MXPA02001367A - Method of treating traumatic brain and spinal cord injuries and other neurogenic conditions using non-steroidal anti-inflammatory drugs and naturally occurring conotoxins - Google Patents

Abstract

A method for treating a patient/subject having neuronal injury, pain, neurotrauma and/or traumatic brain injury, such as diffuse axonal injury, which includes intrathecally and/or intraventricularly administering to the subject a therapeutically effective amount of a non-steroidal anti-inflammatory drug and/or a naturally occurring omega conotoxin, functional fragment thereof, a pharmacologically acceptable salt, ester, amide, or prodrug thereof.

Description

they result in the loss of connections between nerve cells. The progress of events in the ICD continues several weeks after the injury creating a window of opportunity for therapeutic intervention. There are approximately 500,000 new cases of TBI in the United States each year (Frankowski, 1985), and it is estimated that the incidence required for hospitalization is approximately 200-225 / 100,000 (Frankowski, 1986, Carus, 1993). Currently, it is estimated that BS brain injuries account for 12% of all hospital admissions in the United States (Sandel, 1993). When compared to spinal cord injury, which is less than 1% of hospital admissions, it is clear that TBI is a medical care problem that has a significant financial impact within the United States. Approximately 30,000-44. 000 people will survive the Severe TBI with a GCS score < 9 (Glasgow Coma Score Scale, Jennett, 1981) in the United States each year and more than 70, OOC will be significantly disabled by a moderate to severe TB (GCS # 10) (Whyte &Rosenthal, 1988) Even with the new techniques of medical management, less than 10% will remain in a persistent vegetative state Whyte, 1993; Rosner, 1992, Rosner, 1990; A GCS score of eight or less usually reflects a state of unconsciousness in which the patient does not demonstrate eye opening, does not follow simple commands to move muscles, and has vocalizations which are limited to sounds. Such signs are indicative of severe brain injury (Whyte, 1993; Jennett, 1975; Jenndtt, 1981] Approximately 52,000 to 56,000 people die each year from TBI (Kraus et al., 1996), resulting in approximate direct costs of more than $ 50 billion by hand (Max et al., 1991). The costs of severe TBI to individuals and families are extremely high (McMordie, 1988). Acute medical and rehabilitation bills are frequently around $ 100,000 with some being considerably higher (McMordie, 1988). The Database of Model Systems for Traumatic Brain Injury show that there is a correlation between the Assessment Score of Average disability and acute care and rehabilitation charges combined (Bullock et al., 1995). Those with severe TBI (GCS score of 6-8) have combined charges averaging $ 110,842, and those with a very severe BIT (GCS score of 3-5) have average combined charges of $ 154,256 (Leh Kuhl, 1993). Approximately the mitts of all the BITs are related to transportation (Whyte, 1993; Lehmkuhl, 1993) and those patients, have some of the highest combined charges for acute care and rehabilitation (Lehmkuhl, 1993). This can be related to the mechanism of the TBI in high speed motor vehicle crashes, being specifically the presence of the diffuse axonal injury (DAI) the most prevalent in the areas of the midbrain midbrain and the brainstem (Whyte, 1993 >) Clearly, the brain injuries of this severity that occur with acceleration-deceleration injuries at high speed have the highest costs to society. Clearly, the BIT causes more mortality, morbidity and greater probability of economic loss than HIV infection in the United States.

United . Motor vehicle crashes of all types are responsible for approximately 40% -50% of the TBI admissions registered in the Model TBI Systems Databases (Leh Kuhl, 1993). It is considered that the predominant mechanism of damage is diffuse axonal injury (DAI). Approximately 30% -40% of fatal head injuries involve a diffuse axonal session by pathological examination (Bennett et al, 1995; McLellan, 1990). However, based on the immunostaining of the beta-amyloid precursor protein, the axonal injury may be present in all cases with fatal head injury (Gentleman et al., 1995). In cases of persistent vegetative states, Kampfl et al (1998) recently found that all cases had evidence of ICD in magnetic resonance imaging (MRl). Diffuse axonal injury occurs even in the absence of a blow to the head and is more prevalent than previously found. Even in moderate head injury, the diffuse axonal injury is present in almost 1/3 of the cases (Mittl e ": al., 1994) .The defining characteristic of the ICD is the morphological change of the axons that occur in the course of several days to weeks and the fact that multiple regions of the brain are injured, although a component of the IAD is present. in blunt or penetrating traumatic injury, this is located in the periphery of the lesion area and is much less significant than the predominant mechanism of the lesion.IAD is the main mechanism of injury or damage in acceleration-deceleration injuries. at high speed associated with motor vehicle crashes, although the four mechanisms of the TBI (ICD, blunt trauma, penetrating trauma, large house) may be involved in such injury, these are the predominant mechanism of the lesion under this condition, For human head injuries resulting from car collisions, the average speed for the occurrence of severe injuries is 6.7 m / s (or 24.1 km / hour) according to what was mentioned by Lorenzo et al. (nineteen ninety six) . Most of the studies have been directed towards the analysis of the impact of the head. The Head Injury Criterion (HIC) is a method that is commonly used to assess the severity of an impact (Chou and Nyquist, 1974). Although it is considered to be the best indicator of head injury available, a new model of finite element useful to hoist a manikin head has taken into account the effects of rotational and translational acceleration (Ueno and Melvin, 1995) Using this model , the dominant effect between the translacional iceleration was on the main efforts and the rotational acceleration was on the shear forces The current research seems to point towards the plastic deformation inside the axons that leads to the predominant cause of the injury. of the brain have plastic properties, once the level of force is applied to a plastic substance, it is the period of time during which it is applied, which causes or causes the bantity of deformation. exceeds, then There will be cutting and tearing, High speed motor vehicle accidents with a deceleration that lasts more than one to three seconds or several seconds of repetitive shaking can produce enough force for this to happen. The investigation of materials indicates that there is a quantity of force which must be released below which the plastic deformation of the substances does not occur. In effect, the Gadd severity index initially tried to reduce the severity of the injury using an acsleration / time curve (Gadd, 1998).

This critical amount of force seems to be essential in the development of the lesion (McLean &Anderson, 1997). This is very different from the contiguous model of the TBI where the forces are applied last for millisecond. This indicates that once the amount of force has reached a umbrlal, it is the period of time in which the force is applied with the associated plastic deformation which is the predominant factor that causes intracellular damage to the organelles within the axon. Consequently, there is a perjury during which the DAI occurs in the TBI. After reaching the threshold of force necessary to create plastic deformation, it may be the period of time during which it is applied that determines the amount of DAI. This would explain the discoveries of Foda et al. (1994) where some ICD was noted in areas adjacent to injuries or bruise damage in rats. Unfortunately, most of the TBI occurs for several seconds (high-speed transport crashes) where BS is likely to be the DAI's predominant method of reading ion or damage. This is supported by the fact that many patients with severe TBI have minimal changes noted in the CT scan after motor vehicle crashes. Motor vehicle crashes are the predominant cause of the DAI. It is felt that one component of the IAD is present in all motor vehicle crashes where the patient has lost consciousness (Whyte, 1988). For many years, it has been known that the IAD is associated with an immediate onset after the brain injury, but the diagnosis could only be established by the autism. In fact, the clinical syndrome of coma without any preceding lucidity interval, brain stem and automatic dysfunction was frequently ascribed to the primary lesion of the brainstem. However, it is clear that primary lesions do not occur to the brainstem in isolation but rather the association with the IAD and usually involve the cerebral hemispheres and the cerebellum as well as the brain stem (McLellan, 1990). damage can be determined by pathological studies of patients killed by high-velocity transport injuries (Pounder, 199 as well as pathological studies of "shaken baby syndrome", a subset other than the DAI (Nelson et al., 1993). recent case (Pounder, 1997) indicates that the mechanism of shaking of the lesion by ICD also applies to adults.The lesion is characterized by specific neuropathological findings.In CT and MRl, this usually involves hemorrhagic puncture injury of the corpus callosum, meso-mesencephalic junction adjacent to the superior cerebral peduncles and diffuse axonal damage in the white matter of the brain, brainstem and cerebellum which begin to atrophy within two weeks after the injury (Whyte, 1988; Blumbergs, 1994 Diffuse axonal injury in humans is characterized by damage to axons in the cerebral hemispheres, cerebellum, and brainstem and is a consis tent feature of TBI (Adams, 1977, Adams, 1989, McLellan, 1990 ). The histological characteristics of the ICD depend on the period of time after the damage, but within a day or thereafter, there is evidence of damage to the axons in the form of axonal bulbs. The initial findings they are usually characterized microscopically using neurofibrillary stains and microglia stains which are abundant in degenerative white matter. These findings are reproduced by the cut or flow of cytoplasm from the proximal end of a severed axon. Subsequently, the microscopic characteristics correspond to an axonal degeneration of the Wallerian type as the axon disintegrates, which is probably due to ur to metabolic disturbance of the lesion and damage to the internal organelles due to the absence of integrity of the membrane. In the first two years there is active myelinic degenation and in patients who survive long term, demyelination is the final stage of the process (McLellan, 1990). The results of the t raumatic lesion to the axons lead to disconnection with several target sites, which is assumed translates into the observed morbidity (Gennarelli, 1982; Povlishock, 1992). The severity of the injury based on histopathological changes has been graded in humans but not in experimental animals (Adams, 1977; Adam, 1989). The Adams classification (Adams, 1977; Ada, 1989) is used m human autopsy material, to classify the degree of ICD as moderate, moderate or severe. In this classification, the mean (grade 1) is characterized by microscopic changes in the subject white of the cerebral cortex, corpus callosum and brainstem and occasionally in the cerebellum. The moderate (grade 2) is defined based on focal lesions in the corpus callosum. In the severe (grade 3), there are additional focal lesions in the dorsal lateral quadrants of the rostral cereoral dorsum (commonly in the superior cerebellar peduncle). This scheme has not been used for models or primates because different regions of the brain are damaged in the present models. However, it may be possible to apply this scheme to an appropriate DAI model in small animals that is currently under development. When ur occurs to spinal cord injury or traumatic brain injury, a cascade of damaging events begins, the; 1 generally increases the damage to the central nervous system (CNS). A basic factor that has been iden- tified at the center of these events is the ions cale: o (Ca "). Until now, drugs that are only marginally effective in the prevention of this cascade of events have been used. The non-steroidal inflammatory drugs (NSAIDs) have not been useful in animal models of neurotrauma. In part, this can be attributed to the fact that most of the NSAIDs also inhibit the platelet fraction On and consequently they can increase the hemorrhage. In addition, certain NAIDS do not cross the blood brain barrier. Recently, there have been a few articles on the use of int intimal NAL codes for pain (Pain, 1998, Southall et al., J Pharma col, and Exp. Ther 1997; 281: 1381-91). Also,] to US Patent No. ,914,129 to Mauskop describes the use of analgesics containing magnesium for pain relief such as that of migraine headaches. Of these drugs, aspirin, indomethacin, lysine clonixinate and ketoprofen have been used. N r > there have been reports of intrathecal use in neurotirauma, to impart neuroprotective effects, nor for the reduction or prevention of neuronal injury of inflammatory conditions. However, aspirin, which was probably the most potent and / or effective agent, could still significantly inhibit platelets. Aspirin crosses out of the CSF generally through the choroid plexus into the systemic circulation more than the neural tissue. Even an aspirin for baby a day is a potent inhibitor of platelets. In fact, aspirin leads to a considerable increase in the risk of intracerebral hemorrhage (Raymond et al., Neurosurgery Reviews 1992; 15: 21-5). The infl ammatory cascade that can be affected by NSAIDs includes a relationship to arachidonic acid which initiates a metabolic cascade that produces inflammatory eicosanoids that promote neutrophilic invasion and the production of strong antioxidants (Juurlink et al., J. Spin.jJ Cord Medi cine 1998; 21: 309-34). This is more frequent by inflammatory leukotrienes. Even in the absence of arachidonic acid from enzymatic activation by the development of isoleukotrienes, those which are biologically active free radicals. Finally, the NSAIDs produce the production of inflammatory cytokines produced after the CNS trauma, which play a role in the development of secondary damage mechanisms. The NSAIDs are reduced in the bradykinins and can produce the production of platelet-activating factor mediated by the induction of the romboxan A2 t. These substances administered initially with cytokines and activating factors of the plaque can induce a late regeneration of axons and neurons, but it is clear that they cause damage immediately after the injury. In addition to the use of NSAIDs for neurotrauma, a new drug developed from the venom of a mollusk (conotoxin) that forms the conical shell has the potential to stop the initial cascade after of tramatic brain injury or neurotrauma because it is directed to multiple calcium channels (via). It has been reported to have limited success with drugs aimed at blocking calcium channels but with unfortunate lip effects. In addition, many types of calcium channels that have been identified, including L, N, P, Q, and T, do not seem to exist.

Only blockers of type L channels have been marketed to reduce brain injury and they have had limited usefulness only in those with spontaneous intracerebral hemorrhage. However, there has been a particular interest in the blocking of type N channels. The systemic release, via the blood flow, for example, of blockers of the N-channel.

Ca has also been associated with problems in the fall of mean arterial blood pressure in CNS trauma. This results in a drop in cerebral perfusion pressure. Cerebral perfusion pressure, defined as mean arterial blood pressure minus intracranial pressure, is the physiological variable that defines the pressure gradient that drives cerebral blood flow and the release of metabolites, and therefore, is closely related to the ischemia of the central nervous system, the end point in the pathway biochemistry that can double the amount of injury to the nervous system due to initial damage. The use of conotoxins for the treatment of neuronal damage related to an ischemic condition affecting the central nervous system is described in US Pat. No. 5,189,020 to Miljanich et al. '020) issued in Febrelo 23, 1993. Miljanich et al '020 describes the use of conotoxins in a method of treatment for reducing neuronal damage related to an ischemic condition in a human patient by administering a pharmacologically effective amount of a synthetic conotoxin to the patient. The method describes the administration of synthetic conotoxin via intracerebroventricular administration. However, it is well known that ischemic neural injury is very different in diffuse axonal injury or even direct trauma to neurons with tearing of the cell membrane. The ischemic neural lesion seems to involve different cellular mechanisms of cell injury. Additionally, Miljanich et al describes only calcium channel blockers of type L which have only been clearly successful in those conditions where subarachnoid hemorrhage has existed (Neurology 1998; 50: 876-83) but not in traumatic brain injury without hemorrhage. subarachnoid J. Neurosurgery 1994 0: 797-804), or ischemic attack (Stroke 1992; 23: 3-8). Actually, Miljanich et al. suggests that you block > The calcium channels affect the result due to the vasodilatation of the blood vessels, however, the applicants have discovered that blockers of calcium channels act directly on the neurons as well. Accordingly, it would be advantageous and desirable to have a method of treatment for lesions associated with traumatic serebral injury and spinal cord injury (neujrotrauma) by intrathecal and / or inti aventricular administration of non-steroidal anti-inflammatory drugs and / or by the administration of a natural omega conotoxin that interrupts the influx of extracellular calcium thereby preventing or decreasing both the severity of the CNS lesion and also overcoming the advantages and disadvantages of the prior art described above.

SUMMARY OF THE INVENTION According to the present invention, there is disclosed a method for treating a patient / subject having pain, neurotrauma or traumatic brain injury such as diffuse axonal injury which includes administering to the subject a therapeutically effective amount of a non-steroidal anti-inflammatory drug, a natural omega conotoxin or functional fragment thereof or a combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS The following detailed description will be better understood with reference to the following drawings in which: Figure 1 is a graph illustrating cutaneous nociception results; and Figure 2 is a graph illustrating the results of visceral nociception 5n.

Detailed Description of the Invention The present invention provides a method for treating injuries, diseases, conditions, disorders, pain, including neurogenic pain, neuronal injury caused by inflammatory conditions, or neurotrauma frequently associated with traumatic brain injury (TBI) and / or trauma. of the spinal cord (SCT), including diffuse axonal lesions manifested in conditions such as dystonia / spasticity, spinal disorders, seizure disorders or epilepsy by intrathecal and / or intraventricular administration directly in the cerebrospinal fluid (CSF) of a patient or subject having or suspected of having diffuse axonal lesions in development a therapeutically effective amount of a non-steroidal anti-inflammatory drug and / or a natural omega conotoxin, functional fragments thereof, pharmaceutically acceptable salts, esters, amides and prodrugs thereof . The terms "patient" and "subject" mean all animals including humans. Examples of ppaacciieenntteess oo ssuujjeettoossinclude humans, cows, dogs, cats, goats, sheep and cedars. The term "functional fraction thereof" means a fragment or portion of the native conotoxin that retains the desired functions of the connoxin nnaattiivvaa llaass ccuuaalleess ssoonn ddeesseeables for the treatment of diffuse axonal injury ase: traumatic brain injury or injury of the Spinal Cord Those skilled in the art will be able to easily identify patients or subjects who have diffuse axonal lesions, including conditions such as dystonia / spasticity, spinal disorders, seizure disorders and epilepsy. For example, patients who have dystonia / spasticity induced by traumatic brain injury. Additionally, patients or subjects who have pain or conditions inflammatory diseases that affect the nervous system such as Lupus and other inflammatory neuropathies, infections, acquired disorders such as multiple sclerosis, transverse myelitis, Parkinson's disease, CNS vasculitis, and Alzheimer's disease. A therapeutically effective amount is a quantity of non-steroidal anti-inflammatory drug and / or natural omega conotoxin b functional fragments thereof which, when administered to a patient or subject, alleviates a symptom of the condition or disorder. Studies are showing that there will be a reduction of the lesion at the site of the neurological injury, particularly those areas that would be closest to the CSF flow. Those areas of the CSF include those damaged during high-speed motor vehicle crashes associated with diffuse axonal injury (DAI), which account for 50% of the TBI, anoxic BIT (oxytocin deprivation to the brain) and many cases of SCI. . The delivery system selected to release this drug (intrathecal or intraventricular catheters) eliminates side effects, particularly a drop in blood pressure that would negate the cellular protective effects. The drop in blood pressure has been linked to an additional injury and more chronic deficits in the spinal cord injury, placement of the catheter near the site of damage will allow the concentration. pn local drug to a higher level than that obtained by other distribution routes. This method of distribution or release Directed to different points of the CNS and using different techniques (methods) for insertion and subsequent use) is already being used in humans to treat e: sympatheticity, and to distribute drugs to improve the function of Parkinson's disease. The compounds of the present invention can be administered to a patient alone or as part of a pharmaceutical composition. The compositions can be administered to patients intrathecally or intraventricularly. Compositions suitable for intrathecal or intraventricular distribution and delivery may comprise physiologically acceptable solutions or dispersions, suspensions, or aqueous or non-aqueous emulsions, and sterile powders for reconstitution into sterile injectable solutions and dispersions. Examples of suitable carriers, dfluents, solvents or aqueous and non-aqueous vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethiolate. The proper fluidity can be maintained, for example, by the use of a ta 1 coating such as lecithin, by the maintenance of the required particle size in the passage of the dispersions, and by the use of surfactants. In a preferred embodiment, non-rodent antiinflammatory drugs include colin-magnesium trisalicylate, sodium salicylate, salicylamide, other non-cetylated aspirins, analogs, substituted forms, derivatives and / or any salt, ester, amide and pharmaceutically acceptable prodrug of The term "substituted" means that the base organic radical is one or more substituents, In a preferred embodiment, the natural omega conotoxin or functional fragment thereof administered to a patient or subject is natural omega conotoxins such as GVIA and MVI. [, both of which are blockers of calcium channels type N. In addition to intrathecal or intraventricular administration of the natural omega conotoxin or functional fragment thereof for the treatment of Axial diffuse lesion asceciated with traumatic brain injury or traumatic spinal cord injury, a r.o steroidal antiinflammatory drug (NSAID) can be combined with the natural omega conotoxin, preferably an omega conotoxin blocking N-type calcium channels, to further reduce the amount of neurological lesions in sustained neurological injury of a patient such as that associated with traumatic spinal or brain injury, i.e., diffuse axonal injury. The NSAIDs that are suitable for use in combination with the omega cycotoxin include sodium salicylate, salicylamide, colin magnesium trisalicylate or other deacetylated aspirins. Injury to the areas of the brain or spinal cord contiguous to the CSF flux can be significantly protected by direct distribution or release of the compounds of the present invention to the CSF immediately after damage via intraventricular catheters. The distribution and access can be achieved with a catheter ta 1 such as that described in PCT Application Serial No. PCT / US00 / 05740,Applicant, for safety and efficacy A study of the intrathecal distribution of NSAIDs on pain fibers in rats required a equivalent dose of 140 mg in humans (Bustamante et al., J. Pharmacology and Experimen tal Therapeuti cs 1997; 281: P138-91). There are two non-acetylated aspirins which do not inhibit platelets and which are still potent NSAIDs, these are salicylate and trisalicylate of colin magnesium. The latter is very soluble in water and is a magnesium colin salicylate while the former is not. Additionally, magnesium may have neuroprotective effects as well as blockers of N-methyl-D-aspartase (NMDA) channels in a voltage-dependent manner (Mayer et al., Na ture 1984; 309: 261-3; Nowak et al. Nauret 1984; 307: 462-5 thus interrupting a well-known pathway for cell death.The above drugs are easily dissolved in aqueous solution and can cross into the CNS. The NSAIDS are easily eliminated from the CNS.

In addition, colin magnesium trisalicylate apparently causes no more gastric problems than a placebo (PDR, 1999 descriptions of Di salicid, Trilisate). All of the compounds listed above are soluble in water and should reduce the amount of neurological damage either induced by trauma, ischemia, hemorrhage, tumors or inflammatory conditions to the affected areas that are contiguous to the distribution in the CSF. This would include Inflammatory conditions such as cerebral vasculitis and cerebrlal sarcoid It has been clearly demonstrated that after a head injury, traumatic brain injury and spinal cord injury increase prostaglandin synthesis (Shohami et al., J. Cerebral Blood Flow and Ma tabolism 1987; 7: 58-63). Therefore, other inflammatory factors should respond to NSAIDS if they are released quickly to the correct place. However, all of those previous studies have failed because the drugs used affected the platelets by inactivating them at the same time. These co-locations may also contain adjuvants such as preservatives, humectants, emulsifiers and dispersing agents. The prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be carried out by the use of agents that retrace the absorption, for example, aluminum monostearate and gelatin.

The term "pharmaceutically acceptable salts, esters, amides and prodrugs" as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides and prodrugs of the compounds of the present invention which are within the scope of the invention. sanb medical judgment, suitable for use in contact with the tissues of patients without toxicity, irritation, undue allergic response and the like, in proportion to an adequate and effective benefit / risk ratio for their intended use, as well as zwitterionic forms, where possible of the compounds of the invention The term "salts" refers to the non-toxic, inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or separately by reacting the purified compounds in free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the salts of brohydrate, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate , naphthylate, mesylate, glucoheptonate, lactobionate and lauryl sulfin, and the like. These may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as toxic ammonium cations of quaternary ammonium and amine including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamir, dimethylamine, trimethylamine, triethylamine, ethylamine and the like (See, for example, Barge et al., "Pharmaceutic al Salts, J. Pharm. Sci., 1977, 66: 1-19 which is incorporated herein by reference. Examples of non-toxic, pharmaceutically acceptable esters of the compounds of this invention include the C -C6 alkyl esters where the alkyl group is straight or branched chain, acceptable esters also include C5-C cycloalkyl esters as well as arylaki. 1 esters, such as but not limited to benzyl C 1 -C 4 alkyl esters are preferred The esters of the compounds of the present invention can be pre-stopped according to conventional methods. Examples of non-toxic, pharmaceutically acceptable amides of the compounds of this invention include amides derived from ammonia, primary C 1 -C 6 alkylamines and secondary Ci-Cβ dialkylamines where the alkyl groups are linear or branched chain. In the case of secondary amines, the amine may also be in the form of a five or six member heterocycle containing a nitrogen atom. Amides derived from ammonia, primary alkylamines of C? -C3 and secondary dialkylamines of C? ~ C2 are preferred. The amides of the compounds of the present invention can be prepared according to conventional methods. The term "prodrug" refers to compounds that are rapidly trans-formed in vivo to produce the original compound of the above formula, for example, by hydrolysis in the blood. A full discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of A.C.S. Symposium Series, and in the oreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. In addition, the NSAIs DS and / or omega conotoxins of the present invention can exist in unsolvated form as well as solvated with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the present invention.

The NSAIDs of the present invention can be administered to a patient at dose levels in the range of about 100 mg to about 1500 mg per day. The specific dose used, however, may vary. For example, the dose may depend on a number of factors, including patient requirements, the safety of the condition being treated, and the pharmacological activity of a compound that be sieved used. The determination of an optimal dose for a particular patient is well known to those skilled in the art. Natural omega conotoxins and / or NSAIDs can be administered intrathecally or intraventricularly using an intraspinal catheter.

The intraspinal catheter is deposited within the spinal subarachnoid space in the thoracolumbar and sacral spinal regions. Since the omega conotoxin is distributed or intrathecally released, it can rapidly cross out of or pass out of the intrathecal space of the spinal cord, in those patients with dystonia / spasticity complication in the upper extremities, the medical provider who inserts the catheter can desire to insert the more cephalad intraspinal catheter., Meythaler et al., Perspective in Neurosurg. nineteen ninety six; 7 (2): 99-107. It has been shown a similar effect for the intrathecal baclofen where the catheter was threaded more cephaloid than the T-10 level which was found to improve the sustained response in the tone of the upper extremities. Meythaler et al., J. NeuroSurgery 1997; 87: 4l -9; Meythaler et al., Am J. Phys. Med. Rehabi l. 1998; 77-173 As stated above, both intrathecal and intraventricular administrations of NSAIS and / or cmega conotoxins can be supported using an implantable pump Examples of well-known implants and modules using the present invention include: U.S. Patent No. 4,487,603, which describes an implantable microinfusion pump for dispersing drug at controlled rate; Patent No. 4,486,194, which describes a therapeutic device for administering drugs through the skin; US Pat. No. 4,447,233, which describes a drug infusion pump for dispensing medication at an accurate infusion rate; State Patent No. 4,447,224 which describes an implantable variable flow infusion apparatus for continuous drug delivery; U.S. Patent No. 4,439,196 which describes an osmotic drug distribution system having multiple compartments of cávala.ras; and U.S. Patent No. 4,475,136, which describes an osmotic drug distribution system. These patents are incorporated herein by reference. Many other such implants, distribution systems and modules are well known to those skilled in the art.

EXPERIMENTAL PART Intracalcal Pain Salicylate Two rats with chronic spinal cord injury were chosen because they consistently exhibited allodynia. A 1-French silicone tubing was screwed into the intrathecal space of the occipital atlantoic membrane. The intrathecal catheter was connected to an ESOX pump that was implanted subcutaneously. The ESOX pump flowed at a rate of 60 μl per day. Initially, saline was placed in the blasts. When testing on days 2, 12, 14 after pump placement, they were consistently observed; signs of allodynia when the animals were touched > s slightly on particular parts of your body (left flank for rat 1 and right shoulder for rat i 2). The animals vocalized consistently when those areas were touched lightly. A whole behavioral test was carried out by a person who knew the type of drug provided to the expected effects of the drug. The solution to exit was removed from the pumps and the pumps were filled with saline. After repeated testing of these animals, no evidence of allodynia was observed. When the salicylate was removed or replaced with saline solution, consistent allodynia was observed.

Intra Salicylate, Tecal for the Treatment of Acute and Persistent Pain METHODS: GENERAL ASPECTS: Male Sprague-Dawley rats were deeply anesthetized with a mixture of halothane and oxygen and an intrathecal catheter was placed at the level of umbar lengthening of the spinal cord using a technique Esteréril and the method of Yaksh and Rudy. The surgical area is closed, leaving the distal end of the catheter accessible for bolus injections. The rats in group 1 (watery, cutaneous and visceral pain) were allowed to recover during the night and the rats in group 2 (persistent pain, formalin test) were allowed to recover for a week before further tests. The rats were not used if there was evidence of neurodeficit; logical, Group 1 protocol (acute, cutaneous and visceral pain): the rats were assigned to one of four subgroups (n = 5-6 / subgroup) On the day of the test those rats were anesthetized, s slightly with inhaled halothane (0.5 -0.8%) in oxygen distributed by means of a mask and the based responses obtained from the tapping test of the tail and the colorectal distention test. Each subgroup then subsequently received a bolus dose of 20 ml of Colin-Mg Salicylate (0, 2.5, or 10 mg using 500 mg / ml of solution) and / or normal saline. Those rats were then tested using both tapping and colorectal distension tests at four minute intervals beginning one minute after the bolus dose. The tests used are given below and the results are shown in Figures 1 and 2. The glept test of the tail (cutaneous nociception, Figure 1) The tail of the slightly anesthetized rat placed on the test apparatus and an area of 1.5 x 11 mm of the ventral surface in the third half of its tail was exposed to radiant heat (bulb projector) .The latency of the tapping of the tail was defined as the latency from the appearance of the heating movement of the tail until the movement of withdrawal by bending of the tail according to the determined using a photoelectric device and measured closer to 0.1 seconds. The tail was removed from the heat if there was no rftovimiento within 8 seconds to avoid damage to the cabbage. Colorectal Distension Test (visceral nociception, Figure 2): The visceromotor response is a reflex contraction of the abdominal muscles and the hind limbs in response to a slow increase in pressure within a balloon distending in the colon and rectum. Air was used to cool a 7-8 cm flexible latex balloon catheter (end of the balloon 1 cm from the anus) inserted via the anus and held in place by covering the catheter with the base of the tail. The pressure inside the balloon was measured using an in-line manometer. The threshold for the response was defined as the minimum amount of pressure within the balloon of distension, which produces a visible contraction. The Protocol of 1 group 2 (persistent pain, formalin test): The rats were briefly anesthetized with inhaled halothane (2%) with oxygen. Intrathecal catheters were accessed and 0 or 10 mg (of a 500 mg / ml CMS solution) were injected followed by a 10 ml wash of normal saline. HE they injected 50 ml of a 5% formalin solution into the back of the right hind paw and the rat was allowed to recover from anesthesia. The rat was then observed during the next hour and the number of lesions / contusion of the hind paw was measured during a one minute interval. . five minutes. RESULTS: Colin-Mg Salicylate produced an effect in the three models of nociception. In the tests of tail tapping and colorectal distress, the response was shown to be dose dependent. In those tests the response to the bolus was rapid at the beginning suggesting that it had a non-specific effect of the compound or because the CMS crosses from CSF to the spinal cord quickly. The np effects lasted a long time suggesting that an intrathecal distribution is an effective method for intrathecal administration.

Intrathecal Salicylate to Prevent Secondary Damage and Inflammation after Spinal Cord Injury In this study, twenty-four deeply anesthetized rats received a moderate to severe spinal cord injury using a 2-French Fogarty embolometry catheter. Immediately after the damage, a 1-French silicone pipe was threaded into the intrathecal space of the occipital atlantoic membrane. The intrathecal catheter was connected to an ESOX pump that was implanted subcutaneously. The ESOX pump flowed at a rate of 60 μl per day. The animals were randomly assigned to receive saline or salicylate. The animals were tested every week using the locomotive BBB test. All behavioral tests were performed by a person who did not know the type of drug provided with the expected effects of the drug. Animals receiving salicylate exhibited on average lower functional deficits. The average score of rats treated with saline solution was 0 while the average score for rats: rats with salicylate was 5.45. In view of the teachings presented herein, other modifications and variations of the present invention will be readily apparent to those skilled in the art. The discussion and description are illustrative of some embodiments of the present invention, but does not mean that they are limitations on the practice of immisma. The following claims, including all equivalents, define the scope of the invention.

Any patents, applications or publications mentioned in the specification are indicative of the levels of those skilled in the art to which the invention pertains. The patents, applications and publications are incorporated here as a reference in the same rotated as if each individual publication was specific and individually indicated as incorporated in the reference. It is noted that in relation to this date, the best known method for the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (35)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A method for treating neurotrauma, characterized in that the method comprises administering to a subject having neurotrauma a therapeutically effective amount of an anti-inflammatory, nonsteroidal (NSAID), analogous drug, substituted form, derivative, or a salt, ester, amide or pharmaceutically acceptable prodrug thereof.

2. The method according to claim 1, characterized in that the NSAID is distributed or intrathecally released.

3. The method according to claim 1, characterized in that the NSAID is distributed intraventricularly.

The method according to claim 1, characterized in that the non-steroidal antiinflammatory drug comprises magnesium colin trisilacylate

5. The method according to claim 1, characterized in that the drug

Nonsteroidal anti-inflammatory drug comprises sodium salicylate.

6. The method according to claim 1, end-face because the non-stereid anti-inflammatory drug comprises salicylamide.

7. The method according to claim 1, characterized in that the anti-inflammatory drug is not roideo comprises a deacetylated aspirin.

8. A method for treating diffuse axonal injury, the method is characterized in that it comprises administering to a subject having diffuse axonal injury a therapeutically effective amount of a natural omega conotoxin, a functional fragmer thereof, a salt, ester, amide or pharmacologically acceptable prodrug thereof.

9. The method according to claim 8, characterized in that the natural omega conotoxin, the functional fragmer thereof, a pharmaceutically acceptable salt, ester, amide or prodrug thereof is a calcium channel blocker of the N type.

10. The method according to claim 8, characterized in that the conotoxin

Natural omega is selected from the group consisting essentially of GVIA and MVJ [11] The method according to claim 8, characterized in that the administration step further comprises intrathecally distributing the omega conotoxin, the functional fragment thereof, the salt, ester Pharmaceutically acceptable prodrug, amide or prodrug thereof

12. The method according to claim characterized in that the administration step further comprises distributing or intraventricularly releasing the omega onotoxin, the functional fragment thereof, a salt, ester, amide or prodrug Pharmaceutically acceptable thereof

13. The method according to claim 8, characterized in that the administration step further comprises distributing the omega conotoxin, the functional fragment thereof, a pharmaceutically acceptable salt, ester, amide or prodrug thereof. to the subject through an implantable pump

14. The method of according to claim 8, characterized in that the administration step further comprises distributing the omega conotoxin, the functional fragment thereof, a salt,

pharmaceutically acceptable ester, amide or prodrug thereof to the subject through a spinal catheter.

15. The method according to claim 8, characterized in that the diffuse axonal injury is a spastic disorder.

16. The method according to claim 15, characterized in that the spastic disorder is caused by traumatic brain injury.

17. The method according to claim 8, characterized in that it also includes the step of administering a non-steroidal anti-inflammatory drug to the subject.

18. The method according to claim 17, characterized in that the non-steroidal antiinflammatory drug comprises magnesium colin trisalicylate.

19. The method according to claim 17, characterized in that the non-steroidal antiinflammatory drug comprises sodium salicylate,

20. The method according to claim 17, wherein the non-steroidal antiinflammatory drug comprises salicylamide.

21. The method according to claim 17, characterized in that the drug

Anti-inflammatory is not eroid it comprises deacetylated aspirin.

22. A method for treating pain, the method is characterized in that it comprises administering to a subject having pain, a therapeutically effective amount of nonsteroidal anti-inflammatory drug (NSAID), analog, substituted derivative form, or a salt, ester, amide or pharmaceutically acceptable prodrug thereof.

23. The method according to claim 22, characterized in that the NSAID is distributed or freed int time-wise.

24. The method according to claim 22, characterized in that the NSAID is distributed or delivered int :: aventricularly.

25. The method according to claim 22, face < This is because the nonsteroidal antiinflammatory drug comprises colin magnesium trisilacylate.

26. The method according to claim 22, face < This is because the non-esterid anti-inflammatory drug comprises sodium salicylate.

27. The method according to claim 22, face < Terized because the anti-inflammatory drug is not estero deo comprises salicylamide.

28. The method according to claim 22, characterized in that the anti-inflammatory drug is not: Roideo comprises a deacetylated aspirin.

29. A method for treating neuronal injury, the method is characterized in that it comprises administering intrathecally to a subject: or having neuronal injury a therapeutically effective amount of an anti-inflammatory, nonsteroidal drug (NSAID), analogue, substituted form, derivative, or one . pharmaceutically acceptable salt, ester, amide or prodrug thereof.

30. The method according to claim 29, characterized in that the NSAID is distributed or intraventricularly released.

31. The method according to claim 29, characterized in that the non-steroidal antiinflammatory drug comprises magnesium colin trisilacylate.

32. The method according to claim 29, characterized in that the non-steiroid anti-inflammatory drug comprises sodium salicylate.

33. The method according to claim 29, characterized in that the anti-inflammatory drug is not considered to comprise salicylamide.

34. The method according to claim 29, etherified face because the anti-inflammatory drug does not contain this oideo comprises a deacetylated aspirin.

35. The method according to claim 29, characterized in that the neuronal lesion is caused by iLupus, inflammatory neuropathy, infection, acquired disorders, transverse myelitis, Parkinson's disease, CNS vasculitis, or Alzheimer's disease,