The use of certain drugs for the treatment of nerve root damage

 

(57) Abstract:

Proposed: new drugs for the treatment of damage to the nerve root, pharmaceutical compositions and methods of treatment comprising the administration of these funds. The funds represent the inhibitor alpha (TNF-a, selected from the group of inhibitors of metalloprotease (except methylprednisolone), tetracyclines, including chemically modified tetracyclines, quinolones, lazaridou, pentoxifylline derived hydroxamic acids, naphthopyrane, soluble receptors, cytokines, monoclonal antibodies to alpha (TNF-a, amrinona, pimobendan, vesnarinone, inhibitors of phosphodiesterase III, lactoferrin and analogues derived lactoferrin, and melatonin Invention expands the Arsenal of means and methods of treatment of these diseases. 11 N. and 23 C.p. f-crystals, 2 tab.

This invention relates to the use of an inhibitor of TNF - a to obtain pharmaceutical compositions for the treatment of damage to the nerve root, and treatment of damage to the nerve root.

The purpose of this invention is to achieve the ability to heal damage to the nerve root caused by the formation of a hernia is a rotary-related cytokines blocking disk.

Education herniated disc is a violation associated with suffering for the patient where it may be pronounced pain and muscle dysfunction and in connection with this disability. Hernia formation can occur in the spine in any drive, but the most common hernias are formed in the lumbar and cervical spine. Hernia formation in the cervical spine can cause radiating pain and muscle dysfunction in the hand, and hernia formation in the lumbar spine can cause radiating pain and muscle dysfunction in the foot. Radiating pain in the leg is commonly referred to as “ischialgia”. The formation of disc herniation causes suffering in various degrees, and the pain may persist for one or two months or in severe cases up to 6 months. Pain in the arm or leg as a result of formation of a herniated disc can be very intensive and, thus, in the period of pain can affect the life situation of the individual in General.

In U.S. patent US-A-5703092 describes the use of compounds hydroxamic acids and carbocyclic acids as inhibitors of metalloproteinases and TNF and, in particular, for legendary nerve roots, there is no hint.

In U.S. patent US-A-4925833 described the use of tetracyclines to increase protein synthesis in bone and treatment of osteoporosis.

In U.S. patent US-A-4666897 described inhibition collagenolytic enzymes mammals tetracyclines. Collagenolytic activity is manifested by excessive bone resorption, periodontal disease, rheumatoid arthritis, expressions cornea or resorption of the collagen of the skin or other connective tissue.

None of these patents do not mention anything about the damage to the nerve root, nor about his treatment.

Now unexpectedly been shown that there is an opportunity to heal the damage to the nerve root, using a pharmaceutical composition comprising a therapeutically active amount of a TNF inhibitor is selected from the group consisting of inhibitors of metalloproteinases, excluding methylprednisolone, tetracyclines, including chemically modified tetracyclines, quinoline, corticosteroids, thalidomide, lazaridou, pentoxifylline, derivatives of hydroxamic acids, naphthopyrane, soluble receptors, cytokines, monoclonal antibodies to TNF-, amrinona, pimobendan, vesnarinone, inhibitors of phosphodiesterase III, lactoferrins acceptable carrier.

Therapeutically effective amount is a commonly used dosage form when the use of such compounds for other therapeutic purposes. Many of these drugs are commercially known, registered medicines.

Compounds that exhibit this activity are the tetracyclines, such as tetracycline, doxycycline, lymecycline, oxytetracycline, minocycline and chemically modified tetracyclines - demetallization, connections, hydroxamic acids, carbocyclic acids and derivatives, thalidomide, lazaroid, pentoxifyllin, naphthopyrane, soluble receptors, cytokines, monoclonal antibodies to TNF-, amrinone, pimobendan, vesnarinone, inhibitors of phosphodiesterase III, lactoferrin and analogues derived lactoferrin, melatonin, norfloxacin, ofloxacin, ciprofloxacin, Gatifloxacin, pefloxacin, lomefloxacin and temafloxacin. They can be in the form of bases or in the form of salts of joining any of them are the best pharmaceutical effect and have the best properties for introduction into a suitable pharmaceutical composition.

Further, the active compound contains terleukin-1 and nitric oxide (NO) in the form of bases or addition salts.

In addition, the invention relates to a method of inhibiting the symptoms of damage to the nerve root.

Studied the effect of doxycycline, soluble receptors, cytokines, and monoclonal antibodies to cytokines and methods used and the results obtained are described below.

Examples

The purpose of the study

To assess the impact of gelatinous kernel and various therapies to block the activity of TNF - in the experiments with the use of immunohistochemistry and recording the speed of nerve conduction.

The conclusions of the main results:

Meta-analysis of the observed effects induced by gelatinous nucleus revealed that these effects may be associated with one specific cytokine - tumor necrosis factor alpha (TNF-).

Objective

To detect the presence of TNF in cells gelatinous kernel pigs and install, blocks also whether blockade of TNF - induced gelatinous nucleus reduce the speed of conduction of the nerve root.

Ways

Series-1: Cultured cells gelatinous nucleus were stained with immunohistological monoclonal antibody to TNF-.

Series 2: the Gelatinous core extracted from oasn the Igny received 100 mg of doxycycline intravenously, 5 pigs were injected blocking monoclonal antibody to TNF - locally on the jelly-like nucleus, and 4 pigs were not treated and used as control. After three days was determined by the conduction velocity of nerve root above the area applied by local electrical stimulation.

Series-3: Autogenous gelatinous nucleus was placed on the beam sacrococcygeal spinal roots thirteen pigs, as in series 2. Five pigs (body weight 25 kg received RemicadeR(infliximab) 100 mg intravenously before surgery and 8 pigs received EnbrelR(etanercept) 12.5 mg subcutaneously before surgery and an additional 12.5 mg subcutaneously three days after the operation. Seven days after application of the gelatinous nucleus was determined by the conduction velocity of nerve root above coating with local electrical stimulation according to series 2.

Results

Series-1: Found that TNF - a is present in the cells gelatinous kernel.

Series 2: Election of antibodies to TNF - a limited reduction in the speed of nerve conduction, though not statistically significantly relative to the control series. However, treatment with doxycycline significantly blocked the induced gelatinous kernel snpt) effectively blocked the induced gelatinous nucleus and nerve damage detected normal average speed of nerve conduction after treatment, both of these two medicines.

Conclusion

The first specific substance, tumor necrosis factor alpha, is associated with induced gelatinous nucleus effects of the nerve root after local application. Although exposure to this substance can be synergistic with other similar substances, the results of this study can be important for further understanding the biological activity of gelatinous kernel, and can also find potential application for future treatment strategies of ishialgii.

According to the previously considered exactly the same as biologically inactive tissue component compresses the spinal nerve root in the formation of a hernia of a disk, the gelatinous core, as it was recently installed, is highly active, causing both structural and functional changes in the adjacent nerve roots with epidural use(24, 37, 38, 41, 42). It was thus established that autogenic gelatinous kernel can cause changes of axons and characterized by damage to the myelin(24, 38, 41, 42), increased vascular permeability (9, 44), intravascular coagulation (24, 36), and membrane-bound structure or substance cells gelatinous kernel are responsible and cyclosporine a (2, 38). If you carefully look at these data, it seems clear that there is at least one cytokine that is relevant to all these effects, tumor necrosis factor alpha (TNF-). To determine whether TNF - to be involved in induced gelatinous core damage to the nerve root, evaluated the presence of TNF in cells gelatinous kernel and investigated the question of whether the effects induced gelatinous core, to be blocked by doxycycline, soluble TNF receptor and selective monoclonal antibodies to TNF, the latter was introduced as a topical jelly-like nucleus and systematically.

MATERIALS AND METHODS

Series-1. The presence of TNF in cells gelatinous kernel: Gelatinous nucleus (NP), just 13 of the lumbar and thoracic discs were obtained from pigs used for other purposes. NP washed once with medium F12 ham (Ham; Gibco BRL, Paiseley, Scotland) and then centrifuged and suspended in 5 ml of collagenase in the environment F12 Gama (0.8 mg/ml, Sigma Chemical Co., St. Louis, MO, USA) for 40 minutes at S 25 cm2bottles for tissue cultures. The separated precipitate of NP cells suspended in DMEM/F12 1:1 (Gibco BRL, Paisley, Scotland), enriched with 1% L-glutamine 200 mm (Gibco BRL, Paisley, Scotland), 50 μg/ml gentamicin is C and in an atmosphere of 5% CO2within 3-4 weeks, and then were cultured directly on slides treated tissue culture (Becton Dickinson & Co Labware, Franklin Lakes, NJ, USA). After 5 days of cultivation on slides, the cells were fixed in situ with acetone for 10 minutes. After blocking irrelevant antigens by the use of 3% H2O2(Sigma Chemical Co., St. Louis, MO, USA) for 30 minutes, and horse serum (ImmunoPure ABC peroxidase staining of mouse IgG, set # 32028, Pierce, Rockford, IL) for 20 minutes was used primary antibodies (monoclonal antibodies against TNF - pigs, Endogen, Cambridge, MA, USA) overnight at 40C, was diluted to 1:10, 1:20 and 1:40. To control BSA (bovine serum albumin, Intergen, Co., New York, USA), suspended in PBS (phosphate buffered saline solution, Merck, Darmstadt, Germany), was used in the same way. The next day cells were washed in 1% BSA in PBS, and secondary antibodies (ImmunoPure ABC peroxidase staining of mouse IgG, set # 32028, Pierce, Rockford, IL) was applied for 30 minutes. To enhance this reaction, the cells were treated with a complex of avidin-Biotin for an additional 30 minutes (ImmunoPure ABC peroxidase staining of mouse IgG, set # 32028, Pierce, Rockford, IL). Then the cells were treated with 20 mg of DAB (3,3-diaminobenzidine,ETCI were washed in PBS, was obezvozhivani in a series of atenolol, recorded and examined in a light microscope, not taking into account the observation of the appearance of a brown staining, indicating the presence of TNF-.

Series-2. Neurophysiological definition:

Thirteen pigs (body weight 25-30 kg) was intramuscularly injected with 20 mg/kg body weight of ketalarR(ketamine 50 mg/ml, Parke-Davis, Morris Plains, New Jersey) and intravenous fluids were injected with 4 mg/kg body weight hipnoticaR(metomidate chloride 50 mg/ml, AB Leo, Helsingborg, Sweden) and 0.1 mg/kg body weight of strempelR(azaperone 2 mg/ml, Janssen Pharmaceutica, Beerse, Belgium). Anesthesia was maintained with additional intravenous injections of 2 mg/kg body weight hipnoticaRand 0.05 mg/kg body weight of stresnylR. After surgery, the pigs were also injected with intravenous injection of 0.1 mg/kg of stesolid NovumR(diazepam, Dumex, Helsingborg, Sveden).

The gelatinous core extracted from the 5th lumbar disk by retroperitoneal access (42). Approximately 40 mg jelly nuclei were applied to the beam sacrococcygeal spinal roots, making an incision in the midline and laminectomy the first vertebrae of the coccyx. Four pigs received no treatment (untreated). Four other pigs did nutrivene pigs gelatinous kernel before the application was mixed with 100 µl, 1.11 mg/ml suspension anti-TNF-antibodies, used in series 1.

Three days after application pigs have repeated anesthesia by intramuscular injection of 20 mg/kg body weight of ketalarRand intravenous injection of 35 mg/kg body weight of pentothalR(thiopental sodium, Abbott lab, Chicago, IK). Pigs were ventolinbuy power of the device for prolonged artificial respiration. Anesthesia was maintained by intravenous bolus-injection of 100 mg/kg body weight of chloralose-D(+)-glycoforms, Merck, Darmstadt, Germany) and continuous delivery 30 mg/kg/h chloralose. Performed a laminectomy of the 4th sacral and 3rd coccygeal vertebrae. Nerve roots were covered with spongostanR(Ferrosan, Denmark). Continuously watched by the local tissue temperature, maintaining its 37,5-38,0 With using a heating lamp.

Tail beam of spinal roots stimulated using two subcutaneous platinum needle electrodes E2 (Grass Instrument Co., Quincy, MA), which was connected to a Grass stimulator SD9 (grass Instrument Co., Quincy, MA) and gently using a continuous motion was placed on the tail-beam sacral and coccygeal spinal roots, first in 10 mm cranial, and then 10 mm of the tail region exposed environmenta who was ekali the nerve root, which leaves the spinal canal between the two sites of stimulation. EMG was recorded using two subcutaneous platinum needle electrodes, which were placed in parasvanath muscles in the lower part at a distance of approximately 10 mm, This method is reproducible and represents a functional measurement of motor nerve fibers of the bundle of lumbar, sacral and coccygeal nerve roots. EMG visualized using a Macintosh IIci, supplied with software Superscope and transducer MacAdios II AID (GW Instruments, Sommerville, MA) together with the preamplifier Grass P18 (Grass Instrument Co., Quincy, MA). Determined the distance separating the first two EMC peak of the two registrations, and the distance separating the two sites of stimulation in the beam of spinal roots, was measured with a compass. Thus, from these two measurements can be calculated speed of nerve conduction between the two sites of stimulation.

An entity that neurophysiological analysis, knows nothing about the experimental protocols of individual animals, and after a full study data were divided into three experimental groups, and statistical differences between groups were evaluated by the criterion of Art is Oia animals.

Series 3: the Thirteen pigs autogenic gelatinous nucleus was placed on the beam sacrococcygeal spinal roots, as in series 2. Five pigs (body weight 25 kg) was administered monoclonal antibody human mouse/RemicadeR(infliximab, Immunex Corporation, Seattle, WA 98101, USA), 100 mg intravenously before surgery and 8 pigs were administered EnbrelR(etanercept, B. V. Centocor, Leiden, The Netherlands) 12.5 mg subcutaneously before surgery and an additional 12.5 mg subcutaneously three days after the operation. Seven days after application of the gelatinous nucleus was determined by the conduction velocity of nerve root above the area applied by local electrical stimulation according to series 2. To obtain a blind non-selective studies of neurophysiological evaluation was performed in parallel with another study, where the subject is performing the analysis, did not know of any studies of animal and what treatment was subjected to each individual animal. Untreated animals were not included in the series-3, as was previously known, the speed of nerve conduction after seven days of application gelatinous kernel or fat (control). Statistical difference between groups that received either infliximab or etanercept or gelatinous kernel without treatment (full data) has been evaluated, using ANOVA and PLSD-statistics Fischer for 5%.

RESULTS

Series-1. The presence of TNF(cells gelatinous kernel pigs.

Examples of images in the light microscope stained slides. In sections, using BSA in PBS as a "primary antibody (control) did not observe any staining that ensures that there is no tagging and visualization of irrelevant antigens. When used anti-TNF-antibodies in a dilution of 1:40, there was only weak staining. However, staining was increased with decreasing dilutions of antibodies. Staining was observed in the soma of the cells and it was impossible to differentiate, whether localized TNF - a in the cytoplasm, on the cell surface, whether it's associated with the cellular membrane or both.

Series-2. Neurophysiological definition:

The use of unmodified gelatinous kernel and without any treatment induced a decrease in the speed of conduction of the nerve root is similar to the preliminary study (table 1), whereas treatment with doxycycline completely blocked this reduction (p<0.01 criterion Student). Local application of anti-TNF-antibodies also caused partial blocking of this reduction, although not tx2">

Series-3: it was Found that treatment with both drugs prevent induced gelatinous core speeds are reduced conductivity of the nerve root as the average conduction velocity for these two treatment groups were close to the average conductivity in the series, which used the fat, as shown in previous studies (table 2). There is a statistically significant difference between the use of gelatinous kernel, but without any treatment, and the use of two medicines.

DISCUSSION

The results of this study demonstrated that TNF - a could be detected in cells gelatinous kernel pigs. When TNF - blocked applied topically selective monoclonal antibodies, partially blocked induced gelatinous nucleus reduce the speed of conduction of nerve roots, although there is no statistical significance in comparison with a series of untreated animals. However, if for inhibition of TNF - used systemic therapy with doxycycline, infliximab and etanercept, significantly prevented the decrease in the speed of nerve conduction.

In recent years, it was confirmed is at once becomes apparent that damage nerve root observed in the formation of a hernia of an intervertebral disc may not be solely the result of mechanical deformation of the nerve root, and can also be stimulated “biochemical effects” associated with epidural presence of gelatinous kernel that came with the hernia formation outside the cavity. Although this new level of learning raises many experimental studies, the mechanisms involved and the substance is not fully known. It turned out that the local application of autologous gelatinous kernel can cause damage to the axon(24, 37, 38, 0-42), characterized by damage to the myelin sheath (24, 38, 40-42), a local increase in vascular permeability (9, 36, 44), intravascular clotting, reduce blood flow in nerve tissue (43) and leukotoxin (36). Obviously, associated with gelatinous core impact can be effectively blocked by methylprednisolone (38) and cyclosporine a (2), and somewhat less effectively - indomethacin (3) and lidocaine (69). In addition, it is clear that the effects mediated by cells of the gelatinous nucleus (37), in particular substances or structures associated with cell membranes (25). If critically rassmatriva the observed effects, it is a tumor necrosis factor alpha (TNF-). TNF can cause nerve damage(29, 31, 45, 50, 66), manifested mostly as characterized by damage to the myelin, which is quite reminiscent of the damage to the myelin induced gelatinous kernel(29, 47, 51, 54, 62, 64, 66, 70). Also TNF may induce an increase in vascular permeability (47, 66) and to initiate coagulation (22, 34, 63). Moreover, TNF - a can be blocked by steroids(4, 8, 21, 61, 68) and cyclosporine a(11, 55, 67, 68). However, the blocking effect on TNF - was not as pronounced under the action of NSAID (14, 17, 20), and lidocaine were very low or the opposite effect(5, 32, 46, 60). Recently found that local application of gelatinous kernel can cause rats to the pain associated with behavioral activity, particularly increased thermal pain sensitivity (23, 40). Also found that TNF - a is associated with such pain behavioral changes(12, 35, 56, 66), and neuropathies in General(30, 54, 56, 57). However, there are no studies which would identify the potential presence of TNF in cells gelatinous kernel.

To determine whether associated TNF - observed induced gelatinous nucleus decrease in the speed of conduction of the nerve root, you must first t in these cells. TNF - is produced in the form of a precursor (Pro-TNF), which binds to the membrane and is activated as a result of its removal from the cell membrane under the action of zinkevicius metalloendopeptidases (TNF--converting enzyme, TACE) (6, 15, 16, 48, 49). Thus, it may be associated with the results of experiments that use only cell membranes of cells autologous gelatinous kernel causes a decrease in the speed of nerve conduction; this indicates that the effects mediated by membrane-bound substances. Second, the effects of TNF - had to block a controlled way. Then decided first, before applying, to the gelatinous kernel to add the same selective antibody used for immunohistochemistry in a series-1, which, as you know, also inhibits the action of TNF. Also decided to treat pigs doxycycline, which is known to block TNF- (26, 27, 33, 52, 53). However, due to the low pH of the drug doxycycline chose to treat pigs, using intravenous injection instead of local added to the gelatinous nucleus, as has been established, jelly-like nucleus at low pH enhances the action of the gelatinous core (38, 39).

Two recently elaborately iximab is a chimeric monoclonal antibody composed of constant human murine variable regions, and specifically binds TNF - man. Unlike monoclonal antibodies, used in series 2 for 3-day observation period, infliximab was not applied topically in autotransplantation jelly-like nucleus, but instead were injected systemically in clinically recommended dose (4 mg/kg). Etanercept is a dimeric protein consisting of the Fc-region of IgG person. The drug was administered at a dosage comparable with the recommended dose for use in pediatric patients (0.5 mg/kg, twice a week).

Data related to the speed of nerve conduction, showed that the reduction system is completely blocked by treatment, and that the speed of nerve conduction in these series were close to the speed of nerve conduction after application of the control substance (retroperitoneal fat) from the previous study (42). Application of anti-TNF-antibodies on the jelly-like nucleus also partially prevented the decrease in the speed of nerve conduction, but not as pronounced as during the action of doxycycline and speed in this series were not statistically different from the rate in series with untreated justice blocks induced gelatinous nucleus decrease the speed of nerve conduction, a high standard deviation of the data is likely to have at least three different explanations. First, if you pay attention to the characteristic data within this group, it is detected that the speed of nerve conduction was low in 3 animals (average of 37.5 m/s) and high in 3 animals (average 81,3 m/s). In addition there are 2 groups of distinctly different data within the series of treatment with anti-TNF-antibody. This explains the high standard deviation, and may indicate that blocking the action was enough to have 3 animals and inadequate in 2 animals. The lack of effect on these animals may simply be due to the lack of antibodies in binding to molecules of the TNF - and, if you use a higher dose of the antibody, the effect of TNF - will be blocked even in these animals. Such a scenario in this case, theoretically, may indicate that TNF - is itself responsible for the observed effects induced gelatinous nucleus, and that this could not be confirmed experimentally due to the fact that there is a too low number of antibodies.

Second, it is also known that tetracyclines, such as doxycycline and minocycline, can block a number of cytokines, drti, it is known that IL-1 and'IEN - act synergistically with TNF - and that are more or less neurotoxic(7, 10, 13, 18, 19, 56, 59). These compounds also blocked by steroids and cyclosporine a, which is in good agreement with previous studies of induced gelatinous core damage to the nerve root where it was shown that induced gelatinous nucleus effects can be suppressed by these compounds (8, 67). So you can also consider the possibility that selective blocking of TNF - may not be sufficient to fully suppress induced gelatinous nucleus effects on nerve function, and that also requires the simultaneous blocking of other synergistic compounds. Thus, this scenario, on the other hand, implies that not only TNF is responsible for induced gelatinous core effects and what may be needed and other synergistic compounds that are also suppressed by doxycycline.

A third explanation is that the amount of TNF in the jelly-like nucleus may be sufficient to locally, in the nerve root, began pathophysiological cascade, including increased vascular permeability and agreg the e are characterized by the main content of TNF-, and that requires systemic treatment sufficient dose to block the contribution of these cells and thereby block phenomenon, leading to nerve damage.

TNF can trigger a variety of pathophysiological effects. It can directly affect tissues such as nerve tissue and blood vessels, it may in other cells to start the production of other pathogenic substances and can be a trigger release more TNF - like inflammatory cells, and Schwann cells locally to neural tissue (65). Thus, there is reason to believe that even low amounts of TNF - may be sufficient to initiate these processes, and what happens to the local recruiting cells that produce cytokines, and subsequent increase in production and release of other cytokines like TNF-. Therefore, TNF - a can act as an “ignition key” pathophysiological processes and play an important role to initiate the pathophysiological cascade followed by nerve damage induced by gelatinous core. However, the main contribution of TNF - may be derived from the recruitment of leukocytes, aggregated and maybe even out of the vessels of leukocytes, and uspeshna, although the exact role of TNF - cannot be fully understood from the experiments, we can conclude that the first specific substance (TNF-) is associated with damage to the nerve root, induced gelatinous core. This new information can be important for the continuing study of the induced gelatinous nucleus of nerve damage, as well as to the emerging issue of a possible future clinical application of pharmacological interference TNF and related substances for the treatment of ishialgii.

Thus, immunohistochemically established the presence of TNF in cells gelatinous kernel pigs. Blockade of TNF - using topically applied monoclonal antibodies partially restricted induced gelatinous nucleus reduce the speed of conduction of the nerve root, whereas intravenous therapy with doxycycline, infliximab and etanercept significantly blocked this reduction. These results are the first to link one particular substance, TNF-, nerve damage, induced gelatinous kernel.

It is shown that aminoguanidine inhibits the release of nitric oxide (NO) when damage to the nerve roots by inhibiting inducible synthetase nitrogen oxides, such

The connection according to the invention can be introduced in various dosage forms, for example orally in the form of tablets, capsules, pills, coated with sugar or film of liquid solutions; rectally in the form of suppositories; parenterally, e.g. intramuscularly, or via intravenous injection or infusion. Therapeutic scheme for various clinical syndromes should be adapted to the type of pathology, taking into account also, as usual, the route of administration, form in which administered the compound, and the age, weight and condition of the subject, which is treated.

Commonly used oral path for all conditions requiring the administration of such compounds. In urgent cases, the preference for intravenous injection. For these purposes, the connection according to the invention can be administered orally in doses, ranging approximately from 20 to 1500 mg/day. Of course, these schemes use the medicinal product can be adjusted to provide the optimum therapeutic response.

The nature of the pharmaceutical compositions containing the compounds according to the invention in combination with pharmaceutically acceptable carriers or diluents, of course, will depend on the desired method introduced is according to the invention can be introduced in the form of aqueous or oily solutions or suspensions, tablets, pills, gelatin capsules (hard or soft), syrups, drops or suppositories.

Thus, for oral administration the pharmaceutical compositions containing the compounds according to the invention, preferred are tablets, pills or capsules which contain the active compound together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; lubricating agents such as silica, talc, stearic acid, magnesium stearate or calcium and/or polyethylene glycols; or they may also contain binders, such as starches, gelatin, methylcellulose, carboxymethylcellulose, Arabian gum, tragakant, polyvinylpyrrolidone; disaggregated agents, such as starches, alginic acid, alginates, sodium salt chromalveolates acid, microcrystalline cellulose; foaming agents such as carbonates and acid; dyes, sweeteners, wetting agents such as lecithin, Polysorbate, laurylsulfate; and usually non-toxic and pharmaceutically inert substances used in the preparation of compositions. Mentioned pharmaceutical composition can be produced isoso. In the case of providing a film, you can select the connection to secure the release at an appropriate place in the intestinal tract with regard to absorption and maximum effectiveness. Thus, it is possible to apply the substance, forming a pH-sensitive film so as to provide for absorption in the intestine as such, and typically use different phthalates or derivatives of acrylic acid/methacrylic acid and polymers.

Liquid dispersions for oral administration can be, for example, syrups, emulsions and suspensions.

The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.

Suspensions or emulsions may contain as carrier, for example, natural resins, such as the Arabian gum, xanthan gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, polyvinyl alcohol.

The suspensions or solutions for intramuscular injections may contain, together with the active compound in pharmaceutically acceptable carrier, such as sterile water, olive oil, etiloleat, glycols, such as propylene glycol, and, if required, an appropriate number of ghidrah the La intravenous injection or infusion may contain as carrier, for example, sterile water or preferably sterile isotonic saline solution, and adjuvants used in the injection of active connections.

Suppositories may contain together with the active compound in pharmaceutically acceptable media, such as cocoa butter, polyethylene glycol, polietilensorbit fatty acids, essential surfactant or lecithin.

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1. The inhibitor alpha (TNF-a, selected from the group consisting of inhibitors of metalloproteinases, excluding methylprednisolone, tetracyclines, including chemically modified tetracyclines, quinolones, lazaridou, pentoxifylline derived hydroxamic acids, naphthopyrane, soluble receptors, cytokines, monoclonal antibodies to alpha (TNF-a, amrinona, pimobendan, vesnarinone, inhibitors of phosphodiesterase III, lactoferrin and analogues derived lactoferrin, melatonin in the form of a base or as the making, representing the damage to the nerve root caused by the release of alpha-TNF or the presence of alpha-TNF by inhibiting alpha-TNF intervertebral disk.

2. Application under item 1, characterized in that the inhibitor of the alpha (TNF-a is selected from compounds of hydroxamic acids and their derivatives, lazaridou, pentoxifylline, naphthopyrane, amrinona, pimobendan, vesnarinone, inhibitors of phosphodiesterase III, melatonin in the form of bases or addition salts.

3. Application under item 1, characterized in that the inhibitor of the alpha (TNF-a is selected from norfloxacin, ofloxacin, ciprofloxacin, Gatifloxacin, pefloksatsina, lomefloxacin and temafloxacin in the form of bases or addition salts.

4. Application under item 1, characterized in that the inhibitor of the alpha (TNF-a is an inhibitor of metalloproteinases in the form of bases or addition salts.

5. Application under item 1, characterized in that the inhibitor of the alpha (TNF-a is selected from the group consisting of tetracycline, doxycycline, lymecycline, oxytetracycline, minocycline and chemically modified tetracyclines, decamethylenediamine, in the form of bases or addition salts.

6. Application under item 5, characterized in that the inhibitor Alf is the Torah of the cytokine as active substances in pharmaceutical compositions for the treatment of spinal disorders, representing the damage to the nerve root caused by the release of alpha-TNF or the presence of alpha-TNF by inhibiting alpha-TNF intervertebral disk.

8. Application under item 1 or 7, characterized in that the inhibitor of the alpha (TNF-a is a soluble receptor of the cytokine etanercept.

9. The inhibitor alpha (TNF-a in the form of monoclonal antibodies to alpha (TNF-a to obtain a pharmaceutical composition for the treatment of spinal disorders, representing damage to the nerve root caused by the release of alpha-TNF or the presence of alpha-TNF by inhibiting alpha-TNF intervertebral disk.

10. Application under item 1 or 9, characterized in that the inhibitor of the alpha (TNF-a is a monoclonal antibody infliximab.

11. The use of tetracyclines, steroids or cyclosporine And inhibiting the connection is initiated by the release of alpha-TNF, such as interferon-gamma, interleukin-1 and nitric oxide (NO) in the form of bases or addition salts, in obtaining pharmaceutical compositions for the treatment of spinal disorders, such as damage to the nerve root caused by the release of alpha-TNF or the presence of alpha (TNF-a, and by whom the damage to the nerve root caused by the formation of a hernia of an intervertebral disk.

13. The use according to any one of paragraphs.1-11, characterized in that the damage to the nerve root caused by a gelatinous kernel.

14. Application under item 12 or 13, characterized in that the damage to the nerve root is a ischialgia.

15. Pharmaceutical composition for treating damage to the nerve root that contains a pharmaceutically effective amount of a soluble cytokine receptor and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition according to p. 15, characterized in that the soluble cytokine receptor is etanercept.

17. Pharmaceutical composition for treating damage to the nerve root that contains a pharmaceutically effective amount of a monoclonal antibody selective in relation to alpha (TNF-a, and a pharmaceutically acceptable carrier.

18. The pharmaceutical composition under item 17, characterized in that the monoclonal antibody is infliximab.

19. The method of partial blocking induced gelatinous core speed reduction of nerve conduction, which includes the introduction of effectively blocking amount of a monoclonal antibody selectively is infliximab.

21. A method of treating spinal disorders, representing damage to the nerve root caused by the release of alpha-TNF in mammals, including humans, which consists in the introduction of a pharmaceutically effective amount of an inhibitor of the alpha (TNF-a, selected from the group consisting of inhibitors of metalloproteinases, excluding methylprednisolone, tetracyclines, including chemically modified tetracyclines, quinolones, lazaridou, pentoxifylline derived hydroxamic acids, naphthopyrane, soluble receptors, cytokines, monoclonal antibodies to alpha (TNF-a, amrinona, pimobendan, vesnarinone, inhibitors of phosphodiesterase III, lactoferrin and analogs, derivatives lactoferrin, melatonin in the form of a base or additive salts.

22. A method of treating spinal disorders, such as damage to the nerve root caused by the release of alpha-TNF in mammals, including humans, comprising the introduction of a pharmaceutically effective amount of an inhibitor of the alpha (TNF-a in the form of a soluble cytokine receptor.

23. The method according to p. 21 or 22, characterized in that the inhibitor of the alpha (TNF-a is a soluble receptor of the cytokine etanercept.

25. The method according to p. 21 or 24, characterized in that the inhibitor of the alpha (TNF-a is a monoclonal antibody infliximab.

26. The method according to p. 21, characterized in that the inhibitor of the alpha (TNF-a is selected from the group consisting of tetracycline, doxycycline, lymecycline, oxytetracycline, minocycline and chemically modified tetracyclines, decamethylenediamine, in the form of bases or addition salts.

27. The method according to p. 26, characterized in that the inhibitor of the alpha (TNF-a is doxycycline.

28. The method according to p. 21, characterized in that the inhibitor of the alpha (TNF-a is selected from compounds, hydroxamic acids, lazaridou, pentoxifylline, naphthopyrane, amrinona, pimobendan, vesnarinone, inhibitors of phosphodiesterase III, melatonin in the form of bases or addition salts.

29. The method according to p. 21, characterized in that the inhibitor of the alpha (TNF-a is selected from the group consisting of norfloxacin, ofloxacin, ciprofloxacin, Gatifloxacin, pefloksatsina, lomefloxacin and temafloxacin in the form of bases or addition salts.

31. A method of treating spinal disorders, such as damage to the nerve root caused by the release of alpha-TNF and initiated connections in the release or presence of alpha-TNF in mammals, including humans, comprising the introduction of a pharmaceutically effective amount of tetracycline, steroids or cyclosporine And inhibiting connection initiated result in the release of alpha-TNF, such as interferon-gamma, interleukin-1 and nitric oxide (NO) in the form of bases or addition salts.

32. The method according to p. 22, characterized in that the damage to the nerve root caused by the formation of a hernia of an intervertebral disk.

33. The method according to p. 21, characterized in that the damage to the nerve root caused by a gelatinous kernel.

34. The method according to p. 21, characterized in that the damage to the nerve root is ischialgia.

Priority points:

29.10.1998 - on grounds of “chemically modified tetracyclines, quinolones, naphthopyrane, soluble cytokine receptors, monoclonal antibodies to alpha (TNF-a, amrinone, pimobendan, vesnarinone, inhibitors of phosphodiesterase III, melatonin”;

25.09.1998 for the other

 

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