness and the myogenic fatigability in the fast muscle. The possibilities of some change at the site of neuro-muscular junction and a latent abnormality in the soleus muscle are also suggested.

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Treatment of ICR mice i.p. with the antitumor polysaccharide (1→3)-β-D-glucan (TAK-N) or its carboxymethylderivative (CM-glucan) rendered macrophages cytotoxic to L5178Y lymphoma cells in vitro. The ability of macrophages to inhibit tumor cell proliferation appeared on days 4 and 9 after the injections of TAK-N and CM-glucan, respectively. Peritoneal macrophages from normal untreated mice were not cytotoxic. On in vitro incubation with serum from mice treated with the glucans, peritoneal macrophages from normal untreated mice became cytotoxic to tumor cells. This activating effect appeared transitorily in the serum on days 2-4 and 9-10 after administrations of TAK-N and CM-glucan, respectively, to mice. Neither the glucans alone, nor serum from untreated mice induced cytotoxicity of normal mouse peritoneal macrophages in vitro. On fractionation of mouse serum obtained on day 4 after injection of TAK-N at a dose of 80 mg/kg, two in vitro activators of normal macrophage were obtained : one was a peptide (mol.wt., 4, 500 daltons), and the other was probably a peptidoglycan (mol.wt., 9000 daltons).

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In order to learn the effects of a series of aliphatic ω-aminosulfonic acids with varying numbers of carbon chains, changes in the electroencephalogram (EEG) of adult hens were investigated as the criteria. The drug solution (10 μl) was locally injected into the telencephalon of a curarized animal under artificial respiration and Wulst EEG was recorded near the administered region. No influence was seen on EEG by the administration of amino acids with 1-3 carbon chains (short-chain structure) at a concentration of 6×10^-1M. Characteristic biphasic spikes developed after the administration of amino acids with 4 or more carbon chains (long-chain structure) at a concentration higher than 2×10^-2M, and their amplitudes gradually increased over 1.5-2.0 mV. Spikes were induced by guanyl compounds of amino acids of long-chain structure even at a concentration of 2×10^-3M. Convulsant drugs also induced spikes when used in doses similar to the spike-inducing ω-aminosulfonic acids. The development of spikes by ω-aminosulfonic acids was antagonized by aminosulfonic acids with a short-chain structure. On the basis of the above-mentioned results, ω-aminosulfonic acids can be classified into excitants and depressants according to their activities in inducing characteristic spikes with high amplitudes. In the development of spikes, the excitants and depressants are antagonistic to each other. The doses of excitants which induce spikes are comparable to those of convulsants and coincide very well with the earlier reported relationship between convulsion development rates of excitants and dosage administered to the cerebral ventricle of mice.

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Pentanoylcholine iodide and n-hexyltrimethylammonium bromide were muscarinic partial agonists in a sphincter pupillae muscle of rabbit as well as intestinal smooth muscles. Both partial agonists behaved as mydriatics in a constricted pupil and as miotics in a dilated pupil.

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Inclusion complex of antiinflammatory drug flurbiprofen with tri-O-methyl-β-cyclodextrin in 1 : 1 molar ratio was prepared, and its dissolution and absorption characteristics were compared with those of flurbiprofen. The apparent dissolution rate of flurbiprofen in water was significantly increased by the inclusion complexation. The serum level of flurbiprofen following the oral administration of the complex to rabbits was higher than that of the drug alone. The enhanced bioavailability of flurbiprofen suggests the possible utility of tri-O-methyl-β-cyclodextrin in pharmaceutical formulation.

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This study was undertaken to investigate the effects of vitamin E-deficiency on renin release from isolated renin granules. Male Wistar rats were fed either a control or a vitamin E-deficient diet. Renin granules were prepared from the kidney cortex homogenate by a discontinuous sucrose density gradient centrifugation. Renin activity was measured by radioimmunoassay and lipid peroxidation was estimated by means of the thiobarbituric acid test. The intake of vitamin E-deficient diet for 4 weeks resulted in a decrease in α-tocopherol content in renin granules, accompanied by an increased level of endogenous lipid peroxides. When the renin granules were incubated at 37°C, the rate of renin release from the granules in vitamin E-deficient group was significantly higher than that in the control group. These results indicate that vitamin E exists in renin granule membranes and functions in maintenance of membrane integrity by blocking the lipid peroxidation.

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