Nimulid - the hope of antiflogistic therapy

There is the list of characteristics of NIMULID, it is the new nonsteroid anti- inflammatory preparation (NAIP), that selectively inhibits cyclooxigenase-2, the ferment that inhibits production of inflammatory prostaglandin. Due to selectivity is reached expressed anti-inflammatory, analgetic and antipyretic action at smaller (in 2 - 8 times) list of side effects in contrast with other widely used NAIP. There is presented the facts of open investigation of NIMULID of the company "Panacea Biotec" with participation of 70 patients with rheumatoid arthritis in three clinics of Moscow.

Nimesulid is selective nonsteroid anti-inflammatory preparation (NAIP), in its structure as acid group enters sulfonamide. Its selectivity is concluded in primary inhibition of cyclooxigenase-2 (COG-2) - a ferment that inhibits the products of inflammatory prostaglandin (PG). The separation of two isoforms of cyclooxigenase (prostaglandinsynthetase) COG-1 and COG-2 have changed conception about mechanism of the action of NAIP. Exactly COG-2 adjusts the synthesis of PG, that induced by different inflammatory stimulus while the activity of COG-1 defines the product PG, taking part in the normal physiological cellular reactions, that have been not connected with development of the inflammation (Tovares I. A. et al., 1995; Benck M., 1999). Some NAIP in some degree inhibit as COG-1, so and COG-2, while others in 10 - 30 times suppress COG-1more strongly, than COG-2. For strong inhibitors COG-1 are typical frequent side effects, that develops in consequence of long using NAIP. It is well known that PGEz and PPg render the protective action on a mucous membrane of a ventricle that is caused by their ability to reduce the gastric secretion of a hydrochloric acid and to enlarge the synthesis of cytoprotective substances. Erosive changes of a mucous membrane of ventricle and bowels are connected with modification of COG-1. PG also plays important role in regulation of glomerular filtration rennin secretion and support of water-electrolytic balance. The inhibition of PG can bring to different dysfunction of kidneys, especially for the people which have concomitant renal pathology. Another cyclooxigenase product is thromboxane Ag, inhibition of its synthesis NAIP violates thrombocyte aggregation and promotes to the bleeding. Finally, the suppression of cyclooxigenase activity can potentially promote to change over the metabolism of arachidonic acid on lipoxygenase pathway, causing hyperproduction of leukotriene (LT). Exactly this is the cause of the development of bronchospasm and other reactions of immediate hypersensitivity among the small part of the patients, that received NAIP. Above-listed results created the theoretical base for purposeful development of the new chemical compounds, capable to inhibit selectively COG-2, that allows to create the preparations with higher anti-inflammatory activity and low toxicity. NIMULID (nimesulid) is NAIP of the new generation , it practically does not inhibit COG-1, but vastly suppresses COG-2. Due to this it is reached expressed anti-inflammatory, analgetic and antipyretic action at smaller (2 - 8 times) number of side effects in contrast with other widely used NAIP (table 1). Additionally, itself NIMULID as a material has not acid pH (pH 6,2 - 6,5) and does not irritate a ventricle. Many others NAIP have their own low pH.

Table 1. Correlation of clinical effectiveness and side effects of the different NAIP

Preparation Index of effectiveness Side effects, %
Nimesulid 100 7,1
Meloxikam 20 24,2
Proxikam 1,4 30,2
Diclofenac 2,2 20,0

Inflamm. Res., Vol.46, 1997, Drugs, 1996. Mer (57); Drugs of Today, Vol. 32, 1995

Originally in investigations in vitro it seemed that nimesulid weakly influence on COG and for it are typical mechanisms of nonprostaglandin of anti-inflammatory action. Investigations of J. R. Vane and co-authors (1996) about existence of two isoforms of cyclooxigenase - COG-1 (constitutive) and COG-2, that is induced in the course of inflammatory reaction, on the one hand, and row of the researchers, studying its other possible mechanisms, actually they confirmed multimodal action of nimesulid. Therapeutic efficiency of NIMULID is determined by involving of other mechanisms which have been non-connected with regulation of PG synthesis (ref. scheme).

Scheme. The main mechanisms of NAP action.

Suppression of COG-2 activity
Inhibition of superoxide radicals that are separated by stimulated granulocytes by means of suppression protein kinase C and phophodiesterase of the 4 type
Suppression of consecution of signal transduction, leading to activation of integrin (SD 2 v/SD 18)
Inhibition of synthesis plateletactivating factor (PAF), interleykin -1 (IL-1) and IL-8
Prevention of bradykinin-cytokine stimulation of nerves by suppression release tumors-necrotic factor alpha (TNF-alpha)
Blocking of release of histamine from basophile of mast cell
Protection against inactivation of α-proteinase (elastosis, coplagenasa)
Prevention of injuries of gristles by means of inhibition of synthesis of metaloproteas

Each mechanism of the action of NIMULID defines its expressed and firm therapeutic efficiency at the patients with different pathological processes. Anti-inflammatory action of NIMULID was confirmed by its ability in suppression activities of the chemotaxis factor neutrophilic granulocyte (IL-8, platelet-adjuvant factor). Adhesion neutrophilic granulocyte falls under the influence of nimesulid to endothelium container, their ability to migrate through vascular wall to the center of the inflammation (Verboeven A. J. Et al., 1993). It is revealed, that nimesulid avoids cellular destruction and inflammatory stimulus by inhibition of the production superoxide anions activated neutrophilic granulocytes (Capsoni F. et al., 1999), as well as by direct inactivation hypochloride acid, formed under influence myeloperoxidase (Dallegri F. et al., 1990). Nimesulid possesses antianaphylactic and antihistaminic activity due to inhibition of immune secretion histamine from basophile of mast cell chosen from pulmonary parenchyma and kidneys of the human, as well as by suppressions of cte novo synthesis of allergy mediator in basofiles (Caso-ralo V. et al., 1994).This action of the preparation can be successfully used at the treatment of the patients, sensitive to acetylsalicylic acid and inclined to development of asthmatic attacks. The reduction of the separation histamine from basophile and mast cells under influence of nimesulid is conditioned by its ability to inhibit phophodiesterase-4, that brings to increasing of anti-inflammatory activity of endogenous cortisol (Bevilacqua M. et al., 1991). NIMULID possesses the ability to inactivate alpha-1-antitrypsin - a protein, primary synthesized by hepatocyte. It allows to keep the activity of alpha-1-trypsin - a specific inhibitor of neutral elastase and thus to warn tissue damage, including destruction of bone-gristle tissue. Chondroprotectoral action of nimesulid is caused by its ability to reduce the synthesis of metalloprotesa: stromelycin (proteoglycanase) and collagenase (Gottonello L. et al., 1993, Pelletier J. P., Mariel-Pelletier J., 1993). Moreover, NIMULID, blocking phosphodiesterase-4, brings about increasing of cAMF in chondrocyte, and it causes the anabolic process in tissues of the joint gristle in addition to anticatabolic. Besides, NIMULID well penetrates into the joint cavity (50% from concentration blood plasma), rendering expressed local action. On analgesic activities nimesulid is close to indometacin, diclofenac, pyroxicam. Moreover this effect is caused by suppression of the separation of bradykinin and the factor of tumor necrosis without influence upon hyperanalgia, conditioned by IL-1 and IL-8 (Ferreira S. H., 1997). Alongside with IL-1 the important significance in pathogeny the inflammations occupies the factor of tumor necrosis. These anti-inflammatory cytokines are interconnected and cooperate with each other (Vozianov A. F. and co-author, 1998). Nimesulid blocks surplus product of the factor of tumor necrosis. Antipyretic effect of nimesulid is expressed more intense and longer, than paracetamol and in equal degree reveals at children and person of the senior age group (Ceserani R. et al., 1993). Antiaggregatory activity of nimesulid is higher, than cyclopidin, thus hemorrhagic complications are not noted (Ceserani R. et al., 1993). In a usual therapeutic dose (50-200 mg) NIMULID is quickly soaked up at peroral acceptance both in tablets and granulated form. The peak of the concentrations is already reached in 1,2 - 3,8 hours in serum, it varies from 1,98 to 9,8 mg/l. At the reactive entering of the preparation maximal concentration is reached slowly - in 3 - 5 hours. Increasing of concentration of the preparation in blood plasma dependents of dose. So, when NIMULID is taken 2 times a day in 100 mg during 1 week it is noted increasing of its concentration in blood plasma. Its concentration reduces if it is taken with the food (Bemareggj A.,1993). The preparation practically completely links with plasma protein (99%) and actively metabolizes. From 1 to 3% of the preparation deposits in invariable type with urine. The metabolites of NIMULID also basically egest with urine (65-70%) or with excrements (20-30%) and only a small quantity - with bile. The period of partial ejection of the main metabolite of NIMULID - 4-hydrooxinimesilid forms 3 - 5 hours. It is necessary to note that NIMULID well penetrates into joint cavity. During the investigations of synovial fluid at the patients with atrophic, they received 100 mg of nimesulid per day during 1 week, its concentration in plasma and synovial fluid has formed accordingly 5,48 and 2,39 mg/l in 3 hours after the last receiving of the preparation and 2,37 and 1,38 mg/l in 12 hours (Cherie Ligniere G. et. al., 1990). Considering influence of the preparation on the separate mechanisms pathogeny of inflammations, destruction of bone tissue it is justified its use in rheumatology. Pharmacokinetics of NIMULID is not changed at children, people of the elderly age, and also at patients with moderate insufficiency of the secretory function of kidneys. The combination of nimesulid with other preparation is good enough, but it is possible reduction of the effect of methotrexate, furosemide. In comparison with other NAIP it is not noted the influence of the preparation on digoxin action, antidiabetic drug, theophylin, cimetidine, antacides. The tolerance of nimesulid priced at postmarketing investigations on 22938 patients with osteoarthritis (Bourgeois P. et al., 1994). In this group of patients it is noted such side effects as the development of dyspeptic effect (5-8%), skin eruption or itch (0,1%), headache and/or dizziness (0,3-0,4%). All the side reactions disappeared quickly when the preparation was canceled. The patients with bronchial asthma or with hypersensibility to acetylsalicylic acid transmitted well nimesulid in usual daily dose 200 mg (Pochobradsky M. G. et al., 1991). Prescription of NIMESULID to the patients of the elderly age usually does not require the correction of dosing regimen. As the majority of other pharmacological drug, to prescribe NIMULID at the period of pregnancy (particularly in the 3-rd trimester) is nor recommended. At the period of breast feeding if it is necessary the treatment by NIMULID should stop the breast feeding. The cases of NIMULID overdose are not described.. The specific antidote does not exist. The symptomatic therapy is conducted at overdose. NIMULID is widely used as anti-inflammatory and analgetic remedy, by the atrophic arthritis and osteoarthritis, according to the information of foreign authors. Its effect is close to effect of well known NAIP: pyroxicam, naproxen, ibuprofen. The results of multicentral open investigation , that was held on 23000 patients with osteoarthrtis, testify that nimesulid turned out to be efficient in 80% of cases (Pochobradsky M. G. et al., 1991). Dose of the preparation during 1 year has revealed its good tolerance and efficiency in 69% of cases (Davis R., Brogden R. N., 1994). At the same time intensity of pain fell on 30% in 1 month from the beginning of the therapy and on 50% by the end of the investigations. The similar results were received during double blind investigation in comparison of nimesulid with placebo, pyroxicam and ketoprofen (Bemareggi A, 1993; Dreiser R. L., 1993). The open investigation of NIMULID, production of the company "Panacea Biotec", that was held in Russia on 70 patients sick by atrophic arthritis in the three clinics of Moscow (the institute of the rheumatology RAMS,SPA"SKAL" and municipal rheumatological centre), has confirmed its high clinical efficiency (Balabanova R. M.,1976). The dynamics results of clinical and laboratory factors under the influence of NIMULID are cited in the table 2.

Table 2. Dynamics of clinical and laboratory factors, under the influence of NIMULID

INDEX Before treatment After treatment r
Morning constrain, min. 96,6 ± 15,7 57,6 ± 16,9 < 0,05
Intensity of pain, points 2,38 ± 0,29 1,4 ± 0,37 < 0,05
Index of Richi 24,3 ± 5,9 12,5 ± 4,9 < 0,05
Test of Ly 13,5 ± 2,56 9,86 ± 2,3 < 0,05
ESR, mm/h 22,9 ± 0,8 15,2 ± 1,01 < 0,05
C-reactive protein g/l 1,64 ± 0,9 0,85 ± 0,3 < 0,05

The multifunction treatment by nimesulid and diclofenac that was held in Ukraine has also relieved good efficiency in the treatment of patients with osteoarthrisis (Kovalenko V., Sholohova L.B., 2000).

Analgesic effect of NIMULID enables to use it at headache, extraction of the teeth and at stomatologic diseases, in postoperative period, at pain syndrome, caused by oncological and gynaecological pathology (nonspecific inflammations of the small pelvis organs, dysmenorrhea), athletic traumas, burns, trombophlebitis and in the number of other pathological conditions, caused by inflammation, fever and pain. NIMULID renders good febrifuge and anti-inflammatory effect at influenza and other respiratory infections. Because of low probability of the development of side effects and high therapeutic efficiency NIMULID is particularly indicated under the long treatment of osteoathritis, osteoarthrosis, atrophic arthritis, ankylosing spondyoarthritis, bursitis, tendinitis. The high therapeutic efficiency and practically full absence of side effects are typically for NIMULID in the form of transgel. The system of microforms that was patented in the USA (the patent № 5,716809 dt. 10.02.98) allows to penetrate deeply to the active material - nimesulid - in the injured tissues - skin, muscles, joints. The comparative investigation analgesic efficiency of nimesulid and diclofenac in form of gel has revealed more high efficiency of the first one (Sengupta S. et al., 1998). Though both investigated gels rendered analgesic action dependent on a dose, with maximal effect in an interval of 90-120 minutes after application, but nimesulid gel is more intensively blocked the action of the pain nociceptores than diclofenac gel, both in 1 and 2 phases of a pain (table 3).

Table 4. Possible side effects of the main analgetics

Active substance Duration of effect, hours The important side effects
Paracetamol 4 - 6 Toxic affection of liver (>12g), allergy
ASA 4 - 6 Disturbance of digestion, inhibition of thrombocyte aggregation
Metamesol 4 - 6 Agranulocytosis, super-sensitivity
Ibuprofen retard 1 - 2 Skin reactions, metabolic disease, alvealit, tiredness
Indometacin 4 - 6 Expressed toxicity of digestive tract
Diclofenac 8 - 24 Hepatotoxicity

The spectrum of application NAIP and analgesic in the CIS countries are traditionally used in the majority of the states of the world began to narrow. So, for example, metamesol sodium having immuno- and hematotoxicity (down to pancytopenia), and also causing in some cases anaphylactic shock, in all advanced countries it is forbidden to serve without a prescription, and in some of them it completely withdrawn from a chemist’s network. "The pioneer" in long number of NAIP is acetylsalicylic acid (ASA) though it keeps popularity, however by virtue and high gastroaggression ….. and fatal cases from syndrome of Rey arising at children which conducted the treatment of ASA for a flu and other acute respiratory diseases, - it is allowed to sale in many countries only in the event if packing contains the above mentioned cautions. Paracetamol which has the best structure of safety, nevertheless, it is recommended only as an effective antifebrile because the analgesic activity of paracetamol as a monopreparation is rather moderate, and anti-inflammatory is absent completely. Overdose of paracetamol with the purpose of achievement of adequate anesthesia brings to affection of a liver and kidneys or causes allergies. There are variants of side action of most widely used analgesics are submitted in table 4. It is necessary to remember, that the probability of appearance of side effects grows at children and people of elderly age, and also at patients with damages of a digestive tract and renal pathology, and also at simultaneous use of several NAIP. Application of codrug is not recommended, for example paracetamol with codeine or caffeine - benzoate sodium, because it brings to medical dependence. According to information of American consulting company Decision Resources, Inc, the world sales volume of the medical products, that is used at osteoarthrisis, has made 1,6 billion US dollars, and under forecast for 2008 it will reach 4 billion dollars. The results of research of this company testify that recently doctors especially frequently appoint selective inhibitors of NIMULID COG-2. NIMULID which are made by Indian pharmacological company "Panacea Biotec" in strict correspondence of GMP, at more than reasonable price policy will take a worthy place and in the market of Ukraine.

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