U.S. patent application number 10/192903 was filed with the patent office on 2003-04-24 for method and composition for inhibiting post-surgical adhesions.
Invention is credited to Flore, Stephen G., Reeve, Lorraine E..
Application Number | 20030077328 10/192903 |
Document ID | / |
Family ID | 24154554 |
Filed Date | 2003-04-24 |
United States Patent
Application |
20030077328 |
Kind Code |
A1 |
Reeve, Lorraine E. ; et
al. |
April 24, 2003 |
Method and composition for inhibiting post-surgical adhesions
Abstract
A method and compositions for reducing post-surgical adhesion
formation/reformation in mammals following surgical injury to a
body cavity or organs situated therein. The aqueous compositions
comprising pentoxifylline and a polyoxyalkylene block copolymer are
applied to the injured areas subsequent to surgical injury.
Inventors: |
Reeve, Lorraine E.; (Dexter,
MI) ; Flore, Stephen G.; (Bloomfield, MI) |
Correspondence
Address: |
Pillsbury Winthrop, LLP
Suite 200
11682 El Camino Real
San Diego
CA
92130
US
|
Family ID: |
24154554 |
Appl. No.: |
10/192903 |
Filed: |
July 10, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10192903 |
Jul 10, 2002 |
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09516640 |
Mar 1, 2000 |
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6399624 |
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09516640 |
Mar 1, 2000 |
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09141122 |
Aug 27, 1998 |
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6034088 |
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09141122 |
Aug 27, 1998 |
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08540229 |
Oct 6, 1995 |
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5843470 |
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Current U.S.
Class: |
424/486 ;
514/263.36; 514/723 |
Current CPC
Class: |
C08L 71/02 20130101;
C08L 5/00 20130101; C08L 71/02 20130101; C08L 71/02 20130101; A61L
31/16 20130101; C08L 5/04 20130101; C08L 5/08 20130101; A61L 31/16
20130101; C08L 71/02 20130101; C08L 1/28 20130101; C08L 89/06
20130101; A61L 31/041 20130101; A61L 31/06 20130101; A61L 2300/802
20130101; A61L 31/06 20130101; C08G 65/2609 20130101; A61L 2300/204
20130101; Y10S 514/885 20130101; A61L 31/041 20130101; A61L 31/041
20130101; A61L 31/06 20130101; A61L 31/16 20130101; Y10S 514/822
20130101; Y10S 514/975 20130101; Y10S 514/95 20130101; A61L
2300/424 20130101 |
Class at
Publication: |
424/486 ;
514/263.36; 514/723 |
International
Class: |
A61K 031/522; A61K
009/14; A61K 031/08 |
Claims
What is claimed is:
1. A method of inhibiting internal adhesions which comprises
administering to a body cavity of a mammal a hypo-osmotic,
hyperosmotic, or iso-osmotic aqueous composition, said aqueous
composition containing: a surfactant; an effective amount of
pentoxifylline; and a polyoxyalkylene polyether; said
polyoxyalkylene polyether being present in said aqueous composition
in an amount not exceeding about 10 percent and having a molecular
weight of about 10,000 to about 100,000 wherein said
polyoxyalkylene polyether is selected from the group consisting of:
(A) polyoxyalkylene polyethers prepared by reacting ethylene oxide
and at least one lower alkylene oxide having 3 to 4 carbon atoms
with at least one active hydrogen-containing compound having from 3
to 10 carbon atoms and from 3 to 6 active hydrogens to prepare a
heteric or block copolymer intermediate and further reacting said
copolymer intermediate with at least one alpha-olefin oxide having
an average carbon chain length of about 20 to 45 aliphatic carbon
atoms and wherein said alpha-olefin oxide is present in the amount
of about 0.3 to 10 percent by weight based upon the total weight of
said polyether; and, (B) polyoxyalkylene polyethers prepared by
reacting ethlyene oxide with at least one active
hydrogen-containing compound having from 2 to 10 carbon atoms and
from 2 to 6 active hydrogens to prepare a homopolymer intermediate
and further reacting said homopolymer intermediate with at least
one alpha-olefin oxide having an average carbon chain length of
about 20 to 45 aliphatic carbon atoms and wherein said alpha-olefin
oxide is present in the amount of about 0.3 to 10 percent by weight
based on the total weight of said polyether.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No.
09/516,640, filed Mar. 1, 2000, which is a continuation of
application Ser. No. 09/141,122, filed Aug. 27, 1998, now U.S. Pat.
No. 6,034,088, which is a continuation of application Ser. No.
08/540,229, filed Oct. 6, 1995, now U.S. Pat. No. 5,843,470.
FIELD OF THE INVENTION
[0002] This invention relates to methods and compositions for
inhibiting post-surgical adhesions in the mammalian abdominal or
thoracic cavity or other body spaces, whether accidentally or
surgically created.
DESCRIPTION OF THE RELATED ART
[0003] There is a need for improved methods and compositions for
inhibiting adhesion formation/reformation in body spaces of
mammals, whether accidentally or surgically created. According to
Ellis in a review entitled, "The Cause and Prevention of
Post-operative Intraperitoneal Adhesions," in Surgery, Gynecology
and Obstetrics for September 1971, volume 133, pages 497-509, at
pages 502-503, the prevention of adhesions has been the subject of
an enormous amount of work since the beginning of this century.
According to Ellis, these attempts have included means of
preventing the fibrin-coated walls of the intestine from reaching
each other by distending the abdomen with oxygen or filling the
abdomen with saline solution, paraffin, olive oil, lanolin,
concentrated dextrose solution, macromolecular solutions of all
sorts, and silicones.
[0004] Menzies and Ellis in a review entitled, "Intestinal
Obstruction from Adhesions--How Big is the Problem?" Annals of the
Royal College of Surgeons of England, vol. 72, pages 60-63, 1990,
reported finding adhesions in 10.4% of 115 patients with first-time
laparotomies while 93% of 210 patients had intra-abdominal
adhesions due to previous surgery. Admission for intestinal
obstruction was made for 0.9% of 28,297 general surgery patients
while 3.3% of 4,502 laparotomy patients were admitted for
intestinal obstruction due to adhesions. These data emphasize the
magnitude of readhesions after adhesiolysis or from subsequent
surgical procedures. The authors state on p. 62, that there is
currently no effective treatment that prevents their
recurrence.
[0005] High molecular weight dextran either alone or in combination
with dextrose has been used to prevent peritoneal adhesions
subsequent to surgery. Dextran is clinically standardized to a low
molecular weight of about 75,000 by partial hydrolysis and
fractional precipitation of the high molecular weight particles
which normally have molecular weights up to 200,000. Dextran is a
polymer of glucose which has a chain-like structure and is produced
from sucrose by Lenconostoc bacterial. In articles appearing in
Fertility and Sterility, volume 33, number 6, June 1980, pages
660-662, Holtz, Baker, and Tsai and volume 34, number 4, October,
1980, pages 394-395, by Holtz and Baker, results are reported of
the adhesion reducing effects of a 32% (aqueous) solution of
Dextran 70 containing 10% dextrose (sold under the trade name
HYSKON by Pharmacia, of Piscataway, N.J.). Holtz et al. postulate
several mechanisms of action in the prevention of peritoneal
adhesions utilizing HYSKON.RTM. including a simple mechanical
separation of adjacent surfaces, termed a hydroflotation
effect.
[0006] Project coordinator diZerega and several contributors have
reported the results of a large study in an article entitled,
"Reduction of Post-operative Pelvic Adhesions with Intraperitoneal
32% Dextron 70: A Prospective, Randomized Clinical Trial," in
Fertility and Sterility, volume 40, number 5, for November 1983,
pages 612-619. The authors, on page 618, indicate that the use of
Dextran intraperitoneally has limitations such as the reported
tendency of HYSKON to support bacterial proliferation and concern
over the anaphylactoid potential of dextran. In addition, the
benefit of Dextran 70 in preventing post-operative adhesions was
shown to be limited to the lower regions of the pelvis.
[0007] Borten, Seibert, and Taymor in Obstetrics and Gynecology,
vol. 61, number 6, June, 1983, pages 755-756 report in an article
entitled, "Recurrent Anaphylactic Reaction to Intraperitoneal
Dextran 75 Used for Prevention of Postsurgical Adhesions."
[0008] These authors indicate that anaphylactic reaction to Dextran
administered intravenously is well documented and report such a
reaction after intraperitoneal administration of Dextran.
[0009] The use of ethylene oxide/propylene oxide block copolymers
as surfactants in surgical scrub solutions and the topical
application of 10% solutions of these copolymers to wounds is
described in Edlich et al. in the Journal of Surgical Research,
volume 14, number 4, April 1973, pages 277-284. The test results
indicate that copolymers having an ethylene oxide:propylene oxide
ratio of 4:1 provide less inflammatory response in a wound to which
the copolymer is applied in comparison with a copolymer having an
ethylene oxide:propylene oxide ratio of 1:4. There is no indication
by Edlich et al. or any cited prior art that such copolymers are
useful in reducing post-operative adhesions or that isotonic,
aqueous solutions of such copolymers are useful in reducing
post-operative adhesions.
[0010] Over the years, methods have been developed to achieve the
efficient delivery of a therapeutic drug to a mammalian body part
requiring pharmaceutical treatment. Use of an aqueous composition
which can be applied at room temperature as a liquid but which
forms a semi-solid gel when warmed to body temperature has been
utilized as a vehicle for drug delivery. Such a system combines
ease of application with greater retention at the site requiring
treatment than would be the case if the aqueous composition were
not converted to a gel as it is warmed to mammalian body
temperature. In U.S. Pat. No. 4,188,373, PLURONIC.RTM. polyols are
used in aqueous compositions to provide thermally gelling aqueous
systems. Adjusting the concentration of he polymer provides the
desired sol-gel transition, that is, the lower the concentration of
polymer, the higher the sol-gel transition temperature.
[0011] In U.S. Pat. Nos. 4,474,751; 752; 753; and 4,478,822, drug
delivery systems are described which utilize thermosetting
polyoxyalkylene gels; the unique feature of these systems is that
both the gel transition temperature and/or the rigidity of the gel
can be modified by adjustment of the ionic strength, as well as by
the concentration of the polymer.
[0012] Other patents disclosing pharmaceutical compositions which
rely upon an aqueous gel composition as a vehicle for the
application of the drug or cosmetic preparation are U.S. Pat. Nos.
4,883,660; 4,861,760; 4,810,503; 4,767,619; and 4,511,563.
[0013] Steinleitner et al. in an article entitled, "Poloxamer 407
as an Intraperitoneal Barrier Material for the Prevention of
Post-Surgical Adhesion Formation and Reformation in Rodent Models
for Reproductive Surgery, Obstetrics and Gynecology, volume 1,
pages 48-52, 1991, discloses the anti-adhesion properties of
poloxamer 407. Poloxamer 407 is a biocompatible polymer, the
viscosity of which is dependent upon temperature and concentration
in aqueous solutions. The material is a liquid at room temperature
and is a solid at body temperature. In one experiment, poloxamer
solutions in concentrations ranging from 15-35% were applied to
standardized lesions on the uterine horn of hamsters. Significant
reduction in post-traumatic adhesion formation was observed
following treatment with the poloxamer solutions. In a second
experiment, the polymer was used in a paradigm for a typical
situation encountered in fertility surgery, that is, the prevention
of adhesion reformation after lysis of established adhesions. The
effects of applying poloxamer 407 after adhesiotomy in rabbits was
compared to controls that had received no treatments. The adhesion
reformation was reduced by a poloxamer 407 treatment.
[0014] Steinleitner in an article entitled, "New Modalities Under
Development for Adhesion Prevention; "Immunomodulatory Agents and
Poloxamer Barrier Materials," Gynecologic Surgery and Adhesion
Prevention, pages 235-251, 1993 discloses a review of the
pathophysiology of peritoneal wound repair that summarizes studies
evaluating immunomodulatory agents designed to favorably influence
aspects of post-surgical healing. Besides describing the physiology
of peritoneal repairs, the authors of the studies list a number of
immunomodulatory agents used in adhesion prevention such as calcium
channel blocking agents and other agents such as pentoxifylline.
The authors emphasize the application of barrier materials to
effect physical separation of injured viscera stating that it may
be the most effective therapy currently available to surgeons. The
ideal barrier material should be biocompatible, be absorbable and
have a neutral or beneficial effect on the events of peritoneal
healing. Further, the barrier material should serve as a local
delivery system for pharmacologic anti-adhesion treatments.
Poloxamer 407 has been identified as particularly well suited for
use in preventing adhesion formation or reformation as a barrier
material in infertility surgery.
[0015] The Steinleitner review discloses the use of pentoxifylline
in preventing the formation of post-surgical adhesions.
Pentoxifylline is a methylxanthine derivative which improves the
flow properties of blood by decreasing its viscosity. In patients
with chronic peripheral arterial disease, pentoxifylline increases
blood flow to the affected microcirculation and enhances tissue
oxygenation. Steinleitner et al. used the hamster uterine horn
primary injury model and administered doses of 0.1 to 10 mg/kg
subcutaneously at 12-hour intervals. This regimen was found to
provide protection against post-traumatic adhesion formation.
[0016] While the prior art discloses the use of pentoxifylline and
poloxamer 407 separately as agents that may be useful in inhibiting
or reducing the formation/reformation of adhesions in the
peritoneal cavity for mammals, there is a need for an improved
composition that can be applied directly to the body cavity and a
process for reducing post-surgical adhesion
formation/reformation.
SUMMARY OF THE INVENTION
[0017] Polyoxyalkylene compositions, pentoxifylline, and a method
of use are disclosed for inhibiting post-surgical adhesion
formation/reformation in mammals following injury to the organs of
a body cavity. The compositions of the invention are also useful in
reducing adhesion formation/reformation in body cavities. The
useful compositions comprise a combination of pentoxifylline and a
polyether and surfactant or pentoxifylline and polyoxyalkylene
block copolymer.
[0018] Polyphase systems are also useful and may contain
non-aqueous solutes, non-aqueous solvents, and other non-aqueous
additives. Homogeneous, polyphase systems can contain such
additives as water insoluble high molecular weight fatty acids and
alcohols, fixed oils, volatile oils and waxes, mono, di, and
triglycerides, and synthetic, water insoluble polymers without
altering the functionality of the system. In one embodiment of the
invention, the concentration of the block copolymer in the
compositions of the invention can be adjusted to take advantage of
the gelation properties of certain polyoxyalkylene block
copolymers. For instance, aqueous solutions of said block
copolymers at certain concentrations form clear gels at mammalian
body temperatures but are liquids at ambient temperatures. The
aqueous solutions of said block copolymers can be provided as
isomotically and pH balanced compositions which match the pH and
osmotic pressure of mammalian bodily fluids. Subsequent to
deposition of the compositions of the invention on the tissues of
the peritoneal, pelvic, or pleural cavity of a mammal, or other
body spaces, as described above, the polyoxyalkylene block
copolymer is absorbed into the circulatory system and is eventually
excreted, mainly in the urine. In another embodiment of the
invention aqueous gels are produced by combination of an
alpha-olefin epoxide capped polyether and a surfactant as described
in U.S. Pat. No. 4,810,503. In this embodiment, the aqueous,
osmotically balanced gels are applied as gels to injured tissues in
the peritoneal, pelvic or pleural cavities or other body spaces
with pentoxifylline to inhibit post-surgical adhesion
formation/reformation.
[0019] In addition to functioning as a means of reducing
post-operative adhesion formation/reformation in mammals following
surgical or accidental injury or inflammation to the peritoneal,
pelvic or pleural cavity or other body spaces, the pentoxifylline
and polyoxyalkylene compositions provide an osmotically balanced
environment surrounding the surgical injury which reduces adhesion
formation/reformation. For instance, the polyoxyalkylene block
copolymer and pentoxifylline can be instilled within the uterine
cavity as a distending medium during diagnostic or operative
intrauterine endoscopic procedures. This procedure has two
advantages. First, since certain aqueous concentrations of the
preferred polyoxyalkylene block copolymers form a clear gel, their
use is well suited for visualization of the tissues within the
uterine cavity. Second, since these aqueous solutions are liquids
at room temperature and below and form a clear gel at body
temperature, the use of said solutions to separate the uterine
cavity walls will diminish or prevent post-surgical adhesion
formation. Similarly, the application of the aqueous,
polyoxyalkylene, pentoxifylline, capped polyether-surfactant
combination as gels provide a similar adhesion reducing effect.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1 illustrates pentoxifylline release from formulations
of carboxymethylcellulose, hydroxyethylcellulose, sodium alginate,
xanthan gum, and phosphate buffer (vehicle control).
[0021] FIG. 2 illustrates pentoxifylline release from formulations
of low MW hyaluronic acid, high MW hyaluronic acid, collagen, and
phosphate buffer (vehicle control).
[0022] FIG. 3 illustrates pentoxifylline release formulations from
PEG 8000, 14% poloxamer 407 with 20 mg/ml pentoxifylline, PEG 8000,
14% poloxamer 407 with 20 mg/ml pentoxifylline, 14% poloxamer 407
with 24 mg/ml pentoxifylline, and 16% poloxamer 188 with 12 mg/ml
pentoxifylline, and phosphate buffer (vehicle control).
[0023] FIG. 4 illustrates pentoxifylline release from formulations
of 28% poloxamer 407 with 12 mg/ml pentoxifylline, 14% poloxamer
407 with 36 mg/ml pentoxifylline and 14% poloxamer 407 with 12
mg/ml pentoxifylline.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0024] A process and composition are disclosed for inhibiting
post-operative adhesion formation/reformation in mammals following
surgical or accidental injury or inflammation to the organs of the
peritoneal or pleural cavity or other body spaces. In this
specification and claims, the terms "peritoneal" and "abdominal"
cavity are used as synonyms, as are the terms "pleural" and
"thoracic" cavity. By the term "body spaces," we mean cavities or
areas of the body where there is an environment for allowing the
composition of the present invention to be in contact with body
tissues. "Body spaces" may be further defined as peritoneal,
abdominal, and thoracic cavities as well as joints and areas of the
body containing synovial fluid. The compositions include
pentoxifylline, which is a methylxanthine derivative, and indicated
for the treatment of patients with intermittent claudication on the
basis of chronic occlusive arterial disease of the limbs.
[0025] The present invention discloses a novel use for
pentoxifylline, in effective amounts, in combination with the
polyoxyalkylene compositions disclosed herein, by providing for the
inhibition of post-surgical adhesion formation/reformation when
applied directly onto a body tissue following injury.
[0026] In one embodiment of the invention, the preferred aqueous,
polyoxyalkylene block copolymer compositions are prepared at
concentrations so as to take advantage of the gelation properties
of certain of said block copolymers and at a pH and osmotic
pressure which match that of bodily fluids (pH 7.4 and 290
mOsm/kg). When certain of the polyoxyalkylene block copolymers of
the invention are present in aqueous solutions at concentrations
preferably of about 5% to about 30% by weight such compositions can
provide liquid compositions at ambient temperatures or below which
revert to gel compositions upon contact with living mammalian
tissue.
[0027] Alternatively, useful compositions of the invention include
aqueous compositions comprising at least one polyoxyalkylene block
copolymer which do not form gels at mammalian body temperature as
well as aqueous, isotonic, polyoxyalkylene gel polymers comprising
an alpha-olefin epoxide capped polyether and a surfactant. It is
believed that the aqueous compositions of the invention which do
not form gels upon contact with living mammalian tissue as well as
those which are applied to mammalian tissue in the gel state, also
function to prevent the formation/reformation of adhesions
subsequent to surgical procedures incurred by a mechanism of action
which has been termed in the prior art "hydroflotation." Thus, the
injured tissues are prevented from contacting adjacent tissues by
the means of the inclusion of a foreign fluid or gel in the
peritoneal, pelvic, or pleural cavity or other body spaces. It is
believed that the mechanism of action to prevent the
formation/reformation of adhesions is, in addition to
hydroflotation, properly characterized as the result of separating
the adjacent mammalian tissues by a firm, adherent coating.
[0028] The polyoxyalkylene block copolymer compositions of one
embodiment of the invention include at least one block copolymer as
defined below, in combination with pentoxifylline. The copolymer is
applied to injured tissue in combination with pentoxifylline, both
in effective amounts. The block copolymer compositions of the
invention comprise at least one polyoxyalkylene block copolymer of
the formula:
Y[(A).sub.n--E--H].sub.x (I)
[0029] which A is a polyoxyalkylene moiety having an oxygen/carbon
atom ration of less than 0.5, x is at least 1, Y is derived from
water or an organic compound containing x reactive hydrogen atoms,
E is a polyoxyalkylene moiety constituting at least about 60% by
weight of the copolymer, n has a value such that the average
molecular weight of A is at least about 500 to about 900, as
determined by the hydroxyl number of a hydrophobe base
intermediate,
Y[(A).sub.n--H].sub.x (II)
[0030] and the total average molecular weight of the copolymer is
at least about 5000.
[0031] In addition to those polyoxyalkylene polymers described
above, which are suitable in combination with effective amounts of
pentoxifylline in the formation of the compositions of the
invention, other polyoxyalkylene polymers which form gels at low
concentrations in water are suitable. These are described in U.S.
Pat. No. 4,810,503, incorporated herein by reference. These
polymers are prepared by capping conventional polyoxyalkylene
polyether polyols with an alpha-olefin epoxide having an average of
about 20 to about 45 carbon atoms, or mixtures thereof. Aqueous
solutions of these polymers gel in combination with surfactants,
which can be ionic or nonionic. The combination of the capped
polyether polymers and the surfactants provide aqueous gels at low
concentrations of the capped polymer and surfactant which generally
do not exceed 10% by weight total. Detailed methods of preparing
these aqueous gels are disclosed in U.S. Pat. No. 4,810,503.
Preparation of said aqueous gels is generally described below.
Preferred surfactants for use in preparing these gels are also
disclosed in said patent.
[0032] A conventional copolymer polyether polyol is prepared by
preparing block or heteric intermediate polymers of ethylene oxide
and at least one lower alkylene oxide having 3 to 4 carbon atoms as
intermediates. These are then capped with the alpha-olefin epoxide
to prepare the polymers of this invention. Ethylene oxide
homopolymers capped with said alpha-olefin oxides are also useful
as intermediates.
[0033] The heteric copolymer intermediate is prepared by mixing
ethylene oxide and at least one lower alkylene oxide having 3 to 4
carbon atoms with a low molecular weight active hydrogen-containing
compound initiator having at least two active hydrogens and
preferably, 2 to 6 active hydrogen atoms such as a polyhydric
alcohol, containing from 2 to 10 carbon atoms and from 2 to 6
hydroxyl groups, heating said mixture to a temperature in the range
of about 50.degree. C. to 150.degree. C., preferably, from
80.degree. C. to 130.degree. C., under an inert gas pressure,
preferably, from about 30 psig to 90 psig.
[0034] A block copolymer intermediate is prepared by reacting
either the ethylene oxide or said alkylene oxide having 3 to 4
carbon atoms with said active hydrogen-containing compound followed
by reaction with the other alkylene oxide. The ethylene oxide and
the alkylene oxides having from 3 to 4 carbon atoms are used in
said intermediates in amounts so that the resulting polyether
product will contain at least 10% by weight, preferably about 60%
to about 80% by weight, ethylene oxide residue. The ethylene oxide
homopolymer intermediate is prepared by reacting ethylene oxide
with said active hydrogen-containing compound. The reaction
conditions for preparing the block copolymer and ethylene oxide
homopolymer intermediates are similar to those for the heteric
copolymer intermediate. The temperature and pressure are maintained
in the above ranges for a period of about one hour to ten hours,
preferably one to three hours.
[0035] The alpha-olefin oxides which are utilized to modify the
conventional polyether intermediate of the prior art are those
oxides and the commercially available mixtures thereof generally
containing an average of about 20 to 45, preferably about 20 to 30,
carbon atoms. The amount of alpha-olefin required to obtain the
more efficient capped polyethers is generally about 0.3 to 10%,
preferably about 4 to 8%, of the total weight of the polyethers of
the invention.
[0036] Since the preparation of heteric and block copolymers of
alkylene oxides and ethylene oxide homopolymers are well known in
the art, further description of the preparation of said polymers is
unnecessary Further details of the preparation of heteric
copolymers of lower alkylene oxides can be obtained in U.S. Pat.
No. 3,829,506, incorporated hereby by reference. Further
information on the preparation of block copolymers of lower
alkylene oxides can be obtained in U.S. Pat. Nos. 3,535,307;
3,036,118; 2,979,578; 2,677,700; and 2,675,619, incorporated herein
by reference.
[0037] The surfactants may be ionic or non-ionic and many
surfactants and types of surfactants may be employed. While all
surfactants may not be effective in the preparation of osmotically
balanced gels of the instant invention, the fact that many are
effective makes it a simple matter for one skilled in the art to
select such surfactant with a minimum of trial and error.
[0038] The amounts of capped polyether polymer and surfactant may
be as little as 1.0% by weight or less of each depending on the
type and amount of the other components. There appears to be no
maximum amount of either component than that dictated by solubility
and preferred osmolality in an aqueous solution. However, the total
amount of capped polymer and surfactant would generally not exceed
10% by weight.
[0039] Preferably, the block copolymers which are useful are
selected from those defined above in formula I which contain at
least about 60% by weight, preferably at least about 70%, by weight
of the residue of ethylene oxide (polyoxyethylene moiety). Said
copolymers have a total average molecular weight of at least about
5000, and form a gel at mammalian body temperature, when in an
aqueous solution at a concentration generally, of about 10 to about
40%, and preferably, about 15 to about 30% by weight.
[0040] The amount of pentoxifylline used is an amount effective to
inhibit adhesion formation/reformation in combination with the
block copolymers of this invention when applied as a liquid or gel
to a body cavity following surgery. Typically, the amount may be
about 0.05% to about 7.0% by weight, preferably about 1.0% to about
4.0% by weight, based upon the total weight of the compositions of
the invention.
[0041] The proportion of water used is about 60% to about 90%, by
weight, preferably, about 70% to about 85%, by weight based upon
the total weight of the composition of the invention. Useful
polyoxyalkylene block copolymers which will form gels in such
aqueous solutions can be prepared using a hydrophobe base (such as
A in formulas I and II) derived from propylene oxide, butylene
oxide, or mixtures thereof. These block copolymers and
representative methods of preparation are further generally
described in U.S. Pat. Nos. 2,677,700; 2,674,619; and U.S. Pat. No.
2,979,528, incorporated herein by reference.
[0042] Generally, the polyoxybutylene-based block copolymers useful
in the compositions of the invention are prepared by first
condensing 1,2 butylene oxide with a water soluble organic compound
initiator containing 1 to about 6 carbon atoms such as 1,4 butylene
glycol or propylene glycol and at least 2 reactive hydrogen atoms
to prepare a polyoxyalkylene polymer hydrophobe of at least about
500, preferably at least about 1000, most preferably at least about
1500 average molecular weight. Subsequently, the hydrophobe is
capped with an ethylene oxide residue. Specific methods for
preparing these compounds are described in U.S. Pat. No. 2,828,345
and British Patent No. 722,746, both of which are hereby
incorporated by reference.
[0043] Useful polyoxybutylene based block copolymers conform to the
following generic formula:
HO(C.sub.2H.sub.4O).sub.b(C.sub.4H.sub.8O).sub.a(C.sub.2H.sub.4O).sub.bH
(III)
[0044] wherein a is an integer such that the hydrophobe base
represented by (C.sub.4H.sub.8O) has a molecular weight of at least
about 500, preferably at least about 1000 and most preferably at
least about 4000, as determined by hydroxyl number, the
polyoxyethylene chain constituting at least about 60%, preferably
at least about 70% by weight of the copolymer, and the copolymer
having a total average molecular weight of at least about 5000,
preferably at least about 10,000.
[0045] The copolymer is characterized in that all the hydrophobic
oxybutylene groups are present in chains bonded to an organic
radical at the former site of a reactive hydrogen atom thereby
constituting a polyoxybutylene base copolymer. The hydrophilic
oxyethylene groups are used to cap the polyoxybutylene base
polymer.
[0046] Polyoxyethylene-polyoxypropylene block copolymers which can
be used to form aqueous gels can be represented by the following
formula:
HO(C.sub.2H.sub.4O).sub.b(C.sub.3H.sub.6O).sub.a(C.sub.2H.sub.4O).sub.bH
(IV)
[0047] wherein a is an integer such that the hydrophobe base
represented by (C.sub.3H.sub.6O) has a molecular weight of at least
about 900, preferably at least about 2500 average molecular weight,
as determined by hydroxyl number; the polyoxyethylene chain
constituting at least about 60%, preferably at least about 70% by
weight of the copolymer, and the copolymer having a total average
molecular weight of at least about 5000, preferably at least about
10,000.
[0048] Polyoxyethylene-polyoxypropylene block copolymer adducts of
ethylenediamine which can be used may be represented by the
following formula: 1
[0049] wherein a and b are integers such that the copolymer may
have (1) a hydrophobe base molecular weight of at least about 2000,
preferably at least about 3000, and most preferably at least about
4500, (2) a hydrophile content of at least about 60%, preferably at
least about 70% by weight, and (3) a total average molecular weight
of at least about 5000, preferably at least about 10,000.
[0050] The hydrophobe base of the copolymer of formula V is
prepared by adding propylene oxide for reaction at the site of the
four reactive hydrogen atoms on the amine groups of
ethylenediamine. An ethylene oxide residue is used to cap the
hydrophobe base. These hydrophile polyoxyethylene groups are
controlled so as to constitute about 60% to about 80% by weight of
the copolymer.
[0051] The procedure used to prepare aqueous solutions which form
gels of the polyoxyalkylene block copolymers is well known. Either
a hot or cold process for forming the solutions can be used. A cold
technique involves the steps of dissolving the polyoxyalkylene
block copolymer at a temperature of about 5.degree. C. to about
10.degree. C. in water. When solution is complete the system is
brought to room temperature whereupon it forms a gel. If the hot
process of forming the gel is used, the polymer is added to water
heated to a temperature of about 75.degree. C. to about 85.degree.
C. with slow stirring until a clear homogeneous solution is
obtained. Upon cooling, a clear gel is formed. Block copolymer gels
containing polyoxybutylene hydrophobes must be prepared by the
above hot process, since these will not liquefy at low
temperatures.
[0052] As used herein, the term "gel" is defined as a solid or
semisolid solution containing a certain quantity of water. The
solution with water is often called a "hydrogel."
[0053] The organic compound initiator which is utilized in the
process for the preparation of the polyoxyalkylene block copolymers
generally is water or an organic compound and can contain a
plurality of reactive hydrogen atoms. Preferably, Y in formulas I
and II above is defined as derived from a water soluble organic
compound having 1 to about 6 carbon atoms and containing x reactive
hydrogen atoms where x has a value generally, of at least 1,
preferably, a value of at least 2. Y is derived from water soluble
organic compounds having at least two reactive hydrogen atoms.
Falling within the scope of the compounds of the present invention
are water soluble organic compounds such as propylene glycol,
glycerin, pentaerythritol, trimethylolpropane, ethylenediamine, and
mixtures thereof and the like.
[0054] The polyoxypropylene chains can optionally contain small
amounts of at least one of polyoxyethylene or oxybutylene groups.
Polyoxyethylene chains can optionally contain small amounts of at
least one of oxypropylene oxybutylene groups. Polyoxybutylene
chains can optionally contain small amounts of at least one of
polyoxyethylene or polyoxypropylene groups. The physical form of
the polyoxyalkylene block copolymers can be a viscous liquid, a
paste, or a solid granular material depending upon the molecular
weight of the polymer. Useful polyoxyalkylene block copolymers
generally have a total average molecular weight of about 5000 to
about 50,000, preferably about 5000 to about 35,000 and most
preferably about 10,000 to about 25,000.
[0055] Preferably the polyoxyalkylene block copolymer is applied to
surgically injured tissue as an aqueous solution which upon contact
with living mammalian tissue forms an adherent coating. Where a
polyoxyalkylene block copolymer is a viscous liquid or paste, the
compositions can be applied without dilution to areas of surgical
injury in the abdominal or thoracic cavities. The aqueous solution
or viscous liquid or paste may be applied to form an adherent
coating with the body tissue in the body cavity to aid in the
inhibition of the formation or reformation of adhesions. Another
function is to deliver pentoxifylline to the site of treatment.
Serving as a barrier, the composition of the present invention
prevents the close proximity or contact of tissues between surfaces
of which adhesions would form.
[0056] The following examples illustrate the various aspects of the
invention but are not intended to limit its scope. Where not
otherwise specified throughout this specification and claims,
temperatures are given in degrees centigrade, and parts,
percentages, and proportions are by weight.
EXAMPLE 1
[0057] An aqueous solution was made of a
polyoxyethylene-polyoxypropylene block copolymer having the
structure generically shown as formula IV and having a
polyoxypropylene hydrophobe base average molecular weight of about
4000, a total average molecular weight of about 11,500, and
containing oxyethylene groups in the amount of at least about 70%
by weight of the total weight of copolymer. This copolymer is sold
under the trademark PLURONIC.RTM. F-127 by the BASF Corporation,
Parsippany, N.J. (also known as Poloxamer 407). A solution was made
by dissolving said polymer in cold (4.degree. C.) distilled water
to give a concentration of approximately 30% by weight in
accordance with the cold process described above for forming
aqueous solutions. More specific solution procedures are described
in "Artificial Skin I Preparation and Properties of Pluronic F-127
Gels for Treatment of Burns," J. Biomed. Mater. Res. 6, 527, 1972,
incorporated herein by reference. The block copolymer has the
formula:
H[OCH.sub.2--CH.sub.2).sub.49(OCH(CH.sub.3)CH.sub.2].sub.67[OCH.sub.2--CH.-
sub.2].sub.49OH (VI)
[0058] This solution is a liquid at 4.degree. C. and forms a gel
which is adherent to living tissue upon contact.
EXAMPLE 2
[0059] The following formation was prepared:
1 Ingredient Percent by Weight Poloxamer 407, NF 28.00
Pentoxifylline 0.40 Tromethamine (TRIS), USP 0.1091 Maleic Acid
0.1045 Sodium Hydroxide pellets, USP 0.0420 Sterile Water for
Irrigation, USP 71.344
[0060] First, the water was weighed in a tared vessel. Second, the
tromethamine, maleic acid and sodium hydroxide were added to the
water and mixed for twenty minutes. The pH and osmolality of the
solution were tested and found to be 7.6 and 39 mOsm/Kg,
respectively. The solution was cooled to 6.degree. C. and the
poloxamer was added to the solution over a two-hour period with
constant stirring. The solution was stored under a nitrogen
atmosphere at 4.degree. C. for fifteen hours to effect a reduction
in the foam content of the solution. The solution was tested for
pH, osmolality, and viscosity and the results were 7.4, 123 mOsm/kg
and 360,000 centipoise at 30.degree. C., respectively. The solution
was packaged into 30 cc serum vials, capped with rubber stoppers
and sterilized with steam at 121.degree. C. and 15 psi for twenty
minutes. To each vial, an amount of pentoxifylline was added via
sterile filtration, such that a final concentration of 4 milligrams
of pentoxifylline per milliliter of solution was obtained. Each
vial was recapped and sealed as soon as the addition of
pentoxifylline was completed, then cooled to 4.degree. C. and mixed
for ten minutes to ensure uniform distribution of pentoxifylline in
the vial.
EXAMPLE 3
Analytical Method
Measurement of Pentoxifylline Release from Various Formulations
[0061] Approximately 15 cm of SpectraPor regenerated cellulose
dialysis tubing (6000-8000 molecular weight cut off, cat. #132650,
Source: Spectrum Medical Industries, Inc.) is rinsed in distilled
water to remove preservatives. One end is sealed with the
appropriate sized closure.
[0062] 5 ml of the formulation to be tested was placed in the
tubing and the other end sealed as close as possible to the sample.
The tubing is placed in a beaker containing 95 ml of phosphate
buffer (0.05 M KH.sub.2PO.sub.4+0.0391 M NaOH, pH 7.4) and a
magnetic stirring bar. The solution was mixed on low speed at room
temperature. One ml samples were withdrawn (via pipet) at each time
point and diluted to an appropriate volume (either 10 or 25 ml)
with water for UV absorbance measurements.
[0063] UV absorbance of the test solution is determined at 273 nm
versus a water blank. A 100% release standard is prepared by
diluting 5 ml of the formulation to be tested to 100 ml with
phosphate buffer. 1 ml of this solution is then diluted to 25 ml
with water for absorbance measurement.
[0064] Percent released is calculated by ratioing the absorbance of
the test solution at each time point against the 100% release
standard, taking into account any differences in dilution, the
small decrease in volume of the test solution at each time point
caused by earlier sample withdrawals and the amount of
pentoxifylline already removed due to previous samplings.
[0065] The results are summarized in FIGS. 1-4. FIG. 1 illustrates
pentoxifylline release from formulations of carboxymethylcellulose,
hydroxyethylcellulose, sodium alginate, xanthan gum, and phosphate
buffer (vehicle control). FIG. 2 illustrates pentoxifylline release
from formulations of low MW hyaluronic acid, high MW hyaluronic
acid, collagen, and phosphate buffer (vehicle control). FIG. 3
illustrates pentoxifylline release formulations from PEG 8000, 14%
poloxamer 407 with 20 mg/ml pentoxifylline, PEG 8000, 14% poloxamer
407 with 20 mg/ml pentoxifylline, 14% poloxamer 407 with 24 mg/ml
pentoxifylline, and 16% poloxamer 188 with 12 mg/ml pentoxifylline,
and phosphate buffer (vehicle control). FIG. 4 illustrates
pentoxifylline release from formulations of 28% poloxamer 407 with
12 mg/ml pentoxifylline, 14% poloxamer 407 with 36 mg/ml
pentoxifylline and 14% poloxamer 407 with 12 mg/ml
pentoxifylline.
2 Representative Formulations Ingredient Source Weight %
Formulation: Sodium Alginate Gel with Pentoxifylline Sodium
Alginate TIC Gums 2.000 Pentoxifylline ICN 1.200 Tromethamine, USP
Spectrum 0.109 Maleic Acid Spectrum 0.105 Sodium Hydroxide, USP
Spectrum 0.042 Purified Water Bamsted 96.544 Formulation: Collagen
Gel with Pentoxifylline Hydracol Soluble Collagen Gattefasse 1.000
Pentoxifylline ICN 1.200 Tromethamine, USP Spectrum 0.109 Maleic
Acid Spectrum 0.105 Sodium Hydroxide, USP Spectrum 0.042 Purified
Water Bamsted 97.540 Formulation: Vehicle Control with
Pentoxifylline Pentoxifylline ICN 1.200 Tromethamine, USP Spectrum
0.109 Maleic Acid Spectrum 0.105 Sodium Hydroxide, USP Spectrum
0.042 Sodium Chloride Spectrum 0.750 Purified Water Bamsted 97.794
Formula: PEG 8000 with Pentoxifylline PEG 8000 Union Carbide 10.000
Pentoxifylline ICN 1.200 Tromethamine, USP Spectrum 0.109 Maleic
Acid Spectrum 0.105 Sodium Hydroxide, USP Spectrum 0.042 Purified
Water Bamsted 88.544 Formula: 14% Poloxamer 407 with 20 mg/ml
Pentoxifylline Poloxamer 407 BASF 14.000 Pentoxifylline ICN 2.000
Tromethamine, USP Spectrum 0.109 Maleic Acid Spectrum 0.105 Sodium
Hydroxide, USP Spectrum 0.042 Sodium Chloride Spectrum 0.040
Purified Water Bamsted 83.700 Formula: 14% Poloxamer 407 with 24
mg/ml Pentoxifylline Poloxamer 407 BASF 14.000 Pentoxifylline ICN
2.400 Tromethamine, USP Spectrum 0.109 Maleic Acid Spectrum 0.105
Sodium Hydroxide, USP Spectrum 0.042 Sodium Chloride Spectrum 0.020
Purified Water Bamsted 83.324 Formula: 16% Poloxamer 188 with 12
mg/ml Pentoxifylline Poloxamer 188 BASF 16.000 Pentoxifylline ICN
1.200 Tromethamine, USP Spectrum 0.109 Maleic Acid Spectrum 0.105
Sodium Hydroxide, USP Spectrum 0.042 Purified Water Bamsted 82.544
Formula: 28% Poloxamer 407 with 12 mg/ml Pentoxifylline Poloxamer
407 BASF 28.00 Pentoxifylline ICN 1.20 Tromethamine, USP Spectrum
0.109 Maleic Acid Spectrum 0.105 Sodium Hydroxide, USP Spectrum
0.042 Purified Water Bamsted 70.544 Formula: 14% Poloxamer 407 with
36 mg/ml Pentoxifylline Poloxamer 407 BASF 14.00 Pentoxifylline ICN
3.60 Tromethamine, USP Spectrum 0.109 Maleic Acid Spectrum 0.105
Sodium Hydroxide, USP Spectrum 0.042 Purified Water Bamsted 82.144
Formula: 14% Poloxamer 407 with 12 mg/ml Pentoxifylline Poloxamer
407 BASF 14.00 Pentoxifylline ICN 1.20 Tromethamine, USP Spectrum
0.109 Maleic Acid Spectrum 0.105 Sodium Hydroxide, USP Spectrum
0.042 Sodium Chloride Spectrum 0.040 Purified Water Bamsted
84.504
EXAMPLE 4
Surgical Trial on Prospective Study on Adhesions in the Rabbit
Model
[0066] To assess the potential of poloxamer 407 with pentoxifylline
to prevent or reduce adhesions, the following experiment was
performed.
[0067] The following solution of of 14% poloxamer 407 with 1.2%
pentoxifylline was prepared:
3 Ingredient Percent by Weight Poloxamer 407, NF 14.00
Pentoxifylline 1.20 Tromethamine (TRIS), USP 0.1091 Maleic Acid
0.1045 Sodium Hydroxide pellets, USP 0.0420 Sodium Chloride, USP
0.04 Sterile Water for Irrigation, USP 82.54
[0068] Water was weighed into a tared vessel. Pentoxifylline,
tromethamine, maleic acid and sodium hydroxide were added to the
water and mixed for twenty minutes. The pH and osmolality of the
solution were tested and found to be 7.6 and 109 mOsm/Kg,
respectively. The solution was cooled to 6.degree. C. and the
poloxamer was added to the solution over a two-hour period with
constant stirring. The solution was stored under a nitrogen
atmosphere at 4.degree. C. for fifteen hours to effect a reduction
in the foam content of the solution. The solution was tested for pH
and osmolality and the results were 7.4 and 290 mOsm/Kg,
respectively. The solution was packaged into 30 cc serum vials,
capped with rubber stoppers and sterilized with steam at
121.degree. C. and 15 psi for twenty minutes. The vials were cooled
to 4.degree. C. and swirled for ten minutes to ensure uniform
distribution.
[0069] The equipment utilized eighteen, healthy, female, New
Zealand White rabbits. The uterine horn was exteriorized, then
abraded by scraping 20-30 times with a no. 10 scalpel blade until a
wound was produced that had punctate bleeding. Nine of the rabbits
received 3.0 ml of 14% poloxamer 407 with 1.2% pentoxifylline
delivered at 0.degree. C. Five rabbits received a physiologic
buffer also delivered at 0.degree. C. Four rabbits received no
treatment. The opposite uterine horn was untreated. The uterine
horns were returned to the peritoneal cavity and the incision was
closed. On the 12th day after the initial surgery, the animals were
necropsied and the adhesions were scored. The adhesions were scored
as follows: 0=no adhesions, 1=adhesions up to 25% of area,
2=adhesions from 25% to 50% of area, 3=greater than 50% of area,
4=100% adhesions.
4 Treatment Adhesion Score (Mean) 14% poloxamer 407 with 12%
pentoxifylline 0.67 physiologic buffer 2.4 no treatment 2.35
[0070] The following poloxamer 188 solution was prepared:
5 Ingredient Percent by Weight Poloxamer 188, NF 16.00
Pentoxifylline 1.20 Tromethamine (TRIS), USP 0.1091 Maleic Acid
0.1045 Sodium Hydroxide pellets, USP 0.0420 Sterile Water for
Irrigation, USP 82.54
[0071] Water was weighed into a tared vessel. Pentoxifylline,
tromethamine, maleic acid and sodium hydroxide were added to the
water and mixed for twenty minutes. The pH and osmolality of the
solution were tested and found to be 7.7 and 50 mOsm/Kg,
respectively. The solution was cooled to 6.degree. C. and the
poloxamer was added to the solution over a two-hour period with
constant stirring. The solution was stored under a nitrogen
atmosphere at 4.degree. C. for fifteen hours to effect a reduction
in the foam content of the solution. The solution was tested for pH
and osmolality and the rabbits were 7.4 and 140 mOsm/Kg,
respectively. The solution was packaged into 30 cc serum vials,
capped with rubber stoppers and sterilized with steam at
121.degree. C. and 15 psi for twenty minutes. The vials were cooled
to 4.degree. C. and swirled for ten minutes to ensure uniform
distribution of pentoxifylline in the vial.
EXAMPLE 5
Surgical Trial and Prospective Study on Adhesions in the Porcine
Model
[0072] The purpose of this procedure is to evaluate the surgical
performance of laparoscopic pelvic and lower para-aortic
lymphadenectomy and to study the post-operative adhesion formation
in a randomized trial, using an adhesion prevention adjuvant
containing poloxamer with or without pentoxifylline.
[0073] Under general anesthesia twenty-eight female piglets
underwent video-endoscopic transperitoneal lymphadenectomy. On each
side, four lymph node sites were identified: obdurator fossa,
external iliac, para-aortic and internal iliac. These sites were
defined by consistent anatormical borders. The lymph nodes were
surgically removed and hemostasis obtained. All sites on one side,
selected randomly, were treated with the formulation described in
Example 2, a buffered, osmotically balanced formulation of 28%
poloxamer 407 or control buffer. The sites on the contralateral
side were left untreated.
[0074] After 14 days, a laparotomy was performed to evaluate
healing and adhesion formation at the sites of lymph node
removal.
[0075] Evaluation of Type of Adhesions
[0076] Slides/photos were taken, and a score was made. An
independent observer, unaware of the previous procedure was used to
assess the adhesions, in accordance with the procedure described by
Shimanuk T, et al., J. Biomed. Mater. Res. 22, 173-185 (1987),
shown in Table 1 as follows:
6TABLE 1 Grade Points Description 0 0 No adhesions 1 1 Avascular,
is easily lysed but fails to bleed. 2 3 Vascular, is easily lysed
but bleeds at times of lysis. 3 5 Thick, requires extensive sharp
surgical dissection.
[0077] The total score was calculated the following way: the
assigned points for each adhesion grade were multiplied by the
percentage of the surface (0.00-1.00) area involved with that
specific type of adhesion. Statistical analysis was performed using
the Wilcoxon signed rank test.
[0078] The results are shown in Table 2. At the same volume,
formulation with pentoxifylline reduced adhesions significantly at
all 4 sites when compared to control in the animals tested.
[0079] Formulations containing poloxamer 407 without pentoxifylline
reduced adhesions formation at all surgical sites, but the
reduction was statistically significant only at the internal iliac
site.
[0080] While this invention has been described with reference to
certain specific embodiments, it will be recognized by those
skilled in the art that many variations are possible without
departing from the scope and spirit of the invention, and it will
be understood that it is intended to cover all changes and
modifications of the invention, disclosed herein for the purposes
of illustration, which do not constitute departures from the spirit
and scope of the invention.
7TABLE 2 14% Poloxamer 407 with Vehicle Control 14% Poloxamer 407 4
mg/ml Pentoxifylline Treated Control Treated Control Treated
Control Obduratur Mean 1.37 Mean 1.47 Mean 0.72 Mean 0.66 Mean 0.60
Mean 1.26 S.D. 0.61 S.D. 0.61 S.D. 0.61 S.D. 0.70 S.D. 0.41 S.D.
0.73 Internal Mean 1.33 Mean 1.93 Mean 0.78 Mean 1.80 Mean 0.51
Mean 1.20 S.D. 1.00 S.D. 1.22 S.D. 0.60 S.D. 0.97 S.D. 0.36 S.D.
0.91 External Mean 2.25 Mean 1.84 Mean 0.83 Mean 1.27 Mean 0.68
Mean 1.87 S.D. 0.96 S.D. 0.83 S.D. 0.52 S.D. 0.88 S.D. 0.45 S.D.
0.73 Paraortic Mean 158 Mean 1.62 Mean 0.77 Mean 1.15 Mean 0.95
Mean 1.64 S.D. 0.83 S.D. 0.66 S.D. 0.53 S.D. 0.79 S.D. 0.85 S.D.
0.75
* * * * *