U.S. patent application number 11/380157 was filed with the patent office on 2008-04-03 for cerebrospinal fluid shunt having long term anti-occlusion agent delivery.
This patent application is currently assigned to Medtronic, Inc.. Invention is credited to Edouard Koullick, Paul V. Trescony.
Application Number | 20080082036 11/380157 |
Document ID | / |
Family ID | 38335732 |
Filed Date | 2008-04-03 |
United States Patent
Application |
20080082036 |
Kind Code |
A1 |
Trescony; Paul V. ; et
al. |
April 3, 2008 |
CEREBROSPINAL FLUID SHUNT HAVING LONG TERM ANTI-OCCLUSION AGENT
DELIVERY
Abstract
The invention includes a shunt for at least partial implantation
into a patient that includes an elongated conduit having at least
one lumen therethrough, that includes a proximal end for receipt of
bodily fluids for flow through the shunt and a distal end for
discharge of the bodily fluids from the shunt, and a long term
source of at least one occlusion resistant agent, wherein said at
least a portion of the at least one occlusion resistant agent can
permeate through at least a portion of the elongated conduit. The
invention also includes kits and systems.
Inventors: |
Trescony; Paul V.;
(Champlin, MN) ; Koullick; Edouard; (Golden
Valley, MN) |
Correspondence
Address: |
IPLM GROUP, P.A.
POST OFFICE BOX 18455
MINNEAPOLIS
MN
55418
US
|
Assignee: |
Medtronic, Inc.
Minneapolis
MN
|
Family ID: |
38335732 |
Appl. No.: |
11/380157 |
Filed: |
April 25, 2006 |
Current U.S.
Class: |
604/8 ;
604/34 |
Current CPC
Class: |
A61M 2025/0019 20130101;
A61M 25/007 20130101; A61M 27/006 20130101; A61L 2300/42 20130101;
A61L 2300/416 20130101; A61L 2300/41 20130101; A61L 31/16
20130101 |
Class at
Publication: |
604/8 ;
604/34 |
International
Class: |
A61F 2/20 20060101
A61F002/20; A61M 1/00 20060101 A61M001/00 |
Claims
1. A shunt for at least partial implantation into a patient
comprising: an elongated conduit having at least one lumen
therethrough, wherein said elongated conduit comprises a proximal
end for receipt of bodily fluids for flow through said shunt and a
distal end for discharge of said bodily fluids from said shunt; and
a long term source of at least one occlusion resistant agent,
wherein said at least a portion of said at least one occlusion
resistant agent can permeate through at least a portion of the
elongated conduit.
2. The shunt according to claim 1 wherein the long term source
comprises a refill port that is in fluid communication with the
lumen of the elongated conduit.
3. The shunt according to claim 2, wherein the refill port includes
a percutaneous access port.
4. The shunt according to claim 1 wherein said elongated conduit
comprises at least two lumens therethrough.
5. The shunt according to claim 4, wherein said at least two lumens
comprise: a fluid conduit that functions as a conduit for the at
least one occlusion resistant agent; and a drainage conduit that
functions as a conduit for CSF drainage.
6. The shunt according to claim 5, wherein the fluid conduit
comprises a surface through which the at least one occlusion
resistant agent can permeate.
7. The shunt according to claim 5 further comprising a refill port
that is in fluid communication with the fluid conduit.
8. The shunt according to claim 7, wherein the refill port includes
a percutaneous access port.
9. The shunt according to claim 5, wherein at least a portion of
the fluid conduit contains at least one absorptive agent and the at
least one occlusion resistant agent.
10. The shunt according to claim 9, wherein the absorptive agent is
alumina, silica, activated charcoal, cross-linked polystyrene
beads, high molecular weight gels, silicone polyurethanes,
open-celled foams or some combination thereof.
11. The shunt according to claim 4, wherein at least a portion of
the fluid conduit contains a saturated solution that includes the
at least one occlusion resistant agent.
12. The shunt according to claim 11, wherein the at least one
occlusion resistant agent has a solubility of less than 1 mg/mL in
water.
13. The shunt according to claim 11, wherein the at least one
occlusion resistant agent is rapamycin.
14. The shunt of claim 1 further comprising at least one valve.
15. The shunt of claim 1 wherein the occlusion-resistant material
comprises an immunosuppressive, an anti-inflammatory, an
anti-neoplastic, a radiation emitting material, an anti-angiogenic,
an anti-coagulant, an anti-proliferative, an anti-thrombogenic, an
anti-oxidant, a cyclooxygenase inhibitor, a calcium entry blocker,
an anti-neoplastic, an anti-mitotic, an anti-microbial, a nitric
oxide donor, a cell cycle inhibitor, an anti-cancer agent, an
anti-arthritis agent, an anti-diabetic agent, a thrombin inhibitor,
a thrombolytic, an antibiotic, an antiviral agent, a gene therapy
agent, or some combination thereof.
16. The shunt of claim 15 wherein the occlusion-resistant material
includes a material selected from the group consisting of
beta-radiation emitting isotopes, dexamethasone, beclomethasone,
cortisone, hydrocortisone, prednisone, methylprednisone,
fluorometholone, tranilast, ketoprofen, curcumin, cyclosporin A,
deoxyspergualin, FK506, sulindac, myriocin, 2-aminochromone
(U-86983), colchicines, pentosan, antisense oligonucleotides,
mycophenolic acid, paclitaxel, etoposide, actinomycin D,
camptothecin, carmustine, methotrexate, adriamycin, mitomycin,
cis-platinum, mitosis inhibitors, vinca alkaloids, tissue growth
factor inhibitors, platinum compounds, cytotoxic inhibitors,
alkylating agents, antimetabolite agents, tacrolimus, rapamycin,
azathioprine, recombinant or monoclonal antibodies to interleukins,
T-cells, B-cells, and receptors, bisantrene, retinoic acid,
tamoxifen, compounds containing silver, doxorubicin, azacytidine,
homoharringtonine, selenium compounds, superoxide-dismutase,
interferons, heparin, rapamycin ABT-578 and analogs, homologs,
derivatives or combinations of the above group.
17. The shunt of claim 16 wherein the occlusion resistant material
includes a material selected from the group consisting of
mycophenolic acid, rapamycin, rapamycin ABT-578, derivatives or
combinations thereof.
18. The shunt of claim 16 wherein the occlusion resistant material
includes mycophenolic acid.
19. The shunt of claim 16 wherein the occlusion resistant material
includes a combination of mycophenolic acid and, rapamycin or
rapamycin ABT-578.
20. The shunt of claim 15 wherein the occlusion-resistant material
permeates at different rates at different portions of the
shunt.
21. A shunt for at least partial implantation into a patient
comprising: an elongated conduit having a fluid conduit and a
drainage conduit, wherein said elongated conduit comprises a
proximal end for receipt of bodily fluids for flow through said
shunt and a distal end for discharge of said bodily fluids from
said shunt; and a long term source of at least one occlusion
resistant agent, wherein said at least a portion of said at least
one occlusion resistant agent can permeate through at least a
portion of the elongated conduit, wherein said fluid conduit
functions as a conduit for the at least one occlusion resistant
agent and the drainage conduit functions as a conduit for CSF
drainage, and wherein at least a portion of the fluid conduit
contains at least one absorptive agent and the at least one
occlusion resistant agent.
22. The shunt according to claim 21, wherein the absorptive agent
is alumina, silica, activated charcoal, cross-linked polystyrene
beads, high molecular weight gels, silicone polyurethanes,
open-celled foams or some combination thereof.
23. The shunt according to claim 21, wherein at least a portion of
the fluid conduit contains a saturated solution that includes the
at least one occlusion resistant agent.
24. The shunt according to claim 23, wherein the at least one
occlusion resistant agent has a solubility of less than 1 mg/mL in
water.
25. The shunt according to claim 23, wherein the at least one
occlusion resistant agent is rapamycin.
26. The shunt of claim 21 further comprising at least one
valve.
27. A kit comprising: a shunt for at least partial implantation
into a patient comprising: an elongated conduit having at least one
lumen therethrough, wherein said elongated conduit comprises a
proximal end for receipt of bodily fluids for flow through said
shunt and a distal end for discharge of said bodily fluids from
said shunt; and a long term source of at least one occlusion
resistant agent, wherein said at least a portion of said at least
one occlusion resistant agent can permeate through at least a
portion of the elongated conduit; a valve; and a distal
catheter.
28. The kit according to claim 27, wherein the long term source
comprises a refill port that is in fluid communication with the
lumen of the elongated conduit.
29. The kit according to claim 28, wherein the refill port includes
a percutaneous access port.
30. The kit according to claim 27 wherein said elongated conduit
comprises at least two lumens therethrough.
31. The kit according to claim 30, wherein said at least two lumens
comprise: a fluid conduit that functions as a conduit for the at
least one occlusion resistant agent; and a drainage conduit that
functions as a conduit for CSF drainage.
32. The kit according to claim 31, wherein the fluid conduit
comprises a surface through which the at least one occlusion
resistant agent can permeate.
33. The kit according to claim 31 further comprising a refill port
that is in fluid communication with the fluid conduit.
34. The kit according to claim 33, wherein the refill port includes
a percutaneous access port.
35. The kit according to claim 31, wherein at least a portion of
the fluid conduit contains at least one absorptive agent and the at
least one occlusion resistant agent.
36. The kit according to claim 35, wherein the absorptive agent is
alumina, silica, activated charcoal, cross-linked polystyrene
beads, high molecular weight gels, silicone polyurethanes,
open-celled foams or some combination thereof.
37. The kit according to claim 30, wherein at least a portion of
the fluid conduit contains a saturated solution that includes the
at least one occlusion resistant agent.
38. The kit according to claim 37, wherein the at least one
occlusion resistant agent has a solubility of less than 1 mg/mL in
water.
39. The kit according to claim 37, wherein the at least one
occlusion resistant agent is rapamycin.
Description
FIELD OF THE INVENTION
[0001] This invention relates to shunts and techniques to prevent
blockage or occlusion of such a shunt. One embodiment of the
invention relates to a cerebrospinal fluid shunt.
BACKGROUND OF THE INVENTION
[0002] Hydrocephalic shunts are designed to remove excess fluid
from the ventricular region of the brain to a different internal
location, such as the peritoneal cavity. Alternatively, cerebral
spinal fluid (CSF) shunts may have a proximal end placed into the
patient's ventricular region and a distal end being connected
external of the patient. In either configuration, a common problem
involves the immune response and/or an inflammatory response of the
patient or inflammatory response to the insertion of the foreign
body, i.e., the catheter, therein. Additionally, occlusion of the
catheter lumens often occur and preclude effective drainage of the
CSF fluid. It is estimated that 40% of implanted hydrocephalic
shunts fail within 5 years due to tissue proliferation into the
shunt lumen.
[0003] U.S. Pat. No. 6,110,155, issued to Baudino, and commonly
owned by Applicant of the present application, shows an
anti-inflammatory agent loaded catheter distal tip and method for
preventing tissue fibrosis. The device and method utilizes, in one
embodiment, dexamethasone sodium phosphate agent on a ventricular
catheter tip to prevent encapsulation of the catheter. U.S. Pat.
No. 6,348,042 B1, issued to Warren, Jr., discloses a bio-active
shunt device and method by which the interior lumen surface of a
shunt is coated with a matrix forming system having at least one
enzyme configured for inciting activity to preclude the growth of
obstructing cellular material. In one embodiment, the interior
surface of the catheter lumen is impregnated with proteases or a
matrix containing proteases that is impregnated onto the wall of
the lumen to degrade cellular material including cells of the
choroid plexus and peritoneum.
[0004] U.S. Pat. Pub. No. US 2004/0220510, commonly assigned,
discloses an occlusion resistant shunt for implantation into a
patient to treat hydrocephalus. The shunts are constructed to
include one or more occlusion resistant materials. Shunts for the
treatment of hydrocephalus may remain implanted for the lifetime of
a patient, therefore there remains a need for an extended duration
of local delivery of agents to limit or prevent occlusion.
BRIEF SUMMARY OF THE INVENTION
[0005] An occlusion resistant medical shunt, particularly a
hydrocephalic shunt, is provided for implantation into a mammal.
The shunt has an elongate wall structure configured as a tube
having a lumen therethrough and a proximal end for receipt of
bodily fluids. The bodily fluids, such as cerebrospinal fluid,
flows through the shunt to a distal end for discharge of the bodily
fluids. The wall structure of the shunt generally includes a
biocompatible medical device material. The shunts of the present
invention allow for long term delivery of one or more occlusion
resistant materials to resist occlusion of the lumenal passage of
the shunt.
[0006] A fully implanted medical shunt of the invention for use as
a hydrocephalus shunting device has a construction which controls
the immunologic response that the recipient may experience after
receipt of the shunt within the recipient's body, and through the
lifetime of the implantation, which is often the lifetime of the
patient. In various embodiments of the present invention, the shunt
comprises an elongate wall structure configured as a tube having a
lumen therethrough and a proximal end for receipt of bodily fluids
and a distal end for discharge of said bodily fluids into another
portion of the recipient's body. In one embodiment, the proximal
end is located in the ventricular region of the brain and the
distal end is located in the peritoneal structure at the abdomen.
In another embodiment, the proximal end is located in the
ventricular region of the brain and the distal end is located
external of the patient. The wall structure generally includes a
biocompatible elastomer material, such as silicone, and a source of
one or more occlusion resistant materials at one or both of the
proximal and distal ends. In addition to or alternatively, the
distal end may have different material properties than the proximal
end in order to optimize the resistance to both occlusion and/or
infection.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1A is a schematic view of one example of a shunt
catheter in accordance with the invention.
[0008] FIG. 1B is a planar cross section of the portion of the
shunt depicted in FIG. 1A that is distal of the A axis.
[0009] FIG. 1C is a schematic view of the portion of the shunt
depicted in FIG. 1A that is distal of the A axis.
[0010] FIG. 2A is a planar cross section of another example of a
shunt catheter in accordance with the invention.
[0011] FIG. 2B is a cross section of the portion of the shunt
depicted in FIG. 2A that is distal of the B axis.
DETAILED DESCRIPTION OF THE INVENTION
[0012] A shunt in accordance with the invention can be used in any
medical application where it is necessary to move fluid from one
part of the body to another. Examples of types of shunts where the
invention can be utilized include, but are not limited to, cardiac
shunts, cerebral shunts, glaucoma shunts, urinary catheters, and
drainage catheters for trauma or post-surgical applications.
[0013] Shunts for treatment of hydrocephalus are well known and
have evolved over many decades. Typically, a hydrocephalic shunt
includes tubing with a proximal end located in the brain tissue and
a distal end located either within the patient at another location
external to the brain or external of the patient altogether. Such
shunts also typically include a valve structure designed to
accommodate and/or control flow based on the intracranial pressure
and the position of the patient or other factors. One example
includes a valve that is configured for proper flow regulation when
the patient is laying down versus standing up.
[0014] A shunt may be occluded at three different locations. First,
at an entry point such as the proximal location in the brain,
second, at or near the valve system, commonly referred to as a
"valve obstruction", and third, at the distal end, referred to as a
distal catheter occlusion. Shunts in accordance with one embodiment
of this invention focus on either distal or proximal occlusions
rather than valve obstructions, although valve obstructions may be
a sequel of occlusions or infection migrating from the distal or
proximal ends.
[0015] Proximal occlusions are generally more common than distal
occlusions, and often result from blood or cellular debris which
block the lumen and distal holes on ventricular catheters. This
growth may depend on artificial properties (chemistry and geometry)
as well as the distance between catheter and tissues in the
ventricular (catheter positioning and slit ventricles syndrome).
Some ventricular catheter tip designs have been proposed for
maintaining the holes of the ventricular catheter away from the
walls of the ventricles and the choroids plexus in order to resolve
this problem. However, such devices are likely unable to fully
prevent proximal occlusion from occurring or may present further
problems. Moreover, those known as flanged catheters actually
promote firm attachment of the catheter tubing to the choroids
plexus. Although distal obstructions are not as frequent as that at
the proximal end, shunt-type catheters can be obstructed in the
peritoneal cavity by ingrowth of mesothelial cells and
fibroblasts.
[0016] Shunts of the invention provide long term delivery of one or
more occlusion resistant agents. The long term delivery of the one
or more occlusion resistant agents is provided through a long term
source of the one or more occlusion resistant agents. As used
herein, the phrase long term source means that the shunt can
deliver at least one occlusion resistant agent for at least 1 year.
In another embodiment, the phrase long term source means that the
shunt can deliver at least one occlusion resistant agent for at
least 5 years. In yet another embodiment, the phrase long term
source means that the shunt can deliver at least one occlusion
resistant agent for at least 10 years. In a further embodiment, the
term long term source means that the shunt can deliver at least one
occlusion resistant agent for the entire period in which the shunt
is implanted in the patient, or the lifetime of the patient. The
long term source of the occlusion resistant agent can be provided
by having a refilling port in the shunt, or can be provided from
within the shunt itself.
[0017] The at least one occlusion resistant agent can be delivered
at a level, rate, or concentration that is effective to decrease,
diminish, or prevent occlusion. The particular concentration that
the occlusion resistant agent is effective at will depend at least
in part on the identity of the occlusion resistant agent. Many
occlusion resistant agents are effective at a concentration between
about 1 nanomolar (nM) and about 1 millimoloar (mM). In one
embodiment, where the at least one occlusion resistant agent is
rapamycin, the concentration where rapamycin is effective is at a
concentration of about 1 nM or higher.
[0018] FIG. 1 shows one embodiment of the hydrocephalic or CSF
shunt 10 of the present invention, wherein the shunt 10 includes an
elongated conduit 11 having a proximal portion 12, one or more
ports 13, one or more valves 14, a central portion 15, and a distal
portion 16. The elongated conduit 11 may be of any shape or size,
but generally will be in the form of a tube made of an elastomeric
material. As noted above, proximal portion 12 is placed in the
patient's head at the region of the ventricles while the central
portion 15 is routed subcutaneously along the patient's neck and
torso. The distal portion 16 may be placed for drainage of the
cerebral spinal fluid into the peritoneal cavity where the fluid is
then reabsorbed by the normal bodily processes or may extend out of
the patients body for external drainage. In yet another embodiment,
the distal portion 16 of a shunt 20 in accordance with the
invention is connected to a distal catheter that drains cerebral
spinal fluid (for example) into another portion of the body.
[0019] The elongated conduit 11 can be fabricated from a number of
materials, as is known to one of skill in the art having read this
specification. Examples of such materials include, but are not
limited to poly(L-lactic acid), poly(lactide-co-glycolide),
poly(hydroxybutyrate-co-valerate), silicones, polyurethanes,
polyesters, vinyl homopolymers and copolymers, acrylate
homopolymers and copolymers, polyethers, polyethylene,
polypropylene, polycarbonate, polysulfone, cellulosics,
polydimethylsiloxanes, methylhydrosiloxane-dimethylsiloxane
copolymers, polymethylhydrosiloxanes, polyethylhydrosiloxanes,
hydride terminated polyphenyl-(dimethylhydrosiloxy)siloxanes,
methylhydrosiloxane-phenylmethylsiloxane copolymers,
N-vinylpyrrolidone/methyl methacrylate copolymers,
2-hydroxyethylacrylate (e.g. polymacon), various copolymers of
2-hydroxyethylmethacrylate (e.g. hafilcon A and B, vifilcon A,
tetrafilcon, dimefilcon, bufilcon, perfilcon, etc.), copolymers of
N-vinylpyrrolidone (e.g. lidofilcon A and B, scafilcon A,
surfilcon, vifilcon, filcon YA, etc.), polyamides, polyimides,
fluoropolymers, polytetrafluoroethylenes, natural rubber and
polyisoprene.
[0020] In the embodiment depicted in FIG. 1A, the port 13 can
provide long term delivery of one or more occlusion resistant
agents or materials to resist occlusion of the lumenal passage of
the shunt. The at least one port 13 can be constructed as would be
known to those of skill in the art having read this
specification.
[0021] In one embodiment, the port 13 can include a conventional
percutaneous fill port that includes a membrane that can be
penetrated by a hypodermic needle and is self-sealing after the
needle is removed. In one embodiment, the fluid that is injected
from the needle goes through a structure that functions as a funnel
to a reservoir. The fluid, which generally comprises one or more
occlusion resistant agents, flows from the reservoir to the one or
more portions of the shunt where occlusion is to be minimized. In
one embodiment, a percutaneous fill port also includes a valve to
control the rate at which the fluid travels from the reservoir to
the one or more portions of the shunt where occlusion is to be
minimized. An example of a percutaneous fill port that could
function as port 13 can be found in U.S. Pat. No. 5,697,951, the
disclosure of which is incorporated by reference herein. Other
examples of types of structure that could be utilized as a port 13
include, but are not limited to the center reservoir fill ports of
the MEDTRONIC SYNCHROMED.RTM. Infusion System and the MEDTRONIC
ISOMED.RTM. Constant-Flow Infusion System.
[0022] The valve 14 can be, but need not be part of the shunt 20 of
the invention. In one embodiment, the valve 14 is a separate
component that is configured to be connected to and work with a
shunt 20 of the invention. One of skill in the art, having read
this specification, will understand the particular types of valves
that may be utilized. In embodiments of the invention that are to
be used for drainage of cerebral spinal fluid from the brain to
another portion of the body, commercially available valves,
including, but not limited to, PS Medical Strata.RTM. valve, and PS
Medical Delta.RTM. valve can be utilized.
[0023] In one embodiment, depicted in FIGS. 1B and 1C, the proximal
end 12 is at least one of the areas where occlusion is to be
minimized. One embodiment of a shunt 10 includes apertures 17 that
allow the receipt of bodily fluids, such as CSF into the shunt 10.
The wall 18 is generally made of an absorptive material. As used
herein, the term "absorptive material" refers to a material that
can absorb some amount of at least one occlusion resistant agent.
The wall 18 can be constructed of one type of absorptive material,
more than one type of absorptive material, or one or more types of
absorptive material and one or more other materials. For example,
at least the proximal portion 12 can be constructed of one type of
absorptive material and can have apertures 17 formed therein. In
another embodiment, at least the proximal portion 12 can be
constructed of materials that are commonly known to those of skill
in the art for shunt construction, and the absorptive material can
be added to the proximal portion. In such an embodiment, the
absorptive material could be attached to the commonly used shunt
materials. Examples of methods of attachment include, but are not
limited to, solvent bonding, thermal bonding, adhesives, and other
methods known to those of skill in the art having read this
specification.
[0024] In one embodiment, absorptive materials can include any
material that can absorb at least some of at least one occlusion
resistant agent. In one embodiment, an absorptive material can
include a material that has an affinity for the occlusion resistant
agent due at least in part by the fact that it is delivered in
solution. In another embodiment, absorptive materials can have a
selective affinity for at least one occlusion resistant agent.
Selective affinities can include gross chemical properties, such as
hydrophobic attraction, hydrophilic attraction, or ionic
attraction; or more specific affinities such as immuno-based
affinity, and molecular imprinting based affinity. Other
embodiments can include absorptive materials that have affinities
based on gross chemical properties, specific affinities, or any
combination thereof. Examples of types of absorptive materials
include, but are not limited to, alumina, silica, activated
charcoal, cross-linked polystyrene beads, high molecular weight
gels such as polyethylene glycol (PEG), silicone polyurethanes, and
open-celled foams. One particular example of an open-celled foam
that may be useful in embodiments of the invention is a hydrophilic
medical grade foam available from Avitar Technologies (Canton,
Mass.). These exemplary materials or materials like them could then
be modified to provide one or more selective affinities as
discussed above. One of skill in the art, having read this
specification, would understand and be able to modify such
materials in order to alter the affinities thereof in a fashion to
make them more or less selective for one or more occlusion
resistant agents.
[0025] A cross section of another embodiment of the invention that
can provide long term delivery of one or more occlusion resistant
agents is depicted in FIG. 2A. In this embodiment, the elongated
conduit 11 of the shunt 20 includes at least two lumens, the fluid
conduit 21 and the drainage conduit 22. The drainage conduit 22 is
also referred to herein as the CSF drainage conduit 22, because in
some embodiments it serves as the conduit for the CSF from the
apertures 17 of the proximal portion 12 through the central portion
15 (not shown) to the distal portion (also not shown) where it
drains either into another body space of the patient or external to
the patient. The fluid conduit 21 is in fluid communication with
the port 13. The fluid that is injected into the port 13 can travel
from the port 13 into the fluid conduit 21. The fluid, containing
the occlusion resistant agent can then permeate through the surface
of the fluid conduit 21 so that the occlusion resistant agent is
delivered to the space around the shunt 20 in the ventricular
space, the volumes within the apertures 17, and the volume within
the CSF conduit 22 in at least the proximal portion 12 of the CSF
shunt 20. Although not necessarily depicted in FIG. 2A, the fluid
conduit 21 can be used to communicate between the port 13 and the
proximal portion 12 of the shunt 20. The fluid conduit 21 can
therefore allow for fluid communication throughout the length of
the shunt 20.
[0026] In such an embodiment therefore, the material that forms the
fluid conduit 21 is at least somewhat permeable the one or more
occlusion resistant agent. Examples of material that can be used to
construct the fluid conduit 21 include, but are not limited to
silicone rubber, and polyurethane. In one embodiment, the fluid
conduit 21 is made of silicone rubber.
[0027] The fluid conduit 21 can have variable properties across its
length. For example, it may be advantageous to have thicker walls
at some points along the fluid conduit 21 in order to provide
structural integrity to particular portions of the proximal portion
12 of the shunt 12 or to slow the passage of the occlusion
resistant agent across some portions of the fluid conduit 21. It
may also be advantageous to have thinner walls at some points along
the fluid conduit 21 in order to increase the rate and/or the
amount of occlusion resistant agent that is delivered to the space
around some portions of shunt 20. Therefore, in one embodiment of
the invention, the thickness of the wall of the fluid conduit 21
can vary over its length. The particular thicknesses, and locations
of different thicknesses can be chosen based on a number of
factors, including but not limited to, the structural integrity of
the shunt 20, a desire to slow passage or decrease the amount of
the one or more occlusion resistant agent to some portions of the
area around or within the shunt 20, a desire to speed passage or
increase the amount of the one or more occlusion resistant agent to
some portions of the area around or within the shunt 20, or some
combination thereof.
[0028] One exemplary embodiment of the invention includes a shunt
20 with a variable wall thickness fluid conduit 21. One example
includes a fluid conduit 21 that has a wall that is thinner on the
outer surface of the shunt 20 than it is on the inner surface (the
surface facing the CSF conduit 22) of the shunt 20. It should also
be noted that other properties of the material making up the fluid
conduit 21 wall could be modified in order to change the rate
and/or amount of occlusion resistant agent that permeates the fluid
conduit 21.
[0029] FIG. 2B illustrates how a shunt in accordance with this
embodiment of the invention could function to both drain CSF from
the ventricles and release occlusion resistant agent. In this
depiction, the CSF flow is represented by the thin arrows, of which
some are designated 23. The CSF flows from the space around the
shunt 20 through the apertures 17 and into the CSF conduit 22. The
flow of the occlusion resistant agent is represented by the thick
arrows, of which some are designated 25. The occlusion resistant
agent permeates the walls of the fluid conduit 21 and flows into
the space around the shunt 20 (exemplified by arrow 25a), the space
within the CSF conduit 22 (exemplified by arrow 25b), and into the
volume within the apertures 17 (exemplified by arrow 25c). It
should be noted that any one or more of the directions of flow of
the occlusion resistant agent could be controlled or modified at
least in part by changing the thickness of the wall through which
that particular flow occurs. For example, to configure a shunt that
preferentially flows occlusion resistant agent to the space around
the shunt 20 as opposed to flowing occlusion resistant agent to the
area within the CSF conduit 22, the outside walls of the fluid
conduit 21 could be made thinner than the inside walls (those
facing the CSF conduit 22). Such an embodiment may function to
minimize the flow depicted by arrow 25b. Other results could also
be obtained by varying the wall thicknesses of different areas of
the fluid conduit 21.
[0030] Another possible embodiment that is similar to that depicted
in FIG. 2B is to have a spiral configuration to the apertures in
the fluid conduit 21. Such a configuration may provide a compromise
between total aperture volume and structural integrity that may be
advantageous or desirable.
[0031] Another embodiment of the invention includes a shunt 20 that
includes a CSF conduit 22, a fluid conduit 21, and absorptive
material within the fluid conduit 21. In such an embodiment, the
absorptive material can be included in the entire fluid conduit 21,
or some portion thereof. In one embodiment, the absorptive material
is included in a proximal portion of the fluid conduit 21. In such
an embodiment, the fluid that is injected into the fluid conduit 21
via the port 13 would reach the absorptive material via the fluid
conduit 21 and the occlusion resistant agent could be absorbed at
least in part by the absorptive material.
[0032] Another embodiment of the invention includes a shunt 20 that
includes a CSF conduit 22, a fluid conduit 21, and a saturated
solution containing one or more occlusion resistant agents. In one
embodiment, the saturated solution includes at least one carrier
fluid, and at least one occlusion resistant agent in solid form. In
one embodiment, the at least one occlusion resistant agent is at a
concentration that is higher than it's solubility in the carrier
liquid. In one embodiment, the carrier fluid is water, saline,
buffered saline. In one embodiment, the at least one occlusion
resistant agent is a hydrophobic compound with a relatively low
water solubility. In one embodiment the at least one occlusion
resistant agent is a hydrophobic compound with a water solubility
of less than about 1 milligram/milliliter (mg/mL).
[0033] In an embodiment that includes a saturated solution
containing one or more occlusion resistant agents with the
occlusion resistant agent at a concentration that is higher than
it's solubility, an equilibrium will be maintained between the
occlusion resistant agent in the saturated solution in the fluid
conduit 21 and outside wall of the fluid conduit 21. This
equilibrium allows the saturated solution itself to act as a long
term source of the at least one occlusion resistant agent. The
equilibrium of the occlusion resistant agent and diffusion of the
occlusion resistant agent through the wall of the fluid conduit 21
will allow the shunt 20 to deliver an almost constant concentration
of the occlusion resistant agent into the area around and within
the shunt 20.
[0034] Because a large quantity of the occlusion resistant agent
can be stored in the fluid conduit 21 by using a saturated
solution, the saturated solution can be it's own long term source
for the occlusion resistant agent, and therefore a shunt 20 that
utilizes a saturated solution does not necessarily have to include
a port 13.
[0035] The inclusion of an occlusion resistant agent in a shunt 20
can be utilized in any region of the shunt. One of skill in the
art, having read this specification, would understand how to, for
example, utilize a fluid conduit portion in a region other than the
proximal portion 12 of the shunt 20. Other regions that could be
configured to deliver occlusion resistant agents on a long term
basis include the proximal portion 12, the distal portion 18, valve
portion 14, or any combination thereof. Generally, the occlusion
resistant agent is delivered through portions of the shunt where
clotting or tissue growth tend to occlude the lumen of the
shunt.
[0036] Occlusion resistant agents can include a number of different
types of agents that can be selected from multiple classes. Such
classes include anti-inflammatory drugs, immuno-suppressive drugs,
anti-cancer drugs, anti-proliferatives, anti-migratories,
anti-angiogenic drugs, radioactive or radiation-emitting material.
Such classes may further include anti-neoplastics, anti-coagulents,
anti-thrombogenics, anti-oxidants, cyclooxygenase inhibitors,
calcium entry blockers, anti-neoplastics, anti-mitotics,
anti-microbials, nitric oxide donors, cell cycle inhibitors,
anti-arthritis agents, anti-diabetic agents, thrombin inhibitors,
thrombolytics, antibiotics, antiviral agents, anti-proliferatives,
anti-thrombogenics, anti-oxidants, cyclooxygenase inhibitors,
calcium entry blockers, anti-mitotics, anti-microbials, nitric
oxide donors, cell cycle inhibitors, anti-cancer agents, and gene
therapy agents.
[0037] The following classes of anti-occlusion agents with examples
in each class are exemplary occlusion resistant agents that can be
utilized in the invention. For example classes of anti-occlusion
agents that may be utilized in embodiments of the invention include
immunosuppressives, anti-inflammatories, anti-neoplastics,
anti-angiogenics, anti-coagulants, analgesics, antipyretics,
anti-proliferatives, anti-thrombogenics, anti-oxidants,
cyclooxygenase inhibitors, calcium entry blockers,
anti-neoplastics, anti-mitotics, anti-microbials, antifungals,
nitric oxide donors, cell cycle inhibitors, anti-cancer agents,
anti-arthritis agents, anti-diabetic agents, thrombin inhibitors,
thrombolytics, antibiotics, antiviral agents, and gene therapy
agents. The following list provides additional examples of
occlusion resistant agents that may be utilized in the
invention.
[0038] Anti-inflammatory agents that may be utilized in the
invention include, but are not limited to selective NF-kappaB
modulators, NF-kappaB modulators (non-specific), steroids,
inflammatory cytokine inhibitors, P38 inhibitors/stress kinase
inhibitors, IL-1 specific inhibitors, TNF specific inhibitors,
adhesion inhibitors, chemokines and their receptor inhibitors, MMP
inhibitors or other protease inhibitors, NO modulators,
non-steroidal anti-inflammatory drugs (NSAIDs), and COX
inhibitors.
[0039] Non-steroidal anti-inflammatory agents including their
racemic mixtures or individual enantiomers where
applicable--ibuprofen, flurbiprofen, ketoprofen, aclofenac,
diclofenac, aloxiprin, aproxen, aspirin, diflunisal, fenoprofen,
indomethacin, mefenamic acid, naproxen, phenylbutazone, piroxicam,
salicylamide, salicylic acid, sulindac, desoxysulindac, tenoxicam,
tramadol, ketoralac, flufenisal, salsalate, triethanolamine
salicylate, aminopyrine, antipyrine, oxyphenbutazone, apazone,
cintazone, flufenamic acid, clonixerl, clonixin, meclofenamic acid,
flunixin, coichicine, demecolcine, allopurinol, oxypurinol,
benzydamine hydrochloride, dimefadane, indoxole, intrazole, mimbane
hydrochloride, paranylene hydrochloride, tetrydamine,
benzindopyrine hydrochloride, fluprofen, ibufenac, naproxol,
fenbufen, cinchophen, diflumidone sodium, fenamole, flutiazin,
metazamide, letimide hydrochloride, nexeridine hydrochloride,
octazamide, molinazole, neocinchophen, nimazole, proxazole citrate,
tesicam, tesimide, tolmetin, triflumidate, nepafenac, etodolac,
rebamipide, and zaltoprofen.
[0040] Other types of not previously categorized anti-inflammatory
agents may also be utilized in the invention, examples include, but
are not limited to tranilast, rituximab, piroxicam, loxoprofen,
doxycyclin, drotrecogin alfa, and tretinoin.
[0041] Antineoplastic/antiangiogenic--antimetabolite agents,
alkylating agents, cytotoxic antibiotics, vinca alkaloids, mitosis
inhibitors, platinum compounds, tissue growth factor inhibitors,
cisplatin and etoposide
[0042] Immunosuppressant agents--cyclosporine A, mycophenolic acid,
tacrolimus, rapamycin, rapamycin analogues, such as rapamycin
ABT-578 analogue produced by Abbott Laboratories, azathioprine,
recombinant or monoclonal antibodies to interleukins, T-cells,
B-cells and/or their receptors.
[0043] Antithrombogenic Factors--Anticoagulents, such as heparin
and chondroiten sulfate; Platelet inhibitors such as ticlopidine;
Vasodilators such as cyclandelate, isoxsuprine, papaverine,
dipyrimadole, isosorbide dinitrate, phentolamine, nicotinyl
alcohol, co-dergocrine, nicotinic acid, glycerl trinitrate,
pentaerythritol tetranitrate and xanthinol; and Thrombolytic
agents, such as stretokinase, urokinase and tissue plasminogin
activators.
[0044] Antiproliferative agents--paclitaxel, actinomycin D,
rapamycin, tacrolimus, everolimus, dexamethasone and rapamycin
analogue (ABT-578) produced by Abbott Laboratories;
[0045] Analgesics and antipyretics--the opioid analgesics such as
buprenorphine, dextromoramide, dextropropoxyphene, fentanyl,
alfentanil, sufentanil, hydromorphone, methadone, morphine,
oxycodone, papaveretum, pentazocine, pethidine, phenopefidine,
codeine dihydrocodeine; acetylsalicylic acid (aspirin),
paracetamol, and phenazone;
[0046] Antimicrobials--the cephalosporins such as cephalexin,
cefoxytin and cephalothin;
[0047] Antifungals--amorolfine, isoconazole, clotrimazole,
econazole, miconazole, nystatin, terbinafine, bifonazole,
amphotericin, griseo fulvin, ketoconazole, fluconazole and
flucytosine, salicylic acid, fezatione, ticlatone, tolnaftate,
triacetin, zinc, pyrithione and sodium pyrithione;
[0048] Antiviral agents--acyclovir and acyclovir prodrugs,
famcyclovir, zidovudine, didanosine, stavudine, lamivudine,
zalcitabine, saquinavir, indinavir, ritonavir, n-docosanol,
tromantadine and idoxuridine;
[0049] Local anesthetics--benzocaine, bupivacaine, amethocaine,
lignocaine, lidocaine, cocaine, cinchocaine, dibucaine,
mepivacaine, prilocalne, etidocaine, veratridine (specific c-fiber
blocker) and procaine;
[0050] Other miscellaneous antibiotics--chloramphenicol,
clindamycin, erythromycin, erythromycin ethyl carbonate,
erythromycin estolate, erythromycin glucepate, erythromycin
ethylsuccinate, erythromycin lactobionate, roxithromycin,
lincomycin, natamycin, nitrofurantoin, spectinomycin, vancomycin,
aztreonarn, colistin IV, metronidazole, tinidazole, fusidic acid,
trimethoprim, and 2-thiopyridine N-oxide; halogen compounds,
particularly iodine and iodine compounds such as iodine-PVP complex
and diiodohydroxyquin, hexachlorophene; chlorhexidine; chloroamine
compounds; and benzoylperoxide;
[0051] Other pharmaceutical agents--beta-radiation emitting
isotopes, beclomethasone, fluorometholone, tranilast, ketoprofen,
curcumin, cyclosporin A, deoxyspergualin, FK506, sulindac,
myriocin, 2-aminochromone (U-86983), colchicines, pentosan,
antisense oligonucleotides, mycophenolic acid, etoposide,
actinomycin D, camptothecin, carmustine, methotrexate, adriamycin,
mitomycin, cis-platinum, mitosis inhibitors, vinca alkaloids,
tissue growth factor inhibitors, platinum compounds, cytotoxic
inhibitors, alkylating agents, antimetabolite agents, tacrolimus,
azathioprine, recombinant or monoclonal antibodies to interleukins,
T-cells, B-cells, and receptors, bisantrene, retinoic acid,
tamoxifen, compounds containing silver, doxorubicin, azacytidine,
homoharringtonine, selenium compounds, superoxide-dismutase,
interferons, heparin, analogs, homologs, and derivatives of the
above group.
[0052] Embodiments of the invention can include one or more of the
above exemplified occlusion resistant agents. Embodiments of the
invention can also utilize any combination of the above occlusion
resistant agents. Embodiments of the invention can also include
other agents, including but not limited to, stabilizing agents such
as anti-oxidants, radiopaque agents, MRI detectable agents, and
ultrasound detectable agents.
[0053] An example of the use of one of the occlusion resistant
agents is illustrated herein. In an embodiment that includes a
saturated solution, one example of an occlusion resistant agent
that may be utilized includes rapamycin. Rapamycin is an
anti-proliferative agent that can be effective at a concentration
of about 1 nM.
[0054] Generally, the flow rate of CSF in a young patient (mean
28.7 years old) is 26.6.+-.14.4 ml/hr; and in an elderly patient
(mean 77.1 years old) is 11.4.+-.4.2 ml/hr. Therefore, the highest
likely flow rate would be 26.6+14.4 ml/hr or about 41 ml/hr. If one
of skill in the art wanted a CSF shunt with a saturated solution to
deliver an effective concentration of rapaymycin over the period of
10 years (as an example), the amount of rapamycin that would have
to be loaded in the CSF shunt would be about 0.033 g.
914 g 1 mol .times. 10 .times. 10 - 9 mol 1 L .times. 0.041 L 1
hour .times. 24 hours 1 day .times. 365 days 1 year .times. 10
years = 32 , 827 , 224 .times. 10 - 9 g .apprxeq. 0.033 g
##EQU00001##
[0055] Another method of calculating the amount of rapamycin that
would be needed for a CSF shunt containing a saturated solution to
deliver an effective concentration over the period of 10 years (an
exemplary period of time) follows:
If the rate of formation of CSF is about 500 ml/day, then:
10 yrs .times. 365 days 1 year .times. 500 ml day .apprxeq. 1 , 825
, 000 ml .apprxeq. 1 ,825 liters of CSF formed in 10 years
##EQU00002##
If it is assumed that the minimal rapamycin concentration (e.g.
IC.sub.50) of rapaymcin should be about 1.times.10.sup.-8 M,
then:
10 .times. 10 - 9 moles 1 liter .times. 914 g 1 mole = 9 , 140
.times. 10 - 9 g 1 liter ##EQU00003##
Then the amount of rapamycin necessary for 10 years is:
1 , 825 liters CSF .times. 9 , 140 .times. 10 - 9 g 1 liter =
0.01668 grams rapamycin .apprxeq. 0.017 grams rapamycin
##EQU00004##
[0056] If the saturated solution contained 50% solid rapamycin; 10%
anti-oxidant stabilizers; 20% radiopacity agents; and 20% fluid
(saline, water, etc.), then the volume of saturated solution that
would be necessary would be about 0.066 ml (assuming the density of
the saturated solution was about 1.0 g/mL). One of skill in the
art, having read this specification, will be able to adjust the
concentration of the components to achieve iso-osmotic strength
relative to CSF fluid to minimize swelling or shrinkage due to
osmotic driven transport of water across the device wall.
[0057] The invention also includes a system having at least one
shunt of the invention. In one embodiment, a system includes a
shunt in accordance with the invention, having a valve, and a
distal catheter. The invention also includes kits that include at
least one shunt of the invention. In one embodiment, a kit includes
a shunt in accordance with the invention, a valve, and a distal
catheter.
[0058] One skilled in the art will appreciate that the present
invention can be practiced with embodiments other than those
disclosed. The disclosed embodiments are presented for purposes of
illustration and not limitation, and the present invention is
limited only by the claims that follow.
* * * * *