Search for naturally occurring substances to prevent the complications of diabetes. II. Inhibitory effect of coumarin and flavonoid derivatives on bovine lens aldose reductase and rabbit platelet aggregation.

An EtOAc extract of Artemisiae Capillari Spica inhibited both bovine lens aldose reductase (bovine-LAR) and rabbit platelet aggregation. Two simple coumarins, scoparone (1) and scopoletin (2), and three flavonoids, capillarisin (21), cirsimaritin (22) and rhamnocitrin (23), were isolated from this extract. Scoparone (1) and scopoletin (2) exhibit a potent inhibitory effect on rabbit platelet aggregation induced by four types of agent, ADP, PAF, sodium arachidonate and/or collagen. Capillarisin (21) exhibits a potent inhibitory effect on bovine-LAR. In addition, thirteen simple coumarins, five coumarin glycosides and two flavonoids were tested for their inhibitory effect against bovine-LAR and rabbit platelet aggregation.

Biphenyls, a new class of compound that inhibits platelet-activating factors.

Honokiol (1), a constituent of Magnoliae cortex, and related synthetic biphenyls inhibited the platelet aggregation induced by a few aggregating agents. In particular, compounds 3, 5, and 10 had an inhibitory effect on platelet activating factor (PAF), which provides a new class of PAF inhibitor.

[Effects of oxybutynin hydrochloride on the urinary bladder and urethra in in situ preparations].

Effects of oxybutynin on the urinary bladder and urethra were studied in comparison with atropine and flavoxate in cats and rabbits. Oxybutynin at 10 mg/kg, i.v., significantly inhibited the bladder contractions induced by electrical stimulation of the peripheral end in pelvic nerve. Oxybutynin was about one half the potency of atropine. On the contrary, 10 mg/kg of flavoxate, i.v., showed both effects of potentiation and inhibition. The bladder contractions induced by acetylcholine (ACh) and AHR-602 were markedly inhibited by oxybutynin and atropine. Oxybutynin was about one-fifteenth the potency of atropine. DMPP-induced contractions were inhibited by oxybutynin and atropine in a high dose, but oxybutynin was about two-fifths the potency of atropine. In addition, 3 mg/kg of oxybutynin, i.v., inhibited the contraction induced by hypogastric nerve stimulation, but 10 mg/kg of oxybutynin, i.v., significantly inhibited this contraction following initial potentiation. Oxybutynin showed an inhibitory effect on spontaneous rhythmical contraction, bladder tone and pelvic nerve discharge, similar to the effects of atropine. On the contrary, flavoxate potentiated this contraction and increased the bladder tone and pelvic and hypogastric nerve discharge. Urethra contractions induced by norepinephrine, ACh and hypogastric nerve stimulation were inhibited by oxybutynin, but not markedly. Oxybutynin and atropine dose-dependently increased the infusion volume, bladder volume capacity and micturition threshold pressure in the cystometrogram in rabbits. Flavoxate also increased them. From these results, it si suggested that oxybutynin is therapeutically a useful agent for pollakisurea nervosa.

An in situ experimental model in rabbits for the study of rectal absorption.

An in situ experimental model of rectal absorption was studied in rabbits compared with in vivo determination of drug concentration in the plasma of postcaval vein using indomethacin as drug. Pharmacokinetic parameters were similar between in vivo and in situ. When results from both studies were compared, 60% of the drug administered to the rectum was absorbed from the superior hemorrhoidal vein and the remaining 40% was absorbed from the inferior hemorrhoidal vein. When an aspirin suppository was used in this model, the amount of unaltered aspirin absorbed in the rectal mucosa or space was greater than the absorbed salicylic acid which was metabolized or degradated from aspirin. In the case of insulin, these differences were not seen in the insulin concentration of venous plasma between insulin physiological saline and surfactant suspension. However, using the in situ model, the surfactant effect on rectal absorption of insulin was observed. From the above results, it was concluded that this in situ experimental model of rectal absorption has advantages in that it can be used directly to measure the rectal absorption rate and to determine ratios of easily metabolized and poorly absorbed drugs. Therefore, this model appears to be useful in evaluation of rectal absorption.

Effects of drug-induced reduction in oxyhemoglobin affinity on survival time of mice in severe hypoxic conditions.

We studied the effect of ortho-iodo sodium benzoate (OISB) given intraperitoneally to mice. 300 and 600 mg/kg of OISB increased P50 from the control value of 41.2 mmHg to 42.7 mmHg and 45.7 mmHg, respectively. The mice were then exposed to two experimental hypoxias, namely, hypobaric hypoxia and carbon monoxide hypoxia. Mean survival time was prolonged from 67.8 (control saline) to 94.8 sec (OISB 300 mg/kg) and 112.2 sec (OISB 600 mg/kg) in the hypobaric hypoxia, and from 201.3 sec (control saline) to 329.7 sec (OISB 300 mg/kg) and 407.7 sec (OISB 600 mg/kg) in the carbon monoxide hypoxia. We concluded that OISB had prolonged survival time by reducing oxyhemoglobin affinity, thus facilitating oxygen release in severe hypoxic conditions.

[Pharmacological action of bromazepam suppository].

Differences between the pharmacological effects of bromazepam given by oral and rectal administration were investigated in mice and rats. 1) Bromazepam dose-dependently prolonged the sleeping time induced by thiopental-Na, ethanol and ether by both administration routes. 2) The analgesic action of bromazepam was recognized by the hot-plate method and the algolytic test. In the hot-plate test, analgesic actions of morphine and pentazocine were potentiated by bromazepam in a dose of 0.5 mg/kg by both routes. 3) The muscle relaxant effect of bromazepam administered rectally was more potent than that administered orally in the inclined screen test and the rotarod test. This effect of bromazepam by rectal administration was approximately 2 times as potent as that by oral administration. 4) Bromazepam inhibited the convulsion induced by maximum electric shock, pentylenetetrazol and picrotoxin. In pentylenetetrazol-induced convulsion, the inhibitory effect of bromazepam administered rectally was 2 times as potent as that administered orally. In the other convulsion test, no significant differences between oral and rectal administration could be recognized. 5) Hyperemotionality and muricide (mouse-killing behaviour) of rats with bilateral olfactory bulb ablations (OB rat) were reduced by oral and rectal administrations of bromazepam in a dose-dependent manner. The effects by rectal administration were more potent than that by oral administration. Bromazepam was approximately 20 times as potent as diazepam administered by the same route. Fighting behaviour in mice subjected to footshock was suppressed by rectal administration of bromazepam, and this effect was as same as that by oral administration. 6) The rate of lever pressing response in the lateral hypothalamic self-stimulation test in the Skinner box was markedly increased by rectal administration of 0.2 mg/kg bromazepam. 7) Methamphetamine-induced hyperactivity of mice was significantly suppressed only by bromazepam administered rectally in a dose of 5 mg/kg. 8) The falling effect of bromazepam on body temperature in normal rats was the same in both administration routes and was dose-dependent. From these data, significant differences of the pharmacological effects between oral and rectal administration of bromazepam were recognized in the duration of action and, in part, potencies; and therefore, rectal administration of bromazepam may be a useful dosage form for clinical use.

Peripheral and central effects of atropine and chlorpromazine on gastric motility and ulceration in stressed rats.

In rats exposed to restraint and water immersion stress, inhibitory effects of atropine (ATR) and chlorpromazine (CPZ) on stress-induced gastric ulceration and motility were studied to clarify which of central and peripheral origins was responsible for these effects. The drug dose ratio of peripheral (intravenous, i.v.) route versus central (intracerebroventricular, i.c.v.) route required to produce an approx. 50% inhibition of gastric ulceration or motility was estimated. Gastric ulceration was prevented by pretreatment with each drug via either route, and there was no great difference in the dose ratio of each drug (i.v.:i.c.v. = 4:1) for the inhibition. The stress-enhanced gastric motility was immediately depressed by each drug via either route. This inhibitory effect of CPZ was short-lasting as compared with that of ATR, and the complete blockade was observed after administration of i.v. ATR or i.c.v. CPZ at higher doses. The ATR dose ratio for this inhibition was less than 10, while the CPZ dose ratio was from 10 to 25. The treatment with CPZ, but not with ATR, caused a definite change in EEG patterns, along with a decrease in body temperature or heart rate. The effect of pretreatment with ATR or CPZ on gastric motility during stress was also investigated. Only the administration of ATR, via either route, appreciably inhibited the gastric motility. Thus, it was suggested that: (1) the inhibitory effect of ATR on gastric motility may be of peripheral rather than central origin, while that of CPZ predominantly of central origin; (2) the anti-ulcerogenic effect of ATR and CPZ may be predominantly of peripheral origin, and the mechanisms involved in ATR may be associated with inhibition of gastric motility, which is different from those in CPZ.