R. Bruce Martin claimed Zn²⁺ ion concentration to have been 100 percent in saliva -- at pH 2.3, although no evidence to support the salivary pH hypothesis was presented.(25) The hypothesis that pH of saliva produced by an intra-oral dissolution/expectoration of a zinc gluconate with citric acid lozenge would be 2.3 from the acidity of citric acid and lack of buffering by saliva, with consequent 100 percent zinc ion availability(25) can be readily disproved by direct observation. Martin's hypothesis appears to be derived from the observation that the pH of 90 mg citric acid, without zinc or candy lozenge ingredients, in 30 to 35 ml distilled water (roughly equivalent to the amount of saliva generated using such lozenges) is pH 2.3.

NOTE: Upon the retirement of R. Bruce Martin in 1994, he admitted in a leter dated May 9, 1994, that his report was faulty. He wrote, "I very much regret being forced into this theoretical calculation, and have wished for some time that I had not succumbed."

In tests by the present author and others, lozenges chemically identical to those used in this report were subjected to analysis. When dissolved in 30 ml distilled water, the lozenges produced a pH of 3.2. Six unrelated individuals dissolved 12 replicated lozenges and expectorated all saliva flow. Average saliva volume was 35 milliliters. Lozenges required 15 minutes to dissolve. Average pH of 12 intra-oral dissolution/expectorations was 4.35 + 0.08,(28) a value at which little free Zn²⁺ ions exist, as shown in Figures 11 and 12 below.(25,29) No astringency or salivary protein precipitate in expectorated saliva was noted, further suggesting absence of Zn²⁺ ions.

Even with five times the amount of citric acid used in the no-effect lozenges in otherwise identical lozenges, a salivary pH of 2.3 was not possible. The augmented formulation produced a pH of 2.9 in saliva but these lozenges caused significant oral pain and were offensively acidic and bitter in taste.

The first stability constant of zinc citrate is log K₁ = 4.7 at 37°C.(25,29,30-32) At the salivary pH of zinc gluconate-citrate and higher, the amount of Zn²⁺ ion is considerably less than from zinc gluconate. At physiological pH 7.4 there are no Zn²⁺ ions, and several negatively charged species predominate (see figures 11 and 12 below).(25,29)

The only physiologically relevant pH is 7.4, as all others are quickly buffered to pH 7.4 in blood, lymph and tissue.(33,34) Negatively charged zinc complexes are repelled from cell surfaces, because cell surfaces are always electronegative,(35) and they have no theoretical or reported antirhinoviral, astringency, interferon-inducing, or cell plasma membrane stabilizing function.

Therapy with zinc gluconate chelated by extra molar citric acid did not reduce severity or duration of cold symptoms or frequency or duration of viral shedding in either trial and appeared to increase severity of common cold symptoms on day 7 (see Figure 13). A breakdown of symptom scores in both studies showed a statistically significant difference in symptom severity with recipients of citric acid-chelated zinc having more severe symptoms than placebo recipients on day 7. Recipients of citric acid-chelated zinc showed trends to higher mucus weight and a greater number of facial tissues used, but neither trend was statistically significant. During the studies, these patients had a 17 percent higher total symptom score, 15 percent higher mucus weight, and used 58 percent more paper tissues than placebo-treated patients.(26)

The results of the clinical trials of Farr and co-workers, and Gwaltney and co-workers(26) do not represent the effect of Zn²⁺ ions in treatment of common colds. Negatively charged zinc citrate species (pseudo-astringents) in this study increased duration of common colds by approximately 1 day. The best estimate for the ZIA value of the citric acid-chelated zinc gluconate lozenges is negative 11, using linear ZIA relationships (See Chapter 5, Figure 19 equation) to project the value from an estimated 1-day increase in the duration of common colds.