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Title:  Treatment of neurological disease

United States Patent:  6,689,756

Issued:  February 10, 2004

Inventors:  Hesson; David P. (Malvern, PA); Pelura; Timothy J. (Malvern, PA); Frazer; Glen D. (Wynnewood, PA)

Assignee:  Integra LifeSciences Corporation (Plainsboro, NJ)

Appl. No.:  090442

Filed:  March 4, 2002

Abstract

Provided is, among other things, a method of treating in an animal infection or neoplasm of cerebrospinal tissue characterized by a risk of death, the method comprising: (a) injecting a physiologically acceptable fluid for cerebrospinal perfusion into a first catheter into the cerebrospinal pathway, which fluid for cerebrospinal perfusion has an therapeutically effective amount an agent, the agent selected for effectiveness against the infection as identified or diagnosed; (b) withdrawing fluid at a second catheter into the cerebrospinal pathway to create a flow and flow pathway between the first and second catheters; and (c) maintaining the flow for a period of time adapted to perfuse at least 1 CSF volume.

SUMMARY OF THE INVENTION

The invention provides, among other things, a method of treating in an animal an infection or cancer of a cerebrospinal tissue characterized by a risk of death, the method comprising: (a) injecting a physiologically acceptable fluid for cerebrospinal perfusion into a first catheter into the cerebrospinal pathway, which fluid for cerebrospinal agent, the agent selected for effectiveness against the disease as identified or diagnosed; (b) withdrawing fluid at a second catheter into the cerebrospinal pathway to create a flow and flow pathway between the first and second catheters; and (c) maintaining the flow for a period of time adapted to perfuse at least 1 CSF volume.

Also provided is a method of treating in an animal an infection or cancer of a cerebrospinal tissue comprising: (a) injecting a fluid for cerebrospinal perfusion into a first catheter into the cerebrospinal pathway, which fluid has an therapeutically effective amount an antimicrobial or antineoplastic agent, the agent selected for effectiveness against the disease as identified or diagnosed, wherein the fluid for cerebrospinal perfusion further comprises one or both of: (1) an emulsion-forming effective amount of a lipid composition comprised of lipids found in biological membranes, or (2) 0.05-2.0 g/dL albumin; (b) withdrawing fluid at a second catheter into the cerebrospinal pathway to create a flow and flow pathway between the first and second catheters; and (c) maintaining the flow for a period of time adapted to perfuse at least 1 CSF volume.

Further provided is a method of treating bacterial meningitis, bacterial encephalitis, brain abscesses, tuberculous meningitis, neurosyphilis, fungal meningitis or meningoencephalitis, parasitic CNS infections or viral CNS infections comprising: (a) injecting a physiologically acceptable fluid for cerebrospinal perfusion into a first catheter into the cerebrospinal pathway, which fluid for cerebrospinal perfusion has an infection-treating effective amount an antimicrobial agent, the antimicrobial agent selected for effectiveness against the infection as identified or diagnosed; (b) withdrawing fluid at a second catheter into the cerebrospinal pathway to create a flow and flow pathway between the first and second catheters; and (c) maintaining the flow for a period of time adapted to perfuse at least 1 CSF volume.

Additionally provided is a method of treating in an animal an infection of cerebrospinal tissue comprising: (a) injecting a fluid for cerebrospinal perfusion into a first catheter into the cerebrospinal pathway, which fluid has an infection-treating effective amount an antimicrobial agent, the antimicrobial agent selected for effectiveness against the infection as identified or diagnosed, wherein the antimicrobial agent is an antihelminthic, aminoglycoside antibacterial, amphenicol antibacterial, ansamycin antibacterial, .beta.-lactam antibacterial, lincosamide antibacterial, macrolide antibacterial, polypeptide antibacterial, tetracycline class antibacterial, cycloserine antibacterial, tuberin, quinolone class antibacterial, sulfonamide antibacterial, tuberculostatic antibacterial, antifungal, antiprotazoal or antiviral agent; (b) withdrawing fluid at a second catheter into the cerebrospinal pathway to create a flow and flow pathway between the first and second catheters; and (c) maintaining the flow for a period of time adapted to perfuse at least 1 CSF volume.

Further provided is a method of treating neurologic cancers such a gliomas, glioblastomas, astrocytomas, leptomeningeal carcinomas, leptomeningeal leukemia or lymphomas and metastatic cancers from outside the CNS by: (a) injecting a physiologically acceptable fluid for cerebrospinal perfusion into a first catheter into the cerebrospinal pathway, which fluid for cerebrospinal perfusion has an cancer-treating effective amount an antineoplastic agent or agents, the antineoplastic agent selected for effectiveness against the cancer as identified or diagnosed; (b) withdrawing fluid at a second catheter into the cerebrospinal pathway to create a flow and flow pathway between the first and second catheters; and (c) maintaining the flow for a period of time adapted to perfuse at least 1 CSF volume.

Additionally provided is a method of treating in an animal a cancer of the cerebrospinal tissue comprising: (a) injecting a fluid for cerebrospinal perfusion into a first catheter into the cerebrospinal pathway, which fluid has an cancer-treating effective amount an antineoplastic agent, the antineoplastic agent selected for effectiveness against the cancer as identified or diagnosed, wherein the antineoplastic agent is methotrexate (N-[4-[[(2-amino-4-hydroxy-6-pteridinyl)methyl]methylamino]benzoyl]glutami c acid), cytarabine (Ara-C; 4-amino-1-.beta.-D-arabinofuranosylcytosine), thiotepa (triethylenethiophosphoramide or 1,1', 1"-phosphinothioylidynetrisaziridine), topotecan ((S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4': 6,7]indolizino [1,2-b]-quinoline-3,14(4H, 12H)-dione), mafosfamide (an oxazaphosphorine from Baxter Oncology, Frankfurt, Del., which generates its active principle, 4-hydroxy-cyclophosphamide, without hepatic intervention), busulfan (1,4-bis(methanesulfonoxy)butane) or ACNU [(3-[(4-amino-2-methyl-5-pyrimidinyl)-methyl]-1-(2-chloroethyl)-1-nitrosou rea hydrochloride]; (b) withdrawing fluid at a second catheter into the cerebrospinal pathway to create a flow and flow pathway between the first and second catheters; and (c) maintaining the flow for a period of time adapted to perfuse at least 1 CSF volume.

Still additionally provided is a method of treating a toxemia of cerebrospinal tissue, comprising: (a) injecting a physiologically acceptable fluid for cerebrospinal perfusion into a first catheter into the cerebrospinal pathway; (b) withdrawing fluid at a second catheter into the cerebrospinal pathway to create a flow and flow pathway between the first and second catheters; and (c) maintaining the flow for a period of time adapted to perfuse (i) at least 15 CSF volumes or (ii) sufficient volume to reduce a concentration of toxin causing the toxemia in the perfusate at least 5-fold.

DETAILED DESCRIPTION OF THE INVENTION

In addition to providing antibacterial agents into cerebrospinal passageways, the inventive method can also be used to remove infectious organisms, cancer cells and their by-products while optionally providing oxygen, glucose, electrolytes and essential amino acids into neural tissue. If used in a rapidly exchanging cerebrospinal fluid perfusion system, such as is described in WO 01/39819 (the perfusion systems described therein are incorporated by reference, see below), the inventive composition and methods can be used both to supply these nutrients and, at the same time, remove metabolic waste.

Fluid for Cerebrospinal Perfusion

In one embodiment, the fluid for cerebrospinal perfusion ("CSPF") is an oxygen-carrying nutrient emulsion according to the following:

                                                    Still More
                                             More     Preferred
                               Preferred   Preferred  Range or
    Component                    Range       Range     Amount
    Oxygen-Carrying Compound,     5-15         9-11    9.5-10-5
    % v/v
    Lipid, mg/mL                 8-14        10-13      11.5
    Albumin, g/dL,             0.05-2.0     1.5-1.9     1.67
    .alpha.-Ketoglutaric Acid, .mu.g/mL     5-40        22-28       25
    Amino Acids, .mu.g/mL
    L-Isoleucine + L-Leucine     5-50        11-23      17.5
    L-Valine                     5-50        11-22      16.6
    L-Alanine                    5-50        19-38      28.6
    L-Serine                     5-50        16-33      24.6
    L-Histidine                  2-20         7-14      10.3
    L-Methionine                0.1-5       1.4-2.8      2.1
    L-Phenylalanine + L-Lysine     5-50        23-47      35.3
    L-Threonine + L-Arginine     5-50        32-64      48.3
    L-Tyrosine                   1-20         5-11       7.9
    Na+, mM               135-150      137-147      147
    K+, mM                2.5-4.0      2.7-3.9      2.9
    Cl-, mM               110-135      116-135      130
    Ca+2, mM              1.0-1.6      1.0-1.5     1.15
    Mg+2, mM              0.8-1.6      1.0-1.5     1.12
    Glucose (dextrose), mg/dL    10-150       30-100      94

The pH of the emulsion, or vehicle (constituting the above or the like without oxygen-carrying compound), is in the physiological range, such as about 7.3. In one embodiment, the amino acids include tryptophan.

The fluid for cerebrospinal perfusion is preferably formulated such that it is physiologic and can directly contact tissues of the neuraxis for an extended period of time, from hours to days, without causing side effects. For best performance, it is believed that the artificial cerebrospinal fluid should be appropriately buffered and have appropriate amounts of amino acids, electrolytes and other compounds helpful to healthy metabolism. Thus, in preferred methods, these components do not need to be supplied through equilibration with other body fluids. Of course, simpler solutions, such as appropriately balanced salts, are used in neurosurgery and are to some degree acceptable. Where the fluid for cerebrospinal perfusion is formulated with nutrients, it can be termed "artificial cerebrospinal fluid" or "ACSF."

In some embodiments, the fluid for cerebrospinal perfusion is simplified. For example, the poly-fluorinated, oxygen-carrying compound is omitted, for instance according to the following formulation:

                                                     Still More
                                            More      Preferred
                              Preferred   Preferred   Range or
    Component                   Range       Range      Amount
    Albumin, g/dL,            0.05-2.0     1.5-1.9        1.67
    .alpha.-Ketoglutaric Acid, .mu.g/mL    5-40        22-28        25
    Amino Acids, .mu.g/mL
    L-Isoleucine + L-Leucine    5-50        11-23        17.5
    L-Valine                    5-50        11-22        16.6
    L-Alanine                   5-50        19-38        28.6
    L-Serine                    5-50        16-33        24.6
    L-Histidine                 2-20         7-14        10.3
    L-Methionine               0.1-5       1.4-2.8        2.1
    L-Phenylalanine + L-Lysine    5-50        23-47        35.3
    L-Threonine + L-Arginine    5-50        32-64        48.3
    L-Tyrosine                  1-20         5-11         7.9
    Na+, mM              135-150      137-147       147
    K+, mM               2.5-4.0      2.7-3.9        2.9
    Cl-, mM              110-135      116-135       130
    Ca+2, mM             1.0-1.6      1.0-1.5        1.15
    Mg+2, mM             0.8-1.6      1.0-1.5        1.12
    Glucose (dextrose), mg/dL   10-150       30-100       94

In some embodiments, the fluid for cerebrospinal perfusion is simplified further, for instance according to the following table:

                                                     Still More
                                            More      Preferred
                              Preferred   Preferred   Range or
    Component                   Range       Range      Amount
    Albumin, g/dL,            0.05-2.0     1.5-1.9        1.67
    Na+, mM               135-150     137-147       147
    K+, mM                2.5-4.0     2.7-3.9        2.9
    Cl-, mM               110-135     116-135       130
    Ca+2, mM              1.0-1.6     1.0-1.5        1.15
    Mg+2, mM              0.8-1.6     1.0-1.5        1.12
    Glucose (dextrose), mg/dL    10-150      30-100       94

Ions are maintained to the degree required to avoid damage to cerebrospinal tissue. Appropriate amounts of oncotic agents are preferred.

Generally, tissues and cells will not fare well if exposed to large volumes of non-physiologic ionic solutions. Accordingly, appropriate electrolyte compositions at the tissue level are important when it is considered that the circulatory method of the present invention could dilute of electrolytes from the region, to the detriment of cell membrane function. Desirably, sodium, potassium, calcium, magnesium, and chloride ions are carefully balanced in the antimicrobial formulations of the present invention to create, to the degree possible, normal extra-cellular compositions.

The formulations of the invention preferably exclude four amino acids, glutathione, cysteine, ornithine and glutamine, from the group of amino acids included in the formulation, and preferably include sodium bicarbonate in an amount sufficient to increase the buffering capacity of the nutrient solution, in order to more closely resemble cerebrospinal fluid of the subject.

Kits for conveniently and safely generating fluorocarbon nutrient emulsion or a corresponding vehicle lacking poly-fluorinated, oxygen-carrying compound are described for example in U.S. patent application No. 09/619,414, filed Jul. 19, 2000 (the specific formulations and kits described therein are incorporated by reference as outlined below).

While not wishing to be limited to theory, it is believed that the lipid and albumin components help flush or perfuse from cerebrospinal tissue infectious organisms, infection-created components, cells and debris that accentuates the generation for septicemic shock. For example, it is believed that these components help flush endotoxin, reducing the generation of cytokines and TNF.alpha., which are believed to lead to shock.

Antimicrobials

Antimicrobial compounds that can be used with the invention include, without limitation, antihelminthic agents, antibacterial agents (such as aminoglycosides, amphenicols, ansamycins, .beta.-lactams [carbacephems, carbapenems, cephalosporins, cephamycins, monobactams, oxacephems, penicillins or others], .beta.-lactamase inhibitors (also called antibacterial adjuncts), lincosamides, macrolides, polypeptides, tetracyclines, quinolones and analogs, sulfonamides or tuberculostatic agents), antiprotozoals, antivirals (such as purines/pyrimidinones, nucleoside analog reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTI's), or HIV protease inhibitors), and antifungals (such as polyene antibiotics, imidazoles, triazoles, others). Particular examples include the following:

                                                   Concentration
    Disease           Drug                          (.mu.g/mL)
    bacterial infections Amikacin                         1-10
                      Gentamicin                       1-10
                      Tobramycin                       1-10
                      Vancomycin                       3-30
                      Rifampin                       0.5-5
                      Rifamycin                        1-10
                      Chloramphenicol                  6-60
                      Amoxicillin                      1-100
                      Amoxicillin/clavulanate          1-100
                      (Augmentin, SmithKline Beecham)
                      Ampicillin                       3-30
                      Ampicillin/sulbactam             1-100
                      (Unasyn, Pfizer)
                      Penicillin G                     6-60
                      Oxacillin                        1-10
                      Nafcillin                        1-10
                      Methicillin                      5-50
                      Piperacillin                     6-60
                      Piperacillin/tazobactam          1-100
                      (Zosyn, Lederle Laboratories)
                      Dicloxacillin                    5-50
                      Cefotaxime                      30-300
                      Cefuroxime                      30-300
                      Ceftriaxone                     30-300
                      Cefaperazone                    30-300
                      Ceftazidime                     30-300
                      Ciprofoxcin                     30-300
                      Erythromycin                    10-100
                      Streptomycin                     1-10
                      Isoniazid                        2-200
                      Ethambutol                       5-500
                      Ethionizmide or Ethionamide      2-200
                      Pyrazinamide                     2-200
                      Metronidazole                   10-100
                      Co-Trimoxazole                  10-100
    Antivirals        Acyclovir                        1-100
                      Idoxuridine                      1-100
                      Nevirapine                       1-100
                      Didanosine                       1-100
                      Abacavir                       0.1-10
                      Zidovudine                     0.1-10
                      Lamivudine                     0.1-10
                      Indinavir                      0.1-10
                      Efavirenz (Sustiva .TM.)       0.1-10
                      Ritonavir                     0.05-0.5
    Antifungals       Amphotericin B                 100-500
                      Clotrimazole                     1-100
                      Flucaonazole                     1-100
                      Itraconazole                     1-100
                      Ketoconazole                     1-100
                      Grieseofulvin                    5-500
                      Nystatin                         1-100
                      Terbinatine                      1-100
                      Flucytosine                    0.1-10
    Antimicrobials    Chloramphenicol                 10-100
                      Tetracycline                     1-100
                      Sulfadiazein                   0.5-5
                      Pyrimethamine                    1-100
                      Praziquantel                     1-100
                      Thiabendazole                    1-100

Listed above for a number of the antimicrobial agents are preferred concentration ranges for use in the fluid for cerebrospinal perfusion. Any number of antimicrobial agents can be used, such as those identified on pages THER-9 to THER-17 of the twelfth edition of the Merck Index (incorporated by reference). However, it will be recognized that greater care is taken in selecting a compound for administration by perfusion of neural tissue than would be taken for a less direct administration, such an i.v. administration.

In one embodiment, where the antimicrobial is gentamicin, at least one of the following applies:

1. The fluid for cerebrospinal perfusion is adapted to not carry a respiration-supporting amount of oxygen;

2. The fluid for cerebrospinal perfusion contains at least a preferred amount of lipid and/or albumin;

3. The perfusion with fluid for cerebrospinal perfusion is conducted over the course of 24 hours or less as an adjunct to another antimicrobial therapy.

Antineoplastics

Antineoplastic compounds that can be used with the invention include, without limitation, purine and pyrimidine antimetabolites, antifolates, alkylating agents, topoisomerase I or II inhibitors. Particular examples include the following:

                                                   Concentration
    Disease         Drug                            (.mu.g/mL)
    CNS Leukemia    Methotrexate                      0.1-10
                    Cytarabine                        0.1-10
    Lymphomatous    Cytarabine                        0.1-10
    meningitis      DepoCyt (sustained release,         1-100
                    liposomal formulation of Cytarabine
                    from Chiron Corp., Emeryville, CA)
    Neoplastic      Thiotepa                            1-100
    meningitis
    Leukemia's and  Topotecan                        0.01-1
    Solid tumors    Mafosfamide                         1-10
    [DepoCyt: weight of Cytarabine or Cytarabine + lipids?]

Diseases

Non-viral infections of the CNS are considered to be infections caused by bacteria, mycobacteria, fungi, and parasitic organism. Common bacterial meningitis can be caused by organisms such as Haemophilus influenzae, Neisseria meningitides, Streptococcus pneumoniae, Listeria monocyogenes, Staphylococcus aureus, group A streptococci, and others. Bacterial encephalitis can be caused by organisms such as Mycoplasma pneumoniae and Listeria monocytogenes, and others. Brain abscesses can be caused by organisms Bacteroides, Propionbacterium, E. coli, Proteus, Staphylococci, Haemophilus influenzae, Actinomyces and Nocardia, and others. Tuberculous meningitis can be caused by organisms such as Mycobacterium tuberculosis and Mycobacterium bovis. Neurosyphilis can be caused by the organism Treponema pallidum. Fungal infections of the CNS can give cause meningitis, meningoencephalitis and/or brain abscesses. These infections are most commonly caused by Candida albicans, Cryptococcus neoformans, Aspergillus, and Coccidioides immitis, and others. CNS infections can also be caused by parasites such as rickettsias, protozoa and worms. These parasites manifest them selves with diseases such as Typhus, Rocky Mountain Spotted Fever, Q Fever, Toxoplasmosis, Cerebral Malaria, Trichinosis, Trypanosomiasis, Cysticercosis and Schistosomiasis. The invention is believed to be particularly suitable for treating the diseases listed here.

The invention is also believed useful for viral infections of the CNS tissue, such as HIV or Herpes Zoster infections.

Methodology

In accordance with a preferred method of the present invention, the antimicrobial or antineoplastic formulation is circulated through this cerebrospinal fluid route by injecting it into brain vesicles and withdrawing it from the cistema magna or the spinal subarachnoid space to nourish and to treat central nervous tissues. In other instances the fluid can be injected into the subarachnoid space and withdrawn from another subarachnoid position. In a preferred embodiment, oxygenated antimicrobial formulation can be circulated to tissues to be treated in amounts sufficient to provide adequate gas exchange. Where one seeks to perfuse sufficiently to remove toxin, cells or debris, an antimicrobial or antineoplastic agent is optional.

The fluid for cerebrospinal perfusion (for example comprising an antimicrobial or antineoplastic agent) can be introduced into the subarachnoid spaces through a catheter that transverses the skull or spinal column and the meninges. The delivery point can be the lateral ventricles, subarachnoid space around the brain, cisterna magna or anywhere along the spine. The fluid for cerebrospinal perfusion can be withdrawn from the subarachnoid space from any of these locations using a similar catheter. The fluid for cerebrospinal perfusion can be returned to the delivery system, reconditioned as necessary to add components that have been consumed or remove undesirable components that have accumulated, and then returned to the subarachnoid space in recirculating fashion. This process can be continued for days if necessary, thereby directly exposing the neuraxis to the agent over an extended period of time.

Where one seeks to flush out toxins, cells or infectious organisms or particles, the fluid for cerebrospinal perfusion is preferably not recirculated. For example, in some embodiments, the withdrawn fluid for a first 4-8 CSF volumes is preferably not recirculated by injection at the first catheter.

This method has several advantages over other routes of administration, such as direct exposure of the nervous system tissue to the antimicrobial or antineoplastic agent by a simple bolus injection of the agent into the subarachnoid space. This invention provides a method of circulating the antimicrobial or antineoplastic agent throughout the neuraxis, thus exposing nervous system tissue to the agent more uniformly than would otherwise be possible. It also provides a method of maintaining the antimicrobial or antineoplastic agent within a narrow concentration range, avoiding the necessity of high bolus concentrations over time. According to this method, the nervous system tissue can be exposed to the agent for extended period time, such as days, if necessary. Further, this method minimizes the amount of drug necessary to achieve a therapeutic effect.

It is preferable to establish a flow pathway from the entry catheter (e.g., a ventricular catheter into a lateral ventricle of the brain) to an exit point at a different location in the cerebral spinal pathway (e.g., into the intrathecal space of the lumbar (such as L4-L5) region of the spine) without prematurely inserting an fluid for cerebrospinal perfusion containing, for example, antimicrobial agent, oxygen-carrying compound, other emulsified components, or the like.

As illustrated in FIG. 1, a ventricular catheter 1 is inserted into a lateral ventrical 2. Via aqueduct 3, cisterna magna 4 and subarachnoid spaces 5, a flow pathway can be established to a lumbar outflow catheter 6. When the inflow and outflow catheters are established (typically with suitable controls to monitor intracranial and intraspinal pressure), vehicle can be used to establish the existence of a flow pathway (such as that illustrated) from the inflow catheter to the outflow catheter. Preferably, the vehicle is infused under gravity feed, with the pressure head designed to avoid excessive intracranial pressure. Once established, the vehicle can be substituted with the fluid for cerebrospinal perfusion.

It will be apparent that more than two catheters can be used, though additional catheters are not particularly preferred. Care is taken to monitor the intracranial pressure to assure that flow rates do not cause excessive pressure.

Fluid for cerebrospinal perfusion is preferably perfused through the cerebrospinal pathway for a period of time or for a flush volume adapted to effectively reduce the concentration of microbes, microbe products, or other molecular or debris components resulting from infection. Included among the components that can be reduced with the methodology of the invention are immune or other signaling molecules that are associated with adverse consequences such as septicemic shock. The volume perfused can be about 15 CSF volumes, where a "CSF volume" is the average volume of CSF fluid found in animals of comparable age to the subject. Preferably, at least about 1, 2, 4, 8, 15 or 30 CSF volumes are used. In adult humans, for example, a flow rate in the range of 300-3,600 mL/hr is expected, resulting in the exchange of about 2-22 CSF volumes/hr. In human adults, the perfusion is preferably with 300 to 3,600 mL/hr.

Where one seeks to perfuse sufficiently to remove a toxin, perfusion can be maintained for an amount of time or volume effective to diminish toxin concentration at least about 5-50-fold, preferably at least about 10-fold. It will be recognized that the initial "perfusate" against which the reduction is measured is the initial CSF, or that portion of the initial CSF having the highest concentration of toxin.

The perfusion can be conducted, for example, for 6, 12, 24 or 48 or more hours. Preferably the perfusion is conducted for between 6 hours and 48 hours or between 12 hours and 24 hours. More preferably, the perfusion is conducted for at least about 24 hours. Preferably, the perfusion is conducted for no more than about 120 hours (or, in some embodiments, no more than about 72 hours).

In one embodiment, the perfusion is an adjunct to a longer term therapy that primarily seeks to deliver the antimicrobial agent, and does not seek to perfusion out the cerebrospinal tissue. For example, at some point during the course of the infection the perfusion is conducted to reduce the quantity of infectious organisms. Thereafter, the focus is typically on delivery of the antimicrobial agent, rather than perfusing fluid and delivering antimicrobial agent. It will be recognized that where the catheters are left in place, these can be used to deliver antimicrobial agent by injecting for example 0.1, 0.2, 0.4, 1 or 2 or 5 CSF volumes or less. In some cases, the longer-term delivery will be by a less invasive method, such as intravenous, oral, or any other recognized method of delivery. The post-perfusion administrations are typically done at least daily for at least seven days. If additional perfusions are conducted in this embodiment, the number of perfusions is typically small, such as two or three in total (including the original perfusion).

Preferred treatment subjects among animals are mammals, preferably humans.

Analysis of Microbial Susceptibility

A sampling of infected CSF can be collected and assayed for susceptibility to antimicrobial agent. The initial fluid for cerebrospinal perfusion injected to cause the efflux of the CSF can be formulated without antimicrobial agent to assure that such antimicrobial does not interfere with the susceptibility measurement. Or, the collection of CSF for testing can be cutoff before any overlap with fluid for cerebrospinal perfusion which may contain antimicrobial. After conducting susceptibility studies, an antimicrobial composition selected based on the studies can be mixed into the fluid for cerebrospinal perfusion, or the fluid for cerebrospinal perfusion being inserted can be replaced with fluid for cerebrospinal perfusion formulated with the identified antimicrobial composition.

In some embodiments, the perfusion is conducted while susceptibility studies are conducted. The perfusion preferably but not necessarily contains an antimicrobial agent selected from diagnostic information initially available. After susceptibility studies have been conducted, the antimicrobial composition identified can be administered by a new perfusion, non-perfusion use of the catheters to inject fluid for cerebrospinal perfusion with the antimicrobial, or another route of administration. In other embodiments, the initial injection of fluid for cerebrospinal perfusion used to obtain CSF is stopped after collection of the CSF, and fluid for cerebrospinal perfusion injection is not resumed until the antimicrobial composition is identified through the susceptibility studies. Susceptibility studies can be conducted, for example, as taught by Clark et al. U.S. Pat. No. 6,096,272.

Oxygen-Carrying Compounds

Generally, the preferred compounds for use as non-aqueous oxygen transfer components are fluorocarbons, such as perfluorocarbons, perfluorinated alkyl polyethers, fluoroethers, fluoramines, bromofluorocarbons, chlorofluorocarbons, and the like. While compounds within these groups range in molecular weight from 250 to 7000, their selection for use as non-aqueous transport components are based upon the combination of features of the proper vapor pressure, molecular weight, viscosity, and emulsifiability, emulsion stability and tissue distribution. Not only do fluorocarbons possess appropriate properties but they are for the most part non-toxic. One chief advantage of the CSF circulation route is that most or all of the antimicrobial formulation can be removed by washing at the time of treatment termination. In this way long term cellular retention of oxygenating liquids, as previously noted for liver and reticuloendothelial cells in vascular circulations, can be avoided.

Poly-fluorinated, oxygen-carrying compounds are known in the art. The basic requirement is effectiveness in carrying physiologically useful amounts of oxygen. Factors involved in selecting preferred such compounds include oxygen capacity, tissue retention (preferably minimized), emulsion stability, toxicity, and the like. Such compounds are described, for example, in: Riess et al., "Design Synthesis and Evaluation of Fluorocarbons and Surfactants for In vivo Applications New Perfluoroalkylated Polyhydroxylated Surfactants", Biomat. Artif. Cells Artif. Organs, 16:421-430 (1988); Riess, Reassessment of criteria for the Selection of Perfluorochemicals for Second-Generation Blood Substitutes: Analysis of Structure/Property Relationships, Artificial Organs 8:44-56 (1984); Riess, et al., Design, Synthesis and Evaluation of Fluorocarbons and Surfactants for In Vivo Applications New Perfluoroalkylated Polyhydroxylated Surfactants, Biomat. Artif. Cells Artif Organs 16:421-430 (1988); Riess, et al., Solubility and Transport Phenomena in Perfluorochemicals Relevant to Blood Substitution and Other Biomedical Applications, Pure & Applied Chem., 54:2383-2406 (1982); Yamanouchi, et al., Quantitative Structure-In Vivo Half-Life Relationships of Perfluorochemicals for Use as Oxygen Transporters, Chem., Pharm. Bull., 33:1221-1231 (1985); Lowe, et al., Perfluorochemicals: Blood Substitutes and Beyond Adv. Mater, 3:87-93 (February, 1991); Riess, et al., Fluorocarbon-Based In Vivo Oxygen Transport and Delivery Systems Vox Sang, 61:225-239 (December 1991); and Weers, et al., U.S. Pat. No. 5,914,352.

Among preferred poly-fluorinated, oxygen-carrying compounds are those of the formula

Cm Fm+1 --CH=CH--Cn Fn+1,

where m and n or independently at least 1 and m+n equals 6 to 10. Preferably, the double bond is trans. One preferred poly-fluorinated, oxygen-carrying compound is trans-Bis-perfluorobutyl ethylene (m and n each equal 4), which is also known as F44E. F44E formulations have a 25% greater oxygen carrying capacity than that of a prior nutrient solution made with perfluorodecalin, Bell et al., Neurology 37:133, 1987. Formulations comprising F44E are less viscous and relatively easier to perfuse.

Also preferred are those of the formula

Cm Fm+1 --O--Cn Fn+1,

where m and n or independently at least 1 and m+n are equals 6 to 9 (or 8). One of the perfluoro alkyls can be substituted with a halo from Br (preferably), Cl or I. Further preferred are those of the formula

Cm Fm+1 --R,

where m is 8 (or 10) to 12 and R is Br, Cl, I, or C1 -C3 alkyl.

Besides fluorocarbon based products, cell-free hemoglobin and liposome encapsulated hemoglobin may also be used as artificial oxygen carriers. Hemoglobin is a 4 subunit protein that is the naturally occurring oxygen carrier in red blood cells. Cell-free hemoglobin rapidly dissociates in the bloodstream, so artificial hemoglobins are chemically modified to prevent breakdown. Artificial hemoglobins can be the product of surface modification, crosslinkage, or polymerization. The production and use of cell-free hemoglobin is detailed in U.S. Pat. Nos. 5,438,041; 5,770,727; 5,952,470; 5,691,453; 5,618,919; 5,599,907; 5,739,011; 5,563,254; 5,449,759; 5,128,452; 5,827,693, and 5,312,808. Hemoglobin can also be prevented from degradation by being encapsulated within a protective barrier, as in the case with liposome encapsulated hemoglobin, the production and use of which is presented in U.S. Pat. Nos. 5,049,391; 4,133,874; 4,776,991; 4,425,334, and 4,532,130.

Claim 1 of 28 Claims

What is claimed:

1. A method of treating in an animal infection of cerebrospinal tissue characterized by a risk of death, the method comprising:

a. injecting a physiologically acceptable fluid for cerebrospinal perfusion into a first catheter into the cerebrospinal pathway, which fluid for cerebrospinal perfusion has an infection treating effective amount an antimicrobial agent, the antimicrobial agent selected for effectiveness against the infection as identified or diagnosed;

b. withdrawing fluid at a second catheter into the cerebrospinal pathway to create a flow and flow pathway between the first and second catheters; and

c. maintaining the flow for a period of time adapted to perfuse at least 1 CSF volume.




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