Carvedilol can attenuate histamine-induced paw edema and formaldehyde-induced arthritis in rats without risk of gastric irritation

Background and aimRheumatoid arthritis treatment aims to control joint damage and any associated complications such as cardiovascular disease. Most anti-inflammatory drugs have a high tendency to cause gastro-intestinal irritation. The present study is designed to investigate the anti-inflammatory effect of carvedilol and to study its effect on gastric mucosa.Experimental approachLornoxicam (1.3 mg/kg) or carvedilol (10 mg/kg) was administrated orally 1 h before histamine injection into animals of a histamine-induced paw edema model and orally daily for 11 days into animals of a formaldehyde-induced arthritis model. Tumor necrosis factor-α and prostaglandin E₂ were measured in animals of the formaldehyde-induced arthritis model. The effect of lornoxicam and carvedilol on gastric mucosa was assessed in normal rats and after induction of cold stress ulcer.ResultsCarvedilol succeeded in reducing hind paw edema in both histamine-induced paw edema and formaldehyde-induced arthritis and in reducing the elevated level of tumor necrosis factor-α and prostaglandin E₂ nearly with near equal efficacy compared with lornoxicam. Carvedilol did not show any ulcerative effect on the gastric mucosa of normal rats, and its use was associated with an improvement of both the gross and histopathological pictures of gastric ulcers in animals of the cold stress ulcer model compared with lornoxicam treated rats.ConclusionThe current findings support the use of carvedilol both in the management of inflammation as well as the prevention of cardiovascular complications in rheumatoid arthritis patients. The use of carvedilol was not associated with any gastro-intestinal tract irritation.     

Potent anti-inflammatory/analgesic effects of lornoxicam in comparison to other nsaids: A c-fos study in the rat

This study evaluates the anti-inflammatory/analgesic effects of lornoxicam, a new non-steroidal anti-inflammatory drug, using the method of c-Fos protein immunoreactivity in the carrageenan model of inflammatory nociception in the rat. The immunohistochemical revelation of inflammatory/nociceptive stimulation evoked c-Fos expression in spinal neurons was used as an indirect marker of neurons involved in spinal nociceptive transmission. Lornoxicam (0.1, 0.3, 1, 3 and 9 mg/kg; n=10 rats for each group) was preadministered intravenously 25 min before an intraplantar injection of carrageenan (6 mg/150 ml of saline). Three hours after carrageenan, the peripheral oedema (paw and ankle diameters) and the number of c-Fos-protein-like immunoreactive (c-Fos-LI) neurons in the lumbar spinal cord, were assessed. Preadministered lornoxicam dose relatedly reduced the total number of c-Fos-LI neurons (regression coefficient r=0.79; p<0.001) with the strongest effect corresponding to the 75±2% reduction (p<0.001) for the highest dose of 9 mg/kg, and the 45±3% reduction (p<0.001) for the low dose of 0.3 mg/kg. Lornoxicam (0.1, 0.3, 1, 3 and 9 mg/kg iv) significantly reduced the number of c-Fos-LI neurons in both superficial (24±6, 33±5, 53±4, 54±4, and 63±4% reduction, respectively, p<0.001 for all doses) and deep (28±4, 48±4, 62±2, 69±3 and 79±2% reduction, respectively, p<0.001 for all doses) laminae of the dorsal horn of the spinal cord. These reducing effects were dose related in both superficial and deep laminae (regression coefficient r=0.66 and r=0.08, respectively; p<0.001 for both). The lowes dose of lornoxicam (0.1 mg/kg iv) had a similar effect in both superficial and deep laminae, whereas the four higher doses (0.3, 1, 3 and 9 mg/kg iv) had a significantly stronger effect on the number of c-Fos-LI neurons in deep laminae as compared to that in superficial laminae. Lornoxicam (0.1, 0.3, 1, 3 and 9 mg/kg iv) dose relatedly reduced the carrageenan induced oedema at both the paw and ankle levels (regression coefficient r=0.63 and r=0.53, respectively, p<0.001 for both), with a stronger effect on the ankle diameter (34±8, 61±9, 66±8, 80±6 and 83±5% reduction, respectively p<0.001 for all doses). Furthermore reductions of the carrageenan evoked peripheral oedema and spinal c-Fos expression were positively correlated (correlation coefficient r=0.74 and r=0.57 for the paw and ankle diameter respectively, p<0.001 for both). These correlations suggest a predominant peripheral site, without excluding central site of action of lornoxicam in the carrageenan-induced inflammation. Our results provide clear evidence for a potent anti-inflammatory/analgesic effects of low doses of lornoxicam which have a reduced risk of sideeffects. Taken together, the results of the present study revealed the effects of lornoxicam in the same range as those of other previously studied NSAIDs, more precisely, closely comparable to the effects of ketoprofen.     

The antipyretic effect of dipyrone is unrelated to inhibition of PGE(2) synthesis in the hypothalamus

BACKGROUND AND PURPOSE

Bacterial lipopolysaccharide (LPS) induces fever through two parallel pathways; one, prostaglandin (PG)-dependent and the other, PG-independent and involving endothelin-1 (ET-1). For a better understanding of the mechanisms by which dipyrone exerts antipyresis, we have investigated its effects on fever and changes in PGE₂ content in plasma, CSF and hypothalamus induced by either LPS or ET-1.

EXPERIMENTAL APPROACH

Rats were given (i.p.) dipyrone (120 mg·kg⁻¹) or indomethacin (2 mg·kg⁻¹) 30 min before injection of LPS (5 µg·kg⁻¹, i.v.) or ET-1 (1 pmol, i.c.v.). Rectal temperature was measured by tele-thermometry. PGE₂ levels were determined in the plasma, CSF and hypothalamus by elisa.

KEY RESULTS

LPS or ET-1 induced fever and increased CSF and hypothalamic PGE₂ levels. Two hours after LPS, indomethacin reduced CSF and hypothalamic PGE₂ but did not inhibit fever, while at 3 h it reduced all three parameters. Three hours after ET-1, indomethacin inhibited the increase in CSF and hypothalamic PGE₂ levels but did not affect fever. Dipyrone abolished both the fever and the increased CSF PGE₂ levels induced by LPS or ET-1 but did not affect the increased hypothalamic PGE₂ levels. Dipyrone also reduced the increase in the venous plasma PGE₂ concentration induced by LPS.

CONCLUSIONS AND IMPLICATIONS

These findings confirm that PGE₂ does not play a relevant role in ET-1-induced fever. They also demonstrate for the first time that the antipyretic effect of dipyrone was not mechanistically linked to the inhibition of hypothalamic PGE₂ synthesis.     

Effect of celecoxib, a cyclooxygenase-2 inhibitor, on the pathophysiology of adjuvant arthritis in rat

We investigated the efficacy of celecoxib, a specific cyclooxygenase (COX)-2 inhibitor, on arthritic pathophysiology and confirmed its gastric safety in adjuvant-induced arthritis rats. Results were compared with those for loxoprofen, a non-selective COX inhibitor. Arthritis was induced by injection of 1 mg of Mycobacterium butyricum in 50 microl of liquid paraffin into the left footpad of Lewis rats. The drugs were given by twice daily oral administration for 10 days beginning 15 days after adjuvant injection, with celecoxib at 0.01-3 mg/kg/day and loxoprofen at 0.01-3 mg/kg/day. Celecoxib significantly inhibited paw swelling, hyperalgesic response, and joint destruction (radiographic and histopathological findings) in these arthritic rats. These effects of celecoxib were superior to those of loxoprofen. Further, the administration of loxoprofen (3 mg/kg/day) caused significant gastric lesions, whereas celecoxib at the same dose did not. These results suggest that COX-2-mediated prostaglandins may play an important role in the progression of pathophysiology in this model and that celecoxib may be a useful therapeutic agent for the treatment of rheumatoid arthritis, with greater safety than non-selective COX inhibitors.     

Tephrosia sinapou ethyl acetate extract inhibits inflammatory pain in mice: Opioid receptor dependent inhibition of TNFα and IL-1β production

Abstract

Context. Tephrosia toxicaria is currently known as Tephrosia sinapou (Buc'hoz) A. Chev. (Fabaceae) and is a source of compounds such as flavonoids that inhibit inflammatory pain.

Objective: To investigate the analgesic effect and mechanisms of the ethyl acetate extract of T. sinapou in inflammatory pain in mice.

Materials and methods: Behavioral responses were evaluated using mechanical (1–24?h) and thermal hyperalgesia (0.5–5?h), writhing response (20?min) and rota-rod (1–5?h) tests. Neutrophil recruitment (myeloperoxidase activity), cytokines (tumor necrosis factor [TNF]α and interleukin [IL]-1β), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) serum levels were determined by colorimetric assays. Pharmacological treatments were opioid receptor antagonist (naloxone, 0.1–1?mg/kg) and control opioid (morphine, 5?mg/kg). Inflammatory stimuli were carrageenin (100?µg/paw), complete Freund’s adjuvant (CFA, 10?µl/paw), prostaglandin E₂ (PGE₂, 100?ng/paw) and acetic acid (0.8%).

Results: The intraperitoneal pre-treatment with extract inhibited in a dose-dependent (30–300?mg/kg) dependent manner the mechanical hyperalgesia induced by carrageenin (up to 93% inhibition). The post-treatment (100?mg/kg) inhibited CFA-induced hyperalgesia (up to 63% inhibition). Naloxone (1?mg/kg) prevented the inhibitory effect of the extract over carrageenin-induced mechanical (100%) and thermal (100%) hyperalgesia, neutrophil recruitment (52%) and TNFα (63%) and IL-1β (98%) production, thermal threshold in naïve mice (99%), PGE₂-induced mechanical hyperalgesia (88%) and acetic acid-induced writhing response (49%). There was no significant alteration in the rota-rod test, and AST and ALT serum levels by extract treatment.

Discussion and conclusion. Tephrosia sinapou ethyl acetate extract reduces inflammatory pain by activating an opioid receptor-dependent mechanism.     

Letter from the Editor

This study investigated the antinociceptive and anti‐inflammatory activities of the ethanolic extract (EESAl), fractions and the compound 8‐methoxylapachenol (8ML) obtained from the tubers of Sinningia allagophylla. Male Swiss mice were treated with EESAl (3–300 mg/kg) or vehicle by oral route (p.o.) 1 hr before the injection of formalin 2.5% or carrageenan (Cg) into the hind paw. EESAl (3–30 mg/kg) reduced the inflammatory phase of the nociceptive behaviour induced by formalin (around 65% for all doses). EESAl (3–300 mg/kg, p.o.) also reduced Cg‐induced mechanical hyperalgesia and oedema in a dose‐dependent fashion but did not change the hot‐plate latency or the motor performance of the animals. Oral administration of petroleum ether fraction (PE, 3 mg/kg), but not in the methanolic fraction (30 mg/kg), reduced both Cg‐induced oedema and hyperalgesia. Compound 8ML isolated from PE (1.8 mg/kg, p.o.) abolished Cg‐induced hyperalgesia but also did not change hot‐plate latency or motor performance of the animals. 8ML administration into the paw (0.75–750 pg) dose‐dependently reduced Cg‐induced hyperalgesia. 8ML (750 pg) also blocked the hyperalgesia induced by tumour necrosis factor (TNF‐α), interleukin‐1β (IL‐1β) and prostaglandin E₂ (PGE₂) but failed to change the hyperalgesia induced by cytokine‐induced neutrophil chemoattractant‐1 (CINC‐1) and dopamine (Dopa). These results suggest that EESAl has an important antinociceptive and anti‐inflammatory activity, the former one related, at least in part, to the reduction in the hyperalgesia. Similarly, 8ML reduced Cg‐induced oedema and mechanical hyperalgesia and seems to act in peripheral sites and on the prostaglandin rather than on the sympathetic component of the Cg‐inflammatory hyperalgesia.     

氯诺昔康在妇科腹腔镜术后镇痛中的应用

目的 观察妇科腹腔镜患者术后单次使用氯诺昔康的24h镇痛作用。方法 将妇科腹腔镜择期手术患者90例随机分为A组（氯诺昔康8mg）、B组（氯诺昔康16mg）和c组（对照组），每组30例，A，B组均在术毕注射氯诺昔康．采用视觉模拟法（VAS评分）分别于术后1，4，8，24h作痛觉评分，并记录有无恶心等副作用及术后24h内使用镇痛药物的总次数。结果 使用氯诺昔康的两组患者术后24h内VAS评分显著低于对照组（P〈0．05），B组使用镇痛药的次数明显低于对照组（P〈0．05）。结论妇科腹腔镜术毕单次静脉注射8mg或16mg氯诺昔康可有效缓解术后疼痛，16mg组的镇痛作用更强，且均无明显的不良反应。     

Arsenic reduces the antipyretic activity of paracetamol in rats: Modulation of brain COX-2 activity and CB1 receptor expression

We examined whether subacute arsenic exposure can reduce paracetamol-mediated antipyretic activity by affecting COX pathway and cannabinoid CB₁ receptor regulation. Rats were preexposed to elemental arsenic (4 ppm) as sodium arsenite through drinking water for 28 days. Next day pyrexia was induced with lipopolysaccharide and paracetamol's (200 mg/kg, oral) antipyretic activity was assessed. The activities of COX-1 and COX-2, the levels of PGE₂, TNF-α and IL-1β and expression of CB₁ receptors were assessed in brain. Arsenic inhibited paracetamol-mediated antipyretic activity. COX-1 activity was not affected by any treatments. Paracetamol decreased COX-2 activity, levels of PGE₂, TNF-α and IL-1β and caused up-regulation of CB₁ receptors. Arsenic caused opposite effects on these parameters. In the arsenic-preexposed rats, paracetamol-mediated effects were attenuated, while CB₁ receptor up-regulation was reversed to down-regulation. Results suggest that elevated COX-2 activity and reduced CB₁ expression could be involved in the arsenic-mediated attenuation of the antipyretic activity of paracetamol.     

Studies on anti-inflammatory,antipyretic and analgesic properties of Caesalpinia bonducella F. seed oil in experimental animal models

Caesalpinia bonducella FLEMING (Caesalpiniaceae) plant is well known for its medicinal and therapeutic values in Indian Ayurveda. However, to be clinically useful, more scientific data are needed. Therefore, in the present study, we investigated the effects of C. bonducella seed oil on acute and chronic inflammation. To assess the anti-inflammatory, antipyretic and analgesic activities, varied concentrations of the seed oil of C. bonducella (100, 200 and 400 mg/kg orally) were tested in carrageenan-induced rat paw oedema, brewer’s yeast-induced pyrexia, acetic acid-induced writhing and hot plate reaction time in experimental rats. The paw volumes, pyrexia and writhes in experimental rats were reduced significantly (p < 0.05) as compared to that of control, and hot plate test showed significant licking effect in rats. These results clearly indicate that the oil of C. bonducella seeds could be a potential source for using as anti-inflammatory, antipyretic and analgesic agent.     

AKAP-dependent sensitization of Cav3.2 channels via the EP4 receptor/cAMP pathway mediates PGE2-induced mechanical hyperalgesia

Background and Purpose

The Ca_v3.2 isoform of T-type Ca²⁺ channels (T channels) is sensitized by hydrogen sulfide, a pro-nociceptive gasotransmitter, and also by PKA that mediates PGE₂-induced hyperalgesia. Here we examined and analysed Ca_v3.2 sensitization via the PGE₂/cAMP pathway in NG108-15 cells that express Ca_v3.2 and produce cAMP in response to PGE₂, and its impact on mechanical nociceptive processing in rats.

Experimental Approach

In NG108-15 cells and rat dorsal root ganglion (DRG) neurons, T-channel-dependent currents (T currents) were measured with the whole-cell patch-clamp technique. The molecular interaction of Ca_v3.2 with A-kinase anchoring protein 150 (AKAP150) and its phosphorylation were analysed by immunoprecipitation/immunoblotting in NG108-15 cells. Mechanical nociceptive threshold was determined by the paw pressure test in rats.

Key Results

In NG108-15 cells and/or rat DRG neurons, dibutyryl cAMP (db-cAMP) or PGE₂ increased T currents, an effect blocked by AKAP St-Ht31 inhibitor peptide (AKAPI) or KT5720, a PKA inhibitor. The effect of PGE₂ was abolished by RQ-00015986-00, an EP₄ receptor antagonist. AKAP150 was co-immunoprecipitated with Ca_v3.2, regardless of stimulation with db-cAMP, and Ca_v3.2 was phosphorylated by db-cAMP or PGE₂. In rats, intraplantar (i.pl.) administration of db-cAMP or PGE₂ caused mechanical hyperalgesia, an effect suppressed by AKAPI, two distinct T-channel blockers, NNC 55-0396 and ethosuximide, or ZnCl₂, known to inhibit Ca_v3.2 among T channels. Oral administration of RQ-00015986-00 suppressed the PGE₂-induced mechanical hyperalgesia.

Conclusion and Implications

Our findings suggest that PGE₂ causes AKAP-dependent phosphorylation and sensitization of Ca_v3.2 through the EP₄ receptor/cAMP/PKA pathway, leading to mechanical hyperalgesia in rats.     

Anti-inflammatory, analgesic and antipyretic activities of loxoprofen sodium given intramuscularly in animals

The evaluation of the anti-inflammatory, analgesic and antipyretic activities of loxoprofen sodium given in intramuscular route was investigated as compared to oral application in rats and mice. The intramuscular ED50 values of loxoprofen sodium in carrageenan edema and vascular permeability tests are 1.15 and 7.8 mg/kg, respectively, which represent more potent than in case of oral application. Its therapeutic effects in adjuvant arthritis were shown at 6 mg/kg i.m. and 3mg/kg p.o. Analgesic effect was shown to be more potent as given intramuscularly. Similar potency of antipyretic effects was shown in both administration routes. Considerably weak gastric damages were observed in intramuscular application.     

TEMPOL, a membrane-permeable radical scavenger, attenuates peroxynitrite- and superoxide anion-enhanced carrageenan-induced paw edema and hyperalgesia: a key role for superoxide anion

Carrageenan produces both inflammation and pain when injected in rat paws via enhancement of the formation of reactive oxygen species. We have tested the effect of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL), a membrane-permeable superoxide dismutase (SOD) mimetic in carrageenan-induced rat paw edema. Treatment of rats with TEMPOL (15, 30, and 60 mg/kg, 15 min prior to carrageenan) inhibited the paw edema. Furthermore, treatment of rats with the SOD inhibitor diethylthiocarbamate (DETCA, 100 mg/kg, 1 h before carrageenan) enhanced the carrageenan-induced paw edema. Co-administration of peroxynitrite with carrageenan produced a similar fortification of the carrageenan-induced edema. Prior treatment of rats with TEMPOL (30 mg/kg) inhibited the enhancement produced by DETCA treatment (endogenous superoxide anion stress) as well as that produced by the peroxynitrite stress. The effect of TEMPOL as well as the influence of superoxide anion and peroxynitrite stresses was also tested in carrageenan-induced hyperalgesia model. Carrageenan (500 mug/paw) produced significant hyperalgesia presented as shortening of withdrawal latency times using hot plate (52 degrees C) starting 30 min after carrageenan and lasting for 3 h. TEMPOL (60 mg/kg, injected 15 min before carrageenan) ameliorated this hyperalgesia during the first 2 h. Concurrent administration of peroxynitrite promptly intensified the carrageenan hyperalgesia. TEMPOL (60 mg/kg, 15 min before peroxynitrite-carrageenan) inhibited the peroxynitrite enhancement of carrageenan hyperalgesia when tested at 60 min after injection of the cocktail. The present investigation gives the proof for the effectiveness of TEMPOL as anti-inflammation and analgesic agents in carrageenan-induced model of inflammation and hyperalgesia. It further indicated the importance of superoxide anion and peroxynitrite in acute inflammation and inflammatory pain. This raises the chances for considering pharmacologic interventions that interrupt superoxide anion and peroxynitrite stress for putative alternative agents as anti-inflammatory analgesic new medical strategies.     

Pharmacological profile of celecoxib, a specific cyclooxygenase-2 inhibitor

The pharmacological profile of celecoxib (CAS 169590-42-5, SC-58635), a specific cyclooxygenase-2 (COX-2) inhibitor, was investigated. Celecoxib inhibited COX-2-mediated prostaglandin E2 (PGE2) production in human dermal fibroblasts (IC50 = 91 nmol/l), whereas it was a weak inhibitor of COX-1-mediated PGE2 production in human lymphoma cells (IC50 = 2800 nmol/l). In in vivo studies, the effects of celecoxib were compared with those of nonsteroidal anti-inflammatory drugs (NSAIDs) in acute rat models of hyperalgesia and pyrexia. Celecoxib abrogated carrageenan-induced hyperalgesia in the hind paw accompanied by a decrease in PGE2 content in paw exudates and cerebrospinal fluid in a dose-related manner, with an ED30 = 0.81 mg/kg. Its analgesic potency was comparable to those of NSAIDs. In lipopolysaccharide-induced pyrexia, the anti-pyretic potency of celecoxib was equal to that of NSAIDs. On the other hand, in a gastric toxicity study in rats, single oral administration of celecoxib had no effect on gastric mucosa or mucosal PGE2 content at doses up to 200 mg/kg. Additionally, celecoxib did not inhibit thromboxane B2 production of calcium ionophore-stimulated peripheral blood of rats or arachidonic acid-induced aggregation of human platelets. These findings suggest that celecoxib might be a safe and effective alternative to NSAIDs for clinical use.     

Lornoxicam,a new potent NSAID with an improved tolerability profile

Lornoxicam is a member of the oxicam group of nonsteroidal antiinflammatory drugs (NSAIDs). Oxicams have potent antiinflammatory and analgesic effects, but their use is associated with a high risk of gastrointestinal adverse effects. Lornoxicam has been shown to be at least as effective as comparative NSAIDs and more effective than 10 mg morphine when used at doses > or = 8 mg to control pain after oral surgery. In addition, oral doses of lornoxicam of 16-24 mg daily have been more effective than tramadol 300 mg daily in pain following knee surgery. Lornoxicam combines the high therapeutic potency of oxicams with an improved gastrointestinal toxicity profile as compared to naproxen, for example. This is probably due to the short half-life of lornoxicam as compared to the other oxicams. The clinical trials published so far, mostly comparative, clearly do- cument the efficacy of lornoxicam as a potent analgesic with excellent antiinflammatory properties in a range of painful and/or inflammatory conditions, including postoperative pain and rheumatoid arthritis.     

A study of the mechanisms underlying the anti-inflammatory effect of ellagic acid in carrageenan-induced paw edema in rats

Objectives:Ellagic acid (EA) has shown antinociceptive and anti-inflammatory effects. Inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2) enzymes and also cytokines play a key role in many inflammatory conditions. This study was aimed to investigate the mechanisms involved in the anti-inflammatory effect of EA.Results:The results showed that intraplantar injection of carrageenan led to time-dependent development of peripheral inflammation, which resulted in a significant increase in the levels of tumor necrosis factor α (TNF-α) and interleukin 1 (IL-1) β, nitric oxide (NO) and prostaglandin E₂ (PGE₂) and also iNOS and COX-2 protein expression in inflamed paw. However, systemic administration of EA (1–30 mg/kg, intraperitoneal [i.p.]) could reduce edema in a dose-dependent fashion in inflamed rat paws with ED50 value 8.41 (5.26–14.76) mg/kg. It decreased the serum concentration of NO, PGE₂, aspartate aminotransferase and alanine aminotransferase, and suppress the protein expression of iNOS, COX-2 enzymes, and attenuated the formation of PGE_2, TNF-α and IL-1 β in inflamed paw tissue. We also demonstrated that EA significantly decreased the malondialdehyde (MDA) level in liver at 5 h after carrageenan injection. Moreover, histopathological studies indicated that EA significantly diminished migration of polymorphonuclear leukocytes into site of inflammation, as did indomethacin.Conclusions:Collectively, the anti-inflammatory mechanisms of EA might be related to the decrease in the level of MDA, iNOS, and COX-2 in the edema paw via the suppression of pro-inflammatory cytokines (TNFα, IL1 β), NO and PGE₂ overproduction.KEY WORDS: Carrageenan, ellagic acid, inducible nitric oxide synthase, prostaglandin E₂, Rat     

An evaluation of the anti-inflammatory,antipyretic and analgesic effects of hydroethanol leaf extract of Albizia zygia in animal models

Context: The leaves of Albizia zygia (DC.) J.F. Macbr. (Leguminosae-Mimosoideae) are used in Ghanaian traditional medicine for the treatment of pain, inflammatory disorders and fever (including malaria).

Objectives: The present study evaluated the anti-inflammatory, antipyretic and analgesic effects of the hydroethanol leaf extract of Albizia zygia (AZE) in animal models.

Materials and methods: The anti-inflammatory and antipyretic effects of AZE were examined in the carrageenan-induced foot oedema model and the baker’s yeast-induced pyrexia test respectively. The analgesic effect and possible mechanisms of action were also assessed in the formalin test.

Results: AZE (30–300?mg/kg, p.o.), either preemptively or curatively, significantly inhibited carrageenan-induced foot edema in 7-day-old chicks (ED₅₀ values; preemptive: 232.9?±?53.33?mg/kg; curative: 539.2?±?138.28?mg/kg). Similarly, the NSAID diclofenac (10–100?mg/kg, i.p.) significantly reduced the oedema in both preemptive (ED₅₀: 21.16?±?4.07?mg/kg) and curative (ED₅₀: 44.28?±?5.75?mg/kg) treatments. The extract (30–300?mg/kg, p.o.) as well as paracetamol (150?mg/kg, p.o.) also showed significant antipyretic activity in the baker’s yeast-induced pyrexia test (ED₅₀ of AZE: 282.5?±?96.55?mg/kg). AZE and morphine (1–10?mg/kg, i.p.; positive control), exhibited significant analgesic activity in the formalin test. The analgesic effect was partly or wholly reversed by the systemic administration of naloxone, theophylline and atropine.

Conclusion: The results suggest that AZE possesses anti-inflammatory, antipyretic and analgesic properties, which justifies its traditional use. Also, the results show the involvement of the opioidergic, adenosinergic and the muscarinic cholinergic pathways in the analgesic effects of AZE.     

Kaurenic acid: An in vivo experimental study of its anti-inflammatory and antipyretic effects

Objective:

This study was designed to investigate the anti-inflammatory and antipyretic effects of kaurenic acid (KA), a tetracyclic diterpenoid carboxylic acid, using in vivo experimental animal models.

Material and Methods:

The anti-inflammatory activity of KA was evaluated in rats, using egg albumin-induced paw edema (acute test) and Freund’s complete adjuvant-induced paw edema (subacute test), whereas the antipyretic effect was studied in rabbits by peptone-induced pyresis. Acute and subacute toxicity of KA were analyzed in NMRI mice.

Results:

KA showed anti-inflammatory and antipyretic properties, and the effect caused was significantly dose-related (P < 0.001) in both cases. The mean lethal doses of KA were 439.2 and 344.6 mg/kg for acute and subacute toxicity, respectively.

Conclusion:

On the basis of these findings, it may be inferred that KA has an anti-inflammatory and antipyretic potential.     

Celecoxib induces tolerance in a model of peripheral inflammatory pain in rats

Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) that selectively inhibits cyclooxygenase-2 (COX-2). Like most NSAIDs, celecoxib exhibits analgesic effects in models of inflammatory pain but these appear to be dependent on endogenous opioid release. Therefore, this study has assessed the ability of celecoxib to induce tolerance in rats, comparable to that induced by morphine.Rats were injected subcutaneously (s.c.) twice daily with divided doses of celecoxib, morphine or indomethacin. Inflammation was induced in one hind paw of rats by injecting prostaglandin E₂ (PGE₂; 200 ng) 30 min after drug administration, on days 1, 3, 5 and 6 or 7. Nociceptive thresholds to mechanical stimulation were measured 3 h after PGE₂ injection, on the same days. On days 6 or 7, analgesic effects of the full doses of test drugs were assessed.Celecoxib-induced tolerance, as did morphine, an effect not shown by another NSAID, indomethacin. Cross-tolerance between celecoxib and morphine was observed as they did not induce analgesia when animals were chronically treated with morphine or celecoxib, respectively. In addition, tolerance to celecoxib’s analgesic effects persisted for at least two days after the end of the chronic treatment with celecoxib. Naltrexone prevented induction of tolerance to morphine or celecoxib.The present results strengthen the possibility that celecoxib has also mechanisms of analgesia unrelated to COX inhibition but dependent on endogenous opioid release. Our results also imply the existence of a new class of analgesics without the deleterious effects of COX inhibitors.