Liquid purification or separation – Processes – Liquid/liquid solvent or colloidal extraction or diffusing...
Reexamination Certificate
1997-04-21
2001-06-19
Kim, John (Department: 1723)
Liquid purification or separation
Processes
Liquid/liquid solvent or colloidal extraction or diffusing...
C210S500210, C210S500240, C210S500430, C210S645000
Reexamination Certificate
active
06248238
ABSTRACT:
The present invention relates to a medical apparatus for the extracorporeal treatment of blood or plasma, by means of which apparatus it is possible to prevent the adverse consequences of activation of the contact phase. The present invention also relates to processes for producing a medical apparatus for the extracorporeal treatment of blood or plasma, by means of which apparatus it is possible to prevent the adverse consequences of activation of the contact phase, these consequences being known under the name of anaphylactoid reactions.
Anaphylactoid reactions sometimes occur in patients undergoing various forms of treatment of the blood via extracorporeal circulation. These reactions manifest themselves several minutes after the start of the treatment in the form of various symptoms, including a general sensation of heat, numbness of the fingers, lips or tongue, shortness of breath, nausea, and laryngeal oedema.
Anaphylactoid reactions have been observed in particular in patients with renal insufficiency who are treated by haemodialysis, haemofiltration or haemodiafiltration using a membrane exchanger. They have been observed in the case of exchangers having membranes of different chemical compositions, either during a single use thereof or after several uses, when the exchangers, instead of being discarded after a single use, are re-used many times and are recycled after each use. Examples of exchangers whose first use has been accompanied by an adverse reaction are the dialysers which have a membrane of polymethylmethacrylate and polyacrylonitrile. Reactions associated with the reuse of dialysers with a membrane of cellulose acetate and polysulphone have also been well documented (see D. A.Pegues et al. “Anaphylactoid reactions associated with reuse of hollow-fiber hemodialysers and ACE inhibitors” Kidney International 42, 1232-1237 (1992).
Anaphylactoid reactions are attributed to an excessive concentration of a peptide substance, bradykinin, in the blood or plasma. One explanation which has been put forward to account for these adverse reactions in some patients undergoing blood treatment by extracorporeal circulation starts from the premise that the blood, when it comes into contact with the negatively charged surface of some blood treatment apparatuses, is the seat of a biological phenomenon, called activation of the contact phase, leading to the generation of active substances, kallikrein and factor XIII, from inactive substances, pre-kallikrein and factor XII, kallikrein having a catalytic effect on the production of factor XIIa, and vice versa. Now, bradykinin results from the conversion, effected by the kallikrein generated upon activation of the contact phase, of a plasma protein, namely kininogen of high molecular weight.
It should be emphasized that the activation of the contact phase seems to occur especially when a blood treatment device having a negatively charged surface is used, but without the patients experiencing the least discomfort as a result, if there are no interfering factors. Complications do sometimes occur in the presence of interfering factors such as, for example:
The presence, in the blood to be treated, of medicaments for combating high blood pressure by inhibiting the natural mechanism of vasoconstriction, which medicaments are generically designated by the term angiotensin converting enzymes or ACEs. These ACEs are also used for other therapeutic applications, especially for treating certain forms of cardiac insufficiency. Now, another effect of the ACEs is that of preventing the breakdown of bradykinin.
The dilution of the blood entering the dialyser filled with saline solution, and the concomitant lowering of the pH of the blood.
In order to avoid generation of bradykinin at a level greater than 4000 pg/ml, the European Patent Application no. 0,561,379 recommends bringing into contact with the blood or the plasma only those semi-permeable membranes having a limited surface charge density, namely a surface electrical charge greater than or equal to −30 &mgr;eq/g of polymer (i.e. −30 meq/kg of polymer).
It appears, however, that within the meaning of European Patent Application no. 0,561,379 the surface electrical charge is to be interpreted as the global ion capacity. Consequently, the said European Patent Application only concerns semi-permeable membranes having a limited charge density, and not semi-permeable membranes having a high density of negative charges, such as, for example, the membrane produced from a copolymer of acrylonitrile and sodium methallylsulphonate, and known by the trade name AN69.
Furthermore, in order to obtain membranes having a limited surface electrical charge, that is to say also a low global ion capacity, the said patent application proposes treating the polymer in such a way as to lower the ion capacity in the bulk. Now, it is of advantage not to modify the ion capacity of the membranes, since this capacity favours the adsorption of certain undesirable proteins, such as &bgr;2-microglobulin, mediators of inflammation, lipids, complement factors. This is particularly true in the case of membranes having a homogeneous, symmetrical structure.
Moreover, chemical compounds are known which have a substantial anti-protease activity characterized by an inhibitory action in the coagulation system, in the complement system, and in the kallikrein-kinin system (inhibition of plasma and tissue kallikreins). One example which may be mentioned is nafamostat mesylate (chemical name: 6-amidino-2-naphthyl-p-guanidinobenzoate dimethanesulphonate) marketed by the company TORII PHARMACEUTICAL.
Nafamostat mesylate is essentially used as an anticoagulant in extracorporeal circulations in cardiac surgery, in plasmapheresis, in anti-LDL apheresis, and in haemodialysis. The usage protocol generally followed and most often recommended is the following:
(a) addition of 20 mg of nafamostat mesylate in 500 ml of saline solution for rinsing the medical apparatus prior to use;
(b) continuous perfusion of nafamostat mesylate at a rate of 20 to 50 mg/hour.
Such a protocol involves the use of large quantities of nafamostat mesylate, generally more than 100 mg of nafamostat mesylate per haemodialysis session. One drawback of this compound is that it is much more costly than the traditional anticoagulants, such as heparin.
In addition, studies have shown that the results in terms of anticoagulation are not satisfactory when the nafamostat mesylate is used for haemodialysis with negatively charged membranes, such as membranes made of polymethylmethacrylate or polyacrylonitrile, in particular the membrane with the trade name AN69 from the company HOSPAL.
Studies have shown that these unsatisfactory results coincide with the strong adsorption of nafamostat mesylate on these membranes and that this adsorption leads to a decrease in the anticoagulant activity of this compound. This is evident in particular from the following publications:
Y. Tsubakihara et al. “Anticoagulant activity of FUT-175 in polyacrylonitrile membrane dialysers”. [Abstract of the 9th annual meeting of the International Society of Blood Purification] Blood Purification 9, 1, 51-52 (1991).
O. Inagaki et al. “Study of the binding capacity of nafamostat mesylate (NM) to dialysis membranes”. Artif. Org. 15, 4, 287 (1991).
O. Inagaki et al. “Adsorption of nafamostat mesylate by hemodialysis membranes”. Artif. Org. 16, 6, 553-558 (1992).
In order to prepare a plasma having a low content of bradykinin, the Japanese Patent Application published on 13th December 1994 under no. 6-340536 recommends a medical apparatus in which the active adsorption element, with the task of adsorbing and eliminating the undesirable compounds of the plasma, is a carrier of anionic groups. In addition, this medical apparatus is provided with:
a means for mixing together an anti-protease agent, such as nafamostat mesylate, and plasma, before the latter is treated;
a means for perfusion of the anti-protease agent and plasma mixture on the active adsorption element; and
a means for the
Burtin Jacques
Thomas Michel
Valette Pierre
Hospal Industrie
Kim John
Millen, White, Zelano & Branigan, PLC.
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