人参果皂甙的抗应激作用和对垂体—肾上腺皮质系统功能的影响

With various methods (temperature, swimming, hypoxia and toxicant), observations were made on the anti-stress effects of the saponins extracted from panax ginseng fruit (SPGF) injected intraperitoneally into white mice. The results obtained are as follows: SPGF exhibited a highly significant anti-hypoxia effect and anti-fatigue action. In addition, saponins strikingly raised the animals' ability to tolerate temperature stress and impede significantly the elevation of SGPT liver induced by injection of CCl₄. But this effect was abolished by the extirpation of the adrenals. Administration of SPGF by gavage caused marked depletion of adrenal ascorbic acid in intact rats. Stress condition and ACTH depleted the ascorbic acid content of the adrenals in rats. Previous administration of SPGF exhibited an inhibiting effect on such depletion. However, the adrenal ascorbic acid regulating effect of the compound disappeared in hypophysectomized rats. From these results, it would appear that SPGF has a stimulatory action on the hypophyseal—adrenal system.     

汉防已甲素及汉防已乙素之消炎与抗过敏性休克之研究

Tetrandrine and demethyl-tetrandrine are alkaloids isolated from the Chinese drug Han Fang Chi (汉防已), the root of Stephania tetrandra S. Moore. Han Fang Chi is used in the Chinese medicine as an antirheumatic and analgesic. According to another experiment conducted in our department with the Grewal's method, the two alkaloids seem to have only slight analgesic action. Presumably, the drug might be only antiphlogistic, and the analgesia a secondary effect. In the present - paper, we are reporting experiments undertaken to determine whether the two alkaloids be antiphlogistic and possess anti-anaphlactic and anti-histamine shock actions, as many antipyretics do. At the same time, the vitamin C content in the adrenal gland of the experimental animals is also estimated. The results of our experiments are summarized as follows:- 1. Tetrandrine and demethyl-tetrandrine possess definite antiphlogistic action on the formaldehyde-arthritis of the rats. 2. Tetrandrine shows a slight protective action against anaphylactic shock induced by injecting egg albumen to rabbits, but no action against histamine shock in guinea pigs. 3. A significant reduction in vitamin C content of the rat's adrenal glands was observed after tetrandrine (1.5 mg./100 gms., intraperitoneally), indicating a stimulating action on the pituitary-adrenal system, causing hyperfunction of the adrenal cortex, similar to some antipyretics. 4. It seems, therefore, that the two alkaloids studied belong to the so called antipyretic analgetics.     

Anticancer properties of panduratin A isolated from <Emphasis Type="Italic">Boesenbergia pandurata</Emphasis> (Zingiberaceae)

Extract of Boesenbergia pandurata (Kaempferia pandurata) (Zingiberaceae) has been used as a replacement for K. rotunda, the main ingredient of a popular traditional tonic called “jamu” especially for women in Indonesia. From our previous study, ethanolic extract of B. pandurata showed strong inhibitory effects on the growth of cancer cells, similar to ethanolic extract of Curcuma longa. C. longa and its bioactive compound, curcumin, have shown potential anticancer activity in in vitro and in vivo studies and have undergone clinical trials. Panduratin A, a chalcone derivative isolated from B. pandurata, was found to inhibit the growth of MCF-7 human breast cancer and HT-29 human colon adenocarcinoma cells with an IC₅₀ of 3.75 and 6.56 μg/ml, respectively. Panduratin A arrested cancer cells labelled with Annexin-V and propidium iodide in the G0/G1 phase and induced apoptosis in a dose-dependent manner. In an animal model study, male Sprague–Dawley rats were fed with AIN diet containing ethanolic extracts prepared from the equivalent of 4% by weight of dried rhizomes of B. pandurata and C. longa. Aberrant crypt foci (ACFs) were induced by two subcutaneous doses (15 mg/kg body weight) of azoxymethane (AOM) 1 week apart. The rats were killed 10 weeks later, and the ACFs were assessed in the colon. At the dose given to rats, it appeared that the extracts were not toxic. Total ACFs were slightly reduced by B. pandurata extract compared to control group but not significantly different. Extract of B. pandurata may have a protective effect against colon cancer but additional studies using different models, such as a breast cancer model, need to be carried out.     

Saponins from Panax japonicus ameliorates cognition deficits and attenuates oxidative damage in D-galactose-induced brain aging of mice

Aging is an inevitable process featured by intelligence decline,behavioral disorders and cognitive disability.Increasing evidence indicates that oxidative stress plays a key role in the senescent development.Our previous study demonstrated that Saponins from Panax japonicus has a significant anti-oxidative effect in vitro.So the aim of the present study was to investigate the brain protective role of Saponins from Panax japonicus and its underlying mechanism.Mice were subcutaneously injected with D-galactose(D-gal,150 mg·kg-1·d-1) for 8 weeks and administered Saponins from Panax japonicus simultaneously.After 8 weeks of treatment,the animal behavior was observed in the open field test and water maze test,and the morphology of hippocampus was detected.The activities and mRNA expressions of antioxidant enzymes as well as the level of malondialdehyde(MDA) were evaluated.The extent of apoptosis was examined by TUNEL assay.The results indicate that Saponins from Panax japonicus markedly ameliorates the D-gal induced learning and memory impairment in both open field test and Morris water maze.Biochemical examination and RT-PCR method revealed that Saponins from Panax japonicus significantly increases the decreased activities and mRNA expressions of superoxide dismutase(SOD),catalase(CAT) and glutathione peroxidase(GSH-Px) and decreases the raised malondialdehyde(MDA) content in the serum and brain of aging mice induced by D-gal.Furthermore,Saponins from Panax japonicus significantly attenuates the D-gal-induced neuronal degeneration and apoptosis in the hippocampus.These results indicate that Saponins from Panax japonicus has a potential protect role on brain aging mice induced by D-gal and its mechanism,at least in part,via modification of the redox system in the organism.     

The immunosuppressive effect of gossypol in mice is mediated by inhibition of lymphocyte proliferation and by induction of cell apoptosis

Aim： To investigate the immunosuppressive effect of gossypol in mice both in vitro and in vivo. Methods： The in vitro effect of gossypol on the proliferation of lymphocytes isolated from lymph nodes of BALB/c mice was determined by CFSE staining and by an MTS assay. Lymphocyte activation and lymphoblastic transformation were evaluated with immunostaining. Cell apoptosis was detected by Annexin-V and Hoechst 33342 staining. The in vivo immunosuppressive effect of gossypol on the DTH reaction was evaluated using a mouse DTH model induced by 2,4-dinitro-1- fluorobenzene （DNFB）. The thickness of the ears was measured, and the histological changes of the mouse auricles were observed after hematoxylin-eosin staining. The proliferation capacity of lymphocytes from DTH mice was also assayed. Results： In vitro, gossypol could significantly inhibit the proliferation of mouse lymphocytes stimulated with phorbol ester plus ionomycin in a dose-dependent manner. Although the expression of the early activation antigen CD69 was not affected, the lymphoblastic transformation of both T and B lymphocyte subsets was significantly suppressed by gossypol. Moreover, gossypol could induce apoptosis of lymphocytes, and the effect was time- and dose-dependent. In vivo, the DTH reaction in mice was markedly alleviated by gossypol injected intraperitoneally. Lymphocytes from drug-treated DTH mice had a reduced proliferation capacity as compared with lymphocytes from untreated DTH mice. Gossypol treatment also markedly reduced the number of infiltrated lymphocytes in the auricles of DTH mice. Conclusion： Gossypol exhibited immunosuppressive effects in mice, probably by inhibition of lymphocyte proliferation and by induction of cell apoptosis.     

The behavioral effects of sertraline, fluoxetine, and paroxetine differ on the differential-reinforcement-of-low-rate 72-second operant schedule in the rat

Rationale: Endogenous opioid systems within the mesencephalic periaqueductal gray matter (PAG) appear to be intricately involved in many affective, defensive, submissive, and reflexive responses, and these systems are activated by aversive stimuli. Objectives: The present experiments evaluated the influence of opioid receptors within the PAG on affective vocal and reflexive responses to aversive stimuli in socially inexperienced, as well as defensive and submissive responses in defeated, adult male Long-Evans rats. Methods: Defeat stress consisted of: (1) an aggressive confrontation with a ”resident” stimulus rat in which the experimental ”intruder” rat exhibited escape, defensive and submissive behaviors [i.e. upright, supine postures and ultrasonic vocalizations (USV)], and subsequently, (2) protection from the resident rat with a wire mesh screen for ca. 25 min. Defeat stress was immediately followed by an experimental session with thermal antinociceptive and tactile startle stimuli (20 psi airpuffs). Results: The μ opioid receptor agonist morphine (0.3, 1, 3 μg IC) attenuated startle-induced USV and the tail-flick reflex in socially inexperienced and defeated rats, with both groups of rats demonstrating equal sensitivity to morphine. Morphine decreased defeat-induced USV and increased the display of the crouch posture in defeated rats; these morphine effects in socially inexperienced and defeated rats were re- versed with the opioid receptor antagonist naltrexone (0.1 mg/kg IP). Conclusions: These results reveal that the ventrolateral PAG is an important site in which μ opioid receptor agonists such as morphine mediate affective vocal and submissive responses, yet this structure is not critical in the display of defeat stress-augmented effects of morphine. Endogenous opioid mechanisms appear to participate in the organization of defensive behavior, namely, to facilitate a shift from active to passive forms of coping. Received: 9 November 1998 / Final version: 29 April 1999     

Environmental animal models for sensorimotor gating deficiencies in schizophrenia: a review

Rationale: Functional imaging studies have revealed overactivity of the hippocampus in schizophrenic patients. Neuropathological data indicate that hyperactivity of excitatory hippocampal afferents and decreased hippocampal GABA transmission contribute to this overactivity. In rats, excitation of the ventral hippocampus, e.g. by NMDA, results in hyperactivity and disruption of sensorimotor gating measured as prepulse inhibition (PPI) of the acoustic startle response, behavioral effects related to psychotic symptoms in humans. Objective: The present study examined whether disinhibition of the ventral hippocampus by the GABA_A antagonist picrotoxin would result in similar psychosis-related behavioral disturbances (hyperactivity, decreased PPI) as NMDA stimulation. Methods and results: Wistar rats received bilateral infusions of subconvulsive doses of picrotoxin (100 or 150 ng/0.5 μl per side) into the ventral hippocampus and were then immediately tested for open field locomotor activity or startle reactivity and PPI. Only the higher dose induced hyperactivity and decreased PPI. Both doses decreased acoustic startle reactivity to a similar extent. The decreased PPI appeared not to result from decreased startle reactivity, but was associated with a diminished potency of the prepulses to inhibit the startle reaction to the startle pulse, indicating a sensorimotor gating deficit. All effects were temporary, i.e. disappeared when the rats were tested 24 h after infusion. Conclusions: Decreased GABAergic inhibition in the ventral hippocampus of rats yielded psychosis-related behavioral effects, very similar to those induced by NMDA stimulation. Thus, a concurrence of decreased GABAergic inhibition and increased afferent excitation in the hippocampus of schizophrenic patients might contribute to psychotic symptoms. Electronic Publication     

百部生药学研究——Ⅸ.中国百部属植物块根中总生物碱的测定与评估

An acid-dye colorimetric method was reported for the determination oftotal alkaloids in 53 samples of Baibu drugs from their growing destricts in 14 provincesand municipalities and its average recovery and its linear range were 96. 1% ( CV <4%)and 20～150μg respectively. The relationship between the total alkaloid content, geogra-phical origins and morphology were discussed. The results showed that: 1. the content of totalalkaloids of stemona was 0.26～3. 1 %; 2. that of Stemona sessilifolia was 0.26～2.17%with the highest content of the sample from Nanyang country in Henan Province; 3.that of S. japonica was 0.83～1.43%; 4. that of S. tuberosa was 0.53～3.1% with thehighest content of sample from Hengyang in Hunan Province; 5.that of S.parviflora was 0.22～0.74% with the highest content of sample from Qongzhong in Hainan Province;and 6.thatof more yellow, solider and stronger samples was higher than that of any other samples.Howerver, that of all bigger samples in shape was not higher than that of smaller ones.     

Depletion of brain serotonin following intra-raphe injections

Objectives: These experiments investigated the effects of selective serotonin (5-HT) depletion on intravenous self-administration of d-amphetamine. Methods: Depletion of brain 5-HT levels was induced by injecting the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the dorsal and median raphe nuclei. Rats were then trained to self-administer d-amphetamine according to various schedule and access conditions via chronically indwelling intravenous catheters. Results: Large reductions of brain 5-HT did not alter responding for a training dose of 120 μg/kg d-amphetamine delivered according to a fixed ratio 1 schedule during 3-h sessions. When the dose of d-amphetamine was altered (0, 3.75, 7.5, 15, 30, 60 μg/kg per infusion) a characteristic inverted U-shaped dose response function was obtained. The 5-HT depleted rats showed increased responding for the lower doses of d-amphetamine, with a large significant increase in responding for the 7.5 μg/kg dose. In these same rats, the suppressive effect of 10 mg/kg fluoxetine on d-amphetamine (60 μg/kg) self-administration was prevented. The 5,7-DHT lesion also did not alter responding for d-amphetamine (120 μg/kg) in longer (8 h) daily access sessions. Responding for d-amphetamine delivered on a progressive ratio schedule, in which response requirements increased for each successive infusion of d-amphetamine, was also determined in 5-HT depleted rats. The number of d-amphetamine infusions was not different from the number of infusions earned by sham-lesioned rats across a range of doses of d-amphetamine (7.5–60 μg/kg). In a final experiment, spontaneous acquisition of self-administration of low doses of d-amphetamine (10 and 30 μg/kg) was measured in 5-HT depleted and control rats. Again, self-administration behaviour in the 5-HT depleted rats did not differ from controls. Conclusions: These results provide no evidence that reducing 5-HT function alters the primary reinforcing effects of self-administered amphetamine. The increase in self-administration of a low dose of amphetamine observed in experiment 1 probably involves some other process such as increased resistance to extinction. Received: 28 December 1998 / Final version: 28 April 1999     

IL-12 suppression,enhanced endocytosis and up-regulation of MHC-II and CD80 in dendritic cells during experimental endotoxin tolerance

Aim： The aim of this study was to investigate endocytosis, MHC-II expression and co-stimulatory molecule expression, as well as interleukin-12 （IL-12） production, in bone marrow dendritic cells （DCs） derived from endotoxin tolerant mice. Methods： Endotoxin tolerance was induced in C57BL/10J mice through four consecutive daily intraperitoneal injections of 1.0 mg/kg of 055：B5 Escherichia coli lipopolysaccharide （LPS）. Bone marrow DCs were isolated in the presence of GM-CSF and IL-4 and purified by anti-CD11c Micro beads. FITC-dextran uptake by DCs was tested by flow cytometric analysis and the percentage of dextran-containing cells was calculated using a fluorescence microscope. The expression of surface MHC-II, CD40, CD80, and CD86 was also detected by flow cytometric analysis. An ELISA was used for the measurement of IL-12 production by DCs with or without LPS stimulation. Results： Endotoxin tolerance was successfully induced in C57BL/10J mice, evidenced by an attenuated elevation of systemic TNF-α. DCs from endotoxin tolerant mice possessed enhanced dextran endocytosis ability. The expression of surface MHC-II and CD80 was higher in DCs from endotoxin tolerant mice than in DCs from control mice, whereas the expression of CD40 and CD86 was not altered. Compared with DCs from normal control mice, DCs from endotoxin tolerant mice produced less IL-12 after subsequent in vitro stimulation with LPS. Conclusion： These data suggest enhanced endocytosis, selective up-regulation of MHC-II and CD80 and IL-12 suppression in DCs during in vivo induction of endotoxin tolerance.     

六应丸抗炎和镇痛活性的实验研究

目的：观察六应丸的抗炎和镇痛作用,为其在临床应用提供实验依据。方法：采用醋酸致小鼠扭体模型和热刺激致疼痛模型,考察其镇痛活性;采用二甲苯所致的小鼠耳肿胀和酵母所致大鼠足趾肿胀,考察其抗炎作用,并和六神丸的疗效进行比较。结果：六应丸能有效抑制醋酸引起的小鼠扭体反应、二甲苯所致的小鼠耳肿胀和酵母所致大鼠足趾肿胀,其抗炎镇痛作用与六神丸无显著差异。结论：六应丸具有显著的抗炎镇痛作用。     

Coordination of copper with aspirin improves its anti-inflammatory activity

Anti-inflammatory activity of copper aspirinate administered orally was investigated in several models of inflammation. The results showed that copper aspirinate 50 mg/kg markedly inhibited inflammatory processes of either ear swelling induced by xylene in mice or turpentine-elicited air pouch granuloma in rats, with an activity equal to that of aspirin 200 mg/kg. Copper aspirinate 25 mg/kg significantly suppressed acute paw oedema produced by injecting 1% carrageenan, with an action time lasting over 6 h; and that copper aspirinate 100 mg/kg decreased the content of protein in the inflammatory exudate from rats with air pouch synovitis caused by acetic acid. It is suggested that, compared with aspirin, copper aspirinate showed a similar anti-inflammatory spectrum but greater anti-inflammatory activity. Zhiqiang S, Lei WY, Li L, Chen ZH, Liu WP. Coordination of copper with aspirin improves its antiinflammatory activity. Inflammopharmacology 1998;6:357-362     

Cancer chemopreventive activities of S-3-1, a synthetic derivative of danshinone

Salvia miltiorrhiza is a traditional Chinese medicine which has been well documented for its anti-cancer effects. Based on the structure of danshinone, one of the active compounds derived from Salvia miltiorrhiza, we synthesized a simplified phenolic analog, S-3-1, and tried to explore its possible actions in preventing the development of cancer. With the Ames test, S-3-1 was found to efficiently suppress the mutagenicity of benzo[alpha]pyrene. This result is consistent with the inhibitory effect of S-3-1 on the activation of benzo[alpha]pyrene by hepatic microsomal enzymes. Besides the anti-initiation effects, S-3-1 could significantly inhibit the croton oil-induced increase of mouse skin epithermal ornithine decarboxylase activity. Moreover, S-3-1 quenched both superoxide and hydroxyl free radicals whereas it inhibited lipid peroxidation in the in vitro model. These results suggest that S-3-1 might act as anti-initiation and anti-promotion agents through reversing the biochemical alterations induced by carcinogen during carcinogenesis. Therefore, we further investigated the effects of S-3-1 on carcinogenesis. In vitro, S-3-1 inhibited the benzo[alpha]pyrene-induced transformation of V79 Chinese hamster lung fibroblasts. At 10-40 mg/kg, S-3-1 was found to inhibit the development of DMBA/croton oil-induced skin papilloma in mice through decreasing the incidence of papilloma, prolonging the latent period of tumor occurrence and reducing tumor number per mouse in a dose-dependent manner. We concluded from this study that S-3-1 might be developed as a new chemopreventive drug.     

Cancer Chemopreventive Activities of S-3-1, A Synthetic Derivative of Danshinone

Abstract

Salvia miltiorrhiza is a traditional Chinese medicine which has been well documented for its anti-cancer effects. Based on the structure of danshinone, one of the active compounds derived from Salvia miltiorrhiza, we synthesized a simplified phenolic analog, S-3-1, and tried to explore its possible actions in preventing the development of cancer. With the Ames test, S-3-1 was found to efficiently suppress the mutagenicity of benzo[α]pyrene. This result is consistent with the inhibitory effect of S-3-1 on the activation of benzo[α]pyrene by hepatic microsomal enzymes. Besides the anti-initiation effects, S-3-1 could significantly inhibit the croton oil-induced increase of mouse skin epithermal ornithine decarboxylase activity. Moreover, S-3-1 quenched both superoxide and hydroxyl free radicals whereas it inhibited lipid peroxidation in the in vitro model. These results suggest that S-3-1 might act as anti-initiation and anti-promotion agents through reversing the biochemical alterations induced by carcinogen during carcinogenesis. Therefore, we further investigated the effects of S-3-1 on carcinogenesis. In vitro, S-3-1 inhibited the benzo[α]pyrene-induced transformation of V79 Chinese hamster lung fibroblasts. At 10-40 mg/kg, S-3-1 was found to inhibit the development of DMBA/croton oil-induced skin papilloma in mice through decreasing the incidence of papilloma, prolonging the latent period of tumor occurrence and reducing tumor number per mouse in a dose-dependent manner. We concluded from this study that S-3-1 might be developed as a new chemopreventive drug.     

Antidiabetic effect of a new peptide from Squalus mitsukurii liver (S-8300) in streptozocin-induced diabetic mice

We have evaluated the antidiabetic effect of S-8300 (a peptide extracted from shark liver (Squalus mitsukurii)) in streptozocin (streptozotocin)-diabetic mice. Diabetes was induced by a single intravenous injection of streptozocin (150 mg kg(-1)). The effects of S-8300 (3 or 10 mg kg(-1)) on diabetic mice were investigated by observing the changes in the levels of fasting plasma glucose, glycosylated haemoglobin, hepatic glycogen, triglycerides, cholesterol, free fatty acid, superoxide dismutase, and malondialdehyde. Body weight, kidney weight and the degree of injured beta-cells in pancreatic islets were recorded also. Diabetic mice treated with S-8300 showed a significant decrease in the levels of fasting plasma glucose, glycosylated haemoglobin, triglycerides, cholesterol, free fatty acid in plasma and malondialdehyde in tissues. The animals showed a significant increase in the content of hepatic glycogen and the activity of superoxide dismutase. Treatment with S-8300 attenuated the degree of injured beta-cells in the pancreatic islets. The effect of S-8300 was similar to that of glibenclamide (5 mg kg(-1)).     

Effect of a new bronchodilator, S-1540 (Bitolterol) and S-1541 on the tracheo-bronchial and cardiovascular system]

The actions on the bronchial smooth muscle and cardiovascular system S-1540 (Bitolterol) (Shionogi Pharmaceuticals), a new bronchodilator which is chemically related to isoprenaline, and S-1541 which is the active metabolite of S-1540 were studied in comparison with the action of isoprenaline (isoproterenol) and orciprenaline (metaproterenol). 1) The relaxing effect on isolated guinea-pig tracheal muscle constricted previously with histamine BaCl2 or acetylcholine was highest with S-1541, followed by isoprenaline and orciprenaline, in that order, and lowest with S-1540. The relaxing effect of S-1541 on acetylcholine-induced tracheal constriction was reduced and that of S-1540 was completely abolished by a previous treatment with propranolol. The relaxing actions of those drugs on bronchial spasms induced by histamine in vivo were highest with S-1541, followed by isoprenaline, and lowest with S-1540. 2) All these drugs exhibited the depressor and positive chronotropic actions in guinea-pigs. The potencies of the actions were found to be in the following order; isoprenaline was most potent, followed by S-1541 with a little less intensity, orciprenaline much weaker, and S-1540 still weaker with a positive chronotropic action of about 1/1000 of S-1541 and depressor action about 1/500. In the open chest guinea-pig, positive inotropic and chronotropic actions of S-1541 were about the same or slightly more potent than those of isoprenaline; S-1540 had a very weak action, being only about 1/1000 as active as S-1541. These actions of S-1540 were completely eliminated by propranolol pretreatment. S-1540 induced to remarkable changes in the electrocardiogram wave forms even in high doses. 3) Those drugs elicited the depressor, positive chronotropic and inotropic actions in rabbits and dogs. In rabbits, isoprenaline was most potent; S-1541 was similar to or a little weaker than isoprenaline; and S-1540 was extremely weak. In the dog, isoprenaline showed the highest of the above effect, followed by S-1541, orciprenaline and S-1540 in that order, with S-1540 having an extremely low activity. 4) The actions of S-1541 and isoprenaline appeared very rapidly but were of short duration, the duration of orciprenaline was moderate, and the actions of S-1540 rapidly appeared and were of an extremely long duration. It is suggested that S-1540 itself has pharmacological activities in vivo and the active metabolites such as S-1541 also have the activities. S-1540 can be administered by the oral route, is of long duration, and is thus considered to be a bronchodilator with a relative high specificity.     

谷胱甘肽拮抗环磷酰胺和丙烯醛所致PC3细胞毒性及小鼠免疫抑制

观察谷胱甘肽在体外对环磷酰胺及其代谢产物丙烯醛所致正常小鼠脾细胞增殖抑制和人前列腺癌ＰＣ３细胞体外生长抑制的对抗作用,同时观察ＧＨＳ在体内对Ｃｙｃ所致正常小鼠及荷Ｓ－１８０小鼠免疫抑制及抑菌的影响。方法：用ＭＴＴ法和考马斯亮蓝法测定正常小鼠脾细胞及人前列腺癌ＰＣ３细胞体外增殖抑制率,并测定小鼠抗ＳＲＢＣ血清溶血素,凝集素含量及脾细胞增殖反应。     

Diuretic effects of a novel uricosuric antihypertensive S-8666 in rats,mice, monkeys,and dogs: Comparison with furosemide and trichlormethiazide

Oral dose-response relationships of S-8666 to Na excretion were established in male and female Sprague-Dawley rats (3–100 mg/kg), male and female ddy mice (3–300 mg/kg), female cynomolgus monkeys (2–50 mg/kg), and female beagle dogs (3–100 mg/kg). The natriuretic potency of S-8666 was almost comparable to that of furosemide in rats but was lower in mice, monkeys, and dogs. The maximal effects were similar for S-8666 and furosemide, which had higher ceiling values than trichlormethiazide (TCM) in rats, mice, monkeys, and dogs. Thus, S-8666 seems to have a “loop diuretic” property like furosemide. After oral administration of S-8666 to rats (20–100 mg/kg), the onset of natriuresis was rapid, with the peak effect occurring within 1–2 hr. TCM showed a longer lasting pattern of natriuresis than S-8666 and furosemide. With intravenous administration (1–10 mg/kg) to rats, the t_1/2 for natriuresis was 16–20 min for S-8666 and furosemide in rats. S-8666 showed enantioselectivity; its (S)-(–)-form was natriuretic, whereas the (R)-(+)-form was inactive. These results indicate that S-8666 is a diuretic with a high ceiling property that has a lower potency than TCM and a longer lasting effect than furosemide.     

Effect of a novel thromboxane A2 receptor antagonist, S-145, on collagen-induced ECG changes and thrombocytopenia in rodents

The effects of S-145, a newly synthesized thromboxane, A2 (TXA2) receptor antagonist, were studied on collagen-induced changes of electrocardiograms (ECG) in rats and thrombocytopenia in rats and mice. Intravenous injection of collagen induced abnormal ECG changes such as elevation or depression of the ST segment, arrhythmia and in severe cases, cardiac arrest. These changes peaked at 3-5 min and lasted for 10 min. S-145 showed remarkable improvement of the ECG changes by both intravenous and oral administration, and the action lasted over 4 hr with 10 mg/kg, p.o. Reference compounds ONO-3708, dazoxiben and aspirin also improved the ECG changes significantly, but ticlopidine was ineffective. S-145 prevented the collagen-induced thrombocytopenia in rats but did not affect the increase in plasma TXB2 levels. S-145 also prevented collagen-induced thrombocytopenia in mice after either intravenous or oral administration in a dose-dependent manner. The efficacy of S-145 was 4-13 times greater than those of the reference compounds, and the duration of action was over 4 hr with 10 mg/kg, p.o. These results indicate that S-145 is a potent, orally, active and long-lasting TXA2 receptor antagonist, which will be promising as a drug for thromboembolism and ischemic heart disease caused by platelet activation.