|Publication number||USRE39498 E1|
|Application number||US 09/879,002|
|Publication date||Feb 27, 2007|
|Filing date||Dec 22, 1995|
|Priority date||Dec 22, 1994|
|Also published as||CA2208059A1, DE69535418D1, DE69535418T2, EP0799061A1, EP0799061A4, EP0799061B1, WO1996019250A1|
|Publication number||09879002, 879002, PCT/1995/875, PCT/AU/1995/000875, PCT/AU/1995/00875, PCT/AU/95/000875, PCT/AU/95/00875, PCT/AU1995/000875, PCT/AU1995/00875, PCT/AU1995000875, PCT/AU199500875, PCT/AU95/000875, PCT/AU95/00875, PCT/AU95000875, PCT/AU9500875, US RE39498 E1, US RE39498E1, US-E1-RE39498, USRE39498 E1, USRE39498E1|
|Inventors||Karim Rouan Cham, Bill Elliot Cham|
|Original Assignee||Aruba International Pty. Ltd.|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (108), Non-Patent Citations (54), Referenced by (9), Classifications (14), Legal Events (3)|
|External Links: USPTO, USPTO Assignment, Espacenet|
This application is a U.S. National Phase Application filed under 35 U.S.C. § 371 based on International Application No. PCT/AU95/00875, having an International Filing Date of Dec. 22, 1995.
THIS INVENTION relates to plasma or serum delipidation in animals (which term shall indicate humans), to a treatment for cardiovascular disease and to removal of excess fat from the animals. In particular, it is directed to the removal of cholesterol, triglycerides and other lipids, and fat soluble toxins—for example, insecticides—from the blood plasma or serum of such animals.
Cardiovascular diseases are responsible for a significant number of deaths in most industrialised countries.
One such disease is atherosclerosis which is characterised by local fatty thickening in the inner aspects of large vessels supplying blood to the heart, brain and other vital organs. These lesions obstruct the lumen of the vessel and result in ischaemia of the tissue supplied by the vessel. Prolonged or sudden ischaemia may result in a clinical heart attack or stroke from which the patient may or may not recover.
The relationship between dietary lipid, serum cholesterol and atherosclerosis has long been recognised. In many epidemiological studies it has been shown that a single measurement of serum cholesterol has proved to be a significant predictor of the occurrence of coronary heart disease.
Thus diet is the basic element of all therapy for hyperlipidaemia (excessive amount of fat in plasma). However, the use of diet as a primary mode of therapy requires a major effort on the part of physicians, nutritionists, dieticians and other health professionals.
If dietary modification is unsuccessful, drug therapy is an alternative. Several drugs, used singly or in combination, are available. However, there is no direct evidence that any cholesterol-lowering drug can be safely administered over an extended period.
A combination of both drug and diet may be required to reduce the concentration of plasma lipids. Hypolipidaemic drugs are therefore used as a supplement to dietary control.
Many drugs are effective in reducing blood lipids, but none work in all types of hyperlipidaemia and they all have undesirable side effects. There is no conclusive evidence that hypolipidaemic drugs can cause regression of atherosclerosis. Thus, despite progress in achieving the lowering of plasma cholesterol to prevent heart disease by diet, drug therapies, surgical revascularization procedures and angioplasty, atherosclerosis remains the major cause of death in Western Countries.
In view of the above, new approaches have been sought to reduce the amount of lipid in the plasma of homozygotes and that of heterozygotes for whom oral drugs are not effective.
Plasmapheresis (plasma exchange) therapy has been developed and involves replacement of the patient's plasma with donor plasma or more usually a plasma protein fraction. This treatment can result in complications due to the possible introduction of foreign proteins and transmission of infectious diseases. Further, plasma exchange removes all the plasma proteins as well as very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL).
It is known that HDL is inversely correlated with the severity of coronary arterial lesions as well as with the likelihood that these will progress. Therefore, removal of HDL is not advantageous.
Known aphaeresis techniques also exist which can remove LDL from plasma. These techniques include absorption of LDL in heparinagarose beads (affinity chromatography) or the use of immobilised LDL-antibodies. Other methods presently available for the removal of LDL involve cascade filtration absorption to immobilised dextran sulphate and LDL precipitation at low pH in the presence of heparin. Each method specifically removes LDL but not HDL.
LDL aphaeresis has, however, disadvantages. Significant amounts of other plasma proteins are removed during aphaeresis and to obtain a sustained reduction in LDL-cholesterol, LDL aphaeresis must be performed frequently (up to once weekly). Furthermore, LDL removal may be counter productive as, low blood LDL levels may result in increased cellular cholesterol synthesis.
To satisfy the need for a method of achieving a reduction in plasma cholesterol in homozygous familial hypercholesterolemia, heterozygous familial hypercholesterolemia and patients with acquired hyperlipidaemia other than by diet, drug therapy, LDL aphaeresis, or a combination of these, an extra corporeal lipid elimination process, termed “cholesterol aphaeresis”, has been developed. In cholesterol aphaeresis, blood is withdrawn from a subject, plasma separated from the blood and mixed with a solvent mixture which extracts lipid from the plasma, after which the delipidated plasma is recombined with the blood cells and returned to the subject.
In more detail, cholesterol aphaeresis results in the removal of fats from plasma or serum. However, unlike LDL aphaeresis, the proteins that transport the fat (apolipoproteins) remain soluble in the treated plasma or serum. Thus the apolipoproteins of VLDL, LDL and HDL are present in the treated plasma or serum. These apolipoproteins, in particular apolipoproteins A1 from the defatted HDL in the plasma or serum, are responsible for the mobilisation of excessive amounts of deposited fats such as cholesterol in arteries, plaques, or excessive amounts of triglycerides, adipose tissue, or fat soluble toxins that are present in adipose tissue. These excessive amount of fats or toxins are transferred to the plasma or serum, bound to the newly assembled lipoproteins. Thus by applying another cholesterol aphaeresis procedure, these unwanted fats or toxins are successively removed from the plasma and thus the body.
The main advantage of this procedure is that LDL and HDL are thus not removed from the plasma but only cholesterol, some phospholipids and considerable triglycerides. U.S. Pat. No. 4,895,558 describes such a system.
While cholesterol aphaeresis has overcome the shortcomings of dietary and/or drug treatments and other aphaeretic techniques, existing apparatus for cholesterol aphaeresis does not provide a sufficiently rapid and safe process. For use in a clinical setting, apparatus is required which effects delipidation more efficiently. Furthermore, flow rates of the order of 70 ml/min are required for cholesterol aphaeresis of a human subject.
Thus the cholesterol aphaeresis described in the aforementioned U.S. Pat. No. 4,895,558 was improved by incorporating into the system a spinner to disperse the incoming plasma laterally into the extracting solvent in the form of fine droplets to improve separation efficiency. This improved system is described in International Patent Application No. PCT/AU94/00415.
Unfortunately, practice has established that the cholesterol aphaeresis systems described above still suffer from a number of disadvantages.
The first disadvantage is the explosive nature of the solvents used to delipidate this plasma. These solvents are, by the very nature of the continuous systems, in close proximity to the patient and medical staff. This hazard is clearly present for the duration of the delipidation process which usually runs for several hours.
The second disadvantage is that, in the prior continuous systems, a reliable procedure is not available to remove totally all of the solvents used in the delipidation before the treated plasma is returned to the patient.
In particular, the use of the preferred solvent 1-butanol in the delipidation is of concern as it can now be established that that solvent can be present as 1% to 5% of the treated plasma that is returned to the patient. This is because continuous systems can only include a single wash to remove solvents such as 1-butanol and a single wash is now found to be sufficient. It is not possible to provide sequential multi-washes in a continuous system because the patient would have to supply an unacceptable volume of blood to maintain each stage of the system overall and the patient would also be subjected to an increased hazard factor from the prolonged exposure to the solvents.
The long term toxicity of 1-butanol is not known, especially when directly present in the blood stream—it may cross the blood brain barrier. Certainly, external contact with this solvent is known to cause irritation of mucous membranes, contact dermatitis, headaches, dizziness and drowsiness.
A third disadvantage is that the continuous systems described above are not suitable for the delipidation of serum. If serum can be delipidated, there would be the advantage of favourably altering the blood rheology in that the viscosity will decrease following delipidation resulting in better haemodynamics for the originally impaired blood circulation.
Yet a fourth disadvantage is that delipidation in a continuous system is undertaken over several hours. Apart from the prolonged exposure to the hazardous solvents as discussed above, the equipment and staff are committed to a single patient. As the removal of plasma or other blood fractions and their subsequent return to the patient as individual steps each only take a few minutes, it would be advantageous if the relatively lengthy delipidation step could be undertaken off site, thus freeing the patient, medical staff and equipment for other matters.
Finally, in a continuous system, clearly it is only the patient's own blood fraction that can be returned to that patient. However, for example, if the patient's plasma or serum could be removed and treated remote from the patient, then either autologous or non-autologous plasma or serum could be returned to the patient at a later date.
It is an object of the present invention to overcome, or at least ameliorate, the above-mentioned disadvantages in the provision of a method for delipidating not only plasma but also serum and other blood fractions which substantially reduces the exposure of the patient to the potentially hazardous solvents used, which also can effectively remove all traces of solvent(s) used in that delipidation, and which significantly reduces the contact time between the patient and the actual delipidation process.
It is a further object to provide a method whereby advantageous changes to the blood rheology of the originally impaired blood circulation of the patient can be achieved.
It is yet another object to provide a method whereby a patient's Plasma or serum can be treated remote from that patient, thus allowing either autologous or non-autologous plasma or serum to be returned to the patient at a later date.
In one aspect of the present invention, there is provided a method for the removal of cholesterol, triglycerides and other lipids from animal plasma, serum or other suitable blood fractions, as a discontinuous flow system, said method comprising withdrawing blood from a subject, separating the required fraction from the blood and mixing with a solvent mixture which extracts the said lipids from the fraction, after which the delipidated fraction is recombined with the blood cells and returned to the subject, characterised in that the solvent extraction step is carried out separately and remote from the subject.
Preferably, as part of the solvent extraction step, beads are used when mixing the blood fractions with the solvent. More preferably, the beads have a density substantially mid-way between the density of the fraction and the density of the solvent mixture. This ensures efficient mixing with a large surface area, increasing the efficiency of the extraction and also serving as a good separator of the plasma from the solvent when centrifugation is used to isolate the phases after extraction.
Preferably, to obtain a density substantially mid-way between the density of the fraction and the density of the solvent mixture, the beads contain entrapped air.
More preferably, as the density of plasma is approximately 1.006 g/ml and the solvents used generally have a density of approximately 0.8 g/ml, the density of the beads will be around 0.9 g/ml.
The beads may be manufactured from any acceptable material such as glass or plastic.
Once the resultant delipidated fraction-containing phase has been isolated, all traces of the extraction solvent must be removed before the fraction is recombined with the blood cells and/or returned to the subject.
One way of removing this solvent is to wash with another solvent, preferably diethyl ether, to remove substantially all of the original solvent used in the extraction step.
More preferably, four (4) washes are undertaken.
However, as another aspect of the present invention, efficient removal of the extraction solvent can be achieved by mixing the delipidated fraction with an absorbent specific for the solvent that is being removed.
In particular, the absorbent is contained in the pores of sintered spheres.
More preferably, the sintered spheres are approximately 2 to 5 mm in diameter with the pores of the spheres being less than 50 Å in diameter. Most preferably, the spheres are manufactured from glass.
Preferably, the absorbents used in the sintered spheres are the macroporous polymeric beads for absorbing organic molecules from aqueous solutions marketed by Bio-Rad Laboratories under the trade name Bio-Beads SM.
If the solvent used to delipidate the fraction is 1-butanol, then the absorbent is preferably Bio-Beads SM-2.
Preferably, the absorbent is held in a chamber which is adapted to allow the delipidated fraction to pass through or over the absorbent at least twice if a single pass is insufficient to remove all of the solvent.
Preferably, as part of isolating the delipidated fraction-containing phase, that phase is subsequently washed with another solvent, preferably diethyl ether, to remove a substantial amount of the original solvent before the treatment with the absorbent.
More preferably, that phase is washed at least three (3) times.
The plasma may be human plasma or plasma from other living animals. The plasma can be obtained from human or animal blood by known plasma separating techniques which include centrifugal separation, filtration and the like.
Similarly, the serum or other lipid-containing fraction can be derived from human or other living animals by known techniques.
Suitable solvents for the extraction comprise mixtures of hydrocarbons, ethers and alcohols. Preferred solvents are mixtures of lower alcohols with lower ethers. The lower alcohols suitably include those which are not appreciably miscible with the plasma and these can include the butanols (butan-1-ol and butan-2-ol). C1-4 ethers are also preferred and these can include the propyl ethers (di-isopropyl ether and propyl ether). Other solvents which may be applicable include amines, esters, hydrocarbons and mixtures providing that the solvent can (1) rapidly and preferably remove cholesterol from the plasma, (2) is substantially immiscible with the plasma, (3) can be removed from the plasma, and (4) does not denature the desired moieties. Preferred solvent compositions are butanol with di-isopropyl ether and these may be in the ratio of 0%-40% of the alcohol to 100%-60% of the ether.
The roosters used in this study were of White Leghorn Hiline strain and were obtained as one-day old chicks. All roosters from 8 weeks old were transferred into individual cages. Water and feed were supplied unrestricted. At eight weeks of age, 15 control birds were fed a commercial poultry ration for 31 days and another group of 30 birds were injected subcutaneously each day with 5 mg diethylstilboestrol (DES) in sesame oil for a period of 31 days. In addition they were fed on the same commercial diet which was supplemented with 2.6% (w/w) cholesterol for a period of 31 days. Fifteen animals of the DES treated group were then subjected to lipid aphaeresis (LA). Fifteen animals of the DES treated group had sham treatments. Once the LA or sham treatments commenced, all animals were fed the standard poultry ration, except during the actual treatment itself when animals were kept off their feed for three hours following reinfusion of their autologous blood. Animals were sacrificed two days following the 4th treatment, LA or sham.
Lipid Aphaeresis Procedure
Approximately 25% of the calculated blood volume was collected from a brachial vein of the animal with a 21 gauge needle and syringe. The total blood volume was estimated at 8 percent of the body weight. The blood was collected in heparinized tubes and immediately centrifuged at 900 g for 5 minutes at room temperature. The blood cells were suspended in an amount of saline equivalent to the plasma volume and were reinfused into the animal. The plasma was kept refrigerated for twelve hours and was then delipidated for 20 minutes with a mixture of butanol and di-isopropyl ether (DIPE), 25:75 (v/v), in a ratio of one volume of plasma to two volumes of butanol-DIPE mixture (organic phase). Inert plastic beads with a density of 0.9 g/mL (1 g) were added to the mixture. After extraction, the mixture was centrifuged at 900 g for 2 min to separate the plasma and organic phases. The organic phase (upper layer) was removed, free of plasma phase, by careful aspiration with a pasteur pipette under vacuum. Traces of butanol in the plasma phase were washed out with four volumes of diethyl ether (DEE) for 2 min by end-over-end rotation at 30 rpm. The mixture was then centrifuged at 900 g for 2 min to separate plasma and ether phases. The ether phase was subsequently removed by aspiration with a pasteur pipette. Residual ether was removed by evacuation with a water pump aspirator at 37° C. The plasma was then passed through a 5 mL column containing Bio-Beads SM-2.
This procedure yielded delipidated plasma. The delipidated plasma was re-mixed with the blood cells of a subsequent 25% blood collection which was then reinfused through a brachial vein back into the identical donor animals. The duration of the entire procedure, that is, removal of blood from the animal to reinfusion of treated blood back to the animal was approximately 1 hour. After the fourth lipid aphaeresis treatment, the animals were sacrificed and their livers and aortae were dissected. The LA treatment procedures were repeated 3 times after the first treatment.
Sham Treatment Procedures
This was essentially the same as the LA procedure with the exception of the plasma delipidation with the organic solvents. The blood was collected in heparinized tubes and immediately centrifuged at 900 g for 5 min. The plasma was separated from the blood cells. The blood cells were mixed with saline in the same volume of the collected plasma and reinfused into the animal. The plasma was kept refrigerated for twelve hours and was then remixed with blood cells of a subsequent 25% blood collection after the second and/or subsequent plasma separations. After the fourth lipid aphaeresis treatment, the animals were sacrificed and their livers and aortae were dissected. The sham treatment procedures were repeated 3 times after the first treatment.
Tissue Lipid Preparation
The livers were weighed, minced with a scalpel blade and homogenised in 0.9% sodium chloride solution by 10-12 strokes of a motor driven Teflon-glass homogeniser (1900 rpm). The aorta was weighed and three times its weight of 3 mm glass beads were added in a homogenising bottle containing 0.9% sodium chloride. The contents were then homogenised for one minute. The lipid from the homogenised liver and aorta samples were extracted by the Folch procedure and weighed.
TABLE I Effect of LA and sham treatments on the total lipid concentrations in livers and aortas of hyperdiedemic roosters TREATED UNTREATED FOUR APHAFRESIS APPLICATIONS CONTROLS SHAM LA n = 15 n = 15 n = 15 LIVERa 3.65 ± 0.98 5.53 ± 1.50b 3.72 ± 1.002 AORTAc 6.01 ± 0.97 0.11 ± 2.15c 0.32 × 0.95d aTotal lipid concentrations expressed as g lipid per 100 g tissue, mean ± SD b,cp values were <0.05 when sham treatments were compared with LA treatments. There were no statistical differences between the values of corresponding tisues in the untreated control group and the LA treated group. All animals were sacrificed two days after the final apherical treatment.
Patients have the plasmapheresis procedure undertaken using known transvenous techniques and plasmapheresis systems.
Plasmapheresis is performed using vein-to-vein or arteriovenous fistula in the forearm of patients. Heparin is given at the beginning of the procedure as a 5,000 unit bolus, and then by continuous infusion at the rate of 700 units per hour over the course of the procedure. Access through the antecubital veins should provide plasma flow rates of 25 to 40 mls per minute.
Blood taken from a patient is immediately treated with ACD-A (anticoagulant) in a ratio of between 1:8 and 1:16 (ACD-A:blood). The plasma is separated from this solution using a conventional plasmapheresis machine.
Twenty five percent plasma is removed from the patient. This represents one percent of the ideal body weight.
Only the first volume of plasma collection is replaced with plasma replacement fluid to the patient.
The plasma is kept refrigerated up until twelve hours prior to reinfusion of delipidated plasma in exchange for another twenty five percent plasma collection (weekly or biweekly).
The plasma is delipidated and the delipidated plasma is tested to ensure all solvent has been removed before the clean delipidated plasma is exchanged for new untreated plasma.
In one embodiment of the present invention, the continuous flow system described in U.S. Pat. No. 4,895,558 (the entire content of which is included herein) is modified to a discontinuous system by removing the appropriate blood volume to be treated and subjecting that volume to delipidation at a site remote from the patient.
In another embodiment of the present invention, the continuous flow system described in International Patent Application No. PCT/AU94/00415 (the entire content of which is included herein) is modified to a discontinuous system by removing the appropriate blood volume to be a site remote from the patient before the plasma is dispersed into small droplets into the solvent by the dispersing means.
In either of the above embodiments, the extraction step can include, in accordance with the present invention, either multiple washing of the extracted phase and/or using an absorbent.
For example, the plasma is delipidated with a solvent mixture comprising 1-butanol and di-isopropyl ether. The delipidated fraction is then washed three (3) or four (4) times with diethyl ether. After the final wash, the diethyl ether is removed by centrifugation and vacuum extraction at 37° C. The sintered spheres containing Bio-Beads SM-2 are then mixed with the delipidated plasma to remove the final traces of 1-butanol.
DES administration to the roosters resulted in a significant amount of fat (lipid) accumulation in the livers and aortae.
Discontinuous LA treatments corresponding to approximately one plasma volume treated by four applications of 25% of plasma volume treated per time resulted in significant decreases in both hepatic and aortic lipids in hyperlipidaemic animals. Moreover, the LA treated hyperlipidaemic animals ended up with lipid values that were similar to control animals.
Similar results can be expected for human patients.
By adapting the prior art methods to discontinuous flow systems, the present invention can remove or at least significantly reduce any danger to patients and medical staff from the explosive nature of the solvents employed.
Further, by using the improved solvent extraction methods of the present invention, all of the potentially poisonous extraction solvents can be removed before the treated blood is returned to the patient.
Also, the improved solvent extraction method of the present invention is not limited to plasma delipidation but also it is applicable to the delipidation of serum, thus providing advantageous changes to the blood rheology of the originally impaired blood circulation of the patient.
The present invention thus provides for a rapid regression of coronary atherosclerosis in a patient.
Finally, as the present invention is a discontinuous system, it is not essential to return the delipidated blood fraction immediately to the patient. It is already known that plasma or serum can be collected and stored under sterile conditions in a refrigerator or freezer for extended periods and that it can be returned safely to the patient within twelve (12) hours of breaking the sterile seal. Therefore, if necessary, reintroduction of the delipidated fraction can occur several weeks after it was first removed from the patient. This option leads to particular advantages such as, economies of scale when several patients have to be treated simultaneously, the freeing of medical staff and equipment for other duties, and the reduction in stress for the patient whom no longer has to be hooked up to a delipidation apparatus for several continuous hours. Further, it enables a bank of plasma or serum to be maintained which is free of any infection which can be delipidated and exchanged for a patient's plasma or serum as required. Of course, autologous or non-autologous plasma or serum could be returned to the patient under these conditions.
The embodiments are described by way of illustrative examples only and various changes and modifications may be made thereto without departing from the inventive concept as defined in the following claims.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US3647624||Jul 24, 1969||Mar 7, 1972||Wisconsin Alumni Res Found||Treatment of blood with oleaginous substance|
|US3958939||Jan 8, 1975||May 25, 1976||Coulter Electronics, Inc.||Method for clarification of lipemic serum|
|US3983008||May 20, 1975||Sep 28, 1976||Idemitsu Kosan Co., Ltd.||Method of extracting useful components from microbial cells|
|US3989466||Aug 13, 1973||Nov 2, 1976||Pan Samuel C||Liquid-liquid extraction apparatus including fibrous strand packing|
|US4025423||Jan 9, 1976||May 24, 1977||Metallgesellschaft Aktiengesellschaft||Process for removing monohydric and polyhydric phenols from waste water|
|US4103685||Jan 5, 1976||Aug 1, 1978||Lupien Paul J||Method and apparatus for extravascular treatment of blood|
|US4124509||Apr 14, 1977||Nov 7, 1978||Asahi Medical Co., Ltd.||Haemodialyzer employing hollow fibers|
|US4234317||May 24, 1979||Nov 18, 1980||Analytical Products, Inc.||Apparatus and method for fractionation of lipoproteins|
|US4235602||Mar 5, 1979||Nov 25, 1980||Krebs & Cie||Installation for mixing and separating two non-miscible liquids, inter alia for liquid-liquid extraction|
|US4258010||Nov 7, 1977||Mar 24, 1981||Eszakmagyarorszagi Vegyimu_ vek||Solvent extraction apparatus|
|US4350156||May 29, 1980||Sep 21, 1982||Japan Foundation For Artificial Organs||Method and apparatus for on-line filtration removal of macromolecules from a physiological fluid|
|US4391711||Mar 19, 1981||Jul 5, 1983||Davy Mckee (Minerals & Metals) Limited||Method of, and apparatus for, effecting liquid-liquid contact|
|US4399217||Apr 30, 1980||Aug 16, 1983||Laboratoires Goella||Process and a device for the determination of serum lipoproteins|
|US4402940||Sep 17, 1982||Sep 6, 1983||Kuraray Co., Ltd.||Method for treating blood plasma employing a hollow fiber membrane|
|US4435289||Dec 23, 1981||Mar 6, 1984||Romicon, Inc.||Series ultrafiltration with pressurized permeate|
|US4463988||Sep 7, 1982||Aug 7, 1984||Cities Service Co.||Horizontal heated plane process|
|US4481189||Apr 14, 1982||Nov 6, 1984||New York Blood Center Inc.||Process for preparing sterilized plasma and plasma derivatives|
|US4522809||Aug 1, 1984||Jun 11, 1985||Institut Pasteur||Process for obtaining lipid envelope virus sub-units, notably antigens for use as vaccines, the products obtained and their applications|
|US4540401||Feb 22, 1983||Sep 10, 1985||Applied Immune Sciences, Inc.||In vivo therapeutic apheresis using lipid vesicles|
|US4540573||Jul 14, 1983||Sep 10, 1985||New York Blood Center, Inc.||Undenatured virus-free biologically active protein derivatives|
|US4581231||Aug 31, 1983||Apr 8, 1986||The United States Of America As Represented By The Secretary Of Health And Human Services||Inactivation of viruses containing essential lipids|
|US4591505||Feb 21, 1984||May 27, 1986||New York Blood Center, Inc.||Process for inactivating hepatitis B virus|
|US4613501||Dec 21, 1984||Sep 23, 1986||New York Blood Center, Inc.||Inactivation of viruses in labile blood derivatives|
|US4615886||May 18, 1984||Oct 7, 1986||The United States Of America As Represented By The Secretary Of The Department Of Health & Human Services||Utilizing a halohydrocarbon containing dissolved water to inactivate a lipid virus|
|US4643718||Jul 23, 1985||Feb 17, 1987||Applied Immunesciences, Inc.||Therapeutic apheresis|
|US4645512||May 6, 1985||Feb 24, 1987||The Dow Chemical Company||Continuous process for removing water-soluble particles from organic liquids|
|US4647280||Jul 2, 1986||Mar 3, 1987||Akzo Nv||Binder for low density lipoproteins|
|US4648974 *||Mar 14, 1984||Mar 10, 1987||Intermedicat Gmbh||Process for the selective extracorporeal separation of blood constituents|
|US4668398||Aug 14, 1985||May 26, 1987||Colgate-Palmolive Company||Continuous extraction apparatus and process|
|US4671909||Aug 9, 1984||Jun 9, 1987||Torobin Leonard B||Method for making hollow porous microspheres|
|US4676905||Dec 14, 1976||Jun 30, 1987||Toray Industries, Inc.||Fluid separation method and apparatus|
|US4677057||Mar 11, 1985||Jun 30, 1987||Scripps Clinic And Research Foundation||Diagnostic assay for the presence of apolipoproteins associated with plasma high density lipoproteins|
|US4680320||Dec 6, 1985||Jul 14, 1987||Kanegafuchi Kagaku Kogyo Kabushiki Kaisha||Method for preparation of droplets|
|US4696670||Nov 6, 1985||Sep 29, 1987||Kanegafuchi Kagaku Kogyo Kabushiki Kaisha||Method and apparatus for treating blood constituents|
|US4775483||Sep 18, 1986||Oct 4, 1988||Canadian Patents And Development Ltd.||Method to reduce plasma cholesterol|
|US4832034||Apr 9, 1987||May 23, 1989||Pizziconi Vincent B||Method and apparatus for withdrawing, collecting and biosensing chemical constituents from complex fluids|
|US4836928||Apr 26, 1985||Jun 6, 1989||Terumo Kabushiki Kaisha||Separation method, separation device and separation apparatus for separating body fluid into respective components|
|US4879037||Mar 17, 1988||Nov 7, 1989||Utzinger Gustav E||Method and apparatus for counter current liquid-liquid extraction|
|US4895558 *||Jan 20, 1988||Jan 23, 1990||University Of Queensland||Autologous plasma delipidation using a continuous flow system|
|US4908354 *||Nov 20, 1987||Mar 13, 1990||B. Braun-Ssg Ag||Process for the selective extracorporeal precipitation of low-density lipoproteins|
|US4909940||Dec 30, 1987||Mar 20, 1990||New York Blood Center, Inc.||Extraction of process chemicals from labile biological mixtures with organic alcohols or with halogenated hydrocarbons|
|US4909942||Oct 12, 1988||Mar 20, 1990||Tanabe Seiyaku Co., Ltd.||Process for removing pyrogens|
|US4923439||Mar 23, 1988||May 8, 1990||B. Braun-Ssc Ag||Process for the selective extracorporeal precipitation of low-density lipoproteins from whole serum or plasma|
|US4935204 *||Nov 14, 1988||Jun 19, 1990||B. Braun-Ssc Ag||Process and device for the specific adsorption of heparin|
|US4966709||Jul 18, 1988||Oct 30, 1990||The Cleveland Clinic Foundation||Thermofiltration of plasma|
|US4970144||Dec 26, 1985||Nov 13, 1990||International Genetic Engineering||Peptide fragments of human apolipoprotein, type-specific antibodies and methods of use|
|US5026479||Feb 13, 1990||Jun 25, 1991||Union Carbide Industrial Gases Technology Corporation||Fluid separation device|
|US5080796||Feb 12, 1990||Jan 14, 1992||The Cleveland Clinic Foundation||Thermofiltration of plasma|
|US5089602||Mar 11, 1991||Feb 18, 1992||Rotkreuzstiftung Zentrallaboratorium Blutspendedienst Srk||Process for the manufacture of apolipoproteins from human blood plasma or serum|
|US5112956||Mar 17, 1989||May 12, 1992||The Nutrasweet Company||Method for extraction of lipids and cholesterol|
|US5116307||Jul 9, 1990||May 26, 1992||Collins Harvey T||Method and system for treatment of AIDS|
|US5126240||Sep 29, 1986||Jun 30, 1992||Curtiss Linda K||Hybridomas and monoclonal paratopic molecules to apolipoprotein a-i|
|US5128318||Oct 27, 1988||Jul 7, 1992||The Rogosin Institute||Reconstituted HDL particles and uses thereof|
|US5152743||Aug 20, 1990||Oct 6, 1992||Healthdyne, Inc.||Apparatus and method for selective separation of blood cholesterol|
|US5187010||Nov 27, 1990||Feb 16, 1993||W. R. Grace & Co.-Conn.||Membrane having high affinity for low density lipoprotein-cholesterol from whole blood|
|US5203778||Oct 17, 1991||Apr 20, 1993||Boehringer Laboratories||Process and apparatus for removal of insoluble fat from blood of a patient|
|US5211850||Jul 26, 1991||May 18, 1993||Research Medical, Inc.||Plasma filter sorbent system for removal of components from blood|
|US5236644||Oct 31, 1991||Aug 17, 1993||W. R. Grace & Co.-Conn.||Process of making membrane for removal of low density lipoprotein-cholesterol from whole blood|
|US5256767||Nov 10, 1992||Oct 26, 1993||The Immune Response Corporation||Retroviral antigens|
|US5258149||May 5, 1992||Nov 2, 1993||W. R. Grace & Co.-Conn.||Process of making a membrane for high efficiency removal of low density lipoprotein-cholesterol from whole blood|
|US5279540 *||Sep 24, 1992||Jan 18, 1994||Davidson Michael H||Method for reducing the risk of atherosclerosis|
|US5301694||Nov 12, 1991||Apr 12, 1994||Philip Morris Incorporated||Process for isolating plant extract fractions|
|US5354262||Feb 22, 1993||Oct 11, 1994||Boehringer Laboratories||Apparatus for removal of insoluble fat from blood of a patient|
|US5391143||Mar 12, 1993||Feb 21, 1995||Kensey Nash Corporation||Method and system for effecting weight reduction of living beings|
|US5393429||Nov 2, 1992||Feb 28, 1995||Jgc Corporation||Liquid-liquid contactor|
|US5401415 *||Jun 11, 1991||Mar 28, 1995||B. Braun Melsungen Ag||Adsorption material for the selective removal of LDL and/or vLDL and method of using therefor|
|US5401466||Jun 1, 1993||Mar 28, 1995||Miles Inc.||Device for the direct measurement of low density lipoprotein cholesterol|
|US5418061||Jul 21, 1993||May 23, 1995||W. R. Grace & Co.-Conn.||Microporous polysulfone supports suitable for removal of low density lipoprotein-cholesterol|
|US5419759||May 27, 1993||May 30, 1995||Naficy; Sadeque S.||Apparatus and methods for treatment of HIV infections and AIDS|
|US5424068 *||Mar 5, 1993||Jun 13, 1995||P. Doina International Ltd.||Method for immunization of mammals against atherosclerosis and pharmaceutical compositions for obtaining said immunization|
|US5476715||Sep 28, 1993||Dec 19, 1995||Fresenius Ag||Particulate adsorbent for the removal of biomacromolecules such as LDL and endotoxins from whole blood in extracorporeal circuits|
|US5484396||Nov 17, 1988||Jan 16, 1996||Naficy; Sadeque S.||Method and device for treatment of HIV infections and AIDS|
|US5496637||Apr 30, 1993||Mar 5, 1996||W. R. Grace & Co.-Conn.||High efficiency removal of low density lipoprotein-cholesterol from whole blood|
|US5523096||Jun 6, 1995||Jun 4, 1996||Applied Immune Sciences, Inc.||Removal of selected factors from whole blood or its components|
|US5634893||Apr 24, 1995||Jun 3, 1997||Haemonetics Corporation||Autotransfusion apparatus|
|US5637224||Sep 14, 1994||Jun 10, 1997||New Jersey Institute Of Technology||Hollow fiber contained liquid membrane pervaporation for removal of volatile organic compounds from aqueous solutions|
|US5652339||Dec 21, 1994||Jul 29, 1997||Rotkreuzstiftung Zentrallaboratorium||Method of producing reconstituted lipoproteins|
|US5679260 *||Sep 26, 1995||Oct 21, 1997||B. Braun Melsungen Ag||Process for simultaneously removing tumour necrosis factor α and bacterial lipopolysaccharides from an aqueous liquid|
|US5698432||Oct 11, 1996||Dec 16, 1997||Retroscreen Ltd.||Vaccines and methods for their production|
|US5707673||Oct 4, 1996||Jan 13, 1998||Prewell Industries, L.L.C.||Process for extracting lipids and organics from animal and plant matter or organics-containing waste streams|
|US5719194||Jun 7, 1996||Feb 17, 1998||Ausimont S.P.A.||Prevention and treatment of topical viral infections with perfluoropolyethers or compositions thereof|
|US5744038||Jul 22, 1994||Apr 28, 1998||Aruba International Pty Ltd.||Solvent extraction methods for delipidating plasma|
|US5753227||Jul 23, 1993||May 19, 1998||Strahilevitz; Meir||Extracorporeal affinity adsorption methods for the treatment of atherosclerosis, cancer, degenerative and autoimmune diseases|
|US5853725||Apr 26, 1994||Dec 29, 1998||The Immune Response Corporation||Prevention and treatment of retroviral disease|
|US5855782||Aug 10, 1994||Jan 5, 1999||Falkenhagen; Dieter||Arrangement for removing substances from liquids, in particular blood|
|US5858238||Mar 7, 1997||Jan 12, 1999||Baxter Research Medical, Inc.||Salvage of autologous blood via selective membrane/sorption technologies|
|US5877005||Oct 25, 1995||Mar 2, 1999||Aphios Corporation||Viral inactivation method using near critical, supercritical or critical fluids|
|US5885578||Jun 5, 1995||Mar 23, 1999||The Immune Response Corporation||Prevention and treatment of retroviral disease|
|US5895650||Jun 5, 1995||Apr 20, 1999||The Immune Response Corporation||Prevention and treatment of retroviral disease|
|US5911698||Dec 22, 1995||Jun 15, 1999||Aruba International Pty. Ltd.||Treatment for cardiovascular and related diseases|
|US5916806||Jun 5, 1995||Jun 29, 1999||The Immune Response Corporation||Prevention and treatment of retroviral disease|
|US5919369||Jul 16, 1996||Jul 6, 1999||Hemocleanse, Inc.||Hemofiltration and plasmafiltration devices and methods|
|US5928930||Jun 5, 1995||Jul 27, 1999||Immune Response Corporation||Prevention and treatment of retroviral disease|
|US5948441||Jan 3, 1995||Sep 7, 1999||The Liposome Company, Inc.||Method for size separation of particles|
|US5962322||Nov 15, 1996||Oct 5, 1999||Massachusetts Institute Of Technology||Methods for modulation of cholesterol transport|
|US5980478||Oct 10, 1997||Nov 9, 1999||Transvivo, Inc.||Apparatus and method for the treatment of acute and chronic renal disease by continuous passive plasma ultrafiltration|
|US6017543||Jun 5, 1995||Jan 25, 2000||The Immune Response Corporation||Prevention and treatment of retroviral disease|
|US6022333||May 1, 1997||Feb 8, 2000||S.L.I.M. Tech, Ltd.||Method and system for removing materials from lymphatic and other fluids|
|US6037458||Sep 22, 1992||Mar 14, 2000||Kanegafuchi Kagaku Kogyo Kabushiki Kaisha||Adsorbent for serum amyloid protein|
|US6039946||Jul 20, 1994||Mar 21, 2000||Strahilevitz; Meir||Extracorporeal affinity adsorption devices|
|US6193891||Dec 20, 1996||Feb 27, 2001||American National Red Cross||Methods for the selective separation of organic components from biological fluids|
|US6309550||Jun 22, 1995||Oct 30, 2001||Fls Miljo A/S||Mass transfer method and apparatus|
|CA1271708A||Sep 5, 1986||Jul 17, 1990||Schweiz Serum & Impfinst||Process for the preparation of a rabies vaccine and the vaccine obtained by this process|
|CN1189378A||Dec 30, 1997||Aug 5, 1998||长春市中心血站||Application and prodn. method of HDL preparation|
|DE2944138A1||Nov 2, 1979||Jun 11, 1981||Technicon Gmbh||Automatic analysis of separation of deposits from liquids - is by extracting fraction of flowing segmented sample following sedimentation|
|DE3118072A1||May 7, 1981||Nov 25, 1982||Heuck Claus Christian Dr Rer N||Process for separating lipophilic constituents from aqueous colloid solutions for preparative purposes and/or for detecting an analyte in the aqueous phase|
|DE3213390A1||Apr 10, 1982||Oct 20, 1983||Schurek Hans Joachim||Vorrichtung zur bilanzierung des fluessigkeitsaustausches bei haemofiltrationen|
|WO1995003840A1 *||Jul 22, 1994||Feb 9, 1995||The University Of Queensland||A plasma delipidation system|
|1||Agnese, S.T. et al. , "Evaluation of Four Reagents for Delipidation of Serum", Clinical Biochemistry, 16(2): pp. 98-100 (1983).|
|2||Albouz, S. et al. , "Extraction of Plasma Lipids Preserving Antigenic Properties of Proteins and Allowing Quantitation of Gangliosides by Neuraminic Acid Determination", Ann. Biol. Clin. (Paris) (4ZS), 37(5): pp. 287-290 (1979).|
|3||Asztalos et al., Arterioscler. Thromb. Vasc. Biol., Presence and Formation of 'Free Apolipoprotein A-I-Like' Particles in Human Plasma, 15, 1419-1423,. (1995).|
|4||Asztalos et al., Arterioscler. Thromb. Vasc. Biol., Role of Free Apolipoprotein A-I in Cholesterol Efflux, 17, 1630-1636. (1997).|
|5||Badimon, J.J. et al. , "High Density Lipoprotein Plasma Fractions Inhibit Aortic Fatty Streaks in Cholesterol-Fed Rabbits", Laboratory Investigation, vol. 60, No. 3: pp. 455-461 (1989).|
|6||Badimon, J.J. et al. , "Regression of Atherosclerotic Lesions by High Density Lipoprotein Plasma Fraction in the Cholesterol-Fed Rabbit", J. Clinical Investigation, vol. 85, No. 4: pp. 1234-1241 (1990).|
|7||Barrans et al., Biochimica et Biophysica Acta, Pre-beta HDL: Structure and Metabolism, 1300, 73-85. (1996).|
|8||Bloom, et al. "Quantitation of lipid profiles from isolated serum lipoproteins using small volumes of human serum." Clin Biochem 1981 Jun;14(3): 119-25.|
|9||Cham, B.E. et al. , "Changes in Electrophoretic Mobilities of alpha-and beta-Lipoproteins as a Result of Plasma Delipidation", Clinical Chemistry, 22: pp. 305-309 (1976).|
|10||Cham, B.E. et al. , "In Vitro Partial Relipidation of Apolipoproteins in Plasma", J. Biol. Chem., 251 (20): pp. 6367-6371 (1976).|
|11||Cham, B.E., et al. , "A Solvent System for Delipidation of Plasma or Serum Without Protein Precipitation", J. of Lipid Research, vol. 17: pp. 176-181 (1976).|
|12||Cham, B.E., et al. , "Importance of Apolipoproteins in Lipid Metabolism", Chem. Biol. Interactions, 20: pp. 263-277 (1978).|
|13||Cham, B.E., et al. , "Lipid Apheresis in an Animal Model Causes In Vivo Changes in Lipoprotein Electrophoretic Patterns", J. Clin. Apheresis, 11 (2): pp. 61-70 (1996).|
|14||Cham, B.E., et al. , "Lipid Apheresis: An In Vivo Application of Plasma Delipidation with Organic Solvents Resulting in Acute Transient Reduction of Circulating Plasma Lipids in Animals", J. Clin. Apheresis 10: pp. 61-69 (1995).|
|15||Cham, B.E., et al., "Heterogeneity of Lipoprotein B", Biochemical and Biophysical Research Communications, vol. 103, No. 1: pp. 196-206 (1981).|
|16||Cham, B.E., et al., "Lipid Apheresis in an Animal Model Causes Acute Reduction in Plasma Lipid Concentrations and Mobilisation of Lipid from Liver and Aorta", Pharmacol. (Life Sci. Adv.)13: pp. 25-32 (1994).|
|17||Cham, B.E., et al., "Phospholipids in EDTA-Treated Plasma and Serum", Clinical Chemistry, vol. 39, No. 11: pp. 2347-2348 (1993).|
|18||Cham, B.E., et al., "Rapid Regression of Atherosclerosis by Cholesterol Apheresis-A Newly Developed Technique", 59<SUP>th </SUP>Congress European Atherosclerosis Society, Nice France, May 17-21, 1992.|
|19||Cham, B.E., et al., "Rapid, Sensitive Method for the Separation of Free Cholesterol from Ester Cholesterol", Clinica Chimica Acta, 49: pp. 109-113 (1973).|
|20||Cham, B.E., Nature of the Interaction Between Low-Density Lipoproteins and Polyanions and Metal Ions, as Exemplified by Heparin and Ca<SUP>2+</SUP>, Clinical Chemistry, vol. 22, No. 11: pp. 1812-1816 (1976).|
|21||Collet et al., Journal of Biological Chemistry, Differential Effects of Lecithin and Cholesterol on the Immunoreactivity and Confirmation of Apolipoprotein A-I in High Density Lipoproteins, 266 (14), 9145-9152. (May 15, 1991).|
|22||Cruzado et al., Analytical Biochemistry, Characterization and Quantitation of the Apoproteins of High-Density Lipoprotein by Capillary Electrophoresis, 14 (7), 100-109. (1996).|
|23||Deva, et al., J. Hosp. Infect., Establishment of an in-use testing method for evaluating disinfection of surgical instruments using the duck hepatitis B model , 22, 119-130. (abstract only) (Jun. 1996).|
|24||Dwivedy, A.K., "Increase of Reverse Cholesterol Transport by Cholesterol Apheresis: Regression of Atherosclerosis", 18<SUP>th </SUP>Australian Atherosclerosis Society Conference, Surfers Paradise, p. 21 (1992).|
|25||Eisenhauer, T. et al. , "Selective Removal of Low Density Lipoproteins (LDL) by Precipitation at Low pH: First Clinical Application of the HELP System", Klin Wochenschr (KWH), 65 (4): pp. 161-168 (1987).|
|26||Fang, N.X. et al. , "In vivo Rapid Mobilization of Adipose Tissue by Lipid Apheresis-A Newly Developed Technique", 18<SUP>th </SUP>Australian Atherosclerosis Society Conference, Gold Cost, Australia 1992.|
|27||Feinstone, et al., Infection and Immunity, Inactivation of Hepatitis B Virus and Non-A, Non-B Hepatitis by Chloroform, 41, 816-821. (Aug. 1983).|
|28||Hatch et al., Lipoprotein Analysis, Advances in Lipid Research, Practical Methods for Plasma Lipoprotein Analysis, 6, 1-68. (1968).|
|29||Horowitz, et al., Blood Coagulation and Fibrinolysis, Viral safety of solvent/detergent-treated blood products, 5, S21-S28. (1994).|
|30||Innerarity, T.L., et al. , "Enhanced Binding by Cultured Human Fibroblasts of Apo-E-Containing Lipoproteins as Compared with Low Density Lipoproteins", Biochemistry, vol. 17: pp. 1440-1447 (1978).|
|31||Jackson et al., Biochimica et Biophysica Acta, Isolation and Characterization of the Major Apolipoprotein from Chicken High Density Lipoproteins, 420, 342-349. (1976).|
|32||Klimov, et al. "Extraction of Lipids from Blood Plasma and Subsequent Introduction of Autologous Delipidized Plasma into the Body as a Possible Means to Treat Artherosclerosis," English translation from the Russian Journal Kardiologiia, 1978, 18(6): 23-29.|
|33||Koizumi, J. et al. , "Behavior of Human Apolipoprotein A-1: Phospho-Lipid and apoHDL: Phospholipid Complexes in Vitro and After Injection into Rabbits", J. Lipid Research, vol. 29: 1405-1415 (1988).|
|34||Kostner, K. et al., "Increase of APO A1 Concentration in Hypercholesteraemic Chickens After Treatment with a Newly Developed Extracorpreal Lipid Elimination", XI Internet Symp. On Drugs Affecting Lipid Metabolism, Italy, May 13-16, 1992.|
|35||Kostner, K. et al., "Lecithin-cholesterol acyltransferase activity in Normocholesterolaemic and Hypercholesterolaemic Roosters: Modulation by Lipid Apheresis", European Journal of Clinical Investigation, vol. 27; pp. 212-218, May 7, 1997.|
|36||Koudinov et al., Cell Biol Int., Alzheimer's Soluble Amyloid Beta Protein is Secreted by HepG2 Cells as an Apolipoprotein, 21 (5), 265-71. (abstract only) (May 1997).|
|37||Lupien, P.J. et al., "A New Approach to the Management of Familial Hypercholesterolaemia: Removal of Plasma-Cholesterol Based on the Principle of Affinity Chromatography", Lancet (LOS), 1 (7972)L: pp. 1261-1265 (1976).|
|38||Moya et al., Arteriosclerosis and Thrombosis, A Cell Culture System for Screening Human Serum for Ability to Promote Cellular Cholesterol Efflux, 14 (7), 1056-1065. (Jul. 1994).|
|39||Ngu, Medical Hypotheses, Chronic Infections from the Perspective of Evolution: a Hypothesis, 42, 81-88. (1994).|
|40||Ngu, Medical Hypotheses, Human Cancers and Viruses: A Hypothesis for Immune Destruction of Tumours Caused by Certain Enveloped Viruses Using Modified Viral Antigens, 39, 17-21. (1992).|
|41||Ngu, Medical Hypotheses, The viral envelope in the evoluation of HIV: a hypothetical approach to inducing an effective immune response to the virus, 48, 517-521. (1997).|
|42||Okazaki et al., Journal of Chromatography, Biomedical Applications, Improved High-Performance Liquid Chromatographic Method for the Determination of Apolopoproteins in Serum High-Density Lipoproteins, 430, 135-142. (1988).|
|43||Parker, T.S., et al., "Plasma High Density Lipoprotein is Increased in Man When Low Density Lipoprotein (LDL) is Lowered by LDL-Pheresis"; Proc. Nat. Acad. Sci. (USA) 83(3), pp. 777-781 (1986) (Abstract).|
|44||Parker, Thomas S. et al. , "Plasma High Density Lipoprotein is Increased in Man When Low Density Lipoprotein (LDL) is Lowered by LDL-Pheresis", Proceedings of the National Academy of Sciences, vol. 83, pp. 777-781 (1986).|
|45||Robern et al., Experientia, The Application of Sodium Deoxycholate and Sephacryl-200 for the Delipidation and Separation of High Density Lipoproteins, 38, 437-439. (1982).|
|46||Ryan, W.G. et al., "An Improved Extraction Procedure for the Determination of Triglycerides and Cholesterol in Plasma or Serum", Clinical Chemistry, vol. 13: pp. 769-772 (1967).|
|47||Scanu et al., Analytical Biochemistry, Solubility in Aqueous Solutions of Ethanol of the Small Molecular Weight Peptides of the Serum Very Low Density and High Density Lipoproteins: Relevance to the Recovery Problem During Delipidation of Serum Lipoproteins, 44, 576-588. (1971).|
|48||Slater, H.R. et al. , "The Effect of Delipidated High Density Lipoprotein on Human Leukocyte Sterol Synthesis", Atherosclerosis, 35: pp. 41-49 (1980).|
|49||Slater, H.R. et al., "A Comparison of Delipidated Sera Used in Studies of Sterol Synthesis by Human Mononuclear Leukocytes", J. of Lipid Research, 20: pp. 413-416 (1979).|
|50||Thompson, G.R. et al. , "Plasma Exchange in the Management of Homozygous Familial Hypercholesterolaemia", Lancet (LOS, 1 (7918): pp. 1208-1211 (1975).|
|51||Williams et al., Biochim. Biophys. Act., Uptake of Endogenous Cholesterol by a Synthetic Lipoprotein , 875 (2), 183-194. (Feb. 12, 1986).|
|52||Williams, K.J. et al., "Low Density Lipoprotein Receptor-Independent Hepatic Uptake of a Synthetic, Cholesterol-Scavenging Lipoprotein: Implications for the Treatment of Receptor-Deficient Atherosclerosis", Proc. Natl. Acad. Sci. USA, vol. 85: pp. 242-246 (1988).|
|53||Wong, et al. "Retention of gangliosides in serum delipidated by diisopropyl ether-1-butanol extraction," Journal of Lipid Research, 1983, 24, 666-669.|
|54||Yokoyama, S. et al., "Selective Removal of Low Density Lipoprotein by Plasmapheresis in Familial Hypercholesterolemia", Arteriosclerosis (89S), 5 (6): pp. 613-622 (1985).|
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|U.S. Classification||604/5.03, 210/651, 604/4.01, 210/645, 422/44|
|International Classification||A61M37/00, A61M1/34, B01D11/00, A61M1/36, C02F1/44|
|Cooperative Classification||A61M2202/0456, A61M1/3472, A61M1/3486|
|Jan 14, 2002||AS||Assignment|
Owner name: ARUBA INTERNATIONAL PTY. LTD., AUSTRALIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:CHAM, BILL ELLIOT;REEL/FRAME:012779/0827
Effective date: 20011015
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|Jun 15, 2011||LAPS||Lapse for failure to pay maintenance fees|