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Blood Substitutes: How Close to a Solution?

Blood Substitutes: How Close to a Solution?

ABSTRACT: The term "blood substitute" is commonly misused when "red cell substitute" is meant. The ideal red cell substitute should deliver oxygen (O2), require no compatibility testing, cause few side effects, have prolonged storage qualities, persist in the circulation, and be available at reasonable cost. While no drug with all of these qualities is on the near horizon, several early generation red cell substitutes are approaching submission for licensure, at least for limited indications. Hemoglobin-derived red cell substitutes from human bovine and recombinant sources, as well as perfluorochemicals that dissolve O2, are in different stages of development. While each formulation has its own physical characteristics, biologic activities, and adverse reaction profile, all share one characteristic: The physiologic consequences of delivering O2 with small molecules is poorly understood, both accounting for problems seen in the clinical trials and providing therapeutic opportunities for the cancer patient. All the red cell substitutes in phase III trials have a life measured in hours and are unlikely to replace transfusions or drugs that stimulate erythropoiesis for chronic anemia, but they may play a role in cancer surgery, or even in radiation therapy, or in the management of cancer-related vascular occlusive syndromes. [ONCOLOGY 16(Suppl 10):147-151, 2002]

Early transfusion history described the miraculous
recovery of patients suffering life-threatening hemorrhage. However, equally dramatic
reports revealed unexpected, unexplained, and occasionally lethal complications.
The emergence of HIV as a transfusion-transmitted virus was only the latest such
complication and certainly not the last. Little wonder that the medical
establishment, the public, and, more recently, the biotechnology industry place
such high hopes on development of safer alternatives to blood. Despite more than
40 years of focused research and the recent infusion of hundreds of millions of
venture capital dollars, no credible replacement for blood has yet been approved
for use in the United States.

Types of Red Cell Substitutes

The term "blood substitute" is a misnomer.
So-called blood substitutes in fact replace only one or possibly two functions
of transfused blood. By this definition, several blood substitutes are already
in common use: dextran and starch solutions that act as volume expanders;
recombinant proteins that replace, among other things, coagulation factors; and
even anticoagulants, such as warfarin and heparin, that are used on occasion to
substitute for naturally-occurring anticoagulant proteins. For other functions
of blood, those of the platelets and leukocytes, no substitutes are likely to
emerge in the near future.

Whereas, the "holy grail" of blood substitute
research has been to develop a red cells substitute—a small molecule that
delivers oxygen (O2)
efficiently, requires no compatibility testing, can be sterilized, has a long
shelf-life at room temperature, reconstitutes easily, persists in the
circulation for days or weeks, and can be provided at a price competitive with
that of human blood. No such substance is on the near horizon.

Candidate red cell substitutes generally fall into three
classes: perfluorochemicals, hemoglobin-based oxygen carriers, and
liposome-encapsulated hemoglobin. Although it is convenient to review these
drugs as "classes," each formulation should be considered a unique
drug with its own physical characteristics, biologic activities, and adverse
reaction profile. General characteristics of these classes are reviewed in
Tables 1
and 2.

Perfluorochemical Emulsions

Perfluorochemicals are synthetic, inert, hydrophobic
molecules with an almost unlimited ability to dissolve gases including oxygen.
Because these molecules are structurally similar to hydrocarbons, they are not
water-soluble and therefore must be emulsified with surfactants before they are
suitable for intravenous use. This property has complicated their preparation
and storage, and the nature of the emulsifier turns out to be as important as
the perfluorochemical itself. The classic early experiments in which a mouse was
submerged in a beaker of preoxygenated perfluorochemical emulsion and shown to
breathe liquid continues to fascinate medical journalists and catch the public
eye.[1] Similarly, the exchange-transfused "bloodless rat" experiments
seemed to promise a quick transition to a clinically useful oxygen transport
drug.[2] However, early perfluorochemical formulations were impure, persisted
for long periods in the reticuloendothelial system, and proved unsuitable for
clinical trials.

Broad application of perfluorochemicals as red cell
substitutes may be limited by their oxygen-loading and off-loading properties (Figure
1
). Unlike blood and hemoglobin constructs, perfluorochemicals dissolve O2 in a
linear fashion directly related to the partial pressure of O2.
In practice this means that these emulsions can carry a great deal of O2,
but only if the patient inspires high concentrations of supplemental O2.
Furthermore, the compounds may release much of the O2
as blood passes through less well-oxygenated environments and long before it
reaches the most ischemic tissues. The latter property, the need for
refrigerated storage, and the relatively short circulating half-life have led
some investigators to postulate that these chemicals will prove most suitable
for hospital use.

During a 10-year period, thousands of patients with a wide
variety of illnesses received an early perfluorochemical formulation, Fluosol
DA. This agent was even licensed for use in coronary artery balloon angioplasty.
However in controlled clinical trials, patients receiving Fluosol failed to show
substantial physiologic benefit and were plagued with adverse reactions
attributed by some to complement activation.[3] In any case, production of this
drug ceased in 1994. An excellent review of this drug and other early
perfluorochemicals has been published by Keipert.[4]

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