CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit under 35 U.S.C. § 119(e) of U.S. Patent Application No.

61/650,843, filed May 23, 2012, which is hereby incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

[1] Excitatory neurotransmitters are implicated as causing or exacerbating multiple neurologic conditions. This application utilizes a novel methodology for reducing the symptomatology and pathology of those neurologic morbidities which are exacerbated by excitatory neurotransmitters. Those neurologic dysfunctions include:

A. Epileptic seizures

B. Traumatic brain injury (TBI)

C. Cerebrovascular accidents (C VA)-strokes

D. Pseudobulbar palsy

E . Amyotrophic lateral sclerosis (ALS)

[2] A seizure is an abnormal irregular cortical discharge. Approximately 2% of all adults have a seizure at some time during their lifetime. Two thirds of these patients go on to have further seizures. About 40 million people are affected worldwide by seizure disorders. Epilepsy can arise from a variety of underlying conditions and pathophysiologic mechanisms.

Approximately 10-20% of all patients with epilepsy have intractable seizures resistant to multiple antiepileptic drug utilization. Classically, these patients have either utilized vagus nerve stimulation or surgery for better control of their conditions. As is well-known, the vast majority of these patients suffer from the adverse drug effects of chronic long-term utilization of multiple antiepileptic drugs. The enclosed methodology offers an additional option for these patients.

[3] More than two million patients have suffered from traumatic brain injury (TBI) or Chronic Traumatic Encephalopathy (CTE) over the past twelve months. There are 52,000 deaths and 275,000 hospitalizations in the United States each year from TBI and CTE. A head injury occurs in the civilian population of the United States every 7 seconds. The peak morbidity and mortality from TBI and CTE occurs in patients between the ages of 15-24. Men are affected four times as often as women. Excitatory neurotransmitters (EN) are known to greatly exacerbate the symptamatology and neuropathology of TBI, CTE, pseudobulbar palsy and amyotrophic lateral sclerosis (ALS).

[4] Cerebral vascular accident (CVA/strokes) is the fourth leading cause of death in United States. About 750,000 new strokes occur every year in United States and 150,000 people die from stroke each year. The incidence of CVA increases with age, two thirds of old strokes occur in patients over 65 years of age. The incidence of stroke is higher in men than women. The care of patients who suffer morbidity from a cerebrovascular accident is a major cause underlying the rapid increase in healthcare funding in the United States. The release of excitatory

neurotransmitters during a cerebrovascular accident is implicated as a main etiology underlying an increase in morbidity and mortality from a CVA.

SUMMARY OF THE INVENTION

[5] The present invention relates to a method of extracorporeally treating animal or human cerebrospinal fluid (CSF) for the extracorporeal removal of excitatory neurotransmitters (EN). US 13/128,870, US 13/128,177, US 13/254,855, and US 61/612,474 are hereby incorporated by reference.

[6] Specifically, the invention pertains to a method for the extracorporeal treatment of CSF in two stages characterized by passing the CSF through a first stage; applying a treatment to at least one antigen in the CSF to create a antibody-antigen moiety during passage thereof through said first stage; passing the treated CSF through a second stage; and removing the treatment

(antibody-antigen moiety) from the CSF during passage through said second stage.

[7] The method is further characterized by targeting an a excitatory neurotransmitter antigen (EN ) in the CSF , with an antibody to allow and facilitate removal thereof in the second stage. The targeted excitatory neurotransmitter (EN) antigens would include one, or a combination of : glutamate, aspartate, quinolinic acid, homocysteic acid, N-acetylaspartylglutamate (NAAG), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMD A), Quisqualate , Kainate, Ibotenate and Domoate

[8] More specifically, the method is characterized by directing a first antibody against the targeted EN antigen in the first stage; and directing a second antibody conjugated with albumin and /or a protein against the targeted antigen thereby forming an albumin-antibody-EN antigen compound in the second stage; and removing at least a portion of the albumin-antibody-EN antigen compound from the CSF. [9] Still more specifically, the method is further characterized by removing CSF from a person to produce the extracorporeal bodily fluid; and returning the CSF to the patient after substantially removing the treatment in the second stage.

[10] Also, the method is characterized by testing the CSF to determine the efficacy of treatment before returning the CSF to the person.

[11] In the first stage of treatment of CSF, the CSF is removed utilizing a standard lumbar puncture. In the second stage, the CSF is treated with antibodies against the excitatory neurotransmitter (EN) antigen.

BRIEF DESCRIPTION OF THE DRAWINGS

[12] Figure 1 is a partial cross sectional view of a cylinder and tubing used to deliver a treatment to a bodily fluid.

[13] Figure 2 is a partial cross sectional view showing additional detail of the cylinder and tubing of Figure 1.

DETAILED DESCRIPTION OF THE INVENTION

[14] The method of the present invention comprises treating a patient's CSF extracorporeally with a designer antibody containing an albumin moiety which will allow for the efficacious dialysis of the resultant albumin-antibody-EN antigen compound (the targeted EN antigen being respectively, one or a combination of : glutamate, aspartate, quinolinic acid, homocysteic acid, N-acetylaspartylglutamate (NAAG), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMD A), Quisqualate , Kainate, Ibotenate and Domoate ), utilizing standard dialysis methodologies. [15] The albumin-antibody will be directed towards the removal of the targeted EN antigen(s), (glutamate, aspartate, quinolinic acid, homocysteic acid, N-acetylaspartylglutamate (NAAG), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMD A), Quisqualate, Kainate, Ibotenate and Domoate). After the removal of the EN antigen, the cleansed CSF will be returned to the patient utilizing the same catheter which was originally used in first removing the CSF. A treatment of CSF would involve 5-25 cc of CSF during a standard treatment procedure. The frequency and the specifically targeted excitatory

neurotransmitter(s) to be removed would depend upon the underlying symptomatology and pathology of the patient, and would be determined by the patient's physician. The article includes two-stages. The first stage includes a treatment chamber which utilizes an antibody with an attached albumin moiety, which is added to the CSF. A second stage receives the treated CSF and includes a unit for removing the treatment.

[16] The method includes providing a dialysis machine with a first stage and a second stage, and sequentially passing the extracorporeal bodily fluid through the first and second stages. The CSF is removed from the patient utilizing standard lumbar puncture procedure. The first stage applies a treatment utilizing an antibody which was has attached to it an albumin moiety (or alternatively, a moiety which allows for the efficacious dialysis of the antibody-EN antigen), for the treatment of the CSF. The second stage substantially removes the treatment. The purified CSF (CSF with removed targeted EN : glutamate, aspartate, quinolinic acid, homocysteic acid, N-acetylaspartylglutamate (NAAG), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMD A), Quisqualate , Kainate, Ibotenate and Domoate)- is then returned to the patient. [17] The device of the intervention includes a first stage and a second stage. The first stage applies a treatment of an antibody with an attached albumin moiety targeting the EN antigen(s) specifically exacerbating the pathologic condition. The second stage includes substantial removal of the treatment from the extracorporeal CSF bodily fluid. As shown in Figure 1 , the first stage can include an exterior wall to define a treatment chamber 5. The treatment conveniently can be applied in the treatment chamber 5. Residence times of the CSF can be altered by changing the dimensions of the treatment chamber, or by using a dialysis vacuum pump. With reference to Figure 1, CSF fluid enters the inlet 3, passes through the treatment chamber 5, and exits the outlet 4. In embodiments, the treatment of an antibody with an attached albumin moiety targeting the EN antigens can be applied from a delivery tube 6 located within the treatment chamber 5. An inferior wall 9 defines the delivery tube 6. The delivery tube 6 can include at least one lead 7, 8. The lead 7, 8 can deliver the treatment to the treatment chamber 5. Conveniently, the delivery tubes 6 will have a high contact surface area with the CSF. As shown, the delivery tube 6 comprises a helical coil.

[18] With reference to Figure 2, when the treatment includes the administration of a designer antibody, the delivery tube 6 can be hollow and the interior wall 9 can define a plurality of holes 21. The designer antibodies can be pumped through the delivery tube 6 in order to effect a desired concentration of designer antibodies in the CSF. The designer antibodies can perfuse through the holes 21. The delivery tube 6 can include any suitable material including, for example, metal, plastic, ceramic or combinations thereof. The delivery tube 6 can also be rigid or flexible. In one embodiment, the delivery tube 6 is a metal tube perforated with a plurality of holes. Alternatively, the delivery tube 6 can be plastic. The antibody with attached albumin moiety, targeting the EN antigen(s) can be delivered in a concurrent or counter-current mode with reference to the CSF. In counter-current mode, the CSF enters the treatment chamber 5 at the inlet 3. The designer antibody can enter through a first lead 8 near the outlet 4 of the treatment chamber 5. CSF then passes to the outlet 4 and the designer antibodies pass to the second lead 7 near the inlet 3. The removal module of the second stage substantially removes the designer antibodies-antigen molecular compound from the CSF.

[19] The second stage can include a filter, such as a dialysis machine, which is known to one skilled in the art. The second stage can include a molecular filter. For example, molecular adsorbents recirculating system (MARS), which may be compatible and/or synergistic with dialysis equipment. MARS technology can be used to remove small to average sized molecules from the CSF. Artificial liver filtration presently uses this technique.

[20] The method can include a plurality of steps for removing the targeted EN antigens A first step can include directing a first antibody against the targeted antigen. A second step can include a second antibody. The second antibody can be conjugated with albumen, or alternatively a moiety which allows for efficacious dialysis. The second antibody or antibody-albumen complex combines with the first antibody forming an antibody-antibody-moiety complex. A third step is then utilized to remove the complex from the CSF. This removal is enabled by utilizing dialysis and/or MARS. The purified CSF can then be returned to the patient.

[21] In practice, a portion of the purified CSF can be tested to ensure a sufficient portion of the targeted EN antigen(s), (glutamate, aspartate, quinolinic acid, homocysteic acid,

N-acetylaspartylglutamate (NAAG), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMD A), quisqualate, kainate, ibotenate and domoate) have been successfully removed from the CSF. Testing can determine the length of treatment and evaluate the efficacy of the sequential dialysis methodology in removing the targeted antigen(s). CSF with an unacceptably large concentration of complex remaining can then be refiltered before returning the CSF to the patient.

[22] In embodiments, the second stage to remove the antibody-moiety-targeted EN antigen complex by various techniques including, for example, filtering based on molecular size, protein binding, solubility, chemical reactivity, and combinations thereof. For example, a filter can include a molecular sieve, such as zeolite, or porous membranes that capture complexes comprising molecules above a certain size. Membranes can comprise polyacrylonitrile, polysulfone, polyamides, cellulose, cellulose acetate, polyacrylates, polymethylmethacrylates, and combinations thereof. Increasing the flow rate or diasylate flow rate can increase the rate of removal of the antibody with attached albumin moiety targeting the EN antigen(s): glutamate, aspartate, quinolinic acid, homocysteic acid, N-acetylaspartylglutamate (NAAG), alpha-amino- 3-hydroxy-5-methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMDA), quisqualate, kainate, ibotenate and domoate.

[23] Further techniques can include continuous renal replacement therapy (CR RT) which can remove large quantities of filterable molecules from the extracorporeal CSF. CRRT would be particularly useful for molecular compounds that are not strongly bound to plasma proteins. Categories of CRRT include continuous arteriovenous hemofiltration, continuous venovenous hemofiltration, continuous arteriovenous hemodiafiltration, slow continuous filtration, continuous arteriovenous high-flux hemodialysis, and continuous venovenous high flux hemodialysis. The sieving coefficient (SC) is the ratio of the molecular concentration in the filtrate to the incoming CSF. A SC close to zero implies that the moiety-antibody-targeted antigen complex will not pass through the filter. A filtration rate of 50 mL per minute is generally satisfactory. Other methods of increasing the removability of the moiety- antibody- targeted antigen include the use of temporary acidification of the CSF utilizing organic acids to compete with protein binding sites.

[24] Numerous modifications and variations of the present invention are possible. It is, therefore, to be understood that within the scope of the following claims, the invention may be practiced otherwise than as specifically described. While this invention has been described with respect to certain preferred embodiments, different variations, modifications, and additions to the invention will become evident to persons of ordinary skill in the art. All such modifications, variations, and additions are intended to be encompassed within the scope of this patent, which is limited only by the claims appended hereto.

[25] All documents, books, manuals, papers, patents, published patent applications, guides, abstracts and other references cited herein are incorporated by reference in their entirety. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the

specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the following claims.