The pharmacokinetics of micronomicin (MCR) as a model drug of aminoglycoside antibiotics (AGs) was studied in man by applying our results previously obtained in rats. Three-compartment open model analysis of combined serum and total body store (T. B. S.) data obtained from multiple dosing in man was done using a non-linear least-squares regression program MULTI. We found large individual variations of MCR disposition in man and these variations did not appear within the serum cocentration range measurable with conventional assay methods. This finding suggests that the disposition of AGs, included MCR, cannot be estimated by only plasma or serum level analyses. We conclude that the therapeutic drug monitoring of AGs by using T. B. S. data analysis should be an effective method for controlling therapy with AGs in the clinical setting.

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The pharmacokinetics of sulfaguanidine in rats was studied after its intravenous or oral administration. In adult rats, its elimination from plasma, after intravenous administration of 2.5 or 25 mg/kg doses, could be described by a two-compartment open model, while its plasma concentration after oral administration of 25 mg/kg doses, agreed with the one- or two-compartment open model. Neonatal rats displayed a lower elimination of sulfaguanidine than adult rats. Comparison of the drug's gastrointestinal absorption showed that the maximum plasma concentration after oral administration was significantly higher for neonatal than for adult rats. However, there was no significant difference between the times required to reach maximum plasma concentrations. The area under the plasma concentration-time curve at 0-∞ h was significantly higher for neonatal than for adult rats. The absolute bioavailability (57.86%) in neonatal rats was approximately five times that (12.76%) in adult rats. Thus, sulfaguanidine was poorly absorbed by adult rats, but was efficiently absorbed by immature gastrointestines of neonatal rats.

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The enhancement of absorption of water soluble macromolecules by lipidsurfactant mixed micelles (MM) was performed in two in vitro experimental systems using rat large intestine, which were isolated epithelial cells containing transcellular route alone and everted sac involving trans- and paracellular routes. Four kinds of fluorescein isothiocyanate-labelled dextrans (FDs) having different average molecular weights (9K-70K) were used as models of water soluble macromolecules. In the absence of MM, very poor transport of FDs was observed in both isolated epithelial cells and everted sac experiments. Linoleic acid-polyoxyethylated (60 mol) hydrogenated castor oil (HCO60) MM enhanced the transport of FDs in both systems, especially for smaller size FDs. This promotive effect by MM decreased with an increase in molecular weight of FDs in both systems. Although enhanced transport of the largest FD (molecular weight, 70K) by MM was clearly demonstrated in the everted sac, the enhanced transport of the same FD in the isolated cells was negligible. These results suggest the possibility of participation of paracellular route as well as transcellular route in the enhancing effect of MM on the large intestinal absorption of water soluble macromolecules.

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Using the xylene ear method in mice, it was demonstrated that the reduced and carboxamide-methylated fragments of human serum IgG (Fr. I-H and Fr. I-L) significantly suppressed capillary permeability. It was also shown that leucocyte emigration and protein leakage into and esterase activity of the pouch fluid, which was accumulated by carboxymethyl cellulose injections, were suppressed by the administration of the fragments. Moreover, the lipid peroxide level was lowered by both Fr. I-H and Fr. I-L in the liver of either carrageenin-induced, paw edema-bearing or kaolin pouch inflammation in rats. The facts obtained in this study indicated the mechanisms of the antiinflammatory effects of Fr. I-H and Fr. I-L were mainly caused by both the inhibitory effect on leucocyte emigration into the site of injury and stabilization of the membrane by inhibiting lipid peroxidation of the inflammatory tissue.

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The change in endogenous antiarrhythmic peptide (AAP) levels in serum, heart and kidney from rats under several drug-induced arrhythmias was investigated using a sensitive and specific radioimmunoassay. The extracts from serum, heart and kidney were fractionated by Sephadex G-25 chromatography to obtain a fraction which was found at the same position as that of synthetic AAP. In serum, the immunoreactive (IR)-AAP level increased about threefold under CaCl₂-, aconitine- and epinephrine-induced arrhythmias. In heart, the IR-AAP level was doubled by CaCl₂, increased 1.4 times by aconitine and decreased by one third by epinephrine. The levels in serum and heart were slightly increased by ADP. The kidney IR-AAP level was not changed under these drug-induced arrhythmias. Considering the previous result that AAP could protect against CaCl₂- and aconitine-induced arrhythmias but not against epinephrine-induced arrhythmia, the change in the IR-AAP level in heart coincided with the effect of AAP given to animals under arrhythmia. Quinidine, propranolol and verapamil had no effect on serum IR-AAP level. These results suggested that endogenous AAP in heart worked to suppress certain arrhythmia.

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Metoclopramide was found to increase the absorption rate constant (k_a) of cimetidine by the duodenum and jejunum in both ligated and unligated rats. The increase of k_a of cimetidine in the ligated rats cannot be interpreted in terms of an increase in the gastric emptying rate, which has been suggested to be the main effect of metoclopramide. The pH values of the stomach, duodenum and jejunum increased following the administration of metoclopramide. Atropine also increased the pH value of the duodenum, but it did not increase the k_a of cimetidine. Consequently, the increase of k_a of cimetidine, following administration of metoclopramide, was not due to the elevation of intestinal pH. On the other hand, metoclopramide significantly increased the blood flow by about 67.3 and 29.7% at the duodenum and jejunum, respectively, when the intestinal blood flow was measured by the hydrogen clearance method. Attopine had no effect on the intestinal blood flow. Based on these results, it was concluded that the increase of intestinal blood flow may be one of the factors for the increase of k_a of cimetidine following the administration of metoclopramide. From the results of multi-line fittings of the plasma concentration data following oral, intraduodenal, intrajejunal and intraileac administrations of cimetidine with metoclopramide treatment, it was suggested that metoclopramide increased the intestinal transit time of subsequently administered drugs, as well as the gastric emptying rate.

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The tissue distribution of quinidine was investigated at three different steady-state plasma concentrations of quinidine in rats. The tissue distribution of quinidine (tissueto-plasma concentration ratio, C_t/C_p) was studied in the liver, lung, kidney and heart and the highest distribution was found in the lung. Tissue binding characteristics of quinidine was determined in normal tissue homogenates and lipid-depleted tissue homogenates in vitro. No correlation was observed between the tissue bindings (product of association constant (K₁) and number of binding sites (n), nK₁) estimated in each normal tissue homogenate and the values of C_t/C_p in vivo. However, a marked decrease in the tissue binding of quinidine was observed in all lipid-depleted tissue homogenates, and the largest decrease was observed in the lung tissue. This result suggested that lipid may have an important role in the tissue binding of quinidine. However, no good relationship was observed between the values of C_t/C_p and the phospholipid contents in each tissue. In order to investigate the role of lipid in the tissue binding of quinidine, phospholipids extracted from each tissue were used for binding study. The phospholipids binding of quinidine (nK₂) increased in the following order ; heart <liver<kidney<lung, and the plots of the values of C_t/C_p obtained in vivo against the binding ability of phospholipids (product of nK₂ and the content of phospholipid in each tissue) gave a good linear relationship. Based on these observations, it was concluded that some species of phospholipids had an important and determining role in the tissue distribution of quinidine in vivo.

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The contractile effects of leukotrienes (LTs) C₄, D₄ and E₄ were studied in guinea pig isolated taenia caecum. LTs C₄, D₄ and E₄ contracted taenia caecum at low concentrations in a concentration-dependent manner. The response to LTs was not influenced by a γ-glutamyl transpeptidase inhibitor (L-serine borate), aminopeptidase inhibitor (L-cysteine) or cyclooxygenase inhibitor (flurbiprofen), suggesting that LTC₄ and LTD₄ were not metabolized or metabolized only slightly in the guinea pig isolated taenia caecum, and that each of the LTs showed the direct contractile action. Furthermore, FPL55712 antagonized the response to LTD₄ and LTC₄ competitively but not that to LTE₄. These results suggested that the guinea pig isolated taenia caecum is useful preparation to study the pharmacological actions of LTs.

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We studied the effects of propranolol on degradation of cardiac structural proteins resulting from ischemia induced by 24 h ligation of the coronary artery in dogs. Degradation of myocardial myosin heavy chain, α-actinin and troponin-I was used as an indicator of degradation of cardiac structural proteins. In dogs with left circumflex coronary artery ligation, propranolol, given orally in the dose of 10 or 30 mg/kg, significantly reduced degradation of cardiac structural proteins. This can be supported by the facts that treatment with propranolol, 10 or 30 mg/kg, reduced release of cathepsins B, L and D from lysosome to cytosol in the ischemic tissue and that the reduced acidity of the ischemic tissue was improved by treatment with propranolol, 30 mg/kg. In conclusion, propranlol delays the necrotic development of the severely ischemic myocardial tissue as shown by reduced protein degradation.

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When (6)-shogaol (0.5 mg/kg, i. v.) was administered to rats, blood pressure showed a tri-phasic response which was comprised of a rapid fall, followed by a rise and a delayed fall. The rapid fall, which followed immediately after injection of (6)-shogaol, disappeared with the use of atropine and vagotomy. The marked rise, which occured after the rapid fall, was not affected by alpha-adrenoceptor blockades, Ca antagonists and ganglion blockade. However, a combination of alpha-adrenoceptor blockade and Ca antagonist inhibited this pressor response. In hindquarters perfused with a nutrient solution, (6)-shogaol (10^-5g)-induced peripheral pressor response was also not affected by alpha-adrenoceptor blockades and Ca antagonists, but was inhibited by the combination of an alphaadrenoceptor blockade and a Ca antagonist. Furthermore, this peripheral pressor response was eliminated by the removal of Ca ion from the perfusate. (6)-Shogaol did not exhibit a pressor response in an artery and a vein of the tail or an artery of the femur perfused with a nutrient solution. (6)-Shogaol-induced peripheral pressor response in hindquarters was markedly potentiated during the perfusion of norepinephrine (5×10^-6 g/ml), but this potentiation was prevented by pretreatment with reserpine (5 mg/kg, i. p.). Moreover, repeated injections of (6)-shogaol caused a tachyphylaxis in mesenteric and tail vascular beds and a slight tachyphylaxis in hindquaters.

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(6)-Shogaol-induced pressor responses in blood pressure of rats were studied. Intraventricular injection of (6)-shogaol (0.1 to 0.5 μg) caused a pressor response in a dosedependent manner. (6)-Shogaol (0.5 mg/kg, i. v.)-induced pressor response was markedly reduced by a spinal destruction to the sacral cord level. However, norepinephrine (10 μg/kg, i. v.)-induced pressor response was not affected by the spinal destruction. In rats in which the spinal cord was destroyed to the thoracic cord level, (6)-shogaol-induced pressor response was reduced by hexamethonium (10 mg/kg, i. v.) and phentolamine (10 mg/kg, i. v.), etc. When the spinal cord was destroyed to the sacral cord level, the pressor response was not affected by these blockades. In the hindquarters of rats which were perfused with rats'blood, (6)-shogaol caused two pressor responses on the perfusion pressure. The first pressor response, which was accompanied by a rise in systemic blood pressure, was reduced by hexamethonium but was not entirely eliminated by phentolamine. However, the pressor response disappeared with spinal destruction to the sacral cord level. The second pressor response, which occured about when the systemic blood pressure regained its original pressure, was not affected by hexamethonium, phentolamine or spinal destruction. Pressor response induced by the injection of (6)-shogaol (10 μg) into the perfusion circuit was not affected by phentolamine and spinal destruction. Furthermore, (6)-shogaol-induced peripheral pressor response disappeared with the combined treatment of [D-Arg¹, D-Pro², D-Trp^{7, 9}, Leu¹¹]-substance P (0.5 mg/kg, i. v.), phentolamine and the section of the sciatic nerves.

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The antitumor activity of a branched β-1, 3-glucan"grifolan LE"purified from liquid cultures of Grifola frondosa (Ohno et al. Chem. Pharm. Bull., 34, 1709-1715 (1986)) was examined on an allogeneic murine tumor system. By intraperitoneal (i. p.) administration (100-200 μg/mouse/d×5) at days 1 to 9 from the tumor transplantation, grifolan LE showed marked inhibitory activity on the growth of solid form sarcoma 180 in ICR mice. Significant activity was also observed in intravenous (i. v.) or intratumoral (i. t.) administrations. However, the oral (p. o.) administration of grifolan LE was not effective. I. p. administration of grifolan LE at a dose of 100 μg/mouse/d×5 before the tumor transplantation showed significant inhibition of tumor growth. I. p. administration of grifolan LE at day +11 to +19 was also effective. Grifolan LE was not effective on the ascites form of sarcoma 180. The pretreatment of sarcoma 180 cell with grifolan LE in vitro did not affect tumor growth. The mice cured from the solid form of sarcoma 180 by administration of grifolan LE had the ability to reject the same tumor cell. From these results, it is suggested that the antitumor activity of grifolan LE occurred by modification of biological responses.

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