06 December 2008
The invention: Aperfluorocarbon emulsion that serves as a blood plasma substitute in the treatment of human patients. The person behind the invention: Ryoichi Naito (1906-1982), a Japanese physician. Blood Substitutes The use of blood and blood products in humans is a very complicated issue. Substances present in blood serve no specific purpose and can be dangerous or deadly, especially when blood or blood products are taken from one person and given to another. This fact, combined with the necessity for long-term blood storage, a shortage of donors, and some patients’ refusal to use blood for religious reasons, brought about an intense search for a universal bloodlike substance. The life-sustaining properties of blood (for example, oxygen transport) can be entirely replaced by a synthetic mixture of known chemicals. Fluorocarbons are compounds that consist of molecules containing only fluorine and carbon atoms. These compounds are interesting to physiologists because they are chemically and pharmacologically inert and because they dissolve oxygen and other gases. Studies of fluorocarbons as blood substitutes began in 1966, when it was shown that a mouse breathing a fluorocarbon liquid treated with oxygen could survive. Subsequent research involved the use of fluorocarbons to play the role of red blood cells in transporting oxygen. Encouraging results led to the total replacement of blood in a rat, and the success of this experiment led in turn to trials in other mammals, culminating in 1979 with the use of fluorocarbons in humans. Clinical Studies The chemical selected for the clinical studies was Fluosol-DA, produced by the Japanese Green Cross Corporation. Fluosol-DA consists of a 20 percent emulsion of two perfluorocarbons (perfluorodecalin and perfluorotripopylamine), emulsifiers, and salts that are included to give the chemical some of the properties of blood plasma. Fluosol-DA had been tested in monkeys, and it had shown a rapid reversible uptake and release of oxygen, a reasonably rapid excretion, no carcinogenicity or irreversible changes in the animals’ systems, and the recovery of blood components to normal ranges within three weeks of administration. The clinical studies were divided into three phases. The first phase consisted of the administration of Fluosol-DA to normal human volunteers. Twelve healthy volunteers were administered the chemical, and the emulsion’s effects on blood pressure and composition and on heart, liver, and kidney functions were monitored. No adverse effects were found in any case. The first phase ended in March, 1979, and based on its positive results, the second and third phases were begun in April, 1979. Twenty-four Japanese medical institutions were involved in the next two phases. The reasons for the use of Fluosol-DA instead of blood in the patients involved were various, and they included refusal of transfusion for religious reasons, lack of compatible blood, “bloodless” surgery for protection from risk of hepatitis, and treatment of carbon monoxide intoxication. Among the effects noticed by the patients were the following: a small increase in blood pressure, with no corresponding effects on respiration and body temperature; an increase in blood oxygen content; bodily elimination of half the chemical within six to nineteen hours, depending on the initial dose administered; no change in red-cell count or hemoglobin content of blood; no change in wholeblood coagulation time; and no significant blood-chemistry changes. These results made the clinical trials a success and opened the door for other, more extensive ones. IMPACT Perfluorocarbon emulsions were initially proposed as oxygencarrying resuscitation fluids, or blood substitutes, and the results of the pioneering studies show their success as such. Their success in this area, however, led to advanced studies and expanded use of these compounds in many areas of clinical medicine and biomedical research. Perfluorocarbon emulsions are useful in cancer therapy, because they increase the oxygenation of tumor cells and therefore sensitize them to the effects of radiation or chemotherapy. Perfluorocarbons can also be used as “contrasting agents” to facilitate magnetic resonance imaging studies of various tissues; for example, the uptake of particles of the emulsion by the cells of malignant tissues makes it possible to locate tumors. Perfluorocarbons also have a high nitrogen solubility and therefore can be used to alleviate the potentially fatal effects of decompression sickness by “mopping up” nitrogen gas bubbles from the circulation system. They can also be used to preserve isolated organs and amputated extremities until they can be reimplanted or reattached. In addition, the emulsions are used in cell cultures to regulate gas supply and to improve cell growth and productivity. The biomedical applications of perfluorocarbon emulsions are multidisciplinary, involving areas as diverse as tissue imaging, organ preservation, cancer therapy, and cell culture. The successful clinical trials opened the door for new applications of these compounds, which rank among the most versatile compounds exploited by humankind.