U.S. patent application number 15/505039 was filed with the patent office on 2017-09-28 for compositions and methods for treatment of neurological disorders.
The applicant listed for this patent is The General Hospital Corporation. Invention is credited to Richard Rox Anderson, William A. Farinelli, Lilit Garibyan, Emilia Javorsky.
Application Number | 20170274078 15/505039 |
Document ID | / |
Family ID | 55400611 |
Filed Date | 2017-09-28 |
United States Patent
Application |
20170274078 |
Kind Code |
A1 |
Garibyan; Lilit ; et
al. |
September 28, 2017 |
COMPOSITIONS AND METHODS FOR TREATMENT OF NEUROLOGICAL
DISORDERS
Abstract
Described herein are compositions comprising, and methods for
using, biocompatible cold slurries and methods of administering the
same to provide reversible inhibition of peripheral nerves in a
subject in need thereof.
Inventors: |
Garibyan; Lilit; (Brookline,
MA) ; Anderson; Richard Rox; (Boston, MA) ;
Farinelli; William A.; (Danvers, MA) ; Javorsky;
Emilia; (Watertown, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The General Hospital Corporation |
Boston |
MA |
US |
|
|
Family ID: |
55400611 |
Appl. No.: |
15/505039 |
Filed: |
August 27, 2015 |
PCT Filed: |
August 27, 2015 |
PCT NO: |
PCT/US15/47292 |
371 Date: |
February 17, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62042979 |
Aug 28, 2014 |
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62121472 |
Feb 26, 2015 |
|
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62121329 |
Feb 26, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/718 20130101;
A61P 23/02 20180101; A61P 25/02 20180101; A61K 47/26 20130101; A61P
37/08 20180101; A61K 45/06 20130101; A61P 25/00 20180101; A61P
17/04 20180101; A61K 47/18 20130101; A61P 25/04 20180101; A61P
17/06 20180101; A61P 35/00 20180101; A61K 31/045 20130101; A61K
47/10 20130101; A61P 17/00 20180101; A61K 9/0019 20130101; A61P
17/08 20180101; A61K 31/445 20130101; A61K 9/0024 20130101; A61P
17/02 20180101; A61P 19/02 20180101; A61K 31/245 20130101; A61K
33/00 20130101; A61K 31/765 20130101; A61P 25/08 20180101; A61P
13/02 20180101; A61K 31/047 20130101; A61K 31/7004 20130101; A61K
47/02 20130101; A61K 31/167 20130101; A61K 31/137 20130101; A61K
47/28 20130101; A61K 33/00 20130101; A61K 2300/00 20130101; A61K
31/7004 20130101; A61K 2300/00 20130101; A61K 31/718 20130101; A61K
2300/00 20130101; A61K 31/047 20130101; A61K 2300/00 20130101; A61K
31/765 20130101; A61K 2300/00 20130101; A61K 31/137 20130101; A61K
2300/00 20130101; A61K 31/045 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 45/06 20060101
A61K045/06; A61K 31/765 20060101 A61K031/765; A61K 31/7004 20060101
A61K031/7004; A61K 31/718 20060101 A61K031/718; A61K 31/047
20060101 A61K031/047; A61K 31/137 20060101 A61K031/137 |
Claims
1. A method of providing reversible inhibition of one or more
peripheral nerves to a subject in need thereof, said method
comprising providing a biocompatible ice slurry to the peripheral
nerves for a duration sufficient to inhibit the peripheral nerves
in the subject, wherein said inhibition is reversible.
2. The method of claim 1, wherein the biocompatible ice slurry
comprises ice particles and a lactated Ringer's solution,
electrolyte solution or a lactated electrolyte solution.
3. The method of claim 2, wherein the biocompatible ice slurry
further comprises hetastarch or dextrose.
4. The method of claim 2, wherein the biocompatible ice slurry
further comprises about 0.1% to about 20% glucose.
5. The method of claim 2, wherein the biocompatible ice slurry
further comprises about 0.1% to about 20% glycerol.
6. The method of claim 2, wherein the biocompatible ice slurry
further comprises about 0.1% to about 6% hetastarch.
7. The method of claim 1, wherein the biocompatible ice slurry
comprises ice particles and saline.
8. The method of claim 7, wherein the biocompatible ice slurry
further comprises about 0.1% to about 20% glycerol.
9. The method of claim 7, wherein the biocompatible ice slurry
further comprises about 0.1% to about 20% dextrose.
10. The method of claim 7, wherein the biocompatible ice slurry
further comprises about 0.1% to about 5% ethanol.
11. The method of claim 7, wherein the biocompatible ice slurry
further comprises about 0.1% to about 10% poly vinyl alcohol.
12. The method of claim 7, wherein the biocompatible ice slurry
further comprises at least one sugar, ion, polysaccharide, lipid,
oil, lysolecithin, amino acid, caffeine, surfactant,
anti-metabolite, detergent or a combination thereof.
13. The method of claim 12, wherein the at least one sugar is
glucose, mannitol, hetastarch, sucrose, sorbitol or a combination
thereof.
14. The method of claim 12, wherein the at least one ion is
calcium, potassium, hydrogen, chloride, magnesium, sodium, lactate,
phosphate, zinc, sulfur, nitrate, ammonium, carbonate, hydroxide,
iron, barium, salts thereof or a combination thereof.
15. The method of claim 12, wherein the at least one oil is canola
oil, coconut oil, corn oil, cottonseed oil, flaxseed oil, olive
oil, palm oil, peanut oil, safflower oil, soybean oil, sunflower
oil or a combination thereof.
16. The method of claim 12, wherein the surfactant is a
detergent.
17. The method of claim 12, wherein the detergent is at least one
of deoxycholate, sodium tetradecyl sulphate, polidocanol,
deoxycholate, sodium tetradecyl sulphate, polidocanol, polysorbate
20 (polyoxyethylen (20) sorbitan monolaurate), polysorbate 40
(polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60
(polyoxyethylene (20) sorbitan monostearate), polysorbate 80
(polyoxyethylene (20) sorbitan monooleate), sorbitan ester,
poloxamater or a combination thereof.
18. The method of claim 1, wherein the biocompatible ice slurry
comprises a peritoneal dialysis solution.
19. The method of claim 1, wherein the biocompatible ice slurry is
provided along the perineural sheath of a peripheral nerve.
20. The method of claim 1, where in the peripheral nerves are
subcutaneous nerves.
21. The method of claim 1, where in the peripheral nerves are
autonomic nerves.
22. The method of claim 21, where in the autonomic nerves are
sympathetic nerves, parasympathetic nerves or enteric nerves.
23. The method of claim 21, where in the peripheral nerves are
somatic nerves.
24. The method of claim 1, wherein the somatic nerves are sensory
nerves, motor nerves, cranial nerves, or spinal nerves.
25. The method of claim 1, wherein the biocompatible ice slurry
cools the nerves to between about 5.degree. C. and about
-40.degree. C.
26. The method of claim 1, wherein the biocompatible ice slurry has
a first equilibration temperature of between about 4.degree. C. and
about -30.degree. C.
27. The method of claim 1, wherein the biocompatible ice slurry has
a second equilibration temperature of between about 2.degree. C.
and about -30.degree. C.
28. The method of claim 2, wherein the ice particles are spherical
or round with a diameter of about 1 mm to about 0.01 mm.
29. The method of claim 1, wherein the biocompatible ice slurry
further comprises an agent selected from the group consisting of a
vasoconstricting agent, corticosteroid, a nonsteroidal
anti-inflammatory drug (NSAID), anesthetic, glucocorticoid, a
lipoxygenase inhibitor, and combinations thereof.
30. The method of claim 29, wherein the vasoconstricting agent is
epinephrine or norepinephrine.
31. The method of claim 29, wherein the anesthetic is selected from
the group consisting of lidocaine, bupivacaine, prilocaine,
tetracaine, procaine, mepivicaine, etidocaine, QX-314 and
combinations thereof.
32. The method of claim 1, wherein the biocompatible ice slurry is
injected.
33. The method of claim 32, wherein the biocompatible ice slurry is
provided to the peripheral nerves of the subject by injection into
or around the nerve or nerves selected from the group consisting of
the cutaneous nerve, trigeminal nerve, ilioinguinal nerve,
intercostal nerve, interscalene nerve, intercostal nerve,
supraclavicular nerve, infraclavicular nerve, axillary nerve,
paravertebral nerve, transverse abdominis nerve, genitofemoral
nerve, lumbar plexus nerve, femoral nerve, pudental nerve, celiac
plexus nerve, and sciatic nerve.
34. The method of claim 1, wherein the biocompatible ice slurry is
provided to the peripheral nerves of the subject by tumescent
pumping of the slurry.
35. The method of claim 1, further comprising administering
pressure to reduce blood flow at the site of injection.
36. The method of claim 1, further comprising monitoring the
biocompatible ice slurry by ultrasound or imaging.
37. The method of claim 1, wherein the inhibition is reversed after
about 5 months or less.
38. The method of claim 1, wherein the subject in need thereof
suffers from a disorder selected from the group consisting of
neuropathic pain, diabetic neuropathy pain, trigeminal neuralgia,
post-herpetic neuralgia, phantom limb pain, cancer related itch or
pain, burn itch or pain, lichen sclerosus, scalp itch, nostalgia
parastethica, atopic dermatitis, eczema, psoriasis, lichen planus,
vulvar itch, vulvodynia, lichen simplex chornicus, prurigo
nodularis, itch mediated by sensory nerves, peripheral neuropathy,
peripheral nerve damage, post-thoracotomy pain, incisional pain,
chest pain, coccydynia, lower back pain, superficial scars,
neuromas, acute post-operation pain, lumbar facet joint syndrome,
cutaneous pain disorder, and urinary incontinence.
39. The method of claim 38, wherein the cutaneous pain disorder is
selected from the group consisting of reflex sympathetic dystrophy
(RSD), phantom limb pain, neuroma, post herpetic neuralgia, tension
headache, occipital neuralgia and vulvodynia.
40. The method of claim 1, wherein the subject in need thereof
suffers from a motor disorder selected from the group consisting of
hemifacial spasm, bladder spasm and laryngospasm.
41. The method of claim 1, wherein the subject in need thereof
suffers from hyperhidrosis disorder.
42. The method of claim 1, wherein the tissue comprising the
peripheral nerves is externally cooled prior to providing, during
or after providing, the biocompatible ice slurry.
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional
application Ser. No. 62/042,979, filed Aug. 28, 2014, U.S.
provisional application Ser. No. 62/121,472, filed Feb. 26, 2015
and U.S. provisional application Ser. No. 62/121,329, filed Feb.
26, 2015. The entire disclosures of the aforementioned provisional
applications are incorporated herein by reference. This application
contains disclosure that is related to international application
No. PCT/US2015/______, filed on Aug. 27, 2015 (Attorney Docket No.
051588-22211WO1(000386)), the entire disclosure of which is
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Chronic peripheral nerve pain is a common problem in the
general population and, in particular, military veterans. It can
arise from numerous causes, such as surgery, trauma, neuroma,
metabolic or genetic disorder, infection or it can be idiopathic.
It is estimated that 20-30% of all extremity injuries in the US
military involve peripheral nerve damage. Severe peripheral nerve
injury and amputation have devastating effects on quality of life
due to intractable neuropathic pain. Treatment of refractory nerve
pain has been attempted using oral pain medications, such as
narcotics, nonsteroidal anti-inflammatory drugs (NSAIDs), surgical
and various percutaneous procedures, including radiofrequency and
alcohol ablation. However, there are numerous complications
associated with these treatments, including addiction to narcotics
and the need for multiple procedures. Overall, current treatment
options for chronic peripheral nerve pain fail to provide
satisfactory results.
[0003] Cryoneurolysis is the use of cold to target nerves.
Cryoneurolysis is a specialized technique for providing long-term
pain relief in interventional pain management settings. The
application of cold to nerves creates a conduction block similar to
the effect of local anesthetics and, if the nerve is frozen, leads
to Wallerian degeneration of the nerve. Cryoneurolysis has been
used for many years, albeit sparingly, for treatment of phantom
limb pain, pain secondary to trigeminal neuralgia, post-thoracotomy
chest wall pain, peripheral neuritis pain, post herpetic neuralgia
pain. The technique involves a probe 1.4 to 2 millimeters in size
that utilizes pressurized gas (e.g., nitrous oxide or carbon
dioxide) at 600-800 psi to generate temperatures as cold as
-89.degree. C. or lower at the tip of the probe through adiabatic
cooling under the Joule-Thompson effect, thereby forming an ice
ball at the target area. The probe is placed directly on the nerve
and any tissue that comes into contact with the probe is destroyed
due to the extreme cold temperatures used. Because the surrounding
tissue is almost always injured or damaged, this procedure is not
selective. In addition, the damage to the nerves in these
temperature ranges can be permanent.
[0004] Procedures involving cryoneurolysis that selectively target
peripheral nerves without damaging the surrounding tissue and
provide sustained treatment of pain would be highly desirable.
SUMMARY OF THE INVENTION
[0005] In one aspect, the invention provides a method of providing
reversible inhibition of peripheral nerves to a subject in need
thereof. The method comprises providing a biocompatible ice slurry
to the peripheral nerves for a duration sufficient to inhibit the
peripheral nerves in the subject, wherein the inhibition is
reversible. In some embodiments, the inhibition is reversed after
about 5 months or less. The peripheral nerves targeted for
inhibition can be subcutaneous nerves; somatic nerves, including
sensory nerves, motor nerves, cranial nerves or spinal nerves;
[0006] and autonomic nerves, including sympathetic, parasympathetic
or enteric nerves. In some embodiments, the biocompatible ice
slurry is provided along the perineural sheath of a peripheral
nerve.
[0007] In one embodiment, the biocompatible ice slurry comprises
ice particles and a lactated Ringer's solution or a lactated
electrolyte solution.
[0008] In another embodiment, the biocompatible ice slurry further
comprises hetastarch or dextrose.
[0009] In yet another embodiment, the biocompatible ice slurry
further comprises about 0.1% to about 20% glucose.
[0010] In yet another embodiment, the biocompatible ice slurry
further comprises about 0.1% to about 20% glycerol.
[0011] In yet another embodiment, the biocompatible ice slurry
further comprises about 0.1% to about 6% hetastarch.
[0012] In yet another embodiment, the biocompatible ice slurry
comprises ice particles and saline.
[0013] In yet another embodiment, the biocompatible ice slurry
further comprises about 0.1% to about 20% glycerol.
[0014] In yet another embodiment, the biocompatible ice slurry
further comprises about 0.1% to about 20% dextrose.
[0015] In yet another embodiment, the biocompatible ice slurry
further comprises about 0.1% to about 5% ethanol.
[0016] In yet another embodiment, the biocompatible ice slurry
further comprises about 0.1% to about 10% poly vinyl alcohol.
[0017] In yet another embodiment, the biocompatible ice slurry
further comprises at least one ion, sugar, polysaccharide, lipid,
oil, lysolecithin, amino acid, caffeine, surfactant,
anti-metabolite or combinations thereof. The at least one ion
includes, but is not limited to, calcium, potassium, hydrogen,
chloride, magnesium, sodium, lactate, phosphate, zinc, sulfur,
nitrate, ammonium, carbonate, hydroxide, iron, barium or
combinations thereof, including salts thereof. The at least one
sugar includes, but is not limited to, glucose, sorbitol, mannitol,
hetastarch, sucrose, or combinations thereof. The at least one oil
includes, but is not limited to, canola oil, coconut oil, corn oil,
cottonseed oil, flaxseed oil, olive oil, palm oil, peanut oil,
safflower oil, soybean oil, sunflower oil or combinations
thereof.
[0018] In yet another embodiment, the surfactant is a detergent.
The detergent includes, but is not limited to, deoxycholate, sodium
tetradecyl sulphate, polidocanol, polysorbate (including
polysorbate 20 (polyoxyethylen (20) sorbitan monolaurate),
polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate),
polysorbate 60 (polyoxyethylene (20) sorbitan monostearate),
polysorbate 80 (polyoxyethylene (20) sorbitan monooleate)),
sorbitan ester, poloxamater or combinations thereof.
[0019] In yet another embodiment, the biocompatible ice slurry
comprises a peritoneal dialysis solution.
[0020] In yet another embodiment, the biocompatible ice slurry
cools the nerves to between about 5.degree. C. and about
-40.degree. C.
[0021] In yet another embodiment, the biocompatible ice slurry has
a first equilibration temperature of between about 4.degree. C. and
about -30.degree. C.
[0022] In yet another embodiment, the biocompatible ice slurry has
a second equilibration temperature of between about 2.degree. C.
and about -30.degree. C.
[0023] In yet another embodiment, the ice particles are spherical
or round with a diameter of about 1 mm to about 0.01 mm.
[0024] In yet another embodiment, the biocompatible ice slurry
further comprises an agent including, but not limited to, a
vasoconstricting agent, corticosteroid, NSAID, anesthetic,
glucocorticoid and a lipoxygenase inhibitor or combinations
thereof. The vasoconstricting agent includes, but is not limited
to, epinephrine or norepinephrine. The anesthetic includes, but is
not limited to, lidocaine, bupivacaine, prilocaine, tetracaine,
procaine, mepivicaine, QX-314 and etidocaine or combinations
thereof.
[0025] In yet another embodiment, the biocompatible ice slurry is
injected. The injection can be administered into or around any
peripheral nerves including, but not limited to, the cutaneous
nerve, trigeminal nerve, ilioinguinal nerve, intercostal nerve,
interscalene nerve, intercostal nerves, supraclavicular nerve,
infraclavicular nerve, axillary nerve, paravertebral nerve,
transverse abdominis nerve, lumbar plexus nerve, femoral nerve,
pudental, celiac plexus and sciatic nerve, any nerve conducting
painful sensations or any injured nerve producing pain or
disease.
[0026] In yet another embodiment, the biocompatible ice slurry is
provided to the peripheral nerves of the subject by tumescent
pumping of the slurry.
[0027] In yet another embodiment, pressure is applied at the site
of injection to reduce blood flow.
[0028] In yet another embodiment, the tissue comprising the
peripheral nerves is cooled externally prior to, during, or after
providing the biocompatible ice slurry.
[0029] In yet another embodiment, ice content of the biocompatible
ice slurry is monitored by ultrasound or imaging.
[0030] In yet another embodiment, the subject in need of treatment
suffers from a disorder including, but not limited to, neuropathic
pain, diabetic neuropathy pain, trigeminal neuralgia, post-herpetic
neuralgia, phantom limb pain, cancer related itch or pain, burn
itch or pain, lichen sclerosus, scalp itch, nostalgia parastethica,
atopic dermatitis, eczema, psoriasis, lichen planus, vulvar itch,
vulvodynia, lichen simplex chornicus, prurigo nodularis, itch
mediated by sensory nerves, peripheral neuropathy, peripheral nerve
damage, post-thoracotomy pain, incisional pain, chest pain,
coccydynia, lower back pain (with or without radiculopathy), scars,
neuromas, acute post-operation pain, lumbar facet joint syndrome
and cutaneous pain disorder.
[0031] The cutaneous pain disorder includes, but is not limited to,
reflex sympathetic dystrophy (RSD), phantom limb pain, neuroma,
post herpetic neuralgia, headache, occipital neuralgia, tension
headaches and vulvodynia.
[0032] In yet another embodiment, the subject in need of treatment
suffers from a motor disorder including, but not limited to,
hemifacial spasm, bladder spasm, laryngospasm and gustatory
hyperhidrosis.
[0033] Other features and advantages of the invention will be
apparent from the Detailed Description, and from the claims. Thus,
other aspects of the invention are described in the following
disclosure and are within the ambit of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] The following Detailed Description, given by way of example,
but not intended to limit the invention to specific embodiments
described, may be understood in conjunction with the accompanying
figures, incorporated herein by reference.
[0035] FIG. 1 depicts a quantitative model to illustrate the
behavior of injected slurries.
[0036] FIG. 2 depicts three stages of heat exchange following
infusion of a slurry into a tissue.
[0037] FIG. 3 depicts a rat sciatic nerve, exposed via surgical
dissection.
[0038] FIG. 4 depicts a thermocouple placed under a rat sciatic
nerve to record tissue temperature.
[0039] FIG. 5 depicts tissue temperature following injection of a
6% hetastarch lactated ringer slurry on top of a live rat sciatic
nerve.
[0040] FIG. 6 depicts tissue temperature following injection of a
6% hetastarch lactated ringer slurry on top of a live rat sciatic
nerve.
[0041] FIG. 7 depicts tissue temperature following injection of a
6% hetastarch lactated ringer slurry on top of a live rat sciatic
nerve.
[0042] FIG. 8 depicts the blunt exposure of the common sciatic
nerve through the biceps femoris and separation from adjacent
tissue.
[0043] FIG. 9 depicts the injection of ice slurry.
[0044] FIG. 10 depicts the thermal paw withdrawal latencies of rats
with chronic constriction sciatic nerve injury. Following the
constriction sciatic nerve injury, responder rats were either
treated with slurry or left untreated (nonslurry). Increase in
thermal withdrawal latency response times to a heat exposure in
rats exposed to the slurry at 20, 25, and 42 days post-slurry was
observed indicating decreased pain to thermal stimuli.
[0045] FIG. 11 depicts testing results by comparing differences in
thermal withdrawal latencies of responder rates with normalization
to internal control.
[0046] FIG. 12 depicts the effect of increasing glycerol
concentrations (in normal saline) on slurry temperatures.
[0047] FIG. 13 verifies the blind injection of an ice slurry
stained with tattoo ink for visualization adjacent to the rat
sciatic nerve.
[0048] FIG. 14 depicts the thermal paw withdrawal latencies of rats
with chronic constriction sciatic nerve injury scored as "severe."
Differences in paw withdrawal latencies from baseline after
injection of room temperature and ice slurries show that ice slurry
induces decreased pain sensation after the injury.
[0049] FIG. 15 depicts the thermal paw withdrawal latencies of rats
with chronic constriction sciatic nerve injury scored as
"moderate." Differences in paw withdrawal latencies from baseline
after injection of room temperature and ice slurries show that ice
slurry induces decreased pain sensation after the injury.
[0050] FIG. 16 depicts the thermal paw withdrawal latencies of rats
with chronic constriction sciatic nerve injury scored as "mild."
Differences in paw withdrawal latencies from baseline after
injection of room temperature and ice slurries show that ice slurry
induces decreased pain sensation after the injury.
[0051] FIG. 17 depicts methods of removing slurry.
[0052] FIG. 18 depicts the difference in thermal withdrawal
latencies of the left hindpaw at time of follow-up as compared to
baseline measurements. A positive value indicates an increased
tolerance for thermal pain due to decreased sensation.
[0053] FIG. 19 depicts mean thermal withdrawal latency of rats
injected with slurries. Slurries were injected through a needle
around the left sciatic nerve and the right sciatic nerve was left
untreated to serve as control.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0054] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood those
skilled in the art to which this invention pertains. In case of
conflict, the present application, including definitions will
control.
[0055] Unless specifically stated or clear from context, as used
herein, the term "about" is understood as within a range of normal
tolerance in the art, for example within 2 standard deviations of
the mean. "About" is understood as within 10%, 9%, 8%, 7%, 6%, 5%,
4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value.
Unless otherwise clear from context, all numerical values provided
herein are modified by the term about.
[0056] As used herein, the term "biocompatible" refers to a
substance or solution having the capability of coexistence with
living tissues or organisms without causing harm.
[0057] As used herein, the term "ice" refers to the solid state of
water (i.e., frozen water).
[0058] As used herein, the term "water" refers to H.sub.2O and all
isotopes of H.sub.2O, including D.sub.2O, T.sub.2O, etc., and
mixtures thereof.
[0059] As used herein, the term "aqueous solution/aqueous slurry"
refers to a solution/slurry containing H.sub.2O and all isotopes of
H.sub.2O, including D.sub.2O, T.sub.2O, etc., and mixtures thereof.
Such solutions may include water in its solid, semi-solid and/or
liquid states.
[0060] As used herein, the term "equilibrium" or "equilibrium
temperature" refers to a temperature that is between the
temperatures of a slurry and a tissue at the time of initial
contact between the slurry and the tissue.
[0061] As used herein, "reversible inhibition" of peripheral nerves
refers to a loss of function in the nerve which is recovered over
time. Loss of function would include, for example, decreased
thermal or mechanical sensation in the nerve.
[0062] Ranges provided herein are understood to be shorthand for
all of the values within the range. For example, a range of 1 to 50
is understood to include any number, combination of numbers, or
sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,
45, 46, 47, 48, 49, or 50 (as well as fractions thereof unless the
context clearly dictates otherwise).
[0063] A "slurry" refers to solid phase particles (e.g., ice
particles) suspended in a biocompatible liquid phase solution. The
slurry may also contain gas phase bubbles.
[0064] A "subject" is a vertebrate, including any member of the
class mammalia, including humans, domestic and farm animals, and
zoo, sports or pet animals, such as, e.g., horse, cat, dog, mouse,
rabbit, pig, sheep, goat, cattle and higher primates.
[0065] As used herein, the terms "treat," "treating," "treatment"
and the like refer to reducing or ameliorating a disorder and/or
symptoms associated therewith. It will be appreciated that,
although not precluded, treating a disorder or condition does not
require that the disorder, condition or symptoms associated
therewith be completely eliminated.
[0066] In this disclosure, "comprises," "comprising," "containing"
and "having" and the like can have the meaning ascribed to them in
U.S. patent law and can mean "includes," "including," and the like;
"consisting essentially of" or "consists essentially" likewise has
the meaning ascribed in U.S. patent law and the term is open-ended,
allowing for the presence of more than that which is recited so
long as basic or novel characteristics of that which is recited is
not changed by the presence of more than that which is recited, but
excludes prior art embodiments.
[0067] Other definitions appear in context throughout this
disclosure.
Compositions and Methods of the Invention
[0068] In one aspect, the invention involves introducing a
composition comprising a cold slurry (e.g., ice slurry) into
interstitial tissue, i.e., directly into the tissue rather than
through a natural conduit of the body such as arteries, veins, or
gut. When a volume of ice slurry is directly introduced into a
volume of soft tissue, there is rapid heat exchange between the
tissue and the slurry. When rapidly and locally injected, a pool of
slurry is produced that mixes with a target volume of local tissue.
By contrast, if a slurry is infused more slowly and with larger
volume, the slurry penetrates and flows through spaces in the
tissue, producing widespread channels filled with slurry in a
process similar to the administration of tumescent anesthesia. With
infusion, there can be sustained flow of slurry through tissue,
especially tissue nearby the site of introduction. This tissue can
be profoundly cooled to the temperature of the slurry itself, by
the continuous or prolonged flow of slurry.
[0069] In general, there are two periods of heat exchange upon
injection of slurry directly into tissue--a rapid equilibration
between slurry and local tissue, followed by slower warming to body
temperature. During the rapid equilibration, the slurry is warmed
and the local tissue is cooled, until an equilibrium temperature is
reached that is between the initial temperatures of the slurry and
the tissue. During this rapid tissue cooling by heat exchange,
three events occur: 1) heat stored by the heat capacity of the
slurry and the tissue is exchanged; 2) heat released by the
crystallization of tissue lipids is exchanged; and 3) heat absorbed
by melting of slurry ice is exchanged. Some or all of the ice in
the slurry melts, and some or all of the lipids in the tissue are
crystallized, according to the parameters of the tissue and the
slurry. Crystallization of lipids in the myelin sheath of nerves,
or direct cooling of non-myelinated nerves, causes a targeted
relief of pain.
[0070] After the rapid heat exchange with the slurry, there is
gradual warming by heat exchange with the body. Gradual warming
occurs by a combination of heat diffusion from surrounding warm
tissue and by convective heating from blood flow. Blood flow can be
reduced in the local tissue by pressure or by drugs, e.g., blood
flow can be stopped or greatly reduced by applying pressure to the
cold tissue or by addition of epinephrine or other vasoconstrictor
agent(s) to the slurry. The desired level of pain relief may depend
on temperature, rate of cooling, duration of cooling and the number
of cooling cycles.
[0071] Effectiveness of treatment is related to the amount of lipid
crystallization, amount and number of epidermal nerve fiber and
dermal myelinated nerve fiber reduction, the minimum temperature
achieved, the duration of cold temperatures, and the number of cold
cycles (slurry injections can be easily repeated in one treatment
session). All of these parameters can be controlled in a local
tissue volume, by varying the amount and rate of introduction, of
slurries containing various fractions of ice content.
I. Formulations
[0072] Through selection of slurry components, including liquid and
cooled particle content (e.g., ice content), and application
parameters, including placement, rate and volume of infusion,
predictable target tissue cooling can be attained. During melting
of the ice component of a slurry, the temperature of the slurry is
at or near the melting point, keeping the slurry cold during and
after infusion into tissue. Depending on the composition and
osmolality of its liquid component, this melting temperature can be
chosen for desired effects on the tissue, over a range from about
-30 to about 10.degree. C., in particular, over a range from about
-30.degree. C. to about 4.degree. C., more in particular, over a
range from about -30.degree. C. and to about 2.degree. C.
[0073] The temperature of the solution comprising the slurry can be
adjusted by selection of liquid phase components, including various
solvents and solutes and ions that produce a controlled freezing
point depression (e.g., including aqueous solutions of NaCl and
other biocompatible salts, other electrolytes such as potassium or
chloride, glycerol, sugars, polysaccharides, lipids, surfactants,
anti-metabolites and detergents).
[0074] The solution comprising the slurry can include, or consist
essentially of, a lactated Ringer's solution or a saline solution
or hetastarch solution. Slurry formulations can be made with
dextrose, mannitol, glucose, sorbitol, mannitol, hetastarch,
sucrose, glycerol or ethanol or poly vinyl alcohol. Freezing point
depression to about -40.degree. C. can be achieved with saline,
glycerol, glucose, sorbitol, or mixtures thereof. In specific
embodiments, slurry formulations can be made with about 0.1% to
about 5% ethanol or about 0.1% to about 20% glycerol (e.g., in
particular, about 5% to about 10% glycerol).
[0075] In specific embodiments, the solution comprising the slurry
--comprises a lactated Ringer's solution with or without about 0.1%
to about 20% glucose or glycerol; saline with or without about 0.1%
to about 20% dextrose or glycerol; or a lactated Ringer's solution
in 6% hetastarch. In another specific embodiment, the solution
comprising the slurry can include about 0.1% to about 6% hetastarch
in a lactated electrolyte solution.
[0076] Glycerol is desirable for cryoprotection and/or use as a
surfactant. Freezing point depressions for glycerol-water solutions
can be achieved as described below in Table 1.
TABLE-US-00001 TABLE 1 Freezing Points of Glycerol-Water Solutions
Freezing Points Glycerol by Wt. (%) Water (%) (.degree. C.)
(.degree. F.) 0.0 100.0 0.0 32.0 5.0 95.0 -0.6 30.9 10.0 90.0 -1.6
29.1 11.5.sup.(1) 88.5 -2.0 28.4 15.0 85.0 -3.1 26.4 20.0 80.0 -4.8
23.4 22.6.sup.(1) 77.4 -6.0 21.2 25.0 75.0 -7.0 19.4 30.0 70.0 -9.5
14.9 33.3.sup.(1) 67.0 -11.0 12.2 35.0 65.0 -12.2 10.0 40.0 60.0
-15.4 4.3 44.5.sup.(1) 55.5 -18.5 -1.3 45.0 55.0 -18.8 -1.8 50.0
50.0 -23.0 -9.4 53.0.sup.(1) 47.0 -26.0 -14.8 55.0 45.0 -28.2 -18.8
60.0 40.0 -34.7 -30.5 60.4.sup.(1) 39.6 -35.0 -31.0 64.0.sup.(1)
36.0 -41.5 -42.7 64.7.sup.(1) 35.3 -42.5 -44.5 65.0 35.0 -43.0
-45.4 65.6.sup.(1) 34.4 -44.5 -48.1 66.0.sup.(1) 34.0 -44.7 -48.5
66.7.sup.(1) 33.3 -46.5 -51.7 67.1.sup.(1) 32.9 -45.5 -49.9
67.3.sup.(1) 32.7 -44.5 -48.1 68.0.sup.(1) 32.0 -44.0 -47.2 70.0
30.0 -38.9 -38.0 70.9.sup.(1) 29.1 -37.5 -35.5 75.0 25.0 -29.8
-21.6 75.4.sup.(1) 24.6 -28.5 -19.3 79.0.sup.(1) 21.0 -22.0 -7.6
80.0 20.0 -20.3 -4.5 84.8.sup.(1) 15.2 -10.5 13.1 85.0 15.0 -10.9
12.4 90.0 10.0 -1.6 29.1 90.3.sup.(1) 9.7 -1.0 30.2 95.0 5.0 7.7
45.9 95.3.sup.(1) 4.7 7.5 45.5 982.sup.(1) 1.8 13.5 56.3 100.0 0.0
17.0 62.6 .sup.(1)denotes actual determinations. The remaining
values were interpolated from the curve.
[0077] Ions that can be included in the slurry to produce a
controlled freezing point depression include, but are not limited
to calcium, potassium, hydrogen, chloride, magnesium, sodium,
lactate, phosphate, zinc, sulfur, nitrate, ammonium, carbonate,
hydroxide, iron, barium or combinations thereof, including salts
formed thereof.
[0078] Local blood flow is an important factor, e.g., if a long
treatment time is desired, agents that limit or eliminate local
blood flow can be employed. The solution comprising the slurry can
include vasoconstricting agents that reduce local tissue blood
flow. Suitable vasoconstricting agents include, but are not limited
to, epinephrine (e.g., 1/10,000 or less) and norepinephrine. Blood
flow can also be decreased by use of tourniquet,
pressure/compression, and suction of the area to be treated.
Vasoconstriction can also be achieved by precooling the tissue to
be treated with topical application of cold in a form of Peltier
cooling or application of ice or cold pack to the surface of the
skin.
[0079] Addition of physiologically compatible surfactant molecules
can enhance flow and tissue effects. Surfactants can also act as
foaming agents. Suitable surfactant molecules include, but are not
limited to, sodium tetradecyl sulphate, polysorbate, polysorbate 20
(polyoxyethylen (20) sorbitan monolaurate), polyoxyethylene
sorbitan monooleate, sorbitan monooleate polyoxyethylene sorbitan
monolaurate, lecithin, and polyoxyethylene-polyoxypropylene
copolymers, polysorbate, polysorbate 20 (polyoxyethylen (20)
sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20)
sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20)
sorbitan monostearate), polysorbate 80 (polyoxyethylene (20)
sorbitan monooleate), sorbitan ester, poloxamater or combinations
thereof.
[0080] Addition of agents such as lysolecithin, deoxycholate, or
other surfactants or detergent to the slurry will allow targeting
of non-myelinated nerves. For example, lysolecithin is known to
cause reversible degeneration of non-myelinated axons (Mitchell J.
Degeneration of Non-myelinated Axons in the Rat Sciatic Nerve
Following Lysolecithin Injection. Acta Neuropathol (Berl) (1982)
56:187-193). This combination will allow targeting of myelinated
and non-myelinated nerve fibers through slurry injection and thus
lead to complete nerve block.
[0081] Accordingly, the solution comprising the slurry can include
detergents that can function as freezing point depressants or
agents to dissolve myelin sheaths. Such detergents include, but are
not limited to, TWEEN.RTM. polysorbates, deoxycholate, cholate,
phosphatidyl choline and sodium deoxycholate. Exemplary slurry
formulations are shown in Table 2.
TABLE-US-00002 TABLE 2 Exemplary Slurry Formulations Slurry
Composition Temp Normal Saline + 5% Dextrose + 5% -3.9 C. Glycerol
Normal Saline + 5% Dextrose + 5% -3.2 C. Glycerol + Deoxycholate
Normal Saline + 5% Dextrose + 5% -2.9 C. Glycerol + Cholate 5%
Polyethylene glycol + Lactated -0.8 C. Ringer's + 5% Dextrose 5%
Polysorbate (Tween) 20 + -0.6 C. Lactated Ringer's + 5% Dextrose 6%
hetastarch in Lactated Ringers -0.8 C. Normal Saline + 5-10%
Glycerol -4.0 C. Lactated Ringer's + 5-10% -3.2 C. Glycerol Normal
Saline -0.2 C. Ice/Water 0.4 C. 20% Dextrose in Water -1.9 C.
[0082] The solution comprising the slurry can include agents to
reduce inflammation, including but not limited to, corticosteroids,
glucocorticoids, lipoxygenase inhibitors, and NSAIDs.
[0083] The solution comprising the slurry can include anesthetic
agents to further reduce pain, including but not limited to,
polidocanol, lidocaine, bupivacaine, prilocaine, tetracaine,
procaine, mepivicaine and etidocaine.
[0084] In one embodiment, the anesthetic is QX-314, N-ethyl
bromide, a quaternary lidocaine derivative that is a permanently
charged molecule capable of providing long term (over 24 hours)
anesthesia. Unlike lidocaine, QX-314 can provide more selective
blocking of nociceptors and with longer duration of action and less
side effects. QX-314 is a charged molecule that needs to enter the
cell and block the sodium channels intracellularly. The ability of
QX-314 to block from the inside but not the outside of neuronal
membranes could be exploited to block only desired neurons.
Combining QX-314 with the cold slurry injections described herein
can selectively target cold sensing nociceptive sensory neurons to
provide selective and long lasting anesthesia.
[0085] In another specific embodiment the slurry can be composed of
a lipid emulsion, such as, e.g., Intralipid, which is an emulsion
of soy bean oil, egg phospholipids and glycerin, and is available
in 10%, 20% and 30% concentrations. Lipid emulsions can be mixed
with amino acids and dextrose as part of a total nutrient
admixture.
[0086] In another specific embodiment the slurry can be composed of
a peritoneal dialysis solution.
[0087] The solution comprising the slurry can include cooled
particles such as, e.g., ice particles in sizes smaller than the
inner diameter of medical cannulas, catheters, and needles, e.g.,
smaller than about 1 mm and preferably smaller than about 0.1 mm.
The volume percent, size and/or shape of cooled particles
(preferably less than about 0.5 mm and nominally spherical or
ovoid) can be adjusted to optimize flow of the slurry through
needles catheters or cannulas and flow through the various target
tissues during infusion. See, for example, Kauffeld, M et al. Int J
Refrig. 2010. 33(8): 1491-1505. The volume percentage of cooled
particle (e.g., ice particle) within the infused slurry and the
volume of infused slurry determine cooling capacity of the
infusion. In specific embodiments, the volume percentage of ice
within the infused slurry can range from about 0.1% to about 50% of
the solution.
II. Methods of Treatment
[0088] In a given volume of target tissue into which a slurry is
infused, there are three stages of heat exchange. Initially, the
slurry is much colder than the tissue as it infuses into and/or
through the tissue. There is a strong thermal gradient between the
tissue and the slurry that rapidly equilibrates until a local
equilibrium temperature is achieved. During this rapid
equilibration stage, the slurry ice melts. The amount of melting
that occurs depends on the initial ice content, the local volume
fraction of slurry that is mixed with tissue, the starting tissue
temperature, tissue lipid content, and other factors including the
slurry infusion volume and rate. These factors can be modeled using
classical and numerical fluid and heat transfer approximations,
e.g., with finite element models (See Example 1). If ice remains
after this initial equilibration period, the equilibration
temperature will be very close to the melting point of ice in the
slurry, i.e., it can be from about -20.degree. C. to about
4.degree. C. The composition of the slurry fluid component sets the
low temperature limit for this equilibration temperature, i.e., the
equilibration temperature cannot be lower than depressed melting
point of ice in the slurry.
[0089] After reaching a local equilibrium, the second stage begins
in which ice continues to melt as heat is removed from surrounding
tissues. This second stage can last for seconds to many minutes,
depending on many factors. These factors include the amount of ice
per unit volume that remains after the initial equilibration,
dimensions of the tissue volume that contains ice, heat transfer
and composition of the target and surrounding tissues, and local
blood flow. The second stage can be viewed as providing a
"treatment temperature and treatment time" for a target tissue,
because temperature remains relatively stable in the target tissue
during this time, until all of the slurry ice has melted. Treatment
temperature is set mainly by composition of the slurry liquid, and
volume fraction of slurry that is infused into and around the
target tissue. Treatment time is set mainly by ice content and
infusion variables including volume, rate and distribution, and by
the size and shape of the target tissue, and by blood flow in the
target tissue. For example, a greater content of slurry ice will
extend the second stage; a greater infused slurry volume fraction
(ratio of local infused slurry to target tissue and infused slurry)
will extend this second stage; a large dimension of the infused
slurry-and-target tissue will extend this stage approximately in
proportion to the square of the dimension; and blood flow in the
target tissue will reduce the treatment time by causing faster
melting of the slurry ice. Heat transfer from the surrounding
(non-slurry-filled) tissue and by blood flow, melts the slurry ice
during this second stage.
[0090] In specific embodiments, the biocompatible ice slurry has a
first equilibration temperature of between about 4.degree. C. to
about -30.degree. C. and/or a second equilibration temperature of
between about 2.degree. C. to about -30.degree. C. These equilibria
temperature be achieved, for example, as follows: Using a slurry
composition of hetastarch in lactated electrolyte (500 ml), saline
(500 ml) and glycerol (100 ml), a slurry temperature of -5.degree.
C. can be obtained. A single bolus injection of about 25 ml of the
slurry composition into tissue with a starting temperature of
29.degree. C. can rapidly bring the tissue temperature down to
-3.2.degree. C. and maintain it below 0.degree. C. for about 10-15
minutes; Using a slurry composition of hetastarch in lactated
electrolyte (500 ml), saline (500 ml) and glycerol (50 ml), a
slurry temperature of -2.1.degree. C. can be obtained. A first
bolus injection of about 50 ml into tissue using a 15 gauge needle
achieves a tissue temperature of about -2.degree. C. to
-1.3.degree. C. The temperature can be maintained below 0.degree.
C. in the tissue for about 15 minutes. When the temperature of the
tissue is about -0.1.degree. C., a second bolus injection of
another 40-60 ml of slurry brings the tissue temperature down to
about -1.1.degree. C. and maintains that temperature for greater
than 15 minutes. Upon a third bolus injection, the tissue
temperature can be maintained below 0.degree. C. for greater than
20 minutes. About 4-5 injections of the slurry composition can
maintain cold temperatures below zero for 60 minutes to achieve
hypoesthesia. Peripheral nerves subject to temperatures below zero
for about 60 minutes will produce hypoethesia for several weeks
(e.g., 6-8 weeks). Thus multiple cycles of slurry injections can be
done to prolong the cooling effect with slurry injection.
[0091] The rate of ice melting can be monitored in a given
application and anatomic situation. For example, ice is readily
seen by medical ultrasound imaging that can be used to monitor the
ice content, size and shape, and rate of ice melting from a target
tissue. In some applications, ice content in the treatment tissue
can be monitored with ultrasound during and after infusion of the
slurry. During the second stage, treatment can be greatly prolonged
by providing repeated or continuous infusion of the slurry.
Ultrasound guidance can be used to monitor ice content and adjust
the repeated or continuous infusion of slurry accordingly.
[0092] To target a desired nerve, the location of the slurry
placement can be monitored with the use of ultrasound. For example,
during injection of a slurry, a targeted nerve can be monitored
through the use of ultrasound to ensure correct placement of the
slurry. This will allow precise delivery of the slurry and
targeting of the desired nerve.
[0093] Where increased treatment time is desired, methods that
temporarily limit or eliminate local blood flow can be employed.
For example, mechanical forces can be applied to limit blood flow,
including applying simple pressure after infusion of the slurry, or
if appropriate, tourniquet application before during and after
infusion of the slurry. Precooling the tissue prior to slurry
injection can also induce vasoconstriction. Continuous external
cooling after slurry injection can be employed to prolong the
duration for which the slurry is effective in the tissue.
[0094] Methods of the invention provide reversible inhibition of
peripheral nerves. After administration of the slurry, inhibition
can occur for up to about 5 months; for example, inhibition of
peripheral nerves can be achieved for a period of minutes, days,
weeks or months after a single administration of the slurry.
Multiple cycles of administrations of the slurry can be provided to
extend treatment as needed. The tissue can also be prechilled or
precooled prior to infusion of the slurry to allow the tissue
temperature to stay cooler for extended periods of time.
[0095] The third stage after infusion of slurry occurs after the
ice content has melted. The temperature of the target tissue is now
able to return gradually to body temperature by the same processes
that melted ice during the second stage--heat conduction, and heat
convection via blood flow. It may take minutes or even hours for
the target tissue to return to normal body temperature, depending
again on the size, anatomy, and blood flow involved. Temperature in
the target tissue increases in the third stage because all of the
slurry ice has melted. These stages are illustrated schematically
in FIG. 2.
[0096] Lipid-crystallization is one mechanism responsible for the
temporary and prolonged loss of nerve conduction following cooling
of nerves. The myelin sheath that surrounds nerve axons, contains a
high concentration of lipids. A primary function of the lipid-rich
sheath is to isolate the axons, such that action potentials (i.e.,
nerve signals) can propagate. Disruption and/or loss of the myelin
sheath after local cooling appear to follow a similar mechanism,
with crystallization of the myelin lipids followed by stress and
degradation. The myelin sheath is a cytoplasmic extension of
Schwann cells, which are slow to repair this kind of injury.
Prolonged (up to approximately 3 months or more) anesthesia, pain,
or itch reduction is therefore an application for this invention;
for example, a slurry can be used for prolonged nerve block after
injection/infusion at many of the anatomic sites that are
classically used for temporary nerve blocks using an anesthetic
injection.
[0097] Methods of the invention can reduce pain or itch or
eliminate symptoms associated with neurological disorders such as
neuropathic pain, diabetic neuropathy pain, trigeminal neuralgia,
post-herpetic neuralgia, phantom limb pain, cancer related itch or
pain, burn itch or pain, lichen sclerosus, scalp itch, nostalgia
parastethica, atopic dermatitis, eczema, psoriasis, lichen planus,
vulvar itch, vulvodynia, lichen simplex chornicus, prurigo
nodularis, itch mediated by sensory nerves, peripheral neuropathy,
peripheral nerve damage, post-thoracotomy pain, incisional pain,
chest pain, coccydynia, lower back pain (with or without
radiculopathy), superficial scars, neuromas, acute post-operation
pain, lumbar facet joint syndrome and cutaneous pain disorder.
[0098] The cutaneous pain disorder includes, but is not limited to,
reflex sympathetic dystrophy (RSD), phantom limb pain, neuroma,
post herpetic neuralgia, headache, occipital neuralgia, tension
headaches and vulvodynia.
[0099] Methods of the invention can also be used to reduce or
eliminate symptoms associated with pain disorders caused by
peripheral neuropathy, peripheral nerve damage from metabolic,
infectious, trauma, genetic or chemical process. Methods of the
invention can also be used to reduce or eliminate cutaneous
pain.
[0100] Methods of the invention can also be used to reduce or
eliminate symptoms associated with pain disorders caused by
surgery, such as any surgery that makes an incision through the
skin and induces pain. This includes thoracic surgery pain (e.g.,
treatment of incisional surgical pain) caused by thoracic surgery.
The slurry can be injected prior, during or after incision.
[0101] In a specific embodiment, a slurry can be used for
inhibition of pain after thoracic surgery, by injection of about 3
cm.sup.3 of slurry into the subcostal space. The lipid content of
the exemplary subcostal nerve is about 20% (f.sub.tlip=0.2). Prior
to injection, an ice pack is applied that cools the local tissue to
20.degree. C. (T.sub.t=20). A slurry containing 30% ice
(I.sub.o=0.3) and with 0.001% epinephrine added for
vasoconstriction, is injected around the nerve such that an
approximately equal volume of slurry and tissue is created
(f.sub.s=0.5). After the rapid exchange based on heat capacity,
temperature of the slurry-tissue mix is
T.sub.m=(1-f.sub.s)T.sub.t=10.degree. C. Because T.sub.m=10.degree.
C., no additional ice is melted to reach 10.degree. C., i.e.,
Q.sub.to10C=(T.sub.m-10).rho.C=0. Latent heat is exchanged as ice
in the slurry-tissue mix melts, while lipids crystallize in the
myelin sheath of the target nerve. The initial ice content of the
slurry-tissue mix is I.sub.o=f.sub.sI.sub.s, which is
I.sub.o=(0.5)(0.3)=0.15 or 15%. With this ice content, the value of
Q.sub.icetotal=f.sub.sI.sub.sH.sub.ice, or (0.5)(0.3)(74)=11
cal/cm.sup.3. The lipid content of the slurry-tissue mix is
f.sub.mflip=(1-f.sub.s)f.sub.tlip, which is (0.5)(0.2)=0.10 or 10%.
Crystallization (an exothermic process) of all the lipid in the
slurry-tissue mix produces a thermal energy Q.sub.liptotal equal to
the lipid content times the volumetric heat of fusion for lipids,
H.sub.lipid, as given above. With its lipid content of
f.sub.mflip=0.1, and the value of =34 cal/cm.sup.3, the energy
associated with lipid crystallization in the target nerve is
Q.sub.liptotal=f.sub.mlip H.sub.lipid=(0.1)(34)=3.4 cal/cm.sup.3.
All of the lipid in the nerve will be crystallized because
Q.sub.icetotal.gtoreq.Q.sub.liptotal, and residual ice remains. As
this residual ice melts, the temperature drops according to the
value of Q.sub.iceresidual=Q.sub.icetotal-Q.sub.liptotal, which
gives the value of Q.sub.iceresidual=11-3.4=7.6 cal/cm.sup.3. The
final temperature is given by
T.sub.final.about.10-Q.sub.iceresidual/.rho.C. As mentioned, the
value of .rho.C for most soft tissues is close to 1 cal/.degree.
C.-cm.sup.3, such that T.sub.final.about.10-7.6, or 2.4.degree. C.
Gradual warming of the .about.6 cm.sup.3 volume of slurry-tissue
mix then occurs. The diameter of a spherical volume v is given by
d=(6v/.sup.-).sup.1/3 For a 6 cm.sup.3 spherical volume of
slurry-tissue mix, the diameter is therefore about 22 mm. The cold
slurry-tissue mix gradually warms over a time of about
(22).sup.2=480 seconds, or about 8 minutes. A second or further
injection of slurry can also be performed; the effectiveness of
multiple cold cycles is typically greater than one cycle.
[0102] Methods of the invention can also be used to reduce muscle
spasms caused by aberrant nerve firing such as bladder or facial
spasms.
[0103] Methods of the invention can also be used to target motor
nerves if prolonged paralysis of a motor nerve is desired.
[0104] Methods of the invention can also be used to reduce,
eliminate or alter functions controlled by the autonomic nervous
system. For example, the sympathetic nerve system controls
hyperhidrosis through the sympathetic fibers that innervate the
eccrine glands in the axilla. Methods of the invention can be used
to target those autonomic nerve fibers to reduce hyperhidrosis.
[0105] The solution comprising the slurry can be administered to
the peripheral nerves of the subject by injection, infusion or
tumescent pumping of the slurry into a nerve or nerves such as
peripheral, subcutaneous or autonomic nerves of the subject by
injection into a nerve or nerves selected from the group consisting
of the cutaneous nerve, trigeminal nerve, ilioinguinal nerve,
intercostal nerve, interscalene nerve, supraclavicular nerve,
infraclavicular nerve, axillary nerve, pudental nerve,
paravertebral nerve, transverse abdominis nerve, lumbar plexus
nerve, femoral nerve and sciatic nerve.
[0106] Methods of the invention can also reduce or eliminate pain
associated with a nerve plexus (i.e., a group of intersecting
nerves) including but not limited to the cervical plexus that
serves the head, neck and shoulders; the brachial plexus that
serves the chest, shoulders, arms and hands; the lumbar plexus that
serves the back, abdomen, groin, thighs, knees, and calves; the
sacral plexus that serves the pelvis, buttocks, genitals, thighs,
calves, and feet; the celiac plexus (solar plexus) that serves
internal organs; the coccygeal plexus that serves a small region
over the coccyx; the Auerbach's plexus that serves the
gastrointestinal tract; and Meissner's plexus (submucosal plexus)
that serves the gastrointestinal tract.
[0107] Methods of the invention can also be used for renal
sympathetic denervation, which is an emerging therapy for the
treatment of severe and/or resistant hypertension.
[0108] Flowing the slurry through tissue allows cooling over a
great distance from the infusion point, in particular through
tissue structures with minimal resistance to fluid flow, e.g.,
along the perineural sheath of sensory or motor nerves. The
solution can also be administered to any peripheral or cutaneous
nerve that is accessible via a syringe needle percutaneously or
through catheter via the circulatory system.
[0109] The means for injecting the slurry (for example, the needle)
can include additional features, such as, e.g., a sensor for
providing temperature readings to allow monitoring of target tissue
temperature. The means for injecting the slurry can optionally have
the ability to retrieve the melted components of the slurry, while
allowing the injection of new slurry, as depicted in FIG. 17.
[0110] The location of the injection can be verified, e.g., through
MRI or x-ray imaging for example, when the slurry contains imaging
agents known in the art. Pre-activation of nerves and/or
verification of needle placement by electric or chemical
stimulation can also performed in connection with methods of the
invention. Here, correct placement of the slurry can be facilitated
by injecting anesthetic or electrical stimulation to produce
sensation or anesthesia along the targeted nerve prior to injection
of the slurry.
[0111] The duration for which a slurry is administered can be
determined by a physician or other qualified professional or
technician and adjusted, as necessary, to suit observed effects of
the treatment or as is needed, depending on the formulation of the
slurry administered. It is well within the skill in the art to
adjust the duration of treatment according to the methods described
herein.
[0112] Methods of the invention can also be used to treat urinary
incontinence. In a recent survey among women aged 25-84 in the
United States an estimated 15% report experiencing stress
incontinence and 13% report experiencing urge
incontinence/"overactive bladder." These two etiologies of
incontinence are due to separate mechanisms, though both mechanisms
may be experienced by a single patient.
[0113] Stress Incontinence is the most common type of incontinence
in younger women, often from urethral hypermobility due to
insufficient support of the bladder from the pelvic floor. This
lack of support is due to a loss of connective tissue. This loss of
support is also associated with other conditions such as pelvic
organ prolapse and problems with defecation (both constipation and
incontinence). At present the main treatment strategies include
pharmacologic therapies, pessaries and surgical intervention, for
which there are varying degrees of success. Parasympathetic,
sympathetic and somatic nerves play an important function in
controlling the lower urinary tract function. More specifically,
the smooth muscles of the bladder--the detrusor--are innervated
primarily by parasympathetic nerves; those of the bladder neck and
urethra--the internal sphincter--are innervated by sympathetic
nerves. The striated muscles of the external urethral sphincter
(EUS) receive their primary innervation from somatic nerves. The
slurries described herein could be used as an injectable therapy to
treat Stress Incontinence through targeting one or more of these
nerves.
[0114] Urgency incontinence is due to overactivity of the detrusor
muscle. Therapies to treat urgency incontinence are primarily
pharmacologic (e.g., Botulinum toxin) and are targeted toward
decreasing neural input to the bladder muscle to prevent the
frequent bladder spasms. Given the capacity of the ice slurries
described herein to reduce nerve function, another embodiment of
the invention provides treatment of urgency incontinence by
inhibiting neural input to the bladder. In one embodiment, the
treatment comprises an injectable therapy whereby the ice slurry is
administered to, e.g., the neuromuscular junction, to inhibit
neural input to the bladder.
[0115] The present invention is additionally described by way of
the following illustrative, non-limiting Examples that provide a
better understanding of the present invention and of its many
advantages.
EXAMPLES
[0116] The following Examples illustrate some embodiments and
aspects of the invention. It will be apparent to those skilled in
the relevant art that various modifications, additions,
substitutions, and the like can be performed without altering the
spirit or scope of the invention, and such modifications and
variations are encompassed within the scope of the invention as
defined in the claims which follow. The following Examples do not
in any way limit the invention.
Example 1: Quantitative Model to Illustrate the Behavior of
Injected Slurries
[0117] Simplifying and reasonable assumptions are made in a
quantitative model to illustrate the behavior of injected slurries,
as depicted in FIG. 1.
[0118] Heat capacity is an important component of the heat exchange
between a slurry and a tissue. The first heat exchange to consider
is that of the energy stored by the heat capacity of slurry and
tissue. The energy per unit volume in a medium stored by heat
capacity is given by H=T.rho.C, where H is energy density
(cal/cm.sup.3), T is temperature (.degree. C.), .rho. is density
(gm/cm.sup.3) and C is specific heat capacity (cal/.degree. C. gm).
Assume that .rho.C is the same for slurry and tissue and water,
i.e. .rho.C=1 cal/gm-.degree. C. This assumption is approximately
true for all soft tissues except fat, for which .rho.C is lower by
about a factor of 2.
[0119] Consider a local volume of tissue into which slurry has been
introduced. When slurry is introduced with a volume fraction of
f.sub.s into local tissue, the local tissue occupies a volume
fraction of (1-f.sub.s). The stored heat per unit volume of the
resulting slurry-tissue mix due to heat capacity of the slurry is
H.sub.s=f.sub.sT.sub.s.rho.C, and the stored heat per unit volume
due to heat capacity of the tissue is
H.sub.t=(1-f.sub.s)T.sub.t.rho.C. After rapid exchange of the
thermal energy due to heat capacity, a new temperature T.sub.1, is
achieved. Thermal energy due to heat capacity of the mix is given
by H.sub.m=T.sub.m.rho.C. Conservation of energy in the local heat
exchange requires that H.sub.s+H.sub.t=H.sub.m. Combining
equations:
f.sub.sT.sub.s.rho.C+(1-f.sub.s)T.sub.t.rho.C=T.sub.m.rho.C
Solving for Tm, the slurry-tissue mix temperature after this
initial part of heat exchange:
T.sub.m=f.sub.sT.sub.s+(1-f.sub.s)T.sub.t
Because the temperature of physiological ice slurries is generally
close to 0, this simplifies to:
T.sub.m=(1-f.sub.s)T.sub.t
[0120] The rapid heat exchange upon mixing due to heat capacity
alone is the volume-weighted average of the two starting
temperatures. For example, if f.sub.s=0, no slurry is added, and
T.sub.m=T.sub.t, the starting tissue temperature. If f.sub.s=1, the
mix is all slurry, and Tm=0. If f.sub.s=0.5, there is a 50-50 mix
of slurry and tissue, and the resultant temperature after mixing is
the average of the slurry and the tissue starting temperatures.
Typical values off, for interstitial injection of a slurry range
from about 0.2 to about 0.8, i.e., the mixed slurry-tissue volume
may have about 20% to 80% slurry content. Also consider the
situation of f.sub.s=0.5. If the starting tissue temperature
T.sub.t is 37.degree. C., then Tm=18.5.degree. C. after exchange of
heat from heat capacity.
[0121] The volume fraction of ice in a physiological slurry in this
model is defined as I.sub.s, being the volume of ice per unit
volume of slurry. Immediately after injection into tissue, the
initial volume fraction of ice in the local slurry-tissue mix, is
therefore:
I.sub.o=f.sub.sI.sub.s
I.sub.o is the total amount of ice available for melting, per unit
volume of the slurry-tissue mix.
[0122] After the rapid heat exchange from heat capacity, ice in the
slurry component of the slurry-tissue mix begins to melt, absorbing
heat and cooling the slurry-tissue mix. Ice in the slurry-tissue
mix melts until it is gone, or until an equilibrium temperature is
reached, before the period of gradual warming by body heat exchange
briefly discussed above. In pure water, ice and liquid water can
co-exist at equilibrium temperatures between 0.degree. C. and
4.degree. C. In tissue, there are numerous solutes that cause
freezing point depression, such that ice and water co-exist over a
somewhat lower temperature range, e.g., about -8.degree. C. to
0.degree. C. in skin. Lipids in the tissue are in a liquid state at
normal body temperature. As cooling of the slurry-tissue mix occurs
due to ice melting, below a certain temperature lipids can
crystallize. In essence, there is a heat exchange between the
latent heat of fusion from melting ice, and the latent heat of
fusion from lipid crystallization. These two processes proceed in
opposite directions (e.g., the water melts, the lipids crystallize)
because lipid crystallization occurs at temperatures considerably
higher than the freezing point of water. Most animal fats
crystallize at between 10.degree. C. and 15.degree. C., depending
on the length and saturation of the lipid chains in triglyceride
molecules. Wax esters and free fatty acids crystallize at similar
temperatures. Polar lipids crystallize at lower temperatures, for
example the phospholipids of cell membranes can remain somewhat
fluid even well below 0.degree. C.
[0123] Injected physiological slurries are effective to inhibit
pain or itch by affecting nerve myelin sheath lipids. Lipids of the
sheath crystallize well above 0.degree. C. Effective treatment
depends on variables including the starting tissue temperature
T.sub.t, the ice content of slurry I.sub.s, the amount and speed of
slurry injected to achieve an adequate slurry fraction f.sub.s in
the slurry-tissue mix, the target lipid content of the tissue
L.sub.t, its crystallization temperature T.sub.c, and the time for
which some ice remains in the slurry-tissue mix.
[0124] Enthalpy of fusion (also called heat of fusion), describes
how much thermal energy is absorbed (endothermic) or released
(exothermic) due to changing from solid to liquid state. The
melting of ice is an endothermic transition requiring a large
amount of thermal energy. For water, the heat of fusion is 80
cal/gm. The density of ice at 0.degree. C. is 0.92, such that the
volumetric heat of fusion, H.sub.ice (the heat energy needed to
melt a volume of ice) is:
H.sub.ice=74 cal/cm.sup.3
The total heat per unit volume that can be absorbed by melting all
of the ice in the slurry-tissue mix, Q.sub.icetotal, is simply its
total ice content multiplied by H.sub.ice:
Q.sub.icetotal=f.sub.sI.sub.sH.sub.ice
[0125] Typical values as mentioned above for f.sub.s range from
about 0.2 to 0.8, and the ice content of physiological slurry can
be up to about 50% (I.sub.s.about.0.5). For the approximate maximum
of I.sub.s=0.5, the range (without limitation) for Q.sub.icetotal
in the slurry-tissue mix is therefore about 7 to 30
cal/cm.sup.3.
[0126] The heat of fusion for animal fat lipids ranges from about
30-50 cal/gm (Cooling Technology in the Food Industry; Taylor and
Francis, 1976). The density of lipids range from about 0.8-0.9
gm/cm.sup.3 (e.g., palmitic triglyceride in solid phase is 0.85
gm/cm.sup.3). Taking the mean value of 40 cal/gm as the heat of
fusion, the latent heat per unit volume for crystallization of
lipids is about:
H.sub.lipid=34 cal/cm.sup.3.
[0127] Thus, the latent heat for crystallization of lipids is less
than half of that for melting of ice. Cooling of the slurry-tissue
mix proceeds by some ice melting, until the temperature reaches
about 10.degree. C., the temperature necessary for lipid
crystallization to begin. The thermal energy from consumed by
dropping the temperature of the slurry-tissue mix to about
10.degree. C. is given by:
Q.sub.to10C=(T.sub.m-10).rho.C.
[0128] At about that temperature, whatever ice remains from the
slurry will melt, absorbing the energy necessary to crystallize
about twice its own volume of lipid. If all of the tissue lipid is
crystallized, more ice will melt and the temperature will drop
below about 10.degree. C., potentially into the approximately
-8.degree. C. to 0.degree. C. range at which ice and liquid water
can coexist in tissue. The lipid content of the slurry-tissue mix
is therefore another important factor. Defining the lipid content
of the tissue as f.sub.tflip, the lipid content of the
slurry-tissue mix is:
f.sub.mlip=(1-f.sub.s)f.sub.tlip.
[0129] The value of f.sub.tlip depends on tissue type. The lipid
content of most soft tissues ranges from about 5% (most connective
tissues) to about 80% (fat), i.e., f.sub.tlip=0.05 to 0.8. The
energy per unit volume of the slurry-tissue mix that is produced by
crystallizating all of the lipid present, is:
Q.sub.liptotal=f.sub.mlipH.sub.lipid
[0130] During the period of latent heat exchange between ice
melting and lipid crystallization in the slurry-tissue mix, ice in
the slurry melts until all of the lipid is crystallized, or until
the ice is gone.
[0131] The fraction of the lipid in the slurry-tissue mix that
crystallizes is simply given by the energy balance:
f.sub.lipxtal=(Q.sub.icetotal-Q.sub.to10C)/Q.sub.liptotal
If (Q.sub.icetotal-Q.sub.to10C)<Q.sub.liptotal, a fraction of
the lipid will crystallize, given above by f.sub.lipxtal. If
(Q.sub.icetotal-Q.sub.to10C)=Q.sub.liptotal, all of the lipid will
crystallize and all of the ice will melt; the temperature will
remain near about 10.degree. C., the phase transition temperature
for most animal lipids. If
(Q.sub.icetotal-Q.sub.to10C)>Q.sub.liptotal, all of the lipid
will crystallize, and the temperature will thereafter decrease
below about 10.degree. C. until all of the ice is melted or until
an equilibrium exists between ice and liquid water in the tissue,
i.e., in the temperature range of about -8.degree. C. to 0.degree.
C. The lowest temperature reached is determined by heat exchange
between the residual ice melting, and the heat capacity of the
slurry-tissue mix. The lowest temperature T.sub.final can therefore
be estimated by equating the latent heat per unit volume absorbed
by melting of the residual ice, with the heat associated with heat
capacity of the temperature drop below about 10.degree. C.
[0132] The latent heat associated with the residual ice melting
after the lipid is crystallized is
Q.sub.iceresidual=Q.sub.icetotal-Q.sub.to10C-Q.sub.liptotal, and
the amount of residual ice per unit volume is
I.sub.residual=Q.sub.iceresidual/H.sub.ice. The temperature drop to
T.sub.final due to residual ice melting can be estimated by:
Q.sub.iceresidual.about.(10-T.sub.final).rho.C, which rearranges to
T.sub.final.about.10-Q.sub.iceresidual/.rho.C.
[0133] The local heat exchanges modeled above occur over a time
scale of seconds because the slurry is intimately in contact with
tissue, by mixing flowing and/or dissecting through the soft tissue
during interstitial injection. After exchange of the latent heats
from melting ice and crystallizing lipids, the temperature of the
slurry-tissue mix settles at about T.sub.final, then gradually
warms due to conduction and convection. The rate of gradual warming
depends therefore on the rates of conduction and convection. In the
absence of blood flow (convection), warming by conduction involves
a minimum characteristic time, proportional to the square of the
diameter of the local slurry-tissue mix. Typically in soft tissues,
the time in seconds for substantial warming of a region by
conduction (to 1/e of a final equilibrium value) is approximately
equal to the square of the diameter in millimeters. For example, a
10 mm diameter slurry-tissue mix would typically takes about 100
seconds for substantial warming, and a 30 mm diameter slurry-tissue
mix would typically takes about 900 seconds (i.e., 15 minutes) for
substantial warming by conduction. Depending on the ice content,
some ice may remain even after this estimated period of substantial
warming. The model presented here is illustrative, not exact.
Direct measurement of slurry and tissue temperatures can be
performed. As shown below, such measurements are generally
consistent with this approximate model.
Example 2: Inhibition of Sciatic Nerve Function in Rats
[0134] A 6% hetastarch lactated Ringer's slurry (i.e., hetastach
(500 ml), saline (500 ml) and glycerol (50 ml), blended together)
was injected on top of the sciatic nerve of a male rat weighing
about 250-271 g. The procedure was conducted as follows: The rat
was placed under general anesthesia using inhaled isoflurane and
oxygen. The sciatic nerve was exposed via surgical dissection (FIG.
3). A starting slurry temperature of -3.2.degree. C. to
-2.7.degree. C. was obtained and maintained throughout the
experiment. For each of five injections, 5 ml of slurry was
injected on top of the sciatic nerve. A thermocouple placed under
the sciatic nerve was used to record tissue temperature (FIG.
4).
[0135] The 6% hetastarch lactated Ringer's slurry can maintain
nerve tissue temperature below 0.degree. C. for an average of 5
minutes and the tissue temperature was maintained as long as ice
was present in the slurry (FIGS. 5, 6 and 7). The nerve block is
predicted to last days, weeks or months. When the ice turned to
liquid, the tissue temperature rapidly rose above zero. Precooling
the tissue around the nerve made the slurry last longer, as melting
of the ice occurred at a slower rate (FIG. 6).
Example 3: Rat Sensory Testing
[0136] The efficacy of cold therapy in large motor and sensory
nerve, such as the sciatic nerve, can be demonstrated in a rodent
model by assessing nerve tissue staining and conducting assays to
measure motor and sensory function following injection of cold
slurry. Sensory experiments were conducted on 12 adult male rats
having a mass between 250 grams and 350 grams. The rats were
habituated to the testing environment, labeled 1-12, and randomized
into 2 groups of 6 rats each. Baseline sensory testing was
performed 1 day prior to the procedure.
[0137] All rats received chronic constriction injury (CCI) to model
chronic neuropathic pain. The common sciatic nerve was exposed
using blunt dissection through the biceps femoris and was separated
from adjacent tissue as depicted in FIG. 8. A 4-0 chromic gut
suture was loosely tied around the nerve at 2 points about 1 mm
apart from each other. The desired degree of constriction retards,
but does not arrest, circulation through the superficial epineurial
vasculature.
[0138] Sensory testing was repeated on the rats 6 days post-CCI to
demonstrate efficacy of the procedure, i.e., the rats were more
sensitive to heat injury on the injured paw than the uninjured paw
and withdrew their injured paw much more quickly when exposed to
heat pain. All rats had the sciatic nerve exposed using blunt
dissection 1 week post-CCL Six rats received an injection of ice
slurry as depicted in FIG. 9. Six rats were opened and closed
without slurry injection (nonslurry).
[0139] The slurry injected into the six rats in the experimental
group consisted of 5% glycerol (by weight) in normal saline, plus a
5% glycerol spike (by weight) prior to injection. 10 cc of slurry
was injected around the sciatic nerve in each rat. A thermocouple
was placed beside the nerve to record the temperature. The mean
temperature of the slurry overlying the sciatic nerve at the time
of injection was about -1.1.degree. C. When the temperature reached
+5.degree. C., the area was blotted with sterile gauze and an
additional 10 cc of slurry was injected around the sciatic nerve
again. The tissue temperature in the injection site reached
+5.degree. C. in about 5 minutes on average.
[0140] All rats tolerated injection of slurry well. There was no
evidence of necrosis, infection, ulceration, or self-mutilating
behaviors.
[0141] Sensory testing was performed to test the potential
analgesic effect of the ice slurry at days 14, 20, 25, 32, 36, and
42 post-slurry-injection. Although all rats were randomized, some
rats responded better to the chronic constriction injury by
becoming more hypersensitive to thermal pain as expected. These
rats were used to assess reduction of thermal pain by injection of
ice slurry. The results are shown in the Figures described
below.
[0142] FIG. 10 depicts the thermal hindpaw withdrawal latencies of
responder rats showing longer response times to a heat exposure in
rats at 20, 25, and 42 days post-slurry-injection. Longer response
times indicate less pain from thermal stimuli indicating that
slurry reduces thermal pain.
[0143] Because sensory testing in rats is known to be variable one
method of reducing the variability is reporting the difference
between the test side (left hindpaw) and the internal control
(right hindpaw), i.e., right hindpaw latency minus left hindpaw
latency. FIG. 11 depicts testing results by comparing differences
in thermal withdrawal latencies of responder rats with
normalization to internal control. A positive value indicates that
the left paw withdraws quicker to heat pain than the right.
Declining differences in latency between the left paw and the right
paw can be seen after slurry injection indicating that slurry
reduces thermal pain.
Experiment 4: Tolerance to Various Slurry Compositions
[0144] The slurries listed in Table 3 were generated and
successfully injected around the rat sciatic nerve. "NS" is an
abbreviation for "normal saline" (0.90% grams NaCl per ml
H.sub.2O). "hetastarch" is another term for "hydroxyethyl starch",
a nonionic starch derivative. HEXTEND.RTM. (6% hetastarch lactated
electrolyte injection having an average molecular weight of 670,000
Daltons and available from Hospira, Inc. of Lake Forest, Ill.) was
used for the experiment conducted herein. "LR" is an abbreviation
for lactated Ringer's solution Percentages of glycerol are
expressed in terms of g/ml.
TABLE-US-00003 TABLE 3 Exemplary Slurries NS + 5% glycerol NS + 10%
glycerol NS + 20% glycerol Hetastarch + 5% glycerol LR + 10%
glycerol
[0145] One week post injection all rats were checked for
tolerability side effects via observation and via dissection of the
injected area and gross inspection. All the animals tolerated the
injection with no sign of infection, ulceration, necrosis or side
effects up to one week after the injection.
[0146] Table 4 below details additional safety and tolerability
testing on rats. Tattoo ink was added to show the localization of
the injected slurry around the sciatic nerve.
TABLE-US-00004 TABLE 4 Further Safety and Tolerability Testing
Amount Temp Injected Rat Slurry Composition Injection Site
(.degree. C.) (cc) 1. NS + 5% glycerol R thigh sciatic -2.0 7-10 2.
NS + 10% glycerol R thigh sciatic -2.2 7-10 3. NS + 10% glycerol +
Tattoo Ink R thigh sciatic -2.1 7-10 4. NS + 10% glycerol + Tattoo
Ink R thigh sciatic -2.8 7-10 5. NS + 20% glycerol + Tattoo Ink R
thigh sciatic -3.9 7-10 6. NS + 20% glycerol + Tattoo Ink R thigh
sciatic -4.0 7-10 7. Hetastarch + 5% glycerol R thigh sciatic -4.3
7-10 8. Hetastarch + 5% glycerol R thigh sciatic -4.3 7-10 9. LR +
10% glycerol R thigh sciatic -3.0 7-10 10. LR + 10% glycerol R
thigh sciatic -3.1 7-10 11. Ice flakes in cold R thigh sciatic -0.2
7-10 hetastarch .+-. glycerol 12. Ice flakes in cold R thigh
sciatic 0.0 7-10 hetastarch .+-. glycerol
[0147] No evidence of infection, tissue necrosis or ulceration in
any of the rats was seen in any of the rats at 24, 48, and 72 hours
post-injection. The muscle remained intact grossly. There were no
differences in necropsy observations between the side injected with
slurry and the side not injected with slurry 1 week post-injection.
Tattoo ink was found localized around the nerve indicating that
slurry was injected precisely around the target tissue (FIG.
13).
[0148] An additional study was performed to explore the safety and
tolerability limits of cryoslurries with increasing amount of
glycerol injected around the sciatic nerve of rats. The rats were
observed daily for one week post injection, and were checked for
tolerability of side effects via observation, photography and
histology. The results are shown in Table 5.
TABLE-US-00005 TABLE 5 Further Safety and Tolerability Testing
Amount Rat # Slurry Composition Slurry Temperature Injection Site
Injected 5 NS + 20% Glycerol -5.2 C. R Sciatic 15 cc 4 NS + 30%
Glycerol -6.7 C. R Sciatic 10 cc 3 NS + 30% Glycerol -7.4 C. R
Sciatic 9-10 cc 2 NS + 40% Glycerol -8.2 C. R Sciatic 9-10 cc 1 NS
+ 40% Glycerol -10.1 C. R Sciatic 9-10 cc
[0149] All of the animals tolerated the injection with no sign of
infection, ulceration, necrosis or side effects up to one week
after the injection, at which time the animals were sacrificed. No
abnormalities were noted at time of necropsy.
Example 5: Relationship of Solute Concentration to Slurry
Temperature
[0150] In FIG. 12, the effect of increasing glycerol concentrations
(in normal saline) on slurry temperatures are depicted. Increasing
the amount of glycerol in the slurry led to dramatic drop in slurry
temperature. The safety and tolerability limit of lowest tolerable
slurry temperature was tested with the injection s of slurries
shown in Table 5. All of the animals tolerated the injection with
no sign of infection, ulceration, necrosis or side effects up to
one week after the injection, at which time the animals were
sacrificed. No abnormalities were noted at time of necropsy.
Example 6: Feasibility of Blind Cryoneurolysis Injections
[0151] Referring now to FIG. 13, tattoo ink (black pigment) was
added to a slurry composed of normal saline and 20% glycerol. This
slurry was injected in a Sprague-Dawley rat, into the anatomic
pocket containing the sciatic nerve. One week post-injection, the
rat was sacrificed, and the skin overlying the anatomic pocket
containing the sciatic nerve was then dissected to confirm the
placement of the slurry (visible due to the tattoo ink) adjacent to
the sciatic nerve. This image demonstrates the feasibility of
delivering slurry around the sciatic nerve by blind injection
through the skin.
Example 7: Rat Sensory Testing
[0152] Additional sensory testing was conducted on Sprague-Dawley
rats that were habituated to the environment of sensory testing for
three consecutive days prior to obtaining baseline measurements.
Baseline sensory testing of thermal withdrawal latencies was
performed. Thermal withdrawal latencies represent the amount of
time it takes a rat to withdraw its hindpaw from an infrared heat
source, thus a higher value means a higher threshold for pain and a
lower value means that the rat has increased sensitivity to pain.
All rats received chronic constriction injury (CCI) to model
chronic neuropathic pain. The common sciatic nerve was exposed
using blunt dissection through the biceps femoris and was separated
from adjacent tissue. A 4-0 chromic gut suture was loosely tied
around the nerve at 2 points about 1 mm apart from each other. The
desired degree of constriction retards, but does not arrest,
circulation through the superficial epineurial vasculature. Sensory
testing was repeated on the rats 6 days post-CCI to demonstrate
efficacy of the procedure. All rats had the sciatic nerve exposed
using blunt dissection 1 week post-CCI.
[0153] The slurry injected into the rats in the experimental group
consisted of 10% glycerol (by weight) in normal saline, and had a
mean temperature of -3.9.degree. C. A thermocouple was placed
beside the nerve to record the temperature. Initially, 5 cc of
slurry was injected onto the nerve in each rat. Subsequently, using
a syringe smaller than the delivery syringe, slurry was
continuously removed from the site as it melted and was replaced
with new ice slurry. A 15 minute cooling duration of the nerve was
ensured, defined as a temperature of less than +5.degree. C. at the
site of the nerve. A sample of the slurry was removed from the
container and allowed to warm to room temperature. This room
temperature solution of identical composition to the slurry was
injected into control (room temperature slurry) rats.
[0154] All rats tolerated injection of the slurry well. There was
no evidence of necrosis, infection, ulceration, or self-mutilating
behaviors. Sensory testing was performed to test the potential
analgesic effect of the ice slurry at an intermediate time point
(Days 5 and 6 post slurry injection) and then a long term time
point (Day 28 post slurry injection). Selected rats were able to be
matched on the basis of mean injury severity post CCI. Injury
severity was determined by reduction of thermal withdrawal latency
compared to the mean baseline measurement: Injury
Severity=(Baseline Thermal Withdrawal Time)-(Thermal Withdrawal
Time at Time Point X). Hence, a reading of 0 would indicate that
the rat has returned to its baseline (pre-injury) pain threshold.
There were four rats that had perfect matches (.ltoreq.0.2 s
difference), and then an additional two rats were matched by
highest level of severity in the group (.ltoreq.0.5 s
difference).
[0155] In rats with severe sciatic constriction injury, the
addition of ice slurry reduced their pain level to thermal stimuli
at day 6 and day 28 post injection (FIG. 14). When compared to the
rat injected with room temperature slurry (shown in red), the one
injected with ice slurry (shown in blue) had a 4.4 fold reduction
in thermal withdrawal latency at day 28 post ice slurry injection
(1.4 s vs 6.2 s), indicating significantly reduced thermal pain
sensitivity.
[0156] In rats with moderate sciatic constriction injury, the
addition of ice slurry reduced their pain level to thermal stimuli
at day 6 and day 28 post injection (FIG. 15). When compared to the
rat injected with room temperature slurry (shown in red), the one
injected with ice slurry (shown in blue) had an almost 2 fold
reduction in thermal withdrawal latency at day 28 post ice slurry
injection (2.1 s vs 4.1 s) indicating significantly reduced thermal
pain sensitivity.
[0157] In rats with mild sciatic constriction injury, the addition
of ice slurry reduced their pain level to thermal stimuli at day 6
and day 28 post injection (FIG. 16). When compared to the rat
injected with room temperature slurry (shown in red), the one
injected with ice slurry (shown in blue) had an 11 fold reduction
in thermal withdrawal latency at day 28 post ice slurry injection
(0.2 s vs 2.2 s) indicating significantly reduced thermal pain
sensitivity. In fact, by day 28 the ice slurry injected rats had
thermal sensitivity equivalent to baseline levels which means that
addition of ice slurry reduced the pain level back to baseline.
Example 8: Injection of Slurry Around the Sciatic Nerve of Naive
(Uninjured) Rats
[0158] Male Sprague-Dawley rats weighing 250-271 g were obtained
and underwent baseline sensory testing. Thermal withdrawal
latencies of the hindpaws were obtained. Subsequently, the rats
were anesthetized with inhaled isoflurane and oxygen, and their
left thigh area was shaved and cleaned. Slurries of the following
compositions shown in Table 6 were then injected into the anatomic
pocket containing the left sciatic nerve:
TABLE-US-00006 TABLE 6 Injected Slurry Compositions Amount Number
of Slurry Composition Temperature Injected Rats Injected
Intralipid* -1.0 C. 10 cc 2 2.5% Urea in Normal Saline -2.9 C. 10
cc 2 6% hetastarch in Lactated -0.3 C. 10 cc 2 Ringer's Normal
Saline + 5% -3.0 C. 10 cc 2 Glycerol + Epinephrine + Isolecithin**
*Intralipid: 20% Intravenous fat emulsion: 20% soybean oil, 1.2%
egg yolk phospholipids (lecithin), 2.25% glycerin, water and sodium
hydroxide to adjust pH **Dosing of chemical agents: Epinephrine:
1:1,000 diluted, 0.05 cc in 10 cc of slurry, Isolecithin: 10 mg/ml
1 ml in 10 cc of slurry
[0159] All of the rats tolerated the procedure well and no adverse
effects at the site of injection were observed during follow-up.
The rats underwent subsequent sensory testing on days 7, 14 and 25
post-slurry injection (FIG. 18). When compared to baseline, there
was an increased thermal withdrawal latency of the hindpaw injected
with slurry on follow-up days 7, 14 and 25 post-slurry injection.
This increase in thermal latency reflects an increased tolerance
for thermal pain, which is indicative of anesthesia in the left
hindpaw. The difference between left (slurry injected) and right
(no injection) thermal withdrawal latencies is shown in FIG. 19.
The thermal withdrawal latencies of the left hindpaw (which
received the slurry injection) increase, whereas the right remain
relatively stagnant (no change).
[0160] From the foregoing description, it will be apparent that
variations and modifications may be made to the invention described
herein to adopt it to various usages and conditions. Such
embodiments are also within the scope of the following claims. The
recitation of a listing of elements in any definition of a variable
herein includes definitions of that variable as any single element
or combination (or subcombination) of listed elements. The
recitation of an embodiment herein includes that embodiment as any
single embodiment or in combination with any other embodiments or
portions thereof.
REFERENCES
[0161] All patents, patent applications and publications mentioned
in this specification are herein incorporated by reference to the
same extent as if each independent patent and publication was
specifically and individually indicated to be incorporated by
reference. Incorporation by reference herein includes, but is not
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