Gastroprotection and effect of the simultaneous administration of Cuachalalate (Amphipterygium adstringens) on the pharmacokinetics and anti-inflammatory activity of diclofenac in rats

This work aimed to study the effect of Cuachalalate methanol extract (CME) on the anti-inflammatory activity and pharmacokinetics of diclofenac sodium, a frequently prescribed non-steroidal anti-inflammatory drug (NSAID). The gastroprotective effect of CME on the gastric injury induced by diclofenac was studied in rats. CME showed a gastroprotective effect of 15.7% at 1 mg kg(-1) and 72.5% at dose of 300 mg kg(-1). Omeprazole, used as anti-ulcer reference drug, showed gastroprotective effects of 50-89.7% at doses tested (1-30 mg kg(-1)). The value of the 50% effective dose for the anti-inflammatory effect of diclofenac sodium (ED50 = 1.14 +/- 0.23 mg kg(-1)) using carrageenan-induced rat paw oedema model, was not modified by the concomitant administration of 30 or 100 mg kg(-1) of CME. The effect of CME (30, 100 and 300 mg kg(-1), p.o.) on the pharmacokinetics of diclofenac sodium was studied. It was observed that the simultaneous administration of diclofenac sodium and 300 mg kg(-1) of CME decreased significantly the values of Cmax (7.08 +/- 1.42 microg mL(-1)) and AUC (12.67 +/- 2.97 microg h mL(-1)), but not the value of tmax (0.13 (0.1-0.25)h) obtained with the administration of diclofenac alone. The simultaneous administration of 30 or 100 mg kg(-1) of CME did not modify the pharmacokinetic parameters of diclofenac. The experimental findings in rats suggest that CME at doses lower than 100 mg kg(-1) protects the gastric mucosa from the damage induced by diclofenac sodium without altering either the anti-inflammatory activity or the pharmacokinetics of this NSAID.     

Oral administration of Ginkgo biloba extract, EGb-761 inhibits thermal hyperalgesia in rodent models of inflammatory and post-surgical pain

BACKGROUND AND PURPOSE: Studies in vitro suggest that the standardised extract of Ginkgo biloba, EGb-761 has anti-inflammatory properties and modulatory effects on key pain-related molecules. This study investigated the analgesic and anti-inflammatory effects of EGb-761 on carrageenan-induced inflammatory and hindpaw incisional pain. EXPERIMENTAL APPROACH: Adult male Wistar rats (n=6-10/group; 250-420 g) were injected intradermally with carrageenan into the left hindpaw or anaesthetised with isoflurane (2%) and a longitudinal 1 cm incision was made through the skin, fascia and plantaris muscle of the hindpaw. EGb-761 (3, 10, 30, 100 or 300 mg kg(-1)), diclofenac (5 mg kg(-1)) or drug-vehicle was administered 3 h post-carrageenan/post-surgery. Hindpaw withdrawal latency (in seconds) to thermal stimulation, response threshold (in grams) to mechanical stimulation and paw volume were measured. KEY RESULTS: Carrageenan induced significant mechanical allodynia, thermal hyperalgesia and paw oedema at 6 h post-carrageenan, while paw incision surgery induced significant mechanical allodynia and thermal hyperalgesia at 6 and 24 h post-surgery. Administration of EGb-761 dose-dependently inhibited thermal hyperalgesia and was equally effective as diclofenac (5 mg kg(-1)) in both the carrageenan and hindpaw incision model. EGb-761 had no effect on carrageenan- or incision-induced mechanical allodynia or paw oedema. Diclofenac significantly reduced mechanical allodynia in both models and carrageenan-induced paw oedema. CONCLUSIONS AND IMPLICATIONS: EGb-761 dose-dependently alleviates acute inflammatory and surgically induced thermal hyperalgesia and is comparable to diclofenac, a commonly prescribed non-steroidal anti-inflammatory drug. This indicates that EGb-761 has analgesic potential in acute inflammatory pain.     

Evaluation of analgesic and anti-inflammatory activities of Nectandra megapotamica (Lauraceae) in mice and rats

The bioactivity-guided phytochemical investigation of the crude hydralcoholic extract of Nectandra megapotamica was carried out using the abdominal constriction test in mice, which led to the isolation of three active compounds: alpha-asarone (1), galgravin (2) and veraguensin (3). The crude extract (EBCA, 300 mg kg(-1)) and isolated compounds 1,2, and 3, at different doses, were evaluated using the acetic acid-induced abdominal constriction test in mice, carrageenan-induced paw oedema in rats, and hot plate tests in rats. The EBCA showed a significant effect in the abdominal constriction and hot plate tests, but did not show activity in the rat paw oedema assay. All isolated compounds displayed activity in the abdominal constriction test, but only compound 1 was active in the hot plate test. Compounds 2 and 3 displayed activity in the anti-inflammatory assay. It was suggested that the analgesic effects obtained for EBCA could be due mainly to the presence of its major compound, alpha-asarone (1).     

Evaluation of the anti-inflammatory, anti-nociceptive and gastric effects of Ginkgo biloba in the rat.

Ginkgo biloba extract (GbE) was assessed in models of acute inflammation induced by carrageenan, formalin or capsaicin in the rat, in models of nociceptive pain, such as hot-plate (55 degrees C) latency, tail-electric stimulation assay and capsaicin-induced paw licking and in the model of acute gastric damage induced by indomethacin. The agent showed marked anti-inflammatory activity in the carrageenan model of paw oedema. When given subcutaneously (s.c.) (25 and 50 mg kg(-1)) 30 min before challenge, GbE inhibited paw oedema with a maximal effect of 43.7 and 56.9%, respectively, at 2h post-carrageenan. Significant inhibition of oedema was also observed when GbE (50 mg kg(-1), s.c.) was given 30 min after carrageenan challenge. The agent was also active p.o. in acute inflammation caused by carrageenan. The administration of GbE with indomethacin, rofecoxib, celecoxib, dexamethasone or melatonin resulted in an additive effect. GbE (50 mg kg(-1), s.c.) caused significant inhibition of formalin-induced paw oedema, but did not reduce the capsaicin-induced paw oedema. In tests of nociception, GbE (25, 50 or 100 mg kg(-1)) decreased in dose-dependent manner the capsaicin-induced hind paw licking time and was similarly effective in the hot-plate assay of nociception. In contrast, when assessed in the tail-electric stimulation test, GbE was only effective in the highest dose (100 mg kg(-1)). In pylorus-ligated rats, GbE (25 or 50 mg kg(-1)) increased gastric acid secretion, but reduced gastric mucosal damage caused by IND. Results suggest that GbE may be of clinical value as an anti-inflammatory and analgesic drug alone or in conjunction with NSAIDs.     

Anti-inflammatory and antinociceptive effects in rodents of the essential oil of Croton cajucara Benth

The plant Croton cajucara Benth. (Euphorbiaceae) is widely used in Amazonian folk medicine for the treatment of a wide range of illnesses. In this investigation the analgesic and anti-inflammatory properties of the essential oil from the bark of C. cajucara Benth., administered orally, were determined in several standard rodent models of pain and inflammation. We observed that pretreatment with essential oil significantly reduced the latency of sleeping time evoked by pentobarbital compared with the control group (P < 0.001). Doses of 100 or 1000 mg kg(-1) also increased the sleeping time induced by pentobarbital (30.9 +/- 3.91 and 52.1 +/- 15.6 min, respectively) compared with the negative control (12.4 +/- 4.27 min). We investigated the antinociceptive effect of the essential oil in chemical (acetic acid) and thermal (hot-plate) models of nociception in mice. Dipyrone (200 mg kg(-1)) and the highest doses of the essential oil (1000 mg kg(-1)) significantly inhibited acetic acid-induced abdominal constriction in mice (5.00 +/- 1.38 and 6.8 +/- 2.1 constrictions, respectively) compared with the negative control (33.1 +/- 2). The same dose of essential oil also raised the pain thresholds of mice in the hot-plate test and significantly (P < 0.05) increased the latency at all observation times. In acetic acid-induced abdominal constriction in mice pretreatment of the animals with naloxone (5 mg kg(-1)) significantly reversed the analgesic effect of morphine and of the essential oil at the highest dose (1000 mg kg(-1)). The essential oil of C. cajucara was also investigated for its anti-inflammatory properties. At the lowest dose (100 mg kg(-1)) the essential oil had anti-inflammatory effects in animal models of acute (carrageenin-induced paw oedema in mice) and chronic (cotton pellet granuloma) inflammation. The essential oil at doses of 50, 100 and 200 mg kg(-1) significantly and dose-dependently inhibited carrageenan-induced oedema (49 +/- 5; 37 +/- 5; 34 +/- 8 mg, respectively) compared with the negative control (74 +/- 8 mg). The essential oil (100 mg kg(-1)) also inhibited chronic inflammation by 38% whereas diclofenac inhibited it by 36%. However, the essential oil did not inhibit the migration of neutrophils into the peritoneal cavity. These data show that the essential oil from C. cajucara contains compounds that had a significant antinociceptive effect when the oil was administered at the highest dose. This effect seems to be related to interaction with the opioid system. The essential oil also had a significant anti-inflammatory effect in acute and chronic inflammation models when administered at lower doses. This effect seems to be related to cyclooxygenase inhibition.     

Effects of dantrolene sodium in rodent models of cardiac arrhythmia

Dantrolene sodium has been compared with reference antiarrhythmic agents in rodent models of cardiac arrhythmia. In a coronary-artery-ligation model in rats, dantrolene sodium (3, 10 and 20 mg/kg i.v.) significantly decreased extrasystoles, episodes of ventricular tachyarrhythmia, and frequency, duration, and total episodes of ventricular fibrillation in a dose-dependent manner. In an electrically induced fibrillation model in rats, dantrolene sodium (10 and 20 mg/kg i.v.) significantly raised ventricular fibrillation threshold in a dose- and time-dependent manner. In contrast to its activity in these models, dantrolene sodium was not active in two chemically induced models involving automaticity. Aconitine-induced arrhythmias in rats and mice and ouabain-induced arrhythmias in guinea pigs were not suppressed by i.v. (10 or 20 mg/kg) or i.p. (100-3000 mg/kg) doses of the drug. These results show that the antiarrhythmic potential of dantrolene sodium, predicted by in vitro Class III and Class IV electrophysiological effects, is expressed in whole animal models.     

Geldanamycin, an inhibitor of heat shock protein 90 (Hsp90) mediated signal transduction has anti-inflammatory effects and interacts with glucocorticoid receptor in vivo

Histamine, vascular endothelial growth factor, acetylcholine, oestrogen as well as fluid shear stress activates a mechanism that recruits heat shock protein 90 to the endothelial nitric oxide synthase. The interaction between Hsp90 and eNOS enhances the activation of the enzyme in cells and in intact blood vessels leading to NO production. Intraplantar administration of carrageenan (50 microl paw(-1)) to mice causes an oedema lasting 72 h. Geldanamycin (0.1, 0.3, 1 mg kg(-1)), a specific inhibitor of Hsp-90, that inhibits endothelium-dependent relaxations of the rat aorta, mesentery and middle artery inhibits carrageenan-induced mouse paw oedema in a dose dependent manner. Co-administration to mice of dexamethasone (1 mg kg(-1)) with geldanamycin (0.3 mg kg(-1)) at anti-inflammatory dose causes a loss of the total anti-inflammatory effect of each agent alone. RU 486 (10 mg kg(-1)), a well known glucocorticoid receptorial antagonist, does not inhibit oedema formation but prevents the anti-inflammatory action of dexamethasone (1 mg kg(-1)). Similarly, RU 486 prevents the anti-inflammatory action of geldanamycin (0.3 mg kg(-1)). In conclusion we have described for the first time that geldanamycin, an inhibitor of Hsp90 dependent signal transduction, is anti-inflammatory in vivo implying that Hsp90 is critical for pathways involved in carrageenan-induced paw oedema. In addition the ability of GA to block NO release and reduce oedema formation suggests a therapeutic rationale for specific inhibitors of Hsp90 as potential anti-inflammatory drugs.     

Modulation of inflammatory paw oedema by cysteamine in the rat.

Cysteamine, a potent somatostatin depletor, was used in the present study to investigate the role of endogenous somatostatin in acute peripheral inflammation. The acute inflammation was induced by intraplantar injection of carrageenan (1%), histamine (5 micromol), or formalin (2.5%) in the rat hind paw. The induced inflammation and the formation of oedema were determined by measurement of the paw thickness. Given subcutaneously (s.c.) 1 h before carrageenan, cysteamine caused significant, dose-dependent and long-lasting inhibition of rat paw oedema induced by carrageenan. At doses of 12.5, 25, 50 or 100 mg kg (-1), cysteamine significantly inhibited the carrageenan-induced paw oedema at 4 h by 52.3, 40, 40.7 or 26.3%. Cysteamine given at 300 mg kg (-1), a dose well known to deplete tissue somatostatin, reduced oedema by only 16.2% vs control values. Significant inhibition of the carrageenan-induced rat paw oedema was still evident 24 h post-injection at cysteamine doses of 12.5, 25, 50 or 100 mg kg (-1). Given s.c. at 300 mg kg (-1), 4 h prior to carrageenan, cysteamine decreased rat paw oedema at 4 h by 14.9%. Cysteamine (300 mg kg (-1)), 4 h beforehand, had little modulatory effect on the oedema induced by formalin (2.5%) but reduced that caused by intraplantar histamine (5 micromol). The anti-oedematogenic effect of indomethacin, but not that of the selective COX-2 inhibitor celecoxib, was less marked in rats pre-treated with cysteamine at 300 mg kg (-1). Cysteamine (0.3 microg- 0.3 mg paw (-1)) co-administered with carrageenan was devoid of anti-inflammatory effect and even promoted inflammation at low concentrations. Cysteamine given locally alone induced slight paw oedema. These data indicate that systemic cysteamine possesses potent and long-lasting anti-inflammatory effects and modulates the anti-inflammatory effect of cyclooxygenase inhibitors in a model of peripheral inflammation in the rat. The effect of cysteamine is likely to be mediated via central action.     

Studies on the anti-inflammatory and anti-nociceptive effects of melatonin in the rat.

The present study aimed to evaluate the anti-inflammatory and anti-nociceptive effects of melatonin in the rat. Acute inflammation was induced by sub-plantar injection of carrageenan (1%) in the rat hind paw. The rats received vehicle or drug 30 min before carrageenan administration and were evaluated for paw oedema at 1, 2, 3, and 4 h post-carrageenan. The induced inflammation and the formation of oedema were determined by measurement of the paw thickness. Nociception was tested by determining vocalization following electrical stimulation of the tail. Given intraperitoneally (i.p.) 30 min before carrageenan, melatonin caused significant and a dose-dependent reduction of hind paw swelling induced by carrageenan. At doses of 0.5 and 1 mg kg(-1), melatonin inhibited the carrageenan-induced oedema by 20.5 and 29.6% versus control values at 4 h post-carrageenan, respectively. Melatonin (0.5 and 1 mg kg(-1), i.p.) 30 min beforehand displayed anti-nociceptive effect in the electric stimulation of the rat tail test, increasing nociceptive thresholds to electrically-induced pain at 4 h post-treatment by 29.6 and 39.5%, respectively. Melatonin given simultaneously with the non-selective COX-1 and COX-2 inhibitor indomethacin (5 mg kg(-1), i.p.) 30 min prior to carrageenan, enhanced the anti-inflammatory effect of the latter in the carrageenan-induced paw oedema model by 23%. Melatonin (0.5 mg kg(-1), i.p.) increased the anti-nociceptive effect of indomethacin (5 mg kg(-1), i.p.). Meanwhile, the anti-inflammatory and anti-nociceptive effect of the highly selective COX-2 inhibitor rofecoxib (2.25 mg kg(-1), i.p.) was only slightly increased by melatonin administration at 0.5 mg kg(-1). Melatonin enhanced the anti-inflammatory effect of cysteamine (300 mg kg(-1), s.c.) in the carrageenan-induced paw oedema. Melatonin (20 and 40 microg per paw) given prior to carrageenan into the rat hind paw was devoid of anti-inflammatory effect. These results indicate that melatonin possesses anti-inflammatory and anti-nociceptive properties in the rat and enhance those of indomethacin. This effect is likely to be centrally mediated.     

Evaluation of the anti-inflammatory and anti-nociceptive effects of different antidepressants in the rat.

The present study was designed to compare the anti-inflammatory and anti-nociceptive effects of different classes of antidepressant drugs on the carrageenan paw oedema and tail-electric stimulation assays in the rat. Drugs were intraperitoneally administered 30 min prior to carrageenan or nociceptive testing. The non-selective noradrenaline (NA) and serotonin (5-HT) reuptake inhibitors imipramine, amitriptyline and clomipramine displayed anti-inflammatory activity in the carrageenan model of paw inflammation. The maximal degree of oedema inhibitions seen with these agents were 28.8, 41.5 and 46.8% for 5, 10 and 20 mg kg(-1) amitriptyline, 26.2, 38.2 and 51.4% for 3.75, 7.5 and 15 mg kg(-1) imipramine and 51.2 and 54.1% for 16 and 32 mg kg(-1) clomipramine, respectively. The heterocyclic agent trazodone significantly inhibited paw oedema by 46 and 41% at 1 and 2h after dosing at the highest dose (40 mg kg(-1)) examined. Fluoxetine, a selective 5-HT reuptake inhibitor (SSRI) caused dose-related reduction of paw oedema, with 20.7% inhibition at the dose of 10 mg kg(-1). In contrast, sertraline, another SSRI caused dose-dependent enhancement of paw oedema. All antidepressant drugs in the study showed anti-nociceptive properties in the tail-electric stimulation assay with amitriptyline and trazodone being the most effective in this respect. Taken together, data in the present study confirm anti-inflammatory and anti-nociceptive effect for some antidepressant drugs and indicate that SSRIs differently affects inflammation.     

Effect of pranoprofen on sodium urate crystal-induced inflammation

Effect of a non-steroidal anti-inflammatory drug, pranoprofen (PPF), on sodium urate crystal-induced inflammation was investigated in comparison with standard drugs for treating acute gout in experimental animals. PPF inhibited sodium urate crystal-induced paw edema in both rats (1-10 mg/kg, p.o.) and mice (5-25 mg/kg, p.o.) in a dose-dependent manner. On rat sodium urate crystal-induced paw edema, PPF was found to be almost equally active as indomethacin (IM) and colchicine. In addition, PPF (2.5-10 mg/kg, p.o.) inhibited the accumulation of exudate and decreased the leucocyte numbers and the amount of prostaglandin E2 (PGE2)-like substance in sodium urate crystal-induced pleurisy in rats dose-dependently, with a potency slightly greater than that of IM. The specific anti-gout agent colchicine (5 mg/kg, p.o.) also suppressed the accumulation of exudate and decreased the leucocyte numbers, without affecting the amount of PGE2-like substance. Moreover, in mouse peritonitis, PPF (1-10 mg/kg, p.o.) suppressed the sodium urate crystal-induced increase in vascular permeability in a dose-dependent manner. Furthermore, in experimental models of articular gout, PPF inhibited the pain response (abnormal gait) of sodium urate crystal-induced arthritis in both rats (0.25 and 1 mg/kg, p.o.) and dogs (3 mg/kg, p.o.), with a potency greater than that of IM and phenylbutazone, respectively. These results indicate that as an anti-gout agent, PPF is at least as effective as other standard drugs, so that it should have good clinical potential.     

重组人超氧化物歧化酶在大鼠和小鼠的抗炎作用及机理研究

目的:研究重组人超氧化物歧化酶(rhSOD)的抗炎作用及其作用机理.方法:采用角叉菜胶诱导的大鼠和小鼠关节炎、巴豆油诱发的小鼠耳肿模型,研究药物对炎症肿胀度的影响.大鼠炎症渗出液中NOS活性用NADPH黄递酶染色法、β-NAG用对硝基酚比色法、MDA用TBA荧光法测定,IL-1β和TNFα含量用放射免疫法测定.结果:rhSOD 20-80mg/kg ip对大鼠关节炎,10-80mg/kg im对小鼠耳肿、80mg/kg ip对小鼠足肿有显著的抑制作用.同时大鼠炎症渗出液中NOS活性降低,IL-1β和TNFα含量显著减少.其抑制IL-1β中成的作用明显强于地塞术松2mg/kg ip.rhSOD使炎症组织内中性粒细胞浸润减轻,MDA生成减少,闲不影响炎症渗出液中β-NAG活性.结论:rhSOD对大鼠和小鼠实验性炎症有明显的抗炎作用.其抗炎作用机理和清除氧自由基、抗脂质过氧化有关,也和抑制炎症细胞浸润、减少炎症性细胞因子如IL-1β和TNFα的生成有关.     

The anti-inflammatory effects of the phosphodiesterase inhibitor pentoxifylline in the rat.

The present study aimed to evaluate the anti-inflammatory effects of pentoxifylline (PTX), a non-specific phosphodiesterase inhibitor in the rat. Acute inflammation was induced by subplantar injection of carrageenan (1%) in the rat hind paw. Results showed that intraperitoneal (i.p.) administration of PTX (36 or 72 mg kg(-1)) 30 min prior to carrageenan reduced the paw oedema response in dose-dependent manner with a maximal effect of 18.9 and 40.1%, respectively, at 2h post-carrageenan (P<0.001 and <0.001 at respective doses). Theophylline given at equimolar doses (29.9 or 45.8 mg kg(-1), i.p.) did not reduce the oedema response. With higher doses of PTX (144-300 mg kg(-1), i.p.) the anti-oedema effect of the drug was more pronounced, but mainly confined to the first 2h following carrageenan injection and decreasing rapidly thereafter. PTX (72 mg kg(-1), i.p.) given 30 min after carrageenan challenge reduced the oedema response by 24.7 and 26.2% at 1 and 2h after dosing (P<0.05 and <0.05, respectively). PTX (36 or 72 mg kg(-1), i.p.) co-administered with indomethacin (5 mg kg(-1), i.p.) 30 min before carrageenan had little modulatory effect on the anti-oedema effect of indomethacin, but the higher dose of PTX (144 mg kg(-1), i.p.) reduced the anti-inflammatory effect of indomethacin by 24% at 4h post-carrageenan. PTX (72 mg kg(-1), i.p.) enhanced the anti-oedema effect of the selective COX-2 inhibitor celecoxib (33 mg kg(-1), i.p.) by 55.1% at 4h post-carrageenan. In contrast, the higher dose of PTX (144 mg kg(-1), i.p.) reduced the anti-oedema effect of celecoxib by 46.8% at 4h post-carrageenan. PTX (36 or 72 mg kg(-1)) enhanced the anti-oedema effect of dexamethasone (0.1 mg kg(-1)) with maximal effect of 76 and 104.8% at 2h post-carrageenan (P<0.01 and <0.01 for respective doses). PTX (0.6 mg per paw) given with carrageenan into the rat hind paw reduced the oedema response with a maximal effect of 33.4% at 1h following carrageenan. PTX (0.6 mg per paw) given in the contralateral hind paw reduced the carrageenan-induced paw oedema for 1h by 32.2%. Thus, PTX, when given at doses comparable to those used in man for treatment of circulatory disorders displayed anti-inflammatory in vivo and enhanced the anti-inflammatory effect of a selective COX-2 inhibitor or dexamethasone. PTX may have therapeutic potential as anti-inflammatory agent either alone or in combination with non-steroidal anti-inflammatory drugs or with steroids. There is also an intriguing possibility for the use of topical preparations for the management of local inflammatory conditions.     

In vivo anti-inflammatory and analgesic activities of a purified saponin fraction derived from the root of Ilex pubescens

The root of Ilex pubescens (Mao-Dong-Qing in Chinese, MDQ) has been commonly used for treatment of cardiovascular and inflammatory diseases in the Chinese medical system. The current studies aimed to investigate the anti-inflammatory and analgesic effects as well as the underlying mechanisms of a purified saponin fraction (PSF) derived from MDQ. PSF was found to significantly suppress the paw edema of rats induced by histamine given intraperitoneally at dosages ranging from 12.5-100 mg/kg. Meanwhile, PSF given orally at dosages of 200 and 100 mg/kg significantly inhibited acetic acid-induced abdominal writhing response of mice and prolonged the time required for mouse tail flick after exposure to a source of radiant heat. The mechanistic studies showed that cyclooxygenase-2 (COX-2) protein expression in carrageenan-injected paw tissues of rats was markedly attenuated by intraperitoneal injection of PSF at dosages of 12.5 to 100 mg/kg. PSF could also markedly inhibit production of proinflammatory cytokines, especially IL-1 beta, IL-6 and TNF-alpha, but enhance production of anti-inflammatory cytokines of IL-4 and IL-10 in the carrageenan-injected paw tissues in rats. These effects resulted in an overall attenuation of the ratio of proinflammatory/anti-inflammatory cytokines and, ultimately suppression of the paw edema. In conclusion, the current study has demonstrated the in vivo anti-inflammatory and analgesic effects of PSF, and suggested that the molecular mechanisms might be associated with inhibition of the elevated expression of COX-2 protein and the overproduction of the proinflammatory cytokines, as well as augmentation of the anti-inflammatory cytokines IL-4 and IL-10 in the carrageenan-injected paw tissues of rats.     

Anti-inflammatory activity of the steroid alkaloid glycoside, tomatine

1. Tomatine, isolated from extracts of crown gall-infected tomato plants or obtained commercially, was tested for anti-inflammatory activity using three different methods.2. Tomatine administered to intact rats intramuscularly in a dose range of 1-10 mg/kg or orally in doses of 15-30 mg/kg exerted a significant dose dependent inhibition of carrageenan induced paw oedema. The inhibitory effect of tomatine when given in a dose of 10 mg/kg intramuscularly to intact rats lasted more than 24 hr.3. In adrenalectomized rats significant dose-related inhibition of paw oedema was obtained with tomatine and the inhibition at each dose level (0.5-10 mg/kg) was found to be greater than that found in intact animals.4. Tomatine administered subcutaneously to intact rats daily for 7 days in doses of 5 or 10 mg/kg exerted a significant, dose dependent inhibition of granulation tissue formation induced by the subcutaneous implantation of carrageenan impregnated cotton pellets.5. Tomatine administered to intact mice in a dose of 10 mg/kg subcutaneously 1 hr before the intraperitoneal injection of acidified saline and intravenous pontamine sky blue significantly decreased the leakage of the protein bound dye into the peritoneal cavity.6. Tomatidine, the aglycone of tomatine, was not effective at dose levels of 10-20 mg/kg in any of the three tests.     

Antinociceptive and anti-inflammatory effects of the essential oil from Eremanthus erythropappus leaves

The chemical composition of the essential oil from air-dried leaves of Eremanthus erythropappus was studied. The main compounds were beta-pinene (23.24%), beta-caryophyllene (22.92%), beta-myrcene (10.03%) and germacrene D (9.40%). The essential oil had an LD50 of 2.90 g kg(-1) in mice. Doses of 200 and 400 mg kg(-1) inhibited 10.69% and 27.06% of acetic-acid-induced writhing in mice, respectively. In the formalin-induced nociception test in mice, the essential oil inhibited the first phase of paw licking by 29.13% (400 mg kg(-1)) and the second phase by 32.74% (200 mg kg(-1)) and 37.55% (400 mg kg(-1)). In the hot-plate test in mice, doses of 200 mg kg(-1) and 400 mg kg(-1) significantly increased the reaction time after 30, 60 and 90 min of treatment. Doses of 200 and 400 mg kg(-1) inhibited carrageenan-induced paw oedema in rats by 15.18% and 36.61%, respectively. Doses of 200 and 400 mg kg(-1) administered 4 h before intrapleural injection of carrageenan significantly reduced exudate volume (by 20.20% and 48.70%, respectively) and leucocyte mobilization (by 5.88% and 17.29%, respectively). These results demonstrate that E. erythropappus has analgesic and anti-inflammatory properties, supporting the use of this plant in folk medicine.     

Anti-inflammatory activity of bis(3-aryl-3-oxo-propyl)methylamine hydrochloride in rat

In this study the effects of compound B1, bis(3-aryl-3-oxo-propyl)methylamine hydrochloride, and an anti-inflammatory drug, indomethacin, were tested by carrageenan-induced paw edema and cotton pellet granuloma tests, for effects on acute and chronic phases of inflammation, respectively. Their effects on vascular permeability were also determined by hyaluronidase-induced capillary permeability test. Anti-inflammatory activity of B1 was compared with indomethacin. B1 decreased the carrageenan-induced paw edema by 49%, 35%, and 47% at 50, 100, and 200 mg kg(-1) doses, respectively, while this decrease was 82% by indomethacin at 20 mg kg(-1) dose. Antiproliferative effects in cotton pellet test of B1 at 50 mg kg(-1) and indomethacin at 20 mg kg(-1) doses were 44% and 43%, respectively. Indomethacin but not B1 inhibited the hyaluronidase-induced increase in capillary permeability. Our results suggest that B1 inhibits both acute and chronic phases of inflammation probably by an effect not mediated by prevention of increased capillary permeability. Especially, its anti-inflammatory activity against chronic phase of inflammation was comparable with that of indomethacin. Further detailed studies are needed to clarify the mechanism(s) of action responsible for the anti-inflammatory activity of B1.     

Studies on the anti-inflammatory effects of<Emphasis Type="Italic">clerodendron trichotomum</Emphasis> thunberg leaves

Clerodendron trichotomum Thunberg Leaves (CTL) have been used for centuries in Chinese folk medicine for their anti-inflammatory properties. We have studied the anti-inflammatory effects of CTL extracts in rats, mice and in Raw 264.7 cells. 1 mg/kg solutions of the 30% and 60% methanol extracts of CTL were used and a 1 mg/kg of indomethacin was used as a positive anti-inflammatory standard; these were then administrated to rats. Carrageenan was injected subcutaneously to induce hind paw edema in rats. The result of carrageenan-induced rat paw oedema showed that a 1 mg/kg of the 30%, and 60% methanol fraction of CTL and 1 mg/kg of indomethacin inhibited the hind paw edema by 19.5%, 23.0%, and 20.5% respectively. The effect of CTL on inflammation in mice by a capillary permeability assay was examined by detecting Evans blue leakage from capillaries after the intraperitoneal injection of acetic acid, a potent inflammatory stimulus. The 60% methanol fraction of CTL inhibited Evans blue dye leakage by 47.0%, which was 10% higher than that of the inhibition of 1 mg/kg of indomethacin. Also, the 60% methanol fraction of CTL suppressed the prostaglandin E2 (PGE2) generation in RAW 264.7 macrophage cells after treatment with lipopolysaccharide (LPS) by as much as the inhibition of 1 mg/kg of indomethacin and this led to the synthesis of PGE2 by COX-2 induction. The inhibition of the carrageenan-induced rat paw oedema, vascular permeability and the PGE2 generation demonstrates that the 60% methanol fraction of CTL contains a potent anti-inflammatory activity.     

Evaluation of analgesic,antipyretic and anti-inflammatory activity of spirobarbitunylphenothiazines in rodents

Analgesic, antipyretic and anti-inflammatory activities of newly synthesized spirobarbitunylphenothiazines viz 10-[7, 11-Di(4-4' dimethoxphenyl)-3-oxo-9-methylaminoimino-2, 4-diazaspiro [5.5] undecane 1, 5 dione] acetylphenothiazine (test drug A) and 10-[7, 11-Di (N.N-dimethylaminophenyl)-3-oxo-9-methylaminoimino-2, 4-diazaspiro [5, 5] undecane-1, 5 dione] acetylphenothiazine (test drug B) have been screened in Swiss mice and Wistar rats. The peripheral analgesic activity of test drugs A and B was investigated by acetic acid induced writhing test in Swiss mice while the central analgesic action was assessed by hot-wire (tail flick test) of the analgesiometer and tail-clip test in Wistar rats. Antipyretic activity was assessed on Brewer's yeast induced pyrexic model while antiinflammatory activity was seen on carrageenan induced hind paw oedema. Analgesic activity was found to be only of peripheral type as there was reduction of 66% in writhing responses by test drugs A and B in dose of 80 mg/kg in mice. No change in the tail flick responses was observed on analgesiometer or by tail clip by both the test drugs. Reduction of 1.5 to 2.0 degrees C in rectal temperature was observed in pyretic rats by test drugs A and B in dose of 80 mg/kg. 80% reduction in paw volume was noted in 80 mg/kg dose of both the test drugs which was comparable to the anti-inflammatory activity of 300 mg/kg, p.o. of phenylbutazone.     

Therapeutic effect of the endogenous fatty acid amide,palmitoylethanolamide, in rat acute inflammation: inhibition of nitric oxide and cyclo-oxygenase systems

1. The anti-inflammatory activity of the endogenous fatty acid amide palmitoylethanolamide and its relationship to cyclo-oxygenase (COX) activity, nitric oxide (NO) and oxygen free radical production were investigated in the rat model of carrageenan-induced acute paw inflammation and compared with the nonsteroidal anti-inflammatory drug (NSAID) indomethacin. 2. Palmitoylethanolamide (1, 3, 5, 10 mg kg(-1); p.o.) and indomethacin (5 mg kg(-1); p.o.) were administered daily after the onset of inflammation for three days and the paw oedema was measured daily; 24 h after the last dose (fourth day) the rats were killed and the COX activity and the content of nitrite/nitrate (NO(2)(-)/NO(3)(-)), malondialdehyde (MDA), endothelial and inducible nitric oxide synthase (eNOS and iNOS) were evaluated in the paw tissues. 3. Palmitoylethanolamide had a curative effect on inflammation, inhibiting the carrageenan-induced oedema in a dose- and time-dependent manner. This effect was not reversed by the selective CB(2) receptor antagonist (N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3 carboxamide) (SR144528), 3 mg kg(-1) p.o. On the fourth day after carrageenan injection, COX activity and the level of NO(2)(-)/NO(3)(-), eNOS and MDA were increased in the inflamed paw, but iNOS was not present. Palmitoylethanolamide (10 mg kg(-1)) and indomethacin markedly reduced these increases. 4. Our findings show, for the first time, that palmitoylethanolamide has a curative effect in a model of acute inflammation. The inhibition of COX activity and of NO and free radical production at the site of inflammation might account for this activity.