The effects of blended Chinese traditional medicines applied for diabetes mellitus were studied on the pattern of action to the glucose tolerance curves in genetically diabetic KK-CA^y mice. The glucose tolerance curves of KK-CA^y mice (humping curve) were analyzed pharmacokinetically by the mathematical model (Compartment-H model). The curves could be classified into several types of pattern through the analysis for the humping effect. Daisaikoto-Ka-Jio and Byakko-Ka-Ninjinto reduced the humping effect, whereas Hachimigan had a tendency to enhance it. On the combined effect of crude drugs prescribed in the blended medicines, the effect of Daisaikoto was lessened by subtracting Rehmanniae Rhizoma from Daisaikoto-Ka-Jio and Byakkoto (subtracted Ginseng Radix from Byakko-Ka-Ninjinto) had no inhibitory effect on the humping. Rehmanniae Rhizoma or Ginseng Radix alone had the similar effect on decreasing the humping. The hypoglycemic component of Ginseng Radix (DPG3-2) decreased the humping effect in a dose-dependent manner. In conclusion, the effects of crude drugs and the active component of the crude drug supported those of the blended medicines on the humping effect by utilizing the pharmacokinetical analysis.

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The present study was undertaken to determine whether colestipol-phenol red complexes can be used as markers for gastrointestinal transit of solid food. Colestipol (1.0 g) bound completely with phenol red (10 mg) to form a stable complex in water (pH 7.0). Phenol red was more readily eluted from colestipol with 20 ml of 1N HCl than 1N NaOH, but was not eluted with 0.1 N HCl (pH 1.0). It was therefore assumed that the comlex would remain stable in the gastrointestinal tract. Also, phenol red in the gastrointestinal tract was quantitatively eluted from the complex with 20 ml of 1 N HCl. In a study on gastric emptying, phenol red solution (liquid food) was excreted from the stomach in a zero-order manner, and the colestipol-phenol red complex (solid food) in a first-order manner. It was concluded that colestipol-phenol red complexes can be used as markers of gastrointestinal transit.

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1. It was investigated in normal and liver-injured rats administered with trimethadione (TMO) as to whether concentrations of TMO in plasma are able to be predicted from the corresponding saliva levels. 2. The saliva/plasma (S/P) ratio of TMO was about 1, while its metabolite 5, 5-dimethyl-2, 4-oxazolidinedione (DMO) showed a S/P ratio of 0.65. 3. In normal rats, there was a high correlation between saliva and plasma concentration of TMO and DMO. (TMO : r=0.966, DMO : r=0.950) 4. In liver-injured pretreated rats with carbon tetrachloride, α-naphthyl isothiocyanate or D-galactosamine, there was a high correlation between the saliva DMO/TMO ratio and the plasma DMO/TMO raito after oral administration of TMO (r=0.983 at 1 h, r=0.952 at 2 h). 5. The saliva DMO/TMO ratio, as well as the plasma DMO/TMO ratio, may be utilized as an index of drug-metabolizing activity of the liver.

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Antitumor activity of twenty seven 6-alkyl disulfide derivatives of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) were examined in the system of murine L-1210 leukemia. When given by intraperitoneal administration, maximum increase in life span produced by iso-pentyl (75%) and heptyl (68%) disulfides of 6-MP and sec-butyl (83%), pentyl (78%), and naphthyryl (90%) disulfides of 6-TG were higher than that of parent compounds (6-MP : 53%, 6-TG : 64%). Compounds with higher therapeutic ratio than respective parent compound were decyl and naphthyryl disulfide derivatives of 6-MP and almost all the derivatives of 6-TG tested (propyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl, benzyl, and naphthyryl disulfides of 6-TG). Among them, decyl derivatives of both 6-MP and 6-TG showed the highest therapeutic ratio as high as 50 and 48, while those of parent compounds were 6.2 and 5.0, respectively. The improvement of therapeutic effect by the modification to decyl disulfide of 6-MP was demonstrated in the L-1210 system, but it was not found in the Sarcoma-180 system reported previously. By oral administration, these derivatives were active against the leukemia but they were not superior to the parent compounds.

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KF 1492, a new phenylalanine derivative, was administered at a dose of 100 mg/kg or 0.25% (w/w) diet to Wistar rats. After different periods of drug administration, incorporation of ¹⁴C-acetate or ¹⁴C-mevalonic acid into digitonin-precipitable sterols and hepatic 3-hydroxy-3-methylglutaryl-Co A (HMG-CoA) reductase activity were measured. KF 1492 feeding was associated with depressed incorporation of ¹⁴C-acetate into sterols in liver slices or homogenate. There was no effect on incorporation of ¹⁴C-mevalonic acid into sterols. Thus, KF 1492 administration induced inhibition of hepatic HMG-CoA reductase correlated with reduction of incorporation of ¹⁴C-acetate into digitonin-precipitable sterols. KF 1492 feeding also inhibited in vivo sterol synthesis in rats, which was intraperitoneally injected with ¹⁴C-acetate. Stereoisomers, metabolites and chemically similar compounds of KF 1492 reduced HMG-CoA reductase activity, and this was correlated with lowering the activity of plasma cholesterol. These findings indicate that a major site of the action of KF 1492 in the inhibition of sterol synthesis may be at the level of HMG-CoA reductase.

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Lyoniol-A (2 mg/kg, i.v.), a toxic component isolated from the Ericaceous tree, markedly caused the increase in rate of discharges from vagal afferent nerves in the rat. This agent also caused respiratory depression, hypotension and the relief of decerebrate rigidity. These effects of lyoniol-A on the respiration and the rigidity were absent under conditions of bilateral cervical vagotomy, and the hypotension was abolished by sectioning of both vagal and carotid sinus nerves. These results suggest that the excitation by lyoniol-A of the afferent activities reflexly produces respiratory depression, hypotension and the relief of decerebrate rigidity.

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In in situ experiments on spinal rats transected at the C1 level and on non-spinal rats, muscimol (3 mg/kg, i.v.) depolarized the primary afferent fibers and diazepam (3 mg/kg, i.v.) potentiated this effect of muscimol. When diazepam was given for 14 days, the effect of muscimol was significantly reduced in non-spinal, but not in spinal rats. These findings suggest that diazepam probably interacts with GABA-ergic mechanisms more closely in supraspinal regions of the rat.

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Effect of acetazolamide (AZA) on the anticonvulsant potency of phenobarbital (PHB) was investigated in mice by maximal electroshock seizure (MES) test. By coadministration with AZA, a remarkable increase and prolongation of the anticonvulsant activity of PHB was brought about. The type of the synergism of PHB with AZA was not additive but of potentiation. The potentiation of the anticonvulsant activity of PHB with AZA was rather related to inhibition of carbonic anhydrase (CA) in brain than in blood. The anticonvulsant activity of PHB was also increased by coadministration with methazolamide which had a great ability to inhibit brain CA. Furosemide, which had no inhibitory effect on brain CA, on the other hand, failed to show any potentiation on the anticonvulsant activity of PHB. Thus it was inferred that the inhibition of brain CA may play a significant role for the potentiation of the anticonvulsant activity of PHB. Although reserpinization completely abolished the protective effect of AZA on MES, the potentiation of the anticonvulsant activity of PHB was still observed by AZA. These results suggest that pharmacodynamic and/or pharmacokinetic effect of AZA independent of its anticonvulsant action may contribute to the potentiation of the PHB action.

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1. The relationship between the plasma concentration ratio of 5, 5-dimethyl-2, 4-oxazolidinedione (DMO) to trimethadione (TMO) and cytochrome P-450 dependent drug-metabolizing enzyme activities after administration of TMO to rats pretreated with different dose levels of carbon tetrachloride (CCl₄) was investigated. 2. Pretreatment of rats with different dose levels of CCl₄ resulted in a prolongation of TMO half-life, an increase of the area under the curve (AUC), and a decrease of clearance, but the apparent volume of distribution (V_d) was not significantly decreased. 3. Depending on the extent of liver-injury by CCl₄, there was a good correlation between the ratio of DMO to TMO in plasma and hepatic cytochrome P-450 dependent drug-metabolizing enzyme activities such as cytochrome P-450 content (r=0.796 at 1 h, r=0.849 at 2 h), aminopyrine N-demethylase activity (r=0.877 at 1 h, r=0.905 at 2 h), TMO N-demethylase activity (r=0.876 at 1 h, r=0.928 at 2 h) and aniline hydroxylase activity (r=0.900 at 1 h, r=0.936 at 2 h). 4. These results, together with the previous findings, indicate that determination of the plasma levels of TMO and DMO might be a useful tool as an index of drugmetabolizing capacity of rat livers.

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The salivary excretion of phenobarbital was investigated by collecting parotid saliva (Pr) and mandibular-sublingual saliva (MS) separately after intravenous administration in beagle dogs. (1) The alterations in the proportions of saliva secreted by the different glands were produced by salivation stimulants such as citric acid, ascorbic acid, sodium chloride and sodium glutamate. (2) The phenobarbital concentrations in both Pr and MS were lower than those in plasma. The drug concentrations in MS were significantly lower than in Pr with stimulus of 10% citric acid or 15% sodium chloride (p<0.05). There was a significant correlation between phenobarbital concentration in each saliva and plasma specimen (p<0.05). (3) The stimulation with 10% citric acid produced higher saliva/plasma drug concentration ratios (S/P ratios : 0.923±0.175 for Pr, 0.633±0.073 for MS) than that with 15% sodium chloride (S/P ratios : 0.597±0.071 for Pr, 0.509±0.067 for MS). (4) The S/P ratios were hardly influenced by salivary flow rates, at least under the experimental conditions examined in this study. (5) The increased S/P ratios were observed with higher salivary pH and then the equation of Matin et al. seemed to hold for the average values of salivary pH and S/P ratio. (6) The stimulation with 10% citric acid produced higher protein concentration in saliva and higher S/P ratio than that with 15% sodium chloride following alternate stimulations in the same dog.

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