A quantitative structure-activity relationship study has been made of some 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. The HMG-CoA reductase inhibition activities of mevinolin analogs and 6-substituted 4-hydroxypyran-2 ones have been mostly found to be significantly correlated with the molecular size of substituents. In one case, however, the inhibition potency was found to be related to the hydrophobicity of molecules. These findings led us to suggest that the enzyme HMG-CoA reductase possesses an active site which is involved in dispersion interaction and another site which is involved in hydrophobic interaction with inhibitor molecules, depending upon the proper orientation of the latter towards these sites. Furthermore, the results indicate that both active sites possess limited steric bulk tolerance.

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The effects of intracerebroventricular (i. c. v.) administration of adrenergic agonists and antagonists on the increase in serum adrenaline (Ad) induced by immobilization stress were examined in unanesthetized, unrestrained rats. The serum Ad of rats showed a significant linear increase as time elapsed after the induction of immobilization stress. This immobilization stress-induced increase was inhibited by the i. c.v. administration of a small amount of noradrenaline (NA) and phenylephrine. Isoproterinol and clonidine failed to inhibit the immobilization stress-induced increase. The inhibition of the immobilization stress-induced increase by i. c.v. administration of NA was antagonized by pretreatment with phentolamine and prazosin, but not by pretreatment with yohimbine and propranolol. These results suggested that NA administered via an i. c. v. route may inhibit the stress-induced increase in adrenomedullary Ad secretion by an action on the central α₁-adrenoceptor.

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Ocular irritability of neutral or positivcly charged liposomes were assessed by the Draize test, histological examination and the rabbit blinking test. The mean total score (MTS) of the Draize test showed a slight increase immediately following instillation of liposome preparations. However, it did not exceed the"practically nonirritating level", and the MTS rapidly became less than the "nonirritating level". No corneal histological alteration was observed by optical microscopy following 9 instillations of each liposome preparation. Although the neutral liposome preparation failed to increase the rabbit blinking count, the positively charged liposome preparation did so to a significant degree. The neutral liposome preparation was confirmed not to give rise to ocular irritation. However, the positively charged liposome preparation may cause pain or unpleasantness following instillation.

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Amfenac Na is a new non-steroidal analgesic anti-inflammatory drug which is clinically used for ailments such as rheumatoid arthritis and pain and/or inflamation after surgery. In this paper, amfenac Na is studied on the bradykinin induced-flexor reflex and the simultaneous recording of the cortical somatosensory-evoked response (SER) and the electromyogram of digastric muscle (d-EMG) evoked by a tooth pulp stimulation. Amfenac Na at doses of 0.1-1 mg/kg p.o. suppressed hindlimb flexor reflexes induced by bradykinin infusion in the rat. This effect was the most potent among the drugs used ; the order of potency was as follows : amfenac Na > floctafenine > loxoprofen >> piroxicam ≒ emorfazone > mefenamic acid. Similarly, the intravenous injection of amfenac Na completely suppressed the flexor reflex with a dose as low as 0.1 mg/kg ; the potency was almost equal to that of morphine. On the SER and d-EMG evoked by tooth pulp stimulation, a high dose (100 mg/kg i.v.) of amfenac Na showed very weak inhibition, whereas morphine (10 mg/kg i.v.) suppressed those responses. These data suggest that amfenac Na showed a very potent analgesic effect comparable to morphine, and that the site of action is mainly the periphery.

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The effect of oral pretreatment with indomethacin on the intestinal first-pass metabolism of salicylamide (SAM) was studied in rabbits using in situ intestinal sacs with complete mesenteric venous blood collection. The appearance of both SAM and its metabolites into the mesenteric venous blood was measured directly by cannulating the mesenteric vein of exposed rabbit intestine and collecting all venous blood draining from the absorbing region. By oral pretreatment with indomethacin, the total amounts of SAM absorbed in 20 and 120 min were significantly increased compared to the control. These results indicated the alteration of the permeability in the intestinal mucosa. In 20 min, indomethacin pretreatment resulted in increased appearance of SAM and SAM glucuronide in the mesenteric venous blood. In 120 min, increased appearance of SAM and decreased appearance of SAM sulfate were observed, compared to the control. These findings suggested that the change in the intestinal first-pass metabolism of SAM is probably due to the intestinal mucosal damage by oral pretreatment with indomethacin.

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The blood concentrations of salicyluric acid and salicylic acid following oral, intravenous, intracecal and rectal administration of salicyluric acid were determined in rats. After oral administration of salicyluric acid, salicyluric acid was rapidly absorbed. Salicylic acid was detected at low concentration. Following intravenous administration of salicyluric acid, salicyluric acid was detected in the blood and was rapidly eliminated. A trace amount of salicylic acid was detected, suggesting that systemic deconjugation of glycine was involved. Furthermore, in vitro incubation of salicyluric acid with contents of the gut showed that the major source of the hydrolysis was the hind gut. Immediate and very extensive salicylic acid formation in the cecum was found following intracecal administration of salicyluric acid. The blood concentration of salicylic acid was maintained at 2.6-4.0 μg/ml from 4 to 12 h following rectal administration of salicyluric acid (10 mg/kg : salicylic acid equivalent). Species difference in the metabolic fate of salicyluric acid in rats and rabbits reported previously is discussed.

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Cytotoxicities of twenty-seven fungal naphtho-γ-pyrone derivatives to KB cells were examined. Chaetochromins A-D (1-4) and ustilaginoidins D (10) and E (11) exhibited strong effects and the structure-activity relationships are discussed. The antitumor effects in vivo of some of these compounds were examined but, due to their toxicity and to their marginal activity, development as antitumor agents was abandoned. Deoxyribonucleic acid, ribonucleic acid and protein synthesis in KB cells were equally inhibited by chaetochromin A (1), cephalochromin (5), and ustilaginoidin A (7) in parallel with the cytotoxicity of the drugs. Thus it was suggested that other still unknown mechanism (s) might induce cytotoxic leison, resulting in the inhibition of the macromolecule syntheses.

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A diffusion model for in vitro drug penetration through the skin was constructed which considered drug concentration decrease in the donor solution. The Laplace transforms of the equations corresponding to the time courses of the drug amount in the receptor solution, in the skin and in the donor solution were derived. Computer fitting of the penetration profiles of in vitro experiments to the obtained Laplace transformed equation by a non-linear least squares program based on first inverse Laplace transform algorithm (MULTI (FILT)) gave two parameters corresponding to drug diffusion and partitioning. These parameters well estimated the drug amount remaining in the donor solution and in the skin. The mean transit time (MTT) was defined for drug penetration through the skin and was calculated using these parameters. MTT was shown to be a good index of drug penetrability.

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The pharmacological actions of double-enkephalin (biphalin ; (HCl-Try-D-Ala-Gly-Phe-NH-)₂) an analogue of enkephalin, on nociception, respiration and the cough reflex were compared with those of morphine in anesthetized rats. Double-enkephalin (D-Enk), injected i.p., produced significant analgesia at doses of 10 and 20 mg/kg in a hot-plate test. The analgesic effect of D-Enk was antagonized by pretreatment with naloxone (5 mg/kg, i.p.). D-Enk and morphine (M) produced a dosedependent decrease in the frequency of respiration (RF) and in the tidal volume (V_t). However, the effects of D-Enk on RF and V_t were significantly weaker than those of M. The 50% antitussive dose (AtD 50) of D-Enk and M were 0.63 and 0.48 mg/kg, i.p., respectively. The antitussive effect of D-Enk was antagonized by pretreatment with naloxone (0.4 mg/kg, i.p.). These results suggest that D-Enk exerted an antitussive effect similar to that of morphine, and that the involvement of opiate receptors is associated with the antitussive effect of D-Enk.

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