If zinc lozenges are to be useful as a method to reduce the duration and severity of colds, sufficient Zn²⁺ ions must be available to do the job. None of the follow-up studies used the same formulation as the original Eby, Davis, and Halcomb study, and none achieved results nearly as good. To obtain the desired quick results, the lozenge ZIA value should be at least 100. This means that salivary Zn²⁺ ion concentration should be 7.4 mMol, application of Zn²⁺ ions from lozenges should occur over a 30-minute period, and lozenges should be taken 9 times per day.

Increased usage rate or stronger lozenges shorten colds in clinical practice even more than reported in published studies. Early use of ZIA 100 lozenges, perhaps within a few minutes or a few hours of the first observed common cold symptom, most often aborts incipient colds. After a few lozenges, no further treatment is usually required.

What is most surprising about the published research reviewed here is the near total lack of fidelity by other researchers to the original discovery or to each other. The first tenet of scientific research is exact duplication of experiments by others to determine the validity of the original research.

Apparently, other than the interview with Pellegrini concerning the development of the lozenges used in the Medical Research Council Common Cold Unit trial led by David A. J. Tyrrell (Al-Nakib et al. report), no attempt appears to have been made to replicate the solution chemistry of the original Eby et al. zinc gluconate lozenges.

In each case, research appears to have been led or inhibited by commercial, not scientific, interests. Makers of each of the commercial compositions tested were apparently uninterested in the discovery unless they could quickly "make zinc lozenges taste like candy."

Had researchers known that fructose was the only sweet carbohydrate tablet base suitable for use with zinc gluconate, the disappointment with flavor-masking could have been avoided, and zinc gluconate would not have developed its reputation of being objectionable in taste or inefficacious. Countless experiments by the present author showed fructose to be the only suitable tablet base for zinc gluconate.

Unfortunately, the Italian company that sponsored the MRC zinc gluconate lozenge research was purchased by a company uninterested in the over-the-counter common cold market. Those Italian lozenges were the first fully flavor-masked zinc gluconate lozenges and they could have provided considerable relief to common cold suffers had they been commercialized.

Other tightly bound zinc compounds and zinc compounds that release no Zn²⁺ ions at pH 7.4 cannot shorten colds. However, they do not lengthen colds either. Nearly all over-the-counter zinc lozenges available in the retail trade are of this type. Currently, lozenges advertised to contain zinc gluconate and zinc oxide are about 99.99% zinc oxide to eliminate objectionable taste and aftertaste from zinc gluconate reactions with dextrose tablet base.

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

One best explanation for the increase in duration is elimination of endogenous (native) Zn²⁺ ions from oral and nasal tissues by ZnL^N-. Zn²⁺ ions are highly concentrated (4 to 20 mMol) in mast cell and basophil granules. Considerable Zn²⁺ ions are released during degranulation of these cells during inflammation. Clearly, ZnL^N- released from these lozenges binds endogenous Zn²⁺ ions present in oral and nasal tissues and fluids as there are few other positively charged biochemicals to bind. If release of Zn²⁺ ions from mast cells during inflammation has the function of inhibiting viral replication, stimulating T-cells, stabilizing cell membranes, regulating mast cell homeostasis, catabolizing histamine, and stimulating interferon production during common colds as they do in vitro (See Chapter 2), then one could expect that common colds would be lengthened by neutralizing endogenous Zn²⁺ ions with ZnLN^- to render them biologically unavailable at physiologic pH.

Why the 1992 zinc gluconate-glycine formulation was reported to be effective with its negative ZIA value and glycine excess is uncertain. Perhaps the irritating acid effect was more than offset by astringency of Zn²⁺ ions at pH 5.0. Negatively charged zinc species were not the predominant species at pH 7.4, as the great majority (85%) was present as neutrally charged zinc glycinate. In the opinion of the present author, important errors found by Berthon and the present author cast doubt upon the validity of the ZGG study.

Authors of several studies discussed in this chapter may disagree with conclusions expressed by the present author concerning physiologic availability of Zn²⁺ ions in their studies. The present author would have benefited -- and would have been pleased -- had those other authors been correct in their assertions of full bioavailability of Zn²⁺ ions and equivalence to the original Eby study.

Conclusions presented about their claims are opinions of the present author based upon evidence and findings by neutral experts in various fields including solution chemistry, physiology, medicine, drug manufacturing, and pharmacology.