Inhibitory effect of amygdalin on lipopolysaccharide-inducible TNF-alpha and IL-1beta mRNA expression and carrageenan-induced rat arthritis

Amygdalin is a cyanogenic glycoside plant compound found in the seeds of rosaceous stone fruits. We evaluated the antiinflammatory and analgesic activities of amygdalin, using an in vitro lipopolysaccharide (LPS)-induced cell line and a rat model with carrageenan-induced ankle arthritis. One mM amygdalin significantly inhibited the expression of TNF-alpha and IL-1beta mRNAs in LPS-treated RAW 264.7 cells. Amygdalin (0.005, 0.05, and 0.1 mg/kg) was intramuscularly injected immediately after the induction of carrageenan-induced arthritic pain in rats, and the anti-arthritic effect of amygdalin was assessed by measuring the weight distribution ratio of the bearing forces of both feet and the ankle circumference, and by analyzing the expression levels of three molecular markers of pain and inflammation (c-Fos, TNF-alpha, and IL-1beta) in the spinal cord. The hyperalgesia of the arthritic ankle was alleviated most significantly by the injection of 0.005 mg/kg amygdalin. At this dosage, the expressions of c-Fos, TNF-alpha, and IL-1beta in the spinal cord were significantly inhibited. However, at dosage greater than 0.005 mg/kg, the painrelieving effect of amygdalin was not observed. Thus, amygdalin treatment effectively alleviated responses to LPStreatment in RAW 264.7 cells and carrageenan-induced arthritis in rats, and may serve as an analgesic for relieving inflammatory pain.     

Analgesic and anti-inflammatory effects of phosphodiesterase inhibitors

The aim of the present study was to investigate the role of phosphodiesterase (PDE) enzyme inhibitors namely rolipram and theophylline in pain and inflammation in experimental animals. Rolipram, a selective PDE IV inhibitor and theophylline a nonspecific PDE inhibitor exerted dose dependent analgesic and anti-inflammatory effect against acetic acid-induced writhing in mice and carrageenan-induced paw edema in rats, respectively. Nimesulide (1, 2 mg/kg) produced significant anti-inflammatory effect. Further, nimesulide (0.5 mg/kg) potentiated analgesic effect of rolipram but it failed to modulate the anti-inflammatory effect of PDE inhibitors. Present study suggests that PDE enzymes might be playing a role in nociceptive and inflammatory responses in animals.     

Effects of acute prednisolone administration on plasma and liver copper in rats with adjuvant arthritis

Several studies in animals and humans have shown that copper metabolism could be affected by inflammation or by corticosteroids. The relative importance of these two factors, often imbedded in clinical practice, was assessed by investigating the effects of acute prednisolone administration (30 mg/kg, ip) on healthy and adjuvant arthritis rats. Plasma copper levels were significantly higher in arthritic rats compared to healthy animals, whereas there was a slight, but nonsignificant increase in liver copper. Acute prednisolone administration in healthy rats resulted in a significant increase in plasma copper (10–15%) as early as 4 h after corticosteroid administration, which was maintained for 12 h. In arthritic rats, the response was much higher (25–40%), but somewhat delayed and shorter. Liver copper was not clearly modified by prednisolone treatment in both groups. This time-controlled study showed that acute prednisolone administration increased plasma copper in both healthy and arthritic rats, but in different ways, indicating that inflammation and corticosteroids may act synergistically.     

Trace element status and inflammation parameters during chronic indomethacin treatment in adjuvant arthritic rats

Oral indomethacin administration (2 mg/kg/d) was investigated in rats with adjuvant arthritis up to a period of 5 wk. Baseline low serum zinc levels in arthritic rats increased rapidly from the first week of indomethacin treatment (started 1 or 2 wk after disease induction), whereas baseline high serum copper decreased after 1–2 wk. After 3–4 wk of treatment, serum zinc levels returned to control values, but serum copper was somewhat higher in arthritic animals having received indomethacin 2 wk after disease induction than in controls. Clinical indices of inflammation simultaneously improved to reach control values at the end of the trial. Biological indicators of inflammation also improved, but did not reach control levels. Serum zinc correlated negatively with plasma fibrinogen (r=?0.69,p<0.005) and serum copper correlated positively with serum ceruloplasmin (r=0.92,p<0.0005) both in indomethacin-treated and untreated arthritic rats. Contrary to long-term glucocorticoid administration that was previously reported to maintain or aggravate hypozincemia, indomethacin treatment normalized perturbed zinc and copper status in arthritic animals.     

Anti-inflammatory and anti-arthritic effects of new synthetic 3-(4-hydroxyphenyl)-4-(4-thiomethoxyphenyl)-1H-pyrrole-2,5-dione

We previously reported that 3-(4-hydroxyphenyl)-4-(4-thiomethoxyphenyl)-1H-pyrrole-2,5-dione (1, HMP) has a strong inhibitory effect on prostaglandin E(2) (PGE(2)) production. In this study, the anti-inflammatory and anti-arthritic effects of HMP were evaluated on LPS-induced RAW 264.7 macrophages and rats with carrageenan-induced paw edema and adjuvant-induced arthritis (AIA). The attenuation of PGE(2) production by HMP was found to be caused by the inhibition of cyclooxygenase-2 (COX-2) activity, but not COX-1 activity. However, HMP did not affect COX-2 at the protein or mRNA levels, whereas it suppressed the releases and expressions of inflammatory cytokines, such as, interleukin-1β (IL-1β) and IL-6 in LPS-induced macrophages. Furthermore, HMP suppressed LPS-induced nitric oxide (NO) production by down regulating the protein and mRNA expressions of inducible nitric oxide synthase (iNOS). In rats with carrageenan-injected acute inflammation, oral administration of HMP (25 or 50mg/kg, po) reduced paw swelling, and PGE(2) release and myeloperoxidase (MPO) activity in tissue. Furthermore, HMP (25 or 50mg/kg, po) significantly reduced paw swelling, arthritic indices and plasma PGE(2) concentrations in rat with AIA. These results show that HMP reduces swelling in a model acute inflammation and inhibits arthritic responses in a model of chronic inflammation via the inhibition of PGE(2) production. These results suggest that HMP is a potential therapeutic agent for the treatment of arthritis and associated disorders.     

Synthesis, characterization, and biological screening of a copper flurbiprofen complex with anti-inflammatory effects

The flurbiprofen complex of copper(II) was prepared and characterized by IR, UV-VIS and EPR Spectroscopy, magnetic susceptibility, and thermogravimetric analysis. The compound was tested for in vivo anti-inflammatory and analgesic activities in rats. The inhibitory effect on carrageenin-induced paws inflammation and analgesic effect of copper flurbiprofen complex were similar to those of free flurbiprofen. However, the copper complex produced less gastric irritation than the parent drug.     

Further evidence validating adjuvant arthritis as an experimental model of chronic pain in the rat

The experiments described here were aimed at further validating adjuvant arthritis as an animal model of chronic pain. It was found that the relative oral intake of a 0.008 mg/ml solution of fentanyl was higher in arthritic than in normal control rats; this difference was predicted by the notion that the analgesic effect of a substance may reinforce its intake in animals exposed to pain, more so than in normal pain-free animals. It was also found that body weight decreases and that vocalizations of aggregated rats increase as a result of the challenge; these effects suggest that the vegetative signs and the behavioral irritability which are characteristic of chronic pain in humans, also occur in arthritic animals. The pain which thus seems to be associated with adjuvant arthritis was estimated to have its onset on days 10–11, to peak on days 18–21, and to terminate on days 35–40 after inoculation with $\text{Mycobacterium butyricum}$.     

Calcitonin gene-related peptide increases in the dorsal root ganglia of adjuvant arthritic rat

We examined the effect of adjuvant arthritis on the content of immunoreactive calcitonin gene-related peptide (iCGRP) in the dorsal root ganglia at L4-L6 levels and the spinal cord at a lumbar level in rats. Arthritis was induced by inoculating adjuvant into both hind-paws twice at a 10 day interval. In the arthritic rats 15 days after the first inoculation (day 15), the content of iCGRP was significantly increased in the dorsal root ganglia, with no change in the dorsal and ventral horns. The content in the dorsal root ganglia was still high on day 26 and had decreased by day 40. An intrathecal injection of colchicine (0.2 mg, 18 hr before killing) enhanced the increase of iCGRP in the dorsal root ganglia and decreased it in the dorsal horn of arthritic rats, although in noninoculated rats such treatment produced no significant changes in the content of iCGRP in both regions. The arthritis-induced increase in the content of iCGRP in the dorsal root ganglia was significantly reduced after treatment with the antiinflammatory analgesic, diclofenac sodium, in a dose of 3 mg/kg/day, PO for 10 days. Swelling and hyperalgesia in the hind-paw were depressed after such treatment. These results suggest that adjuvant arthritis with long-lasting inflammation with pain facilitates the turnover, especially biosynthesis, of CGRP in primary afferent neurons.     

A comparison of chronic aspartame exposure to aspirin on inflammation, hyperalgesia and open field activity following carrageenan-induced monoarthritis.

The purpose of the present study was to investigate whether chronic aspartame exposure possesses analgesic and anti-inflammatory actions in the carrageenan-induced monoarthritis model similar to those properties of aspirin. Prior research demonstrated that aspartame can reduce second phase formalin pain and increase motor activity in arthritic patients. Fifty-eight male Sprague-Dawly rats were treated with aspartame (25, 50, 100 mg/kg) or saline for six days. An additional group of animals received daily injections of saline and on the sixth treatment day, received a 150-mg/kg dose of aspirin 30-minutes prior to behavioral testing. On Day 6, animals received an intra-articular (i.a.) injection of 2% lambda carrageenan (CARR) or an equal volume of saline and were tested four hours later on threshold to mechanical and thermal stimuli, open field activity, and knee joint diameter. Aspirin-treated arthritic animals exhibited significantly less mechanical hyperalgesia and knee joint inflammation compared with vehicle treated arthritic animals. However, aspirin did not reverse thermal hyperalgesia or increase motor activity to control levels. Aspartame did not reduce inflammation, increase motor activity, or attenuate thermal allodynia, but at 50 mg/kg did attenuate mechanical allodynia compared with vehicle treated arthritic animals. The anti-hyperalgesic effect on mechanical hyperalgesia was not seen at 25 mg/kg or 100 mg/kg aspartame. These results suggest that a certain amount of aspartame may provide relief of arthritic pain to a similar degree as aspirin in some individuals. The specific effect of aspartame and aspirin on mechanical hyperalgesia should be considered when these agents are used for the therapeutic treatment of arthritic conditions.     

A mechanistic approach to understanding conjugated linoleic acid's role in inflammation using murine models of rheumatoid arthritis

A naturally occurring fatty acid, conjugated linoleic acid (CLA), reduces immune-induced TNF and inducible cyclooxygenase (COX-2) expression; key mediators of inflammation in rheumatoid arthritis (RA). On the basis of previous work, it was hypothesized that dietary CLA would act as an anti-inflammatory agent in select animal models of RA. In the collagen antibody-induced arthritis (CAIA) model, mice fed CLA (mixed isomers of c9, t11, and t10, c12-CLA) for 3 wk before anticollagen antibody injection had reduced lipopolysaccharide-induced plasma TNF levels and had arthritic scores that were 60% of mice fed corn oil (CO). In the collagen-induced arthritis (CIA) model, mice fed mixed isomers of CLA for 21 days before immunization had lower IgG(1) titers, earlier signs of joint inflammation, but similar arthritis scores compared with CO fed mice during the remaining 70-day post-injection period. Beginning on day 80 to 133, CLA-fed mice had arthritic scores 70% that of the CO-fed mice. In a second CIA experiment, CLA was fed only after the booster injection. Plasma IgG(1) levels were not reduced and arthritis onset was delayed 4 days in CLA-fed mice compared with the CO-fed mice. Peak arthritis score was similar between CLA and CO-fed mice from day 35 to 56. Because CLA reduced inflammation in the CAIA model, delayed onset of arthritis in the CIA model (CIA experiment 2) and reduced arthritis score after day 80 in the CIA model (CIA experiment 1), we concluded that dietary CLA exhibited anti-inflammatory activity that was dependent on antibody.     

L-carnitine and Zinc supplementation impedes intestinal damage in methotrexate-treated adjuvant-induced arthritis rats: Reinstating enterocyte proliferation and trace elements

BackgroundMethotrexate (MTX), a folic acid analogue, is used as a first-line treatment for rheumatoid arthritis (RA) since it has more therapeutic mechanisms than any other drug. Being an undeniable drug for the treatment of arthritis, even low-dose MTX provokes intestinal toxicity as a primary adverse effect and does not revive an anti-inflammatory element. Thus, our study aims to elucidate the anti-arthritic and prophylactic activity of supplements L-carnitine (L) and zinc (Z) against MTX-mediated intestinal damage in arthritis rats.MethodsThe rats were assessed for arthritic parameters such as body weight, paw volume, x-ray scan, and serum trace elements level. To analyze the toxic effects of MTX in the rats, intestine pH, mucosal weight, digestive enzymes, myeloperoxidase, histopathological, and immunohistochemical analysis were performed.ResultsOur study demonstrated that the arthritic parameters have shown that MTX has an ameliorative effect on arthritic rats. Besides, our findings showed that low-dose MTX (2.5 mg/kg b.w.) given once a week for two weeks during arthritis treatment had toxic effects in the rat's intestine, as evidenced by changes in intestine pH and mucosal weight, decreased digestive enzymes, increased MPO, and degenerative changes in histopathological analysis. Concurrent therapy of LZ with MTX, on the other hand, restored the modifications in these parameters.ConclusionMTX in combination with LZ effectively manages arthritis than monotherapy and significantly prevents MTX-induced intestinal damage in arthritis rats. Thus, LZ could be used as an improved therapeutic and safety for MTX-instigated intestinal damage during arthritis treatments. Therefore, our combination of L-carnitine and zinc with MTX would be promising prophylactic activity for arthritis patients.     

Boswellic acids and glucosamine show synergistic effect in preclinical anti-inflammatory study in rats

The present study revealed the synergistic effect of boswellic acid mixture (BA) and glucosamine for anti-inflammatory and anti-arthritic activities in rats. Two studies were conducted, that is, acute anti-inflammatory by carrageenan edema and chronic anti-arthritic by Mycobacterium-induced developing arthritis. Five groups of animals were included in each of the study: the vehicle control, positive control (ibuprofen 100mg/kg), boswellic acids (250 mg/kg), glucosamine (250 mg/kg) and a combination of boswellic acids (125 mg/kg) and glucosamine (125 mg/kg). BA when administered at 250 mg/kg in rats, carrageenan-induced paw edema and Mycobacterium-induced developing arthritis were significantly inhibited. In comparison to boswellic acids, glucosamine when administered at 250 mg/kg showed a mild effect in carrageenan-induced edema and moderate inhibition of paw swelling against developing arthritis. Although the combination of boswellic acids and glucosamine did not affect the acute inflammation to a greater extent yet a significant anti-arthritic activity was observed in rats. In conclusion, a synergistic effect was observed in chronic inflammatory conditions when two chemical entities were administered in combination in preclinical study.     

Oral buprenorphine is anti-inflammatory and modulates the pathogenesis of streptococcal cell wall polymer-induced arthritis in the Lew/SSN rat

This study was carried out to determine an effective regimen for pain management in streptococcal cell wall (SCW)-induced arthritis in female Lew/SSN rats. Forty weanling rats lin 2 groups) were trained to accept disks of jelly as part of their dietary regimen. At 8 weeks of age weighing 150 g, SCW arthritis was induced and sublingual buprenorphine tablets were incorporated into the jelly disks to alleviate the pain of acute arthritis, which developed 24 h post-induction. Group A rats received buprenorphine at a rate of 1 mg/kg 12 hourly. Group B rats received buprenorphine at a rate of 2 mg/kg 12 hourly. Both groups of rats were monitored for symptoms of distress using an adaptation of the Morton and Griffin scale of adverse reactions. Group A rats with severe arthritis required additional subcutaneous (s.c.) injections of buprenorphine to alleviate the adverse effects of arthritis. Group B rats, with twice the dose of buprenorphine did not require additional s.c. injections of buprenorphine. Histological sections of rat hocks indicated that the inflammation was suppressed in Group B rats. We concluded that oral administration of buprenorphine is an effective method of pain management in the pathogenesis of SCW-induced arthritis in Lew/SSN rats. In this model of arthritis, oral buprenorphine has a significant anti-inflammatory effect and appears to modulate the destructive arthritic phase in joints in this animal model of arthritis.     

Mass-Spectrometric Identification of T-Kininogen I/Thiostatin as an Acute-Phase Inflammatory Protein Suppressed by Curcumin and Capsaicin

Curcumin and capsaicin are dietary xenobiotics with well-documented anti-inflammatory properties. Previously, the beneficial effect of these spice principles in lowering chronic inflammation was demonstrated using a rat experimental model for arthritis. The extent of lowering of arthritic index by the spice principles was associated with a significant shift in macrophage function favoring the reduction of pro-inflammatory molecules such as reactive oxygen species and production and release of anti-inflammatory metabolites of arachidonic acid. Beyond the cellular effects on macrophage function, oral administration of curcumin and capsaicin caused alterations in serum protein profiles of rats injected with adjuvant to develop arthritis. Specifically, a 72 kDa acidic glycoprotein, GpA72, which was elevated in pre-arthritic rats, was significantly lowered by feeding either curcumin or capsaicin to the rats. Employing the tandem mass spectrometric approach for direct sequencing of peptides, here we report the identification of GpA72 as T-kininogen I also known as Thiostatin. Since T-kininogen I is an early acute-phase protein, we additionally tested the efficiency of curcumin and capsaicin to mediate the inflammatory response in an acute phase model. The results demonstrate that curcumin and capsaicin lower the acute-phase inflammatory response, the molecular mechanism for which is, in part, mediated by pathways associated with the lowering of T-kininogen I.     

Effects of selective iNOS inhibition on type II collagen-induced arthritis in mice

Nitric oxide as well as prostaglandins has been reported to play an important role in inflammatory diseases including arthritis. In the present study, the effects of iNOS inhibition on development of disease were examined in type II collagen-induced arthritis (CIA) in male DBA/1J mice. From 4 weeks after the first immunization with bovine type II collagen, 1400W (10 mg/kg/day, p.o.), a selective iNOS inhibitor, indomethacin (1 mg/kg/day, p.o.), a cyclooxygenase (COX) inhibitor, or 1400W + indomethacin was administered for 8 weeks. Immunization with type II collagen evoked arthritic inflammation of paws and bone destruction accompanied by increases in urinary nitrite/nitrate (NOx) excretion, plasma NOx and PGE2 levels. Administration of 1400W reduced urinary NOx excretion and increased plasma PGE2 levels, while it had no effect on arthritic inflammation or bone destruction. Indomethacin slightly reduced the inflammatory signs and bone destruction with marked reduction of plasma PGE2. Combination of 1400W and indomethacin reduced urinary NOx and PGE2 levels, and showed greater amelioration of inflammatory signs and bone destruction than either alone. In conclusion, 1400W, a selective iNOS inhibitor, failed to prevent CIA probably due to its increasing effect on PGE2 production, but showed a synergistic ameliorative effect in combination with indomethacin.     

Morphine tolerance in arthritic rats and serotonergic system

To understand whether chronic inflammation alters the development of morphine tolerance, the tail-flick test was used to evaluate the analgesic effect of morphine (75 mg tablet, s.c.) in the arthritic rats at the day 9-12 after the inoculation with Freund's adjuvant. Spinal cord monoamines and amino acid neurotransmitters were concomitantly measured. Chronic inflammation attenuated the antinociceptive effect of morphine as tolerance developed faster in the arthritic rats compared to the vehicle-treated controls. In addition, ratio of 5-hydroxyindole-3-acetic acid/5-hydroxytryptamine (5-HIAA/5-HT) increased in the lumbar spinal cord of arthritic rats without any change in the concentrations of norepinephrine, glutamate, aspartate or GABA. Interestingly, increased serotonin turnover in the spinal cord was observed in both control and arthritic rats 24 hours after morphine treatment. Overall, the results suggest a significant role of serotonin up-regulation in the spinal cord during chronic pain and the development of morphine tolerance.     

Trikatu,an herbal compound as immunomodulatory and anti-inflammatory agent in the treatment of rheumatoid arthritis – An experimental study

In the present study, trikatu, an herbal compound was evaluated for its immunomodulatory and anti-inflammatory properties with reference to cell mediated immune responses (delayed type hypersensitivity reaction), humoral immune response (haemagglutination titer and plaque forming assay), macrophage phagocytic index, circulating immune complex and inflammatory mediators in rats. For comparison purposes, indomethacin was used as a reference drug for anti-inflammatory studies. The results obtained in our study showed a significant decrease in cell mediated immune responses, humoral immune responses (haemagglutination titre and plaque forming assay) and macrophage phagocytic index in trikatu treated rats (1000 mg/kg/b.wt.) compared to control animals implying its immunosuppressive property. In addition, significant anti-inflammatory effects were observed in trikatu treated adjuvant induced arthritic rats by a reduction in the levels of circulating immune complexes and inflammatory mediators (TNF-alpha and Interleukin-1beta). Thus, in conclusion, our data suggest that trikatu could be considered as a potential anti-inflammatory agent for treating autoimmune inflammatory disorders like rheumatoid arthritis with immunosuppressive property.     

Ceruloplasmin and metallothionein induction by zinc and 13-cis-retinoic acid in rats with adjuvant inflammation

The induction of ceruloplasmin and metallothionein was investigated in rats with the early inflammatory phase of adjuvant arthritis. When examined at the peak of the acute inflammatory response, 5 days after adjuvant treatment, zinc given daily (2 mg/kg, intraperitoneally) increased serum ceruloplasmin levels by 2.0 times that found in nonarthritic rats and 1.2 times that found in non-zinc-treated arthritic rats. 13-cis-Retinoic acid (160 mg/kg, orally) given daily increased serum ceruloplasmin 2.2 and 2.7 times that found in nontreated arthritic rats when given alone and with zinc (2 mg/kg, intraperitoneally), respectively. Reduction in the inflammatory response was measured by weight of the adjuvant-injected paw, 5 days after adjuvant was administered. The reduction in inflammation was 13 and 19-20% for 13-cis-retinoic acid and zinc, respectively, when given alone, and between 26 and 31% when the treatments were combined. Zinc markedly increased liver metallothionein levels whereas 13-cis-retinoic acid was a much less potent inducer of the protein in liver. The results are discussed in light of the probable physiological roles of both ceruloplasmin and metallothionein.     

Anti-inflammatory and analgesic activity of ononitol monohydrate isolated from Cassia tora L. in animal models

Ononitol monohydrate (OM) was isolated from Cassia tora L. leaves. The anti-inflammatory and analgesic activities of OM have been examined in male Wistar rats and mice. The efficacy of OM against inflammation was studied by using carrageenan-induced paw oedema, croton oil-induced ear oedema, acetic acid-induced vascular permeability, cotton pellet-induced granuloma and adjuvant-induced arthritis. The analgesic activity of OM was assessed using the acetic acid-induced abdominal constriction response, formalin-induced paw licking response and the hot-plate test. In acute type inflammation models, maximum inhibitions of 50.69 and 61.06% (P < .05) were noted with 20 mg/kg of OM in carrageenan-induced hind paw oedema and croton oil-induced ear oedema, respectively. Treatment of OM (20 mg/kg) meaningfully (P < .05) reduced the granuloma tissue formation by cotton pellet study at a rate of 36.25%. OM (20 mg/kg) inhibited 53.64% of paw thickness in adjuvant-induced arthritis model. OM has also been produced significant (P < .05) analgesic activity in acetic acid-induced abdominal constriction response, formalin-induced paw licking response and in hot-plate test suggesting its peripheral and central analgesic potential. The outcomes of the present study proposed that OM influenced on the anti-inflammatory and analgesic activities.     

TT-232: An Anti-tumour and Anti-inflammatory Peptide Therapeutic in Clinical Development

TT-232 is a structural derivative of the peptide hormone somatostatin with selective anti-proliferative and anti-inflammatory properties. It has a strong anti-tumour activity both in vitro and in vivo on a wide range of tumour models and induces apoptosis. Its anti-tumour activity is mediated through the SSTR1 receptor and by the tumour specific isoform of pyruvate kinase. TT-232 has been shown to be a potent neurogenic inflammation inhibitory, anti-inflammatory and analgesic agent with a broader spectrum than presently available anti-inflammatory/analgesic drugs. In animal models it is effective against neurogenic inflammation and blocks neuropathic hyperalgesia where COX-1 or COX-2 inhibitors (e.g. diclofenac or meloxicam) proved ineffective. TT-232 has passed phase I clinical trials without toxicity and significant side effects. Human phase II efficacy studies are ongoing in melanoma indication. Two more oncological indications and phase II clinical trials in inflammatory diseases, including rheumatoid arthritis and burn injuries are in preparation. This compound has the perspective to become the first drug in molecularly targeted therapy of inflammation where a combined effect of anti-inflammatory, analgesic and neurogenic inflammation inhibiting activity can be achieved.