FDA APPROVAL PROCESS

MANNAN TOXICITY EXPERIMENTS
Several pre-clinical animal experiments were conducted with an independent laboratory to study the reduction of toxicity of 5-Fluorouracil in combination with each of four different proprietary mannan compounds selected for the study. Results of the study (00-5953-N1 of 02/15/01) indicated that one of the mannan compounds significantly reduced the toxicity of 5-FU.

In the first study, ten groups of five animals each were used. In five groups, treated respectively with a placebo and each of four mannan compounds designed by Pro-Pharmaceuticals, the animals showed no signs of toxicity. This was an expected result because neither the placebo nor the mannans are known to be toxic. In the four groups treated respectively with 5-FU alone and 5-FU in combination with each of three mannan structures, the animals showed signs of severe toxicity. In the fourth group, treated with 5-FU in combination with a fourth mannan structure, no clinical signs of toxicity were observed. This provides a preliminary indication of the potential for the reduction of toxicity in a cancer drug combined with this particular mannan.

A second, similar study (01-0557-N1 of 03/01/01) was performed to test the potential reduction of toxicity of another anticancer drug, Adriamycin, in combination with each of two mannan compounds selected for the study. Results indicated that one particular mannan compound decreased the toxicity of Adriamycin. In two groups, treated with Adriamycin alone and Adriamycin in combination with one of the mannan structures, the animals showed signs of severe toxicity (three animals out of five died in each of the two groups). In one group, treated with the same amount of Adriamycin (a lethal dose for more than half of the animals) in combination with the other mannan structure, only one animal out of five died. Again, this provides preliminary data indicating the potential reduction of the toxicity in a cancer drug combined with this particular mannan structure. The implication that two different cancer drugs with chemically unrelated structures both showed a noted reduction of their toxicity when in combination with a specific mannan indicates a fundamental underlying biological reasons for the toxicity reduction related to the mannan rather than the drugs.

A third study was performed in a more aggressive and acute way. A much higher amount of 5-FU was administered to the animals. The mannan used in this study was different from that used in the first studies, and was administered at one-half the dose of the previous study. Eight groups of six animals each were used, and amounts of 5-FU administered to each of the four groups ranged from what would be considered almost lethal in the first group, progressing to four times higher in the fourth group. After 8 days, 17 out of 24 animals died. The surviving animals showed an average weight loss of 1.9 g each. However, in the other four groups of animals, in which the same amount of 5-FU was injected in combination with the second mannan, no animals had died by the 8th day of the study. The average weight loss was only 0.6 g per animal (see Table). This data indicates that 5-FU, when administered with a specific mannan structure either had a delayed or diminished toxicity.

All three studies showed that our proprietary mannan compound has been found to reduce toxicity in laboratory studies across two different chemotherapy technologies.

Table: Mannan Toxicity Experiments