Anti-inflammatory and anti-ulcer properties of hypolaetin-8-glucoside, a novel plant flavonoid

The anti-inflammatory, analgesic and anti-ulcer activities of a novel flavonoid, hypolaetin-8-glucoside, obtained from Sideritis mugronensis, have been tested in the rat. The flavonoid was more potent than phenylbutazone in suppressing the acute phase of adjuvant-carrageenan-induced inflammation, but had less effect in the prolonged inflammatory phase. However, unlike phenylbutazone, it did not cause gastric erosions. Both compounds were equiactive in inhibiting the development of carrageenan-induced abscesses, whereas phenylbutazone had greater analgesic activity in tests on pressure pain threshold. The flavonoid and cimetidine both prevented the formation of cold-restraint induced gastric lesions, but cimetidine was more potent. These results show that hypolaetin-8-glucoside combines both anti-inflammatory and anti-ulcer properties and suggest that it may offer useful alternatives to anti-inflammatory drugs of the aspirin type.     

Some aspects of the inhibitory activity of hypolaetin-8-glucoside in acute inflammation

Hypolaetin-8-glucoside (H-8-G) has been examined for its mode of action in several models of acute inflammation. Its anti-inflammatory activity in carrageenan-induced inflammation of the rat hind-paw is not affected either by adrenalectomy or by phentolamine given with propranolol. H-8-G and its aglycone, hypolaetin, did not antagonize the actions of histamine, 5-hydroxytryptamine (5-HT), bradykinin or prostaglandin E2 (PGE2) on various smooth muscle preparations in-vitro, but protected erythrocytes from heat-induced lysis. The glycoside was more potent than troxerutin on capillary permeability increased by histamine and exerted inhibitory effects on protein exudation, leucocyte migration and beta-glucuronidase activity in the carrageenan air pouch, thereby showing some difference from indomethacin. These results are discussed in relation to the features of non-steroidal anti-inflammatory drugs (NSAID) and flavonoid anti-inflammatory actions.     

Lipid peroxidation modifies the effect of phenolic anti-inflammatory drugs on prostaglandin biosynthesis

The effects of phenolic anti-inflammatory drug, MK-447, on prostaglandin (PG) I2 and thromboxane (TX) A2 biosynthesis by rat dental pulp tissue were evaluated in the presence of 10 mM mannitol (MA) or 1 mM ascorbic acid with 0.3 mM Fe2+ (A + F). Although MK-447 alone at 1 and 10 microM had no significant effects, MK-447 at 100 microM stimulated both PGI2 and TXA2 biosynthesis, and suppressed the lipid peroxidation in the pulp tissue as estimated by thiobarbituric acid method. MA also reduced the lipid peroxidation, but had no effect on PG and TX production. However, in the presence of MA, the stimulatory effect of MK-447 was potentiated, and the significant effects were observed at concentrations higher than 1 microM. In contrast, A + F remarkably stimulated the lipid peroxidation, and inhibited both PG and TX biosynthesis. In the presence of A + F, MK-447 showed no stimulatory effect, and contrary, at 100 microM inhibited PG and TX production. These results suggest that the cellular levels of lipid peroxidation exert a significant influence on the effects of phenolic anti-inflammatory drugs like MK-447 on PG biosynthesis. The possible mechanism of action for such drugs has been discussed in view of the significance of lipid peroxidation in inflammatory condition.     

Effect of a new anti-inflammatory drug (oxametacine) on the prostaglandin biosynthesis

The influence of oxametacine, 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indoyl]acetohydroxamic acid, a new non-steroidal anti-inflammatory drug, on prostaglandin-synthetase was studied in vitro on rat spleen tissue. The drug exerts an inhibitory effect on prostaglandin biosynthesis which closely mimics that of indomethacin. On the other hand, oxametacine proves more active than other non-steroidal anti-inflammatory agents, namely ketoprofen, flufenamic acid, phenylbutazone and acetylsalicylic acid.     

Correlation between anti-inflammatory properties and inhibition of prostaglandin biosynthesis in vitro

Four chemically related compounds (two benzofurans, one thianaphthene and one indolyl derivative) have been compared with aspirin and indomethacin in their ability to inhibit prostaglandin (PG) synthesis in vitro by microsomes of bull seminal vesicles with tritiated arachidonate as substrate. Two of these substances [L 8027:3-(2-isopropyl indolyl)-3 pyridyl ketone and L 8109:(5-chloro-3-methyl-2-benzo [b] thienyl) acetic acid] inhibit the synthesis and show marked anti-inflammatory action in the usual pharmacological tests; however, there is no strict correlation, the most powerful inhibitor being the least active anti-inflammatory agent. A benzofuran derivative with a low anti-inflammatory action, but distinctly fibrinolytic [L 2197:2-ethyl-3-(4-hydroxybenzoyl) benzofuran] does not inhibit PG synthesis. A powerful fibrinolytic agent (L 7035:2-isopropyl-3-isonicotinoyl benzofuran), practically devoid of anti-inflammatory action, is a more active inhibitor of PG synthesis than aspirin. It seems that the PG synthetase system of the seminal vesicles does not react in vitro to inhibitors in the same way as that responsible for PG synthesis in tissues damaged by carrageenan or the Freund adjuvant. Such a discrepancy might be due to differences in the tissue distribution of the inhibitors and this could explain the lack of correlation between the in vivo and the in vitro potencies of drugs like L 8027 and L 8109. Localization of L 7035, on the other hand, would be such that the anti-aggregating properties can fully develop, while the inflamed sites remain out of reach of the drug.     

黄酮衍生物的合成及其抗炎活性研究

目的 设计合成一系列黄酮衍生物,并考察其抗炎活性。方法 采用Baker-Venkataraman反应合成单羟基取代的黄酮,进而经Williamson反应合成黄酮衍生物;以布洛芬为阳性对照药,采用巴豆油致小鼠耳肿胀实验对5个目标化合物（1a、1c、1d、2a、2c）的抗炎活性进行了评价。结果与结论 以2’,5’-二羟基苯乙酮或2’,4’-二羟基苯乙酮为原料,合成了12个未见文献报道的新化合物,其结构经核磁共振氢谱、高分辨质谱及红外光谱确证。初步的药理筛选结果表明化合物6-[2-(4-吗啉基)乙氧基]黄酮(1a)和2’-氟-7-(2-二甲氨基甲酰甲氧基)黄酮(2c)具有潜在的抗炎活性。     

Antiedema effects of basic nonsteroidal anti-inflammatory drugs that are not inhibitors of prostaglandin biosynthesis

Antiedema effects of basic nonsteroidal anti-inflammatory drugs that don't inhibit prostaglandin biosynthesis were investigated with carrageenin-induced hind paw edema in rats. Locally administered mepirizole, tiaramide.HCl and aminopyrine, the basic nonsteroidal anti-inflammatory drugs, didn't show any suppression against the edema formation. In the case of indomethacin, phenylbutazone and ketoprofen, inhibitors of prostaglandin biosynthesis, they inhibited the edema formation. Inhibitory effects of orally and subcutaneously administered basic nonsteroidal anti-inflammatory drugs such as tiaramide.HCl and benzydamine on the edema formation were more potent in fasted rats than in nonfasted rats. In the case of acidic nonsteroidal anti-inflammatory drugs such as indomethacin and ibuprofen, their inhibitory activities were almost the same in both the fasted rats and nonfasted rats. These results suggest that the site of action of the basic nonsteroidal anti-inflammatory drugs such as tiaramide.HCl and mepirizole is not the inflamed site, and certain systemic effects may contribute to the anti-edema effects.     

Actions of two novel prostaglandin analogs, SC-29169 and SC-31391, on guinea pig and human isolated urinary bladder.

1. We examined the effects of two novel PGE1 analogs, SC-29169 and SC-31391, on bladder muscle isolated preparations from guinea pig and man, in comparison with some naturally-occurring prostanoids and misoprostol. 2. In the guinea pig detrusor muscle, both prostaglandin analogs enhanced twitch responses elicited by field stimulation in the following order of potency: SC-31391 greater than SC-29169 greater than PGF2 alpha greater than or equal to PGE2, while a well-defined contractile effect was elicited only by SC-31391. 3. In the human detrusor muscle, nerve-mediated responses were not modified by prostaglandin analogs, as well as by PGF2 alpha or PGE2, while a contractile effect was observed with the same compounds: PGF2 alpha = SC-31391 greater than SC-29169 = PGE2 = PGE1. 4. The selective EP1-agonist, misoprostol did not induce any effect, in both guinea pig and human bladder. 5. These data suggest that the effect of prostaglandins in the bladder muscle differs according to the animal species and that, in the human detrusor muscle, SC-31391 and SC-29169 probably stimulate FP receptors.     

Actions of prostaglandin E2 metabolites on skin microcirculation

The actions of prostaglandin, E2 on skin microcirculation were compared with two of its metabolites. 2-10 ng prostaglandin E2, 2-10 micrograms 15-keto prostaglandin E2 and 5-10 micrograms 13,14-dihydro-15-keto prostaglandin E2 produced the following dose-related effects: increased area and intensity of erythema in human skin, increased vascular permeability in rat skin, potentiation of the increased vascular permeability elicited by either histamine or bradykinin, potentiation of carrageenan-induced oedema in the rat paw. The prostaglandin E2 metabolites are about 1000 times less active than the parent prostaglandin and are unlikely to account for the inflammatory actions of prostaglandin E2.     

Curcumin,resveratrol and flavonoids as anti-inflammatory,cyto- and DNA-protective dietary compounds

Numerous dietary compounds, ubiquitous in fruits, vegetables and spices have been isolated and evaluated during recent years for their therapeutic potential. These compounds include flavonoid and non-flavonoid polyphenols, which describe beneficial effects against a variety of ailments. The notion that these plant products have health promoting effects emerged because their intake was related to a reduced incidence of cancer, cardiovascular, neurological, respiratory, and age-related diseases. Exposure of the body to a stressful environment challenges cell survival and increases the risk of chronic disease developing. The polyphenols afford protection against various stress-induced toxicities through modulating intercellular cascades which inhibit inflammatory molecule synthesis, the formation of free radicals, nuclear damage and induce antioxidant enzyme expression. These responses have the potential to increase life expectancy. The present review article focuses on curcumin, resveratrol, and flavonoids and seeks to summarize their anti-inflammatory, cytoprotective and DNA-protective properties.     

黄芩茎叶总黄酮的抗炎作用机制的研究

中药黄芩传统以其地下部分入药 ,而产量是其 2倍的黄芩茎叶长期废弃不用 ,造成了极大的资源浪费。近几年 ,承德医学院中药研究所对黄芩茎叶有效成分进行了系统研究。本文为研究黄芩茎叶总黄酮的抗炎作用及其机制 ,采用了大鼠足趾肿模型和小鼠腹膜炎模型两种模型检测治疗组、对照组之间前列腺素Ｅ2 、一氧化氮等物质的含量 ,旨在为黄芩地上部分合理利用提供一些实验依据。1　材料黄芩茎叶总黄酮室温干燥保存 ,纯度为 60 .2 8% ,由承德医学院中药所提供 ,实验时用生理盐水溶液溶解成适当浓度的药液供用。ＳＸ72 1分光光度计 (山东高密仪器厂 )…     

Effects of sulphasalazine and its metabolites on prostaglandin synthesis, inactivation and actions on smooth muscle

1 We have investigated the effects of sulphasalazine and of its principal colonic metabolites (5-aminosalicylic acid and sulphapyridine) on prostaglandin inactivation, synthesis and actions on gastrointestinal smooth muscle.

2 Sulphasalazine inhibits prostaglandin F_2α breakdown in 100,000 g supernatants in all organs so far tested from 7 species with an ID₅₀ of approx. 50 μM; it has a selective action on prostaglandin 15-hydroxydehydrogenase and does not inhibit prostaglandin Δ-13 reductase, prostaglandin 9-hydroxydehydrogenase or `enzyme X' at millimolar concentrations. Enzyme activities were measured radiochemically or by bioassay.

3 Sulphapyridine and 5-aminosalicylic acid do not inhibit prostaglandin inactivation in vitro (4 species tested). A methyl analogue of sulphasalazine is a more potent inhibitor than the parent compound. Rabbit colon prostaglandin F_2α metabolism in vitro was inhibited by the following drugs with ID₅₀ values (μM) of: diphloretin phosphate 20, sulphasalazine 50, indomethacin 220, frusemide 1000 and aspirin 10,000. A similar rank order of potencies was obtained with rabbit kidney.

4 Sulphasalazine at 50 to 100 μM inhibited inactivation of prostaglandin E₂ in the perfused rat and guinea-pig lung by 3 to 40% (rat) and 32 to 100% (guinea-pig) when measured by superfusion cascade bioassay and of prostaglandin F_2α by 43.6 ± 6.5% in rat lung perfused with 50 μM sulphasalazine and assayed radiochemically.

5 Prostaglandins E₁ and E₂ were 97.0 ± 8.2% and 92.3 ± 6.8% inactivated in the lungs after intravenous injection in the anaesthetized rat as measured by reference to their vasodepressor potencies when injected intra-arterially. Prostaglandin A₂ was not similarly inactivated. Pulmonary inactivation was prevented in the presence of an intravenous infusion of 16.3 μg kg^-1 min^-1 sulphasalazine and partially inhibited at a lower infusion rate.

6 Prostaglandin biosynthesis from arachidonic acid was measured in microsomal preparations from four sources by bioassay and radiochemical methods. Indomethacin was a potent inhibitor (ID₅₀ 0.8 to 4.1 μM) but sulphasalazine and its methyl analogue were very weak inhibitors (ID₅₀ 1500 to > 5000 μM), 5-aminosalicylic acid was weaker still and sulphapyridine inactive.

7 Sulphasalazine at 50 μM did not affect the actions of prostaglandins on five smooth muscle preparations; at 500 μM there was a rapidly reversible and probably non-specific antagonism of responses to low doses of prostaglandins.

8 The specificity and selectivity of the interaction of sulphasalazine and its metabolites with the formation, breakdown and actions of prostaglandins are discussed.

     

The effect of indomethacin and carprofen on gastric prostaglandin biosynthesis

The effect of indometacin (3 X 50 mg daily), carprofen (Imadyl) (2 X 150 mg daily) and placebo (3 X daily) on gastric juice secretion, acidity, prostanoid concentration (PGE2, PGF2 alpha and TXB2) and excretion of the major urinary metabolite of PGF (PGF-MUM) were investigated in a single-blind cross-over study in nine healthy volunteers after 3-day treatment periods separated by one-week washout periods between treatments. Indometacin proved to be a classical cyclooxygenase inhibitor (strong inhibition of PGE2 and TXB2 before and after pentagastrin stimulation and of PGF-MUM) while carprofen was an atypical inhibitor (weak inhibition of PGE2 before pentagastrin stimulation and no inhibition after, strong inhibition of TXB2 but without influence on PGF-MUM). The weak inhibition of PGE2-biosynthesis by carprofen might be related to its low incidence of gastric side effects.