Green Cross and Fluosol

The entrance of the Green Cross Pharmaceutical Company of Japan into this field resulted in the preparation of a commercial PFC oxygen transport product, Fluosol-DA20 ('Fluosol'), the only synthetic oxygen transport product approved by the US FDA.

Fluosol-DA20 is a 20 per cent by weight, 10.6 per cent by volume emulsion of two PFCs, per-fluorodecalin (PFD) and perfluorotripropylamine (PFTPA), emulsified by Pluronic-F68 containing a small amount of egg-yolk phospholipid (EYP). It is not stable in the liquid state and must be stored frozen (Mitsuno et al, 1984; Yokoyama et al., 1984). The required addition of PFTPA to the formulation for stability purposes detracts from the emulsion's medical usefulness because its half-life in the liver and other organs of the reticuloendothelial system (RES) is longer than desirable (65 days). Finally, the fact that the emulsion contains only about 10.6 per cent PFCs by volume limits its therapeutic efficacy because of low oxygen transport capacity. However, Fluosol-DA20 was a well-defined, reproducible product, and its availability led to generation of consistent physiologic and toxicological data. In addition to data from animals, Fluosol was administered to thousands of patients for several potential indications over several years. Many of these patients received Fluosol as part of a clinical trial, but many others received Fluosol because they refused blood transfusion for religious reasons. In a study of this latter group, with Hb levels less than 10 gm per cent, Fluosol failed to provide any more than a transient increase in arterial oxygen levels (Gould et al., 1986). Fluosol did, however, contribute 28 per cent of the oxygen consumption of these patients. Because of the low PFC concentration in Fluosol, the gain in oxygen carried by the PFCs was offset by the dilution of the hemoglobin and decrease in oxygen carried by the red cells. The conclusion of Gould's study was that Fluosol-DA20 was safe but ineffective.

The early clinical trials in Japan and the USA were at doses of 20-30 ml/kg of emulsion. Subsequently, dosages of emulsion went up to 40 ml/kg as a single dose and 56 ml/kg in repeated doses (2, 3, 4 and 5.6 ml of PFC). Despite these very large dosages (for example, 40 ml/kg provided 3 kg of emulsion and over 0.5 kg of PFC), patients showed only minor toxic symptoms. These symptoms were benign, reversible, and without meaningful functional impairment. In the various studies, from 10 to 30 per cent of patients experienced flulike symptoms beginning 4 hours after infusion and generally disappearing at about 24 hours. These were found to be due to the surfactant Pluronic-68 (Tremper et al., 1984), which causes C3 conversion and generation of C5a-related neutrophil-aggregating activity, transient neutropenia and thrombocytopenia. These adverse reactions were readily blocked by corticosteroids. In addition there was a temporary increase in the size of the liver and spleen, wherein the RES culled PFC particles from the bloodstream, and transient elevation of some liver enzymes (SGOT, SGPT and alkaline phosphatase).

These data strongly suggest that PFC emulsions can be administered safely in the therapeutic range. The FDA approved Fluosol-DA20 only for perfusion of arteries distal to obstructions during angioplasty procedures. With the introduction of catheters that perfused blood distal to the site of angioplasty, this market for Fluosol-DA20 eroded and Green Cross Pharmaceuticals withdrew the product.

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