Chemistry: molecular biology and microbiology – Differentiated tissue or organ other than blood – per se – or... – Including perfusion; composition therefor
Reexamination Certificate
2000-05-04
2003-01-14
Witz, Jean C. (Department: 1651)
Chemistry: molecular biology and microbiology
Differentiated tissue or organ other than blood, per se, or...
Including perfusion; composition therefor
C435S001100, C435S001300, C435S002000
Reexamination Certificate
active
06506549
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to aqueous solutions and methods for using aqueous solutions to perfuse a mammalian subject in need of perfusion and which act as effective substitutes for blood.
BACKGROUND OF THE INVENTION
Two clinically applied preservation methods for organs are known: (1) initial perfusion for about 5 min with subsequent cold storage (2° C.), and (2) continuous perfusion using aqueous solutions.
Many of the solutions used for initial perfusion with subsequent cold storage are based on the solutions of Collins et al. (1969) Lancet 2:1219 and Sacks et al. (1973) Lancet 1:1024 (see also, Ross et al. (1976) Transplantation 21:498, Wall et al. (1977) Transplantation 23:210, Bishop & Ross (1978) Transplantation 25:235, Fischer et al. (1985) Transplantation 39:122, Belzer et al. (1985) Transplantation 39:118, Kallerhoff et al. (1985) Transplantation 39:485, and Klebanoff & Phillips (1969) Cryobiology 6:121).
Segall et al. (U.S. Pat. Nos. 4,923,442 and 5,130,230) describe blood substitute capable of maintaining a subject and its organs at temperatures below 20° C. composed of two to four solutions—a base solution, a cardioplegia-inducing solution, a cardioplegia-maintaining solution, and a recovery solution, with potassium ion concentrations ranging from 4-45 mEq.
SUMMARY OF THE INVENTION
The invention features solutions and methods for their use as plasma expanders and blood substitutes in mammals, including primates.
Accordingly, the invention features a solution to replace all or a portion of the blood of a mammalian subject, including a primate, comprising K
+
, Mg
++
, Na
+
, Ca
++
, Cl
−
; one or more water soluble oncotic agents; an organic carboxylic acid or salt thereof; and physiological levels of a sugar, with the proviso that the solution does not contain a conventional biological buffer.
The solutions of the invention may be used to replace all or a portion of the blood of a mammalian subject, including a primate, at normal temperatures or at temperatures substantially below those normally maintained by a mammal, generally less than 37°-38° C. and greater than −2° C.
In one embodiment, the solution includes one or more water soluble oncotic agents selected from the group consisting of high molecular weight hydroxyethyl starch, low molecular weight hydroxyethyl starch, dextran 70, dextran 40, albumin, and mannitol.
By the term “water soluble oncotic agent” is meant a molecule whose size is sufficient to prevent its loss from the circulation by readily traversing the fenestrations of the capillary bed into the interstitial spaces of the tissues of the body. Examples of water soluble oncotic agents include starches, proteins, and sugars.
The use of blood-free plasma expanders and blood substitutes may result in substantial hemodilution. This is of concern because it may place a subject at risk for hemorrhage. It would be advantageous to administer a blood clotting factor to a subject undergoing blood substitution. Also, when a subject has undergone substantial blood loss and continues to lose blood, it would be advantageous to administer both a blood substitute and a blood clotting factor. Accordingly, one aspect of the invention encompasses blood substitute solutions containing a blood clotting factor. Another aspect of the invention encompass a method of administering a blood substitute followed by or with the simultaneous administration of a blood clotting factor. Preferably, the blood clotting factor is selected from the group consisting of vitamin K, Factors I, II, V, VII, VIII, VIIIC, IX, X, XI, XII, XIII, protein C, von Willebrand factor, Fitzgerald factor (prekallikrein), Fletcher factor (high molecular weight kininogen), and a proteinase inhibitor, such as aprotinin. An example of an aprotinin is Trasylol® (Miles, West Haven, Conn.), a saline solution of aprotinin containing 10,000 Kallikrein-Inhibitor Units (KIU)/ml. By the term “blood clotting factor” is meant a factor which accelerates, promotes, or allows the formation of a blood clot. Preferably, the blood clotting factor is present in an amount that results in a blood concentration in the subject of between 100-100,000 KIU/ml.
Oxygen-carrying solutions have been developed based on hemoglobin from human or animal sources, or made by genetic engineering, and modified by techniques such as crosslinking or the addition of polyethylene glycol (Spahn et al. (1994) Anesth. Analg. 78:1000-1021). However, these solutions are toxic in high quantities. When a subject has lost blood, it would be advantageous to administer a blood substitute with a physiological or hyperphysiological oxygen-carrying capacity. Accordingly, in another aspect, the solution of the invention includes an oxygen-carrying component. When the solution contains an oxygen-carrying component, such as cross-linked or high molecular weight hemoglobin, it may be desirable to reduce the amount of oncotic agent present such that colloid osmotic pressure approximately that of normal human serum, about 28 mm Hg. Preferably, the oxygen-carrying component is selected from the group consisting of hemoglobin or other respiratory pigments extracted from natural sources, such as hemocyanin, chlorocruorin, and hemerythrin, respiratory pigments made by recombinant DNA techniques, a crosslinked form of hemoglobin, and fluorocarbons. The oxygen-carrying component may be modified by methods known to the art, for example, a fluorocarbon component may be encapsulated by a liposome, and respiratory pigments altered by crosslinking or reaction with polyethylene glycol. By the term “oxygen-carrying component” is meant a component which forms an easily reversible interaction with oxygen, which allows more oxygen to be solubilized than would otherwise be possible, and that results in delivery of the excess oxygen to the tissue. A prefered oxygen-carrying component is hemoglobin, present in the concentration range of about between 20-200 g/l.
In a related aspect, the solutions of the invention are useful for harvesting and/or delivering red blood cells to patients in need thereof. Red blood cells for delivery may be obtained from a number of sources, including human donors, transgenic animals, or derived in vitro.
Plasma expanders and blood substitutes having two or more oncotic agents with differential clearance rates are particularly advantageous in providing extensive protection of oncotic pressure without inhibiting the subject's production of replacement plasma proteins. The present invention includes solutions having two or more oncotic agents with differential clearance rates. By the term “differential clearance rates” is meant the rate at which a first oncotic agent is removed from the blood circulation is faster than the rate at which a second oncotic agent is removed.
The solutions of the present invention include physiological levels of a sugar. Preferably, the sugar is a simple hexose sugar such as glucose. By “physiological levels of a sugar” is meant a sugar concentration of between 2 mM to 50 mM. The preferred concentration of glucose is 5 mM.
Particular advantages of the solutions are that they are relatively inexpensive, contain components naturally occurring in the human body or which have been shown to be safe for use in the human body. The solutions of the present invention can be terminally heat sterilized, and can support life when replacing 50%-80% of a subject's blood at normal body temperature, or 100% of a subject's blood at hypothermic temperatures.
DETAILED DESCRIPTION
It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a formulation” includes mixtures of different formulations and reference to “the method of treatment” includes reference to equivalent steps and methods known to those skilled in the art, and so forth.
Unless defined otherwise, all technical and scientific terms used here
Segall Judith M.
Segall Paul E.
Sternberg Hal
Waitz Harold D.
BioTime, Inc.
Bozicevic, Field & Francis
Field Bret E.
Witz Jean C.
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