WO2015091842A2 - Procédé pour éliminer des toxines urémiques liées aux protéines par adsorption au niveau d'additifs dialysables - Google Patents

Procédé pour éliminer des toxines urémiques liées aux protéines par adsorption au niveau d'additifs dialysables Download PDF

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Publication number
WO2015091842A2
WO2015091842A2 PCT/EP2014/078538 EP2014078538W WO2015091842A2 WO 2015091842 A2 WO2015091842 A2 WO 2015091842A2 EP 2014078538 W EP2014078538 W EP 2014078538W WO 2015091842 A2 WO2015091842 A2 WO 2015091842A2
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blood
dialyzable
excipient
cyclodextrin
substitution
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PCT/EP2014/078538
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German (de)
English (en)
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WO2015091842A3 (fr
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Rainer Fislage
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Fresenius Medical Care Deutschland Gmbh
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Publication of WO2015091842A2 publication Critical patent/WO2015091842A2/fr
Publication of WO2015091842A3 publication Critical patent/WO2015091842A3/fr

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    • 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
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/1654—Dialysates therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • 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
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/28—Peritoneal dialysis ; Other peritoneal treatment, e.g. oxygenation
    • A61M1/287—Dialysates therefor
    • 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
    • A61M1/342—Adding solutions to the blood, e.g. substitution solutions
    • A61M1/3424—Substitution fluid path
    • A61M1/3431—Substitution fluid path upstream of the filter
    • A61M1/3434—Substitution fluid path upstream of the filter with pre-dilution and post-dilution
    • 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
    • A61M1/342—Adding solutions to the blood, e.g. substitution solutions
    • A61M1/3424—Substitution fluid path
    • A61M1/3437—Substitution fluid path downstream of the filter, e.g. post-dilution with 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
    • A61M1/342—Adding solutions to the blood, e.g. substitution solutions
    • A61M1/3455—Substitution fluids
    • 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
    • A61M1/342—Adding solutions to the blood, e.g. substitution solutions
    • A61M1/3455—Substitution fluids
    • A61M1/3465—Substitution fluids using dialysate as substitution fluid
    • 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
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3679—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by absorption

Definitions

  • the present invention relates to dialyzable excipients for hemodialysis, a method for removing protein-bound uremic toxins by adsorption on these excipients and to an apparatus for carrying out this method.
  • the task of the healthy kidney is the elimination of end products of the metabolism (urinary substances) and toxins (uraemia toxins) from the body through the formation of urine.
  • the kidney removes a wide range of substances of different molecular weight.
  • a review of uremic toxins has been reviewed by R. Vanholder et al. released. (Vanholder, R., et al ., Kidney International, 63 (2003) 1934-1943).
  • the uremic toxins are classified into three classes based on their molecular weight. Toxins with a molecular weight below 500 daltons form the low molecular weight group.
  • the middle molecules are in a middle region with a molecular weight of between 500 and 12,000 D.
  • the middle molecules include, for example, ⁇ 2 -microglobulin (11800 D).
  • the third class of uremic toxins form molecules with a molecular weight of over 12,000 D.
  • uremic toxins examples include urea, creatinine, oxalates, guanidines and uric acid.
  • uremic toxins examples include p- cresol, indoxyl sulfate, phenol, hippuric acid and homocysteine. These uremic toxins are predominantly bound to proteins in serum.
  • the uremic toxins are excreted into the urine via the kidney. However, in chronic renal failure, the uremic toxins remain in the patient's blood and must be removed by hemodialysis or peritoneal dialysis.
  • GB 1 466 702 discloses polymer coated activated carbon for the adsorption of uremic toxins in the digestive tract.
  • US 4,140,652 discloses the use of polymer-coated activated carbon to adsorb uremic toxins from blood.
  • WO 2009/157877 discloses a method for removing toxins from a dialysis fluid by adsorption on zirconia particles.
  • WO 2010/045474 discloses a method of separating protein-bound uremic toxins by adding a substance which displaces the toxins from their binding sites on the protein and thus makes it dialyzable.
  • US 4,889,634 discloses a hydroxypropyl- ⁇ -cyclodextrin-containing solution for peritoneal dialysis.
  • Well water-soluble toxins such as urea or creatinine can be easily removed by hemodialysis.
  • the removal of poorly water-soluble hydrophobic uremic toxins by hemodialysis process because of binding to proteins is much more difficult. It is generally believed that there is a chemical balance between the free, dissolved toxin and the protein-bound toxin, which is largely on the side of the protein-bound toxin. This means that the vast majority of these uremic toxins are bound to proteins and only a small part is dissolved in the blood plasma.
  • albumin acts as a binding partner of the hydrophobic uremic toxins.
  • Albumin is retained by dialysis membranes due to its molecular weight. Albumin is therefore not removed by hemodialysis.
  • the adjustment of the balance under the dialysis becomes the rate-determining step. While it is expected that after removal of the dissolved toxins from the blood, the balance between free and protein-bound toxins will re-adjust and remove a significant portion of the toxins if the dialysis time is long enough, however, this time will not be available in hemodialysis treatments.
  • albumin Due to its molecular weight, albumin is retained by the usual dialysis membranes and thus also by the toxins bound to it. However, when the protein-bound uremic toxins are transferred to a low molecular weight binding partner such that the resulting complex of binding partner and uremic toxin has a molecular weight within the dialyzable range, both the free-solution toxin and the previously albumin-binding species may pass through the dialyzer Toxin are removed.
  • a low molecular weight binding partner is also referred to below as a dialyzable excipient.
  • the non-toxin-loaded dialyzable excipient may also be removed.
  • the binding partner must bind the toxin either with a higher association constant than is the case with albumin, or the molar concentration of the dialyzable excipient must be correspondingly higher to be able to separate the largest possible proportion of protein-bound toxins.
  • the dialysable excipient may not itself be bound to the binding site of the albumin.
  • the complex of binding partner and Urämietoxin must be in terms of its molecular weight in the well dialyzable range. Ideally, the molecular weight of the complex is less than about 10,000 g / mol, preferably less than about 5,000 g / mol, more preferably less than 2,500 g / mol. In any case, however, the molecular weight of the complex should be less than 69 kD.
  • the binding partner must not be toxic or interact undesirably with the patient's blood.
  • the binding partner must be water-soluble to be dialysable. At the same time, it must have a hydrophobic binding pocket to which the toxin can bind with the desired affinity.
  • the dialyzable excipient comes, for example, from the structural class of the cavitands (host-guest molecules).
  • An example of this class of substances are the cyclodextrins known for the binding of hydrophobic compounds.
  • cyclodextrins such as water solubility can be influenced by substitution of the hydroxyl groups.
  • the water solubility of ⁇ -cyclodextrin increases by a factor of 150 due to methyl substitution.
  • the adsorption properties of the cyclodextrins can be altered by targeted substitution.
  • ⁇ -cyclodextrin must not be administered intravenously because it forms insoluble complexes with cholesterol.
  • HPBCD hydroxypropyl- ⁇ -cyclodextrin
  • SBECD sulfobutyl ether- ⁇ -cyclodextrin
  • molecules can also be used which simulate the binding pockets of albumin or other transport proteins for hydrophobic uremic toxins.
  • a Cavitandentyp groups of specific binding molecules can be used, each binding a type of uremic toxin or a small number of different uremic toxins.
  • those skilled in the art are aware of the antibodies and their derivatives, e.g. Fab fragments known.
  • Fab fragments e.g. Fab fragments known.
  • specific binding peptides are possible, which are obtained by the method of phage display or other high-throughput screening methods.
  • the dialyzable excipient can advantageously be dosed on the blood side into the inlet tube of the dialyzer, so that the desired equilibrium between binding partner and toxin is formed on the way to the dialyzer.
  • the toxin is removed from its binding sites on albumin or other proteins.
  • the binding partner with the bound toxin can then be removed efficiently by a conventional dialysis procedure.
  • Suitable cyclodextrins for an application have molecular weights in the range of 500 to 5000 g / mol, preferably 1000 to 2000 g / mol.
  • the rate of complex formation is described by the rate constant k a , that of the decay by k d .
  • the values for the association (K A ) and dissociation constants (K D ) result from the ratio of the rate constants.
  • the equilibrium constants thus describe the ratio of bound to free toxin in the equilibrium state.
  • the equilibrium constants can be determined by determining the concentrations of the reactants in equilibrium.
  • association constant The unit of association or affinity constants is given in l / mol.
  • the reciprocal of KA is the dissociation constant (KD) with the dimension mol / l.
  • KD dissociation constant
  • the dialyzable excipient binds a uremic toxin having an affinity constant of at least 250 l / mol, preferably greater than 500 l / mol, more preferably greater than 1000 l / mol.
  • the dialyzable excipient in dissolved form is metered into the blood-side inlet tube of the dialyzer.
  • the dialyzable excipient is dissolved in a physiological solution.
  • the dialyzable excipient is dissolved in a dialysis or substitution solution.
  • the solution containing the dialyzable excipient can be obtained in a variety of ways.
  • the dialyzable excipient is a solid at room temperature in a pure form
  • the solution can be prepared in the dialysis machine by dissolving the solid adjuvant in, for example, a dialysis or substitution solution.
  • the dialyzable excipient in this case is preferably in powder form.
  • the dialysable excipient is in a physical mixture with salts, such as sodium chloride.
  • salts such as sodium chloride.
  • the mixture is dissolved in water for injection.
  • the dialyzable excipient is already dissolved in a solvent, for example in the form of a concentrate or a ready-to-use solution.
  • a concentrate may be diluted to ready-to-use solution prior to use, for example, in a hemodialysis machine.
  • Such a ready-to-use solution is also suitable as an infusion solution.
  • the dialyzable excipient is in the form of a sterile, ready to use solution.
  • a ready-to-use solution contains, for example:
  • the cyclodextrin in the ready-to-use solution is preferably selected from hydroxypropyl- ⁇ -cyclodextrin (HPBCD) and sulfobutyl ether- ⁇ -cyclodextrin (SBECD).
  • calix [n] arenes
  • calix [4] arenes
  • calix [5] arenes
  • calix [6] arenes or calix [8] arenes
  • cyclophanes and Cucurbituril derivatives (CB [n]), in particular CB [5], CB [6], CB [7], CB [8] or CB [10].
  • the present invention further relates to an apparatus and a method for removing protein-bound toxins by adding a dialyzable excipient.
  • the present invention relates to an apparatus for carrying out the described method of removing protein-bound toxins
  • an extracorporeal circuit for receiving blood to be purified, and a hemodialyzer and / or hemofilter communicating with the bloodstream, wherein the bloodstream is upstream and optionally downstream from the hemodialyzer and / or hemofilter each have at least one supply line for the supply of a substitution liquid.
  • the substitution fluid supplied upstream of the hemodialyzer and / or hemofilter via a supply line comprises the dialyzable excipient.
  • the present invention thus provides a method that shifts the location of the balance between protein bound and non-protein bound toxins and allows effective removal of uremic toxins during dialysis treatment.
  • the blood After passage through the pump, the blood is passed through the blood chamber of the dialyzer and finally returned to the patient through a venous drip chamber and associated venous blood line.
  • a venous pressure monitor is connected to the venous drip chamber as a protection system for immediate detection of blood loss to the environment.
  • two needles required for the arterial and venous cannula can be replaced by a single needle.
  • the extracorporeal circuit consists of a needle needle with attached Y-piece. From the dialyzer, the venous line leads back to the Y-piece. The arterial and venous lines are alternately closed by clamping.
  • One or more blood pumps are running to provide alternate flow to and from the Y-piece.
  • Hemodiafiltration is a combination of hemodialysis and hemofiltration. Hemodiafiltration is performed by combining the extracorporeal circuits of a hemofiltration and a hemodialysis machine. Hemodialysis machines with volumetrically controlled ultrafiltration can be easily adapted for hemodiafiltration, which is more cost effective. This is particularly cost effective if the substitution fluid is prepared online from the DiaIyse Eatkeit.
  • the blood of the patient is purified by diffusing the substances to be removed of the blood due to a concentration gradient across the membrane of the dialyzer through the membrane and thereby reach the dialysis fluid.
  • the driving force behind hemofiltration is essentially a difference in pressure across the membrane, which causes convective transport of substances through the membrane, thereby purifying the blood, especially of higher molecular weight substances.
  • fluid is removed from the patient's blood which, except for a small differential, must be substituted to control fluid equalization.
  • the ratio of the infusion rates (Q s pre, Q s post) of the substitution fluid is controlled so that Q s pre is always greater than or equal to Q s post.
  • the ratio of infusion rates Q s pre / Q s post is at least 1.2.
  • the document WO 98/50091 relates to a method for controlling a blood purification device comprising upstream and downstream of the filter at least one supply line to the blood circulation for supplying a substitution liquid.
  • a control unit is provided for monitoring a blood pump, an ultrafiltrate pump and the substitution fluid pumps, and monitoring means for weighing the corresponding amount of fluid.
  • the control unit monitors the pumps at predetermined intervals to adjust the instantaneous flow rates of the blood stream, ultrafiltrate, and substitution products, respectively.
  • the document WO 00/09182 relates to a fluid driving device which is adapted to withdraw certain blood elements and / or blood constituents by diffusion through a semipermeable membrane.
  • the device is provided with a blood pump, a pump for feeding predilution substitution liquid, a pump for feeding after-dilution substitution liquid and an ultrafiltration pump. Valves are arranged so that the liquid is passed through a container which can be brought into fluid communication with each of the pumps to control the operation of the pumps and, consequently, the flow rates of the respective liquids.
  • U.S. Patent 5,578,223 discloses an artificial kidney that operates in a post-dilution mode and is suitable for use in hemofiltration, hemodialysis and hemodiafiltration treatment.
  • the apparatus comprises means for perfusing a bicarbonate-containing fluid into the extracorporeal blood circuit after passing through the replacement and dosing means for adjusting the bicarbonate concentration in the blood of a patient to a desired level.
  • An extraction pump connected to the outlet of the exchanger is controlled by a control unit to obtain a desired amount of weight loss during the duration of the treatment.
  • the flow rate of the bicarbonate solution is controlled by the control unit depending on the flow rate of the extraction pump, the desired bicarbonate concentration in a patient's blood, and the concentration of the bicarbonate solution before perfusion into the extracorporeal circuit.
  • the object of the present invention is to provide a device for hemodialysis and / or haemofiltration for blood purification, with which the advantages of the predilution mode and the post-dilution mode can be combined and at the same time the cleaning effect of the protein-bound hemodialyzer and / or protein-bound hemofilter is improved.
  • the device further comprises measuring devices for recording the transmembrane pressure and / or hematocrit and / or the blood density, wherein the measuring devices with a control unit (100) for controlling a or are connected by a plurality of transmembrane pressure and / or hematocrit and / or blood density, wherein the control unit is constructed so that the control is performed by means of at least one of the infusion rates of the substitution liquid and the blood to be purified prior to contact with the dialyzer, a dialyzable excipient is added.
  • the benefits of post-dilution and predilution can be combined, i.
  • the infusion rates of one or both upstream and downstream substitution fluids are used to control operational and / or blood parameters.
  • the infusion rate of the substitution solution added upstream of the dialyzer can be increased until the desired values for the values to be controlled are reached or the values fall below given limits. Accordingly, in the case of a low transmembrane pressure or a low hematocrit value, the rate of infusion of the substitution fluid supplied downstream of the dialyzer can be increased, resulting in an improvement of the diffusive transport of substances due to the then resulting greater concentration gradient across the membrane. leads to an improved cleaning effect for low molecular weight substances.
  • the infusion rate of the substitution solutions supplied upstream of the hemodialyzer and / or hemofilter preferably increases with respect to the rate of infusion supplied downstream of the hemodialyzer and / or hemofilter with increasing transmembrane pressure and / or increasing blood density and / or blood hematocrit.
  • the transmembrane pressure and / or hematocrit and / or the blood density can be detected continuously.
  • the infusion rates of the substitution solutions are selected such that a substantially fixed boundary membrane is formed on the side of the membrane of the hemodialyzer and / or hemofilter opposite the chamber through which the blood flows. This results in the advantage that the efficiency and the spectrum of the sieving coefficient of the hemodialyzer and / or hemofilter remain constant during the time of treatment.
  • the ratio of the infusion rates (Q s pre, Q s post) of the substitution fluid controls so that Q s pre is always greater than or equal to Q s post.
  • the ratio of the infusion rates Q s pre / Q s post is preferably at least 1.2.
  • the ratio of the infusion rates Q s pre / Q s post is particularly preferably at least 1.5.
  • the ratio of infusion rates of the substitution solutions Q s pre / Q s post in the bloodstream may be changed after termination of the treatment to dissolve the limiting membrane. Thereby, a majority of the limiting membrane forming proteins can be returned to the patient after completion of the blood treatment.
  • the measuring devices may comprise pressure sensors arranged respectively in the extracorporeal circuit and / or in the dialysis fluid circuit upstream and / or downstream of the hemodialyzer and / or hemofilter.
  • the measuring devices comprise sensors in the extracorporeal circuit upstream and / or downstream of the hemodialyzer and / or hemofilter for detecting the hematocrit value.
  • means for controlling the at least one of the infusion rates (Q s pre, Q s post) are pumps in the leads.
  • means for controlling the at least one of the infusion rates are valves in the leads.
  • Figure 1 shows a schematic representation of a portion of the extracorporeal circuit and the dialysis fluid circuit with hemodialyzer and hemofilter and leads for the substitution liquids.
  • Figure 1 shows a part of the extracorporeal circuit 10, is brought by the blood at the flow rate Q B by a blood pump 11 in the arrow direction in circulation.
  • a pressure sensor 40 and a sensor 50 for detecting the arterial blood pressure P art and the hematocrit value HKT in before the blood purification are arranged.
  • corresponding measuring devices 40 and 50 Downstream from the hemodialyzer and / or hemofilter 20 are corresponding measuring devices 40 and 50 for detecting the corresponding values P ven and HKT out after blood purification.
  • dialysis fluid flows in the direction of the arrow at the flow rate Q D through the hemodialyzer or hemofilter 20.
  • the dialysis fluid line 30 has pressure sensors 40 upstream and downstream of the hemodialyzer or hemofilter for the respective pressure P D in and P D out of the dialysis fluid.
  • the circulation of the dialysis fluid is controlled by pumping and / or balancing means 31 and 32.
  • the hemodialyzer and / or hemofilter is subdivided by a semipermeable membrane 21 into a blood chamber 22 and a dialysis fluid chamber 23.
  • Upstream and downstream of the hemodialyzer and / or hemofilter 20 are provided feed lines 12, 14 with liquid pumps 13 and 15, respectively, which supply substitution fluid to the blood flowing in the extracorporeal circuit 10 during the treatment.
  • the respective flow rates are marked Q s pre and Q s post.
  • Via the feed line 12, a substitution solution containing the dialyzable excipient is metered from a container 16.
  • the two infusion rates Q s pre and Q s post of the substitution fluid can be changed according to the present invention by means of a control unit 100.
  • the control unit 100 is connected to all illustrated actuators and sensors by means not shown.
  • the change in the infusion rates takes place in accordance with the measured values of the control values to be controlled.
  • the measured values are the arterial and venous blood pressure P art , P ven, and the pressure of the dialysis fluid P D in and P D out before and after passage through the hemodialyzer and hemofilter 20.
  • the transmembrane pressure TMP determined therefrom becomes is set to the desired target value by a suitable change of the flow velocities Q s pre and Q s post or is maintained at this value.
  • the hematocrit values HKT in , HKT out can be used as control values.
  • TMP can also be approached by less than the four pressure sensors shown. In the currently used dialysis machines, pressure sensors are normally used only for P ven and P Dout .
  • the boundary membrane which is based on the chamber in which the blood is present, opposite side of the membrane of the hemodialysis or hemofilter, can be kept in a stationary state, resulting in a constant cleaning spectrum as well results in a constant degree of cleaning during treatment.
  • the transmembrane pressure can be kept constant during the treatment, since the pressure loss caused by the membrane and the limiting membrane also remains constant.
  • transmembrane pressure By limiting the transmembrane pressure to a predeterminable value, the risk of extensive loss of albumin through the membrane due to large convective forces can be avoided. When using high flow membranes limiting the transmembrane pressure is particularly important.
  • the combination of pre- and post-dilution reduces the consumption of heparin, which is normally infused into the blood to prevent extracorporeal blood clotting. If the blood is diluted upstream of the hemodialyzer and / or hemofilter, less anticoagulant fluid is required to reduce the risk of blood clotting in the hemodialyzer and / or hemofilter since the latter presents the most significant potential for blood clotting in the extracorporeal blood circuit.
  • a good cleaning performance for protein-bound uremic toxins can be achieved by the combination of predilution and after-dilution as well as by the action of an auxiliary agent added to the bloodstream.
  • Another application of the present invention is its use in the therapy of liver failure.
  • the proportion of free p-cresol from albumin-containing solutions was determined photometrically from the ultrafiltrate of the test solutions.
  • the test solutions were filtered through an ultrafiltration membrane (Microcon YM-30, Millipor) with a cutoff of 30 kD according to the manufacturer's instructions.
  • an ultrafiltration membrane Microcon YM-30, Millipor
  • the concentration was determined after HPLC separation by evaluating the peak areas against a standard series with p-cresol dilutions at a measurement wavelength of 280 nm.
  • the samples were acidified with HCl and then shaken with ethyl acetate to convert the p-cresol into the organic phase, which is then amenable to HPLC analysis.
  • 100 ⁇ l of sample were adjusted to a pH of 1.0 with a solution of 1 M HCl and saturated with 100 mg of NaCl.
  • 300 .mu.l of ethyl acetate was added by shaking for 10 min and then centrifuged for 5 min at 1300xg.
  • the HPLC was determined from the supernatant after centrifugation. The volume change due to acidification may need to be considered during the evaluation.
  • a dialysate solution (SK-F 119/4 Fresenius Medical Care) was adjusted to a concentration of 202 ⁇ M p-cresol and 638 ⁇ M bovine serum albumin (BSA). After stirring overnight at room temperature, the free fraction of p-cresol in the solution was 14.8 ⁇ M (determined according to Example 1).
  • ⁇ -cyclodextrin was added to reach a concentration of 10 mM. Again, it was stirred overnight at room temperature. The next day, a 300 ⁇ l sample was purified by Microcon YM-30 centrifugation according to the manufacturer's instructions and 300 ⁇ l of physiological saline solution were then added. The filtrate containing ⁇ -cyclodextrin and bound as well as unbound p-cresol was discarded. This process was repeated twice more. Then, the total content of p-cresol in the albumin-containing solution was determined according to Example 2.
  • the total content of p-cresol in the albumin-containing phase after removal of the ⁇ -cyclodextrin and the unbound fraction was 120 ⁇ M compared to 202 ⁇ M in the starting solution.
  • a dialysate solution (SK-F 119/4 Fresenius Medical Care) with a concentration of 202 ⁇ M of p-cresol and 638 ⁇ M of bovine serum albumin (BSA) was pumped through the lumen of a hemodialyzer (Fresenius FX60) at a flow rate of 100 ml / min .
  • a solution of 224 g / l of hydroxypropyl- ⁇ -cyclodextrin was metered in at 10 ml / min to give, prior to the dialyzer, a concentration of 22.4 g / l (16 mM) of hydroxypropyl- ⁇ -cyclodextrin.
  • the flow on the dialysate side of the module was 500 ml / min.
  • the filtrate flow through the dialysis membrane was adjusted to 10 ml / min.
  • the experiment was carried out with a Fresenius 4008 dialysis machine.
  • the total concentration of p-cresol directly at the dialyzer inlet was 181.8 ⁇ M due to dilution. After passage through the dialyzer, the total concentration of p-cresol on the lumen side of the membrane was 100 ⁇ M. Concentration determinations were carried out as described in Examples 1-3.

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Abstract

La présente invention concerne un procédé pour éliminer des toxines urémiques liées aux protéines par adsorption au niveau d'additifs dialysables, un dispositif permettant de mettre ledit procédé en œuvre, ainsi que l'utilisation d'additifs dans le cadre de ce procédé.
PCT/EP2014/078538 2013-12-20 2014-12-18 Procédé pour éliminer des toxines urémiques liées aux protéines par adsorption au niveau d'additifs dialysables WO2015091842A2 (fr)

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DE102013021957.4A DE102013021957A1 (de) 2013-12-20 2013-12-20 Verfahren zur Entfernung proteingebundener Urämietoxine durch Adsorption an dialysierbare Hilfsstoffe

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102017113853A1 (de) 2017-06-22 2018-12-27 B. Braun Avitum Ag Hämokompatibler Adsorber zur Dialyse proteingebundener Urämietoxine
WO2024073056A1 (fr) * 2022-09-29 2024-04-04 Kureha America, Inc. Compositions de cucurbiturile, produits et procédés d'utilisation

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GB1466702A (en) 1973-02-09 1977-03-09 Sandoz Ltd Polymer encapsulated-activated carbon
US4140652A (en) 1977-01-12 1979-02-20 Korshak Vasily V Method of preparing blood-compatible sorbents for recovering exo- and endogenic poisons
US4889634A (en) 1988-10-04 1989-12-26 Gynex, Inc. Dialysate solution containing hydroxypropyl-beta-cyclodextrin and method of using same
FR2680975B1 (fr) 1991-09-10 1998-12-31 Hospal Ind Rein artificiel muni de moyens pour doser une substance dans le sang.
JPH0871146A (ja) * 1994-09-09 1996-03-19 Baxter Kk シクロデキストリン又はその誘導体を含有する腹膜透析液
EP0980275A1 (fr) 1997-05-07 2000-02-23 Infomed S.A. Procede de controle de dispositif d'epuration de sang
WO2000009182A1 (fr) 1998-08-11 2000-02-24 Alpamed S.A. Dispositif d'entrainement de fluide
EP1362605A1 (fr) * 2002-05-14 2003-11-19 Bernhard Dr. Kreymann Appareil de dialyse pour éliminer des substances liées à des protéines
EP1747785A1 (fr) * 2005-07-28 2007-01-31 Istituto Clinico Humanitas Cyclodextrines pour la detoxification du sang
NZ590467A (en) 2008-06-23 2013-03-28 Temasek Polytechnic A sorbent for a dialysis device where the pressure drop over across the layer is dependent of the size of the particles in the primary layer of immbolized uremic toxin-treating enzyme particles intermixed with cation exchange particles
US8206591B2 (en) 2008-10-16 2012-06-26 Fresenius Medical Care Holdings, Inc. Method of removing protein-bound deleterious substances during extracorporeal renal replacement treatment
DE102010012282A1 (de) * 2010-03-22 2011-09-22 Fresenius Medical Care Deutschland Gmbh Pharmazeutische Zusammensetzung enthaltend Cyclodextrin-Copolymer
DE102010012281A1 (de) * 2010-03-22 2011-09-22 Fresenius Medical Care Deutschland Gmbh Pharmazeutische Zusammensetzungen enthaltend substituiertes 6-Deoxy-6-sulfanylcyclodextrin

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102017113853A1 (de) 2017-06-22 2018-12-27 B. Braun Avitum Ag Hämokompatibler Adsorber zur Dialyse proteingebundener Urämietoxine
US10625241B2 (en) 2017-06-22 2020-04-21 B. Braun Avitum Ag Hemocompatible adsorber for the dialysis of protein-bound uremic toxins
EP3417937B1 (fr) * 2017-06-22 2021-04-14 B. Braun Avitum AG Adsorbant hémocompatible destinée à la dialyse des toxines urémiques liées aux protéines
WO2024073056A1 (fr) * 2022-09-29 2024-04-04 Kureha America, Inc. Compositions de cucurbiturile, produits et procédés d'utilisation

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