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WO2003015710A2 - Therapies et systemes combinant l'administration de medicament et l'extraction de liquide cephalorachidien - Google Patents

Therapies et systemes combinant l'administration de medicament et l'extraction de liquide cephalorachidien Download PDF

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Publication number
WO2003015710A2
WO2003015710A2 PCT/US2002/026435 US0226435W WO03015710A2 WO 2003015710 A2 WO2003015710 A2 WO 2003015710A2 US 0226435 W US0226435 W US 0226435W WO 03015710 A2 WO03015710 A2 WO 03015710A2
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WIPO (PCT)
Prior art keywords
csf
conduit
space
therapeutic agent
implantable
Prior art date
Application number
PCT/US2002/026435
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English (en)
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WO2003015710A3 (fr
Inventor
Dawn Mcguire
Tom Saul
Denise F. Gottfried
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Eunoe, Inc.
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Priority to AU2002313778A priority Critical patent/AU2002313778A1/en
Publication of WO2003015710A2 publication Critical patent/WO2003015710A2/fr
Publication of WO2003015710A3 publication Critical patent/WO2003015710A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M3/00—Medical syringes, e.g. enemata; Irrigators
    • A61M3/02—Enemata; Irrigators
    • A61M3/0233—Enemata; Irrigators characterised by liquid supply means, e.g. from pressurised reservoirs
    • A61M3/0254—Enemata; Irrigators characterised by liquid supply means, e.g. from pressurised reservoirs the liquid being pumped
    • A61M3/0258—Enemata; Irrigators characterised by liquid supply means, e.g. from pressurised reservoirs the liquid being pumped by means of electric pumps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M27/00—Drainage appliance for wounds or the like, i.e. wound drains, implanted drains
    • A61M27/002—Implant devices for drainage of body fluids from one part of the body to another
    • A61M27/006—Cerebrospinal drainage; Accessories therefor, e.g. valves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/04—Liquids
    • A61M2202/0464—Cerebrospinal fluid

Definitions

  • the present invention relates to methods and devices for the treatment of Alzheimer's disease (AD) and other diseases of the central nervous system associated with the accumulation of substances, such as proteins, peptides, and waste products.
  • the present invention relates to methods and systems for the concurrent delivery of therapeutic compounds to the central nervous system (CNS) and removal of the compounds and/or other substances related to the compounds or disease from the CNS.
  • CNS central nervous system
  • Cerebrospinal fluid is secreted by the choroid plexus and fills the four cerebral ventricles.
  • CSF circulates from ventricular sites of secretion, around the spinal cord and over the convexity of the brain, where the CSF is absorbed into the superior sagittal sinus by way of specialized processes in the meninges (e.g., the arachnoid granulations).
  • the CSF is continuous with brain interstitial (extracellular) fluid, and solutes, including macromolecules, are exchanged freely between CSF and interstitial fluid. This exchange is driven primarily by concentration gradients, osmotic pressures and, in the case of proteins, oncotic pressures, and bulk flow.
  • Cytotoxic and pro-inflammatory secretions can cause further cell injury and neuronal cell death.
  • Diseases for which abnormal protein aggregation appears to be a critical component of pathophysiology include, but are not limited to, Alzheimer's disease, Parkinson's disease, Progressive Supranuclear Palsy, Lewy-body dementia, Frontotemporal Dementia, Creutzfeld- Jacob disease and other "prion" diseases, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and the like.
  • therapeutic agents designed to reduce or reverse protein aggregation or abnormal processing require two elements. First, they must be able to reach therapeutic, yet nontoxic concentrations in brain tissue. Second, any products resulting from the breaking up of abnormal protein aggregates must be cleared effectively from the CNS. Protein aggregation is concentration dependent. If protein breakdown products are not cleared from the brain interstitial fluid, re-aggregation is likely, and the net therapeutic effect of "disaggregation" will be lost. In other words, soluble products resulting from the action of therapeutic agents in the CNS diffuse down a concentration gradient into the CSF. If normal CSF circulation and turnover is impaired, as has been shown to be the case with normal aging; then the accumulation of the "macromolecular debris" will severely limit clearance of such products from brain interstitial fluid.
  • AD Alzheimer's disease
  • Such accumulation is presently believed to result from a failure of the mechanisms governing clearance of these substances, failure of the mechanisms that inhibit aggregation of the substances, or failure of other clearance mechanisms resulting from altered cerebrospinal fluid (CSF) dynamics. Such alterations may include diminished CSF production, diminished CSF turnover, increased resistance to absorption of CSF, and altered CSF outflow patterns.
  • CSF cerebrospinal fluid
  • ABeta production (such as inhibitors of gamma secretase, beta secretase or aspartic proteases) or break up ABeta plaques (such as anti-aggregating monoclonal antibodies).
  • Other drugs or biologies are being developed to block tangle-prone alterations (e.g., hyperphosphorylation) of Tau protein.
  • Anti-inflammatory or antioxidant therapies are being developed to reduce the inflammation associated with the amyloidosis and tauopathy of AD.
  • the stem cell or neuronal precursor cell therapies are being developed to enhance neuroregeneration in damaged brain. The success of these potential treatments will likely be limited by the difficulty in delivering them safely to the target tissue.
  • Implantable pumps for delivering drugs to the brain for the treatment of Alzheimer's disease are described in U.S. Patent Nos. 5,846,220 and 6,056,725, and published U.S. Patent Application US2001/0023709A1.
  • Implantable shunts for draining cerebrospinal fluid (CSF) to treat Alzheimer's disease are described in U.S. Patent Nos. 5,980,480; 6,264,625B1; and 6,383,159B1, assigned to the assignee of the present application, the full disclosures of which are incorporated herein by reference.
  • Systems and methods for exchanging CSF for the treatment of drug overdoses and other conditions are described in published PCT Application No.
  • the present invention provides methods and systems for treating diseases of the central nervous system (CNS).
  • the present invention is intended to treat patients suffering from conditions, which are treatable by administering a therapeutic agent to a patient's cerebrospinal fluid wherein the activity or efficacy of the therapeutic agent is enhanced by removing CSF from the patient concurrently or sequentially with the administration of the therapeutic agent.
  • Delivery of the therapeutic agent directly to the CSF achieves one level of enhancement by bypassing the blood-brain barrier which can inhibit therapeutic agents delivered by other routes.
  • the removal of CSF concurrently or sequentially with the delivery of the therapeutic agent can further enhance the activity of the therapeutic agent in one or more ways.
  • the removal of CSF can remove and lower the concentration of an endogenous substance responsible for the condition being treated.
  • the removal of CSF can lower the concentration of harmful byproducts of the treatment, including metabolites of the therapeutic agent, toxic products generated by the action of the therapeutic agent on the endogenous pathogenic agent, and breakdown products of the endogenous substance which may reform or reaggregate if left in the CSF.
  • the latter mechanism is typified by the treatment of patients suffering from Alzheimer's disease by therapeutic agents which breakdown the ABeta plaque. In those instances, the breakdown products of the ABeta plaque can reform into the plaque if not removed from the CSF.
  • Methods according to the present invention are thus suitable for treating patients suffering from conditions treatable by administering a therapeutic agent to a patient's cerebrospinal fluid.
  • the methods comprise delivering the therapeutic agent to the patient's CSF and concurrently or sequentially removing CSF from a CSF space of the patient.
  • Delivering the therapeutic agent may comprise passing the drug through an implanted conduit to an administration site in the patient's CSF space, typically the lateral ventricles, a lumbar region, other central nervous system cisternal spaces, or the like.
  • passing the agent through the implanted conduit may comprise pumping the agent from an implanted reservoir connected to the conduit, injecting the agent to an implanted port connected to the implanted conduit, or the like.
  • Removing CSF from the patient's CSF space typically comprises draining
  • the CSF through a conduit implanted at a removal site in the CSF space, typically the lateral ventricles, a lumbar region, other central nervous system cisternal spaces, or the like.
  • the removal site may be the same as or different than the administration site, as described in more detail below.
  • the implanted conduit may lead to an internal or external drainage site, typically to an internal drainage site, such as the peritoneal cavity, right atrium, pleural cavity, bladder, or the like.
  • the use of such implanted conduits will usually provide for a continuous, low- flow drainage of the CSF from the CSF space, typically being in the range from 15 ml to 1500 ml in each one-day period, preferably being in the range from 40ml to 300 ml in each one-day period, and more preferably being in the range from 60 ml to 100 ml in each one-day period.
  • the methods of the present invention are not limited to continuous removal of CSF, and may instead comprise a periodic removal which may be coordinated or synchronized to occur concurrently with or shortly after the administration of the therapeutic agent, particularly when it is desired to remove substances produced by the administration of the therapeutic agent.
  • the therapeutic agents utilized in the methods of the present invention may be selected to have a wide variety of therapeutic activities.
  • therapeutic agents may be selected to lyse or breakdown toxic CSF substances to produce breakdown products in the CSF. Removal of the CSF will thus lower the concentrations of both the toxic CSF substance and the breakdown products of the toxic CSF substance, which breakdown products may themselves be toxic, may be otherwise deleterious, or may be subject to reaggregation or reformation of the toxic CSF substance which has been lysed.
  • the therapeutic agent may be selected to lyse the ABeta plaque, or the precursors to ABeta plaque, such as anti-aggregating enzymes and antibodies which break down plaque.
  • Such therapeutic agents include neprilysin, insulin degrading enzyme, endothelin converting enzyme, angiotensin converting enzyme, or pharmacologies which activate these proteolytic enzmes which lyse the ABeta plaque, or the like. Removal of the breakdown products of the ABeta plaque or its precursors can thus reduce the opportunity for the breakdown products to reform into the ABeta plaque or its precursors.
  • the methods of the present invention may be utilized with therapeutic agents, which are themselves potentially toxic, particularly at elevated concentrations or when present in the CSF for prolonged periods.
  • therapeutic agents which are themselves potentially toxic, particularly at elevated concentrations or when present in the CSF for prolonged periods.
  • the residence time of those agents in the CSF can be controlled to permit efficacy while preventing or inhibiting any deleterious effects from the therapeutic agents themselves.
  • caspase 3 inhibitors such as lithium, which reduce apoptotic cell death in several neurodegenerative diseases, may be administered.
  • the residence time and concentration of the agent may then be moderated by the rate of CSF drainage.
  • the methods of the present invention provide an enhancement or synergy of the independent actions of the therapeutic agent and the CSF removal.
  • the combined therapeutic action of the two treatment modalities can be more effective than either modality alone.
  • the administration of an anti -ABeta antibody in order to clear cerebral amyloid into the peripheral circulation would be synergistic with CSF drainage since the residence times of both the antibody and the solubilized ABeta in the CSF would be minimized; thus limiting the inflammatory response to the antibody and the deleterious effects of the solubilized ABeta.
  • Such a treatment offers benefit in a number of diseases associated with primary or secondary ABeta accumulations, such as Alzheimer's disease, frontotemporal dementias, and hereditary cerebral hemorrage with amyloidosis of the Dutch type. Treatments using antibodies to tau and tau mutations associated with various tauopathies, including, frontotemporal dementias and progressive supranuclear palsy would benefit similarly.
  • Beta synuclein or local dopaminergic system inhibitors may be administered to interfere with alpha synuclein aggregation in such diseases as Parkinson's and Lewy body dementia.
  • the methods of the present invention will allow for control or modulation of the concentration of the therapeutic agent, particularly potentially toxic agents, such as secretases, immune system inhibitors, vasopeptidases and the like.
  • Particular agents include alpha secretase and gamma secretase inhibitors, which block the normal pathways of amyloid formation.
  • Such a treatment would have benefit in diseases associated with amyloidosis as indicated above.
  • Other such agents include imunomodulators, immunosupressants, and anti-inflammatory agents whose residence times should be controlled in order to to preserve normal, functional brain immunity.
  • Systems according to the present invention will provide for concurrent or sequential delivery of the therapeutic agent to a patient's CSF space and drainage of CSF from the CSF space.
  • Systems will comprise a first conduit having an end which implantable in the patient's CSF space, a second conduit having an end which is implantable outside of the CSF space, and means for delivering the therapeutic agent to the CSF space through the first conduit and for removing CSF from the CSF space through the second conduit.
  • the means for draining will further comprise a chamber containing the therapeutic agent which is connected to the first conduit and the means for removing CSF will comprise a flow control valve attachable between the first and second conduits.
  • systems according to the present invention may comprise a first conduit having an end implantable in a patient's CSF space, a second conduit having an end implantable in the CSF space, and a third conduit having an end implantable outside of the CSF space.
  • Systems will include means for delivering a therapeutic agent to the CSF space through the first conduit, removing CSF through the second conduit, and disposing of the removed CSF through the third conduit.
  • Such systems which have two conduits implantable in the CSF space are advantageous since they permit the concurrent delivery of the therapeutic agent and removal of the CSF.
  • first and second conduits may be implanted within different regions of the CSF space to assure that the drug will have a minimum residence time within the CSF space and/or to induce preferred flow patterns of the therapeutic agent from the location in the CSF space where the first conduit is implanted to the location where the second conduit is implanted.
  • Such systems may further comprise chambers containing the therapeutic agent connectable to the second conduit, flow mechanisms disposed between the chambers in the first conduit, flow control mechanisms disposed between the second and third conduits, and the like.
  • Alzheimer's disease in a patient may comprise a therapeutic agent which breaks down the ABeta plaque or fibrillar ABeta to produce breakdown products in the patient's cerebrospinal fluid.
  • Such systems further comprise means for removing CSF to lower the concentration of the ABeta breakdown products to, for example, reduce the likelihood that such breakdown products may reform into the ABeta plaque or precursors of the ABeta plaque.
  • Suitable therapeutic agents include neprilysin, and vasopeptidases such as insulin degrading enzyme, endothelin converting enzyme, angiotensin converting enzyme, or pharmacologies which activate these proteolytic enzymes which lyse the ABeta plaque, and the like.
  • the CSF removal means will typically comprise implantable shunts, usually comprising shunts which are able to drain from 15 ml to 1500 ml of CSF in a day, usually from 40 ml to 300 ml of CSF in a day, and preferably from 60 ml to 100 ml of CSF in a day.
  • implantable shunts usually comprising shunts which are able to drain from 15 ml to 1500 ml of CSF in a day, usually from 40 ml to 300 ml of CSF in a day, and preferably from 60 ml to 100 ml of CSF in a day.
  • Such shunts will have one end implanted at a location in the patient's CSF space and another end implanted in the peritoneal cavity.
  • the shunts will include means for delivering the therapeutic agent to a desired location in the patient's CSF space.
  • FIG. 1 is an illustration of the CSF space including the brain and the spinal column.
  • Fig. 2 is a block diagram of a system constructed in accordance with the principles of the present invention for removing CSF from the CSF space and delivering a therapeutic agent to the CSF space using a common conduit.
  • FIG. 3 is a block diagram illustrating a system similar to that shown in Fig. 2 comprising a ventricular catheter for draining CSF and delivering a therapeutic agent to a ventricle of the brain and a peritoneal catheter for draining the removed CSF to the peritoneal cavity.
  • FIG. 4 is block diagram illustrating a third system constructed in accordance with the principles of the present invention and including a ventricular catheter for delivering a therapeutic agent using a pump, a lumbar catheter for removing CSF from the lumbar region of the CSF space, and a peritoneal catheter for draining the removed CSF to the peritoneal cavity.
  • Fig. 5 illustrates a system similar to that shown in Fig. 4 and further including a synchronization mechanism to coordinate the delivery of a therapeutic agent to the CSF space with removal of CSF from the CSF space.
  • CNS central nervous system
  • the methods and systems are particularly intended for the treatment of Alzheimer's disease and other conditions which are caused by or otherwise related to the retention and/or excessive accumulation of toxic and other substances in the CSF.
  • the present invention will be useful for treating other conditions resulting from the accumulation of toxic substances and resulting lesions in the patient's brain, such as Down's Syndrome, hereditary cerebral hemorrhage with amyloidosis of the
  • HCVWA-D Dutch-Type
  • Other treatable conditions relating to the presence or excessive accumulation of potentially harmful substances include epilepsy, Parkinson's disease, Progressive Supranuclear Palsy, Lewy-body dementia, Frontotemporal Dementia, Creutzfeld- Jacob disease and other "prion" diseases, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and the like.
  • Devices and methods of the present invention are particularly intended for treating conditions in patients having "normal" intracranial pressures, i.e. intracranial pressures below 200 mm H O when the patient is reclining and above -170 mm H 2 O when the patient is upright (where the pressures are measured relative to the ambient).
  • patients suffering from hydrocephalus will have constant or periodic elevated intracranial pressures above 200 mm H O (when reclining), often attaining levels two or three times the normal level if untreated.
  • the devices and methods of the present invention are generally not intended for the treatment of patients having chronically elevated intracranial pressures in general and patients suffering from hydrocephalus in particular.
  • the brain and spinal cord are bathed in cerebrospinal fluid (CSF) and encased within the cranium and vertebral column inside a thin membrane known as the meninges (Fig. 1).
  • the space within the meninges M which is the three-membrane complex enveloping the brain and spinal cord, consists of the subarachnoid space (SAS), including the ventricles (including the lateral ventricle (LV), third ventricle (3V), and fourth ventricle (4V)), the vertebral column, and the brain interstitial spaces.
  • SAS subarachnoid space
  • the total space within the meninges M is referred to herein as the "CSF space.”
  • the volume of the brain intracranial spaces is on average about 1700 ml.
  • the volume of the brain is approximately 1400 ml, and the volume of the intracranial blood is approximately 150 ml.
  • the remaining 150 ml is filled with CSF (this volume will typically vary within 60 ml to 290 ml).
  • the CSF circulates within the CSF space.
  • CSF is formed principally by the choroid plexis, which secrete about 80% of the total volume of the CSF.
  • the sources of the remainder are the vasculature of the subependymal regions, and the pia matter.
  • the total volume of the CSF is normally renewed several times per day, so that about 500 ml are produced every 24 hours (equivalent to about 20 ml/hr or 0.35 ml/min) in healthy adults. The production rate varies in the old and the young, declining in the elderly.
  • the cerebrospinal fluid is absorbed through the arachnoid villi, located principally over the superior surfaces of the cerebral hemispheres. Some villi also exist at the base of the brain and along the roots of the spinal nerves.
  • the absorptive processes include bulk transport of large molecules and as well as diffusion across porous membranes of small molecules. The production and absorption of CSF are well described in the medical literature. See, e.g., Adams et al. (1989) "Principles of Neurology," pp. 501-502.
  • CSF While CSF is naturally absorbed and removed from circulation, as just described, it is presently believed that certain toxic or other substances may be present in the CSF, such as those associated with Alzheimer's disease, and may accumulate or persist to an extent which can cause Alzheimer's disease or other disorders. Such substances are either produced in excess, removed at a rate slower than their production rate, or not properly circulated so that they accumulate or stagnate and increase in toxicity and/or reach a threshold concentration in which they become toxic in the brain or elsewhere within CSF space.
  • the present invention will employ known and as-yet-to-be-developed therapeutic agents and drugs intended for the treatment of diseases and conditions of the CNS, including those listed above.
  • the therapeutic agents will be directed at a toxic or other substance present in the CSF space, including the CSF and brain parenchyma (target tissue), which is responsible in some way for the condition to be treated.
  • the therapeutic agents could be neuronal precursors, stem cells, embryoid bodies, catalysts, growth factors, enzymes, and other substances.
  • Such therapeutics may, in themselves, result in production of toxic or otherwise deleterious contribution to the condition to be treated.
  • CSF drainage according to the present invention will benefit by learing such products.
  • CSF drainage according to the present invention will benefit by learing such products. For example, in the case of
  • the therapeutic agents could be directed at any of the proteins or other factors which lead to the formation of the ABeta plaque or other materials responsible for the condition.
  • the disaggregation produces soluble ABeta proteins which, if not cleared, are toxic to selective brain cell populations.or soluble ABeta proteins, if not cleared, are toxic to selective brain cell populations.
  • the therapeutic agent is an enzyme or monoclonal antibody which is directed against ABeta plaque, breaking up the plaque to produce breakdown products.
  • the therapeutic agent acts directly on one of the substances directly responsible for the condition, while the removal of CSF removes both endogenous precursors to the ABeta plaque as well as the breakdown products of the plaque, which are subject to reaggregation if not removed.
  • the therapeutic agents may be of any conventional form, including small molecule drugs, typically having a molecular weight below 2 kilodaltons, large molecule drugs, biological agents such as proteins, nucleic acids, embryonic and other stem cells or progenitor cells, other therapeutic cellular products, and the like.
  • the therapeutic agents may be incorporated into conventional forms for delivery, typically being present in a liquid carrier at a concentration selected to permit delivery of a desired dosage using the methods and systems described below. While the concentrations and volumes of the therapeutic agents delivered will vary greatly depending on the nature of the particular agent, the concentrations will often be in the range from 1 mM to 1 pM, with total dosage delivered in any one-day period being in the range from 1 mM to 1 nM. [39] The therapeutic agents may be delivered continuously or discontinuously.
  • the therapeutic agents may be delivered to the CSF space as infrequently as once per day, once per week, or even less often, typically using an injection port or programmable delivery system having only a limited amount of agent to be delivered, but may also be delivered on a substantially continuous basis, typically using a pump having a replenishable reservoir for holding the therapeutic agent.
  • CSF removal from the CSF space will be performed continuously or semi-continuously. CSF removal will typically be accomplished using implanted catheters or cannulas having at least one port or access point implanted within the CSF space, typically, in a ventricle or in the lumbar space, and at least one other port or drainage point implanted at a disposal site in the body, typically the peritoneal cavity.
  • Controlled, typically low, drainage rates are preferred, usually being in the range from 15 ml/day to 1500 ml/day, typically from 40 ml/day to 300 ml/day, preferably from 60 ml/day to 100 ml/day.
  • a variety of catheter systems suitable for achieving such drainage rates are described in patents and pending patent applications of the assignee herein. See, for example, U.S. Patent Nos. 5,980,480; 6,264,625B1; and 6,383,159B1; as well as co-pending application nos. 10/ ; (Attorney Docket No. 18050-001000), the full disclosures of which are incorporated herein by reference.
  • the systems of the present invention will combine and integrate the capabilities for both delivering the therapeutic agent to the CSF space and draining CSF from the CSF space.
  • the systems will be able to coordinate and synchronize the delivery of therapeutic agent with the removal of CSF, e.g., by draining CSF in a coordinated fashion with delivering the therapeutic agent, typically during and/or immediately after the delivery of the therapeutic agent.
  • the combined systems may combine one or more component which act to both deliver therapeutic agent and drain CSF.
  • the systems may combine a single ventricular catheter for delivering the therapeutic agent to the CSF and removing CSF from the CSF space.
  • the catheter may have a single lumen, in which case therapeutic agent delivery and CSF removal would have to be performed successively.
  • the ventricular catheter could have two or more lumens, enabling concurrent therapeutic agent delivery and CSF removal.
  • the systems will also often include a single "flow controlling" component or module which acts to both control the drainage of CSF from the CSF space and to deliver the therapeutic agent to the CSF space.
  • the flow control module will typically also include a reservoir for holding the drug, a percutaneously accessible port for replenishing the reservoir or directly injecting the therapeutic agent, as well as the components for controlling the drainage volumes and rates.
  • systems 10 constructed in accordance with the principles of the present invention will provide at least one access point or "input space” 12 within the CSF space and at least one other access point or “output space” 14 at a body location outside of the CSF space.
  • the input space 12 will provide both delivery of the therapeutic agent and drainage of the CSF from the CSF space, where delivery of the therapeutic agent is controlled by a fluid input device 16, such as a pump, injection port, or the like, and drainage of the CSF to the output space is modulated by a fluid control device 18.
  • a fluid input device 16 such as a pump, injection port, or the like
  • Suitable injection ports are described, for example, in U.S. Patent Nos. 5,053,031; 5,057,084; and 6,258,079, the full disclosures of which are incorporated herein by reference.
  • Suitable fluid control devices for controlling drainage of the CSF are described in the patents and pending applications of the assignee of the present application, as listed above.
  • the fluid input device 16 and fluid control device 18 may be connected to the input space 12 and output space 14 using suitable connection conduits, such as ventricular catheters and peritoneal catheters, as also described in the patents and pending applications of the assignee of the present application, as listed above.
  • a first exemplary system 30 incorporating the principles of the present invention is illustrated in Fig. 3.
  • a ventricular catheter 32 is implanted at one end in the patient's ventricle and connected at its other end to an antechamber 34 and fluid control device 36.
  • the antechamber 34 comprises a reservoir which is filled or fillable with the desired therapeutic agent which can be delivered to the ventricle through the ventricular catheter, using either a common lumen which also provides for drainage or a separate lumen specifically intended for the delivery of the agent.
  • the therapeutic agent will typically be delivered using a pump in the fluid control device 36 which may be powered by a motor, by patient motion, patient muscular contraction, or the like.
  • the ventricular catheter 32 also provides for drainage of CSF from the ventricle, where the drainage rate and timing are controlled by the fluid control device 36.
  • the CSF drains to the peritoneal cavity through a separate peritoneal catheter 38.
  • Particular examples of suitable fluid control devices 36 are provided in the patents and pending applications of the assignee of the present application, listed above.
  • System 50 shown in Fig. 4 differs from systems 10 and 30 in that it includes separate subsystems for delivering the therapeutic agent and for draining CSF.
  • the therapeutic agent is delivered to the CSF space, typically to ventricle 12 through a ventricular catheter 52 by a fluid pump 54 connected to a reservoir 56.
  • the reservoir 56 will typically be replenishable but in some instances could include only a single dosage or limited number of dosages of the therapeutic agent.
  • System 50 includes a separate lumbar catheter 60 for draining CSF from a lumbar space 62 to a fluid control device 64.
  • the peritoneal catheter 66 is provided to drain the CSF from the fluid control device 64 to the peritoneal cavity 14, as with prior systems.
  • the synchronization mechanism may perform a variety of functions, but will typically at least coordinate the timing and/or relative flow rates provided by the fluid pump 54 and fluid control device 64. For example, in many instances it will be desirable to deliver the therapeutic agent on a predetermined schedule and dosage level.
  • the synchronization mechanism 72 may both control the fluid pump 54 to provide the desired delivery schedule and dosages, and may further control the fluid control device 64 to drain the CSF in a coordinated manner. As described above, for potentially toxic therapeutic agents, it may desirable to initiate or increase the removal of CSF at or immediately following the delivery of the therapeutic agent. Conversely, for therapeutic agents requiring long residence times, it may be desirable to decrease or stop the CSF drainage at or following the delivery of the therapeutic agent.

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Abstract

Selon l'invention, des maladies et d'autres états pathologiques du système nerveux central sont traités par administration d'un agent thérapeutique dans un espace occupé par le fluide céphalorachidien et, de manière simultanée ou séquentielle, évacuation du fluide céphalorachidien de l'espace qu'il occupe. Des systèmes prévus à cet effet comprennent au moins un cathéter implantable servant à accéder à l'espace occupé par le fluide céphalorachidien, en général un espace ventriculaire ou lombaire, ainsi qu'au moins un cathéter servant à évacuer le fluide céphalorachidien vers un autre emplacement, par exemple vers la cavité péritonéale. Des pompes implantables servent à administrer l'agent thérapeutique par l'intermédiaire du cathéter donnant accès à l'espace occupé par le fluide céphalorachidien et des mécanismes de régulation de débit implantables sont utilisés pour réguler le débit et le volume du fluide céphalorachidien évacué dudit espace.
PCT/US2002/026435 2001-08-21 2002-08-19 Therapies et systemes combinant l'administration de medicament et l'extraction de liquide cephalorachidien WO2003015710A2 (fr)

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AU2002313778A AU2002313778A1 (en) 2001-08-21 2002-08-19 Combined drug and csf removal therapies and systems

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US6905474B2 (en) 2000-09-11 2005-06-14 Csf Dynamic A/S Fluid shunt system and a method for the treatment of hydrocephalus
WO2008031911A1 (fr) * 2006-09-14 2008-03-20 Fundación Para Investigaciones Neurológicas Dispositif pour l'élimination de substances neurotoxiques
WO2011114260A1 (fr) 2010-03-19 2011-09-22 Pfizer Inc. Système de purification de liquide céphalorachidien
US8435204B2 (en) 2006-10-09 2013-05-07 Neurofluidics, Inc. Cerebrospinal fluid purification system
US20150038948A1 (en) * 2013-07-31 2015-02-05 G-Tech Electronic Research & Development, LLC Apparatus and use of a neurochemisrty regulator device insertable in the cranium for the treatment of cerebral cortical disorders
WO2015049588A3 (fr) * 2013-10-01 2015-06-18 Md Start Sa Systèmes et procédés de déplacement et de circulation de fluide pour traiter la maladie d'alzheimer
CN107088257A (zh) * 2017-04-27 2017-08-25 哈尔滨医科大学 一种y型两用双腔两囊引流器
US10632237B2 (en) 2006-10-09 2020-04-28 Minnetronix, Inc. Tangential flow filter system for the filtration of materials from biologic fluids
US10850235B2 (en) 2006-10-09 2020-12-01 Minnetronix, Inc. Method for filtering cerebrospinal fluid (CSF) including monitoring CSF flow
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US11147540B2 (en) 2015-07-01 2021-10-19 Minnetronix, Inc. Introducer sheath and puncture tool for the introduction and placement of a catheter in tissue
US11278657B2 (en) 2019-04-11 2022-03-22 Enclear Therapies, Inc. Methods of amelioration of cerebrospinal fluid and devices and systems therefor
US20220096744A1 (en) * 2020-09-29 2022-03-31 Enclear Therapies, Inc. Subarachnoid fluid management method and system
US11419921B2 (en) 2018-07-23 2022-08-23 Enclear Therapies, Inc. Methods of treating neurological disorders
US11577060B2 (en) 2015-12-04 2023-02-14 Minnetronix, Inc. Systems and methods for the conditioning of cerebrospinal fluid
US11752200B2 (en) 2018-07-23 2023-09-12 Enclear Therapies Inc. Methods of treating neurological disorders
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US5957912A (en) * 1998-04-16 1999-09-28 Camino Neurocare, Inc. Catheter having distal stylet opening and connector
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US6913589B2 (en) * 2002-01-14 2005-07-05 Codman & Shurtleff, Inc. Multi-catheter insertion device and method

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US6905474B2 (en) 2000-09-11 2005-06-14 Csf Dynamic A/S Fluid shunt system and a method for the treatment of hydrocephalus
WO2008031911A1 (fr) * 2006-09-14 2008-03-20 Fundación Para Investigaciones Neurológicas Dispositif pour l'élimination de substances neurotoxiques
ES2307396A1 (es) * 2006-09-14 2008-11-16 Fundacion Para Investigaciones Neurologicas (Fin) Sistemas de eliminacion de sustancias neurotoxicas causantes de enfermedades neurodegenerativas mediante su atrapamiento selectivo por inmunoafinidad en el liquido cefalo-raquideo circulante.
ES2307396B1 (es) * 2006-09-14 2009-09-30 Fundacion Para Investigaciones Neurologicas (Fin) Sistemas de eliminacion de sustancias neurotoxicas causantes de enfermedades neurodegenerativas mediante su atrapamiento selectivo por inmunoafinidad en el liquido cefalo-raquideo circulante.
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US8435204B2 (en) 2006-10-09 2013-05-07 Neurofluidics, Inc. Cerebrospinal fluid purification system
EP3827841A1 (fr) 2006-10-09 2021-06-02 Neurofluidics, Inc. Système de purification de fluide cérébrospinal
US10850235B2 (en) 2006-10-09 2020-12-01 Minnetronix, Inc. Method for filtering cerebrospinal fluid (CSF) including monitoring CSF flow
US11529452B2 (en) 2006-10-09 2022-12-20 Minnetronix, Inc. Tangential flow filter system for the filtration of materials from biologic fluids
US10632237B2 (en) 2006-10-09 2020-04-28 Minnetronix, Inc. Tangential flow filter system for the filtration of materials from biologic fluids
US10398884B2 (en) 2006-10-09 2019-09-03 Neurofluidics, Inc. Cerebrospinal fluid purification system
US20200046954A1 (en) 2006-10-09 2020-02-13 Neurofluidics, Inc. Cerebrospinal fluid purification system
WO2011114260A1 (fr) 2010-03-19 2011-09-22 Pfizer Inc. Système de purification de liquide céphalorachidien
US20150038948A1 (en) * 2013-07-31 2015-02-05 G-Tech Electronic Research & Development, LLC Apparatus and use of a neurochemisrty regulator device insertable in the cranium for the treatment of cerebral cortical disorders
US9919138B2 (en) 2013-10-01 2018-03-20 Ecole Polytechnique Federale De Lausanne (Epfl) Systems and methods for moving and circulating fluid to treat Alzheimer's disease
US9421348B2 (en) 2013-10-01 2016-08-23 Ecole Polytechnique Federale De Lausanne (Epfl) Systems and methods for moving and circulating fluid to treat alzheimer's disease
WO2015049588A3 (fr) * 2013-10-01 2015-06-18 Md Start Sa Systèmes et procédés de déplacement et de circulation de fluide pour traiter la maladie d'alzheimer
US11147540B2 (en) 2015-07-01 2021-10-19 Minnetronix, Inc. Introducer sheath and puncture tool for the introduction and placement of a catheter in tissue
US12364952B2 (en) 2015-08-05 2025-07-22 Minnetronix, Inc. Tangential flow filter system for the filtration of materials from biologic fluids
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US11577060B2 (en) 2015-12-04 2023-02-14 Minnetronix, Inc. Systems and methods for the conditioning of cerebrospinal fluid
CN107088257B (zh) * 2017-04-27 2023-06-09 哈尔滨医科大学 一种y型两用双腔两囊引流器
CN107088257A (zh) * 2017-04-27 2017-08-25 哈尔滨医科大学 一种y型两用双腔两囊引流器
US11419921B2 (en) 2018-07-23 2022-08-23 Enclear Therapies, Inc. Methods of treating neurological disorders
US11752200B2 (en) 2018-07-23 2023-09-12 Enclear Therapies Inc. Methods of treating neurological disorders
US12350416B2 (en) 2019-04-11 2025-07-08 Enclear Therapies, Inc. Methods of amelioration of cerebrospinal fluid and devices and systems therefor
EP3952947A4 (fr) * 2019-04-11 2024-07-03 Enclear Therapies, Inc. Procédés d'amélioration du liquide céphalorachidien et dispositifs et systèmes à cet effet
US11278657B2 (en) 2019-04-11 2022-03-22 Enclear Therapies, Inc. Methods of amelioration of cerebrospinal fluid and devices and systems therefor
WO2021207457A1 (fr) * 2020-04-08 2021-10-14 Medtronic, Inc. Moyen de traiter la maladie d'alzheimer par rinçage du parenchyme cérébral
US11559626B2 (en) 2020-04-08 2023-01-24 Medtronic, Inc. Means to treat Alzheimer's disease via flushing of brain parenchyma
US20220096744A1 (en) * 2020-09-29 2022-03-31 Enclear Therapies, Inc. Subarachnoid fluid management method and system
US12329930B2 (en) 2020-09-29 2025-06-17 Enclear Therapies, Inc. Subarachnoid fluid management method and system
US12337140B2 (en) 2020-09-29 2025-06-24 Enclear Therapies, Inc. Subarachnoid fluid management method and system with varying rates
JP2023543868A (ja) * 2020-09-29 2023-10-18 エンクリアー セラピーズ， インク． くも膜下液管理方法およびシステム
US20220096743A1 (en) * 2020-09-29 2022-03-31 Enclear Therapies, Inc. Subarachnoid fluid management method and system with varying rates

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