Analgesic medicinal agent

FIELD: biochemistry, nucleotides, pharmacy.

SUBSTANCE: invention relates to using adenosine 5'-triphosphate-2',3'-dialdehyde for preparing analgesic medicinal agent.

EFFECT: valuable medicinal property of agent.

2 tbl, 3 dwg, 2 ex

 

The present invention relates to the use of adenosine-5'-triphosphate-2',3'-dialdehyde (oatt) to obtain the medicines used for the treatment of inflammatory diseases.

Molecule oath is formed from ATP by oxidation of the hydroxyl present in the ribose at positions 2' and 3' dialdehydes. This oxidation can be carried out with salt periodni acid, as described in .N.Lowe et al., "Preparation and chemical properties of periodate-oxidized adenosine triphosphate and some related compounds". Biochemical Society Transactions, Vol.7: 1131-1133, 1979.

Derivative of 2',3'-dialdehyde ATP is usually used as a marker affinity for the enzymatic sites of nucleotides (Eastcrbrook-Smith C., Wallace, J.C. & Keech, D.B. (1976) Eur. J. Biochem.62, 125-130), because it has the ability to interact with deprotonirovannymi lysine residues present in a nucleotide sites, with the formation of Schiff bases or dihydromorphine derivatives (Colman, R.F. (1990) in The Enzymes - Sigman, D.S., and Boyer, P.D, eds - Vol.19, pp.283-323, Academic Press, San Diego). Molecule oath can also be used to study platelet activation and inhibition of stimulation of skeletal muscle chick ATP (Pearce, P.H., Wright, J.M. Egan C.M. & Scrutton, M.C. (1978) Eur. J. Biochem. 88, 543-554; Thomas, S.A., Zawisa, M.J., Lin, X. & Hume, R.I. (1991) Br. J. Pharmacol. 103, 1963-1969). In addition, studies of cell lines, macrophages proved that oath able to block the effect of permeability of plasma m is mpany, induced ATP, to reduce hydrolysis of exogenous ATP membrane ecto-ATPase and inhibition effects swelling, vacuolization and cell lysis induced by ATP (Murgia et al. The Journal of Biological Chemistry, (1993) by The American Society for Biochemistry and Molecular Biology, inc., Vol 268, No. 11, pp.8199). It has been suggested that oath has an antagonistic activity against P2z/P2X7 of purinoreceptors. IL-1β (interleukin 1β) LPS (lipopolysaccharide)-dependent release of microglial cells expressing P2z/P2X7, indeed selectively inhibited oath (D. Ferrari et al., J. Exp. Med., (1997) Vol.185, No. 3, Pag. 579-582).

It was found that in vivo oath has significant anti-inflammatory and analgesic action. As an experimental model was used unilateral inflammation of the hind legs of rats after injection in the foot sole complete adjuvant's adjuvant (PAF). As a control took the foot of the other side of the immunized animals, and the foot is not treated. Inflammation induced by PAF, are evident from 3 h to 24 to 48 h after injection by an increase in the feet, redness and increased sensitivity to pain. The latter was measured algesimeter test (test by pressing the tab), giving an opportunity to assess the threshold of pain sensitivity. Injection oath in the sole of the foot considerably what about reduces pain perception (nociception), i.e. increases the threshold of pain sensitivity. Different doses oath in all cases induced a significant, dose-dependent analgesic effect, which lasts for approximately 12-24 hours, with a maximum effect within an hour after injection. Moreover, in the paws of rats treated oath, decreased the expression of other signs of inflammation (swelling and hyperthermia). In the subsequent test comparison between off and diclofenac - known anti-inflammatory drug, used for arthritic pathologies, reliably shown that oath has a much higher analgesic action than diclofenac. The test, in which rats pre-injected with fucoidin - inhibitor of leukocyte diapedesis showed that the activity oath does not depend on the number of leukocytes in inflammation. The levels of ATP in the foci of inflammation were significantly higher than in untreated animals, which means that oath can partly block the production of exogenous ATP, thus preventing its Pro-inflammatory action.

The present invention relates to the use of off as a drug for the treatment of inflammation and conditions involving pain. The invention also relates to pharmaceutical compositions containing oath as the active ingredient in the natural with pharmaceutically acceptable excipients. Forms suitable for oral, external or parenteral administration, represents, for example, tablets, beads coated with sugar, capsules, granules, powders, suppositories, syrups, solutions, suspensions, creams, ointments, gels, pastes, lotions, emulsions, sprays. The pharmaceutical compositions can be obtained in accordance with the method described in Remington''s Pharmaceutical Sciences Handbook, Mack Pub. Co., NY. USA, XVII Ed. The amount of active substance in a unit dose may be in the range from 0.05 to 100 mg per kg of body weight, for single or multiple injections per day, depending on the severity of the disease to be treated, and the condition of the patient. The dose is usually from 1 to 300 mg, preferably from 10 to 100 mg.

The connection according to this invention can also be used in combination with other commonly used anti-inflammatory drugs.

Further, the invention is illustrated by the following examples.

Example 1: the pharmacological activity outf

Induction of inflammation in rats.

Were used inbred male Fischer rats (Charies River Italy, Caico, Lecco, Italy) weighing about 250 g Under the action of short-term anaesthesia with isoflurane rats spent vnutripolostnoe injection complete adjuvant's adjuvant (PAF) in the right hind paw (0.15 ml). This injection caused odnostoronie vocal the tion (from 3 h to 24 to 48 h after injection), manifested in the increase of the legs, hyperthermia and increased pain sensitivity. Increased pain sensitivity was assessed algesimeter test using algesimeter (Ugo Basile, Comerio, Italy) to determine the threshold pressure, expressed in grams, namely the pressure at which OTDELENIE feet, showing the threshold of pain sensitivity. For each test case used from 6 to 8 rats. During these tests, animals were treated in accordance with the standard ethical principles" (NIH, 1985).

Treatment outf

After 24 h after injection of PAF received inflamed paw of the rat, conducted vnutripolostnoe injection of different doses oath (from 56 to 336 μm), assuming zero time stamp of the moment of introduction oath. Received levels of the threshold of pain sensitivity are presented in Table 1.

TABLE 1
The THRESHOLD of PAIN SENSITIVITY OR THRESHOLD PRESSURE ON the PAW"
OATH 56 mcm112 microns224 mcm336 mcm
0 min60±1,665±2,050±1,560±1,9
30 min 120±2,1*140±3,5*350±5,4*300±3,4*
60 min190±2,3*180±4,2*400±10,3*≥750 *1
90 min85±2,5*150±3,8*300±11,2*≥750 *2
120 min75±1,8*100±3,0*185±7,1*600±20,8*
240 min75±2,6*105±4,3*180±8,9*550±18,4*
*1,2 = excluded
Data are presented as mean value ± srcpos. the threshold pressure paw (moderate in g) p<0,05 compared with 0 time (inflamed foot, without treatment)

* Test Mann-Whitney

Similar results were obtained using 35 microns off instead of 56 μm oatp 56 or inflammation caused (by injection of PAF) for 6 or 12 hours instead of 24 hours additionally, the tabs that were treated oath were less painful, and they were reduced signs of inflammation (swelling, redness) compared with untreated paws.

Has been proven dose-dependent effect oath, although significantly high results were achieved with minimal used dose. However, neither is the cue dose had less long lasting analgesic effect, possibly due to incomplete saturation RH receptors.

In a subsequent series of experiments examined the effect of the maximum usable doses off for longer periods of time on his paws rats inflammation caused 48 hours (table 2). These data confirm that the injection oatp significantly increases the threshold of pain sensitivity for a very long time, although there is a progressive reduction actions during the time.

TABLE 2
The THRESHOLD of PAIN SENSITIVITY OR THRESHOLD PRESSURE ON the PAW"
OATH 336 mcm
0 min55±2,0
30 min210±10,7
60 min360±25,8
90 min395±30,2
120 min450±38,1
180 min550±45,9
240 min690±56,6
12 hours400±29,7
24 hours210+7,2
26 hours190+3,3

Threshold of pain sensitivity feet in control (as nevospalennyh legs and the other hand, and tarsi without treatment) was approximately 100-150 expressed as the threshold of pain sensitivity or threshold pressure on the paw measured in,

Vnutripolostnaja injection of ATP (0.9 mmol) (extracellular ATP is cytolytic and may, therefore, has the ability to initiate the signals of pain sensitivity) caused a decrease in the threshold of pain sensitivity is greater in nevospalennyh legs than in inflamed paws (values 120±3.2 to 25±3,0 installed in nevospalennyh legs, 240 min after vnutripolostnoe injection ATP), compared with a decrease from 65±4.2 to 50±4,1 in inflamed paws. These results may indicate that the cytolytic ATF is already present in higher amounts in inflamed paws than in nevospalennyh. On the other hand, oath was effective in raising the threshold of pain sensitivity in a short time also in nevospalennyh legs, being effective at the lowest concentration oath (=56 μm). Curves dose/effect nevospalennyh legs were actually imposed (up to 120 min after injection off) using different concentrations of the molecule. To establish whether the analgesic effect oath is associated with activation of inflammatory cells capable of producing engage the nye β -endorphins, some rats intravenously injected with fucoidin (10 µg/kg). Indeed, fucoidan inhibits leukocyte diabetes and the accumulation of leukocytes at the site of inflammation. Conducted pre-treatment fucoidin both legs for 30 min before the injection in one PAF. The threshold pressure pain sensitivity (PDB) was measured as in nevospalennyh and inflamed paws, before and after the introduction oath (224 μm).

The obtained results are presented graphically in figure 1. Injection oath was not significantly modify the levels of the PDB in nevospalennyh legs, while the treatment of inflamed paws off restored the levels of the PDB, which were greatly reduced by the injection of proinflammatory PAF. Thus, the analgesic effect oath depended on the increase in the number of leukocytes.

In conclusion, the analgesic effects off compared with diclofenac - known anti-inflammatory and analgesic drug. After determining the lower threshold of pain sensitivity in rats caused unilateral inflammation of the hind paw injection of PAF. After 3 hours after injection the animals were divided into 2 groups, one of which is locally processed off (336 μm), and the other diclofenac (15 mg). Analgesic effect oath was significantly higher than that of diclofenac (the standard results of the experiment provedenia Figure 2). Concentration oath and diclofenac were selected to ensure good dissolution of the molecules in sterile saline solution prior to introduction into the sole of the foot rats.

Finally, intravenous oath rats when analyzed for vnutripochvennogo injection doses caused a dose-dependent decrease in pain for approximately two hours, although reflexes are still clearly present.

The ATP content was determined in the paws of rats treated oath and untreated legs of the other party. The inflamed and nevospalennyh feet removed subcutaneous tissue and rapidly frozen in liquid nitrogen. Frozen tissue samples were weighed, homogenized in phosphate buffer, and then were treated To a2CO3and neutralized and centrifuged at the end. The supernatant was used for analysis of ATP luminescence method.

The ATP values were significantly higher in homogenates obtained from untreated legs than in the treated off (1050±90 nmol/g fresh tissue from untreated animals compared to 320±22 nmol/g fresh tissue in animals treated off - each value is the average ± srcpos. 7 experiments). This indicates that oath blocks the formation of exogenous ATP in the same fabric structure by binding to their membrane receptors, thus reduces the damage caused by exogenous ATP.

Example 2: change in ATP content in the peripheral subcutaneous tissues after treatment outf

Study the content of ATP in the paws of rats.

Established in separate groups of rats changes in ATP content, caused by inflammation in the tissue of the sole and/or impact oath. In time removed the subcutaneous tissues of the feet and quickly frozen in liquid nitrogen for blocking any metabolic activity. Frozen tissue is homogenized with Poltrona (Kinematica GmbH, Luzern, Switzerland) in chilled on ice 6% (wt./volume) HClO4for the extraction of nucleotides. The homogenate was centrifuged and supernatant was used for determination of ATP by the previously described method (Marni et al. Transplantation (1988), 46: 830-835). The ATP analysis conducted by the luminescence method (Ferrero et al., Res Commun Chem Path Pharmac 1984; 45: 55-67).

Results

Measured ATP levels in inflamed (24-hour treatment PAF) and nevospalennyh legs, processed oath, 6 and 12 hours after administration oath, and raw paws the other hand. As shown in Figure 3, in nevospalennyh tissues treated oath, ATP levels did not change significantly: the data could reflect intracellular metabolite levels, which was not significantly changed by treatment oath. In contrast, the ATP levels in inflamed tissues, which is significantly higher than in nanoplankton, were significantly reduced by treatment oath. Indeed, the release of ATP (extracellular ATP from cells requires their damage occurs when inflammation or other degenerative processes. Binding of ATP with receptors on many cells and also on the sensitive nerve endings were able to competitively block the binding of extracellular ATP with the same structures, thus limiting associated with ATP cytotoxicity and causing the pain. Our results indicate that treatment of inflamed tissues off further restricts the production of ATP inflammatory or other cells, possibly by blocking their activation.

Figure 3: impact on the levels of ATP injection oath in the sole inflamed or nevospalennyh feet.

The ATP content in 6 and 12 hours after injection oath (35 μm) in the soles of the paws of rats: inflamed (24 hours introduction PAF) (black columns), inflamed processed off (hatched columns), nevospalennyh (not shaded columns), nevospalennyh processed off (bars with horizontal lines), *p<0,005 compared with raw inflamed paws, test Wilkson. Data are presented as averages ± srcpos. 7 experiments.

The use of adenosine-5'-triphosphate-2'3'-dialdehyde to obtain analgesic, in addition to the public funds.



 

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