CA1163517A - Method and apparatus for on-line filtration removal of macromolecules from a physiological fluid - Google Patents
Method and apparatus for on-line filtration removal of macromolecules from a physiological fluidInfo
- Publication number
- CA1163517A CA1163517A CA000377362A CA377362A CA1163517A CA 1163517 A CA1163517 A CA 1163517A CA 000377362 A CA000377362 A CA 000377362A CA 377362 A CA377362 A CA 377362A CA 1163517 A CA1163517 A CA 1163517A
- Authority
- CA
- Canada
- Prior art keywords
- plasma
- stream
- macromolecules
- solution
- plasma stream
- 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
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
- A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
- A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
- A61M1/3482—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate by filtrating the filtrate using another cross-flow filter, e.g. a membrane filter
Abstract
ABSTRACT OF THE INVENTION
An on-line filtration system for the removal of macromolecules greater than 70,000 mol. wt. from a physio-logical solution, such as blood, in the therapeutic treat-ment of various disease states. For blood, the plasma (which contains the macromolecules) is separated continu-ously from the blood using a first membrane filter with a membrane porosity of nominally 0.2 to 1.0 micron. The separated plasma is then continuously filtered in a physi-ological temperature state or a cooled state through a second membrane filter with a membrane porosity of nomi-nally 0.01 to 0.2 micron, which retains the macromolecules.
In the cooled state, separation of the macromolecules is effected more efficiently than could be done in the non-cooled state. The treated plasma (macromolecules removed) is then reunited with the blood flow coming from the first plasma filter and returned to the patient. The blood flow and filtration processes are generally continuous. Suit-able agent(s) may be added to the separated plasma to promote formation of macromolecules.
An on-line filtration system for the removal of macromolecules greater than 70,000 mol. wt. from a physio-logical solution, such as blood, in the therapeutic treat-ment of various disease states. For blood, the plasma (which contains the macromolecules) is separated continu-ously from the blood using a first membrane filter with a membrane porosity of nominally 0.2 to 1.0 micron. The separated plasma is then continuously filtered in a physi-ological temperature state or a cooled state through a second membrane filter with a membrane porosity of nomi-nally 0.01 to 0.2 micron, which retains the macromolecules.
In the cooled state, separation of the macromolecules is effected more efficiently than could be done in the non-cooled state. The treated plasma (macromolecules removed) is then reunited with the blood flow coming from the first plasma filter and returned to the patient. The blood flow and filtration processes are generally continuous. Suit-able agent(s) may be added to the separated plasma to promote formation of macromolecules.
Description
~3~7 --1~
MæT~OD AMD APPARATUS FOR 0~ LINE FILTRATION REMOVAL
OF ~CROMO~ECULES FROM A P~YSIOLOGICAL FLUID _ ~his invention relata~ to pla mQph~r~ and more particularly to the removal of unde~irabla ~olute~
from plasma in a plasmaph~resi~ process.
ACKGROUND OF THE INVENTION
Plasmapheresis ~the r~moval of blood, separa-tion of the plasma and the rein~usion of the ~lood ~ells) - with or wit~out tha r~placement o~ the patient' 8 pla~a by donor plasma, a pla~ma ~raction, or other physiologi-cal solution, i8 becoming more useful in the clinical treatment of v~rious di ea3e statesO Such di ease 8tate9 have in co~mon the pre~ence of undesirable elevated levels o~ pla~ma solute~. Such solutes (due to their increa~ed size) ~annot be effectively removed by techniques ~uch as dialyses and hemofiltration. Therefore pla~ma removal with the infusion of physiological ~olution~ i~ ef~ectiYe in depleting their concentration. Variou~ disea~e ~ate~
:~eated by plasmapheresis are as follows.
~yasthenia gravis Glomerulonephritis - Goodpasture' 3 ~yndrome Skin diseases pemphigus herpes ge~tationi~
Severe asthma Immune complex diseases : 25 crescentic ~ephritis .~ i ~ ~G3~ ~
systemic lupus erythematosu~
Wegner'~/polyarteritis ubacute bacterial endo~arditis cryoglobulinemia cutaneous va~culitis Diabetic hypertriglyce~ridemia I Hypercholesterolemia Macroglobulinemia Waldenstrom's ~yndrome hypervisco~ity syndromas paxaproteiniemias, myeloma Hematological di~eases hemolytic anemia x d cell agglutini~
auto-antibody lymphocytes i thrombotic throm~ocytopenia ,,1 purpura immune thrombocytopenia factor VIII inhibitor or antibodies Raynaud'~ disease and phenomenon Renal transplantation }.~,~. Rhesus incompatibility ~epatic coma ~yperten~ion Motor neurone disca-~
amyotrophic lateral 8clero8i8 : auto polyn~uropa~hy Refsum's disea~e Guillain-Barre syndrome Arthritis - Removal of protein bound toxins poisons - methyl parathion, pois4nous mushrooms, paraquat :: 35 hormones - thyroid protein bound aluminum - dialysis ~- dementia ~ Cancer :; Insulin resistant diabetes .
While this list is ~ot exhaus~ive9 it exempli-fie~ the wide range of diseases a~sociated with biochemi-cal abnormalities; such biochemical agents being of high molecular weight.
. ~
~. ,, 3 5 ~ ~
At present the number of cases of plasma ex-I change are amall and in many instances without control~.
¦~ The success in some cases is quite impressive.
The treatments pre~ently being carried out by plasmapheresi~ may be generally grouped into two type~:
(1) removal of an abnormal metabolite(s) or toxin(s~ and
MæT~OD AMD APPARATUS FOR 0~ LINE FILTRATION REMOVAL
OF ~CROMO~ECULES FROM A P~YSIOLOGICAL FLUID _ ~his invention relata~ to pla mQph~r~ and more particularly to the removal of unde~irabla ~olute~
from plasma in a plasmaph~resi~ process.
ACKGROUND OF THE INVENTION
Plasmapheresis ~the r~moval of blood, separa-tion of the plasma and the rein~usion of the ~lood ~ells) - with or wit~out tha r~placement o~ the patient' 8 pla~a by donor plasma, a pla~ma ~raction, or other physiologi-cal solution, i8 becoming more useful in the clinical treatment of v~rious di ea3e statesO Such di ease 8tate9 have in co~mon the pre~ence of undesirable elevated levels o~ pla~ma solute~. Such solutes (due to their increa~ed size) ~annot be effectively removed by techniques ~uch as dialyses and hemofiltration. Therefore pla~ma removal with the infusion of physiological ~olution~ i~ ef~ectiYe in depleting their concentration. Variou~ disea~e ~ate~
:~eated by plasmapheresis are as follows.
~yasthenia gravis Glomerulonephritis - Goodpasture' 3 ~yndrome Skin diseases pemphigus herpes ge~tationi~
Severe asthma Immune complex diseases : 25 crescentic ~ephritis .~ i ~ ~G3~ ~
systemic lupus erythematosu~
Wegner'~/polyarteritis ubacute bacterial endo~arditis cryoglobulinemia cutaneous va~culitis Diabetic hypertriglyce~ridemia I Hypercholesterolemia Macroglobulinemia Waldenstrom's ~yndrome hypervisco~ity syndromas paxaproteiniemias, myeloma Hematological di~eases hemolytic anemia x d cell agglutini~
auto-antibody lymphocytes i thrombotic throm~ocytopenia ,,1 purpura immune thrombocytopenia factor VIII inhibitor or antibodies Raynaud'~ disease and phenomenon Renal transplantation }.~,~. Rhesus incompatibility ~epatic coma ~yperten~ion Motor neurone disca-~
amyotrophic lateral 8clero8i8 : auto polyn~uropa~hy Refsum's disea~e Guillain-Barre syndrome Arthritis - Removal of protein bound toxins poisons - methyl parathion, pois4nous mushrooms, paraquat :: 35 hormones - thyroid protein bound aluminum - dialysis ~- dementia ~ Cancer :; Insulin resistant diabetes .
While this list is ~ot exhaus~ive9 it exempli-fie~ the wide range of diseases a~sociated with biochemi-cal abnormalities; such biochemical agents being of high molecular weight.
. ~
~. ,, 3 5 ~ ~
At present the number of cases of plasma ex-I change are amall and in many instances without control~.
¦~ The success in some cases is quite impressive.
The treatments pre~ently being carried out by plasmapheresi~ may be generally grouped into two type~:
(1) removal of an abnormal metabolite(s) or toxin(s~ and
(2) treatm~nt of a disorder of the immune ystem. Exam-ples of the fir~t type include hepati~ ~upport, hyper-triglyceridemia, hyperchole~terolemia, and the removat . iO of protein or lipid bound toxin~. Examples of the second ¦' type include m~asthenia gravi~, glomerulonephriti3, m~cro-globulinemias, arthriti~, and ~ystemic lupu~ erythema-tosis.
1 ~ Whila in some of the disease~ there i little .~ 15 known concerning the correlation o the disea3e wi~h the increased plasma factor~, for other disea~es ~he factor(s) i~ Xnown or correlation between the i~crea~ed factor and the disease ~tate can be shown a~ outlined in Table 1 and .~ Table 2 as follows.
~' :i G 3 5 1 'i~
~AB~ 1 Disease Increasad Factor(.) or _.
~' Myasthenia g~avi~ Antibody ~peci~ic ~or acetyl-choline receptor Renal tran~plant rejection (Antibody to glomerular base-(ment membran~
Goodpastur~'3 ~yndrome (Antibody to ba~ement membrane (o~ lung 0 Rhe8u3 incompatibility Anti-D-antibody Sygtemic lupu8 erythema- DNA antibodie~ and immune tosu~ complexes of D~A
Glom~rulo~ephritis Immune complexe~ or auto~;
antibodie~
15 Macroglobuline~ia Ig~ and h~pervisco~ity (Walden~trom'~ ~yndrome) ¦ ~ Pemphigu~ vulgaris IgG anti~odie3 ;,............................................................... .
A~thma bronchiti~ IgB
My loma Myeloma globulin ~: 20 Raynaud's disease and Macroglobulin, i~creased Vi3-:i; pnenomena cosity ~hrombocytopenic purpura Immunocomplex ~ancer ~ 2 globuline~, ~-globulins, ~ antitryp-i 25 sin, c~rulopla~min, oroso~u-I coid, hap~oglobin, IgA
Breast cancer Circulating Lmmune complex Polyneuropathy Antibodies to myelin ~heumatoid arthritis "Serum factor"
30 Diabete~ Au~oantibodies to insulin receptor Autolm~une he lytic Antibody to RBC
. anemia _ _.
l ~ 6~S~7 METABOLIC DISO~DERS T~EATED B~ PLASMAPHERE5IS
Disea3e Increa~ed Factor ( 3 ) or '~`1 ~
.5 Hepatic coma Metabolic factors (bilirubin) Refsum's disease Phytanic acid (bound to lipo-proteins) PoisOning~ Protein bound drug Dialysis dementia Protein bound aluminum ¦ 10 Hypertriglyceridemia ~riglyceride~ and hypervi~-co~it~
Hypercholesterolemia Cholesterol Am~t~ophic lateral Cytotoxic factor~, immune complexe~ suspected ~clero~ls I ~isted are various diseases for which increa~ed levels of ~ntibodie3 or macromolecule~ exi~t and for which pla~mapheresis has been u eful by its reduction of these substances. For example, in myasthenia gravis, an~ibodies specific for the acetycholine receptors are elevated. Removal of these antibodies by plasmaph~resi~
s~ows improvement in the patients. In macroglobulinemia, there is an increased level of gamma globulin. Reducing this level by plasmapheresis is clinically effec~ive.
The conventional method of plasmapheresis ¦ employs a cell cent~iuge involving bulky and expensive equipment which is not portable and is very costly, and carries with it potential hazards. Namely, essential plasma products are lost that are not being replenished in the substitution fluids and the potential exist~ for acquiring hepatitis. In addition, the effectiveness of ~ ' "
.. , .. _ .
`:~
~ .
~ ~ li 3 ~ 1 7 the procedure is limited due to the limited removal that can be accomplished in discarding a limited volume.
If conventional plasmapheresis were to be accepted for the treatment of many of these disea4es there would be created a greater need for plasma products than could be met nationally. Obviously, to take advantage of plasma-pheresis in treating these disease~, new techniques must be developed for removal of the plaQma "toxins", A major improvement would be to develop "on-: 10 line" removal ~y~tems to remove the "toxin" in que~tion ~ and to return the ~reated pla~ma back to the patient. The i advantage~ are quite obviou The recent development of membrane systems for the on-line removal of pla~ma from whole blood has added impetus to the development work.
Extra~orporeal t.reatment of plasma generated by either membrane plasma separators or centrifugé~ has been c~rried , out by either ~pecific or non-specific ~orbent3 such as ¦~ activated charcoal, nonionic or ionic ,resins and i~mobil-ized proteins, cells or tissue.
In many of the disease ~tates multiple biochemi-cal abnormalities exist, and due to the nature of the abnormal substances involved, multiple sorbent ~y.~tem~
may be required. Such developments will take many years.
Therefore due to the nature of the substances (larger 25 molecular weights of generally over lO0,000 dalton~) or the nature of the disease state, where the speciPic macro-: molecule that is causative for the ymptoms of the di~ease is not defined, the more general approach of removing all molec~les o~er a specific molecular weight can be chosen.
Membranes having a molecular cutoff of about lO0,000 dal-tons are chosen as they can pass albumin thereby negat-ing the need ~o infuse this plasma product as is done by ~ the conventional plasmapheresis process.
,.,~
35~7 Therefore it is an object of the invention to provide a plasmapheresis method and apparatus for removin~
macromolecules of predetermined size from a plasma solution.
A further object is to remove molecules from the plasma which form a macromolecule after adding a complexing a~ent to the plasma.
A still further object of the invention is to provide a plasmapheresis apparatus for "on-line" re~oval of macromolecules o~ predetermined size from a patient's physiological solution that is simple in construction, inexpensive to manufacture, and highly effective in operation.
In a process aspect of the invention there is provided a method of removiny macromolecules from a plasma solution comprising; providing a plasma solution containing macromolecules including a minimum size thereof, effecting predetermined cooling of the plasma solution to a temperature not lower than just above the freezing point of the plasma solution, and filtering the cooled plasma solution with a membrane filter having a porosity up to the minimum size to remove macromolecules of predetermined size from the plasma solution.
In such method, cooling the plasma solution to a temperature between about just above the freezing point of the plasma solution and about 35C causes the macromolecules to gel or precipitate. Also, a complexing agent may be added to the plasma solution to promote formation of macromolecules.
In a further process aspect of the invention there is provided a method of removing macromolecules from a physiological solution comprising; separating the physiological .
J
ch/ ~
,, .
.
~ .
, ~35 ~7 solution into a concentrated cellular element stream and a plasma stream containing macromolecules therein, effectin~
predetermined coolin~ of the plasma stream to a temperature of between just above the freezing point of the plasma stream and 35 centigrade, filtering macromolecules of predetermined size out of the cooled plasma stream to form a filtered plasma stream, combining the filtered plasma stream and the cellular element stream to form a processed stream, and heating the processed stream to the starting temperature of the physiological solution.
The invention also provides an apparatus for removing macro~olecules from a patient's physiological solution (such as blood) including plasma separation means (such as a centrifuge or a membrane filter) for dividing a physiological solution containing macromolecules into a concentrated cellular element stream and a plasma stream, a cooler in fluid flow communication with the plasma separation means for receiving the plasma stream therefrom and cooling such plasma stream to a predetermined temperature to cause the macromolecules therein to gel or precipitate, filter means (such as a memhrane filter) in fluid flow communication with the cooling unit for receiving the cooled plasma stream therefrom and filtering such cooled :~ plasma stream to remove macromolecules of a predetermined ; size therefrom, fluid flow communication means for receiving the filtered plasma stream from the filter means and for receiving the concentrated cellular element stream and combining the two last-named streams to form a processed stream for return to the patient.
.
cb/f~
~ ~3~ ~V~
A pump may be employed in fluid flow communication with the plasma separation means and with the patient to pump the physiological solution from the patient to the plasma separation means. Instead of blood the physiological solution may be lymph or ascitic fluid.
The cooling unit cools the separated plasma stream to a -8a-' '~
:, ~ .
cb/~
, . ~
~ ~ P~351~
g temperature of between ju.~t above the freezing point of the separated plasma stream and approximately 35 ' centigrade. A heater unit may be operatively ~ecured to the fluid flow communication means at a point in such fluid flow communica~ion means after which the filtered plasma stream and the concentrated cellular element ~tream are combined to heat the processed stream to approximately body temperature before it i~ returned to the patient~ A~ an alternative, the filter means may ke enca~ed in the cooling unit for receiving the cooled plasma ~tream therefrom to further cool such cooled plasma stream.
Other objec~s and advantages of the invention will be apparent from the ~ollowing description taXen in conjunction with the drawing~ w~erein:
BRIEF DESCRIPTIO~ OF THE DRAWINGS
FIGURE 1 is a schematic flow diagram illustrat-~: ing the method and apparatus of the inventio~;
FIGURE 2 is a schematic flvw diagram similar to FIGURE 1, but showing a modification thereof:
FIGI~E 3 is a chart showing albumin retentionin a pla~ma solution filtexed by the method and apparatus YhOwn in FIGURE l; and - FIGU~E 4 i~ a chart showing the cryo-protein 25 ~removal i~ the same plasma solution used in the FI~UR~ 3 chart and employing the method and apparatu~ shown in FIGUR~ 1.
In the drawings, like numbers and letters are used to identify li~e and similar part~ throughout the several views.
, DEFI~ITIO~S;
cryoPrec~i ates: Serum globulins that precipitate or gel on cooling at low tem-peratures (4-35C~ and redissolve on warming ''. , `` ~ 5 ~7 Cr~o~lobu~l~ins: Homogenous proteins that have becs:~me phy~ically alt~red (myeloma, mixtures 05E i~nunoglobulins las IgG and (IgM, or immlme complexes ~as antigen and antibody), po~sible S with compleinent ~as irs SLE) Mol. Wt. lOO,OûO -1, 8û0, 000 Macromolecules: Mole~ules of 100,000 dalton~
molecular weight or higher The use of the artificial kidney, blood o~y-10 genators, and artificial joint~ is well recognized today.
However, ~or a variety c:>f disea~e ~tates, applic~tions o~
the techrli~aue of extracorporeal circulatiorA and mechani . cal or mass tran~fer ~upport are becoming more recognized.
. `.- Significant advances have been made in ~he areas of ~ardiac, .
. 15 pancrea~ic and liv2r support in recen. year~. Within the past decade, wi~h the availability of the co~tinuous flow blood cell centrifug~s, many different diqea~e 9tate9, ~ mostly of an immunological nature, have been investigated : ~ in response to pla~ma excha~ge.
. ~ 20 For many of the di~eases, the nonspecific rem~val . ~
~'~ of pla~ma factors has csrrela~ed with improvements in the disea e state. Problems with thi~ convention~l methodolo-gy in chronic applications are the limited removal re lated to the volume o ~xehange and dilution by the required infusion solution, the requirement for plasma product~
and the potential hazards of such infusions, and the ~eed ` 'for bulky and expensive capital equipment. The removal of the speci~ic plasma factors as antibodies, Lmmune ! complexe~, and i~nunoglobulin~ by specific agents as ;, 30 sorbents l;ay be desirable; however, in most disease states the etiology is not known.
In most imanunologically related disea~e states the presence and abnormal concentration of plasma factors . ~ ,,i , ` ' . .
1 ~ Whila in some of the disease~ there i little .~ 15 known concerning the correlation o the disea3e wi~h the increased plasma factor~, for other disea~es ~he factor(s) i~ Xnown or correlation between the i~crea~ed factor and the disease ~tate can be shown a~ outlined in Table 1 and .~ Table 2 as follows.
~' :i G 3 5 1 'i~
~AB~ 1 Disease Increasad Factor(.) or _.
~' Myasthenia g~avi~ Antibody ~peci~ic ~or acetyl-choline receptor Renal tran~plant rejection (Antibody to glomerular base-(ment membran~
Goodpastur~'3 ~yndrome (Antibody to ba~ement membrane (o~ lung 0 Rhe8u3 incompatibility Anti-D-antibody Sygtemic lupu8 erythema- DNA antibodie~ and immune tosu~ complexes of D~A
Glom~rulo~ephritis Immune complexe~ or auto~;
antibodie~
15 Macroglobuline~ia Ig~ and h~pervisco~ity (Walden~trom'~ ~yndrome) ¦ ~ Pemphigu~ vulgaris IgG anti~odie3 ;,............................................................... .
A~thma bronchiti~ IgB
My loma Myeloma globulin ~: 20 Raynaud's disease and Macroglobulin, i~creased Vi3-:i; pnenomena cosity ~hrombocytopenic purpura Immunocomplex ~ancer ~ 2 globuline~, ~-globulins, ~ antitryp-i 25 sin, c~rulopla~min, oroso~u-I coid, hap~oglobin, IgA
Breast cancer Circulating Lmmune complex Polyneuropathy Antibodies to myelin ~heumatoid arthritis "Serum factor"
30 Diabete~ Au~oantibodies to insulin receptor Autolm~une he lytic Antibody to RBC
. anemia _ _.
l ~ 6~S~7 METABOLIC DISO~DERS T~EATED B~ PLASMAPHERE5IS
Disea3e Increa~ed Factor ( 3 ) or '~`1 ~
.5 Hepatic coma Metabolic factors (bilirubin) Refsum's disease Phytanic acid (bound to lipo-proteins) PoisOning~ Protein bound drug Dialysis dementia Protein bound aluminum ¦ 10 Hypertriglyceridemia ~riglyceride~ and hypervi~-co~it~
Hypercholesterolemia Cholesterol Am~t~ophic lateral Cytotoxic factor~, immune complexe~ suspected ~clero~ls I ~isted are various diseases for which increa~ed levels of ~ntibodie3 or macromolecule~ exi~t and for which pla~mapheresis has been u eful by its reduction of these substances. For example, in myasthenia gravis, an~ibodies specific for the acetycholine receptors are elevated. Removal of these antibodies by plasmaph~resi~
s~ows improvement in the patients. In macroglobulinemia, there is an increased level of gamma globulin. Reducing this level by plasmapheresis is clinically effec~ive.
The conventional method of plasmapheresis ¦ employs a cell cent~iuge involving bulky and expensive equipment which is not portable and is very costly, and carries with it potential hazards. Namely, essential plasma products are lost that are not being replenished in the substitution fluids and the potential exist~ for acquiring hepatitis. In addition, the effectiveness of ~ ' "
.. , .. _ .
`:~
~ .
~ ~ li 3 ~ 1 7 the procedure is limited due to the limited removal that can be accomplished in discarding a limited volume.
If conventional plasmapheresis were to be accepted for the treatment of many of these disea4es there would be created a greater need for plasma products than could be met nationally. Obviously, to take advantage of plasma-pheresis in treating these disease~, new techniques must be developed for removal of the plaQma "toxins", A major improvement would be to develop "on-: 10 line" removal ~y~tems to remove the "toxin" in que~tion ~ and to return the ~reated pla~ma back to the patient. The i advantage~ are quite obviou The recent development of membrane systems for the on-line removal of pla~ma from whole blood has added impetus to the development work.
Extra~orporeal t.reatment of plasma generated by either membrane plasma separators or centrifugé~ has been c~rried , out by either ~pecific or non-specific ~orbent3 such as ¦~ activated charcoal, nonionic or ionic ,resins and i~mobil-ized proteins, cells or tissue.
In many of the disease ~tates multiple biochemi-cal abnormalities exist, and due to the nature of the abnormal substances involved, multiple sorbent ~y.~tem~
may be required. Such developments will take many years.
Therefore due to the nature of the substances (larger 25 molecular weights of generally over lO0,000 dalton~) or the nature of the disease state, where the speciPic macro-: molecule that is causative for the ymptoms of the di~ease is not defined, the more general approach of removing all molec~les o~er a specific molecular weight can be chosen.
Membranes having a molecular cutoff of about lO0,000 dal-tons are chosen as they can pass albumin thereby negat-ing the need ~o infuse this plasma product as is done by ~ the conventional plasmapheresis process.
,.,~
35~7 Therefore it is an object of the invention to provide a plasmapheresis method and apparatus for removin~
macromolecules of predetermined size from a plasma solution.
A further object is to remove molecules from the plasma which form a macromolecule after adding a complexing a~ent to the plasma.
A still further object of the invention is to provide a plasmapheresis apparatus for "on-line" re~oval of macromolecules o~ predetermined size from a patient's physiological solution that is simple in construction, inexpensive to manufacture, and highly effective in operation.
In a process aspect of the invention there is provided a method of removiny macromolecules from a plasma solution comprising; providing a plasma solution containing macromolecules including a minimum size thereof, effecting predetermined cooling of the plasma solution to a temperature not lower than just above the freezing point of the plasma solution, and filtering the cooled plasma solution with a membrane filter having a porosity up to the minimum size to remove macromolecules of predetermined size from the plasma solution.
In such method, cooling the plasma solution to a temperature between about just above the freezing point of the plasma solution and about 35C causes the macromolecules to gel or precipitate. Also, a complexing agent may be added to the plasma solution to promote formation of macromolecules.
In a further process aspect of the invention there is provided a method of removing macromolecules from a physiological solution comprising; separating the physiological .
J
ch/ ~
,, .
.
~ .
, ~35 ~7 solution into a concentrated cellular element stream and a plasma stream containing macromolecules therein, effectin~
predetermined coolin~ of the plasma stream to a temperature of between just above the freezing point of the plasma stream and 35 centigrade, filtering macromolecules of predetermined size out of the cooled plasma stream to form a filtered plasma stream, combining the filtered plasma stream and the cellular element stream to form a processed stream, and heating the processed stream to the starting temperature of the physiological solution.
The invention also provides an apparatus for removing macro~olecules from a patient's physiological solution (such as blood) including plasma separation means (such as a centrifuge or a membrane filter) for dividing a physiological solution containing macromolecules into a concentrated cellular element stream and a plasma stream, a cooler in fluid flow communication with the plasma separation means for receiving the plasma stream therefrom and cooling such plasma stream to a predetermined temperature to cause the macromolecules therein to gel or precipitate, filter means (such as a memhrane filter) in fluid flow communication with the cooling unit for receiving the cooled plasma stream therefrom and filtering such cooled :~ plasma stream to remove macromolecules of a predetermined ; size therefrom, fluid flow communication means for receiving the filtered plasma stream from the filter means and for receiving the concentrated cellular element stream and combining the two last-named streams to form a processed stream for return to the patient.
.
cb/f~
~ ~3~ ~V~
A pump may be employed in fluid flow communication with the plasma separation means and with the patient to pump the physiological solution from the patient to the plasma separation means. Instead of blood the physiological solution may be lymph or ascitic fluid.
The cooling unit cools the separated plasma stream to a -8a-' '~
:, ~ .
cb/~
, . ~
~ ~ P~351~
g temperature of between ju.~t above the freezing point of the separated plasma stream and approximately 35 ' centigrade. A heater unit may be operatively ~ecured to the fluid flow communication means at a point in such fluid flow communica~ion means after which the filtered plasma stream and the concentrated cellular element ~tream are combined to heat the processed stream to approximately body temperature before it i~ returned to the patient~ A~ an alternative, the filter means may ke enca~ed in the cooling unit for receiving the cooled plasma ~tream therefrom to further cool such cooled plasma stream.
Other objec~s and advantages of the invention will be apparent from the ~ollowing description taXen in conjunction with the drawing~ w~erein:
BRIEF DESCRIPTIO~ OF THE DRAWINGS
FIGURE 1 is a schematic flow diagram illustrat-~: ing the method and apparatus of the inventio~;
FIGURE 2 is a schematic flvw diagram similar to FIGURE 1, but showing a modification thereof:
FIGI~E 3 is a chart showing albumin retentionin a pla~ma solution filtexed by the method and apparatus YhOwn in FIGURE l; and - FIGU~E 4 i~ a chart showing the cryo-protein 25 ~removal i~ the same plasma solution used in the FI~UR~ 3 chart and employing the method and apparatu~ shown in FIGUR~ 1.
In the drawings, like numbers and letters are used to identify li~e and similar part~ throughout the several views.
, DEFI~ITIO~S;
cryoPrec~i ates: Serum globulins that precipitate or gel on cooling at low tem-peratures (4-35C~ and redissolve on warming ''. , `` ~ 5 ~7 Cr~o~lobu~l~ins: Homogenous proteins that have becs:~me phy~ically alt~red (myeloma, mixtures 05E i~nunoglobulins las IgG and (IgM, or immlme complexes ~as antigen and antibody), po~sible S with compleinent ~as irs SLE) Mol. Wt. lOO,OûO -1, 8û0, 000 Macromolecules: Mole~ules of 100,000 dalton~
molecular weight or higher The use of the artificial kidney, blood o~y-10 genators, and artificial joint~ is well recognized today.
However, ~or a variety c:>f disea~e ~tates, applic~tions o~
the techrli~aue of extracorporeal circulatiorA and mechani . cal or mass tran~fer ~upport are becoming more recognized.
. `.- Significant advances have been made in ~he areas of ~ardiac, .
. 15 pancrea~ic and liv2r support in recen. year~. Within the past decade, wi~h the availability of the co~tinuous flow blood cell centrifug~s, many different diqea~e 9tate9, ~ mostly of an immunological nature, have been investigated : ~ in response to pla~ma excha~ge.
. ~ 20 For many of the di~eases, the nonspecific rem~val . ~
~'~ of pla~ma factors has csrrela~ed with improvements in the disea e state. Problems with thi~ convention~l methodolo-gy in chronic applications are the limited removal re lated to the volume o ~xehange and dilution by the required infusion solution, the requirement for plasma product~
and the potential hazards of such infusions, and the ~eed ` 'for bulky and expensive capital equipment. The removal of the speci~ic plasma factors as antibodies, Lmmune ! complexe~, and i~nunoglobulin~ by specific agents as ;, 30 sorbents l;ay be desirable; however, in most disease states the etiology is not known.
In most imanunologically related disea~e states the presence and abnormal concentration of plasma factors . ~ ,,i , ` ' . .
3 ~5 ~
;
greater than the molecular weight of albumin, suggest~
the application of membrane ~iltrationO In practice, I , plasma is ~eparated on-line from whole blood in an extra-7 corporeal circuit. The pla~ma which contains the molecules j 5 of interst is then filtered through a membrane filter which reject~ those macromolecules greater than albumin and allows albumin and the smaller size plasma solutes ¦ to pas~ and be returned to the patient. The return of the albumin o~viates the requirement for infu~ion of large 10 volume~ of donor plasma. Such ~echniques are pre~ently being applied cliniaally in the trea~ment o~ rheumatoid ¦ arthriti~ and certain other di~ease states~
Plasma exchange has been sh~wn to be effective in the treatment of various diseases, including the immu-15 nologically based disease states. This technique, however, has severe limitations in chronic applications, ~uch a~
limited removal related to the volume of exchange and dilu-I tion by the infusion solution and the requirement for pla~-: ~ ma products. Removal of the macromolecules as imml~ne 20 complexes by specific ~orbent-~ in most cases requires ex-tensive devel~pment worX. The nonspecific removal of macromolecules by membrane filtration maXes the treatment simpler and more universal in application.
In practice, plasma is separated on-line from `¦ 25 whole blood. The plasma which contains the macromolecules 1 _ tben ~iltered through a membrane filter which rejecta .I the macromolecules and pas5es the albumin and ~maller size plasma ~olutes which are rein~used into the patient.
; With rheumatoid arthriti plasma and membranes of homi~a 30 pore -~ize of 0.1 microns, over 9P~ passage of albumin was achieved with greater than 25~ rejection in a single pa~s of rheumatoid factor and Clq binding immune complexe~.
In certain immunologically related disease states, the ~ ~ ~ 3 ~
; -12-in~ea~ed le~els o~ cryQprecipitates containing antigen ' and or antibody in the form of immune complexe~ with or ¦~ ' without complement suggest~ that their removal could be therapeutic. Modification o~ the on-line pla3ma filtra-~ion circuit i~ made to include a heat exchanger to cool the plasma to below 10C before filtration. U~ing rh~uma-I toid axthritis plasma with cryoprecipitate concentration~i of gr2ater than 5 time~ normal, reductions to con~entra-tions below normal values were achieved in single pas~
with over 9~ passage of albumin~
The techniqu2~ of on-line plasma filtration through ~elect memhrane~ and the cooling of plasma to promote gel ~ormation of abnormal pla ma protein~ to maxi-miz~ their removal are simple and ea~y to apply. They do not require the infusion of expensive plasma pxoduct~.
~ Referri~g to the drawings, FIG~RE 1 illustrate~
j the method and apparatu~ of the invention as applied to the filtrakion of blood, although it wil~ be under~tood that , any other type of physiological fluid such as, for example, ~1 20 lymph, ascitic ~luid, etc7, may be treated.
In FIGURE 1, blood is drawn from a patient into line lO and fed into a pump 12 from which it is pumped into a line 14 and then into membrane filter 1.
In place of membrane filter 1, a centrifuge may b~ em-! ~ 25 ployed as the function at this point is to separat~ th~
~¦ blood into a plasma solution ~tream ~fed into line 18) and a concentrated cellular element stream (which i~ fed into line 1~).
:~ I From the membrane filter l, the plasma ~olution is led down a line 18 to a cooling unit 20 where theplasma ~olution is cooled to a temperature of between ju~t above the freezing point of the plasma solution and about - 35 centigrade to cause th~ macromolecules to gel or ,, :
.
3 5 ~ ~
precipitate. Next, the cool~d plasma solution i~ led down the line 22 ~o membrane filter 2, where the macro-molecules are retained (and th~ albumin and lower molec-ular weight component~ pa~s through).
From filter 2, the filtered pla~ma (plasma) minus larger molecular weight solute) is led through the line 24 to ~he juncture 26, where the filtered plasma stream and the concentrated cellular element ~tream are joined or united ~to form a processed stream~ and the~
fed into line 28 and thence into the h2ater unit 30.
: The heater unit 30 heats the processed stream to body temperature. The heated proce~ed stream i~ then fed int,o the line 32 and returned to the patient in a con-tin:uous proces3.
In the FIGURE 2 modification, the ~ooling unit 20a i5 ~hown encasing the filter 2 (and a portion of the : inc~ming line 22) such filter 2 being enclosed in a layer :- of insulation 34. This tructure assures proper ~ooled~
emperature maintenance within filter 2 during the fil-~0 t0ring process.
j It is to be understood that, if required, it wou~d be in order to inject into line 22 (before cooling) a c~mplexing agent for effecting gelling or precipitation . or macromolecule formation. A complexing agent i~ an .;; 25 ge~t which will allow single or multiple pla~ma factors ~o form a ~omplex of higher molecular weight. Such agent could be a sorbing agent or ion exchange material :such as, for example, heparin which formR complexes with chol~s~erol and lipid containing components.
~ Thus, FIGURES 1 and 2 outline filtration for the,separation of plasma from whole blood. A cell centri-fuge~could also be u~ed in place of me~brane filter 1 for the generation of the plasma flow stream. The plasma, , ~, .
~ 1 G 3 5 1 ~
which contains the factors of interest, is directed to a membrane filter 2 designed to filter out the macro-molecule~s) o~ interest, but pas~ tho~e pla~ma ~olutes of smallex ~ize. The pla~ma ic then reunited with the blood fl~w (concentrated cellular el~ment stream) ~om filter 1 ~or in the ca~e of a centrifuge the blood flow from the centrifuge) before being returned to the patient.
For ~ilter 1, a membrane with a ~ormal porosity o~ O.2-1 micro~ would be required to generate the pla~ma - 10 Pa3t inve~tigations with me~brane~ in the lower range porosity have indicated that sieving coefficient of certain plasma macromoleculas in the normal and the disea~e states are low (less than 0.8). In addition, operational conditions o~ filter 1, including blood and plasma flow~, and ~elocitie~ and transmembrane pressures may ~eriously ~` affect the 8 ieving properties o the macromolecule3 of interest. The filtration of blood in filter 1 i3 CrO3~
flow. Fil~er 2, which employ~ a mem~rane with a poro~ity of nominally 0.01 to 0.2 microns, would be re~uired to : 20 remove macromolecules of 100,000 daltons molecular weight or greater. For this porosity, e~sential substance~ as albumin and lower molecular weight solutes will pa~s through the membrane filter 2 and be returned to the patient. The filtration of the plasma in this fil~er may be cros~ flow or conventional (fIow directly into filtration media). In ,-ross flow, a recirculation circuit and an additional pump are required. Il~ this recirculati~n circuit a vari-able resistor (as a screw clamp) may be placed to regulate - the rate of fil~ration.
Serum globulins that precipitate or gel on cool-ing at low temperatures (nominally 35- 4C and generally 25-49C) and redissolve on warming may occur in a variety of disorders such as myeloma, kala-azar, macroglobinemia, 3 ~ ~ ~
~15 -mali~nant lymphoma, collagen diseases as lupus ~ glomeru-lonephritis, infectious mononucleosis, syphilis, cytome-: galovirus disea~e, rheumatoid arthriti~, and other auto-immune di3eases. ~he globulins may represent hom~geneous proteins that have become physically altered (myeloma), : mixt~res of immunoglobulins (as IgG and IgM), or immune complexe~ (such as antigen and zntibody), possibly with complement (as in systemic lupus erythematosus). The term cryoglobulins re~ers to those a~normal globulin~.
The molecular weight o~ cryoglobulins vary from 100,000 to 1,800,000 daltons molecular weight. By taking adva~-tage oX the precipitation or gelling effect of cryoglobu-lins their removal can be ef~ected. As the plasma i~
separated from blood it is cooled. While in some clinical situation~ only a small temperature change from phy~iologi cal temperature of 37ÇC is needed to start gelling or ; precipitation~ in the clinical situations temperature~ a~
low~a~ near freezing for extended times are nece3sary to cause precipitation in collected serum.
; 20 Occasionally cryoglobulins will precipitate out at room temperature, but as a rule, ~era have ~o be cool~d to 10C or lower, before precipitation OCCUr3.
Wlth ~he cryoglobulins cooled to a level to cause precipi-tation or gelling the filtration of these substances ~rom the plasma is greatly facilitated. ~he advantage of ~his scheme over the direct filtration scheme without excessive cooling is that the membrane poro~ity or pore size may be increased allowing for higher ~ieving of the normal proteins in the plasma and therefore more efficient re-; 30 turn to the patient. While cooling of the pla~m~ would normally ta~e place in the circuit the temperature decrease may not always be uniform or low enough therefore a heat exchange system would be most desirable to cool ~he pla~ma.
~ ~33S ~'~
To avoid chills to the patient or precipitation or gel-ling of the cryoglobulins in the blood circuit returning to the patient, the blood should be rewarmed by heater 30 to physiological temperature on its return to the patient.
EXPERIMENT~L STUDIES
ExPeriment t$1 Asahi* (Asahi ~ed ical Co., Tokyo; Japan) S-type filter containing c~llulose acetate hollow fiber membranes with a nominal pore size of 0.2 microns with 84% porosity : 10 was evaluated for sieving properties o~ Clq bindi~g immune complexes that are present i~ rheumatoid arthritis. Plas-~` ma obtained by centrifugation from patient ~.L. who had high value~ of Clq binding immune complexes was perfused through the S-type filter. Sievi~g coefficients (concen-tration of filtrate divided by t~e concentration in the fluid flow stream to the filter3 for the Clq binding im-mune ccmplexe~ averaged 0.49 over a two-hour perfusion : period. This study demonstrated that the~e complexe~
can be filtered from plasma but that its efficiency is ~ 20 lo~, allowing only about 5~ of ~he complexes to be re-v moved. This would necessitate long~x treatment time.
Experiment #2 Due to the relatively l~w efficiency of the Asahi*S-type filter various available membrane3 of nomi-~ 25 nal pore ~ize of 0.2 to 0.1 micron were selected or : studyO The membranes wexe Tuffryn HT-100 (polysul~one) with pore size of 0.1 micron fxom Gelman Sciences (Ann Arbor, Michigan), X~00 (acrylic copolymer~(approximate-ly ~.02 micron pore size) from Amicon (Lexington, Massa-30 chusetts), (V~WP-approximately 0.05 micron pore size) MF
~mixed cellulose acetate and nitrate) from Millipore Corp. ~Bedord, Massachusetts).
Plasma from a patient suffering from rheumatoid - * trade mark ~ 1 (i 3 ~
arthritis was procured by centrifugation. Such plasma contained elevated levels of rheumatoid factor and Cl~
binding immune complexes~ The membranes were assembled into small test cells giving a total surface area of 56 cm . The plasm~ was recirculated through the test cells at a~bient temperature. For testing the XM-30a membrane the plasma was filtered first through an Asahi filter.
This filtration process reduces the concentration of macromolecules in the plasma. For one of the ~-100 membrane, in addition ~o first filtering the plasma through an Asahi filter, the plasma was used af~er decan-tation following refrigeration. This procedure re~ults in the removal o~ a significant amount of cryoglobulins ; ~rom the plasma. For the other HT-100 membrane te5ted and t~e MX O.05 membrane tested the cryoprecipitates were resuspended in the plasma for the study. It i~
noted that for all membranes, complete sieving (no rejec-; tion) of small molecule weight solutes is achi~ved. Par-ticularly noteworthy is the sieving of albumin. In the 20 initial stages of the filtration studies ~less t~an 30 minutes) nearly complete rejection (low sieving coefficient) was seen for the XM-300 membranes. There was about 2~
rejection of Clq binding immune complexes and 32~ rejec-tion of rheumatoid factor for the HT-100 membrane at 10 minutes.
Experiment #3 A 54-year old ~hite female was selected with extremely aggressive seropositive rheumatoid arthxitis who failed all accepted modes of therapy and in addition failed cytotoxic drugs including ~ethotrexa~e and Cytoxanu The only therapeutic modality to which she has transiently responded has been plasmapheresis. ~he subject's ~lood was treated by the method and apparatus of FIGURE 1, such . ...
~ ~3~17 treatment reducing her immune complex Clq Binding ( c~74 u/ml. 9~ from 2256 units down to 688 unik~ with a i resultant LmprOvement in symptomatology.
: Experiment #4 Re~erence i~ now made to FIGURES 3 and 4. In this exp~rimen~0 a patient 9 c plasma was treated ~y the method and apparatus of FIGURE 1. It will be no~ed in -FIGURE 3 that the albumin 108s was only about 20~, while as shown in FIGURE 5, the cryo-protein reduction wa~
about 95%~
Both charts (FIGURES 3 and-4) are from the same 3ingle experiment, which was done un~er a cooled state.
Such experiment shows that the albumin substantially re-mains in solution (which is highly desirable) and the cryo-protein (which represents ~he macromolecules~ are almost all removed from the plasma solutio~.
In the method and apparatus o FIGURE 1, treat-ment time is normally about two to four hours, wi~h roughly 1.7 to 3.0 liters of plasma being treatea.
; 20 Controlled recirculation of the treated plasma rro~ line 24 over to line 18 could be effected i~ desired.
Thus, the invention provides a method of remov ~: ing macromolecules from a plasma solution including pro-viding a plasma solution containing macromolecules includ-: 25 ing a minLmum size thereof, cooling the placma ~olution t~ a temperature not low2r than ju~t above the freezing point o~ the plasma solution 9 and filtering the plasma solution with a membrane filter 2 having a porosity up : to sa}d minimum size to remove macromolecules of predeter-mined size *rom the plasma solution.
Also provided is a method of removing macro-molecule from a physiological solution such as blood including, securing a physiological solution from a .: ~
~ ~3~
patient, -~eparating the physiological solution stream into a concentrated cellular element ~tream and a plasma ` stream containing macromolecul~s therein by either a mem-brane filter or a centrifuge, filtering macromolecules of predetermine~ size out of the plasma stream to fon~ a filtered plasma stream, combining the filtered plasma stream and ~he cellular element stream to ~orm a processed stream, and returning the processed stream to the patient in a continuous proce~s. The step of heati~g the processed 10 ~tream to approximately body temperature before it is re-turned to the patient may also be included.
In s~ch method the membrane filter for removing the macromolPcule~ out of the separated stream has a por-osity of nominally 0.01 to 0.2 microns to pas~ macro-15 moiecules of approximately 70, 000 molecular weight and be-low and re ject or collect macromolecules of approximately 105, 000 molecular weight and over .
The invention also contemplates an apparatus ior removing macromolecules from a patient's physiological solution including, plasma separation means 1 for divid-ing a physiological solution such as blood containing : macromolecules into a conce~trated cellular element ~tream and a plasma stream, a cooler 20 in fluid flow communica-~ion with the plasma separation means 1 for receiving ~5 the,plasma stream therefrom and cooling such plasma tream to cause the macromolecules therein to gel or pre-cip~tate, filter means 2 in fluid flow communication with the cooling unit 20 for receiving the cooled plasma stream therefrom and filtering such cooled plasma stream to re-movq macro~olecules of a predetermined size therefrom,fluid flow communication means 26 for receiving the filtered plasma macrosolute stream from the filter means and for receiving the concentrated cellular element stream _ u 3 ~ .t ~
: -20-and combining said two last-named streams ~o form a proce~sed stream for return to ~he patient in a continuous process.
I ' ~ Further included is a pump 12 in fluid flow ¦~ communication with ~he plasma separation means 1 and with . j :
:~ 5 the patient to pump the physiological solution from the patient to the plasma separation means 1.
The cooling unit 20 cools the separated plasma stream to a temperature of bet~een just above the freez-ing poink of the separated plasma stream and approximately 35 centigrade, al~hough it iq to be understood that ~he cooler 20 may be eliminated in certain instances.
; Also, the heater unit 30 i~ preferred, but may ~e ~liminated if the temperature in the line 28 i~ near i body ~emperature.
h 15 The terms and expressions which have bee~ em-I ployed are u ed as terms of description, and not of l~i-~ tation, and there is no intention, in the u~e of such i terms and expressions, of excluding a~y equivalent~ of the feature shown and described or portions thereof, but it is recognized that various modifications are possible wit~in ~he s~ope of the invention claimed.
i ' ~
,~
;
greater than the molecular weight of albumin, suggest~
the application of membrane ~iltrationO In practice, I , plasma is ~eparated on-line from whole blood in an extra-7 corporeal circuit. The pla~ma which contains the molecules j 5 of interst is then filtered through a membrane filter which reject~ those macromolecules greater than albumin and allows albumin and the smaller size plasma solutes ¦ to pas~ and be returned to the patient. The return of the albumin o~viates the requirement for infu~ion of large 10 volume~ of donor plasma. Such ~echniques are pre~ently being applied cliniaally in the trea~ment o~ rheumatoid ¦ arthriti~ and certain other di~ease states~
Plasma exchange has been sh~wn to be effective in the treatment of various diseases, including the immu-15 nologically based disease states. This technique, however, has severe limitations in chronic applications, ~uch a~
limited removal related to the volume of exchange and dilu-I tion by the infusion solution and the requirement for pla~-: ~ ma products. Removal of the macromolecules as imml~ne 20 complexes by specific ~orbent-~ in most cases requires ex-tensive devel~pment worX. The nonspecific removal of macromolecules by membrane filtration maXes the treatment simpler and more universal in application.
In practice, plasma is separated on-line from `¦ 25 whole blood. The plasma which contains the macromolecules 1 _ tben ~iltered through a membrane filter which rejecta .I the macromolecules and pas5es the albumin and ~maller size plasma ~olutes which are rein~used into the patient.
; With rheumatoid arthriti plasma and membranes of homi~a 30 pore -~ize of 0.1 microns, over 9P~ passage of albumin was achieved with greater than 25~ rejection in a single pa~s of rheumatoid factor and Clq binding immune complexe~.
In certain immunologically related disease states, the ~ ~ ~ 3 ~
; -12-in~ea~ed le~els o~ cryQprecipitates containing antigen ' and or antibody in the form of immune complexe~ with or ¦~ ' without complement suggest~ that their removal could be therapeutic. Modification o~ the on-line pla3ma filtra-~ion circuit i~ made to include a heat exchanger to cool the plasma to below 10C before filtration. U~ing rh~uma-I toid axthritis plasma with cryoprecipitate concentration~i of gr2ater than 5 time~ normal, reductions to con~entra-tions below normal values were achieved in single pas~
with over 9~ passage of albumin~
The techniqu2~ of on-line plasma filtration through ~elect memhrane~ and the cooling of plasma to promote gel ~ormation of abnormal pla ma protein~ to maxi-miz~ their removal are simple and ea~y to apply. They do not require the infusion of expensive plasma pxoduct~.
~ Referri~g to the drawings, FIG~RE 1 illustrate~
j the method and apparatu~ of the invention as applied to the filtrakion of blood, although it wil~ be under~tood that , any other type of physiological fluid such as, for example, ~1 20 lymph, ascitic ~luid, etc7, may be treated.
In FIGURE 1, blood is drawn from a patient into line lO and fed into a pump 12 from which it is pumped into a line 14 and then into membrane filter 1.
In place of membrane filter 1, a centrifuge may b~ em-! ~ 25 ployed as the function at this point is to separat~ th~
~¦ blood into a plasma solution ~tream ~fed into line 18) and a concentrated cellular element stream (which i~ fed into line 1~).
:~ I From the membrane filter l, the plasma ~olution is led down a line 18 to a cooling unit 20 where theplasma ~olution is cooled to a temperature of between ju~t above the freezing point of the plasma solution and about - 35 centigrade to cause th~ macromolecules to gel or ,, :
.
3 5 ~ ~
precipitate. Next, the cool~d plasma solution i~ led down the line 22 ~o membrane filter 2, where the macro-molecules are retained (and th~ albumin and lower molec-ular weight component~ pa~s through).
From filter 2, the filtered pla~ma (plasma) minus larger molecular weight solute) is led through the line 24 to ~he juncture 26, where the filtered plasma stream and the concentrated cellular element ~tream are joined or united ~to form a processed stream~ and the~
fed into line 28 and thence into the h2ater unit 30.
: The heater unit 30 heats the processed stream to body temperature. The heated proce~ed stream i~ then fed int,o the line 32 and returned to the patient in a con-tin:uous proces3.
In the FIGURE 2 modification, the ~ooling unit 20a i5 ~hown encasing the filter 2 (and a portion of the : inc~ming line 22) such filter 2 being enclosed in a layer :- of insulation 34. This tructure assures proper ~ooled~
emperature maintenance within filter 2 during the fil-~0 t0ring process.
j It is to be understood that, if required, it wou~d be in order to inject into line 22 (before cooling) a c~mplexing agent for effecting gelling or precipitation . or macromolecule formation. A complexing agent i~ an .;; 25 ge~t which will allow single or multiple pla~ma factors ~o form a ~omplex of higher molecular weight. Such agent could be a sorbing agent or ion exchange material :such as, for example, heparin which formR complexes with chol~s~erol and lipid containing components.
~ Thus, FIGURES 1 and 2 outline filtration for the,separation of plasma from whole blood. A cell centri-fuge~could also be u~ed in place of me~brane filter 1 for the generation of the plasma flow stream. The plasma, , ~, .
~ 1 G 3 5 1 ~
which contains the factors of interest, is directed to a membrane filter 2 designed to filter out the macro-molecule~s) o~ interest, but pas~ tho~e pla~ma ~olutes of smallex ~ize. The pla~ma ic then reunited with the blood fl~w (concentrated cellular el~ment stream) ~om filter 1 ~or in the ca~e of a centrifuge the blood flow from the centrifuge) before being returned to the patient.
For ~ilter 1, a membrane with a ~ormal porosity o~ O.2-1 micro~ would be required to generate the pla~ma - 10 Pa3t inve~tigations with me~brane~ in the lower range porosity have indicated that sieving coefficient of certain plasma macromoleculas in the normal and the disea~e states are low (less than 0.8). In addition, operational conditions o~ filter 1, including blood and plasma flow~, and ~elocitie~ and transmembrane pressures may ~eriously ~` affect the 8 ieving properties o the macromolecule3 of interest. The filtration of blood in filter 1 i3 CrO3~
flow. Fil~er 2, which employ~ a mem~rane with a poro~ity of nominally 0.01 to 0.2 microns, would be re~uired to : 20 remove macromolecules of 100,000 daltons molecular weight or greater. For this porosity, e~sential substance~ as albumin and lower molecular weight solutes will pa~s through the membrane filter 2 and be returned to the patient. The filtration of the plasma in this fil~er may be cros~ flow or conventional (fIow directly into filtration media). In ,-ross flow, a recirculation circuit and an additional pump are required. Il~ this recirculati~n circuit a vari-able resistor (as a screw clamp) may be placed to regulate - the rate of fil~ration.
Serum globulins that precipitate or gel on cool-ing at low temperatures (nominally 35- 4C and generally 25-49C) and redissolve on warming may occur in a variety of disorders such as myeloma, kala-azar, macroglobinemia, 3 ~ ~ ~
~15 -mali~nant lymphoma, collagen diseases as lupus ~ glomeru-lonephritis, infectious mononucleosis, syphilis, cytome-: galovirus disea~e, rheumatoid arthriti~, and other auto-immune di3eases. ~he globulins may represent hom~geneous proteins that have become physically altered (myeloma), : mixt~res of immunoglobulins (as IgG and IgM), or immune complexe~ (such as antigen and zntibody), possibly with complement (as in systemic lupus erythematosus). The term cryoglobulins re~ers to those a~normal globulin~.
The molecular weight o~ cryoglobulins vary from 100,000 to 1,800,000 daltons molecular weight. By taking adva~-tage oX the precipitation or gelling effect of cryoglobu-lins their removal can be ef~ected. As the plasma i~
separated from blood it is cooled. While in some clinical situation~ only a small temperature change from phy~iologi cal temperature of 37ÇC is needed to start gelling or ; precipitation~ in the clinical situations temperature~ a~
low~a~ near freezing for extended times are nece3sary to cause precipitation in collected serum.
; 20 Occasionally cryoglobulins will precipitate out at room temperature, but as a rule, ~era have ~o be cool~d to 10C or lower, before precipitation OCCUr3.
Wlth ~he cryoglobulins cooled to a level to cause precipi-tation or gelling the filtration of these substances ~rom the plasma is greatly facilitated. ~he advantage of ~his scheme over the direct filtration scheme without excessive cooling is that the membrane poro~ity or pore size may be increased allowing for higher ~ieving of the normal proteins in the plasma and therefore more efficient re-; 30 turn to the patient. While cooling of the pla~m~ would normally ta~e place in the circuit the temperature decrease may not always be uniform or low enough therefore a heat exchange system would be most desirable to cool ~he pla~ma.
~ ~33S ~'~
To avoid chills to the patient or precipitation or gel-ling of the cryoglobulins in the blood circuit returning to the patient, the blood should be rewarmed by heater 30 to physiological temperature on its return to the patient.
EXPERIMENT~L STUDIES
ExPeriment t$1 Asahi* (Asahi ~ed ical Co., Tokyo; Japan) S-type filter containing c~llulose acetate hollow fiber membranes with a nominal pore size of 0.2 microns with 84% porosity : 10 was evaluated for sieving properties o~ Clq bindi~g immune complexes that are present i~ rheumatoid arthritis. Plas-~` ma obtained by centrifugation from patient ~.L. who had high value~ of Clq binding immune complexes was perfused through the S-type filter. Sievi~g coefficients (concen-tration of filtrate divided by t~e concentration in the fluid flow stream to the filter3 for the Clq binding im-mune ccmplexe~ averaged 0.49 over a two-hour perfusion : period. This study demonstrated that the~e complexe~
can be filtered from plasma but that its efficiency is ~ 20 lo~, allowing only about 5~ of ~he complexes to be re-v moved. This would necessitate long~x treatment time.
Experiment #2 Due to the relatively l~w efficiency of the Asahi*S-type filter various available membrane3 of nomi-~ 25 nal pore ~ize of 0.2 to 0.1 micron were selected or : studyO The membranes wexe Tuffryn HT-100 (polysul~one) with pore size of 0.1 micron fxom Gelman Sciences (Ann Arbor, Michigan), X~00 (acrylic copolymer~(approximate-ly ~.02 micron pore size) from Amicon (Lexington, Massa-30 chusetts), (V~WP-approximately 0.05 micron pore size) MF
~mixed cellulose acetate and nitrate) from Millipore Corp. ~Bedord, Massachusetts).
Plasma from a patient suffering from rheumatoid - * trade mark ~ 1 (i 3 ~
arthritis was procured by centrifugation. Such plasma contained elevated levels of rheumatoid factor and Cl~
binding immune complexes~ The membranes were assembled into small test cells giving a total surface area of 56 cm . The plasm~ was recirculated through the test cells at a~bient temperature. For testing the XM-30a membrane the plasma was filtered first through an Asahi filter.
This filtration process reduces the concentration of macromolecules in the plasma. For one of the ~-100 membrane, in addition ~o first filtering the plasma through an Asahi filter, the plasma was used af~er decan-tation following refrigeration. This procedure re~ults in the removal o~ a significant amount of cryoglobulins ; ~rom the plasma. For the other HT-100 membrane te5ted and t~e MX O.05 membrane tested the cryoprecipitates were resuspended in the plasma for the study. It i~
noted that for all membranes, complete sieving (no rejec-; tion) of small molecule weight solutes is achi~ved. Par-ticularly noteworthy is the sieving of albumin. In the 20 initial stages of the filtration studies ~less t~an 30 minutes) nearly complete rejection (low sieving coefficient) was seen for the XM-300 membranes. There was about 2~
rejection of Clq binding immune complexes and 32~ rejec-tion of rheumatoid factor for the HT-100 membrane at 10 minutes.
Experiment #3 A 54-year old ~hite female was selected with extremely aggressive seropositive rheumatoid arthxitis who failed all accepted modes of therapy and in addition failed cytotoxic drugs including ~ethotrexa~e and Cytoxanu The only therapeutic modality to which she has transiently responded has been plasmapheresis. ~he subject's ~lood was treated by the method and apparatus of FIGURE 1, such . ...
~ ~3~17 treatment reducing her immune complex Clq Binding ( c~74 u/ml. 9~ from 2256 units down to 688 unik~ with a i resultant LmprOvement in symptomatology.
: Experiment #4 Re~erence i~ now made to FIGURES 3 and 4. In this exp~rimen~0 a patient 9 c plasma was treated ~y the method and apparatus of FIGURE 1. It will be no~ed in -FIGURE 3 that the albumin 108s was only about 20~, while as shown in FIGURE 5, the cryo-protein reduction wa~
about 95%~
Both charts (FIGURES 3 and-4) are from the same 3ingle experiment, which was done un~er a cooled state.
Such experiment shows that the albumin substantially re-mains in solution (which is highly desirable) and the cryo-protein (which represents ~he macromolecules~ are almost all removed from the plasma solutio~.
In the method and apparatus o FIGURE 1, treat-ment time is normally about two to four hours, wi~h roughly 1.7 to 3.0 liters of plasma being treatea.
; 20 Controlled recirculation of the treated plasma rro~ line 24 over to line 18 could be effected i~ desired.
Thus, the invention provides a method of remov ~: ing macromolecules from a plasma solution including pro-viding a plasma solution containing macromolecules includ-: 25 ing a minLmum size thereof, cooling the placma ~olution t~ a temperature not low2r than ju~t above the freezing point o~ the plasma solution 9 and filtering the plasma solution with a membrane filter 2 having a porosity up : to sa}d minimum size to remove macromolecules of predeter-mined size *rom the plasma solution.
Also provided is a method of removing macro-molecule from a physiological solution such as blood including, securing a physiological solution from a .: ~
~ ~3~
patient, -~eparating the physiological solution stream into a concentrated cellular element ~tream and a plasma ` stream containing macromolecul~s therein by either a mem-brane filter or a centrifuge, filtering macromolecules of predetermine~ size out of the plasma stream to fon~ a filtered plasma stream, combining the filtered plasma stream and ~he cellular element stream to ~orm a processed stream, and returning the processed stream to the patient in a continuous proce~s. The step of heati~g the processed 10 ~tream to approximately body temperature before it is re-turned to the patient may also be included.
In s~ch method the membrane filter for removing the macromolPcule~ out of the separated stream has a por-osity of nominally 0.01 to 0.2 microns to pas~ macro-15 moiecules of approximately 70, 000 molecular weight and be-low and re ject or collect macromolecules of approximately 105, 000 molecular weight and over .
The invention also contemplates an apparatus ior removing macromolecules from a patient's physiological solution including, plasma separation means 1 for divid-ing a physiological solution such as blood containing : macromolecules into a conce~trated cellular element ~tream and a plasma stream, a cooler 20 in fluid flow communica-~ion with the plasma separation means 1 for receiving ~5 the,plasma stream therefrom and cooling such plasma tream to cause the macromolecules therein to gel or pre-cip~tate, filter means 2 in fluid flow communication with the cooling unit 20 for receiving the cooled plasma stream therefrom and filtering such cooled plasma stream to re-movq macro~olecules of a predetermined size therefrom,fluid flow communication means 26 for receiving the filtered plasma macrosolute stream from the filter means and for receiving the concentrated cellular element stream _ u 3 ~ .t ~
: -20-and combining said two last-named streams ~o form a proce~sed stream for return to ~he patient in a continuous process.
I ' ~ Further included is a pump 12 in fluid flow ¦~ communication with ~he plasma separation means 1 and with . j :
:~ 5 the patient to pump the physiological solution from the patient to the plasma separation means 1.
The cooling unit 20 cools the separated plasma stream to a temperature of bet~een just above the freez-ing poink of the separated plasma stream and approximately 35 centigrade, al~hough it iq to be understood that ~he cooler 20 may be eliminated in certain instances.
; Also, the heater unit 30 i~ preferred, but may ~e ~liminated if the temperature in the line 28 i~ near i body ~emperature.
h 15 The terms and expressions which have bee~ em-I ployed are u ed as terms of description, and not of l~i-~ tation, and there is no intention, in the u~e of such i terms and expressions, of excluding a~y equivalent~ of the feature shown and described or portions thereof, but it is recognized that various modifications are possible wit~in ~he s~ope of the invention claimed.
i ' ~
,~
Claims (19)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method of removing macromolecules from a plasma solution comprising; providing a plasma solution containing macromolecules including a minimum size thereof, effecting predetermined cooling of said plasma solution to a temperature not lower than just above the freezing point of the plasma solution, and filtering said cooled plasma solution with a membrane filter having a porosity up to said minimum size to remove macromolecules of a predeter-mined size from the plasma solution.
2. A method of removing macromolecules from a physiological solution comprising; separating said physio-logical solution into a concentrated cellular element stream and a plasma stream containing macromolecules therein, effecting predetermined cooling of said plasma stream to a temperature of between just above the freezing point of the plasma stream and 35° centigrade, filtering macro-molecules of predetermined size out of the cooled plasma stream to form a filtered plasma stream, combining said filtered plasma stream and said cellular element stream to form a processed stream, and heating the processed stream to the starting temperature of said physiological solution.
3. The method of claim 2 wherein the separa-tion of said physiological solution into a concentrated cellular element stream and a plasma stream is effected by a centrifuge.
4. The method of claim 2 wherein the separation of said physiological solution into a concentrated cellular element stream and a plasma stream is effected by a mem-brane filter, and further including the step of adding a complexing agent to the plasma stream before it is filtered to promote macromolecule formation.
5. The method of claim 2, 3 or 4 wherein said physiological solution is blood.
6. The method of claim 2, 3 or 4 wherein said physiological solution is lymph or ascitic fluid.
7. An apparatus for removing macromolecules from a patient's physiological solution comprising; plasma separation means for dividing a physiological solution con-taining macromolecules into a concentrated cellular element stream and a plasma stream, a cooler in fluid flow communi-cation with said plasma separation means for receiving the plasma stream therefrom and cooling such plasma stream to a predetermined temperature to cause the macromolecules therein to gel or precipitate, filter means in fluid flow communication with said cooling unit for receiving the cooled plasma stream therefrom and filtering such cooled plasma stream to remove macromolecules of a predetermined size therefrom, fluid flow communication means for receiving the filtered plasma stream from the filter means and for receiving the concentrated cellular element stream and com-bining said two last-named streams to form a processed stream for return to the patient.
8. The structure of claim 7 and further in-cluding a pump in fluid flow communication with the plasma separation means and with the patient to pump the physio-logical solution from the patient to the plasma separation means.
9. The structure of claim 7 wherein a com-plexing agent is added to the plasma stream before it is filtered by the filter means to promote macromolecule forma-tion.
10. The structure of claim 7 wherein said phy-siological solution is blood.
11. The structure of claim 10 wherein the separated plasma stream is blood plasma containing macro-molecules.
12. The structure of claim 7, 8 or 9 wherein the physiological solution is lymph or ascitic fluid.
13. The structure of claim 7, 8 or 9 wherein said cooling unit cools the separated plasma stream to a temperature of between just above the freezing point of the separated plasma stream and approximately 35° centigrade.
14. The structure of claim 7, 8 or 9 wherein said plasma separation means is a centrifuge.
15. The structure of claim 7, 8 or 9 wherein said plasma separation means is a membrane filter.
16, The structure of claim 7, 8 or 9 and further including a heater unit operatively secured to the fluid flow communication means at a point in such fluid flow communication means after said two last-named streams are combined to heat the processed stream to approximately body temperature before it is returned to the patient.
17. An apparatus for removing macromolecules from a patient's physiological solution comprising; plasma separation means for dividing a physiological solution con-taining macromolecules into a concentrated cellular ele-ment stream and a plasma stream, a cooler in fluid flow communication with said plasma separation means for receiving the plasma stream therefrom and cooling such plasma stream to a predetermined temperature to cause the macromolecules therein to gel or precipitate, filter means in fluid flow communication with and encased in said cooling unit for receiving the cooled plasma stream therefrom and filtering and further cooling such cooled plasma stream to remove macromolecules of a predetermined size therefrom, fluid flow communication means for receiving the filtered plasma stream from the filter means and for receiving the concentrated cellular element stream and combining said two last-named streams to form a processed stream substantially free of macromolecules of said predetermined size for return to the patient.
18. The structure of claim 17 wherein the cooler cools the plasma stream to a temperature of between just above the freezing point of the plasma stream and approxi-mately 35° centigrade.
19. The structure of claim 17 or 18 and further including a heater unit operatively secured to the fluid flow communication means at a point in such fluid flow communication means after said two last-named streams are combined to heat the processed stream to approximately body temperature before it is returned to the patient.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000426017A CA1170138A (en) | 1980-05-29 | 1983-04-15 | Method and apparatus for on-line filtration removal of macromolecules from a physiological fluid |
| CA000436234A CA1176574A (en) | 1980-05-29 | 1983-09-07 | Method and apparatus for on-line filtration removal of macromolecules from a physiological fluid |
| CA000436233A CA1176573A (en) | 1980-05-29 | 1983-09-07 | Method and apparatus for on-line filtration removal of macromolecules from a physiological fluid |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US154,581 | 1980-05-29 | ||
| US06/154,581 US4350156A (en) | 1980-05-29 | 1980-05-29 | Method and apparatus for on-line filtration removal of macromolecules from a physiological fluid |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000436233A Division CA1176573A (en) | 1980-05-29 | 1983-09-07 | Method and apparatus for on-line filtration removal of macromolecules from a physiological fluid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1163517A true CA1163517A (en) | 1984-03-13 |
Family
ID=22551904
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000377362A Expired CA1163517A (en) | 1980-05-29 | 1981-05-12 | Method and apparatus for on-line filtration removal of macromolecules from a physiological fluid |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US4350156A (en) |
| EP (1) | EP0041350B1 (en) |
| JP (1) | JPS5731869A (en) |
| BR (1) | BR8103271A (en) |
| CA (1) | CA1163517A (en) |
| DE (1) | DE3174039D1 (en) |
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| WO2009094666A2 (en) * | 2008-01-25 | 2009-07-30 | Baylor College Of Medicine | Cryoaggregate filtration for the treatment of cardiomyopathy and other autoimmune diseases |
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| US9694128B1 (en) * | 2010-02-24 | 2017-07-04 | Brian LeBerthon | Device and method for administering an anti-cancer substance |
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| CN106999640B (en) * | 2014-12-26 | 2019-10-29 | 旭化成医疗株式会社 | Body cavity liquid treating system |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3579441A (en) * | 1968-04-19 | 1971-05-18 | Hydronautics | Blood purification by dual filtration |
| US3705100A (en) * | 1970-08-25 | 1972-12-05 | Amicon Corp | Blood fractionating process and apparatus for carrying out same |
| US3788319A (en) * | 1971-07-30 | 1974-01-29 | Univ Iowa State Res Found Inc | System for exchanging blood ultrafiltrate |
| US3802432A (en) * | 1972-05-18 | 1974-04-09 | I Djerassi | Apparatus for filtration-leukopheresis for separation and concentration of human granulocytes |
| US4006078A (en) * | 1974-07-08 | 1977-02-01 | The United States Of America As Represented By The Secretary Of Agriculture | Preparation of soluble edible protein from leafy green crops |
| US3941356A (en) * | 1974-11-13 | 1976-03-02 | The United States Of America As Represented By The Department Of Health, Education And Welfare | Method and apparatus for continuous mixing of blood plasma and additives |
| GB1558370A (en) * | 1975-09-26 | 1979-12-28 | Asahi Chemical Ind | Blood treating apparatus |
| DE2553416A1 (en) * | 1975-11-27 | 1977-06-02 | Hager & Elsaesser | Sepn. of dissolved substances from solns. - by raising the soln. temp. before concentration and cooling |
| US4103685A (en) * | 1976-01-05 | 1978-08-01 | Lupien Paul J | Method and apparatus for extravascular treatment of blood |
| JPS52155888A (en) * | 1976-06-22 | 1977-12-24 | Mitsui Toatsu Chemicals | Device for continuously removing material in blood flow |
| US4111199A (en) * | 1977-03-31 | 1978-09-05 | Isaac Djerassi | Method of collecting transfusable granulocytes by gravity leukopheresis |
| JPS5416896A (en) * | 1977-06-21 | 1979-02-07 | Asahi Medical Co | Blood dialyser |
| US4191182A (en) * | 1977-09-23 | 1980-03-04 | Hemotherapy Inc. | Method and apparatus for continuous plasmaphersis |
| US4223672A (en) * | 1979-02-08 | 1980-09-23 | Baxter Travenol Laboratories, Inc. | Variable volume plasma treatment chamber for an apparatus for the extracorporeal treatment of disease |
| US4215688A (en) * | 1979-02-09 | 1980-08-05 | Baxter Travenol Laboratories, Inc. | Apparatus for the extracorporeal treatment of disease |
| US4350594A (en) * | 1980-04-16 | 1982-09-21 | Kuraray Co., Ltd. | Blood purification using plural ultrafiltration stages |
-
1980
- 1980-05-29 US US06/154,581 patent/US4350156A/en not_active Expired - Lifetime
-
1981
- 1981-05-12 CA CA000377362A patent/CA1163517A/en not_active Expired
- 1981-05-22 EP EP81302297A patent/EP0041350B1/en not_active Expired
- 1981-05-22 DE DE8181302297T patent/DE3174039D1/en not_active Expired
- 1981-05-26 BR BR8103271A patent/BR8103271A/en unknown
- 1981-05-29 JP JP8371481A patent/JPS5731869A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| EP0041350B1 (en) | 1986-03-12 |
| EP0041350A3 (en) | 1982-02-17 |
| EP0041350A2 (en) | 1981-12-09 |
| JPH0134626B2 (en) | 1989-07-20 |
| US4350156A (en) | 1982-09-21 |
| JPS5731869A (en) | 1982-02-20 |
| BR8103271A (en) | 1982-02-16 |
| DE3174039D1 (en) | 1986-04-17 |
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