CA1179264A - Condranol for transplants - Google Patents

Condranol for transplants

Info

Publication number
CA1179264A
CA1179264A CA000389215A CA389215A CA1179264A CA 1179264 A CA1179264 A CA 1179264A CA 000389215 A CA000389215 A CA 000389215A CA 389215 A CA389215 A CA 389215A CA 1179264 A CA1179264 A CA 1179264A
Authority
CA
Canada
Prior art keywords
transplant
according
coated
coated surgical
implant
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
CA000389215A
Other languages
French (fr)
Inventor
Lester M. Morrison
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BIOMED RESEARCH Inc
Original Assignee
BIOMED RESEARCH Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US26378881A priority Critical
Priority to US263,788 priority
Application filed by BIOMED RESEARCH Inc filed Critical BIOMED RESEARCH Inc
Application granted granted Critical
Publication of CA1179264A publication Critical patent/CA1179264A/en
Expired legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L29/00Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08Materials for coatings
    • A61L29/085Macromolecular materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K6/00Preparations for dentistry
    • A61K6/20Protective coatings for natural or artificial teeth, e.g. sealings, dye coatings or varnish
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28Materials for coating prostheses
    • A61L27/34Macromolecular materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L33/00Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/06Use of macromolecular materials
    • A61L33/08Polysaccharides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/06Immunosuppressants, e.g. drugs for graft rejection

Abstract

ABSTRACT OF THE INVENTION
A method which comprises the administration of an effective amount of "active" chondroitin sulfate A, "active" chondroitin sulfate C, or mixtures thereof to humans just prior to, during, and/or following the transplantation or implantation into the body of tissue or organs from the same or another human or animal, or inanimate prosthetic and orthopedic devices, surgical instru-ments and the like, to mitigate rejection or failure of the trans-plant or implant.

Description

B~CKGROUND OF THE INVENTION
The use of "active" chondroitin sulfate A and C~ and mixtures of these drugs are known for use in the treatment of a variety of cardiovascular diseases and as preventative therapy for these diseases. These drugs including their method of production are described in Morrison United States Patent No. 3,895,106 and 3,895,107 issued July 15, 1975.
It has now been discovered that "active" chondroitin sulfate A, "active" chondroitin sulfate C, and mixtures thereof, have a unique and very different therapeutic use. It has been reported in the literature in numerous instances that organ Of tissue transplants are subject to rejection by the human host. This problem is also present to a degree in relation to inanimate implants such as tooth implants, hip prosthesis, intraocular implant, heart valve, etc. It is generally believed that the transplant rejection phenomena is ; associated with the immune system of the body and/or physiologic processes or surgical procedures. The immune system recogni~es the transplanted tissue as foreign and produces antibodies which attack the object foreign to the human host. Surgical failure and physiologic failure may be related to mechanical tissue damage, clotting with decreased blood flow, etc. Various approaches have been followed in attempting to diminish or eliminate the rejection or failure problem.

1 We have found that "active" chondroitin sulfate A, "active"

2 chondroitin sulfate C, or admixtures of the drugs seems to signi-

3 ficantly reduce the tendency of the human body to reject trans-

4 plants and increase the acceptance of implants.
The rejection of implants is due to additional factors 6 including direct mechanical injury to adjacent tissues, devascu-7 larization of tissues with resultant poor oxygen supply, tissue 8 unacceptance of the foreign body whether due to direct lack of 9 adherence of adjacent cells, lack of proper electrostatic forces, or poor regeneration of tissues.
11 The coating of the foreign bodies and/or host treatment 12 with the drugs of this invention reduces rejection and may result 13 in better acceptance of the implant by the surrounding tissues.
14 It is believed that this development represents a signi-ficant advance in this area of therapy.
16 The coating of surgical instruments will reduce direct 87 tissue damage resulting from contact with these instruments. Like-wise, the coating of indwelling catheters or needles will reduce 19 mechanical damage to contiguous endothelial cells within the vascu-O lar channel.
21 It is believed that this development represents a signi-24 nt advance in this area of therapy.

SU~ARY OF TIIE INV~NTION
Briefly, the present invention comprehends a method which comprises the administration of an effective amount ot "active" chondroitin sulfate A, "active" chondroitin sulfate C, or mixtures thereof to humans just prior to, dur-ing, and/or following the transplantation or implantation into the body of tissue or organs from the same or another human or animal, and inanimate pro-sthetic and orthopedic devices, surgical instruments and the like, to mitigate rejection or failure of the transplant or implant.
It is an object to provide a new mode of therapy.
It is also an object of my invention to provide a new and improved therapy for combating the problem of rejection, and stimulating and promoting acceptance of both living and inanimate transplants or implants on the human body.
More particularly, it is an object of this invention to provide a significant new mode or use of the drugs known as "active" chondroitin sulfate A, "active" chondroitin sulfate C and combinations of these drugs.
As used herein, the term "transplant" or "transplantation" refers to the grafting of tissue taken from the same or another person. More specifically, it refers to the operation of transplanting or of applying to a part of the body tissues taken from another body or from another part of the same body. This invention covers the full ar-ay of such procedures and is particularly used in heart, kidney, lung and skin transplants. The term "implant" or "implantation"
means the placement within the body tissues of a foreign, usually inanimate sub-stance. A hip joint ll~t3~,~4 ' ~
1 mechanical heart valve, surgica:L staples and intraocular lens are 2 examples. The implanting of pi~ tissue into humans for heart valve 3 reconstruction is also contemplated by this invention, whether re-4 garded as an implant or a transplant. The "implant" need not be permanent~ Thus, the term "implant" herein is broader than in the 6 conventional sense and includes the use of the drugs to coat surgi-7 cal instruments just prior to their temporary use in the human body.
8 An indwelling catheter or needle can be beneficially coated with the 9 drugs prior to placement into the patient. Likewise, IV tubing, sutures and even surfical instruments. The coating of implants 11 such as titanium rods to act as a bone, and mechanical metal knee 12 and hip joints is of considerable value. As used herein, a "pros-13 thetic" device refers to any artificial substitute for a missing 14 part, as denture, hand, leg or eye.
While not bound by any theory, it is believed that the 16 present invention improves the implantation of inanimate devices by 17 virtue of the fact that the drug has a negative electrical charge 18 and the implants bear a positive surface charge. The hypothesis 19 is that the drugs lead to the neutralization of the positive charge or create a resultant negative charge which provides for less 21 damage to contiguous cells or tissues. Another likely factor is 22 the lubricating properties of the drugs which seem to increase com-231 patability of the implant with the surrounding living tissues and 241 prevents direct mechanical cell damage. The lubricating properties of the drugs via direct application to intraperitoneal surfaces or 26 structures at the time of abdominal surgical procedures may reduce 27 the occurrence of post-operative adhesions.
28 These and other objects and advantages of this invention 29 will be apparent from the more detailed description which follows.

~ t~

DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is applicable to the transplantation, human-to--human, animal-to-human, of all organs and tissues including kidney, heart, lungs, skin, etc. It also appears to be useful in cases of re-attachment of tissues or organs such as in cases requiring the re-attachment of the cornea or retina.
The drug can be administered beginning three to four days prior to the transplantation or implant and can usefully be continued for weeks, months, or even years thereafter. In any case, the drug would be administered essentially concurrently with transplantation. The mode of administration is by injectible aqueous solution, orally, or the like. The administration in the case of major organ transplant is intra-peritoneally, intravenously or orally or powder, oint-ment, eye drops, as an aqueous solution. The dosage would be an effective amount on the order of 0.1 to 10 or more grams per 24 hour period.
It is also beneficial to soak, infuse, coat or incubate the transplant or implant, that is, the skin, heart, kidney or lung or artificial, synethetic devices with the drug just before transplantation or implant in the human recipi-ent.
In the case of inanimate implants for the eye or joints such as intra-ocular lens, tooth implant, knee implant, orthopedic plates or pins, hip pro-sthesis, the inanimate transplant or implant, can be beneficially coated with the drug just prior to placement in the hunlan body, and fortified periodically by local applications or injections and the like of the "active" drug.
The soaking or coating procedures just described are usually 1~ 4 1 in addition to the more protracted systemic administration of the 2 drug earlier described hereinabove. The solution used to coat is 3 a 1 to 30% by weight of a physiologically compatible, normally 4 aqueous, solution of the drug. The drug can be applied to the eye in drop form. The drugs can also be combined with conventional car-6 riers to form a viscOIls ointment and coated onto a skin transplant 7 to mitigate rejection. The drugs used in the practice of this inven _ 8 tion are prepared as follows:

EXA~IPLE 1 12 One hundred pounds of trimmed bovine trachea was chopped 13 into 1 inch square segments and added to about 50 gallons of de-14 ionized water in a tank. The pH was adjusted to about 4.5 by addi-tion of approximately 400 ml of glacial acetic acid. The resulting 16 suspension was agitated while the contents of the tank was raised 17 to about 50C. One and one-quarter pounds of pepsin was added 18 and the agitation continued for 30 minutes. Another 50 gallons 19 of de-ionized water was added to the tank and mild stirring con-tinued for 12 hours at 50C until the trachealcartilage is freed 21 of connective tissue. The temperature of the suspension is then 22 raised to 80C and 2 fat layer formed on the top of the liquid.
23 The digestion liquor was drained off through a basket centrifuge 24 and discarded.
The remaining solids were twice washed with 50 gallons of 26 hot water (60-80C). A sodium hydroxide solution was prepared 27 by adding 1.5 lbs. of NaOH to 5 gallons of de-ionized water in a 28 tank. The twice washed solids were added to the sodium hydroxide 1 solution, and the volume adjusted with de-ionized water to 12 gal-2 lons and the pH to 9-10. The contents of the tank was agitated 3 for 12 hours at 37C. The pH was then adjusted to 6.5 with 4 glacial acetic acid. The liquid was heated to boiling and then

5 permitted to cool. The liquid was filtered through a basket

6 centrifuge and the filtrate collected and retained. To the

7 retained filtrate was added 1.5 pounds of cetyl pyridinium chloride

8 followed by stirring for 30 minutes. The liquid was allowed to

9 stand for 16 hours. A precipitate form The supernatant was

10 decanted and the precipitate collected by continuous centrifugation

11 in a Sharples centrifuge. The collected precipitate was in 5

12 gallons of 0.5N sodium hydroxide. Ten gallons of methanol was

13 added and allowed to stand for 12 hours at room temperature. The

14 precipitate formed was again collected by continuous centrifuga-tion and washed with 5 gallons of methanol. The precipitate was 16 dissolved in two gallons distilled water, the pH adjusted to 7.0 17 with glacial acetic acid and 1/4 pound of sodium chloride was 18 added, followed by stirring. Four gallons of methanol was added 19 and agitation was aarried out for 15 minutes. After standing for 12 hours at room temperature, a precipitate had formed which 21 was collected by centrifugation. The precipitate was dried under 22 vacuum. Analysis showed the precipitate to be essentially CSA.
23 The material manifested a prolongation of plasma thrombus forma-24 tion time 6 to 12 hours after administration in rabbits as des-25 cribed by the Chandler loop method of over 80%.
26¦ A sterile solution suitable for intravenous injection or 27 local applicable is obtained by dissolving 125 mg. of the drug in 2.5 28 ml of USP sterile water for injection. If necessary,the solution canbe .31. ~
1 finally sterilized by passing it through a sterilizing membrane fil-2 ter. When donor human skin was soaked for five minutes in this sol-3 ution and applied to an area of third degree burn, the rejection was 4 reduced.

An ointment containing the drugs is prepared by adding 6 from about 1 to 30% by weight of the drug to a vehicle or carrier 7 which is normally viscous such as petroleum jelly or made viscous 8 by the addition of emulsifiers or thickeners to water~ The vehicle 9 or carrier are usually composed of various mixtures of fats, waxes, animal and vegatable oils, and solid or liquid hydrocarbons.

14 One starting material for the preparation of active chon-droitin sulfate A is bovine trachea. This material is obtained 16 from the slaughter houses as soon as possible after the animals 17 are slaughtered. It is then frozen until processed. In processing, 18 it is trimmed free of tissue and finely ground. This ground tis-19 sue is defatted with five parts of acetone. Two extractions are 20 made to reduce the fat content to approximately 1 percent or less.
21 The defatted material is dried and re-ground. A 5 percent solution 22 of the latter is made up in a 0.lM calcium acetate buffer containing 2~ 1 percent papain plus 0.005 M cystein hydrochloride and 0.005 M
24 disodium versenate as enzyme activators. The entire-mixture is 25 maintained at 62C + 3C for 24 to 30 hours with gentle stirring.
26¦ Approximately 85 to 95 percent solubilization of the trachea is 271 obtained. This supernatant is decanted and is precipitated with 28 two volumes of acetone. The acetone supernatant is decanted.

~ 3~
1 The remaining precipitated material is dissolved in isotonic saline 2 to make a solution of 3-5 percent. To the latter is added a satur-3 ated solution of potassium permanganate in 2 to 5 ml. portions 4 with constant stirring, adding each portion until the purple color 5 has been totally discharged. Depending on the various raw materials 6 started with, this may take anywhere from 50 to 200 ml. of potas-7 sium permanganate solution per 6 lbs. of starting raw material.
8 When at the interval between addition and discharge, the color 9 becomes long (sic) (more than 5 minutes), no further permanganate lO is added. The solution is then allowed to stand overnight to 11 permit flocculation of the manganese dioxide and completion of any 12 reactions. The manganese dioxide is removed either by centrigu-13 gation or filtration through a coarse filter paper. The mangan-14 ese dioxide cake is washed with additional isotonic saline. In

15 some cases the addition of a small amount of foma]dehyde or

16 methanol will cause flocculation of manganese dioxide which is

17 then precipitated with one volume of aceton~. The resultant oily

18 precipitate is collected by decantation, the solvent evaporated

19 or the cake dissolved in a minimum amount of water and the final

20 product obtained by lyophilization. It appears on paper chroma-

21 tography to be essentially pure chondroitin sulfate A. Analysis

22 of the product shows a typical chondroitin sulfate A infra-red

23 spectrophotometric absorption curve. Optical rotation determination

24 gives values of (a)D24= -24; nitrogen content, 3.3%.

1 EXAMPL~ 3 3 One starting material for the preparation of active 4 chondroitin sulfate C is shark cartilage. This material obtained in dry form is ground and defatted with three to five parts 6 acetone. One extraction is usually sllfficient. This extracted 7 shark cartilage is then treated as indicated above for the dried 8 bovine trachea after the defatting stage.
9 The drugs prepared as in Example 2 and 3 are usePul in al~
of the procedures described hereinabove.
11 Having fully described the invention, it is intended that 13 it be limited only by the lawful scope of the appended claims.

lg .

Claims (14)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A surgical implant or transplant coated with an amount of "active"
chondroitin sulfate A or "active" chondroitin sulfate C sufficient to ameliorate rejection of the implant or transplant.
2. A coated surgical implant according to claim 1 which is an indwelling catheter, needle, or I.V. tubing.
3. A coated surgical implant according to claim 1 which is a heart valve.
4. A coated surgical implant according to claim 1 which is a tooth prosthesis.
5. A coated surgical implant according to claim 1 which is a bone prosthesis.
6. A coated surgical implant according to claim 1 which is an artificial prosthesis.
7. A coated surgical implant according to claim 1 which is an intraocular implant.
8. A coated surgical implant according to claim 1 which is a suture.
9. A coated surgical transplant according to claim 1 which is an organ transplant.
10. A coated surgical transplant according to claim 1 which is a heart transplant.
11. A coated surgical transplant according to claim 1 which is a kidney transplant.
12. A coated surgical transplant according to claim 1 which is a lung transplant.
13. A coated surgical transplant according to claim 1 which is a skin transplant.
14. A coated surgical transplant according to claim 1 which is a surgical graft.
CA000389215A 1981-05-14 1981-11-02 Condranol for transplants Expired CA1179264A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US26378881A true 1981-05-14 1981-05-14
US263,788 1981-05-14

Publications (1)

Publication Number Publication Date
CA1179264A true CA1179264A (en) 1984-12-11

Family

ID=23003232

Family Applications (1)

Application Number Title Priority Date Filing Date
CA000389215A Expired CA1179264A (en) 1981-05-14 1981-11-02 Condranol for transplants

Country Status (7)

Country Link
JP (1) JPS57188522A (en)
CA (1) CA1179264A (en)
DE (1) DE3144236C2 (en)
DK (1) DK70382A (en)
FR (1) FR2505656A1 (en)
GB (1) GB2098506B (en)
SE (1) SE8107352L (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0121008A3 (en) * 1983-03-29 1985-03-27 Marcel E. Nimni Coating for bioprosthetic device and method of making same
GB2297931B (en) * 1992-04-07 1996-10-16 Wilhelm Env Tech Inc Flue gas conditioning system
EP0634955A4 (en) * 1992-04-07 1995-03-01 Wilhelm Environmental Technologies, Inc. Flue gas conditioning system.
US6444447B1 (en) * 1998-11-11 2002-09-03 The Board Of Regents Of The University Of Oklahoma Polymer grafting by polysaccharide synthases

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2037942C2 (en) * 1970-04-15 1982-11-18 Biomed Research, Inc., 90048 Los Angeles, Calif., Us
US3895106A (en) * 1970-04-15 1975-07-15 Morrison L M Novel CSA and CSC for use in man and mammals to inhibit atherosclerosis and the recurrence of cardiovascular incidents in atherosclerotic mammals
JPS5331446B2 (en) * 1975-09-16 1978-09-02
US4302577A (en) * 1979-10-05 1981-11-24 Biomed Research Inc. Process for preparing CSA or CSC

Also Published As

Publication number Publication date
FR2505656A1 (en) 1982-11-19
GB2098506A (en) 1982-11-24
DE3144236C2 (en) 1987-04-30
DE3144236A1 (en) 1982-11-25
GB2098506B (en) 1984-10-03
JPS57188522A (en) 1982-11-19
DK70382A (en) 1982-11-15
SE8107352L (en) 1982-11-15
CA1179264A1 (en)

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