Estimating Allowable Dose Reductions Due to Synergism

A primary reason we are so interested in synergistic interactions is that they will allow lower doses of each compound to be used. As stated, the calculations in Part III suggest that dose reductions due to synergistic interactions are required for most direct-acting compounds, if they are to be useful. A method for estimating allowable dose reductions follows; but keep in mind that it is based on results from our research, which was conducted in vitro. Translation of in-vitro data to in-vivo conditions is always full of uncertainties. Nonetheless, the method provides some logical basis for making an initial estimate of allowable dose reductions.

In spite of the promising preliminary results presented in Figure 13.3, our group still cannot statistically show that supra-additive effects were occurring. The data were obtained from three replicate samples for each individual test. Because of variations in the replicate samples, additional replicates are still needed to provide solid support for supra-additive effects. Although true synergism appears to be occurring, at this point it is safe to assume that, at the very least, additive effects were produced. Still, even additive effects are noteworthy and are sufficient to make the use of natural compounds seem practical.

Assuming additive interactions, allowable dose reductions can now be estimated. The estimating process is straightforward. For example, if 10 compounds were

TABLE 13.1 MINIMUM DEGREE OF SYNERGISM NEEDED AND MAXIMUM DOSE INCREASE OVER COMMON DOSE

COMPOUND

MINIMUM DEGREE OF SYNERGISM NEEDED (fold increase in potency)

RATIO OF MAXIMUM RECOMMENDED DOSE TO COMMON DOSE

Apigenin

1.0

180

Arctigenin

2.3

1.0

Boswellic acid

1.0

2.8

Centella

1.0

19

Emodin

3.0

41

EPA/DHA

1.1

1.1

Garlic

6.1

1.0

Genistein

1.4

22

Geraniol

1.0

uncertain^

Limonene

7.9

uncertain

Luteolin

1.4

uncertain

Melatonin

1.0

6.7

Parthenolide

4.3

2.9

Perillyl alcohol

2.1

uncertain

Quercetin

2.1

1.8

Selenium

3.4

5.5

Vitamin E

1.0

1.0

Average

2.5 (all values) 3.0 (values greater than 1)

5.2*

A value of 1.0 means no increase or decrease is required.

^ Uncertain means that no common dose is available.

* Geometric average.

5-fold lower than the target dose of 5 grams (the target when the compound is used alone), synergistic interactions generated from using the compound in combination would need to compensate for the 5-fold dose reduction to maintain the same effectiveness. This should be possible, since according to our estimates, the use of 10 compounds in combination would allow a 10-fold maximum reduction.

used in combination at equal concentrations, then due to additive effects, the concentration of each compound within the combination could be reduced by a factor of 10. If 15 compounds were used, the concentration of each could be reduced by a factor of 15, and so on. To translate this to in-vivo conditions, we will simply assume that dose reductions will parallel the reductions in concentration seen in-vitro. Thus, if 15 compounds are used, the dose of each can be reduced by a factor of 15. As an example, suppose that to produce an anticancer effect, the target dose for a compound is 5 grams per day. If we use 10 compounds in combination, the target dose could theoretically be reduced 10-fold, and a 0.5-gram dose would be effective.

This does not necessarily mean, however, that a 0.5-gram dose should be used; the highest safe dose would generally be most appropriate because it would minimize the need for synergism and maximize the effect. Let's say that adverse reactions for this compound begin to appear at a dose of 1 gram per day. Then a 1-gram, rather than 0.5-gram, dose could be taken. Although synergism would still be needed, less would be needed than with a 0.5-gram dose. Because the 1-gram dose is

This method assumes each compound appears in the plasma at an equal concentration. Although this is not exactly the case based on the dose estimates contained in Part III, it is often not far off. Similar plasma concentrations should be produced for most direct-acting compounds, since the dose estimates for most compounds used the same target plasma concentration (15 mM, as discussed later). For many direct-acting compounds, the calculated target dose is too high to be taken and the 15mM plasma concentration will not be achieved, but plasma concentrations for most compounds still should not be much below 15 mM. (As we see below, the average dose reduction needed is about 3-fold; therefore, most compounds should occur in the plasma at concentrations between about 5 and 15 mM.)

For simplicity in analyzing dose requirements, we will assume that a maximum of 15 direct-acting compounds will be used in combination. Therefore, the maximum allowable dose reduction for each is 15-fold. As indicated in Table 13.1, a 15-fold dose reduction is more than enough to make essentially all direct-acting compounds seem practical. The first column of numbers in the table indicates how much the target dose would need to be reduced to make each direct-acting compound safe and practical (values taken from discussions in Part III). As shown at the bottom of the column, only a 2.5- to 3fold dose reduction is required on the average. Some direct-acting compounds are not listed in the table because the target dose for these compounds was too uncertain to use as a base for calculations. Also, melatonin is listed, even though it is not categorized as a direct-acting compound, because it can still produce direct effects.

The 2.5- to 3-fold reduction in dose required by most compounds is well below the allowable 15-fold dose reduction estimated above, making it possible that all these compounds could be effective at safe and practical doses when used in combinations. The two compounds with the highest dose reduction requirements, garlic and limonene, are not as likely to be included in combinations, since other compounds may be more potent.a Removing these two compounds would lower the average required dose reduction even further (to 1.8).

Because the average required dose reduction due to synergism is 3-fold or lower does not mean that only three compounds should be used in combination. The values discussed here are only rough approximations that represent the minimum degree of synergism required, which means that for some compounds, a greater degree of synergism may be needed. This can be produced by using a larger number of compounds in combination. Equally important, larger combinations are necessary to target all seven primary clusters of procancer events (see Chapter 1).

The second column of numbers in Table 13.1 lists ratios of the maximum recommended dose and the commonly prescribed dose for noncancerous conditions; as shown, the maximum recommended doses are generally well above those normally prescribed. The average ratio is 5.2 (geometric average), but the range is rather large. (The high dose requirements are one reason concentrated extracts will be required for most compounds.) This average ratio would be a bit lower if we included indirect-acting and immune stimulant compounds in the calculation, since these compounds are used near their commonly prescribed dose. Although the tentative recommended doses are relatively large, in all cases they are at or below the dose estimated to be safe when used as single compounds.

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