ZIA Factors

Data collected during analysis of lozenge performance and daily ZIA calculations include mg zinc, fraction of zinc as hydrated Zn²⁺ ions, length of time to dissolve lozenges in minutes, number of doses/day, and saliva volume produced by zinc lozenges (numerically equivalent to weight of saliva minus lozenge weight). Data are summarized in Table 7.

Table 8 data (excluding negative values) were analyzed to determine correlation between zinc ion availability (ZIA) and change in duration of common colds in these studies. Spearman's rank difference correlation method was used. Spearman's is most useful with samples of small size.(1) The statistic was r (rho) = 0.96. The test of the hypothesis that the population correlation is zero is significant beyond 0.02 level in a 2-tailed test. From a statistician's perspective, "one is warranted in rejecting the null hypothesis that there is no relationship between ZIA values and reduction in duration in common colds." Additional data using lozenges above ZIA value 70 would be helpful in confirming and extending these observations.

By comparing daily ZIA values and reduction in duration of common colds, a linear relationship can be established between these (Figure 19), and linearity is the central finding of this report. Reasonable linearity through the range shows that there is a good relationship between ZIA values and reduction in duration of common colds in these studies. This linearity can be used to predict the efficacy of clinically untested zinc lozenges based upon ZIA values of experimental lozenges having zinc complexed with very weak ligands and no added zinc chelators. Linearity shows that seemingly divergent results of studies by Eby, Douglas, Farr, Smith, and others are reconciled by considering zinc ionization availability (ZIA).

Figure 19. Relationship of zinc ion availability (ZIA) values and reduction in duration of common colds in days (y = 0.077x - 0.16).

The highly efficacious lozenges tested by Eby and colleagues in 1984 had a ZIA value more than twice as high as the next highest lozenge (MRC), and much higher than the other lozenges. Absence of a significant effect from Zn²⁺ ions on the rate and amount of viruses excreted by volunteer in the study by Al-Nakib and co-workers at the Medical Research Council Common Cold Unit,(3) does not mean antirhinoviral effect is absent using lozenges with higher, more efficacious ZIA values and higher Zn²⁺ ion salivary concentrations. A ZIA value of 50 and a 5 mMol salivary Zn²⁺ ion concentration appear to be thresholds for significant early Zn²⁺ ion effects on the severity and duration of colds. One might expect antirhinoviral activity, interferon induction, histamine mitigation, and cell membrane stabilization and drying effects to occur at sufficiently high ZIA, perhaps at about ZIA 100 and 7.4 mMol Zn²⁺ ion concentration, where a much stronger clinical effect was observed.

Linearity is attributed to diffusion of hydrated Zn²⁺ ions across biologic membranes and through tissues according to Fick's first and second laws with electrophoretic effects. These observations are the most readily observable examples of biologically closed electric circuits, as first proposed by Nordenström.(4)

Along with the strong repelling effects of nasal mucus and cilia on foreign substances introduced to the nose, as noted by Aoki(5) and many others, the differential repels intranasally introduced Zn²⁺ ions from mucosal surfaces, further explaining lack of efficacy from zinc nasal sprays.

The importance of the amount of zinc available, the fraction as Zn²⁺ ion, lozenge dissolution times, saliva generation, and dosages per day can all be understood as equally important in this system, as no factor was emphasized over another. Within certain limits, the system demonstrates an important tool needed to design successful common cold lozenges. Dissolution times and saliva production are as important as amount of Zn²⁺ ions released and appear to be important areas for developmental efforts, while increasing the number of lozenges used per day is a simple method of increasing efficacy.

Negative ZIA values for 2 of the 3 zinc lozenges having excess strong zinc chelators were estimated by straight-line projection of the non-negative values using the equation found in the legend of Figure 19. The zinc gluconate-glycine data-point, actually a horizontal line at +1.27 days, would be located in the upper-left quadrant of Figure 19, but it was omitted as it would have caused confusion and it was meaningless information. No negative value was used in determining r or the curve. Lengthened colds were associated with several lozenge formulations having negative ZIA values -- that is -- lozenges releasing negatively (and neutrally) charged zinc species at pH 7.4.

One may question the validity of negative ZIA value estimates, but the fact remains that lozenges releasing negatively charged zinc species (ZnLN-) increased the duration of common colds in a dose-response manner relative to placebo.

Lozenge taste is a crucial criterion for commercialization of zinc lozenges. Each of the studies following Eby and co-workers used lozenges selected for pleasant tastes. Zinc gluconate lozenges known not to have a pleasant taste were not considered for testing. Even though the McNeil-sponsored lozenges had a bitter taste at the time of the study, it is safe to assume McNeil and General Nutrition representatives did not know zinc gluconate in combination with dextrose molecule would become dreadfully bitter after aging, or if they did, they had no idea how to correct the flavor-masking problem.

Had the eight studies been rated on a taste scale, relationships concerning ZIA values and taste could have been better developed. Volunteers have carefully taste-tested each of the lozenges (or nearly exact chemical copies) used in the eight clinical studies and offer the following subjective, relative ranking of zinc lozenge taste acceptability. Although taste preferences are highly subjective, differences noted were obvious. On a scale of 0 to 10 (with 0 being dreadfully bitter, 5 being acceptable but not particularly pleasant, and 10 being as pleasant as candy or no taste sensation other than astringency), the lozenges are rated in Table 9 below.

Taste acceptability is dependent upon the zinc complex, other lozenge ingredients and their reactions with zinc, but taste acceptability is not dependent upon ZIA.

* Near aftertaste is aftertaste observed during the first 2 hours after completion of lozenge.

Before the Eby 1984 clinical trial, the author determined that the minimum dosage should be about 50 mg zinc from zinc gluconate every 2 hours, not the 23-mg dosage used in the trial. However, lozenge harshness suggested some patients would reject treatment, and the dosage was compromised to 23 mg doses every 2 hours. The full dosage (46 mg zinc) was retained as a loading dose because considerable anecdotal evidence was available to the author that the first dose taken was important to achieve extremely rapid treatment responses when taken sufficiently early in a cold.

Treatment responses more rapid than documented occur frequently in field use. Faster responses are possible using larger doses or more frequent dosing with zinc gluconate or zinc acetate. Extremely rapid responses occur if treatment is started upon announcement by a throat or nose tickle of an incipient cold.

In 1989, Vincent J. Merluzzi, and co-workers showed antirhinoviral effects of zinc in HeLa cells were directly related to the amount of Zn²⁺ ion available and unrelated to the total amount of zinc complex available.(2)

Similarly, the present author has shown the reduction in duration of common colds to depend upon ZIA, which depends upon Zn²⁺ ion concentration and time of contact with oral mucosal membranes, -- not the amount of zinc compound.

Salivary Zn²⁺ ion concentration is an oversimplified and misleading indicator of efficacy. High salivary Zn²⁺ ion concentrations may have a low ZIA value if lozenges dissolve too quickly. The time that Zn²⁺ ion is applied (as time to dissolve lozenges) and number of doses per day are important variables in determining ZIA values of experimental lozenges.

Good examples of the limited relationship in ZIA values between chemically similar 23-mg zinc as zinc acetate lozenges may be seen in Chapter 7, Table 11.